CN108218765A - A kind of production method for improving manidipine hydrochloride II crystal forms - Google Patents
A kind of production method for improving manidipine hydrochloride II crystal forms Download PDFInfo
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- CN108218765A CN108218765A CN201711188311.5A CN201711188311A CN108218765A CN 108218765 A CN108218765 A CN 108218765A CN 201711188311 A CN201711188311 A CN 201711188311A CN 108218765 A CN108218765 A CN 108218765A
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- manidipine
- production method
- filter cake
- manidipine hydrochloride
- alkali
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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 discloses a kind of production methods for improving manidipine hydrochloride II crystal forms, and the method includes the concentration grease containing Manidipine alkali is added in ethyl alcohol, stirring and crystallizing, the filter cake being obtained by filtration is beaten washing, obtains Manidipine alkali;Again high-purity hydrochloric acid Manidipine crude product is obtained into salt through hydrochloric acid;Manidipine hydrochloride crude product is dissolved by heating by aqueous methanol, by keeping the temperature filtering, crystallization, filtering, the crystal of precipitation is collected, by dry obtained manidipine hydrochloride II crystal forms.The purity of II crystal forms that the production method of the present invention obtains is more than 99.8%, and this method has very big directive significance for the research of manidipine hydrochloride crystal form and the clinical practice of manidipine hydrochloride.
Description
Technical field
The invention belongs to medicinal chemistry art, specifically, the present invention relates to a kind of improvement manidipine hydrochloride II crystal forms
Production method.
Background technology
Shown in the structure of the crystal of manidipine hydrochloride such as formula (I):
Manidipine hydrochloride (Manidipine Hydrochloride), entitled Isosorbide-5-Nitrae-dihydro -1, the 6- dimethyl -4- of chemistry
(3- nitrotoleunes) -3,5- pyridines dicarboxyl -2 [4- (benzhydryl) -1- piperazinyls] ethyl methyl esters dihydrochloride, is a kind of parent
The third generation dihydropyridines of lipid and have L-type, T-shaped calcium ion binary channels retarding agent concurrently.
Manidipine hydrochloride is developed by Japanese Takede Chemical Industries Ltd, and tablet is in nineteen ninety with trade name
Calslot is listed in Japan.The medical instrument has stronger loose arterial smooth muscle, expansion blood vessel, reduces peripheral vascular resistance and move
The effect of pulse pressure is mainly used for treating light, Moderate Essential Hypertension, the antihypertensive effect of low renin hypertension is become apparent from,
And uric acid metabolism can be improved, good effect can also be obtained to the hypertensive patient with renal failure, for hypertensive patients II types
The patient and gerontal patient that diabetic, sugar tolerance reduce are respectively provided with good antihypertensive effect, are the ideal anti-height of a line
Blood pressure medication.
Patent EP94159, WO8304023, EP138505, JP06199789 all describe the synthesis work of manidipine hydrochloride
Skill route, but its technique is unsuitable for work in reaction process there are various drawbacks using high vacuum rectification, silica gel column chromatography etc.
The operation of industry metaplasia production, and its purity to intermediate and finished product is without very effective control measure;Xiao Fangqing etc. exists《Salt
The synthesis of sour Manidipine》Chinese Medicine industry impurity 2004,35 (2), 65~66 report its synthetic method, but this method exists
Impurity is not controlled in technique, purity cannot ensure, be unable to reach medicinal rank;Chinese patent CN200910064113.7 is retouched
The method avoided using column chromatography has been stated, has been to use hot water wash after Manidipine alkali crude product is dissolved in ethyl acetate
It washs, organic phase is passed directly into hydrogen chloride gas into salt, and obtained hydrochloric acid purity salt is only 92.2%, because of manidipine hydrochloride
Process contaminants in the more difficult removal of hydrochloride state, and obtain the other manidipine hydrochloride of pharmaceutical grade with the method, then need more
Secondary purifying, so as to reduce yield.Chinese patent CN201210097005.1 describes the preparation method of Manidipine alkali, makes
Existed with Xiao Fangqing etc.《The synthesis of manidipine hydrochloride》Chinese Medicine industry impurity 2004,35 (2), the synthesis side of 65~66 reports
Method obtains Manidipine alkali reaction solution, and concentration later adds in washing after ethyl acetate dissolving, into salt, again dissociate, wash again, is dense
It contracts, later mixed solvent stirring and crystallizing.This method is cumbersome, and the generation three wastes are more, are unfavorable for industrialized production.Hydrochloric acid horse Buddhist nun
The technological difficulties of Horizon kind are the generations of control impurity or effectively reduce, removal impurity.
