CN102977104A

CN102977104A - Synthesis of 2,4-dichloro-7-hydroxy-pyrrolo(2,3)pyrimidine

Info

Publication number: CN102977104A
Application number: CN2012104840057A
Authority: CN
Inventors: 张福治; 丁炬平; 张仁延; 余强
Original assignee: Cgenetech Suzhou China Co Ltd
Current assignee: Cgenetech Suzhou China Co Ltd
Priority date: 2012-11-26
Filing date: 2012-11-26
Publication date: 2013-03-20

Abstract

The invention discloses a synthesis method of 2,4-dichloro-7-hydroxy-pyrrolo(2,3)pyrimidine. According to the shortcomings that the traditional synthesis method of 2,4-dichloro-7-hydroxy-pyrrolo(2,3)pyrimidine has low reaction yield, requires strict conditions and does not easily realize purification, the invention proposes a way of cyclizing 1,3-dyhydroxy-5-aminophenylamine serving as an initial raw material with chloroacetaldehyde and then performing chlorination to obtain 2,4-dichloro-7-hydroxy-pyrrolo(2,3)pyrimidine; and the whole process has high yield, the operation is easy, the product is easy to purity, column chromatography is avoided, the method is suitable for industrialization, and the cost of raw materials is greatly reduced.

Description

Synthesizing of 2,4-, two chloro-7-hydrogen-pyrrolo-(2,3) pyrimidines

Technical field

The present invention relates to the synthetic of 2,4-, two chloro-7-hydrogen-pyrrolo-(2,3) pyrimidines, also relate to the synthetic of its intermediate and use, belong to medicine, chemical technology field.

Background technology

2,4-two chloro-7-hydrogen-pyrrolo-es (2,3) pyrimidine is important chemistry, and chemical intermediate is widely used in medicine and pesticide field, especially aspect antineoplastic new drug synthetic, be seen at present the analogue synthetic route of report seldom, and severe reaction conditions mostly, yield is low, be difficult for purifying, be difficult to industrialization.

Summary of the invention

It is low to the present invention is directed to 2,4-, two chloro-7-hydrogen-pyrrolo-(2,3) pyrimidines synthetic method reaction yield in the past, condition is harsh, is difficult for the deficiency of purifying, has invented described with 1,3-dihydroxyl-5-amino aniline is that starting raw material and monochloroacetaldehyde close ring, and chlorination obtains 2,4-, two chloro-7-hydrogen-pyrrolo-es (2 again, 3) route of pyrimidine makes whole process yield high, easy handling, the good purifying of product, avoid column chromatography, be fit to industrialization, raw materials cost reduces greatly.

Described 2,4-two chloro-7-hydrogen-pyrrolo-es (2,3) pyrimidine is synthetic, synthesize (2) used alkali including but not limited to sodium acetate, potassium acetate by 1,3-dihydroxyl-5-amino aniline and monochloroacetaldehyde reaction, sodium bicarbonate, yellow soda ash etc., first-selected sodium acetate, solvent is including but not limited to tetrahydrofuran (THF), dioxane, the mixing solutions of glycol dimethyl ether and water etc., first-selected solution is tetrahydrofuran (THF)/water=1:1, temperature of reaction is not limited to zero degree to 100 degree, time was not limited to 0.5 hour to 48 hours, wherein because of the chlorine activity of monochloroacetaldehyde a little less than, the catalyzer that adds activation includes but not limited to potassiumiodide, sodium iodide.

Described 2,4-two chloro-7-hydrogen-pyrrolo-(2,3) pyrimidines are synthetic, by synthetic 2,4-, two chloro-7-hydrogen-pyrrolo-(2, the 3) pyrimidines of intermediate (2) reaction, upper chlorine reagent is including but not limited to sulfur oxychloride, oxalyl chloride, phosphorus oxychloride, dichlorophenyl oxygen phosphorus etc., first-selected dichlorophenyl oxygen phosphorus, temperature of reaction is not limited to 25 degree to 250 degree, first-selected 180 degree, and the time is not limited to half an hour to 72 hour, first-selected 4 hours, the organic bases that wherein adds is including but not limited to triethylamine, diisopropyl ethyl amine, N, accelerine, N, N-Diethyl Aniline, first-selected diisopropyl ethyl amine.

