IkB kinase inhibitors , SANOFI, for osteoarthritis

The inventors describe two routes for preparing the desired compounds. The first route (Figure 1, top) begins with the reaction of indoleboronic acid 1 and chloropyrimidine 2in the presence of (Ph3P)4Pd to form 3, which is isolated in 93% yield and 96% purity. Compound 3 is converted to amine derivative 4 by treating it with MeNH2. The product was isolated in quantitative yield and with 97.6% purity. If desired, the ester group in 4can be hydrolyzed with NaOH to produce sodium salt 5.

Indoleboronic acid 1 is obtained by treating tert-butoxycarbonyl (Boc)–protected indole6 with B(O-i-Pr)3 in the presence of LiN-i-Pr2 (Figure 1, bottom) The reaction initially forms Boc-protected compound 7. After acid hydrolysis, 1 is isolated in 61% yield with 92.7% purity.

The inventors mention the advantage of using unprotected indole 1 in the reaction with2 rather than the N-protected compound. Their explanation is that although some 6 is formed by the loss of the boronate group from 1 during the coupling reaction with 2, 6does not subsequently react with 2. Hence the yield of 3 in the coupling step is not reduced.

The second route to the desired compound is quite different from the first. Figure 2 outlines the process for preparing 12, the methyl ester analogue of 4. This route starts with the preparation of silylated acetylene compound 8, isolated in 90% yield with 99% purity after what is described as an aqueous workup. In the next step, the silyl group is removed, and primary alkyne 9 is isolated in quantitative yield. Alkyne 9 is treated with chloropyrimidine 10 in the presence of CuI and a palladium catalyst in DMF to give 11, which is isolated after aqueous workup in 85% yield and 99.7% purity. The cyclization of 11 to form 12 is carried out with a strong base such as KO-t-Bu. The product is isolated after an aqueous workup in 58% yield and 92.3% purity.

Although the inventors do not provide details for preparing 10, they state that it can be synthesized by the route shown at the bottom of Figure 2. The reaction produces isomers 10 and 13, which can be separated by chromatographic methods or steam distillation.

The inventors describe an alternative route to 4 in which 1 reacts with 10 in place of 2. They point out that 1 reacts with a mixture of 10 and 13 to give 4. Although it may be expected that 13 would react to give an isomer of 4, they claim that this reaction does not take place. No examples of the reaction of 1 and 10 with or without 13 are given Also, the inventors mention “aqueous workup” several times but do not explain what this means.

These processes provide alternative routes to a drug intermediate that overcome product isolation problems. (Sanofi [Paris]. US Patent 8,232,395, July 31, 2012;

US8546567

EXAMPLE 1 Synthesis of ethyl 2-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylate

28 g (114 mmol) of 2-borono-5-ethoxycarbonylindole, 12 g (113 mmol) of sodium carbonate and 17.2 g of 2,4-(113 mmol) dichloropyrimidine were initially charged in 412 ml of ethanol. The clear solution was freed of oxygen by vigorous stirring and passing argon through (20 minutes). At RT, 2.67 g of tetrakis(triphenylphosphine)palladium(0) were added. The mixture was heated to from 65° C. to 70° C. for 2 hours (h). Subsequently, 112 ml of water and 112 ml of 30% hydrochloric acid were added and the mixture was cooled to 0° C. After filtration and drying under reduced pressure, 37.3 g (93% of theory) of ethyl 2-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylate were obtained (HPLC >96%).

The purity was determined by high-pressure liquid chromatography (HPLC):

EXAMPLE 2 Synthesis of ethyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate

30 g (95.4 mmol) of ethyl 2-(2-chloropyrimidin-4-yl)-1H-indole-5-carboxylate were initially charged and suspended in 150 ml of ethanol. 53.9 g of methylamine solution in ethanol (8 M) were added to this suspension which was heated to from 75° C. to 80° C. in an autoclave for 4 h. After concentration and washing with ethanol, 29.7 g of ethyl 2-(2-methylamino-pyrimidin-4-yl)-1H-indole-5-carboxylate were obtained (97.6 HPLC area %). LCMS: [M+H]⊕ 297.12

