CN104119325B - Preparation method of aprepitant polymorphic substance - Google Patents
Preparation method of aprepitant polymorphic substance Download PDFInfo
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- CN104119325B CN104119325B CN201410336829.9A CN201410336829A CN104119325B CN 104119325 B CN104119325 B CN 104119325B CN 201410336829 A CN201410336829 A CN 201410336829A CN 104119325 B CN104119325 B CN 104119325B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a preparation method of an aprepitant polymorphic substance, and specifically relates to a preparation method of two polymorphic substances of 5-[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxyl]-3(S)-(4-fluorophenyl)morpholine-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazole-3-one. The preparation method of the polymorphic substance I comprises steps of dissolving, crystallizing, collecting crystals, and drying. The preparation method of the polymorphic substance II comprises the steps of dissolving, condensing, collecting crystals, and drying. The preparation method can directly obtain two polymorphic substance of aprepitant, has the advantages of simple technology, high product purity, and high yield, and is especially suitable for drug effect research and industrial production.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, is related to 5- [2 (R)-[1 (R)-[3,5- bis- (trifluoromethyl) phenyl] second
Epoxide] -3 (S)-(4- fluorophenyls) morpholine -4- ylmethyls] -3,4- dihydros -2H-1,2,4- triazoles -3- ketone (also known as aprepitant)
Polymorph I and polymorph II preparation method.
Background technology
Aprepitant (Aprepitant), chemical entitled 5- [[(2R, 3S) -2- [(1R) -1- [3,5- bis- (trifluoromethyls)
Phenyl] ethyoxyl] -3- (4- fluorophenyls) -4- morpholinyls] methyl] -1,2- dihydro -3H-1,2,4- triazole -3- ketone, are the U.S.
Neurokinine-1 (NK-1) receptor antagonist of Merck＆Co companies research and development, Jing U.S. FDAs approval listing in 2003, is used for
Prevention is high to be caused acute and Delayed onset nausea caused by telling property antineoplastic chemotherapy medicine (including High-dose Cisplatin Chemotherapy therapeutic scheme), vomits
Tell.Aprepitant can pass through blood brain barrier, play antiemetic effect [yellow east woods .2003 with brain nk 1 receptor selective binding
The new drug [J] of U.S.'s approval. Shanghai medicine, 2004,25 (9):418-422], [Nie Ying, Bi little Ling, You Qidong. aprepitant
[J]. Chinese Journal of New Drugs, 2006,15 (3):238-239].
Polymorphic is significant to the physicochemical property of medicine, bioavailability, preparation process and quality.The medicine not isomorphous
Between type, the stability of the differentia influence medicine of physicochemical property, the crystal formation of same medicine is if it is different, bioavailability may be deposited
In larger difference, larger is affected on preparation, the biological activity of medicine can be also had a strong impact on.As the different crystal formation of medicine can affect
The dissolution rate of medicine, and the surface free energy of different crystal forms can be variant, causes the adhesion between crystalline particle different, shadow
Ring the mobility and tabletting hardness, tablet weight variation, content uniformity and physical stability of medicine.Therefore the crystalline substance to aprepitant
It is very necessary and significant that type carries out research.
Published aprepitant polymorph has four kinds at present.Merck＆Co companies patent US6583142,
Aprepitant polymorph I and polymorph II, relevant nature and preparation method thereof is disclosed in US6096742.Glenmark
Pharmaceuticals Ltd disclose the preparation method of aprepitant type III crystal in patent WO2008044102.
UsvLimited discloses a series of preparation method of aprepitant II type crystal in patent WO2010092591, particularly also wraps
Include aprepitant IV type crystal and preparation method thereof.WO2007088483 discloses aprepitant indefinite form crystal, different proportion
I, II type mixed crystal and preparation technology.WO2008026216, US2009149462 disclose aprepitant II type crystal
Preparation method, including dissolving, concentration, solid-liquid separation, water beating, four steps of separation.
The content of the invention
The purpose of the present invention is to overcome bad, the unstable defect of repeatability in disclosed preparation method, there is provided system
The polymorph I of standby aprepitant and polymorph II methods.
The purpose of the present invention can be reached by following measures：
Two kinds of crystal formations prepared by the method for the present invention, which is respectively compound 5- [2 (R)-[1 (R)-[3,5- bis- (fluoroforms
Base) phenyl] ethyoxyl] -3 (S)-(4- fluorophenyls) morpholine -4- ylmethyls] -3,4- dihydro -2H-1,2,4- triazole -3- ketone (Ahs
Auspicious pyrrole is smooth) polymorph I and polymorph II.
