CN112500414B - Preparation method of O-monoacetylganciclovir - Google Patents
Preparation method of O-monoacetylganciclovir Download PDFInfo
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- CN112500414B CN112500414B CN202011370329.9A CN202011370329A CN112500414B CN 112500414 B CN112500414 B CN 112500414B CN 202011370329 A CN202011370329 A CN 202011370329A CN 112500414 B CN112500414 B CN 112500414B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 19
- PEZKHGVZZSQDPY-UHFFFAOYSA-N [2-[(2-acetamido-6-oxo-3h-purin-9-yl)methoxy]-3-acetyloxypropyl] acetate Chemical compound O=C1NC(NC(=O)C)=NC2=C1N=CN2COC(COC(C)=O)COC(C)=O PEZKHGVZZSQDPY-UHFFFAOYSA-N 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 12
- 238000001704 evaporation Methods 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims description 17
- 238000010438 heat treatment Methods 0.000 claims description 15
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 12
- 238000004321 preservation Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- 238000011534 incubation Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 5
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000005119 centrifugation Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 14
- 239000002904 solvent Substances 0.000 abstract description 13
- 238000001035 drying Methods 0.000 abstract description 10
- 238000003912 environmental pollution Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000000706 filtrate Substances 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 abstract 1
- 229960002963 ganciclovir Drugs 0.000 description 15
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 15
- 238000005070 sampling Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000004064 recycling Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 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 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 229960002149 valganciclovir Drugs 0.000 description 3
- 108090000371 Esterases Proteins 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- OBABDJMYPMAQEP-UHFFFAOYSA-N [[2-[(2-amino-6-oxo-3h-purin-9-yl)methoxy]-3-hydroxypropoxy]-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound N1C(N)=NC(=O)C2=C1N(COC(CO)COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C=N2 OBABDJMYPMAQEP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 description 1
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000001512 anti-cytomegaloviral effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
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- 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
- Y02P20/582—Recycling of unreacted starting or intermediate materials
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of O-monoacetylganciclovir, which belongs to the technical field of medicine preparation, and is characterized in that triacetyl ganciclovir is used as a raw material, organic weak base is used as a solvent, and simultaneously the raw material is used as an alkaline hydrolysis condition, and can be directly hydrolyzed under a little water content, the time and the temperature are controlled, the reaction process is monitored by HPLC, the content of the monoacetylganciclovir is obviously increased, the content of the triacetyl ganciclovir is reduced, the solvent is evaporated under reduced pressure after the reaction is finished, and ethyl acetate is added, stirred and crystallized; centrifugally drying to obtain a finished product; and collecting solvent vapor, evaporating to dryness under reduced pressure to recover solvent, and distilling the filtrate to recover ethyl acetate. The raw materials are cheap and easy to obtain, the reaction is easy to complete, and the post-treatment is simpler; the method has the advantages of simple reaction process, short process steps, low production cost, high conversion rate of finished products, no environmental pollution, suitability for industrial production compared with the traditional process, and better accordance with the green chemical concept.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a preparation method of O-monoacetylganciclovir.
Background
Valganciclovir is a synthetic 2-deoxyguanosine analogue, is a prodrug of ganciclovir (ganciclovir), an antiviral drug, and can greatly reduce the toxicity of ganciclovir. Its pharmacodynamic properties are the same as ganciclovir. Valganciclovir is rapidly hydrolyzed to ganciclovir under the action of intestinal mucosal cellular esterase and liver esterase after oral administration, ganciclovir is generated into ganciclovir triphosphate under the action of in-virus and intracellular enzyme phosphorylation, and the ganciclovir triphosphate competes with deoxyguanosine triphosphate (dGTP) as a substrate of virus DNA polymerase, so that the synthesis of virus DNA is inhibited, and the anti-Cytomegalovirus (CMV) activity is generated. The O-monoacetylganciclovir is used as one of main raw materials of valganciclovir, is widely applied, and the current main synthesis processes comprise two processes:
(1) adding ganciclovir, trimethyl orthoacetate and DMF into a reaction kettle, stirring uniformly, then adding 1% trifluoroacetic acid as a catalyst, heating to about 50 ℃, and carrying out heat preservation reaction for 2 hours; then cooling to 5-10 ℃, adding a little methanol and 2 times of DMF water, heating to dissolve and clear, and cooling to crystallize overnight; and centrifuging, washing with methanol, and spin-drying.
