CN101613280B - Preparation method of felodipine synthetic intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate - Google Patents
Preparation method of felodipine synthetic intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate Download PDFInfo
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- CN101613280B CN101613280B CN200910116763A CN200910116763A CN101613280B CN 101613280 B CN101613280 B CN 101613280B CN 200910116763 A CN200910116763 A CN 200910116763A CN 200910116763 A CN200910116763 A CN 200910116763A CN 101613280 B CN101613280 B CN 101613280B
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Abstract
The invention discloses a preparation method of methyl 2-(2,3-dichlorobenzylidine)acetoacetate which is a synthetic intermediate of antihypertensive drug felodipine. The method is characterized by allowing a condensation reaction between 2, 3-dichlorobenzaldehyde and methyl acetoacetate in alcohol solution under the catalytic action of a novel combined catalyst consisting of secondary amine and quinoline carboxylic acid. Reaction liquid is cooled at room temperature for crystallization, filtered, washed and dried after the condensation reaction to obtain primary eluent of the intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate with purity not less than 98%. Mother liquor is subject to vacuum condensation, cooling crystallization, filtering and recrystallization to obtain secondaryeluent product of the intermediate methyl 2-(2,3-dichlorobenzylidine)acetoacetate with purity not less than 98%. Compared with the prior art, the new method helps enhance synthetic yield of the felodipine intermediate, and provide ideal intermediate purity. The method is also applicable to preparing other 4-sustituted-1,4-dihydropyridine antihypertensive drug intermediates with chemical structure and pharmaceutical and clinical actions similar to those of felodipine.
Description
Technical field
The present invention relates to organic (medicine) the field of chemical synthesis, specifically is antihypertensive drug felodipine synthetic intermediate 2, the preparation method of 3-dichlorin benzylidene methyl acetoacetate.This method is equally applicable to chemical structure and replaces-1, the preparation of 4-dihydropyridines antihypertensive drug synthetic intermediate with pharmacology, clinical effect other 4-similar with felodipine.
Background technology
Felodipine [4-(2, the 3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl--3,5-pyridine dicarboxylic acid methyl ethyl ester] is well-known 1, the representative drugs in the 4-dihydropyridine blood-pressure reducing medicine.Chemical structure is following:
The chemosynthesis of felodipine is generally accomplished via the step of two shown in following formula synthesis method:
In the first step condensation reaction, because condensation product---the chemical activity of ethylene linkage in the benzal structure makes it all compare responsive for acid or alkali.When with basic catalyst (like piperidines, diethylamine etc.), condensation reaction can only be carried out at low temperatures.And established tolylene midbody product also possibly produce a kind of diadduct with the methyl acetoacetate effect of another molecule.This thing is the condensation reaction by product, and makes troubles to later separation.When using acid as catalyst, then possibly generate the aldol condensation by product, it also is a kind of isolating impurity that is difficult to.
For this reason, US4600778 has invented a kind of condensation reaction of Piperidineacetic acid salt as catalyzer of in alcoholic solvent, using.Though so overcome the vice proper of above-mentioned acid base catalysator, yield and purity are not high, must just can obtain the midbody of qualified purity through recrystallization.
Up to 2004, US 2004/204604A disclosed a kind of binary combination catalyst system that is made up of piperidines and pyridine first salt that is applicable to the preparation of felodipine and other 1-4-dihydropyridines pharmaceutical intermediates.When this system was used for the condensation reaction of felodipine midbody, the condensation yield was increased to 80%.Midbody purity reaches 99%, but unexposed follow-up treating process and condition.The applicant presses its disclosed method and condition experiment, condensation yield 70%-75%, and midbody purity 94%-97% (HPLC). with the level of this patent report certain gap is arranged.
Summary of the invention
The object of the invention will filter out one group than piperidines---the novel combination catalyst system that pyridine carboxylic acid salt is more superior; A kind of antihypertensive drug felodipine synthetic intermediate 2 is proposed; The preparation method of 3-dichlorin benzylidene methyl acetoacetate; Make felodipine and other 4-replace-1, the synthesis yield and the midbody purity of 4-dihydropyridines pharmaceutical intermediate are even more ideal than preceding method.
Technical scheme of the present invention is following:
Antihypertensive drug felodipine synthetic intermediate 2; The preparation method of 3-dichlorin benzylidene methyl acetoacetate; It is characterized in that: under the katalysis of the combination catalyst that second amine and quinoline carboxylic acid form, 2,3 dichloro benzaldehyde and methyl acetoacetate are accomplished condensation reaction in pure solvent.
