CN111763207B - Preparation method of valganciclovir hydrochloride - Google Patents
Preparation method of valganciclovir hydrochloride Download PDFInfo
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- CN111763207B CN111763207B CN201910261917.XA CN201910261917A CN111763207B CN 111763207 B CN111763207 B CN 111763207B CN 201910261917 A CN201910261917 A CN 201910261917A CN 111763207 B CN111763207 B CN 111763207B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- ZORWARFPXPVJLW-MTFPJWTKSA-N [2-[(2-amino-6-oxo-3h-purin-9-yl)methoxy]-3-hydroxypropyl] (2s)-2-amino-3-methylbutanoate;hydron;chloride Chemical compound Cl.N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 ZORWARFPXPVJLW-MTFPJWTKSA-N 0.000 title description 6
- 229960004983 valganciclovir hydrochloride Drugs 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 9
- -1 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] -3-hydroxy L-valine propyl ester hydrochloride Chemical compound 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 30
- 238000005406 washing Methods 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000001035 drying Methods 0.000 description 13
- 239000007788 liquid Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 229960002963 ganciclovir Drugs 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 206010048843 Cytomegalovirus chorioretinitis Diseases 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- WPVFJKSGQUFQAP-GKAPJAKFSA-N Valcyte Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COC(=O)[C@@H](N)C(C)C)C=N2 WPVFJKSGQUFQAP-GKAPJAKFSA-N 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000001763 cytomegalovirus retinitis Diseases 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960002301 trazodone hydrochloride Drugs 0.000 description 1
- OHHDIOKRWWOXMT-UHFFFAOYSA-N trazodone hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 OHHDIOKRWWOXMT-UHFFFAOYSA-N 0.000 description 1
- 229960002149 valganciclovir Drugs 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] -3-hydroxy L-valine propyl ester hydrochloride shown in a formula I. The method has higher yield and stable product quality, and is beneficial to industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and mainly relates to a purification method of trazodone hydrochloride shown in a formula I.
Background
Valganciclovir (I) (Valganciclovir hydrochloride) hydrochloride, 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] -3-hydroxy L-valine propyl ester hydrochloride, developed by Switzerland F Hoffman La Roche, and approved by the United states FDA for use in month 3 of 2001. The product is used for treating cytomegalovirus retinitis of patients with acquired immunodeficiency syndrome, and preventing cytomegalovirus infection of patients with high risk solid organ transplantation.
Disclosure of Invention
The invention provides a preparation method of 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] -3-hydroxy L-valine propyl ester hydrochloride shown in a formula I.
The preparation method of the invention comprises the following steps:
(1) Halogenating ganciclovir (II) in an organic solvent to obtain (III);
(2) (III) reacting with (IV) to obtain a compound of formula (V);
(3) The compound of formula (V) is subjected to alkaline hydrolysis to obtain a compound (VI);
(4) Removing BOC from the compound of formula (VI I) to obtain a compound of formula (VI I);
(5) Deprotection of a compound of formula (VI I) to give a compound of formula (I);
Wherein step 1 is preferably under the following conditions:
The reaction solvent is recommended to be tetrahydrofuran, dichloromethane, isopropyl ether, methyl tert-butyl ether, preferably tetrahydrofuran; the solvent amount is recommended to be 5 to 7 times (here, volume to mass ratio) that of the compound II;
The reaction temperature is 05 ℃;
After the reaction materials are added, the reaction time is 1-2 hours.
Step 2 preferably the following conditions:
The solvent used in the reaction is one of methanol, ethanol, isopropanol and butanol;
The solvent is used in an amount of 5 to 7 times (volume to mass ratio here) that of the compound III; the reaction temperature is recommended to be 20-25 DEG C
The reaction time after the addition of the compound IV is recommended to be 2 to 3 hours;
step 3 preferably the following conditions:
The solvent used in the reaction is one of methanol, ethanol, isopropanol and tert-butanol;
the reaction organic base can be one of N, N-diisopropylethylamine, triethylamine, N, N-diethyl ethylamine.
The solvent is used in an amount of 10 to 15 times (volume to mass ratio here) that of the compound V; the reaction temperature is recommended to be 20-25 ℃;
the reaction time is recommended to be 20-30 hours;
Step 4 preferably the following conditions:
The solvent used in the reaction is one of dichloromethane, methanol and ethanol;
The solvent is used in an amount of 10 to 15 times (in this case in volume/mass ratio) that of the compound VI; the reaction temperature is recommended to be 20-25 ℃;
the reaction time is recommended to be 10-15 hours;
Step 5 preferably the following conditions:
the solvent used in the reaction is one of acetone, butanone and ethanol;
the solvent is used in an amount of 5 to 6 times (herein, volume to mass ratio) that of the compound VII; the reaction temperature of adding hydrochloric acid is 0-10 ℃;
The reaction temperature is recommended to be 20-25 ℃;
The reaction time is recommended to be 2-3 hours;
the invention avoids the use of the DCC condensing agent and is convenient for purification and industrial production.
