CN1903854B - Method of synthesizing valaciclovir hydrochloride - Google Patents
Method of synthesizing valaciclovir hydrochloride Download PDFInfo
- Publication number
- CN1903854B CN1903854B CN 200610104357 CN200610104357A CN1903854B CN 1903854 B CN1903854 B CN 1903854B CN 200610104357 CN200610104357 CN 200610104357 CN 200610104357 A CN200610104357 A CN 200610104357A CN 1903854 B CN1903854 B CN 1903854B
- Authority
- CN
- China
- Prior art keywords
- acyclovir
- xie ansuan
- reaction
- formic acid
- amido protecting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a method for synthesizing valacyclovir hydrochloride. Said method is characterized by that said method includes the following steps: making the aminoprotected L-valine-acyclovir implement reaction in the solvent containing formic acid or form ate under the action of Pd/C catalyst, after the reaction is completed, using hydrochloric acid to make acidification so as to obtain the invented product.
Description
Technical field
The present invention relates to the medicine compound method, particularly relate to a kind of method for synthesizing valacyclovir hydrochloride.
Background technology
Acyclovir is the no ring analogues of natural nucleus glycoside, and its chemical name is 9-(2-hydroxyl ethoxymethyl) guanine (CAS registration number 59277-89-3), and US4199574 at first discloses with acyclovir and treated virus infection, and its structural formula is suc as formula shown in the I.Acyclovir has very strong antiviral activity to herpes-like virus, and the curative as bleb, zoster etc. is widely used in the world now.But, the water-soluble and oral absorption property of acyclovir poor (about 20%), thereby exist in order to keep the problem of the necessary a large amount of administrations of effective antiviral concentration in the blood plasma.
For improving these character, it is best at aspects such as oral absorption property to have developed acyclovir and amino acids formed ester, particularly acyclovir-L-L-valine ester.EP99493 has announced that at first the glycocoll of acyclovir, alanine ester can obviously improve its solubleness and bioavailability problem; EP0308065 and US4957924 have announced that the Xie Ansuan of acyclovir and Isoleucine ester salt have better its solubleness and the bioavailability problem improved, especially its L configuration.Glaxo company with acyclovir-L-L-valine ester as the list marketing of acyclovir prodrug; Commodity are called VALTREX; Chinese is a valacyclovir hydrochloride; Chemical name is L-Xie Ansuan-2-[(the amino dihydro of 6-oxo-9H-purine-9-yl) methoxyl group] ethyl ester hydrochloride (CAS registration number 124832-26-4), and its structural formula is suc as formula shown in the II.
(formula II)
Valacyclovir hydrochloride is acyclovir-L-L-valine ester prodrug; This drug oral post-absorption also is converted into acyclovir rapidly in vivo very soon; Its antivirus action is brought into play by acyclovir, and acyclovir gets into after the herpes infection cell, competes viral thymidine kinase or cell kinase with deoxynucleoside; Medicine is changed into activated form ACV-TP ester by phosphoric acid; As the substrate and the deoxy-guanine triguaiacyl phosphate competition viral DNA polymerase of virus replication, thereby it is synthetic to have suppressed viral DNA, shows antivirus action.The intravital antiviral activity of valacyclovir hydrochloride is superior to acyclovir, to the therapeutic index of herpes simplex virus I type and II type respectively than acyclovir high 42.91% and 30.13%; Varicella zoster virus also there is very high curative effect; Toxicity to mammalian host cell is very low, and the LD50 of rat and mouse stomach administration is respectively 4.4g/kg and 1.51g/kg.Because valacyclovir hydrochloride is converted into acyclovir in vivo very soon, its metabolite is not accumulated phenomenon in vivo.In the long term toxicity test of different steps, has identical security with acyclovir.The oral back of valacyclovir hydrochloride absorbs rapidly and is converted into acyclovir, and the acyclovir peak time is 0.88-1.75 hour in the blood; Oral administration biaavailability is 67 ± 13%, is 3-5 times of acyclovir.Valacyclovir hydrochloride gets into extensively distribution of back in the body, can be distributed in the multiple tissue, and wherein concentration is the highest in stomach, small intestine, kidney, liver, lymphoglandula and the skin histology, and the concentration in the cerebral tissue is minimum; All be converted into acyclovir in vivo, metabolite is mainly got rid of from urine, and wherein acyclovir accounts for 46%-59%, and 8-hydroxyl-9-guanine accounts for 25%-30%, and 9-hydroxyl methoxyl group guanine accounts for 11%-12%.The acyclovir original shape is single-phase elimination, and it is 2.86 ± 0.39 hours that blood is eliminated the transformation period (t1/2 β).