HPLC method as in example 1; retention time of title compound: 5.8 min

EXAMPLE 3 Synthesis of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid sodium salt

25 g of ethyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate were admixed with 200 ml of ethanol and 24.5 g of 33% sodium hydroxide solution, and heated to from 65° C. to 70° C. for 4 h. After cooling, the mixture was filtered with suction and the precipitate was washed with 15 ml of ethanol/water (9:1). 24.5 g (87.6% of theory) of 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylic acid sodium salt were obtained (98.1 HPLC area %). LCMS: [M+H]⊕ 269.10

HPLC method as in example 1; retention time of title compound: 3.3 min

EXAMPLE 4 Synthesis of methyl 4-amino-3-trimethylsilylethynylbenzoate

5.83 g (20 mmol) of methyl 4-aminobenzoate, 20.2 g (198 mmol) of triethylamine and 80 ml of toluene were initially charged. The clear solution was freed of oxygen by vigorous stirring and passing argon through (20 minutes). At an internal temperature of 20° C., 3.2 g (33 mmol) of trimethylsilylacetylene, 76 mg of copper(I) iodide and 52 mg of triphenylphosphine were added. After aqueous workup, 5.45 g of 4-amino-3-trimethylsilylethynylbenzoate were obtained (HPLC: >99 area %). HPLC method as in example 1.

EXAMPLE 5 Synthesis of methyl 4-amino-3-ethynylbenzoate

1.9 g (7.7 mmol) of methyl 4-amino-3-trimethylsilylethynylbenzoate were initially charged in 20 ml of tetrahydrofuran (THF). At from 5° C. to 8° C., 8.45 ml (8.5 mmol) of tetrabutylammonium fluoride solution (1 M in THF) were added dropwise within 5 minutes. After 25 min at 2° C., 438 ml of acetic acid were added. After addition of water and extraction with dichloromethane, and after removal of the solvent, 1.35 g of methyl 4-amino-3-ethynylbenzoate were obtained. HPLC method as in example 1.

EXAMPLE 6 Synthesis of methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)-ethynylbenzoate

3.0 g (17 mmol) of methyl 4-amino-3-ethynylbenzoate and 2.6 g (19 mmol) of 4-chloro-2-methylaminopyrimidine were initially charged in 20 ml of dimethylformamide (DMF) and 8.7 g (85 mmol) of triethylamine, and degassed with argon while stirring for 5 min. Subsequently, 65 mg of copper(I) iodide and 20 mg of tetrakis(triphenylamine)palladium(0) were added and the mixture was heated to 71° C. for 3 h. After aqueous workup, 4.1 g of methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)ethynylbenzoate were obtained. (HPLC: 99.7 area %) HPLC method as in example 1.

EXAMPLE 7 Synthesis of methyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate by cyclizing methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)ethynylbenzoate

73 mg (0.7 mmol) of potassium tert-butoxide were dissolved in 1 ml of NMP and admixed with a solution of 140 mg (0.5 mmol) of methyl 4-amino-3-(1-methylaminopyrimidin-4-yl)ethynylbenzoate in 1 ml of NMP. Subsequently, stirring was continued at RT for 24 h. Aqueous workup afforded 115 mg of methyl 2-(2-methylaminopyrimidin-4-yl)-1H-indole-5-carboxylate (HPLC: 92.3 area %).

EXAMPLE 8 Synthesis of 2-borono-5-ethoxycarbonylindole

150 g (519 mmol) of N-Boc-5-ethoxycarbonylindole and 192 ml (833 mmol) of triisopropyl borate in 350 ml of toluene were admixed at from 5° C. to 10° C. with 350 ml of a 1.8 molar solution of LDA in THF. The mixture was stirred for a further 5 min and the reaction mixture was added to a solution of 278 g of 30% hydrochloric acid and 940 ml of water. Subsequently, the mixture was stirred at from 5° C. to 10° C. for 30 min. Thereafter, the mixture was filtered and the filtercake was suspended in 530 ml of ethanol. This suspension was added at 40° C. to a solution of 500 ml of 30% hydrochloric acid and 224 ml of ethanol. Subsequently, the mixture was stirred at from 40° C. to 45° C. for 2.5 h and admixed at 30° C. with 380 ml of water. The mixture was then cooled to from 10° C. to 15° C., stirred at this temperature for 30 min and filtered. Drying under reduced pressure afforded 79.5 g (61% of theory) of 2-borono-5-ethoxycarbonylindole (HPLC: 92.7 area %).

