CN103275062B - The purification process of a kind of Pomalidomide - Google Patents
The purification process of a kind of Pomalidomide Download PDFInfo
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Abstract
The invention provides the crystallization purifications of a kind of Pomalidomide.Application the method purifying Pomalidomide can make single foreign matter content lower than 0.15%, and total impurities is lower than 0.5%.
Description
Technical field
The present invention relates to chemical pharmacy field, be specifically related to Pomalidomide purification process.
Background technology
Pomalidomide, chemistry 3-amino-N-(2,6-dioxo-3-piperidyl)-phthalic imidine by name, structural formula is as structural formula 1.It is the derivative of Thalidomide, is the 3rd of this class medicine.It is by regulating human immune system, and destruction of cancer cells also suppresses it to increase.The existing approved of Pomalidomide is used for multiple myeloma, particularly to the treatment of the multiple myeloma of Thalidomide, Revlimid and bortezomib drug resistant.
The chemical structure of structural formula 1Pomalidomide
The document of Pomalidomide synthesis and purifying is less.WO9803502 (CN97180299.8) and WO2002064083 (US8153806) discloses the synthetic method of Pomalidomide two chiral isomers, but does not disclose the synthetic method of Pomalidome.The purification process of two chiral isomers disclosed in WO9803502 is all that purification effect is poor by crude product stirring to pulp together with the ethyl acetate of heat.WO2002064083 adopts method purifying two chiral isomer of dioxane and ethyl acetate mixed solvent crystallization, at last a kind of improvement.But because Pomalidomide had both made under reflux conditions also to need the dioxane with 40 times to dissolve, and Pomalidomide is substantially insoluble in ethyl acetate, and therefore this crystallization method obviously exists the excessive shortcoming of solvent consumption.First public Pomalidomide synthetic method be WO2007005972 (CN200680031945.3), its purification process is be dissolved in by Pomalidomide in the methyl-sulphoxide of 6 times amount, then at the temperature of 75 ~ 80C, slowly be added drop-wise in the water of 36 times, but the method purification effect is not good.Open source literature (Chinese Journal of Pharmaceuticals 2009; 40 (10): 721-3) report that Shanghai Communications University Tang Mei etc. adopts column chromatography purification Pomalidomide, significant discomfort is used for industrial production.Patents WO2012177678 discloses the synthetic method of the isotope-labeled Pomalidomide of deuterium, and its purification process is also the ethyl acetate stirring to pulp by heat, frontly analyzes, and this method purification effect is poor.
To sum up, the recrystallization purifying method of Pomalidomide do not reported by existing document, and purification process existing defects, requires further improvement.
Summary of the invention
The invention provides the purification process of a kind of Pomalidomide, it is characterized in that at least employing following a kind of solvent carries out purifying: at normal temperatures and pressures for liquid amides, be the sulfone compound of liquid at normal temperatures and pressures.
Wherein, at normal temperatures and pressures for the amides of liquid is preferably methane amide, DMF, N,N-dimethylacetamide, N, N-diethylformamide, N, N-diethyl acetamide, N-Methyl pyrrolidone or N-ethyl pyrrolidone.Most preferably DMF, N,N-dimethylacetamide and N-Methyl pyrrolidone.At normal temperatures and pressures for the sulfone compound of liquid is preferably tetramethylene sulfone and vinyl sulfone(RemzaolHuo Xingranliaohuoxingjituan).
Pomalidomide purification process provided by the invention, preferably employs at least two kinds of solvents, wherein the first solvent be at normal temperatures and pressures for liquid amides or be the sulfone compound of liquid at normal temperatures and pressures.Wherein, at normal temperatures and pressures for the amides of liquid is preferably methane amide, DMF, N,N-dimethylacetamide, N, N-diethylformamide, N, N-diethyl acetamide, N-Methyl pyrrolidone or N-ethyl pyrrolidone.Most preferably DMF, N,N-dimethylacetamide and N-Methyl pyrrolidone.At normal temperatures and pressures for the sulfone compound of liquid is preferably tetramethylene sulfone and vinyl sulfone(RemzaolHuo Xingranliaohuoxingjituan).The second solvent is preferably water, alcohols, ester class, ethers, ketone and halogenated hydrocarbon organic solvent.Be preferably water, methyl alcohol, ethanol, Virahol, acetone, methyl iso-butyl ketone (MIBK), ethyl acetate, propyl acetate, butylacetate, methyl tertiary butyl ether, diisopropyl ether, methylene dichloride and trichloromethane.Most preferably water, methyl alcohol, ethanol, acetone, methyl iso-butyl ketone (MIBK), ethyl acetate, butylacetate, methyl tertiary butyl ether, diisopropyl ether and trichloromethane.
