A process for the preparation of a key intermediate of a JAK kinase inhibitor

Abstract

The application provides a preparation method of a JAK kinase inhibitor key intermediate (3aR, 5S, 6aS)-5-(methylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-formic acid tert-butyl ester methanesulfonic acid salt, and belongs to the field of pharmaceutical intermediates. Cis-5-oxohexahydrocyclopenta[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester is used as raw material to react with a methylamine equivalent to obtain an intermediate A; then a reduction reaction occurs in sodium metal and isopropyl alcohol to obtain a crude product, L-DBTA is added to form a salt, isomer is removed, and after re-ionization and methanesulfonic acid salt formation, a pure product is obtained. The method greatly shortens the reaction steps, reduces the raw material cost, and is simple and reliable in process, and easy to industrialized production.

Description

Technical Field

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

[0002] Janus kinase (JAK) is a class of intracellular non-receptor tyrosine kinases and a very important drug target. Some research has 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 to treat diseases such as rheumatoid arthritis, polycythemia vera, psoriasis, essential thrombocythemia, and myelofibrosis. Although a series of JAK inhibitors have been disclosed, there is still room for improvement in efficacy and safety among these marketed or investigational JAK inhibitors. New JAK inhibitors with better efficacy and safety are still needed to provide better treatment and reduce adverse reactions in patients. US14365497 discloses a novel pyrrole six-membered heteroaryl ring derivative compound and found that compounds with this structure exhibit excellent effects and benefits.

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

[0004]

[0005] 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 a low atom utilization rate 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.

[0006] The synthetic methods reported in US2014336207 and US2016102098, and the synthetic routes are as follows:

[0007]

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

[0009] To overcome the aforementioned technical deficiencies, this invention provides a scale-up preparation method for (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 as a starting material, it reacts with an equivalent of methylamine to obtain intermediate A; subsequently, a reduction reaction occurs in metallic sodium and isopropanol to obtain the crude product. The crude product is then salted by adding L-DBTA to remove isomers, and the pure product is obtained after re-salting. This method significantly shortens the reaction steps, reduces raw material costs, and is simple, reliable, and 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.

[0010] The preparation methods of (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate described in this invention all use cis-5-oxohexahydrocyclopentadieno[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester and methylamine as raw materials, and are represented by the following reaction equation:

[0011] The preparation method of the technical solution described in this invention includes the following steps:

[0012] Step 1: Using cis-5-oxohexahydrocyclopentadienyl[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester and N-methyl-N,O-bis(trimethylsilyl)carbamic acid as raw materials, an organic solvent was used to react with a catalyst to obtain intermediate A;

[0013] Furthermore, in the above technical solution, the organic solvent is selected from acetic acid or a mixture of acetic acid with acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide, and tetrahydrofuran. Furthermore, in the above technical solution, the molar ratio of cis-5-oxohexahydrocyclopentadieno[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester to N-methyl-N,O-bis(trimethylsilyl)carbamate is 1:1-2.

[0014] Furthermore, in the above technical solution, 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.

[0015] During the experiment, when trifluoroacetic acid was used, a large amount of deBoc salt formation byproducts were generated, preventing the further formation of imines. Optimization revealed that using B(C6F5)3 in acetic acid could solve this problem.

[0016] Step 2: Intermediate A and sodium metal react in isopropanol to give (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester; then L-DBTA and ethyl acetate are added to form a salt, and the mixture is filtered to obtain intermediate B.

[0017] 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 to 5S is 6-8 / 92-94, with a yield greater than 95%.

[0018] Furthermore, in the above technical solution, 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 salt formation of the reduction product with L-DBTA in ethyl acetate solution can effectively remove other isomers. After purification, the 5R ratio is reduced to below 0.03, and the 5S ratio is increased to above 99.5%.

[0019] Step 3: After adding alkali to the intermediate B in an organic solvent to release it, methanesulfonic acid is added to form a salt to obtain (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate.

[0020] Furthermore, in the above technical solution, the organic solvent is selected from dichloromethane and 1,2-dichloroethane.

[0021] Furthermore, in the above technical solution, the alkali is selected from sodium hydroxide or potassium hydroxide.

[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 shows the 1H NMR spectrum of the product (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester methanesulfonate;

[0024] Figure 2 Example 1 shows the HPLC chromatogram of the product (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 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] 14.87 g (66 mmol) of cis-5-oxohexahydrocyclopentadieno[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester, N-methyl-N,O-bis(trimethylsilyl)carbamate (15.96 g (72.6 mmol), tris(pentafluorophenyl)borane (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 mixture, and the mixture was extracted twice. The extract was washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was then slurried with MTBE and heptane (v / v = 1 / 5) to give 14.63 g of intermediate A, with a yield of 93%.

