Synthetic method of edoxaban intermediate

Abstract

The invention relates to a synthesis method of an edoxaban intermediate, which comprises the following steps: by taking N-methyl-4-piperidone as a raw material, carrying out halogenation reaction and thioformamide cyclization, and then carrying out Friedel-Crafts acylation and hydrolysis reaction to synthesize 4, 5, 6, 7-tetrahydro-5-methylthiazolo [5, 4-c] pyridine-2-formic acid hydrochloride. In the reaction process, thioformamide is used for cyclization, so that the existing dangerous diazo reaction is omitted, and the process operation is safe; meanwhile, the diazo reaction is omitted, a large amount of alkali is not needed for adjusting the pH value in the post-treatment process to generate a large amount of high-salinity wastewater, the post-treatment steps are simple, and the burden on the environment is reduced; the method disclosed by the invention is low in reaction cost, high in product purity and yield and relatively high in industrial value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediates, and in particular to a method for synthesizing an edoxaban intermediate. Background Art

[0002] Edoxaban is a coagulation factor inhibitor and the first oral anticoagulant drug to be marketed worldwide. It was developed by Daiichi Sankyo Co., Ltd. of Japan, launched in Japan in July 2011 and included in the Essential Medicines List. It was approved by the China National Drug Administration in 2018 and is also known as "Edoxaban" in my country.

[0003] At present, the main synthetic route of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride has been disclosed in U.S. Pat. No. 9,233,980 B2, such as Figure 1 . This route uses N-methyl-4-piperidone as the starting material, and cyclizes with a monocyanamide aqueous solution and elemental sulfur to obtain the corresponding thiazole amine 109C2-00; forms a salt with hydrobromic acid to obtain 109C2-10; uses sodium nitrite and hydrobromic acid to convert the amino group into the corresponding bromide 109C3-00 through a diazotization reaction; under deep cold conditions, n-butyl lithium and carbon dioxide gas are used to prepare 109C6-10; and hydrochloric acid is used to neutralize and form a salt to obtain compound 109C6-20. This route requires the use of flammable and explosive elemental sulfur; deep cold conditions and expensive and extremely flammable n-butyl lithium. From the perspective of production safety, there are many hidden dangers, and it is not conducive to cost control, and it is not suitable for industrial-scale production.

[0004] U.S. patent application US2005119486A1 discloses another synthetic route, such as Figure 2 . This route uses N-Boc-4-piperidone as the starting material, and cyclizes with a monocyanamide aqueous solution and elemental sulfur to obtain 109J1-00; uses tert-butyl nitrite and bromide to convert the amino group into the corresponding bromide 109J2-00 through a diazotization reaction; removes the Boc protecting group to obtain 109J3-00; then reacts with iodomethane to obtain 109C3-00 through an N-alkylation reaction; under deep cold conditions, uses n-butyl lithium and carbon dioxide gas to prepare 109C6-10; neutralizes with hydrochloric acid and forms a salt to obtain compound 109C6-20. Due to the presence of the Boc-protecting group, this route requires the use of relatively expensive tert-butyl nitrite as a diazotization agent; requires the use of iodomethane with an extremely low boiling point and expensive as an N-alkylation agent; requires deep cold conditions and requires the use of expensive and extremely flammable n-butyl lithium. From the perspective of production safety, there are many hidden dangers, and it is not conducive to cost control, and is not suitable for industrial-scale production.

[0005] U.S. patent application US2005119486A1 also discloses a synthetic route, such as Figure 3 . This route uses 4-aminopyridine as a starting material to react with Boc-anhydride to obtain 109H1-00; under deep cold conditions, a combination of n-butyl lithium and elemental sulfur is used to prepare compound 109H 1-00; a ring-closure reaction with formic acid is performed to obtain compound 109H3-00; and then reacting with iodomethane to obtain compound 109H4-10; reduction with sodium borohydride to obtain 109C4-00; under deep cold conditions, n-butyl lithium and carbon dioxide gas are used to prepare 109C6-10; and hydrochloric acid is used to neutralize and form a salt to obtain compound 109C6-20. This route uses deep cold conditions twice and uses expensive and highly flammable n-butyl lithium; requires flammable and explosive elemental sulfur; requires carbon dioxide gas as a carboxylation source; and requires iodomethane with a very low boiling point and expensive as an N-alkylating agent. From the perspective of production safety, there are many hidden dangers, which is not conducive to cost control and is not suitable for industrial-scale production.

