CN102993169A - Method for refining crude lenalidomide product - Google Patents
Method for refining crude lenalidomide product Download PDFInfo
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- CN102993169A CN102993169A CN2012104226169A CN201210422616A CN102993169A CN 102993169 A CN102993169 A CN 102993169A CN 2012104226169 A CN2012104226169 A CN 2012104226169A CN 201210422616 A CN201210422616 A CN 201210422616A CN 102993169 A CN102993169 A CN 102993169A
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Abstract
The invention discloses a method for refining a crude lenalidomide product. The method comprises the following steps of: (1) adding the crude lenalidomide product to a mixed solution of isopropanol and water; (2) heating, after the crude lenalidomide product is completely dissolved, adding activated carbon and nanometer ceramic powder and carrying out heat preservation for the first time; (3) filtering when the solution is hot, and cooling filtrate till crystals precipitate; and (4) carrying out heat preservation for the second time, carrying out suction filtering after the crystal precipitation is finished, and finally drying. Due to adoption of the technical scheme, the method for refining the crude lenalidomide product has the beneficial effects of low isopropanol toxicity, high safety, simpleness in process, no need of special equipment and environment requirements, suitability for industrial production, high product content and high refining yield; and the purify of the lenalidomide is remarkably improved.
Description
Technical field
The invention belongs to the purification techniques field of organic compound, especially relate to a kind of process for purification of Revlimid crude product.
Background technology
The Revlimid chemical name is 3-(4-amino-1-oxo-1,3-dihydro-isoindole-2-yl) piperidines-2, and 6-diketone, chemical structural formula be,
, 2008, FDA (Food and Drug Adminstration) (FDA) ratified a New indication of the Revlimid of U.S. Celgene Corp., namely share the multiple myeloma patients that at least a therapy had been accepted in dexamethasone (Dexamethasone) treatment.
Revlimid is the antitumour drug of new generation of U.S. Celgene exploitation, its effective constituent is Revlimid (lenalidomide), be mainly used in treating chronic myelomatosis and the myelodysplastic syndrome (Myelodysplastic syndrome, MDS) that the 5q disappearance is arranged.Revlimid is the derivative of new generation of Thalidomide, but does not find that it has clastogenic toxicity, and drug effect is stronger 100 times than Thalidomide.According to the result of phase iii clinical trial, Revlimid is to treat at present the most significant medicine of multiple myeloma curative effect, and the clothes for patients that surpasses half can prolong the survival time after with this medicine and reach more than 3 years.In addition, it also is effectively to treat the unique medicine of myelodysplastic syndrome (MDS), and patient MDS of clinical effectiveness discovery 64% need not to treat MDS with blood transfusion again after treating with Revlimid.
Revlimid and Thalidomide are similar, have the multiple actions such as antitumor, immunomodulatory and angiogenesis inhibitor.It can suppress the secretion of front inflammatory cytokine, increases the secretion of peripheral blood lymphocytes anti-inflammatory cytokines.In vitro tests shows that this product can suppress some cell strain such as Namalwa hyperplasia.Revlimid can suppress the growth of patient's multiple myeloma cells and MM1S cell.In addition, this product also can suppress the expression of cyclooxygenase 2 (COX-2), but to COX-1 without effect.
Revlimid has immunomodulatory and anti-neovascularity nucleus formation.After the oral administration administration, Revlimid is absorbed in the body rapidly.Experiment in vitro shows that the Revlimid plasma protein binding ratio is about 30%.Have approximately 2/3 Revlimid with original shape with urine excretion, it is eliminated transformation period and is about 3 hours.
Revlimid process for purification bibliographical information: Chinese Journal of Pharmaceuticals 2008.39(12) people such as Fang Feng washes crude product with water at the synthetic bibliographical information of Revlimid, and the product purity that obtains is not high, and yield is lower, and yield is 76%.Chinese Journal of Pharmaceuticals 2010.41(3) people such as Wu Han reports in the synthetic document of Revlimid, uses dichloromethane extraction, and anhydrous sodium sulfate drying filters, underpressure distillation, and drying, the product yield that obtains is low, and yield is 69%.
