Elemental Impurity Analysis in Pharmaceuticals

A method to identify the presence of heavy metals in pharmaceuticals was introduced in the United States Pharmacopeia more than 100 years ago.

Pharmaceutical companies are still using essentially the same method, known as the USP Heavy Metals Limit Test.

This paper will provide an overview of current method limitations, considerations for the new methodology and risk-based assessments being carried out by manufacturers.

Automation of Process Control within the Pharmaceutical Industry

http://www.pharmaceutical-technology.com/downloads/whitepapers/process_automation/automation_process_control-pharma/?WT.mc_id=WN_WP

Abaloparatide

WALTHAM, Mass., Dec. 21, 2014 (GLOBE NEWSWIRE) — Radius Health, Inc. today announced positive top-line 18-month fracture results from the Company’s Phase 3 clinical trial (ACTIVE) evaluating the investigational drug abaloparatide-SC for potential use in the reduction of fractures in postmenopausal osteoporosis.

https://in.finance.yahoo.com/news/radius-announces-positive-phase-3-042531179.html

Abaloparatide
BA058
BIM-44058
UNII-AVK0I6HY2U

BA058; BIM-44058; CAS  247062-33-5

MW 3960.5896, MF C174 H300 N56 O49

NAME………C2.29-methyl(22-L-glutamic acid(F>E),23-L-leucine(F>L),25-L-glutamic acid(H>E),26-L-lysine(H>K),28-L-leucine(I>L),30-L-lysine(E>K),31-L-leucine(I>L))human parathyroid hormone-related protein-(1-34)-proteinamide
L-Alaninamide, L-alanyl-L-valyl-L-seryl-L-alpha-glutamyl-L-histidyl-L-glutaminyl-L-leucyl-L-leucyl-L-histidyl-L-alpha-aspartyl-L-lysylglycyl-L-lysyl-L-seryl-L-isoleucyl-L-glutaminyl-L-alpha-aspartyl-L-leucyl-L-arginyl-L-arginyl-L-arginyl-L-alpha-glutamyl-L-leucyl-L-leucyl-L-alpha-glutamyl-L-lysyl-L-leucyl-L-leucyl-2-methylalanyl-L-lysyl-L-leucyl-L-histidyl-L-threonyl-

L-​Alaninamide, L-​alanyl-​L-​valyl-​L-​seryl-​L-​α-​glutamyl-​L-​histidyl-​L-​glutaminyl-​L-​leucyl-​L-​leucyl-​L-​histidyl-​L-​α-​aspartyl-​L-​lysylglycyl-​L-​lysyl-​L-​seryl-​L-​isoleucyl-​L-​glutaminyl-​L-​α-​aspartyl-​L-​leucyl-​L-​arginyl-​L-​arginyl-​L-​arginyl-​L-​α-​glutamyl-​L-​leucyl-​L-​leucyl-​L-​α-​glutamyl-​L-​lysyl-​L-​leucyl-​L-​leucyl-​2-​methylalanyl-​L-​lysyl-​L-​leucyl-​L-​histidyl-​L-​threonyl-

CLINICAL……….https://clinicaltrials.gov/search/intervention=Abaloparatide%20OR%20BA058%20OR%20BIM-44058

BIM-44058 is a 34 amino acid analog of native human PTHrP currently in phase III clinical trials at Radius Health for the treatment of postmenopausal osteoporosis. Radius is also developing a microneedle transdermal patch using a 3M drug delivery system in phase II clinical trials. The drug candidate was originally developed at Biomeasure (a subsidiary of Ipsen), and was subsequently licensed to Radius and Teijin Pharma.

………………………….

PATENT

http://www.google.com/patents/EP2206725A1?cl=en

1. A peptide of the formula:

   [Glu^{22, 25}, Leu^{23, 28}, ³¹, Lys²⁶, Aib²⁹, Nle³⁰]hPTHrP(1-34)NH₂;

   [Glu^{22, 25}, Leu^{23, 28, 30}, ³¹, Lys²⁶, Aib²⁹]hPTHrP(1-34)NH₂; [Glu^{22, 25,29}, Leu^{23, 28, 30, 31}, Lys²⁶]hpTHrP(1-34)NH₂; [Glu^{22, 25, 29}, Leu^{23, 28, 31}, Lys²⁶, Nle³⁰]hPTHrP(1-34)NH₂; [Ser¹, Ile⁵, Met⁸, Asn¹⁰, Leu^{11, 23, 28, 31}, His¹⁴, Cha¹⁵, Glu^{22, 25}, Lys^{26, 30}, Aib²⁹]hPTHrP (1-34)NH₂; [Cha²², Leu^{23, 28, 31}, Glu^{25, 29}, Lys²⁶, Nle³⁰]hPTHrP(1-34)NH₂; [Cha^{7, 11}, ¹⁵]hPTHrP(1-34)NH₂; [Cha^{7, 8, 15}]hPTHrP(1-34)NH₂; [Glu²², Leu^{23, 28}, Aib^{25, 29}, Lys²⁶]hpTHrP(1-34)NH₂; [Aib²⁹]hPTHrP(1-34)NH₂; [Glu^{22, 25}, Leu^{23, 28, 31}, Lys²⁶, Aib^{29, 30}]hPTHrP(1-34)NH₂; [Glu^{22, 25}, Leu^{23, 28, 31}, Lys²⁶, Aib²⁹]hPTHrP(1-34)NH₂; [Glu^{22, 25}, Leu^{23, 28, 31}, Aib^{26, 29}, Lys³⁰] hPTHrP(1-34)NH₂; or [Leu²⁷, Aib²⁹]hPTH(1-34)NH₂; or a pharmaceutically acceptable salt thereof.

…………………

SEE……http://www.google.com.ar/patents/US8148333?cl=en

………………..

SEE…………http://www.google.im/patents/US20090227498?cl=pt

BMS-582664,  brivanib alaninate

((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-
methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate

Brivanib alaninate  is a new oncology therapy with potential applications against a wide variety of tumor types and several stages of disease progression

A prodrug of BMS-540215.

• BMS-540215
• BMS540215
• Brivanib
• UNII-DDU33B674I

BMS 540215, 649735-46-6

 

This manuscript describes the control strategy for the commercial process to manufacture brivanib alaninate. The active pharmaceutical ingredient is a prodrug which is susceptible to hydrolysis. In addition to controlling hydrolysis, a robust strategy was required in order to control input and process-related impurities. Three significant aspects of control include understanding of the reaction parameters in order to minimize the regioisomer during the alkylation with (R)-propylene oxide, development of a design space through statistical models to control impurity formation, and the use of in situ FT-IR to monitor the hydrogenolysis of the Cbz protecting group.

(S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-aminopropanonate (1)

¹H NMR (400 MHz, CDCl₃) 8.31 (1 H, s), 7.83 (1 H, s), 7.25 (1 H, s), 7.00 (1 H, d, J= 8.6 Hz), 6.95 (1 H, dd, J = 15.4, 8.6 Hz), 6.28 (1 H, s), 5.36–5.30 (1 H, m), 4.08–4.00 (2 H, m), 3.57 (1 H, dd, J = 14.0, 6.9 Hz), 2.47 (3 H, s), 2.40 (3 H, s), 1.66 (3 H, s), 1.38 (3 H, d, J = 6.4 Hz), 1.35 (3 H, d, J = 7.1 Hz).

(S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-(benzyloxycarbonylamino)propanonate

¹H NMR (400 MHz, CDCl₃) 8.17 (1 H, br s), 7.84 (1 H, s), 7.41 (1 H, s), 7.35–7.28 (5 H, m), 7.03 (1 H, d, J = 8.6 Hz), 6.95 (1 H, t, J = 7.7 Hz), 6.30 (1 H, s), 5.36–5.32 (2 H, m), 5.11 (2 H, br s), 4.43–4.40 (1 H, m), 4.02–3.99 (2 H, m), 2.46 (3 H, s), 2.41 (3 H, s), 1.44 (3 H, d, J = 7.2 Hz), 1.38 (3 H, d, J = 7.2 Hz).

Ongoing clinical development program

To further investigate the benefits of brivanib in patients with advanced HCC, a broad-spectrum, global, phase III clinical development plan called the Brivanib studies in HCC patients at RISK (BRISK), has been initiated. Clinical benefits seen with brivanib in the first-line setting, and following the failure of sorafenib therapy, highlight the potential to improve the clinical course of patients with advanced HCC. Brivanib may provide a novel therapeutic option to a growing number of patients for whom no other treatment choice exists.

Regulatory status

On 27 October 2011, orphan designation (EU/3/11/918) was granted by the European Commission to Bristol-Myers Squibb for brivanib alaninate for the treatment of hepatocellular carcinoma.^[11] Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorization. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorization. At the time of the orphan designation, several medicines were authorized in the EU for the treatment of hepatocellular carcinoma.

Submission and application

At the time of submission of the application for orphan designation, clinical trials with brivanib alaninate in patients with hepatocellular carcinoma were ongoing. As part of the submission process, Bristol-Myers Squibb has provided sufficient information to show that brivanib alaninate might be of significant benefit for patients with hepatocellular carcinoma because it could provide an alternative for patients who cannot take or for whom existing treatments do not work. Early studies show that it might improve the treatment of patients with this condition, particularly if used when existing treatment had failed. However, this assumption needs to be confirmed at the time of EU marketing authorization, in order to maintain the orphan status.

Synthesis of Brivanib

Route 1

Route 2

…………………………….

http://www.google.com/patents/US7932383

[(1R), 2S]-2-Aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester, has the structure of formula I:

and is referred to herein as “Compound I”. Compound I, compositions comprising Compound I, and methods of using Compound I are disclosed in U.S. Pat. No. 6,869,952 B2, which is assigned to the present assignee and is incorporated herein by reference in its entirety.Compound I, a prodrug, is suitable for inhibiting tyrosine kinase activity of growth factor receptors such as VEGFR-2 and FGFR-1 and is useful in the treatment of cancer. Compound I is also useful in the treatment of diseases, other than cancer, which are associated with signal transduction pathways operating through growth factors and anti-angiogenesis receptors such as VEGFR-2.

Typically, in the preparation of a pharmaceutical composition, a form of the active ingredient having desired properties such as dissolution rate, solubility, bioavailability, and/or storage stability is sought. For example, a form of the active ingredient, which has the desired solubility and bioavailability, has sufficient stability that it does not convert during manufacture or storage of the pharmaceutical composition to a different form having different solubility and/or bioavailibility. A form of Compound I is desired having properties and stability that allow the preparation of pharmaceutical compositions suitable for the treatment of diseases such as cancer.

…………………………………..

 http://www.google.com/patents/US6869952

EXAMPLE 81

[(1R), 2S]-2-Aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester

Step A

A mixture of Example 15 (60 mg, 0.0.16 mmol), N-Cbz-L-alanine (89 mg, 0.4 mmol), HATU (253 mg, 0.4 mmol), DIPEA (103 mg, 0.8 mmol), and DMAP (5 mg) in DMF (1 mL) was stirred overnight. The volatiles were removed in vacuo, and the residue was purified by preparative HPLC to afford homochiral 2-benzyloxyearbonylamino-propionic acid [2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]]-l-methylethyl ester as a white solid (77 mg, 84% yield).

Step B

A mixture of the compound from step A above (60 mg, 0.11 mmol), Pd/C (6 mg), and ammonium formate (200 mg) in DMF (1.5 mL) were stirred at RT for 30 min. The mixture was diluted with ethyl acetate, and then filtered through a pad of Celite®. The filtrate was washed with water, dried over Na₂SO₄, and concentrated. The product was mixed with 1 N aqueous HCl and lyophilized to afford the title compound as a white solid (53 mg, 99% yield). MS: (M+H)⁺=442. ¹HNMR (CD₃OD): δ 1.45 (d, 3H, J=6.60 Hz), 1.56 (d, 3H, J=7.47 Hz), 2.44 (s, 3H), 2.46 (s, 3H), 4.13 (q, 1H), 4.18 (d, 2H, J=3.96 Hz), 5.45 (m 1H); 6.23 (s, 1H); 6.90 (dd, 1H); 7.10 (d, 1H); 7.66 (s, 1H), 7.75 (s, 1H).

…………………………

Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215)
J Med Chem 2008, 51(6): 1976

http://pubs.acs.org/doi/abs/10.1021/jm7013309

A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug1 in in vitro and in vivo systems. The l-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.

(R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (1)

A mixture of 6 (7.5 g, 24 mmol), R-(+)-propylene oxide (120 mmol), LiCl (3.02 g, 72 mmol), and NEt₃ (300 μL) in EtOH (50 mL)………………………………………..o afford 1 (7.2 g, 81% yield) as an off-white solid. MS (ESI⁺) m/z 371.2 (M + H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 7.72 (s, 1H), 7.61 (s, 1H), 7.10 (d, 1H, J = 8.80 Hz), 6.90 (t, 1H, J = 7.15 Hz), 6.23 (s, 1H), 4.12–4.20 (m, 1H), 3.92 (d, 2H, J = 6.55 Hz), 2.48 (s, 3H), 2.43 (s, 3H), 1.29 (d, 3H, J = 6.6 Hz). Mp 208–210 °C. Anal. (C₁₉H₁₉FN₄O₃): C, H, N, F.

 (S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-
yloxy)propan-2-yl) 2-aminopropanoate (8)
1H NMR (500 MHz, CD3OD): 7.75 (s, 1H), 7.66 (s, 1H), 7.10 (d, 1H, J= 10.95 Hz), 6.90 (t, 1H,
J=9.60 Hz), 6.23 (s, 1H), 5.45 (m 1H), 4.18 (d, 2H, J= 3.96 Hz), 4.13 (q, 1H), 2.46 (s, 3H), 2.44 (s,3H), 1.56 (d, 3H, J=7.47 Hz), 1.45 (d, 3H, J=6.60 Hz). LC/MS(ESI+) m/z 442.1 (M+H)+.
M.p. 136-142 oC. Elemental analysis: (C22H24FN5O4:1H2O:1.09HCl): Calc’d: C, 52.95; H, 5.47; N,14.03; F, 3.81; Cl, 7.74. Found: C, 53.16; H, 5.35; N, 14.07; F, 3.72; Cl, 7.74HRMS (calc’d for C22H24FN5O4 M+H+): 442.1891, found: 442.1897.

……………………..

Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor
J Med Chem 2006, 49(7): 2143

http://pubs.acs.org/doi/abs/10.1021/jm051106d

A series of substituted 4-(4-fluoro-1H-indol-5-yloxy)pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of vascular endothelial growth factor receptor-2 kinase is reported. Structure−activity relationship studies revealed that a methyl group at the 5-position and a substituted alkoxy group at the 6-position of the pyrrolo[2,1-f][1,2,4]triazine core gave potent compounds. Biochemical potency, kinase selectivity, and pharmacokinetics of the series were optimized and in vitro safety liabilities were minimized to afford BMS-540215 (12), which demonstrated robust preclinical in vivo activity in human tumor xenograft models. The l-alanine prodrug of12, BMS-582664 (21), is currently under evaluation in clinical trials for the treatment of solid tumors.

 Preparation of (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-ol (12).
A mixture of 7 (650 mg, 2.08 mmol), (R)-(+)-propylene oxide (595 mg, 10.4 mmol), and
triethylamine (30 µl) in ethanol (8 mL) was heated at 70 °C in a sealed tube. After 2 h, the solvent was removed in vacuo and the product was purified by flash column chromatography (silica gel, 20% EtOAc/ CH2Cl2) to afford a solid, which was triturated with 50% Et2O in CH2Cl2 to give 12 (410 mg,53% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.41 (s, 1H), 7.11 (d, 1H,J = 11 Hz), 7.02 (t, 1H, J = 8.8 Hz), 6.39 (s, 1H), 4.20-4.30 (m, 1H), 3.8-4.00 (m, 2H), 2.51 (s, 3H),2.45 (s, 3H), 1.31 (d, 3H, J = 8.2 Hz). 13C NMR (125 MHz, DMSO-d6) δ 8.36, 13.3, 20.0, 64.5, 76.36,95.1, 100.0, 105.75, 106.66, 110.17, 115.47, 117.66, 117.8, 129.83, 136.34, 137.64, 144.13, 144.6,146.53, 148.15, 160.71. LC/MS (ESI) m/z 371 ((M+H)+. HPLC Method / tR / purity: method A/ 3.95min/ 99%. HRMS for C19H20FN4O3, calcd: 371.1519, found: 371.1522. Anal. (Calcd. ForC19H19FN4O3): theoretical %C 61.61, %H 5.17, %N 15.13, %F 5.13; found %C 61.35, %H 5.06, %N 14.99, %F 4.88.

…….