[0006] Therefore, the current synthesis method of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride needs to be further improved. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a method for synthesizing edoxaban intermediate 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride in view of the current status of the prior art. The method is mainly obtained by developing a new synthesis route of 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine, and 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine is reacted with trichloroacetyl chloride through Friedel-Crafts acylation and hydrolysis to synthesize 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride. The method has safe process operation, mild reaction conditions, simple post-treatment, high product yield and industrial value.

[0008] The technical solution adopted by the present invention to solve the above technical problems is:

[0009] A method for synthesizing an edoxaban intermediate comprises the following steps:

[0010] (1) Using N-methyl-4-piperidone as a raw material, the compound V is synthesized by reacting with a halide under the action of acetic acid.

[0011]

[0012] Wherein, X is a halogen or a leaving group, and R is one of methyl, ethyl, tert-butyloxycarbonyl and benzyloxycarbonyl.

[0013] (2) In a solvent, thioformamide reacts with compound V to synthesize compound IV;

[0014]

[0015] (3) In a C1-C4 straight-chain branched alcohol solvent and a base, a haloform-like compound IV reacts to synthesize compound III;

[0016]

[0017] (4) Adding compound III to a C1-C4 straight-chain branched alcohol solvent and reacting with lithium hydroxide monohydrate to synthesize compound II;

[0018]

[0019] (5) Adding compound II to a C1-C4 straight-chain branched alcohol solvent (preferably ethanol in the present invention) to react with an acid to synthesize compound I,

[0020]

[0021] Compound I is the target product 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride.

[0022] Preferably, the X is selected from chlorine, bromine, iodine or a leaving group such as methanesulfonate or trifluoromethanesulfonate; and the R is tert-butyloxycarbonyl or benzyloxycarbonyl.

[0023] Preferably, in step (2), the solvent is one or more of 1,4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, tetrahydrofuran, toluene, and diethyl ether. In step (2), halogenation reaction, thiocarboxamide cyclization, deprotection, and methylation reaction are sequentially performed to obtain compound IV, i.e., 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine.

[0024] Preferably, in step (3), the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate; and the solvent is selected from one or more of dichloromethane, toluene, and acetonitrile.

[0025] Preferably, in step (5), the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, and oxalic acid.

[0026] Preferably, in step (1), the molar ratio of N-methyl-4-piperidone to the halide is 1:1.0 to 1:2.0.

[0027] Preferably, the reaction temperature in step (1) is 0 to 80°C.

[0028] Preferably, the reaction temperature in step (2) is 25-80°C.

[0029] Preferably, in step (2), the compound V is an α-halogenated carbonyl compound, and the molar ratio of the compound V to thioformamide is 1:1.0 to 1:2.0.

[0030] Compared with the prior art, the advantages of the present invention are as follows: the present invention uses N-methyl-4-piperidone as a raw material, undergoes halogenation reaction, thioformamide cyclization, and then undergoes Friedel-Crafts acylation and hydrolysis reaction to synthesize 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride. During the reaction, thioformamide cyclization is used to eliminate the existing dangerous diazo reaction, and the process operation is safe; at the same time, since the diazo reaction is omitted, the post-treatment does not require a large amount of alkali to adjust the pH to produce a large amount of high-salt wastewater, and the post-treatment steps are simple, reducing the burden on the environment; the present invention has low reaction cost, high product purity and high yield, and has high industrial value. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The reaction flow chart of the background technology of the present invention is as follows;

[0032] Figure 2 The reaction flow chart of the background technology of the present invention is as follows;

[0033] Figure 3 The reaction flow chart of the background technology of the present invention is as follows;

[0034] Figure 4 The reaction flow chart of the embodiment of the present invention. DETAILED DESCRIPTION

[0035] The present invention is further described in detail below with reference to the accompanying drawings.