Patent WO2011023954A2 provides the preparation method of several different crystal forms of manidipine hydrochloride, use into salt
Mode is using isopropanol hydrogen chloride solution, and the preparation method of crystal form II is that the manidipine hydrochloride crude product of 0.5g is added in methanol
With alcohol by volume than 1:1 mixed solvent 8ml heats 65 DEG C of dissolvings, is cooled to and 12h-14h is stirred at room temperature, and filters, methanol washing,
40-45 DEG C of baking material 10-12h obtains crystal form II 0.4g, yield 80%, purity 99.89%.The patent tested number is small, by reality
Repetition discovery is tested, the manidipine hydrochloride crude product application above method of high-purity can not dissolve, also can not just carry out crystallization and obtain
Required crystal form.
Since the bioavilability or stability of polymorph medicine different crystal forms are all there are notable difference, can prepare with protecting
Hinder the purpose of clinical drug safety in utilization validity, prepare high-purity, the good crystal form of bioavilability high stable seems outstanding
It is important.
Invention content
Inventor developed a kind of production methods of improved manidipine hydrochloride II crystal forms, are obtained by this method
The purity of manidipine hydrochloride crystal form II is more than 99.8%, it is maximum single it is miscellaneous is not more than 0.06%, impurity number is not more than 2, and
Process stabilizing.
The object of the present invention is to provide a kind of production methods of improved manidipine hydrochloride II crystal forms.
In embodiments of the invention, the present invention provides a kind of producers of improved manidipine hydrochloride II crystal forms
Method includes the following steps:
(1) the concentration grease of Manidipine alkali reaction solution is added in ethyl alcohol and dissolved by heating, cooling stirring analysis after dissolved clarification
Filter cake 1 is collected in crystalline substance, filtering;The filter cake 1 is added in ethyl alcohol, heating stirring, then cool down stirring and crystallizing, and filter cake is collected in filtering
2, it is dry, obtain Manidipine alkali solid;
(2) the Manidipine alkali solid that step (1) obtains is added at room temperature in dichloromethane and methanol mixed solvent,
Stirring and dissolving, it is preferably 0~10 DEG C to be cooled to 0~20 DEG C, and hydrochloric acid is added dropwise, is stirred to react;Then methyl tertiary butyl ether(MTBE) is added dropwise,
Filter cake 3 is collected in stirring and crystallizing, filtering;Methylene chloride reflux mashing is added in, cool down stirring and crystallizing, and filter cake 4 is collected in filtering, is dried
It is dry, obtain manidipine hydrochloride crude product;
(3) the manidipine hydrochloride crude product for obtaining step (2) is added in aqueous methanol, is dissolved by heating, is then cooled down,
Filter cake 5 is collected in stirring and crystallizing, filtering, and drying obtains manidipine hydrochloride crystal form II.
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the concentration grease of Manidipine alkali reaction solution can be prepared according to art methods in step (1), such as
With reference to Chinese patent CN 107337632A embodiments 1, by 2- (4- benzhydryl -1- piperazinyls) ethyl acetoacetic ester, nitre
Benzaldehyde, METHYL 3 AMINO CROTONATE are dissolved in isopropanol and are heated to reflux, and after completion of the reaction, steam isopropanol, residue
Add in dichloromethane dissolving, washing, liquid separation, concentration and obtain.
