阅读说明：本技术 一种恩替卡韦中间体的合成方法 (Synthetic method of entecavir intermediate ) 是由 张磊 贺绍杰 苏旭 刘纯军 涂金荣 于 2018-08-14 设计创作，主要内容包括：本发明涉及一种恩替卡韦中间体的合成方法,具体而言,涉及一种式Ⅰ化合物的合成方法,该方法先将6-苄氧基鸟嘌呤的氨基进行保护,该步骤避免了柱层析,再发生开环反应,提高了开环反应生成目标产物式Ⅰ化合物的选择性,进而提高了收率和纯度。<Image he="314" wi="534" file="DDA0001764762140000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a method for synthesizing an entecavir intermediate, in particular to a method for synthesizing a compound shown in a formula I.)

1. A process for preparing an entecavir intermediate compound of formula i comprising:

(1) reacting the compound shown in the formula IV with triphenylchloromethane or substituted triphenylchloromethane in a base and a solvent to generate a compound shown in the formula II, wherein the solvent is selected from one or more of DMF, DMSO and N-methylpyrrolidone, the base is selected from one of triethylamine, N-diisopropylethylamine and diethylamine,

(2) reacting a compound shown in the formula II with a compound shown in the formula III in a base and DMF to obtain a compound shown in the formula I, wherein the base is selected from one of lithium hydride or sodium hydride,

wherein R is₁Is triphenylmethyl or substituted triphenylmethyl, R₂、R₃Is benzyl or substituted benzyl.

2. The method according to claim 1, wherein the solvent used in step (1) is DMF.

3. The preparation method according to claim 1, wherein the mass ratio of the solvent used in step (1) to the compound of formula IV is 4 to 5.5: 1.

4. the process according to claim 1, wherein the base used in the step (1) is triethylamine.

5. The production process according to any one of claims 1 to 4, wherein the reaction temperature in the step (1) is from-10 to-5 ℃.

6. The process according to claim 1, wherein the purification of the compound of formula II in step (1) is carried out by slurrying with methylene chloride and acetone.

7. The process according to claim 1, wherein the ratio of the molar amount of the base used in the step (2) to the compound of the formula III is 1.1 to 2: 1.

Technical Field

The invention relates to the field of pharmacy, in particular to a method for synthesizing an entecavir intermediate.

Background

Entecavir (entecavir) is a carbocyclic guanosine analog and is a potent therapeutic against hepatitis b virus. The compound of formula I is an important intermediate for synthesizing entecavir.

WO9809964 describes a process for the preparation of a carbocyclic nucleoside, which is essentially a synthesis of a cyclopentane epoxide, followed by direct opening of the oxygen ring with 6-benzyloxyguanine under base catalysis, which has the following disadvantages:

1. the ring-opening reaction has low selectivity, and when the ring-opening reaction is catalyzed by alkali, two C-O bonds of an epoxy part in a compound II in the formula are likely to be broken, and two attack sites exist: n in 6-benzyloxyguanine₇Or N₉Therefore, the ring-opening reaction of the step can generate 4 isomers, so that the selectivity of the ring-opening reaction is low, and further the yield is low, the conversion rate of the ring-opening reaction in WO9809964 is 51%, and the yield of the crude product obtained by the ring-opening reaction is 80-85%; the yield of the protecting group on the amino group on the guanine in the next step in WO9809964 is 82 percent; therefore, the total yield of the two steps is lower than 35 percent.

2. The protection of the amino group on guanine in subsequent reactions is difficult, the reaction is complicated to separate and requires the use of column chromatography, for example, WO9809964 reports that the reaction in which the amino group on guanine is protected with MMT is difficult to complete, the product needs to be subjected to silica gel column chromatography during subsequent purification, and the product is easily decomposed on silica gel.

Disclosure of Invention

The invention aims to provide a method for synthesizing an entecavir intermediate compound shown as a formula I.

The synthesis method provided by the invention comprises the following steps:

(1) reacting the compound shown in the formula IV with triphenylchloromethane or substituted triphenylchloromethane in a base and a solvent to generate a compound shown in the formula II, wherein the solvent is selected from one or more of DMF, DMSO and N-methylpyrrolidone, the base is selected from one of triethylamine, N-diisopropylethylamine and diethylamine,

(2) reacting a compound shown in the formula II with a compound shown in the formula III in a base and DMF to obtain a compound shown in the formula I, wherein the base is selected from one of lithium hydride or sodium hydride,

wherein R is₁Is triphenylmethyl or substituted triphenylmethyl, R₂、R₃Is benzyl or substituted benzyl.

In some embodiments, the solvent used in step (1) is DMF; in some embodiments, the mass ratio of the solvent used in step (1) to the compound of formula iv is 4 to 5.5: 1.

in some embodiments, the base used in step (1) is triethylamine.

In some embodiments, the reaction temperature of step (1) is from-10 to-5 ℃; in some embodiments, the compound of formula II obtained in step (1) is purified by slurrying with dichloromethane and acetone.

In some embodiments, the ratio of the molar amount of base used in step (2) to the compound of formula III is from 1.1 to 2: 1.

in a specific embodiment, the amino group of 6-benzyloxyguanine is protected to obtain a compound of formula II-a, namely 2- [ (triphenylmethyl) amino ] -6-benzyloxy-9H-purine, then the compound of formula II-a and the compound of formula III-a are subjected to a ring-opening reaction of a 1, 2-epoxy compound, the reaction solution of the ring-opening reaction is subjected to high performance liquid detection, the target product of the ring-opening reaction, namely the compound of formula I-a accounts for 63.92%, and the sum of the other three isomers is 23.95%; in the step of generating the compound III in the formula disclosed in WO9809964, the reaction liquid is subjected to high performance liquid detection, the compound III in the target product of the ring opening reaction accounts for 51.18%, and the sum of the other three isomers is 35.44%. According to the technical scheme, the amino of the 6-benzyloxy guanine is protected, and column chromatography is avoided in the step. In addition, the amino of the nucleophilic reagent 6-benzyloxy guanine is protected, and then the ring-opening reaction is carried out, so that the steric hindrance of the nucleophilic reagent is increased, the selectivity of the target product compound shown in the formula I generated by the ring-opening reaction is improved, and the yield and the purity are further improved.

Detailed Description