CN-117209435-B - Method for preparing 2, 6-dimethoxy-4-aminopyrimidine through micro-channel

CN117209435BCN 117209435 BCN117209435 BCN 117209435BCN-117209435-B

Abstract

The invention discloses a method for preparing 2, 6-dimethoxy-4-aminopyrimidine through a micro-channel, which comprises the steps of taking 2,4, 6-trichloropyrimidine as a raw material, reacting with sodium methoxide solution in a micro-reactor to obtain a methanol solution of 2, 6-dimethoxy-4-chloropyrimidine, carrying out aftertreatment, dissolving the 2, 6-dimethoxy-4-chloropyrimidine with toluene to obtain a toluene solution thereof, carrying out coupling reaction on the obtained toluene solution with a mixed solution of sodium cyanate, methanol, palladium catalyst, ligand and toluene to obtain (4, 6-dimethoxy pyrimidine-2-yl) carbamic acid tertiary methyl ester, and then carrying out reaction with hydrochloric acid to obtain 2, 6-dimethoxy-4-aminopyrimidine. Compared with the traditional synthesis route, the method adopts a continuous synthesis mode of the microreactor, greatly shortens the synthesis steps, and has the advantages of simple synthesis, simple operation, high yield, no need of extremely toxic and high-risk materials.

Inventors

YANG JI
DING ZUNLIANG
HE JIA
MAO DEWEN
LI XIAOLONG
LI WENHUI
Ye shanhai

Assignees

浙江海昇药业股份有限公司

Dates

Publication Date: 20260512
Application Date: 20230804

Claims (4)

1. A method for preparing 2, 6-dimethoxy-4-aminopyrimidine through a microchannel, comprising the steps of: S1, preparing 2, 6-dimethoxy-4-chloropyrimidine, namely respectively adding a methanol solution of trichloropyrimidine and a sodium methoxide methanol solution into a micro-reactor to react by a metering pump, distilling the obtained reaction liquid in a reaction bottle to recover methanol, then adding water and toluene, extracting for phase separation, and separating and discarding a water phase to obtain a toluene organic phase of the 2, 6-dimethoxy-4-chloropyrimidine; S2, preparing N- (2, 6-dimethoxy-4-pyrimidinyl) methyl carbamate, namely respectively adding sodium cyanate, a palladium catalyst, methanol, an acid binding agent, a ligand and toluene, stirring to obtain a sodium cyanate mixed solution, respectively pumping the sodium cyanate mixed solution and a toluene solution of 2, 6-dimethoxy-4-chloropyrimidine into a microreactor through a metering pump for heating reaction to obtain a toluene solution of N- (2, 6-dimethoxy-4-pyrimidinyl) methyl carbamate after the reaction is finished, adding water for extraction and phase separation, separating a water phase, distilling and recovering toluene, and then adding methanol to obtain a methanol solution of N- (2, 6-dimethoxy-4-pyrimidinyl) methyl carbamate; S3, preparing 2, 6-dimethoxy-4-aminopyrimidine, namely respectively pumping diluted hydrochloric acid and a methanol solution of N- (2, 6-dimethoxy-4-pyrimidinyl) carbamic acid methyl ester into a microreactor to react by a metering pump, transferring a reaction solution into a reaction bottle, adding liquid alkali to adjust pH to be neutral, separating out materials, filtering to remove a methanol aqueous solution, washing a filter cake by water to obtain a wet 2, 6-dimethoxy-4-aminopyrimidine product, and drying to obtain a dry 2, 6-dimethoxy-4-aminopyrimidine product; In the step S1, the reaction temperature in the micro-reactor is 0-25 ℃, and the reaction residence time is 30-180 seconds; In the step S2, the reaction temperature of the toluene solution of 2, 6-dimethoxy-4-chloropyrimidine in the sodium cyanate solution in the micro-reactor is 120-155 ℃ and the reaction time is 80-120S, wherein the palladium catalyst is one of palladium chloride, palladium acetate, DBA palladium and triphenylphosphine palladium chloride, the ligand is one of triphenylphosphine and dppf, and the acid binding agent is one of diisopropylethylamine and triethylamine; In the step S3, the reaction temperature of the methanol solution of the N- (2, 6-dimethoxy-4-pyrimidinyl) methyl carbamate and the diluted hydrochloric acid in a microreactor is 50-60 ℃ and the reaction time is 30-50S.
2. The method for preparing 2, 6-dimethoxy-4-aminopyrimidine through the micro-channel according to claim 1, wherein in the step S1, the molar ratio of trichloropyrimidine to sodium methoxide to methanol is 1 (2.0-2.2): 10-22.
3. The method for preparing 2, 6-dimethoxy-4-aminopyrimidine through the micro-channel according to claim 1, wherein in the step S2, the molar ratio of 2, 6-dimethoxy-4-chloropyrimidine, sodium cyanate, palladium catalyst, ligand, acid binding agent, methanol and toluene is 1 (1.00-1.30): (0.03-0.10): (0.05-0.15): (0.08-2.00): (1.00-10.00): (5.50-17.00).
4. The method for preparing 2, 6-dimethoxy-4-aminopyrimidine through micro-channel according to claim 1, wherein in the step S3, the molar ratio of N- (2, 6-dimethoxy-4-pyrimidinyl) carbamate to diluted hydrochloric acid is 1 (1.0-5.0).

