CN105061297A - Preparation method for synthesizing nicardipine hydrochloride - Google Patents
Preparation method for synthesizing nicardipine hydrochloride Download PDFInfo
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- CN105061297A CN105061297A CN201510419406.8A CN201510419406A CN105061297A CN 105061297 A CN105061297 A CN 105061297A CN 201510419406 A CN201510419406 A CN 201510419406A CN 105061297 A CN105061297 A CN 105061297A
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- nicardipine hydrochloride
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- methyl
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- 0 CC(CC(*)=O)=*C1=CC([N+]([O-])=O)=CCC=C1 Chemical compound CC(CC(*)=O)=*C1=CC([N+]([O-])=O)=CCC=C1 0.000 description 2
- DMGHPOMKYNTQPS-KIYNQFGBSA-N CC(CC(OC[C@H](C)NCc1ccccc1)=O)NI Chemical compound CC(CC(OC[C@H](C)NCc1ccccc1)=O)NI DMGHPOMKYNTQPS-KIYNQFGBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a preparation method for synthesizing nicardipine hydrochloride. 3-amino-2-butenoic acid-2'-(N-benzyl-N-methyl)aminoethyl ester and 3-methyl-4-(3'-nitrophenyl)-3-methyl crotonate are used as raw materials and react in an inert solvent, the reaction is tracked through TLC (thin layer chromatography) or HPLC (high performance liquid chromatography) until being finished, decoloration and filtration are performed, a filtrate is concentrated to be viscous, a crystal solvent is added for dissolution, decoloration is performed by the aid of activated carbon, the temperature is decreased to be proper, hydrochloric acid forms salt crystals, and high-purity alpha-crystal-form nicardipine hydrochloride or beta-crystal-form nicardipine hydrochloride is obtained. The synthesis process of the nicardipine hydrochloride is improved and optimized, with the adoption of the preparation method, the production process is simple to operate, the cost is saved, mass production is facilitated, and the high-purity and high-yield alpha-crystal-form nicardipine hydrochloride and beta-crystal-form nicardipine hydrochloride can be conveniently obtained.
Description
Technical field
The invention belongs to medical art, relate to a kind of process for preparing medicine for the treatment of cardio-cerebrovascular disease, be specifically related to synthetic hydrochloric acid nicardipine [2,6-dimethyl-4-m-nitro base-1,4-dihydropyridine-3,5-dicarboxylic acid methylester-2-(N-benzyl-N-methylamine base) carbethoxy hydrochloride] novel method, relate to the preparation method of nicardipine hydrochloride α-crystal formation and beta-crystal simultaneously.
Background technology
Nicardipine hydrochloride, another name hydrochloric acid Vasonase, hydrochloric acid Ni Kaji pyridine, a kind of pale yellow powder or off-white color crystalline powder, chemical name: 2,6-dimethyl-4-m-nitro base-Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic acid methylester-2-(N-benzyl-N-methylamine base) carbethoxy hydrochloride, structural formula is as follows:
Nicardipine hydrochloride is the potent calcium antagonist of dihydropyridines, flow of calcium ions can be suppressed, the phosphodiesterase of brain and coronary artery is optionally suppressed to make CAMP level in cell increase, thus lax vascular smooth muscle, produce obvious vasodilation effect, thus realize rapid depressurization, significantly increase cerebral blood flow (CBF), treatment hypertension, cerebro-vascular diseases, cerebral thrombosis or apoplexy sequela and arteriosclerosis Be very effective, also have certain curative effect to coronary heart diseases and angina pectoris simultaneously.Nicardipine hydrochloride because it is efficient, be suitable for the advantages such as the wide and side effect of disease is little, quite like by market.
At present, existing document nicardipine hydrochloride being carried out to study on the synthesis.In recent years, Japanese Yamanouchi drugmaker and lujuboAntoncic etc. successively disclose the synthetic method (patent No.: DE2407115, US3985758, US4769465) of several nicardipine hydrochloride, as route 1 ~ route 4.Route 1 is as follows:
Route 2 is as follows:
Route 3 is as follows:
Route 4 is as follows:
Synthetic method described in route 1 ~ route 4 not only total yield of products is lower, and is difficult to obtain high-quality nicardipine hydrochloride.Such as, in US3985758 case study on implementation 29, (as route 3) adopts 3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl and 3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters to be raw material, back flow reaction in isopropanol solvent, nicardipine hydrochloride crude product is obtained again through hcl acidifying, concentrated, ethyl acetate crystallization, crude product is through dissolve with methanol, concentrated, add acetone crystallization again and obtain α-crystal formation nicardipine hydrochloride, product yield 42%.Meanwhile, adopt Virahol as solvent, react under long-time high temperature and also there is solvent Virahol and exist with two kinds of raw materials the possible of transesterify occurs, virtually add quality risk and the post-processing difficulty of product.
