Preparation method for key intermediate of JAK kinase inhibitor

Abstract

The present invention relates to the field of medical intermediates, and provides a preparation method for a key intermediate tert-butyl (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate mesylate of a JAK kinase inhibitor. The method comprises: reacting tert-butyl cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylate as a raw material with a methylamine equivalent to obtain intermediate A; and then carrying out a reduction reaction in metallic sodium and isopropanol to obtain a crude product, adding L-DBTA to form a salt, removing isomers, and then carrying out re-liberation and salt formation with methanesulfonic acid to obtain a purified product. The method significantly reduces reaction steps, reduces raw material costs, has a simple and reliable process, and is easy for industrial production.

Description

Process for the preparation of a key intermediate for JAK kinase inhibitors TECHNICAL FIELD

[0001] The present application belongs to the technical field of synthesis of pharmaceutical intermediates, and particularly relates to a preparation method of a key intermediate (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate for JAK kinase inhibitors. BACKGROUND

[0002] Janus kinase (JAK) is a class of intracellular non-receptor tyrosine kinases, which is a very important drug target. Some researches have been carried out on JAK inhibitors (for example, Norman, P. Selective JAK inhibitors in development for rheumatoid arthritis. Expert Opin. lnvestig. Drugs, 2014, 23, 1067-1077), and JAK inhibitors can be used for the treatment of rheumatoid arthritis, polycythemia vera, psoriasis, essential thrombocytosis and myelofibrosis. Although a series of JAK inhibitors have been disclosed, there is still room for improvement in terms of efficacy and safety for the JAK inhibitors that have been marketed or are in the research stage. New JAK inhibitors with better efficacy and safety need to be developed to provide better efficacy and reduce adverse reactions in patients. US143654 97 provides a new pyrrole six-membered heteroaryl ring derivative compound, and it is found that the compound with this structure exhibits excellent effect and effect.

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

[0004]

[0005] In the above method, potassium permanganate is used as the starting material, and the use of heavy metals is serious pollution to the environment. In the third step, palladium-carbon is used to remove the benzyl group, which has a large molecular weight, and the atomic utilization rate is not high. Therefore, it is not suitable for industrial scale production, and a new synthesis process needs to be developed to meet the growing market demand.

[0006] US2014336207 and US2016102098 reported the synthesis method, the synthetic route as follows:

[0007]

[0008] The starting material of the synthesis method is expensive and in short supply in the market, which is not suitable for industrial scale production, so it is necessary to develop a new synthesis process to meet the growing market demand. SUMMARY

[0009] In order to overcome the above technical defects, the present application provides an amplification preparation method of (3aR, 5S, 6aS)-5-(methylamino) hexahydrocyclopenta[c] pyrrole-2(1H)-tert-butyl formate methanesulfonic acid salt. The intermediate A is obtained by reacting cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester with a methylamine equivalent; then a reduction reaction occurs in sodium metal and isopropyl alcohol to obtain a crude product, which is salted by adding L-DBTA, removing isomers, and then re-freezing to obtain a pure product. This method greatly shortens the reaction steps, reduces the cost of raw materials, and is simple and reliable, easy to industrialize, and provides a new reaction path for the synthesis of (3aR, 5S, 6aS)-5-(methylamino) hexahydrocyclopenta[c] pyrrole-2(1H)-tert-butyl formate methanesulfonic acid salt.

[0010] The preparation method of (3aR, 5S, 6aS)-5-(methylamino) hexahydrocyclopenta[c] pyrrole-2(1H)-tert-butyl formate methanesulfonic acid salt described in the present application 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 technical solution preparation method described in the present application comprises the following steps:

[0013] Step 1: cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester and N-methyl-N,O-bis(trimethylsilyl) carbamic acid are used as raw materials, a catalyst is added in an organic solvent to obtain 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] Further, in the technical scheme, 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 trifluoroacetic acid is used, a large amount of Boc-removing salt by-product is generated, which prevents the reaction from further generating imine. It is found through optimization that using B(C6F5)3 in acetic acid can solve the problem.

[0017] In the second step, intermediate A and sodium are reacted in isopropyl alcohol to obtain (3aR,5S,6aS)-tert-butyl 5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate; then L-DBTA and ethyl acetate are added to form a salt, and intermediate B is obtained through filtration.

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

[0019] Further, in the technical scheme, the molar ratio of intermediate A to L-DBTA is 1:1.1-1.2; during the optimization experiment, it is found that the salt formation of the reduction product with L-DBTA in ethyl acetate solution can effectively remove the other isomer, and after purification, the ratio of 5R is reduced to below 0.03, and the ratio of 5S is increased to above 99.5%.

[0020] In the third step, after intermediate B is neutralized in an organic solvent, methanesulfonic acid is added to form (3aR,5S,6aS)-tert-butyl 5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate.

[0021] Further, in the technical scheme, the organic solvent is selected from dichloromethane and 1,2-dichloroethane.

[0022] Further, in the technical scheme, the base is selected from sodium hydroxide and potassium hydroxide.

