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

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

Technical Field

[0001] 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 Art

[0002] Abacavir and its sulfate are human immunodeficiency virus nucleoside reverse transcriptase inhibitors developed by GlaxoSmithKline, a British company. Ziagen, a single-drug abacavir preparation, was launched in 1999, and compound preparations were subsequently approved for marketing. Abacavir is one of the important components of the current multi-drug cocktail therapy.

[0003] Amino-4,6-dichloro-5-formamidopyrimidine (FADCP) is an important intermediate for the synthesis of abacavir. According to existing domestic and foreign patents and literature reports, there are three main methods for synthesizing FADCP from different raw materials:

[0004] The first method: using diethyl malonate and guanidine hydrochloride as raw materials, 2-amino-4,6-dihydroxypyrimidine is obtained by cyclization reaction, and then 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride (DADHP) is obtained by nitrosation and reduction reaction. The chloride is obtained by Vilsmeier reaction of DADHP, DMF and phosphorus oxychloride. FADCP is obtained by multi-step hydrolysis under acidic conditions. However, the total yield of FADCP obtained from DADHP is only 27.6%. For the same reaction, GlaxoWellcome's patent US5917041A discloses a yield of 52.3%. In order to improve the yield, patent US6271376B discloses a reaction route of obtaining 2,5-diamino-4,6-dichloropyrimidine from DADHP by chlorination, and then reacting with formic acid to obtain FADCP. Although the yield of its formylation reaction is 90%, the yield of the chlorination reaction is still low at 65%.

[0005] The second method: using diethyl 2-oximemalonate and guanidine hydrochloride as raw materials, FADCP is prepared through a multi-step reaction.

[0006] The third method: using 2-aminomalonate hydrochloride or its derivatives and guanidine hydrochloride as raw materials, directly cyclizing to obtain DADHP, and then hydrolyzing to obtain FADCP. The raw materials used in the second and third methods are uncommon raw materials with few sources and need to be made by themselves. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine, so as to solve the problems of limited raw material sources, high cost and low yield proposed in the above background technology.

[0008] To achieve the above object, the present invention provides the following technical solution: a method for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine, the method comprising the following steps:

[0009] S1. Cyclization reaction: dimethyl malonate and guanidine hydrochloride are reacted in a sodium methoxide / methanol solution, and the methanol is evaporated and acidified after the reaction to obtain a compound of formula II;

[0010] S2. Nitrosation reaction: The compound represented by formula II is reacted with sodium nitrite and hydrochloric acid to obtain a compound represented by formula III;

[0011] S3. Chlorination reaction: The compound represented by formula III reacts with a chlorinating agent to obtain a compound represented by formula IV;

[0012] S4. Reduction reaction: The compound represented by formula IV is selectively hydrogenated and reduced in the presence of a catalyst to obtain a compound represented by formula V;

[0013] S5. Formylation reaction: The compound represented by formula V reacts with formic acid to generate a compound represented by formula I, i.e., the target product;

[0014] The intermediates of the above steps are as follows:

[0015] .

[0016] Preferably, the chlorinating agent in S3 is triphosgene, thionyl chloride or phosphorus oxychloride.

[0017] Preferably, the catalyst in S4 is Raney nickel, platinum carbon or palladium carbon.

[0018] Preferably, the reaction temperature of the selective hydrogenation reduction in S4 is 20 to 60°C.

[0019] Compared with the prior art, the invention has the following beneficial effects: the method for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine adopts a reaction route of first chlorinating 2-amino-4,6-dihydroxy-5-nitrosopyrimidine, then reducing it, and finally formylation, thereby improving the reaction yield of the chlorination step, avoiding the final continuous hydrolysis step, and improving the total yield to 66.8%; in addition, the raw materials are simple, and the product competitiveness is improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is a schematic diagram of the preparation process route of the present invention;

[0021] Figure 2 FADCP 1 HNMR spectrum. DETAILED DESCRIPTION

[0022] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0023] See also Figure 1 The present invention provides a technical solution: a method for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine, the method comprising the following steps:

[0024] S1. Cyclization reaction: dimethyl malonate and guanidine hydrochloride are reacted in a sodium methoxide / methanol solution, and the methanol is evaporated and acidified after the reaction to obtain a compound of formula II;

[0025] S2. Nitrosation reaction: The compound represented by formula II is reacted with sodium nitrite and hydrochloric acid to obtain a compound represented by formula III;

[0026] S3. Chlorination reaction: The compound represented by formula III reacts with a chlorinating agent to obtain a compound represented by formula IV; the chlorinating agent is triphosgene, thionyl chloride or phosphorus oxychloride;

[0027] S4. Reduction reaction: The compound represented by formula IV is selectively hydrogenated and reduced in the presence of a catalyst to obtain a compound represented by formula V; the catalyst is Raney nickel, platinum carbon or palladium carbon; the reaction temperature for selective hydrogenation reduction is 20 to 60 ° C;

[0028] S5. Formylation reaction: The compound represented by formula V reacts with formic acid to generate the compound represented by formula I, i.e., the target product.

