CN103073485B - A kind of preparation method of butyrate clevidipine - Google Patents
A kind of preparation method of butyrate clevidipine Download PDFInfo
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- BDPZFQLKFUONAG-UHFFFAOYSA-N CCCC(OCCl)=O Chemical compound CCCC(OCCl)=O BDPZFQLKFUONAG-UHFFFAOYSA-N 0.000 description 2
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- LLMLNAVBOAMOEE-UHFFFAOYSA-N O=Cc1cccc(Cl)c1Cl Chemical compound O=Cc1cccc(Cl)c1Cl LLMLNAVBOAMOEE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a kind of preparation method of butyrate clevidipine, comprise 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid aromatic nucleus replaces methyl esters hydrogenation and prepares 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid, then react with butanic acid chloromethyl ester and prepare butyrate clevidipine.This synthetic route raw material is easy to get, and reaction conditions is gentle, and easy and simple to handle, cost is low, is applicable to suitability for industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, more particularly, relate to the preparation method of a kind of novel antihypertensive medicament butyrate clevidipine (Clevidipine Butyrate).
Background technology
Hypertension critical illness and perioperative hypertension are all common and very harmful to patient diseases, adopt intravenous injection depressor to carry out treatment to it and can control blood pressure fast, thus reduce the generation of various complication.Butyrate clevidipine is a kind of intravenous injection dihydropyridine calcium channel antagonist, is also the first used for intravenous injection antihypertensive drug that U.S. FDA is ratified nearly ten years simultaneously.Its onset is rapid, action time is short, be easy to regulation and control, few side effects, in blood and tissue, carry out metabolism, because of but very good used for intravenous injection antihypertensive drug, will be the important selection of emergency room, Operation theatre and intensive care unit patient controlling of blood pressure.
The synthetic method relating to butyrate clevidipine bulk drug mainly contains following patent and article: WO2000/31035, WO1995/12578, CN101759631A, " Chinese Journal of Pharmaceuticals ", 2009,40(10), 791, " Chinese Journal of Pharmaceuticals " 2010,41 (3), 170, " Chinese Journal of Pharmaceuticals " 2011,42(7), 484, " modern medicines and clinical " 2011,26(1), 40, Chem.Pharm, Bull.1994,42,1579, Chem.Pharm, Bull.1993,41,1049, Chem.Pharm, Bull.1993,41,108.The synthetic method of report respectively has its relative merits.
Patent WO1995/12578 reports the synthetic route of many butyrate clevidipines, embodiment describe only from the route of intermediate II by lactate synthesis butyrate clevidipine, patent WO1995/13066 also reports from intermediate II by lactate synthesis butyrate clevidipine, but the response situation of the synthesis of intermediate II and other synthetic routes is all not mentioned.
Patent WO1995/31035 reports from 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid propionitrile ester sets out synthetic butyric acid Clevidipine, but the preparation of not mentioned intermediate VI.
Patent CN101759631A, " Chinese Journal of Pharmaceuticals " 2011,42(7), 484, " modern medicines and clinical " 2011,26(1), 40, Chem.Pharm, Bull.1994,42,1579, Chem.Pharm, Bull.1993,41,1049, Chem.Pharm, Bull.1993,41,108 synthesis reporting butyrate clevidipine, this method employs the more expensive 3-itrile group propyl alcohol of price, and produces a large amount of waste water containing alcohol during hydrolysis.
" Chinese Journal of Pharmaceuticals " 2010,41 (3), 170 synthetic routes reporting butyrate clevidipine, but the wherein inevitable formation with two hydrolysate in methyl esters hydrolytic process, therefore severe reaction conditions, more difficult control, and the wastewater flow rate produced containing alcohol is large, is not suitable for large industrial production.
