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Preparation method of 4-chloropyrrolo[2,3-d]pyrimidine

A technology for chloropyrrolopyrimidine and pyrimidine, applied in the field of preparation of 4-chloropyrrolopyrimidine, which can solve the problems of complex 4-chloropyrrolopyrimidine process, high precision requirements for condition control, and low product yield, and achieve product purification Easy, low requirements for production conditions, high yield

Inactive Publication Date: 2016-06-01
ABA CHEM SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The present invention aims to solve the problems of complex technical process for preparing 4-chloropyrrolopyrimidine, high precision requirements for condition control, low product yield and difficult purification

Method used

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  • Preparation method of 4-chloropyrrolo[2,3-d]pyrimidine
  • Preparation method of 4-chloropyrrolo[2,3-d]pyrimidine
  • Preparation method of 4-chloropyrrolo[2,3-d]pyrimidine

Examples

Experimental program
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Effect test

Synthetic example 1

[0035] Add 29.24g (258.5mmol) ethyl cyanoacetate, 0.52g (3.46mmol) NaI, 7.41g (53.6mmol) K 2 CO 3 , slowly dropwise added 9.185 g (55 mmol) of 2-bromomethyl-1,3-dioxolane.

[0036] After the dropwise addition of 2-bromomethyl-1,3-dioxolane was completed, the temperature was slowly raised to 80° C., and the reaction was stirred for 4 h while the temperature was raised, and then the temperature was slowly raised to 100° C. and continued to stir for 20 h. Afterwards, add 50 mL of water to dissolve the reaction system, then add methyl tert-butyl ether for extraction (100 mL*2), dry the organic phase, filter, evaporate to dryness with a water pump, and distill the residue under reduced pressure with an oil pump to collect 118 -122°C (2mmHg) fraction, the product was a colorless liquid, 7.8g (theoretical yield 10.96g), yield 71.2%. LCMS (EI) m / e 200.1 (M++H). 1HNMR(CDCl3,300MHz)δppm5.08-5.10(t,1H),4.26-4.28(m,2H),4.00-4.01(m,2H),3.89-3.90(m,2H),3.68-3.69(m, 1H), 2.34-2.37(m, 2H)...

Synthetic example 2

[0038] Add 15.55g (137.5mmol) ethyl cyanoacetate, 1.12g (3.46mmol) tetrabutylammonium bromide, 17.46g (53.6mmol) Cs 2 CO 3 , slowly dropwise added 9.185 g (55 mmol) of 2-bromomethyl-1,3-dioxolane.

[0039] After the dropwise addition, the temperature of the reaction system was slowly raised to 70° C., stirred and reacted for 4 hours while the temperature was raised, and then slowly raised to 90° C. and stirred for 20 hours. After that, add 50mL of water to dissolve, add methyl tert-butyl ether for extraction (100ML*2) and carry out successively drying of the organic phase, filtration, and evaporation to dryness under reduced pressure with a water pump. ) fraction, product 7.1g (theoretical yield 10.96g) colorless liquid was obtained, and the yield was 64.8%. LCMS (EI) m / e 200.1 (M++H). 1HNMR(CDCl3,300MHz)δppm5.08-5.10(t,1H),4.26-4.28(m,2H),4.00-4.01(m,2H),3.89-3.90(m,2H),3.68-3.69(m, 1H), 2.34-2.37(m, 2H), 1.31-1.34(t, 3H).

Synthetic example 3

[0041] Add 15.55g (137.5mmol) ethyl cyanoacetate and 50mL DMF to a 250ml three-necked flask, and slowly add 5.5g (137.5mmol, 60% sodium hydride) under ice cooling.

[0042]After adding sodium hydride, stir at room temperature for 10 minutes, then slowly raise the temperature to 70°C, stir for 2 hours, cool to room temperature, and slowly add 9.185g (55mmol) of 2-bromomethyl-1,3-dioxolane in DMF The solution was 30 mL, after the dropwise addition, the temperature was slowly raised to 50°C, and after stirring for 3 hours, the temperature was slowly raised to 70°C, and the stirring was continued for 20 hours. Under cooling in an ice bath, slowly add 50 mL of ice water dropwise to dissolve the reaction system, then add methyl tert-butyl ether for extraction (100 mL*2) and sequentially dry the organic phase, filter, and evaporate to dryness under reduced pressure with a water pump. Oil pump vacuum distillation, collecting 118-122 ° C (2 mmHg) fractions, to obtain 6.8 g (theoretical...

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Abstract

The invention relates to a preparation method of 4-chloropyrrolo[2,3-d]pyrimidine.The method includes the following steps of obtaining 2-cyano-3-(1,3-dioxolan)ethyl propionate after 2-bromomethyl-1,3-dioxolane and ethyl cyanoacetate which are used as the raw materials react with alkaline matter as the catalyst; conducting cyclization on obtained 2-cyano-3-(1,3-dioxolan)ethyl propionate and formamidine acetate with alkaline matter as the catalyst, and adding hydrochloric acid for hydrolysis cyclization to obtain pyrrolo[2,3-d]pyrimidin-4-ol; making obtained pyrrolo[2,3-d]pyrimidin-4-ol react with phosphorus oxychloride to obtain 4-chloropyrrolo[2,3-d]pyrimidine.The method for preparing 4-chloropyrrolo[2,3-d]pyrimidine is simple in technological process, the requirement for production conditions is low, the product is easy to purify and high in yield, and the production efficiency and product quality of 4-chloropyrrolo[2,3-d]pyrimidine are remarkably improved.

Description

technical field [0001] The present invention relates to a preparation method of 4-chloropyrrolopyrimidine, in particular to a method for preparing 4-chloropyrrolopyrimidine using 2-bromomethyl-1,3-dioxolane and ethyl cyanoacetate as starting materials Methods. Background technique [0002] 4-Chloropyrrolopyrimidine is an important pharmaceutical intermediate that is used, for example, as an intermediate for the raw material tofacitinib in adult patients with moderate to severe rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate body. At present, its synthesis methods are mainly as follows. [0003] Method 1: Using diethyl malonate as a raw material to prepare 4-chloropyrrolopyrimidine using the following reaction formula (Non-Patent Document 1). [0004] [0005] Method 2: 4-chloropyrrolopyrimidine is prepared by using 4,6-dihydroxypyrimidine as a raw material through the following reaction formula (Patent Document 1). [0006] ...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 林志刚徐军江岳恒
Owner ABA CHEM SHANGHAI
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