CN104311536A - Method for preparing lenalidomide - Google Patents
Method for preparing lenalidomide Download PDFInfo
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- CN104311536A CN104311536A CN201410579059.0A CN201410579059A CN104311536A CN 104311536 A CN104311536 A CN 104311536A CN 201410579059 A CN201410579059 A CN 201410579059A CN 104311536 A CN104311536 A CN 104311536A
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- 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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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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Abstract
The invention discloses a method for preparing lenalidomide. The method comprises the following steps: firstly, etherifying 2-methyl-3-nitrobenzoic acid to obtain 2-methyl-3-nitrobenzoic acid methyl ester, brominating to obtain 2-brooethyl-3-nitrobenzoic acid methyl ester, reacting L-glutamine and tert-butyl dicarbonate to obtain N-Boc glutamic acid, acquiring 3-amino-2,6-piperidine diketone protected by Boc from N-Boc-glutamic acid in the presence of a condensing agent and a catalyst, further reacting with acid to prepare 3-amino-2,6-piperidine diketone hydrochloride, reacting 3-amino-2,6-piperidine diketone with 2-brooethyl-3-nitrobenzoic acid methyl ester so as to obtain 3-(4-nitryl-1,3 dihydro-1-oxo-2 hydrogen-isobenzazole-2-yl) piperidine-2,6-diketone, and finally reducing, thereby obtaining lenalidomide. The method disclosed by the invention is high in product yield.
Description
Technical field
The invention belongs to organic chemistry filed, particularly relate to a kind of Revlimid, specifically a kind of method preparing Revlimid.
Background technology
Revlimid (lenalidomide) is used for the treatment of myelodysplastic syndrome, a kind of new immunity moderation type, non-chemically therapy cancer therapy drug, it is the upgrading medicine of Thalidomide, it has impact to biological approach multiple in cell, it is the new immunomodulator researched and developed by Celgene company of the U.S., obtain FDA approval listing in January, 2006, trade(brand)name Revlimid, is mainly used in myelodysplastic syndrome (MDS) hypotype and the multiple myeloma (MM) for the treatment of 5q disappearance (the gap genetically deficient of the 5th pair of chromosome long arm).
Myeloproliferative disorder (MDS) is Clonal hematopoetic tumor, a kind of malignant hematologic disease, when the hemocyte in marrow is in the immature stage all the time, when can not play its due function, myelodysplastic syndrome will occur, make in marrow, to be full of jejune cell, inhibit Normocellular development.The symptoms such as myeloproliferative disorder patient constantly relies on blood transfusion to resist anaemia, tired, finally develop into life-threatening iron overload or iron poisoning.Multiple myeloma (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.
The treatment of MM and MDS starts from the sixties in 20th century, after this in 30 years, melphalan associating prednisone is the treatment standard scheme of this type of disease always, high-dose chemotherapy adds stem cell transplantation and really can bring benefit for patient within 1996, just to have research to confirm, but the recurrence rate of this type of disease is very high, spendable rescue therapy is little.Along with deep and some new drugs be familiar with disease mechanisms such as Thalidomide and Revlimid are approved for treatment MDS and MM successively, the treatment of this type of disease achieves significant achievement, and the survival region of patient significantly improves.
Revlimid is the derivative of new generation of Thalidomide, 100 times more eager to excel in whatever one does than Thalidomide of drug effect, there are stronger Agiogenesis inhibition, immunomodulatory, cell death inducing and directly kill the effects such as tumor promotion, and almost there is no teratogenecity and neurotoxicity, safer relative to Thalidomide, untoward reaction is less.It can pass through activated T cell, produces interleukin-2 (IL-2), strengthens the immunocompetence of NK cell, plays immunoregulation effect.Can Apoptosis in Marrow Cells be made, suppress the generation of the drug resistant tumor cells mediated by cytokine and marrow stromal cell, there is blood vessel formation against function.
The structural formula of Revlimid is:
The preparation method of Revlimid is more, wherein Fang Feng (Chinese Journal of Pharmaceuticals 2008, 39, 12, 888-891) adopt N-carbobenzoxy-(Cbz)-L-glutaminate first through methanol esterification, L-glutaminate methyl esters is obtained again with 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, enter Pd/C catalytic hydrogenation again and obtain N-(4-amino-1-oxo-1, 3-dihydro-2H-isoindole-2-base)-L-glutaminate methyl esters, last intramolecular condensation obtains target product Revlimid, see reaction formula.There is the shortcoming that step is long, total recovery is low in the method.
