CN118852029B

CN118852029B - A method for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine

Info

Publication number: CN118852029B
Application number: CN202411319886.6A
Authority: CN
Inventors: 黄忠林; 曾淼; 宋肖锴; 沈洁; 郝建君; 徐剑锋
Original assignee: SUZHOU KAIYUAN MINSHENG CHEMICALS TECHNOLOGY CO LTD
Current assignee: SUZHOU KAIYUAN MINSHENG CHEMICALS TECHNOLOGY CO LTD
Priority date: 2024-09-23
Filing date: 2024-09-23
Publication date: 2025-02-07
Anticipated expiration: 2044-09-23
Also published as: CN118852029A

Abstract

The present invention is used in the technical field of organic synthesis, and discloses a method for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine, wherein malonic acid ester and guanidine hydrochloride or guanidine nitrate are used as raw materials, and 2-amino-4,6-dihydroxy-5-nitrosopyrimidine is prepared through cyclization reaction and nitrosation reaction, and 2-amino-4,6-dichloro-5-formamidopyrimidine is prepared through chlorination, selective hydrogenation reduction and formylation reaction. Through the route scheme of first chlorination and then reduction, the yield of the chlorination reaction is improved, the last continuous hydrolysis step is avoided, and the total yield is increased to 66.8%. In addition, the raw materials are simple, and the product competitiveness is improved.

Description

Method for preparing 2-amino-4, 6-dichloro-5-carboxamido pyrimidine

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a method for preparing 2-amino-4, 6-dichloro-5-formamidopyrimidine.

Background

Abacavir (Abacavir) and its sulfate are human immunodeficiency virus nucleoside reverse transcriptase inhibitors developed by GlaxoSmithKline, UK. Abaca Wei Shanfang formulations Ziagen were marketed 1999, after which the compound formulations were also marketed in batches. Abacavir is one of the important components of current multi-drug combination cocktail therapies.

Amino-4, 6-dichloro-5-carboxamido pyrimidine (FADCP) is an important intermediate for synthesizing abacavir, and according to the existing domestic and foreign patent and literature reports, the method for synthesizing FADCP mainly comprises the following three steps of:

The first method is to prepare 2-amino-4, 6-dihydroxypyrimidine by cyclization reaction and nitrosation and reduction reaction of diethyl malonate and guanidine hydrochloride as raw materials to prepare 2, 5-diamino-4, 6-dihydroxypyrimidine hydrochloride (DADHP). The chloride is prepared from DADHP, DMF and phosphorus oxychloride by Vilsmeier reaction. Under acidic conditions, through multi-step hydrolysis, FADCP is obtained. However, the overall yield of FADCP from DADHP was only 27.6%. The same reaction, glaxoWellcom company patent US5917041A, discloses a yield of 52.3%. To increase the yield, patent US6271376B discloses a reaction scheme for preparing 2, 5-diamino-4, 6-dichloropyrimidine from DADHP by chlorination, and then reacting with formic acid to obtain FADCP. Although the formylation reaction yield reaches 90%, the chlorination reaction yield is still lower than 65%.

The second method is to prepare FADCP by multi-step reaction by taking diethyl 2-oximinomalonate and guanidine hydrochloride as raw materials.

The third method is that 2-amino malonate hydrochloride or its derivative and guanidine hydrochloride are used as raw materials, and then the product is directly cyclized to obtain DADHP, and then hydrolyzed to obtain FADCP. The raw materials used in the second method and the third method are unusual raw materials, so that the sources are few, and homemade is needed.

Disclosure of Invention

The invention aims to provide a method for preparing 2-amino-4, 6-dichloro-5-formamidopyrimidine, which aims to solve the problems of less sources of raw materials, higher cost and low yield in the prior art.

In order to achieve the aim, the invention provides the following technical scheme that the method for preparing the 2-amino-4, 6-dichloro-5-formamidopyrimidine comprises the following steps:

S1, carrying out cyclization reaction on dimethyl malonate and guanidine hydrochloride in sodium methoxide/methanol solution, and acidifying after the reaction is finished and methanol is distilled off to obtain a compound shown in a formula II;

s2, nitrosation reaction, namely reacting the compound shown in the formula II with sodium nitrite and hydrochloric acid to obtain a compound shown in the formula III;

s3, a chlorination reaction, namely, reacting a compound shown in a formula III with a chlorinating agent to prepare a compound shown in a formula IV;

s4, carrying out reduction reaction, namely carrying out selective hydrogenation reduction on the compound shown in the formula IV under the action of a catalyst to obtain a compound shown in the formula V;

s5, formylation reaction, namely reacting a compound shown in a formula V with formic acid to generate a compound shown in a formula I, namely a target product;

the intermediates of the steps are as follows:

。

preferably, the chlorinating agent in S3 is triphosgene, thionyl chloride or phosphorus oxychloride.

Preferably, the catalyst in S4 is raney nickel, platinum carbon or palladium carbon.

Preferably, the reaction temperature of the selective hydrogenation reduction in the step S4 is 20-60 ℃.

Compared with the prior art, the method for preparing the 2-amino-4, 6-dichloro-5-formamido pyrimidine has the beneficial effects that the reaction route of chloridizing and then reducing the 2-amino-4, 6-dihydroxy-5-nitrosopyrimidine and finally formylating is adopted, so that the reaction yield of the chloridizing step is improved, the final continuous hydrolysis step is avoided, the total yield is improved to 66.8%, in addition, the raw materials are simple, and the product competitiveness is improved.