(2) Adding ganciclovir, triphenylchloromethane and DMF (dimethyl formamide) into a reaction kettle, then adding potassium carbonate and a catalytic amount of potassium iodide, stirring, heating to about 90 ℃, and carrying out heat preservation reaction for 8 hours; then cooling and centrifuging, evaporating the mother liquor to dryness, adding dichloromethane, refluxing trifluoroacetic acid for 2 hours, evaporating dichloromethane to dryness, adding ethyl acetate, stirring and crystallizing; and finally, centrifugally drying.
The raw material ganciclovir of the first process is difficult to react completely, water is added for reverse hydrolysis, ganciclovir is difficult to remove, and the recovery post-treatment is troublesome; the second process is long and the cost is high.
Disclosure of Invention
1. Technical problem to be solved
The technical problem to be solved by the invention is to provide a preparation method of O-monoacetylganciclovir, which has cheap and easily obtained raw materials, easy complete reaction and simpler post-treatment; the method has the advantages of simple reaction process, short process steps, low production cost, high conversion rate of finished products, no environmental pollution, suitability for industrial production compared with the traditional process, and better accordance with the green chemical concept.
2. Technical scheme
In order to solve the problems, the invention adopts the following technical scheme:
a preparation method of O-monoacetylganciclovir comprises the following steps:
s1, adding triacetyl ganciclovir and organic weak base into a reaction kettle, adding water, wherein the weight ratio of the triacetyl ganciclovir to the organic weak base to the water is 10:30:1, stirring, heating to 70-80 ℃, and carrying out heat preservation reaction until the reaction is complete;
s2, heating and decompressing to evaporate the organic weak base, collecting the evaporated gas, decompressing and evaporating the evaporated gas to dryness, and recovering the organic weak base;
s3, adding ethyl acetate into the reaction kettle, wherein the weight ratio of the ethyl acetate to the raw material triacetyl ganciclovir is 5:1, stirring and refluxing for 3 hours, and then cooling and crystallizing;
s4, after solid-liquid separation is realized by centrifugation, collecting solids, and drying to obtain a finished product of O-monoacetylganciclovir; the liquid was collected, distilled and ethyl acetate recovered.
Further, the organic weak base is any one of organic amines.
Further, in step S1, the reaction time of the incubation reaction is 36 to 40 hours.
Further, in step S2, the temperature is raised to 90 to 100 ℃.
3. Advantageous effects
(1) The invention takes triacetyl ganciclovir as a raw material, takes organic weak base as a solvent, and simultaneously takes the triacetyl ganciclovir as an alkaline hydrolysis condition, and can be directly hydrolyzed under the condition that the weight is one tenth of that of the raw material to generate monoacetyl ganciclovir; and after the reaction is finished, the solvent is evaporated under reduced pressure, ethyl acetate is added, stirring and crystallization are carried out, and finally centrifugal drying is carried out to obtain the O-monoacetylganciclovir finished product.
(2) When the solvent is evaporated under reduced pressure, the solvent steam is collected and subjected to reduced pressure evaporation treatment, and the solvent can be recovered for recycling; according to the invention, after the filtrate collected in the centrifugal treatment is distilled, ethyl acetate can be recovered for recycling. The solvent and the crystallization auxiliary agent adopted in the invention can be recovered and reused, and the production cost can be greatly reduced.
(3) The method comprises the steps of hydrolyzing triacetyl ganciclovir and an organic weak base solvent to generate monoacetyl ganciclovir, removing the solvent, adding ethyl acetate, stirring for crystallization, and finally centrifugally drying to obtain the O-monoacetyl ganciclovir finished product, wherein the organic weak base solvent and the ethyl acetate can be recycled, so that the O-monoacetyl ganciclovir finished product has the advantages of few impurities, no by-products, high conversion rate of the finished product, total yield of over 93 percent, no environmental pollution, suitability for industrial production compared with the traditional process and better accordance with the green chemical concept.
In conclusion, the raw materials are cheap and easy to obtain, the reaction is easy to complete, and the post-treatment is simpler; the method has the advantages of simple reaction process, short process steps, low production cost, high conversion rate of finished products, no environmental pollution, suitability for industrial production compared with the traditional process, and better accordance with the green chemical concept.
