A preparation method of upadacitinib intermediate WP3

Abstract

The present invention belongs to the technical field of organic synthesis, and specifically discloses a method for preparing an upadacitinib intermediate WP3, comprising the following steps: using an ethanol / water mixed solution as a solvent, under a nitrogen range, heating a compound WP2 under the action of 10% palladium carbon, ammonium formate and hydrochloric acid to react, and after the reaction is completed, post-processing to obtain an intermediate WP3. The original research adopts a high-risk process for pressurized hydrogenation, which has high requirements for factory hardware. The present invention solves the limitation of high-pressure equipment by transfer hydrogenation. The present invention can effectively remove the above-mentioned impurities in the compound WP3 step through the free base separation operation of the compound WP3, and can well control the related substances in the API step without going through a refining process, thereby reducing the process cost. The present invention can also remove the pigments generated by the process through the free base separation operation of the compound WP3, thereby controlling the color of the upadacitinib API to off-white, and this color gradation control is much higher than the color control standard of the original research raw material drug, and improves product safety by controlling pigment impurities.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, relates to the preparation of an upadacitinib intermediate, and specifically relates to a method for preparing an upadacitinib intermediate 8-((3R, 4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine dihydrochloride. Background Art

[0002] Upadacitinib is a selective JAK inhibitor developed by Abbvie. The chemical name of Upadacitinib is (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-A]pyrrolo[2,3-E]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-amide, molecular formula: C17H19F3N6O, molecular weight: 380.37, CAS: 1310726-60-3.

[0003] The drug was approved by the U.S. FDA in August 2019 for the treatment of moderately to severely active rheumatoid arthritis in adults who have a poor response or intolerance to one or more TNF inhibitors. In addition, the new drug has also been used in multiple phase III clinical trials to treat a variety of inflammatory diseases such as atopic dermatitis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis and Crohn's disease. Therefore, upadacitinib will have broad commercial value, and its API will also have huge industrial value.

[0004] During the hydrogenation process of upadacitinib intermediate 8-((3R, 4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine dihydrochloride (WP3), the solvent ethanol is converted into acetaldehyde under the action of a catalyst. Acetaldehyde and compound WP3 are easily reduced and aminated to produce a series of ethyl impurities, which are finally converted into impurities of upadacitinib API through derivatization. The removal of this series of impurities is the key to the impurity control of upadacitinib process.

[0005] The synthesis of the key intermediate WP3 is reported in Chinese patent CN108368121A. The process uses pressurized hydrogenation to remove Cbz protection:

[0006]

[0007] However, this method has the following defects: 1) Patent CN108368121A uses a high-risk process of pressurized hydrogenation (H2, 20psig) to prepare WP3, which has high requirements for factory hardware and requires professional workshops and production lines; 2) WP3 is a key intermediate in the synthesis of upadacitinib. During the reaction, ethanol will be converted into acetaldehyde under catalysis, and acetaldehyde will further react with WP3 to produce a series of acetyl impurities. The patent reports that deprotection of Cbz requires another 16 hours of reaction under pressurized conditions. Long-term pressurized hydrogenation will bring the risk of excessive growth of impurities, and the control of this series of impurities is related to the quality of upadacitinib API; 3) During the post-treatment process of the deprotection reaction of Cbz, salt formation and solid separation are carried out, and the impurity removal method is single; 4) The color of WP3 has a crucial impact on upadacitinib API, and the original patent did not remove the color impurities of WP3. Summary of the invention

[0008] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing an upadacitinib intermediate 8-((3R, 4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine dihydrochloride (WP3). The present invention adopts a transfer hydrogenation method to prepare the intermediate WP3, thereby solving the limitation of high-pressure equipment; and through the free base separation operation of the compound WP3, the effects of impurity removal and color removal are achieved, thereby improving the safety of the product.

[0009] The present invention is achieved through the following technical solutions:

[0010] A method for preparing upadacitinib intermediate WP3 comprises the following steps:

[0011] Using an ethanol / water mixed solution as a solvent, under nitrogen, compound WP2 is heated to react under the action of 10% palladium carbon, ammonium formate and hydrochloric acid. After the reaction is completed, the intermediate WP3 is obtained after post-treatment. The reaction equation is as follows:

[0012]

[0013] A further improvement of the present invention is:

[0014] In the ethanol / water mixed solution, the volume ratio of ethanol to water is 1:0-0.3.