The reagent used in the invention is a conventional reagent, and has little pollution to the environment.
The invention provides a new method for preparing valganciclovir hydrochloride.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to be limiting.
Example 1:
(1) 30g of ganciclovir (II) is weighed and dissolved in 300ml of tetrahydrofuran, the temperature is reduced to 0 ℃, 53.9g of phosphorus pentachloride is added in batches, after the dripping is finished, the reaction temperature is controlled to be not higher than 10 ℃ for 1h, then saturated NH 4 Cl solution is used for quenching the reaction, 2X 100ml of ethyl acetate is used for washing water phase after the tetrahydrofuran is removed by rotary evaporation, 3L of saturated sodium chloride solution is used for washing organic phase after the washing, liquid is separated after the washing, the organic phase is collected after the washing, the solvent is dried for 2h to obtain yellow solid, the obtained solid is recrystallized by methanol (60 ml) and n-hexane (120 ml), the light yellow solid compound III is obtained after suction filtration, and 31.7g of product is obtained after the drying, the yield is 92.7%, and the purity is 98.5%.
(2) 30G of compound III and 53.8g of compound IV are taken and dissolved in 150ml of ethanol, the mixture is stirred for 2 hours at 25 ℃ and then filtered by suction, 450ml of isopropyl ether is added into the filtrate, a large amount of solids are separated out, stirring is continued for 2 hours, the white-like solid and compound V are obtained by suction filtration, 62.9g of product is obtained after drying, the yield is 93.6%, and the purity is 97.9%.
(3) Dissolving 60g of a compound V in 600ml of methanol, adding 95.1g of N, N-diisopropylethylamine into the solution, reacting for 30 hours at 25 ℃, regulating to neutrality by 120ml of 3mol/L hydrochloric acid, spin-drying the methanol, washing the liquid by 2X 120ml of ethyl acetate, collecting an organic phase after washing, washing the organic phase by 600ml of saturated sodium chloride solution, separating the liquid, drying the organic phase for 2 hours, filtering the spin-drying solvent to obtain brown solid, washing the brown solid by using a mixed solvent of ethyl acetate (60 ml) and water (120 ml) for 2 hours, filtering, washing a filter cake by using 30ml of ethyl glacial acetate, collecting the filter cake to obtain white-like solid which is the compound VI, and drying to obtain 41.3g of white-like solid, wherein the yield is 98.2% and the purity is 98.3%.
(4) 40G of compound VI is dissolved in 400ml of dichloromethane, 50g of trifluoroacetic acid is added at 25 ℃ after stirring and dissolution, stirring is carried out for 3 hours, the reaction solution is poured into a mixed solution of methyl tertiary butyl ether (480 ml)/dichloromethane (120 ml) after the reaction is finished, stirring and crystallization are carried out for 1 hour after the reaction is finished, filtration is carried out, a filter cake is washed by a mixed solution of methyl tertiary butyl ether (20 ml) and dichloromethane (5 ml), and then drying is carried out to obtain white solid, namely compound VII, and 38.2g of product is obtained, the yield is 96.4%, and the purity is 99.2%.
(5) Dissolving 30g of compound VII in 150ml of acetone, cooling the system temperature to 10 ℃, adding 32ml of concentrated hydrochloric acid into the system, heating to 25 ℃ after adding, stirring for 3 hours, carrying out suction filtration, washing the obtained solid with 100ml of water for 2 hours, carrying out suction filtration, washing a filter cake with 30ml of water, and carrying out vacuum drying after washing to obtain a white solid, namely valganciclovir hydrochloride (I), wherein the total yield of the white solid is 24.7g, and the purity of the white solid is 99.3%.
Example 2:
(1) 30g of ganciclovir (II) is weighed and dissolved in 300ml of dichloromethane, the temperature is reduced to 0 ℃, 53.9g of phosphorus pentachloride is added in batches, after the dripping is finished, the reaction temperature is controlled to be not higher than 10 ℃ for 1h, then the saturated NH 4 Cl solution is used for quenching the reaction, 2X 100ml of dichloromethane is used for washing water phase after liquid separation, 3L of saturated sodium chloride solution is used for washing organic phase after liquid separation, after liquid separation after liquid washing, the organic phase is collected after liquid separation after liquid washing, the solvent is dried for 2h to obtain yellow solid, the obtained solid is recrystallized by methanol (60 ml) and n-hexane (180 ml), the light yellow solid compound III is obtained after suction filtration, 30.1g of product is obtained after drying, the yield is 88.0%, and the purity is 96.3%.