Summary of the invention
The object of the invention is to the shortcoming overcoming above-mentioned prior art, 3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl and 3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters is adopted to be raw material, the synthesis technique of nicardipine hydrochloride is improved and optimizated, provide a kind of simple in production process operation, cost-saving, be convenient to large production, and easyly can obtain high purity, the α-crystal formation nicardipine hydrochloride of high yield and the preparation method of beta-crystal nicardipine hydrochloride.
The invention discloses nicardipine hydrochloride synthetic route chart, as accompanying drawing 2.
As shown in Scheme 5, the method of synthetic hydrochloric acid nicardipine disclosed by the invention is for raw material with 3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl and 3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters, react in inert solvent, TLC or HPLC follows the tracks of reaction to complete, decolorization filtering, filtrate is concentrated into thickness, add recrystallisation solvent to dissolve, activated carbon decolorizing, be cooled to proper temperature, hydrochloric acid becomes salt-pepper noise, and can obtain highly purified α-crystal formation nicardipine hydrochloride or beta-crystal nicardipine hydrochloride, route 5 is as follows:
Beneficial effect of the present invention there are provided and can obtain high purity, the α-crystal formation nicardipine hydrochloride of high yield or the synthetic method of beta-crystal nicardipine hydrochloride.
The inert solvent of synthetic hydrochloric acid nicardipine disclosed by the invention is that occur with two kinds of raw materials can not transesterify or other solvent reacted, comprise methyl alcohol, chloroform, toluene, normal hexane, tetracol phenixin, methylene dichloride, acetone etc., particular methanol, methylene dichloride and acetone.
The recrystallisation solvent of nicardipine hydrochloride disclosed by the invention comprises methyl alcohol, chloroform, tetracol phenixin, methylene dichloride, acetone and mixed solvent thereof etc.Particular methanol, chloroform, acetone and mixed solvent thereof during preparation α-crystal formation nicardipine hydrochloride, particular methanol, acetone and mixed solvent thereof when preparing beta-crystal nicardipine hydrochloride.
The hydrochloric acid salify temperature of preparation α-crystal formation nicardipine hydrochloride disclosed by the invention is 10 ~ 50 DEG C, preferably 20 ~ 40 DEG C.
The hydrochloric acid salify temperature preparing beta-crystal nicardipine hydrochloride disclosed by the invention is-30 ~ 10 DEG C, preferably-20 ~ 0 DEG C.
Nicardipine hydrochloride α of the present invention-crystal formation, fusing point 179 ~ 185 DEG C, uses Cu-Ka radiation, has extremely strong absorption peak with the X-ray powder diffraction that 2 θ angles represent 22 ± 0.2,8 ± 0.2,14 ± 0.2,16 ± 0.2,18 ± 0.2,26 ± 0.2, there is stronger characteristic peak, 12 ± 0.2,15 ± 0.2,20.5 ± 0.2,21 ± 0.2,23 ± 0.2,27 ± 0.2,29 ± 0.2,30 ± 0.2,32 ± 0.2 also have more weak characteristic peak.
Nicardipine hydrochloride beta-crystal of the present invention, fusing point 167 ~ 171 DEG C, is water-solublely better than α-crystal formation, uses Cu-Ka radiation, extremely strong characteristic peak is had at 22 ± 0.2 places with the X-ray powder diffraction that 2 θ angles represent, stronger characteristic peak is had at 20.5 ± 0.2 places, 8 ± 0.2,14 ± 0.2,16 ± 0.2,16 ± 0.2,19 ± 0.2, there is more weak characteristic peak at 32 ± 0.2 places.
Accompanying drawing explanation
Fig. 1 is α of the present invention-crystal formation nicardipine hydrochloride powder x-ray diffraction figure;
Fig. 2 is beta-crystal nicardipine hydrochloride powder x-ray diffraction figure of the present invention;
Fig. 3 is α of the present invention-crystal formation nicardipine hydrochloride 1H-NMR spectrogram;
Fig. 4 is beta-crystal nicardipine hydrochloride 1H-NMR spectrogram of the present invention.
