CN110818714A

CN110818714A - Synthetic method of entecavir intermediate

Info

Publication number: CN110818714A
Application number: CN201810923238.XA
Authority: CN
Inventors: 张磊; 贺绍杰; 苏旭; 刘纯军; 涂金荣
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd; Lianyungang Runzhong Pharmaceutical Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd; Lianyungang Runzhong Pharmaceutical Co Ltd
Priority date: 2018-08-14
Filing date: 2018-08-14
Publication date: 2020-02-21

Abstract

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.

Description

Synthetic method of entecavir intermediate

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

Example 1

Synthesis of 2- [ (triphenylmethyl) amino ] -6-benzyloxy-9H-purine, a compound of formula II-a:

188kg of DMF and 40kg of the compound of the formula IV are added into a glass lining reaction tank under stirring, and stirred for 10 minutes at-5 to +5 ℃ to dissolve the clear solution (even if a small amount of undissolved clear solution does not affect the reaction). The temperature of the feed liquid is controlled to be-10 to-5 ℃, 46.6kg of triphenylchloromethane and 24L of triethylamine are slowly added in 19 batches, and the interval of each batch is 10 min. After the addition, the mixture is kept warm and is continuously stirred for reaction for 0.5 to 1 hour. Detection, HPLC < 5%. And (3) filtering by throwing, adding a filter cake into a glass lining reaction tank, adding dichloromethane and water, pulping at 35 +/-5 ℃ and stirring for 2 hours, separating a DCM phase, adding 40kg of DCM into a water phase, extracting, combining the DCM phases, and evaporating to dryness to obtain a crude compound of the formula II-a.

Refining:

adding the crude product of the compound shown in the formula II-a into a 1L reaction bottle, adding 1V dichloromethane and 3V acetone, heating to reflux for 1h, cooling to 20-30 ℃, performing suction filtration, performing forced air drying on a filter cake at 50 ℃ overnight, and performing HPLC calibration on the purity of 99.5% to obtain the total yield of 79% after reaction and purification.

Example 2

Synthesis of Compounds of formula I-a

Adding 10.0kg of anhydrous DMF and 2.57kg of 2- [ (triphenylmethyl) amino ] -6-benzyloxy-9H-purine which is a compound of formula II-a into a reaction tank under stirring, stirring for 10min, adding 28.5g of lithium hydride, heating to 58-62 ℃, and stirring for 30min after reaching the temperature; the DMF solution of the compound of formula III-a is added dropwise at a temperature of 60 +/-3 ℃. After the dropwise addition, the temperature is raised to 116 ℃ and 120 ℃, the stirring reaction is carried out for 0.5h, sampling HPLC detection shows that the compound of the formula I-a in the reaction liquid is 63.92 percent, and the other 3 isomers are 1.52 percent, 6.91 percent and 15.53 percent respectively, and the post-treatment is carried out after the reaction is finished. After the reaction is finished, cooling to 70 ℃, slowly adding purified water, concentrating under reduced pressure until the liquid does not flow out basically, namely adding ethyl acetate, stirring to dissolve, adding purified water, cooling to 10-15 ℃, stirring and crystallizing for more than 12 hours; filtering (solid retention), separating out an organic phase, washing the organic phase twice by using 10% of salt water, drying the organic phase by using anhydrous sodium sulfate, concentrating the dried organic phase to be dry (adding ethyl acetate and normal hexane for concentrating and drying once respectively), adding dichloromethane for dissolving and clearing after concentrating and drying, and putting down for later use. Column chromatography: dry loading on silica gel with a diameter to height ratio of 1/5, wetting with dichloromethane, adding a dichloromethane solution of the compound of formula i-a (loading), adsorbing, adding 6.0Kg of dichloromethane, adsorbing once more, and eluting with V dichloromethane: and V, methanol is 100:1, and the column elution is carried out until the column passing is finished. The total yield after reaction and purification was 58.5%.

Example 3

Synthesis of Compounds of formula III

To a solution of compound of formula IV 6-benzyloxyguanine (46.489g, 192.9mmol) in anhydrous DMF (250ml, dried overnight in a vacuum oven at 50 ℃ C.) was added lithium hydride (0.772g, 96.45 mmol). After stirring the mixture at room temperature for 10 minutes, the mixture was heated at 60 ℃ for 15 minutes and then a solution of compound of formula II (29.9g, 96.45mmol) in dry DMF (150mL) was added. The resulting dark brown solution was stirred at 60 ℃ for 15 minutes and the temperature of the mixture was raised to 125 ℃ over 45 minutes. After 2 hours of reaction at 125 ℃, a sample is taken for HPLC detection, and the target product, namely the compound III in the formula, in the reaction liquid is 51.18%, and the other 3 isomers are respectively 2.90%, 5.30% and 27.24%.

Claims

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

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.