CN107325043A - A kind of crystal formation of left-handed Aranidipine and preparation method thereof - Google Patents
A kind of crystal formation of left-handed Aranidipine and preparation method thereof Download PDFInfo
- Publication number
- CN107325043A CN107325043A CN201710697614.3A CN201710697614A CN107325043A CN 107325043 A CN107325043 A CN 107325043A CN 201710697614 A CN201710697614 A CN 201710697614A CN 107325043 A CN107325043 A CN 107325043A
- Authority
- CN
- China
- Prior art keywords
- aranidipine
- handed
- crystal formation
- preparation
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- C07D211/80—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
-
- 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
- C07B2200/07—Optical isomers
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Abstract
The invention discloses a kind of S configurations Aranidipine（Left-handed Aranidipine）Crystal formation and its crystallization preparation method, its X ray powder diffractions principal character is in 2 θ values：8.3 ± 0.2,10.3 ± 0.2,11.1 ± 0.2,12.5 ± 0.2,13.7 ± 0.2,16.3 ± 0.2,17.9 ± 0.2,19.2 ± 0.2,19.7 ± 0.2,20.3 ± 0.2,22.1 ± 0.2,22.8 ± 0.2,23.9 ± 0.2,24.3 ± 0.2,25.3 ± 0.2,26.4 ± 0.2,27.1 ± 0.2, have characteristic peak at 27.6 ± 0.2 and 29.4 ± 0.2 degree.Present invention also offers the preparation method of the crystal formation.Operating procedure is simple, easy to operate；The product purity prepared is higher than 99%, product yield 90% or so.
Description
Technical field
The present invention relates to a kind of S configurations Aranidipine（Left-handed Aranidipine）Crystal formation and preparation method thereof, belong to medicine
Technical field.
Background technology
Left-handed Aranidipine (S-Aranidipine), molecular formula is C19H19N2O7, molecular weight is 388.37, its structural formula
(Formulas I) is as follows:
I
Its chemistry is entitled（S）- 2,6- dimethyl -4-（2- nitrobenzophenones）- Isosorbide-5-Nitrae-dihydro -3,5- pyridinedicarboxylic acid methyl -2- oxygen
Propyl group diester, is that the laevoisomer obtained is split from Aranidipine racemic modification.There are some researches show in Ca2+It is caused from
In body rabbit arterial bar shrinkage test, S- types enantiomer retardance Ca2+The activity of inflow is about higher 150 times than R- type,（S）Type and（R）
Interaction is had no between type.In clear-headed spontaneous hypertensive rat, the hypotensive activity of S- types is Aranidipine（Racemization
Body）Twice, and R- types, without effect, the pharmacological activity of Aranidipine mainly comes from S- type isomers.Therefore to left-handed A Lei
The research of Horizon has bigger clinical value.
In general, medicinal crystal-form product should possess the good character of operation, the pattern for being easy to filtering and easily drying should be.Separately
Outside, preferable medicinal crystal-form product should be the product that can stablize without special preservation condition within the pot-life.Left-handed A Lei
Horizon belongs to slightly water-soluble compound, can typically apply in solid form in the formulation, therefore has ten to the research of its crystal formation
Divide important meaning.
US4446325A discloses a kind of preparation method of Aranidipine.
Taiho Pharmaceutical Co. Ltd on disclosed in Aranidipine capsulae enterosolubilis specification with reporting medicinal A Lei
Flat fusing point is 148~151 DEG C.
Zhao Rui etc. reports a kind of Aranidipine crystal formation and preparation method thereof, and X-ray powder of the crystal formation in CuK α sources spreads out
Penetrating has 7.45 °, 10.02 °, 10.83 °, 16.72 °, 20.03 ° and 25.01 ± 0.2 ° in collection of illustrative plates, crystal formation DSC collection of illustrative plates shows
The fusing point for showing Aranidipine is 151 DEG C or so, consistent with the medicinal Aranidipine crystal formation of roc pharmaceutical industries strain formula meeting.
