Dacomitinib

(2E)-N-{4-[(3-Chloro-4-fluorophenyl)amino]-7-methoxy-6-quinazolinyl}-4-(1-piperidinyl)-2-butenamide

4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide 

4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide

1042385-75-0

pf299804…… pfizer

EGFR (HER1; erbB1) Inhibitors
HER4 (erbB4) Inhibitors
HER2 (erbB2) Inhibitors 

• Molecular formula:C24H25ClFN5O2
• Molecular mass:469.95

Dacomitinib (PF-00299804) is an experimental drug candidate under development by Pfizer for the treatment of non-small-cell lung carcinoma. It is a selective and irreversible inhibitor of EGFR.^[1]

Dacomitinib has advanced to several Phase III clinical trials. The results of the first trials were disappointing, with a failure to meet the study goals,^[2][3][4] Additional Phase III trials are ongoing.^[2]

Dacomitinib is a HER (erbB) inhibitor in clinical trial development at Pfizer for the treatment of advanced non-small cell lung cancer (NSCLC) and for the treatment of relapsed/recurrent glioblastoma.

No recent development has been reported for research into the treatment of recurrent and/or metastatic head and neck squamous cell cancer. In 2012, Pfizer and SFJ Pharmaceuticals signed a codevelopment agreement for dacomitinib for the treatment of patients with locally advanced or metastatic NSCLC with activating mutations of epidermal growth factor receptor.

Substituted 4-phenylamino-quinazolin-6-yl-amides useful in the treatment of cancer have been described in the art, including those of U.S. Pat. No. 5,457,105 (Barker), U.S. Pat. No. 5,760,041 (Wissner et al.), U.S. Pat. No. 5,770,599 (Gibson), U.S. Pat. No. 5,929,080 (Frost), U.S. Pat. No. 5,955,464 (Barker), U.S. Pat. No. 6,251,912 (Wissner et al.), U.S. Pat. No. 6,344,455 (Bridges et al.), U.S. Pat. No. 6,344,459 (Bridges et al.), U.S. Pat. No. 6,414,148 (Thomas et al.), U.S. Pat. No. 5,770,599 (Gibson et al.), U.S. patent application 2002/0173509 (Himmelsbach et al.), and U.S. Pat. No. 6,323,209 (Frost).

Dacomitinib is a pan-human epidermal growth factor receptor (pan-HER) inhibitor developed by Pfizer, as ー small molecules targeting ffiR-1, HER-2 and HER-4 tyrosine kinase inhibitor by irreversibly binding to HER-l, HER-2, HER-4 and anti-tumor effect. Ni-line treatment of non-small cell lung cancer (NSCLC) display, Dacomitinib in non-small cell lung cancer Dinner erlotinib compared to some extend on progression-free survival and quality of life have mentioned the smell.

_4] Structural formula for Dacomitinib

[0005] U.S. patent US7772243 Dacomitinib first proposed a synthesis method, first, a fluorine-2_ _4_ amino acid and formamidine ring closure reaction to give 7 – fluoro-4 – quinazolinone, nitration and then successively chlorination reaction, to give 4 – chloro-7 – fluoro-6 – nitro-quinazoline; another aspect ー 3 – chloro-4 – amino-substituted on a fluoroaniline to give 3 – chloro – # – (3,4 – ni section yl methoxy)-4_ fluoro-aniline, obtained after the coupling of both an amino-protected N-(3 – chloro-4 – fluorophenyl)-7 – fluoro-6 – nitro-quinazoline -4 – amine, protected amino N-(3 – chloro-4 – fluorophenyl

Yl)-7_ fluoro-6 – nitro-quinazolin-4 – amine is of formula

Followed by a methoxy group, an amidation reaction and hydrogenation, the final deprotection ko under the action of trifluoroacetic acid to give the final product Dacomitinib. Throughout the reaction as follows:

synthesis

http://www.google.com/patents/CN103304492A?cl=en

Synthesis ー kind EGFR inhibitors Dacomitinib, synthetic route for

A synthetic method EGFR inhibitors Dacomitinib, concrete steps are as follows:

Step I, 7 – fluoro-4 – Synthesis of quinazolinone:

30 g (0.1934mol) 2 – fluoro-amino acid was dissolved in 250 ml _4_ formamide among the reaction was heated to 150 ° C for 6 inch, TLC plates to determine the point of completion of the reaction. The reaction was poured hot into 2000 ml of ice water, filtered, the filter cake was washed with water, vacuum dried at 50 ° C for 14 hours to give a pale brown solid powder 7 – fluoro-4 – quinazolinone, 28 g, yield 88%.

