CN106565552A - Belinostat crystal and preparation method therefor - Google Patents
Belinostat crystal and preparation method therefor Download PDFInfo
- Publication number
- CN106565552A CN106565552A CN201610985194.4A CN201610985194A CN106565552A CN 106565552 A CN106565552 A CN 106565552A CN 201610985194 A CN201610985194 A CN 201610985194A CN 106565552 A CN106565552 A CN 106565552A
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- China
- Prior art keywords
- crystalline solid
- preparation
- baily department
- baily
- belinostat
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
- 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 relates to a belinostat crystal and a preparation method therefor. An X-ray powder diffraction spectrum has characteristic diffraction peak at diffraction angles, expressed by 2<theta> (degrees), of 4.49 plus or minus 0.2, 11.16 plus or minus 0.2, 14.68 plus or minus 0.2, 20.80 plus or minus 0.2, 21.15 plus or minus 0.2 and 26.45 plus or minus 0.2. By adoption of the belinostat crystal and the preparation method therefor, the problems existing in the prior art are solved; the belinostat crystal is high in product purity, low in raw material impurity content, and qualified in appearance; and the belinostat crystal can be used in drug processing favorably.
Description
Technical field
The present invention relates to a kind of medicine, and in particular to a kind of his crystalline solid of Baily department and preparation method thereof.
Background technology
Baily department his (Belinostat, having structure) is a kind of small molecule of different hydroxyl valeric acid structure, be I type, II type and
IV type inhibitors of histone deacetylase (HDACI), is to be developed jointly by TopoTarget and Spectrum companies, mainly
For treating relapsed or stubborn periphery lymphoma (PTCL).Histone acetyltransferase and histone deacetylase are genes
Actuator during expression, the acetylation of histone can make gene expression, and deacetylated effect then can suppressor gene
Expression, in tumor cell, histone deacetylation effect can make the suppressor gene silence of tumor, so as to promote tumor to increase.
Therefore, inhibitors of histone deacetylase can recover tumor suppressor gene so as to suppress tumour growth.
Baily department he obtain U.S. FDA on July 3rd, 2014 and tentatively ratify, drench for treating adult's recurrent and refractory periphery
Bar tumor, the medicine are intravenous injection.Baily department he be since two thousand nine be used for PTCL treatment the 3rd kind of medicine.Face in II phase
The bed stage, Baily department he improved 25.8% state of an illness in 129 PTCL patients.At present clinic studying Baily department he
Single medicine or drug combination to leukemia and the therapeutical effect of solid tumor.
There is not the relevant report of his crystal formation of Baily department at present.
It is poor that current his feed purification of Baily department has a product purity, and raw material impurity content is high, and outward appearance is unqualified, and
And existing crystal formation affects the defects such as the quality of final preparation.
The content of the invention
It is an object of the invention to provide a kind of his crystalline solid, preparation method and applications of Baily department, solve prior art
The problems referred to above, specific product purity are high, and raw material impurity content is low, and outward appearance is qualified, beneficial to which used in medicine processing.
The present invention is a kind of his crystalline solid of Baily department for being more conducive to be prepared into preparation.
In order to solve above-mentioned technical problem, the present invention proposes a kind of his crystalline solid of Baily department, is penetrated with the X that 2 θ angles are represented
Line powder diffraction spectrum 4.49 ± 0.2,11.16 ± 0.2,14.68 ± 0.2,20.80 ± 0.2,21.15 ± 0.2,26.45 ±
There is at 0.2 characteristic diffraction peak；
His crystalline solid of described Baily department, in the powder X-ray diffraction collection of illustrative plates of described crystalline solid, with including 2 θ of the angle of diffraction
(°)：4.49±0.2、11.16±0.2、13.64±0.2、14.68±0.2、15.54±0.2、16.65±0.2、19.08±
0.2nd, there is characteristic diffraction peak at 20.80 ± 0.2,21.15 ± 0.2,22.69 ± 0.2,26.45 ± 0.2.
The preparation method of described his crystalline solid of Baily department, by Baily department, his crude product is added in acetonitrile, is heated to reflux, heat
Filter cooling crystallize, filters, solvent washing, vacuum drying.
During his crude product of Baily department is added to acetonitrile, solution temperature is 50 DEG C～81 DEG C.
Recrystallization temperature is -20 DEG C～20 DEG C, and the crystallize time is 3-5 hours.
The consumption of acetonitrile is 5～30 for the envelope-bulk to weight ratio of his crude product of Baily department.I.e. the volumetric usage of acetonitrile is Baily department
5～30 times of the weight of his crude product.
His the concrete preparation process of crystalline solid of Baily department of the present invention is as follows：
Take in his crude product addition reactor of Baily department, add 2.5-15L commercial product acetonitriles to be heated to 50 DEG C of -81 DEG C of backflows, plus
Thermal agitation is completely dissolved up to crude product, continues stirring 30 minutes, and filtered while hot, filtrate slow cooling are stirred to -20 DEG C -20 DEG C
Crystallize 3-5 hours, filter, and filter cake is washed with acetonitrile beating, 40-50 DEG C of drying under reduced pressure, obtain product, and HPLC determines purity, and
Calculated yield.
