CN103601717A - Novel preparation method of lenalidomide - Google Patents
Novel preparation method of lenalidomide Download PDFInfo
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- CN103601717A CN103601717A CN201310469416.3A CN201310469416A CN103601717A CN 103601717 A CN103601717 A CN 103601717A CN 201310469416 A CN201310469416 A CN 201310469416A CN 103601717 A CN103601717 A CN 103601717A
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- 0 *c1c(CBr)c([N+]([O-])=O)ccc1 Chemical compound *c1c(CBr)c([N+]([O-])=O)ccc1 0.000 description 3
- FKGOIWFLNHSMLJ-UHFFFAOYSA-N Cc(c(N=O)ccc1)c1C(OC)=O Chemical compound Cc(c(N=O)ccc1)c1C(OC)=O FKGOIWFLNHSMLJ-UHFFFAOYSA-N 0.000 description 1
- YPQAFWHSMWWPLX-UHFFFAOYSA-N Cc(c([N+]([O-])=O)ccc1)c1C(O)=O Chemical compound Cc(c([N+]([O-])=O)ccc1)c1C(O)=O YPQAFWHSMWWPLX-UHFFFAOYSA-N 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N Nc1cccc2c1CN(C(CCC(N1)=O)C1=O)C2=O Chemical compound Nc1cccc2c1CN(C(CCC(N1)=O)C1=O)C2=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- JKPJLYIGKKDZDT-UHFFFAOYSA-N [O-][N+](c1cccc2c1CN(C(CCC(N1)=O)C1=O)C2=O)=O Chemical compound [O-][N+](c1cccc2c1CN(C(CCC(N1)=O)C1=O)C2=O)=O JKPJLYIGKKDZDT-UHFFFAOYSA-N 0.000 description 1
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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
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Abstract
The invention discloses a novel preparation method of lenalidomide. Glutarimide and 4-nitro-isoindolin-1-one are used as raw materials of the lenalidomide. The lenalidomide is prepared by (1) performing bromination in the alpha position of the carbonyl of the glutarimide to obtain 3; (2) condensing 4-nitro-isoindolin-1-one and the 3 to obtain 4; and (3) subjecting the 4 to reduction to obtain 5, namely the lenalidomide. The preparation method has easily available raw materials, short steps, simple operation, high reaction yield and low production cost, and is environmental friendly. The preparation method has large implement value and social and economic benefit.
Description
Technical field
The present invention relates to a kind of novel preparation method of chemicals, particularly a kind of novel preparation method of compound Revlimid.
Technical background
Revlimid (Lenalidomide), trade name REVLIMID
tM, chemical name 3-(7-amino-3-oxo-1h-isoin-dol-2-yl) piperidine-2,6-dione, CAS:191732-72-6, structural formula is:
The Novel immune of Revlimid Shi You U.S. Celgene company research and development regulates oral preparations, is used for the treatment of the medicine of lethality hematologic disease and cancer.Revlimid is all influential to multiple biological approach in cell.Celgene company still, carrying out hematology and the oncology therapeutic action assessment of this product, comprises multiple myeloma, myelodysplastic syndrome, chronic lymphocytic leukemia and solid tumor.Myelodysplastic syndrome is a kind of malignant hematologic disease, nearly 300,000 patients in the whole world.The hemocyte in marrow is all the time when thereby the immature stage can not be fulfiled its necessary function, and myelodysplastic syndrome will occur.In marrow, be full of these immature cells, suppressed Normocellular development.Patients With Myelodysplastic Syndrome must often rely on blood transfusion to resist the symptoms such as anaemia, fatigue, until develop into life-threatening iron overload or iron poisoning.The treatment of this disease is not only control symptom in the urgent need to a kind of method of effecting a permanent cure.The Patients With Myelodysplastic Syndrome that surpasses half is diagnosed out cell chromosome variation, comprises an above chromosomal partially or completely disappearance.In myelodysplastic syndrome, modal cell chromosome appears at chromosomal q disappearance extremely 5,7 and No. 20.Another commonplace variation is chromosomally additionally to copy for No. 8.The ratio of the chromosomal disappearance of 5q in Patients With Myelodysplastic Syndrome can reach 20%～30%.
