CN103193850A - Novel crystal form of steroidal compound, and preparation method thereof - Google Patents
Novel crystal form of steroidal compound, and preparation method thereof Download PDFInfo
- Publication number
- CN103193850A CN103193850A CN2012100005167A CN201210000516A CN103193850A CN 103193850 A CN103193850 A CN 103193850A CN 2012100005167 A CN2012100005167 A CN 2012100005167A CN 201210000516 A CN201210000516 A CN 201210000516A CN 103193850 A CN103193850 A CN 103193850A
- Authority
- CN
- China
- Prior art keywords
- zafirlukast
- gifted
- acetic acid
- alcohol solvent
- solvent compound
- 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
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a method for purifying ulipristal acetate. A crude product of the compound is re-crystallized in ethanol, such that an ethanol solvate is obtained; and any known method is adopted, for example a proper solvent is used in re-crystallization, such that a high-purity target product is obtained. The ethanol solvate is a novel stable ulipristal acetate crystal form, and can be used as a useful intermediate in preparing high-purity ulipristal acetate.
Description
Technical field
The present invention relates to alcohol solvent compound crystal formation of a kind of steroidal compounds and preparation method thereof.
Background technology
Compound 17 α-acetoxyl group-11 β-(4-N, N-dimethylamino phenyl)-19-norpregna-4,9-diene-3, the structural formula of 20-diketone (acetic acid gifted zafirlukast) is as follows:
The acetic acid gifted zafirlukast is a kind of synthetic progesterone receptor modulator, has antiprogestin and anti-cortin activity, can be used for contraception, treatment gynaecopathia, hypercortisolism and glaucoma etc.
Described compound and preparation method thereof is open in patent US4954490.
After disclosing acetic acid gifted zafirlukast crude product employing acetone/normal hexane mixed solvent recrystallization among the WO2004078709, obtain a kind of yellow crystals; Described crystal is yellow, shows wherein to have impurity.
Virahol half solvate crystal formation of acetic acid gifted zafirlukast and preparation method thereof is disclosed among the patent CN1753905: with acetic acid gifted zafirlukast crude product in Virahol after the crystallization, generate half solvate, with its recrystallization in the solvent that is selected between ethanol/water and the ether, obtain required product again.
Summary of the invention
The invention provides a kind of method of purifying acetic acid gifted zafirlukast.With crude product recrystallization in ethanol of described compound, obtain the alcohol solvent compound.By any known method, for example adopt suitable solvent to carry out recrystallization again, can obtain target product with high purity.Described alcohol solvent compound is a kind of new stable urethane acetate polymorph zafirlukast, can be used as the useful intermediates of preparation high purity acetic acid gifted zafirlukast.
Present method refining effect is good, and the molar yield that obtains acetic acid gifted zafirlukast alcohol solvent compound can reach more than 90%; Agents useful for same is easy to get safely, and is with low cost.Present method is practical, and is lower to requirements such as equipment, not only can be used for laboratory study, also is well suited for industrialized amplification production.
Acetic acid gifted zafirlukast crude product can obtain by any method known in the art.For example, can be according to US4954490, US5929262, WO2004078709, disclosed method preparation among the CN101466723.
Described acetic acid gifted zafirlukast alcohol solvent compound can obtain through following method: the acetic acid gifted zafirlukast is dissolved in the ethanol, then forms described alcohol solvent compound crystal.Be dissolved in the process of ethanol, preferably under heating condition, carry out, for example under the temperature that comprises between 40 ℃ and the solvent refluxing temperature, carry out, then with the cooling of gained solution, form alcohol solvent compound crystal.Can adopt any known mode cooling solution, for example can adopt the stirring method of cooling, the temperature of cooling preferably includes the temperature between-10 ℃ and 30 ℃.Solvent in the described solvent refluxing temperature specifically refers to the alcohol solvent that present method is used, and normal atmospheric is depressed, and its reflux temperature is about 78 ℃, because the change of external environment and solvent for use concentration has the variation of certain limit, decides with concrete experiment condition.
