CN111763207A - Preparation method of valganciclovir hydrochloride - Google Patents
Preparation method of valganciclovir hydrochloride Download PDFInfo
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- CN111763207A CN111763207A CN201910261917.XA CN201910261917A CN111763207A CN 111763207 A CN111763207 A CN 111763207A CN 201910261917 A CN201910261917 A CN 201910261917A CN 111763207 A CN111763207 A CN 111763207A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 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 12
- -1 2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl Chemical group 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 9
- 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 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 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
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 26
- 238000005406 washing Methods 0.000 description 20
- 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 14
- 238000000967 suction filtration Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000012065 filter cake Substances 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
- 239000007788 liquid Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000000203 mixture Substances 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
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 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
- 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
- 238000000926 separation method Methods 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
- 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 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000005303 weighing 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
- 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
- 239000003814 drug Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000009987 spinning 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 shown in formula I, 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxyl]A preparation method of (E) -3-hydroxy L-valine propyl ester hydrochloride.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and mainly relates to a method for purifying trazodone hydrochloride shown in a formula I.
Background
Valganciclovir (i) hydrochloride (Valganciclovir hydrochloride), 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxy ] -3-hydroxy L-valine propyl ester hydrochloride, developed by the company Hoffman La Roche, switzerland, was approved by the FDA in us 3 months of 2001 for marketing. The product is a medicine for treating cytomegalovirus retinitis of patients with acquired immunodeficiency syndrome and preventing cytomegalovirus infection of high-risk solid organ transplantation patients.
Disclosure of Invention
The invention provides a preparation method shown as a formula I, namely a preparation method of 2- [ (2-amino-1, 6-dihydro-6-oxo-9H-purin-9-yl) methoxyl ] -3-hydroxy L-valine propyl ester hydrochloride.
The preparation method comprises the following steps:
(1) in an organic solvent, ganciclovir (II) is halogenated to obtain (III), and (III) and (IV) react to obtain a compound shown in a formula (V);
(2) the compound of the formula (V) is subjected to alkaline hydrolysis to obtain a compound of the formula (VI).
(3) Deprotection of a compound of formula (VI) affords a compound of formula (I).
Wherein the following conditions are preferred for step 1:
the reaction solvent is preferably tetrahydrofuran, dichloromethane, isopropyl ether, methyl tert-butyl ether, preferably tetrahydrofuran;
the dosage of the solvent is 5 to 15 times of that of the compound II, preferably 5 to 7 times (volume to mass ratio);
the reaction temperature is 0-10 ℃, and preferably 0-5 ℃;
after the addition of the reaction materials is finished, the reaction time is 1-5 hours, preferably 1-2 hours.
Step 2 preferably comprises the following conditions:
the solvent used for the reaction is methanol, ethanol, isopropanol, butanol, preferably methanol;
the dosage of the solvent is 5 to 15 times of that of the compound III, preferably 5 to 7 times (volume to mass ratio);
the reaction temperature is recommended to be 10-30 ℃; preferably 20-25 DEG C
The reaction time after the compound IV is added is recommended to be 1-5 hours, preferably 2-3 hours;
the following conditions are preferred for step 3:
the solvent used for the reaction is preferably methanol, ethanol, isopropanol, tert-butanol, preferably methanol;
the organic base can be N, N-diisopropylethylamine, triethylamine, N, N-diethylethylamine, preferably N, N-diisopropylethylamine.
The dosage of the solvent is 10 to 30 times of that of the compound V, preferably 10 to 15 times (volume to mass ratio);
the reaction temperature is recommended to be 10-30 ℃; preferably 20-25 DEG C
The reaction time is recommended to be 10-30 hours, and preferably 20-30 hours;
step 4 preferably comprises the following conditions:
the solvent used for the reaction is preferably dichloromethane, methanol, ethanol, preferably dichloromethane;
the dosage of the solvent is 10 to 30 times, preferably 10 to 15 times (volume to mass ratio) of the compound VI;
the reaction temperature is recommended to be 10-30 ℃; preferably 20-25 DEG C
The reaction time is recommended to be 10-30 hours, preferably 10-15 hours;
step 5 preferably comprises the following conditions:
the solvent used for the reaction is acetone, butanone and ethanol, preferably acetone;
the dosage of the solvent is 5 to 10 times of that of the compound VII, preferably 5 to 6 times (volume to mass ratio);
the reaction temperature of adding hydrochloric acid is 0-15 ℃, preferably 0-10 DEG C
The reaction temperature is recommended to be 10-30 ℃; preferably 20-25 DEG C
The reaction time is recommended to be 1-5 hours, preferably 2-3 hours;
the invention avoids the use of DCC condensing agents, 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 to be construed as limiting the invention thereto.