The preparation process of polymorph I is divided into dissolution process, crystallize operation, crystal collection, drying process；Polymorph II
Preparation process be divided into dissolution process, enrichment process, crystal collection, drying process.
Polymorph I
The crystalline polymorph I of aprepitant, is radiated using Cu-K α, the X-ray powder diffraction figure of its feature, to spend table
2 θ for showing 11.96,15.22,16.48,16.98,17.5,19.34,19.94,21.84,23.5,23.8,24.7 ± 0.20 °
There is characteristic diffraction peak at place.As shown in Figure 1.
The preparation method of aprepitant crystalline polymorph I, comprises the following steps：A, at a temperature of 10 DEG C -140 DEG C, will
Aprepitant is dissolved in good solvent, and aprepitant quality with solvent volume ratio is：1g:(5～200mL)；B, be added to it is bad
In solvent, stir；C, filtration；D, 20 DEG C～100 DEG C vacuum drying, obtain final product aprepitant polymorph I.
In step A, good solvent may be selected from, but be not limited to acetone, methyl iso-butyl ketone (MIBK), acetonitrile, ethyl acetate, N, N- bis-
One or more in methylformamide, dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol, normal propyl alcohol and isopropanol；Further
Ground, preferably one or more in acetone, methanol and dimethyl sulfoxide.Aprepitant quality with solvent volume ratio is：1g:(5
～200mL), it is preferred that aprepitant quality with solvent volume ratio is：1g:(10～100mL)；It is further preferred that being 1g:
(25～75mL).In step B, poor solvent may be selected from, but be not limited to water, normal heptane, normal hexane, hexamethylene, petroleum ether, different
One or more in propyl ether and methyl tertiary butyl ether(MTBE)；Further, it is preferable to be the one kind or many in water, normal heptane and normal hexane
Kind.Poor solvent is 1 with good solvent volume ratio:(0.2～2)；Further, it is preferable to be 1:(0.5～1).Aprepitant solution
Can be added in poor solvent, it is also possible to which poor solvent is added in aprepitant solution.Aprepitant solution can be without
Cooling is directly added into, and adds after being also cooled to 0 DEG C～30 DEG C.
Polymorph II
The crystalline polymorph II of aprepitant, is radiated using Cu-K α, the X-ray powder diffraction figure of its feature, to spend table
2 θ for showing 12.52, at 16.7,17.1,17.5,18.0,20.1,20.6,21.04,22.84,23.88,24.82 ± 0.20 °
There is characteristic diffraction peak.As shown in Figure 2.
The preparation method of aprepitant crystalline polymorph II, comprises the following steps：A, at a temperature of 10 DEG C -110 DEG C, will
In good solvent, aprepitant quality with solvent volume ratio is aprepitant solid dissolving：1g:(10～200mL)；B, addition silicon
Glue is stirred, and is filtered；C, distillation and concentration solvent directly obtain crystal；D, the vacuum drying at 20 DEG C～100 DEG C, obtain final product aprepitant
Polymorph II.
In step A, good solvent may be selected from, but be not limited to acetone, ethyl acetate, dichloromethane, chloroform, toluene, diformazan
One kind in benzene, DMF, dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, ammonia or
It is various.Further, it is preferable to be ethyl acetate, dichloromethane, one or more in ammonia.In step A, aprepitant quality
With solvent volume ratio it is：1g:(20～100mL)；Further, it is preferable to be 1g:(25～75mL).In step B, aprepitant with
Silica gel mass ratio is：1g:(1～10g)；Further, it is preferable to be 1g:(2～6g).
The test condition that X-ray powder diffraction (PXRD) is characterized is carried out to aprepitant polymorph I and polymorph II
For：
Instrument：Rigaku (Rigaku) D/max-1200
Sample size：About 100mg
Target：Cu
Filter disc：It is monochromatic
Voltage/current：40kV/100mA
Scanning speed：4 °/point
Stepping：0.02°
Scanning angle：5～45 ° of 2 θ
Description of the drawings
Fig. 1 is the X-ray powder diffraction figure of aprepitant crystalline polymorph I；
Fig. 2 is the X-ray powder diffraction figure of aprepitant crystalline polymorph II.
