CN105949095A - Method for preparing bicalutamide of crystal form I - Google Patents
Method for preparing bicalutamide of crystal form I Download PDFInfo
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- CN105949095A CN105949095A CN201610360152.1A CN201610360152A CN105949095A CN 105949095 A CN105949095 A CN 105949095A CN 201610360152 A CN201610360152 A CN 201610360152A CN 105949095 A CN105949095 A CN 105949095A
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- bicalutamide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
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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 method for preparing bicalutamide of a crystal form I. The method comprises the following steps of enabling the bicalutamide to be completely dissolved in a ketone solvent, mixing with an ether solvent to precipitate crystals, and then filtering and drying to obtain the bicalutamide of the crystal form I. The method for preparing the bicalutamide of the crystal form I has the advantages of yield not lower than 80%, environment friendliness of a crystallization solvent, low production cost, simple process and short period, and is suitable for industrial production.
Description
Technical field
The invention belongs to technical field of chemical medicine, relate to preparing the method with regulation crystal-form compound, particularly relate to a kind of method preparing bicalutamide I crystal.
Background technology
Bicalutamide (bicalutamide); common name bicalutamide; chemical name: (±)-N-[4-cyano group-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) sulfonyl]-2-hydroxy-2-methyl propionic acid amide., chemical formula is as follows.
Bicalutamide is the non steroidal antiandrogen of ICI drugmaker of Britain exploitation, and nineteen ninety-five lists in Ireland, Britain, the U.S. with trade name Casodex simultaneously.China's approval of import bicalutamide tablet (specification 50mg) in 1999, import licence X-1999-0358.Bicalutamide is a pure androgen antagonist medicine, and action specificity is strong, oral effective, convenient drug administration, better tolerance, and has the longer half-life.Due to the curative effect of its uniqueness, at home and abroad it is used for the therapeutic alliance of advanced prostate cancer.150mg dosage bicalutamide is clinically for early prostate cancer, and its therapeutic effect is identical with the curative effect of male castration, has wide application space.It addition, low dose of bicalutamide applies also for the treatment of some androgen-dependent disorders, such as, can treat female hirsutism, acne, bicalutamide also can treat prostatic hyperplasia.Therefore, bicalutamide has good potential applicability in clinical practice.
Polymorphism is widely present in medicine.The different crystal forms of same medicine has significant difference at aspects such as dissolubility, fusing point, density, stability, thus the stability of medicine, homogeneity, bioavailability and safety can be produced impact in various degree.Therefore, in medicament research and development, research to drug crystal forms is an important content.
The crystal formation of bicalutamide is divided into crystal type and unformed, and crystal type is divided into again I type and II type.The commercially available mixture that some bicalutamide crude drug are crystal formation I and crystal formation II.But the former crystal formation grinding bicalutamide is I type, and this crystal formation is the most stable and drug effect is best.Therefore, stable I type bicalutamide is obtained by controlled preparation process significant.
So far, three kinds are mainly had: 1, bicalutamide crude drug recrystallization in ethyl acetate and hydrocarbon solvent can be obtained I crystal by CN 1602299A report about the method preparing I type bicalutamide, but the method uses and has arrived some two kind solvents, belong to not environment friendly type solvent；2, " synthesis of bicalutamide " (Zhejiang chemical industry, 2013,44 (6), 7-9) report, bicalutamide crude drug recrystallization in dehydrated alcohol can be obtained I crystal, but the recrystallization method yield that the document relates to is relatively low, only 77.9%, it is unfavorable for industrial amplification production；null3、" anti-solvent recrystallization method prepares polymorphic bicalutamide " (Beijing University of Chemical Technology's journal, 2008, 35(4),14-17) report，With four kinds of single solvent dimethyl sulfoxide、Ethanol、Acetone or oxolane make positive solvent，Distilled water is that anti-solvent prepares bicalutamide，Result is that the bicalutamide using dimethyl sulfoxide and ethanol to prepare presents crystal formation II，Then there is the mixing situation of crystal formation I and crystal formation II in product prepared by oxolane and acetone，Illustrate that the crystals of bicalutamide using above four kinds of single solvents to prepare all can not meet the requirement of preparation I type bicalutamide，Additionally，Although doing good solvent with the mixed solvent of acetone (dimethyl sulfoxide) and ethanol，Water makees poor solvent，Available I crystal is prepared with cosolvent，But the method high to equipment requirements (mixing speed 2500r/min)，Industrialization is difficult to.
Based on this, exploitation yield is high, operates, processes simply, is suitable for the industrial new method of bicalutamide I crystal significant.
