Method for synthesizing key intermediate of jak kinase inhibitor

Abstract

The present invention belongs to the field of pharmaceutical intermediates. Provided in the present invention is a scale-up preparation method for tert-butyl (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate. The method comprises: subjecting tert-butyl cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylate and a reducing agent, which serve as raw materials, to a reaction in an organic solvent to obtain intermediate 1; subsequently, subjecting the intermediate to a Mitsunobu reaction with CH 3NHCbz to obtain intermediate 2; and finally, performing palladium-on-carbon catalyzed hydrogenation, followed by salt formation with methanesulfonic acid to obtain the product tert-butyl (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate. The method reduces raw material costs, has a simple and reliable process with easy industrialization, and provides a new reaction route for the synthesis of tert-butyl (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate.

Description

Synthesis method of a key intermediate of JAK kinase inhibitor TECHNICAL FIELD

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

[0002] As an important protein kinase, JAK3 can regulate the functions of lymphocytes, macrophages and mast cells. It is predicted that JAK3 inhibitors will be involved in the treatment or prevention of diseases related to the functions of lymphocytes, macrophages or mast cells. A JAK2 selective inhibitor named Ruxolitinib (INCB-018424) developed by INCYTE in cooperation with NOVARTIS has been approved by FDA and successfully put into the market. Patent applications disclose a series of JAK inhibitors, including WO2001042246, WO2002000661, WO2009054941 and WO2011013785.

[0003] Although JAK kinase inhibitors with a series of functions in immune diseases have been disclosed, there is still a need to develop new compounds with better efficacy. After continuous efforts, US14365497 provides a new compound of a pyrrole six-membered heteroaryl ring derivative, and it is found that the compound with this structure exhibits excellent effects and effects.

[0004] At present, there are few reports on the synthesis of the compound (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate. The synthesis method reported in US2014336207 and US2016102098 is as follows:

[0005]

[0006] In the above method, the starting material is expensive and in short supply on the market, which is not suitable for industrial scale-up production, and therefore it is necessary to develop a new synthesis process to meet the growing market demand.

[0007] Patent 2020116436020 discloses a preparation method of (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate, and the synthesis route is as follows:

[0008]

[0009] In the above method, potassium permanganate is required as a starting material, and the use of heavy metals is seriously polluting to the environment, and a palladium-carbon debenzylization is required in the third step to remove a group with a large molecular weight, which is not high in atomic utilization and is not suitable for industrial scale-up production, so a new synthesis process needs to be developed to meet the growing market demand. SUMMARY

[0010] In order to overcome the above technical defects, the present application provides a preparation method of (3aR, 5S, 6aS)-5-(methylamino) hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl formate methanesulfonate. The intermediate 1 is obtained by reacting the cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl formate and a reducing agent in an organic solvent; then the photo extension reaction with CH3NHCbz is carried out to obtain the intermediate 2; finally, catalytic hydrogenation is carried out, and then the formic acid sulfonic acid is salted to obtain the (3aR, 5S, 6aS)-5-(methylamino) hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl formate methanesulfonate product. The method reduces the cost of raw materials, and the process 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 methanesulfonate.

[0011] The amplification preparation method of (3aR, 5S, 6aS)-5-(methylamino) hexahydrocyclopenta[c]pyrrole-2(1H)-tert-butyl formate methanesulfonate is represented by the following reaction equation:

[0012]

[0013] The technical scheme preparation method disclosed by the present application is divided into three steps, and specifically comprises the following steps:

[0014] The first step: using cis-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-formate as a raw material, reacting in an organic solvent in the presence of a Lewis acid catalyst and a reducing agent at an ultra-low temperature to obtain an intermediate 1;

[0015] Further, in the above technical scheme, the reducing agent is selected from sodium borohydride, sodium borohydride acetate and sodium cyanoborohydride; and the Lewis acid catalyst is triphenylboron (BPh3). In the reduction process, when sodium borohydride is used at 0-20℃, the isomer product ratio is 8 / 1-10 / 1, and since the polarity difference between the two is very small, it is difficult to separate. After optimization, it is found that the addition of triphenylboron can increase the ratio of main product to by-product to more than 30 / 1 when sodium borohydride is used at an ultra-low temperature.