[0015] Furthermore, the mass ratio of the compound WP2, 10% palladium carbon, ammonium formate and hydrochloric acid is 1: 0.05-0.20: 0.25-0.60: 0.15-0.40.

[0016] Furthermore, the mass concentration of the hydrochloric acid is 36-38%.

[0017] Furthermore, the temperature of the temperature-raising reaction is 40-50° C., and the time is 2-5 hours.

[0018] Furthermore, the post-treatment process is as follows: after the reaction is completed, the palladium carbon is filtered out, the filtrate is evaporated with water, the pH value is adjusted to 7-13, the temperature is lowered to 0-10°C and filtered, the obtained solid is dissolved in ethanol, hydrochloric acid is added, the system is concentrated, ethyl acetate is added, stirred at room temperature, filtered and vacuum dried to obtain pure WP3.

[0019] The beneficial effects of the present invention are:

[0020] The present invention solves the limitation of high-pressure equipment through transfer hydrogenation reaction. The present invention can effectively remove the above impurities in the compound WP3 step through the compound WP3 free base separation operation, and can well control related substances in the API step without going through a refining process, thereby reducing process costs. The present invention can remove the pigments produced by the process through the compound WP3 free base separation operation, thereby controlling the color of upadacitinib API to off-white. This color scale control is much higher than the color control standard of the original raw material drug, and the product safety is improved by controlling the pigment impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 : is the HPLC spectrum of the intermediate WP3 obtained in Example 1;

[0022] Figure 2 This is the proton spectrum of the intermediate WP3 obtained in Example 1. DETAILED DESCRIPTION

[0023] The present invention is described in detail below in conjunction with specific embodiments.

[0024] The present invention provides a method for preparing an upadacitinib intermediate 8-((3R, 4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine dihydrochloride (WP3), and the specific steps are as follows:

[0025] To the ethanol / water mixed solution of WP2, hydrochloric acid, 10% palladium carbon, and ammonium formate were added in sequence, and the temperature was raised to 40-50° C. for reaction for 3 hours after nitrogen substitution. After the reaction, the palladium carbon was removed by filtration. The filtrate was evaporated with water, the pH value was adjusted to 7-13, and the temperature was lowered to 0-10° C. for filtration. The obtained solid was dissolved in ethanol, and hydrochloric acid was added. After concentrating the system, ethyl acetate was added, and stirred at room temperature for 1 hour. WP3 was obtained by filtration and vacuum drying; (the purity can reach 99%, and the yield can reach 91%). The reaction equation is as follows:

[0026]

[0027] Example 1

[0028] To 120 ml of WP2 ethanol / water solution (actual amount of WP2 charged: 10 g, ethanol / water = 100 / 16) were added 2.6 g of 36 wt% hydrochloric acid, 1.5 g of 10% Pd / C, and 4.9 g of ammonium formate in sequence, and the mixture was stirred at 45°C for 2 hours. After the reaction was completed, the palladium carbon was removed by filtration, and the filtrate was evaporated with water to remove ethanol. After the evaporation, the pH was adjusted to 7-13 with sodium hydroxide, the solid was filtered out and dissolved in ethanol, 6.5 g of 36 wt% hydrochloric acid was added, and the mixture was concentrated under reduced pressure. After the concentration was completed, 80 ml of ethyl acetate was added to the system, and the mixture was stirred at 25°C for 1 hour. The solid was filtered out and vacuum-dried WP3 (7.7 g, purity: 99%, yield: 91%).

[0029] Example 2

[0030] To 120 ml of WP2 ethanol / water solution (actual amount of WP2 charged: 10 g, ethanol / water = 100 / 5) were added 1.5 g of hydrochloric acid (36 wt%), 1.0 g of 10% Pd / C, and 3.24 g of ammonium formate in sequence, and the mixture was stirred at 45°C for 2 hours. After the reaction was completed, the palladium carbon was filtered out, and the filtrate was evaporated with water to remove ethanol. After the evaporation, the pH was adjusted to 7-13 with sodium hydroxide, the solid was filtered out and dissolved in ethanol, 6.5 g of hydrochloric acid (36 wt%) was added, and the mixture was concentrated under reduced pressure. After the concentration was completed, 80 ml of ethyl acetate was added to the system, and the mixture was stirred at 25°C for 1 hour. The solid was filtered out and vacuum-dried WP3 (7.3 g, purity: 99%, yield: 87%).