Example 1:
(1) weighing 30 g of ganciclovir (II), dissolving in 300 ml of tetrahydrofuran, cooling to 0 ℃, adding 53.9 g of phosphorus pentachloride in batches, after dropwise adding, controlling the reaction temperature to be not more than 10 ℃, reacting for 1 h, and then using saturated NH4The reaction is quenched by Cl solution, tetrahydrofuran is removed by rotary evaporation, the water phase is washed by 2 × 100 ml ethyl acetate, and after washing, the product is collectedWashing an organic phase with 3L of saturated sodium chloride solution, separating liquid after washing, collecting the organic phase, drying for 2 hours, then spin-drying the solvent to obtain yellow solid, recrystallizing the obtained solid with methanol (60 ml) and n-hexane (120 ml), and performing suction filtration to obtain a light yellow solid compound III, wherein the product is 31.7 g after drying, the yield is 92.7%, and the purity is 98.5%.
(2) Dissolving 30 g of compound III and 53.8 g of compound IV in 150 ml of ethanol, stirring at 25 ℃ for 2h, performing suction filtration, adding 450 ml of isopropyl ether into the filtrate, separating out a large amount of solids, continuing stirring for 2h, performing suction filtration to obtain off-white solids and a compound V, and drying to obtain 62.9g of a product, wherein the yield is 93.6%, and the purity is 97.9%
(3) 60 g of compound V are dissolved in 600 ml of methanol and 95.1 g N, N-diisopropylethylamine is added to the solution
Reacting at 25 ℃ for 30 h, adjusting the reaction solution to be neutral by 120ml of 3mol/L hydrochloric acid, spin-drying methanol, washing the liquid by 2 x 120ml of ethyl acetate, collecting an organic phase after washing, washing the organic phase by 600 ml of saturated sodium chloride solution, separating the liquid, drying the organic phase for 2h, performing suction filtration on the spin-dried solvent to obtain brown solid, washing the brown solid by a mixed solvent of ethyl acetate (60 ml) and water (120 ml) for 2h, performing suction filtration, washing a filter cake by 30 ml of ethyl glacial acetate, collecting the filter cake to obtain a white-like solid, namely a compound VI, and drying to obtain 41.3 g of white-like solid, wherein the yield is 98.2% and the purity is 98.3%.
(4) Dissolving 40 g of a compound VI in 400 ml of dichloromethane, adding 50 g of trifluoroacetic acid at 25 ℃ after stirring and dissolving, stirring for 3 h, pouring a reaction solution into a mixed solution of methyl tert-butyl ether (480 ml)/dichloromethane (120 ml) after the reaction is finished, stirring and crystallizing for 1 h after the addition is finished, filtering, washing a filter cake with a mixed solution of methyl tert-butyl ether (20 ml) and dichloromethane (5 ml), and drying to obtain a white solid, namely a compound VII, wherein 38.2 g of a product is obtained totally, the yield is 96.4%, and the purity is 99.2%.
(5) And (2) dissolving 30 g of the compound VII in 150 ml of acetone, reducing the temperature of the system to 10 ℃ after the compound VII is dissolved, adding 32 ml of concentrated hydrochloric acid into the system, heating to 25 ℃ after the concentrated hydrochloric acid is added, stirring for 3 h, carrying out suction filtration, washing the obtained solid with 100 ml of water for 2h, carrying out suction filtration, washing the filter cake with 30 ml of water, and carrying out vacuum drying after the washing to obtain a white solid, namely valganciclovir hydrochloride (I), wherein 24.7g of the white solid is obtained, the yield is 95.4%, and the purity is 99.3%.
Example 2:
(1) weighing 30 g of ganciclovir (II), dissolving in 300 ml of dichloromethane, cooling to 0 ℃, adding 53.9 g of phosphorus pentachloride in batches, after dropwise adding, controlling the reaction temperature not to exceed 10 ℃, reacting for 1 h, and reacting with saturated NH4And (3) quenching the reaction by using a Cl solution, washing a water phase by using 2 × 100 ml of dichloromethane after liquid separation, collecting an organic phase after washing, washing by using 3L of saturated sodium chloride solution, collecting the organic phase by liquid separation after washing, drying for 2h, then spin-drying the solvent to obtain a yellow solid, recrystallizing the obtained solid by using methanol (60 ml) and n-hexane (180 ml), and performing suction filtration to obtain a light yellow solid compound III, wherein the yield is 88.0% and the purity is 96.3% after drying.
(2) Dissolving 30 g of compound III and 53.8 g of compound IV in 150 ml of methanol, stirring for 2h at 25 ℃, performing suction filtration, adding 510 ml of methyl tert-butyl ether into the filtrate, separating out a large amount of solids, continuing stirring for 2h, performing suction filtration to obtain a white-like solid and a compound V, and drying to obtain 61.3 g of a product, wherein the yield is 91.2 percent, and the purity is 96.6 percent
(3) 60 g of compound V is dissolved in 600 ml of ethanol, 74.4 g of triethylamine is added into the solution, the mixture reacts for 25 hours at 25 ℃, 120ml of 3mol/L hydrochloric acid is used for adjusting the mixture to be neutral, the ethanol is dried in a spinning mode, the liquid is washed by 2X 120ml of ethyl acetate, after the washing is finished, an organic phase is collected and washed by 600 ml of saturated sodium chloride solution, liquid separation is carried out, the organic phase is dried for 2 hours, the spin-dried solvent is filtered to obtain brown solid, the mixed solvent of ethyl acetate (60 ml) and water (180 ml) is used for washing for 2 hours, the filtration is carried out, a filter cake is washed by 30 ml of ethyl glacial acetate, the white-like solid which is the compound VI is obtained after the filter cake is collected, 40.8 g of white-like solid is obtained through drying, the.
