Preparation method of key intermediate of JAK kinase inhibitor

Abstract

The invention provides a preparation method of a key intermediate (3aR, 5S, 6aS)-5-(methylamino) hexahydrocyclopenta [c] pyrrol-2 (1H)-tert-butyl formate mesylate of a JAK kinase inhibitor, and belongs to the field of medical intermediates. The preparation method comprises the following steps: taking cis-5-oxohexahydrocyclopenta [C] pyrrol-2 (1H)-carboxylic acid tert-butyl ester as a raw material to react with methylamine equivalent to obtain an intermediate A; then carrying out reduction reaction in metal sodium and isopropanol to obtain a crude product, adding L-DBTA to form salt, removing isomers, and carrying out re-dissociation and salt formation with methanesulfonic acid to obtain a pure product. The method greatly shortens the reaction steps, reduces the raw material cost, is simple and reliable in process, and is easy for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and specifically relates to a method for preparing a key intermediate of a JAK kinase inhibitor, (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate. Background Art

[0002] Janus kinase (JAK) is a class of intracellular non-receptor tyrosine kinases and a very important drug target. Some studies have been conducted on JAK inhibitors (e.g., Norman, P. Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin. Investig. Drugs, 2014, 23, 1067-1077). JAK inhibitors can be used for the treatment of rheumatoid arthritis, polycythemia vera, psoriasis, essential thrombocythemia and myelofibrosis. Although a series of JAK inhibitors have been disclosed, these JAK inhibitors that have been marketed or are in the research stage still have room for improvement in terms of efficacy and safety. It is still necessary to develop new JAK inhibitors with better efficacy and safety to provide better efficacy and reduce adverse reactions in patients. US14365497 provides a new pyrrole six-membered heteroaryl ring derivative compound, and it is found that the compound with this structure exhibits excellent effects and functions.

[0003] At present, there are few public literature reports on the synthesis of the compound of the present invention (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate. ZL2020116436020 provides a method for preparing (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate, and the synthesis route is as follows:

[0004]

[0005] In the above method, potassium permanganate is required as the starting material. The use of heavy metals causes serious environmental pollution. The third step is to use palladium carbon for debenzylation, which removes a large molecular weight group. The atomic utilization rate is not high and is not suitable for industrial scale-up production. Therefore, it is necessary to develop a new synthesis process to meet the growing market demand.

[0006] The synthesis method reported in US2014336207 and US2016102098, the synthesis route is as follows:

[0007]

[0008] The starting raw materials of this synthesis method are expensive and in short supply on the market, making it unsuitable for industrial scale-up production. Therefore, it is necessary to develop new synthesis processes to meet the growing market demand. Summary of the invention

[0009] In order to overcome the above technical defects, the present invention provides a method for enlarging the preparation of (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate. Cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester is used as a raw material to react with a methylamine equivalent to obtain an intermediate A; then a reduction reaction occurs in metallic sodium and isopropanol to obtain a crude product, which is then salified by adding L-DBTA, isomers are removed, and a pure product is obtained after re-free salification. This method greatly shortens the reaction steps, reduces the cost of raw materials, has a simple and reliable process, and is easy to industrialize, providing a new reaction path for the synthesis of (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate.

[0010] The preparation method of (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate of the present invention uses cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester and methylamine as raw materials, and the reaction equation is as follows:

[0011]

[0012] The preparation method of the technical solution of the present invention comprises the following steps:

[0013] The first step: using cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester and N-methyl-N,O-bis(trimethylsilyl)carbamic acid as raw materials, adding a catalyst in an organic solvent to react to obtain an intermediate A;

[0014] Further, in the above technical solution, the organic solvent is selected from acetic acid or a mixture of acetic acid and acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide and tetrahydrofuran. Further, in the above technical solution, the molar ratio of cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester to N-methyl-N,O-bis(trimethylsilyl)carbamic acid is 1:1-2.

