CN105384682A - Cilnidipine preparation method - Google Patents
Cilnidipine preparation method Download PDFInfo
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- CN105384682A CN105384682A CN201510971204.4A CN201510971204A CN105384682A CN 105384682 A CN105384682 A CN 105384682A CN 201510971204 A CN201510971204 A CN 201510971204A CN 105384682 A CN105384682 A CN 105384682A
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- cilnidipineb
- concentrated hydrochloric
- hydrochloric acid
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- 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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/84—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 two 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- 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 provides a cilnidipine preparation method. The method includes the steps that 2-(3-nitrophenyl methylidene) methoxyethyl acetoacetate and 3-amino-2-butenoic acid cinnamyl ester serve as reaction raw materials and react under catalysis of concentrated hydrochloric acid to obtain cilnidipine. A common inorganic catalyst is adopted in the method for catalysis reaction so that reaction time can be effectively shortened; besides, quality of a crude product is high, the yield is high, and cilnidipine has metallic luster. The requirement for refining of reaction is low. Purity of the crude product is good, and the quality requirement can be basically met through one time of refining. The technology is reasonable in design, purity of the refined cilnidipine product is high, and the quantity of any impurity and total impurities is small.
Description
Technical field
The present invention relates to medicinal chemistry art, in particular to a kind of preparation method of cilnidipineb.
Background technology
Cilnidipineb (cilnidipine), chemistry by name 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid-2-methoxy acrylate (E)-cinnamic ester, belongs to Isosorbide-5-Nitrae-dihydropyridine type calcium antagonists, by Japanese fuji, Co., Ltd. develops, and December nineteen ninety-five in Japanese Initial Public Offering.Cilnidipineb be the 3rd generation two channels dihydropyridine calcium channel blocker, except possessing the effect of most of calcium channel blocker L channel blocking, also act on perineural N channel.The booster reaction that after can not causing step-down, increased heart rate and pressure receptor stimulate Acute Cold, thus become the new calcium channel blocker with unique pharmacological action.Cilnidipineb is because being the new calcium antagonist with L-type and N-type calcium channel blocking action.It not only can reduce blood pressure effectively, sympathetic reflex effectively can also be prevented excited, together with other beneficial effects of this medicine, have certain effect to the target organ damage of alleviating hypertension.Clinically be mainly used in treatment that is light, moderate hypertension, curative effect is better than the medicine such as nifedipine, nimodipine.
Domestic people in the industry has carried out large quantifier elimination to the synthesis of cilnidipineb.At present the more outstanding method for the synthesis of cilnidipineb is for synthetic intermediate with 2-(3-oil of mirbane fork base) etheric acid methoxy acrylate and 3-amino-2-butylene acid cinnamic ester.Wherein, mainly contain dry method and wet method two kinds of techniques, namely dry method carries out heated and stirred when not adding solvent to above-mentioned two kinds of materials, and the yield obtaining finished product cilnidipineb is 80.1%; Wet method uses dehydrated alcohol to stir above-mentioned two kinds of materials as solvent refluxing, and the yield obtaining finished product cilnidipineb is 78.8%.
Above two kinds of methods, only describe basic craft course and only a few product performance data in bibliographical information, and the finished product cilnidipineb purity obtained is very not outstanding, single assorted and total assorted all higher, therefore need to improve technique.
In view of this, the present invention is proposed.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of cilnidipineb, described method uses organic catalyst catalyzed reaction, and it is thorough fast that reaction is carried out, and by rational process parameters design, the cilnidipineb productive rate that the present invention obtains is high, and purity is good.
In order to realize above-mentioned purpose of the present invention, spy by the following technical solutions:
The present invention relates to a kind of preparation method of cilnidipineb, described method, using 2-(3-oil of mirbane fork base) etheric acid methoxy acrylate and 3-amino-2-butylene acid cinnamic ester as reaction raw materials, carries out being obtained by reacting cilnidipineb under the catalysis of concentrated hydrochloric acid.
Preferably, described method concrete steps are as follows:
1) in reactor, solvent, 2-(3-oil of mirbane fork base) etheric acid methoxy acrylate and 3-amino-2-butylene acid cinnamic ester is added, temperature rising reflux;
2) to described step 1) in add concentrated hydrochloric acid in the reaction system that obtains, continue backflow;
3) lucifuge cooling, crystallization, filtration, obtain cilnidipineb crude product, and recrystallization obtains cilnidipineb finished product.
