CN103193763B - A kind of preparation method of Revlimid - Google Patents
A kind of preparation method of Revlimid Download PDFInfo
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- CN103193763B CN103193763B CN201310122874.XA CN201310122874A CN103193763B CN 103193763 B CN103193763 B CN 103193763B CN 201310122874 A CN201310122874 A CN 201310122874A CN 103193763 B CN103193763 B CN 103193763B
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Abstract
The invention discloses one and prepare Revlimid (3-(7-amino-3-oxo-1H-isoindole-2-base) piperidines-2; 6-diketone) method; comprise the steps such as intramolecular cyclization, deprotection, phase-transfer-catalyzed reactions, catalytic hydrogenation, alkalization; this operational path is novel; step is short; reaction yield is high, and production cost is low, has larger implementary value and economic results in society.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis field, specifically a kind of new preparation process of Revlimid.
Background technology
Revlimid (lenalidomide) (3-(7-amino-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone), it is the new immunomodulator researched and developed by Celgene company of the U.S., U.S. FDA approval listing is obtained in January, 2006, trade(brand)name Revlimid, clinical being mainly used in treats myelodysplastic syndrome (MDS) hypotype and the multiple myeloma that 5q lacks (the gap genetically deficient of the 5th pair of chromosome long arm).
Multiple myeloma (multiplemgeloma, MM) is the malignant B-cell diseases that a kind of refractory is healed, and the continuous hyperplasia of marrow malignant cell of patient causes normal cell to play a role.Myeloproliferative disorder (myelodysplastic syndrome, MDS) be Clonal hematopoetic tumor, when the hemocyte in marrow is in the immature stage all the time and can not fulfils its necessary function, myelodysplastic syndrome will occur, be filled with these immature cells in marrow, inhibit Normocellular development.
The chemotherapy of MM and MDS starts from the sixties in 20th century, after this in 30 years, melphalan associating prednisone is the standard regimens of this type of disease always, high-dose chemotherapy adds stem cell transplantation and really can be patient and bring benefit within 1996, just to have research to confirm, but the recurrence rate of this type of disease is high, and spendable rescue therapy is little.Along with deep and some new drugs be familiar with disease mechanisms such as Thalidomide (thalidomide) and Revlimid are approved for treatment MM and MDS successively, make the treatment of such disease there occurs epoch-making change, the survival region of patient obtains remarkable improvement.
Revlimid, by activated T cell, produces interleukin-2 (IL-2), strengthens the immunocompetence of NK cell, plays immunoregulation effect; The apoptosis of myeloma cell can be caused, suppress the generation of the drug resistant tumor cells mediated by cytokine and marrow stromal cell, there is blood vessel formation against function.Revlimid is the derivative of new generation of Thalidomide, its chemical property is more stable than Thalidomide, there is stronger Agiogenesis inhibition, immunomodulatory, cell death inducing and directly kill the effects such as tumor promotion, and almost impassivity toxicity and teratogenecity, safer relative to Thalidomide clinical application, untoward reaction is less, and this medicine has obtained the Orphan drug status for the treatment of MM and MDS at present.
The structural formula of Revlimid is:
The preparation method of Revlimid is more, wherein (the Chinese Journal of Pharmaceuticals 2008 such as Fang Feng, 39, 888) adopt N-carbobenzoxy-(Cbz)-L-glutaminate through methanol esterification, L-glutaminate methyl esters is obtained again through Pd/C catalysis deprotection, intermediate N (4-nitro-1-oxo-1 is obtained with the condensation of 2-brooethyl-3-nitrobenzene methyl, 3-dihydro-2H-isoindole-2-base)-L-glutaminate methyl esters, N-(4-amino-1 is obtained through Pd/C catalytic hydrogenation, 3-dihydro-1-oxo-2H-isoindole-2-base)-L-glutaminate methyl esters, last intramolecular condensation obtains Revlimid, see following reaction formula.There is the shortcoming that step is long, total recovery is low in the method.
Summary of the invention
In view of this, long in order to solve existing Revlimid technology of preparing step, total recovery is low, not easily realizes industrialized shortcoming, the invention provides a kind of new preparation method, this preparation technology is easy, and raw material is cheap and easy to get, yield is high, and security is high, is applicable to suitability for industrialized production.