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the concentration grease of Manidipine alkali reaction solution and the w/v of ethyl alcohol are 1 in step (1):1~3 (unit
For Kg:L);The w/v of ethyl alcohol of the filter cake 1 with adding in filter cake 1 is 1:1~3 (unit Kg:L).
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the temperature dissolved by heating in step (1) is 55~65 DEG C;The temperature of heating stirring is 55~65 DEG C.
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the temperature of cooling stirring and crystallizing is 10~30 DEG C in step (1).
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the volume ratio of methanol and dichloromethane is 0.5~10 in step (2):1, preferably 1~5:1.
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the dosage that hydrochloric acid is added dropwise in step (2) is 2.0~4.0 equivalents of Manidipine alkali.
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, 5~10 times volumes (g/ml) of the dosage of methyl tertiary butyl ether(MTBE) for the quality of Manidipine alkali are added dropwise in step (2).
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the dosage of reflux mashing dichloromethane is 5~10 times of volume (g/ of the quality of Manidipine alkali in step (2)
ml)。
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the recrystallization temperature in step (2) is 0~30 DEG C.
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the mass volume ratio of manidipine hydrochloride crude product and aqueous methanol is 0.5~2 in step (3):5~100 (g:
Ml), preferably 0.8~1.6:7~80 (g:Ml), it is more preferably 1~1.4:8~60 (g:Ml), more preferably 1.1~1.3:10
~50 (g:ml).
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, water content described in step (3) in aqueous methanol is the volume % of 1 volume %~15, preferably 3 volume %~
The volume % of 12 volume %, more preferably 4 volume %~8.
In embodiments of the invention, the producer of a kind of improved manidipine hydrochloride II crystal forms provided by the invention
Method, wherein, the temperature dissolved by heating in step (3) is 30~100 DEG C, preferably 50~90 DEG C;The temperature of the crystallization for 0~
50 DEG C, preferably 20~30 DEG C;The time of crystallization is 3~20h, more preferably 5~12h.
The beneficial effects of the present invention are,
1st, the purification operations such as previous high vacuum and column chromatography have been got rid of or have been dissociated again into salt, mixed solvent stirs the purifying washed
Method makes it be more suitable for industrialized production.
2nd, post-processing approach of the invention, it is easy to operate, impurity can not only be effectively removed, and reduce cost, subtracted
The discharge of the three wastes is lacked.
3rd, higher by resulting product purity of the present invention, it is difficult to pass through to overcome the process contaminants in other processes
The difficulty that later stage refines and effectively reduces, the present invention can make the purity of manidipine hydrochloride alkali by conventional method removal of impurities purification
75% is increased to more than 97%, and yield is 30.5%~40.8%, continues purifying to be subsequent or provides safeguard into purifying after salt.
4th, using hydrochloric acid into salt, avoid using hydrogen chloride gas into salt without standard measure the drawbacks of, while reduce using chlorination
The production cost of hydrogen alcohols solvent is more advantageous to industrialized production, and has obtained the very high manidipine hydrochloride crude product of purity, pure
Degree is more than 99.5%.
5th, crystalline substance is secondly turned using the mixed solvent of first alcohol and water, obtains the crystal of the excellent of manidipine hydrochloride,
It is with good temperature and appropriate stability, and purity is high, and dissolvent residual is qualified after drying, is more convenient for preparation process mistake
The adaptability of journey also allows for storing for a long time, and the crystal form high income and purity which prepares are high, and specific impurities are removed
Ability is strong, and obtained product purity is more than 99.8%, and maximum list is miscellaneous to be not more than 0.06%, and impurity number is not more than 2, and work
Skill is stablized.
In order to make it easy to understand, the present invention refers to open source literature, these documents be in order to more clearly describe the present invention,
Entire contents are included in and are referred to herein, just look like that their full text herein go over by entire teachings.