Second amine is selected diethylamine, n n dimetylaniline or piperidines for use; The quinoline carboxylic acid selects 2-quinolinecarboxylic acid or 2-quinoline acetate for use, 3-quinolinecarboxylic acid or 3-quinoline acetate; Alcohol solvent nail alcohol, ethanol, Virahol or the trimethyl carbinol.
The molar ratio of the condensation reaction raw material 2,3 dichloro benzaldehyde and second amine is 1: 0.01～0.1; Second amine and quinoline carboxylic acid's molar ratio is 1 in the combination catalyst: .0.5～1: 1.5; The molar ratio of 2,3 dichloro benzaldehyde and methyl acetoacetate is 1: 0.8～1: 1.8.
Setting-up point is 30～60 ℃, and the reaction times is 4～10 hours; Be preferably: setting-up point: 38-47 ℃, reaction times: 6-8 hour.
Second amine is selected piperidines for use, and the quinoline carboxylic acid selects the 2-quinolinecarboxylic acid for use, and pure solvent is selected Virahol or absolute ethyl alcohol for use.
The molar ratio of the condensation reaction raw material 2,3 dichloro benzaldehyde and second amine is 1: 0.03～1: 0.07; Second amine and quinoline carboxylic acid's molar ratio is 1: 0.8～1: 1.3 in the combination catalyst.
Reaction solution crystallisation by cooling under ℃ condition of room temperature～0 that condensation reaction obtains after finishing, crystallisate obtain the midbody 2 of purity >=97%, precipitate of 3-dichlorin benzylidene methyl acetoacetate after filtration, washing and drying. One time the precipitate mother liquor obtains midbody secondary precipitate bullion through vacuum concentration, cooling crystallization and dry back; This bullion can obtain the midbody 2 of purity >=98%, 3-dichlorin benzylidene methyl acetoacetate behind the recrystallization in absolute ethyl alcohol or Virahol.
Secondary precipitate bullion mother liquor through water carry, cooling crystallization and vacuum distilling method separate the raw material 2,3 dichloro benzaldehyde of quinoline carboxylic acid, piperidines, not effect one by one with methyl acetoacetate, and after purification, be back in the condensation reaction again.
The inventive method is equally applicable to chemical structure and replaces-1, the preparation of 4-dihydropyridines antihypertensive drug synthetic intermediate with pharmacology, clinical effect other 4-similar with felodipine.This type pharmaceutical intermediate comprises nifedipine (Nifedipine), nitrendipine (Nitrendipine), nimodipine (Nimodipine), nicardipine (Nicardipine), nisoldipine Nisoldipine) and amlodipine pharmaceutical intermediates such as (amlodipine).
Reaction formula of the present invention is following:
The inventive method is not only applicable to the preparation of felodipine midbody, is applicable to that too chemical structure replaces-1, the preparation of the synthetic intermediate of 4-dihydropyridines vasodilation medicine with pharmacology, clinical effect other all 4-similar with felodipine.As: nifedipine (Nifedipine), nimodipine (Nimdipline), nitrendipine (Nitr dipline), nisoldipine (Nisoldipline), nicardipine (Nicardipine), amlodipine pharmaceutical intermediates such as (Amlodipine).
Compared with prior art, this novel combination catalyzer provided by the present invention has following characteristics:
1), condensation reaction yield (80-85%) and intermediate product purity (>=98%) are the highest;
2), the condensation product crystal formation is good, bright in color;
3), condensation reaction by product and foreign body object be minimum, thereby brings great convenience for the subsequent processes of reaction solution;
4) a precipitate bullion that, accounts for ultimate production about 85% need not made with extra care and directly reach high-quality purity.The secondary precipitate also only needs once simple treating process just can reach high-quality purity;
5), because quinoline carboxylic acid's molten Jie's degree in cold water is more much lower than pyridine carboxylic acid.Thereby on industrial production, only need with two analyse thing bullion mother liquor with simple water carry, the method for cooling crystallization; Can reclaim the quinoline carboxylic acid easily; From its mother liquor, reclaim piperidines and methyl acetoacetate with distillating method again; In organic phase, reclaim 2,3 dichloro benzaldehyde at last, thereby realize cleaner production more conveniently.
