A method for preparing high purity tofacitinib citrate

Abstract

The application discloses a preparation method of high-purity tofacitinib citrate, which adopts a two-step method to prepare tofacitinib citrate, and is divided into two steps of tofacitinib preparation and final product preparation. In the preparation of tofacitinib, the reaction liquid is first extracted with an acidic aqueous solution, then the pH value is adjusted with an alkali solution, tofacitinib is extracted with dichloromethane, tofacitinib fine products are obtained by crystallization in an alcohol aqueous solution after concentration, and finally tofacitinib citrate is obtained by salification with citric acid. The total yield of the final product prepared by the method can reach 74.4%, the purity of the prepared tofacitinib citrate is as high as 99.81%, and the maximum single impurity can be as low as below 0.03%. Compared with the prior art, the yield of tofacitinib citrate prepared by the preparation method of the application is increased by about 7.1%, and the purity is effectively improved. The preparation method of the application can not only effectively remove impurities, but also make the color meet the pharmaceutical requirements.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of drug synthesis, more particularly, to a preparation method of high-purity tofacitinib citrate. BACKGROUND

[0002] Tofacitinib citrate, also known as tofacitinib citrate, is an orally effective protein tyrosine kinase (JAK) inhibitor developed by Pfizer, USA. On November 6, 2012, the FDA approved the tablet for marketing, which is used for moderate to severe active rheumatoid arthritis adult patients who are not adequately responsive to methotrexate treatment or intolerant. So far, tofacitinib citrate has been approved for marketing in more than 80 countries around the world, and on March 10, 2017, it obtained the marketing license of CFDA.

[0003] Tofacitinib citrate (CAS: 540737-29-9; chemical name: (3R, 4R)-4-methyl-3-(methyl-1H-pyrrolo[2,3-d]pyrimidin-4-amino)-β-oxo-1-piperidine propionitrile, 2-hydroxy-1,2,3-propanetricarboxylic acid (1:1)) has the following structure:

[0004]

[0005] At present, there are many literatures reported on the synthesis method of tofacitinib citrate. The original research Pfizer company discloses the following synthesis route in CN101233138A:

[0006]

[0007] Among them, compound 1 (2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine) and compound 2 ((3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine) undergo substitution reaction to generate compound 3, compound 3 is reduced by hydrogenation to obtain compound 4, compound 4 undergoes nucleophilic substitution reaction with ethyl cyanoacetate, and then one-pot reaction with citric acid to prepare tofacitinib citrate. However, in the synthesis route, the final product tofacitinib citrate prepared has many impurities, and the maximum single impurity is as high as 0.28%, and the product color is yellow, which cannot meet the pharmaceutical requirements.

[0008] Therefore, it is urgent to develop a preparation method of high-purity tofacitinib citrate with color meeting the pharmaceutical requirements. SUMMARY

[0009] The purpose of the present application is to overcome the defects and deficiencies in the prior art, and to provide a preparation method of high-purity tofacitinib citrate.

[0010] The above object of the present application is achieved by the following technical solutions.

[0011] Step S1. The cyanoacetic acid is activated by pivaloyl chloride, and then subjected to a substitution reaction with N-[(3R, 4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine in an organic solvent to obtain a reaction solution;

[0012] Step S2. An acidic aqueous solution is added to the reaction solution obtained in S1 to adjust the pH value to 1-3, and the solution is separated to collect the aqueous phase;

[0013] Step S3. The aqueous phase in S2 is adjusted to a pH value of 7-8, extracted with dichloromethane, and the organic phase is collected and concentrated;

[0014] Step S4. The concentrate obtained in S3 is added with an alcohol-water mixed solvent to crystallize tofacitinib;

[0015] Step S5. The tofacitinib obtained in S4 is salted with citric acid to obtain high-purity tofacitinib citrate.

[0016] In the reaction solution in S1, the main component is tofacitinib, and then an acidic aqueous solution is added to combine tofacitinib in the reaction solution with the acid to form a soluble salt. At this time, the solution is divided into two layers of aqueous phase and organic phase, and most of the impurities are dissolved in the organic phase. The separation effect of impurities can be achieved by liquid separation. Further, a pH regulator is added to the aqueous phase containing the soluble salt of tofacitinib, and dichloromethane is added to extract tofacitinib. After concentration, the obtained concentrate, i.e. tofacitinib oil, is further purified through processes such as alcohol-water mixed solvent crystallization, filtration and drying, to obtain high-quality tofacitinib with a chemical purity of not less than 99.5% and a maximum single impurity of less than 0.03%. Finally, salt formation with citric acid can obtain high-purity tofacitinib citrate meeting the requirements of pharmaceutical use.

