CN117534603A - A kind of preparation method of tofacitinib intermediate - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a tofacitinib intermediate. The preparation method comprises the following steps: n-hydroxysuccinimide and cyanoacetic acid react under condensing agent conditions to form cyanoacetic acid-N-hydroxysuccinimide ester, and the compound of formula 3 is a tofacitinib intermediate. The condensing agent comprises at least one of N, N' -carbonyl diimidazole, dicyclohexylcarbodiimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride. The invention provides a novel method for synthesizing a tofacitinib intermediate, which has better yield and is beneficial to the preparation of tofacitinib bulk drug.

Description

A kind of preparation method of tofacitinib intermediate

Technical field

The invention belongs to the technical field of pharmaceutical chemical industry, and specifically relates to a preparation method of tofacitinib intermediate.

Background technique

Tofacitinib is a drug for the treatment of rheumatoid arthritis developed by the American pharmaceutical company Pfizer. Xeljanz, a Janus kinase inhibitor, is used for adult patients with moderately to severely active rheumatoid arthritis (RA) who have an inadequate response to or are intolerant to methotrexate therapy. On November 6, 2012, the U.S. Food and Drug Administration (FDA) and Pfizer jointly announced that tofacitinib citrate was approved for the treatment of moderately to severely active rheumatoid joints in patients with inadequate response to or intolerance to methotrexate therapy. rheumatoid arthritis (RA) in adults. . Xeljanz can be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). Its structural formula is as follows:

Patent documents such as WO2008029237A2, CN105348287A, CN108640921A and other patent documents mention a synthesis method of tofacitinib, which is synthesized from the following intermediate formula 4 and active ester formula 3:

The synthesis method of the active ester of Formula 3 has not been reported in domestic and foreign literature and patents. This active ester raw material is used in the final step of the synthesis of APIs, and its quality directly affects the quality of tofacitinib APIs. Therefore, it is urgent to provide a simple and efficient synthesis method of active esters.

Contents of the invention

In view of the above shortcomings of the prior art, the purpose of the present invention is to provide a preparation method of tofacitinib intermediate with better yield, and the intermediate is beneficial to the preparation of tofacitinib API.

In order to achieve the above objects and other related objects, the present invention provides the following technical solutions:

A preparation method of tofacitinib intermediate, the preparation route is as follows:

The preparation method includes the following steps:

The compound of formula 1 and the compound of formula 2 react under condensing agent conditions to form the compound of formula 3, and the compound of formula 3 is an intermediate of tofacitinib.

In one embodiment of the present invention, the preparation further includes the following steps: under protective gas conditions, add the compound of formula 1 and the compound of formula 2 into the reaction vessel, control the temperature for the first time, then add the condensing agent, and again A temperature-controlled reaction is performed to obtain a crude product of the compound of Formula 3, which is filtered and purified to obtain a refined product of the crude product of the compound of Formula 3.

In one embodiment of the present invention, the temperature for the first temperature control is less than 25°C, and the temperature for the second temperature control is 0˜65°C. The temperature for temperature control again is preferably 15 to 25°C.

In one embodiment of the present invention, the preparation further includes the following steps: the steps of filtration and purification are: filter first, then rinse with tetrahydrofuran, evaporate the filtrate to dryness under reduced pressure, then add methylene chloride, beat, and filter. , a filter cake is obtained, and the filter cake is dried under reduced pressure to obtain a refined product of the crude product of the compound of formula 3.

In one embodiment of the present invention, the preparation further includes the following steps: under protective gas conditions, first add a solvent to the reaction vessel, and then add the compound of formula 1 and the compound of formula 2; the solvent includes tetrahydrofuran, N , at least one of N'-dimethylformamide and dichloromethane. The preferred solvent is tetrahydrofuran.

In one embodiment of the invention, the condensing agent includes N,N'-carbonyldiimidazole, dicyclohexylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide At least one of the amine hydrochlorides. Preferably it contains dicyclohexylcarbodiimide.

In one embodiment of the present invention, the equivalent of the condensation agent is 1.0 to 3.0, and the equivalent is the ratio of the amount of the condensation agent to the amount of the compound of Formula 1, which is 1.0 to 3.0. Preferably the equivalent weight of the condensing agent is 1.0. When the condensation agent is excessive, it will degrade into DCU (dicyclohexyl urea) in the product, which is difficult to remove. When there is too little condensation agent, there will be more raw material residues, affecting the yield.

The beneficial effects of the present invention are:

(1) This application requires fewer steps to prepare intermediates, shortens the synthesis time, and can obtain high-yield intermediates.

(2) Intermediates also play an important role in the pharmaceutical process. The choice of intermediates directly determines the efficiency and yield of the entire synthesis process. Intermediates help speed up the reaction, reduce the production of side reaction products, and optimize reaction conditions.

