CN1651413A - Synthetic method of single optical isomer nitrendipine - Google Patents
Synthetic 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
- single optical
- quinine
- synthetic method
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- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 title claims abstract description 35
- 229960005425 nitrendipine Drugs 0.000 title claims abstract description 35
- 230000003287 optical effect Effects 0.000 title claims abstract description 14
- 238000010189 synthetic method Methods 0.000 title claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 8
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000002194 synthesizing effect Effects 0.000 claims abstract 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract 2
- 230000000707 stereoselective effect Effects 0.000 claims abstract 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 20
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 14
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 13
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 13
- 229960000948 quinine Drugs 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 7
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- -1 ethyl benzylidene acetoacetate Chemical compound 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- XKORCTIIRYKLLG-ARJAWSKDSA-N methyl (z)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(\C)N XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 claims 2
- QJFMCHRSDOLMHA-UHFFFAOYSA-N phenylmethanamine;hydrobromide Chemical compound Br.NCC1=CC=CC=C1 QJFMCHRSDOLMHA-UHFFFAOYSA-N 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- ZJMLFAMHTKBCGN-UHFFFAOYSA-N formaldehyde nitrobenzene Chemical compound C=O.[O-][N+](=O)c1ccccc1 ZJMLFAMHTKBCGN-UHFFFAOYSA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- KNUYHVRRBLEIHT-UHFFFAOYSA-N ethyl 3-oxo-5-phenylpent-4-enoate Chemical compound CCOC(=O)CC(=O)C=CC1=CC=CC=C1 KNUYHVRRBLEIHT-UHFFFAOYSA-N 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 201000004239 Secondary hypertension Diseases 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 150000003939 benzylamines Chemical class 0.000 description 1
- 230000002902 bimodal effect Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000000547 structure data Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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)
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|---|---|---|---|
| CN 200410089136 CN1281587C (en) | 2004-11-25 | 2004-11-25 | Synthesis method of single optical isomer nitrendipine |
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|---|---|---|---|
| CN 200410089136 CN1281587C (en) | 2004-11-25 | 2004-11-25 | Synthesis method of single optical isomer nitrendipine |
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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 |
-
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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