[0021] 2 walk 7 – fluoro-6 – nitro-4_ (hydrogen) _ Synthetic quinazolinones of:

Concentrated sulfuric acid (50 ml) and fuming nitric acid (50 ml) mixture was cooled with an ice bath to (TC hereinafter under stirring slowly added 25 g (0.1523mol) 7 – fluoro-4 – quinazolinone , the addition was complete, the reaction mixture was stirred at room temperature for I hour and then the reaction was heated to 110 ° C for 2 inch, TLC plates to determine the point of completion of the reaction the reaction was cooled to room temperature, 300 ml of ice water, the precipitated solid was stirred for 30 minutes , filtered, the filter cake was washed with water, vacuum dried at 50 ° C in 14 hours to give a yellow solid powder 7 – fluoro-6 – nitro-4 – (hydrogen) – quinazolinone, 26 g, yield 82%.

[0022] Step 3 6 – amino-7 – fluoro-4 – (hydrogen) – quinazolinone Synthesis:

24 g (0.1148mol) 7 – fluoro-6 – nitro _4_ (hydrogen) – quinazolinone was dissolved in 400 ml of methanol was added 2 g of palladium / carbon catalyst was added 8 ml of concentrated hydrochloric acid, and hydrogen was 2 small inch atmospheric reaction, TLC plates to determine the point of the reaction is complete. The catalyst was removed by suction filtration through celite, washed several fitness methanol, and the filtrate was concentrated by rotary evaporation to dryness to give 6 – amino-7_ fluoro-4 – (hydrogen) – quinazolinone, yellow powder, 20 g, yield 97%.

[0023] 4 walk, ⑶ -4 – (piperidin – Suites yl) -2 – butene acid methyl ester synthesis:

18 g (0.1006mol) 4 – bromo-methyl crotonate dissolved in 180 ml of methylene chloride ni added 27.9 g (0.2019mol) potassium carbonate, cooled to ice-bath (TC, was slowly added dropwise 10 ml (0.1012mol ) piperidine, (I reaction was stirred under a small inch TC, TLC plates to determine the point of completion of the reaction was concentrated by rotary evaporation to dryness, to give (E) -4 – (piperidin-1 – yl) – 2 – butenoic acid methyl Cool as a yellow solid, 17.1 g, yield 93%.

[0024] 5th walk, Buddhist) -4 – (piperidin-1 – yl) -2 – butene acid hydrochloride synthesis:

16 g (0.0873mol) of W) -4 – (piperidin-_1_ yl) -2 – butenyl acetate and 80 ml of concentrated hydrochloric acid was added to 250 ml of 1,4 – ni oxygen dioxane, heated under reflux 20 hours inch, TLC plate point the reaction was determined complete, the reaction solution was concentrated by rotary evaporation to dryness surplus was recrystallized from isopropanol to give a pale yellow solid, Buddhist) _4-(piperidin-1 – yl) -2 – butene acid hydrochloride, 14.5 g, yield 81%.

[0025] Step 6, (E) -4 – (piperazine Jie fixed -1 – yl) – 2 – butenyl chloride synthesis:

13 g (0.0632mol) of (K) ~ 4 ~ (piperidin-1 – yl) -2 – butene acid hydrochloride was dissolved in 750 ml of methylene chloride ni, 5 ml of DMF, was slowly added dropwise 8 ml ( 0.0933mol) of oxalyl chloride, the reaction was stirred at room temperature for I h, TLC plates to determine the point of completion of the reaction, the reaction solution was concentrated to dryness by rotary evaporation to give a pale yellow oil, Buddhist) _4-(piperidin-1 – yl) -2 – butyl allyl chloride, 11.8 g, yield 99%.

[0026] Step 7 (cargo) – # – (7 – fluoro-4 – oxo-3 ,4 – ni hydrogen quinazolin-6 – yl) -4 – (piperidin-1 – yl) -2 – butene amide Synthesis:

11 g (0.0586mol) of the) -4 – (piperidin-1 – yl) – 2 – butenyl chloride ni chloride (50 ml) was slowly added dropwise to 6 – amino-1 – fluoro-4 – ( hydrogen) – quinazolinone (7 g, 0.0391mmol), three ko amine (14 ml) and the mixture was ni chloride (200 ml), the reaction mixture was stirred at room temperature for 2 hours the reaction inch, TLC determined the completion of reaction points board , was added 800 liters of halo ni halo chloroformate and 500 liters of burning the separated organic phase was washed with 500 liters of halo, halo and then with 500 liters of brine, dried over magnesium sulfate, and concentrated by rotary evaporation to dryness was subjected to silica gel surplus Column chromatography (30% acid ko ko acetate / hexane) to give (M)-N-(7 – fluoro-4 – oxo-3 ,4 – ni hydrogen quinazolin-6 – yl) -4 – (piperidin-1 – yl) -2 – butenamide, as a pale yellow solid, 12.3 g, yield 95%.