Summary of the invention
For above-mentioned technical problem of the prior art, the invention provides a kind of method preparing Revlimid, the described this method preparing Revlimid solve in prior art prepare Revlimid method exist step long, total recovery is low, not easily realize industrialized technical problem.
The method of preparation 3-of the present invention (amino-1, the 3 dihydro-1-oxo-2H-isoindole-2-bases of 4-) piperidines-2,6-diketone comprises the steps:
(1) with 2-methyl-3-nitro phenylformic acid for raw material, take thionyl chloride as acylating reagent, react the 2-methyl-3-nitro methyl benzoate of the formula 1 made with methyl alcohol;
(2) 2-methyl-3 nitrobenzene methyl of gained and bromide reagent are reacted, the 2-brooethyl-3-nitrobenzene methyl of the formula 2 of system;
(3) take L-glutaminate as raw material, react with dimethyl dicarbonate butyl ester in the basic conditions, the N-Boc L-glutamic acid of the formula 3 of system;
(4) obtained N-Boc-L-glutamic acid is carried out under the existence of condensing agent and catalyzer amino-2, the 6-dioxopiperidines of 3-of the Boc protection of 4 of intramolecular cyclization;
(5) amino for the 3-of obtained Boc protection-2,6-dioxopiperidines and hydrochloric acid reaction are obtained amino-2, the 6-dioxopiperidine hydrochlorides of 3-of formula 5;
(6) by the 3-of obtained formula 5 amino-2,6-dioxopiperidine and the 2-brooethyl-3-nitrobenzene methyl of obtained formula 2 react 3-(the 4-nitro-1 of obtained formula 6 under weak basic condition, 3 dihydro-1-oxo-2H-isoindole-2-bases) piperidines-2,6-diketone;
(7) by obtained 3-(4-nitro-1,3 dihydro-1-oxo-2H-isoindole-2-bases)-2, the nitro of 6-dioxopiperidine is reduced into the Revlimid 3-(4-amino-1 of amino obtained target product 7 in acid condition, 3 dihydro-1-oxo-2H-isoindole-2-bases) piperidines-2,6-diketone;
In one preferred embodiment, catalysis prepare 2-methyl-3-nitro methyl benzoate ester words reaction used catalyst be selected from thionyl chloride or Acetyl Chloride 98Min.; The bromide reagent of preparation 2-brooethyl-3-nitrobenzene methyl is selected from bromo-succinimide, bromine; Bromination reaction activator is selected from benzoyl peroxide or Diisopropyl azodicarboxylate; The condensing agent of Intra-molecular condensation is selected from N, N-carbonyl dimidazoles (CDI), dicyclohexyl carbodiimide (DCC) or 1-hydroxyl-benzotriazole (HoBt) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI); Intra-molecular condensation catalyzer used is DMAP (DMAP); The hydrochloric acid removing Boc protection is hydrochloric acid or the organic solution that can discharge hydrogen chloride gas; Preparation formula 6 weak base used is selected from one or more mixtures in triethylamine, saleratus, sodium bicarbonate; Reduction nitro is that amino reductive agent is selected from iron powder, zinc powder or zinc granule, and Glacial acetic acid or concentrated hydrochloric acid are selected in acid used.
Another preferred embodiment in, the solvent that the described benzoic esterification of 2-methyl-3-nitro is used is methyl alcohol; The solvent of bromination reaction is one or more mixtures of water, tetracol phenixin, chloroform, methylene dichloride, 1,2-ethylene dichloride; The solvent of Intra-molecular condensation is one or more mixtures in THF, methylene dichloride, Isosorbide-5-Nitrae-dioxane; Removing Boc, to react the solvent adopted be the mixture of one or more in ethyl acetate, methylene dichloride, dioxane; The solvent that preparation 3-(4-nitro-1,3 dihydro-1-oxo-2H-isoindole-2-base) piperidines-2,6-diketone adopts is selected from acetonitrile, DMF, THF, acetone; One or more mixtures of the solvent selected from methanol of described reduction nitro, ethanol, tetrahydrofuran (THF), water.