References

1.  National Cancer Institute Dictionary of Cancer Terms
2.  National Cancer Institute Adult Primary Liver Cancer Treatment (PDQ®)
3.  National Cancer Institute Adult Primary Liver Cancer Treatment (PDQ®)/Treatment Option Overview
4.  Huynh, H.; Ngo, V. C.; Fargnoli, J.; Ayers, M.; Soo, K. C.; Koong, H. N.; Thng, C. H.; Ong, H. S. et al. (2008). “Brivanib Alaninate, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Tyrosine Kinases, Induces Growth Inhibition in Mouse Models of Human Hepatocellular Carcinoma”. Clinical Cancer Research 14 (19): 6146–53. doi:10.1158/1078-0432.CCR-08-0509. PMID 18829493.
5.  Cai, Zhen-wei; Zhang, Yongzheng; Borzilleri, Robert M.; Qian, Ligang; Barbosa, Stephanie; Wei, Donna; Zheng, Xiaoping; Wu, Lawrence et al. (2008). “Discovery of Brivanib Alaninate ((S)-((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), A Novel Prodrug of Dual Vascular Endothelial Growth Factor Receptor-2 and Fibroblast Growth Factor Receptor-1 Kinase Inhibitor (BMS-540215)”. Journal of Medicinal Chemistry 51 (6): 1976–80. doi:10.1021/jm7013309. PMID 18288793.
6.  Ayers, M.; Fargnoli, J.; Lewin, A.; Wu, Q.; Platero, J. S. (2007). “Discovery and Validation of Biomarkers that Respond to Treatment with Brivanib Alaninate, a Small-Molecule VEGFR-2/FGFR-1 Antagonist”. Cancer Research 67 (14): 6899–906. doi:10.1158/0008-5472.CAN-06-4555. PMID 17638901.
7.  Bhide, Rajeev S.; Cai, Zhen-Wei; Zhang, Yong-Zheng; Qian, Ligang; Wei, Donna; Barbosa, Stephanie; Lombardo, Louis J.; Borzilleri, Robert M. et al. (2006). “Discovery and Preclinical Studies of (R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5- methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan- 2-ol (BMS-540215), an in Vivo Active Potent VEGFR-2 Inhibitor”. Journal of Medicinal Chemistry 49 (7): 2143–6. doi:10.1021/jm051106d. PMID 16570908.
8.  ClinicalTrials.gov NCT00640471 Cetuximab With or Without Brivanib in Treating Patients With K-Ras Wild Type Tumours and Metastatic Colorectal Cancer
9.  Allen, E.; Walters, I. B.; Hanahan, D. (2011). “Brivanib, a Dual FGF/VEGF Inhibitor, is Active Both First and Second Line against Mouse Pancreatic Neuroendocrine Tumors Developing Adaptive/Evasive Resistance to VEGF Inhibition”. Clinical Cancer Research 17 (16): 5299–310. doi:10.1158/1078-0432.CCR-10-2847. PMC 3156934. PMID 21622725.
10.  Finn, R. S.; Kang, Y.-K.; Mulcahy, M.; Polite, B. N.; Lim, H. Y.; Walters, I.; Baudelet, C.; Manekas, D.; Park, J.-W. (2012). “Phase II, Open-label Study of Brivanib as Second-line Therapy in Patients with Advanced Hepatocellular Carcinoma”. Clinical Cancer Research 18 (7): 2090–8. doi:10.1158/1078-0432.CCR-11-1991. PMID 22238246.
11.  orphan designation

External links

• [1] Brivanib (BMS-582664) in advanced solid tumors (AST): Results of a phase II randomized discontinuation trial (RDT).
• ClinicalTrials.gov NCT00798252 Ascending Multiple-Dose Study of Brivanib Alaninate in Combination With Chemotherapeutic Agents in Subjects With Advanced Cancers
• ClinicalTrials.gov NCT00437437 A Phase I Study to Determine the Effect of Food on Brivanib (BMS-582664)
• ClinicalTrials.gov NCT00633789 Phase II Study of Brivanib (BMS-582664) to Treat Multiple Tumor Types
• ClinicalTrials.gov NCT00888173 Brivanib Alaninate in Treating Patients With Recurrent or Persistent Endometrial Cancer
• ClinicalTrials.gov NCT01253668 Brivanib Metastatic Renal Cell Carcinoma
• [2] Public summary of opinion on orphan designation. Brivanib alaninate for the treatment of hepatocellular carcinoma
• [3] New drug information/Abbreviated Scientific Narrative

US6869952 *	Jul 18, 2003	Mar 22, 2005	Bristol Myers Squibb Company	Such as 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methyl-pyrrolo(2,1-f)(1,2,4)triazin-6-ol; for treament of cancer
US6982265	May 18, 2000	Jan 3, 2006	Bristol Myers Squibb Company	Pyrrolotriazine inhibitors of kinases
US7671199 *	Apr 20, 2007	Mar 2, 2010	Britsol-Myers Squibb Company	dual inhibitor of VEGFR and FGFR tyrosine kinases; cancer
WO2006030941A1	Sep 13, 2005	Mar 23, 2006	Eisai Co Ltd	Simultaneous use of sulfonamide-containing compound and angiogenesis inhibitor
WO2006124689A2	May 12, 2006	Nov 23, 2006	Squibb Bristol Myers Co	Combination therapy

* Cited by examiner

NON-PATENT CITATIONS

Reference
1		Bennett, J.C. et al., eds., Cecil Textbook of Medicine, 20th Edition, vol. 1, W.B. Saunders Company, publ., pp. 1004-1010 (1996).
2		Fabbro, D. et al., “Protein kinases as targets for anticancer agents: from inhibitors to useful drugs“, Pharmacology & Therapeutics, vol. 93, pp. 79-98 (2002).
3		Gautschi, O. et al., “Aurora Kinases as Anticancer Drug Targets“, Clin. Cancer Res., vol. 14, No. 6, pp. 1639-1648 (2008).
4		Huynh, H. et al., “Brivanib Alaninate, a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor and Fibroblast Growth Factor Receptor Tyrosine Kinases, Induces Growth Inhibition in Mouse Models of Human Hepatocellular Carcinoma“, Clin. Cancer Res., vol. 14, No. 19, pp. 6146-6153 (2008).
5		Mass, R.D. , “The HER Receptor Family: a Rich Target for Therapeutic Development“, Int, J. Radiation Oncology Biol. Phys., vol. 58, No. 3, pp. 932-940 (2004).
6		Mountzios, G. et al., “Aurora kinases as targets for cancer therapy“, Cancer Treatment Reviews, vol. 34, pp. 175-182 (2008).
7		National Cancer Institute, http://www.cancer.gov, Brivanib Active Trial Listing (ID#: 5552473) (Dec. 15, 2008).

 

hplc

HPLC methods
Method A :A linear gradient program using 10% methanol, 90% water, 0.2% H3PO4 (solvent A) and
90% methanol, 10% water, 0.2% H3PO4 (solvent B); t = 0 min, 0% B, t = 4 min, 100% B was
employed on a YMC S5 Combiscreen 4.6 × 50 mm column. Flow rate was 4 mL/min and UV detection
was set to 220 nm. The LC column was maintained at ambient temperature.
Method B: A linear gradient program using 10% methanol, 90% water, 0.2% H3PO4 (solvent A) and
90% methanol, 10% water, 0.2% H3PO4 (solvent B); t = 0 min, 0% B, t = 4 min, 100% B was
employed on a YMC ODS 4.6 x 50 mm column. Flow rate was 4 mL/min and UV detection was set to
220 nm. The LC column was maintained at ambient temperature.
Method C: A linear gradient program using 10% methanol, 90% water, 0.1% trifluoroacetic acid (TFA)
(solvent A) and 90% methanol, 10% water, 0.1% TFA (solvent B); t = 0 min, 0% B, t = 4 min, 100% B
was employed on a Chromolith SpeedROD, 4.6 × 50 mm column. Flow rate was 4 mL/min and UV
detection was set to 254 nm. The LC column was maintained at ambient temperature.
Method D: A linear gradient program using 10% methanol, 90% water, 0.1% TFA (solvent A) and 90%
methanol, 10% water, 0.1% TFA (solvent B); t = 0 min, 0% B, t = 2 min, 100% B was employed on a
Waters Xterra 5 m, 4.6 mm × 30 mm column. Flow rate was 4 mL/min and UV detection was set to
220 nm. The LC column was maintained at ambient temperature.

 

http://www.google.com/patents/EP2364699A1?cl=en

• (R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-ol (hereinafter also referred to as “BMS-540215″; Proceedings of the American Association for Cancer Research., 46, (Abstract 3033), 2005) (see Formula (XXXIII)):

  and

• (28) (S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2-f][1,2,4]triazin-6-yloxy)propan-2-ol) 2-aminopropanonate (hereinafter also referred to as “BMS-582664″; Proceedings of the American Association for Cancer Research., 46, (Abstract 3033), 2005) (see Formula (XXXIV)):

Bafetinib

4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[(4-pyrimidin-5-ylpyrimidin-2-yl)amino]phenyl]-3-(trifluoromethyl)benzamide, cas 859212-16-1

4-[(S)-3-(dimethylamino)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

859212-07-0 (hydrochloride)

1. bafetinib
2. INNO-406
3. NS-187

Bafetinib , previously as INNO-406 , NS-187 and CNS-9 refers is an experimental drug from the substance group ofbenzamides , who as Tyrosinkinasehemmstoff to be used. ^[2] It was originally developed by the Japanese company Nippon Shinyaku and 2006 Innovive Pharmaceuticals licensed. ^[3] Innovive was established in June 2008 by the CytRx Corp. adopted. ^[4]

Bafetinib, also known as INNO-406,  is an orally bioavailable 2-phenylaminopyrimidine derivative with potential antineoplastic activity. Bafetinib specifically binds to and inhibits the Bcr/Abl fusion protein tyrosine kinase, an abnormal enzyme produced by Philadelphia chromosomal translocation associated with chronic myeloid leukemia (CML). This agent also inhibits the Src-family member Lyn tyrosine kinase, upregulated in imatinib-resistant CML cells and in a variety of solid cancer cell types. The inhibitory effect of bafetinib on these specific tyrosine kinases may decrease cellular proliferation and induce apoptosis in tumor cells that overexpress these kinases. CML patients may be refractory to imatinib, which sometimes results from point mutations occurring in the kinase domain of the Bcr/Abl fusion product. Due to its dual inhibitory activity, the use of bafetinib has been shown to overcome this particular drug resistance.

INNO-406 (formerly NS-187) is a potent, orally available, rationally designed, dual Bcr-Abl and Lyn kinase inhibitor that is currently in early clinical studies at CytRx Oncology for the treatment of B-cell chronic lymphocytic leukemia, metastatic prostate cancer and glioblastoma multiforme. CytRx is also conducting phase I clinical studies for the treatment of recurrent high-grade glioma or metastatic disease to the brain that has progressed after treatment with whole brain radiation therapy or stereotactic radiosurgery.

The company is developing INNO-406 in preclinical studies for the prevention of bone loss in multiple myeloma patients. Nippon Shinyaku is also evaluating the compound for the treatment of chronic myeloid leukemia. The compound had been under evaluation for the treatment of certain forms of acute myeloid leukemia (AML) that are refractory or intolerant of other approved treatments; however, no recent development has been reported for this indication.

Based on its mechanisms of action, INNO-406 is expected to be effective in treating Gleevec-resistant CML and may delay or even prevent the onset of resistance in treatment naive CML patients. The ability of INNO-406 to specifically target the Bcr-Abl and Lyn kinases may result in a better side effect profile than compounds that target multiple kinases such as a pan-Src inhibitor.

In 2005, the compound was licensed to Innovive Pharmaceuticals (acquired by CytRx Oncology in 2008) by Nippon Shinyaku on a worldwide basis, with the exception of Japan, for the treatment of CML. Orphan drug designation was assigned to the compound for the treatment of CML in the U.S in 2007 and in the E.U. in 2010.

Bafetinib is an inhibitor of tyrosine kinases . It affects the formation of the fusion protein Bcr-Abl , as well as that of theenzyme Lyn kinase and should in mice ten times stronger effect than the imported Tyrosinkinasehemmstoff imatinib .^[5]

Clinical Development 

Bafetinib currently has no indication for an authorization as medicines .

The drug is intended for the treatment of chronic lymphocytic leukemia are developed (CLL). For this indication is Bafetinib is in the development phase II (June 2011). ^[6]

Bafetinib is also in phase II for the treatment of hormone-refractory prostate cancer . ^[7]

The US regulatory authority FDA had Bafetinib end of 2006, the status of a drug orphan (orphan drug) awarded. ^[8]This status could allow an accelerated development and approval.

N-[3-([5,5′-Bipyrimidin]-2-ylamino)-4-methylphenyl]-4-[[(3S)-3-(dimethyl-amino)-1-pyrrolidinyl]methyl]-3-(trifluoromethyl)benzamide

CAS No .:         887650-05-7

MW:  576.62

Formula: C ₃₀ H ₃₁ F ₃ N ₈ O

Synonym:        INNO-406, NS-187

Synthesis of Bafetinib

Analytical Chemistry Insights 2007:2 93–106

U.S. Patent 7,728,131

http://www.google.im/patents/US7728131?cl=fi

Reference Example 31

4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamideStep 1

4-(bromomethyl)-3-trifluoromethylbenzoic acidTo 60.0 g of 4-methyl-3-trifluoromethylbenzoic acid was added 600 ml of isopropyl acetate. Under stirring at room temperature, a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water were added in turn. The mixture was gradually heated from 30° C. up to 50° C. at intervals of 10° C. and stirred until the color of the reaction solution disappeared. The aqueous layer was separated to remove, and to the organic layer were added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and then the mixture was gradually heated up to 60° C. as above. After separation, to the organic layer were further added a solution of 133.0 g of sodium bromate in 420 ml of water and a solution of 91.7 g of sodium hydrogensulfite in 180 ml of water, and the mixture was gradually heated as above and heated to the temperature the mixture was finally refluxed. After the completion of the reaction, the reaction solution was separated, the organic layer was washed twice with a 5% aqueous sodium thiosulfate solution and twice with 15% saline, dried over anhydrous magnesium sulfate, and, then the solvent was distilled off under reduced pressure. To the residue was added 120 ml of n-heptane, the mixture was stirred, and then the crystals were collected by filtration to obtain 50.0 g of the objective compound as colorless crystals.

Melting point: 140-143° C.

Step 2

4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide7.69 g of 4-(bromomethyl)-3-trifluoromethylbenzoic acid obtained in the step 1 was suspended in 154 ml of anhydrous dichloromethane. Under ice-cool stirring, 6.59 ml of oxalyl chloride and 0.1 ml of anhydrous N,N-dimethylformamide were added dropwise. Under ice cooling, the mixture was further stirred for 3 hours, and then the reaction solution was concentrated under reduced pressure. To the residue was added 70 ml of anhydrous 1,4-dioxane, and then 7.00 g of 4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]aniline (Reference Example 18) and 4.18 g of potassium carbonate were added in turn, followed by stirring at room temperature for 18 hours. To the reaction solution was added 175 ml of water, and the mixture was violently stirred for one hour. Then, the deposit was collected by filtration and washed in turn with water, a small amount of acetonitrile, ethyl acetate and diisopropyl ether to obtain 8.10 g of the objective compound as pale yellow crystals.

Melting point: 198-202° C. (with decomposition)

Example 47

4-[(S)-3-(dimethylamino)pyrrolidin-1-ylmethyl]-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide

To a solution of 6.00 g of 4-(bromomethyl)-3-trifluoromethyl-N-{4-methyl-3-[4-(5-pyrimidinyl)pyrimidin-2-ylamino]phenyl}benzamide (Reference Example 31) in 60 ml of anhydrous N,N-dimethylformamide were added 1.51 g of (S)-(−)-3-(dimethylamino)pyrrolidine and 1.83 g of potassium carbonate, followed by stirring at room temperature for 14 hours. To the reaction solution were added water and an aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.57 g of pale yellow crystals.

Melting point: 179-183° C. (with decomposition)

……………………………..

Bioorg Med Chem Lett 2006, 16(5): 1421

 http://www.sciencedirect.com/science/article/pii/S0960894X05014538

A series of 3-substituted benzamide derivatives of STI-571 (imatinib mesylate) was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562. Several 3-halogenated and 3-trifluoromethylated compounds, including NS-187, showed excellent potency.

 

Bafetinib

Figure 1.

Chemical structures of STI-571 and NS-187 (9b).

 

Scheme 2.

Reagents and conditions: (a) NaBrO₃, NaHSO₃, EtOAc; (b) (COCl)₂, cat. DMF, CH₂Cl₂, rt; (c) 7, K₂CO₃, dioxane, rt; (d) cyclic amines, K₂CO₃, DMF, rt.

 

………………………………

Bioorganic and Medicinal Chemistry Letters, 2007 ,  vol. 17,  10  pg. 2712 – 2717

 

Bafetinib

References 

1.  This substance has not yet been rated on their dangerousness either in terms of which a reliable and quotable source for this purpose has not been found.
2.  A. Quintas-Cardama include: Flying under the radar: the new wave of BCR-ABL inhibitors. In: Nature Reviews Drug Discovery 6/2007, pp 834-848, PMID 17853901 .
3. Nippon Shinyaku. press release dated January 5, 2006 (s.) , accessed on 25 February 2011th
4.  Drugs.com: Signs Definitive Agreement Cytrx Corporation to Acquire Innovive Pharmaceuticals, Inc. Retrieved June 17, 2011
5. H. Naito include: In vivo antiproliferative effect of NS-187, a dual Bcr-Abl / Lyn tyrosine kinase inhibitor, on leukemic cells harbourage ring-Abl kinase domain mutations.In: . Leukemia Research 30/2006, pp 1443-1446, PMID 16546254 .
6.  ClinicalTrials.gov: Study of Bafetinib as Treatment for relapsed or Refractory Chronic Lymphocytic Leukemia B-Cell (B-CLL). Retrieved on June 17, 2011th
7. ClinicalTrials.gov: Study of Bafetinib (INNO-406) as Treatment for Patients With Hormone-Refractory Prostate Cancer (PROACT). Retrieved on June 17, 2011th
8.  Food and Drug Administration: Database summary of 27 December of 2006. Accessed on 16 September, 2009.

Literature 

• E. Weisberg, inter alia: Second generation inhibitors of BCR-ABL for the treatment of chronic myeloid leukemia imatinib-resistant. In: Nature Reviews Cancer 7/2007, pp 345-356. PMID 17457302
• A. Yokota include: INNO-406, a novel BCR-ABL / Lyn tyrosine kinase inhibitor dual, Suppresses the growth of Ph ⁺ leukemia cells in the central nervous system and cyclosporine A Augments its in vivo activity. (PDF, 735 kB) In : Blood 109/2007, pp 306-314. PMID 16954504

External links 

• Entries in the NIH study Register

1: Peter B, Hadzijusufovic E, Blatt K, Gleixner KV, Pickl WF, Thaiwong T, Yuzbasiyan-Gurkan V, Willmann M, Valent P. KIT polymorphisms and mutations determine responses of neoplastic mast cells to bafetinib (INNO-406). Exp Hematol. 2010 Sep;38(9):782-91. doi: 10.1016/j.exphem.2010.05.004. Epub 2010 May 26. PubMed PMID: 20685234.

2: Kantarjian H, le Coutre P, Cortes J, Pinilla-Ibarz J, Nagler A, Hochhaus A, Kimura S, Ottmann O. Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer. 2010 Jun 1;116(11):2665-72. doi: 10.1002/cncr.25079. PubMed PMID: 20310049; PubMed Central PMCID: PMC2876208.

3: Rix U, Remsing Rix LL, Terker AS, Fernbach NV, Hantschel O, Planyavsky M, Breitwieser FP, Herrmann H, Colinge J, Bennett KL, Augustin M, Till JH, Heinrich MC, Valent P, Superti-Furga G. A comprehensive target selectivity survey of the BCR-ABL kinase inhibitor INNO-406 by kinase profiling and chemical proteomics in chronic myeloid leukemia cells. Leukemia. 2010 Jan;24(1):44-50. doi: 10.1038/leu.2009.228. Epub 2009 Nov 5. PubMed PMID: 19890374.

4: Kamitsuji Y, Kuroda J, Kimura S, Toyokuni S, Watanabe K, Ashihara E, Tanaka H, Yui Y, Watanabe M, Matsubara H, Mizushima Y, Hiraumi Y, Kawata E, Yoshikawa T, Maekawa T, Nakahata T, Adachi S. The Bcr-Abl kinase inhibitor INNO-406 induces autophagy and different modes of cell death execution in Bcr-Abl-positive leukemias. Cell Death Differ. 2008 Nov;15(11):1712-22. doi: 10.1038/cdd.2008.107. Epub 2008 Jul 11. PubMed PMID: 18617896.

5: Morinaga K, Yamauchi T, Kimura S, Maekawa T, Ueda T. Overcoming imatinib resistance using Src inhibitor CGP76030, Abl inhibitor nilotinib and Abl/Lyn inhibitor INNO-406 in newly established K562 variants with BCR-ABL gene amplification. Int J Cancer. 2008 Jun 1;122(11):2621-7. doi: 10.1002/ijc.23435. PubMed PMID: 18338755.

6: Deguchi Y, Kimura S, Ashihara E, Niwa T, Hodohara K, Fujiyama Y, Maekawa T. Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines. Leuk Res. 2008 Jun;32(6):980-3. doi: 10.1016/j.leukres.2007.11.008. Epub 2008 Jan 8. PubMed PMID: 18191450.