Reaction formula of the present invention is:
Prepare a method for Revlimid, it is characterized in that comprising the following steps:
1) with N-Boc-L-glutamine for raw material, carry out intramolecular cyclization and obtain 3-N-Boc-amino piperidine-2,6-diketone;
2) in the saturated organic solvent of HCl, deprotection obtains 3-amino piperidine-2,6-dione hydrochloride;
3) under phase transfer catalysis condition, 3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone is obtained with 2-brooethyl-3-nitrobenzene methyl;
4) in acid system, the hydrochloride of Revlimid is obtained through Pd/C catalytic hydrogenation, obtained target product Revlimid after alkalization.
Described method, it is characterized in that the condensation reagent of ring closure reaction in step 1) Middle molecule is dicyclohexylcarbodiimide, solvent is a kind of or wherein several mixture in tetrahydrofuran (THF), 2-methyltetrahydrofuran, methylene dichloride, Isosorbide-5-Nitrae-dioxane, chloroform.
Described method, is characterized in that step 2) in organic solvent be wherein a kind of in ethyl acetate, tetrahydrofuran (THF), dioxane, or the mixture of wherein a kind of and methyl alcohol in above-mentioned solvent or ethanol.
Described method, the solvent that it is characterized in that in step 3) is the mixture of one or more in methylene dichloride, chloroform, toluene, the alkali of catalyzed reaction is the one in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, phase-transfer catalyst is quaternary ammonium compound, comprises Tetrabutyl amonium bromide, tetrabutylammonium chloride, cetyl trimethylammonium bromide etc.
Described method, it is characterized in that the catalyzer in step 4) is the Pd/C of 5%-10%, solvent is the mixture of one or more in ethanol, methyl alcohol, Virahol, water, the acid added is the one in concentrated hydrochloric acid, the vitriol oil, perchloric acid, trifluoroacetic acid, trifluoromethanesulfonic acid etc., alkalizing agent is supercarbonate and carbonate, comprises sodium bicarbonate, saleratus, sodium carbonate, salt of wormwood.
Described method, is characterized in that step 1) to the temperature of reaction in step 4) between room temperature and the reflux temperature of solvent.
Present invention process route is novel, and processing condition are reasonable, and reactions steps is short, simple to operate, and reaction yield is high, and manufacturing cost is lower, substantially without the three wastes, has larger implementary value and economic results in society.
Embodiment
Embodiment 1:
(1) preparation of 3-N-Boc-amino piperidine-2,6-diketone
N-Boc-L-glutamine 41.6g is dissolved in 200mL 2-methyltetrahydrofuran, under 0 DEG C of ice bath, adds DCC 35.1g, room temperature reaction 10 hours.Recycling design, ethyl acetate extracts three times, merges organic layer, uses saturated NaHCO successively
3, saturated common salt water washing, anhydrous sodium sulfate drying, recycling design obtains 28.9g white solid, yield 75%.
1H NMR (500 MHz, CDCl
3) δ: 8.17 (brs, 1H), 5.36 (brs, 1H), 4.33-4.30 (m, 1H), 2.82-2.77 (m, 1H), 2.72-2.64 (m, 1H), 2.54-2.51 (m, 1H), 1.91-1.82 (m, 1H), 1.46 (s, 9H)
Embodiment 2:
N-Boc-L-glutamine 41.6g is dissolved in 200mL 2-methyltetrahydrofuran, under 0 DEG C of ice bath, adds DCC 35.1g, 40 DEG C of room temperature reactions 10 hours.Recycling design, ethyl acetate extracts three times, merges organic layer, uses saturated NaHCO successively
3, saturated common salt water washing, anhydrous sodium sulfate drying, recycling design obtains white solid, yield 78%.
Embodiment 3:
(2) preparation of 3-amino piperidine-2,6-dione hydrochloride
3-N-Boc-amino piperidine-2,6-diketone 10g is dissolved in the saturated ethyl acetate of 30mL HCl, stirring at room temperature 8 hours, and suction filtration, obtains 6.47g white solid, yield 90%.
1H NMR (500 MHz, DMSO-d
6): 11.26 (s, 1H), 8.74 (s, 3H), 4.21 (dd,
J 1 =13.0 Hz,
J 2 = 5.0 Hz, 1H), 2.76-2.68 (m, 1H), 2.61-2.51 (m, 1H), 2.25-2.23 (m, 1H), 2.09-2.00 (m, 1H).