[0029] The intermediates of the above steps are as follows:

[0030] .

[0031] Example 1: Preparation of 2-amino-4,6-dihydroxypyrimidine (II):

[0032] Add 298.7g of 28% sodium methoxide solution and 86.4g of guanidine hydrochloride into a four-necked reaction bottle, stir and heat to 50°C, and add 114.4g of dimethyl malonate dropwise. After the addition is completed, keep the temperature at 50°C for 3h. After the reaction is completed, recover the methanol by vacuum distillation. Add 400g of water to the distillation residue, add concentrated hydrochloric acid to adjust the pH to 3-4, and use 165g of hydrochloric acid. Cool the reaction solution to room temperature, filter with suction, and dry the solid to obtain 2-amino-4,6-dihydroxypyrimidine.

[0033] Example 2: Preparation of 2-amino-4,6-dihydroxy-5-nitrosopyrimidine (III):

[0034] In a reaction flask, add compound II prepared in Example 1, 320g of water and 208g of 30% sodium hydroxide aqueous solution, stir and heat to 40°C, add 63.5g of sodium nitrite. Add concentrated hydrochloric acid dropwise to adjust the pH to 2-3, drip it in about 1 hour, and keep stirring at 50°C for 2 hours. The reaction solution is cooled to room temperature, filtered, and the solid is dried to obtain 116.0g of 2-amino-4,6-dihydroxy-5-nitrosopyrimidine with a purity of 98.2% and a total yield of 85.8% for the two-step reaction.

[0035] Example 3: Preparation of 2-amino-4,6-dichloro-5-nitrosopyrimidine (IV):

[0036] Add 15.6g of compound III and 61.2g of phosphorus oxychloride to the reaction flask. Heat to 45-50°C, add 40.4g of triethylamine dropwise, heat to 100-105°C, and keep warm for 3h. Liquid phase detection shows that the raw material is less than 0.5%, and the reaction is over. Add toluene to the reaction solution, cool to room temperature, pour into an ice-water mixture, and stir until all phosphorus oxychloride is decomposed. Separate the organic phase, extract the aqueous phase with toluene, and merge it into the organic phase. Wash the organic phase with sodium bicarbonate until neutral, concentrate toluene under reduced pressure, and precipitate solids after the concentrate is cooled. Filter, wash the solids with water, and dry to obtain 17.6g of 2-amino-4,6-dichloro-5-nitrosopyrimidine with a purity of 98.8% and a yield of 91.2%.

[0037] Example 4: Preparation of 2,5-diamino-4,6-dichloropyrimidine (V):

[0038] In a 500ml high-pressure reactor, add 13.5g of compound IV, 0.5g of 5% Pt / C, and 150ml of methanol. After nitrogen and hydrogen replacement, the hydrogen pressure is maintained at 11MPa. Start stirring and control the reaction temperature at 30-40°C. After about 4 hours, there is no more hydrogen pressure drop. Release the pressure, open the reactor, and filter. The filtrate is concentrated to obtain 12.1g of the product 2,5-diamino-4,6-dichloropyrimidine, with a purity of 98.5% and a yield of 96.6%.

[0039] Example 5: Preparation of 2-amino-4,6-dichloro-5-formamidopyrimidine (I):

[0040] Add 17.9 g of compound V and 92 g of 99% anhydrous formic acid into the reaction flask, heat to 50-55°C, and react for 5 h. Add toluene and remove excess formic acid by azeotropic distillation under reduced pressure. After the distillation is completed, cool, filter, wash the solid with water, and dry to obtain 18.3 g of the target product 2-amino-4,6-dichloro-5-formamidopyrimidine with a purity of 98.2% and a yield of 88.4%.

[0041] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine, characterized in that: The method comprises the following steps: S1. Cyclization reaction: dimethyl malonate and guanidine hydrochloride are reacted in a sodium methoxide / methanol solution, and the methanol is evaporated and acidified after the reaction to obtain a compound of formula II; S2. Nitrosation reaction: The compound represented by formula II is reacted with sodium nitrite and hydrochloric acid to obtain a compound represented by formula III; S3. Chlorination reaction: The compound represented by formula III reacts with a chlorinating agent to obtain a compound represented by formula IV; the chlorinating agent is triphosgene, thionyl chloride or phosphorus oxychloride; S4. Reduction reaction: The compound represented by formula IV is selectively hydrogenated and reduced in the presence of a catalyst to obtain a compound represented by formula V; S5. Formylation reaction: The compound represented by formula V reacts with formic acid to generate a compound represented by formula I, i.e., the target product; The intermediates of the above steps are as follows: 。 2. A method for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine according to claim 1, characterized in that: The catalyst in S4 is Raney nickel, platinum carbon or palladium carbon.

3. A method for preparing 2-amino-4,6-dichloro-5-formamidopyrimidine according to claim 1, characterized in that: The reaction temperature of the selective hydrogenation reduction in S4 is 20-60°C.

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