7: Pan J, Quintás-Cardama A, Manshouri T, Cortes J, Kantarjian H, Verstovsek S. Sensitivity of human cells bearing oncogenic mutant kit isoforms to the novel tyrosine kinase inhibitor INNO-406. Cancer Sci. 2007 Aug;98(8):1223-5. Epub 2007 May 22. PubMed PMID: 17517053.

8: Kuroda J, Kimura S, Strasser A, Andreeff M, O’Reilly LA, Ashihara E, Kamitsuji Y, Yokota A, Kawata E, Takeuchi M, Tanaka R, Tabe Y, Taniwaki M, Maekawa T. Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia. Cell Death Differ. 2007 Sep;14(9):1667-77. Epub 2007 May 18. PubMed PMID: 17510658.

9: Maekawa T. [Innovation of clinical trials for anti-cancer drugs in Japan–proposals from academia with special reference to the development of novel Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406 (NS-187) for imatinib-resistant chronic myelogenous leukemia]. Gan To Kagaku Ryoho. 2007 Feb;34(2):301-4. Japanese. PubMed PMID: 17301549.

10: Niwa T, Asaki T, Kimura S. NS-187 (INNO-406), a Bcr-Abl/Lyn dual tyrosine kinase inhibitor. Anal Chem Insights. 2007 Nov 14;2:93-106. PubMed PMID: 19662183; PubMed Central PMCID: PMC2716809.

11: Yokota A, Kimura S, Masuda S, Ashihara E, Kuroda J, Sato K, Kamitsuji Y, Kawata E, Deguchi Y, Urasaki Y, Terui Y, Ruthardt M, Ueda T, Hatake K, Inui K, Maekawa T. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity. Blood. 2007 Jan 1;109(1):306-14. Epub 2006 Sep 5. PubMed PMID: 16954504.

Bafetinib

Foretinib (Exelixis, GlaxoSmithKline) (XL-880)

CAS No.：849217-64-7, 937176-80-2
Formula：C34H34F2N4O6
M.Wt：632.24

GSK1363089, XL880

1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Foretinib is an experimental drug candidate for the treatment of cancer.^[1] It was discovered by Exelixis and is under development by GlaxoSmithKline.^[2] It is currently in Phase II clinical trials.^[3] As of December 2012 no phase III trials are registered.^[3]

Foretinib is an inhibitor of the kinase enzymes c-Met and vascular endothelial growth factor receptor 2 (VEGFR-2).^[4]

Foretinib is an orally bioavailable small molecule with potential antineoplastic activity. MET/VEGFR2 inhibitor GSK1363089 binds to and selectively inhibits hepatocyte growth factor (HGF) receptor c-MET and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in the inhibition of tumor angiogenesis, tumor cell proliferation and metastasis. The proto-oncogene c-MET has been found to be over-expressed in a variety of cancers. VEGFR2 is found on endothelial and hematopoietic cells and mediates the development of the vasculature and hematopoietic cells through VEGF signaling.

Foretinib (GSK1363089) is an ATP-competitive inhibitor of HGFR and VEGFR, mostly for Met and KDR with IC50 of 0.4 nM and 0.9 nM. Less potent against Ron, Flt-1/3/4, Kit, PDGFRα/β and Tie-2, and little activity to FGFR1 and EGFR. Phase 2.

………………………………..

………………………………….

http://www.google.com/patents/WO2014067417A1?cl=en

Foretinib (GSK1363089, XL880) quinoline compounds are, an oral c-Met and VEGFR / KDR kinase inhibitor of c-Met kinase and KDR kinase IC _5Q Wo port respectively 0.4 0.8 nM, the current has entered Phase II clinical study (WO2010036831Al). Clinical studies have shown that, Foretinib variety of people, such as human lung cancer cells, human gastric cancer cells and other tumor cell lines showed a significant inhibitory effect, an IC ₅₀ value of 0.004 g / mL.

……………………………

http://www.google.com/patents/WO2014145693A1?cl=en

Accordingly, small-molecule compounds that specifically inhibit, regulate, and/or modulate the signal transduction of kinases, particularly including Ret, c-Met, and VEGFR2 described above, are particularly desirable as a means to treat or prevent disease states associated with abnormal cell proliferation and angiogenesis. One such small-molecule is XL880, known variously as N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4- ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide and alternatively as foretimb. Foretimb has the chemical structure:

[0007] WO 2005/030140 describes the synthesis of foretinib (Example 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate, and/or modulate the signal transduction of kinases (Assays, Table 4, entry 312). Example 44 begins at paragraph [0349] in WO 2005/030140.

……………………………………

WO 2012044577 A1…….Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases

Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)WO 2012044577 A1…….Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases
 http://www.google.com/patents/WO2012044577A1?cl=en

In another embodiment, the compound of Formula I is Compound 1 :

Compound 1

or a pharmaceutically acceptable salt thereof. Compound I is known as N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N’-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide. WO 2005/030140 describes the synthesis of N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy }phenyl)-N’-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide (Example 12, 37, 38, and 48) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 289). Example 48 is on paragraph [0353] in WO 2005/030140.

[0013] In another embodiment, the compound of Formula I is Compound 2:

Compound 2
Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)

or a pharmaceutically acceptable salt thereof. Compound 2 is known as is N-[3-fluoro-4- ({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N’-(4- fluorophenyl)cyc!opropane- 1,1 -dicarboxamide. WO 2005-030140 describes the synthesis of Compound (I) (Examples 25, 30, 36, 42, 43 and 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 312). Compound 2 has been measured to have a c-Met IC50 value of about 0.6 nanomolar (nM). PC1YUS09/064341, which claims priority to U.S. provisional application 61/199,088, filed November 13, 2008, describes a scaled-up synthesis of Compound I.

Scheme 2

Preparation of 4-Chloro-6,7-dimethoxy-quinoIine

[00173] A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCl₃, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3% of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg) and the filter bed was washed with DCM (1 18.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).

Preparation of -(6, 7 -Dimethoxy-quinoline- -yloxy)-phenylamine

[00174] 4-Aminophenol (24.4 kg) dissolved in N,N-dimethylacetamide (DMA, 184.3 kg) was charged to a reactor containing 4-chloro-6,7-dimethoxyquinoline (35.3 kg), sodium t- butoxide (21.4 kg) and DMA (167.2 kg) at 20-25 °C. This mixture was then heated to 100- 105 °C for approximately 13 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-20 °C and water (pre-cooled, 2-7 °C, 587 L) charged at a rate to maintain 15-30 °C temperature . The resulting solid precipitate was filtered, washed with a mixture of water (47 L) and DMA (89.1 kg) and finally with water (214 L). The filter cake was then dried at approximately 25 °C on filter to yield crude 4-(6, 7-dimethoxy-quinoline-4- yloxy)-phenylamine (59.4 kg wet, 41.6 kg dry calculated based on LOD). Crude 4-(6, 7- dimethoxy-quinoline-4-yloxy)-phenylamine was refluxed (approximately 75 °C) in a mixture of tetrahydrofuran (THF, 21 1.4 kg) and DMA (108.8 kg) for approximately lhour and then cooled to 0-5 °C and aged for approximately 1 hour after which time the solid was filtered, washed with THF (147.6 kg) and dried on a filter under vacuum at approximately 25 °C to yield 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (34.0 kg). Alternative Preparation of 4-(6, 7-Dimethoxy-quinoIine-4-yloxy)-phenylamine

[00175] 4-chloro-6,7-dimethoxyquinoline (34.8 kg) and 4-aminophenoI (30.8 kg) and sodium tert pentoxide (1.8 equivalents) 88.7 kg, 35 weight percent in THF) were charged to a reactor, followed by N₍N-dimethylacetamide (DMA, 293.3 kg). This mixture was then heated to 105-1 15 °C for approximately 9 hours. After the reaction was deemed complete as determined using in-process HPLC analysis (less than 2 percent starting material remaining), the reactor contents were cooled at 15-25 °C and water (315 kg) was added over a two hour period while maintaining the temperature between 20-30 °C. The reaction mixture was then agitated for an additional hour at 20-25 °C. The crude product was collected by filtration and washed with a mixture of 88kg water and 82.1 kg DMA, followed by 175 kg water. The product was dried on a filter drier for 53 hours. The LOD showed less than 1 percent w/w.

[00176] In an alternative procedure, 1.6 equivalents of sodium tert-pentoxide were used and the reaction temperature was increased from 1 10-120 °C. In addition , the cool down temperature was increased to 35-40 °C and the starting temperature of the water addition was adjusted to 35-40 °C, with an allowed exotherm to 45 °C.

Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid

[00177] Triethylamine (19.5 kg) was added to a cooled (approximately 5 °C) solution of cyclopropane-l,l-dicarboxylic acid (24.7 kg) in THF (89.6 kg) at a rate such that the batch temperature did not exceed 5 °C. The solution was stirred for approximately 1.3 hours, and then thionyl chloride (23.1 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, the solution was stirred for approximately 4 hours keeping temperature below 10 °C. A solution of 4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 10 hours after which the reaction was deemed complete. The reaction mixture was then diluted with isopropyl acetate (218.1 kg). This solution was washed sequentially with aqueous sodium hydroxide (10.4 kg, 50 percent dissolved in 1 19 L of water) further diluted with water (415 L), then with water (100 L) and finally with aqueous sodium chloride (20.0 kg dissolved in 100 L of water). The organic solution was concentrated by vacuum distillation (100 L residual volume) below 40 °C followed by the addition of n- heptane (171.4 kg), which resulted in the precipitation of solid. The solid was recovered by filtration and washed with n-heptane ( 102.4 kg), resulting in wet, crude l-(4-fluoro- phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg). The crude, l-(4-fluoro- phenylcarbamoy -cyclopropanecarboxylic acid was dissolved in methanol (139.7 kg) at approximately 25 °C followed by the addition of water (320 L) resulting in slurry which was recovered by filtration, washed sequentially with water (20 L) and n-heptane (103.1 kg) and then dried on the filter at approximately 25 °C under nitrogen to afford the title compound (25.4 kg).

Preparation of l-(4-Fluoro-phenyIcarbamoyl)-cyclopropanecarbonyl chloride

[00178] Oxalyl chloride ( 12.6 kg) was added to a solution of I -(4-fluoro- phenylcarbamoyD-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N, N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not exceed 25 °C. This solution was used in the next step without further processing.

Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride

[00179] A reactor was charged with l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarboxylic acid (35 kg), 344 g DMF, and 175kg THF. The reaction mixture was adjusted to 12-17 °C and then to the reaction mixture was charged 19.9 kg of oxalyl chloride over a period of 1 hour. The reaction mixture was left stirring at 12-17 °C for 3 to 8 hours. This solution was used in the next step without further processing.

Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

[00180] The solution from the previous step containing l-(4-fluoro-phenylcarbamoyl)- cyclopropanecarbonyl chloride was added to a mixture of compound 4-(6,7-dimethoxy- quinoline-4-yloxy)-phenylamine (23.5 kg) and potassium carbonate (31.9 kg) in THF (245.7 kg) and water (116 L) at a rate such that the batch temperature did not exceed 30 °C. When the reaction was complete (in approximately 20 minutes), water (653 L) was added. The mixture was stirred at 20-25 °C for approximately 10 hours, which resulted in the precipitation of the product. The product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25 °C and then at approximately 45 °C under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD). Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoIine-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide

[00181] A reactor was charged with 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (35.7 kg, 1 equivalent), followed by 412.9 kg THF. To the reaction mixture was charged a solution of 48.3 K₂C0₃ in 169 kg water. The acid chloride solution of described in the

Alternative Preparation of l-(4-Fluoro-phenylcarbamoyl)-cvclopropanecarbonyl chloride above was transferred to the reactor containing 4-(6,7-dimethoxy-quinoline-4-yloxy)- phenylamine while maintaining the temperature between 20-30 °C over a minimum of two hours. The reaction mixture was stirred at 20-25 °C for a minimum of three hours. The reaction temperature was then adjusted to 30-25 °C and the mixture was agitated. The agitation was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. To the remaining upper organic phase was added 804 kg water. The reaction was left stirring at 15-25 °C for a minimum of 16 hours.

[00182] The product precipitated. The product was filtered and washed with a mixture of 179 kg water and 157.9 kg THF in two portions. The crude product was dried under a vacuum for at least two hours. The dried product was then taken up in 285.1 kg THF. The resulting suspension was transferred to reaction vessel and agitated until the suspension became a clear (dissolved) solution, which required heating to 30-35 °C for approximately 30 minutes. 456 kg water was then added to the solution, as well as 20 kg SDAG-1 ethanol (ethanol denatured with methanol over two hours. The mixture was agitated at 15-25 °C fir at least 16 hours. The product was filtered and washed with a mixture of 143 kg water and 126.7 THF in two portions. The product was dried at a maximum temperature set point of 40 °C.

[00183] In an alternative procedure, the reaction temperature during acid chloride formation was adjusted to 10-15 °C. The recrystallization temperature was changed from 15-25 °C to 45-50 °C for 1 hour and then cooled to 15-25 °C over 2 hours.

Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4- yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide, malate salt

[00184] Cyclopropane- 1 , 1 -dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (1-5; 13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg) and water (37.3 kg) were charged to a reactor and the mixture was heated to reflux (approximately 74 °C) for approximately 2 hours. The reactor temperature was reduced to 50 to 55 °C and the reactor contents were filtered. These sequential steps described above were repeated two more times starting with similar amounts of starting material (13.3 kg), L-Malic acid (4.96 kg), MEK (198.6 kg) and water (37.2 kg). The combined filtrate was azeotropically dried at atmospheric pressure using MEK (1 133.2 kg) (approximate residual volume 71 1 L; KF < 0.5 % w/w) at approximately 74 °C. The temperature of the reactor contents was reduced to 20 to 25 °C and held for approximately 4 hours resulting in solid precipitate which was filtered, washed with MEK (448 kg) and dried under vacuum at 50 °C to afford the title compound (45.5 kg).

Alternative Preparation of cyclopropane-l,l-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yIoxy)-phenyl]-amide (4-fluoro-phenyI)-amide, (L) malate salt

[00185] Cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)- phenyl]-amide (4-fluoro-phenyI)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg methyl ethyl ketone, and 129.1 kg water (37.3 kg) were charged to a reactor and the mixture was heated 50-55 °C for approximately 1-3 hours, and then at 55-60 °C for an addition al 4-5 hours. The mixture was clarified by filtration through a 1 μπι cartridge. The reactor temperature was adjusted to 20-25 °C and vacuum distilled with a vacuum at 150-200 mm Hg with a maximum jacket temperature of 55 °C to the volume range of 558-731 L.

[00186] The vacuum distillation was performed two more times with the charge of 380 kg and 380.2 kg methyl ethyl ketone, respectively. After the third distillation, the volume of the batch was adjusted to 18 v/w of cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy- quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyI)-amide by charging 159.9 kg methyl ethyl ketone to give a total volume of 880L. An addition al vacuum distillation was carried out by adjusting 245.7 methyl ethyl ketone. The reaction mixture was left with moderate agitation at 20-25 °C for at least 24 hours. The product was filtered and washed with 415.1 kg methyl ethyl ketone in three portions. The product was dried under a vacuum with the jacket temperature set point at 45 °C.

[00187] In an alternative procedure, the order of addition was changed so that a solution of 17.7 kg L-malic acid dissolved in 129.9 kg water was added to cyclopropane- 1,1- dicarboxylic acid [4-(6,7-dimethoxy-quinoHne-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)- amide (48.7 kg) in methyl ethyl ketone (673.3 kg).

Preparation of Compound 2

[00188] Compound 2 was prepared as provided in Scheme 3 and the accompanying experimental examples. Scheme 3

Toluene

[00189] In Scheme 1, Xb is Br or CI. For the names of the intermediates described within the description of Scheme 1 below, Xb is referred to as halo, wherein this halo group for these intermediates is meant to mean either Br or CI.Preparation of l-[5 methoxy-4 (3-halo propoxy)- 2 nitro-phenyl]- ethanone

[00190] Water (70 L) was charged to the solution of l-[4-(3-halo propoxy)- 3-methoxy phenyl] ethanone (both the bromo and the chloro compound are commercially available). The solution was cooled to approximately 4 °C. Concentrated sulfuric acid (129.5 kg) was added at a rate such that the batch temperature did not exceed approximately 18 °C. The resulting solution was cooled to approximately 5 °C and 70 percent nitric acid (75.8 kg) was added at a rate such that the batch temperature did not exceed approximately 10 °C. Methylene chloride, water and ice were charged to a separate reactor. The acidic reaction mixture was then added into this mixture. The methylene chloride layer was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride layers were washed with aqueous potassium bicarbonate solution and concentrated by vacuum distillation. 1- Butanol was added and the mixture was again concentrated by vacuum distillation. The resulting solution was stirred at approximately 20°C during which time the product crystallized. The solids were collected by filtration, washed with 1-butanol to afford compound the title compound, which was isolated as a solvent wet cake and used directly in the next step. ‘HNMR (400MHz, DMSO-d6): δ 7.69 (s, 1H), 7.24 (s, 1H); 4.23 (m, 2H), 3.94 (s, 3H), 3.78 (0-3.65 (t) (2H), 2.51 (s, 3H), 2.30-2.08 (m, 2H) LC/MS Calcd for [M(CI)+H]⁺ 288.1, found 288.0; Calcd for [M(Br)+H]⁺ 332.0, 334.0, found 331.9, 334.0.

Preparation of l-[5-methoxy-4-(3-morpholin-4-yl-propoxy)-2-nitro-phenyl]-ethanone

[00191] The solvent wet cake isolated in the previous step was dissolved in toluene. A solution of sodium iodide (67.9 kg) and potassium carbonate (83.4 kg) was added to this solution, followed by tetrabutylammonium bromide (9.92 kg) and morpholine (83.4 kg). The resulting 2 phase mixture was heated to approximately 85°C for about 9 hours. The mixture was then cooled to ambient temperature. The organic layer was removed. The aqueous layer was back extracted with toluene. The combined toluene layers were washed sequentially with two portions of saturated aqueous sodium thiosulfate followed by two portions of water. The resulting solution of the title compound was used in the next step without further processing. ‘HNMR (400MHz, DMSO-d6): δ 7.64 (s, 1 H), 7.22 (s, 1H), 4.15 (t, 2H), 3.93 (s, 3H), 3.57 (t, 4H), 2.52 (s, 3H), 2.44-2.30 (m, 6H), 1.90 (quin, 2H); LC/MS Calcd for [M+H]⁺ 339.2, found 339.2.

Preparation of l-[2-amino-5-methoxy-4-(3-morpholin-4-yl- propoxy)-phenyl]-ethanone

[00192] The solution from the previous step was concentrated under reduced pressure to approximately half of the original volume. Ethanol and 10 percent Pd C (50 percent water wet, 5.02 kg) were added; the resulting slurry was heated to approximately 48 °C and an aqueous solution of formic acid (22.0 kg) and potassium formate (37.0 kg) was added. When the addition was complete and the reaction deemed complete by thin layer chromatography (TLC), water was added to dissolve the by-product salts. The mixture was filtered to remove the insoluble catalyst. The filtrate was concentrated under reduced pressure and toluene was added. The mixture was made basic (pH of about 10) by the addition of aqueous potassium carbonate. The toluene layer was separated and the aqueous layer was back extracted with toluene. The combined toluene phases were dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the resulting solution was used in the next step without further processing. ‘HNMR (400MHZ, DMSO-d6): δ 7.1 1 (s, 1H)„ 7.01 (br s, 2H), 6.31 (s, 1H), 3.97 (t, 2H), 3.69 (s, 3H), 3.57 (t, 4H), 2.42 (s, 3H), 2.44-2.30 (m, 6H), 1.91 (quin, 2H LC/MS Calcd for [M+H]⁺ 309.2, found 309.1.

