CN1651413A - Synthesis method of single optical isomer nitrendipine - Google Patents
Synthesis method of single optical isomer nitrendipine Download PDFInfo
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- CN1651413A CN1651413A CN 200410089136 CN200410089136A CN1651413A CN 1651413 A CN1651413 A CN 1651413A CN 200410089136 CN200410089136 CN 200410089136 CN 200410089136 A CN200410089136 A CN 200410089136A CN 1651413 A CN1651413 A CN 1651413A
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- nitrendipine
- optical isomer
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Abstract
A process for synthesizing the simple optical isomer nitrendipine features that under existance of quinine-ammonium benzylbromide as chiral phase-transfer catalyst, 2-(3-nitrobenzilidene) ethyl acetylacetate and beta-methyl amino crotonate take part in stereoselective condensating reaction in absolute alcohol to obtain target product.
Description
Technical field
The present invention relates to a kind of 2,6-dimethyl-4-(3-nitro) phenyl-1, the synthetic method of 4-dihydropyridine-3-ethyl formate-5-methyl-formiate (abbreviation nitrendipine), a kind of synthetic method of single optical isomer nitrendipine.
Background technology
2,6-dimethyl-4-(3-nitro) phenyl-1,4-dihydropyridine-3-ethyl formate-5-methyl-formiate (nitrendipine) has another name called " nitrendipine " (being designated hereinafter simply as nitrendipine), it is a kind of dihydropyridine type calcium antagonists, the clinical treatment that is mainly used in primary, secondary hypertension, the effect that also has other cardiovascular disorder of treatment simultaneously.Outward appearance is glassy yellow crystallization or crystalline powder.The structure of nitrendipine represents that it contains a chiral carbon, exists two kinds of enantiomorphs.For chiral drug, the physiologically active of two kinds of isomer has the existing many reports of other example of evident difference.Can prepare the single chiral compound by splitting.The continuous increase of chiral drug is changing the formation of chemicals, has pointed out the new direction of chirality new drug research exploitation.The synthetic nitrendipine is a racemic modification all at present, does not see the synthetic method that individual isomer is arranged.For example, " Changde college of education journal (natural science edition) " the 12nd rolled up the 2nd phase 50-51 page or leaf " process modification of the synthetic nitrendipine of a two-step approach " literary composition, introduced a kind of method of synthetic nitrendipine.Use the 3-nitrobenzaldehyde, under the acid catalyst effect, generate pure 3-nitro benzal base methyl aceto acetate,, under the effect of benzylamine class composite catalyst, generate nitrendipine again with this material and the effect of beta-amino methyl crotonate with methyl aceto acetate." applied chemistry " the 18th volume the 6th phase 507-508 page or leaf " the applied microwave radiotechnology is synthesized nitrendipine " literary composition, having introduced with m-nitrobenzaldehyde, methyl aceto acetate, ammonium acetate (or bicarbonate of ammonia or urea) is raw material, with the method for microwave technology one-step synthesis nitrendipine.Synthetic is the racemize nitrendipine in the above-mentioned document, and the synthetic method with individual isomer nitrendipine of opticity of chiral catalysis is not appeared in the newspapers.
Summary of the invention
The present invention is intended to propose the method for the synthetic nitrendipine of a kind of chiral catalysis, a kind of synthetic method of single optical isomer nitrendipine.
The synthetic method of this single optical isomer nitrendipine is to make solvent with dehydrated alcohol, with 2-(3-nitro) subunit methyl aceto acetate and beta-amino methyl crotonate in the presence of chiral phase-transfer catalyst quinine benzyl brometo de amonio, carry out the stereoselectivity condensation reaction and product.
Present method has utilized quinine benzyl brometo de amonio chiral phase-transfer catalyst to exist chiral catalysis environment and phase-transfer catalysis two big performances.2-(3-nitro) ethyl benzalacetoacetate is one and contains potential chirality carbon compound, during with the condensation of beta-amino methyl crotonate, can produce a chiral carbon, so this condensation product has opticity.And the product that common condensation reaction obtains is a racemic modification.Present method improves the condensation reaction stereoselectivity by the use of chiral catalyst performance, and the levoisomer ratio of nitrendipine is improved.Product is by the structural analysis of X-diffraction crystal, and is identical with the R type nitrendipine structure of document (A.Burger et al:J.Pharm Sci.86 (1997) 674) report.Measure through polarimeter, this isomer is left-handed.Product is carried out analyses such as infrared spectra, nucleus magnetic resonance, the structure of product conforms to the structure of nitrendipine.On the other hand,, improved the quality of nitrendipine, reduced foreign matter content by the use of phase-transfer catalyst performance.The adding that this mainly has benefited from catalyzer is shortened the reaction times, and heated time reduces, and has suppressed the generation of dimethyl ester counterpart and diethyl ester counterpart.The catalyzer that this method adopts is easy to remove with recrystallizing methanol the time, can be not residual in finished product.