EP0308065 and US4957924 patent disclose the synthetic route of valacyclovir hydrochloride; Promptly prepare valacyclovir: the 4-Dimethylamino pyridine (DMAP) and the coupling reagent dicyclohexylcarbodiimide (DCC) that in the dimethyl formamide solution of acyclovir, add CBZ-L-Xie Ansuan, catalytic amount through condensation acyclovir and protected Xie Ansuan; Make acyclovir become ester with the CBZ-L-Xie Ansuan; Obtain CBZ-L-Xie Ansuan-acyclovir, then, through catalytic hydrogenation remove the protection basic CBZ group after the salt acidifying; Promptly can obtain valacyclovir hydrochloride, react as follows:
There is following problem during this compound method suitability for industrialized production: because condenses solubleness in common solvent of acyclovir and CBZ-L-Xie Ansuan is lower, react completely, generally use DMF or methyl alcohol, THF mixed solvent to do solvent in order to make.At first, DMF is preferable to condenses solubleness, but it is not the good carrier of hydrogen, and owing to contain amide structure, has poisoning effect to make to catalyzer and the large usage quantity and the difficult recovery of precious metal palladium carbon cause suitability for industrialized production uneconomical; Secondly, though methyl alcohol, THF mixed solvent are the good carriers of hydrogen, it is not good to condenses solubleness; Need be fitted on 2% concentration, and reaction also need add hydrochloric acid, and in autoclave, add hydrochloric acid; Non-corrosibility to reaction kettle is had relatively high expectations; Therefore need special devices, even on producing, also be danger close like this, can't scale operation.
Summary of the invention
The objective of the invention is the gentle method for synthesizing valacyclovir hydrochloride of reaction conditions.
Method for synthesizing valacyclovir hydrochloride provided by the present invention is that the L-Xie Ansuan-acyclovir with amido protecting reacts in the solvent that is containing formic acid or formate under the Pd/C catalyst action, and reaction is after hcl acidifying obtains valacyclovir hydrochloride.
Wherein, the solvent that contains formic acid or formate is a formic acid, perhaps, is the mixed solvent of one or more and formic acid and/or formate in water, organic alcohol, THF and the dioxane.Preferably, be the mixed solvent of water/ethanol/formic acid, the mixed solvent of the mixed solvent of water/Virahol/formic acid or water/THF/formic acid.The volumn concentration of formic acid is 1-100% in mixed solvent.Formate is selected from formic acid ammonia, sodium formiate, potassium formiate, formic acid triethylamine.
In the reaction system, the L-Xie Ansuan-acyclovir of amido protecting and the mol ratio 1 of formic acid or formate: 1-20.The Pd/C catalyst consumption is the 5%-50% of the L-Xie Ansuan-acyclovir weight of amido protecting.
Reaction conditions of the present invention as mild as a dove, temperature of reaction is 10-60 ℃; Reaction times is 1h-6h.
In the present invention, the L-Xie Ansuan-acyclovir of amido protecting commonly used is CBZ-L-Xie Ansuan-acyclovir (formula III), PNZ-L-Xie Ansuan-acyclovir (formula IV), PMZ-L-Xie Ansuan-acyclovir (formula V).L-Xie Ansuan-the acyclovir of these amido protectings can prepare according to literature method; Also can be synthetic: in 4-(dimethylamino) pyridine and 1 according to following method; Under the katalysis of 3-NSC 57182, the L-Xie Ansuan of acyclovir and amido protecting carried out condensation reaction obtains.
