Synthesis method of key intermediate of JAK kinase inhibitor

Abstract

The invention provides an amplified preparation method of (3aR, 5S, 6aS)-5-methylaminohexahydrocyclopenta [c] pyrrol-2 (1H)-tert-butyl formate mesylate, and belongs to the field of medical intermediates. The preparation method comprises the following steps: by taking cis-5-oxohexahydrocyclopenta [C] pyrrol-2 (1H)-carboxylic acid tert-butyl ester and a reducing reagent as raw materials, reacting in an organic solvent to obtain an intermediate 1; then carrying out a Mitsunobu reaction with CH < 3 > NHCbz to obtain an intermediate 2; and finally, carrying out palladium-carbon catalytic hydrogenation, and salifying formic acid and sulfonic acid to obtain a (3aR, 5S, 6aS)-5-methylaminohexahydrocyclopenta [c] pyrrol-2 (1H)-tert-butyl formate mesylate product. According to the method, the raw material cost is reduced, the process is simple and reliable, industrial production is easy, and a new reaction path is provided for synthesis of (3aR, 5S, 6aS)-5-(methylamino) hexahydrocyclopenta [c] pyrrol-2 (1H)-tert-butyl formate mesylate.

Description

Technical Field

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

[0002] As an important protein kinase, JAK3 can regulate the functions of lymphocytes, macrophages and mast cells. It is expected 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 collaboration with NOVARTIS has been approved by the FDA and successfully launched on 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 functions.

[0004] 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. The synthesis methods reported in US2014336207 and US2016102098 are as follows:

[0005]

[0006] In the above methods, the starting raw materials are expensive and in short supply on the market, which is not suitable for industrial scale-up production. Therefore, it is necessary to develop new synthesis processes to meet the growing market demand.

[0007] Patent 2020116436020 discloses a method for preparing (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate. The synthetic route is as follows:

[0008]

[0009] In the above method, potassium permanganate is required as the starting material, and 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. Summary of the invention

[0010] In order to overcome the above technical defects, the present invention provides a method for preparing (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 and a reducing agent are used as raw materials to react in an organic solvent to obtain intermediate 1; then, a Mitsunobu reaction is carried out with CH3NHCbz to obtain intermediate 2; finally, catalytic hydrogenation is carried out, and then formic acid sulfonic acid is used to form a salt to obtain (3aR, 5S, 6aS)-5-methylaminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate product. The method reduces the cost of raw materials, has a simple and reliable process, and is easy for industrial production, and provides a new reaction pathway for the synthesis of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate.

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

[0012]

[0013] The preparation method of the technical solution of the present invention is divided into three steps, specifically including the following steps:

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

[0015] Furthermore, in the above technical solution, the reducing agent is selected from sodium borohydride, sodium acetic acid borohydride and sodium cyanoborohydride; the Lewis acid catalyst is triphenylboron (BPh3). In the reduction process of the reaction, when only sodium borohydride is used for reduction at 0-20°C, the ratio of isomer products is 8 / 1-10 / 1. Since the polarity difference between the two is very small, separation is more difficult. After optimization, it was found that: by adding triphenylboron and reducing with sodium borohydride at ultra-low temperature, the ratio of main and side products can be increased to more than 30 / 1.

[0016] Furthermore, 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: Intermediate 1, phosphine ligand and azodicarboxylate react in an organic solvent to obtain intermediate 2.

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

[0019] Furthermore, 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: Intermediate 2 is mixed with methanesulfonic acid, and subjected to hydrogenolysis reaction 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] Furthermore, in the above technical solution, the catalyst is selected from palladium hydroxide, 10% palladium carbon, 5% palladium carbon or platinum dioxide.

[0022] 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

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

[0024] 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.