Myelodysplastic syndrome (the Myclodysplastic syndrome that this medicine is mainly used in treating the strong knurl of chronic bone and has 5q disappearance, MDS), Revlimid is the derivative of new generation of Thalidomide, but do not find that it has the toxicity that causes rugged change, and drug effect is stronger 100 times than Thalidomide. according to the result of three clinical examination faces of phase, Revlimid is to treat at present the most significant medicine of the sharp knurl curative effect of multiple labor, the clothes for patients that surpasses half reaches more than 3 years with extending the survival time after this medicine. and it is also effectively to treat the unique medicine of myelodysplastic syndrome (MDS) in addition, clinical effectiveness find 64% patient MDS be used for that degree by treatment after without treating MDS. with transfusing blood again
According to open report data, the preparation method of Revlimid has a lot.Patent WO2010100476 discloses a kind of method of preparing Revlimid, and its synthetic route is as follows:
This route obtains 3-amino-2,6-dioxopiperidine with N-(tertbutyloxycarbonyl carbonyl)-L-glutaminate through intramolecular condensation, deprotection.Separately with 2-methyl-3-nitro phenylformic acid, through esterification, bromo, obtain 2-brooethyl-3-nitrobenzene methyl.Then 3-amino-2, and the shortcoming that the process condensation again of 6-dioxopiperidine and 2-brooethyl-3-nitrobenzoic acid first, reduction obtain 5. the method is that yield is low, purification difficult.
2008, Fang Feng, Xu Xu, Ji Yafei (Chinese Journal of Pharmaceuticals, 2008,39(12): 888-89.) reported that another synthetic route is as follows:
This route obtains L-glutaminate methyl esters with N-(carbobenzoxy-(Cbz))-L-glutaminate through over-churning, debenzylation.Separately with 2-methyl-3-nitro phenylformic acid, through esterification, bromo, obtain 2-brooethyl-3-nitrobenzene methyl.Then L-glutaminate methyl esters and 2-brooethyl-3-nitrobenzene methyl obtain intermediate N (4-nitro-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-L-glutaminate methyl esters through condensation, then obtain 5 through nitroreduction, intramolecular condensation.Or first after intramolecular condensation, reduce and also can obtain 5.This technique exists that route is long, yield is low, environmental pollution is serious, the shortcoming that industrialization cost is high.
Summary of the invention
The invention discloses a kind of novel preparation method of Revlimid, take glutarimide and 4-nitro-1-isoindolinone is raw material, two kinds of raw materials are all cheap and easy to get, thereby significantly shortened processing step, improved product yield, having alleviated environmental, reduced production cost, is an operational path that very suitability for industrialized is produced.
Disclosed by the inventionly take the method that glutarimide and 4-nitro-1-isoindolinone prepare Revlimid as raw material and comprise that step is as follows:
(1) take glutarimide (1) is starting raw material, halogen substitution reaction occurs in carbonyl α position with halogenating agent and obtain 3;
Wherein, X represents chlorine, bromine or iodine atom;
(2) 2 and 3, under alkaline condition, carry out nucleophilic substitution reaction, lose a small molecules condensation and obtain 4;
(2) finally 4 use reductive agent reduction are obtained to 5, i.e. Revlimid.
One preferred embodiment in, described preparation 3-halo-2, the halogenating reaction halide reagent used of 6-dioxopiperidine is selected from bromine, bromo-succinimide, chlorosuccinimide, N-iodosuccinimide; Described intermolecular condensation reaction preparation 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the catalyzer of 6-dioxopiperidine is selected from one or more the mixture in lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, salt of wormwood, triethylamine, pyridine, triisopropylamine, sodium bicarbonate, saleratus; Reduction reaction is prepared Revlimid reductive agent used and is selected from iron powder, glass putty, tin protochloride, zinc powder, palladium carbon, palladium hydroxide, Raney's nickel, nickel-aluminium alloy.
Another preferred embodiment in, described preparation 3-halo-2, the halogenating reaction solvent used of 6-dioxopiperidine is methylene dichloride, chloroform, tetracol phenixin, dithiocarbonic anhydride, the mixture of one or more in Glacial acetic acid; Described preparation 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the condensation reaction solvent for use of 6-dioxopiperidine is tetrahydrofuran (THF), acetonitrile, N, the mixture of one or more in N '-dimethyl formamide, dimethyl sulfoxide (DMSO), benzene, toluene, o-Xylol, m-xylene, p-Xylol, ethyl acetate, chloroform, tetracol phenixin, acetone, water, methyl alcohol, ethanol, Virahol, propyl carbinol.The solvent of described reduction nitro is selected from methyl alcohol, water, ethanol, acetic acid the mixture of one or more.