Up to now, not yet it is related to the report of left-handed Aranidipine crystal formation and crystallization preparation method.
The content of the invention
The technical problems to be solved by the invention are in view of the shortcomings of the prior art there is provided one kind with disappearing outside Aranidipine
Revolve the crystal formation of the different new left-handed Aranidipine of body crystal formation.
Another technical problem to be solved by this invention there is provided the preparation side of the crystal formation of foregoing left-handed Aranidipine
Method.
The technical problems to be solved by the invention are realized by following technical scheme.The present invention is a kind of left-handed
The crystal formation of Aranidipine, is characterized in：Its X-ray powder diffraction collection the angle of diffraction 8.3 ± 0.2,10.3 ± 0.2,
11.1±0.2、12.5±0.2、13.7±0.2、16.3±0.2、17.9±0.2、19.2±0.2、19.7±0.2、20.3±
0.2、22.1±0.2、22.8±0.2、23.9±0.2、24.3±0.2、25.3±0.2、26.4±0.2、27.1±0.2、
There is characteristic peak at 27.6 ± 0.2 and 29.4 ± 0.2 degree.
More preferably the crystal formation for the left-handed Aranidipine that the present invention is provided has x-ray powder substantially as described in Figure 1
Diffraction pattern.
The fusing point of the more preferably left-handed Aranidipine that the present invention is provided is about 110 DEG C, its means of differential scanning calorimetry（DSC）Figure
Spectrum is as shown in Figure 2.
On the other hand the present invention also provides a kind of preparation method of the crystal formation of left-handed Aranidipine, and step is as follows：Will be left-handed
Aranidipine bulk drug is dissolved in organic solvent, adds appropriate purified water, and rising temperature for dissolving, cooling stirring and crystallizing, filtering, drying is separated out
Left-handed Aranidipine.
Mixing plant used has the reactor or reactor of mixing effect from this area.
One or more of the organic solvent in polar solvent；More preferably methanol, ethanol, acetonitrile and third
One or more in ketone；More preferably acetonitrile.
The w/v of the left-handed Aranidipine bulk drug and organic solvent is 1g：（1~10）mL；Further preferably
For 1g：1.5mL.
The left-handed Aranidipine bulk drug and the w/v of purified water are（0.5~50）g：1mL；Further preferably
For 0.7g：1mL.
The solution temperature is 30 ~ 60 DEG C；Described is cooled to 20 ~ 55 DEG C, and described drying temperature is 25 ~ 60 DEG C.
The inventive method has the advantages that：Operating procedure of the present invention is simple, easy to operate；The product purity prepared
Higher than 99%, product yield 90% or so, preferably, crystal formation is relatively stable, is suitable for pharmaceutical manufacturing for sample flow.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of left-handed Aranidipine prepared by the inventive method.
Fig. 2 is the means of differential scanning calorimetry figure of left-handed Aranidipine prepared by the inventive method.
Embodiment
The present invention is expanded on further below by specific embodiment and with reference to accompanying drawing.It should be appreciated that following examples
Simply to further illustrate the features and advantages of the present invention, to those skilled in the art, the present invention is not being departed from
On the premise of design, various modifications and improvements can be made.These belong to protection scope of the present invention.
Universal testing method：
X-ray powder diffraction (XRD) instrument：Bruker D8 Advance X-ray diffractometers, test condition：40kv
40mA, slit：1.0/1.0/Ni/0.2, step-length：0.02 °, target type：Cu, Range:3.00-40.00 Deg, scan Rate：
10.00 Deg/min。
Differential scanning calorimetry analyzes (DSC) instrument：The type differential thermal analyzers of NETZSCH DSC 204, temperature range：30-
230 DEG C, heating rate：10℃/min.
Melting point detector：WRS-2 computer digital displaying melting point detectors, 1.0 DEG C/min of heating rate.
