CN104109164B - A kind of preparation method who is applicable to industrialized high-purity hydrochloric acid Vardenafil trihydrate - Google Patents
A kind of preparation method who is applicable to industrialized high-purity hydrochloric acid Vardenafil trihydrate Download PDFInfo
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- CN104109164B CN104109164B CN201310135429.7A CN201310135429A CN104109164B CN 104109164 B CN104109164 B CN 104109164B CN 201310135429 A CN201310135429 A CN 201310135429A CN 104109164 B CN104109164 B CN 104109164B
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Abstract
The present invention relates to a kind of preparation method of highly purified Vardenafil hydrochloric acid trihydrate. Method improvement of the present invention post processing mode in existing method, the intermediate obtaining is stable, improved the yield of reaction, and product purity is high, more meets the requirement of drug chemical, has very strong industrial applicibility.
Description
Technical field
The present invention relates to a kind of preparation method of Vardenafil hydrochloric acid trihydrate.
Technical background
Vardenafil hydrochloric acid trihydrate (Vaedenafil, trade name: Ai Lida), its structure is as follows, is by German BayerA kind of efficient selective 5 type phosphodiesterase (PED-5) inhibitor that company developed in calendar year 2001 are treatment male sexThe medicine safely and effectively of erectile dysfunction (ED).
The mechanism of action of Vardenafil hydrochloric acid trihydrate is: by suppressing to encircle the sweet acid of bird in degradation of cell in human body corpora cavernosa penis(cGMP) PED-5, increases the release of the local endogenic NO of cavernous body under sexual stimulus effect, and it is thin that NO activates smooth muscleBorn of the same parents' the sweet cyclase of acid of bird, increases cGMP level, finally causes smooth muscle relaxation, increases CBF in penis, makes penisErect.
About the synthetic method of Vardenafil hydrochloric acid trihydrate, mainly contain two kinds at present:
The first route (referring to patent ZL01820817.7, CN101050217), reaction scheme is as follows:
The method obtains 4-second by 2-(2-ethoxyphenyl)-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4]-tri-nitrogen-4-ketone by reaction AOxygen base-3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole [1,5-f] [1,2,4-, tri-nitrogen-4-ketone]) benzene sulfonic acid (product I) is then logicalCross reaction B and obtain 2-[2-ethyoxyl-5-(4-ethyl piperazidine-1-sulfonyl) phenyl]-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4]Three nitrogen-4-ketone (product II), finally obtains end product 2-[2-ethyoxyl-5-(4-ethyl piperazidine-1-sulfonyl) benzene by reaction CBase]-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-ketone list hydrochloric acid trihydrate (product III).
But there are some problems in the method for this route:
1) reactions steps is long;
2) product viscosity after concentrated acid sulfonation is large and granularity is little, is difficult to filter, and industrialization is difficult to realize;
3) the thionyl chloride severe toxicity of using in reaction and to water sensitive, the bad control of industrial operation. In addition patent ZL01820817.7,In the dimethylbenzene boiling point used high, be difficult to remove, product purity is not high.
The second route (referring to patent ZL98811092.X), reaction scheme is as follows:
The method is reacted 2-(2-ethoxyphenyl)-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4]-tri-nitrogen-4-ketone with perchloric acid, frozen water is quenchedAfter going out, obtain 4-ethyoxyl-3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole [1,5-f] [1,2,4-, tri-nitrogen-4-with dichloromethane extractionKetone]) benzene sulfonyl chloride (product IV), then to react with NEP, dry concentrated after washing, from ether, crystallization obtains 2-[2-Ethyoxyl-5-(4-ethyl piperazidine-1-sulfonyl) phenyl]-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-ketone (productII), finally obtain end product 2-[2-ethyoxyl-5-(4-ethyl piperazidine-1-sulfonyl) phenyl by reaction G]-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-ketone list hydrochloric acid trihydrate (product III).
Also there are some problems in the method for this route:
1) reaction E uses after chlorosulfonic acid sulfonation, only passes through simple extraction, and the product IV that this post processing obtains easily becomes to salt out, extraction effectFruit is undesirable, and the unstable products and the purity that obtain are low, affect the next step yield;
2) this route is lab scale route, and method is not suitable for industry and amplifies.