In a preferred experimental program again, described halogenating reaction temperature is the reflux temperature of-40 ℃-solvent; Described preparation 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the setting-up point of 6-dioxopiperidine is the reflux temperature of 0 ℃-solvent; The temperature of reaction of described reduction nitro is the reflux temperature of 0 ℃-solvent.
In a preferred experimental program again, the method according to claim 1-5, is characterized in that, described halogenating reaction temperature is the reflux temperature of solvent; Described preparation 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the temperature of reaction of 6-dioxopiperidine is the reflux temperature of solvent; The temperature of reaction that described reduction nitro is prepared Revlimid is room temperature.
The present invention is a kind of novel process of preparing of Revlimid, and raw materials technology is easy to get, and step is short, easy and simple to handle, and overall yield of reaction is high, and production cost is low, environmentally friendly, has larger implementary value and economic results in society.
The present invention is further described by the following embodiment, and these descriptions are not that content of the present invention is further limited.One skilled in the art will understand that the replacement that is equal to that technical characterictic of the present invention is done, or improve accordingly, within still belonging to protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) 3-is bromo-2, the preparation of 6-dioxopiperidine
10.2g glutarimide joins in 20 milliliters of acetic acid, add again 4.5 milliliters of bromines, be heated to reflux, stir 3 hours, be cooled to room temperature, unnecessary acetic acid and bromine are removed in decompression, and residuum is joined in chloroform and water and extracted, and organic phase is dry, concentrated, with ethyl alcohol recrystallization, obtain the white solid compound 3(yield 99% of 17.1g), 1H-NMR (CDCl3,400MHz) δ: 8.34(s, 1H), 4.64 (t, 1H), 2.91-3.00 (m, 1H), 2.66-2.73 (m, 1H), 2.28-2.47 (m, 2H).
(2) 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2,6-dioxopiperidine
8.9g4-nitro-1-isoindolinone and 9.5g compound 3 join 150ml N, in N '-dimethyl formamide, then add 13.8g K
2cO
3, be heated with stirring to backflow, react 8 hours, stop heating, be cooled to room temperature, add 1000ml water, fully stir, add 300ml ethyl acetate, extraction separatory, collects organic phase again, dry, concentrated, residuum is crossed post separation and is obtained white solid 12.43g compound 4(yield 86%), 1H-NMR (DMSO-d6,400MHz) δ: 11.04 (s, 1H), 8.16 (d, 1H), 7.82 (t, 1H), 5.15 (d, 1H), 4.87 (dd, 2H), 2.83～2.95 (m, 1H), 2.54～2.60 (m, 1H), 2.44～2.50 (m, 1H), 1.97～2.01 (m, 1H).
(3) Revlimid 3-(7-amino-3-oxo-1H-isoindole-2-yl) piperidines-2, the preparation of 6-diketone
8g compound 4, iron powder 6.5g and concentrated hydrochloric acid 260ml three mix, stirring at room 5 hours, be cooled to room temperature, add saturated aqueous sodium carbonate and adjust pH=7. dichloromethane extraction, collect organic phase, dry, concentrated, residuum is crossed post separation and is obtained 6.4g white solid 5 (89%), 1H-NMR (DMSO-d6,400MHz) δ: 10.98 (s, 1H), 7.69 (t, 1H), 6.88 (d, 1H), 6.76 (d, 1H), 5.41 (s, 2H), 5.07 (dd, 1H), 4.12 (dd, 2H), 2.83～2.95 (m, 1H), 2.61 (m, 1H), 2.20～2.35 (m, 1H), 1.95～2.01 (m, 1H).
Claims (6)
1. a method of preparing Revlimid, is characterized in that take that glutarimide and 4-nitro-1-isoindolinone are starting raw material, through bromo, condensation, reduction three-step reaction, is prepared into Revlimid, and synthetic route is as follows.
2. according to the method for claim 1,3 steps described in it is characterized by are reacted and are,
(1) take glutarimide (1) is starting raw material, with halogenating agent, in carbonyl α position, there is halogen substitution reaction and obtain 3,
Wherein, X represents chlorine, bromine or iodine atom;
(2) 2 and 3, under alkaline condition, carry out nucleophilic substitution reaction, lose a small molecules condensation and obtain 4;
(3) finally 4 use reductive agent reduction are obtained to 5, i.e. Revlimid.