Therefore, be necessary to provide a kind of method of refining Revlimid crude product newly, improve the rate of utilization of Revlimid crude product, reduce cost.
Summary of the invention
The technical problem to be solved in the present invention is, provides a kind of yield high, and purity is good, and the process for purification of the Revlimid bulk drug of suitable suitability for industrialized production.
For solving the problems of the technologies described above, the technical solution used in the present invention is: the method for this refining Revlimid crude product comprises the steps:
(1) the Revlimid crude product is added in the mixing solutions of isopropyl alcohol and water;
(2) intensification heating, after Revlimid crude product solid dissolved fully, adding gac, nano-ceramic powder carried out the insulation first time;
(3) filtered while hot is cooled to crystallization with filtrate;
(4) carry out the insulation second time, after crystallization is complete, suction filtration, drying.
Adopt the technical scheme of the refining Revlimid crude product of the present invention, because the Virahol that adopts is industrial chemicals commonly used, and toxicity is low, security is good, do not need special equipment and environmental requirement in the operating process, be more suitable for suitability for industrialized production, purity has had obvious improvement, high, the refining yield of product content is large, effective; Technical solution of the present invention is not that to adopt merely Virahol be solvent, but Virahol is mixed as solvent with water, the beneficial effect of its generation is, reduced the volatilization of Virahol in technique, in addition Virahol is mixed the effect that has reached good dissolving Revlimid crude product with water, reduced the usage quantity of simple Virahol as solvent; In addition, adopt gac that the Revlimid crude product solution is adsorbed, effectively reduce the foreign matter content in the solution, soaking time is 30 ~ 60min, for the impurity in the abundant absorbent solution of gac provides temperature condition and time conditions, simultaneously, the nano-ceramic powder of adding helps the Revlimid crystallization.
As the further improvement of technical solution of the present invention, Virahol and water volume ratio 1～3:1 in the mixing solutions.Through contriver's repeatedly creative work, experimental result shows Virahol and water volume ratio 1～3:1, and is better for dissolving Revlimid crude product effect.
As the further improvement of technical solution of the present invention, 40～55 ℃ of the temperature of for the second time insulation, soaking time is 2h.Can adopt various ways to be incubated, such as lagging material, water bath heat preservation or oil bath insulation all are fine, and temperature is maintained 40～55 ℃, and it mainly is to provide good condition for Crystallization Process.
As the further improvement of technical solution of the present invention, preferred Virahol and water volume ratio are 3:1.Virahol in the mixing solutions and water volume ratio are decided to be 3:1, and dissolving Revlimid crude product is more complete; Simultaneously, the nano-ceramic powder of adding is 1/10 of gac weight, makes its two proportioning reach best.
Embodiment
1, Comparative Examples is the method for existing purification Revlimid crude product: add Revlimid crude product 10.0g in reaction flask, acetone: water (1:1) 300mL, after being warming up to the whole dissolvings of Revlimid crude product solid, add proper amount of active carbon, be incubated 30 minutes, heat filtering, filtrate cooling crystallization is down to room temperature naturally, 0 ~ 5 ℃ of insulation 2h, suction filtration, filter cake is washed with cold acetone, normal temperature filter cake drying under reduced pressure, go out white solid 6.9g, yield 69% uses the HPLC(high performance liquid chromatography) to measure, its purity is 95.0%.
2, add Revlimid crude product 10.0g in the reaction flask, Virahol: water (1:1) 300mL is warming up to Revlimid crude product solid all after the dissolving, add proper amount of active carbon 5g, nano-ceramic powder 0.5g, be incubated 30 minutes, heat filtering, filtrate cooling crystallization is down to room temperature naturally, 40 ~ 45 ℃ of insulation 2h, suction filtration, filter cake is washed with cold isopropanol, normal temperature filter cake drying under reduced pressure, go out white solid 7.9g, yield 79% uses the HPLC(high performance liquid chromatography) to measure, its purity is 98.0%.