CBZ-L-Xie Ansuan-acyclovir (formula III)
PNZ-L-Xie Ansuan-acyclovir (formula IV)
PMZ-L-Xie Ansuan-acyclovir (formula V)
The present invention with the solvent that contains formic acid or formate as reaction solvent; With Pd/C is catalyzer; Can carry out the reduction reaction of the L-Xie Ansuan-acyclovir of amido protecting at normal temperatures, reaction conditions is gentle, and equipment requirements is low; Avoided being suitable for industrialized production because of difficulties such as the needed high pressure reactors of hydrogenation reduction; The inventive method has the yield height, and advantages such as good product purity have a extensive future.
Embodiment
This paper is when being used to describe purity or related substance, and percentage (%) is meant the color atlas area percentage of measuring with HPLC (HPLC), calculates with equation:
Impurity percentage=100 * (impurity/main peak area)
Method is following:
Chromatographic condition: as weighting agent, methyl alcohol-0.02mol/L potassium dihydrogen phosphate (20: 80) is a moving phase with octadecylsilane chemically bonded silica, and the detection wavelength is 251nm.
Get the about 50mg of trial-product, accurate claim surely, put in the 100ml measuring bottle, dissolve and be diluted to scale, shake up with the 0.02mol/L potassium dihydrogen phosphate; Precision is measured 2ml, puts in the 50ml measuring bottle, is diluted to scale with moving phase, shakes up; Get 20ul and inject liquid chromatograph, the record color atlas is measured peak area.Calculate the impurity percentage according to area normalization method.
Embodiment 1, preparation valacyclovir hydrochloride
The preparation of a, CBZ-L-Xie Ansuan-acyclovir
With the CBZ-L-Xie Ansuan (3.1g, 0.012mol), (0.2g 0.0016mol) is dissolved in 20mlN to 4-(dimethylamino) pyridine (DMAP), in the dinethylformamide (DMF); The adding acyclovir (2.0g, 0.009mol), dropping is dissolved in 1 of DMF (10ml) in this reaction; 3-NSC 57182 (DCC) (5g, solution 0.024mol), room temperature reaction 12 hours; Add entry 1ml termination reaction, filter, filtrating is concentrated into small volume; Add methyl alcohol and be heated to dissolving, be cooled to-10 ℃ of stirred overnight under stirring, vacuum-drying gets pure article 3.7g
B, preparation valacyclovir hydrochloride
(5g 0.011mol) joins and contains formic acid 15ml, in the mixed solvent of water 15ml, adds 5% palladium carbon 1g, stirring at room with CBZ-L-Xie Ansuan-acyclovir; Constantly have gas to emerge in the reaction, TLC monitoring reaction to raw material consumption is intact, needs 3 hours approximately, adds concentrated hydrochloric acid 5ml; Continue to stir 0.5 hour, filter, add Virahol 150ml in the filtrating, be cooled to-10 ℃ of stirred overnight; Filter, obtain white solid, vacuum-drying gets pure article 2.8g, and productive rate reaches 71.2%.HPLC measures, and its purity is 99.2%.
Embodiment 2,
The preparation of a, PMZ-L-Xie Ansuan
With L-Xie Ansuan (25g; 0.21mol) place the 500ml three-necked bottle; With 110ml2N NaOH dissolving, stir the also slow 120ml of dropping down at-5~0 ℃ and contain PMZ-Cl (50g, dichloromethane solution 0.25mol); Constantly drip 2N NaOH (130ml) simultaneously and be reflected at about pH9, add and at room temperature continue stirring reaction 1h to keep.Use the ether washed twice then, the ether layer discards, and after water layer adds 150ml ETHYLE ACETATE, under constantly stirring, slowly drips 6N hydrochloric acid to PH1, tells ethyl acetate layer; Water layer is with ethyl acetate extraction twice, about at every turn 50ml, combined ethyl acetate, with the washing of 5% sodium-chlor to neutral; Use anhydrous magnesium sulfate drying, concentrating under reduced pressure ETHYLE ACETATE obtains glutinous thick liquid again, adds a small amount of petroleum ether and stirring; Add bulk petroleum ether again, filter and washing, get little yellow solid 47.9g, yield 80.9%.
