CN101955481B - A kind of preparation method of Valganciclovir hydrochloride - Google Patents
A kind of preparation method of Valganciclovir hydrochloride Download PDFInfo
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- CN101955481B CN101955481B CN201010504756.1A CN201010504756A CN101955481B CN 101955481 B CN101955481 B CN 101955481B CN 201010504756 A CN201010504756 A CN 201010504756A CN 101955481 B CN101955481 B CN 101955481B
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- ganciclovir
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- alcohol
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Abstract
The invention discloses a kind of preparation method of Valganciclovir hydrochloride I, step is: 1. phosphorus oxychloride is dissolved in inert solvent, reacts with alcohol liquid, obtains phosphinylidyne dihalo-II; 2. ganciclovir and step phosphinylidyne dihalo-II are 1. obtained by reacting ganciclovir monoesters III; 3. step ganciclovir phosphate monoester III is 2. obtained ganciclovir dibasic acid esters IV with the esterification of N-benzyloxy-oxo-L-valine; 4. step ganciclovir dibasic acid esters IV acidifying dephosphorylation is 3. obtained N-benzyloxy-oxo-L-valine ganciclovir monoesters V; 5. last step product is 4. obtained Valganciclovir hydrochloride reason I by hydrogenation.The method produces the ganciclovir monoesters of high purity, high yield.Its aftertreatment is more prone to, and reduces post-processing difficulty.
Description
Technical field
The present invention relates to medical art, particularly a kind of new preparation method of Valganciclovir hydrochloride.
Background technology
Valganciclovir hydrochloride is a kind of novel antiviral medicine, it is the prodrug of ganciclovir, be mainly used in treatment HIV person (AIDS patient) because infecting cytomegalovirus (CMV) the induced Acute retinitis, and prevent the cmv infection of high-risk solid organ transplant patients.The oral administration biaavailability of valganciclovir exceeds much than ganciclovir, and toxicity reduces greatly, and domestic also not this marketing drugs, has wide market outlook at present.
Current Valganciclovir hydrochloride mainly prepares generation method to be had: be 1. raw material with ganciclovir, directly and N-benzyloxycarbonyl-Valine-N-acetyl anhydride (or N-carbobenzoxy-(Cbz)-L--α-amino-isovaleric acid) condensation, ganciclovir monoesters is obtained by controlling reaction conditions, then through hydro-reduction synthetic hydrochloric acid valganciclovir; 2. be raw material with ganciclovir, first with an orthoester-protected hydroxyl, then with N-benzyloxy-oxo-L-valine and another hydroxyl condensation, obtain dibasic acid esters ester, then by hydrolysis reaction and hydro-reduction Reactive Synthesis Valganciclovir hydrochloride.3. take purine compound as raw material, be obtained by reacting the mono-ester product of ganciclovir with active electrophilic reagent, then obtain Valganciclovir hydrochloride through hydrogenation and deprotection.Method 1 reaction process has dibasic acid esters to produce, and monoesters is more difficult with being separated of dibasic acid esters, is unfavorable for suitability for industrialized production.Method 2 ortho ester used is expensive, and Deprotection is more difficult.Method 3 technique is loaded down with trivial details, and cost is too high, is unfavorable for suitability for industrialized production.
Summary of the invention
For above-mentioned shortcoming, the technical problem to be solved in the present invention is to provide the preparation method of Valganciclovir hydrochloride of a kind of high purity, high yield.
