CN104557857A - Method for purifying pomalidomide - Google Patents
Method for purifying pomalidomide Download PDFInfo
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- CN104557857A CN104557857A CN201310520848.2A CN201310520848A CN104557857A CN 104557857 A CN104557857 A CN 104557857A CN 201310520848 A CN201310520848 A CN 201310520848A CN 104557857 A CN104557857 A CN 104557857A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a method for purifying pomalidomide. The method comprises the following steps: mixing a pomalidomide crude product with high-performance liquid phase purity of 80-90% with a mixed solvent, and crystallizing, wherein the mixed solvent is a mixed solvent of an organic solvent and water; the organic solvent is an amide solvent or a ketone solvent; when the organic solvent is the amide solvent, the volume ratio of the amide solvent to water is 4:1 to 8:1; and when the organic solvent is the ketone solvent, the volume ratio of the ketone solvent to water is 3:1 to 1:3. The purification method disclosed by the invention is simple and convenient to operate, high in yield, high in purity and suitable for the requirements of industrial production regulated by good manufacturing practice.
Description
Technical field
The present invention relates to a kind of purification process mooring sharp degree amine.
Background technology
Moor sharp degree amine, English name is Pomalidomide, chemistry 4-amino-2-(2,6-dioxopiperidin-3-base) isoindoline-1,3-diketone by name, and its chemical structural formula is as follows:
Moor the new immunomodulator that sharp degree amine is researched and developed by Celgene company at first, moor the derivative that sharp degree amine is Thalidomide (thalidomide), adjustable T cell also suppresses it to breed, and plays immunoregulation effect; By activating natural killer (natural killer) cell, promote the apoptosis of tumour cell, clinical being mainly used in treats multiple myeloma.
CN101253163 provides the preparation method of the sharp degree amine of a kind of highly purified pool, the mixture of the pool thick product of sharp degree amine and DMSO is encased in reactor, the soup compound obtained is heated to 45 ~ 50 DEG C of stirring and dissolving to clarification, then DMSO(400mL is used) rinse, solution is added in purified water (7.2L) about 75 ~ 80 DEG C time, the suspension obtained is cooled to 15 ~ 20 DEG C, stir 1.5 ~ 2 hours, filter, (2 × 2L purified water is see Pharmacopoeia of People's Republic of China version two the 411st page (version two the 303rd page in 2005) washing in 2010 by purified water for solid, purified product is dried to constant weight.The method solvent-oil ratio is large, and recrystallization DeGrain, impurity removes out not obvious, and purity promotes little, is unfavorable for industrializing implementation.
Summary of the invention
Subject matter to be solved by this invention overcomes in existing purification process the not high enough defect of the purity of mooring sharp degree amine and provides a kind of purification process mooring sharp degree amine.Purification process of the present invention is simple to operate, yield is high, purity is high, is applicable to the requirement of the suitability for industrialized production that Good Manufacturing Practice and Quality Control of Drug (GMP) specifies.
The invention provides a kind of purification process mooring sharp degree amine, its comprise the following steps: by high performance liquid phase (HPLC) purity be 80 ~ 99% pool profit degree amine crude product mix with mixed solvent after, crystallization; Wherein, described mixed solvent is the mixed solvent of organic solvent and water; Described organic solvent is amide solvent or ketones solvent; When organic solvent is amide solvent, the volume ratio of amide solvent and water is 4:1 ~ 8:1; When organic solvent is ketones solvent, the volume ratio of ketones solvent and water is 3:1 ~ 1:3.
Wherein, described purification process, preferably, after comprising the following steps: sharp for pool degree amine crude product to mix with mixed solvent, mixes with gac, heat filtering, crystallization at 60 ~ 70 DEG C again.
Wherein, described amide solvent and the volume ratio of water are preferably 6:1 ~ 8:1; Described ketones solvent and the volume ratio of water are preferably 1:1 ~ 1:2.
Described amide solvent is preferably N,N-dimethylacetamide.Described ketones solvent is preferably N-Methyl pyrrolidone.
