CN103664944A

CN103664944A - Preparation method of acyclovir

Info

Publication number: CN103664944A
Application number: CN201310696447.2A
Authority: CN
Inventors: 张京玉; 买文超; 祝海奇; 武红霞; 许超; 李元果
Original assignee: XINXIANG WEIDE CHEMICAL Co Ltd
Current assignee: XINXIANG WEIDE CHEMICAL Co Ltd
Priority date: 2013-12-18
Filing date: 2013-12-18
Publication date: 2014-03-26

Abstract

The invention discloses a preparation method of acyclovir, and belongs to the field of organic compound synthesis. According to the method, guanosine is taken as a starting raw material and is subjected to reactions of acylation, condensation and hydrolysis to prepare the acyclovir. Compared with the prior art, the synthesis method has stable and abundant raw material sources, market fluctuation influences are small, reaction conditions are mild, the operation is simple and safe, the reaction yield is high, the production cost is low, three wastes are few, and greater implementation value and socioeconomic benefits are provided.

Description

A kind of preparation method of ACV

Technical field

The present invention relates to the synthesis technique of ACV, belong to organic synthesis field.

Background technology

ACV（ACV）, also known as acyclovir, English name acyclovir, entitled 9- [(2- hydroxyl-oxethyls) the methyl]-guanine of chemistry, is a kind of antiviral agent of high-efficiency broad spectrum, the synthesis application first of Britain in 1981, it has been put into the national base therapy medicine of China, the huge market demand now.The medicine is effective to I types and II types herpe simplex and varicella zoster virus height, and with going deep into that people study, such medicine can also be applied to AntiHIV1 RT activity virus.

Research on the synthetic method and production technology of ACV is constantly subjected to the attention of people, so far existing a variety of synthetic methods：

1) using the chloro- 6-iodopurines of 2- as raw material, first with trimethyl silica ethyl iodide methyl ether condensation generation 2- chloro- 9- [(2- hydroxy ethoxies) methyl] -6-iodopurine, then in K₂CO₃Make 6 iodine by oxa- under effect, pressurization makes 2 chlorine ammonifications obtain product, total recovery 60%.The technique requires -78 DEG C of low temperature and strict anhydrous condition in the 1st step.

2) with 2, the guanine of 6,9 silanizations is raw material, with 2- oxa-s-BDO diethylester（OBDDA）, condensation turns into the 9- products replaced under iodine and phosphatic catalysis, then hydrolyzes to obtain product again, yield 35%, and yield is relatively low.

3) using guanine as raw material, acetylation generation N is first passed through²,N⁹- biacetyl guanine（DAG）, then with 2- oxa-s-BDO diethyl ester condensation generation biacetyl ACV（DACV）, then target product is hydrolyzed to obtain, but 7 biacetyl ACVs can be generated in the condensation process（7-DACV）, increase purifying products difficulty, influence the stability and product quality of product yield.

4) using 2- amido-6-chloropurines as raw material, after silanization, it is condensed with acetyl bromide for methoxy ethyl ester, hydrolyzes to obtain target product, yield 64%.Use poisonous reagent Hg (CN)₂, it is larger to environment and workman's harm.

Although the production technology of ACV is increasingly ripe, unfortunately, existing process generally there is problems：Expensive raw material price, uses toxic reagent, and reaction condition requires harsh, and product quality is low, yield is low, separation and purification of products difficulty etc..Above drawback make it that the synthesis technique of ACV bulk drug is difficult to industrialized production.

The content of the invention

It is to overcome the shortcomings of that prior art is gentle there is provided a kind of reaction condition that the purpose of the present invention, which is, and safety simple to operate, reaction yield is high, and production cost is low, and environmental protection is suitable for the synthesis technique of industrialized production ACV bulk drug.

In order to reach foregoing invention purpose, the present invention, as initiation material, is sequentially passed through acylated, condensation, ammonolysis reaction and high-quality ACV bulk drug is made, concrete technical scheme is as follows using guanosine：

A) synthesis of diacetyl guanine

Guanosine, aceticanhydride, boric acid are added in reactor, 110 DEG C -120 DEG C reactions are warming up to, reaction terminates cooling.Vacuum distillation goes out partial reaction liquid.Cooling, blowing is centrifuged, and is eluted with aceticanhydride, is dried, is obtained diacetyl guanine.

The weight ratio preferably 1 of boric acid and guanosine:0.001~0.01.

B) preparation of diacetyl ACV

By in toluene, diacetyl guanine, catalyst input reactor, backflow is to slowly warm up to, 2- oxa-s -1 are added dropwise in point water, after 4- diethyl-butanediols, continue to be incubated backflow, detection reaction terminates, and steams reactive moieties reaction solution, cooling, is centrifuged, and washing obtains diacetyl ACV crude product.By in crude product and methanol input reactor, backflow washing, cooling is centrifugally separating to obtain diacetyl ACV, and content is more than 99.3%.

Used catalyst is the one or two in anhydrous zinc chloride, alchlor, naphthalene sulfonic acids, benzene sulfonic acid, p-methyl benzenesulfonic acid.

C) synthesis of ACV

Diacetyl ACV and ammoniacal liquor are added in reactor, stirring reaction, reaction cools after terminating, filtering, obtain ACV bulk drug, content is more than 99.5%.