Step 8 [0027] (2 ^) – # – (7 – methoxy – 4 – oxo _3, 4_ ni hydrogen quinazolinyl _6_ yl)-4_ (piperidin-1 – yl) – Synthesis 2_ butenamide:

I ^ xN MeONa N. Under nitrogen atmosphere, to 100 ml of anhydrous methanol was slowly added 1.52 g of sodium metal (0.0661mol), stirred for 10 minutes to dissolve all of the sodium metal to the completion of the reaction, to obtain a freshly prepared solution of sodium methoxide, and the The sodium methoxide solution was added 11 g (0.0333mol) of (receive) (7 – fluoro-4 – oxo-3 ,4 – ni hydrogen quinazolin-6 – yl) -4 – (piperidin-1 – yl) 2_ butene-amide, the reaction was heated to reflux for 3 inch, TLC plates to determine completion of the reaction point, cooled to room temperature, acidified with 2N hydrochloric acid solution to pH = 3 ~ 4, and concentrated by rotary evaporation to dryness, the residue was washed with water beating, filtration, The filter cake was washed with water, vacuum dried at 50 ° C in 14 hours to give (article) – # – (7 – methoxy – 4 – oxo – ni hydrogen quinazolin-6 – yl) – 4_ (piperidin-1 – yl)-2_ butenamide yellow solid, 10.6 g, yield 93%.

[0028] Step 9, {W,-N-(4 – chloro-7 – methoxy-quinazoline _6_ yl)-4_ (piperidin _1_ yl)-amide <EMI butene 2_:

9 g (0.0263mol) of (receive) – # – (7 – methoxy _4_ oxo – ni hydrogen quinazolin-6 – yl)-4_ (piperidin-1 – yl) – 2_ butenamide were added to 40 ml of phosphorus oxychloride was heated under reflux for 2 inch, TLC plates to determine the point of completion of the reaction, the reaction solution was concentrated to dryness by rotary evaporation, ice water was added surplus, beating, filtered, the cake washed with washed with water, vacuum dried at 50 ° C in 14 hours to give {W,-N-(4 – chloro-7 – methoxy-quinazolin-6 – yl) -4 – (piperidin-1 – yl) – 2 – butene amide as a yellow solid, 7 g, yield 74%

(2E)-N-(4 – chloro-7 – methoxy-quinazolin-6 – yl) -4 – (piperidin-1 – yl) -2 – butene amide (6 g,

0.0166mol), 3 – chloro-4-fluoro-aniline (2.6 g, 0.0179mol) and three ko amine (2.6 ml, 0.0186mol) was added to 140 ml of isopropanol and the reaction was heated to reflux for 3 inch, TLC plates to determine the point completion of the reaction, cooled to room temperature, filtered, the filter cake washed with methanol, vacuum dried at 50 ° C in 14 hours to give the final product Dacomitinib, a yellow solid, 6.6 g, yield 84%.

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synthesis

US7772243

http://www.google.com/patents/US7772243

 Scheme 1, wherein the 4-position aniline group is represented a 4-fluoro-3-chloro aniline group.

4-Chloro-7-fluoro-6-nitroquinazoline (7) can be prepared by methods similar to those described in J.Med. Chem. 1996, 39, 918-928. Generally, 2-amino-4-fluoro-benzoic acid (1) can be reacted with formamidine (2) and acetic acid (3) in the presence of 2-methoxyethanol to provide 7-Fluoro-3H-quinazolin-4-one (4). The 7-fluoro-3H-quinazolin-4-one (4) can be nitrated to 7-fluoro-6-nitro-3H-quinazolin-4-one (5), which can be treated with thionyl chloride to yield 4-chloro-6-nitro-7-fluoro-3H-quinazoline (6). The 4-chloro-quinazoline compound (6) can be combined with a desirably substituted aniline, represented above by 4-fluoro-3-chloro-aniline, in the presence of a tertiary amine and isopropanol to provide the 4-anilino-6-nitro-7-fluoro-quinazoline (7).

The 4-anilino-6-nitro-7-fluoro-quinazoline (7) may be reacted with an alcohol of the formula R₃OH, wherein R₃ is as defined above, to yield the 7-alkoxylated compound (8). Reduction of the 6-nitro compound (8) provides the 6-amino analog (9).

