CN103509003A - Preparation method of azelnidipine - Google Patents
Preparation method of azelnidipine Download PDFInfo
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- CN103509003A CN103509003A CN201210214898.3A CN201210214898A CN103509003A CN 103509003 A CN103509003 A CN 103509003A CN 201210214898 A CN201210214898 A CN 201210214898A CN 103509003 A CN103509003 A CN 103509003A
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- azelnidipine
- methyl
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- ethyl acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a preparation method of azelnidipine as a dihydropyridine calcium channel blocker, belonging to the field of medicines. The preparation method provided by the invention is characterized in that an intermediate and a final product are refined by using a method which is easy to realize industrial production.
Description
Technical field:
The preparation method who the present invention relates to a kind of dihydropyridine calcium channel blocker Azelnidipine, belongs to field of medicaments.
Background of invention:
Azelnidipine (Azelnidipine), chemistry 3-(1-diphenyl-methyl azetidin-3-yl) 5-sec.-propyl 2-amino-1 by name, 4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate, is developed and is got permission to go on the market in Japan in late May, 2003 by Japanese Sankyo Co., Ltd.The synthetic method of existing Azelnidipine is loaded down with trivial details, and the preparation of intermediate (VI) takes column chromatography method, and the purifying of product (I) is also used column chromatography method, is not suitable for suitability for industrialized production.
Summary of the invention:
Main purpose of the present invention has been to provide a kind of preparation method who is suitable for the Azelnidipine of industrial application.
Technical scheme of the present invention is:
A preparation method for Azelnidipine, it is characterized in that preparing through following steps.
The first step 3-nitrobenzaldehyde (II) is prepared 2-with ISOPROPYL ACETOACETATE effect, and (3-nitrobenzal and ISOPROPYL ACETOACETATE (III), make solvent with Virahol.
Second step is under alkaline condition, and benzhydrylamine (IV) and epoxy chloropropane effect, prepare 1-diphenyl-methyl-3-hydroxy azetidine (V).
The 3rd step 1-diphenyl-methyl-3-hydroxy azetidine (V), at N, with cyanoacetic acid effect, is prepared cyanoacetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester (VI) under the effect of N '-dicyclohexyl diimine.
The 4th step cyanoacetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester (VI) and hydrogenchloride effect, prepare amidino groups acetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester acetate (VII), with methylene dichloride, makees solvent.
The 5th step amidino groups acetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester acetate (VII), with 2-(3-nitrobenzal ISOPROPYL ACETOACETATE (III) cyclization under sodium methylate effect, preparation 3-(1-diphenyl-methyl azetidin-3-yl) 5-sec.-propyl 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate (Azelnidipine).
Refining of the 6th step Azelnidipine
The process for purification of the preferred Azelnidipine of the present invention, is characterised in that, by Azelnidipine dissolving crude product in the mixed solvent of ethyl acetate and normal hexane, stirring and dissolving, add gac, filter, the mixed solvent washing of ethyl acetate and normal hexane for filter cake, washing lotion and filtrate merge, be cooled to 0～5 ℃ of crystallization, collect product, dry at 45-55 ℃ of temperature in Hotaircirculatingoven, obtain Azelnidipine fine work, high-efficient liquid phase chromatogram technique measuring purity 99.3%.
The process for purification of the preferred Azelnidipine of the present invention, is characterised in that, the ratio of refining dissolving ethyl acetate used and normal hexane is (1～2): 1 (volume ratio).
The process for purification of the preferred Azelnidipine of the present invention, is characterised in that, the ratio of refining dissolving ethyl acetate used and normal hexane is 1: 1 (volume ratio).
The process for purification of the preferred Azelnidipine of the present invention, is characterised in that, the ratio of refining dissolving ethyl acetate used and normal hexane is 1.5: 1 (volume ratio).
The invention has the beneficial effects as follows a kind of preparation method who is suitable for the Azelnidipine of industrialized production is provided.
Accompanying drawing explanation:
Fig. 1 is the synthesis process flow diagram of Azelnidipine.
The preparation of embodiment 12-(3-nitrobenzal) ISOPROPYL ACETOACETATE (III)
In reactor, add 2.1kg3-nitrobenzaldehyde, 5L Virahol, start stirring, add ISOPROPYL ACETOACETATE 3kg, stir.Add the anhydrous piperidines of 43ml and 12ml glacial acetic acid, continue to be stirred to solid entirely molten.Be heated to 45 ℃ of insulation reaction 6h, cooling, stirring and crystallizing 16h.Filter, collect gained filter cake.Gained filter cake and 16L ethanol (industry) are dropped in reactor, start stirring, making beating, filters, and collects filter cake.Filter cake is put into drip pan, put into baking oven, 70-80 ℃ dry.Collect product 2-(3-nitrobenzal) ISOPROPYL ACETOACETATE (III), about 2.7kg.