[0036] like Figure 4 As shown, the synthesis method of the edoxaban intermediate of the embodiment of the present invention comprises the following steps:

[0037] (1) Using N-methyl-4-piperidone as a raw material, reacting with a halide in the presence of acetic acid to synthesize compound V; wherein X is a halogen or a leaving group, and R is one of methyl, ethyl, tert-butyloxycarbonyl, and benzyloxycarbonyl;

[0038] (2) In a solvent, thioformamide reacts with compound V to synthesize compound IV;

[0039] (3) In a C1-C4 straight-chain branched alcohol solvent and a base, a haloform-like compound IV reacts to synthesize compound III;

[0040] (4) Adding compound III to a C1-C4 straight-chain branched alcohol solvent and reacting with lithium hydroxide monohydrate to synthesize compound II;

[0041] (5) Compound II is added to a C1-C4 straight-chain branched alcohol solvent to react with an acid to synthesize Compound I. Compound I is the target product 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride.

[0042] In the above synthesis process, in step (1), X is selected from chlorine, bromine, iodine or a leaving group methanesulfonate, trifluoromethanesulfonate; R is tert-butyloxycarbonyl or benzyloxycarbonyl. In step (1), the molar ratio of N-methyl-4-piperidone to the halide is 1:1.0 to 1:2.0. The reaction temperature is 0 to 80°C.

[0043] In step (2), the solvent is one or more of 1,4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, tetrahydrofuran, toluene, and ether. In step (2), halogenation reaction, thiocarboxamide cyclization, deprotection, and methylation reaction are sequentially performed to obtain compound IV, i.e., 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine. The reaction temperature in step (2) is 25 to 80° C. Compound V is an α-halogenated carbonyl, and the molar ratio of compound V to thiocarboxamide is 1:1.0 to 1:2.0.

[0044] In step (3), the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate; and the solvent is selected from one or more of dichloromethane, toluene, and acetonitrile.

[0045] In step (5), the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, and oxalic acid.

[0046] Embodiment 1:

[0047] The synthesis method of edoxaban intermediate 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt in this embodiment comprises the following steps:

[0048] (1) Synthesis of 3-bromo-1-methyl-4-piperidinone hydrobromide

[0049]

[0050] Add glacial acetic acid (500g) to the reaction kettle, control the temperature not to exceed 25°C, add 1-methyl-4-piperidone (100g, 0.88moL) dropwise, then add 48% hydrobromic acid aqueous solution (150g, 0.90moL) dropwise; control the temperature not to exceed 20°C, add liquid bromine (141.6g, 0.89moL) dropwise, after the dropwise addition, stir at room temperature overnight; filter, collect the white solid, and dry; obtain about 223g (theoretical amount: 241.2g) of 3-bromo-1-methyl-4-piperidone hydrobromide dry product. Yield: 92.5%.

[0051] (2) Synthesis of 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine

[0052]

[0053] Add 2 kg of ethyl acetate to the reaction kettle, add the dry product of 3-bromo-1-methyl-4-piperidone hydrobromide obtained in step (1) (200 g, 0.73 mol), raise the temperature to 45-50° C., add thioformamide solution (67.2 g, 1.1 mol) dropwise, stir overnight at 45-50° C., and perform TLC detection. After the raw materials react completely, evaporate the solvent, add sodium hydroxide solution to adjust the pH to 8-9, add dichloromethane for extraction, and spin-dry the organic phase to obtain 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine as an oily substance (88.3 g (theoretical amount: 113.2 g), with a yield of 78%.

[0054] (3) Synthesis of 2,2,2-trichloro-1-(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridinium-1-yl)ethanone chloride

[0055]

[0056] Add toluene (800g) to the reaction kettle, add 4,5,6,7-tetrahydro-5-methyl-thiazo[5,4-C]pyridine (80g, 0.52moL) obtained in step (2), then add triethylamine (78.7g, 0.78moL), control the temperature not to exceed 35°C, and add trichloroacetyl chloride (141.5g, 0.78moL) dropwise; after the addition is complete, keep warm for about 2 to 4 hours. After the reaction is complete, cool down, add saturated sodium bicarbonate aqueous solution to the reaction system, stir thoroughly, continue cooling and crystallizing for 2 to 3 hours; filter, collect solids, and the obtained solids are kept warm at 10 to 20°C for about 2 to 3 hours with drinking water and ethanol in turn, and slurryed at about 2 to 3 hours; filter; collect solids, dry, and obtain 140.8g of dry product (theoretical amount: 155.4g). Yield: 90.6%.