[0017] Preferably, the acidic aqueous solution in step S2 is one or more of hydrochloric acid, dilute sulfuric acid and hydrobromic acid.

[0018] More preferably, the acidic aqueous solution is hydrochloric acid.

[0019] More preferably, the concentration of the hydrochloric acid is 0.5-5 mol / L.

[0020] More preferably, the concentration of the hydrochloric acid is 1-2 mol / L.

[0021] Preferably, the alcohol-water mixed solvent in step S4 is a mixed solvent of methanol and water or a mixed solvent of ethanol and water.

[0022] More preferably, the alcohol-water mixed solvent is a mixed solvent of methanol and water.

[0023] More preferably, the volume ratio of methanol and water is 2:1 to 1:5.

[0024] Preferably, the pH regulator in step S3 is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, and ammonia water.

[0025] Preferably, the extraction in step S3 is performed 1 to 3 times. Specifically, the aqueous phase obtained in step S3 is extracted with dichloromethane, and the obtained organic phase is combined with the organic phase in step S3, and the cycle is repeated 1 to 3 times, followed by concentration.

[0026] Compared with the prior art, the present application has the following beneficial effects:

[0027] (1) The total yield of tofacitinib citrate prepared by the two-step method of the present application can reach 74.4%, and the purity of tofacitinib citrate prepared by the method can reach 99.81%, and the maximum single impurity can be as low as less than 0.03%. Compared with the prior art, the yield of tofacitinib citrate prepared by the preparation method of the present application is increased by about 7.1%, and the purity is also effectively improved.

[0028] (2) The color of the final product tofacitinib citrate prepared by the present application is significantly improved, and completely meets the pharmaceutical standard.

[0029] (3) The preparation method of tofacitinib citrate of the present application has a simple synthesis route, easy-to-control and easy-to-operate reaction conditions, high total yield of product, high purity, less impurities, stable final product, and is beneficial to industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 is the HPLC purity detection chromatogram of tofacitinib citrate prepared in Example 1. DETAILED DESCRIPTION

[0031] In order to more clearly and completely describe the technical solutions of the present application, the present application will be further described in detail through specific examples below. It should be understood that the specific examples described herein are only used to explain the present application and do not limit the present application, and various changes can be made within the scope of the present application.

[0032] Example 1

[0033] A preparation method of high-purity tofacitinib citrate, comprising the following steps:

[0034] Step S1. Into a 100 L glass-lined reaction kettle, 37.89 kg of dichloromethane, 3.48 kg of cyanoacetic acid and 4.15 kg of triethylamine were sequentially added, and then nitrogen was introduced for protection. The temperature was lowered to -10-0 °C. 4.62 kg of tert-pivaloyl chloride was added dropwise into the reaction kettle. The temperature was controlled at -10-0 °C for 2 h. After the reaction was completed, 25.26 kg of dichloromethane and 3.35 kg of a mixed solution of (N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine) were added dropwise into the reaction kettle. After the addition was completed, the temperature was maintained for 1.5 h. The reaction progress was monitored by sampling. After the reaction was completed, a reaction solution was obtained;

[0035] Step S2. To the reaction solution obtained in S1, 49.98 L of 1 mol / L hydrochloric acid was added to adjust the pH value to 1-3. After stirring, the solution was allowed to stand and separate. The aqueous phase was collected by extraction.

[0036] Step S3. To the aqueous phase in S2, about 19.41 kg of saturated sodium carbonate solution was added dropwise under stirring to adjust the pH value to 7-8. 55 kg of dichloromethane was added. After standing, the organic phase was collected by extraction. The aqueous phase was extracted again with dichloromethane. The two organic phases were combined and concentrated.

[0037] Step S4. To the concentrate obtained in S3, 18.31 kg of methanol and 35.42 kg of purified water were added. The temperature was raised to 40-50 °C and stirred for 1 h. The temperature was then lowered to 10-25 °C and stirred for 1 h. The filter cake was washed with 12.4 kg of purified water. The obtained solid was dried at 55-65 °C under reduced pressure to obtain 3.15 kg of tofacitinib as a white solid, with a yield of 73.9%.