Embodiment 4
3-N-Boc-amino piperidine-2,6-diketone 10g is dissolved in the saturated ethyl acetate of 20mL HCl and 10mL methyl alcohol, stirring at room temperature 8 hours, and suction filtration, obtains white solid, yield 92%.
Embodiment 5
3-N-Boc-amino piperidine-2,6-diketone 10g is dissolved in the saturated ethyl acetate of 20mL HCl and 10mL ethanol, stirring at room temperature 8 hours, and suction filtration, obtains white solid, yield 91%.
Embodiment 6
(3) preparation of 3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone
2-brooethyl-3-nitrobenzene methyl 21.2g, 3-amino piperidine-2,6-dione hydrochloride 12.7g, Tetrabutyl amonium bromide 25mg, 10% NaOH solution 80mL and 150mL methylene dichloride add in reaction flask, heating reflux reaction 2 hours, decompression removing methylene dichloride, residue suction filtration, washes with water repeatedly, obtain purple solid product 19.9g, yield 89%.
1H NMR(500 MHz, DMSO-d
6) δ: 11.02 (s, 1H), 8.48 (dd,
J 1= 8.5 Hz,
J 2= 1.0 Hz, 1H), 8.20 (dd,
J 1= 7.5 Hz,
J 2= 1.0 Hz, 1H), 7.86 (t,
J = 8.0 Hz, 1H), 5.20 (dd,
J 1= 8.0 Hz,
J 2= 5.0 Hz, 1H), 4.93 (
J = 19.0 Hz, 1H), 4.82 (
J = 19.0 Hz, 1H), 2.95-2.88 (m, 1H), 2.63-2.56 (m, 1H), 2.55-2.50 (m, 1H), 2.05-2.00 (m, 1H)。
Embodiment 7
Change Tetrabutyl amonium bromide 25mg into cetyl trimethylammonium bromide 30mg, other are with embodiment 6, and the yield obtaining 3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone is 91%.
Embodiment 8
(4) preparation of Revlimid 3-(7-amino-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone
3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone 19.8g is dissolved in 400mL methyl alcohol, adds 0.2g 10% palladium-carbon catalyst and 8.0 mL concentrated hydrochloric acids, pass into hydrogen, room temperature reaction 4 hours.Cross and filter palladium carbon, filtrate adjusts pH 8 with the sodium hydrogen carbonate solution of 7%, obtains white solid 17g, yield 96%.
1H NMR (500 MHz, DMSO-d
6) δ: 11.0 (s, 1H), 7.21 (t,
J = 7.5 Hz, 1H), 6.92 (d,
J = 7.5 Hz, 1H), 6.81 (d,
J = 8.0 Hz, 1H), 5.42 (s, 2H), 5.12 (dd,
J 1= 8.0 Hz,
J 2= 5.0 Hz, 1H), 4.20 (
J = 19.0 Hz, 1H), 4.12 (
J = 19.0 Hz, 1H), 2.96-2.88 (m, 1H), 2.63-2.60 (m, 1H), 2.34-2.26 (m, 1H), 2.05-2.02 (m, 1H)。
Embodiment 9
3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone 19.8g is dissolved in 400mL(methyl alcohol: water=1:1) in mixed solvent, add 0.3g 5% palladium-carbon catalyst and 8.0 mL trifluoroacetic acids, pass into hydrogen, room temperature reaction 4 hours.Cross and filter palladium carbon, filtrate adjusts pH 8 with the sodium hydrogen carbonate solution of 7%, obtains white solid yield 94%.
Embodiment 10
3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone 19.8g is dissolved in 400mL(ethanol: water=1:1) mixed solvent in, add 0.3g 5% palladium-carbon catalyst and 8.0 mL trifluoromethanesulfonic acids, pass into hydrogen, room temperature reaction 4 hours.Cross and filter palladium carbon, filtrate adjusts pH 8 with the sodium hydrogen carbonate solution of 7%, obtains white solid yield 95%.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any amendments done within the spirit and principles in the present invention, equivalent replacement and improvement etc., be all included within protection scope of the present invention.
