CN105440012A - Lenalidomide and lenalidomide intermediate preparation method - Google Patents
Lenalidomide and lenalidomide intermediate preparation method Download PDFInfo
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- CN105440012A CN105440012A CN201410387101.9A CN201410387101A CN105440012A CN 105440012 A CN105440012 A CN 105440012A CN 201410387101 A CN201410387101 A CN 201410387101A CN 105440012 A CN105440012 A CN 105440012A
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Abstract
A lenalidomide and lenalidomide intermediate preparation method includes the following four steps: (1) intramolecular ring-closure of N-Boc-glutamine methyl ester (I) in the presence of a condensing agent and a catalyst to obtain 3-Boc-imino-piperidine-2,6-dione (II); (2) deprotection reaction of the compound (II) obtained by the step (1) to obtain 3-(N-Boc-imino) - piperidine-2,6-dione (III); (3) condensation reaction of the compound (III) obtained by the step (2) and 2-bromomethyl-3-nitrobenzoate (IV) to obtain 3-( 7-nitro-3-oxo-1H-isoindole-2-yl)-piperidine-2,6-dione (V); and (4) nitro group reduction reaction of the compound (V) obtained by the step (3) to obtain lenalidomide (VI); and a synthetic route is shown in the specification.
Description
Technical field
The present invention relates to a kind of preparation method of antitumor drug, particularly relate to the preparation method of a kind of Revlimid and intermediate thereof.
Background technology
Revlimid (Lenalidomide) is the new immunomodulator of Celgene drugmaker of U.S. exploitation, and commodity are called revlimid.This medicine is used for the treatment of recurrent and Refractory Multiple Myeloma and myeloproliferative disorders, and its chemical structure is as follows:
Along with the continuous increase of Revlimid share of market, its market requirement increases, and impels more pharmaceutical manufacturer to update existing production technique, reduces costs, obtain larger economic benefit.The synthetic route that Chinese patent CN101665484B discloses a kind of Revlimid is:
Existing production technique uses acidic substance example hydrochloric acid etc. when removing N-Boc protecting group, can produce the spent acid being difficult in a large number process, cause environmental pollution.And Chinese document---the N-Boc protecting group that boiling water promotes removes synthesis and the applied research (Wang Jia of the chiral phosphoric acid of reaction and dinaphthol skeleton; Nankai University master Diplomarbeit; in May, 2011) disclose adopt boiling water reaction is removed to different substrate N-Boc protecting group; the document shows, different reaction substrates is used for the selectivity, yield, reaction times etc. of reaction when boiling water N-Boc protecting group removes and all there is larger difference.When we adopt the relevant intermediate of Revlimid to react, get 1mmol substrate in 20ml boiling water, react 12h after transformation efficiency very low, only have an appointment 70%.Based on pharmacy value and the good market outlook of Revlimid, find a kind of method easy and simple to handle, cost is lower, controllability is strong applicable suitability for industrialized production Revlimid imperative.
Summary of the invention
For the deficiencies in the prior art; quasi-solution of the present invention certainly provides that a kind of cost is low, yield is high, be suitable for the preparation method of the Revlimid of suitability for industrialized production (VIII) and intermediate thereof; improving technique; boiling water is adopted to remove reaction to N-Boc protecting group; improve the transformation efficiency of reaction, reduce the discharge of pollution.
The invention provides the preparation method of a kind of Revlimid and intermediate thereof, comprise following four-step reaction,
(1) N-Boc-glutamine methyl esters (I) carries out intramolecular cyclization and obtains 3-Boc imino-piperidines-2,6-diketone (II) under the existence of condensing agent and catalyzer;
(2) compound (II) that step (1) obtains is carried out deprotection reaction and obtain 3-(N-Boc-imino-)-piperidines-2,6-diketone (III);
(3) compound (III) step (2) obtained and 2-brooethyl-3-nitrobenzene methyl (IV) carry out condensation reaction and obtain 3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone (V);
(4) compound (V) that step (3) obtains is carried out nitro-reduction reaction and obtain Revlimid (VI);
Synthetic route is as follows,
It is characterized in that; the deprotection reaction condition of described step (2) is: in as the water of solvent, add sodium-chlor; the weight ratio of sodium-chlor and water is 0.25-0.28:1; temperature of reaction is below reaction system boiling point at ambient pressure to this boiling point 5 DEG C, and compound (III) is 1:150-450 with the weight ratio of water.
Described step (2), preferred compound (II) is 1:200-250 with the weight ratio of water.