A kind of his novel crystallization body of anticarcinogen-Baily department is specifically related to, is applied to treat the medicine of tumor.
The present invention can be used in pharmaceutical composition, wherein comprising his crystalline solid of described Baily department and one or more medicine
Carrier, excipient or diluent on.
The present invention uses Cu-K α1X radiation x.
Compared with prior art, the invention has the advantages that：
The present invention plants his crystalline solid of Baily department and preparation method thereof, solves the problems referred to above of prior art, and specific product is pure
Degree is high, and raw material impurity content is low, and outward appearance is qualified, beneficial to which used in medicine processing.
Description of the drawings
XRPD collection of illustrative plates of the Fig. 1 for his crystalline solid of 1 Baily department of embodiment.
XRPD tables of data of the Fig. 2 for his crystalline solid of 1 Baily department of embodiment.
HPLC collection of illustrative plates of the Fig. 3 for his crystalline solid of 1 Baily department of embodiment.
Solid state NMR collection of illustrative plates (one) of the Fig. 4 for his crystalline solid of 1 Baily department of embodiment.
Solid state NMR collection of illustrative plates (two) of the Fig. 5 for his crystalline solid of 1 Baily department of embodiment.
Specific embodiment
The present invention is described in detail below according to embodiment.But the scope of the present invention is not limited to the following example.
Embodiment 1
His preparation process of crystalline solid of Baily department is as follows：
Take in his crude product addition reactor of 500g Bailies department, add 2.5L commercial product acetonitriles to be heated to 81 DEG C of backflows, heating is stirred
Mix until crude product is completely dissolved, continue stirring 30 minutes, filtered while hot, filtrate slow cooling to 20 DEG C, stirring and crystallizing 4 hours,
Filter, filter cake is washed with acetonitrile beating, 40 DEG C of drying under reduced pressure, obtain product, it is 99.96% that HPLC determines purity, and calculates receipts
Rate is 94.3%.
His crystalline solid of Baily department is characterized by XRPD
The measurement of X-ray powder diffraction (XRPD) collection of illustrative plates, using Cu-K α1X radiation x.Thereafter XRPD collection of illustrative plates is adopted
Similar measuring method.
His quality relevant comparative such as table 1 of the Baily department of his crystalline solid of 1 Baily department of embodiment and existing crystallization purifying.
From dissolution velocity relatively, his crystalline solid of Baily department of the invention compared with prior art outward appearance, dissolubility,
The aspects such as impurity, redissolution time are respectively provided with advantage, are more suitable for which and apply in pharmaceutical preparation processing.
Freeze-dried powder prepared by the Baily Si Taxin crystalline solid of embodiment 1 and the redissolution time of reference substance outward appearance it is right
Such as table 2.
The redissolution time of freeze-dried powder prepared by the Baily Si Taxin crystalline solid of 3 embodiment 1 of table and reference substance outward appearance
Contrast
| Sample | The redissolution time (second) | Outward appearance |
| Freeze-dried powder prepared by the present invention | 10 | Light orange solid |
| Listing preparation | 60 | Yellow solid |
Embodiment 2
His preparation process of crystalline solid of Baily department is as follows：
Take in his crude product addition reactor of 500g Bailies department, add 15L commercial product acetonitriles to be heated to 50 DEG C of backflows, heated and stirred
Until crude product is completely dissolved, continue stirring 30 minutes, filtered while hot, extremely -20 DEG C of filtrate slow cooling, stirring and crystallizing 4 hours, mistake
Filter, filter cake are washed with acetonitrile beating, 50 DEG C of drying under reduced pressure, obtain product, and it is 99.97% that HPLC determines purity, and calculated yield
For 93.7%.
Embodiment 3
His preparation process of crystalline solid of Baily department is as follows：
Take in his crude product addition reactor of 500g Bailies department, add 10L commercial product acetonitriles to be heated to 65 DEG C of backflows, heated and stirred
Until crude product is completely dissolved, continue stirring 30 minutes, filtered while hot, filtrate slow cooling to 0 DEG C, stirring and crystallizing 4 hours, mistake
Filter, filter cake are washed with acetonitrile beating, 45 DEG C of drying under reduced pressure, obtain product, and it is 99.96% that HPLC determines purity, and calculated yield
For 93.9%.
The testing result of embodiment 2-3 is similar with the testing result of embodiment 1.
Although those skilled in the art is it should be understood that for illustrative purposes, this document describes the tool of the present invention
Body embodiment, but various modifications can be carried out to which without departing from the spirit and scope of the present invention.Therefore, the present invention's is concrete
Embodiment and embodiment should not be considered as limiting the scope of the invention.The present invention is limited only by the appended claims.This Shen
Please in quote all documents be fully incorporated herein by reference.