Drawings
FIG. 1 is a graph showing the results of sample detection (HPLC) after 12 hours of the incubation reaction in example 1;
FIG. 2 is a graph showing the results of sample detection (HPLC) after the reaction was carried out for 36 hours under the incubation in example 1.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples.
Example 1
S1, putting 40kg of triacetylganciclovir and 120kg of pyridine into a 500L reaction kettle, adding 4kg of water, stirring and heating to 70 ℃;
s2, carrying out sampling detection (HPLC) after the reaction is carried out for 12 hours under the condition of heat preservation, wherein the detection results are shown in figure 1 and table 1, and as can be seen from figure 1 and table 1, the content of monoacetylganciclovir is obviously increased, and the content of triacetylganciclovir is reduced;
s3, sampling and detecting after the reaction is carried out for 36 hours under the condition of heat preservation, wherein the detection result is shown in figure 2 and table 2, and the figure 2 and the table 2 show that the reaction is completely carried out under the condition of heat preservation;
s4, heating to 100 ℃, decompressing, collecting steam and pyridine evaporated, reserving main reactants and part of water in liquid state in the reaction kettle, decompressing and evaporating pyridine, and recycling;
s5, adding 200kg of ethyl acetate into the reaction kettle, stirring and refluxing for 3 hours, and then cooling and crystallizing;
s6, performing centrifugal treatment, after solid-liquid separation is realized, collecting solids, and drying the solids to obtain 29.2kg of O-monoacetylganciclovir finished product; the liquid was collected, distilled and ethyl acetate recovered.
The calculated yield of O-monoacetylganciclovir is 93.7%.
TABLE 1 Table of measurement data of sampling measurement (HPLC) after 12 hours of incubation reaction
TABLE 2 Table of measurement data of sampling measurement (HPLC) after 36 hours of incubation reaction
Example 2
S1, putting 40kg of triacetyl ganciclovir and 120kg of piperidine into a 500L reaction kettle, adding 4kg of water, stirring, and heating to 80 ℃;
s2, carrying out heat preservation reaction for 12 hours, then sampling and detecting (HPLC), and completing half of the reaction;
s3, keeping the temperature and reacting for 36 hours, then sampling and detecting, and reacting completely;
s4, heating to 90 ℃, decompressing, collecting evaporated water vapor and piperidine, reserving a main liquid reactant and part of water in the reaction kettle, decompressing and evaporating the piperidine for recycling;
s5, adding 200kg of ethyl acetate into the reaction kettle, stirring and refluxing for 3 hours, and cooling and crystallizing;
s6, performing centrifugal treatment, after solid-liquid separation is realized, collecting solids, and drying to obtain 29.6kg of O-monoacetylganciclovir finished product; the liquid was collected, distilled and ethyl acetate recovered.
The calculated yield of O-monoacetylganciclovir is 95%.
Example 3
S1, putting 40kg of triacetyl ganciclovir and 120kg of N-methylmorpholine into a 500L reaction kettle, adding 4kg of water, stirring and heating to 75 ℃;
s2, preserving the temperature, reacting for 12 hours, then sampling and detecting (HPLC), wherein the reaction is not complete;
s3, carrying out heat preservation reaction for 40 hours, then sampling and detecting, and carrying out complete reaction;
s4, heating to 95 ℃, decompressing, collecting evaporated water vapor and N-methylmorpholine, reserving liquid main reactant and part of water in the reaction kettle, decompressing and evaporating N-methylmorpholine, and recycling;
s5, adding 200kg of ethyl acetate into the reaction kettle, stirring and refluxing for 3 hours, and cooling and crystallizing;
s6, centrifugal drying to obtain 29.5kg of O-monoacetylganciclovir finished product, and distilling to recover ethyl acetate.
The calculated yield of O-monoacetylganciclovir is 94.3%.