[0057] (4) Synthesis of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt

[0058]

[0059] Add 95% ethanol (500g) to the reaction bottle, add 2,2,2-trichloro-l-(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridinium-1-yl)ethanone chloride (100g, 0.33moL) obtained in step (3); under stirring, control the temperature not to exceed 25°C, add lithium hydroxide monohydrate (15.2g, 0.36moL), keep the temperature at 20-30°C, stir and react overnight. Then raise the temperature to 40-50°C and react for about 6-8h; a large amount of solid precipitates in the system; filter, rinse the filter cake with anhydrous ethanol, collect the solid; dry to obtain about 65.1g (theoretical amount: 68.14g) of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt dry product. Yield: 95.5%.

[0060] (5) Synthesis of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride

[0061]

[0062] Add 90% ethanol (200g) to the reaction bottle, add 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt (50g, 0.24moL) obtained in step (4); heat to 40-50°C under stirring to completely dissolve the material; then add activated carbon (5g-10g), stir and decolorize for about 20min, filter hot, and rinse the filter residue with anhydrous ethanol; collect the filtrate, cool to 0-5°C, control the temperature not to exceed 5°C, add hydrochloric acid dropwise to adjust the pH to 1-2; keep warm at 0-5°C for crystallization for 2-3h. Filter, rinse the filter cake with anhydrous ethanol, collect the solid; control the temperature at 40°C, and dry with air blast to obtain 38.9g (theoretical amount: 57.5g) of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride dry product. Yield: 67.8%.

[0063] Embodiment 2:

[0064] This embodiment provides a method for synthesizing 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride, the steps of which are as follows:

[0065] (1) Synthesis of 3-chloro-1-methyl-4-piperidone hydrochloride

[0066]

[0067] Add 100g of dichloromethane and N-methyl-4-piperidone (10g, 0.09moL) to the reaction bottle, control the temperature not to exceed 25°C, add N-chlorosuccinimide (14.2g, 0.11moL) in batches, react overnight at room temperature, monitor the reaction of the raw materials by TLC, add 8% sodium thiosulfate aqueous solution to quench, stir, separate, and yield dichloromethane phase. The dichloromethane phase is spin-dried, and n-heptane is added for crystallization for 2-3h, filtered, and dried to obtain 9.8g of dry product (theoretical weight: 16.3g). Yield: 60.1%.

[0068] (2) Synthesis of 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine

[0069]

[0070] Add 25 g of ethyl acetate to the reaction kettle, add the dry product of 3-chloro-1-methyl-4-piperidone hydrochloride obtained in step (1) (5 g, 0.03 mol), raise the temperature to 45-50° C., add thioformamide solution (2.5 g, 0.04 mol) dropwise, stir overnight at 45-50° C., and perform TLC detection. After the raw materials react completely, evaporate the solvent, add sodium hydroxide solution to adjust the pH to 8-9, add dichloromethane for extraction, and spin dry the organic phase to obtain 4,5,6,7-tetrahydro-5-methyl-thiazo[5,4-C]pyridine as an oily substance (2.93 g (theoretical amount: 4.2 g), with a yield of 69.8%.

[0071] (3) Synthesis of 2,2,2-trichloro-1-(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridinium-1-yl)ethanone chloride

[0072]

[0073] Add toluene (800g) to the reaction kettle, add 4,5,6,7-tetrahydro-5-methyl-thiazo[5,4-C]pyridine (80g, 0.52moL) obtained in step (2), then add triethylamine (78.7g, 0.78moL), control the temperature not to exceed 35°C, and add trichloroacetyl chloride (141.5g, 0.78moL) dropwise; after the addition is complete, keep warm for about 2 to 4 hours. After the reaction is complete, cool down, add saturated sodium bicarbonate aqueous solution to the reaction system, stir well, continue cooling and crystallization for 2 to 3 hours; filter, collect solids, and the obtained solids are kept warm at 10 to 20°C with drinking water and ethanol for about 2 to 3 hours; filter; collect solids, dry, and obtain 142.1g of dry product (theoretical amount: 155.4g). Yield: 91.4%.