Drawings

FIG. 1 is a schematic diagram of a preparation process route of the present invention;

FIG. 2 is a diagram of the HNMR spectrum of the present invention FADCP ¹.

Detailed Description

The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

Referring to FIG. 1, the invention provides a technical scheme of a method for preparing 2-amino-4, 6-dichloro-5-carboxamido pyrimidine, which comprises the following steps:

s3, a chlorination reaction, namely, reacting a compound shown in a formula III with a chlorinating agent to obtain a compound shown in a formula IV, wherein the chlorinating agent is triphosgene, thionyl chloride or phosphorus oxychloride;

S4, carrying out reduction reaction, namely carrying out selective hydrogenation reduction on the compound shown in the formula IV under the action of a catalyst to obtain a compound shown in the formula V, wherein the catalyst is Raney nickel, platinum carbon or palladium carbon, and the reaction temperature of the selective hydrogenation reduction is 20-60 ℃;

S5, formylation reaction, namely reacting the compound shown in the formula V with formic acid to generate a compound shown in the formula I, namely a target product.

The intermediates of the steps are as follows:

。

Example 1 preparation of 2-amino-4, 6-dihydroxypyrimidine (II):

into a four-port reaction flask, 298.7g of 28% sodium methoxide solution and 86.4g of guanidine hydrochloride were introduced, and the mixture was stirred and heated to 50℃to dropwise add 114.4g of dimethyl malonate. After the completion of the dropwise addition, the reaction was continued at 50℃for 3 hours. After the reaction, methanol was recovered by distillation under reduced pressure. 400g of water and then concentrated hydrochloric acid are added to the distillation residues to adjust the pH to 3-4, and 165g of dehydrohydrochloric acid is shared. And cooling the reaction liquid to room temperature, carrying out suction filtration, and drying the solid to obtain the 2-amino-4, 6-dihydroxypyrimidine.

Example 2 preparation of 2-amino-4, 6-dihydroxy-5-nitrosopyrimidine (III):

In a reaction flask, 208g of compound II prepared in example 1, 320g of water and 30% aqueous sodium hydroxide solution were charged, and the mixture was stirred and heated to 40℃to add 63.5g of sodium nitrite. And (3) dropwise adding concentrated hydrochloric acid to adjust the pH to 2-3, and after finishing dropwise adding, keeping the temperature at 50 ℃ and stirring for 2 hours. The reaction solution is cooled to room temperature, suction filtration and solid drying are carried out, 116.0g of 2-amino-4, 6-dihydroxyl-5-nitrosopyrimidine is obtained, the purity is 98.2%, and the total yield of the two steps is 85.8%.

EXAMPLE 3 preparation of 2-amino-4, 6-dichloro-5-nitrosopyrimidine (IV):

15.6g of compound III and 61.2g of phosphorus oxychloride were charged into the reaction flask. Heating to 45-50 ℃, dropwise adding 40.4g of triethylamine, heating to 100-105 ℃ after the dropwise adding is finished, and carrying out heat preservation reaction for 3h. The liquid phase detection raw material is less than 0.5%, and the reaction is finished. Toluene is added into the reaction liquid, cooled to room temperature, poured into an ice-water mixture and stirred until all phosphorus oxychloride is decomposed. The organic phase was separated, the aqueous phase was extracted with toluene and the organic phase was incorporated. The organic phase is washed to be neutral by sodium bicarbonate, the toluene is concentrated under reduced pressure, the solid is separated out after the concentrated solution is cooled, the solid is filtered by suction, washed by water and dried to obtain 17.6g of 2-amino-4, 6-dichloro-5-nitrosopyrimidine, the purity is 98.8%, and the yield is 91.2%.

EXAMPLE 4 preparation of 2, 5-diamino-4, 6-dichloropyrimidine (V):

In a 500ml autoclave, 13.5g of Compound IV, 0.5g of 5% Pt/C and 150ml of methanol were charged. After the nitrogen and hydrogen substitution, the hydrogen pressure was maintained at 11MPa. Stirring is started, and the reaction temperature is controlled to be 30-40 ℃. After about 4 hours there is no more hydrogen pressure drop. Decompression, kettle opening and suction filtration. The filtrate is concentrated to obtain 12.1g of 2, 5-diamino-4, 6-dichloropyrimidine with the purity of 98.5 percent and the yield of 96.6 percent.

EXAMPLE 5 preparation of 2-amino-4, 6-dichloro-5-carboxamido pyrimidine (I):

And adding 17.9g of compound V and 92g of 99% anhydrous formic acid into a reaction bottle, heating to 50-55 ℃ and reacting for 5h. Toluene was added and excess formic acid was removed by azeotropic distillation under reduced pressure. After distillation, cooling, filtering, washing and drying the solid to obtain 18.3g of target product 2-amino-4, 6-dichloro-5-formamidopyrimidine, wherein the purity is 98.2%, and the yield is 88.4%.

Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.

Claims

1. A method for preparing 2-amino-4, 6-dichloro-5-carboxamido pyrimidine is characterized in that the method comprises the following steps:

the intermediates of the steps are as follows:

。

2. A process for preparing 2-amino-4, 6-dichloro-5-carboxamido pyrimidine according to claim 1 wherein the catalyst in S4 is Raney nickel, platinum carbon or palladium carbon.

3. The method for preparing 2-amino-4, 6-dichloro-5-carboxamido pyrimidine according to claim 1, wherein the reaction temperature of the selective hydrogenation reduction in S4 is 20-60 ℃.