The preparation of embodiment 21-diphenyl-methyl-3-hydroxy azetidine (intermediate V)
In reactor, add 9.6L methyl alcohol, 5.4kg benzhydrylamine (IV) and 3.33kg epoxy chloropropane, stirring at room 48 hours, reaction is finished, and is warming up to 68 ℃, back flow reaction 72h.Be cooled to room temperature.Concentrating under reduced pressure removes methyl alcohol, filters and collects filter cake.Filter cake drops in reactor, adds ether 19.2L and 3mol/LNaOH solution 13.75L, stirs, and water layer is emitted after standing.After ether layer water, saturated brine washing, anhydrous sodium sulfate drying, filters, and collects filtrate.Reclaim under reduced pressure ether, to dry, obtains the about 3.05kg of 1-diphenyl-methyl-3-hydroxy azetidine (intermediate V).
The preparation of embodiment 3 cyanoacetic acids (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester (intermediate VI)
About 3.05g intermediate (V), 27L tetrahydrofuran (THF) and 1.7kg cyanoacetic acid are dropped in reactor, start stirring, open the cooling of reactor refrigerated water, in reactor, slowly add 3.1kgN, N '-dicyclohexyl diimine, controls temperature at 10 ℃-15 ℃, finish off-response still refrigerated water.Open heating system, be slowly warming up to 55-60 ℃, reaction 10h.Feed liquid is cooled to room temperature, filters, and filtrate is concentrated into dry.16.8L ethyl acetate is dropped in reactor, stirring and dissolving, then washing, anhydrous sodium sulfate drying, filter, and collects filtrate.Reclaim under reduced pressure ethyl acetate, adds petroleum ether and stirring in solid residue, filter to obtain cyanoacetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester (intermediate VI), about 3.19kg.
The preparation of embodiment 4 amidino groups acetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester acetate (VII)
Methylene dichloride 25L, the about 3.19kg of intermediate (VI), ethanol 430g are dropped in reactor, start stirring, be cooled to below 0 ℃, pass into hydrogen chloride gas to temperature-stable below 0 ℃, at 0 ℃ standing 14 hours.Concentrating under reduced pressure is removed most of hydrogen chloride gas and is reclaimed methylene chloride, adds methylene dichloride 25L in reactor residue, stirs, and is cooled to below 0 ℃, passes into ammonia, to temperature-stable, below 0 ℃, filters.Filtrate is poured in reactor, concentrating under reduced pressure reclaims solvent, obtains colourless liquid, adds 22.8L acetonitrile and 905g amine acetate, be warming up to 55-60 ℃ of insulation reaction 1.5 hours, stopped reaction, filtered while hot, filtrate decompression reclaims solvent to dry, in residue, add 3L ether crystallization, filter, dry, obtain the about 3.2kg of amidino groups acetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester acetate (intermediate VII).
Embodiment 5, in reactor, add about 3.2kg intermediate (VII), about 2.7kg intermediate (III), 21L Virahol and 585g sodium methylate, start stirring, be heated to back flow reaction 4 hours, be cooled to below 10 ℃, filter, filtrate decompression reclaims solvent to dry, in residue, add 35L acetic acid ethyl dissolution, washing with 6.5L * 3, emit water layer, to ethyl acetate layer, add anhydrous sodium sulfate drying, filter, collect filtrate, reclaim under reduced pressure ethyl acetate, in residue, add 4.2L toluene, 3.4L normal hexane heating for dissolving, filter, filtrate stirring is down to room temperature crystallization, filter to collect and be dried, product is put in baking oven, 45-55 ℃ dry, obtain Azelnidipine crude product (I), about 2.3kg.
Embodiment 6, refining
8.8L ethyl acetate, 8.8L normal hexane are dropped in reactor, open stirring, about 2.3kg Azelnidipine crude product is dropped in reactor, slowly be warming up to material dissolution, add gac 180g to stir 0.5h, filtered while hot, by feed liquid press filtration, to crystallization kettle, 5.5L ethyl acetate and the washing of 4.5L hexane solution for filter cake, merge with filtrate, be cooled to 0～5 ℃ of crystallization, filter, collect product, dry at 45-55 ℃ of temperature in Hotaircirculatingoven, obtain 2.2g Azelnidipine fine work, high-efficient liquid phase chromatogram technique measuring purity 99.6%.Refining yield is 96.0%.
Embodiment 7 Azelnidipine are refining
The ratio that is 2: 1 in ethyl acetate and normal hexane volume ratio preparation mixed solvent, 22L mixed solvent is dropped in reactor, about 2.3kg Azelnidipine crude product is dropped in reactor, slowly be warming up to material dissolution, add gac 180g to stir 0.5h, filtered while hot, by feed liquid press filtration, to crystallization kettle, filter cake washs with mixed solvent, and washing lotion and filtrate merge, be cooled to 0～5 ℃ of crystallization, filter, collect product, dry at 45-55 ℃ of temperature in Hotaircirculatingoven, obtain 2.2g Azelnidipine fine work, high-efficient liquid phase chromatogram technique measuring purity 99.7%.