Preparation of 6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinoiin- 4-ol, sodium salt

[00193] A solution of sodium ethoxide (85.0 kg) in ethanol and ethyl formate (70.0 kg) was added to the solution from the previous step. The mixture was warmed to approximately 44 °C for about 3 hours. The reaction mixture was cooled to approximately 25°C. Methyl t- butyl ether (MTBE) was added which caused the product to precipitate. The product was collected by filtration and the cake was washed with MTBE and dried under reduced pressure at ambient temperature. The dried product was milled through a mesh screen to afford 60.2 kg of the title compound. ‘HNMR (400MHz, DMSO-d6): δ 1 1.22 (br s, 1H), 8.61 (d, 1H), 7.55 (s, 1H), 7.54 (s, 1H), 7.17 (d, 1H), 4.29 (t, 2 H), 3.99 (m, 2H), 3.96 (s, 3H), 3.84 (t, 2H), 3.50 (d, 2H), 3.30 (m, 2H), 3.1 1 (m, 2H), 2.35 (m, 2H), LC/MS Calcd for [M+H]⁺ 319.2, found 319.1.

Preparation of 4-chIor-6-methoxy-7-(3 morpholin-4-yl)-quinoline

[00194] Phosphorous oxychloride (26.32 kg) was added to a solution of 6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ol (5.00 kg) in acetonitrile that was heated to 50-55 °C. When the addition was complete, the mixture was heated to reflux (approximately 82 °C) and held at that temperature, with stirring for approximately 18 hours at which time it was sampled for in process HPLC analysis. The reaction was considered complete when no more than 5 percent starting material remained. The reaction mixture was then cooled to 20-25 °C and filtered to remove solids. The filtrate was then concentrated to a residue. Acetronitrile was added and the resulting solution was concentrated to a residue. Methylene chloride was added to the residue and the resulting solution was quenched with a mixture of methylene chloride and aqueous ammonium hydroxide. The resulting 2 phase mixture was separated and the aqueous layer was back extracted with methylene chloride. The combined methylene chloride solutions were dried over anhydrous magnesium sulfate, filtered and concentrated to a solid. The solids were dried at 30-40 °C under reduced pressure to afford the title compound (1.480 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.61 (d, 1H), 7.56 (d, 1H), 7.45 (s, 1H), 7.38 (s, 1H), 4.21 (t, 2 H), 3.97 (s, 3H), 3.58 (m, 2H), 2.50-2.30 (m, 6H), 1.97 (quin, 2H) LC MS Calcd for [M+Hf 458.2, found 458.0.

Preparation of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morphoIin-4-yl

propoxy)quinoline

[00195] A solution of 4-chIoro-6-methoxy-7-(3 morpholin-4-yl)-quinoline (2.005 kg, 5.95 mol) and 2 fluoro-4-nitrophenol (1.169 kg, 7.44 mol) in 2,6-Iutidine was heated to 140-145 °C, with stirring, for approximately 2 hours, at which time it was sampled for in process HPLC analysis. The reaction was considered complete when less than 5 percent starting materia! remained. The reaction mixture was then cooled to approximately 75 °C and water was added. Potassium carbonate was added to the mixture, which was then stirred at ambient temperature overnight. The solids that precipitated were collected by filtration, washed with aqueous potassium carbonate, and dried at 55-60 °C under reduced pressure to afford the title compound (1.7 kg). ‘HNMR (400MHz, DMSO-d6): δ 8.54 (d, 1H), 8.44 (dd, 1H), 8.18 (m, 1H), 7.60 (m, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 6.75 (d, 1H), 4.19 (t, 2H), 3.90 (s, 3H), 3.56 (t, 4H), 2.44 (t, 2H), 2.36 (m, 4H), 1.96 (m, 2H). LC/MS Calcd for [M+H]⁺ 337.1 , 339.1 , found 337.0, 339.0.

Preparation of 3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yIoxy]- phenylamine

[00196] A reactor containing 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4- yl propoxy)quinoline (2.5 kg) and 10 percent palladium on carbon (50 percent water wet, 250 g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 L) was pressurized with hydrogen gas (approximately 40 psi). The mixture was stirred at ambient temperature. When the reaction was complete (typically 2 hours), as evidenced by in process HPLC analysis, the hydrogen was vented and the reactor inerted with argon. The reaction mixture was filtered through a bed of Celite® to remove the catalyst. Potassium carbonate was added to the filtrate until the pH of the solution was approximately 10. The resulting suspension was stirred at 20-25 °C for approximately 1 hour. The solids were collected by filtration, washed with water and dried at 50-60 °C under reduced pressure to afford the title compound (1.164 kg)._’H NMR (400MHz, DMSO-d6): δ 8.45 (d, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.08 (t, 1H), 6.55 (dd, 1H), 6.46 (dd, 1H), 6.39 (dd, 1H), 5.51 (br. s, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H). LC/MS Calcd for

[M+H]⁺ 428.2, found 428.1.

Preparation of l-(4-fluoro-phenylcarbamoyl)-cycIopropanecarboxylic acid

[00197] Triethylamine (7.78 kg) was added to a cooled (approximately 4°C) solution of commercially available cyclopropanel.l-dicarboxylic acid (9.95 kg) in THF, at a rate such that the batch temperature did not exceed 10 °C. The solution was stirred for approximately 30 minutes and then thionyl chloride (9.14 kg) was added, keeping the batch temperature below 10 °C. When the addition was complete, a solution of 4 fluoroaniline (9.4 kg) in THF was added at a rate such that the batch temperature did not exceed 10 °C. The mixture was stirred for approximately 4 hours and then diluted with isopropyl acetate. The diluted solution was washed sequentially with aqueous sodium hydroxide, water, and aqueous sodium chloride. The organic solution was concentrated by vacuum distillation. Heptane was added to the concentrate. The resulting slurry was filtered by centrifugation and the solids were dried at approximately 35 °C under vacuum to afford the title compound (10.2 kg). Ή NMR (400 MHz, DMSO-d6): δ 13.06 (br s, 1H), 10.58 (s, 1H), 7.65-7.60 (m, 2H), 7.18-7.12 (m, 2H), 1.41 (s, 4H), LC/MS Calcd for [M+H]⁺ 224.1 , found 224.0.

Preparation of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

[00198] Oxalyl chloride (291 mL) was added slowly to a cooled (approximately 5°C) solution of l-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid in THF at a rate such that the batch temperature did not exceed 10°C. When the addition was complete, the batch was allowed to warm to ambient temperature and held with stirring for approximately 2 hours, at which time in process HPLC analysis indicated the reaction was complete. The solution was used in the next step without further processing.

Preparation of cyclopropane-l,l-dicarbox lic acid {3-fluoro-4-[6-methoxy-7-(3- morphoIin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluorophenyl)-amide

[00199] The solution from the previous step was added to a mixture of 3-fluoro-4-[6- methoxy-7-(3-mo holin-4-yl-propox )-quinolin-4-ylo y]-phenylamine (1 160 kg) and potassium carbonate (412.25 g) in THF and water at a rate such that the batch temperature was maintained at approximately 15-21 °C. When the addition was complete, the batch was warmed to ambient temperature and held with stirring for approximately 1 hour, at which time in process HPLC analysis indicated the reaction was complete. Aqueous potassium carbonate solution and isopropyl acetate were added to the batch. The resulting 2-phase mixture was stirred and then the phases were allowed to separate. The aqueous phase was back extracted with isopropyl acetate. The combined isopropyl acetate layers were washed with water followed by aqueous sodium chloride and then slurried with a mixture of magnesium sulfate and activated carbon. The slurry was filtered over Celite® and the filtrate was concentrated to an oil at approximately 30°C under vacuum to afford the title compound which was carried into the next step without further processing. Ή NMR (400MHz, DMSO- d6): δ 10.41 (s, 1H), 10.03 (s, 1H), 8.47 (d, 1H), 7.91 (dd, 1H), 7.65 (m, 2H), 7.53 (m, 2H), 7.42 (m, 2H), 7.16 (t, 2H), 6.41 (d, 1H), 4.20 (t, 2H), 3.95 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H), 1.47 (m, 4H). LC MS Calcd for [M+H]⁺ 633.2, found 633.1.

Preparation of the bisphosphate salt of cyclopropane-l,l-dicarboxylic acid {3-fluoro-4- [6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-ylamino]phenyl}-amide (4-fluoro- phenyl)-amide

[00200] Cyclopropane- 1,1-dicarboxy lie acid {3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl- propoxy)-quinolin-4-ylamino]phenyl}-amide-(4 fluoro phenyl)-amide from the previous step was dissolved in acetone and water. Phosphoric acid (85%, 372.48 g) was added at a rate such that the batch temperature did not exceed 30 °C. The batch was maintained at approximately 15- 30 °C with stirring for 1 hour during which time the product precipitated. The solids were collected by filtration, washed with acetone and dried at approximately 60 °C under vacuum to afford the title compound (1.533 kg). The title compound has a c-Met IC50 value of less than 50 nM. The bisphosphate salt is not shown in scheme 1. Ή NMR (400

MHz, DMSO-d6): (diphosphate) δ 10.41 (s, 1H), 10.02 (s, 1H), 8.48 (d, 1 H), 7.93 (dd, 1H), 7.65 (m, 2H), 7.53 (d, 2H), 7.42 (m, 2H), 7.17 (m, 2H), 6.48 (d, 1H), 5.6 (br s, 6H), 4.24 (t, 2H), 3.95 (s, 3H), 3.69 (bs, 4H), 2.73 (bs, 6H), 2.09 (t, 2H), 1.48 (d, 4H).

Foretinib
IUPAC name[hide] N1’-[3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
Other names[hide] XL880; EXEL-2880; GSK1363089; GSK089
Identifiers
CAS number	849217-64-7
ChemSpider	24608641
UNII	81FH7VK1C4
Jmol-3D images	Image 1
SMILES [show]
InChI [show]
Properties
Molecular formula	C34H34F2N4O6
Molar mass	632.65 g mol−1
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)

References

1. Hedgethorne, K., Huang, P.H. (2010). “Foretinib. c-Met and VEGFR-2 inhibitor, Oncolytic”. Drugs Fut 35 (11): 893–901. doi:10.1358/dof.2010.35.11.1529012 (inactive 2014-03-22).
2. “XL880 (GSK1363089)”. Exelixis, Inc.
3. “Foretinib”. clinicaltrials.gov.
4. Qian, F; Engst, S; Yamaguchi, K; Yu, P; Won, KA; Mock, L; Lou, T; Tan, J et al. (2009). “Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases”. Cancer Research 69 (20): 8009–16. doi:10.1158/0008-5472.CAN-08-4889. PMID 19808973.

 

CN102227164A *	Sep 25, 2009	Oct 26, 2011	葛兰素史密斯克莱有限责任公司	Preparation of quinolinyloxydiphenylcyclopropanedicarboxamide
CN102977014A *	Nov 5, 2012	Mar 20, 2013	沈阳药科大学	New quinoline compounds and uses thereof

* Cited by examiner

Non-Patent Citations

Reference
1	*	BAOHUI QI ET AL.: ‘Discovery and optimization of novel 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazones as c-Met Kinase Inhibitors.‘ BIOORGANIC & MEDICINAL CHEMISTRY. vol. 21, 19 June 2013, pages 5246 – 5260
2	*	BAOHUI QI ET AL.: ‘Synthesis and Biological Evaluation of 4-Phenoxy-6, 7-disubstituted Quinolines Possessing Semicarbazone Scaffolds as Selective c-Met Inhibitors.‘ ARCH. PHARM. CHEM. LIFE SCI. vol. 346, no. 8, 2013, pages 596 – 609

(2E)-N-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2-propenamide (1)

(S)-2′[2-1-(methyl-2-piperidyl) ethyl] cinnamanilide

(2E)-Λ/-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2- propenamide

CAS  951155-17-2

C₂₃H₂₈ N₂O, 348.48

It was reported that the (S)-enantiomer of 2′-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide (MSA100, 1) is an active 5-HT (5-hydroxytryptamine or serotonin) receptor antagonist; however, its (R)-isomer is totally or substantially devoid of the same activity.(1)

• 1.

  (a) Amer, M. S., U.S. Patent 5,780, 487, 1998.

  (b) Prashad, M.; Liu, Y.; Hu, B.; Girgis, M. J.; Schaefer, F., WO2007/111705, 2007.

  (c) Prashad, M.; Liu, Y.; Hu, B.; Girgis, M. J.; Schaefer, F., WO2007/111706, 2007.

…………………………………………………………………..

http://www.google.com/patents/WO2007111706A2?cl=en

Example 4:

Synthesis of (2E)-/V-[2-[2-[(2S)~1 -Methyl-2-piperidinyl]ethyI]phenyl]-3-phenyl-2- propenamide

(a) Free Base Generation:

A 250-mL, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer and nitrogen inlet-outlet, heating cooling bath, and addition funnel, is charged with 6.28 g (S)-2-[2-(1-methyl-2-piperidinyl)ethyl]-benzenamine (1R,3S)-(+)-camphoric acid salt (1 :1) and 60 mL of isopropyl acetate. Stir the mixture at 20-25 ⁰C under nitrogen and add a solution of 1.60 g of sodium hydroxide in 20 mL of water over a period of 5 min while maintaining an internal temperature at 20-25 ⁰C. Stir the suspension efficiently until all the solid dissolves (5 min). Separate the organic layer and save. Extract the aqueous layer with 20 mL of isopropyl acetate. Combine the organic layers and wash it with 20 mL of water. Separate the organic layer and concentrate it under vacuum (20-100 mbar) at an internal temperature at 20-40 ⁰C (external temperature 30-60 ⁰C) to obtain ~65 mL of a solution of (S)-2-[2-(1-methyl-2-piperidinyl)ethyl]-benzenamine (containing 3.28 g of free base) in isopropyl acetate. Save this solution for the next step and store it under nitrogen.

(b) Reaction:

A 250-mL, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, nitrogen inlet-outlet, heating mantle, condenser, and addition funnel is charged with -65 mL of a solution of (S)-2-[2-(1-methyl-2-piperidinyl)ethyl]-benzenamine (containing 3.28 g of free base) in isopropyl acetate and 6.22 g of potassium carbonate. Stir the reaction mixture under nitrogen at an internal temperature at 23 ± 3 ⁰C to afford a suspension. Add 3.75 g of cinnamoyl chloride over a period of 5 min while maintaining an internal temperature at 23 ± 3 ⁰C to obtain a slurry. Heat the reaction mixture to an internal temperature at 85 ± 5 ⁰C (external temperature 90-100 ⁰C) over a period of 30-60 min. Stir the reaction mixture at this temperature for an additional 2 h. Cool the reaction mixture to 23 ± 3 ⁰C over a period of 1 h. Add 50 mL of water. Stir the reaction mixture at 23 ± 3 ⁰C for 30-60 min to obtain a bi-phasic solution. Separate the organic layer. Add 80 mL of 0.5 N HCI solution over a period of 10 min while maintaining an internal temperature at 23 ± 3 ⁰C to afford a bi-phasic solution. Separate the aqueous layer. Add 60 mL of isopropyl acetate. Stir the reaction mixture and add a solution of 2.00 g of sodium hydroxide in 25 mL of water over a period of 10 min while maintaining an internal temperature at 23 ± 3 ⁰C to afford a bi- phasic solution. Separate the organic layer and save. Extract the aqueous layer with 60 mL of isopropyl acetate. Combine the organic layers and wash it with 40 mL of water. Separate the organic layer and concentrate it under vacuum (20-100 mbar) at an internal temperature at 20-40 ⁰C (external temperature 30-60 ⁰C) to obtain 22mL (19.3 g) of a solution of (iii) in isopropyl acetate. Stir and heat the reaction mixture to an internal temperature at 85 ± 5 ⁰C (external temperature 90-100 ⁰C) over a period of 30-60 min. Add 96 mL of hepatane over a period of 10 min while maintaining an internal temperature at 85 ± 5 ⁰C. Stir and Cool the reaction mixture to 23 ± 3 ⁰C over a period of 1 h. Stir the resulting slurry at 23 ± 3 ⁰C for an additional 2 h. Collect the solid by filtration over a polypropylene filter paper in a Buchner funnel with suction. Wash the solid with a total of 28 mL of a mixture of isopropyl acetate and heptane (1/6) in two equal portions of 14 mL each. Dry the solid at 45-50 ⁰C under vacuum (13-40 mbar) with nitrogen bleeding to obtain a constant weight (LOD < 1%, 4 h) of 4.06 g of (2£)-A/-[2-[2-[(2S)-1-methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2-propenamide as an off white solid.

Theoretical Yield: 5.23 g

Yield: 77.6%

Purity: 99.8% (HPLC area %).

Enantiomeric purity: (R)-(iii) was not detected by Chiral HPLC. Example 5:

Alternative synthesis of (2£)-/V-[2-[2-[(2S)-1-MethyI-2-piperidinyl]ethyl]phenyI]-3- phenyl-2-propenamide

(a) Free base generation:

In a 500 ml round bottomed flask equipped with a mechanical stirrer the resolved camphoric acid salt (IV) (20 g) in isopropyl acetate (120 g) is added at an internal temperature of 20 to 25 ⁰C (external temperature 20 ⁰C). Then, at an internal temperature of 25 to 30 ⁰C (external temperature 20 ⁰C) a solution of sodium hydroxide (38.24 g) in water (60 g) is added to the reaction mixture over a period of 5 minutes. The reaction mixture (suspension) is then stirred for a further 30 minutes. The resulting orange emulsion is then allowed to separate into a two-phase mixture and the water phase is removed. The organic phase is then subjected to a rotary evaporator and the isopropyl acetate is distilled at an internal temperature of 60 ⁰C and under reduced pressure (250 mbar). Approximately 90 g of isopropyl acetate is distilled. Prior to distilling, the organic phase is a clear, bright orange colour and of a volume of approximately 160 ml ( 13Og),

(b) Reaction:

In a 1.5 I flask equipped with a mechanical stirrer and at an internal temperature of 35 ⁰C (external temperature 38 ⁰C) and under inert conditions (nitrogen) 2-butanone (160 g) and isopropyl acetate (20 g) is added to the reaction mixture of part (a). Then, at an internal temperature of 35 ⁰C (external temperature of 38 ⁰C) a solution of cinnamoyl chloride (8.9 g) in 2-butanone (20 g) is added drop wise. Then, the reaction mixture is treated with more 2- butanone (2 x 5 g). The resulting suspension is then stirred for 20 minutes at an internal temperature of 35⁰C. The pH of the mixture is between 6 and 8.

