CN101613280A - Felodipine synthetic intermediate 2, the preparation method of 3-dichlorin benzylidene methyl acetoacetate - Google Patents
Felodipine synthetic intermediate 2, the preparation method of 3-dichlorin benzylidene methyl acetoacetate Download PDFInfo
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- CN101613280A CN101613280A CN200910116763A CN200910116763A CN101613280A CN 101613280 A CN101613280 A CN 101613280A CN 200910116763 A CN200910116763 A CN 200910116763A CN 200910116763 A CN200910116763 A CN 200910116763A CN 101613280 A CN101613280 A CN 101613280A
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Abstract
The invention discloses a kind of synthetic intermediate 2 of antihypertensive drug felodipine, the novel preparation method of 3-dichlorin benzylidene methyl acetoacetate ester, specifically be under the katalysis of the novel combination catalyst that second amine and quinoline carboxylic acid form, 2,3 dichloro benzaldehyde and methyl acetoacetate are finished condensation reaction in alcoholic solvent.After condensation reaction finishes with reaction solution in the following crystallisation by cooling of room temperature, after filtration, washing and dry back obtain the intermediate 2 of purity 〉=98%, 3-dichlorin benzylidene methyl acetoacetate one is analysed thing.Its mother liquor is through the get back intermediate-2 of 98% above purity of vacuum concentration, cooling crystallization, filtration and recrystallization, 3-dichlorin benzylidene methyl acetoacetate secondary precipitate product.Compared with prior art, this novel method makes that the synthesis yield of felodipine intermediate is higher, and intermediate purity is even more ideal.The technology of the present invention is equally applicable to chemical structure and replaces-1, the preparation of 4-dihydropyridines antihypertensive drug intermediates with pharmacology, clinical effect other 4-similar to 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 to 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 as follows:
The chemosynthesis of felodipine is generally finished 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 (as piperidines, diethylamine etc.), condensation reaction can only be carried out at low temperatures.And established benzylidene midbody product also may 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 being with acid as catalyst, then may 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 using in alcoholic solvent.Though so overcome the inherent defect of above-mentioned acid base catalysator, yield and purity are not high, must just can obtain the intermediate of qualified purity through recrystallization.
Up to 2004, US 2004/204604A disclosed a kind of binary combination catalyst system that is made 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 intermediate, the condensation yield was increased to 80%.Intermediate 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 intermediate purity 94%-97% (high performance liquid chromatography). with the level of this patent report certain gap is arranged.
Summary of the invention
Purpose of the present 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 intermediate purity of 4-dihydropyridines pharmaceutical intermediate are even more ideal than preceding method.
Technical scheme of the present invention is as follows:
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 finished condensation reaction in pure solvent.
Second amine is selected diethylamine, dimethylamine or piperidines for use; The quinoline carboxylic acid selects 2-quinolinecarboxylic acid or 2-quinoline acetate, 3-quinoline for use. formic 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 dehydrated 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.
The reaction solution crystallisation by cooling under ℃ condition of room temperature～0 that obtains after condensation reaction finishes, crystallisate are after filtration, washing and dry back obtain the intermediate 2 of purity 〉=97%, precipitate of 3-dichlorin benzylidene methyl acetoacetate. One time the precipitate mother liquor obtains intermediate secondary precipitate crude product through vacuum concentration, cooling crystallization and dry back; This crude product can obtain the intermediate 2 of purity 〉=98% behind the recrystallization in dehydrated alcohol or Virahol, 3-dichlorin benzylidene methyl acetoacetate.
Secondary precipitate crude product 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 be back in the condensation reaction after purifying 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 to felodipine.This class 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 as follows:
The inventive method is not only applicable to the preparation of felodipine intermediate, 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 to 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 catalyst 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 crude product 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 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 crude product 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 at last, the 3-dichlorobenzaldehyde, thus realize cleaner production more conveniently.
Embodiment
Example 1: felodipine synthetic intermediate-2, the preparation of 3-dichlorin benzylidene methyl acetoacetate
In the 1000ml. reaction flask, drop into the 600ml. dehydrated 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 (determining 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 intermediate crystallization (precipitate).Output 138.6g., purity 98.7%.
Precipitate mother liquor and washing lotion are merged, in water-bath vacuum concentration to 1/4 of about original volume, static crystallization 6 hours under 15 ℃ ± 2 ℃ conditions again.According to last method filtration, drying, obtain secondary precipitate crude product 52.2g, purity 95.3%.This two analyses the thing crude product with identical solvent recrystallization once, obtains the glossy intermediate crystallization of 44.1g white, output 44.1g, purity 99.2%, total recovery 82.46%.