The preparation of b, PMZ-L-Xie Ansuan-acyclovir
With the PMZ-L-Xie Ansuan (10g, 0.036mol), (0.5g 0.004mol) is dissolved in 50mlN to 4-(dimethylamino) pyridine (DMAP), in the dinethylformamide (DMF); The adding acyclovir (5g, 0.022mol), dropping is dissolved in 1 of DMF (25ml) in this reaction; 3-NSC 57182 (DCC) (14.8g, solution 0.072mol), room temperature reaction 12 hours; Add entry 3ml termination reaction, filter, filtrating is concentrated into small volume; Add methyl alcohol and be heated to dissolving, be cooled to-10 ℃ of stirred overnight under stirring, vacuum-drying gets pure article 9.8g
C, preparation valacyclovir hydrochloride
(10g 0.02mol) joins in the mixed solvent of ethanol 60ml, water 30ml, adds 5% palladium carbon 2.5g, and temperature control is at 40 ℃ with PMZ-L-Xie Ansuan-acyclovir; Drip formic acid 5g, TLC monitoring reaction to raw material consumption is intact, needs 2 hours approximately, adds concentrated hydrochloric acid 3.5ml; Continue to stir 0.5 hour, filter, add acetone 100ml in the filtrating, be cooled to-10 ℃ of stirred overnight; Filter, obtain white solid, vacuum-drying gets pure article 5.3g, and productive rate reaches 73.6%.HPLC measures, and its purity is 99.1%.
Embodiment 3,
The preparation of a, PNZ-L-Xie Ansuan
With L-Xie Ansuan (10g; 0.085mol) place the 250ml three-necked bottle; With 50ml 2N NaOH dissolving, under-5~0 degree, stirring also slowly, Dropwise 5 0ml contains PNZ-Cl (22g, dichloromethane solution 0.1mol); Constantly drip 2N NaOH (50ml) simultaneously and be reflected at about PH9, add and at room temperature continue stirring reaction 1h to keep.Use the ether washed twice then, the ether layer discards, and after water layer adds 60ml ETHYLE ACETATE, under constantly stirring, slowly drips 6N hydrochloric acid to PH1, tells ethyl acetate layer; Water layer advocates twice with ETHYLE ACETATE, about at every turn 20ml, and combined ethyl acetate, extremely neutral with the washing of 5% sodium-chlor; Use anhydrous magnesium sulfate drying, concentrating under reduced pressure ETHYLE ACETATE obtains glutinous thick liquid again, adds a small amount of petroleum ether and stirring; Add bulk petroleum ether again, filter and washing, get light yellow solid 20.7g, yield 82.0%.
The preparation of b, PNZ-L-Xie Ansuan-acyclovir
With the PNZ-L-Xie Ansuan (9.8g, 0.033mol), (0.5g 0.004mol) is dissolved in 50mlN to 4-(dimethylamino) pyridine (DMAP), in the dinethylformamide (DMF); The adding acyclovir (5g, 0.022mol), dropping is dissolved in 1 of DMF (25ml) in this reaction; 3-NSC 57182 (DCC) (13.4g, solution 0.066mol), room temperature reaction 12 hours; Add entry 2ml termination reaction, filter, filtrating is concentrated into small volume; Add methyl alcohol and be heated to dissolving, be cooled to-10 ℃ of stirred overnight under stirring, vacuum-drying gets pure article 10.4g
C, preparation valacyclovir hydrochloride
(10g 0.02mol) joins in the mixed solvent of THF 50ml, water 20ml, adds 5% palladium carbon 1.5g, and temperature control is at 35 ℃ with PNZ-L-Xie Ansuan-acyclovir; Drip formic acid 4g, TLC monitoring reaction to raw material consumption is intact, needs 3 hours approximately, adds concentrated hydrochloric acid 3.5ml; Continue to stir 0.5 hour, filter, add Virahol 100ml in the filtrating, be cooled to-10 ℃ of stirred overnight; Filter, obtain white solid, vacuum-drying gets pure article 5.1g, and productive rate reaches 71.4%.HPLC measures, and its purity is 99.1%.