(2) Taking 30g of compound III and 53.8g of compound IV, dissolving in 150ml of methanol, stirring at 25 ℃ for 2 hours, filtering, adding 510ml of methyl tertiary butyl ether into the filtrate, precipitating a large amount of solid, continuously stirring for 2 hours, filtering to obtain off-white solid and compound V, drying to obtain 61.3g of product with the yield of 91.2% and the purity of 96.6%
(3) Dissolving 60g of a compound V in 600ml of ethanol, adding 74.4g of triethylamine into the solution, reacting at 25 ℃ for 25 hours, regulating the solution to be neutral by 120ml of 3mol/L hydrochloric acid, spin-drying the ethanol, washing the liquid by 2X 120ml of ethyl acetate, collecting an organic phase after washing, washing the organic phase by 600ml of saturated sodium chloride solution, separating the liquid, drying the organic phase for 2 hours, filtering the spin-dried solvent to obtain brown solid, washing the brown solid by using a mixed solvent of ethyl acetate (60 ml) and water (180 ml) for 2 hours, filtering the brown solid by suction, washing a filter cake by using 30ml of ethyl glacial acetate, collecting the filter cake to obtain white solid which is the compound VI, and drying to obtain 40.8g of white solid, wherein the yield is 97.0% and the purity is 98.1%.
(4) 40G of compound VI is dissolved in 400ml of dichloromethane, 50g of trifluoroacetic acid is added at 25 ℃ after stirring and dissolution, stirring is carried out for 3 hours, the reaction solution is poured into a mixed solution of isopropyl ether (480 ml)/dichloromethane (120 ml) after the reaction is finished, stirring and crystallization are carried out for 1 hour after the reaction is finished, filtration is carried out, a filter cake is washed by a mixed solution of methyl tertiary butyl ether (20 ml) and dichloromethane (5 ml), and then drying is carried out to obtain a white solid, namely compound VII, 36.3g of product is obtained, the yield is 91.6%, and the purity is 98.8%.
(5) Dissolving 30g of compound VII in 150ml of acetone, cooling the system temperature to 10 ℃, adding 32ml of concentrated hydrochloric acid into the system, heating to 25 ℃ after adding, stirring for 3 hours, carrying out suction filtration, washing the obtained solid with 100ml of water for 2 hours, carrying out suction filtration, washing a filter cake with 30ml of water, and carrying out vacuum drying after washing to obtain a white solid, namely valganciclovir hydrochloride (I), wherein the total yield of the white solid is 24.7g, and the purity of the obtained white solid is 98.9%.
Claims (6)
- A process for the preparation of 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] -3-hydroxy L-valine propyl ester hydrochloride comprising the steps of:1) Dissolving a compound of a formula II in an organic solvent, adding phosphorus pentachloride, and reacting at 0-10 ℃ to obtain a compound of a formula III;2) Dissolving the compound shown in the formula III in an organic solvent, and reacting with the compound IV at 25 ℃ to obtain a compound shown in the formula V;3) Dissolving the formula V in an organic solvent, and performing alkaline hydrolysis at 25 ℃ under the action of N, N-diisopropylethylamine to obtain a compound of the formula VI;4) Dissolving a formula VI in an organic solvent, and deprotecting a protecting group at 25 ℃ under the action of trifluoroacetic acid to obtain a compound of a formula VII;5) Dissolving the formula VII in an organic solvent, dropwise adding concentrated hydrochloric acid at 0-10 ℃, and then reacting at 20-25 ℃ to obtain a compound of the formula I;。
- 2. the process according to claim 1, wherein the organic solvent used in step 1 is preferably tetrahydrofuran and the solvent is preferably used in an amount of 5 to 7 times the amount of compound II, in this case in volume to mass ratio.
- 3. The process according to claim 1, wherein the organic solvent used in step 2 is preferably methanol and the solvent is preferably used in an amount of 5 to 7 times the amount of compound III, in this case in volume to mass ratio.
- 4. The process according to claim 1, wherein the organic solvent used in step 3 is preferably methanol and the solvent is preferably used in an amount of 10 to 15 times the amount of compound V, in this case in volume to mass ratio.
- 5. The process according to claim 1, wherein in step 4, a solvent, preferably methylene chloride, is used, preferably in an amount of 10 to 15 times the amount of compound VI, in this case in volume to mass ratio.
- 6. The process according to claim 1, wherein in step 5 the reaction is carried out using a solvent, preferably acetone, in an amount of preferably 10 to 15 times the amount of compound VII, in this case in volume to mass ratio.
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|---|---|---|---|---|
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|---|---|---|---|---|
| US8586738B2 (en) * | 2009-08-12 | 2013-11-19 | Ranbaxy Laboratories Limited | Process for the preparation of valganciclovir hydrochloride |
| WO2013076688A1 (en) * | 2011-11-25 | 2013-05-30 | Piramal Enterprises Limited | A process for the preparation of valacyclovir hydrochloride |
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2019
- 2019-04-02 CN CN201910261917.XA patent/CN111763207B/en active Active
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|---|---|---|---|---|
| US5700936A (en) * | 1996-01-26 | 1997-12-23 | Syntex (U.S.A.) Inc. | Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy-1,3-propanediol valinate |
| CN1301702A (en) * | 1999-12-29 | 2001-07-04 | 湖北省医药工业研究院 | Internmediate of anti viral medicine, their preparation and use |
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