Specific embodiment
With reference to embodiment, the invention will be further described.But protection scope of the present invention must not believe that and be limited only to
Following specific embodiments.On the premise of without departing from basic idea of the present invention, what those skilled in the art made accordingly
It is simple to deduce or equal alternative, belong to protection scope of the present invention.
Embodiment 1
2g aprepitants, add 20mL methanol, and completely, solution is added in 20mL water 65 DEG C of stirring and dissolving, stirs 2 hours
Room temperature is cooled to, is filtered, solid is vacuum dried at 40 DEG C.Obtain 1.82g aprepitant polymorph I.
Embodiment 2
2g aprepitants, add 10mL dimethyl sulfoxide, and completely, solution is added in 60mL water 25 DEG C of stirring and dissolving, stirs
Mix 2 hours, filter, solid is vacuum dried at 60 DEG C.Obtain 1.63g aprepitant polymorph I.
Embodiment 3
2g aprepitants, add 20mL acetone, and completely, solution is added in 60mL normal hexane 60 DEG C of stirring and dissolving, stirring 2
Hour, filtering, solid is vacuum dried at 45 DEG C.Obtain 1.5g aprepitant polymorph I.
Embodiment 4
2g aprepitants, add 100mL dichloromethane, and 50 DEG C of stirring and dissolving, solution are added in 100mL normal hexane, stir
Mix 2 hours, filter, solid is vacuum dried at 40 DEG C.Obtain 1.62g aprepitant polymorph I.
Embodiment 5
2g aprepitants, add 30mL tetrahydrofurans, and completely, solution is added in 60mL petroleum ether 68 DEG C of stirring and dissolving,
Stirring 3 hours, filters, and solid is vacuum dried at 45 DEG C.Obtain 1.64g aprepitant polymorph I.
Embodiment 6
2g aprepitants, add 400mL toluene, and completely, solution is added in 200mL normal hexane 110 DEG C of stirring and dissolving, stirs
Mix 2 hours, filter, solid is vacuum dried at 55 DEG C.Obtain 1.89g aprepitant polymorph I.
Embodiment 7
2g aprepitants, add 300mL dimethylbenzene, and completely, solution is added in 150mL normal hexane 140 DEG C of stirring and dissolving,
Stirring 2 hours, filters, and solid is vacuum dried at 60 DEG C.Obtain 1.85g aprepitant polymorph I.
Embodiment 8
2g aprepitants, add 125mL ethyl acetate, add the dry silica gel of 6g, stir 30 minutes, mistake after 70 DEG C of stirring and dissolving
Filter, be evaporated to it is dry, solid 45 DEG C be vacuum dried.Obtain 1.75g aprepitant polymorph II.
Embodiment 9
2g aprepitants, add 50mL acetone, add the dry silica gel of 2g, stir 30 minutes, filter, subtract after 30 DEG C of stirring and dissolving
Pressure is concentrated to dryness, and solid is vacuum dried at 45 DEG C.Obtain 1.80g aprepitant polymorph II.
Embodiment 10
2g aprepitants, add 200mL tetrahydrofurans, add the dry silica gel of 4g, stir 30 minutes, mistake after 25 DEG C of stirring and dissolving
Filter, be evaporated to it is dry, solid 45 DEG C be vacuum dried.Obtain 1.81g aprepitant polymorph II.
Embodiment 11
2g aprepitants, add 150mL dichloromethane, add the dry silica gel of 5g, stir 30 minutes, mistake after 39 DEG C of stirring and dissolving
Filter, be evaporated to it is dry, solid 40 DEG C be vacuum dried.Obtain 1.76g aprepitant polymorph II.
Claims (3)
1. a kind of preparation method of aprepitant crystalline polymorph II, comprises the following steps：A, at 10 DEG C -110 DEG C, by Ah
In good solvent, aprepitant quality with solvent volume ratio is the smooth solid dissolving of auspicious pyrrole：1g:(10～200mL)；B, addition silica gel
Stirring, filters；C, distillation and concentration solvent directly obtain crystal；D, the vacuum drying at 20 DEG C～100 DEG C, obtain final product aprepitant many
Crystal formation thing II；In step B, aprepitant with silica gel mass ratio is：1g:(1～10g).