Another one preferred embodiment in, described esterification reaction temperature is the reflux temperature of room temperature to solvent; Described bromination reaction is the reflux temperature of 0 DEG C-solvent; The temperature of described intramolecular cyclization reaction is the reflux temperature of 0 DEG C-solvent; The temperature of reaction of acidolysis Boc is the reflux temperature of 0 DEG C-solvent; The temperature of reaction of described preparation 3-(4-nitro-1,3 dihydro-1-oxo-2H-isoindole-2-base) piperidines-2,6-diketone is the reflux temperature of 0 DEG C-solvent; The temperature of reaction of described reduction nitro is the reflux temperature of 0 DEG C-solvent.
In another one preferred implementation, described esterification reaction temperature is the reflux temperature of solvent; The temperature of described bromination reaction is the reflux temperature of solvent; The temperature of described intramolecular cyclization reaction is the reflux temperature of solvent; The temperature of reaction removing Boc is room temperature; The described temperature of reaction preparing compound 6 is 50 DEG C; The temperature of reaction of described reduction nitro is room temperature.
Reaction formula of the present invention is:
The present invention compares with prior art, and its technical progress is significant.Operational path of the present invention is easy, and processing condition are reasonable, and reactions steps is short, simple to operate, and reaction yield is high, is applicable to suitability for industrialized production, has larger implementary value and economic results in society.
Embodiment
The present invention is further described by way of example more below, provides implementation detail of the present invention, but be not be intended to limit in protection scope of the present invention.
Embodiment 1:
(1) preparation of 2-methyl-3-nitro methyl benzoate
2-methyl-3-nitro phenylformic acid 30g, is dissolved in 100mL anhydrous methanol, keeps less than 0 DEG C to drip 15mL sulfur oxychloride, after dropwising, and reflux 5 hours.Pour into after evaporate to dryness methyl alcohol in frozen water, regulator solution is to neutral, and filter out the solid of precipitation, be washed with distilled water to filtrate clear, colorless, dry cake obtains 31g, yield 96%.
1HNMR(500MHz,CDCl
3)δ：2.6(s，3H)，3.95(s，3H)，7.35(m，1H)，7.90(m，2H)
(2) preparation of 2-brooethyl-3-nitrobenzene methyl
2-methyl-3-nitro methyl benzoate 20g is dissolved in 250mL tetracol phenixin, adds 22gN-bromo-succinimide (NBS), 2.5g benzoyl peroxide (BPO), stirring reaction 8 hours at being heated to 75 DEG C.After cooling, with 250mL extraction into ethyl acetate three times, combined ethyl acetate, with saturated sodium bicarbonate solution washing, saturated nacl aqueous solution washs, then uses anhydrous sodium sulfate drying.Concentrate after being spin-dried for, obtain light yellow crystal 23.5g with 200mL sherwood oil recrystallization, yield 85%.
1H?NMR(500MHz,CDCl3)δ8.11(d,J＝7.8Hz,1H),7.96(d,J＝9.0Hz,1H),7.54(t,J＝8.0Hz,1H),5.15(s,2H),4.00(s,3H).
(3) preparation of N-Boc-L-glutamine
L-glutaminate 14.6g, 4g sodium hydroxide, is dissolved in 100mL distilled water, after 22gBoc acid anhydrides dissolves with 50mL tetrahydrofuran (THF), be added drop-wise in above-mentioned solution in condition of ice bath, go to stirring at room temperature after dropwising and react 24 hours, decompression removing tetrahydrofuran (THF), regulates PH to (1 ~ 2) with dilute hydrochloric acid, with 500mL extraction into ethyl acetate three times, again with after anhydrous sodium sulfate drying, concentrated ethyl acetate obtains 23.3g white solid, yield 95%.
1H?NMR(300MHz，CD3OD)δ：1.44(s，9H)，1.91(m，1H)，2.50～2.56(m，1H)，2.66～2.74(m，1H)，2.76～2.78(m，1H)4.31(t,1H),5.35(s,1H)，8.08(s,1H)
(4) preparation of 3-N-Boc-amino-piperadine diketone
N-Boc-L-glutamine 23.3g is dissolved in 200mL tetrahydrofuran (THF), adds 15.5gCDI, 0.115g DMAP, heating reflux reaction 10 hours.Decompression and solvent recovery, with dichloromethane extraction three times, merges organic phase, uses saturated NaHCO successively
3solution, saturated common salt water washing, with anhydrous sodium sulfate drying, obtain 16.5g white solid with ethyl alcohol recrystallization, yield 75% after concentrated.