[0031] Example 3

[0032] To 120 ml of WP2 ethanol / water solution (actual amount of WP2 charged: 10 g, ethanol / water = 100 / 30) were added 4.0 g of hydrochloric acid (36 wt%), 2.0 g of 10% Pd / C, and 5.6 g of ammonium formate in sequence, and the mixture was stirred at 45°C for 2 hours. After the reaction was completed, the palladium carbon was filtered out, and the filtrate was evaporated with water to remove ethanol. After the evaporation, the pH was adjusted to 7-13 with sodium hydroxide, the solid was filtered out and dissolved in ethanol, 6.5 g of hydrochloric acid (36 wt%) was added, and the mixture was concentrated under reduced pressure. After the concentration was completed, 80 ml of ethyl acetate was added to the system, and the mixture was stirred at 25°C for 1 hour. The solid was filtered out and vacuum-dried WP3 (7.8 g, purity: 99%, yield: 92%).

[0033] Comparative Example 1

[0034] WP3 was synthesized according to the method described in patent CN108368121A. The process used pressurized hydrogenation to remove Cbz protection. The specific process was as follows: 10% palladium hydroxide was added to the ethanol solution of WP2, and stirred at 50°C and 20 psig of hydrogen pressure for 16 hours. After the reaction was completed, it was filtered at room temperature, and 35% HCl was added. After the system was concentrated under reduced pressure, it was stirred in anhydrous ethanol and ethyl acetate system, filtered, and vacuum dried to obtain WP3.

[0035] The processes of Example 1 of the present invention and Comparative Example 1 were compared, and the results are shown in the following table:

[0036]

[0037] The present invention can effectively remove the above impurities in the compound WP3 step through the compound WP3 free base separation operation, and can well control related substances in the API step without going through a refining process, thereby reducing process costs. The present invention can remove the pigments produced by the process through the compound WP3 free base separation operation, thereby controlling the color of upadacitinib API to off-white, and this color scale control is much higher than the color control standard of the original research raw material drug, and improves product safety by controlling pigment impurities.

[0038] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing upadacitinib intermediate WP3, characterized in that: The following steps are involved: Using an ethanol / water mixed solution as a solvent, under nitrogen, compound WP2 is heated to react under the action of 10% palladium carbon, ammonium formate and hydrochloric acid. After the reaction is completed, the intermediate WP3 is obtained after post-treatment. The reaction equation is as follows:

2. The method for preparing an upadacitinib intermediate WP3 according to claim 1, characterized in that: In the ethanol / water mixed solution, the volume ratio of ethanol to water is 1:0-0.

3.

3. The method for preparing an upadacitinib intermediate WP3 according to claim 1, characterized in that: The mass ratio of the compound WP2, 10% palladium carbon, ammonium formate and hydrochloric acid is 1: 0.05-0.20: 0.25-0.60: 0.15-0.

40.

4. The method for preparing an upadacitinib intermediate WP3 according to claim 1 or 3, characterized in that: The mass concentration of the hydrochloric acid is 36-38%.

5. The method for preparing an upadacitinib intermediate WP3 according to claim 1, characterized in that: The temperature of the temperature-raising reaction is 40-50° C. and the time is 2-5 hours.

6. The method for preparing an upadacitinib intermediate WP3 according to claim 1, characterized in that: The post-treatment process is as follows: after the reaction is completed, the palladium carbon is removed by filtering, the filtrate is evaporated with water, the pH value is adjusted to 7-13, the temperature is lowered to 0-10°C and filtered, the obtained solid is dissolved in ethanol, hydrochloric acid is added, the system is concentrated, ethyl acetate is added, and after stirring at room temperature, the WP3 pure product is obtained by filtering and vacuum drying.

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