(4) 40 g of compound VI is dissolved in 400 ml of dichloromethane, 50 g of trifluoroacetic acid is added at 25 ℃ after the mixture is stirred and dissolved for 3 h, the reaction solution is poured into the mixed solution of isopropyl ether (480 ml)/dichloromethane (120 ml) after the reaction is finished, the mixture is stirred and crystallized for 1 h after the reaction is finished, the mixture is filtered, the filter cake is washed by the mixed solution of methyl tert-butyl ether (20 ml) and dichloromethane (5 ml), and then the white solid, namely the compound VII, is obtained after drying, and 36.3 g of product is obtained totally, the yield is 91.6 percent, and the purity is 98.8 percent.
(5) And (2) dissolving 30 g of the compound VII in 150 ml of acetone, reducing the temperature of the system to 10 ℃ after the compound VII is dissolved, adding 32 ml of concentrated hydrochloric acid into the system, heating to 25 ℃ after the concentrated hydrochloric acid is added, stirring for 3 h, carrying out suction filtration, washing the obtained solid with 100 ml of water for 2h, carrying out suction filtration, washing the filter cake with 30 ml of water, and carrying out vacuum drying after the washing to obtain a white solid, namely valganciclovir hydrochloride (I), wherein 24.7g of the white solid is obtained, the yield is 95.4%, and the purity is 98.9%.
Claims (9)
- 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, characterized in that it comprises the following steps:1) dissolving a compound shown in a formula II in an organic solvent, adding phosphorus pentachloride, and reacting at 0-10 ℃ to obtain a compound shown in a formula III;2) dissolving the formula III in an organic solvent, and reacting with a compound IV at 25 ℃ to obtain a compound of a formula V;3) dissolving the compound shown in the formula V in an organic solvent, and carrying out alkaline hydrolysis under the action of N, N-diisopropylethylamine at 25 ℃ to obtain a compound shown in the formula VI;4) dissolving the formula VI in an organic solvent, and deprotecting under the action of trifluoroacetic acid at 25 ℃ to obtain a compound shown in the formula VII;5) dissolving the formula III in an organic solvent, and reacting with hydrochloric acid at 25 ℃ to obtain a compound shown in the formula I;
。
- 2. the process according to claim 1, wherein the organic solvent used in step 1 is preferably tetrahydrofuran, and the amount of the solvent is 5 to 15 times, preferably 5 to 7 times (volume to mass ratio) that of the compound II.
- 3. The process according to claim 1, wherein the reaction temperature used in step 1 is preferably 0 to 10 ℃.
- 4. The process according to claim 1, wherein the organic solvent used in step 2 is preferably methanol, and the amount of the solvent is preferably 5 to 15 times, preferably 5 to 7 times (volume to mass ratio) that of compound III.
- 5. The process according to claim 1, wherein the organic solvent used in step 3 is preferably methanol, and the amount of the solvent is preferably 10 to 30 times, preferably 10 to 15 times (volume to mass ratio) the amount of the compound V.
- 6. The process according to claim 1, wherein the reaction in step 4 is carried out using a solvent, preferably dichloromethane, preferably in an amount of 10 to 30 times, preferably 10 to 15 times (volume to mass ratio) the amount of the compound VI.
- 7. The process according to claim 1, wherein the reaction of step 5 is carried out using a solvent, preferably acetone, preferably 10 to 30 times, preferably 10 to 15 times (volume to mass ratio) the amount of the compound VII.
- 8. The method according to claim 1, wherein the reaction temperature of the hydrochloric acid is preferably 0 to 10 ℃ in step 5.
- 9. The process according to claim 1, wherein the reaction temperature after the addition of hydrochloric acid in step 5 is preferably 20 to 25 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US20120190850A1 (en) * | 2009-08-12 | 2012-07-26 | Ranbaxy Laboratories Limited | Process for the preparation of valganciclovir hydrochloride |
| CN102718765A (en) * | 2011-03-31 | 2012-10-10 | 四川科伦药物研究有限公司 | Method for preparing and purifying Valganciclovir hydrochloride |
| US20140296520A1 (en) * | 2011-11-25 | 2014-10-02 | Piramal Enterprises Limited | Process for the preparation of valacyclovir hydrochloride |
-
2019
- 2019-04-02 CN CN201910261917.XA patent/CN111763207B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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