Embodiment
Instance 1: felodipine synthetic intermediate-2, the preparation of 3-dichlorin benzylidene methyl acetoacetate
In the 1000ml. reaction flask, drop into the 600ml. absolute ethyl alcohol successively, (pure: 1.02mol.) (pure: 41mmol.) (pure: 44mmol.) 2-quinolinecarboxylic acid and 141.4g are (pure: 0.8mol) 2,3 dichloro benzaldehyde for piperidines, 7.68g for methyl acetoacetate, 3.53g for 119.2g.Finish, warming-in-water to 41 ℃～45 ℃ continues stirring reaction 6 hours (confirming reaction end with the TLC method).Reaction solution was placed on 15 ℃ ± 2 ℃ cool baths stirred crystallization 2 hours, crosses the elimination mother liquor, filter cake through washing after with an amount of cold cut matchmaker in vacuum-drying below 50 ℃ to dried, obtain white glossy midbody crystallization (precipitate).Output 138.6g., purity 98.7%.
Precipitate mother liquor and washing lotion are merged, in water-bath 1/4 of vacuum concentration to about original volume, static crystallization 6 hours under 15 ℃ ± 2 ℃ conditions again.According to last method filtration, drying, obtain secondary precipitate bullion 52.2g, purity 95.3%.This two analyses the thing bullion with identical solvent recrystallization once, obtains the glossy midbody crystallization of 44.1g white, output 44.1g, purity 99.2%, total recovery 82.46%.
Instance 2. felodipine synthetic intermediates-2, the preparation of 3-dichlorin benzylidene methyl acetoacetate
In the present embodiment; Replace absolute ethyl alcohol to make condensation reaction and recrystallization solvent with Virahol (640ml.); Other all raw materials, catalyzer specification, consumption and ratio are identical with instance 1, and obtain precipitate 140.1g., purity 98.5% one time according to the preparation method of instance 1; Secondary precipitate bullion 50.3g., purity 95.6%.This bullion through use Virahol refining obtain after once purity be 99.1% two analyse thing 44.3g..Condensation, refining total recovery: 83.06%.
Instance 3. felodipine synthetic intermediates-2, the preparation method of 3-dichlorin benzylidene methyl acetoacetate (the contrast patented process of instance 1)
The 2,3 dichloro benzaldehyde of 141.4g (pure 0.8moL) is dissolved in the 660ml. Virahol, adds the methyl acetoacetate of 4.97g (pure 0.04mol) picoloy acid, 3.44g (pure 0.04mol) piperidines and 119.6g (pure 1.02mol) more successively.Finish, warming-in-water is to 40-45 ℃, stirring reaction 6 hours.Reaction solution stirred crystallization 2 hours in 15 ℃ ± 2 ℃ water-baths.Vacuum elimination mother liquor, filter cake is extremely done in vacuum-drying below 50 ℃ after with the washing of small amount of cold Virahol alcohol, obtains off-white powder crystallisate 131.4g, purity 97.6% (performance liquid chromatography normalization method).
Precipitate mother liquor and washing lotion are merged, and according to the facts method vacuum concentration, crystallisation by cooling, filtration and the recrystallization of example 1 obtain two and analyse thing highly finished product 35.9g, purity 98.6%.Condensation, refining total recovery 74.9%.
Instance 4. nitrendipines (Nitrendipine) midbody---the preparation of 3-nitro tolylene methyl acetoacetate
In the 1000ml. reaction flask, drop into the 450ml. absolute ethyl alcohol successively, (pure: 1.0mol.) (pure: 40mmol.) (pure: 43mmol.) 2-quinolinecarboxylic acid and 121.0g are (pure: 0.8mol) 3-nitrobenzaldehyde for piperidines, 7.51g for methyl acetoacetate, 3.44g for 117.4.0g.Finish, warming-in-water to 42 ℃～46 ℃ continues stirring reaction 6 hours (confirming reaction end with the TLC method).Reaction solution was placed on 13 ℃ ± 2 ℃ cool baths stirred crystallization 2 hours.Cross the elimination mother liquor.Filter cake is extremely done in vacuum-drying below 50 ℃ after washing with an amount of cold cut matchmaker, obtains white glossy midbody---3-nitro tolylene methyl acetoacetate crystallization (precipitate), output 141.2g., purity 98.9%.
With one analyse thing mother liquor and washing lotion merge the back by the method for instance 1 concentrate successively, crystallization, filtration and recrystallization handle, obtain the glossy midbody two of 44.1g white and analyse the thing crystallization, purity 99.3%; One analyses thing, two analyses thing ultimate production 185.3g, condensation, refining total recovery 92%.