Summary of the invention
The present invention is unstable and purity is low according to the intermediate product of prior art, and route is not suitable for the deficiencies such as industry amplification, and hydrochloric acid is cut down groundThe preparation technology of that non-trihydrate has done further research, object be to provide a kind of simple to operation, yield is high, purityThe synthetic method of high and applicable industrialized Vardenafil hydrochloric acid trihydrate. The method comprises the following steps:
1,, under nitrogen protection, 2-(2-ethoxyphenyl)-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4]-tri-nitrogen-4-ketone is added in batchesEnter in chlorosulfonic acid, maintain the temperature at-15～15 DEG C, after feeding in raw material, be warming up to 20～30 DEG C of reactions. Reaction is finished, and will reactSystem adds frozen water-carrene system, maintains the temperature at-5～10 DEG C, continues to stir 1 hour, has a large amount of solids to analyseGo out, filter gained solid, separate organic phase, water continuation dichloromethane extraction, merges organic phase, adds newFrozen water, adds carrene-frozen water mixed solvent by the solid of filtration, and after dissolving, separating and extracting obtains 4-ethyoxyl-3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole [1,5-f] [1,2,4-, tri-nitrogen-4-ketone]) benzene sulfonyl chloride (product 1).
2, the product 1 step 1 being obtained is dissolved in inert organic solvents, adds NEP at-5～5 DEG C, adds and is warming up to20～30 DEG C of reaction 10～30min, reaction is finished, and in reactant liquor, adds inorganic alkali solution, filters and obtains solid, waterWash, after being dried, crude product is dissolved again, add inorganic alkali solution, filter the solid of separating out, washing, the dry 2-[2-that to obtainEthyoxyl-5-(4-ethyl piperazidine-1-sulfonyl) phenyl]-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-ketone(product 2).
3, the product 2 step 2 being obtained is dissolved in acetone-water mixed solution, adds concentrated hydrochloric acid at 40～45 DEG C, after be warming up to60 DEG C of backflow 10min, are cooled to 20～30 DEG C of reaction 30～60min, at-5～0 DEG C, stir 1.5～2h, filter,Solid rinses with acetone-water solution, is dried to obtain 2-[2-ethyoxyl-5-(4-ethyl piperazidine-1-sulfonyl) phenyl]-5-methyl-7-Propyl group-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-ketone list hydrochloric acid trihydrate (product 3).
Wherein, in step 1, the reaction time is 8～10h;
In step 2, inert organic solvents is oxolane;
In step 2, inorganic alkali solution is 0.3～0.8% sodium carbonate liquor, preferably 0.5% sodium carbonate liquor.
In step 2, the volume ratio of oxolane and sodium carbonate liquor is 1:2～1:5, and preferred volume ratio is 1:3.
Synthetic route of the present invention is as follows:
Compared with prior art, method of the present invention has following advantage:
1) directly use chlorosulphonic acid, route shortens, and product viscosity is little, and industrial operation is simple and convenient;
2) in the reaction a post processing of preparing product 1, the solid that filtration is obtained is dissolved in carrene again, and frozen water is washed, dichloroThe product that methane re-extract obtains is more stable, is conducive to industry and amplifies, and has washed away acid ion, and purity is higher, under being conducive toSingle step reaction;
3), in the reaction b last handling process of preparing product 2, use 0.5%Na2CO3: the system of THF=3:1 is separated out product,Can better removal of impurities, product purity can reach 99.9%.
4) the Vardenafil hydrochloric acid trihydrate purity making by this route is high, and yield is high, and operating process is simple and convenient, centreBody compound is easy to purify, and meets the requirement that industrialization is amplified.