Description of drawings
Accompanying drawing 1 is X-ray diffraction crystalline structure figure;
Accompanying drawing 2 is an infrared spectrogram.
Embodiment
The synthetic method of this single optical isomer nitrendipine is: make solvent with dehydrated alcohol, with 2-(3-nitro) ethyl benzalacetoacetate and beta-amino methyl crotonate in the presence of chiral phase-transfer catalyst quinine benzyl brometo de amonio, carry out the stereoselectivity condensation reaction, obtain product.
Its reaction formula is as follows:
Concrete synthetic example is: add dehydrated alcohol 20ml in three-necked bottle successively, 2-(3-nitro benzylidene) methyl aceto acetate (II) 13.2g (0.05mol), beta-amino methyl crotonate (I) 5.75g (0.05mol), quinine benzyl brometo de amonio (IV) 0.13g, the stirring and refluxing reaction, temperature is controlled at 78 ℃, 4 hours reaction times.After reaction finishes,, boil off part ethanol with the reaction solution underpressure distillation, again with freezing 3 hours of reaction solution, suction filtration, yellow crystals, use recrystallizing methanol again, fluorescent yellow powder 15.4g, productive rate 85.7%; Liquid-phase chromatographic analysis purity 99.12%.
The said products is measured through polarimeter, proof synthetic nitrendipine is a left-handed isomer, specific rotatory power is-34.25 °, be individual isomer R type nitrendipine (III), fusing point is 163-164 ℃, racemic modification fusing point than report exceeds 4 ℃ for 158-159 ℃, meets the rule that single isomerism bulk melting point in the optically active substance is higher than racemic modification.
The said products has also carried out the analysis of X line crystalline diffraction.Measure temperature 293.2K, wavelength 0.71073 .Collect the crystalline structure data and get the two-dimensional space structure, crystalline size 0.350 * 0.272 * 0.117mm.Single cell a=8.8577 (15) A, alpha=90deg.; B=15.581 (3) A, beta=92.458 (4) deg.; C=12.999 (2) , gamma=90deg..Resulting X-ray diffraction crystalline structure figure as shown in Figure 1, the X-ray diffraction result meets the constitutional features of R type nitrendipine.This product has also carried out nuclear magnetic resonance measuring on AVANCE D MX500 nuclear magnetic resonance analyser, each hydrogen-like ownership of the nuclear magnetic resonance spectrum that obtains sees the following form.
| The nucleus magnetic resonance absorption peak | ??H 1The peak ownership |
| ??δ H(1.2 3H triplet) | ??C 18COOCH 2CH 3(CH 3) |
| ??δ H(2.3 6H is unimodal) | ??C 7，C 6-CH 3 |
| ??δ H(3.6 3H is unimodal) | ??C 9COOCH 3 |
| ??δ H(4.1 2H multiplet) | ??C 17COOCH 2CH 3(CH 2) |
| ??δ H(5.1 1H is unimodal) | ??C 3C-H |
| ??δ H(5.8 1H is bimodal) | ??N-H |
| ??δ H(7.3-8.1 4H multiplet) | ??C 11，13，14，15?Ar-H |
C in the last table
nIn n mark reference crystal structure iron (Fig. 1) shown in.This product is also through Infrared spectroscopy, and infrared spectrogram as shown in Figure 2.The IR spectroscopic data is: 3358cm
-1S N-H stretching vibration, 1704cm
-1C=O stretching vibration on the s ester, 1646cm
-1C=C stretching vibration on the s phenyl ring, 1128cm
-1S C-H stretching vibration.Meet nitrendipine infrared spectrogram spectrum signature.
Catalyzer quinine benzyl brometo de amonio in the synthetic method of this single optical isomer nitrendipine can be to be dissolved in the mixed solution of benzene and dehydrated alcohol with quinine, adds the benzyl bromine, purifies after the reacting by heating in water-bath and makes.
Its reaction formula is as follows:
Specific implementation process is: in three-necked bottle, add 77.25g (0.25mol) quinine (V), and 20ml benzene, the 4ml dehydrated alcohol installs agitator, reflux condensing tube and thermometer, the dissolving quinine.After treating that quinine is all dissolved, add 42.5g (0.25mol) benzyl bromine (VI), heat in water-bath, temperature is controlled at 65-70 ℃, stirs.When solution colour by the faint yellow red-brown that becomes, reaction solution is moved in the matrass, in water-bath, distill, water temperature is controlled to be 86-98 ℃, the bottle in a temperature be 75-85 ℃.When solution becomes sticky shape, change underpressure distillation into, heat up in a steamer dried, loose bright yellow solid.Go in the beaker, with acetone mixed solution (1: 1, V/V) dissolving, heating in water bath to 50 ℃ treats that solid all reduces to room temperature after the fusion, (1 gram crude product adds 2.5 milliliters of acetone mixed solutions to add an amount of ether again, 7.5 the milliliter ether), separate out a large amount of crystal, filter, through 4-5 recrystallization, chiral phase-transfer catalyst quinine benzyl brometo de amonio (IV) that must be purer.Fusing point 144-146 ℃, specific rotatory power-101.8 °.
