A process for the synthesis of a key intermediate of a jak kinase inhibitor

Abstract

The application provides a method for preparing (3aR,5S,6aS)-5-methylaminohexahydrocyclopenta[c]pyrrole-2(1H)-formic acid tert-butyl ester methyl sulfonate on a large scale and belongs to the field of pharmaceutical intermediates. Cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester and a reducing reagent are used as raw materials to react in an organic solvent to obtain an intermediate 1; then photo-elongation reaction is carried out with CH 3 NHCbz to obtain an intermediate 2; finally, palladium-carbon catalytic hydrogenation is carried out, and then formic acid sulfonic acid is salted to obtain (3aR,5S,6aS)-5-methylaminohexahydrocyclopenta[c]pyrrole-2(1H)-formic acid tert-butyl ester methyl sulfonate product. The method reduces the cost of raw materials, is simple and reliable, and is easy for industrial production, and provides a new reaction path for the synthesis of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-formic acid tert-butyl ester methyl sulfonate.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for synthesizing (3aR,5S,6aS)-5-methylaminohexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate, a key intermediate for JAK kinase inhibitors. Background Technology

[0002] As an important protein kinase, JAK3 can regulate the function of lymphocytes, macrophages, and mast cells. JAK3 inhibitors are expected to be involved in the treatment or prevention of diseases related to lymphocyte, macrophage, or mast cell function. Ruxolitinib (INCB-018424), a selective JAK2 inhibitor developed by INCYTE in collaboration with NOVARTIS, has received FDA approval and has been successfully launched on the market. Patent applications have disclosed a series of JAK inhibitors, including WO2001042246, WO2002000661, WO2009054941, and WO2011013785.

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

[0004] Currently, there are few published reports on the synthesis of the compound of this invention, (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate. The synthetic methods reported in US2014336207 and US2016102098 are as follows:

[0005]

[0006] The above methods involve expensive starting materials with insufficient market supply, making them unsuitable for industrial-scale production. Therefore, it is necessary to develop new synthesis processes to meet the ever-growing market demand.

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

[0008]

[0009] The above method requires potassium permanganate as a starting material, and the use of heavy metals causes serious environmental pollution. The third step requires palladium on carbon to remove benzyl groups, which has low atom utilization and is not suitable for industrial scale-up production. Therefore, it is necessary to develop new synthesis processes to meet the ever-growing market demand. Summary of the Invention

[0010] To overcome the above-mentioned technical defects, this invention provides a method for preparing (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate. Using cis-5-oxohexahydrocyclopentadieno[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester and a reducing agent as raw materials, the reaction is carried out in an organic solvent to obtain intermediate 1; then, a photo-electrophoretic reaction is performed with CH3NHCbz to obtain intermediate 2; finally, catalytic hydrogenation is carried out, followed by formic acid sulfonic acid salt formation to obtain the (3aR,5S,6aS)-5-methylaminohexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate product. This method reduces raw material costs, is simple and reliable, and is easy to industrialize, providing a new reaction route for the synthesis of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate.

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

[0012]

[0013] The preparation method of the technical solution described in this invention consists of three steps, specifically including the following steps:

[0014] Step 1: Using cis-tert-butyl 5-oxohexahydrocyclopentane[c]pyrrole-2(1H)-carboxylate as a raw material, the reaction was carried out in an organic solvent at ultra-low temperature 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 borohydride acetate, and sodium cyanoborohydride; the Lewis acid catalyst is triphenylboron (BPh3). During the reduction process, when only sodium borohydride is used at 0-20℃, the ratio of isomer products is 8 / 1-10 / 1, and separation is difficult due to the small difference in polarity between the two. Optimization revealed that adding triphenylboron and using sodium borohydride for reduction at ultra-low temperatures can increase the ratio of main to byproducts to over 30 / 1.

[0016] Furthermore, in the above technical solution, the molar ratio of cis-5-oxohexahydrocyclopentadienyl[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 azodicarboxylic acid ester 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 azodicarboxylic acid ester is selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate. The molar ratio of the phosphine ligand to the azodicarboxylic acid ester is 1:1.

[0020] Step 3: Intermediate 2 is mixed with methanesulfonic acid and hydrogenoly reacted in the presence of a metal catalyst to obtain (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[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 on carbon, 5% palladium on carbon, or platinum dioxide.

[0022] The method of this invention is simple, reliable, and easy to industrialize; it reduces the amount of isomers generated, increases the reaction yield, and significantly reduces the overall production cost compared to existing literature or patents, making the product more competitive in the market. Attached Figure Description

[0023] Figure 1 Example 1 is the product (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid.

[0024] ¹H NMR spectrum of tert-butyl methanesulfonate; Detailed Implementation

[0025] The present invention will be further illustrated below with reference to specific embodiments. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations 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.

[0026] Example 1

[0027]

[0028] first step:

[0029] Sodium borohydride (2.52 g, 66.6 mmol) was added in portions to a solution of cis-tert-butyl-5-oxohexahydrocyclopentane[c]pyrrole-2(1H)-carboxylate (5 g, 22.2 mmol) and triphenylboron (0.3 g, 1.24 mmol) in methanol (50 mL) at a controlled temperature of -78 °C. The temperature during the addition process did not exceed -65 °C. After the addition was complete, the mixture was stirred at this temperature for 1 h, quenched with water, and then the solvent was distilled off. The crude mixture was redissolved in EtOAc (50 mL) and washed successively with water, dilute hydrochloric acid, and brine. 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 a ratio of two isomers dr = 98.2 / 1.8.

