CN112661757B

CN112661757B - Method for synthesizing valganciclovir hydrochloride

Info

Publication number: CN112661757B
Application number: CN202011543922.9A
Authority: CN
Inventors: 刘振强; 刘新元; 梁丙辰; 王宇栋
Original assignee: Hebei Hejia Pharmatech Group Co ltd
Current assignee: Hebei Hejia Pharmatech Group Co ltd
Priority date: 2020-12-23
Filing date: 2020-12-23
Publication date: 2022-07-22
Anticipated expiration: 2040-12-23
Also published as: CN112661757A

Abstract

The invention discloses a method for synthesizing valganciclovir hydrochloride, which takes 1, 3-dichloro-2-acetoxy methoxypropane as an initial raw material, and prepares the valganciclovir hydrochloride through esterification, hydrolysis and deprotection to form salt. The invention provides a method for synthesizing valganciclovir hydrochloride, which avoids the problem of separation and transformation of N-7 and N-9 isomers in a diacetyl guanine condensation process, directly synthesizes monochloro ganciclovir without ganciclovir, replaces the synthesis of monoacetyl ganciclovir in the prior art, and avoids the problem of separation of diester derivatives caused by ganciclovir residue.

Description

Method for synthesizing valganciclovir hydrochloride

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing valganciclovir hydrochloride.

Background

Valganciclovir hydrochloride is a Cytomegalovirus (CMV) nucleoside analogue DNA polymerase inhibitor, is a prodrug of antiviral drug ganciclovir, has the bioavailability 10 times that of the traditional drug ganciclovir, and has greatly reduced toxicity. It is used clinically in treating acute retinitis caused by CMV infection in patients with acquired immunodeficiency syndrome (AIDS), and preventing and treating CMV infection secondary to organ transplants. Valganciclovir is the best new drug for treating CMV infection by virtue of safer, more convenient administration and higher bioavailability. The structural formula is as follows:

for the synthesis of valganciclovir hydrochloride, the existing production process at home and abroad is mostly referred to a similar method described in US5840890A, EP1870411A1, ganciclovir is used as a main starting material, an intermediate monoacetylganciclovir is prepared by ortho-ester protection, then CBZ-valganciclovir monoester is prepared by esterification and hydrolysis, and finally deprotection is carried out to form salt. The industrial production process of ganciclovir, the main raw material, is described in U7078524B2, CN1301702A and CN103130642A, 1, 3-dichloro-2-propanol is used as a starting material to prepare 1, 3-dichloro-2-acetoxy methoxypropane, the 1, 3-diacetoxy-2- (acetoxy methoxy) propane is obtained by acetylation, and then the 1, 3-diacetoxy-2- (acetoxy methoxy) propane is obtained by condensation with diacetylguanine to obtain triacetyl ganciclovir, and finally the ganciclovir is obtained by hydrolysis. The industrial synthesis route of valganciclovir hydrochloride is as follows:

the process route has the problems of separation and conversion of N-7 and N-9 isomers in the synthesis process of intermediate triacetyl ganciclovir, the separation process is complicated, and the process yield is seriously influenced; in the process of preparing valganciclovir hydrochloride from ganciclovir, the generation of diester in the subsequent process can be caused by a large amount of ganciclovir residue in the ortho-ester protection process, the separation is also difficult, extra purification steps are often needed to obtain a product with higher purity, the steps are complicated, and the process yield is seriously influenced. The existing production technology of valganciclovir hydrochloride has the problems of long process route, tedious industry, low yield, being not beneficial to industrial production and the like.

Disclosure of Invention

The invention provides a method for synthesizing valganciclovir hydrochloride, which avoids the problem of separation and conversion of N-7 and N-9 isomers in a condensation process of diacetylguanine, directly synthesizes monochloro ganciclovir without ganciclovir, replaces the synthesis of monoacetyl ganciclovir in the prior art, and avoids the problem of separation of diester substitutes caused by ganciclovir residue.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a method for synthesizing valganciclovir hydrochloride comprises the following steps:

step one, carrying out acetylation reaction on 1, 3-dichloro-2-acetoxy methoxypropane and acetate in a DMF solvent in the presence of a phase transfer catalyst, distilling to remove the DMF solvent after the reaction is finished, adding an organic solvent and water for washing, and distilling to remove the organic solvent after the washing is finished to obtain a compound 11;

step two, adding a catalyst into the compound 11 and the compound 4 in a DMF solvent for condensation reaction to obtain a compound 12, directly hydrolyzing the compound 12 with methylamine water, neutralizing and crystallizing with hydrochloric acid, filtering out solids, and recrystallizing with water to obtain a compound 13;

step three, carrying out esterification reaction on the compound 13 and CBZ-L-valine under the action of DCC and DMAP, filtering, evaporating to remove a solvent, hydrolyzing in an isopropanol and NaOH aqueous solution system, and regulating pH by acetic acid to crystallize to obtain a compound 10;

step four, hydrogenating and deprotecting the compound 10 to form salt to obtain valganciclovir hydrochloride;

the reaction steps are as follows:

further, the molar ratio of the acetate salt to the 1, 3-dichloro-2-acetoxymethoxypropane in step one is from 0.9 to 1.1: 1.