Detailed description of the invention
Embodiment 1
2.5L chlorosulfonic acid is added in 10L retort, logical nitrogen protection, cooling, by 1kg2-(2-ethoxyl phenenyl)-5-methyl-7-Propyl group-3H-imidazo [5,1-f] [1,2,4]-triazine-4-ketone is added in retort in batches, in reinforced process, maintain the temperature at-15～15 DEG C, after rise to stirring at room temperature 8～10h. Reaction is finished, and gets frozen water 25L and carrene 20L and mixes, and stirs, will after coolingReactant liquor adds wherein, maintains the temperature at-5～10 DEG C, dropwises, and continues to stir 1h, has a large amount of solids to separate out, and filters (mistakeFilter solid is sticky, is Powdered), separate organic phase, water extracts once with carrene 5L, by the organic phase of 2 separation25L and new frozen water 25L system are mixed, and mechanical agitation is crossed filter solid and added wherein, stirs 15～30min basic to solidDissolve (may have minute quantity insoluble matter be present in two alternate), separate organic phase, frozen water 10L washing for organic phase, anhydrous sulphurAcid sodium is dry, and organic phase is surveyed HPLC, filters, and is spin-dried for, and solid is surveyed HPLC, weighs. Obtain product 1, i.e. 4-ethyoxyl-3-(3,4-Dihydro-5-methyl-4-oxo-7-propyl imidazole [1,5-f] [1,2,4-, tri-nitrogen-4-ketone]) benzene sulfonyl chloride 1.21kg, purity 97.1%, yield92.1％。
Embodiment 2
The product of embodiment 1 (10kg) is dissolved in to 50L oxolane, and 4.6LN-ethyl piperazidine adds in reactant liquor at 0 DEG C, protectsHold temperature not higher than 25 DEG C, dropwise, be warming up to stirring at room temperature 10～30min, solution change muddiness (or solution clarification, the endThere is sticky matter in portion), HPLC monitors reaction. Reaction is finished, and in reactant liquor, drips 0.5% sodium carbonate liquor 150L, and it is clear that solution becomesClearly, solid is separated out in a large number, continues stirring at room temperature 1h, filters, and (water volume and sodium carbonate liquor are overall with 150L washing for solidLong-pending identical), washing lotion PH ≈ 7,45 DEG C of vacuum drying 2～4h of solid, survey HPLC, survey moisture, moisture≤7.0%.Crude product (weight after deduction moisture) is dissolved in to 4 times of oxolanes again, and solution temperature is 20～50 DEG C, after dissolving completely,Be cooled to 15～25 DEG C of room temperatures, drip 3 times of 0.5% sodium carbonate liquor (oxolane volume number 3 times), time for adding 1.0～1.5h, dropwises, and stirs 1h, filter, and the washing of 0.5% sodium carbonate liquor equal-volume number for solid, washing lotion PH ≈ 7, Gu45 DEG C of vacuum drying 2～4h of body, survey HPLC, moisture≤4.0%. Obtain product 2, i.e. 2-[2-ethyoxyl-5-(4-ethylPiperazine-1-sulfonyl) phenyl]-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-ketone 10.2kg, product purity 99.8%,Yield 85.6%.
Embodiment 3
The product of 6.0kg embodiment 2 (weight after deduction moisture) is dissolved in the solution of 18L acetone: water=12:1, and 40～45 DEG C addThermal agitation, adds 1.16L concentrated hydrochloric acid, stirs, and solid dissolves at once, is heated to about 60 DEG C and refluxes (10min), keeps away as far as possibleExempt from solid and separate out, be cooled to stirring at room temperature 30～60min, stir 1.5～2h at-5～0 DEG C, filter solid 3L acetone:The solution of water=12:1 rinses, and HPLC is surveyed in solid sampling, and solid room temperature is dried or vacuum tightness is dried, and surveys moisture, fusing point. WillCrude product (not deducting moisture) is dissolved in the solution of 5 times of acetone: water=9:1, and 50～55 DEG C of heating for dissolving, are cooled to stirring at room temperature30～60min, then stir 1.5～2h at-5～0 DEG C, filtering, the solution of solid acetone: water=9:1 rinses (former acetone waterVolume 1/10), HPLC is surveyed in solid sampling, solid room temperature dry or vacuum tightness dry, survey moisture, fusing point. Obtain product3, i.e. 2-[2-ethyoxyl-5-(4-ethyl piperazidine-1-sulfonyl) phenyl]-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-Ketone list hydrochloric acid trihydrate 5kg, product purity 99.9%, yield 74.9%.