Pomalidomide purification process provided by the invention, preferably includes and is mixed in proportion by Pomalidomide and two kind of a solvent, heating for dissolving, then the process of cooling crystallization.
Pomalidomide purification process provided by the invention, preferably includes and is dissolved in by Pomalidomide in the first solvent in a heated condition; Add the second solvent again, the process of crystallisation by cooling.Disposablely can add when adding the second solvent, also can slowly add.Heating can be stopped, also can continuing heating.
In Pomalidomide purification process provided by the invention, Heating temperature is not particularly limited, and is generally 20 DEG C ~ backflow.By the ratio of the boiling point of the first solvent and the second solvent, the first solvent and the second solvent and the first solvent and the second solvent, the solubleness of Pomalidomide is determined.
In Pomalidomide purification process provided by the invention, cooling temperature is not particularly limited, and is generally-10 DEG C ~ 25 DEG C.
In further embodiment, the consumption of preferred solvent is the first solvent: Pomalidomide is 0.1 ~ 40: 1, more preferably 1 ~ 20: 1.
In the above-described embodiment, the consumption of the second solvent suitably can adjust according to different solvents, is generally the second solvent: Pomalidomide0.1 ~ 90: 1, and preferably 1 ~ 45: 1.
In Pomalidomide purification process provided by the invention, the Pomalidomide reference substance or highly finished product that previously obtain can be added in crystallisation by cooling process.
Accompanying drawing explanation
Fig. 1 is that the HPLC of Pomalidomide crude product analyzes collection of illustrative plates;
Fig. 2 is that the HPLC of reference example Pomalidomide analyzes collection of illustrative plates;
Fig. 3 is that the HPLC of embodiment 1Pomalidomide analyzes collection of illustrative plates.
The present invention is further illustrated below by embodiment.It should be understood that the preparation method of the embodiment of the present invention is only used for the present invention is described, instead of limitation of the present invention, under concept thereof of the present invention, all the scope of protection of present invention is belonged to the simple modifications of preparation method of the present invention.Except as otherwise noted, " % " in the present invention is all quality criterias.
Embodiment
Embodiment
Prepared by Pomalidomide crude product reference literature US2006160854A1.
Embodiment 1
Pomalidomide crude product 1g, adds DMF 7.0mL, is heated to 110 DEG C of stirring and dissolving, stop heating, slowly drip water 5.0mL, drip and finish, be slowly down to room temperature, 5-10 DEG C of crystallization 24 hours, filter, vacuum-drying obtained Pomalidomide crystallization, yield 80%.
Embodiment 2
By Pomalidomide crude product 1g, add DMF 7.0mL, methyl alcohol 10.0mL, stirs together, mixing, is heated to dissolve, stops heating, be slowly down to room temperature, 20 ~ 25 DEG C of crystallizations 24 hours, filter, vacuum-drying obtained Pomalidomide crystallization, yield 65%.
Embodiment 3
By Pomalidomide crude product 1g, N,N-dimethylacetamide 7.0mL, ethyl acetate 10.0mL, stir together, mix, be heated to dissolve, stop heating, be slowly down to room temperature, 0 ~ 5 DEG C of crystallization 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 77%.
Embodiment 4
Pomalidomide crude product 1g, adds tetramethylene sulfone 20.0mL, is heated to 110 DEG C of stirring and dissolving, stops heating, slowly drip water 20.0mL, drip and finish, be slowly down to room temperature, 5-10 DEG C of crystallization 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 83%.
Embodiment 5
Pomalidomide crude product 1g, adds vinyl sulfone(RemzaolHuo Xingranliaohuoxingjituan) 30.0mL, is heated to 110 DEG C of stirring and dissolving, stops heating, slowly drip Virahol 40.0mL, drip and finish, be slowly down to room temperature, 5-10 DEG C of crystallization 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 45%.
Embodiment 6
Pomalidomide crude product 1g, adds N-Methyl pyrrolidone 10.0mL, is heated to 50 DEG C of stirring and dissolving, stops heating, slowly drip methyl iso-butyl ketone (MIBK) 20.0mL, drip and finish, be slowly down to room temperature, 5-10 DEG C of crystallization 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 65%.