(3) The intermediates prepared in this application can also be used as raw materials for pharmaceutical synthesis, and can also be beneficial to the preparation of standard intermediates of cyanoacetic acid-N-hydroxysuccinimide ester.

(4) The added amounts of the compound of Formula 1, the compound of Formula 2 and the condensation agent of the present invention can be selected at the kg level or the g level. The preparation method of this application is suitable for large-scale and small-scale preparation of tofacitinib intermediates.

The invention provides a new method for synthesizing tofacitinib intermediate, which has a better yield, and the intermediate is beneficial to the preparation of tofacitinib raw material drug.

Description of drawings

The drawings are used to provide a further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention.

In the attached picture:

Figure 1 is a schematic diagram of ¹ H NMR spectrum of cyanoacetic acid-N-hydroxysuccinimide ester of the present invention.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the scope of protection of the present invention.

Unless otherwise specified, the reagents used in the examples can be easily obtained from commercial companies or homemade.

The invention provides a preparation method of tofacitinib intermediate, and the preparation route is as follows:

The compound of formula 1 is N-hydroxysuccinimide, the compound of formula 2 is cyanoacetic acid, and the compound of formula 3 is cyanoacetate-N-hydroxysuccinimide ester. The compound of formula 3 is an intermediate of tofacitinib.

This application performs the large-scale and small-scale preparation of tofacitinib intermediates as described below.

Large-scale preparation of tofacitinib intermediates:

Example 1

A preparation method of tofacitinib intermediate, including the following steps:

Table 1

compound Add parameters Cyanoacetic acid 1.48Kg, 17.4mol N-Hydroxysuccinimide 2Kg，17.4mol dicyclohexylcarbodiimide 3.59Kg, 17.4mol

Referring to the above Table 1, vacuum 50L tetrahydrofuran into a 100L glass kettle, protect it with nitrogen, add cyanoacetic acid and N-hydroxysuccinimide with stirring. Control the temperature to less than 25°C and add 20L of tetrahydrofuran solution containing dicyclohexylcarbodiimide. After the addition is completed, react at 15-25°C for 3 hours to obtain the crude product of cyanoacetic acid-N-hydroxysuccinimide ester. Filter to obtain filter cake 1. Elute filter cake 1 with 10L tetrahydrofuran to obtain filtrate. The filtrate was evaporated to dryness under reduced pressure at 40°C, then 17L of methylene chloride was added, beaten at 10-20°C for 2 hours, and filtered to obtain filter cake 2. The filter cake 2 was dried under reduced pressure at 50°C and dried to obtain 2.32Kg of white solid, which was the refined product of cyanoacetic acid-N-hydroxysuccinimide ester, with a yield of 73.5%.

The ¹ H NMR spectrum of cyanoacetate-N-hydroxysuccinimide ester is shown in Figure 1. The hydrogen nuclear magnetic resonance spectrum data is ¹ H NMR (400MHz, DMSO-d6) δ2.85 (4H, s), δ4.67 ( 2H, s).

Small-scale preparation of tofacitinib intermediates:

Example 2

A preparation method of tofacitinib intermediate, including the following steps:

Table 2

compound Add parameters Cyanoacetic acid 1.48g, 17.4mmol N-Hydroxysuccinimide 2g, 17.4mmol dicyclohexylcarbodiimide 3.59g, 17.4mmol

Referring to the above Table 2, vacuum 50 mL of tetrahydrofuran into a 100 mL reaction bottle, protect it with nitrogen, and add cyanoacetic acid and N-hydroxysuccinimide with stirring. Control the temperature to less than 25°C and add 20 mL of a tetrahydrofuran solution containing dicyclohexylcarbodiimide. After the addition is completed, react at 15-25°C for 3 hours to obtain the crude product of cyanoacetic acid-N-hydroxysuccinimide ester. Filter to obtain filter cake three. Elute filter cake three with 10 mL of tetrahydrofuran to obtain the filtrate. The filtrate was evaporated to dryness under reduced pressure at 40°C, then 17 mL of methylene chloride was added, beaten at 10-20°C for 2 hours, and filtered to obtain filter cake 4. The filter cake 4 was dried under reduced pressure at 50°C and dried to obtain 2.32g of white solid, which was the refined product of cyanoacetic acid-N-hydroxysuccinimide ester, with a yield of 72%.

Result analysis: From the above Examples 1 to 2, it can be seen that the preparation method of the present application can obtain better yields in both small-scale and large-scale preparations, and is suitable for small-scale experiments and/or large-scale production.

In addition, N,N’-carbonyldiimidazole and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride can also be used as the condensation agent. When 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is used as the condensation agent, the by-products are removed by washing with water, dichloromethane is selected as the reaction solvent, and the post-treatment is to wash with water and then concentrate the organic phase. . When N,N’-carbonyldiimidazole is used as the condensing agent, select solid and add it in batches. The by-products are removed by washing with water, the reaction solvent is methylene chloride, and the post-processing is by washing with water and then concentrating the organic phase.