Embodiment
Below in conjunction with accompanying drawing, the present invention is described in further detail:
Case study on implementation 1: acetone synthesizes α-crystal formation nicardipine hydrochloride as solvent
By 250kg acetone suction PM-R-C-01 retort, open stirring, open dog-house, add 100kg3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl successively, 100kg3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters builds dog-house.Be heated to 50 DEG C, insulation reaction 8h, add 1kg activated carbon decolorizing, filter, filtrate, is cooled to 35 DEG C, adds 44kg hydrochloric acid, stirred crystallization 12h at 30 ~ 35 DEG C, centrifugal, dry to obtain 148kg α-crystal formation nicardipine hydrochloride, yellow-green colour crystalline powder, fusing point: 182 ~ 184 DEG C, HPLC content: 99.2%, yield 76.68%.
Case study on implementation 2: chloroform synthesizes α-crystal formation nicardipine hydrochloride as solvent
By 250kg chloroform suction PM-R-C-01 retort, open stirring, open dog-house, add 100kg3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl successively, 100kg3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters builds dog-house.Be heated to 60 DEG C, insulation reaction 6h, add 1kg activated carbon decolorizing, filter, filtrate, is cooled to 35 DEG C, adds 44kg hydrochloric acid, stirred crystallization 12h at 30 ~ 35 DEG C, centrifugal, dry to obtain 158.5kg α-crystal formation nicardipine hydrochloride, yellow-green colour crystalline powder, fusing point: 181 ~ 183 DEG C, HPLC content: 99.5%, yield 82.02%.
Case study on implementation 3: methyl alcohol synthesizes α-crystal formation nicardipine hydrochloride as solvent
By 250kg methyl alcohol suction PM-R-C-01 retort, open stirring, open dog-house, add 100kg3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl successively, 100kg3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters builds dog-house.Be heated to 70 DEG C, insulation reaction 2h, add 1kg activated carbon decolorizing, filter, filtrate is concentrated into thick, adds 250kg chloroform and dissolves, be cooled to 35 DEG C, add 44kg hydrochloric acid, stirred crystallization 12h at 30 ~ 35 DEG C, centrifugal, dry to obtain 135.6kg α-crystal formation nicardipine hydrochloride, yellow-green colour crystalline powder, fusing point: 182 ~ 183 DEG C, HPLC content: 99.8%, yield 70.02%.
Case study on implementation 4: acetone is as solvent synthesis beta-crystal nicardipine hydrochloride
By 250kg acetone suction PM-R-C-01 retort, open stirring, open dog-house, add 100kg3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl successively, 100kg3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters builds dog-house.Be heated to 50 DEG C, insulation reaction 5h, add 1kg activated carbon decolorizing, filter, filtrate, is cooled to-10 DEG C, adds 44kg hydrochloric acid, stirred crystallization 12h at 0 ~-10 DEG C, centrifugal, dry to obtain 165kg beta-crystal nicardipine hydrochloride, yellow-green colour crystalline powder, fusing point: 168 ~ 170 DEG C, HPLC content: 99.6%, yield 85.23%.
Case study on implementation 5: methyl alcohol is as solvent synthesis beta-crystal nicardipine hydrochloride
By 250kg methyl alcohol suction PM-R-C-01 retort, open stirring, open dog-house, add 100kg3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl successively, 100kg3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters builds dog-house.Be heated to 70 DEG C, insulation reaction 2h, add 1kg activated carbon decolorizing, filter, filtrate, is cooled to-10 DEG C, adds 44kg hydrochloric acid, stirred crystallization 12h at 0 ~-10 DEG C, centrifugal, dry to obtain 155kg beta-crystal nicardipine hydrochloride, yellow-green colour crystalline powder, fusing point: 168 ~ 170 DEG C, HPLC content: 99.8%, yield 80.21%.
Above content is in conjunction with concrete preferred implementation further description made for the present invention; can not assert that the specific embodiment of the present invention is only limitted to this; for general technical staff of the technical field of the invention; without departing from the inventive concept of the premise; some simple deduction or replace can also be made, all should be considered as belonging to the present invention by submitted to claims determination scope of patent protection.
Claims (9)
1. a preparation method for synthetic hydrochloric acid nicardipine, is characterized in that:
With 3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl and 3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters for raw material, react in inert solvent, TLC or HPLC follows the tracks of reaction to complete, decolorization filtering, and filtrate is concentrated into thickness, add recrystallisation solvent to dissolve, activated carbon decolorizing, is cooled to proper temperature, and hydrochloric acid becomes salt-pepper noise, namely highly purified α-crystal formation nicardipine hydrochloride or beta-crystal nicardipine hydrochloride is obtained, as follows:
2. preparation method as claimed in claim 1, is characterized in that: described inert solvent is that all occur with 3-amino-2-butylene acid-2'-(N-Benzyl-N-methyl) aminoethyl and 3-methyl-4-(3'-nitrophenyl)-3-butenoic acid methyl esters can not transesterify or other solvent reacted.