[0074] (4) Synthesis of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt

[0075]

[0076] Add 95% ethanol (500g) to the reaction bottle, add 2,2,2-trichloro-l-(4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridinium-1-yl)ethanone chloride (100g, 0.33moL) obtained in step (3); under stirring, control the temperature not to exceed 25°C, add lithium hydroxide monohydrate (15.2g, 0.36moL), keep the temperature at 20-30°C, stir and react overnight. Then raise the temperature to 40-50°C and react for about 6-8h; a large amount of solid precipitates in the system; filter, rinse the filter cake with anhydrous ethanol, collect the solid; dry to obtain about 64.8g (theoretical amount: 68.14g) of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt dry product. Yield: 95.1%.

[0077] (5) Synthesis of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride

[0078]

[0079] Add 90% ethanol (200g) to the reaction bottle, add 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid lithium salt (50g, 0.24moL) obtained in step (4); heat to 40-50°C under stirring to completely dissolve the material; then add activated carbon (5g-10g), stir and decolorize for about 20min, filter hot, and rinse the filter residue with anhydrous ethanol; collect the filtrate, cool to 0-5°C, control the temperature not to exceed 5°C, add hydrochloric acid dropwise to adjust the pH to 1-2; keep warm at 0-5°C for crystallization for 2-3h. Filter, rinse the filter cake with anhydrous ethanol, collect the solid; control the temperature at 40°C, and dry with air blast to obtain 39.5g (theoretical amount: 57.5g) of 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride dry product. Yield: 68.7%.

Claims

1. A method for synthesizing an edoxaban intermediate, characterized in that The following steps are involved: (1) Using N-methyl-4-piperidone as a raw material, the compound V is synthesized by reacting with a halide under the action of acetic acid. Wherein, X is a halogen or a leaving group, and R is one of methyl, ethyl, tert-butyloxycarbonyl, and benzyloxycarbonyl; (2) In a solvent, thioformamide reacts with compound V to synthesize compound IV; (3) In a C1-C4 straight-chain branched alcohol solvent and a base, a haloform-like compound IV reacts to synthesize compound III; (4) Adding compound III to a C1-C4 straight-chain branched alcohol solvent and reacting with lithium hydroxide monohydrate to synthesize compound II; (5) Adding compound II to a C1-C4 straight-chain branched alcohol solvent to react with an acid to synthesize compound I, Compound I is the target product 4,5,6,7-tetrahydro-5-methylthiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride.

2. The method for synthesizing an edoxaban intermediate according to claim 1, wherein: The X is selected from chlorine, bromine, iodine or a leaving group such as methanesulfonate or trifluoromethanesulfonate; and the R is tert-butyloxycarbonyl or benzyloxycarbonyl.

3. The method for synthesizing an edoxaban intermediate according to claim 2, wherein: In step (2), the solvent is one or more of 1,4-dioxane, ethylene glycol dimethyl ether, ethyl acetate, tetrahydrofuran, toluene, and diethyl ether. In step (2), halogenation reaction, thiocarboxamide cyclization, deprotection, and methylation reaction are sequentially performed to obtain compound IV, i.e., 4,5,6,7-tetrahydro-5-methyl-thiazolo[5,4-C]pyridine.

4. The method for synthesizing an edoxaban intermediate according to claim 1, characterized in that: In step (3), the base is selected from triethylamine, N,N-diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, potassium carbonate; and the solvent is selected from one or more of dichloromethane, toluene, and acetonitrile.

5. The method for synthesizing an edoxaban intermediate according to claim 1, characterized in that: In step (5), the acid is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, p-toluenesulfonic acid, and oxalic acid.

6. The method for synthesizing an edoxaban intermediate according to any one of claims 1 to 6, characterized in that: In step (1), the molar ratio of N-methyl-4-piperidone to the halide is 1:1.0 to 1:2.

0.

7. The method for synthesizing an edoxaban intermediate according to any one of claims 1 to 6, characterized in that: The reaction temperature in step (1) is 0 to 80°C.

8. The method for synthesizing an edoxaban intermediate according to any one of claims 1 to 6, characterized in that: The reaction temperature in step (2) is 25-80°C.

9. The method for synthesizing an edoxaban intermediate according to any one of claims 1 to 6, characterized in that: In step (2), the compound V is an α-halogenated carbonyl compound, and the molar ratio of the compound V to thioformamide is 1:1.0 to 1:2.0.

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