Comparative example 1

A preparation method of tofacitinib intermediate, including the following steps:

table 3

compound Add parameters Cyanoacetic acid 662mg, 7.8mmol N-Hydroxysuccinimide 1.0g, 8.7mmol dicyclohexylcarbodiimide 2.17g, 10.5mmol

Referring to the above Table 3, under nitrogen protection, add 20 mL of N,N'-dimethylformamide into a 50 mL three-necked flask, add cyanoacetic acid and N-hydroxysuccinimide with stirring. Add dicyclohexylcarbodiimide while controlling the temperature to less than 25°C. After the addition is completed, react at 15-25°C for 4 hours to obtain the crude product of cyanoacetic acid-N-hydroxysuccinimide ester. Filter and discard the filter cake to obtain filtrate two. Evaporate filtrate two to dryness under reduced pressure at 60°C, then add 6 mL of methylene chloride, beat at 10-20°C for 2 hours, and filter to obtain filter cake five. The filter cake 5 was dried under reduced pressure at 50°C and dried to obtain 407 mg of white solid, which was the refined product of cyanoacetic acid-N-hydroxysuccinimide ester, with a yield of 28.7%.

Result analysis: Compared with Example 2, in Comparative Example 1, the reaction solvent was changed from tetrahydrofuran to N,N'-dimethylformamide, and the subsequent purification solvent was not changed. It was found that the yield of Comparative Example 1 and Example 2 was the same. The rate can vary by 43.3%. Possibly due to the higher boiling point of N,N’-dimethylformamide, it is easy to remain in the crude product, resulting in greater product loss in the subsequent beating and purification steps.

Comparative example 2

A preparation method of tofacitinib intermediate, including the following steps:

Table 4

Referring to the above Table 4, under nitrogen protection, add 10 mL of methylene chloride into a 50 mL three-necked flask, stir and add cyanoacetic acid and N-hydroxysuccinimide. Control the temperature to less than 25°C and add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride. After the addition is completed, react at 15-25°C for 16 hours to obtain the crude product of cyanoacetic acid-N-hydroxysuccinimide ester. Wash twice, use 20 ml of water for each wash, and dry the organic phase with an appropriate amount of anhydrous sodium sulfate. Filter, and the filtrate is evaporated to dryness under reduced pressure at 35°C to obtain 732 mg of off-white solid, which is the refined product of cyanoacetic acid-N-hydroxysuccinimide ester, with a yield of 34.3%.

Result analysis: During the post-treatment water washing process, the cyanoacetate-N-hydroxysuccinimide ester partially reacted with water, degraded back to the raw material and was taken away with the water phase. The yield of the compound dropped significantly, and the yield could vary by 39.2%.

The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the foregoing embodiments. Modify the recorded technical solutions, or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims (7)

1. The preparation method of the tofacitinib intermediate is characterized by comprising the following steps of:

the preparation method comprises the following steps:

the compound of formula 1 and the compound of formula 2 react under condensing agent conditions to form a compound of formula 3, wherein the compound of formula 3 is a tofacitinib intermediate.

2. A process for the preparation of a tofacitinib intermediate according to claim 1, wherein the condensing agent comprises at least one of N, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.

3. The process for the preparation of a tofacitinib intermediate according to claim 1, characterized in that the ratio of the amount of substance of the condensing agent to the amount of substance of the compound of formula 1 is 1.0 to 3.0.

4. A process for the preparation of a tofacitinib intermediate according to claim 1, comprising the steps of: under the condition of protective gas, adding the compound of the formula 1 and the compound of the formula 2 into a reaction container, controlling the temperature for the first time, adding the condensing agent, controlling the temperature again for reaction, obtaining a crude product of the compound of the formula 3, filtering, and purifying to obtain a refined product of the compound of the formula 3.

5. The process for the preparation of a tofacitinib intermediate according to claim 4, characterized in that the steps of filtration and purification are: filtering, eluting with tetrahydrofuran, evaporating the filtrate under reduced pressure, adding dichloromethane, pulping, filtering to obtain filter cake, and drying the filter cake under reduced pressure to obtain refined product of the compound of formula 3.

6. The process for the preparation of a tofacitinib intermediate according to claim 4, wherein the solvent is added to the reaction vessel under protective gas conditions before the compound of formula 1 and the compound of formula 2 are added; the solvent comprises at least one of tetrahydrofuran, N' -dimethylformamide and dichloromethane.

7. The process for preparing a tofacitinib intermediate according to claim 4, wherein the temperature of the first temperature control is less than 25 ℃ and the temperature of the second temperature control is 0-65 ℃.