[0015] Furthermore, in the above technical solution, the catalyst is selected from tris(pentafluorophenyl)boron; and the molar ratio of the catalyst to N-methyl-N,O-bis(trimethylsilyl)carbamic acid is 0.01-0.05:1.

[0016] During the experiment, when trying to use trifluoroacetic acid, a large amount of de-Boc salt byproducts were generated, which prevented the reaction from further generating imines. After optimization, it was found that using B(C 6 F 5 ) 3 can solve the problem.

[0017] Step 2: Intermediate A reacts with sodium metal in isopropanol to obtain (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester; then L-DBTA and ethyl acetate are added to form a salt, and intermediate B is obtained by filtration.

[0018] Furthermore, in the above technical solution, the molar ratio of metallic sodium to intermediate A is 5-8: 1. After the reduction reaction is completed, the ratio of 5R and 5S generated is 6-8 / 92-94, and the yield is greater than 95%.

[0019] Furthermore, in the above technical scheme, the molar ratio of intermediate A to L-DBTA is 1:1.1-1.2; during the optimization experiment, various methods were tried, and it was found that the reduction product was salted with L-DBTA in ethyl acetate solution, which can effectively remove other isomers. After purification, the 5R ratio was reduced to below 0.03, and the 5S ratio was increased to more than 99.5%.

[0020] Step 3: After intermediate B is freed by adding a base in an organic solvent, methanesulfonic acid is then added to form a salt to obtain (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate.

[0021] Furthermore, in the above technical solution, the organic solvent is selected from dichloromethane and 1,2-dichloroethane.

[0022] Furthermore, in the above technical solution, the base is selected from sodium hydroxide or potassium hydroxide.

[0023] The method of the invention has simple and reliable process and is easy for industrial production; the amount of isomers generated is reduced, the reaction yield is improved, the comprehensive production cost is greatly reduced compared with the production process in the existing literature or patents, and the product is more competitive in the market. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The HNMR spectrum of the product (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate of Example 1;

[0025] Figure 2The HPLC spectrum of the product (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate of Example 1 is shown. DETAILED DESCRIPTION

[0026] The present invention will be further described below in conjunction with specific embodiments. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0027] Example 1

[0028] Cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester (14.87 g, 66 mmol), N-methyl-N,O-bis(trimethylsilyl)carbamic acid (15.96 g, 72.6 mmol), triphenylborane (0.676 g, 1.32 mmol) and acetic acid (19.82 g, 330 mmol) were added to 70 mL of tetrahydrofuran and stirred at 25-35° C. for 4 hours. 50 mL of water and 250 mL of ethyl acetate were added to the reaction solution, extracted twice, washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, filtered and spin-dried, and slurried with MTBE and heptane (v / v=1 / 5) to obtain 14.63 g of intermediate A with a yield of 93%.

[0029] Under nitrogen protection, sodium metal (6.75 g, 293.7 mmol) was added in batches to the intermediate A (14 g, 58.7 mmol) / n-propanol (70 mL) solution at 0 ° C, and the reaction solution was stirred at 40-45 ° C for 3 hours. After the reaction, the reaction solution was cooled to 0 ° C, the reaction was carefully quenched, extracted twice with 120 mL of ethyl acetate (60 mL * 2), washed with saturated brine, and L-(-)-dibenzoyltartaric acid monohydrate (24.31 g, 64.6 mmol) / ethyl acetate (90 mL) solution was added to the above solution, and the temperature was raised to reflux for 1 hour. After cooling and precipitation, 28.81 g of crude intermediate B was obtained by filtration.

[0030] 2N sodium hydroxide aqueous solution was added to the above intermediate B (28.81 g) / dichloromethane (150 mL) solution, the pH was adjusted to 9-10, and stirred at room temperature for 3 hours. The pH was tested again and it was still alkaline. After the reaction was completed, the organic layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, added with methanesulfonic acid (6.21 g, 64.61 mmol), stirred at room temperature for 0.5 hours, filtered, and dried to obtain 14.61 g of the product. The total yield of the two steps was 74%. The HNMR detection result was Figure 1 HPLC 98.8%, analysis results Figure 2The HPLC peak was consistent with that of the standard sample.