3, add Revlimid crude product 10.0g in the reaction flask, Virahol: water (3:1) 300mL is warming up to solid all after the dissolving, add proper amount of active carbon 9g, nano-ceramic powder 0.9g, be incubated 30 minutes, heat filtering, filtrate cooling crystallization is down to room temperature naturally, 45 ~ 55 ℃ of insulation 2h, suction filtration, filter cake is washed with cold isopropanol, normal temperature filter cake drying under reduced pressure, go out white solid 8.8g, yield 88% uses the HPLC(high performance liquid chromatography) to measure, its purity is 99.2%.
The technical scheme of the refining Revlimid crude product of the present invention, because the Virahol that adopts is industrial chemicals commonly used, and toxicity is low, security is good, do not need special equipment and environmental requirement in the operating process, be more suitable for suitability for industrialized production, purity has had obvious improvement, high, the refining yield of product content is large, effective.
Claims (4)
1. the process for purification of a Revlimid crude product is characterized in that, comprises the steps:
(1) the Revlimid crude product is added in the mixing solutions of isopropyl alcohol and water;
(2) intensification heating, after Revlimid crude product solid dissolved fully, adding gac, nano-ceramic powder carried out the insulation first time;
(3) filtered while hot is cooled to crystallization with filtrate;
(4) carry out the insulation second time, after crystallization is complete, suction filtration, drying.
2. the process for purification of Revlimid crude product according to claim 1 is characterized in that, the volume ratio of isopropyl alcohol and water is 1～3:1.
3. the process for purification of Revlimid crude product according to claim 1 and 2 is characterized in that, the temperature of the described insulation second time is 40～55 ℃.
4. the process for purification of Revlimid crude product according to claim 1 and 2 is characterized in that, in the mixing solutions of described isopropyl alcohol and water, Virahol and water volume ratio are 3:1, and the nano-ceramic powder of adding is 1/10 of gac weight.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275062A (en) * | 2013-05-17 | 2013-09-04 | 宁波市鄞州百特佳医药科技有限公司 | Purification method for Pomalidomide |
| CN103288797A (en) * | 2013-05-17 | 2013-09-11 | 宁波市鄞州百特佳医药科技有限公司 | Method for purifying Pomalidomide by using sulfoxide solvent |
| CN104016966A (en) * | 2014-01-30 | 2014-09-03 | 上海创诺制药有限公司 | Novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal forms and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011111053A1 (en) * | 2010-03-08 | 2011-09-15 | Natco Pharma Limited | Anhydrous lenalidomide form-i |
| CN102643266A (en) * | 2011-02-17 | 2012-08-22 | 江苏先声药物研究有限公司 | New preparation method of Lenalidomide B crystal form |
| WO2012127493A1 (en) * | 2011-03-23 | 2012-09-27 | Hetero Research Foundation | Polymorphs of lenalidomide |
-
2012
- 2012-10-30 CN CN2012104226169A patent/CN102993169A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011111053A1 (en) * | 2010-03-08 | 2011-09-15 | Natco Pharma Limited | Anhydrous lenalidomide form-i |
| CN102643266A (en) * | 2011-02-17 | 2012-08-22 | 江苏先声药物研究有限公司 | New preparation method of Lenalidomide B crystal form |
| WO2012127493A1 (en) * | 2011-03-23 | 2012-09-27 | Hetero Research Foundation | Polymorphs of lenalidomide |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103275062A (en) * | 2013-05-17 | 2013-09-04 | 宁波市鄞州百特佳医药科技有限公司 | Purification method for Pomalidomide |
| CN103288797A (en) * | 2013-05-17 | 2013-09-11 | 宁波市鄞州百特佳医药科技有限公司 | Method for purifying Pomalidomide by using sulfoxide solvent |
| CN103288797B (en) * | 2013-05-17 | 2016-03-02 | 宁波百思佳医药科技有限公司 | A kind of method of sulfoxide type solvents purifying Pomalidomide |
| 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 |
| CN104016966A (en) * | 2014-01-30 | 2014-09-03 | 上海创诺制药有限公司 | Novel 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-piperidinedione crystal forms and preparation method thereof |
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Application publication date: 20130327 |