Claims (1)
1. prepare a method for Revlimid, it is characterized in that comprising the following steps:
1) N-Boc-L-glutamine 41.6g is dissolved in 200mL2-methyltetrahydrofuran, under 0 DEG C of ice bath, adds DCC35.1g, 40 DEG C are reacted 10 hours, recycling design, and ethyl acetate extracts three times, merge organic layer, use saturated NaHCO successively
3, saturated common salt water washing, anhydrous sodium sulfate drying, recycling design obtains 3-N-Boc-amino piperidine-2, the 6-diketone of white solid, yield 78%;
2) be dissolved in the saturated ethyl acetate of 30mlHCl by 3-N-Boc-amino piperidine-2,6-diketone 10g, stirring at room temperature 8 hours, suction filtration obtains 3-amino piperidine-2, the 6-dione hydrochloride of 6.47g white solid, yield 90%;
3) by 2-brooethyl-3-nitrobenzene methyl 21.2g, 3-amino piperidine-2,6-dione hydrochloride 12.7g, cetyl trimethylammonium bromide 30mg, 10% NaOH solution 80mL and 150mL methylene dichloride add in reaction flask, heating reflux reaction 2 hours, decompression removing methylene dichloride, residue suction filtration, washes with water repeatedly, obtains 3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2 of violet solid, 6-diketone, yield 91%;
4) by 3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone 19.8g is dissolved in 400ml methyl alcohol, add 0.2g10% palladium-carbon catalyst and 8.0mL concentrated hydrochloric acid, pass into hydrogen, room temperature reaction 4 hours, crosses and filters palladium carbon, and filtrate adjusts pH 8 with the sodium hydrogen carbonate solution of 7%, obtain the Revlimid 17g of white solid, yield 96%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105440012A (en) * | 2014-08-07 | 2016-03-30 | 天津法莫西医药科技有限公司 | Lenalidomide and lenalidomide intermediate preparation method |
| CN109305935A (en) * | 2017-07-27 | 2019-02-05 | 杭州惠诺医药科技有限公司 | A kind of preparation method of 3- amino -2,6- piperidine dione hydrochloride |
| CN108191828B (en) * | 2018-04-04 | 2020-06-09 | 梯尔希（南京）药物研发有限公司 | Method for synthesizing lenalidomide metabolite |
| CN110498759A (en) * | 2019-09-12 | 2019-11-26 | 天津瑞岭化工有限公司 | The synthetic method of isoindoline ketone compound |
Citations (3)
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|---|---|---|---|---|
| CN101665484A (en) * | 2009-07-20 | 2010-03-10 | 上海皓元生物医药科技有限公司 | Method for preparing lenalidomide |
| CN101959856A (en) * | 2008-03-11 | 2011-01-26 | 雷迪博士实验室有限公司 | Preparation of lenalidomide |
| CN102838586A (en) * | 2012-09-20 | 2012-12-26 | 重庆泰濠制药有限公司 | Method for preparing lenalidomide |
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| CA2773012A1 (en) * | 2009-09-03 | 2011-03-10 | Ranbaxy Laboratories Limited | Process for the preparation of lenalidomide |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101959856A (en) * | 2008-03-11 | 2011-01-26 | 雷迪博士实验室有限公司 | Preparation of lenalidomide |
| CN101665484A (en) * | 2009-07-20 | 2010-03-10 | 上海皓元生物医药科技有限公司 | Method for preparing lenalidomide |
| CN102838586A (en) * | 2012-09-20 | 2012-12-26 | 重庆泰濠制药有限公司 | Method for preparing lenalidomide |
Non-Patent Citations (2)
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| Charlotte Chaulet, et al.Design, synthesis and biological evaluation of new thalidomide analoguesas TNF-α and IL-6 production inhibitors.《Bioorganic Medicinal Chemistry Letters》.2010,第21卷1019-1022. * |
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Address after: 501, room 3, building 4280, 310053 South Ring Road, Hangzhou, Zhejiang, Binjiang District Patentee after: HANGZHOU BAICHENG PHARMACEUTICAL TECHNOLOGY CO., LTD. Address before: 501, room 3, building 4280, 310053 South Ring Road, Hangzhou, Zhejiang, Binjiang District Patentee before: Hangzhou Baicheng Medical Science & Technology Co., Ltd. |