Further, the molar ratio of the acetate salt to the 1, 3-dichloro-2-acetoxymethoxypropane in step one is 1: 1.

Further, in step one, the acetate is sodium acetate or potassium acetate.

Further, in the first step, the phase transfer catalyst is tetrabutylammonium bromide or benzyltriethylammonium chloride.

Further, the temperature of acetylation reaction in the first step is 20-40 ℃.

Further, the molar ratio of the compound 11 to the diacetylguanine in the second step is 1.2-1.6: 1.

Further, in the second step, the catalyst is p-toluenesulfonic acid, the mass ratio of the p-toluenesulfonic acid to the diacetylguanine is 1:10-20, and the condensation reaction temperature is 110-140 ℃; the hydrolysis temperature is 40-60 ℃, and the mass ratio of 40% of methylamine water to diacetyl guanine is 1-2: 1; neutralizing the pH value to 6-7 with hydrochloric acid; the temperature of the filtered solid is 5-10 ℃; the mass ratio of the purified water to the diacetylguanine during recrystallization is 10-20: 1.

Further, 1-3ml of isopropanol is added into each gram of the compound 13 in the third step; adding 2-4ml of 4% sodium hydroxide aqueous solution into each gram of compound 13; the hydrolysis temperature is 20-40 ℃; adjusting the pH value to 7-8 by acetic acid.

Further, the hydrogenation pressure in the fourth step was 0.3 MPa.

As the invention adopts the invention, compared with the prior art, the invention has the technical progress that:

(1) the method for synthesizing ganciclovir hydrochloride avoids the problem of separation and transformation of N-7 and N-9 isomers in the process of synthesizing an intermediate triacetyl ganciclovir, and avoids a large amount of yield loss of the intermediate triacetyl ganciclovir hydrochloride;

(2) the synthesis method of the invention directly synthesizes CBZ-valganciclovir monoester through monochloro ganciclovir without synthesizing ganciclovir, greatly simplifies the process steps, avoids the generation of diester impurities caused by ganciclovir residue, and reduces a large number of purification steps;

(3) the synthesis method has the advantages of simple overall process operation, mild conditions, good yield and convenience for industrial production.

In conclusion, the synthetic method provided by the invention has the advantages of short process steps, simplicity in operation, convenience in purification, low cost, contribution to industrial production and suitability for the synthetic method of valganciclovir hydrochloride.

Detailed Description

The following description is given in connection with preferred embodiments of the invention. It should be understood that the preferred embodiments described herein are only for illustrating and explaining the present invention and are not to be considered as limiting the present invention.

Example 1 preparation of Compound 11

Adding 120g of 1, 3-dichloro-2-acetoxy methoxy propane, 300ml of N, N-dimethylformamide, 70g of anhydrous potassium acetate and 5g of benzyltriethylammonium chloride into a reaction bottle, controlling the temperature to be 20-30 ℃, stirring for reaction for 4 hours, after the reaction is finished, evaporating under reduced pressure to remove the N, N-dimethylformamide, adding 100ml of dichloromethane and 100ml of purified water, stirring and washing, separating out an organic phase, and distilling to remove a solvent to obtain 103g of residue, namely the compound 11.

Example 2 preparation of Compound 11

Adding 120g of 1, 3-dichloro-2-acetoxy methoxy propane, 200ml of N, N-dimethylformamide, 54g of anhydrous sodium acetate and 4g of tetrabutylammonium bromide into a reaction bottle, stirring and reacting for 4 hours at the temperature of 30-40 ℃, after the reaction is finished, evaporating under reduced pressure to remove the N, N-dimethylformamide, adding 100ml of dichloromethane and 100ml of purified water, stirring and washing, separating out an organic phase, and distilling to remove a solvent to obtain 108g of residue, namely the compound 11.

Example 3 preparation of Compound 13

Adding 75g of diacetylguanine, 4g of p-toluenesulfonic acid and 200ml of N, N-dimethylformamide into a reaction bottle, heating to 120 ℃ of 115 ℃, slowly adding 100g of the compound 11 prepared in example 1, continuously reacting for 24h at the temperature, cooling the system to 50 ℃ after the reaction is finished, slowly adding 100ml of 40% methylamine water solution, stirring and reacting for 4h at 50-60 ℃, adjusting the pH value to 6-7 by using concentrated hydrochloric acid, cooling to 5-10 ℃, filtering out solids, and recrystallizing a filter cake by using 1200ml of purified water to obtain 56.5g of the compound 13.