The 6-position amino compound (9) may be reacted with a haloalkenoyl chloride (12), such as a 4-bromo-but-2-enoyl chloride, 5-bromo-pent-2-enoyl chloride, 4-chloro-but-2-enoyl chloride, or 5-chloro-pent-2-enoyl chloride, to provide an alkenoic acid[4-anilino]-7-alkoxylated-quinazolin-6-yl-amide (13). Haloalkenoyl chloride agents useful in this scheme may be prepared by methods known in the art, such as the treatment of a relevant haloalkenoic acid, represented by bromoalkenoic acid ester (10), with a primary alcohol, yielding the corresponding haloalkenoic acid (11), which may in turn be treated with oxalyl chloride to provide the desired haloalkenoyl chloride (12).

Finally, the quinazoline-6-alkanoic acid compound (13) may be treated with a cyclic amine, such as piperidine, piperazine, etc., to provide the desired final compound (14).

EXAMPLE 2

4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide (Synthetic Route No. 1)

The title compound and other 7-methoxy analogs of this invention can be prepared as described in Example 1 by replacing the 2-fluoroethanol used in Example 1 with stoichiometric amount of methanol.

EXAMPLE 3 4-Piperidin-1 -yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxv -quinazolin-6-yl]-amide (Synthetic Route No. 2)

An alternative synthetic route for compounds of this invention involves preparing the 6-position substituent chain as a Het-alkenoyl chloride as depicted in Scheme 2, below.

It will be understood that other compounds within this invention may be prepared using Het-butenoyl halide, Het-pentenoyl halide and Het-hexenoyl halide groups of the formula:

wherein R₄ is as described herein and halo represents F, Cl, Br or I, preferably Cl or Br. One specific group of these Het-alkenoyl halides includes those compounds in which halo is Cl or Br, R₄ is —(CH₂)_m-Het, m is an integer from 1 to 3, and Het is piperidine or the substituted piperidine moieties disclosed above.

EXAMPLE 4 4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinazolin-6-yl]-amide (Synthetic Route No. 3)

3-Chloro-4-fluoro-phenylamine 15 (50.31, 345.6 mmole) and 3,4-Dimethoxy-benzaldehyde 16 (57.43 g, 345.6 mmole) were mixed in 500 ml of IPA and cooled in an ice-water. The glacial acetic acid was added (20.76 g, 345.6 mole) and then sodium cyanoborohydride in one portion. The reaction was stirred at room temperature (RT) for 24 hrs. 250 mL of 10% NaOH was added dropwise at RT after the reaction was completed. The mixture was stirred for ½ hr. The slurry was then filtered and washed with IPA and dried in vacuo. The mass weight 88.75 g (17, 87%).

Compounds 6 (3 g, 13.18 mmole) and 17 (3.9 g, 13.18 mmole) were combined in CH₃CN (25 mL) and heated for one hr. Mass spectroscopy indicated no starting material. Saturated K₂CO₃ was added and the reaction was extracted 3× with EtOAc. The organic layers were combined, washed with brine and concentrated in vacuo to give 6.48 g of 7 (78.4%).

Compound 7 (72.76 g, 149.4 mmole) was added to a cool solution of NaOMe in 1.5 L of dry MeOH under N₂. The cooling bath was removed and the mixture was heated to reflux and stirred for 1 hr. The reaction was cooled to room temperature and quenched with water until the product precipitated out. The solid was filtered and washed with water and hexanes. The product was slurred in refluxing EtOAc and filtered hot to provide 68.75 g of yellow soled 8 (73%).

Compound 8 (63.62 g, 127.5 mole) was hydrogenated using Raney/Ni as catalyst to obtain 43.82 g of 9 (100%). Oxalyl chloride (6.5 g, 51.18 mmole) was added slowly to a suspension of 13 (10.5 g, 51.2 mmole) in 200 ml of dichloromethane containing 8 drops of DMF, after the reaction become homogeneous, the solvent was removed and the residual light yellow solid was slurred in 200 ml of DMAC and 9 (20 g, 42.65 mmole) was added gradually as a solid. The reaction was stirred for 15 min. and poured slowly into 1N NaOH. The mixture was extrated 3× EtOAc. The combined organic layers were washed with brine, filtered and concentrated in vacuo to obtain 28.4 g (100%) 10.

Compound 10(13.07 g, 21.08 mmole) was dissolved in trifluoroacetic acid (TFA) (74 g, 649 mmole) and heated to 30° C. for 24 hrs. The reaction was cooled to RT and poured gradually into a cooled 1 N NaO H-brine solution. Precipitate formed and was filtered and washed with 3X water then dried. The precipitate was recrystallized from toluene to obtain pure 4-Piperidin-1-vl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino) -7-methoxv-puinazolin-6-yl]-amide (9.90 g, 89%).