The ratio preparation mixed solvent that embodiment 8 is 1.5: 1 in ethyl acetate and normal hexane volume ratio, 22L mixed solvent is dropped in reactor, about 2.3kg Azelnidipine crude product is dropped in reactor, slowly be warming up to material dissolution, add gac 180g to stir 0.5h, filtered while hot, by feed liquid press filtration to crystallization kettle, filter cake washs with mixed solvent, washing lotion and filtrate merge, be cooled to 0～5 ℃ of crystallization, filter, collect product, dry at 45-55 ℃ of temperature in Hotaircirculatingoven, obtain 2.2g Azelnidipine fine work, high-efficient liquid phase chromatogram technique measuring purity 99.6%.
Claims (5)
1. a preparation method for Azelnidipine, is characterised in that,
2-is prepared in the first step 3-nitrobenzaldehyde and ISOPROPYL ACETOACETATE effect, and (3-nitrobenzal and ISOPROPYL ACETOACETATE, make solvent with Virahol;
Second step is under alkaline condition, and benzhydrylamine and epoxy chloropropane effect, prepare 1-diphenyl-methyl-3-hydroxy azetidine;
The 3rd step 1-diphenyl-methyl-3-hydroxy azetidine, at N, with cyanoacetic acid effect, is prepared cyanoacetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester under the effect of N '-dicyclohexyl diimine;
The 4th step cyanoacetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester and hydrogenchloride effect, prepare amidino groups acetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester acetate, with methylene dichloride, makees solvent;
The 5th step amidino groups acetic acid (1-dibenzo-p-methyl-aza-cyclobutane-3-yl) ester acetate, with 2-(3-nitrobenzal ISOPROPYL ACETOACETATE cyclization under sodium methylate effect, preparation 3-(1-diphenyl-methyl azetidin-3-yl) 5-sec.-propyl 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate;
The 6th one-step refining.
2. the preparation method of Azelnidipine described in claim 1, be characterised in that, its purification step be by Azelnidipine dissolving crude product in the mixed solvent of ethyl acetate and normal hexane, stirring and dissolving, adds gac, filter, the mixed solvent washing of ethyl acetate and normal hexane for filter cake, washing lotion and filtrate merge, and are cooled to 0～5 ℃ of crystallization, collect product, in Hotaircirculatingoven, at 45-55 ℃ of temperature, be dried %.
3. the preparation method of Azelnidipine described in claim 1, is characterised in that, using volume ratio is (1～2): 1 ethyl acetate and the mixed solvent of normal hexane.
4. the preparation method of Azelnidipine described in claim 1, is characterised in that, the ethyl acetate that use volume ratio is 1: 1 and the mixed solvent of normal hexane.
5. the preparation method of Azelnidipine described in claim 1, is characterised in that, the ethyl acetate that use volume ratio is 1.5: 1 and the mixed solvent of normal hexane.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014139410A1 (en) * | 2013-03-14 | 2014-09-18 | 沈阳中海药业有限公司 | Method for preparing intermediate of azelnidipine |
| CN105461691A (en) * | 2015-12-31 | 2016-04-06 | 威海迪素制药有限公司 | Preparation method of azelnidipine |
| CN106279109A (en) * | 2016-08-18 | 2017-01-04 | 威海迪素制药有限公司 | A kind of preparation method of azelnidipine |
| CN106543061A (en) * | 2016-10-20 | 2017-03-29 | 威海迪素制药有限公司 | The preparation method of 3 alcohol of N benzhydryl ring fourths heterocycle |
| CN113956237A (en) * | 2021-10-20 | 2022-01-21 | 成都大学 | Azelnidipine ethyl acetate adduct |
-
2012
- 2012-06-27 CN CN201210214898.3A patent/CN103509003A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014139410A1 (en) * | 2013-03-14 | 2014-09-18 | 沈阳中海药业有限公司 | Method for preparing intermediate of azelnidipine |
| CN105461691A (en) * | 2015-12-31 | 2016-04-06 | 威海迪素制药有限公司 | Preparation method of azelnidipine |
| CN105461691B (en) * | 2015-12-31 | 2019-01-11 | 威海迪素制药有限公司 | A kind of preparation method of Azelnidipine |
| CN106279109A (en) * | 2016-08-18 | 2017-01-04 | 威海迪素制药有限公司 | A kind of preparation method of azelnidipine |
| CN106543061A (en) * | 2016-10-20 | 2017-03-29 | 威海迪素制药有限公司 | The preparation method of 3 alcohol of N benzhydryl ring fourths heterocycle |
| CN106543061B (en) * | 2016-10-20 | 2019-08-16 | 威海迪素制药有限公司 | The preparation method of N- benzhydryl ring fourth heterocycle -3- alcohol |
| CN113956237A (en) * | 2021-10-20 | 2022-01-21 | 成都大学 | Azelnidipine ethyl acetate adduct |
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Application publication date: 20140115 |