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WO2004022553A1

C) Synthesis of the heterocyclic base

C.1) indole base synthesis. Of 2 – (2-methylamino-pyrimidin-4-yl) -1 H-indole-5-carboxylic acid (20) C.1.1) 1-Dimethylamino-4 ,4-dimethoxy-pent. -1-en-3-one (18)

100 g (0.76 mol) of 3,3-dimethoxy-2-butanone (16) of (17) (0.76 mol) at 120 ° C with stirring 90.2 g of 48 N, N-dimethylformamide dimethyl acetal h. The methanol formed during the reaction was continuously removed from the reaction solution by distillation. On cooling, the solution became a spontaneous crystallization, which was brought by adding a little heptane to completion. This gave 128.24 g of crude 18 (90% yield), which was reacted without further purification. Molecular formula C ₉ Hι ₇ N0 _3, MW = 187.24, MS (M + H) 188.2 ⁱ H NMR (DMSO-de) 1.22 (s, 3H), 2.80 (s, 3H), 3.10 (s, 9H), 5.39. (d, J = 15 Hz, 1 H), 7:59 (d, J = 15 Hz, 1 H). . . . . . . .

C.1.2). [4 - (1,1-Dimethoxy-ethyl)-pyrimidin-2-yl]-methyl-amine (19)

1:22 g (53 mmol) of sodium were dissolved in 100 ml absolute ethanol. This was

Stirring 5.8 g (53 mmol) Methylguanidinhydrochlorid and 10 g (53 mmol) of 1-dimethylamino-4,4-dimethoxy-penM-en-3-one (18) and heated to boiling for 4 h. To stop the reaction, the ethanol was evaporated. The product 19 thus obtained was used without further purification for the subsequent reaction. Yield 11.5 g (58 mmol, quantitative) Molecular Formula C9H15N3O2, MW = 197.24, MS (M + H) 198.2 ¹ H NMR (DMSO-de) 1.45 (s, 3H), 2.78 (s, 3H), 3.10 (s,. 6H), 6.75 (d, J = .3 Hz, 1 H), 7.0 – 7.1 (s (b), 1 H), 8.30 (d, J = 3 Hz, 1 H).

C.1.3) 2 -. (2-methylamino-pyrimidin-4-yl) -1 H-indole-5-carboxylic acid (20) Into 150 ml of 50% sulfuric acid at room temperature 5 g (25 mmol) [4 - ( 1, 1 - dimethoxy-ethyl)-pyrimidin-2-yl]-methyl-amine (19) and, 3.85 g of 4-hydrazinobenzoic acid with stirring and heated 4 h at 130 ° C. The methanol formed during the reaction was continuously removed from the reaction solution by distillation. After cooling to 10 ° C the reaction mixture was poured into 200 mL of ice and adjusted to a pH of about 5.5 with concentrated sodium hydroxide solution. The precipitate formed from sodium sulfate, and the product mixture was filtered and the filter residue was extracted several times with methanol. The combined methanol extracts were concentrated and the product 20 by flash chromatography (DCM / methanol 9:1). Yield: 0.76 g (11%) Molecular formula Oι Hι₃ N _{4 4} 0 _2, MW = 268.28, MS (M + H) 269.1.

¹ H NMR (DMSO-de) 2.95 (s, 3H), 6.90 – 7.10 (s (b), 1 H), 7.18 (d, J = 3 Hz, 1H), 7.4 (s, 1 H), 7:58 (d, J = 4.5 Hz, 1H), 7.80 (d, J = 4.5 Hz, 1H), 8.30 (s, 1H), 7.80 (d, J = 4.5 Hz, 1H), 8:38 (d, J = 3 Hz, 1H), 11.85 (s, 1H), 12:40 – 12.60 (s (b), 1 H).