Example 4 preparation of Compound 13

Adding 75g of diacetylguanine, 6g of p-toluenesulfonic acid and 200ml of N, N-dimethylformamide into a reaction bottle, heating to 135-140 ℃, slowly adding 100g of the compound 11 prepared in the example 2, continuously reacting for 12h at the temperature, cooling the system to 50 ℃ after the reaction is finished, slowly adding 120ml of 40% methylamine water solution, stirring and reacting for 4h at 50-60 ℃, adjusting the pH value to 6-7 by using concentrated hydrochloric acid, cooling to 5-10 ℃, filtering out solids, and recrystallizing a filter cake by using 1000ml of purified water to obtain 52.8g of the compound 13.

Example 5 preparation of CBZ-valganciclovir monoester

50g of the compound 13 prepared in example 3 and 200ml of N, N-dimethylformamide are added into a reaction flask, 65g of N, N' -dicyclohexylcarbodiimide and 4.5g of 4-dimethylaminopyridine are added, 56g of CBZ-L-valine are added under stirring, the mixture is stirred and reacted for 10 hours at room temperature, insoluble substances are removed by filtration, 100ml of isopropanol and 150ml of 10% sodium hydroxide solution are added after the solvent is removed by distillation from the filtrate, the mixture is stirred and reacted for 20 hours at 30-40 ℃, the pH value of the reaction solution is adjusted to 7-8 by acetic acid, 350ml of purified water is added continuously, the temperature is reduced to 0-5 ℃, and crystallization is carried out, so 32g of white solid, namely CBZ-valganciclovir monoester, is obtained.

Example 6 preparation of valganciclovir hydrochloride

Adding 25g of CBZ-valganciclovir monoester, 400ml of ethanol and 100ml of purified water into a hydrogenation reaction bottle, adding 3.8g of 10% target carbon and 5.5ml of concentrated hydrochloric acid, filling hydrogen to 0.3MPa at room temperature, stirring for reaction for 15h, filtering, evaporating filtrate under reduced pressure, adding 40ml of purified water into residue, slowly adding 500ml of isopropanol, and crystallizing to obtain 16.8g of valganciclovir hydrochloride.

Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing valganciclovir hydrochloride is characterized in that: the synthesis method comprises the following steps:

step one, performing acetylation reaction on 1, 3-dichloro-2-acetoxy methoxy propane and sodium acetate in a DMF solvent in the presence of a phase transfer catalyst, distilling to remove the DMF solvent after the reaction is finished, adding an organic solvent and water for washing, and distilling to remove the organic solvent after the washing is finished to obtain a compound 11;

the reaction steps are as follows:

。

2. the method for synthesizing valganciclovir hydrochloride according to claim 1, wherein: in the first step, the molar ratio of the sodium acetate to the 1, 3-dichloro-2-acetoxy methoxypropane is 0.9-1.1: 1.

3. The method for synthesizing valganciclovir hydrochloride according to claim 2, wherein: in the first step, the molar ratio of the sodium acetate to the 1, 3-dichloro-2-acetoxy methoxypropane is 1: 1.

4. The method for synthesizing valganciclovir hydrochloride according to claim 1, wherein: in the first step, the phase transfer catalyst is tetrabutylammonium bromide or benzyltriethylammonium chloride.

5. The method for synthesizing valganciclovir hydrochloride according to claim 1, wherein: in the first step, the temperature of acetylation reaction is 20-40 ℃.

6. The method for synthesizing valganciclovir hydrochloride according to claim 1, wherein: in the second step, the molar ratio of the compound 11 to the diacetylguanine is 1.2-1.6: 1.

7. The method for synthesizing valganciclovir hydrochloride according to claim 1, wherein: in the second step, the catalyst is p-toluenesulfonic acid, the mass ratio of the p-toluenesulfonic acid to the diacetyl guanine is 1:10-20, and the condensation reaction temperature is 110-140 ℃; the hydrolysis temperature is 40-60 ℃, and the mass ratio of 40% methylamine water to diacetyl guanine is 1-2: 1; neutralizing the pH value to 6-7 with hydrochloric acid; the temperature of the filtered solid is 5-10 ℃, and the mass ratio of the purified water to the diacetylguanine during recrystallization is 10-20: 1.

8. The method for synthesizing valganciclovir hydrochloride according to claim 1, wherein: in the third step, 1-3mL of isopropanol is added into each gram of the compound 13; adding 2-4mL of 4% sodium hydroxide aqueous solution into each gram of compound 13; the hydrolysis temperature is 20-40 ℃; adjusting the pH value to 7-8 by acetic acid.

9. The method for synthesizing valganciclovir hydrochloride according to claim 1, wherein: the hydrogenation pressure in the fourth step is 0.3 MPa.