Embodiment 4: the preparation valacyclovir hydrochloride
(5g 0.011mol) joins and contains Virahol 30ml, in the mixed solvent of water 15ml, adds 5% palladium carbon 2g, adds formic acid 2g with CBZ-L-Xie Ansuan-acyclovir; Stirring at room constantly has gas to emerge in the reaction, TLC monitoring reaction to raw material consumption is intact, needs 3 hours approximately, adds concentrated hydrochloric acid 3ml; Continue to stir 0.5 hour, filter, add Virahol 100ml in the filtrating, be cooled to-10 ℃ of stirred overnight; Filter, obtain white solid, vacuum-drying gets pure article 2.73g, and productive rate reaches 69.5%.HPLC measures, and its purity is 99.4%.
Embodiment 5,
(10g 0.02mol) joins in the mixed solvent of dioxane 50ml, water 20ml, adds 5% palladium carbon 1.5g, and temperature control is at 55 ℃ with PNZ-L-Xie Ansuan-acyclovir; Add sodium formiate 20g, TLC monitoring reaction to raw material consumption is intact, needs 3 hours approximately, adds concentrated hydrochloric acid 3.5ml; Continue to stir 0.5 hour, filter, add Virahol 100ml in the filtrating, be cooled to-10 ℃ of stirred overnight; Filter, obtain white solid, vacuum-drying gets pure article 5.24g, and productive rate reaches 73.4%.HPLC measures, and its purity is 99.1%.
Embodiment 6,
(5g 0.011mol) joins in the 5g formic acid, adds 5% palladium carbon 2g, stirring at room with CBZ-L-Xie Ansuan-acyclovir; Constantly have gas to emerge in the reaction, TLC monitoring reaction to raw material consumption is intact, needs 3 hours approximately, adds concentrated hydrochloric acid 3ml; Continue to stir 0.5 hour, filter, add Virahol 100ml in the filtrating, be cooled to-10 ℃ of stirred overnight; Filter, obtain white solid, vacuum-drying gets pure article 2.83g, and productive rate reaches 72.0%.HPLC measures, and its purity is 99.4%.
Claims (6)
1. method for synthesizing valacyclovir hydrochloride; Be that L-Xie Ansuan-acyclovir with amido protecting reacts in the solvent that is containing formate under the Pd/C catalyst action; Reaction is after hcl acidifying obtains valacyclovir hydrochloride; Wherein said reaction is carried out in room temperature; The mixed solvent that the wherein said solvent that contains formate is water/Virahol/formic acid or the mixed solvent of water/THF/formic acid, and the L-Xie Ansuan of wherein said amido protecting is PNZ-L-Xie Ansuan or PMZ-L-Xie Ansuan.
2. method according to claim 1 is characterized in that: in the reaction system, and the L-Xie Ansuan-acyclovir of amido protecting and the mol ratio 1 of formate: 1-20.
3. method according to claim 1 is characterized in that: the Pd/C catalyst consumption is the 5%-50% of the L-Xie Ansuan-acyclovir weight of amido protecting.
4. according to the arbitrary described method of claim 1-3, it is characterized in that: said formate is selected from formic acid ammonia, sodium formiate, potassium formiate, formic acid triethylamine.
5. according to the described method of claim 1-3, it is characterized in that: the reaction times is 1 hour-6 hours.