Summary of the invention
It is an object of the invention to provide the preparation method of a kind of bicalutamide I crystal, on the basis of using safety solvent, high yield prepares bicalutamide I crystal.
The preparation method of bicalutamide I crystal of the present invention is first to make bicalutamide be completely dissolved in ketones solvent, then mixes with ether solvent to separate out crystal, and filtration drying obtains the bicalutamide of I crystal.
Wherein, indefiniteness, described ketones solvent is acetone, butanone or methyl iso-butyl ketone (MIBK), and described ether solvent is ether, methyl tertiary butyl ether(MTBE) or three fourth MEEs.
Further, described ketones solvent is preferably acetone, and ether solvent is preferably ether.
In the present invention, preferably bicalutamide is dissolved in ketones solvent the solution obtaining 40～150mg/mL.
Further, described ketones solvent is preferably 1: 1～10 with the consumption volume ratio of ether solvent.
Usually, described ether solvent can mix with ketones solvent by any way, does not affect crystal formation and the yield of final products.
In the present invention, the crystallize time after addition ether solvent is generally 5min～48h.
The preparation method production cost of the bicalutamide I crystal that the present invention provides is low, the cycle is short, technological operation is easy, preparation process all use three kind solvents as recrystallisation solvent, environmentally friendly, it is suitable for industrialized production, and high yield (being not less than 80%) has obtained bicalutamide I crystal, drug quality is made to have been further upgraded.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of the bicalutamide I crystal of embodiment 1 preparation.
Detailed description of the invention
Below in conjunction with specific embodiment, technical solution of the present invention is further detailed.Embodiment of the present invention is only used for explaining the present invention, and is not construed as limiting scope.On the premise of without departing substantially from technical solution of the present invention, any change that the those skilled in the art done by the present invention are easily realized, all it is considered as present disclosure.
Embodiment 1
Weigh 2g bicalutamide, join in 15mL acetone and be completely dissolved, in system, be slowly added dropwise 75mL ether, have white solid to separate out, continue stirring and crystallizing 2h, filter, filter cake is dried in 60 DEG C, obtains solid crystal product 1.89g, yield 94.5%.
Products obtained therefrom is analyzed by the D8 Advance x-ray powder diffraction instrument using Bruker company of Germany, voltage and current 40KV/40mA, X-ray wavelength 1.5406, sweep limits 5～60 °, step-length 0.02 °, 0.1 second/step of scanning speed, obtain the X-ray powder diffraction figure shown in Fig. 1.
As shown in Figure 1, sample XRPD is presented at the lower group of angle of diffraction has maximum diffraction peak: 6.06 ± 0.12,9.43 ± 0.12,11.74 ± 0.12,12.21 ± 0.12,13.86 ± 0.12,14.04 ± 0.12,16.88 ± 0.12,17.24 ± 0.12,18.32 ± 0.12,19.82 ± 0.12,23.12 ± 0.12,23.82 ± 0.12,24.74 ± 0.12,29.50 ± 0.12,31.42 ± 0.12, with " Conformational
polymorphism in bicalutamide”(International Journal of
Pharmaceutics, 2007, 328, 112 118) etc. document report bicalutamide I crystal X-ray powder diffraction spectrogram consistent, it was demonstrated that it is bicalutamide I crystal that the present embodiment prepares sample.
Embodiment 2
Weigh 2g bicalutamide, join in 15mL acetone and be completely dissolved, in system, be slowly added dropwise 15mL ether, have white solid to separate out, continue stirring and crystallizing 48h, filter, filter cake is dried in 60 DEG C, obtains solid crystal 1.82g, yield 91.0%.X-ray powder diffraction figure shows that products obtained therefrom is bicalutamide I crystal.
Embodiment 3
Weigh 2g bicalutamide, join in 30mL acetone and be completely dissolved, in system, be slowly added dropwise 300mL ether, have white solid to separate out, continue stirring and crystallizing 2h, filter, filter cake is dried in 60 DEG C, obtains solid crystal 1.65g, yield 82.5%.X-ray powder diffraction figure shows that products obtained therefrom is bicalutamide I crystal.
Embodiment 4
Weigh 2g bicalutamide, join in 50mL acetone and be completely dissolved, in system, be slowly added dropwise 250mL ether, have white solid to separate out, continue stirring and crystallizing 2h, filter, filter cake is dried in 60 DEG C, obtains solid crystal 1.62g, yield 81.0%.X-ray powder diffraction figure shows that products obtained therefrom is bicalutamide I crystal.