For solving the problems of the technologies described above, the technical solution adopted in the present invention is: a kind of preparation method of Valganciclovir hydrochloride I, and step is: 1. phosphorus oxychloride is dissolved in inert solvent, reacts with alcohol liquid, obtains phosphinylidyne dihalo-II; 2. ganciclovir and step phosphinylidyne dihalo-II are 1. obtained by reacting ganciclovir monoesters III; 3. step ganciclovir phosphate monoester III is 2. obtained ganciclovir dibasic acid esters IV with the esterification of N-benzyloxy-oxo-L-valine; 4. step ganciclovir dibasic acid esters IV acidifying dephosphorylation is 3. obtained N-benzyloxy-oxo-L-valine ganciclovir monoesters V; 5. last step product is 4. obtained Valganciclovir hydrochloride reason I by hydrogenation;
The molecular structural formula of described Valganciclovir hydrochloride I is:
The molecular structural formula of described phosphinylidyne dihalo-II is:
The molecular structural formula of described ganciclovir monoesters III is:
The molecular structural formula of described ganciclovir dibasic acid esters IV is:
The molecular structural formula of described N-benzyloxy-oxo-L-valine ganciclovir monoesters V is:
In above kind formula, R is (CH
3)
3c-, (C
6h
5)
3c-, CH
2cH
2cl, CNCH
2cH
2, 2,2,2-Cl
3cCH
2in one.
Further: in the preparation method of above-mentioned Valganciclovir hydrochloride I, its concrete steps are: be 1. dissolved in inert solvent by phosphorus oxychloride, be cooled to less than 0 DEG C, drip alcohol, then be naturally warming up to room temperature reaction 3-4 hour, low boiling point solvent is removed in first underpressure distillation, then uses oil pump underpressure distillation, collect fractionation, obtain phosphinylidyne dihalo-II; 2. phosphinylidyne dihalo-II is dissolved in inert solvent, be cooled to less than 0 DEG C, under nitrogen protection, add ganciclovir, then add acid scavenger, then heat up in 20-50 DEG C of reaction 4-6 hour, poured into by reactant in frozen water, go out ganciclovir monoesters III with organic solvent extraction, decompression evaporates solvent, obtain ganciclovir monoesters III, described ganciclovir and the weight ratio of acid scavenger are 100: 5-15; 3. ganciclovir monoesters III is joined in inert solvent, be cooled to less than 5 DEG C, add α-amino-isovaleric acid CBZ-L-Val successively, DMAP DMAP, 1,3-dicyclohexyl carbodiimide DCC, insulation reaction 5-6 hour, filter, filtrate 90-110 DEG C of decompression is dense dry, adding alcohol when being cooled to 50-60 DEG C stirs clearly molten, and slow cooling, to 5-10 DEG C of suction filtration, dries to obtain ganciclovir dibasic acid esters IV; 4. be dissolved in alcohol by ganciclovir dibasic acid esters, add acid, in 50-100 DEG C of reaction 3-4 hour, then steam most of alcohol, room temperature adds water, and cooling is filtered, and dries to obtain N-benzyloxy-oxo-L-valine ganciclovir monoesters V.5. N-benzyloxy-oxo-L-valine ganciclovir monoesters and palladium carbon are joined in the alcohol of cooling, add acid, be evacuated to-0.08Mpa, then fill hydrogen, room temperature reaction 5-10 hour, filter, the dense dry solvent of filtrate decompression, adds water and alcohol heats up clearly molten, cooling crystallization, be cooled to less than 0 DEG C filtration, dry to obtain product Valganciclovir hydrochloride I; One or more in described alcohol methyl alcohol in above steps, ethanol, propyl alcohol, Virahol, propyl carbinol, amylalcohol; Described acid is one or more in hydrochloric acid, sulfuric acid, Phenylsulfonic acid.The preparation method of above-mentioned Valganciclovir hydrochloride I, reaction mechanism be
In above two kinds of formulas, R is (CH
3)
3c-, (C
6h
5)
3c-, CH
2cH
2cl, CNCH
2cH
2, 2,2,2-Cl
3cCH
2in one.
The acid scavenger of described step 2 is one or more in triethylamine, pyridine, sodium hydroxide calcium hydroxide.Pyridine is pyridine again, is the 6-membered heterocyclic compound containing a nitrogen heteroatom, the compound a that-CH=namely in benzene molecular is replaced by nitrogen and generates, molecular formula C5H5N
Described inert solvent is one or both in methylene dichloride, trichloromethane, acetone, toluene, tetrahydrofuran (THF), methyl alcohol, ethanol, dimethyl formamide DMF.Preferred phosphinylidyne dihalo-II is tertiary fourth oxygen phosphinylidyne dichloro.