The temperature of described mixing can be the conventional temperature of this area mixing, and being preferably 60 ~ 80 DEG C, is more preferably 60 ~ 70 DEG C.The time of described mixing can be this area mixing conventional time, and obtaining homogeneous clear soln, is preferably 0.5h ~ 2h, is more preferably 1h ~ 2h.The temperature of described crystallization can be the temperature of this area crystallization routine, is preferably-10 ~ 30 DEG C, is more preferably-10 ~ 0 DEG C.The time of described crystallization can be the time of this area crystallization routine, is preferably 1h ~ 12h, is more preferably 2h ~ 6h.
Described amide solvent and the consumption of the mixed solvent of water and the volume mass of described pool profit degree amine crude product are 20 ~ 30mL/g than preferably, are preferably 22 ~ 28mL/g.Described ketones solvent and the mixed solvent consumption of water and the volume mass of described pool profit degree amine crude product are 15 ~ 25mL/g than preferably, are preferably 17 ~ 22mL/g.
Described gac can be conventional commercial gac reagent in this area, this area, is preferably gas-chromatography GC26 ~ 35 object gac.The consumption of described gac can be the conventional consumption of this area recrystallization decolouring, and being preferably 3% ~ 10% of described pool profit degree amine crude product quality, is more preferably 5% ~ 8%.
After described crystallization terminates, preferably, suction filtration, obtains filter cake, washing, dry, must moor sharp degree amine sterling.
Described heat filtering preferably for after recrystallization terminates, filters when not separating out the sharp degree amine solid of pool with recrystallization system.
Confirmed by a large amount of experiments, N,N-dimethylacetamide and the water mixed solution recrystallization effect to the sharp degree amine crude product of pool is better, and confirm through a large amount of experiments, when the volume ratio of N,N-dimethylacetamide and water is 4:1 ~ 8:1, the best results of recrystallization.
In the present invention, sharp degree amine crude product can be moored according to the pool profit degree amine crude product preparation method of this area routine is obtained, and this crude product HPLC purity is 80 ~ 99%, is namely applicable to above-mentioned purification process and carries out purifying.The pool profit degree amine HPLC purity obtained through above-mentioned purification process can reach 99.9%.
In the present invention, the preparation method of described pool profit degree amine crude product, preferably, it comprises the following steps: N, N-N,N-DIMETHYLACETAMIDE, or in the mixed solvent of N,N-dimethylacetamide and other kind solvents, under the catalysis of palladium carbon, carry out reduction reaction as follows by such as formula the compound shown in II and hydrogen;
Wherein, other described kind solvents are alcoholic solvent, ketones solvent or water.
The volume ratio of described N,N-dimethylacetamide and other described kind solvents is preferably 1:1 ~ 100:1, is more preferably 1:1 ~ 20:1, is 1:1 ~ 10:1 best.
Described alcoholic solvent can be described in the routine of this area, preferably for carbon chain lengths is C
1~ C
4alkyl alcohol (preferred monohydroxy-alcohol).Described carbon chain lengths is C
1~ C
4alkyl alcohol be preferably methyl alcohol, ethanol, propyl alcohol or 2-propyl alcohol, be more preferably ethanol.Described ketones solvent can be described in the routine of this area, is preferably acetone, methyl ethyl ketone or N-Methyl pyrrolidone, is more preferably acetone.
Shown in described N,N-dimethylacetamide with described formula II, the volume mass of compound is 10 ~ 30mL/g than preferably, is more preferably 15 ~ 25mL/g.The mixed solvent of N,N-dimethylacetamide and alcoholic solvent, or N,N-dimethylacetamide and the consumption of the mixed solvent of water and the volume mass of compound shown in described formula II are 20 ~ 30mL/g than preferably, are more preferably 21 ~ 24mL/g.N,N-dimethylacetamide and the consumption of the mixed solvent of ketones solvent and the volume mass of compound shown in described formula II are 15 ~ 30mL/g than preferably, are more preferably 20 ~ 28mL/g.
Described palladium carbon can be conventional commercial palladium carbon reagent in this area, and be preferably the palladium carbon reagent that mass percent is 5% ~ 10%, described mass percent refers to that the quality of palladium accounts for the per-cent of palladium carbon reagent total mass.The consumption of described palladium carbon is preferably 2% ~ 8% of compound quality shown in described formula II.