6. according to the arbitrary described method of claim 1-3; It is characterized in that: the L-Xie Ansuan-acyclovir of said amido protecting is in 4-(dimethylamino) pyridine and 1; Under the katalysis of 3-NSC 57182, the L-Xie Ansuan of acyclovir and amido protecting carried out condensation reaction obtains.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 200610104357 CN1903854B (en) | 2006-08-09 | 2006-08-09 | Method of synthesizing valaciclovir hydrochloride |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 200610104357 CN1903854B (en) | 2006-08-09 | 2006-08-09 | Method of synthesizing valaciclovir hydrochloride |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1903854A CN1903854A (en) | 2007-01-31 |
CN1903854B true CN1903854B (en) | 2012-05-23 |
Family
ID=37673234
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 200610104357 Active CN1903854B (en) | 2006-08-09 | 2006-08-09 | Method of synthesizing valaciclovir hydrochloride |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1903854B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104045639B (en) * | 2014-06-10 | 2015-11-25 | 广东肇庆星湖生物科技股份有限公司 | A kind of preparation method of figured silk fabrics acyclovir |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101314603B (en) * | 2007-05-28 | 2011-06-01 | 上海医药工业研究院 | Valine protected imidazolo [1,2-a] purine tricyclic base ring-opening nucleoside compounds, processes for their preparation and uses |
CN101787027B (en) * | 2010-03-19 | 2011-12-14 | 常州康丽制药有限公司 | Preparation method of high-purity carbamazepine (CBZ)-valaciclovir |
CN102020642A (en) * | 2010-12-30 | 2011-04-20 | 湖北华龙生物制药有限公司 | Preparation method of valaciclovir hydrochloride |
CN102584825B (en) * | 2011-01-17 | 2014-04-02 | 四川科伦药物研究有限公司 | Method for synthesizing valaciclovir hydrochloride |
CN106632335A (en) * | 2016-12-27 | 2017-05-10 | 河南康达制药有限公司 | Preparation method of valaciclovir hydrochloride |
CN108037205A (en) * | 2017-12-20 | 2018-05-15 | 宜昌天仁药业有限责任公司 | A kind of method of high performance liquid chromatography measure CBZ- Valaciclovir contents |
CN109651371B (en) * | 2018-12-31 | 2021-02-23 | 辰欣药业股份有限公司 | Preparation method of valaciclovir hydrochloride |
CN110204505B (en) * | 2019-05-31 | 2023-02-03 | 荆门医药工业技术研究院 | Preparation process of (S) -3-benzyloxycarbonyl-4-isopropyl-2, 5-oxazolidinedione |
CN111233865A (en) * | 2020-03-27 | 2020-06-05 | 上药康丽(常州)药业有限公司 | Method for preparing valacyclovir hydrochloride by using microchannel reactor |
CN111398464B (en) * | 2020-04-02 | 2022-03-08 | 广州隽沐生物科技股份有限公司 | Method for detecting 2-ethylbutyl ((perfluorophenoxy) (phenoxy) phosphoryl) -L-alanine ester |
CN112176011B (en) * | 2020-10-26 | 2022-10-18 | 辰欣药业股份有限公司 | Method for preparing valaciclovir hydrochloride through enzyme catalysis |
CN114621227B (en) * | 2022-02-28 | 2024-07-09 | 海南久常制药有限公司 | Valacyclovir hydrochloride, preparation and preparation method thereof |
CN116041259A (en) * | 2023-01-13 | 2023-05-02 | 武汉科技大学 | Hydroxychloroquine derivative and preparation method thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997025989A1 (en) * | 1996-01-19 | 1997-07-24 | Glaxo Group Limited | Use of valaciclovir for the manufacture of a medicament for the treatment of genital herpes by a single daily application |
CN1179159A (en) * | 1995-01-20 | 1998-04-15 | 惠尔康基金会集团公司 | Guanine derivatives |
CN1612878A (en) * | 2001-11-14 | 2005-05-04 | 特瓦制药工业有限公司 | Synthesis and purification of valacyclovir |