(c) Resolution:

The suspension of step (b) is then cooled to an internal temperature of 25 ⁰C (external temperature 20 ⁰C) and at the same time a mixture of water (200 g) and isopropyl acetate (60 g) is added. The reaction mixture is then stirred for a further 15 minutes at an internal temperature of 25 ⁰C (external temperature 20 ⁰C). The resulting two-phase reaction mixture is then separated and the water phase removed. The resulting yellow upper layer is then treated with 2.5 mol/l hydrochloric acid (200 g). The resulting two-phase mixture is then separated and the water phase is transferred into a 750 ml flask equipped with a mechanical stirrer. The organic phase is then washed with 2.5 mol/l hydrochloric acid (200 g) and the resulting two-phase mixture is separated and the water phase is added to the first water phase. The combined water phases are then treated with acetic acid (300 g) and sodium hydroxide (150 g) is added. The reaction mixture is then stirred at an internal temperature of 25 to 30 ⁰C (external temperature 20 ⁰C) for 15 minutes. The resulting two-phase reaction mixture is then separated.

(d) Crystallization

The organic phase from the above reaction step (c) is reduced in volume on a rorary evaporator at an external temperature of 60 ⁰C and at 250 mbar. Then, the reduced-volume reaction mixture is treated with isopropanol (60 g) and the resulting reaction mixture is reduced in volume on a rotary evaporator at an external temperature of 60 ⁰C and under a vacuum of 150 mbar. Then, at an internal temperature of 50 to 55 ⁰C (external temperature 60 ⁰C) the reaction mixture is treated with water (20 g) and the resulting suspension is further treated with the product (iv) (10 mg) in isopropanol (0.01 g). The reaction mixture is then stirred for a further 15 minutes at an internal temperature of 50 to 55 ⁰C (external temperature 60 ⁰C). Then, further water is added over a period of 15 to 30 minutes and the reaction mixture is maintained at an internal temperature of 50 to 55 ⁰C (external temperature 60 ⁰C). Then, the resulting suspension is cooled to an internal temperature of 22 to 22 ⁰C (external temperature 20 ⁰C. Then, the suspension is stirred for a further 30 minutes at an internal temperature of 22 to 22 ⁰C (external temperature 20 ⁰C) and the resulting solid is collected by filtration and washed with a mixture of water and isopropyl acetate (2 x 20 g), where the water: isopropyl acetate ratio is of 5:1 g/g. The resulting solid may then be dried under a vacuum at a temperature of 55 ⁰C.

Yield: 14.8 g (89.3% of theory). mp: 127.3 to 130.2 ⁰C

Example 6: Recrystallisation of (2E)-Λ/-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2- propenamide

(a) In a 200 ml round bottomed flask equipped with a magnetic stirrer, containing the product (iv) (15 g) is added isopropanol (25 g) and heptane (heptane fraction from petroleum having a boiling point of 65 to 100 ⁰C) (25 g) is added. Then, the reaction mixture is heated to an internal temperature of 75 ⁰C (external temperature 95 ⁰C) and refluxed for approximately 30 minutes, whilst stirring. Then, the reaction mixture is filtered over a glass fibre filter at an internal temperature of 70 to 75 ⁰C (external temperature 85 ⁰C) in to a 350 ml flask equipped with a magnetic stirrer. Then, a mixture of isopropanol (5 g) and heptane (5 g) is added and the reaction mixture is heated to an internal temperature of 70 ⁰C (external temperature 95 ⁰C). Then, further heptane is added drop wise to the reaction mixture at an internal temperature of 65 to 75 ⁰C (external temperature 75 ⁰C).

(b) Crystallization

The solution from step (a) is then cooled to an internal temperature of 40 ⁰C (external temperature 40 ⁰C) over a period of 15 minutes. The, at an internal temperature of 40 ⁰C, the solution is treated with a suspension of the recrystallized product (v) (11 mg) in heptane is added and the reaction mixture is stirred for 30 minutes at an internal temperature of 40 ⁰C (external temperature 40 to 45 ⁰C). Then, the reaction mixture is treated with some further heptane (15 g) at an internal temperature of 40 ⁰C. The resulting suspension is then cooled to an internal temperature of -10 ⁰C (external temperature -10 to -15 ⁰C) over a period of 30 minutes and then further stirred for a further hour. The reaction mixture is then filtered at an internal temperature of -10 ⁰C (external temperature -10 to -15 ⁰C) and the resulting solid may be washed in a mixture of isopropanol and heptane, where the isopropanohheptane ratio is 1 :1.5. The solid may be washed twice (2 x 11.25 g). The solid may then be dried in a vacuum at a temperature of 60 ⁰C.

Yield: 17.8 g (89% of theory) mp: 127.4 to 132.0 ⁰C.

………………………………………………………………..

An efficient process was developed for the manufacture of MSA100, a serotonin receptor antagonist, via a five-step synthetic route furnishing a high quality of active pharmaceutical ingredient. Highlights of this synthesis include: (1) replacing carcinogenic methyl iodide with methyl p-toluenesulfonate as the methylating reagent; (2) a hydrogenation protocol with optimized temperature, pressure, and mass-transfer conditions that avoided one side product and reduced the other one effectively; (3) chemical resolution employing D-camphoric acid in a mixed-solvent system; (4) amidation under anhydrous conditions for controlling a Michael adduct impurity; and (5) plausible mechanisms for the formation of side products.

(2E)-N-[2-[2-[(2S)-1-Methyl-2-piperidinyl]ethyl]phenyl]-3-phenyl-2-propenamide (1)

To a mixture of 14 (6.28 g, 15 mmol) ……………………………………………………to obtain 1 (4.06 g, 78% yield) as an off-white solid: mp 125–127 °C (lit. ref 1a, mp 128 °C);

Chiral HPLC for (S)-1 (t_R = 19.3 min), >99.9% ee; (R)-1 (t_R = 18.5 min): Chiralcel AD-H, 250 × 4.6 mm, flow rate = 1.0 mL/min, 25 °C, 900:100:1 A:B:C isocratic; A = hexanes; B = ethanol; C = diethylamine; UV λ = 230 nm. HPLC for 1 (t_R = 11.2 min) 99.8% purity; 8 (t_R = 5.4 min); 9 (t_R = 12.3 min): Waters Symmetry-C18 150 × 4.6 mm, flow rate = 1 mL/min, 25 °C, gradient elution from 93:7 A–B to 85:15 A–B over 5 min, to 10:90 A–B over 10 min and held for 2 min, to 93:7 A–B over 1 min; A = 0.1% TFA in water; B = acetonitrile; UV λ = 230 nm.

…………………

http://www.google.com/patents/EP0973741A1

Example I PREPARATION AND CONFIRMATION OF S-MPEC

racemic-APEMEP-HI -5/1-

- 6 -

1. 2 – nitrobenzaldehyde

2. 2 – picoline

3. 2 – (o-nitrostyryl) pyridine (NSP)

4. 2 – ^“(o-nitrostyryl)- 1 -methylpyridinium iodide 5. RS-2- (o-aminophenethyl)-l-methylpiperidine. HI

6. S-[2-(o-aminophenethyl)- 1 -methylpiperidine-dibenzoyl-L-tartrate] (S-APEMP. DBLT OR .L-DBT)

7. S-2′- [2-(l-methyl-2-piperidyl) ethyl] cinnamanilide (S-MPEC) 7a. Cinnamoyl chloride S-MPEC CHEMICAL PROCESS

(A) 2-(O-Nitrostyryl) – 1 -Methylpyridinium Iodide fNSMP-P

To a 50 L round bottomed flask was added 2-nitrobenzaldehyde (3,500 g. 23.2 moles), 2-picoline (3.2L., 32.8 moles) and acetic anhydride. The mixture was stirred efficiently under an inert atmosphere (nitrogen or another inert gas) and heated to reflux for 27 hrs. The mixture was cooled to under 100 C, for safe handling, and quenched in a suitable vessel equipped with external cooling and efficient stirring on 10.5 Kg. of ice. The pH was adjusted to 11 with 45% aqueous sodium hydroxide at a rate to keep the temperature below 50°C. After cooling to 20-30°C, the granular solid was collected by filtration, washed well with water. Yield 6572 g. of crude 2-(o-nitrostyryl) pyridine (NSP).

This solid was transferred to a 50L, round bottomed flask, dissolved in acetone (14L.) and iodomethane (2.94L., 47.7 moles) (quaternizing methylating agent) was added. (Other such (alkylating) agents may be used, generally having the formula CH₃X, X being an anion such as sulfate, methyl sulfate, halide (Cl, Br, I), etc.). The mixture was heated to reflux under an inert atmosphere (nitrogen or another inert gas) for 18 hrs. After cooling to 20°C. the precipitate was collected by filtration and washed with acetone or a 1 :1 mixture of acetone:ethyl acetate (3×3.5L.). Drying to constant weight at 50-60°C. yielded 6,839 g. (80%) of NSMP.I. (B) RS- 2-(o-Aminophenethyl)-l-Methylpiperidine. Hvdroiodide

ΓRS-APEMP.HΠ

In a 5 gallon reactor, a solution of NSNP.I (935 g., 2.5 moles) in – 7 – methanol (14L.) was reduced in a hydrogen atmosphere (Psi. 55) in the presence of Pt/C (5 or 10%, 98g.). After removal of the catalyst and evaporation of the filtrate in the usual manner, the residue was dissolved in hot methanol (2.8L.). Ethyl acetate (2.8L) was added to the hot mixture to induce crystallization, yield 516.3 g. (59%) of RS-APEMP.HI.

(C) S-[2-(o-Aminophenethv0- 1 -Methylpiperidine Dibenzoyl-L-Tartrate] (S- APEMP.DBLT)

A solution of RS-APEMP.HI (516g., 1.5 mole) ethyl acetate (5.5g.) (or other low boiling water immiscible solvent such as benzene, toluene etc.) was extracted with 5% aqueous sodium hydroxide to liberate the free base (organic phase), washing the organic phase with water, drying over a suitable drying agent (such as anhydr. sodium sulfate, magnesium sulfate, potassium carbonate etc.) After separating the solvent from the drying agent the solution was evaporated in vacuo and the residual RS-APEMP free base was dissolved in methanol (l .O.L.) and a solution of dibenzoyl-L-tartaric acid (540 g., 1.5 moles) in methanol (2.3 L.) was added. The mixture was held overnight at room temperature. The crystalline precipitate was collected and recrystallized from methanol (3.4 L.), yield 246g. of S-APEMP.DBLT. (28.6%, wt; 57.2% of the S-APEMP). (O) S-2′-r2-π-Methyl-2-Piperidvnethyll Cinnamanilide f S-MPEC) A solution of S-APEMP.DBLT (287 g, 0.5 mole) in ethyl acetate

(3.2 L.) (or other low boiling water immiscible solvent) was extracted with 7.5% aqueous sodium bicarbonate (3.2 L.) to liberate the S-APEMP. After a water wash and drying over a suitable drying agent the solvent was removed in vacuo. The oily residue, S-APEMP, was dissolved in ethyl acetate (1.0 L.) and anhydrous potassium carbonate (412 g, 3.0 moles) (or other suitable acid acceptor such as triethyl amine, pyridine etc.) was added. Cinnamoyl chloride (143 g., 0.7 mole) in 700 ml. of ethyl acetate was added slowly. After the initial reaction, the mixture was refluxed for 14 hrs. After cooling to room temperature the mixture was extracted with water (1.7 L.) and dried over a suitable drying agent. After removing the drying agent the solvent was removed in vacuo and the residue was dissolved in hot ethyl acetate (280 ml.) and allowed to slowly cool to room temperature; filtration yielded S-MPEC, (136 g., 79% yield). Analysis: Calcd. For C, H, N : C, 79.27; H, 8.10;N, 8.04. Found: C, 79.27; H, 8.06; N, 8.07. HPLC(chiral)purity: 99.5%, [oc ]_D25, -46° (c=0.01,EtOH); Melting point: 128°C.
TABLE 2 CERTIFICATE OF ANALYSIS Compound Name: (-)-2′-[2-(l-Methyl-2 piperidyl)ethyl]cinnamanilide(/-MPEC,S- MPEC

……………………………….

http://www.google.com/patents/US20080300410?cl=en

synthesis of 2′[2-1-(methyl -2-piperidyl) ethyl] cinnamanilide (Y1), which is a compound of formula (Y) where R^a is hydrogen and R¹ is methyl:

Processes for the preparation of compounds of formula (Y) are described in U.S. Pat. No. 3,931,195 which comprises the step of alkylating compounds of formula (i) (below) with an alkyl halide, such as methyl iodide for methylation. The same methylation step is described in EP0973741 for the synthesis of compound (Y1).

Thus, the processes described in the prior art involve the use of a highly toxic reagent (e.g. methyl iodide) and provides a yield of about 50%

US4064254 *	Oct 21, 1976	Dec 20, 1977	Mead Johnson & Company	Substituted piperidines therapeutic process and compositions
US5780487 *	Feb 28, 1997	Jul 14, 1998	Amer Moh Samir	S-2′- 2-(1-methyl-2-piperidyl) ethyl! cinnamanilide

Cilomilast (Ariflo, SB-207,499)

cas 153259-65-5

cis-{-4-cyano-4-[3- (trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-l -carboxylic acid}

cis-4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-r-1-cyclohexanecarboxylic acid

C20-H25-N-O4, 343.4205

GSK….INNOVATOR

• Ariflo
• Cilomilast
• SB 207499
• SB207499
• UNII-8ATB1C1R6X

A selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease.

CLINICAL   https://clinicaltrials.gov/search/intervention=Cilomilast

Cilomilast (Ariflo, SB-207,499) is a drug which was developed for the treatment of respiratory disorders such as asthma and Chronic Obstructive Pulmonary Disease (COPD). It is orally active and acts as a selective Phosphodiesterase-4 inhibitor.^[1]

SB-207499 is a potent second-generation inhibitor of PDE4 (phosphodiesterase-4) with decreased side effects versus those of the well-known first-generation inhibitor, (R)-rolipram. SB-207499 is in clinical development both for asthma and chronic obstructive pulmonary disease (COPD)……..J. Med. Chem. 1998, 41, 821

Cilomilast (Ariflo™, SB 207499) is an orally active, second-generation phosphodiesterase (PDE) 4 inhibitor that is being developed by GlaxoSmithkline for the treatment of chronic obstructive pulmonary disease (COPD). The results of Phase I and Phase II studies have demonstrated that cilomilast significantly improves lung function and quality of life to a clinically meaningful extent, which has led to a comprehensive Phase III programme of research evaluating efficacy, safety and mechanism of action. However, the results of those Phase III studies are unremarkable and disappointing, raising doubt over the future of cilomilast as a novel therapy for COPD. This review summarizes data obtained from the Phase III clinical development programme, highlights some of the potential concerns both specific to cilomilast and to PDE4 inhibitors in general and assesses the likelihood that cilomilast will reach the market.

Cilomilast is GlaxoSmithKline’s selective phosphodiesterase type 4 (PDE4) inhibitor. The drug candidate had been preregistered in the U.S. for the maintenance of lung function in patients with chronic obstructive pulmonary disease (COPD) who are poorly responsive to albuterol. GlaxoSmithKline received an approval letter from the FDA in October 2003, however, in 2007, the company discontinued development of the compound. In 2008, the product was licensed to Alcon by GlaxoSmithKline for the treatment of eye disorders.

Phosphodiesterase (PDE) inhibitors, such as theophylline, have been used to treat Chronic Obstructive Pulmonary Disease (COPD) for centuries; however, the clinical benefits of these agents have never been shown to out-weigh the risks of their numerous adverse effects. Four clinical trials were identified evaluating the efficacy of cilomilast, the usual randomized, double-blind, and placebo-controlled protocols were used. It showed reasonable efficacy for treating COPD, but side effects were problematic and it is unclear whether cilomalast will be marketed, or merely used in the development of newer drugs.^[2][3]

Cilomilast is a second-generation PDE4 inhibitor with antiinflammatory effects that target bronchoconstriction, mucus hypersecretion, and airway remodeling associated with COPD.

4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid
Clinical data
Legal status	?
Identifiers
CAS number	153259-65-5
ATC code	None
PubChem	CID 151170
ChemSpider	18826005
UNII	8ATB1C1R6X
Chemical data
Formula	C20H25NO4
Mol. mass	343.417 g/mol

Synthesis

Christensen, Siegfried B.; Guider, Aimee; Forster, Cornelia J.; Gleason, John G.; Bender, Paul E.; Karpinski, Joseph M.; Dewolf,, Walter E.; Barnette, Mary S. et al. (1998). “1,4-Cyclohexanecarboxylates: Potent and Selective Inhibitors of Phosophodiesterase 4 for the Treatment of Asthma”. Journal of Medicinal Chemistry 41 (6): 821–35. doi:10.1021/jm970090r. PMID 9526558.

The reaction of 3-cyclopentyloxy-4-methoxybenzaldehyde (I) with LiBr, trimethylsilyl chloride (TMS-Cl) and 1,1,3,3-tetramethyldisiloxane in acetonitrile gives the corresponding benzyl bromide (II), which by reaction with NaCN in DMF affords 2-(3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (III).

The condensation of (III) with methyl acrylate (IV) by means of Triton B in refluxing acetonitrile yields the 4-cyanopimelate (V), which is cyclized by means of NaH in refluxing DME, giving the 2-oxocyclohexanecarboxylic ester (VI). The decarboxylation of (VI) by means of NaCl in DMSO/water at 150 C yields the cyclohexanone (VII), which is condensed with 2-(trimethylsilyl)-1,3-dithiane (VIII) by means of BuLi in THF, affording the cyclohexylidene-dithiane (IX).

The methanolysis of (IX) catalyzed by HgCl2 and HClO4 in refluxing methanol gives a mixture of the cis- and trans-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid methyl ester which is submitted to flash chromatography to obtain the cis-isomer (XII). Finally, this compound is hydrolyzed with KOH in methanol/THF/water.

The synthesis of SB-207499 is described. Investigation and development of new strategies for the homologation of ketone, 4-cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-cyclohexan-1-one 2 are described which produce SB-207499. Our ultimate route of synthesis to SB-207499 is robust and operationally simple and produces the final drug substance in good yield and purity.

cis-4-Cyano-4-[3-(cyclopentyloxy)-4-(methoxyphenyl)]-r-1-cyclohexanecarboxylic acid (1a):

mp 148−150 °C; IR (KBr pellet) cm^-1 3300−2400, 2231, 1707, 1694;

¹H (400 MHz, CDCl₃) δ 11.75 (1Η, br s), 7.02 (1H, d, J = 2.3 Hz), 6.98 (1H, dd, J = 2.3, 8.4 Hz), 6.87 (1H, d, J = 8.4 Hz), 4.82 (1H, m), 3.86 (3H, s), 2.43 (1H, tt, J = 3.7, 12.2 Hz), 2.29 (2H, br d, J = 15.6 Hz), 2.25 (2H, br d, J = 16.4 Hz), 2.05 (2H, m), 1.94 (4H, m), 1.86 (2H, m), 1.82 (2H, m), 1.64 (2H, m); ¹³C (100 MHz, CDCl₃) δ 180.5, 149.8, 147.8, 132.8, 122.2, 117.3, 112.9, 111.9, 80.7, 56.1, 43.0, 41.7, 36.4, 32.8, 25.9, 24.0.