[0038] Step S5. Into a 50 L glass reaction kettle, 14.75 kg of acetone, 5.19 kg of purified water and 2.95 kg of tofacitinib obtained in S4 were sequentially added. The system was heated to 50-55 °C. 2.02 kg of a solution of citric acid in 8.08 kg of water was added into the reaction kettle. The system was stirred at 50-55 °C for 1 h, and then the temperature was lowered to 0-10 °C. The system was allowed to stand at 0-10 °C for 1 h for crystallization. The filter cake was washed with 2.90 kg of acetone. The obtained solid was dried at 55-65 °C to obtain 4.72 kg of tofacitinib citrate as a white solid, with a yield of 94.4%. The purity of tofacitinib citrate was detected by HPLC. The results are shown in the attached table. The purity of tofacitinib citrate obtained was 99.87%, and the maximum single impurity was 0.03%. Figure 1

[0039] Example 2

[0040] ​A preparation method of high purity tofacitinib citrate is basically same as that of Example 1, the difference is that only the kind and concentration of the acidic aqueous solution is changed, the yield, purity and impurities of the final product tofacitinib citrate are investigated, see Table 1 (the final product in this application refers to tofacitinib citrate).

[0041] Table 1

[0042]

[0043]

[0044] Example 3

[0045] A preparation method of high purity tofacitinib citrate is basically same as that of Example 1, the difference is that only the kind and concentration of the acidic aqueous solution is changed, the yield, purity and impurities of the final product tofacitinib citrate are investigated, see Table 1 (the final product in this application refers to tofacitinib citrate).

[0046] Table 2

[0047] Serial No. Alkaline solution Final product purity Final product maximum single impurity Final product color Overall yield Sample 1 Potassium carbonate 99.87％ 0.06％ White 74.5％ Sample 2 Sodium hydroxide 99.65％ 0.08％ White 73.2％ Sample 3 Ammonia 99.78％ 0.05％ White 74.1％ Sample 4 Sodium bicarbonate 99.87％ 0.03％ White 72.5％

[0048] Comparative Example 1

[0049] Tofacitinib citrate is prepared by referring to the method of Example 13 of patent CN101233138A.

[0050] Table 3

[0051] Serial No. Hydrochloric acid concentration Final product purity Final product maximum single impurity Final product color Comparative Example 3 None 98.78％ 0.28％ Yellowish

[0052] From the comparison of Table 1 to Table 3, compared with tofacitinib citrate prepared by other preparation methods, tofacitinib citrate prepared by the present application has higher purity, the maximum single impurity is significantly reduced, and the product color can also completely meet the pharmaceutical requirements.

[0053] The above examples use specific embodiments and tests to make a detailed description of the present application, but some modifications or improvements can be made on the basis of the present application without deviating from the main idea of the present application, which is obvious to those skilled in the art. Therefore, these modifications or improvements made without deviating from the main idea of the present application are within the scope of the present application.

Claims

1. A method for preparing tofacitinib citrate, characterized in that: The following steps are involved: Step S1. Cyanoacetic acid is activated with pivaloyl chloride, and then reacted with N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine in an organic solvent to produce a reaction solution; Step S2. Add an acidic aqueous solution to the reaction solution obtained in S1 and adjust the pH to 1 to 3, let it stand, separate the liquids, and collect the aqueous phase; Step S3. The aqueous phase in S2 is adjusted to a pH of 7 to 8, extracted with dichloromethane, and the organic phase is collected and concentrated; Step S4. adding an alcohol-water mixed solvent to the concentrate obtained in S3, and crystallizing to obtain tofacitinib; Step S5. salting the tofacitinib prepared in S4 with citric acid to obtain tofacitinib citrate; In step S3, the acidic aqueous solution is hydrochloric acid, and the concentration of the acidic aqueous solution is 1-2 mol / L; The alcohol-water mixed solvent in step S4 is a mixed solvent of methanol and water; The volume ratio of the methanol to water is 2:1 to 1:

5.

2. The preparation method according to claim 1, wherein In step S3, the pH regulator for adjusting the aqueous phase to a pH value of 7 to 8 is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, and ammonia water.

3. The preparation method according to any one of claims 1 to 2, characterized in that The number of extractions in step S3 is 1 to 3 times.

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