Description

Method for preparing 2, 6-dimethoxy-4-aminopyrimidine through micro-channel Technical Field The invention belongs to the technical field of medicine synthesis, and particularly relates to a novel synthetic route preparation method and application of 2, 6-dimethoxy-4-aminopyrimidine. Background The prior art methods for synthesizing 2, 6-dimethoxy-4-aminopyrimidine mainly include (1) literature Diaminouracil Hydrochloride [ J ] Organic Syntheses,1957,37:15-17 and Synthesis of Purine Antiviral SAgents,Hypoxanthine and 6-Mercaptopurine[J]Russian Journal of Organic Chemistry,2002,38(7): 1053-1055 Uses urea and ethyl cyanoacetate as starting materials, and synthesizes 2, 6-dimethoxy-4-aminopyrimidine through cyclization, chlorination, and oxidation. The method mainly uses ethyl cyanoacetate with high toxicity as a raw material. (2) In the literature Preparation of 4-Aminouracil [ P ] US2804459,1957.08.27 and Preparation of Cyanoacetyl Ureas [ P ] US2553022,1951-05-15, russel D et al report that the synthesis of 2, 6-dihydroxy-4-aminopyrimidine from cyanuric acid as a raw material, the chlorination of 2, 6-dihydroxy-4-aminopyrimidine with phosphorus oxychloride, and the final reaction with sodium methoxide to obtain 2, 6-dimethoxy-4-aminopyrimidine, but the first step of the method uses water as a solvent, which can lead to material decomposition and affect the yield. (3) In Guangdong chemical industry, 1993 (4): 49-50, it is described that phosphorus oxychloride and barbituric acid are firstly used to generate trichloropyrimidine, and then ammonification is carried out to obtain 2, 6-dimethoxy-4-aminopyrimidine, 4, 6-dichloro-2-amino-pyrimidine, and the former is taken for methoxylation to obtain 4-amino-2, 6-dimethoxy pyrimidine, or a method of first methoxylation and then separation can be adopted, and a large amount of isomers are generated in the ammonification process, so that the impurities are more and the yield is low. (4) In chemical journal 2020,34 (09): 12, the green process for synthesizing 4-amino-2, 6-dimethoxy pyrimidine by using 4-amino-2, 6-dihydroxy pyrimidine sodium salt as raw material and dimethyl carbonate as green methyl reagent in one step can avoid the generation of phosphorus-containing wastewater, but has lower yield. In view of this, there is a need to develop a synthetic route and a preparation method of 2, 6-dimethoxy-4-aminopyrimidine with simple reaction conditions and high product yield. Disclosure of Invention In order to solve the defects of the prior art, the invention aims to provide a preparation method of 2, 6-dimethoxy-4-aminopyrimidine with simple reaction conditions and high product yield. In order to achieve the above object, the present invention adopts the following technical scheme: a preparation method of 2, 6-dimethoxy-4-aminopyrimidine, which comprises the following steps: S1, preparing 2, 6-dimethoxy-4-chloropyrimidine, namely respectively adding a methanol solution of trichloropyrimidine and a sodium methoxide methanol solution into a microreactor to react by a metering pump, distilling the obtained reaction liquid in a reaction bottle to recover methanol, then adding water and toluene, extracting for phase separation, separating and discarding a water phase to obtain a toluene organic phase of the 2, 6-dimethoxy-4-chloropyrimidine, wherein the reaction equation is as follows: S2, respectively adding sodium cyanate, a palladium catalyst, a ligand, methanol, an acid binding agent and toluene into a flask, stirring to obtain sodium cyanate mixed solution, respectively pumping the sodium cyanate mixed solution and a toluene solution of 2, 6-dimethoxy-4-chloropyrimidine into a microreactor through a metering pump, heating for reaction to obtain a toluene solution of (4, 6-dimethoxy-pyrimidin-2-yl) carbamic acid tertiary methyl ester after the reaction is finished, adding water for extraction and phase separation, separating and discarding a water phase, distilling and recovering toluene, and then adding methanol to obtain a methanol solution of (4, 6-dimethoxy-pyrimidin-2-yl) carbamic acid tertiary methyl ester, wherein the reaction equation is as follows: S3, preparing 2, 6-dimethoxy-4-aminopyrimidine, namely respectively pumping diluted hydrochloric acid and a methanol solution of (4, 6-dimethoxy-2-yl) carbamic acid tertiary methyl ester into a microreactor for reaction through a metering pump, transferring a reaction solution into a reaction bottle, adding liquid alkali to adjust pH to be neutral, separating out materials, filtering to remove a methanol aqueous solution, washing a filter cake with water to obtain a wet 2, 6-dimethoxy-4-aminopyrimidine product, and drying to obtain a dry 2, 6-dimethoxy-4-aminopyrimidine product, wherein the reaction equation is as follows: Preferably, in the step S1, the sodium alkoxide is sodium methoxide, and the solvent is methanol. Preferably, in the step S1, the molar ratio of the trichloropyrimidine to the sodium methoxide t