Example 1 is similar but not same…caution

EXAMPLE 1 4-Piperidin-1-yl-but-2-enoic acid [4-(3-chloro-4-fluoro-phenylamino)-7-(2-fluoro-ethoxy)-quinazolin-6-yl]-amide

7-fluoro-6-nitro-4-chloroquinazoline (14.73,g, 65 mmol) was combined with 3-choro-4-fluoroaniline (9.49 g, 65 mmol) and triethylamine (10 mL, 72 mmol) in 150 mL of isopropanol. The reaction was stirred at room temperature for 1.5 hours, resulting in a yellow slurry. The solid was collected by filtration, rinsing with isopropanol and then water. The solid was dried in a 40° C. vacuum oven overnight to give 19.83 g (91%) of the product as an orange solid.

MS (APCI, m/z, M+1): 337.0

NaH (60% in mineral oil, 3.55 g, 88 mmol) was added, in portions, to a solution of 2-fluoroethanol (5.19 g, 80 mmol) in 200 mL THF. The reaction was stirred for 60 minutes at room temperature. To the reaction was added 7-fluoro-6-nitro-4-(3-chloro-4-fluoroaniline)quinazoline (18.11 g, 54 mmol) as a solid, rinsing with THF. The reaction was heated to 65° C. for 26 hours. The reaction was cooled to room temperature and quenched with water. THF was removed in vacuo. The resulting residue was sonicated briefly in water then the solid collected by filtration. The solid was triturated with MeOH, filtered and dried in a 40° C. vacuum oven overnight to 12.63 g of the product. Additional product was obtained by concentrating the MeOH filtrate to dryness and chromatography eluting with 50% EtOAc/hex. The isolated material was triturated with MeOH (2×), filtered and dried. 3.90 g

Total yield: 16.53 g, 81%

MS (APCI, m/z, M+1): 381.0

7-(2-fluoroethoxy)-6-nitro-4-(3-chloro-4-fluoroaniline)quinazoline (0.845 g, 2.2 mmol) in 50 mL THF was hydrogenated with Raney nickel (0.5 g) as the catalyst over 15 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.77 g of product. (99%)

MS (APCI, m/z, M+1): 351.2

Methyl 4-bromocrotonate (85%, 20 mL, 144 mmol) was hydrolyzed with Ba(OH)₂ in EtOH/H₂O as described in J.Med.Chem. 2001, 44(17), 2729-2734.

MS (APCI, m/z, M−1): 163.0

To a solution of 4-bromocrotonic acid (4.17 g, 25 mmol) in CH₂Cl₂ (20 mL) was added oxalyl chloride (33 mL, 38 mmoL) and several drops of DMF. The reaction was stirred at room temperature for 1.5 hours. The solvent and excess reagent was removed in vacuo. The resulting residue was dissolved in 10 mL THF and added to a 0° C. mixture of 6-amino-7-(2-fluoroethoxy)-4-(3-chloro-4-fluoroaniline)quinazoline (5.28 g, 15 mmol) and triethylamine (5.2 mL, 37 mmol). The reaction was stirred at 0° C. for 1 hour. Water was added to the reaction and the THF removed in vacuo. The product was extracted into CH₂Cl₂ (400 mL). The organic layer was dried over MgSO₄, filtered and concentrated. The crude material was chromatographed on silica gel eluting with 0-4% MeOH/CH₂Cl₂. An isolated gold foam was isolated. Yield: 4.58 g, 61%

MS (APCI, m/z, M−1): 497.1

Piperidine (0.75 mL, 6.7 mmol) was added to a solution of the above compound (3.35 g, 6.7 mmol) and TEA (2.80 mL, 20 mmol) in 10 mL DMA at 0° C. The reaction was stirred at 0° C. for 17 hours. Water was added to the reaction until a precipitate was evident. The reaction was sonicated for 40 minutes and the liquid decanted. The residue was dissolved in CH₂Cl₂, dried over MgSO₄, filtered and concentrated. The material was chromatographed on silica gel eluting with 4-10% MeOH/CH₂Cl₂. The isolated residue was triturated with acetonitrile (2×) and collected by filtration. Impurity found: Michael addition of piperidine (2.2% in first trituration of acetonitrile). Additional material can be obtained from the acetonitrile filtrates.

Yield: 0.95 g, 27%

MS (APCI, m/z, M+1): 502.3

……………

US 20050250761 A1, 

References

• Dacomitinib Fact Sheet, Pfizer