Embodiment 1, a kind of preparation method of the crystal formation of left-handed Aranidipine
Left-handed Aranidipine bulk drug 10.0g is taken, acetonitrile 15mL is added, is warming up to 55 DEG C of dissolvings, adds purified water 7mL, is delayed
Slowly it is cooled to after room temperature, stirring and crystallizing 5h, filters, 50 DEG C are dried in vacuo to obtain left-handed Aranidipine product 9.05g, and yield is
90.5%, purity is 99.9%.Aranidipine crystal formation left-handed to gained carries out XRD tests, fusing point and DSC tests, its XRD spectrum
As shown in figure 1, its DSC collection of illustrative plates is as shown in Fig. 2 110 DEG C of fusing point.
Embodiment 2, a kind of preparation method of the crystal formation of left-handed Aranidipine
Left-handed Aranidipine bulk drug 10.0g is taken, acetonitrile 15mL is added, is warming up to 55 DEG C of dissolvings, adds purified water 7mL, is delayed
Slowly crystallization 5h after 25 DEG C is cooled to, filtered, 40 DEG C are dried in vacuo to obtain left-handed Aranidipine product 9.12g, and yield is 91.2%, pure
Spend for 99.9%.XRD spectrum, fusing point and the DSC collection of illustrative plates and embodiment 1 of the left-handed Aranidipine crystal formation of gained are consistent.
Embodiment 3, a kind of preparation method of the crystal formation of left-handed Aranidipine
Left-handed Aranidipine bulk drug 10.0g is taken, methanol 15mL is added, is warming up to 55 DEG C of dissolvings, adds purified water 7mL, is delayed
Slowly 25 DEG C of crystallization 5h are cooled to, filtered, 40 DEG C are dried in vacuo to obtain left-handed Aranidipine product 9.38g, and yield is 93.8%, purity
For 99.9%.XRD spectrum, fusing point and the DSC collection of illustrative plates and embodiment 1 of the left-handed Aranidipine crystal formation of gained are consistent.
Embodiment 4, a kind of preparation method of the crystal formation of left-handed Aranidipine
Left-handed Aranidipine bulk drug 10.0g is taken, ethanol 15mL is added, is warming up to 55 DEG C of dissolvings, adds purified water 7mL, is delayed
Slow to be cooled to 25 DEG C, stirring and crystallizing 5h is filtered, 60 DEG C are dried in vacuo to obtain left-handed Aranidipine product 9.37g, and yield is
93.7%, purity is 99.9%.XRD spectrum, fusing point and the DSC collection of illustrative plates and embodiment 1 of the left-handed Aranidipine crystal formation of gained are consistent.
Embodiment 5, a kind of preparation method of the crystal formation of left-handed Aranidipine
Left-handed Aranidipine bulk drug 10.0g is taken, acetone 15mL is added, is warming up to 55 DEG C of dissolvings, adds purified water 10mL,
Slow cooling is to 25 DEG C, and stirring and crystallizing 5h is filtered, 40 DEG C are dried in vacuo to obtain left-handed Aranidipine product 9.25g, and yield is
92.5%, purity is 99.9%.XRD spectrum, fusing point and the DSC collection of illustrative plates and embodiment 1 of the left-handed Aranidipine crystal formation of gained are consistent.
Embodiment 6, a kind of preparation method of the crystal formation of left-handed Aranidipine
Left-handed Aranidipine bulk drug 10.0g is taken, acetonitrile 10mL, ethanol 5mL is sequentially added into, heating makes dissolving, added pure
Change water 7mL, slow cooling is to 25 DEG C, and stirring and crystallizing 5h is filtered, 40 DEG C are dried in vacuo to obtain left-handed Aranidipine product 9.02g, is received
Rate is 90.2%, and purity is 99.9%.XRD spectrum, fusing point and the DSC collection of illustrative plates and embodiment 1 of the left-handed Aranidipine crystal formation of gained
Unanimously.