[0025] Example 1

[0026]

[0027] first step:

[0028] Under -78°C, sodium borohydride (2.52 g, 66.6 mmol) was added in batches to a solution of cis-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (5 g, 22.2 mmol) and triphenylborane (0.3 g, 1.24 mmol) in methanol (50 mL) in a controlled temperature range of -65°C. After the addition was complete, the mixture was stirred and reacted for 1 h, quenched with water, and then the solvent was distilled. The crude mixture was redissolved in EtOAc (50 mL) and washed with water, dilute hydrochloric acid, and brine in sequence. The organic layer was dried over Na2SO4, filtered and concentrated to provide tert-butyl (3aR,5R,6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (4.99 g, 99%) as a colorless oil with two isomer ratio dr = 98.2 / 1.8.

[0029] Step 2:

[0030] Under nitrogen protection at 15-20°C, triphenylphosphine (10.39 g, 39.6 mmol) and benzyl methylcarbamate (3.6 g, 21.78 mmol) were added to a tetrahydrofuran solution of tert-butyl (3aR, 5R, 6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (4.5 g, 19.8 mmol), and then a tetrahydrofuran solution of DIAD (8.01 g, 39.6 mmol) was slowly added to the above reaction solution. The reaction solution was stirred at room temperature for 4 hours, and the reaction of the detection system 5R raw material was completed, and the 5S isomer raw material remained. The reaction solution was frozen below -60°C overnight, and >95% of the by-product (PPh3O-DIADH2) was filtered out. Then, methyl tert-butyl ether was added and extracted twice. The organic layer was dried and spin-dried, and methyl tert-butyl ether / isopropanol was used for slurrying to obtain intermediate 2 (containing 6.73 g of product, yield 91%). HPLC detection of isomers was 0.13%.

[0031] Step 3:

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

[0033] Example 2

[0034] first step:

[0035] Under -78°C, sodium borohydride acetate (188.15 g, 887.76 mmol) was added in batches to a solution of cis-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (100 g, 443.88 mmol) and triphenylboron (4.2 g, 17.35 mmol) in methanol (1000 mL). The temperature did not exceed -65°C during the batch addition. After the addition was completed, the mixture was stirred and reacted for 1 h, quenched with water, and then the solvent was distilled. The crude mixture was redissolved in EtOAc (500 mL) and washed with water, dilute hydrochloric acid, and brine in sequence. The organic layer was dried over Na2SO4, filtered and concentrated to provide tert-butyl (3aR,5R,6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (98.87 g, 98%) as a colorless oil with two isomer ratio dr = 97.8 / 2.2.

[0036] Step 2:

[0037] Under nitrogen protection at 15-20°C, trimethylphosphine (47.70 g, 626.93 mmol) and benzyl methylcarbamate (82.85 g, 501.54 mmol) were added to a tetrahydrofuran solution of tert-butyl (3aR, 5R, 6aS)-5-hydroxy-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (95 g, 417.95 mmol), and then a tetrahydrofuran solution of DEAD (109.18 g, 626.93 mmol) was slowly added to the above reaction solution. After the reaction of the 5R raw material of the detection system is completed, the 5S isomer raw material remains. The reaction solution is frozen below -60°C overnight, and >95% of the by-product (PPh3O-DEADH2) is filtered out. Then, methyl tert-butyl ether is added and extracted twice. The organic layer is dried and spin-dried, and methyl tert-butyl ether / isopropanol is used for slurrying to obtain intermediate 2 (containing 143.99 g of product, yield 92%). HPLC detection of the isomer is 0.13%.

[0038] Step 3:

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

[0040] 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 key intermediate of JAK kinase inhibitor A method for synthesizing tert-butyl (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate methanesulfonate, characterized in that: The steps include: The first step: using cis-tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as a raw material, reacting at ultra-low temperature in an organic solvent in the presence of a Lewis acid catalyst and a reducing agent to obtain intermediate 1; Step 2: Intermediate 1, phosphine ligand and azodicarboxylate react in an organic solvent to obtain intermediate 2; Step 3: Intermediate 2 is mixed with methanesulfonic acid, and subjected to hydrogenolysis reaction 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.

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

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 the reducing agent is 1:1.5-3.

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 second step, the phosphine ligand is selected from triphenylphosphine, trimethylphosphine, tributylphosphine and diphenylmethoxyphosphine; and the azodicarboxylate is selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate.

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 the phosphine ligand to the azodicarboxylate is 1:

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

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