Further obtain the acetic acid gifted zafirlukast by described alcohol solvent compound, can adopt any method known in the art, for example can adopt method shown in the embodiment 3.
Acetic acid gifted zafirlukast alcohol solvent compound crystal formation of the present invention can be differentiated and characterize by exotherm, powder x-ray diffraction figure (XRD), infrared (IR) spectrogram of dsc (DSC), it is characterized in that:
The exotherm of dsc (Fig. 1) shows at about 146.0 ℃ has located a peak, and it is consistent at the absorption melting phenomenon of high temperature with described alcohol solvent compound;
Its shows in fact and similar powder x-ray diffraction figure shown in Figure 2 that there is characteristic peak at 2 θ places at 8.800,9.080,17.720 degree.In particular, listed feature in the XRD analysis indicator gauge 1 of described alcohol solvent compound;
Its shows in fact and similar Potassium Bromide particle infrared spectra shown in Figure 3,1733,1717,1663,1596,1514,1459,1438,1366,1262,1202,1168,1139,1090,1076,1015,949,863,831,794 and 771cm
-1The place has remarkable bands of a spectrum.
Table 1 acetic acid gifted zafirlukast alcohol solvent compound powder X-ray RD feature
D: distance; Intensity: peak intensity; Rel.I: relative intensity
Description of drawings
Fig. 1 shows the exotherm of the dsc (DSC) of acetic acid gifted zafirlukast alcohol solvent compound, in the container of a sealing, carry out, under the temperature that comprises between 10 ℃ and 200 ℃, rate of heating is 10 ℃/min, show the energy that per time unit (mV) absorbs or sees through on the Y-axis, displays temperature on the X-axis (℃).
Fig. 2 shows X-ray diffraction (XRD) spectrogram of acetic acid gifted zafirlukast alcohol solvent compound, adopts Japanese Rigaku Dmax2400 type X-ray polycrystal powder diffractometer of science, the Cu target, and voltage 40kV, electric current 100mA, use has
The source of radiation of wavelength, Y-axis shows peak intensity, X-axis shows angle 2 θ.
Fig. 3 shows infrared (IR) spectrogram of acetic acid gifted zafirlukast alcohol solvent compound, and it uses the Potassium Bromide particle to carry out at Perkin Elmer1600 Fourier transform IR (FT-IR) spectrophotometer, shows transmittance on the Y-axis, shows wave number (cm on the X-axis
-1).
Embodiment
Embodiment 1: the preparation of acetic acid gifted zafirlukast alcohol solvent compound
Add the 300ml dehydrated alcohol in the 100g acetic acid gifted zafirlukast crude product (adopt CN101466723 in disclosed method preparation) and be heated in 40 ℃ to the 80 ℃ temperature ranges till the dissolving.Then reaction solution is cooled to the temperature that comprises between-10 ℃ and 10 ℃, kept this temperature 2 hours.Filter the gained suspension liquid, and with cold washing with alcohol filter cake, get acetic acid gifted zafirlukast alcohol solvent compound, molar yield is 92.3%.The content that adopts vapor-phase chromatography to record ethanol in this solvate is 2.6%.
Embodiment 2: the preparation of acetic acid gifted zafirlukast alcohol solvent compound
Add 500ml 95% ethanol in the 100g acetic acid gifted zafirlukast crude product (adopt CN101466723 in disclosed method preparation) and be heated in 40 ℃ to the 80 ℃ temperature ranges till the dissolving.Then reaction solution is cooled to the temperature that comprises between 10 ℃ and 40 ℃, kept this temperature 3 hours.Filter the gained suspension liquid, and with cold washing with alcohol filter cake, get acetic acid gifted zafirlukast alcohol solvent compound, molar yield is 90.2%.The content that adopts vapor-phase chromatography to record ethanol in this solvate is 2.5%.