[0016] Further, in the above technical solution, the molar ratio of cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester to the reducing agent is 1:1.5-3.

[0017] Step 2: reaction of intermediate 1, phosphine ligand and azodicarboxylate in an organic solvent to obtain intermediate 2.

[0018] Further, in the above technical solution, the phosphine ligand is selected from triphenylphosphine, trimethylphosphine, tributylphosphine and diphenylphosphine.

[0019] Further, in the above technical solution, the azodicarboxylate is selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate. The molar ratio of the phosphine ligand to the azodicarboxylate is 1:1.

[0020] Step 3: hydrogenolysis reaction of intermediate 2 with methanesulfonic acid in the presence of a metal catalyst to obtain (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate.

[0021] Further, in the above technical solution, the catalyst is selected from palladium hydroxide, 10% palladium on carbon, 5% palladium on carbon or platinum dioxide.

[0022] The method of the present application is simple and reliable, easy to industrialize production; reduces the generation amount of isomers, improves the reaction yield, and greatly reduces the comprehensive production cost compared with the production process in the existing literature or patent, and the product has more market competitiveness. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 is the HNMR spectrum of the product (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate in Example 1; DETAILED DESCRIPTION

[0024] The present application will be further described below in conjunction with specific examples. These examples should be understood as merely illustrating the present application and not limiting the scope of protection of the present application. After reading the content described in the present application, those skilled in the art can make various changes or modifications to the present application, and these equivalent changes and modifications also fall within the scope of the present application as defined in the claims.

[0025] Example 1

[0026]

[0027] Step 1:

[0028] To a solution of cis-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (5 g, 22.2 mmol) and triphenylboron (0.3 g, 1.24 mmol) in methanol (50 mL) was added sodium borohydride (2.52 g, 66.6 mmol) portionwise at -78 °C. The temperature did not exceed -65 °C during the addition. After the addition was complete, the reaction was stirred for 1 h at -78 °C, quenched with water, and the solvent was distilled off. The crude mixture was dissolved in EtOAc (50 mL) and washed sequentially with water, dilute hydrochloric acid, and brine. The organic layer was dried over Na2S04, filtered, and concentrated to give tert-butyl (3aR,5R,6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (4.99 g, 99%) as a colorless oil in a 98.2 / 1.8 d.r. ratio of two isomers.

[0029] Second step:

[0030] To a solution of tert-butyl (3aR,5R,6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole-2-carboxylate (4.5 g, 19.8 mmol) in tetrahydrofuran was added triphenylphosphine (10.39 g, 39.6 mmol) and benzyl methylcarbamate (3.6 g, 21.78 mmol) at 15-20 °C under nitrogen protection, followed by the slow addition of a solution of DIAD (8.01 g, 39.6 mmol) in tetrahydrofuran. The reaction was stirred at room temperature for 4 h. The 5R starting material was consumed, and the 5S isomer remained. The reaction was cooled to below -60 °C overnight, and >95% of the by-product (PPh3O-DIADH2) was removed by filtration. Methyl tert-butyl ether was then added twice to extract the product. The organic layer was dried and concentrated. The intermediate 2 (6.73 g, 91% yield) was obtained by slurry in methyl tert-butyl ether / isopropyl alcohol. HPLC analysis showed 0.13% of the isomer.

[0031] Third step:

[0032] Intermediate 2 (6.5 g, 17.36 mmol) was dissolved in methanol (26 mL). The mixture was purged with nitrogen and palladium on carbon (10% wt, 0.65 g) was added. The reaction mixture was then saturated with a hydrogen atmosphere. After stirring at room temperature for 16 h, the mixture was filtered through a pad of celite, which was washed thoroughly with methanol. The filtrate was concentrated and dissolved in dichloromethane. Methanesulfonic acid (0.177 g, 1.84 mmol) was slowly added to the reaction. After stirring at room temperature for 0.5 h, the product was filtered and dried (5.55 g, 95% yield). HPLC analysis showed 99.3% of the product and 0.04% of the isomer.