3. according to the method for claim 1-2, it is characterized in that, described preparation 3-halo-2, the halogenating reaction halide reagent used of 6-dioxopiperidine is selected from bromine, bromo-succinimide, chlorosuccinimide, N-iodosuccinimide; Described intermolecular condensation reaction preparation 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the catalyzer of 6-dioxopiperidine is selected from one or more the mixture in lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, sodium carbonate, salt of wormwood, triethylamine, pyridine, triisopropylamine, sodium bicarbonate, saleratus; Reduction reaction is prepared Revlimid reductive agent used and is selected from iron powder, glass putty, tin protochloride, zinc powder, palladium carbon, palladium hydroxide, Raney's nickel, nickel-aluminium alloy.
4. according to the method for claim 1-2, it is characterized in that, described preparation 3-halo-2, the halogenating reaction solvent used of 6-dioxopiperidine is methylene dichloride, chloroform, tetracol phenixin, dithiocarbonic anhydride, the mixture of one or more in Glacial acetic acid; Described preparation 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the condensation reaction solvent for use of 6-dioxopiperidine is tetrahydrofuran (THF), acetonitrile, N, the mixture of one or more in N '-dimethyl formamide, dimethyl sulfoxide (DMSO), benzene, toluene, o-Xylol, m-xylene, p-Xylol, ethyl acetate, chloroform, tetracol phenixin, acetone, water, methyl alcohol, ethanol, Virahol, propyl carbinol.The solvent of described reduction nitro is selected from methyl alcohol, water, ethanol, acetic acid the mixture of one or more.
5. according to the method for claim 1-2, it is characterized in that, described halogenating reaction temperature is the reflux temperature of-40 ℃-solvent; Described preparation 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the setting-up point of 6-dioxopiperidine is the reflux temperature of 0 ℃-solvent; The temperature of reaction of described reduction nitro is the reflux temperature of 0 ℃-solvent.
6. according to the method for claim 1-5, it is characterized in that, described halogenating reaction temperature is the reflux temperature of solvent; Described preparation 3-(4-nitro-1,3-dihydro-1-oxo-2H-isoindole-2-yl)-2, the temperature of reaction of 6-dioxopiperidine is the reflux temperature of solvent; The temperature of reaction that described reduction nitro is prepared Revlimid is room temperature.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910132A (en) * | 2014-03-14 | 2015-09-16 | 天津永生生物技术有限公司 | Preparation method of pomalyst and intermediate thereof |
| WO2016024286A3 (en) * | 2014-08-11 | 2016-04-07 | Avra Laboratories Pvt. Ltd. | An improved process for synthesis of lenalidomide |
| CN106957299A (en) * | 2017-03-31 | 2017-07-18 | 常州制药厂有限公司 | A kind of lenalidomide preparation method |
| CN107488167A (en) * | 2017-09-29 | 2017-12-19 | 青岛辰达生物科技有限公司 | A kind of preparation method of antineoplastic lenalidomide intermediate |
| WO2019227968A1 (en) * | 2018-06-01 | 2019-12-05 | 上海博志研新药物技术有限公司 | Method for preparing lenalidomide |
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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 |
| CN102414196A (en) * | 2009-03-02 | 2012-04-11 | 基因里克斯(英国)有限公司 | Improved process |
| 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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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910132A (en) * | 2014-03-14 | 2015-09-16 | 天津永生生物技术有限公司 | Preparation method of pomalyst and intermediate thereof |
| WO2016024286A3 (en) * | 2014-08-11 | 2016-04-07 | Avra Laboratories Pvt. Ltd. | An improved process for synthesis of lenalidomide |
| US10392364B2 (en) | 2014-08-11 | 2019-08-27 | Avra Laboratories Pvt. Ltd. | Process for synthesis of lenalidomide |
| CN106957299A (en) * | 2017-03-31 | 2017-07-18 | 常州制药厂有限公司 | A kind of lenalidomide preparation method |
| CN106957299B (en) * | 2017-03-31 | 2021-02-26 | 常州制药厂有限公司 | Preparation method of lenalidomide |
| CN107488167A (en) * | 2017-09-29 | 2017-12-19 | 青岛辰达生物科技有限公司 | A kind of preparation method of antineoplastic lenalidomide intermediate |
| WO2019227968A1 (en) * | 2018-06-01 | 2019-12-05 | 上海博志研新药物技术有限公司 | Method for preparing lenalidomide |
| CN110551100A (en) * | 2018-06-01 | 2019-12-10 | 上海博志研新药物技术有限公司 | preparation method of lenalidomide |
| US11591310B2 (en) | 2018-06-01 | 2023-02-28 | Shanghai Bocimed Pharmaceutical Co., Ltd. | Method for preparing lenalidomide |
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Application publication date: 20140226 |