[0023] The method is simple, reliable and easy to industrialize; the generation amount of isomers is reduced, the reaction yield is improved, the comprehensive production cost is greatly reduced compared with the production process in the existing literature or patent, and the product has more market competitiveness. BRIEF DESCRIPTION OF DRAWINGS

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

[0025] Figure 2 is an HPLC chromatogram of the product of Example 1, (3aR,5S,6aS)-5- (methylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester methanesulfonic acid salt. DETAILED DESCRIPTION

[0026] The application is further described below in connection with specific embodiments. These embodiments are intended to be illustrative only and the scope of the present application is not limited to the embodiments. After reading the present disclosure, those skilled in the art will be able to affect various modifications and variations of the present application, which are also within the scope of the present application as defined by the claims.

[0027] Example 1

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

[0029] Sodium metal (6.75 g, 293.7 mmol) was added to a solution of intermediate A (14 g, 58.7 mmol) in n-propanol (70 mL) in batches under nitrogen protection at a temperature of 0 °C, and the reaction solution was stirred at 40-45 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, and the reaction was carefully quenched. The reaction solution was extracted twice with 120 mL of ethyl acetate (60 mL*2), washed with saturated brine, and then a solution of L-(-)-dibenzoyl tartaric acid monohydrate (24.31 g, 64.6 mmol) in ethyl acetate (90 mL) was added to the above solution, and the solution was heated to reflux for 1 hour. After cooling, the precipitate was filtered to obtain 28.81 g of crude intermediate B.

[0030] A solution of 2N sodium hydroxide aqueous solution was added to the above-mentioned intermediate B (28.81 g) / dichloromethane (150 mL) solution, the pH was adjusted to 9-10, and stirring was performed at room temperature for 3 hours. The pH was still alkaline after re-detection, the organic layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and methyl sulfonic acid (6.21 g, 64.61 mmol) was added. After stirring at room temperature for 0.5 hours, filtration was performed, and drying was performed to obtain 14.61 g of product, with a total yield of 74% for two steps. The HNMR detection result is shown in FIG. 1; the HPLC is 98.8%, and the analysis result is shown in FIG. 2. The HPLC peak is consistent with that of the standard sample.

[0031] Example 2

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

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

[0034] A solution of 2N sodium hydroxide aqueous solution was added to the above-mentioned intermediate B (1.9 kg) / dichloromethane (11 L) solution, the pH was adjusted to 9-10, and stirring was performed at room temperature for 3 hours. The pH was still alkaline after re-detection, the organic layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and methyl sulfonic acid (0.4 kg, 4.16 mol) was added. After stirring at room temperature for 0.5 hours, filtration was performed, and drying was performed to obtain 0.97 kg of product, with a total yield of 76.4% for two steps; HPLC analysis detection 99.1%.

[0035] The above examples describe the basic principles, main features and advantages of the present application. Those skilled in the art should understand that the present application is not limited to the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the principles of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application.

Claims

1. A process for the preparation of a key intermediate for JAK kinase inhibitors, (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester methanesulfonic acid salt, characterized in that, The method comprises the following steps: ； Step 1: using cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester and N-methyl-N,O-bis(trimethylsilyl)carbamate as raw materials, adding a catalyst in an organic solvent to obtain an intermediate A; Step 2: reacting the intermediate A and sodium metal in isopropanol to obtain (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester; then adding L-DBTA and ethyl acetate to form a salt, and filtering to obtain an intermediate B; Step 3: after the intermediate B is freed from salt by adding a base in an organic solvent, then adding methanesulfonic acid to form a salt to obtain (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate.

2. Process for the preparation of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester methanesulfonic acid salt according to claim 1, characterized in that: In step 1, 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. A process for the preparation of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester methanesulfonic acid salt according to claim 1, characterized in that: In step 1, the molar ratio of cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester to N-methyl-N,O-bis(trimethylsilyl)carbamate is 1:1-2.

4. A process for the preparation of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester methanesulfonic acid salt according to claim 1, characterized in that: In step 1, the catalyst is selected from tris(pentafluorophenyl)boron; the molar ratio of the catalyst to N-methyl-N,O-bis(trimethylsilyl)carbamate is 0.01-0.05:

1.

5. A process for the preparation of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester methanesulfonic acid salt according to claim 1, characterized in that: In step 2, the molar ratio of sodium metal to the intermediate A is 5-8:

1.

6. A process for the preparation of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester methanesulfonic acid salt according to claim 1, characterized in that: In step 2, the molar ratio of the intermediate A to L-DBTA is 1:1.1-1.

2.

7. A process for the preparation of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester methanesulfonic acid salt according to claim 1, characterized in that: In step 3, the organic solvent is selected from dichloromethane and 1,2-dichloroethane.

8. A process for the preparation of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester methanesulfonic acid salt according to claim 1, characterized in that: In step 3, the base is selected from sodium hydroxide or potassium hydroxide.

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