The pressure of described reduction reaction can be the pressure of this type of reduction reaction routine of this area, is preferably 0.35Mpa ~ 0.45Mpa.The temperature of described reduction reaction can be the temperature of this type of reduction reaction routine of this area, is preferably 30 ~ 50 DEG C.The process of described reduction reaction can adopt the traditional test methods in this area (as TLC, HPLC or NMR) to monitor, and for reaction end when generally disappearing with compound shown in formula II, the reaction times is preferably 5 ~ 7 hours, is more preferably 6 ~ 7 hours.
After described reduction reaction terminates, preferably, also comprise the following steps:, by the reacting liquid filtering of reduction reaction, to obtain filtrate; The filtrate of gained is concentrated, obtains enriched material; The making beating of enriched material water is spent the night, the sharp degree amine crude product of obtained pool.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
Positive progressive effect of the present invention is:
Purification process of the present invention, easy and simple to handle, yield is high, purity is high, HPLC purity can reach 99.9%, meets the requirement of drug's GMP suitability for industrialized production; Meanwhile, purification process of the present invention is environmentally friendly.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1 moors the preparation of sharp degree amine crude product
By 1,3-dioxy-2-(2,6-dioxopiperidin-3-base) the palladium carbon 0.4g of-5-nitro isoindoline 5g and 10% is mixed in the N,N-dimethylacetamide of 70mL, then under 0.4Mpa, carries out hydrogenation reaction, temperature of reaction is 30 DEG C, last 6 hours, filter out catalyzer, vacuum concentrated filtrate, residue 40mL water is spent the night in 40 DEG C of making beating, obtains the pool profit degree amine crude product of 3.7g greenish yellow solid.It is 99.0% that HPLC records purity.
Embodiment 2 moors the preparation of sharp degree amine crude product
By 1,3-dioxy-2-(2,6-dioxopiperidin-3-base) the palladium carbon 0.1g of-5-nitro isoindoline 5g and 5% is mixed in the N,N-dimethylacetamide of 70mL, then under 0.4Mpa, carries out hydrogenation reaction, temperature of reaction is 40 DEG C, last 6 hours, filter out catalyzer, vacuum concentrated filtrate, residue 40mL water is spent the night in 40 DEG C of making beating, obtains the pool profit degree amine crude product of 3.7g greenish yellow solid.It is 95.3% that HPLC records purity.
Embodiment 3 moors the purifying of sharp degree amine crude product
By the pool profit degree amine crude product 1g in embodiment 1, add the N,N-dimethylacetamide of 30mL and the mixed solvent (volume ratio of N,N-dimethylacetamide and water is 4:1) of water and 0.08g gac, be heated to 60 DEG C and dissolve 1h ~ 2h, suction filtration while hot, filtrate is cooled to-10 DEG C, crystallization 12h, suction filtration, by 15mL water washing filter cake, 40 DEG C of dried overnight, obtain 0.7g and moor sharp degree amine sterling.It is 99.9% that HPLC records purity.
Embodiment 4 moors the purifying of sharp degree amine crude product
By the pool profit degree amine crude product 1g in embodiment 1, add (N-Methyl pyrrolidone and water volume ratio are 1:3) in the N-Methyl pyrrolidone of 15mL and the mixed solvent of water, be heated to 60 DEG C and dissolve 1h ~ 2h completely, add 0.08g gac filtered while hot, filtrate is cooled to-10 DEG C, crystallization 1h, suction filtration, by 15mL water washing filter cake, 40 DEG C of dried overnight, obtain 0.6g and moor sharp degree amine sterling.It is 99.5% that HPLC records purity.
Embodiment 5 moors the purifying of sharp degree amine crude product
By the pool profit degree amine crude product 1g in embodiment 2, add the N,N-dimethylacetamide of 30mL and the mixed solvent (volume ratio of N,N-dimethylacetamide and water is 7:1) of water and 0.12g gac, be heated to 70 DEG C and dissolve 1h ~ 2h, suction filtration while hot, filtrate is cooled to 0 DEG C, crystallization 6h ~ 12h, suction filtration, by 15mL water washing filter cake, 40 DEG C of dried overnight, obtain 0.6g and moor sharp degree amine sterling.It is 99.1% that HPLC records purity.