Compared with the preparation technology of existing Valganciclovir hydrochloride, the present invention adopts phosphinylidyne dihalo-cheap and easy to get as the phosphorylation agent of ganciclovir, because phosphinylidyne dihalo-is with an alkyl group, with the bond angle of P-0-C key after a hydroxyl reaction of ganciclovir, bond distance affects, add that molecular structure has very high steric effect, another hydroxyl is difficult to continue to react with phosphinylidyne dihalo-again, by controlling the amount of phosphinylidyne dihalo-and ganciclovir, be obtained by reacting ganciclovir phosphate monoester, therefore there is single defencive function of two hydroxyl, side reaction is few, impurity is few, easy purification.Phosphorylation reaction yield of the present invention is up to 95% ~ 98%.Because phosphorylation reaction side reaction of the present invention is few, by product is few, easy purifying, thus can produce the ganciclovir monoesters of high purity, high yield.And make not need purifying at subsequent reactions, reduce post-processing difficulty.
Embodiment
Be described in further detail content of the present invention below in conjunction with embodiment, content mentioned in embodiment is not limitation of the invention, and in preparation process, each raw-material selection can be suited measures to local conditions and there is no substantial effect to result.
Embodiment 1
The preparation of tertiary fourth oxygen phosphinylidyne dichloro
Phosphorus oxychloride 30.7g, methylene dichloride 30ml are added in the reaction flask of 100ml, is cooled to less than 0 DEG C, drip trimethyl carbinol 22.2g, then room temperature reaction 3 hours are naturally warming up to, first decompression evaporates solvent, then steams tertiary fourth oxygen phosphinylidyne dichloro 36.4g, yield 95.1% with oil pump decompression.
Embodiment 2
The synthesis of ganciclovir phosphate monoester III
Tertiary for embodiment 1 fourth oxygen phosphinylidyne dichloro-4,4 0.0g, methylene dichloride 400ml are added in the reaction flask of 1000ml, is cooled to less than 0 DEG C, under nitrogen protection, adds 76.3g ganciclovir, then add triethylamine 12ml, then heat up in 20-50 DEG C of reaction 5 hours.Reaction poured in frozen water, separate organic layer, water layer 200ml methylene dichloride extracts once again, merges organic layer, washes with water, organic over anhydrous dried over sodium sulfate, filters, and decompression evaporates solvent.Vacuum drying, obtains ganciclovir monoesters III 73.86g, yield 96.8%.
Embodiment 3
The synthesis of ganciclovir dibasic acid esters IV
By embodiment 2 ganciclovir monoesters 49g, DMF392mL adds in the reaction flask of 1000ml, stirring is cooled to 0 ~ 5 DEG C, add CBZ-L-Val53.9g successively, DMAP2.1g, DCC51.1g, room temperature reaction is after 6 hours, be cooled to 0 DEG C of suction filtration, 10mLDMF foam washing, filtrate 110 DEG C decompression is dense to be done to white solid, then adding 490mL methyl alcohol stirs clearly molten, slow cooling to 10 DEG C suction filtration, filter cake 80 DEG C dries to obtain ganciclovir dibasic acid esters IV crude product: 74g, crude product adds 1295mL ethanol, stirring be warming up to 75 DEG C clearly molten, slow cooling to 0 DEG C suction filtration, filter cake 80 DEG C oven dry: 96.42g, yield: 88%, purity: 99.1%.
Embodiment 4
The synthesis of N-benzyloxy-oxo-L-valine ganciclovir monoesters V
Ganciclovir phosphate diester IV 60g, 600ml methyl alcohol of embodiment 3 is joined in the reaction flask of 1000ml, pass into appropriate concentrated hydrochloric acid, then heat up in 50-60 DEG C of reaction 4 hours, then normal pressure steams 500mL methyl alcohol, be down to room temperature, add 764.4mL water, stir and be cooled to 0-5 DEG C, suction filtration, vacuum drying, obtain N-benzyloxy-oxo-L-valine ganciclovir monoesters V 35.3g, yield 90%, purity 98.5%.