………………………………………..

http://www.google.com/patents/WO1995024381A1?cl=en

cis-{-4-cyano-4-[3- (trans-3-hydroxycyclopentyloxy)-4-methoxyphenyl]cyclohexane-l -carboxylic acid} or the corresponding compounds as defined by Formula I. The preparation of any remaining compounds of the Formula (I) not described therein may be prepared by the analogous processes disclosed herein which comprise:

Example 1

Preparation of cis-r4-cvano-4-⁽3-cyclopentyloxy-4-methoxyphenyl)cvclohexane- 1 – carboxylic acid]

1 fa (3-Cyclopentyloxy-4-methoxyphenv acetonitrile

To a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (20 g, 90.8 mmol) in acetonitrile (100 mL) was added lithium bromide (15 g, 173 mmol) followed by the dropwise addition of trimethylsilylchloride (17.4 mL, 137 mmol). After 15 min, the reaction mixture was cooled to 0° C, 1,1,3,3-tetramethyldisiloxane (26.7 mL, 151 mmol) was added dropwise and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered through Celite®. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide a light tan oil. To a solution of this crude a- bromo-3-cyclopentyloxy-4-methoxy toluene in dimethylformamide (160 mL) under an argon atmosphere was added sodium cyanide (10.1 g, 206 mmol) and the resulting mixture was stirred at room temperature for 18 h, then poured into cold water (600 mL) and extracted three times with ether. The organic extract was washed three times with water, once with brine and was dried (K2CO3). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to provide an off-white solid ( m.p. 32-34^g C); an additional quantity of slightly impure material also was isolated. Kb Dimethyl 4-cvano-4-(‘3-cvclopentyloxy-4-methoxyphenv pimelate

To a solution of (3-cyclopentyloxy-4-methoxyphenyl)acetonitrile (7 g, 30.3 mmol) in acetonitrile (200 mL) under an argon atmosphere was added a 40% solution of Triton-B in methanol (1.4 mL, 3.03 mmol) and the mixture was heated to reflux. Methyl acrylate (27 mL, 303 mmol) was added carefully, the reaction mixture was maintained at reflux for 5 h and then cooled. The mixture was diluted with ether, was washed once with IN hydrochloric acid and once with brine, was dried (MgSO4) and the solvent was removed in vacuo. The solid residue was triturated with 5% ethanol/hexane to provide a white solid (m.p. 81-82° C); an additional quantity was also obtained from the filtrate. Anal. (C22H29NO6) calcd: C 65.49, H 7.25, N 3.47. found: C 65.47, H 7.11, N 3.49. 1. c) 2-Caf bomethoxy-4-cvano-4-⁽3-cyclopentyloxy-4-methoxyphen vDcvclohexan- 1 -one To a suspension of sodium methoxide (350 mL, 1.55 mol, 25% w/w in methanol) in toluene (2.45 L) heated to 80° C under a nitrogen atmosphere was added a solution of dimethyl 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)pimelate (350.0 g, 0.87 mol) in toluene (1.05 L) over 10 min. The reaction was heated to 85° C by distilling away 250 mL of solvent and was vigorously stirred under nitrogen for 2 hours. The reaction was cooled to 50° C and was quenched with 3N (aq) HC1 (700 mL, 2.1 mol). The organic layer was isolated, was washed once with deionized water (700 mL) and once with brine (700 mL). The organic layer was concentrated via low vacuum distillation to afford crude 2- carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -one in toluene. This was dissolved in 4.2 L of dimethyl sulfoxide and used in the next step. 1 (d) 4-Cvano-4-f3-cyclopentyloxy-4-methoxyphenyl cvclohexan- 1-one

To a suspension of sodium chloride (315 g, 5.39 mol) and deionized water ( 315 mL) was added the dimethyl sulfoxide (4.2 L) solution of 2-carbomethoxy-4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexane-l-one ( 323 g, 0.87 mol) and the resulting suspension was heated to 155° C for 1.75 h. The reaction was cooled to 40° C, was quenched into 8 L of iced water (2² C) and was extracted with ethyl acetate (3.5 L). The aqueous layer was isolated and re-extracted with 2.5 L of ethyl acetate. The combined organic extract (6 L) was washed two times with deionized water (2 x 1 L) and once with brine (1 L). The organic layer was isolated and concentrated in vacuo to afford a residue. This residue was dissolved in refluxing isopropanol (500 mL), was cooled to 0° C and held at this temperature for 1 hour. The crystals were isolated by filtration, were washed with 250 mL of isopropanol (0° C), and were dried in a vacuum oven (45° C at 20 inches) to produce 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l -one . m.p. 111-112° C; Anal. (C₁₉H₂3NO ) calcd: C 72.82, H 7.40, N 4.47; found: C 72.72, H 7.39, N 4.48. 1 (e) 2-r4-Cyano-4-G-cyclopentyloxy-4-methoxyphenyl)cvclohexylidenel- 1.3-dithiane To a solution of 2-trimethylsilyl-l,3-dithiane (9.25 mL, 48.7 mmol) in dry tetrahydrofuran (80 mL) at 0° C under an argon atmosphere was added rapidly n- butyllithium (2.5M in hexanes, 19.2 mL, 48 mmol). After 10 min, the mixture was cooled to -78° C and a solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l- one (7.53 g, 23 mmol) in tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodium chloride was added, the mixture was allowed to warm to room temperature and was diluted with water. This mixture was combined with the product of three substantially similar reactions conducted on ketone (3.04, 6.01 and 6.1 g, 48.3 mmol total), the combined mixture was extracted three times with methylene chloride, the extract was dried (MgSO4) and evaporated. Purification by flash chromatography (silica gel, 10% ethyl acetate/hexanes) provided a white solid, m.p. 115-116° C. \⁽f) cis-r4-Cyano-4-⁽3-cyclopentyloxy-4-methoxyphenyl^‘)cyclohexane- 1 -carboxylic acidl

To a suspension of 2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclo- hexylidene]-l,3-dithiane ( 140.0 g, 0.34 mol) in acetonitrile (500 mL) and deioinized water (140 mL) under nitrogen was added trifluoroacetic acid (136 g, 1.19 mol). The suspension was heated to 65² C for 1.25 h followed by the addition of 20% sodium hydroxide (420 g, 2.1 mol). The solution was heated at 70 to 75° C for an additional 1.25 h, was cooled to 45° C, deionized water (420 mL)was added followed by 3N (aq) HC1 (392 mL, 1.18 mol). The suspension was cooled to 5° C and held for 1 h. The suspension was filtered, was washed with cold (5^e C) deionized water ( 200 mL), and was dried in a vacuum oven (40°C at 20 inches) to obtain crude cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane-l -carboxylic acid]. This material was assayed at 98.5% and was found to a 98.8:1.2 mixture of cis-to-trans isomers, which was contaminated with 0.1% of residual 1,3-propanedithiol. This material was purified via an oxidative workup as follows.

To a hot solution (65° C) of crude cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexane-l -carboxylic acid] (85 g, 0.247 mol) in acetonitrile (425 mL) was added 1M sodium hydroxide ( 425 mL, 0.425 mol). To the solution (60° C) was added 4.25 g of calcium hypochlorite and the suspension was vigorously stirred for 2 h. The reaction was concentrated by distilling out 320 mL of solvent, followed by the addition of ethyl acetate ( 425 mL). The reaction was again concentrated by distilling out 445 mL of solvent, was cooled to 55° C followed by the addition of ethyl acetate (1.0 L) and 6N (aq.) HC1 (100 mL). The organic layer was isolated, was washed three times with deionized water (3 x 300 mL), was filtered and was concentrated by distilling out 530 mL of solvent. To the solution was added ethyl acetate (635 mL) with continued distillation to remove 750 mL of solvent. The solution was cooled to 65° C followed by the addition of hexane ( 340 mL). The suspension was cooled to 5° C, held at this temperature for 1 hour, was filtered and was washed with cold (5° C) 10% ethyl acetate/ hexane ( 200 mL). The solid was collected and was dried in a vacuum oven (40° C at 20 inches) to obtain cis- [4- cyano-4- (3-cyclopentyloxy-4-methoxyphenyl)cyclohexane- 1 -carboxylic acid] . This material was found to contain no trans isomer. Anal.(C2θH25-Nθ4) calcd: C 69.95, H 7.34, N 4.08; found: C 69.90, H 7.35, N 4.02. Example 2

Preparation of cis-f 4-cvano-4-r3-(trans-3-hydroxycyclopentyloxy)-4-methoxyphenyll- cyclohexane-1 -carboxylic acid)

2(a’) cis-F4-Cyano-4-(3-hvdroxy-4-methoxyphenvDcyclohexane- 1 -carboxylic acid]

To a solution of boron tribromide in dichlorormethane (0.1M, 335 mL, 33.5 mmol) under an argon atmosphere at -78° C was slowly added a solution of cis-[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexane-l -carboxylic acid] (4.03 g, 11.7 mmol) in dichloromethane (180 mL). The mixture was stirred for 5 min, 15% sodium methoxide in methanol was added to pH 8-9 and the reaction was warmed to RT. Water (lOOmL) was added and the mixture was acidified with 3N aqueous hydrochloric acid to pH 1-2. The organic layer was separated, was dried (MgSO4/Na2SO4), was filtered and was evaporated. The residue was twice dissolved in chloroform and the solution was evaporated to yield a white solid. -1H NMR(400 MHz, CDCI3) δ 7.01 (d, J=2.4 Hz, 1H), 6.96 (d of d, J=2.4, 8.5 Hz, 1H), 3.89 (s, 3H), 2.31 (m, 1H), 2.21 (br t, J=13.6 Hz, 4H), 1.98 (m,2H), 1.77 (m, 2H); mp 190-193° C. Kb) Methyl cis- r-4-cvano-4-⁽3-hvdroxy-4-methoxyphenyl^‘)cvclohexane-l-carboxylatel -Toluenesulfonic acid monohydrate (0.015 g, 0.08 mmol) was added to a solution of the compound of Example 2(a) (0.70 g, 2.54 mmol) in dry methanol (20 mL) under an argon atmosphere and the reaction was stirred for 6 h at 45-50⁹ C. The reaction was cooled to RT and was stirred for an additional 16 h. The solution was evaporated and the residue was purified by flash chromatography (silica gel, 50% hexane/ethyl acetate) to yield the tide compound as a white solid. -1H NMR(400 MHz, CDC1₃) δ 7.01 (m, 2H), 6.85 (d, J=9.1 Hz, IH), 3.90 (s, 3H), 3.72 (s, 3H), 2.35 (t of t, J=3.6, 12.2 Hz, IH), 2.14-2.25 (m, 4H), 2.00 (app q, J=13.4 Hz, IH), 1.99 (app q, J=13.4 Hz, IH), 1.77 (app t, J=13.4 Hz, IH), 1.76 (app t, J=13.4 Hz, IH); mp 106-107° C.

2(c) Methyl cis- f -4-cvano-4-r3-(trans-3-hydroxycvclopentyloxy )-4-methoxyphenyl – cvclohexane- 1 -carboxylate 1

The compound of Example 2(b) (0.69 g, 2.37 mmol) was dissolved in tetrahydrofuran (20 mL) under an argon atmosphere and was treated with triphenylphosphine (1.24 g, 4.74 mmol) and cis-l,3-cyclopentanediol (0.49 g, 4.74 mmol). Diethyl azodicarboxylate (0.83 g, 4.74 mmol) was added and the mixture was stirred at RT for 16 h. The solution was evaporated, the residue was diluted with ether and the white solid was removed by filtration. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 50% hexane/ethyl acetate) to yield a mixture of the title compound and triphenylphosphine oxide. The mixture was diluted with ether and the white solid triphenylphosphine oxide was removed by filtration. Evaporation of the filtrate yielded the title compound as a sticky, colorless semi-solid. 1H NMR(400 MHz, CDCI3) δ 7.07 (d, J=2.4 Hz, IH), 7.02 (d of d, J=2.4, 8.8 Hz, IH), 6.87 (d, J=8.8 Hz, IH), 4.99 (m, IH), 4.37 (m, IH), 3.85 (s, 3H), 3.74 (s, 3H), 3.16 (d, J=9.1 Hz, IH), 2.39 (m, IH), 1.88-2.25 (m, 12H), 1.80 (br t, J=13.5 Hz, 2H).

2(d) cis-f-4-cyano-4-r3-(trans-3-hydroxycyclopentyloxy )-4- methoxyphenyllcyclohexane-1 -carboxylic acid )

The compound of Example 2(c) (0.10 g, 0.27 mmol) was dissolved in 5:5:2 tetrahydrofuran methanol/water (5 mL), sodium hydroxide (0.035 g, 0.88 mmol) was added and the mixture was stirred at RT for 3 h. The solvent was evaporated, the residue was partitioned between 5% aqueous NaOH and dichloromethane and the layers were separated. The aqueous layer was acidified to pH 3 with 3N aqueous hydrochloric acid and was extracted three times with 5% methanol in chloroform. The organic extracts were combined, were dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 90:10:1 chloroform/methanol water) to yield a solid which was slurried in ether, was collected by filtration and was dried in vacuo to afford the title compound. MS(d/NH₃) m e 377 [M + NH ]+; 1H NMR(400 MHz, CDCI3) δ 7.08 (br s, IH), 7.03 (br d, J=8.5Hz, IH), 6.88 (d, J=8.5 Hz, IH), 4.98 (m, IH), 4.38 (m, IH), 3.84 (s, IH), 2.41 (m, IH), 1.77-2.29 (m, 16H); Anal. (C₂oH₂5NO₅-»0.9 H₂O) calcd: C, 63.95; H,7.19; N,3.73. found: C, 64.06; H, 6.88; N, 3.77; mp 161-163° C.

Example 3 Preparation of cis- f 4-cvano-4-r3-(cis-3-hvdroxycvclopentyloxy)-4-methoxyphenyll- cyclohexane-1 -carboxylic acid) 3(a) Methyl cis-(-4-cvano-4-r3-⁽cis-3-formyloxycvclopentyloxy)-4-methoxyphenyll- cvclohexane- 1 -carboxylate ) The compound of Example 2(c) (0.68 g, 1.83 mmol) was dissolved in tetrahyrofuran (20 mL) under an argon atmosphere and was treated with triphenylphosphine ( 0.96 g, 3.66 mmol) and formic acid (0.17 g, 3.66 mmol). Diethyl azodicarboxylate (0.64 g, 3.66 mmol) was added and d e mixture was stirred at RT for 16 h. The solution was evaporated, ether was added and the white solid was removed by filtration. The filtrate was concentrated and die residue was purified by flash chromatography (silica gel, 65% hexane/ethyl acetate) to yield the title compound as a clear colorless oil. ^**-H NMR(400 MHz, CDC1₃) δ 8.02 (s,lH), 7.0 (d of d, J=2.4, 8.2 Hz, IH), 6.99 (d, J=2.4 Hz, 1 H), 6.87 (d, J=8.2 Hz, IH), 5.48 (m, IH), 4.95 (m, IH), 3.84 (s, 3H), 3.72 (s, 3H), 2.31-2.40 (m, 2H), 2.13-2.28 (m, 7H), 1.96-2.06 (m, 3H), 1.74-1.87 (m, 3H).

3⁽h⁾ cis- ⁽ -4-cvano-4-r3-⁽cis-3-hvdroxvcvclθDentvloxy⁾-4-methoχyphenyllcvclohexane- 1 -carboxylic acid)

The compound of Example 3(a) (0.52 g, 1.31 mmol) was dissolved in 5:5:2 tetrahydrofuran/methanol/water (20mL), sodium hydroxide (0.32 g, 8.0 mmol) was added and die mixture was stirred at RT for 2.5 h. The solvent was evaporated and the aqueous residue was acidified to pH 1-2 with 3N aqueous hydrochloric acid. The white solid product was collected, was washed with water and was dried in vacuo to afford the title compound as a white solid. MS(CI/NH3) m/e 377 [M + NH3]+;

IH NMR(250 MHz, CDCI3) δ 6.98 (m, 2H), 6.86 (d, J=8.2 Hz, IH), 4.97 (m, IH), 4.59 (m, IH), 3.85 (s, 3H), 1.64-2.47 (m, 17H);

mp 143-145° C.

References

1. http://www.medscape.com/viewarticle/549357
2. Torphy TJ, Barnette MS, Underwood DC, Griswold DE, Christensen SB, Murdoch RD, Nieman RB, Compton CH. Ariflo (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD: from concept to clinic. Pulmonary Pharmacology and Therapeutics. 1999;12(2):131-5. PMID 10373396
3. Ochiai H, Ohtani T, Ishida A, Kusumi K, Kato M, Kohno H, Kishikawa K, Obata T, Nakai H, Toda M. Highly potent PDE4 inhibitors with therapeutic potential. Bioorganic and Medicinal Chemistry Letters. 2004 Jan 5;14(1):207-10. PMID 14684329

CMI 977

Millennium (Originator), Taisho (Licensee)

(2S,5S)-1-[4-[5-(4-Fluorophenoxymethyl)tetrahydrofuran-2-yl]-3-butynyl]-1-hydroxyurea 175212-04-1 CMI-977 is a potent 5-lipoxygenase inhibitor that intervenes in the production of leukotrienes and is presently being developed for the treatment of chronic asthma. It is a single enantiomer with an all-trans (2S,5S) configuration. Of the four isomers of CMI-977, the S,Sisomer was found to have the best biological activity and was selected for further development. The enantiomerically pure product was synthesized on a 2-kg scale from (S)-(+)-hydroxymethyl-γ-butyrolactone.

CytoMed, Inc. announced y the initiation of Phase I clinical trials for CMI-977, its orally active therapeutic product for the treatment of asthma.  CMI-977 inhibits the 5-lipoxygenase (5-LO) cellular inflammation pathway to block the generation of leukotrienes, which play a key role in triggering bronchial asthma.  The Company also announced that it has received a U.S. patent covering a number of 5-LO inhibitor compounds, including CMI-977, and their use in treating inflammatory and other disorders.
     "Asthma is a chronic, persistent inflammatory disease of the airways characterized by coughing and wheezing.  These symptoms are induced by the release of inflammatory mediators, including leukotrienes, from inflammatory cells in the lining of the airways," said Colin Scott, Vice President, Clinical and Regulatory Affairs of CytoMed.  "CMI-977 inhibits the production of all classes of leukotrienes by inhibiting the 5-LO pathway.   Preclinical studies of CMI-977 have shown similar efficacy to steroid treatment in reducing inflammation, without any evidence of the significant toxicity that has been associated with long-term use of steroids."
     "CytoMed's product development strategy focuses on leveraging its expertise in molecular biology, medicinal chemistry and pharmacology to develop a broad range of product candidates," commented Thomas R. Beck, M.D., Chairman and CEO of CytoMed.  "Moving our second product into the clinic is a significant step towards the Company's goal of developing a portfolio of safe and efficacious anti-inflammatory compounds."  The Company's lead product, CMI-392, is currently in Phase II studies in collaboration with Stiefel Laboratories as a topical treatment for inflammation-related skin disorders.
     The Phase I trial of CMI-977, which involves 56 healthy human volunteers, is being conducted at a single site.  The double blind, randomized, escalating single dose study is designed to assess CMI-977's safety and tolerability.
 The Company plans to complete the study in mid-1998.     Over 14.6 million Americans suffer from chronic asthma.  The disease is characterized by a widespread narrowing of the airways due to a contraction (spasm) of smooth muscle and overproduction of mucous, which blocks the air passages.  These changes are caused by the release of spasmogens and vasoactive substances, including leukotrienes.  Current long-term therapies include corticosteroids, which function by non-selectively suppressing a variety of cellular pathways that initiate inflammation.  Steroids, while often effective, are associated with significant adverse side effects.  CMI- 977 is a leukotriene modulator, part of a new class of drugs designed to
 provide patients with a viable alternative to steroids.
     CytoMed, Inc. is a growing biopharmaceutical company committed to the discovery and development of novel proprietary products for the treatment of inflammatory disease.  The Company has three products in clinical or preclinical stage of development:  CMI-392 in Phase II studies for the treatment of inflammatory skin disorders in collaboration with Stiefel
 Laboratories; CMI-977, an orally active product in Phase I clinical trials for the treatment of asthma; and CMI-CAB-2, in late-stage preclinical development for the treatment of acute pulmonary and cardiovascular inflammation.  To date, the Company has been funded primarily by investments from institutional and venture investors including Schroder Ventures, Oracle Strategic Partners, Atlas Venture, CIP Capital, BioAsia Investors, WPG Farber, Gateway Ventures, HealthCare Ventures and New York Life Insurance.