Description of the drawings
Fig. 1 shows be the Manidipine alkali that the embodiment of the present invention 1 obtains HPLC collection of illustrative plates.
What Fig. 2 was represented is the HPLC collection of illustrative plates for the manidipine hydrochloride crude product that the embodiment of the present invention 1 obtains.
What Fig. 3 was represented is the HPLC collection of illustrative plates of II crystal form manidipine hydrochloride that the embodiment of the present invention 1 obtains.
What Fig. 4 was represented is the X-ray powder diffraction collection of II crystal form manidipine hydrochloride that the embodiment of the present invention 1 obtains.
What Fig. 5 was represented is the HPLC collection of illustrative plates for the Manidipine alkali that the embodiment of the present invention 2 obtains.
What Fig. 6 was represented is the HPLC collection of illustrative plates for the manidipine hydrochloride crude product that the embodiment of the present invention 2 obtains.
What Fig. 7 was represented is the HPLC collection of illustrative plates of II crystal form manidipine hydrochloride that the embodiment of the present invention 2 obtains.
Fig. 8 shows be the X-ray powder diffraction collection of II crystal form manidipine hydrochloride that the embodiment of the present invention 2 obtains.
Specific embodiment
The present invention will be described in detail by specific embodiment and attached drawing below.It is important to note that
These descriptions are only exemplary description, and be not meant to limit the scope of the invention.According to the discussion of this specification, this hair
Bright many variations change and will be apparent from for those skilled in the art.
Embodiment 1
The preparation of Manidipine alkali
The reaction treatment liquid of the free alkali containing Manidipine is concentrated under reduced pressure at 45~55 DEG C, and ethyl alcohol is added in after obtaining grease
15.2L (1~3L/kg, with the gauge of grease) dissolves at 55~65 DEG C, 20~30 DEG C is naturally cooling to after dissolved clarification, stirring
Crystallization for 24 hours more than, filtering, filter cake add in ethyl alcohol 12L (1~3L/kg, with M2 gauge) 55~65 DEG C stir 30min after cools down
It is filtered to 20~30 DEG C of crystallization 17h, obtains yellow filter cake drying, obtain yellow powder 5.0kg, (yield:40.8%, HPLC are pure
Degree:97.86%) HPLC collection of illustrative plates is shown in Fig. 1.
The preparation of manidipine hydrochloride crude product
Manidipine alkali 2.25kg is added to dichloromethane 6.75L, 0~10 DEG C is cooled to after methanol 4.5L dissolvings, drop
Enriching hydrochloric acid 1.07L, adds, then insulated and stirred reaction 1h adds in methyl tertiary butyl ether(MTBE) 13.5L, then stirs 1h, has a large amount of
Solid is precipitated, and filtering, filter cake is washed with a small amount of methyl tertiary butyl ether(MTBE), and filter cake is flowed back with dichloromethane 22L and is beaten 1h, is cooled to room
Temperature, filtering.Filter cake is washed with a small amount of methyl tertiary butyl ether(MTBE), and 40~50 DEG C of air blast drying obtain 2.05kg faint yellow solids.Yield
81.8%, purity 99.8869%, HPLC collection of illustrative plates is shown in attached drawing 2.
The preparation of manidipine hydrochloride II crystal forms
Manidipine hydrochloride crude product 2.04kg is added in 95% methanol of 15L, is heated to stirring while 60~70 DEG C,
To being completely dissolved, filter, then filtrate is cooled to 20~30 DEG C, 5h is kept the temperature, then filtering is directly dried in 40~50 DEG C of baking ovens
It is dry, obtain 1.8kg faint yellow solids.Purity 99.9451%, maximum single miscellaneous 0.05%, HPLC collection of illustrative plates are shown in Fig. 3, fusing point 209~
213 DEG C, yield 88.2%.Take crystal powder PIINIIlyticIIl companies of Holland (the former Philips analytical instrument public affairs of acquisition
Department) X ' Pert PRO MPD X-ray diffractometers, test parameter is:Cuk α are radiated;0.15418nm pipe pressures:40kv;Guan Liu:
40mII;Ni filter plates.