Embodiment 7
Pomalidomide crude product 1g, adds DMF 7.0mL, is heated to 110 DEG C of stirring and dissolving, stop heating, add trichloromethane 10.0mL, be slowly down to room temperature, 5 ~ 10 DEG C of crystallizations 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 68%.
Embodiment 8
Pomalidomide crude product 1g, adds N respectively, N-diethylformamide 10.0mL and methyl tertiary butyl ether 10.0mL, is heated to backflow, stop heating after stirring and dissolving, be slowly down to room temperature, then 0 ~ 5 DEG C of crystallization 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 40%.
Embodiment 9
Pomalidomide crude product 1g, adds N,N-dimethylacetamide 7.0mL, is heated to 110 DEG C of stirring and dissolving, slowly drip butylacetate 35.0mL under heat-retaining condition, drip and finish, be slowly down to room temperature, 0 ~ 5 DEG C of crystallization 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 45%.
Embodiment 10
Pomalidomide crude product 1g, adds methane amide 20.0mL, is heated to 110 DEG C of stirring and dissolving, slowly drips ethanol 30.0mL under heat-retaining condition, drip and finish, be slowly down to room temperature, 5 ~ 10 DEG C of crystallizations 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 69%.
Embodiment 11
Pomalidomide crude product 1.0g is added in 5mLN-methyl-2-pyrrolidone, after being heated to 110 DEG C of stirring and dissolving, slowly drips water 5mL at this temperature, drip and finish, filtered while hot, is slowly down to room temperature, puts in refrigerator and refrigerates 48 hours, filter, vacuum-drying obtains 0.71g yellow solid, yield 71%.
Embodiment 12
By Pomalidomide crude product 1g, DMF 5.0mL, acetone 30.0mL, stir together, mix, be heated to dissolve, stop heating, be slowly down to room temperature ,-10 ~-5 DEG C of crystallizations 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 63%.
Embodiment 13
By Pomalidomide crude product 1g, N-ethyl pyrrolidone 5.0mL, butylacetate 25mL stirs together, mix, be heated to dissolving, stop heating, be slowly down to room temperature, 0 ~ 5 DEG C of crystallization 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 40%.
Embodiment 14
Pomalidomide crude product 1g, adds methane amide 20.0mL, is heated to 110 DEG C of stirring and dissolving, stops heating, slowly drip diisopropyl ether 35.0mL, drip and finish, be slowly down to room temperature, 5-10 DEG C of crystallization 24 hours, filter, vacuum-drying obtains Pomalidomide crystallization, yield 20%.
Embodiment 15
Pomalidomide crude product 1g, adds N,N-dimethylacetamide 5.0mL, be heated to 110 DEG C of stirring and dissolving, stop heating, drip methyl alcohol 10.0mL, slowly drip, be slowly down to room temperature, 5-10 DEG C of crystallization 24 hours, filter, vacuum-drying obtained Pomalidomide crystallization, yield 79%.
Reference example
Pomalidomide crude product 1g, adds dimethyl sulfoxide (DMSO) 6mL, heating for dissolving, in 75-80 DEG C, is slowly added drop-wise in water 36.0mL, stirs when dripping simultaneously, and drip complete slow slow cool down and be down to room temperature, filter, vacuum-drying obtains Pomalidomide crystallization, yield 90%.
Embodiment 16 purification effect contrast experiment
By same batch sample (crude product) respectively by embodiment 1,2,3,4,5 and reference example purifying, use high-performance liquid chromatogram determination foreign matter content, compare purification result.
High-efficient liquid phase determining method
Instrument: Shimadzu SPD-20A, UV-detector, determined wavelength 240nm
Chromatographic column: PromosilC18,250mmX4.6mm, 5 μm;
Column temperature: normal temperature
Moving phase: acetonitrile-0.1% phosphoric acid (30: 70)
Flow velocity: 1.0ml/min
Sample concentration: 0.2mg/ml
Sample size: 20 μ l
Measurement result
| Relative retention time | 0.67 | 0.79 | 0.88 | 1.58 | 4.80 | Total impurities |
| Crude product | 0.15 | 0.51 | 0.50 | 0.44 | 0.12 | 1.99 |
| Reference example | 0.12 | 0.26 | 0.37 | 0.35 | 0.11 | 1.45 |
| Embodiment 1 | 0.09 | 0.02 | 0.09 | 0.05 | 0.00 | 0.38 |
| Embodiment 2 | 0.10 | 0.00 | 0.10 | 0.05 | 0.00 | 0.35 |
| Embodiment 3 | 0.06 | 0.06 | 0.11 | 0.10 | 0.00 | 0.46 |
| Embodiment 4 | 0.08 | 0.05 | 0.10 | 0.06 | 0.00 | 0.41 |
| Embodiment 5 | 0.09 | 0.05 | 0.09 | 0.07 | 0.00 | 0.42 |
Conclusion:
Crude product total impurities content 1.99%, has five single foreign matter contents more than 0.10%, and by reference example method purifying, total impurities only declines the content of 0.5%, five content more than 0.10% single impurity still more than 0.10%, and refining effect is not obvious.Refine by embodiment 1,2,3,4 and 5 method, single impurity is all lower than 0.15%, and total impurities is lower than 0.5%, and purification effect is obvious.