Embodiment 5
The synthesis of Valganciclovir hydrochloride I
By embodiment 4N-benzyloxy-oxo-L-valine ganciclovir monoesters V 45.6g, palladium-carbon catalyst Pd-C3.0g, refrigerated methanol 365mL, concentrated hydrochloric acid 8.4mL, drop in high pressure resistant bottle successively, be evacuated to-0.08Mpa, fill hydrogen to 0.2Mpa, room temperature reaction 18 hours, filter, filtrate 45 DEG C decompression is dense dry, add pure water 36.5mL, Virahol 36.5mL, stir intensification clearly molten, filter, filtrate temperature control 60 ~ 70 DEG C drips Virahol 164.3mL, drip off slow cooling, separate out white solid, be cooled to-11 DEG C of suction filtrations, filter cake 50 DEG C of decompression dryings obtain Valganciclovir hydrochloride I 30g, yield: 82%, purity: 99.4%.
Above-described embodiment all uses high performance liquid chromatograph purity check, and its condition is as follows:
Instrument: high performance liquid chromatograph (Agilent1100)
Post: CR40 × 150mm; Hypersil, ODS, 5 μm, 4.6 × 150mm
Column temperature: 25 DEG C
Moving phase:
Flow velocity: 1.0ml/ second.
Claims (5)
1. a preparation method of Valganciclovir hydrochloride I, step is:
1. phosphorus oxychloride is dissolved in inert solvent, reacts with alcohol liquid, obtains phosphinylidyne dihalo-II;
2. ganciclovir and step phosphinylidyne dihalo-II are 1. obtained by reacting ganciclovir monoesters III;
3. step ganciclovir phosphate monoester III 2. and the esterification of N-benzyloxy-oxo-L-valine are obtained ganciclovir dibasic acid esters IV;
4. step ganciclovir dibasic acid esters IV acidifying dephosphorylation is 3. obtained N-benzyloxy-oxo-L-valine ganciclovir monoesters V;
5. last step product is 4. obtained Valganciclovir hydrochloride I by hydrogenation;
The molecular structural formula of described Valganciclovir hydrochloride I is:
The molecular structural formula of described phosphinylidyne dihalo-II is:
The molecular structural formula of described ganciclovir monoesters III is:
The molecular structural formula of described ganciclovir dibasic acid esters IV is:
The molecular structural formula of described N-benzyloxy-oxo-L-valine ganciclovir monoesters V is:
In various above, R is (CH
3)
3c-, (C
6h
5)
3c-, CH
2cH
2cl, CNCH
2cH
2, 2,2,2-Cl
3cCH
2in one.
2. the preparation method of Valganciclovir hydrochloride I according to claim 1, is characterized in that: phosphinylidyne dihalo-II is tertiary fourth oxygen phosphinylidyne dichloro.