In sum, in the preparation of butyrate clevidipine, all adopting 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid is as its necessary intermediate (hereinafter referred to as " monocarboxylic acid " intermediate).And " monocarboxylic acid " intermediate adopting aforesaid method to prepare is all inevitably containing impurity 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydro-3,5-pyridines-dicarboxylic acid (hereinafter referred to as: " dicarboxylic acid " impurity); The existence of " dicarboxylic acid " impurity can introduce corresponding impurity in butyrate clevidipine, therefore will obtain meeting the purge process that the butyrate clevidipine needs of medicinal requirements are loaded down with trivial details, complicated.Therefore, the preparation method improving butyrate clevidipine is further necessary.
Summary of the invention
The present inventor, through a large amount of experiments, have surprisingly been discovered that the preparation method of a kind of butyrate clevidipine and midbody compound thereof, and the butyrate clevidipine purity obtained by this preparation method is high, and hardly containing " dicarboxylic acid " impurity.
An object of the present invention is to provide the preparation method of clevidipine butyrate intermediate compound.
Another object of the present invention is to provide a kind of preparation method of butyrate clevidipine.
Specifically, the invention provides a kind of clevidipine butyrate intermediate compound 4-(2,3-dichlorophenyl)-2,6-dimethyl-1, the preparation method of 4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid (hereinafter referred to as " monocarboxylic acid " intermediate), comprises the steps:
(1) 2,3 dichloro benzaldehyde, etheric acid aromatic nucleus are replaced methyl esters, 3-amino-2-butylene acid methyl esters hybrid reaction, obtain 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid aromatic nucleus replacement methyl esters;
(2) by 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid aromatic nucleus replaces methyl esters and carries out hydrogenolysis, obtains 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid.
In embodiments of the invention, the preparation method of " monocarboxylic acid " provided by the invention intermediate, wherein, etheric acid aromatic nucleus replaces methyl esters or 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, it is phenyl methyl esters that 4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid aromatic nucleus replaces the aromatic nucleus replacement methyl esters described in methyl esters, benzene methyl (as: (p-methoxyl group) benzene methyl replaced, (p-chloro) benzene methyl, (2, 4-dichloro-) benzene methyl etc.), picolyl, or substituted pyridines methyl esters is (as (2-methyl) picolyl, (2, 5-dimethyl) picolyl, (2-ethyl oxygen formyl radical) picolyl etc.), preferably, for phenyl methyl esters.
In embodiments of the invention, the preparation method of " monocarboxylic acid " provided by the invention intermediate, wherein, described hydrogenolysis carries out in organic solvent, preferably, carries out in methyl alcohol or ethanol.
In embodiments of the invention, the preparation method of " monocarboxylic acid " provided by the invention intermediate, wherein, described hydrogenolysis temperature is 0-30 DEG C; Preferable temperature is 20-25 DEG C.
In embodiments of the invention, the preparation method of " monocarboxylic acid " provided by the invention intermediate, wherein, the reaction times of described hydrogenolysis is 2-40 hour.
In embodiments of the invention, the preparation method of " monocarboxylic acid " provided by the invention intermediate, wherein, described hydrogenolysis carries out under the condition that there is catalyzer; Here, described catalyzer is palladium carbon, platinum, platinum oxide or Raney's nickel etc., preferably, is palladium carbon.
In embodiments of the invention, the preparation method of " monocarboxylic acid " provided by the invention intermediate, wherein, described hydrogenolysis carries out under pressure, and preferably, pressure is 0.5-5atm.More preferably pressure is 1-1.2atm.
In a preferred embodiment of the present invention, the invention provides a kind of clevidipine butyrate intermediate compound 4-(2,3-dichlorophenyl) preparation method of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid, comprise the steps:
(1) by 2,3 dichloro benzaldehyde, etheric acid benzene methyl, 3-amino-2-butylene acid methyl esters hybrid reaction, 4-(2 is obtained, 3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid benzyl ester;
(2) by 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid benzyl ester carrying out hydrogenolysis, obtain 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid;
Wherein, described hydrogenolysis carries out in organic solvent, preferably, carries out in methyl alcohol or ethanol;
Described hydrogenolysis temperature is 0-30 DEG C; Preferable temperature is 20-25 DEG C.
The reaction times of described hydrogenolysis is 2-40 hour.
Described hydrogenolysis carries out under the condition that there is catalyzer; Here, described catalyzer is palladium carbon, platinum, platinum oxide or Raney's nickel etc., preferably, is palladium carbon.
Described hydrogenolysis carries out under pressure, and preferably, pressure is 0.5-5atm.More preferably pressure is 1-1.2atm.
In embodiments of the invention, described etheric acid aromatic nucleus replaces methyl esters majority to be had commercially available, and also can replace Methanol by ketene dimer and aromatic nucleus standby, involved raw material is cheap and easy to get.Such as, etheric acid benzene methyl has commercially available, also can be reacted in tetrahydrofuran solution under triethylamine exists by phenylethyl alcohol and ketene dimer and obtain (reference: Chinese journal ofpharmaceuticals2011,42(7): 484-486).
On the other hand, the invention provides the preparation method of butyrate clevidipine, comprising:
I) 4-(2,3-dichlorophenyl) preparation of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid;
Ii) 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid and butanic acid chloromethyl ester react, and obtains butyrate clevidipine;
Here, described 4-(2,3-dichlorophenyl) preparation of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid comprises the following steps:
(1) 2,3 dichloro benzaldehyde, etheric acid aromatic nucleus are replaced methyl esters, 3-amino-2-butylene acid methyl esters hybrid reaction, obtain 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid aromatic nucleus replacement methyl esters;
(2) by 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid aromatic nucleus replaces methyl esters and carries out hydrogenolysis, obtains 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid.
In embodiments of the invention, the preparation method of butyrate clevidipine provided by the invention, wherein, etheric acid aromatic nucleus replaces methyl esters or 4-(2, 3-dichlorophenyl)-2, 6-dimethyl-1, it is phenyl methyl esters that 4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid aromatic nucleus replaces the aromatic nucleus replacement methyl esters described in methyl esters, benzene methyl (as: (p-methoxyl group) benzene methyl replaced, (p-chloro) benzene methyl, (2, 4-dichloro-) benzene methyl etc.), picolyl, or substituted pyridines methyl esters is (as (2-methyl) picolyl, (2, 5-dimethyl) picolyl, (2-ethyl oxygen formyl radical) picolyl etc.), preferably, for phenyl methyl esters.
In embodiments of the invention, the preparation method of butyrate clevidipine provided by the invention, wherein, described hydrogenolysis carries out in organic solvent, preferably, carries out in methyl alcohol or ethanol.
In embodiments of the invention, the preparation method of butyrate clevidipine provided by the invention, wherein, described hydrogenolysis temperature is 0-30 DEG C; Preferable temperature is 20-25 DEG C.
In embodiments of the invention, the preparation method of butyrate clevidipine provided by the invention, wherein, the reaction times of described hydrogenolysis is 2-40 hour.
In embodiments of the invention, the preparation method of butyrate clevidipine provided by the invention, wherein, described hydrogenolysis carries out under the condition that there is catalyzer; Here, described catalyzer is palladium carbon, platinum, platinum oxide or Raney's nickel etc., preferably, is palladium carbon.
In embodiments of the invention, the preparation method of butyrate clevidipine provided by the invention, wherein, described hydrogenolysis carries out under pressure, and preferably, pressure is 0.5-5atm.More preferably pressure is 1-1.2atm.
In a preferred embodiment of the present invention, the invention provides a kind of preparation method of butyrate clevidipine, comprising:
I) 4-(2,3-dichlorophenyl) preparation of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid;
Ii) 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid and butanic acid chloromethyl ester react, and obtains butyrate clevidipine;
Here, described 4-(2,3-dichlorophenyl) preparation of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid comprises the following steps:
(1) by 2,3 dichloro benzaldehyde, etheric acid benzene methyl, 3-amino-2-butylene acid methyl esters hybrid reaction, 4-(2 is obtained, 3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid benzyl ester;
(2) by 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid benzyl ester carries out hydrogenolysis, obtains 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid;
Here, described hydrogenolysis carries out in organic solvent, preferably, carries out in methyl alcohol or ethanol;
Described hydrogenolysis temperature is 0-30 DEG C; Preferable temperature is 20-25 DEG C.
The reaction times of described hydrogenolysis is 2-40 hour.
Described hydrogenolysis carries out under the condition that there is catalyzer; Here, described catalyzer is palladium carbon, platinum, platinum oxide or Raney's nickel etc., preferably, is palladium carbon.
Described hydrogenolysis carries out under pressure, and preferably, pressure is 0.5-5atm.More preferably pressure is 1-1.2atm.
Under normal circumstances, the aromatic nucleus of " monocarboxylic acid " intermediate replaces methyl esters and can react generation 4-(2,3-dichlorophenyl further in hydrogenolysis process)-lupetidine-3-carboxylate methyl ester-5-carboxylic acid, be difficult to obtain " monocarboxylic acid " intermediate; The present inventor, in the favorite outer discovery of the impurity preparing butyrate clevidipine, by Isosorbide-5-Nitrae-dihydropyridine ring being avoided to be converted into phenyl ring at hydrogenolytic conditions of the present invention, surprisingly obtains " monocarboxylic acid " intermediate of high yield.It is high that further research finds to adopt present method preparation " monocarboxylic acid " midbody product purity, during for the preparation of bulk drug butyrate clevidipine, greatly can simplify last handling process, reduce production cost.
Compared with prior art, the present invention has following features.
1. raw material etheric acid aromatic nucleus replaces methyl esters (such as benzene methyl) and can replace methyl alcohol (such as phenylcarbinol) by ketene dimer and aromatic nucleus and prepare, and involved raw material is cheap and easy to get.
2. aromatic nucleus can be replaced the complete dissociation of methyl esters and methoxycarbonyl is unaffected by hydrogenolysis, can obtain hardly containing high purity " monocarboxylic acid " intermediate of " dicarboxylic acid " impurity.
3. adopt the method for hydrogenolysis, avoid by alkaline hydrolysis produce containing alcohol waste water, clean environment firendly.
4. " monocarboxylic acid " intermediate adopting this law to prepare prepares the butyrate clevidipine as bulk drug, and purge process is simple and easy to do, and yield significantly improves, and production cost significantly reduces.
Accompanying drawing explanation
The HPLC collection of illustrative plates of the embodiment of the present invention that what Fig. 1 represented is.
The HPLC collection of illustrative plates of what Fig. 2 represented is butyrate clevidipine prepared by comparative example.
Embodiment
Describe the present invention in detail by the following examples, but it not limitation of the present invention.
The test condition of NMR is: with DMSO-d
6or CDCl
3for solvent, TMS are the examination of interior mapping; Testing tool is AVANCE DRX500M nuclear magnetic resonance spectrometer.
HPLC test condition is: with C18 silane group silica gel for weighting agent; With methyl alcohol/acetonitrile/water (40:40:20) wash-out; Determined wavelength is 246nm.
Embodiment 1:4-(2,3-dichlorophenyl) synthesis of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid
Step 1: the synthesis of etheric acid benzene methyl
By benzylalcohol 27g(0.15mol), the triethylamine (1.8g) of catalytic amount is dissolved in 100ml tetrahydrofuran (THF), and solution is heated to boiling.In solution, ketene dimer 22g(0.26mol is dripped under return stirring), after being added dropwise to complete, then return stirring reacts 3 hours.Add 10% citric acid solution 200ml after reaction terminates, stir 10 minutes.Layering, the chloroform extraction of water layer 100ml × 3.Combining extraction liquid, successively with the saturated common salt water washing of the water of 80ml × 3,100ml × 2.Add appropriate anhydrous sodium sulphate, stirring at room temperature 2 hours.After filtering siccative, filtrate reduced in volume obtains yellow oil.Do not add purifying, be directly used in the next step.
Step 2:4-(2,3-dichlorophenyl) synthesis of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid benzyl ester
By 2,3 dichloro benzaldehyde 24.4g(0.14mol), upper step reaction gained etheric acid benzene methyl crude product 28.8g(is about 0.15mol), 3-amino-2-butylene acid methyl esters 16.1g(0.14mol) join in 200ml methyl alcohol, stir and make material dissolution.Heating reflux reaction about 5 hours.After reaction terminates, underpressure distillation is except desolventizing.Gained resistates do not add refining, be directly used in the next step.
Step 3:4-(2,3-dichlorophenyl) synthesis of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid
4-(2 is added, 3-dichlorophenyl in hydrogenation still)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid benzyl ester's crude product (44.6g, 0.1mol), methyl alcohol 300ml, 10% palladium carbon 2g, passes into hydrogen at 20 DEG C, and pressure is 1atm, to not absorbing hydrogen, filter, use methyl alcohol drip washing, merging filtrate, is concentrated into about 100ml, cooling, filter, obtain 23.9g faint yellow solid, productive rate 67%.
1H NMR(DMSO-d
6，ppm):δ=11.62（s，1H）,8.81(s,1H)，7.38-7.21(m，3H)，5.29（s，1H），3.48（s，3H）、2.22（s，3H）、2.21（s，3H）。
Embodiment 2:4-(2,3-dichlorophenyl) synthesis of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid
With 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid-(p-methyl) benzene methyl is that raw material is prepared according to the method similar to embodiment 1, yield is 63%.
Embodiment 3: the synthesis of butyrate clevidipine
In there-necked flask, add 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid 35.6g(0.1mol) (preparation method is shown in embodiment 1, embodiment 2), saleratus 20g(0.2mol), DMF500ml, add butanic acid chloromethyl ester 20.5g(0.15mol under stirring), again in 60 DEG C of reactions 12 hours, be cooled to room temperature, join in 3L water, use CH
2cl
2(1L × 3) extract, and after anhydrous sodium sulfate drying, are evaporated to dry, refine, obtain white solid 28.7g, productive rate 63% with Virahol.
Mp.：136.5℃～138.2℃。HPLC:99.7%; Single contaminant is no more than 0.2%.Fig. 1 is shown in by HPLC collection of illustrative plates.
1H NMR(CDCl
3，ppm):δ=7.01~7.27(m,3H)，6.29(s,1H)，5.73(d,1H)，
5.68(d,1H)，5.39(s,1H)，3.48(s,1H)，2.19~2.25(m,8H)，1.55(m,2H)，0.83(t,3H)。
Comparative example: the synthesis of butyrate clevidipine
Step 1: the synthesis of etheric acid (2-cyano ethyl) ester
By 3-hydroxypropionitrile 10g(0.14mol), the triethylamine (1.8g) of catalytic amount is dissolved in 100ml tetrahydrofuran (THF), and solution is heated to boiling.In solution, ketene dimer 22g(0.26mol is dripped under return stirring), after being added dropwise to complete, then return stirring reacts 3 hours.Add 10% citric acid solution 200ml after reaction terminates, stir 10 minutes.Layering, the dichloromethane extraction of water layer 100ml × 3.Merge organic layer, successively with the saturated common salt water washing of the water of 100ml × 2,100ml × 2.Add appropriate anhydrous sodium sulphate, stirring at room temperature 2 hours.After filtering siccative, filtrate reduced in volume obtains yellow oil.Do not add purifying, be directly used in the next step.
Step 2:4-(2,3-dichlorophenyl) synthesis of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid (2-cyano ethyl) ester
By 2,3-dichlorobenzaldehyde 23.5g(0.135mol), upper step reaction gained etheric acid (2-cyano ethyl) ester crude product 21.0g(is about 0.135mol), 3-amino-2-butylene acid methyl esters 15.5g(0.135mol) join in 200ml methyl alcohol, stir and make material dissolution.Heating reflux reaction about 5 hours.After reaction terminates, underpressure distillation is except desolventizing.Residuum, through pillar layer separation (eluent: ethyl acetate-light petrol (1:1)), obtains faint yellow solid 41.6g, yield 76%.（mp103-105℃）。
Step 3:4-(2,3-dichlorophenyl) synthesis of-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid
By upper step gained intermediate 41.6g(0.10mol) be dissolved in the mixing solutions of 240ml methylene dichloride and 120ml the formation of methanol, add sodium sulphite 16.8g(0.22mol), stirring at room temperature 5 hours.Add 200ml after reaction terminates, with the washing of methylene dichloride 200ml × 3, water layer uses 3mol/L hcl acidifying to pH3-4 under condition of ice bath, and solid is separated out.Collecting by filtration gained solid, is drying to obtain required intermediate, and weigh to obtain 28.1g, yield 65%.
Step 4: the synthesis of butyrate clevidipine
With reference to the step operation that " embodiment 3 " is identical, obtain butyrate clevidipine, yield 64%.
Fig. 2 is shown in by the HPLC collection of illustrative plates of gained butyrate clevidipine.Test result shows, butyrate clevidipine retention time t
rfor 16.3min, area percentage is 99.6%; At 0.8t
rplace's impurity peak area reaches 0.24%, has exceeded the limit that quality standard specifies (the standard regulation of butyrate clevidipine, calculate by area normalization method, single related substance must not be greater than 0.2%).
Refine rear related substance with Virahol further and reach the limit that quality standard specifies, refining yield 87%.
Claims (1)
1. a preparation method for butyrate clevidipine, comprising:
In there-necked flask, add 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid 35.6g, saleratus 20g, DMF 500ml, adds butanic acid chloromethyl ester 20.5g under stirring, again in 60 DEG C of reactions 12 hours, be cooled to room temperature, join in 3L water, with the CH of 1L × 3
2cl
2extraction, after anhydrous sodium sulfate drying, is evaporated to dry, refines, obtain white solid butyrate clevidipine 28.7g with Virahol;
Wherein, the preparation of 4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid comprises the steps:
Step 1: the synthesis of etheric acid benzene methyl
The 1.8g triethylamine of benzylalcohol 27g, catalytic amount is dissolved in 100ml tetrahydrofuran (THF), solution is heated to boiling; In solution, drip ketene dimer 22g under return stirring, after being added dropwise to complete, then return stirring reacts 3 hours; Add 10% citric acid solution 200ml after reaction terminates, stir 10 minutes; Layering, the chloroform extraction of water layer 100ml × 3; Combining extraction liquid, successively with the saturated common salt water washing of the water of 80ml × 3,100ml × 2; Add appropriate anhydrous sodium sulphate, stirring at room temperature 2 hours; After filtering siccative, filtrate reduced in volume obtains yellow oil; Do not add purifying, be directly used in the next step;
The synthesis of step 2:4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid benzyl ester
By 2,3 dichloro benzaldehyde 24.4g, amino-2-butylene acid methyl esters 16.1g joins in 200ml methyl alcohol for upper step reaction gained etheric acid benzene methyl crude product 28.8g, 3-, stirs and makes material dissolution; Heating reflux reaction about 5 hours; After reaction terminates, underpressure distillation is except desolventizing; Gained resistates do not add refining, be directly used in the next step;
The synthesis of step 3:4-(2,3-dichlorophenyl)-2,6-dimethyl-Isosorbide-5-Nitrae-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid
4-(2,3-dichlorophenyl)-2,6-dimethyl-1 are added in hydrogenation still, 4-dihydropyridine-3-carboxylic acid methyl-5-carboxylic acid benzyl ester crude product 44.6g, methyl alcohol 300ml, 10% palladium carbon 2g, pass into hydrogen at 20 DEG C, pressure is 1atm, to not absorbing hydrogen, filter, use methyl alcohol drip washing, merging filtrate, be concentrated into about 100ml, cooling, filter, obtain 23.9g faint yellow solid, productive rate 67%.
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| CN101638379A (en) * | 2009-08-21 | 2010-02-03 | 武汉武药科技有限公司 | Preparation method for dihydropyridine type compound |
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