Example 2. felodipine synthetic intermediates-2, the preparation of 3-dichlorin benzylidene methyl acetoacetate
In the present embodiment, replace dehydrated alcohol to make condensation reaction and recrystallization solvent with Virahol (640ml.), other all raw materials, catalyzer specification, consumption and ratio are identical with example 1, and obtain precipitate 140.1g., purity 98.5% one time according to the preparation method of example 1; Secondary precipitate crude product 50.3g., purity 95.6%.This crude product through with Virahol refining obtain after once purity be 99.1% two analyse thing 44.3g..Condensation, refining total recovery: 83.06%.
Example 3. felodipine synthetic intermediates-2, the preparation method of 3-dichlorin benzylidene methyl acetoacetate (the contrast patented method of example 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 a small amount of cold isopropanol alcohol, obtains off-white powder crystallisate 131.4g, purity 97.6% (high 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%.
Example 4. nitrendipines (Nitrendipine) intermediate---the preparation of 3-nitro benzylidene methyl acetoacetate
In the 1000ml. reaction flask, drop into the 450ml. dehydrated 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 (determining 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 intermediate---3-nitro benzylidene 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 example 1 concentrate successively, crystallization, filtration and recrystallization handle, obtain the glossy intermediate 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 finished condensation reaction in pure solvent.
2, 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 is selected diethylamine, dimethylamine or piperidines for use; The quinoline carboxylic acid selects 2-quinolinecarboxylic acid or 2-quinoline acetate, 3-quinoline for use. formic acid or 3-quinoline acetate; Alcohol solvent nail alcohol, ethanol, Virahol or the trimethyl carbinol.
3, 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; 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.
4, 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.
5, according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 2, 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 dehydrated alcohol for use.
6, according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 3, 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; Second amine and quinoline carboxylic acid's molar ratio is 1: 0.8～1: 1.3 in the combination catalyst.
7, according to the described antihypertensive drug felodipine synthetic intermediate 2 of claim 4, 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 after filtration, washing and dry back obtain the intermediate 2 of purity 〉=97%, precipitate of 3-dichlorin benzylidene methyl acetoacetate. One time the precipitate mother liquor obtains intermediate secondary precipitate crude product through vacuum concentration, cooling crystallization and dry back; This crude product can obtain the intermediate 2 of purity 〉=98% behind the recrystallization in dehydrated alcohol or Virahol, 3-dichloro industry benzyl methyl acetoacetate.
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 crude product 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 one by one with methyl acetoacetate, and is back in the condensation reaction after purifying again.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN111233672A (en) * | 2020-03-24 | 2020-06-05 | 合肥立方制药股份有限公司 | Method for synthesizing nifedipine intermediate by using combined catalyst |
| 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 |
| CN113234009A (en) * | 2020-03-24 | 2021-08-10 | 合肥立方制药股份有限公司 | Preparation method of nifedipine |
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| WO1993006082A1 (en) * | 1991-09-13 | 1993-04-01 | Merck & Co., Inc. | Process for the preparation of 4-substituted-1,4-dihydropyridines |
| ES2055652B1 (en) * | 1992-09-22 | 1995-03-01 | Elmuquimica Farm Sl | PROCEDURE FOR OBTAINING 2,6-DIMETIL-4- (2,3-DICLOROFENIL) -1,4-DIHIDROPIRIDIN-3,5-DICARBOXILATO DE 3-ETIL-5-METHYL. |
| SE9600086D0 (en) * | 1996-01-10 | 1996-01-10 | Astra Ab | New manufacturing process |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| CN111233672A (en) * | 2020-03-24 | 2020-06-05 | 合肥立方制药股份有限公司 | Method for synthesizing nifedipine intermediate by using combined catalyst |
| CN113234009A (en) * | 2020-03-24 | 2021-08-10 | 合肥立方制药股份有限公司 | Preparation method of nifedipine |
| CN113248421A (en) * | 2020-03-24 | 2021-08-13 | 合肥立方制药股份有限公司 | Preparation method of nifedipine |
| CN113234009B (en) * | 2020-03-24 | 2022-03-08 | 合肥立方制药股份有限公司 | Preparation method of nifedipine |
| CN113248421B (en) * | 2020-03-24 | 2022-03-08 | 合肥立方制药股份有限公司 | Preparation method of nifedipine |
| CN111233672B (en) * | 2020-03-24 | 2023-06-27 | 合肥立方制药股份有限公司 | Method for synthesizing nifedipine intermediate by using combined catalyst |
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