Org. Proc. Res. Dev., 1999, 3 (1), pp 73–76

http://pubs.acs.org/doi/abs/10.1021/op980209l

…………………………

 http://www.sciencedirect.com/science/article/pii/S0957416603001575 ……………………………….   The reaction of oxirane (I) with vinylmagnesium bromide in THF gives 1-(4-fluorophenoxy)-4-penten-2(S)-ol (II), which is treated with ethyl vinyl ether and mercuric trifluoroacetate to yield the vinyl ether (III). The cyclization of (III) by means of Grubb’s catalyst in refluxing benzene affords the dihydrofuran (IV), which is treated with benzenesulfinic acid in dichloromethane to give the sulfone (V). The reaction of (V) with the acetylenic tetrahydropyranyl ether (VI) by means of isopropylmagnesium bromide in THF yields the expected addition product (VII), which is treated with TsOH to eliminate the tetrahydropyranyl group and provide the alcohol (VIII). The condensation of (VIII) with N,O-bis (phenoxycarbonyl)hydroxylamine (IX) by means of PPh3 and DEAD in THF affords the protected carbamate derivative (X), which is finally treated with ammonia in methanol.http://www.chemdrug.com/databases/8_0_sluqxnnnfcuabcvj.html

””””””””””””””””””””

J. Braz. Chem. Soc. vol.24 no.2 São Paulo Feb. 2013

http://dx.doi.org/10.5935/0103-5053.20130024

http://www.scielo.br/scielo.php?pid=S0103-50532013000200003&script=sci_arttext Asthma is a chronic inflammatory disease of the respiratory system that results in the reduction or even the obstruction of air flow into the lungs.¹ Over the last 40 years, there have been sharp increases in the global prevalence of asthma and the mortality due to this condition. In 2006, approximately 300 million people worldwide developed asthma, and there are approximately 180,000 deaths annually.² In Brazil, asthma is the third most common cause of hospitalization in the Brazilian Unified Health System (SUS).³ The underdiagnosis and undertreatment of this disease have motivated the scientific community to search for new target-specific drugs to treat asthma and related respiratory diseases.⁴The compound CMI-977 (LDP-977) (1) was discovered by Cyto-Med Inc., USA,⁵ and has been demonstrated to be a prominent candidate for the treatment of chronic asthma (Figure 1). This compound inhibits the 5-lipoxygenase pathway, thus blocking the production of leukotrienes.⁶ LDP-977 (1), containing a THF-2,5-trans-substituted ring with a (2S,5S) configuration, is orally active, and exhibits a good safety profile, a high degree of potency and excellent oral bioavailability relative to the three other stereoisomers.⁵

 (2S,5S)-trans-5-[(4-Fluorophenoxy)methyl]-2-(4-N-hydroxyureidyl-1-butynyl)tetrahydrofuran, CMI-977 Over the years, several synthetic routes have been proposed for the stereoselective synthesis of the THF moiety present in CMI-977 (1) (Scheme 1).^5,7,8    Intermediate 4 was prepared by Cyto-Med Inc., USA, using the first synthetic route developed,⁵ which involved a chiral pool approach for the creation of the C9 stereogenic center (Scheme 1). A nucleophilic attack involving an oxonium electrophile intermediate, obtained from 3, produced C6, but a disappointing low degree of selectivity was observed. In a similar oxonium strategy, Ley and co-workers⁷ employed an anomeric oxygen to promote the carbon rearrangement of an alkynyltributylstannane to access the THF unit, but their reaction also exhibited low selectivity (Scheme 1). Other similar strategies have led to similar results.⁸ Gurjar et al.⁹ reported a new stereoselective approach that installs the stereocenters at C6 and C9 in 6 using both Jacobsen hydrolytic kinetic resolution (HKR) and a Sharpless asymmetric epoxidation step (Scheme 1). The formation of a tandem propargyl alkoxide followed by intramolecular substitution resulted in the creation of the key tetrahydrofuran ring intermediate 7. Ley and co-workers¹⁰ also explored a similar tandem strategy providing the Retrosynthetic analysis of CMI-977 (LDP-977) (1) suitable intermediate 11, which in turn afforded the key fragment 7. These two new approaches were clearly Our disconnection approach began with a superior for the construction of the 2,5-anti THF unit as higher levels of diastereoselectivity were achieved. However, numerous steps are involved in these synthetic epoxide routes. In this paper, it is described our approach for the total synthesis of CMI-977 (LDP-977) (1). The biological importance of the target molecule and its structural features inspired us to devise a more concise and diastereoselective route to achieve the THF-2,5-trans ring of intermediate 7. Results and Discussion Retrosynthetic analysis of CMI-977 (LDP-977) (1) Our disconnection approach began with a long-established strategy for the insertion of the N-hydroxy urea moiety by alkylation involving acetylene 7 and epoxide 13, followed by a Mitsunobu-like reaction involving alcohol 4 and hydroxycarbamate 12 (Scheme 2).^9,10 The terminal acetylene 7 can be assembled via Seyferth-Gilbert homologation (using the Ohira-Bestmann protocol)¹¹ involving the aldehyde prepared from alcohol 14. It was intended to create the trans-THF configuration in our key fragment 14 using a Mukaiyama oxidative cyclization protocol with homoallylic alcohol 15.¹² The functional groups in fragment 15 could be installed starting from commercially available and inexpensive 4-fluorophenol 16, rac-epichlorohydrin 17 and allylbromomagnesium 18, in a strategy similar to that applied by Gurjar et al.⁹ Preparation of the key fragment 14 Our approach to the total synthesis of CMI-977 (LDP-977) (1) began with the reaction of p-fluorophenol 16 with rac-epichlorohydrin 17 in the presence of KOH, providing rac-5 in 97% yield (Scheme 3).¹³    The epoxide rac-5was resolved by hydrolytic kinetic resolution under Jacobsen conditions,¹⁴ using the catalyst (R, R)-(salen)Co^III(OAc) (19, 0.5 mol%) and H₂O (0.57 equiv) in tert-butyl methyl ether, providing (S)-5 in a 48% yield.⁹ The next step involved the epoxide ring-opening of (S)-5 with allylmagnesium bromide (18), providing homoallylic alcohol 15 in a quantitative yield (Scheme 4).  The subsequent oxidative cyclization of 15 according to the Mukaiyama protocol,¹² mediated by the Co(modp)₂ (20) (30 mol%) catalyst,¹⁵ provided trans-THF 14 as the only observed diastereoisomer in an 84% yield.⁸ This approach has proven to be a powerful strategy for accessing the 2,5-trans-THF unit in a highly diastereoselective fashion. Preparation of the key fragment 4 and conclusion of the synthesis The alcohol 14 was then oxidized to aldehyde 21 under Parikh-Doering conditions, followed by Seyferth-Gilbert homologation¹⁶ using the Ohira-Bestmann reagent 22,¹¹ assembling the terminal acetylene 7 in a 75% yield over two steps (Scheme 5).    The ¹H NMR and ¹³C NMR spectra and the optical rotation of trans-THF 7 matched the reported values for this compound.⁹ Next, the treatment of 7 with n-BuLi and ethylene oxide 13 led to alcohol 4 in a 70% yield. As shown in Scheme 5, the preparation of hydroxycarbamate 26 (53% yield), followed by its acetylation using acetyl chloride 27, provided 12 in a quantitative yield. A Mitsunobu-like reaction between alcohol 4 and N-hydroxycarbamate 12 provided 23 in a 93% yield. Finally, 23 was ammonolysed with NH₃·MeOH, yielding CMI-977 as a white solid in a 38% yield. The spectral and physical data of the synthetic sample were in complete agreement with those reported in the literature.^5,7-9

SPECTRAL DATA (2S,5S)-trans-5-[(4-Fluorophenoxy)methyl]-2-(4-N-hydroxyureidyl-1-butynyl)tetrahydrofuran, CMI-977 (1) To a round-bottomed flask, it was added 15 (85 mg, 0.19 mmol) at 0 ºC. Then, NH₃ (2 mL, 14 mmol, 7 mol L^-1in MeOH) was added, and the mixture was stirred at 0 ºC for 36 h. The reaction was concentrated under reduced pressure and purified by flash column chromatography using a mixture of CHCl₃/MeOH (20:1) as the eluent, providing the compound CMI-977 (1) (24 mg, 0.074 mmol) as a colorless solid in a 38% yield; mp 106-107 ºC, 106-107 ºC;⁹

[α]_D²⁰ -40 (c 1.1, MeOH), [α]_D -46.0 (c 1.1, MeOH);⁹

¹H NMR (CDCl₃, 250 MHz) δ 1.19 (s, 1H), 1.67-1.81 (m, 1H), 1.86-1.98 (m, 1H), 2.08-2.21 (m, 2H), 2.46 (t, 2H, J 6.5 Hz), 3.60 (t, 2H, J 6.8 Hz), 3.77-3.89 (m, 2H), 4.34-4.43 (m, 1H), 4.63-4.67 (m, 1H), 5.48 (s, 2H), 6.74-6.92 (m, 4H), 8.60 (br, 1H);

¹³C NMR (CDCl₃, 150.9 MHz) δ 17.2 (CH₂), 27.7 (CH₂), 33.3 (CH₂), 48.7 (CH₂), 69.1 (CH), 70.7 (CH₂), 76.9 (CH), 80.7 (C₀), 82.9 (C₀), 115.5 (CH), 115.7 (CH), 115.9 (CH), 154.8 (C₀), 156.6 (C₀), 158.2 (C₀), 161.7 (C₀);

IR (film) ν_max/cm^-1 3445, 3331, 3178, 2918, 2878, 1639, 1583, 1512, 1454, 1362, 1302, 1229, 1097, 1078, 1038, 937, 827, 762;

HRMS (ESI-TOF) m/z [M + H]⁺ for C₁₆H₂₀FN₂O₄ calcd. 323.1407, observed 323.1438.

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Millan, D. S.; Ballard, S. A.; Chunn, S.; Dybowski, J. A.; Fulton, C. K.; Glossop, P. A.; Guillabert, E.; Hewson, C. A.; Jones, R. M.; Lamb, D. J.; Napier, C. M.; Payne-Cook, T. A.; Renery, E. R.; Selby, M. D.; Tutt, M. F.; Yeadon, M.; Bioorg. Med. Chem. Lett.2011,21, 5826;         [ Links ]

Sun, X. S.; Wasley, J. W. F.; Qiu, J; Blonder, J. P.; Stout, A. M.; Green, L. S.; Strong, S. A.; Colagiovanni, D. B.; Richards, J. P.; Mutka, S. C.; Chun, L.; Rosenthal, G. J.; ACS Med. Chem. Lett. 2011,2, 402;         [ Links ]

Semko, C. M.; Chen, L.; Dressen, D. B.; Dreyer, M. L.; Dunn, W.; Farouz, F. S.; Freedman, S. B.; Holsztynska, E. J.; Jefferies, M.; Konradi, A. K.; Liao, A.; Lugar, J.; Mutter, L.; Pleiss, M. A.; Quinn, K. P.; Thompson, T.; Thorsett, E. D.; Vandevert, C.; Xu, Y.-Z.; Yednock, T. A.; Bioorg. Med. Chem. Lett .2011,21,1741.         [ Links ]

5. Cai, X.; Hwang, S.; Killan, D.; Shen, T. Y.; US pat. 5,648,486 1997;         [ Links ] Cai, X.; Grewal, G.; Hussion, S.; Fura, A.; Biftu, T.; US pat. 5,681,966 1997;         [ Links ]

Cai, X.; Cheah, S.; Eckman, J.; Ellis, J.; Fisher, R.; Fura, A.; Grewal, G.; Hussion, S.; Ip, S.; Killian, D. B.; Garahan, L. L.; Lounsbury, H.; Qian, C.; Scannell, R. T.; Yaeger, D.; Wypij, D. M.; Yeh, C. G.; Young, M. A.; Yu, S.; Abs. Pap. Am. Chem. Soc.,1997,214,214-MEDI.         [ Links ]

6. Cai, X.; Chorghade, M. S.; Fura, A.; Grewal, G. S.; Juaregui, K. A.; Lounsbury, H. A.; Scannell, R. T.; Yeh, C. G.; Young, M. A.; Yu, S.; Org. Process Res. Dev. 1999,3,73.

7. Dixon, D. J.; Ley, S. V.; Reynolds, D. J.; Chorghade, M. S.; Synth. Commun. 2000,30, 1955;         [ Links ]Dixon, D. J.; Ley, S. V.; Reynolds, D. J.; Chorghade, M. S.; Indian J. Chem., Sect B 2001,40,1043.

8. Chorgade, M. S.; Gurjar, M. K.; Adikari, S. S.; Sadalapure, K.; Lalitha, S. V. S.; Murugaiah, A. M. S.; Radhakrishna, P.; Pure Appl. Chem. 1999,71, 1071;         [ Links ] Gurjar, M. K.; Murali Krishna, L.; Sridhar Reddy, B.; Chorghade, M. S.; Synthesis 2000, 557;         [ Links ] Chattopadhyay, A.; Vichare, P.; Dhotare, B.;Tetrahedron Lett. 2007,48,2871.

9. Gurjar, M. K.; Murugaiah, A. M. S.; Radhakrishna, P.; Ramana, C. V.; Chorghade, M. S.; Tetrahedron: Asymmetry 2003,14,1363.

10. Sharma, G. V. M.; Punna, S.; Prasad, T. R.; Krishna, P. R.; Chorghade, M. S.; Ley, S. V.; Tetrahedron: Asymmetry 2005,16,1113.

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read

Pure Appl. Chem., Vol. 71, No. 6, pp. 1071-1074, 1999.

http://pac.iupac.org/publications/pac/pdf/1999/pdf/7106×1071.pdf

Full text – pdf 322 kB – IUPAC

………………………………………………… US 5703093; US 5792776; WO 9600212 Ether (III) was prepared by condensation of (S)-4-(hydroxymethyl)butyrolactone (I) and 4-fluorophenol (II) in the presence of diisopropylazodicarboxylate (DIAD) and triphenylphosphine under Mitsunobu conditions. Then, reduction of lactone (III) with DIBAL-H in toluene at -78 C gave lactol (IV), which was converted to silyl ether (V) by treatment with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole. Subsequent reaction of (V) with TBDMS-Br in CH2Cl2 at -78 C, followed by condensation with the lithium acetylide derived from acetylene (VI), yielded compound (VII) as a mixture of isomers. Chromatographic separation of the mixture provided the desired trans isomer, which was deprotected by treatment with tetra-n-butylammonium fluoride to give alcohol (VIII). This was then condensed with N,O-bis(phenoxycarbonyl)hydroxylamine (IX) in the presence of DIAD and Ph3P to furnish the hydroxamic acid derivative (X). Finally, concomitant deprotection of the O-phenoxycarbonyl group and substitution of the remaining phenoxy group for an amino group by treatment with methanolic ammonia in a pressure tube, provided the title compound.http://www.chemdrug.com/databases/8_0_sluqxnnnfcuabcvj.html…………………………………………………. PAPER

Title:	A short and efficient stereoselective synthesis of the potent 5-lipoxygenase inhibitor, CMI-977†
Authors:	Dixon, Darren J Ley, Steven V Reynolds, Dominic J Chorghade, Mukund S
Issue Date:	Nov-2001
Publisher:	NISCAIR-CSIR, India
Abstract:	A short and efficient synthesis of the potent 5-lipoxygenase inhibitor CMI-977 has been accomplished, utilising an oxygen to carbon rearrangement of an anomerically linked alkynyl stannane tetrahydrofuranyl ether derivative as the key step.
Page(s):	1043-1053
CC License:	CC Attribution-Noncommercial-No Derivative Works 2.5 India
Source:	IJC-B Vol.40B(11) [November 2001]

http://nopr.niscair.res.in/bitstream/123456789/22437/1/IJCB%2040B%2811%29%201043-1053.pdf……………………………………………….

http://www.google.com.ar/patents/US20080081835 Specific inhibitors of 5-LO that may be mentioned include the following.

• • (1) Zileuton (synonyms: A-64077, ABT 077, Zyflo®), described in, for example, EP 0 279 263, U.S. Pat. No. 4,873,259, Int. J. Immunopharmacol. 14, 505 (1992), Br. J. Cancer 74, 683 (1996) and Am. J. Resp. Critical Care Med. 157, Part 2, 1187 (1998).

• • (2) A-63162, described in, for example, Anticancer Res. 14, 1951(1994).

• • (3) A-72694.

• • (4) A-78773, described in, for example, Curr. Opin. Invest. Drugs 2, 69 (1993).

• • (5) A-79175 (the R-enantiomer of A 78773), described in, for example, Carcinogenesis 19, 1393 (1998) and J. Med. Chem. 40, 1955 (1997).

• • (6) A-80263.

• • (7) A-81834.

• • (8) A-93178

• • (9) A-121798, described in, for example, 211th Am. Chem. Soc. Meeting. 211: abstr. 246, 24 Mar. 1996.
  • (10) Atreleuton (synonyms ABT-761 and A-85761), described in, for example, Exp. Opin. Therap. Patents 5 127 (1995).

• • (11) MLN-977 (synonyms LPD-977 and CMI-977), described in, for example, Curr. Opin. Anti-Inflamm. &Immunomod. Invest. Drugs 1, 468 (1999). This, as well as similar compounds are described in U.S. Pat. No. 5,703,093.