Embodiment 3: obtain the acetic acid gifted zafirlukast by acetic acid gifted zafirlukast alcohol solvent compound
The acetic acid gifted zafirlukast alcohol solvent compound (by the preparation of method shown in the embodiment 1) of 50g is added in the reaction flask, add the ethyl acetate of 200ml, after the heating for dissolving, slowly drip the normal hexane of 200ml again, be cooled to crystallization between 0 ℃ and 10 ℃ after dropwising again, filter the gained crystal.Under 70-80 ℃, be dried to constant weight, obtain the acetic acid gifted zafirlukast of 40g.
Claims (8)
1. the method for a purifying acetic acid gifted zafirlukast comprises acetic acid gifted zafirlukast crude product recrystallization in ethanol is formed acetic acid gifted zafirlukast alcohol solvent compound.
2. according to the method for claim 1, the formation that it is characterized in that acetic acid gifted zafirlukast alcohol solvent compound is included under the heating condition acetic acid gifted zafirlukast dissolving crude product in ethanol, then gained solution is cooled off.
3. according to the method for claim 2, after it is characterized in that the acetic acid gifted zafirlukast is dissolved in ethanol, the solution of cooling gained between-10 ℃ and 30 ℃.
4. acetic acid gifted zafirlukast alcohol solvent compound crystal formation, the exotherm that it is characterized in that dsc shows at about 146.0 ℃ has located a peak.
5. according to the described urethane acetate polymorph zafirlukast of claim 4, it is characterized in that it is presented at the powder x-ray diffraction figure that there is characteristic peak at 8.800,9.080,17.720 degree, 2 θ places.
6. according to the described urethane acetate polymorph zafirlukast of claim 5, it is characterized in that its infrared spectra is presented at 1733,1717,1663,1596,1514,1459,1438,1366,1262,1202,1168,1139,1090,1076,1015,949,863,831,794 and 771cm
-1The place has remarkable bands of a spectrum.
7. method that obtains acetic acid gifted zafirlukast alcohol solvent compound is included under the heating condition acetic acid gifted zafirlukast is dissolved in the ethanol, then gained solution is cooled to the temperature that comprises between-10 ℃ and 30 ℃.
Acetic acid gifted zafirlukast alcohol solvent compound in purifying acetic acid gifted zafirlukast process as the application of intermediate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100005167A CN103193850A (en) | 2012-01-04 | 2012-01-04 | Novel crystal form of steroidal compound, and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100005167A CN103193850A (en) | 2012-01-04 | 2012-01-04 | Novel crystal form of steroidal compound, and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103193850A true CN103193850A (en) | 2013-07-10 |
Family
ID=48716682
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012100005167A Pending CN103193850A (en) | 2012-01-04 | 2012-01-04 | Novel crystal form of steroidal compound, and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103193850A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014050106A1 (en) * | 2012-09-28 | 2014-04-03 | Aska Pharmaceutical Co., Ltd. | Crystalline polymorphic form of ulipristal acetate |
| CN104861025A (en) * | 2015-05-16 | 2015-08-26 | 南京海纳医药科技有限公司 | Purification method of ulipristal acetate |
| US9643994B2 (en) | 2012-09-28 | 2017-05-09 | Aska Pharmaceutical Co., Ltd. | Crystalline polymorphic form of ulipristal acetate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1753905A (en) * | 2003-01-22 | 2006-03-29 | 克利斯托制药股份有限公司 | Method of obtaining 17alpha-acetoxy-11beta-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process |
-
2012