[0028] Under nitrogen protection and controlled temperature of 0°C, metallic sodium (6.75 g, 293.7 mmol) was added in portions to a solution of intermediate A (14 g, 58.7 mmol) / n-propanol (70 mL). The reaction mixture was stirred at 40-45°C for 3 hours. After the reaction was completed, the reaction mixture was cooled to 0°C, the reaction was carefully quenched, and the mixture was extracted twice with 120 mL of ethyl acetate (60 mL * 2). The mixture was washed with saturated brine, and a solution of L-(-)-dibenzoyl tartaric acid monohydrate (24.31 g, 64.6 mmol) / ethyl acetate (90 mL) was added to the above solution. The mixture was then refluxed for 1 hour. After cooling and precipitation, the mixture was filtered to obtain 28.81 g of crude intermediate B.

[0029] A 2N sodium hydroxide aqueous solution was added to the above intermediate B (28.81 g) / dichloromethane (150 mL) solution to adjust the pH to 9-10. The mixture was stirred at room temperature for 3 hours. The pH was checked again and found to be alkaline. After the reaction was complete, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and then methanesulfonic acid (6.21 g, 64.61 mmol) was added. After stirring at room temperature for 0.5 hours, the mixture was filtered again and dried to obtain 14.61 g of product. The overall yield of the two steps was 74%. The HNMR results were as follows: Figure 1 HPLC 98.8%, analytical result is Figure 2 The HPLC peaks were consistent with those of the standard sample.

[0030] Example 2

[0031] 1 kg (4.44 mol) of cis-5-oxohexahydrocyclopentadieno[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester, N-methyl-N,O-bis(trimethylsilyl)carbamate (1.56 kg, 7.10 mol), tris(pentafluorophenyl)borane (36.35 g, 0.071 mol), and acetic acid (1.07 kg, 17.76 mol) were added to 5 L of acetonitrile, and the mixture was stirred at 25-35 °C for 4 hours. 5 L of water and 12 L of ethyl acetate were added to the reaction mixture, and the mixture was extracted twice. The extract was washed with saturated sodium carbonate, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was then slurried with MTBE and heptane (v / v = 1 / 5) to give 0.97 kg of intermediate A, with a yield of 92%.

[0032] Under nitrogen protection and controlled temperature of 0°C, metallic sodium (0.61 kg, 26.46 mol) was added in portions to a solution of intermediate A (0.9 kg, 3.78 mol) / isopropanol (3 L). The reaction mixture was stirred at 40-45°C for 3 hours. After the reaction was completed, the reaction mixture was cooled to 0°C, the reaction was carefully quenched, and the mixture was extracted twice with 3 L of ethyl acetate (1.5 L * 2). The mixture was 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 solution. The mixture was then refluxed for 1 hour. After cooling and precipitation, the mixture was filtered to obtain 1.9 kg of crude intermediate B.

[0033] A 2N sodium hydroxide aqueous solution was added to the above intermediate B (1.9 kg) / dichloromethane (11 L) solution, the pH was adjusted to 9-10, and the mixture was stirred at room temperature for 3 hours. The pH was checked again and found to be alkaline. After the reaction was completed, the organic layer was washed with water and saturated brine, dried with anhydrous sodium sulfate, filtered, and methanesulfonic acid (0.4 kg, 4.16 mol) was added. After stirring at room temperature for 0.5 hours, the mixture was filtered and dried to obtain 0.97 kg of product. The overall yield of the two steps was 76.4%; HPLC analysis showed a yield of 99.1%.

[0034] 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 preparing (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-5-oxohexahydrocyclopentadienyl[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester and N-methyl-N,O-bis(trimethylsilyl)carbamate as raw materials, the catalyst tri(pentafluorophenyl)borane was added to an organic solvent to react and obtain intermediate A; Step 2: Intermediate A and metallic sodium react in isopropanol to give (3aR,5S,6aS)-5-(methylamino)hexahydrocyclopentano[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester; then L-DBTA and ethyl acetate are added to form a salt, and the mixture is filtered to obtain intermediate B; Step 3: After adding alkali to the intermediate B in an organic solvent to release it, methanesulfonic acid is added to form a salt 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 organic solvent is selected from acetic acid or a mixture of acetic acid with acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide and tetrahydrofuran.

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-oxohexahydrocyclopentadieno[C]pyrrole-2(1H)-carboxylic acid tert-butyl ester to N-methyl-N,O-bis(trimethylsilyl)carbamate is 1:1-2.

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 first step, the molar ratio of catalyst to N-methyl-N,O-bis(trimethylsilyl)carbamate is 0.01-0.05:

1.

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 metallic sodium to intermediate A is 5-8:

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 second step, the molar ratio of intermediate A to L-DBTA is 1:1.1-1.

2.

7. 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 organic solvent is selected from dichloromethane and 1,2-dichloroethane.

8. 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 alkali is selected from sodium hydroxide or potassium hydroxide.

Images