[0031] Example 2

[0032] Cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1kg, 4.44mol), N-methyl-N,O-bis(trimethylsilyl)carbamic acid (1.56kg, 7.10mol), triphenylborane (36.35g, 0.071mol) and acetic acid (1.07kg, 17.76mol) were added to 5L of acetonitrile and stirred at 25-35°C for 4 hours. 5L of water and 12L of ethyl acetate were added to the reaction solution, extracted twice, washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, filtered and spin-dried, and slurried with MTBE and heptane (v / v=1 / 5) to obtain 0.97kg of intermediate A with a yield of 92%.

[0033] Under nitrogen protection, sodium metal (0.61kg, 26.46mol) was added to the intermediate A (0.9kg, 3.78mol) / isopropanol (3L) solution in batches at 0℃, and the reaction solution was stirred at 40-45℃ for 3 hours. After the reaction, the reaction solution was cooled to 0℃, the reaction was carefully quenched, extracted twice with 3L ethyl acetate (1.5L*2), washed with saturated brine, and L-(-)-dibenzoyltartaric acid monohydrate (1.71kg, 4.54mol) / ethyl acetate (3L) solution was added to the above solution, and the temperature was raised to reflux for 1 hour. After cooling and precipitation, 1.9kg crude intermediate B was obtained by filtration.

[0034] Add 2N sodium hydroxide aqueous solution to the above intermediate B (1.9 kg) / dichloromethane (11 L) solution, adjust pH = 9-10, stir at room temperature for 3 hours, and check again that the pH is still alkaline. After the reaction, wash the organic layer with water, wash with saturated brine, dry over anhydrous sodium sulfate, filter and add methanesulfonic acid (0.4 kg, 4.16 mol). Stir at room temperature for 0.5 hour, filter and dry to obtain 0.97 kg of product. The total yield of two steps is 76.4%; HPLC analysis detects 99.1%.

[0035] The above embodiments describe the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the scope of the principles of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of protection of the present invention.

Claims

1. A method for preparing a key intermediate of a JAK kinase inhibitor, (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate, characterized in that: The steps include: The first step: using cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester and N-methyl-N,O-bis(trimethylsilyl)carbamic acid as raw materials, adding a catalyst in an organic solvent to react to obtain an intermediate A; Step 2: Intermediate A reacts with sodium metal in isopropanol to obtain (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester; then L-DBTA and ethyl acetate are added to form a salt, and the intermediate B is obtained by filtration; Step 3: After intermediate B is freed by adding a base in an organic solvent, methanesulfonic acid is then added to form a salt to obtain (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate.

2. The method for preparing tert-butyl (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate according to claim 1, characterized in that: In the first step, the organic solvent is selected from acetic acid or a mixture of acetic acid and acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide and tetrahydrofuran.

3. The method for preparing tert-butyl (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate according to claim 1, characterized in that: In the first step, the molar ratio of cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester to N-methyl-N,O-bis(trimethylsilyl)carbamic acid is 1:1-2.

4. The method for preparing tert-butyl (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate according to claim 1, characterized in that: In the first step, the catalyst is selected from tris(pentafluorophenyl)boron; the molar ratio of the catalyst to N-methyl-N,O-bis(trimethylsilyl)carbamic acid is 0.01-0.05:

1.

5. The method for preparing tert-butyl (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate according to claim 1, characterized in that: In the second step, the molar ratio of metallic sodium to intermediate A is 5-8:

1.

6. The method for preparing tert-butyl (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate according to claim 1, characterized in that: In the second step, the molar ratio of intermediate A to L-DBTA is 1:1.1-1.

2.

7. The method for preparing tert-butyl (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate according to claim 1, characterized in that: In the third step, the organic solvent is selected from dichloromethane and 1,2-dichloroethane.

8. The method for preparing tert-butyl (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate according to claim 1, characterized in that: In the third step, the base is selected from sodium hydroxide or potassium hydroxide.

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