Embodiment 7, a kind of preparation method of the crystal formation of left-handed Aranidipine
Take left-handed Aranidipine bulk drug 10.0g, be sequentially added into acetonitrile 8mL, ethanol 5mL, methanol 5mL, heating make left-handed Ah
Thunder Horizon dissolves, and adds purified water 7mL, slow cooling is to 25 DEG C, and stirring and crystallizing 5h is filtered, 40 DEG C are dried in vacuo left-handed
Aranidipine product 9.12g, yield is 91.2%, and purity is 99.9%.It is the XRD spectrum of the left-handed Aranidipine crystal formation of gained, molten
Point and DSC collection of illustrative plates are consistent with embodiment 1.
Described above is only the citing of embodiments of the present invention, it is noted that for the ordinary skill of the art
For personnel, to left-handed Aranidipine crystal formation of the present invention on the premise of present invention, spirit and scope is not departed from
And preparation method thereof be modified or suitably change with combining, to realize the technology of the present invention, all similar improvement and modification
Apparent to those skilled in the art, these improvement and modification are considered as being included in present disclosure, essence
In god and scope.
Claims (9)
1. a kind of crystal formation of left-handed Aranidipine, it is characterised in that：Its X-ray powder diffraction collection is in the θ of the angle of diffraction 2：8.3±
0.2、10.3±0.2、11.1±0.2、12.5±0.2、13.7±0.2、16.3±0.2、17.9±0.2、19.2±0.2、
19.7±0.2、20.3±0.2、22.1±0.2、22.8±0.2、23.9±0.2、24.3±0.2、25.3±0.2、26.4±
0.2nd, 27.1 ± 0.2, there is characteristic peak at 27.6 ± 0.2 and 29.4 ± 0.2 degree.
2. a kind of crystal formation of left-handed Aranidipine as claimed in claim 1, it is characterised in that：Its fusing point is 104 ~ 115 DEG C.
3. a kind of crystal formation of left-handed Aranidipine as claimed in claim 1, it is characterised in that：Its means of differential scanning calorimetry DSC schemes
Spectrum, has single absworption peak at 110 ± 10 DEG C.
4. the method that one kind prepares the left-handed Aranidipine crystal formation any one of claim 1 ~ 3, it is characterised in that：Including
Following steps：Left-handed Aranidipine bulk drug is added in polar organic solvent, dissolved by heating, purifying is added into system while hot
Water, is cooled to room temperature, and stirring and crystallizing, filtering is drained, and left-handed Aranidipine crystal formation is obtained after vacuum drying.
5. method as claimed in claim 4, it is characterised in that：Described polar organic solvent be selected from methanol, ethanol, acetonitrile and
One or more of mixed solvents in acetone.
6. method as claimed in claim 4, it is characterised in that：Described left-handed Aranidipine and the weight of polar organic solvent
Volume ratio is 1g：1 mL ~ 10mL；Preferably 1g：1.5mL.
7. method as claimed in claim 4, it is characterised in that：The left-handed Aranidipine and the w/v of purified water are
（0.5~50）g：1mL；Preferably 0.7g：1mL.