Example 4
S1, putting 40kg of triacetylganciclovir and 120kg of diethanolamine into a 500L reaction kettle, adding 4kg of water, stirring and heating to 70 ℃;
s2, preserving the temperature, reacting for 12 hours, then sampling and detecting (HPLC), wherein the reaction is not complete;
s3, sampling and detecting after reacting for 38 hours in a heat preservation way, and completely reacting;
s4, heating to 100 ℃, reducing pressure, collecting evaporated water vapor and diethanolamine, reserving liquid main reactants and part of water in the reaction kettle, and then evaporating the diethanolamine to dryness under reduced pressure for recycling;
s5, adding 200kg of ethyl acetate into the reaction kettle, stirring and refluxing for 3 hours, and cooling and crystallizing;
s6, centrifugal drying to obtain 29.4kg of O-monoacetylganciclovir finished product, and distilling to recover ethyl acetate.
The calculated yield of O-monoacetylganciclovir is 93.4%.
According to the invention, the recovered organic solvent, ethyl acetate and the like can be recycled, and the raw material triacetyl ganciclovir is cheaper and easier to obtain than ganciclovir, so that the cost is saved, and no environmental pollution is caused; the reaction process is simple, almost no by-products are generated, the impurities in the reaction process are few, the conversion rate of the finished product is high, and the total yield reaches more than 93%. Compared with the traditional process, the method is more suitable for industrial production and more conforms to the green chemical concept.
It should be understood by those skilled in the art that the above embodiments are only for illustrating the present invention and are not to be used as a limitation of the present invention, and that changes and modifications to the above embodiments are within the scope of the claims of the present invention as long as they are within the spirit and scope of the present invention.
Claims (3)
1. A preparation method of O-monoacetylganciclovir is characterized by comprising the following steps:
s1, adding triacetyl ganciclovir and organic weak base into a reaction kettle, adding water, wherein the weight ratio of the triacetyl ganciclovir to the organic weak base to the water is 10:30:1, stirring, heating to 70-80 ℃, and carrying out heat preservation reaction until the reaction is complete; the organic weak base is any one of pyridine, piperidine, N-methylmorpholine and diethanolamine;
s2, heating and decompressing to evaporate the organic weak base, collecting the evaporated gas, decompressing and evaporating the evaporated gas to dryness, and recovering the organic weak base;
s3, adding ethyl acetate into the reaction kettle, wherein the weight ratio of the ethyl acetate to the raw material triacetyl ganciclovir is 5:1, stirring and refluxing for 3 hours, and then cooling and crystallizing;
s4, after solid-liquid separation is realized through centrifugation, the solid is collected and dried to obtain the O-monoacetylganciclovir finished product; the liquid was collected, distilled and ethyl acetate recovered.
2. The method of claim 1, wherein the incubation reaction is carried out for a period of 36-40 hours in step S1.
3. The method for preparing O-monoacetylganciclovir according to claim 1, wherein in step S2, the temperature is raised to 90-100 ℃.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1837336A1 (en) * | 2006-03-21 | 2007-09-26 | Cipla Ltd. | Preparation of valganciclovir |
| CN105693722A (en) * | 2016-04-20 | 2016-06-22 | 安徽海康药业有限责任公司 | Preparation method of CBZ-valganciclovir |
| CN107163050A (en) * | 2017-07-10 | 2017-09-15 | 湖北天义药业有限公司 | A kind of novel synthesis of valganciclovir hydrochloride |
| CN108503642A (en) * | 2018-04-29 | 2018-09-07 | 安徽海康药业有限责任公司 | A kind of preparation method of high-purity single acetyl Ganciclovir |
| CN108503641A (en) * | 2018-04-29 | 2018-09-07 | 安徽海康药业有限责任公司 | A method of synthesis high-purity single acetyl Ganciclovir |
-
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- 2020-11-30 CN CN202011370329.9A patent/CN112500414B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1837336A1 (en) * | 2006-03-21 | 2007-09-26 | Cipla Ltd. | Preparation of valganciclovir |
| CN105693722A (en) * | 2016-04-20 | 2016-06-22 | 安徽海康药业有限责任公司 | Preparation method of CBZ-valganciclovir |
| CN107163050A (en) * | 2017-07-10 | 2017-09-15 | 湖北天义药业有限公司 | A kind of novel synthesis of valganciclovir hydrochloride |
| CN108503642A (en) * | 2018-04-29 | 2018-09-07 | 安徽海康药业有限责任公司 | A kind of preparation method of high-purity single acetyl Ganciclovir |
| CN108503641A (en) * | 2018-04-29 | 2018-09-07 | 安徽海康药业有限责任公司 | A method of synthesis high-purity single acetyl Ganciclovir |
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