Compared with prior art, the present invention has following features：The present invention is using guanosine as initiation material, and raw material is cheap and easy to get, steady sources, and technique is simple, and small toxicity, simple and safe operation, the three wastes are few, pollutes small, high income, reaches more than 78.8%, product is easy to purifying, can be advantageously applied to industrialized production.

Embodiment

It is as follows especially exemplified by embodiment to be better illustrated to the present invention：

Embodiment one

A) synthesis of diacetyl guanine

By guanosine, aceticanhydride, boric acid with 1:6.4:0.006 weight is warming up to 110 DEG C -120 DEG C than adding in reactor, is incubated 6 hours.Then 100 DEG C of insulations reaction in 6 hours is cooled to terminate.Vacuum distillation goes out partial reaction liquid（The 40% of inventory）.It is cooled to 5 DEG C to be kept for 5 hours, blowing is centrifuged, is eluted 3 times with aceticanhydride, dries, obtain diacetyl guanine.¹H NMR (400 MHz,

DMSO)：δ=8.45 (s, 1H, Ar-H), 2.81 (s, 3H, CH₃), 2. 21 (s, 3H, CH₃)；¹³C NMR (DMSO, 100 MHz): δ= 173.4, 168.0, 154.4, 148.3, 147.6, 137.4, 24.6, 24.0。

B) preparation of diacetyl ACV

Toluene, diacetyl guanine, aluminum trichloride catalyst are put into reactor in proportion, backflow is to slowly warm up to, 2- oxa-s -1 are added dropwise in point water, after 4- diethyl-butanediols, continue to be incubated backflow 15 hours, detection reaction terminates, and steams reactive moieties reaction solution, it is cooled to 10 DEG C or so, centrifugation, washing, obtains diacetyl ACV crude product.By crude product and methanol（1:10 parts by weight）Put into reactor, backflow washing 10 minutes, be cooled to 20 DEG C and be centrifugally separating to obtain the diacetyl ACV that content is more than 99.3%.¹H NMR(400 MHz, DMSO): δ= 12.04 (S, 1H, NH), l1. 75(s, 1H, NH), 8. 12 (s, 1H, CH), 5.47 (s, 2H, NCH₂), 4.06 (t, J=4.8 Hz, 2H, OCH₂), 3.68 (t, J=4.8 Hz, 2H, CH₂O), 2.18(s, 3H, CH₃CO), 1.95 (s, 3H, COCH₃)；¹³C NMR (DMSO, 100 MHz):δ= 173.2, 169.9, 154.6, 148.6, 147.9, 139.8, 120.0, 72.3, 66.6, 62.6, 23.8, 20.6; MS(ESI): m/z=310.0[M+H]⁺。

C) synthesis of ACV

The ammoniacal liquor of diacetyl ACV and mass percent 15% is added in reactor, 40 DEG C are stirred 2 hours, are cooled, and filtering, filter cake is secondary with 60% alcohol crystal, obtains content more than 99.5% ACV bulk drug.¹H NMR(400 MHz, DMSO): δ= 10.56 (s, 1H, NH), 7.76 (s, 1H, NCHN), 6.46 (s, 2H, NH₂), 5.31 (s, 2H, NCH₂O), 4.65 (s, 1H, OH), 3.45-3.41 (m, 4H, OCH₂CH₂O); ¹³C NMR(DMSO, 100 MHz): δ= 156.6, 153.6, 151.2, 137.6, 116.3, 72.0, 70.4, 59.9; MS(APCI): m/z=226.1[M+H]⁺。

Embodiment two

B) catalyst used is anhydrous zinc chloride and benzene sulfonic acid, and both part by weight are 1:2.Other same above-described embodiments.Content is obtained more than 99.5% ACV bulk drug.

Claims

1. a kind of Synthesis of Acyclovir, it is characterised in that synthesized by following steps：

1）The synthesis of diacetyl guanine

Guanosine, aceticanhydride, boric acid are added in reactor, 110 DEG C -120 DEG C reactions are warming up to, reaction terminates cooling；Vacuum distillation goes out partial reaction liquid；Cooling, blowing is centrifuged, and is eluted with aceticanhydride, is dried, is obtained diacetyl guanine；

2）The preparation of diacetyl ACV

By in toluene, diacetyl guanine, catalyst input reactor, backflow is to slowly warm up to, 2- oxa-s -1 are added dropwise in point water, after 4- diethyl-butanediols, continue to be incubated backflow, detection reaction terminates, and steams reactive moieties reaction solution, cooling, is centrifuged, and washing obtains diacetyl ACV crude product；By in crude product and methanol input reactor, backflow washing, cooling is centrifugally separating to obtain diacetyl ACV；

Used catalyst is the one or two in anhydrous zinc chloride, alchlor, naphthalene sulfonic acids, benzene sulfonic acid, p-methyl benzenesulfonic acid；

3）The synthesis of ACV

Diacetyl ACV and ammoniacal liquor are added in reactor, stirring reaction, reaction cools after terminating, filtering obtains ACV bulk drug.

2. Synthesis of Acyclovir according to claim 1, it is characterised in that the weight ratio of boric acid and guanosine is 1:0.001~0.01.