3. the preparation method of Valganciclovir hydrochloride I according to claim 1, is characterized in that: its concrete steps are
1. be dissolved in inert solvent by phosphorus oxychloride, be cooled to less than 0 DEG C, drip alcohol, be then naturally warming up to room temperature reaction 3-4 hour, low boiling point solvent is removed in first underpressure distillation, then uses oil pump underpressure distillation, collects fractionation, obtains phosphinylidyne dihalo-II;
2. phosphinylidyne dihalo-II is dissolved in inert solvent, be cooled to less than 0 DEG C, under nitrogen protection, add ganciclovir, then add acid scavenger, then heat up in 20-50 DEG C of reaction 4-6 hour, poured into by reactant in frozen water, go out ganciclovir monoesters III with organic solvent extraction, decompression evaporates solvent, obtain ganciclovir monoesters III, described ganciclovir and the weight ratio of acid scavenger are 100: 5-15;
3. ganciclovir monoesters III is joined in inert solvent, be cooled to less than 5 DEG C, add N-benzyloxy-oxo-L-valine successively, DMAP DMAP, 1,3-dicyclohexyl carbodiimide DCC, insulation reaction 5-6 hour, filter, filtrate 90-110 DEG C of decompression is dense dry, adding alcohol when being cooled to 50-60 DEG C stirs clearly molten, and slow cooling, to 5-10 DEG C of suction filtration, dries to obtain ganciclovir dibasic acid esters IV;
4. be dissolved in alcohol by ganciclovir dibasic acid esters, add acid, in 50-100 DEG C of reaction 3-4 hour, then steam most of alcohol, room temperature adds water, and cooling is filtered, and dries to obtain N-benzyloxy-oxo-L-valine ganciclovir monoesters V;
5. N-benzyloxy-oxo-L-valine ganciclovir monoesters and palladium carbon are joined in the alcohol of cooling, add acid, be evacuated to-0.08MPa, then fill hydrogen, room temperature reaction 5-10 hour, filter, the dense dry solvent of filtrate decompression, adds water and alcohol heats up clearly molten, cooling crystallization, be cooled to less than 0 DEG C filtration, dry to obtain product Valganciclovir hydrochloride I;
Above-mentioned 3. to 5. step, described alcohol is one or more in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, amylalcohol; Described acid is one or more in hydrochloric acid, sulfuric acid, Phenylsulfonic acid.
4. the preparation method of Valganciclovir hydrochloride I according to claim 3, is characterized in that: described step acid scavenger is 2. one or more in triethylamine, pyridine, sodium hydroxide, calcium hydroxide.
5. the preparation method of Valganciclovir hydrochloride I according to claim 3, is characterized in that: described inert solvent is one or both in methylene dichloride, trichloromethane, acetone, toluene, tetrahydrofuran (THF), dimethyl formamide DMF.
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| CN102718765B (en) * | 2011-03-31 | 2015-01-07 | 四川科伦药物研究有限公司 | Method for preparing and purifying Valganciclovir hydrochloride |
| CN103562207B (en) * | 2011-05-31 | 2016-08-17 | 法尔玛赞公司 | For preparing the preparation method of 2-amino-9-((2-phenyl-1,3-dioxane-5-base epoxide) methyl)-1H-purine-6 (9H) the-one compound of valganciclovir |
| CN103012404B (en) * | 2012-11-14 | 2016-05-25 | 宁波百思佳医药科技有限公司 | Valganciclovir hydrochloride polymorph and pharmaceutical composition thereof |
| CN108218871A (en) * | 2018-03-13 | 2018-06-29 | 上药康丽（常州）药业有限公司 | A kind of process for purification of CBZ- valganciclovirs |
| CN110988246B (en) * | 2019-11-29 | 2022-03-08 | 荆门医药工业技术研究院 | Method for detecting contents of Z-L-valine and intermediate (S) -4-isopropyloxazole-2, 5-diketone thereof |
| CN112409359A (en) * | 2020-11-30 | 2021-02-26 | 沃德药业(安徽)股份有限公司 | Preparation method of valganciclovir hydrochloride |
| CN113880838B (en) * | 2021-11-15 | 2024-03-19 | 仁合益康集团有限公司 | Method for synthesizing valganciclovir hydrochloride by micro-channel reactor |
| CN115286632B (en) * | 2022-09-16 | 2023-05-09 | 河北医科大学 | Preparation process of valganciclovir hydrochloride |
| CN116925079A (en) * | 2023-07-19 | 2023-10-24 | 湖北天义药业有限公司 | Amplified preparation method of valganciclovir hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5840890A (en) * | 1996-01-26 | 1998-11-24 | Syntex (U.S.A.) Inc. | Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative |
| US20070225305A1 (en) * | 2006-03-21 | 2007-09-27 | Ramchandra Rao D | Preparation of ester of purine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5840890A (en) * | 1996-01-26 | 1998-11-24 | Syntex (U.S.A.) Inc. | Process for preparing a 2-(2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxy-1,3-propanediol derivative |
| US20070225305A1 (en) * | 2006-03-21 | 2007-09-27 | Ramchandra Rao D | Preparation of ester of purine derivatives |
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