The present invention is in the reaction process of 2-(3-oil of mirbane fork base) etheric acid methoxy acrylate and 3-amino-2-butylene acid cinnamic ester, and the concentrated hydrochloric acid adding chemical field very common and with low cost reacts as catalyst.
Above-mentioned two kinds of materials are in reaction process, reaction system becomes dark-brown by colourless, and now system temperature is high, and the species distribution generating the intermediate state molecular structure of product and final molecular structure in system is homogeneous, reaction system is colloidal, is unfavorable for that reaction is carried out toward positive the Direction of Reaction.Therefore, in order to make intermediate state molecular structure transform toward final molecular structure, can only time expand, but effect is poor, and yield is not high.
Present method adds hydrochloric acid in reaction process, makes colloidal dispersion overbalance, therefore, after colloidal dispersion is destroyed, the finished product can from reaction liquid crystallization, but not change into intermediate state material.
In addition, hydrochloric acid can also provide acidic conditions for reaction of the present invention, and itself is also conducive to the generation of this reaction.The present invention take hydrochloric acid as the synthetic method of catalyzer, and generated time is short, and productive rate is high, and crude product quality better, has metalluster.The method requires low to refining, and product is easy to refining.The doping property of primary purification product shows as: kind is little, content is extremely low.The quality of primary purification product is fine, meets medicinal standard.
Preferably, described step 1) in, 2-(3-oil of mirbane fork base) the etheric acid methoxy acrylate added and the mol ratio of 3-amino-2-butylene acid cinnamic ester are 0.8-1.2:1, preferred 1:1.
Adopt aforementioned proportion to carry out feeding intake and can guarantee that reaction is successfully reacted fast, especially preferably use the material ratio of 1:1 to feed intake, both served the effect of saving reaction cost, can avoid again due to single material in feeding intake excessive and cause purifying time inconvenience.
Preferably, described step 1) in solvent be polar solvent, preferred alcohols kind solvent.
Preferably, described alcoholic solvent is the alcoholic solvent containing 1-4 carbon, preferred alcohol.
Select polar solvent, as ethers and alcoholic solvent, two materials of the present invention's reaction can be dissolved well, and when adding concentrated hydrochloric acid, can dissolve each other preferably with the water wherein contained.
Preferably, described step 1) in stirring under reflux conditions carry out, churning time is 0.5-2 hour, preferably 1 hour.
Preferably, described step 2) in the add-on of concentrated hydrochloric acid be that every mole of 3-amino-2-butylene acid cinnamic ester adds 15-25ml concentrated hydrochloric acid, the mass concentration of described concentrated hydrochloric acid is not less than 35%.
Preferably, the add-on of described concentrated hydrochloric acid is that every mole of 3-amino-2-butylene acid cinnamic ester adds 18-20ml concentrated hydrochloric acid.
The add-on of concentrated hydrochloric acid can not be very few, otherwise catalytic effect is not obvious, but excessively add hydrochloric acid, can give in reaction system and bring too much water, due to reaction intermediate Schiff's base hydrolabil, excessive water can cause reaction carry out to opposite direction thus affect efficiency and the ultimate yield of reaction.
Preferably, described step 2) in, under reflux conditions stir 0.5-3 hour after adding the vitriol oil, preferably 1 hour.
Preferably, described step 3) in, use dehydrated alcohol to carry out recrystallization to described crude product.
Compared with prior art, beneficial effect of the present invention is:
(1) the present invention adopts common organic catalyst catalyzed reaction, can effective Reaction time shorten, and crude product quality height yield is good, has metalluster.
(2) reaction of the present invention is lower to refining requirement, because the purity of crude product own is better, refines and once substantially can meet specification of quality.
(3) technological design of the present invention is reasonable, and the cilnidipineb finished product purity after refining is high, single assorted and total assorted all less.
Embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting the scope of the invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturers suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, be and can buy by commercially available the conventional products obtained.
Embodiment 1
Cilnidipineb is prepared according to following steps:
1. in 250ml bottle, drop into material a:2-(3-oil of mirbane fork base) etheric acid methoxy acrylate (54g, 0.184mol) with material b:3-amino-2-butylene acid cinnamic ester (40g, 0.184mol) and dehydrated alcohol (80g), temperature rising reflux 1 hour;
2. the reaction system in step 1 adds concentrated hydrochloric acid (> 35%) 3.68ml, and continue backflow 1 hour, rear cooling crystallization, filters to obtain cilnidipineb crude product;
Crude yield: 80.7g
Yield 88.98%,
M.P.:106.1～106.7℃
Maximum list is mixed: 0.2%
Totally 10 small impurities peaks
Content: 99.25%
3. according to weight ratio ethanol: the add-on of crude product=3:1 uses dehydrated alcohol to carry out recrystallization to the crude product cilnidipineb obtained in step 2, obtains finished product cilnidipineb.