Embodiment 6 moors the purifying of sharp degree amine crude product
By the pool profit degree amine crude product 1g in embodiment 1, add the N,N-dimethylacetamide of 25mL and the mixed solvent (volume ratio of N,N-dimethylacetamide and water is 8:1) of water and 0.08g gac, be heated to 60 DEG C and dissolve 1h ~ 2h, suction filtration while hot, filtrate is cooled to-10 DEG C, crystallization 12h, suction filtration, by 15mL water washing filter cake, 40 DEG C of dried overnight, obtain 0.7g and moor sharp degree amine sterling.It is 99.9% that HPLC records purity.
Embodiment 7 moors the purifying of sharp degree amine crude product
By the pool profit degree amine crude product 1g in embodiment 1, add the N,N-dimethylacetamide of 35mL and the mixed solvent (volume ratio of N,N-dimethylacetamide and water is 6:1) of water and 0.08g gac, be heated to 60 DEG C and dissolve 1h ~ 2h, suction filtration while hot, filtrate is cooled to-10 DEG C, crystallization 12h, suction filtration, by 15mL water washing filter cake, 40 DEG C of dried overnight, obtain 0.7g and moor sharp degree amine sterling.It is 99.9% that HPLC records purity.
Embodiment 8 moors the purifying of sharp degree amine crude product
By the pool profit degree amine crude product 1g in embodiment 1, add (N-Methyl pyrrolidone and water volume ratio are 1:1) in the N-Methyl pyrrolidone of 15mL and the mixed solvent of water, be heated to 60 DEG C and dissolve 1h ~ 2h completely, add 0.08g gac filtered while hot, filtrate is cooled to-10 DEG C, crystallization 1h, suction filtration, by 15mL water washing filter cake, 40 DEG C of dried overnight, obtain 0.6g and moor sharp degree amine sterling.It is 99.9% that HPLC records purity.
Embodiment 9 moors the purifying of sharp degree amine crude product
By the pool profit degree amine crude product 1g in embodiment 1, add (N-Methyl pyrrolidone and water volume ratio are 1:2) in the N-Methyl pyrrolidone of 12mL and the mixed solvent of water, be heated to 60 DEG C and dissolve 1h ~ 2h completely, add 0.08g gac filtered while hot, filtrate is cooled to-10 DEG C, crystallization 1h, suction filtration, by 15mL water washing filter cake, 40 DEG C of dried overnight, obtain 0.6g and moor sharp degree amine sterling.It is 99.9% that HPLC records purity.
Embodiment 10 moors the purifying of sharp degree amine crude product
The pool profit degree amine crude product 1g obtained according to the preparation method of the sharp degree amine of highly purified pool a kind of disclosed in CN101253163, it is 81% that HPLC records purity, add (N-Methyl pyrrolidone and water volume ratio are 1:1) in the N-Methyl pyrrolidone of 12mL and the mixed solvent of water, be heated to 60 DEG C and dissolve 1h ~ 2h completely, add 0.08g gac filtered while hot, filtrate is cooled to-10 DEG C, crystallization 1h, suction filtration, with 15mL water washing filter cake, 40 DEG C of dried overnight, obtain 0.6g and moor sharp degree amine sterling.It is 99.9% that HPLC records purity.
Comparative example 1 moors the purifying of sharp degree amine crude product
By the pool profit degree amine crude product 1g in embodiment 1, add the N-Methyl pyrrolidone of 40ml and the mixed solvent (N-Methyl pyrrolidone and water volume ratio are 4:1) of water and 0.08g gac, be heated to 90 DEG C and dissolve 2h, suction filtration while hot, filtrate is cooled to-10 DEG C, crystallization 12h, suction filtration, by 15mL water washing filter cake, 40 DEG C of dried overnight, obtain 0.7g and moor sharp degree amine sterling.It is 98.5% that HPLC records purity.
Claims (10)
1. moor a purification process for sharp degree amine, it is characterized in that, its comprise the following steps: by high performance liquid phase purity be 80 ~ 99% pool profit degree amine crude product mix with mixed solvent after, crystallization; Wherein, described mixed solvent is the mixed solvent of organic solvent and water; Described organic solvent is amide solvent or ketones solvent; When organic solvent is amide solvent, the volume ratio of amide solvent and water is 4:1 ~ 8:1; When organic solvent is ketones solvent, the volume ratio of ketones solvent and water is 3:1 ~ 1:3.