Claims (6)
1. his crystalline solid of a kind of Baily department, it is characterised in that in the powder X-ray diffraction collection of illustrative plates of described crystalline solid, with including spreading out
2 θ (°) of firing angle：At 4.49 ± 0.2,11.16 ± 0.2,14.68 ± 0.2,20.80 ± 0.2,21.15 ± 0.2,26.45 ± 0.2
With characteristic diffraction peak.
2. his crystalline solid of Baily department according to claim 1, it is characterised in that the powder X-ray diffraction figure of described crystalline solid
In spectrum, with including 2 θ (°) of the angle of diffraction：4.49±0.2、11.16±0.2、13.64±0.2、14.68±0.2、15.54±
0.2nd, 16.65 ± 0.2,19.08 ± 0.2,20.80 ± 0.2,21.15 ± 0.2,22.69 ± 0.2,26.45 ± 0.2 nearby have
Characteristic diffraction peak.
3. the preparation method of his crystalline solid of Baily department described in a kind of claim 1 or 2, it is characterised in that he is thick by Baily department
Product are added in acetonitrile, are heated to reflux, heat filter cooling crystallize, are filtered, solvent washing, vacuum drying.
4. the preparation method of his crystalline solid of Baily department according to claim 3, it is characterised in that Baily department he crude product add
To in acetonitrile, solution temperature is 50 DEG C～81 DEG C.
5. the preparation method of his crystalline solid of Baily department according to claim 3, it is characterised in that recrystallization temperature is -20 DEG C
～20 DEG C, the crystallize time is 3-5 hours.
6. the preparation method of his crystalline solid of Baily department according to claim 3, it is characterised in that the consumption of acetonitrile is Baily
The envelope-bulk to weight ratio for taking charge of his crude product is 5～30.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610985194.4A CN106565552A (en) | 2016-10-31 | 2016-10-31 | Belinostat crystal and preparation method therefor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610985194.4A CN106565552A (en) | 2016-10-31 | 2016-10-31 | Belinostat crystal and preparation method therefor |
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| CN106565552A true CN106565552A (en) | 2017-04-19 |
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| CN201610985194.4A Pending CN106565552A (en) | 2016-10-31 | 2016-10-31 | Belinostat crystal and preparation method therefor |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109574889A (en) * | 2018-12-26 | 2019-04-05 | 深圳万乐药业有限公司 | A kind of his purification process of Baily department |
| CN115724775A (en) * | 2022-11-22 | 2023-03-03 | 天津大学 | Belinostat pharmaceutical co-crystal as well as preparation method and application thereof |
| CN115838343A (en) * | 2022-11-22 | 2023-03-24 | 天津大学 | belinostat-L-proline zwitter-ion eutectic and preparation method and application thereof |
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| CN101868446A (en) * | 2007-09-25 | 2010-10-20 | 托波塔吉特英国有限公司 | The synthetic method of some hydroxamic acid compound |
| CN102531972A (en) * | 2010-12-31 | 2012-07-04 | 北京万全阳光医药科技有限公司 | Preparation method of intermediate of antitumor medicament Belinostat |
| CN102675153A (en) * | 2011-10-18 | 2012-09-19 | 华东理工大学 | Antitumor action and preparation method of dicarboxylic acid monoester derivatives of hydroxamic acid |
| CN102786448A (en) * | 2012-08-09 | 2012-11-21 | 深圳万乐药业有限公司 | Method of synthesizing belinostat |
| CN102850244A (en) * | 2012-09-07 | 2013-01-02 | 北京万全德众医药生物技术有限公司 | Preparation method for 3-(3-phenylsulfamoyl-phenyl)-acrylic acid |
| CN103787924A (en) * | 2014-01-14 | 2014-05-14 | 北京万全德众医药生物技术有限公司 | New purification method of antitumor drug Belinostat |
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| CN105732444A (en) * | 2016-03-28 | 2016-07-06 | 大连理工大学 | Synthesis method of belinostat |
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| CN101868446A (en) * | 2007-09-25 | 2010-10-20 | 托波塔吉特英国有限公司 | The synthetic method of some hydroxamic acid compound |
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| CN102675153A (en) * | 2011-10-18 | 2012-09-19 | 华东理工大学 | Antitumor action and preparation method of dicarboxylic acid monoester derivatives of hydroxamic acid |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109574889A (en) * | 2018-12-26 | 2019-04-05 | 深圳万乐药业有限公司 | A kind of his purification process of Baily department |
| CN109574889B (en) * | 2018-12-26 | 2021-11-09 | 深圳万乐药业有限公司 | Method for purifying belinostat |
| CN115724775A (en) * | 2022-11-22 | 2023-03-03 | 天津大学 | Belinostat pharmaceutical co-crystal as well as preparation method and application thereof |
| CN115838343A (en) * | 2022-11-22 | 2023-03-24 | 天津大学 | belinostat-L-proline zwitter-ion eutectic and preparation method and application thereof |
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| PB01 | Publication | ||
| PB01 | Publication | ||
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Application publication date: 20170419 |