[0033] Example 2

[0034] First step:

[0035] To a solution of cis-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate (100 g, 443.88 mmol) and triphenylboron (4.2 g, 17.35 mmol) in methanol (1000 mL) was added portionwise sodium borohydride in acetic acid (188.15 g, 887.76 mmol) at -78 °C. The temperature did not exceed -65 °C during the addition. After the addition was complete, the reaction was stirred for 1 h, quenched with water, and the solvent was distilled off. The crude mixture was re-dissolved in EtOAc (500 mL) and washed sequentially with water, dilute hydrochloric acid, and brine. The organic layer was dried over Na2S04, filtered, and concentrated to give tert-butyl (3aR,5R,6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-lH-cyclopenta[c]pyrrole-2-carboxylate (98.87 g, 98%) as a colorless oil in a ratio of two isomers d.r = 97.8 / 2.2.

[0036] Second step:

[0037] To a solution of tert-butyl (3aR,5R,6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-lH- cyclopenta[c]pyrrole-2-carboxylate (95 g, 417.95 mmol) in tetrahydrofuran was added trimethylphosphine (47.70 g, 626.93 mmol) and benzyl methylcarbamate (82.85 g, 501.54 mmol) at 15-20 °C under nitrogen protection, then a solution of DEAD (109.18 g, 626.93 mmol) in tetrahydrofuran was slowly added to the above reaction solution. After the 5R starting material was consumed, the 5S isomer starting material remained. The reaction solution was frozen to below -60 °C overnight, and >95% of the by-product (PPh3O-DEADH2) was filtered off, then methyl tert-butyl ether was added to extract twice, and the organic layer was dried and rotary evaporated to give the intermediate 2 (equivalent product 143.99 g, yield 92%) with an isomer content of 0.13% by HPLC.

[0038] Third step:

[0039] Intermediate 2 (reduced weight 140 g, 373.86 mmol) was dissolved in ethanol (700 ml). The mixture was purged with nitrogen and palladium on carbon (10% wt, 14 g) was added. The reaction mixture was then saturated with a hydrogen atmosphere. After stirring at room temperature for 16 h, the mixture was filtered through a pad of celite which was washed thoroughly with ethanol. The filtrate was concentrated and dissolved in dichloromethane and methanesulfonic acid (395.25 g, 411.25 mmol) was slowly added to the reaction. After stirring at room temperature for 0.5 h, the mixture was filtered and dried to give the product (118.23 g, 94% yield). HPLC indicated 99.1% product and 0.05% isomer.

[0040] The above examples describe the basic principles, main features and advantages of the present application. It should be understood by those skilled in the art that the present application is not limited by 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 synthesis 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-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as raw material, reacting in an organic solvent in the presence of a Lewis acid catalyst and a reducing agent at an ultra-low temperature to obtain intermediate 1; Step 2: reacting intermediate 1, a phosphine ligand and azodicarboxylate in an organic solvent to obtain intermediate 2; Step 3: mixing intermediate 2 with methanesulfonic acid in the presence of a metal catalyst to obtain (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate through hydrogenolysis.

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 reducing agent is selected from sodium borohydride, sodium borohydride acetate or sodium cyanoborohydride; and the Lewis acid catalyst is triphenyl boron.

3. 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-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate to the reducing agent is 1:1.5-3.

4. 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 phosphine ligand is selected from triphenyl phosphine, trimethyl phosphine, tributyl phosphine and diphenyl methyl phosphine; and the azodicarboxylate is selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate.

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 the phosphine ligand to the azodicarboxylate is 1:

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 3, the catalyst is selected from palladium hydroxide, 10% palladium on carbon, 5% palladium on carbon or platinum dioxide.

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