Claims (1)
1. a preparation method for Vardenafil hydrochloric acid trihydrate, is characterized in that comprising the following steps:
(1) under nitrogen protection, by 2-(2-ethoxyphenyl)-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4]-tri-nitrogen-4-ketone adds in chlorosulfonic acid, maintains the temperature at-15～15 DEG C, after feeding in raw material, is warming up to room temperature reaction, the reaction timeBe 8～10h, reaction is finished, and reaction system is added to frozen water-carrene mixed solvent system, maintains the temperature at-5～10 DEG C, continue to stir, there are a large amount of solids to separate out, filter gained solid, separate organic phase, water continues to useDichloromethane extraction, merges organic phase, adds new frozen water, and the solid of filtration is added to above-mentioned mixed solvent,After dissolving, extract and separate obtains 4-ethyoxyl-3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole[1,5-f] [1,2,4-, tri-nitrogen-4-ketone]) benzene sulfonyl chloride (product 1);
(2) product 1 step 1 being obtained is dissolved in inert organic solvents, adds NEP at-5～5 DEG C,The reinforced complete room temperature reaction 10～30min that is warming up to, reaction is finished, and adds inorganic alkali solution, mistake in reactant liquorFilter gained solid, washing, is dissolved in organic solvent again by crude product after being dried, and after dissolving completely, adds inorganic base moltenLiquid, filters, and washing is dried to obtain 2-[2-ethyoxyl-5-(4-ethyl piperazidine-1-sulfonyl) phenyl]-5-methyl-7-thirdBase-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-ketone (product 2), described inert organic solvents is oxolane, instituteStating inorganic alkali solution is 0.5% sodium carbonate liquor, and the volume ratio of oxolane and sodium carbonate liquor is 1:3;
(3) product 2 step 2 being obtained is dissolved in acetone-water mixed solution, adds concentrated hydrochloric acid at 40～45 DEG C,After be warming up to 60 DEG C of backflow 10min, be cooled to room temperature reaction 30～60min, then at-5～0 DEG C stir1.5～2h, filters, and solid rinses with acetone-water mixed solution, is dried to obtain 2-[2-ethyoxyl-5-(4-ethyl piperazinePiperazine-1-sulfonyl) phenyl]-5-methyl-7-propyl group-3H-imidazoles [5,1-f] [1,2,4] three nitrogen-4-ketone list hydrochloric acid trihydrate(product 3).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1278822A (en) * | 1997-11-12 | 2001-01-03 | 拜尔公司 | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
| US20070197535A1 (en) * | 2006-03-13 | 2007-08-23 | Eswaraiah Sajja | Polymorphic forms of vardenafil |
| WO2011079935A2 (en) * | 2009-12-30 | 2011-07-07 | Zaklady Farmaceutyczne Polpharma Sa | A process for the preparation and isolation of vardenafil and salts thereof |
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2013
- 2013-04-18 CN CN201310135429.7A patent/CN104109164B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1278822A (en) * | 1997-11-12 | 2001-01-03 | 拜尔公司 | 2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors |
| US20070197535A1 (en) * | 2006-03-13 | 2007-08-23 | Eswaraiah Sajja | Polymorphic forms of vardenafil |
| WO2011079935A2 (en) * | 2009-12-30 | 2011-07-07 | Zaklady Farmaceutyczne Polpharma Sa | A process for the preparation and isolation of vardenafil and salts thereof |
Non-Patent Citations (2)
| Title |
|---|
| Imidazo[5,1-f ][1,2,4]triazin-4(3H)-ones, a New Class of Potent PDE 5 Inhibitors;Helmut Haning et al.;《Bioorganic & Medicinal Chemistry Letters》;20021231;第12卷;第865-868页 * |
| Synthesis and Spectral Characterization of Related Substances of Vardenafil, an Erectile Dysfunction Drug;Vajrala Venkata Reddy et al.;《Synthetic Communications》;20121231;第42卷(第23期);第3513-3523页 * |
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