Claims (9)
1. the antihypertensive drug felodipine synthetic intermediate 2; The preparation method of 3-dichlorin benzylidene methyl acetoacetate; It is characterized in that: under the katalysis of the combination catalyst that second amine and quinoline carboxylic acid form; 2,3 dichloro benzaldehyde and methyl acetoacetate are accomplished condensation reaction in pure solvent;
Second amine is selected diethylamine, n n dimetylaniline or piperidines for use; The quinoline carboxylic acid selects 2-quinolinecarboxylic acid or 2-quinoline acetate for use, 3-quinolinecarboxylic acid or 3-quinoline acetate; Alcohol solvent nail alcohol, ethanol, Virahol or the trimethyl carbinol; Second amine and quinoline carboxylic acid's molar ratio is 1: 0.5～1: 1.5 in the combination catalyst.
2. according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 1; The preparation method of 3-dichlorin benzylidene methyl acetoacetate; It is characterized in that: the molar ratio of the condensation reaction raw material 2,3 dichloro benzaldehyde and second amine is 1: 0.01～0.1; The molar ratio of 2,3 dichloro benzaldehyde and methyl acetoacetate is 1: 0.8～1: 1.8.
3. according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 1, the preparation method of 3-dichlorin benzylidene methyl acetoacetate is characterized in that: setting-up point is 30～60 ℃, and the reaction times is 4～10 hours.
4. according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 1; The preparation method of 3-dichlorin benzylidene methyl acetoacetate ester; It is characterized in that: second amine is selected piperidines for use, and the quinoline carboxylic acid selects the 2-quinolinecarboxylic acid for use, and pure solvent is selected Virahol or absolute ethyl alcohol for use.
5. according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 1, the preparation method of 3-dichlorin benzylidene methyl acetoacetate is characterized in that: second amine and quinoline carboxylic acid's molar ratio is 1: 0.8～1: 1.3 in the combination catalyst.
6. according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 2; The preparation method of 3-dichlorin benzylidene methyl acetoacetate; It is characterized in that: the molar ratio of the condensation reaction raw material 2,3 dichloro benzaldehyde and second amine is 1: 0.03～1: 0.07.
7. according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 3, the preparation method of 3-dichlorin benzylidene methyl acetoacetate is characterized in that: setting-up point: 38-47 ℃, and reaction times: 6-8 hour.
8. antihypertensive drug felodipine synthetic intermediate 2 according to claim 1; The preparation method of 3-dichlorin benzylidene methyl acetoacetate; It is characterized in that: reaction solution crystallisation by cooling under ℃ condition of room temperature～0 that condensation reaction obtains after finishing; Crystallisate obtains the midbody 2 of purity >=97%, precipitate of 3-dichlorin benzylidene methyl acetoacetate after filtration, washing and drying; One time the precipitate mother liquor obtains midbody secondary precipitate bullion through vacuum concentration, cooling crystallization and dry back; This bullion can obtain the midbody 2 of purity >=98%, 3-dichlorin benzylidene methyl acetoacetate behind the recrystallization in absolute ethyl alcohol or Virahol.
9. according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 8; The preparation method of 3-dichlorin benzylidene methyl acetoacetate; It is characterized in that: secondary precipitate bullion mother liquor through water carry, cooling crystallization and vacuum distilling method be quinoline carboxylic acid, piperidines, the raw material 2 of effect not; The 3-dichlorobenzaldehyde separates with methyl acetoacetate one by one, and after purifying, is back in the condensation reaction again.
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| CN102442912A (en) * | 2011-12-21 | 2012-05-09 | 蚌埠丰原医药科技发展有限公司 | Synthesis method of methoxy ethyl 2-(3-nitrobenzylidene)acetacetate |
| CN104974042A (en) * | 2014-04-09 | 2015-10-14 | 上海信谊金朱药业有限公司 | Preparation method of compound |
| CN111423362A (en) * | 2020-03-11 | 2020-07-17 | 山东省药学科学院 | Preparation method of two high-purity clevidipine butyrate impurities |
| CN116425635A (en) * | 2020-03-24 | 2023-07-14 | 合肥立方制药股份有限公司 | Method for synthesizing nifedipine intermediate by using combined catalyst |
| CN111253304B (en) * | 2020-03-24 | 2021-07-06 | 合肥立方制药股份有限公司 | Preparation method of nifedipine |
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