The X-ray powder diffraction collection of II crystal forms prepared by 1 method of example is using Cu-K α in 2 θ Data Detections of angle of reflection
The results are shown in Figure 4.
Embodiment 2
The preparation of Manidipine alkali
The reaction treatment liquid of the free alkali containing Manidipine is concentrated under reduced pressure at 45~55 DEG C, obtains grease and adds in ethyl alcohol 16L
(1~3L/kg, with the gauge of grease) dissolves at 55~65 DEG C, 20~30 DEG C is naturally cooling to after dissolved clarification, stirring and crystallizing
More than for 24 hours, filtering, after filter cake (5.9kg) addition ethyl alcohol 12L (1~3L/kg, with M2 gauge) stirs 30min at 55~65 DEG C
20~30 DEG C of crystallization 2h filterings are cooled to, yellow filter cake drying is obtained, obtains yellow powder 5.5kg, (yield:35.0%, HPLC
Purity:97.45%), HPLC collection of illustrative plates is shown in attached drawing 5.
The preparation of manidipine hydrochloride crude product
Manidipine hydrochloride free alkali 2.34kg is added to dichloromethane 7L, 0~10 is cooled to after methanol 4.6L dissolvings
DEG C, concentrated hydrochloric acid 1.12L is added dropwise, adds, then insulated and stirred reaction 1h adds in methyl tertiary butyl ether(MTBE) 11.6L, then stirs 1h,
There are a large amount of solids to be precipitated, filtering, filter cake is washed with a small amount of methyl tertiary butyl ether(MTBE), and filter cake is flowed back with dichloromethane 23L is beaten 1h, drop
It warms to room temperature, filters.Filter cake is washed with a small amount of methyl tertiary butyl ether(MTBE), and 40~50 DEG C of air blast drying obtain 2.13kg pale yellow colored solids
Body.Yield 81.0%, purity 99.8542%, HPLC collection of illustrative plates are shown in Fig. 6.
The preparation of manidipine hydrochloride II crystal forms
Manidipine hydrochloride crude product 2.12kg is added in 95% methanol of 15.9L, is heated to stirring while 60~70 DEG C
It mixes, until being completely dissolved, filters, then filtrate is cooled to 20~30 DEG C, keeps the temperature 5h, filtering, then directly in 40~50 DEG C of baking ovens
Drying, obtains 1.9kg faint yellow solids.Purity 99.9161%, maximum single miscellaneous 0.06%, HPLC collection of illustrative plates are shown in attached drawing 7, fusing point 208
~212 DEG C, yield 89.6%.Take crystal powder PIINIIlyticIIl companies of Holland (the former Philips analytical instrument of acquisition
Company) X ' Pert PRO MPD X-ray diffractometers, test parameter is:Cuk α are radiated;0.15418nm pipe pressures:40kv;Guan Liu:
40mII;Ni filter plates.
The X-ray powder diffraction collection of crystal form II prepared by 2 method of example is using Cu-K α in 2 θ Data Detections of angle of reflection
The results are shown in Figure 8.