Above-mentioned is that the chemical reaction route of starting raw material is as follows with 1,3-dihydroxyl-5-amino aniline:

Embodiment

Preparation compound (2):

Starting raw material 1,3-dihydroxyl-5-amino aniline 250 grams (2.0 moles) are dissolved in tetrahydrofuran (THF)/water of 2.5 liters of 1:1, add the 50% monochloroacetaldehyde aqueous solution, 345.4 grams (2.2 moles), sodium acetate 328 grams (4.0 moles), potassiumiodide 0.5 gram, add rear room temperature reaction 24 hours, revolve tetrahydrofuran (THF), resistates is transferred PH to 11 with the sodium hydroxide of 1N, 1.5 liters of * 3 secondary clearings extractions of ethyl acetate, the organic phase washing, the saturated salt washing, anhydrous sodium sulfate drying filters, be spin-dried for, re-crystallizing in ethyl acetate obtains beige solid 256.7 grams (yield 85%).

Preparation compound (3) namely 2,4-two chloro-7-hydrogen-pyrrolo-(2,3) pyrimidines:

Compound (2) 151.1 grams (1.0 moles) that the upper step makes and dichlorophenyl oxygen phosphorus 429 grams (2.2 moles) and diisopropyl ethyl amine 222.2 grams (2.2 moles) mix; reaction solution is warmed up to 180 degree; reaction is 4 hours under the nitrogen protection; cool to room temperature; add 1 liter of anhydrous diethyl ether to resistates; stirred 1 hour, and filtered, vacuum-drying obtains pink solid 143.3 grams (yield 77%).

Do chlorinating agent with phosphorus oxychloride and prepare compound 2,4-two chloro-7-hydrogen-pyrrolo-(2,3) pyrimidines:

Compound (2) 151.1 grams (1.0 moles) that the upper step makes and phosphorus oxychloride 765 grams (5 moles) and diisopropyl ethyl amine 202.2 grams (2.0 moles) mix; reaction solution is warmed up to 130 degree; reaction is 24 hours under the nitrogen protection; cool to room temperature; evaporate excessive phosphorus oxychloride, add 1 liter of anhydrous diethyl ether to resistates, stirred 1 hour; filter, vacuum-drying obtains garnet solid 30.1 grams (yield 16%).

Claims

1. described is that starting raw material and monochloroacetaldehyde close ring with 1,3-dihydroxyl-5-amino aniline, and chlorination obtains 2,4-, two chloro-7-hydrogen-pyrrolo-es (2 again, 3) route of pyrimidine makes whole process yield high, easy handling, the good purifying of product, avoid column chromatography, be fit to industrialization, raw materials cost reduces greatly.

2. described 2,4-two chloro-7-hydrogen-pyrrolo-es (2,3) pyrimidine is synthetic, synthesize (2) used alkali including but not limited to sodium acetate, potassium acetate by 1,3-dihydroxyl-5-amino aniline and monochloroacetaldehyde reaction, sodium bicarbonate, yellow soda ash etc., first-selected sodium acetate, solvent is including but not limited to tetrahydrofuran (THF), dioxane, the mixing solutions of glycol dimethyl ether and water etc., first-selected solution is tetrahydrofuran (THF)/water=1:1, temperature of reaction is not limited to zero degree to 100 degree, time was not limited to 0.5 hour to 48 hours, wherein because of the chlorine activity of monochloroacetaldehyde a little less than, the catalyzer that adds activation includes but not limited to potassiumiodide, sodium iodide.

3. described 2,4-two chloro-7-hydrogen-pyrrolo-(2,3) pyrimidines are synthetic, by synthetic 2,4-, two chloro-7-hydrogen-pyrrolo-(2, the 3) pyrimidines of intermediate (2) reaction, upper chlorine reagent is including but not limited to sulfur oxychloride, oxalyl chloride, phosphorus oxychloride, dichlorophenyl oxygen phosphorus etc., first-selected dichlorophenyl oxygen phosphorus, temperature of reaction is not limited to 25 degree to 250 degree, first-selected 180 degree, and the time is not limited to half an hour to 72 hour, first-selected 4 hours, the organic bases that wherein adds is including but not limited to triethylamine, diisopropyl ethyl amine, N, accelerine, N, N-Diethyl Aniline, first-selected diisopropyl ethyl amine.