CN104447513B - A kind of preparation method of high-purity hydrochloric acid Manidipine beta crystal - Google Patents
A kind of preparation method of high-purity hydrochloric acid Manidipine beta crystal Download PDFInfo
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- CN104447513B CN104447513B CN201410687126.0A CN201410687126A CN104447513B CN 104447513 B CN104447513 B CN 104447513B CN 201410687126 A CN201410687126 A CN 201410687126A CN 104447513 B CN104447513 B CN 104447513B
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- manidipine
- beta crystal
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- manidipine hydrochloride
- crystal
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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 preparation methods of high-purity hydrochloric acid Manidipine beta crystal.This method is to dissolve the mixed solvent of manidipine hydrochloride crude product acetone and water, and pharmaceutical grade activated carbon is added in into solution, and warm stirring, while hot filtering, crystallization, the crystal that precipitation is collected by filtration and drying are made.High using this method product yield, using solvent environmental protection, dissolvent residual meets the requirements after drying；Its preparation method is simple, is suitble to large-scale production.Simultaneously, the beta crystal manidipine hydrochloride prepared using the present invention, X diffracting spectrums show that product beta crystal purity is high, impurity content is low, quality stability is good, it is highly suitable for storing as bulk pharmaceutical chemicals and pharmaceutical preparation being made, the clinical practice for manidipine hydrochloride drug provides safety guarantee.
Description
Technical field
The invention belongs to pharmaceutical technology field, specifically to a kind of preparations of high-purity hydrochloric acid Manidipine beta crystal
Method.
Background technology
Manidipine hydrochloride (Manidipine Hydrochloride), entitled Isosorbide-5-Nitrae-dihydro -2, the 6- dimethyl -4- of chemistry
(3- nitrobenzophenones) -3,5- pyridinedicarboxylic acids 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, structural formula is：
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 hyperpietic 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 preferable anti-height of a line
Blood pressure medication.
Manidipine hydrochloride has two kinds of crystal forms of α and β, and wherein beta crystal is Clinical practice crystal form.Beta crystal is faint yellow fine grain,
Methanol is slightly soluble in, atomic to be dissolved in ethyl alcohol, acetone and ether, almost insoluble in water, 174 DEG C~180 DEG C of fusing point, heat analysis DSC
Method fusing point is 227.06 DEG C.The beta crystal X-ray powder diffraction (XRD) of manidipine hydrochloride is in 2 θ of angle of reflection using Cu-K α
11.2±0.2°、12.0±0.2°、12.8±0.2°、13.7±0.2°、15.0±0.2°、16.2±0.2°、17.7±0.2°、
There is characteristic absorption at 18.2 ± 0.2 °, 19.2 ± 0.2 °, 21.2 ± 0.2 °, 22.2 ± 0.2 °, 23.0 ± 0.2 °, 25.1 ± 0.2 °
Peak.
Manidipine hydrochloride beta crystal has been only referred in patent CN103120651A as Clinical practice crystal form, and has used and is somebody's turn to do
Crystal form raw material has carried out the research of tablet, but is not directed to the preparation of manidipine hydrochloride beta crystal.
Document Chem.Pharm.Bull., 33 (9), 3787 (1985) give a kind of system of manidipine hydrochloride beta crystal
Preparation Method：With the manidipine hydrochloride of acetone stirring and dissolving alpha-crystal form, left at room temperature over night, crystallization, filtering, acetone washing, in 75
DEG C~80 DEG C be dried in vacuo to obtain product.This technique greatest drawback is that the manidipine hydrochloride of alpha-crystal form must first be made, then brilliant with α
Beta crystal is made as turning a brilliant raw material in type, complex process, and yield is low.
A kind of method that patent WO2011023954A2 provides preparation manidipine hydrochloride beta crystal is to use mixed solvent,
Methanol and toluene or ethyl alcohol and toluene, dissolve by heating manidipine hydrochloride, room temperature are cooled to after being completely dissolved, stirring and crystallizing 12 is small
When more than, filtering, 70 DEG C~80 DEG C are dried in vacuo to obtain product.Although this technique can obtain the manidipine hydrochloride of beta crystal,
Prepare medicinal crystal-form using two class solvent methanols, toluene, and there are stirring and crystallizing overlong time, yield is low and quality is unstable
The drawbacks of, it is unfavorable for industrialized production.
Since polymorph medicine different crystal forms bioavilability or therapeutic effect are there are notable difference, in order to greatest extent
Reduce influence of the poorly efficient or even invalid crystal form to drug effect, it is ensured that clinical drug uses safe and effective, prepares the hydrochloric acid of high-purity
Manidipine beta crystal is just particularly important.
The content of the invention
It is an object of the invention to provide a kind of preparation method of high-purity hydrochloric acid Manidipine beta crystal, the preparation methods
Simply, product purity is high, high income, is suitble to large-scale industrial production.
To achieve the above object, the technical solution adopted in the present invention is：Manidipine hydrochloride crude product is added to first
The in the mixed solvent of acetone and water, is dissolved by heating, and activated carbon is then added in into solution, by keeping the temperature, stirring, filtering,
Crystallization refilters, and collects the solid of precipitation, and the solid vacuum drying of collection is just finally obtained the manidipine hydrochloride of beta crystal.
The manidipine hydrochloride crude product purity requirement is more than 90%.
The mass ratio of the manidipine hydrochloride crude product and acetone, water, pharmaceutical grade activated carbon is 1: (4~10): (0.1
~2): (0.02~0.5) is preferably 1: (5~8): (0.2~1): (0.05~0.2).