Claims (10)
1. a kind of production method of improved manidipine hydrochloride II crystal forms, includes the following steps:
(1) the concentration grease of Manidipine alkali reaction solution is added in ethyl alcohol and dissolved by heating, cool down stirring and crystallizing after dissolved clarification, mistake
Filter cake 1 is collected in filter;The filter cake 1 is added in ethyl alcohol, heating stirring, then cool down stirring and crystallizing, and filter cake 2 is collected in filtering, is done
It is dry, obtain Manidipine alkali solid;
(2) the Manidipine alkali solid that step (1) obtains is added in into dichloromethane in methanol mixed solvent, stirring at room temperature
Dissolving, it is preferably 0~10 DEG C to be cooled to 0~20 DEG C, and hydrochloric acid is added dropwise, is stirred to react;Then methyl tertiary butyl ether(MTBE) is added dropwise, stirs
Filter cake 3 is collected in crystallization, filtering;Methylene chloride reflux mashing is added in, cool down stirring and crystallizing, filtering, collects filter cake 4, and drying obtains
To manidipine hydrochloride crude product;
(3) the manidipine hydrochloride crude product for obtaining step (2) is added in aqueous methanol, is dissolved by heating, is then cooled down, and is stirred
Filter cake 5 is collected in crystallization, filtering, and drying obtains manidipine hydrochloride crystal form II.
2. production method as described in claim 1, wherein, in step (1) the concentration grease of Manidipine alkali reaction solution with
The w/v of ethyl alcohol is 1:1~3, unit Kg:L;It the filter cake 1 and adds in the w/v of ethyl alcohol of filter cake 1 and is
1:1~3, unit Kg:L.
3. production method as described in claim 1, wherein, the temperature dissolved by heating in step (1) is 55~65 DEG C;Heating is stirred
The temperature mixed is 55~65 DEG C.
4. production method as described in claim 1, wherein, the temperature of cooling stirring and crystallizing is 10~30 DEG C in step (1).
5. production method as described in claim 1, wherein, the volume ratio 0.5~10 of methanol and dichloromethane in step (2):
1, preferably 1~5:1.
6. production method as described in claim 1, wherein, the dosage that hydrochloric acid is added dropwise in step (2) is the 2.0 of Manidipine alkali
~4.0 equivalents.
7. production method as described in claim 1, wherein, the temperature of crystallization is 0~30 DEG C in step (2).
8. production method as described in claim 1, wherein, manidipine hydrochloride crude product and aqueous methanol in step (3)
Mass volume ratio is 0.5~2:5~100, unit g:ml;Preferably 0.8~1.6:7~80, unit g:ml;More preferably it is
1~1.4:8~60, unit g:ml;More preferably 1.1~1.3:10~50, unit g:ml.
9. production method as described in claim 1, wherein, the water content described in step (3) in aqueous methanol is 1 body
The volume % of product %~15 volume %, preferably 3 volume %~12 volume %, more preferably 4 volume %~8.
10. production method as described in claim 1, wherein, the temperature of the heating for dissolving described in step (3) is 30~100
DEG C, preferably 50~90 DEG C;The temperature of the crystallization is 0~50 DEG C, preferably 20~30 DEG C;The time of crystallization is 3~20h,
More preferably 5~12h.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06199789A (en) * | 1991-11-22 | 1994-07-19 | Takeda Chem Ind Ltd | Production of unsymmetrical dihydropyridine derivative |
WO2011023954A2 (en) * | 2009-08-27 | 2011-03-03 | Cipla Limited | Polymorphic forms of manidipine |
CN103408483A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Calcium ion channels antagonist manidipine preparation method |
CN107337632A (en) * | 2017-08-22 | 2017-11-10 | 江西永通科技股份有限公司 | A kind of preparation method of CV-4093 |
-
2017
- 2017-11-24 CN CN201711188311.5A patent/CN108218765A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06199789A (en) * | 1991-11-22 | 1994-07-19 | Takeda Chem Ind Ltd | Production of unsymmetrical dihydropyridine derivative |
WO2011023954A2 (en) * | 2009-08-27 | 2011-03-03 | Cipla Limited | Polymorphic forms of manidipine |
CN103408483A (en) * | 2013-07-17 | 2013-11-27 | 张家港威胜生物医药有限公司 | Calcium ion channels antagonist manidipine preparation method |
CN107337632A (en) * | 2017-08-22 | 2017-11-10 | 江西永通科技股份有限公司 | A kind of preparation method of CV-4093 |
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Application publication date: 20180629 |