Yield 91.3%,
M.P.:107.2～108.1℃
Maximum list is mixed: 0.1380%
Minimum list is mixed: 0.0370%
Totally 2 small impurities peaks
Content: 99.8%
Embodiment 2
Cilnidipineb is prepared according to following steps:
1. in 2500ml bottle, drop into material a:2-(3-oil of mirbane fork base) etheric acid methoxy acrylate (432g, 1.47mol) with material b:3-amino-2-butylene acid cinnamic ester (400g, 1.84mol) and propyl carbinol (800g), temperature rising reflux 0.5 hour;
2. the reaction system in step 1 adds concentrated hydrochloric acid (> 35%) 46ml, and continue backflow 0.5 hour, rear cooling crystallization, filters to obtain cilnidipineb crude product;
Crude yield: 618g
Yield 85.19%,
M.P.:107.2～107.9℃
Maximum list is mixed: 0.28%
Totally 12 small impurities peaks
Content: 98.56%
3. according to weight ratio ethanol: the add-on of crude product=3:1 uses dehydrated alcohol to carry out recrystallization to the crude product cilnidipineb obtained in step 2, obtains finished product cilnidipineb.
Yield 89.8%,
M.P.:107.1～108.0℃
Maximum list is mixed: 0.1380%
Minimum list is mixed: 0.0370%
Totally 4 small impurities peaks
Content: 99.23%
Embodiment 3
Cilnidipineb is prepared according to following steps:
1. in 500ml bottle, drop into material a:2-(3-oil of mirbane fork base) etheric acid methoxy acrylate (65g, 0.221mol) with material b:3-amino-2-butylene acid cinnamic ester (40g, 0.184mol) and tetrahydrofuran (THF) (90g), temperature rising reflux 2 hours;
2. the reaction system in step 1 adds concentrated hydrochloric acid (> 35%) 2.76ml, and continue backflow 3 hours, rear cooling crystallization, filters to obtain cilnidipineb crude product;
Receive product: 77.8g
Yield 85.78%,
M.P.:106.0～106.8℃
Maximum list is mixed: 0.27%
Totally 11 small impurities peaks
Content: 99.21%
3. according to weight ratio ethanol: the add-on of crude product=3:1 uses dehydrated alcohol to carry out recrystallization to the crude product cilnidipineb obtained in step 2, obtains finished product cilnidipineb.
Yield 87.5%,
M.P.:107.4～108.2℃
Maximum list is mixed: 0.1460%
Minimum list is mixed: 0.0502%
Totally 4 small impurities peaks
Content: 99.35%
Embodiment 4
Cilnidipineb is prepared according to following steps:
1. in 250ml bottle, drop into material a:2-(3-oil of mirbane fork base) etheric acid methoxy acrylate (54g, 0.184mol) with material b:3-amino-2-butylene acid cinnamic ester (40g, 0.184mol) and dehydrated alcohol (80g), temperature rising reflux 1 hour;
2. the reaction system in step 1 adds concentrated hydrochloric acid (> 35%) 3.31ml, and continue backflow 1 hour, rear cooling crystallization, filters to obtain cilnidipineb crude product; Crude product amount: 80.7g; Yield 88.98%; M.P.:106.1 ~ 106.7 DEG C; Maximum list is mixed: 0.2%, totally 10 small impurities peaks, content: 99.25%.
Receive product: 80.77g
Yield 89.07%,
M.P.:106.0～106.8℃
Maximum list is mixed: 0.29%
Totally 9 small impurities peaks
Content: 99.18%
3. according to weight ratio ethanol: the add-on of crude product=3:1 uses dehydrated alcohol to carry out recrystallization to the crude product cilnidipineb obtained in step 2, obtains finished product cilnidipineb.
