CN103664944A - Preparation method of acyclovir - Google Patents
Preparation method of acyclovir Download PDFInfo
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- CN103664944A CN103664944A CN201310696447.2A CN201310696447A CN103664944A CN 103664944 A CN103664944 A CN 103664944A CN 201310696447 A CN201310696447 A CN 201310696447A CN 103664944 A CN103664944 A CN 103664944A
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- acv
- diacetyl
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- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 229960004150 aciclovir Drugs 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 13
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 claims abstract description 8
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940029575 guanosine Drugs 0.000 claims abstract description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- QNXFUWFRTWSSOK-UHFFFAOYSA-N n-acetyl-n-(6-oxo-3,7-dihydropurin-2-yl)acetamide Chemical compound O=C1NC(N(C(C)=O)C(=O)C)=NC2=C1NC=N2 QNXFUWFRTWSSOK-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 5
- 239000004327 boric acid Substances 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- 238000007664 blowing Methods 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000009833 condensation Methods 0.000 abstract description 6
- 230000005494 condensation Effects 0.000 abstract description 6
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 150000002894 organic compounds Chemical class 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 11
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002444 silanisation Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- HCRLJEBMLJCCRJ-UHFFFAOYSA-N 2-chloro-6-iodo-7h-purine Chemical class ClC1=NC(I)=C2NC=NC2=N1 HCRLJEBMLJCCRJ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- -1 methoxy ethyl Chemical group 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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
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 (2)
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310696447.2A CN103664944A (en) | 2013-12-18 | 2013-12-18 | Preparation method of acyclovir |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310696447.2A CN103664944A (en) | 2013-12-18 | 2013-12-18 | Preparation method of acyclovir |
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| CN103664944A true CN103664944A (en) | 2014-03-26 |
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| CN201310696447.2A Pending CN103664944A (en) | 2013-12-18 | 2013-12-18 | Preparation method of acyclovir |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106243107A (en) * | 2016-07-19 | 2016-12-21 | 广东肇庆星湖生物科技股份有限公司 | A kind of N2, the preparation method of 9 diacetyl guanines |
| CN107903268A (en) * | 2017-11-16 | 2018-04-13 | 湖北省宏源药业科技股份有限公司 | A kind of method of purification of acyclovir |
| CN110818715A (en) * | 2019-12-04 | 2020-02-21 | 湖北省宏源药业科技股份有限公司 | Production method of diacetylacyclovir |
| CN111362944A (en) * | 2020-04-22 | 2020-07-03 | 通辽德胜生物科技有限公司 | Method for synthesizing diacetylacyclovir by using guanosine |
| CN111440170A (en) * | 2020-04-22 | 2020-07-24 | 通辽德胜生物科技有限公司 | Method for synthesizing guanine by using guanosine |
| CN113620955A (en) * | 2021-07-29 | 2021-11-09 | 浙江浙北药业有限公司 | Preparation method of acyclovir |
| CN113735857A (en) * | 2021-10-14 | 2021-12-03 | 湖北省宏源药业科技股份有限公司 | Acyclovir potential impurity and preparation method thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106243107A (en) * | 2016-07-19 | 2016-12-21 | 广东肇庆星湖生物科技股份有限公司 | A kind of N2, the preparation method of 9 diacetyl guanines |
| CN106243107B (en) * | 2016-07-19 | 2018-02-09 | 广东肇庆星湖生物科技股份有限公司 | A kind of N2, the preparation method of 9 diacetyl guanines |
| CN107903268A (en) * | 2017-11-16 | 2018-04-13 | 湖北省宏源药业科技股份有限公司 | A kind of method of purification of acyclovir |
| CN110818715A (en) * | 2019-12-04 | 2020-02-21 | 湖北省宏源药业科技股份有限公司 | Production method of diacetylacyclovir |
| CN111362944A (en) * | 2020-04-22 | 2020-07-03 | 通辽德胜生物科技有限公司 | Method for synthesizing diacetylacyclovir by using guanosine |
| CN111440170A (en) * | 2020-04-22 | 2020-07-24 | 通辽德胜生物科技有限公司 | Method for synthesizing guanine by using guanosine |
| CN111440170B (en) * | 2020-04-22 | 2021-09-14 | 通辽德胜生物科技有限公司 | Method for synthesizing guanine by using guanosine |
| CN113620955A (en) * | 2021-07-29 | 2021-11-09 | 浙江浙北药业有限公司 | Preparation method of acyclovir |
| CN113735857A (en) * | 2021-10-14 | 2021-12-03 | 湖北省宏源药业科技股份有限公司 | Acyclovir potential impurity and preparation method thereof |
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