Claims (5)
1. a purification process of Pomalidomide, is characterized in that:
By Pomalidomide crude product 1g, with 7.0mlN, dinethylformamide mixes, and is heated to 110 DEG C of stirring and dissolving, stop heating, slowly drip 5ml water, drip and finish, be slowly down to room temperature, 5-10 DEG C of crystallization 24 hours, filter, vacuum-drying obtained Pomalidomide crystallization, yield 80%.
2. a purification process of Pomalidomide, is characterized in that:
By Pomalidomide crude product 1g, with 7.0mlN, dinethylformamide and 10.0ml methyl alcohol, stir together, mixing, is heated to dissolve, stops heating, be slowly down to room temperature, and 20 ~ 25 DEG C of crystallizations 24 hours, filter, vacuum-drying obtained Pomalidomide crystallization.
3. a purification process of Pomalidomide, is characterized in that:
By Pomalidomide crude product 1g, with 7.0mlN, dinethylformamide and 10.0ml ethyl acetate, stir together, mix, be heated to dissolve, stop heating, be slowly down to room temperature, 0 ~ 5 DEG C of crystallization 24 hours, filter, vacuum-drying obtained Pomalidomide crystallization.
4. a purification process of Pomalidomide, is characterized in that:
Mixed with 20.0ml tetramethylene sulfone by Pomalidomide crude product 1g, be heated to 110 DEG C of stirring and dissolving, stop heating, slowly drip 20ml water, drip and finish, be slowly down to room temperature, 5-10 DEG C of crystallization 24 hours, filter, vacuum-drying obtained Pomalidomide crystallization.
5. a purification process of Pomalidomide, is characterized in that:
By Pomalidomide crude product 1g, mix with 30.0ml vinyl sulfone(RemzaolHuo Xingranliaohuoxingjituan), be heated to 110 DEG C of stirring and dissolving, stop heating, slowly drip 40.0ml Virahol, drip and finish, be slowly down to room temperature, 5-10 DEG C of crystallization 24 hours, filter, vacuum-drying obtained Pomalidomide crystallization.
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| EP2981532A4 (en) * | 2013-04-01 | 2016-12-14 | Hetero Research Foundation | Process for pomalidomide |
| CN104557857A (en) * | 2013-10-29 | 2015-04-29 | 上海医药工业研究院 | Method for purifying pomalidomide |
| US20160362391A1 (en) * | 2013-11-25 | 2016-12-15 | Mylan Laboratories Ltd. | Improved Process for the Preparation of Pomalidomide and its Purification |
| CN103626738B (en) * | 2013-12-23 | 2016-03-16 | 重庆泰濠制药有限公司 | A kind of pool horse degree amine crystal formation and preparation method thereof |
| ITUB20169994A1 (en) * | 2016-01-14 | 2017-07-14 | Phf Sa | New crystalline forms of immunomodulatory drugs |
| CN110790746B (en) * | 2019-11-18 | 2020-10-30 | 南京恒通医药开发有限公司 | Synthesis process for continuously preparing pomalidomide by using microchannel reactor |
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| CN101253163A (en) * | 2005-06-30 | 2008-08-27 | 细胞基因公司 | Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds |
| CN102993169A (en) * | 2012-10-30 | 2013-03-27 | 南通原亚精密机械有限公司 | Method for refining crude lenalidomide product |
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| CN101253163A (en) * | 2005-06-30 | 2008-08-27 | 细胞基因公司 | Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds |
| CN102993169A (en) * | 2012-10-30 | 2013-03-27 | 南通原亚精密机械有限公司 | Method for refining crude lenalidomide product |
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| 抗肿瘤药pomalidomide的合成工艺改进;吴刚 等;《中国药物化学杂志》;20130430;第23卷(第2期);第108-110页 * |
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