8. method as claimed in claim 4, it is characterised in that：The solution temperature is 30 ~ 60 DEG C；It is described be cooled to 20 ~
55℃。
9. method as claimed in claim 4, it is characterised in that：Described drying temperature is 25 ~ 60 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710697614.3A CN107325043A (en) | 2017-08-15 | 2017-08-15 | A kind of crystal formation of left-handed Aranidipine and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710697614.3A CN107325043A (en) | 2017-08-15 | 2017-08-15 | A kind of crystal formation of left-handed Aranidipine and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107325043A true CN107325043A (en) | 2017-11-07 |
Family
ID=60200937
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710697614.3A Pending CN107325043A (en) | 2017-08-15 | 2017-08-15 | A kind of crystal formation of left-handed Aranidipine and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107325043A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108752263A (en) * | 2018-06-08 | 2018-11-06 | 威海迪素制药有限公司 | A kind of preparation method of high-purity nifedipine crystallization |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557678A (en) * | 2013-10-23 | 2015-04-29 | 丹阳恒安化学科技研究所有限公司 | Method for preparing aranidipine |
| CN106226427A (en) * | 2016-07-18 | 2016-12-14 | 江苏德源药业股份有限公司 | A kind of supercritical fluid chromatography quickly splits the method for aranidipine racemic modification |
-
2017
- 2017-08-15 CN CN201710697614.3A patent/CN107325043A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557678A (en) * | 2013-10-23 | 2015-04-29 | 丹阳恒安化学科技研究所有限公司 | Method for preparing aranidipine |
| CN106226427A (en) * | 2016-07-18 | 2016-12-14 | 江苏德源药业股份有限公司 | A kind of supercritical fluid chromatography quickly splits the method for aranidipine racemic modification |
Non-Patent Citations (3)
| Title |
|---|
| 李玲: "阿雷地平的合成", 《中国医药工业杂志》 * |
| 赵桂森: "《新药设计与开发基础》", 30 November 2015, 山东大学出版社 * |
| 赵蕊: "阿雷地平的合成研究", 《天津理工大学硕士学位论文》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108752263A (en) * | 2018-06-08 | 2018-11-06 | 威海迪素制药有限公司 | A kind of preparation method of high-purity nifedipine crystallization |
| CN108752263B (en) * | 2018-06-08 | 2021-10-26 | 迪嘉药业集团有限公司 | Preparation method of high-purity nifedipine crystal |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR20150036336A (en) | Crystalline form i of tyrosine kinase inhibitor dimaleate and preparation methods thereof | |
| CN107325043A (en) | A kind of crystal formation of left-handed Aranidipine and preparation method thereof | |
| CN114276290A (en) | Rifenacin anhydrous crystal form and preparation method thereof | |
| CN107286220B (en) | 1,2, 4-triazole coupled dihydromyricetin derivative and preparation method and application thereof | |
| WO2017177781A1 (en) | Ahu377 crystal forms, and preparation method therefor and use thereof | |
| CN111171015A (en) | Berberine-cinnamic acid derivative monocrystal, and preparation method and application thereof | |
| US20170051002A1 (en) | Rebaudioside A Crystal And Its Preparation Method And Use | |
| CN107043345A (en) | Preparation, structure and the purposes of the diketone Schiff base of 4-acetylbiphenyl hydrazone indoline 2,3 | |
| CN111393454A (en) | Novel crystalline form of midostaurin and process for its preparation | |
| CN108530365B (en) | 1, 4-naphthoquinone/anthraquinone imidazole derivative and preparation and application thereof | |
| KR102458566B1 (en) | Mepuparib hydrochloride polycrystalline material and its manufacturing method and application | |
| CN105315278A (en) | PQQ (pyrroloquinoline quinone) A crystal form and preparation method thereof | |
| CN113896649B (en) | Prilocaine crystal form and preparation method thereof | |
| CN107474009A (en) | A kind of crystal formation of dextrorotation Aranidipine and preparation method thereof | |
| CN109761993B (en) | Spirobenzofuran-3, 3' -quinoline derivative and synthesis method and application thereof | |
| CN101121693B (en) | Lercanidipine hydrochloride crystal and preparation method thereof | |
| EP2114910A1 (en) | A novel crystalline mycophenolate sodium polymorph and processes to manufacture same | |
| WO2020224208A1 (en) | Pyridone derivative crystal form and preparation method and application therefor | |
| CN107759609A (en) | A kind of purification process of asenapine | |
| JP2011105649A (en) | Azelnidipine crystal | |
| CN107311993A (en) | A kind of crystal formation II of canagliflozin and preparation method thereof | |
| CN115745913B (en) | Qu Faluo statin polymorphism and preparation method thereof | |
| CN107353248A (en) | A kind of novel crystal forms Cisatracurium besylate and its purification process | |
| CN110105361B (en) | Preparation method of Evodikine and derivative thereof | |
| CN110078679A (en) | A kind of lamotrigine pharmaceutical co-crystal and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20171107 |