CN1812990A (en) * | 2003-04-30 | 2006-08-02 | 特瓦制药工业有限公司 | Process for the preparation of famciclovir |
-
2006
- 2006-08-09 CN CN 200610104357 patent/CN1903854B/en active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1179159A (en) * | 1995-01-20 | 1998-04-15 | 惠尔康基金会集团公司 | Guanine derivatives |
WO1997025989A1 (en) * | 1996-01-19 | 1997-07-24 | Glaxo Group Limited | Use of valaciclovir for the manufacture of a medicament for the treatment of genital herpes by a single daily application |
CN1612878A (en) * | 2001-11-14 | 2005-05-04 | 特瓦制药工业有限公司 | Synthesis and purification of valacyclovir |
CN1812990A (en) * | 2003-04-30 | 2006-08-02 | 特瓦制药工业有限公司 | Process for the preparation of famciclovir |
Non-Patent Citations (2)
Title |
---|
刘力军等.盐酸伐昔洛韦的波谱学研究.波谱学杂志22 3.2005,22(3),309-314. |
刘力军等.盐酸伐昔洛韦的波谱学研究.波谱学杂志22 3.2005,22(3),309-314. * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104045639B (en) * | 2014-06-10 | 2015-11-25 | 广东肇庆星湖生物科技股份有限公司 | A kind of preparation method of figured silk fabrics acyclovir |
Also Published As
Publication number | Publication date |
---|---|
CN1903854A (en) | 2007-01-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1903854B (en) | Method of synthesizing valaciclovir hydrochloride | |
KR960002849B1 (en) | Therapeutic nucleosides | |
CN102791707A (en) | Method for producing methyl-{4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridino-3-yl]pyrimidino-5-yl}methyl carbamate and its purification for use thereof as pharmaceutical substance | |
CN102584825B (en) | Method for synthesizing valaciclovir hydrochloride | |
CN109651371A (en) | A kind of preparation method of valaciclovir hydrochlordide | |
CN104292231A (en) | Preparation method of tofacitinib citrate | |
CN101402662B (en) | Process for producing nelarabine | |
CN106632335A (en) | Preparation method of valaciclovir hydrochloride | |
CN104529895B (en) | Synthetic method of replacing nitrogen-containing heterocyclic compound | |
CN102070635B (en) | Preparation method for ganciclovir valine ester derivative | |
Wehlauch et al. | Nitrocatechols as tractable surface release systems | |
US20150353593A1 (en) | Novel Process for the Preparation of (1-pyrazole-4-yl)-N-methylcarboxamide | |
CN106905193B (en) | Aroyl guanidine radicals Oseltamivir carboxylic acid derivates and its preparation method and application | |
CN103709164A (en) | Synthetic method for adenine | |
CN109280044B (en) | Raltitrexed impurity C and preparation and application thereof | |
CN107011382A (en) | A kind of tenofovir prodrug and preparation method thereof | |
CN103073606A (en) | Method for synthesizing and preparing 5'-S-(4, 4'-dimethoxytriphenylmethyl)-2'-deoxyinosine | |
CN101531636B (en) | Method for synthesizing 2-(1-imidazol)ethylamine | |
CN102020642A (en) | Preparation method of valaciclovir hydrochloride | |
CN101314603B (en) | Valine protected imidazolo [1,2-a] purine tricyclic base ring-opening nucleoside compounds, processes for their preparation and uses | |
GB1561380A (en) | Esters of hydroxyalkoxyalkyl purines their preparation and pharmaceutical compositions containing them | |
CN108373491B (en) | Preparation method of nelarabine | |
CN112028939B (en) | Preparation method of tenofovir disoproxil dimer | |
CN114920663B (en) | Biphenyl oseltamivir derivative and preparation method and application thereof | |
WO2024098856A1 (en) | Anti-influenza-virus derivatives and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |