CN101613314B - Preparation method of antihypertensive drug felodipine - Google Patents
Preparation method of antihypertensive drug felodipine Download PDFInfo
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- CN101613314B CN101613314B CN2009101167627A CN200910116762A CN101613314B CN 101613314 B CN101613314 B CN 101613314B CN 2009101167627 A CN2009101167627 A CN 2009101167627A CN 200910116762 A CN200910116762 A CN 200910116762A CN 101613314 B CN101613314 B CN 101613314B
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Abstract
The invention discloses a preparation method of felodipine. The method is mainly characterized by adding strong acid cation exchange resin to alcoholic solution of methyl 2-(2,3-dichlorobenzylidine)acetoacetate and ethyl-3-aminocrotonate as a catalyst, which shortens reaction time by more than 1/4 and improve yield of cyclization reaction by 6-8%. A crude product felodipine prepared by the preparation method has increased refining yield and product purity. The method is also applicable to preparing other 4-sustituted-1,4-dihydropyridine antihypertensive drugs with chemical structure and pharmaceutical and clinical actions similar to felodipine.
Description
Technical field
The present invention relates to organic (medicine) the field of chemical synthesis, specifically is that antihypertensive drug felodipine and other 4-replace-1, the preparation method of 4-dihydropyridines antihypertensive drug.
Background technology
EP007293 has disclosed with 2, and the amino ethyl crotonate of 3-dichlorin benzylidene methyl acetoacetate and 3-is a raw material, prepares the method for felodipine through the cyclization addition reaction.This reaction is a solvent with the trimethyl carbinol, without catalyzer, only reaction mixture is placed under room temperature 4 days, steams alcoholic solution then, and residue gets felodipine through the isopropyl ether recrystallization.Yield 75%.
US5310970 discloses with 2, and the amino ethyl crotonate of 3-dichlorin benzylidene methyl acetoacetate and 3-is a raw material, and ethanol is alcoholic solution, and the appropriateness cooling adds 6～12mol. hydrochloric acid or toluenesulphonic acids again as cyclization catalyst behind the back flow reaction appropriate time.After reaction finished, the sequence of operations processes such as cooling, freezing and crystallizing, filtration, washing, drying of reaction solution being gone through the long period obtained felodipine.Purity (99%) and yield (80～83%) are higher.
It is solvent that CN1207726 (being equal to WO97/25313) discloses with ethanol, makes 2 in the presence of pyridine, the amino ethyl crotonate generation of 3-dichlorin benzylidene methyl acetoacetate and 3-cyclization addition reaction.Steam alcoholic solution after reaction finishes, residue is acidified with acid after with ethyl acetate or chloroform extraction, is washed with water to nearly neutrality again, and drying agent dehydration back reconcentration is to doing, behind recrystallization felodipine.Productive rate is about 85%, but does not have purity data.
US2004/0204604A discloses a kind of without catalyzer, is alcoholic solution with the Virahol, makes 2, and the amino ethyl crotonate generation of 3-dichlorin benzylidene methyl acetoacetate and 3-cyclization addition reaction prepares the method for felodipine.This is reflected under the reflux state and carries out, and goes through 12 hours.Reaction finishes the back only to be needed can directly obtain the felodipine product through once concentration, precipitation process.Yield (86%) and purity (99%) are higher, but unexposed follow-up treating process and condition.
In sum, though above-mentioned each tool advantage of 4 kinds of patented methods also exists defective or deficiency.Mainly show:
1. according to the method for EP0072793, ring-closure reaction does not add catalyzer, though exempted the later separation of catalyzer and reaction solution, yield is low and the reaction times is long partially.
2. according to the method for US5310907, though the reaction times is shorter, because concentration of hydrochloric acid is higher in the reaction solution, can not obtain the felodipine crude product with direct method of enrichment, so must experience a very long cryogenic freezing crystallization, take advantage of after cold the filtration with ice-cold Diluted Alcohol and repeatedly, repeatedly wash crude product (except that acid group) and than the process of vacuum drying of length.Therefore, later separation, purifying time span are about more than 20 times of cyclization addition reaction time, make the Inherent advantage of this method have a greatly reduced quality.
3. according to the CN1207726 method,, and can obtain felodipine crude product residue with direct method of enrichment though yield is higher.Since contain a large amount of pyridines in this residue, necessary again in order to eliminate pyridine through a series of separation, purge process, thereby post-processing operation becomes tediously long, cumbersome.
4.US2004/0204604A though the preparation method need not any catalyzer, and under refluxad the reaction times shorten dramatically than the EP007293 method, the later separation operating process is also comparatively simple, science.The applicant copies the disclosed data of resulting yield and purity data and the disclosure patent document by the method for example 1 in this patented technology scheme certain gap.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of antihypertensive drug felodipine, this method can high purities, obtain target product with high yield, and the reaction times is shorter, and the later separation purification process is easier, economical and practical.
Technical scheme of the present invention is as follows:
The preparation method of antihypertensive drug felodipine is characterized in that: 2, add a kind of strong acid cation exchange resin catalyst in the alcoholic solution of the amino ethyl crotonate of 3-dichlorin benzylidene methyl acetoacetate and 3-and carry out cyclization addition reaction (seeing formula 1).
Described storng-acid cation exchange resin is selected the polystyrene sulfonic resin for use, comprises macropore, inferior hole or common aperture resin; Alcoholic solvent is selected the lower aliphatic alcohols of dehydrated alcohol, Virahol or other 1～5 carbon atom for use in the described alcoholic solution.
Described cyclization addition reaction temperature is the boiling temperature of room temperature～reaction solution; Reaction times is 6～16 hours.
Described 2, the part by weight of 3-dichlorin benzylidene methyl acetoacetate and polystyrene sulfonic resin is 1: 0.005～1: 0.2; 2, the part by weight of 3-dichlorin benzylidene methyl acetoacetate and alcoholic solvent is 1: 1～1: 10; 2, the molar ratio of the amino ethyl crotonate of 3-dichlorin benzylidene methyl acetoacetate and 3-is 1: 0.8～1.8.
Described 2, the part by weight of 3-dichlorin benzylidene methyl acetoacetate and sulfonic resin is 1: 0.03～1: 0.13; 2, the part by weight of 3-dichlorin benzylidene methyl acetoacetate and alcoholic solvent is 1: 2.0～1: 5.0; 2, the molar ratio of the amino ethyl crotonate of 3-dichlorin benzylidene methyl acetoacetate and 3-is 1: 1.0～1.4.
Described cyclization addition reaction temperature is the boiling temperature of 65 ℃～reaction solution; Reaction times is 8～12 hours; Implement protection of inert gas in the described cyclization addition reaction process.
Described cyclization addition reaction finishes the first filtration catalizer in back, and decompression steams the part alcoholic solvent again, adds a kind of non-polar organic solvent then in concentrated solution, and the reaction product precipitation is separated out; Throw out after filtration, directly obtain the felodipine crude product of higher degree after the washing, drying; This crude product promptly gets highly purified felodipine finished product after with the recrystallization solvent recrystallization.
Described recrystallization solvent is selected acetone, butanone, pentanone or isopropyl ether, n-butyl ether, methyl tertiary butyl ether or alcohol-ester mixed solvent or alcohol-water mixed solvent for use; Non-polar organic solvent is meant that naphthenic hydrocarbon, the boiling range of the alkane of 2～10 carbon atoms, 3～10 carbon atoms are 30 ℃～120 ℃ sherwood oil, lower halogenated hydrocarbon, liquid aromatic hydrocarbons or fragrant halocarbon; Described alcohol-ester mixed solvent is selected ethanol-ethyl acetate, ethanol-butylacetate, Virahol-ethyl acetate or Virahol-butylacetate for use.
Non-polar organic solvent is selected normal hexane, normal heptane, octane-iso for use; Hexanaphthene, suberane or sherwood oil.
Described this preparation method of felodipine is equally applicable to chemical structure and replaces-1, the preparation of 4-dihydropyridines antihypertensive drug with pharmacology, clinical effect other 4-similar to felodipine.
The main selection of recrystallization solvent is according to being in the inventive method:
1) target product is fully separated under this purification condition with raw material, by product and/or the isomer of not effect;
2) solvent toxicity is low, safe in utilization;
3) the solvent boiling point should not be too high, in order to finishing drying operation under lower drying temperature, is dried guaranteeing, product exempts from unnecessary destruction in drying process, and the dissolvent residual in the product is minimized.
According to mentioned above principle, select ethanol-ethyl acetate, Virahol-ethyl acetate or acetone recrystallization solvent as the felodipine crude product.Wherein, the proportioning between alcohol-ester is 1: 0.1～1: 9.0, and the part by weight of felodipine crude product and this mixed solvent is 1: 1.0～15.0; The part by weight of felodipine crude product and acetone is 1: 0.5～10.0.
The leading indicator of true reflection felodipine quality product is related substance (impurity).The representative composition of related substance is in the felodipine product: 1) dibasic acid esters isomer (comprising dimethyl ester and diethyl ester) (seeing formula 2-a, formula 2-b); 2) the oxidized byproduct of dihydropyridine---4-(2, the 3-dichlorophenyl-)-2,6-dimethyl-3,5-pyridine dicarboxylic acid methyl ethyl ester (seeing formula 3).
Formula 2-a formula 2-b formula 3
By the foreign matter content of the inventive method gained felodipine product general＜0.5%.Be starkly lower than " Chinese pharmacopoeia standard (≤1.5%).And can reach the degree of any control.
Compared with the prior art, preparing felodipine by the inventive method, to have a yield higher, and purity is even more ideal, and the reaction times is short, later separation, easy, the economic multiple advantage of purification process.Be particularly suitable for suitability for industrialized production.
The inventive method is equally applicable to chemical structure and pharmacology, other 4-that clinical effect is similar or identical with felodipine replace-1, the preparation of 4-dihydropyridines antihypertensive drug is as nifedipine (Nifedipine) nimodipine (Nimdipine), nitrendipine (Nitrdipine), nisoldipine (Nisoldipine), nicardipine (Nicardipine) and amlodipine (Amlodipine) etc.
Embodiment
The preparation of example 1 felodipine:
1.1. cyclization addition:
In 1000ml is furnished with the four-hole reaction flask of sealed stirrer, thermometer, condenser and nitrogen ingress pipe (being connected bubbler and nitrogen steel cylinder), delivery line (being connected the condensator outlet place), drop into the 640ml dehydrated alcohol successively, 77.5g is (pure: 0.59mol.) amino ethyl crotonate of 3-and 6.9g D072 type resin.Stir down and in bottle, feed nitrogen gas stream, add 138.2g (pure 0.5mol) 2 again, 3-dichlorin benzylidene methyl acetoacetate.Finish warming-in-water to 65 ℃～70 ℃, and sustained reaction 6 hours.Be warming up to reflux state again and continue reaction 2hr (available TLC method is determined reaction end).Reaction solution is cooled to 30 ℃, filtration catalizer, and extremely clear with identical solvent rinsing.Merge filter, washing lotion, add the 400ml hexanaphthene during 1/3 left and right sides, finish, continue to stir 10min., static again 1 hour after-filtration in vacuum concentration in the water-bath to original volume.Filter cake is extremely clear through washing with hexanaphthene, and extremely does in vacuum-drying below 50 ℃. obtain the Powdered crystal crude product of 179.1g off-white color class.Purity 98.7% (liquid phase chromatography, normalization method).Cyclization addition yield: 92%.
1.2. felodipine crude product recrystallization:
First method:: ethyl acetate-isopropyl alcohol mixed solvent method for refining: get above-mentioned crude product 85.0g, add 300ml. ethyl acetate-Virahol (5: 1) mixing solutions, add 0.17g gac, reflux decolour 10 minutes, filtered while hot in the water-bath after the heating for dissolving.Filtrate places cool bath～cooling bath stirred crystallization, filters, and filter cake washs the back with the cold cut matchmaker and extremely does in vacuum-drying below 50 ℃, obtains the glossy felodipine highly finished product of 73.6g white.Purity 99.3%, total related substance 0.48%.Results of elemental analyses:
C H N
Theoretical value (%) 52..26 4.98 3.65
Measured value (%) 56.27 4.96 3.66
Refinement mother liquor and washing lotion merge vacuum concentration to 1/4 left and right sides volume in the rearmounted water-bath, according to last method crystallisation by cooling, filter to such an extent that reclaim crude product.This crude product once gets 5.8g. felodipine finished product, purity 99.2% with identical solvent recrystallization.Treating process total recovery 90.3%.
Second method:. the acetone refining method.Get cyclization crude product 85.0g, add 280ml acetone, add 0.17g gac, reflux decolour 10 minutes, filtered while hot in the water-bath after the heating for dissolving.Filtrate places cold water～cooling bath stirred crystallization. and filter, filter cake washs the back with the cold cut matchmaker and extremely does in vacuum-drying below 50 ℃, obtains the glossy felodipine highly finished product of 75.4g white.Purity 99.7%.Total related substance 0.46%.Results of elemental analyses is identical with the A method.Refinement mother liquor and washing lotion according to first method do to concentrate, crystallization, filtration.Reclaim the identical again solvent recrystallization of crude product once, obtain the glossy felodipine highly finished product of 5.4g white.Purity 99..6%.Treating process yield 91.1%.
The preparation of embodiment 2. felodipines:
1. cyclization addition
In this experiment, the specification of each raw material, catalyzer, consumption and temperature of reaction, time, concentrate, precipitation, drying conditions be with example 1, only uses dehydrated alcohol and normal hexane in Virahol (640ml.) the normal heptane alternate example 1.Obtain the Powdered felodipine crude product of 177.9g off-white color class, purity 98.9%, yield 91.6% in accordance with the law.
2. felodipine crude product recrystallization
Method, condition and result are with example 1.
Embodiment 3. felodipine crude products preparation (imitative US2004/0204604A method):
124.4g (pure: 0.45mol) 2,3-dichlorin benzylidene methyl acetoacetate is with to add 70.6g after the Virahol of 590ml mixes again (pure: 0.54mol) the amino ethyl crotonate of 3-.This reaction mixture back flow reaction 12 hours in water-bath.Place in the water-bath decompression to steam Virahol reaction solution, add the 390ml normal heptane, the felodipine precipitation is separated out in stirring.Static 1 hour after-filtration of room temperature.Filter cake to doing, obtains the yellow lump shape of 147.9g felodipine crude product in vacuum-drying below 50 ℃ through with normal heptane washing three times.Purity 96.3%, pure yield 82.4%.
The preparation of embodiment 4. nisoldipines (Nisoldipine):
1. cyclization addition:
In experimental installation as example 1, the amino ethyl crotonate of the 3-of 77.5g (rolling over pure 0.59ml) is dissolved in the 650ml Virahol, add 7.4gD072 type resin, in stirring the downhill reaction bottle, feed nitrogen gas stream, add 147.5g (pure 0.5mol.) 2-nitro benzylidene isobutyl acetoacetate then.Finish, warming-in-water, and in 65 ℃～70 ℃ insulation reaction 7 hours, back flow reaction was 2 hours again.Elimination catalyzer when reaction solution is chilled to 30 ℃ (and extremely clear) with identical solvent washing.Merge filter, washing lotion, in water-bath, add the 425ml normal heptane while hot during vacuum concentration to 1/3 volume, stir evenly and static 1 hour.According to the facts the method for example 1 is done filtration, washing and drying operation, obtains the Powdered nisoldipine crude product of the faint yellow class of 167.1g.Purity: 97.8% (returning) with the change method; Yield: 82.6%.
2. recrystallization:
Get the cyclization crude product 150.0g in the example 4, add 550ml. ethyl acetate-Virahol (5: 1) mixed solvent, after heating for dissolving in the water-bath, add the 0.3g gac, according to the facts example 1 first method is done decolouring, filtration, crystallisation by cooling, filtration, washing and drying operation, obtains 131.1g white crystals shape nisoldipine highly finished product.Purity 99.3%, 151 ℃～152 ℃ of fusing points.. treating process total recovery 91.6%.
Claims (8)
1. the preparation method of antihypertensive drug felodipine, it is characterized in that: 2, add a kind of strong acid cation exchange resin catalyst in the alcoholic solution of the amino ethyl crotonate of 3-dichlorin benzylidene methyl acetoacetate and 3-and carry out the cyclization addition reaction, the cyclization addition reaction finishes the first filtration catalizer in back, decompression steams the part alcoholic solvent again, in concentrated solution, add a kind of non-polar organic solvent then, the reaction product precipitation is separated out; Throw out after filtration, directly obtain the felodipine crude product of higher degree after the washing, drying, non-polar solvent wherein is cyclohexane or normal heptane.
2. according to the described preparation method of felodipine of claim 1, it is characterized in that: described storng-acid cation exchange resin is selected macropore, inferior hole or common aperture polystyrene sulfonic resin for use; Alcoholic solvent is selected the lower aliphatic alcohols of dehydrated alcohol, Virahol or other 1～5 carbon atom for use in the described alcoholic solution.
3. according to the described preparation method of felodipine of claim 1, it is characterized in that: described cyclization addition reaction temperature is the boiling temperature of room temperature～reaction solution; Reaction times is 6～16 hours.
4. according to the described preparation method of felodipine of claim 2, it is characterized in that: described 2, the part by weight of 3-dichlorin benzylidene methyl acetoacetate and polystyrene sulfonic resin is 1: 0.005～1: 0.2; 2, the part by weight of 3-dichlorin benzylidene methyl acetoacetate and alcoholic solvent is 1: 1～1: 10; 2, the molar ratio of the amino ethyl crotonate of 3-dichlorin benzylidene methyl acetoacetate and 3-is 1: 0.8～1.8.
5. according to the described preparation method of felodipine of claim 4, it is characterized in that: described 2, the part by weight of 3-dichlorin benzylidene methyl acetoacetate and sulfonic resin is 1: 0.03～1: 0.13; 2, the part by weight of 3-dichlorin benzylidene methyl acetoacetate and alcoholic solvent is 1: 2.0～1: 5.0; 2, the molar ratio of the amino ethyl crotonate of 3-dichlorin benzylidene methyl acetoacetate and 3-is 1: 1.0～1.4.
6. according to the described preparation method of felodipine of claim 3, it is characterized in that: described cyclization addition reaction temperature is the boiling temperature of 65 ℃～reaction solution; Reaction times is 8～12 hours; Implement protection of inert gas in the described cyclization addition reaction process.
7. preparation method of felodipine according to claim 1 is characterized in that: gained felodipine crude product promptly gets highly purified felodipine finished product after carrying out recrystallization with recrystallization solvent.
8. preparation method of felodipine according to claim 7 is characterized in that: described recrystallization solvent is selected acetone, butanone, pentanone or isopropyl ether, n-butyl ether, methyl tertiary butyl ether or alcohol-ester mixed solvent or alcohol-water mixed solvent for use; Described alcohol-ester mixed solvent is selected ethanol-ethyl acetate, ethanol-butylacetate, Virahol-ethyl acetate or Virahol-butylacetate for use.
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| WO2012123966A1 (en) | 2011-03-04 | 2012-09-20 | Arch Pharmalabs Limited | Process for the preparation of 4 -substituted -1, 4-dihydropyridines |
| CN102304079B (en) * | 2011-09-29 | 2013-09-25 | 合肥立方制药股份有限公司 | Method for purifying felodipine from cyclization reaction solution by direct elutriation |
| CN113248421B (en) * | 2020-03-24 | 2022-03-08 | 合肥立方制药股份有限公司 | Preparation method of nifedipine |
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