2-in the synthetic method of this single optical isomer nitrendipine (3-nitro benzylidene) methyl aceto acetate can be synthetic in the presence of the vitriol oil with m-nitrobenzaldehyde and methyl aceto acetate.
The building-up reactions formula of 2-(3-nitro benzylidene) methyl aceto acetate is as follows:
Implementation process is: m-nitrobenzaldehyde (VII) 30.2g (0.2mol) and methyl aceto acetate (VIII) 78g (0.6mol) (excessive methyl aceto acetate is made reaction solvent) are added in the three-necked bottle of 250ml successively, and under the condition of ice bath, temperature is controlled at about 4 ℃.After treating that m-nitrobenzaldehyde dissolves fully, slowly drip vitriol oil 1ml, continue to stir about half an hour, the adularescent crystal is separated out, reacted again 3 hours, and leached crystal, washing, recrystallization gets product 41.5g in ethanol, and the compound that obtains is 2-(3-nitro) ethyl benzalacetoacetate (II).Productive rate 84.2%.Measure 109～110 ℃ of fusing points with the micro-fusing point instrument of binocular.
Beta-amino methyl crotonate in the synthetic method of this single optical isomer nitrendipine can get with methyl acetoacetate and ammonia react.Reaction formula is:
Implementation process is: add methyl acetoacetate (IX) 58g (0.5mol) in three-necked bottle, methyl alcohol 25ml, ice bath are cooled to below 5 ℃, evenly feed ammonia about 2 hours, have a large amount of white crystals to separate out, and continue to feed ammonia half an hour again, and reaction finishes.Suction filtration gets 49 gram crystal (compound) beta-amino methyl crotonates (I), fusing point: 85-87 ℃, yield 85%.
Claims (4)
1, a kind of synthetic method of single optical isomer nitrendipine, make solvent with dehydrated alcohol, with 2-(3-nitro) ethyl benzalacetoacetate and beta-amino methyl crotonate in the presence of phase-transfer catalyst, carry out condensation reaction and get product, it is characterized in that described phase-transfer catalyst is a chiral phase-transfer catalyst quinine benzyl brometo de amonio, described condensation reaction is the stereoselectivity condensation reaction.
2, the synthetic method of single optical isomer nitrendipine as claimed in claim 1 is characterized in that described chirality quinine benzyl brometo de amonio is that quinine is dissolved in the mixed solution of benzene and dehydrated alcohol, adds the benzyl bromine, gained after the reacting by heating in water-bath.
3, the synthetic method of single optical isomer nitrendipine as claimed in claim 1 or 2 is characterized in that described 2-(3-nitro) ethyl benzalacetoacetate is with m-nitrobenzaldehyde and methyl aceto acetate synthetic in the presence of the vitriol oil.
4, the synthetic method of single optical isomer nitrendipine as claimed in claim 3 is characterized in that described beta-amino methyl crotonate is to get with methyl acetoacetate and ammonia react.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101544596B (en) * | 2008-03-25 | 2013-09-04 | 中国医学科学院药物研究所 | Preferred crystal-form substance of nitrendipine and preparation method, pharmaceutical composition and application thereof |
| CN104860873A (en) * | 2015-05-28 | 2015-08-26 | 石家庄学院 | Preparation method for (S)-1,4-dihydropyridine calcium ion antagonist |
| CN109734656A (en) * | 2018-12-29 | 2019-05-10 | 嘉实（湖南）医药科技有限公司 | A kind of preparation method of nitrendipine |
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2004
- 2004-11-25 CN CN 200410089136 patent/CN1281587C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101544596B (en) * | 2008-03-25 | 2013-09-04 | 中国医学科学院药物研究所 | Preferred crystal-form substance of nitrendipine and preparation method, pharmaceutical composition and application thereof |
| CN104860873A (en) * | 2015-05-28 | 2015-08-26 | 石家庄学院 | Preparation method for (S)-1,4-dihydropyridine calcium ion antagonist |
| CN109734656A (en) * | 2018-12-29 | 2019-05-10 | 嘉实（湖南）医药科技有限公司 | A kind of preparation method of nitrendipine |
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