Preparation method of baricitinib

A baricitinib and compound technology, applied in the field of drug preparation, can solve the problems of unsuitability for industrial production, long reaction route, complicated operation, etc., so as to reduce the possibility of by-product generation, improve the quality and the total yield, reaction short route effect

Inactive Publication Date: 2018-06-08
JIANGSU ZHONGBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reaction route is too long, the total yield is low, the operation is cumbersome, and palladium is used twice in the reaction, the finished product is relatively high, and it is not suitable for industrial production

Method used

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  • Preparation method of baricitinib
  • Preparation method of baricitinib
  • Preparation method of baricitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Synthesis of Compound 4

[0043] Put 15.4g (0.1mol) of compound 2, 11.4g (0.05mol) of dipotassium hydrogen phosphate, 26.2g (0.12mol) of di-tert-butyl dicarbonate, 300g of tetrahydrofuran and 70g of water into a 1L reaction bottle, stir at room temperature for 12 hours, and then control , the reaction of the raw materials was complete, the layers were separated, the aqueous layer was extracted with 200 g of tetrahydrofuran, the organic layers were combined, and the organic layers were directly used in the next step.

[0044] 5.1 g (0.1 mol) of hydrazine hydrate and 5.6 g (0.1 mol) of acrolein were added to the above system, and the mixture was refluxed for 8 hours under an oxygen atmosphere. Stop heating after the reaction of the central control raw material is complete, cool the system down to room temperature, pour the system into 100g of ice water with stirring, layer after stirring for 10min, dry and filter the organic layer, and rotary evaporate the filtrate to obt...

Embodiment 2

[0055] Synthesis of Compound 4

[0056] Put 15.4g (0.1mol) of compound 2, 11.4g (0.05mol) of dipotassium hydrogen phosphate, 31.0g (0.12mol) of fluorenylmethoxycarbonyl chloride, and 400g of dichloromethane into a 1L reaction bottle, stir at room temperature for 12 hours, and control in the central control. After the reaction was complete, filter, add 300 g of ice water to the filtrate, stir for 10 min, then separate the liquids, extract the water layer with 200 g, combine the organic layers, spin the organic layers to dry, and use the obtained system directly in the next reaction.

[0057] 10.2 g (0.2 mol) of hydrazine hydrate, 500 g of toluene and 11.2 g (0.2 mol) of acrolein were added to the above system, and the reaction was refluxed for 8 h under an oxygen atmosphere. Stop heating after the reaction of the central control raw material is complete, cool the system down to room temperature, pour the system into 100g of ice water with stirring, layer after stirring for 10mi...

Embodiment 3

[0067] Synthesis of Compound 4

[0068] Put 15.4g (0.1mol) of compound 2, 27.6g (0.2mol) of potassium carbonate, 19.1g (0.1mol) of p-toluenesulfonyl chloride, 500g of acetonitrile into a 1L reaction bottle, stir at room temperature for 8 hours, and then control in the middle, the raw materials react completely, filter, The filtrate was spin-dried under reduced pressure and used directly in the next step.

[0069] 20.4 g (0.4 mol) of hydrazine hydrate, 450 g of o-dichlorobenzene and 22.4 g (0.4 mol) of acrolein were added to the above system, and the reaction was refluxed under an oxygen atmosphere for 4 h. Stop heating after the reaction of the central control raw material is complete, cool the system down to room temperature, pour the system into 100g of ice water with stirring, layer after stirring for 10min, dry and filter the organic layer, and rotary evaporate the filtrate to obtain the crude sticky substance. About 27.7 g of compound 4 was obtained by recrystallization ...

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Abstract

The invention discloses a preparation method of baricitinib and belongs to the technical field of drug preparation. The method comprises that 4-chloropyrrolopyrimidine as a starting raw material is subjected to amino protection, the product, hydrazine hydrate and acrolein undergo a one-pot displacement reaction and a cyclization reaction to produce an intermediate 4, a starting raw material 1, 3-dibromoacetone and ethylene glycol undergo a condensation reaction to produce an intermediate 5, the intermediate 5 and ethyl sulfonamide undergo a condensation reaction to produce an intermediate 6, the intermediate 6 and diethyl cyanomethylphosphonate undergo a reaction under action of a strong base to produce an intermediate 7, the intermediate 4 and the intermediate 7 undergo an addition reaction under the action of a catalyst, and the product undergoes a deprotection reaction to produce a desired product 1. The preparation method needs mild reaction conditions. The intermediate purification method is simple and easy, has a total yield of 40-55% and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of baricitinib, a selective JAK1 and JAK2 inhibitor. technical background [0002] Baricitinib, chemical name 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-D]pyrimidin-4-yl)-1H-pyrazole-1 -Base]-3-azetidine acetonitrile is a selective oral JAK1 / JAK2 inhibitor developed jointly by Eli Lilly and Incyte Pharmaceuticals, which can inhibit various inflammatory cells such as IL-6 and IL-23 Intracellular signal transduction of factors, this product can be used for the treatment of moderate to severe rheumatoid arthritis. In a study involving more than 1,300 patients, Eli Lilly and Incyte's daily dose of baricitinib significantly improved RA symptoms compared with placebo after 12 weeks, meeting the primary endpoint. For two common clinical indicators of RA, the drug has also been proven to be superior to adalimumab (Humira), achieving the seconda...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 徐强吴四清黄双李维思唐景玉杨健
Owner JIANGSU ZHONGBANG PHARMA
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