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Industrial production method applicable to citric acid tofacitinib

A technology of tofacitinib and a production method, which is applied in the industrialized production field of tofacitinib citrate, can solve the problems of increasing production costs and potential safety hazards, no suppliers, and unsatisfactory costs, and achieves high economic value and cost. Social benefits, shortened response time, less harsh production conditions

Inactive Publication Date: 2015-07-22
NANJING CHENGONG PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The patent reports that the hydrogenation reaction takes 3 days, which is too long, which increases production costs and safety hazards in large-scale production, and in the reaction of preparing formula V, the introduction of formula SM 3a Condensation reaction, this reagent can provide very few suppliers on the market after searching, and the price is expensive after inquiry, and the yield of this step is reported in the patent at the same time. Preparation methods do not meet the needs of large-scale production in industry
Chinese patent CN201310537835 also reported the preparation method of formula V, the formula SM 3a Replaced with cyanoacetyl chloride, this method can reduce reagent cost, but because cyanoacetyl chloride is very easy to hydrolyze in water, this method has increased uncontrollable risk on suitability for industrialized production (involved equipment and material in the reaction all need for anhydrous treatment)
[0009] Based on the above facts, although this route can produce finished products, the quality cannot meet the requirements of pharmaceutical-grade raw materials
On the basis of this literature, it is mentioned in the article of China Pharmaceutical Industry Journal 2014, 45(3) page 201 that the formula SM 2 Alternative SM 1 , but the retrieval formula SM 2 At present, there is no supplier on the market, which cannot meet the needs of mass production.
J.Med.Chem.2010,53,8468~8484 documents disclose another preparation method, using the formula SM 3 Alternative SM 1 , but found that the substitution reaction of the first project is difficult to react completely, and the yield is very low (optimized by changing the feed ratio, increasing the temperature, and prolonging the reaction time), and this method cannot be scaled up.
In combination with the above prior art processes, there are relatively large defects, which basically cannot adapt to industrialized production

Method used

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  • Industrial production method applicable to citric acid tofacitinib
  • Industrial production method applicable to citric acid tofacitinib
  • Industrial production method applicable to citric acid tofacitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The specific operation steps of producing tofacitinib citrate are as follows:

[0037] 1. Preparation of formula IIa compound

[0038]

[0039] Drop into 0.7Kg 7H-pyrrole [2,3-D] pyrimidine (formula SM 1a shown compound), 0.6Kg (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride (formula SM 2 shown compound) to the reactor, start stirring, vacuum pump 3kg of methanol successively, put in 0.5kg of powdered potassium carbonate, heat up to 60-65°C, keep stirring for 8 hours, and detect SM by engineering inspection HPLC 1a Remain 1.0%, lower the temperature to 40-45°C, vacuum pump 0.6kg of acetonitrile, heat and stir for 3 hours, centrifuge and dry to obtain a wet product, sprinkle and wash the wet product twice with 1.5kg of water, and dry again to obtain a wet product of 1.68kg, keep Blast drying at 40-50°C for 12 hours gave 0.75kg of off-white solid formula IIa with a yield of 75%, a purity of 97.2%, and SM 1a 0.5% residual, 1.0% moisture residual....

Embodiment 2

[0057] The specific operation steps of producing tofacitinib citrate are as follows:

[0058] 1. Preparation of formula IIa compound

[0059]

[0060] Drop into 0.7Kg 7H-pyrrole [2,3-D] pyrimidine (formula SM 1a shown compound), 0.6Kg (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride (formula SM 2 shown compound) to the reactor, start stirring, vacuum pump 2.8kg methanol successively, put in 0.4kg powdered sodium carbonate, heat up to 60-65°C, keep stirring for 10 hours, and detect SM by engineering inspection HPLC 1a Residual 1.2%, lower the temperature to 40-45°C, vacuum pump 0.56kg of acetonitrile, heat and stir for 3 hours, centrifuge and dry to obtain a wet product, sprinkle and wash the wet product twice with 1.5kg of water, and dry again to obtain a wet product of 1.6kg, keep 40~50 ℃ air-dried for 12 hours, obtain 0.71kg off-white solid formula IIa, yield 72.4%, purity 96.8%, SM 1a 0.8% remains and 1.2% moisture remains.

[0061] 2. Preparation...

Embodiment 3

[0078] The specific operation steps of producing tofacitinib citrate are as follows:

[0079] 1. Preparation of formula IIa compound

[0080]

[0081] Drop into 0.72Kg 7H-pyrrole [2,3-D] pyrimidine (formula SM 1a shown compound), 0.6Kg (3R,4R)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine hydrochloride (formula SM 2 shown compound) to the reaction kettle, vacuum pump 2.8kg isopropanol successively after starting stirring, put in 0.45kg powdered sodium carbonate, heat up to 75-80°C, keep stirring for 12 hours, and detect SM through engineering inspection HPLC 1a Remain 1.3%, lower the temperature to 40-45°C, vacuum pump 0.6kg of acetonitrile, heat and stir for 4 hours, centrifuge and dry to obtain a wet product, sprinkle and wash the wet product twice with 1.8kg of water, and dry again to obtain a wet product of 1.7kg, keep 40~50 DEG C blast drying 14 hours, obtain 0.70kg off-white solid formula IIa, yield 70%, purity 97.3%, SM 1a 1.0% remained and 1.4% moisture remained...

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Abstract

The invention relates to an industrial production method applicable to citric acid tofacitinib. The invention relates to a novel industrial production method of a high-purity orally taken JAK inhibitor and a medicine for treating rheumatoid arthritis. Raw materials are subjected to substitution, protecting group removal, reduction debenzylation, condensation and salifying to obtain a compound shown in a formula I, and the defects of a synthetic route reported in existing literatures that the impurity content in the prepared finished product is high, cost is high and yield is low are overcome. The novel industrial production method provided by the invention has the advantages that cost of a used reagent is low, environmental pollution is hardly caused, operation is easy, and short time is consumed, so that the novel industrial production method is applicable to industrial production; meanwhile, product quality is good, total impurity content is low, content of each individual impurity is controlled to be 0.1% or below, the finished product is controlled to be in a single stable crystal form, and medicinal-grade raw material requirements can be met.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical production, and in particular relates to a production method suitable for the industrialization of tofacitinib citrate. Background technique [0002] Tofacitinib citrate is a new type of oral JAK inhibitor developed by Pfizer of the United States. It was approved by the FDA in November 2012. Its product name is Xeljanz. Tofacitinib citrate is one of Pfizer's most promising new drugs for the treatment of adult patients with moderately to severely active rheumatoid arthritis. [0003] Chinese patent ZL 02823587.8 (the original patent of Pfizer, USA) discloses the following synthetic route: [0004] [0005] The patent reports that the hydrogenation reaction takes 3 days, which is too long, which increases production costs and safety hazards in large-scale production, and in the reaction of preparing formula V, the introduction of formula SM 3a Condensation reaction, this reagent can prov...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCY02P20/55C07D487/04
Inventor 郭昭
Owner NANJING CHENGONG PHARM CO LTD
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