3. preparation method as claimed in claim 2, is characterized in that: described inert solvent comprises methyl alcohol, chloroform, toluene, normal hexane, tetracol phenixin, methylene dichloride, acetone.
4. preparation method as claimed in claim 2, is characterized in that: the recrystallisation solvent of described nicardipine hydrochloride comprises methyl alcohol, chloroform, tetracol phenixin, methylene dichloride, acetone and mixed solvent thereof.
5. preparation method as claimed in claim 4, is characterized in that: during preparation α-crystal formation nicardipine hydrochloride, recrystallisation solvent is methyl alcohol, chloroform, acetone and mixed solvent thereof; When preparing beta-crystal nicardipine hydrochloride, recrystallisation solvent is methyl alcohol, acetone and mixed solvent thereof.
6. preparation method as claimed in claim 4, is characterized in that: the hydrochloric acid salify temperature of preparation α-crystal formation nicardipine hydrochloride is 10 ~ 50 DEG C, and the hydrochloric acid salify temperature preparing beta-crystal nicardipine hydrochloride is-30 ~ 10 DEG C.
7. preparation method as claimed in claim 6, is characterized in that: the hydrochloric acid salify temperature of preparation α-crystal formation nicardipine hydrochloride is 20 ~ 40 DEG C, and the hydrochloric acid salify temperature preparing beta-crystal nicardipine hydrochloride is-20 ~ 0 DEG C.
8. preparation method as claimed in claim 1, is characterized in that: described nicardipine hydrochloride α-crystal formation, fusing point 179 ~ 185 DEG C, uses Cu-Ka radiation, extremely strong absorption peak is had 22 ± 0.2 with the X-ray powder diffraction that 2 θ angles represent, 8 ± 0.2,14 ± 0.2,16 ± 0.2,18 ± 0.2,26 ± 0.2, there is stronger characteristic peak, 12 ± 0.2,15 ± 0.2,20.5 ± 0.2,21 ± 0.2,23 ± 0.2,27 ± 0.2,29 ± 0.2,30 ± 0.2,32 ± 0.2 also have more weak characteristic peak.
9. preparation method as claimed in claim 1, is characterized in that: described nicardipine hydrochloride beta-crystal, fusing point 167 ~ 171 DEG C, water-solublely be better than α-crystal formation, use Cu-Ka radiation, have extremely strong characteristic peak with the X-ray powder diffraction that 2 θ angles represent at 22 ± 0.2 places, have stronger characteristic peak at 20.5 ± 0.2 places, 8 ± 0.2,14 ± 0.2,16 ± 0.2,16 ± 0.2, there is more weak characteristic peak at 19 ± 0.2,32 ± 0.2 places.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3985758A (en) * | 1973-02-20 | 1976-10-12 | Yamanouchi Pharmaceutical Co., Ltd. | 1,4-Dihydropyridine derivatives |
| EP0445987A2 (en) * | 1990-03-07 | 1991-09-11 | HIGASHIKAWA, Tetsuro | Novel process for producing 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate-3-methyl ester-5-beta-(N-benzyl-N-methylamino)ethyl ester |
| CN1927837A (en) * | 2006-09-27 | 2007-03-14 | 上海应用技术学院 | Process for preparing amlodipine benzenesulphonate |
| CN103739542A (en) * | 2013-12-06 | 2014-04-23 | 迪沙药业集团山东迪沙药业有限公司 | Preparation method of 3-(2-nitrile-ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate |
-
2015
- 2015-07-16 CN CN201510419406.8A patent/CN105061297A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3985758A (en) * | 1973-02-20 | 1976-10-12 | Yamanouchi Pharmaceutical Co., Ltd. | 1,4-Dihydropyridine derivatives |
| EP0445987A2 (en) * | 1990-03-07 | 1991-09-11 | HIGASHIKAWA, Tetsuro | Novel process for producing 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate-3-methyl ester-5-beta-(N-benzyl-N-methylamino)ethyl ester |
| CN1927837A (en) * | 2006-09-27 | 2007-03-14 | 上海应用技术学院 | Process for preparing amlodipine benzenesulphonate |
| CN103739542A (en) * | 2013-12-06 | 2014-04-23 | 迪沙药业集团山东迪沙药业有限公司 | Preparation method of 3-(2-nitrile-ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate |
Non-Patent Citations (1)
| Title |
|---|
| MASARU IWANAMI，等: "Synthesis of new water-soluble dihydropyridine vasodilators", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
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Application publication date: 20151118 |