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WO 0001381 The reaction of 4-fluorophenol (I) with epichlorohydrin (II) by means of K2CO3 in refluxing acetone gives 2-(4-fluorophenoxymethyl)oxirane (III), which is submitted to an enantioselective ring opening with the Jacobsen (R,R)-catalyst yielding a mixture of the (R)-diol (IV) and unaltered epoxide (V), easily separated by column chromatography. The reaction of (IV) with tosyl chloride and pyridine in dichloromethane affords the primary monotosylate (VI), which is converted into the chiral epoxide (VII) by reaction with NaH in THF/DMF. The reaction of (VII) with allylmagnesium bromide (VIII) in ethyl ether gives the 2-hexenol derivative (IX), which is treated with benzenesulfonyl chloride and DMAP yielding the sulfonate (X). The ozonolysis of (X) with ozone in dichloromethane affords the aldehyde (XI), which is condensed with ethoxycarbonylmethylene(triphenyl)phosphorane (XII) yielding the 2-heptenoic ester (XIII). The reduction of (XIII) with diisobutylaluminum hydride (DIBAL) in toluene/dichloromethane provides the 2-hepten-1-ol (XIV), which is epoxidized with cumene hydroperoxide in the presence of diisopropyl (+)-tartrate and Ti(Oi-Pr)4 in dichloromethane to give the chiral epoxyalcohol (XV). The reaction of (XV) with triphenylphosphine/CCl4 in chloroform affords the corresponding chloride (XVI).   …………………………………….

WO 0001381 Intermediate (XVI) is treated with BuLi and diisopropylamine in THF giving the chiral acetylenic tetrahydrofuran (XVII). The addition of ethylene oxide (XVIII) to the terminal acetylene of (XVII) by means of BF3/Et2O in THF gives the 3-butyl-1-ol derivative (XIX), which is condensed with N,O-bis(phenoxy- carbonyl)hydroxylamine (XX) by means of PPh3 and diisopropylazodicarboxylate (DIAD) in THF yielding the final intermediate (XXI). Finally, this compound is treated with ammonia in methanol to obtain the target urea derivative.

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poster

http://www.prp.rei.unicamp.br/pibic/congressos/xxcongresso/paineis/092085.pdf

SÍNTESE TOTAL DO CMI-977 (LDP-977), UM PODEROSO AGENTE ANTIASMÁTICO
Lui Strambi Farina (IC), Marco Antonio Barbosa Ferreira (PG) e Luiz Carlos Dias (PQ)*
INSTITUTO DE QUÍMICA, UNIVERSIDADE ESTADUAL DE CAMPINAS, C.P. 6154, 13084-971, CAMPINAS, SP, BRASIL
*ldias@iqm.unicamp.br
Agência Financiadora: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ).
Palavras-Chave: Síntese orgânica, Tetrahidrofuranos, CMI-977 (LDP-977)

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Synthesis of (+)-Muricatacin and a Formal Synthesis of CMI-977 from l-Malic Acid

https://www.thieme-connect.de/DOI/DOI?10.1055/s-0033-1338934

A total synthesis of (+)-muricatacin and a formal synthesis of CMI-977 have been achieved using commercially available l-malic acid based on our furan approach to oxacyclic systems, the proven scope of which is thus broadened.

Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor.

B. Gutmann, J.-P. Roduit, D. Roberge, C. O. Kappe, J. Flow Chem. 2012, 2,8-19.

http://www.akademiai.com/content/l622j82k3171t080/?p=0213e26b691f494d8eb782308d34fe77&pi=2

Authors

Bernhard Gutmann¹, David Obermayer¹, Jean-Paul Roduit², Dominique M. Roberge² , C. Oliver Kappe² 

¹Christian Doppler Laboratory for Microwave Chemistry and Institute of Chemistry, Karl-Franzens-University Graz A-8010 Heinrichstrasse 28 Graz Austria
²Microreactor Technology, Lonza AG CH-3930 Visp Switzerland

Abstract

Keywords

Filed under: flow synthesis Tagged: Continuous Flow Reactor, flow chemistry, hydrazoic acid, microreactor, process intensification, tetrazoles

Chiral alpha-halo ketones derived from N-protected amino acids are key building blocks for the synthesis of HIV protease inhibitors such as atazanavir used in HAART combination therapy.

Kappe and De Souza have reported a continuous flow through route to these intermediates which utilises a tube-in-tube reactor to introduce diazomethane generated on demand into the reaction stream containing mixed anhydride derivatives of N-protected amino acids. The resulting alpha-diazo ketones are then decomposed with HCl or HBr to afford the corresponding alpha-halo ketones.

This process allows the safe generation, separation and use of diazomethane in a continuous integrated multi-step synthesis of important API intermediates.

The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor.

The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber.

The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide.

This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ∼4.5 h (87% yield).

V. D. Pinho, B.Gutmann, L. S. M. Miranda, R. O. M. A. de Souza, C. O. Kappe, J. Org. Chem., 2014, 79, 4, 1555.

http://pubs.acs.org/doi/abs/10.1021/jo402849z

2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid

Meclinertant (SR-48692) is a drug which acts as a selective, non-peptide antagonist at the neurotensin receptor NTS₁, and was the first non-peptide antagonist developed for this receptor.^[1][2] It is used in scientific research to explore the interaction between neurotensin and other neurotransmitters in the brain,^{[3][4][5][6][7][8]} and produces anxiolytic, anti-addictive and memory-impairing effects in animal studies.^{[9][10][11][12]}

PatentSubmittedGranted1-(7-chloroquinolin-4-yl)pyrazole-3-carboxamide N-oxide derivatives, method of preparing them, and their pharmaceutical compositions [US5561234]1996-10-01

Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin [US5585497]1996-12-17

3-amidopyrazole derivatives, process for preparing these and pharmaceutical composites containing them [US5420141]1995-05-30

Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin, their preparation and pharmaceutical compositions containing them [US5523455]1996-06-04

3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5607958]1997-03-04

3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5616592]1997-04-01

3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5635526]1997-06-03

Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them [US5965579]1999-10-12

Systematic (IUPAC) name
2-([1-(7-Chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl]amino)admantane-2-carboxylic acid
Clinical data
Legal status	?
Identifiers
CAS number	146362-70-1
ATC code	?
PubChem	CID 119192
IUPHAR ligand	1582
UNII	5JBP4SI96H
Chemical data
Formula	C32H31ClN4O5
Mol. mass	587.064

 A Machine-Assisted Flow Synthesis of SR48692: A Probe for the Investigation of Neurotensin Receptor-1 (pages 7917–7930)

Meclinertant (SR 48692)
We developed an improved synthesis of the neurotensin antagonist biological probe SR 48692. The preparation includes an number of  chemical conversions and strategies  involving the use of flow chemistry platforms which helped overcome some of the limiting synthetic transformations in the original chemical route .

Meclinertant (SR 48692): The synthesis of neurotensin antagonist SR 48692 for prostate cancer research I.R. Baxendale, S. Cheung, M.O. Kitching, S.V. Ley, J.W. Shearman Bio. Org. Med. Chem. 2013, 21, 4378-4387.

A synthesis of the neurotensin 1 receptor probe Merclinertant (SR48692) has been reported using a range of continuous flow through synthesis, in-line reaction monioring and purification techniques. This strategy has been contrasted with a more conventional batch synthesis approach.

Notably the safe use of phosgene gas (generated in situ), the superheating of solvents to accelerate reaction rates, the processing of a reagent suspension under continuous flow-through conditions and the application of semi-permeable membrane technology to facilitate work-up and purification were all techniques that could be beneficially applied in the synthetic scheme.

C. Battilocchio, B. J. Deadman, N. Nikbin, M. O. Kitching, I. R. Baxendale, S. V. Ley, Eur. J. Chem., 2013, DOI: 10.1002/chem.201300696

…………………….

Abstract:

An improved synthesis of the molecule SR 48692 is presented and its use as a neurotensin antagonist biological probe for use in cancer research is described. The preparation includes an number of enhanced chemical conversions and strategies to overcome some of the limiting synthetic transformations in the original chemical route.

The Synthesis of Neurotensin Antagonist SR 48692 for Prostate Cancer Research.Bioorg. Med. Chem. 2013, 21, 4378-4387.

Link: 10.1016/j.bmc.2013.04.075Baxendale, I. R.; Cheung, S.; Kitching, M. O.; Ley, S. V. Shearman, J. W.

/////////////////////////////

Meclinertant, Reminertant, SR-48692
The condensation of 2′,6′-dimethoxyacetophenone (I) with diethyl oxalate (II) by means of sodium methoxide in refluxing methanol gives the dioxobutyrate (III), which is cyclized with 7-chloroquinoline-4-hydrazine (IV) in refluxing acetic acid yielding the pyrazole derivative (V). The hydrolysis of the ester group of (V) with KOH in refluxing methanol/water affords the corresponding carboxylic acid (VI), which is finally treated with SOCl2 in refluxing toluene and condensed with 2-aminoadamantane-2-carboxylic acid.

EP 0477049; FR 2665898; JP 1992244065; US 5420141; US 5607958; US 5616592; US 5635526; US 5744491; US 5744493

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1.  Gully D, Canton M, Boigegrain R, Jeanjean F, Molimard JC, Poncelet M, Gueudet C, Heaulme M, Leyris R, Brouard A (January 1993).“Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor”. Proceedings of the National Academy of Sciences of the United States of America 90 (1): 65–9. doi:10.1073/pnas.90.1.65. PMC 45600. PMID 8380498.
2.  Gully D, Jeanjean F, Poncelet M, Steinberg R, Soubrié P, Le Fur G, Maffrand JP (1995). “Neuropharmacological profile of non-peptide neurotensin antagonists”. Fundamental & Clinical Pharmacology 9 (6): 513–21. doi:10.1111/j.1472-8206.1995.tb00528.x.PMID 8808171.
3.  Rostene W, Azzi M, Boudin H, Lepee I, Souaze F, Mendez-Ubach M, Betancur C, Gully D (April 1997). “Use of nonpeptide antagonists to explore the physiological roles of neurotensin. Focus on brain neurotensin/dopamine interactions”. Annals of the New York Academy of Sciences 814: 125–41. doi:10.1111/j.1749-6632.1997.tb46151.x. PMID 9160965.
4. Jump up^ Jolas T, Aghajanian GK (August 1997). “Neurotensin and the serotonergic system”. Progress in Neurobiology 52 (6): 455–68.doi:10.1016/S0301-0082(97)00025-7. PMID 9316156.
5. Jump up^ Dobner PR, Deutch AY, Fadel J (June 2003). “Neurotensin: dual roles in psychostimulant and antipsychotic drug responses”. Life Sciences73 (6): 801–11. doi:10.1016/S0024-3205(03)00411-9. PMID 12801600.
6. Jump up^ Chen L, Yung KK, Yung WH (September 2006). “Neurotensin selectively facilitates glutamatergic transmission in globus pallidus”.Neuroscience 141 (4): 1871–8. doi:10.1016/j.neuroscience.2006.05.049. PMID 16814931.
7.  Petkova-Kirova P, Rakovska A, Della Corte L, Zaekova G, Radomirov R, Mayer A (September 2008). “Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis”. Brain Research Bulletin 77 (2–3): 129–35. doi:10.1016/j.brainresbull.2008.04.003. PMID 18721670.
8.  Petkova-Kirova P, Rakovska A, Zaekova G, Ballini C, Corte LD, Radomirov R, Vágvölgyi A (December 2008). “Stimulation by neurotensin of dopamine and 5-hydroxytryptamine (5-HT) release from rat prefrontal cortex: possible role of NTR1 receptors in neuropsychiatric disorders”.Neurochemistry International 53 (6–8): 355–61. doi:10.1016/j.neuint.2008.08.010. PMID 18835308.
9.  Griebel G, Moindrot N, Aliaga C, Simiand J, Soubrié P (December 2001). “Characterization of the profile of neurokinin-2 and neurotensin receptor antagonists in the mouse defense test battery”. Neuroscience and Biobehavioral Reviews 25 (7–8): 619–26. doi:10.1016/S0149-7634(01)00045-8. PMID 11801287.
10.  Tirado-Santiago G, Lázaro-Muñoz G, Rodríguez-González V, Maldonado-Vlaar CS (October 2006). “Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats”. Behavioral Neuroscience 120 (5): 1093–102. doi:10.1037/0735-7044.120.5.1093. PMID 17014260.
11.  Felszeghy K, Espinosa JM, Scarna H, Bérod A, Rostène W, Pélaprat D (December 2007). “Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference”. Neuropsychopharmacology 32 (12): 2601–10. doi:10.1038/sj.npp.1301382. PMC 2992550. PMID 17356568.
12. Lévesque K, Lamarche C, Rompré PP (October 2008). “Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine”.European Journal of Pharmacology 594 (1–3): 132–8. doi:10.1016/j.ejphar.2008.07.048. PMID 18706409.

The Application of Flow Microreactors to the Preparation of a Family of Casein Kinase I Inhibitors.
Venturoni, F.; Nikbin, N.; Ley S. V.; Baxendale, I. R.
Org. Biomol. Chem. 2010, 8, 1798-1806. Link: 10.1039/b925327k http://pubs.rsc.org/en/Content/ArticleLanding/2010/OB/b925327k#!divAbstract

In this article we demonstrate how a combination of enabling technologies such as flow synthesis, solid-supported reagents and scavenging resins utilised under fully automated software control can assist in typical medicinal chemistry programmes. In particular automated continuous flow methods have greatly assisted in the optimisation of reaction conditions and facilitated scale up operations involving hazardous chemical materials. Overall a collection of twenty diverse analogues of a casein kinase I inhibitor has been synthesised by changing three principle binding vectors.

DOI: 10.1039/B925327K

Fanetizole

Fanetizole shows immunoregulating activity.
RN: 79069-95-7

Fanetizole mesylate [USAN]

CP-48,810-27
Fanetizole mesylate
UNII-D3OG7B0G4M

Synthesis

Thioureas serve as a convenient starting material for 2-aminothiazoles.

Reaction of β-phenethylamine with ammonium isothiocyanate gives the corresponding thiourea. Treatment of that product with phenacyl bromide thus affords the thiazole product.^[1]

Systematic (IUPAC) name
4-Phenyl-N-(2-phenylethyl)-1,3-thiazol-2-amine
Clinical data
Legal status	?
Pharmacokinetic data
Protein binding	%
Identifiers
CAS number	79069-94-6
ATC code	?
PubChem	CID 54339
ChemSpider	49083
UNII	BH48F620JA
Chemical data
Formula	C17H16N2S
Mol. mass	280.39 g/mol

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Journal of the Chinese Chemical Society, 2009, 56, 455-458

http://proj3.sinica.edu.tw/~chem/servxx6/files/paper_10990_1246593848.pdf

Fanetizole (3j)
mp 114-115 C (Lit.,30 116-117 C). IR (KBr) :3192, 2957, 1562, 1481, 1445, 1332, 698 cm-1;

1H NMR(CDCl3) : 2.81 (t, J = 7.4 Hz, 2H), 3.42 (dd, J = 6.8, 10.8
Hz, 2H), 6.32 (s, 1H), 6.64 (s, 1H), 7.08 (d, J = 6.8 Hz, 2H),
7.15-7.28 (m, 4H), 7.34-7.37 (m, 2H), 7.77-7.80 (m, 2H).

30=. Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V. Tetrahedron
2008, 64, 5019-5022.

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A remarkably high-speed solution-phase combinatorial synthesis of 2-substituted-amino-4-aryl thiazoles in polar solvents in the absence of a catalyst under ambient conditions and study of their antimicrobial activities
ISRN Organic Chemistry (2011), 434613, 6 pp. Publisher: (Hindawi Publishing Corp., )

http://www.hindawi.com/journals/isrn/2011/434613/

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Fanetizole
Ley et al  had previously developed a tube-in-tube reactor based on a semipermeable polymer membrane to  enable the transfer of gases into liquid flow streams. and here, we demonstrate the scalability and throughput of this reactor when used with ammonia gas. This was made possible by a the inclusion of a titration method to assess parameters including the liquid and gas configuration, reactor temperatures, flow rates, and solvent polarity. These data were then employed in a scaling-up process affording alkyl thioureas which were ultimately used in a telescoped procedure for the preparation of anti-inflammatory agent fanetizole on a multigram scale.

Researchers at Cambridge have shown how it is possible to calibrate a ‘tube-in-tube’ reactor containing ammonia gas using a simple in-line colourimetric titration technique.

This information was then used to deliver an ammonia solution of stoichiometrically to effect the telescoped 2 stage synthesis of the anti-inflammatory agent Fanetizole.

The automated continuous flow synthesiser was able to produce drug substance at a rate of approximately 10 g per hour, isolating the product by direct precipitation from the outflow reaction stream.

Fanetizole: Scaling-up of continuous flow processes with gases using a tube-in-tube reactor: in-line titrations and fanetizole synthesis with ammonia J. Pastre, D.L. Browne, M. O’Brien and S.V. Ley, Org. Proc. Res. Dev. 2013, 17, 1183-1191.

http://pubs.acs.org/doi/full/10.1021/op400152r

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Bioorganic and Medicinal Chemistry Letters, 1996 ,  vol. 6,   12  pg. 1409 – 1414

http://www.sciencedirect.com/science/article/pii/0960894X96002417

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ref

Heterocycles, 2010 ,  vol. 81,   12  pg. 2849 – 2854

Journal of the Chinese Chemical Society, 2009 ,  vol. 56,  3  pg. 455 – 458

Bioorganic and Medicinal Chemistry Letters, 1996 ,  vol. 6,   12  pg. 1409 – 1414

Pfizer Patent: DD144055DE2922523 , 1979 ;Chem.Abstr.,  vol. 92,  111001

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J. Flow Chem. 2012, 2(3), 77–82

http://www.akademiai.com/content/8652651g3378x686/?p=ab7c1bc4cd7740e1855623297649f542&pi=3

http://www.akademiai.com/content/8652651g3378x686/fulltext.pdf

Authors

Tuong Doan¹, Petr Stavárek¹, Claude Bellefon^{1 * Author for correspondence: claude.debellefon@lgpc.cpe.fr}

¹CNRS, CPE Lyon University of Lyon Villeurbanne France

Abstract

http://www.akademiai.com/content/u87p126856085276/?p=2f48c96a10a64882aeb5c47c657a10b7&pi=4

Authors

Gellért Sipos¹, Viktor Gyollai¹, Tamás Sipőcz¹, György Dormán¹, László Kocsis¹ , Richard V. Jones¹, Ferenc Darvas¹

¹ThalesNano Zahony u. 7 1031 Budapest Hungary

László Kocsis holds a Masters degree in Bioorganic Chemistry from the Eötvös Lóránd University in Budapest, Hungary (2001) and a PhD in Organic Chemistry from the Eötvös Lóránd University in Budapest, Hungary (2008). In 2004 he began working as a research chemist at the Reanal Finechemical Company in Budapest, Hungary. He became the Head of the R&D laboratory in 2007 and a manager of production in 2008. In 2011 he joined ThalesNano Inc. as Head of Chemistry. He has experience in organic chemistry, with emphasis on sythesis of amino acid derivatives and peptides, focusing mainly on the following subjects: structure – relationship studies in opiod peptides, methodological studies in the internal solubilization of the sekf-aggregating peptides, industrial scale sythesis of protected amino acid derivatives, and peptides, heterogeneous catalysis, reactions under continuous flow conditions. He is the co-author of 10 pulications and a member of the European Peptide Society.

Abstract