- 2012-01-04 CN CN2012100005167A patent/CN103193850A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1753905A (en) * | 2003-01-22 | 2006-03-29 | 克利斯托制药股份有限公司 | Method of obtaining 17alpha-acetoxy-11beta-(4-n,n-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione |
| CN101466723A (en) * | 2006-06-14 | 2009-06-24 | 吉瑞工厂 | Industrial process for the synthesis of 17a-acetoxy-11ss-[4-(n,n-dimethyl-amino)- phenyl]-19-norpregna-4,9-diene-3,20-dione and new intermediates of the process |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014050106A1 (en) * | 2012-09-28 | 2014-04-03 | Aska Pharmaceutical Co., Ltd. | Crystalline polymorphic form of ulipristal acetate |
| US9643993B2 (en) | 2012-09-28 | 2017-05-09 | Aska Pharmaceutical Co., Ltd. | Crystalline polymorphic form of ulipristal acetate |
| US9643994B2 (en) | 2012-09-28 | 2017-05-09 | Aska Pharmaceutical Co., Ltd. | Crystalline polymorphic form of ulipristal acetate |
| CN104861025A (en) * | 2015-05-16 | 2015-08-26 | 南京海纳医药科技有限公司 | Purification method of ulipristal acetate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW200930702A (en) | Indolinone derivatives and process for their manufacture | |
| CN103193850A (en) | Novel crystal form of steroidal compound, and preparation method thereof | |
| CN104725335A (en) | Preparation method of high-purity vortioxetine hydrobromide | |
| CN112500361B (en) | Preparation method of (S) -4-phenyl-2-oxazolidinone | |
| WO2016161826A1 (en) | Method for preparing 4-isopropylamino-1-butanol | |
| CN105884644B (en) | Neutral endopeptidase inhibitor salt dominant form and preparation method thereof | |
| CN102344478B (en) | Crystal of 17 alpha-acetoxyl group-11 beta-(4-N, N-dimethylamino phenyl)-19-norpregna-4, 9- diene-3, 20- ketone and preparation method thereof | |
| KR20150090207A (en) | Synthesis of UV Absorbing Compounds | |
| CN111039852A (en) | N-ethylpyridine methylamine hydrochloride crystal, preparation process and application thereof in preparation of tropicamide | |
| CN114292203B (en) | Preparation method of DL-panthenol | |
| CN112194608B (en) | Synthesis method of visible light promoted 3-methyl-3-difluoroethyl-2-oxindole compound | |
| MX2008013801A (en) | Process for the synthesis of (+) and (-)-1-(3,4-dichlorophenyl)-3 -azabicyclo[3.1.0]hexane. | |
| JP6040079B2 (en) | Method for producing amide derivative | |
| CN112694427A (en) | Method for preparing 2, 3-dimethyl sulfide | |
| US20150246877A1 (en) | Aryl tetrafluorosulfanyl compounds | |
| CN112441978B (en) | Preparation method of 1-methyl-5-hydroxypyrazole-4-carboxylic acid ethyl ester | |
| WO2020048343A1 (en) | Synthesis method for 6-furfurylaminopurine | |
| CN107417754A (en) | A kind of preparation method of dexamethasone and betamethasone key intermediate | |
| CN111253303B (en) | Method for synthesizing 3-selenium-spiro (2-cyclopentene-1,3-indole) -4-ketone | |
| CN109180462A (en) | A method of preparing n-nonanoic acid and azelaic acid | |
| CN101898973A (en) | Preparation method of L-valine methyl ester hydrochloride | |
| CN104447522B (en) | The preparation method of 5 nitro, 2 aminopyridine | |
| CN112159336B (en) | Preparation method of high-purity aryne substituted nitrile compound | |
| AU2005209382A1 (en) | Method for producing a 2-(ethoxymethyl)tropane derivative | |
| CN105541818A (en) | Novel crystal form of canagliflozin hydrate and preparation method of novel crystal form |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 100024 No. 27 Chaoyang North Road, Beijing, Chaoyang District Applicant after: CHINA?RESOURCES?ZIZHU?PHARMACEUTICAL?CO., LTD. Address before: 100024 No. 27 Chaoyang North Road, Beijing, Chaoyang District Applicant before: Zizhu Pharmaceutical Co., Ltd., Beijing |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: ZIZHU PHARMACEUTICAL CO., LTD., BEIJING TO: HUARUN ZIZHU PHARMACEUTICAL CO., LTD. |
|
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130710 |