2. the preparation method of a kind of aprepitant crystalline polymorph II according to claim 1, it is characterised in that：It is described
In step A, good solvent include acetone, ethyl acetate, dichloromethane, chloroform, toluene, dimethylbenzene, DMF, two
One or more in methyl sulfoxide, tetrahydrofuran, methanol, ethanol, propanol, isopropanol and ammonia.
3. the preparation method of a kind of aprepitant crystalline polymorph II according to claim 1, it is characterised in that：It is described
In step A, aprepitant quality with solvent volume ratio is：1g:(20～100mL).
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6096742A (en) * | 1997-07-02 | 2000-08-01 | Merck & Co., Inc. | Polymorphic form of a tachykinin receptor antagonist |
| CN1261882A (en) * | 1997-07-02 | 2000-08-02 | 麦克公司 | Polymorphic form of tachykinin receptor antagonist 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-5(oxo-1H,4H-1,2,4-triazolo methylmorpholine |
| WO2007088483A1 (en) * | 2006-02-03 | 2007-08-09 | Glenmark Pahrmaceuticals Limited | Amorphous and crystalline forms of aprepitant and processes for the preparation thereof |
| WO2007112457A2 (en) * | 2006-03-29 | 2007-10-04 | Dr. Reddy's Labortories, Ltd. | Aprepitant polymorph mixtures |
| WO2010092591A2 (en) * | 2008-06-30 | 2010-08-19 | Usv Limited | Novel crystalline polymorphs of 5-[[(2r,3s)-2-[(1r)-1-[3,5- bis(trifluoromethyl) phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2- dihydro-3h-1,2,4-triazol-3-one and process for preparation thereof |
| WO2010140132A1 (en) * | 2009-06-02 | 2010-12-09 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline aprepitant having form i content |
| WO2012146692A1 (en) * | 2011-04-29 | 2012-11-01 | Sandoz Ag | Novel intermediates for the preparation of highly pure aprepitant or fosaprepitant |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1912651A4 (en) * | 2005-07-29 | 2010-12-22 | Reddys Lab Ltd Dr | Amorphous aprepitant coprecipitates |
| WO2008026216A2 (en) * | 2006-08-28 | 2008-03-06 | Hetero Drugs Limited | Process for purification of aprepitant |
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- 2014-07-15 CN CN201410336829.9A patent/CN104119325B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6096742A (en) * | 1997-07-02 | 2000-08-01 | Merck & Co., Inc. | Polymorphic form of a tachykinin receptor antagonist |
| CN1261882A (en) * | 1997-07-02 | 2000-08-02 | 麦克公司 | Polymorphic form of tachykinin receptor antagonist 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl) phenyl) ethoxy)-3-(S)-(4-fluoro) phenyl-4-(3-5(oxo-1H,4H-1,2,4-triazolo methylmorpholine |
| WO2007088483A1 (en) * | 2006-02-03 | 2007-08-09 | Glenmark Pahrmaceuticals Limited | Amorphous and crystalline forms of aprepitant and processes for the preparation thereof |
| WO2007112457A2 (en) * | 2006-03-29 | 2007-10-04 | Dr. Reddy's Labortories, Ltd. | Aprepitant polymorph mixtures |
| WO2010092591A2 (en) * | 2008-06-30 | 2010-08-19 | Usv Limited | Novel crystalline polymorphs of 5-[[(2r,3s)-2-[(1r)-1-[3,5- bis(trifluoromethyl) phenyl] ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2- dihydro-3h-1,2,4-triazol-3-one and process for preparation thereof |
| WO2010140132A1 (en) * | 2009-06-02 | 2010-12-09 | Ranbaxy Laboratories Limited | Process for the preparation of crystalline aprepitant having form i content |
| WO2012146692A1 (en) * | 2011-04-29 | 2012-11-01 | Sandoz Ag | Novel intermediates for the preparation of highly pure aprepitant or fosaprepitant |
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Address after: 528473 Guangdong province Zhongshan Torch Development Zone Zhongjing Road No. 6 Applicant after: Zhongshan Enantiotech Corporation Ltd. Address before: 528473 Guangdong city in Zhongshan Province, the national Torch Development Zone health base Zhongjing Road No. 6 Applicant before: Zhongshan Enantiotech Corporation Ltd. |
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Denomination of invention: Preparation of aripiptam polymorphs Effective date of registration: 20200914 Granted publication date: 20170322 Pledgee: China Co. truction Bank Corp Zhongshan branch Pledgor: ENANTIOTECH Corp.,Ltd. Registration number: Y2020440000271 |