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Industrial production method of citric acid tofacitinib

A production method and technology of tofacitinib, applied in the directions of organic chemistry, carboxylate preparation, drug combination, etc., can solve the problems of unsuitability for industrial production, difficulty in ensuring product quality, and few active ester suppliers, etc. The effect of industrialized production, low production cost and short time consumption

Active Publication Date: 2018-03-13
YANGTZE RIVER PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the amidation reaction of the key intermediate 3 in this route, the cost of using cyanoacetic acid-N-hydroxysuccinimide ester is relatively high, and the active ester has fewer suppliers and poor material stability, so it is difficult to ensure batch scale-up product quality after
CN105085527A discloses that cyanoacetic acid reacts under DCC condensation, but the by-product DCU of DCC is difficult to remove in the post-treatment, which makes the method have certain limitations
The hydrodebenzylation reaction uses acetic acid as a solvent, and after the reaction is completed, it is filtered and concentrated, but the target compound is difficult to form a solid, making the product less pure
Chinese patent CN1195755C discloses the hydrodebenzylation reaction under hydrochloric acid and ethanol conditions, the reaction conditions are mild, but the reaction time is long, and the target product needs to be obtained by column chromatography, which is not suitable for industrial production
However, when the p-toluenesulfonyl protecting group is removed by hydrolysis in sodium hydroxide solution, the reaction system is a heterogeneous system, and there is a risk of incomplete reaction, and the p-toluenesulfonate ester produced is a known genotoxic impurity, which is difficult to obtain. In this process, the problem will become more prominent as the batch scales up

Method used

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  • Industrial production method of citric acid tofacitinib
  • Industrial production method of citric acid tofacitinib
  • Industrial production method of citric acid tofacitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The specific synthesis operation of the intermediate INA is as follows:

[0044] Example 1a: Add 11.0kg of SMA, 12.8kg of SMB, 19.5kg of DIPEA, 50.0kg of DMSO, and 15.0kg of purified water into a 200L reactor, and raise the temperature to 107°C for reaction. After the reaction is complete, cool down to room temperature and add 24.0 kg of absolute ethanol and 30.0 kg of purified water, stir and crystallize for 2 hours, filter with suction, and dry at 60±5°C to obtain 17.2 kg of off-white solid. Yield 93.0%, SMB remaining 0.3%, HPLC purity 98.9%.

[0045] Example 1b: Add 11.0kg of SMA, 12.8kg of SMB, 19.5kg of DIPEA, 48.0kg of DMSO, and 12.0kg of purified water into a 200L reactor, and raise the temperature to 112°C for reaction. After the reaction is complete, cool down to room temperature and add 24.0 kg of absolute ethanol and 30.0 kg of purified water, stir and crystallize for 2 hours, filter with suction, and dry at 60±5°C to obtain 16.9 kg of off-white solid. Yiel...

Embodiment 2

[0051] The specific synthesis operation of intermediate INB is as follows:

[0052] Example 2a: 15kg of the intermediate INA prepared in Example 1c, 65kg of DMSO, 15kg of purified water, and 6.15kg of sodium hydroxide were added to a 100L reactor, and the temperature was raised to 80°C for reaction. After the reaction is complete, cool down to room temperature, stir and crystallize for 2 hours, shake off the filter, and dry at 60±5°C to obtain 9.8kg of yellow solid.

[0053] Example 2b: Put 2.0kg of the dried sample obtained in Example 2a into a 20L reaction kettle, add 12kg of absolute ethanol, heat to 63°C until the solid is completely dissolved, add 100g of medicinal charcoal for decolorization for 15min, suction filter while it is hot, and transfer the filtrate to 20L In the reaction kettle, cool down to 0-30°C, stir and crystallize for 2h, filter with suction, and dry at 60±5°C to obtain 1.80kg of yellow solid. The total yield was 85.8%, the intermediate INA was not dete...

example 2

[0062] Example 2g: 15kg of the intermediate INA prepared in Example 1c, 60kg of DMSO, 30kg of purified water, and 6.15kg of sodium hydroxide were added to a 100L reactor, and the temperature was raised to 65-95°C for reaction. After the reaction is complete, cool down to room temperature, stir and crystallize for 2 hours, shake off filter, and dry at 60±5°C to obtain 9.6kg of yellow solid.

[0063] Place the dried sample in a 100L reaction kettle, add 57.6kg of absolute ethanol, heat to 64°C until the solids are completely dissolved, add 480g of medicinal charcoal for decolorization for 15min, suction filter while it is hot, transfer the filtrate to a 200L reaction kettle, and cool down to Stir and crystallize at 0-30°C for 2h, filter with suction, and dry at 60±5°C to obtain 8.5kg of yellow solid. The total yield was 82.7%, the intermediate INA was not detected, and the HPLC purity was 100.0%.

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Abstract

The invention discloses an industrial production method of citric acid tofacitinib. The method comprises the following steps: (1) adding a compound SMA and a compound SMB to a mixed solvent 1 which comprises DMSO and purified water, and catalyzing through DIPEA to react to obtain an intermediate INA; (2) carrying out a homogeneous reaction of the INA under an alkaline condition to obtain a rough intermediate INB; (3) refining the rough INB through low-level alcohol and water to obtain fine INB; (4) treating the fine INB by debenzylation and acidification to obtain an intermediate INC (salt form); (5) carrying out a reaction between the INC and SMC to obtain an intermediate IND which is tofacitinib free alkali; (6) preparing salt through the IND and citric acid monohydrate in purified waterto obtain citric acid tofacitinib. According to the method, the defects of preparation technologies in existing literatures can be solved; the used solvents are three types of solvents, so that the environmental pollution is low; the time consumption is small; the operation processes are simple; industrial production can be carried out. The formula is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of organic drug synthesis, and in particular relates to a preparation method of tofacitinib citrate. Background technique [0002] Rheumatoid arthritis is an autoimmune disease, the incidence rate in my country is about 0.4%, and the number of patients has exceeded 5 million. Tofacitinib citrate is a novel oral Janus kinase (JAKs) inhibitor developed by Pfizer. Approved by the US FDA in November 2012, it is used for the treatment of moderate to severe rheumatoid arthritis in adults with insufficient response or intolerance to methotrexate. Tofacitinib citrate mainly adopts the condensation of piperidine amine structure intermediates and pyrrolopyrimidine structure intermediates to obtain the parent ring structure, and after cyanoacetyl condensation, it is then salted with citric acid. At present, the synthetic route of tofacitinib citrate reported in the literature has: [0003] Route 1: Pfizer reported i...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07C59/265C07C51/41A61P29/00A61P19/02
CPCC07D487/04
Inventor 肖灿徐镜人蔡伟朱晓鹤张海波吕慧敏胡涛吴剑华顾诚徐辰俊
Owner YANGTZE RIVER PHARM GRP CO LTD
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