2. purification process as claimed in claim 1, it is characterized in that, it comprises the following steps: will moor after sharp degree amine crude product mixes with mixed solvent, and at 60 ~ 70 DEG C, then mix with gac, heat filtering, crystallization.
3. purification process as claimed in claim 1 or 2, it is characterized in that, described amide solvent and the volume ratio of water are 6:1 ~ 8:1; Described ketones solvent and the volume ratio of water are 1:1 ~ 1:2.
4. purification process as claimed in claim 1 or 2, it is characterized in that, described amide solvent is N,N-dimethylacetamide; Described ketones solvent is N-Methyl pyrrolidone.
5. purification process as claimed in claim 1 or 2, it is characterized in that, the temperature of described mixing is 60 ~ 80 DEG C; The time of described mixing is 0.5h ~ 2h.
6. purification process as claimed in claim 5, it is characterized in that, the temperature of described mixing is 65 ~ 75 DEG C; The time of described mixing is 1h ~ 2h.
7. purification process as claimed in claim 1 or 2, it is characterized in that, the temperature of described crystallization is-10 ~ 30 DEG C; The time of described crystallization is 1h ~ 12h.
8. purification process as claimed in claim 7, it is characterized in that, the temperature of described crystallization is-10 ~ 20 DEG C; The time of described crystallization is 2h ~ 6h.
9. purification process as claimed in claim 1 or 2, is characterized in that, the consumption of described amide solvent and the mixed solvent of water is 20 ~ 30mL/g with the volume mass ratio of described pool profit degree amine crude product; Or the mixed solvent consumption of described ketones solvent and water is 15 ~ 25mL/g with the volume mass ratio of described pool profit degree amine crude product.
10. purification process as claimed in claim 9, is characterized in that, the consumption of described amide solvent and the mixed solvent of water is 22 ~ 28mL/g with the volume mass ratio of described pool profit degree amine crude product; Or the mixed solvent consumption of described ketones solvent and water is 17 ~ 22mL/g with the volume mass ratio of described pool profit degree amine crude product.
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| CN201310520848.2A CN104557857A (en) | 2013-10-29 | 2013-10-29 | Method for purifying pomalidomide |
| CN201710552437.XA CN107188884A (en) | 2013-10-29 | 2013-10-29 | A kind of purification process of pomalidomide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924426A (en) * | 2016-06-20 | 2016-09-07 | 浙江海正药业股份有限公司 | Crystallization process for pomalidomide |
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| CN109748954B (en) * | 2017-11-06 | 2022-03-01 | 正大天晴药业集团股份有限公司 | Purification method of degarelix |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ES2529190T3 (en) * | 1996-07-24 | 2015-02-17 | Celgene Corporation | 2- (2,6-Dioxopiperidin-3-yl) -amino-substituted phthalimides to reduce TNF-alpha levels |
| US8927725B2 (en) * | 2011-12-02 | 2015-01-06 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Thio compounds |
| CN103275062B (en) * | 2013-05-17 | 2016-04-13 | 宁波百思佳医药科技有限公司 | The purification process of a kind of Pomalidomide |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105924426A (en) * | 2016-06-20 | 2016-09-07 | 浙江海正药业股份有限公司 | Crystallization process for pomalidomide |
| WO2017219953A1 (en) * | 2016-06-20 | 2017-12-28 | 浙江海正药业股份有限公司 | Pomalidomide crystallization technology |
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Inventor after: Liu Hang Inventor after: Yuan Zhedong Inventor after: Yang Yulei Inventor after: Hu Zhi Inventor after: Zhang Hao Inventor after: Zhang Xiquan Inventor after: Wang Shanchun Inventor before: Liu Hang Inventor before: Yuan Zhedong Inventor before: Yang Yulei Inventor before: Hu Zhi Inventor before: Zhang Hao |
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Effective date of registration: 20160411 Address after: 200040 Beijing West Road, Shanghai, No. 1320, No. Applicant after: Shanghai Institute of pharmaceutical industry Applicant after: China State Institute of Pharmaceutical Industry Applicant after: Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Address before: 200040 Beijing West Road, Shanghai, No. 1320, No. Applicant before: Shanghai Institute of pharmaceutical industry Applicant before: China State Institute of Pharmaceutical Industry |
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