Described step (1), described condensing agent is selected from one or more in CDI, DCC, DEPBT; Described catalyzer is DMAP (DMAP).
The reaction of described step (3) is preferably by compound (III) and compound (IV) direct reaction in organic solvent, do not add weak base, described compound (III) is 1:1.2 ~ 1.4 with the mol ratio of compound (IV).
Described step (4), preferably adopts iron powder/ammonium chloride to carry out nitro-reduction reaction, and the mol ratio of iron powder and compound (V) is 60-80:1, and the mol ratio of iron powder and ammonium chloride is 15-25:1.React and carry out in the mixing solutions of ethanol and water, temperature of reaction is 80-100 DEG C.
Described Boc refers to tertbutyloxycarbonyl.
The preparation method of Revlimid provided by the invention and intermediate thereof; improve N-Boc protecting group in its step (2) and remove the method for reaction; unexpected found employing sodium chloride aqueous solution replace pure water as reaction solvent time; speed and the yield of reaction can be improved significantly; make N-boc deprotection reaction in boiling water can be applicable to the reaction of this step; avoid the raw material of the height such as the high pollution that uses hydrochloric acid corrosion, decrease environmental pollution.And we find, the ratio of sodium-chlor and water also has significant impact to the yield reacted, and when lower or better sodium-chlor add-on, the yield of reaction is all lower, only under preferred proportion provided by the invention, just can have better yield.In addition; deprotection method provided by the invention; both strong acid such as adding a large amount of hydrochloric acid had been avoided; when carrying out subsequent reactions and preparing compound (IV); can not also add alkali and can complete condensation reaction, and when suitably increasing compound (III) add-on and do not add alkali, the condensation reaction yield of step (3) is improved on the contrary; and reduce cost, decrease waste pollution.Step (4) replaces high-pressure hydrogenation with iron powder/ammonium chloride system simultaneously, greatly reduces danger and the running cost of reaction, is more suitable for suitability for industrialized production.
Embodiment:
Below in conjunction with specific embodiment, the invention will be further described, and reaction scheme is as follows:
The synthesis of embodiment 1:3-(N-Boc-imino-)-piperidines-2,6-diketone (II)
N-Boc-glutamine methyl esters (I) 260g (1mol) is dissolved in 3L anhydrous tetrahydro furan, adds CDI (N, N-carbonyl dimidazoles) 300g, DMAP (DMAP) 10g, reflux 48 hours.Be spin-dried for tetrahydrofuran (THF), add 200ml water, methyl tertiary butyl ether 300ml extracts at twice, uses diluted acid successively, saturated sodium bicarbonate, and saturated sodium-chloride washs, anhydrous sodium sulfate drying.Be spin-dried for, obtain 200g white solid, in ethyl acetate/petroleum ether (30/70), recrystallization 2-3 time, obtains white solid 146g, yield 64%.
The synthesis of embodiment 2:3-amino-piperadine-2,6-diketone (III)
In reaction flask, first add distilled water 3L, 0.8kg sodium-chlor stirring and dissolving, then add 3-N-t-butoxycarbonyl amino-2,6-dioxopiperidine (II) 140g adopting embodiment 1 method obtained, then under be heated to the 4h that refluxes.Filter to obtain 3-amino-piperadine-2,6-diketone (III) 77g after cooling, hold over night, the yield of target product (III) is 98%, can be directly used in the next step.
Comparative example 2-1, as the contrast experiment of embodiment 2, first adds distilled water 3L, then adds compound (II) 140g in reaction flask, then under be heated to reflux 12h.The yield detecting target product (III) is 70%.
Comparative example 2-2, as the contrast experiment of embodiment 2, first adds distilled water 3L and sodium-chlor 0.9kg, then adds compound (II) 140g in reaction flask, then under be heated to reflux 12h.The yield detecting target product (III) is 80%.
Comparative example 2-3, as the contrast experiment of embodiment 2, first adds distilled water 3L and sodium-chlor 1.2kg, then adds compound (II) 140g in reaction flask, then under be heated to reflux 12h.The yield detecting target product (III) is 80%.
Embodiment 3: the synthesis of compound (V)
2-chloromethyl-3-nitrobenzene methyl (IV) 230g (1mol) and compound (III) 173g (1.35mol) is dissolved in DMF2L.Stir lower reflux 3h.Be cooled to room temperature, slowly pour in 50L frozen water, Keep agitation 2h, filter, washing, oven dry, obtain product Compound (V) 277.6g, yield 96% (in compound IV).