The heating temperature is 30~60 DEG C, is preferably 45~60 DEG C；When the insulated and stirred time is 0.5~6 small, preferably
For 1~4 it is small when.
The recrystallization temperature is -5 DEG C~30 DEG C, is preferably -5 DEG C~10 DEG C；It is preferably 2 when the crystallization time 1~12 is small
~8 it is small when.
The drying temperature is 30 DEG C~100 DEG C, is preferably 40~60 DEG C；When drying time is 1~10 small, it is preferably
2~8 it is small when.
Beneficial effects of the present invention：First, due to using acetone and water as solvent, so the manidipine hydrochloride β prepared
Crystal form, X- diffracting spectrums show that purity is high, and fusing point is consistent with literature value；Second is that product yield is high, impurity content is low, uses solvent
Environmental protection, dissolvent residual meets the requirements after drying, can be used as bulk pharmaceutical chemicals；Third, its preparation method is simple, it is suitble to extensive
Industrialized production.
Specific embodiment
With reference to the following examples, the present invention can be explained in greater detail, it should however be noted that not office of the invention
It is limited to following embodiments.
Embodiment 1
The manidipine hydrochloride crude product that 50g purity is 92% is added in the in the mixed solvent of 225g acetone and 50g water first,
50 DEG C of dissolvings are heated to, 2.5g pharmaceutical grade activated carbons are then added in into solution, when insulated and stirred 3 is small, are filtered while hot.At 10 DEG C
When crystallization 5 is small, the crystal of precipitation is collected by filtration.Finally the crystal of precipitation is dried in vacuo, 65 DEG C of drying temperature, drying time 5
Hour, obtain product 43g, yield 86%.174.5 DEG C~180.1 DEG C of fusing point, miscellaneous maximum list is 0.03%, and always miscellaneous is 0.4%.
The crystal form samples X-ray powder diffraction (XRD) of embodiment 1 is using Cu-K α in the data that angle of reflection is 2 θ：11.1
±0.2°、12.0±0.2°、12.8±0.2°、13.8±0.2°、15.0±0.2°、16.3±0.2°、17.8±0.2°、18.2
±0.2°、19.2±0.2°、21.3±0.2°、22.3±0.2°、23.0±0.2°、25.1±0.2°。
Embodiment 2
The manidipine hydrochloride crude product that 50g purity is 90% is added in the in the mixed solvent of 328g acetone and 22g water first,
60 DEG C of dissolvings are heated to, 2.1g pharmaceutical grade activated carbons are then added in into solution, when insulated and stirred 2 is small, are filtered while hot.At -5 DEG C
When crystallization 4 is small, the crystal of precipitation is collected by filtration.Finally the crystal of precipitation is dried in vacuo, 55 DEG C of drying temperature, drying time 6
Hour, obtain product 43.5g, yield 87%.175.0 DEG C~179.8 DEG C of fusing point, miscellaneous maximum list is 0.04%, and always miscellaneous is 0.4%.
The crystal form samples X-ray powder diffraction (XRD) of embodiment 2 is using Cu-K α in the data that angle of reflection is 2 θ：11.2
±0.2°、12.1±0.2°、12.8±0.2°、13.7±0.2°、15.0±0.2°、16.2±0.2°、17.7±0.2°、18.2
±0.2°、19.2±0.2°、21.3±0.2°、22.3±0.2°、23.1±0.2°、25.2±0.2°。
Claims (2)
1. a kind of preparation method of manidipine hydrochloride beta crystal, it is characterised in that：Manidipine hydrochloride crude product is added to first
The in the mixed solvent of acetone and water, is dissolved by heating, and heating temperature during heating for dissolving is 45-60 DEG C；Then into solution
Pharmaceutical grade activated carbon is added in, by keeping the temperature, stirring, filtering, crystallization, refilters, collects the solid of precipitation, the insulated and stirred time is
When 1-4 is small, temperature during crystallization is -5 DEG C -10 DEG C, finally when crystallization time 2-8 is small, vacuum drying by solid of collection just
To the manidipine hydrochloride of beta crystal, drying temperature when dry is 40-60 DEG C, when drying time is 2-8 small, the hydrochloric acid
Manidipine crude product and the mass ratio of acetone, water, pharmaceutical grade activated carbon are 1：(5-8)：(0.2-1)：(0.05-0.2).
2. the preparation method of manidipine hydrochloride beta crystal according to claim 1, it is characterised in that：The hydrochloric acid horse
Buddhist nun's Horizon crude product purity requirement is more than 90%.
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| CN201410687126.0A CN104447513B (en) | 2014-11-26 | 2014-11-26 | A kind of preparation method of high-purity hydrochloric acid Manidipine beta crystal |
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| CN201410687126.0A CN104447513B (en) | 2014-11-26 | 2014-11-26 | A kind of preparation method of high-purity hydrochloric acid Manidipine beta crystal |
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| CN104447513B true CN104447513B (en) | 2018-05-29 |
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Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011023954A2 (en) * | 2009-08-27 | 2011-03-03 | Cipla Limited | Polymorphic forms of manidipine |
| CN102875451B (en) * | 2012-04-05 | 2014-12-03 | 常州制药厂有限公司 | Improved method for synthesis process of manidipine hydrochloride |
| CN103467364B (en) * | 2013-06-21 | 2015-07-15 | 四川海思科制药有限公司 | Manidipine hydrochloride compound |
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