Embodiment 5
Weigh 2g bicalutamide, join in 15mL acetone and be completely dissolved, in system, be slowly added dropwise 75mL ether, have white solid to separate out, continue stirring and crystallizing 5min, filter, filter cake is dried in 60 DEG C, obtains solid crystal 1.79g, yield 89.5%.X-ray powder diffraction figure shows that products obtained therefrom is bicalutamide I crystal.
Embodiment 6
Weigh 2g bicalutamide, join in 15mL acetone and be completely dissolved, in system, be slowly added dropwise 75mL methyl tertiary butyl ether(MTBE), have white solid to separate out, continue stirring and crystallizing 2h, filter, filter cake is dried in 60 DEG C, obtains solid crystal 1.83g, yield 91.5%.X-ray powder diffraction figure shows that products obtained therefrom is bicalutamide I crystal.
Embodiment 7
Weigh 2g bicalutamide, join in 20mL hexone and be completely dissolved, in system, be slowly added dropwise 75mL methyl tertiary butyl ether(MTBE), there is white solid to separate out, continue stirring and crystallizing 2h, filter, filter cake is dried in 60 DEG C, obtains solid crystal 1.78g, yield 89.0%.X-ray powder diffraction figure shows that products obtained therefrom is bicalutamide I crystal.
Embodiment 8
Weigh 2g bicalutamide, join in 20mL butanone and be completely dissolved, in system, be slowly added dropwise 75mL tri-fourth MEE, have white solid to separate out, continue stirring and crystallizing 2h, filter, filter cake is dried in 60 DEG C, obtains solid crystal 1.81g, yield 90.5%.X-ray powder diffraction figure shows that products obtained therefrom is bicalutamide I crystal.
Embodiment 9
Weigh 2kg bicalutamide, join in 15L acetone and be completely dissolved, in system, be slowly added dropwise 75mL ether, have white solid to separate out, continue stirring and crystallizing 4h, filter, filter cake is dried in 60 DEG C, obtains solid crystal 1.92kg, yield 96.0%.X-ray powder diffraction figure shows that products obtained therefrom is bicalutamide I crystal.
Claims (6)
1. a preparation method for bicalutamide I crystal, is first to make bicalutamide be completely dissolved in ketones solvent, then mixes with ether solvent to separate out crystal, and filtration drying obtains the bicalutamide of I crystal.
Preparation method the most according to claim 1, is characterized in that described ketones solvent is acetone, butanone or methyl iso-butyl ketone (MIBK), and ether solvent is ether, methyl tertiary butyl ether(MTBE) or three fourth MEEs.
Preparation method the most according to claim 1, is characterized in that described ketones solvent is acetone, and ether solvent is ether.
4., according to the preparation method described in claim 1,2 or 3, it is characterized in that bicalutamide is dissolved in ketones solvent the solution obtaining 40～150mg/mL.
5., according to the preparation method described in claim 1,2 or 3, it is characterized in that described ketones solvent is 1: 1～10 with the consumption volume ratio of ether solvent.
6., according to the preparation method described in claim 1,2 or 3, it is characterized in that the crystallize time after adding ether solvent is 5min～48h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201610360152.1A CN105949095A (en) | 2016-05-27 | 2016-05-27 | Method for preparing bicalutamide of crystal form I |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004074350A2 (en) * | 2003-02-21 | 2004-09-02 | Hetero Drugs Limited | Bicalutamide polymorphs |
| CN1602299A (en) * | 2001-12-13 | 2005-03-30 | 住友化学工业株式会社 | Crystals of bicalutamide and process for their production |
| CN1819992A (en) * | 2003-06-25 | 2006-08-16 | 特瓦药厂私人有限公司 | Process for purifying and separating rac-bicalutamide |
| WO2006103689A1 (en) * | 2005-03-29 | 2006-10-05 | Usv Limited | Process for preparation of bicalutamide |
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- 2016-05-27 CN CN201610360152.1A patent/CN105949095A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1602299A (en) * | 2001-12-13 | 2005-03-30 | 住友化学工业株式会社 | Crystals of bicalutamide and process for their production |
| WO2004074350A2 (en) * | 2003-02-21 | 2004-09-02 | Hetero Drugs Limited | Bicalutamide polymorphs |
| CN1819992A (en) * | 2003-06-25 | 2006-08-16 | 特瓦药厂私人有限公司 | Process for purifying and separating rac-bicalutamide |
| WO2006103689A1 (en) * | 2005-03-29 | 2006-10-05 | Usv Limited | Process for preparation of bicalutamide |
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