Embodiment 4: the synthesis of Revlimid (VI)
Ammonium chloride 150g is slowly added in the water (0.5L) and ethanol (2.5L) solution stirred, then iron powder 3200g is slowly added, Keep agitation is heated to 90 DEG C, in 30min, compound (V) 277.6g (0.96mol) is added in system, return stirring 1h, concentrated, then methyl alcohol 2L is added, filter, by the methanol solution containing Revlimid (VI), concentrated, crystallization, can obtain finalization compound Revlimid (VI) 224g again, yield 90%, purity is greater than 99%.
The magnetic resonance detection data of described Revlimid are as follows:
1HNMR(DMSO-d
6)δ11.01(s,1H).7.19(t,J＝7.6Hz,1H).6.90(d.J＝7.3Hz,1H),6.78(d,J＝7.8Hz,1H),5.42(s,2H).5.12(dd.J＝5.1and13.1Hz,1H),4.17(dd,J＝17.0and28.8Hz,2H),2.92-2.85(m,1H).2.64-2.49(m,1H).2.34-2.27(m,IH),2.06-1.99(m,IH)
Claims (5)
1. a preparation method for Revlimid and intermediate thereof, comprises following four-step reaction,
(1) N-Boc-glutamine methyl esters (I) carries out intramolecular cyclization and obtains 3-Boc imino-piperidines-2,6-diketone (II) under the existence of condensing agent and catalyzer;
(2) compound (II) that step (1) obtains is carried out deprotection reaction and obtain 3-(N-Boc-imino-)-piperidines-2,6-diketone (III);
(3) compound (III) step (2) obtained and 2-brooethyl-3-nitrobenzene methyl (IV) carry out condensation reaction and obtain 3-(7-nitro-3-oxo-1H-isoindole-2-base) piperidines-2,6-diketone (V);
(4) compound (V) that step (3) obtains is carried out nitro-reduction reaction and obtain Revlimid (VI);
Synthetic route is as follows,
It is characterized in that; the deprotection reaction condition of described step (2) is: in as the water of solvent, add sodium-chlor; the weight ratio of sodium-chlor and water is 0.25-0.28:1; temperature of reaction is below reaction system boiling point at ambient pressure to this boiling point 5 DEG C, and compound (III) is 1:150-450 with the weight ratio of water.
2. the preparation method of Revlimid and intermediate thereof as claimed in claim 1, is characterized in that step (2), and compound (II) is 1:200-250 with the weight ratio of water.
3. the preparation method of Revlimid and intermediate thereof as claimed in claim 1, it is characterized in that described step (1), described condensing agent is selected from one or more in CDI, DCC, DEPBT; Described catalyzer is DMAP (DMAP).
4. the preparation method of Revlimid and intermediate thereof as claimed in claim 1, it is characterized in that the reaction of described step (3) is by compound (III) and compound (IV) direct reaction in organic solvent, do not add weak base, described compound (III) is 1:1.2 ~ 1.4 with the mol ratio of compound (IV).
5. the preparation method of Revlimid and intermediate thereof as claimed in claim 1, it is characterized in that described step (4), iron powder/ammonium chloride is adopted to carry out nitro-reduction reaction, the mol ratio of iron powder and compound (V) is 60-80:1, and the mol ratio of iron powder and ammonium chloride is 15-25:1.React and carry out in the mixing solutions of ethanol and water, temperature of reaction is 80-100 DEG C.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106957299A (en) * | 2017-03-31 | 2017-07-18 | 常州制药厂有限公司 | A kind of lenalidomide 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 |
| CN110407807A (en) * | 2019-06-19 | 2019-11-05 | 甘肃泰升化工科技有限公司 | A kind of preparation method of lenalidomide |
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103193763A (en) * | 2013-04-10 | 2013-07-10 | 杭州百诚医药科技有限公司 | Novel preparation method of lenalidomide |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103193763A (en) * | 2013-04-10 | 2013-07-10 | 杭州百诚医药科技有限公司 | Novel preparation method of lenalidomide |
Non-Patent Citations (1)
| Title |
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| 王嘉: "沸水促进的N-Boc保护基脱除反应和联萘酚骨架的手性磷酸的合成及应用研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
| CN110407807A (en) * | 2019-06-19 | 2019-11-05 | 甘肃泰升化工科技有限公司 | A kind of preparation method of lenalidomide |
| 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 |
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