[0030] Step Two:

[0031] 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-cyclopentyl[c]pyrrole-2-carboxylate (4.5 g, 19.8 mmol). 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. After the reaction of the 5R reactant was completed, the remaining 5S isomer reactant was detected. The reaction solution was frozen to below -60°C overnight. >95% of the byproduct (PPh3O-DIADH2) was removed by filtration. Then, methyl tert-butyl ether was added for extraction twice. The organic layer was dried by rotary evaporation and slurryed with methyl tert-butyl ether / isopropanol to obtain intermediate 2 (equivalent to 6.73g of product, yield 91%). The isomer content was 0.13% by HPLC.

[0032] Step 3:

[0033] Intermediate 2 (equivalent weight 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 hydrogen. After stirring at room temperature for 16 h, the mixture was filtered through a diatomaceous earth filter and thoroughly washed with methanol. The filtrate was concentrated and dissolved in dichloromethane. Methylsulfonic acid (0.177 g, 1.84 mmol) was slowly added to the reaction mixture, stirred at room temperature for 0.5 h, filtered, and dried to give the product (5.55 g, 95% yield). HPLC analysis showed that the product was 99.3% pure and contained 0.04% isomers.

[0034] Example 2

[0035] first step:

[0036] Sodium borohydride acetate (188.15 g, 887.76 mmol) was added in portions to a solution of cis-tert-butyl-5-oxohexahydrocyclopentane[c]pyrrole-2(1H)-carboxylate (100 g, 443.88 mmol) and triphenylboron (4.2 g, 17.35 mmol) in methanol (1000 mL) at a controlled temperature of -78 °C. The temperature during the portion additions did not exceed -65 °C. After the additions were complete, the mixture was stirred at this temperature for 1 h, quenched with water, and then the solvent was distilled off. The crude mixture was redissolved in EtOAc (500 mL) and washed successively with water, dilute hydrochloric acid, and brine. 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 a ratio of two isomers dr = 97.8 / 2.2.

[0037] Step Two:

[0038] 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-cyclopentyl[c]pyrrole-2-carboxylate (95 g, 417.95 mmol). Then, a tetrahydrofuran solution of DEAD (109.18 g, 626.93 mmol) was slowly added to the above reaction solution. After the 5R reactant was completely reacted, the remaining 5S isomer reactant was frozen to below -60°C overnight. Filtering removed >95% of the byproduct (PPh3O-DEADH2). Then, methyl tert-butyl ether was added for extraction twice. The organic layer was dried by rotary evaporation and then slurried with methyl tert-butyl ether / isopropanol to obtain intermediate 2 (equivalent to 143.99g of product, yield 92%). HPLC analysis showed that the isomer content was 0.13%.

[0039] Step 3:

[0040] Intermediate 2 (equivalent 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 hydrogen. After stirring at room temperature for 16 h, the mixture was filtered through a diatomaceous earth filter and thoroughly washed with ethanol. The filtrate was concentrated and dissolved in dichloromethane. Methylsulfonic acid (395.25 g, 411.25 mmol) was slowly added to the reaction mixture. 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 analysis showed that the product was 99.1% pure and the isomers were 0.05%.

[0041] 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 to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate, a key intermediate for JAK kinase inhibitors, characterized in that, Includes the following steps: Step 1: Using cis-tert-butyl 5-oxohexahydrocyclopentane[c]pyrrole-2(1H)-carboxylate as the raw material, the reaction was carried out in an organic solvent at ultra-low temperature in the presence of Lewis acid catalyst triphenylboron and a reducing agent to obtain intermediate 1; Step 2: Intermediate 1, phosphine ligand and azodicarboxylic acid ester react in an organic solvent to obtain intermediate 2; Step 3: Intermediate 2 is mixed with methanesulfonic acid and hydrogenoly reacted in the presence of a metal catalyst to obtain (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate.

2. The method for preparing (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate according to claim 1, characterized in that: In the first step, the reducing agent is selected from sodium borohydride, sodium borohydride acetate, or sodium cyanoborohydride.

3. The method for preparing (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate according to claim 1, characterized in that: In the first step, the molar ratio of cis-5-oxohexahydrocyclopentadienyl[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester to the reducing agent is 1:1.5-3.

4. The method for preparing (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate according to claim 1, characterized in that: In the second step, the phosphine ligand is selected from triphenylphosphine, trimethylphosphine, tributylphosphine, and diphenylmethoxyphosphine; the azodicarboxylic acid ester is selected from diethyl azodicarboxylate or diisopropyl azodicarboxylate.

5. The method for preparing (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate according to claim 1, characterized in that: In the second step, the molar ratio of the phosphine ligand to the azodicarboxylic acid ester is 1:

1.

6. The method for preparing (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate according to claim 1, characterized in that: In the third step, the metal catalyst is selected from palladium hydroxide, 10% palladium on carbon, 5% palladium on carbon, or platinum dioxide.

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