Yield 91.5%,
M.P.:107.4～108.2℃
Maximum list is mixed: 0.1460%
Minimum list is mixed: 0.0502%
Totally 2 small impurities peaks
Content: 99.8%
Comparative example 1
Adopt the dry process cilnidipineb of prior art
Amino for 3-β-crotonic acid Cinoxolone 70g (0.343mol) and 2-(3-nitrobenzal) etheric acid methoxy ethyl ester 100g (0.342mol) are added in 500ml three-necked bottle, 120 DEG C of reaction 3h are slowly warming up under stirring, reaction adds dehydrated alcohol 200ml, gac 2g after stopping in reaction flask, reflux 15min, filtered while hot, filtrate cooling crystallization, filters, dry crude product cilnidipineb 102g, yield is 75.6%.mp105～108℃。Dehydrated alcohol recrystallization, obtains light yellow crystal cilnidipineb 81.7g, yield 80.1%.Product mp is 106 ~ 107 DEG C.
Comparative example 2
Adopt the wet-layer preparation cilnidipineb of prior art
Amino for 3-β-crotonic acid Cinoxolone 21.7g (0.10mol), 2-(3-nitrobenzal) etheric acid methoxy ethyl ester 29.3g (0.10mol) and dehydrated alcohol 140mL are added in 250mL reaction flask, stirring and refluxing 24h, cooling crystallization, suction filtration obtains crude product, use dehydrated alcohol recrystallization, obtain light yellow crystal cilnidipineb 38.8g, yield 78.8%, product mp is 108 ~ 110 DEG C.
Can be found out by above embodiment and comparative example, use method of the present invention to prepare cilnidipineb, the yield of crude product and highly finished product is all very high, and the purity of highly finished product is good, and impurity is few.By contrast, conventional dry and wet-layer preparation cilnidipineb is used then in reaction times, yield and purity, to be all inferior to the present invention.
Although illustrate and describe the present invention with specific embodiment, however it will be appreciated that can to make when not deviating from the spirit and scope of the present invention many other change and amendment.Therefore, this means to comprise all such changes and modifications belonged in the scope of the invention in the following claims.
Claims (10)
1. the preparation method of a cilnidipineb, it is characterized in that, described method, using 2-(3-oil of mirbane fork base) etheric acid methoxy acrylate and 3-amino-2-butylene acid cinnamic ester as reaction raw materials, carries out being obtained by reacting cilnidipineb under the catalysis of concentrated hydrochloric acid.
2. method according to claim 1, is characterized in that, described method concrete steps are as follows:
1) in reactor, solvent, 2-(3-oil of mirbane fork base) etheric acid methoxy acrylate and 3-amino-2-butylene acid cinnamic ester is added, temperature rising reflux;
2) to described step 1) in add concentrated hydrochloric acid in the reaction system that obtains, continue backflow;
3) lucifuge cooling, crystallization, filtration, obtain cilnidipineb crude product, and recrystallization obtains cilnidipineb finished product.
3. method according to claim 2, is characterized in that, described step 1) in, 2-(3-oil of mirbane fork base) the etheric acid methoxy acrylate added and the mol ratio of 3-amino-2-butylene acid cinnamic ester are 0.8-1.2:1, preferred 1:1.
4. method according to claim 2, is characterized in that, described step 1) in solvent be polar solvent, preferred alcohols kind solvent.
5. method according to claim 4, is characterized in that, described alcoholic solvent is the alcoholic solvent containing 1-4 carbon, preferred alcohol.
6. method according to claim 2, is characterized in that, described step 1) in return time be 0.5-2 hour, preferably 1 hour.
7. method according to claim 2, is characterized in that, described step 2) in the add-on of concentrated hydrochloric acid be that every mole of 3-amino-2-butylene acid cinnamic ester adds 15-25ml concentrated hydrochloric acid, the mass concentration of described concentrated hydrochloric acid is not less than 35%.
8. method according to claim 7, is characterized in that, the add-on of described concentrated hydrochloric acid is that every mole of 3-amino-2-butylene acid cinnamic ester adds 18-20ml concentrated hydrochloric acid.
9. method according to claim 2, is characterized in that, described step 2) in, return time is 0.5-3 hour, preferably 1 hour.
10. method according to claim 2, is characterized in that, described step 3) in, use dehydrated alcohol to carry out recrystallization to described crude product.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072552A (en) * | 2019-12-11 | 2020-04-28 | 湖南九典制药股份有限公司 | Preparation method of cilnidipine |
| CN112375031A (en) * | 2020-11-18 | 2021-02-19 | 蚌埠丰原医药科技发展有限公司 | Preparation method of cilnidipine |
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| CN111072552B (en) * | 2019-12-11 | 2021-06-04 | 湖南九典制药股份有限公司 | Preparation method of cilnidipine |
| CN112375031A (en) * | 2020-11-18 | 2021-02-19 | 蚌埠丰原医药科技发展有限公司 | Preparation method of cilnidipine |
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