1H?NMR(500MHz,CDCl
3)δ8.38(s,1H),8.38(s,1H),5.39(d,J＝5.1Hz,1H),4.37–4.28(m,1H),2.79(d,J＝17.0Hz,1H),2.72–2.63(m,1H),2.56–2.47(m,1H),1.87(m,J＝12.8,4.2Hz,1H),1.46(s,9H).
(5) preparation of amino-2, the 6-dioxopiperidine hydrochlorides of 3-
Amino-2, the 6-dioxopiperidine 15g of 3-N-Boc-are dissolved in 100mL dioxane, and pass into dry HCl gas 1h, then at room temperature stir 10h, suction filtration obtains 10.3g white solid, yield 95%.
1HNMR(500MHz,CDCl
3)δ：1.44(s，9H)，1.70-2.05(m，1H)，2.53-2.91(m，3H)，4.3(br，s，1H)，5.3(br，s，1H)，7.9(br，s，1H)
(6) preparation of 3-(4-nitro-1,3 dihydro-1-oxo-2H-isoindole-2-base) piperidines-2,6-diketone
2-brooethyl-3-nitrobenzene methyl 23g, 3-amino-2,6-dioxopiperidine hydrochloride 16g, NaHCO
316g and 150mL acetonitrile adds in reaction flask, stirring reaction 10 hours at 50 DEG C, and removal of solvent under reduced pressure, pours out rear washing with water respectively repeatedly, and ethyl acetate washing repeatedly, obtains light purple solid product 20.5g, yield 71%.
1H?NMR(501MHz,DMSO)δ11.05(s,1H),8.48(s,1H),8.20(s,1H),7.85(t,J＝7.8Hz,1H),5.18(m,1H),4.85(m,2H),2.91(m,1H),2.65–2.51(m,2H),2.02(m,1H).
(7) 3-(amino-1, the 3 dihydro-1-oxo-2H-isoindole-2-bases of 4-) piperidines-2,6-diketone
3-(4-nitro-1,3 dihydro-1-oxo-2H-isoindole-2-bases) piperidines-2,6-diketone 14.5g is dissolved in 100mL methyl alcohol, add 6g zinc powder, 10mL acetic acid, at room temperature stirring reaction 8 hours, cross and filter zinc powder, filtrate regulates PH to neutral, obtains white solid 12.5g, yield 95%.
1H?NMR(500MHz,DMSO)δ11.01(s,1H),7.19(t,J＝7.6Hz,1H),6.92(d,J＝7.4Hz,1H),6.80(d,J＝7.9Hz,1H),5.43(s,2H),5.11(dd,J＝13.3,4.9Hz,1H),4.15(dd,J＝49.1,16.9Hz,2H),3.00–2.84(m,1H),2.61(d,J＝17.3Hz,1H),2.30(m,1H),2.08–1.94(m,1H)。
Claims (5)
1. prepare a method for Revlimid, it is characterized in that comprising the steps:
The step of (1) preparation 2-methyl-3-nitro methyl benzoate, in the step of described preparation 2-methyl-3-nitro methyl benzoate, with 2-methyl-3-nitro phenylformic acid for raw material, under acylating reagent exists, react the 2-methyl-3-nitro methyl benzoate shown in acquisition formula 1 with methyl alcohol;
The step of (2) preparation 2-brooethyl-3-nitrobenzene methyls, in the step of described preparation 2-brooethyl-3-nitrobenzene methyl, 2-methyl-3 nitrobenzene methyl of above-mentioned acquisition and bromide reagent are reacted, obtains the 2-brooethyl-3-nitrobenzene methyl shown in formula 2;
The step of (3) preparation N-Boc L-glutamic acid, in the step of described preparation N-Boc L-glutamic acid, take L-glutaminate as raw material, reacts in the basic conditions with dimethyl dicarbonate butyl ester, obtain the N-Boc L-glutamic acid shown in formula 3;
(4) preparation 3-amino-2, the step of 6-dioxopiperidine, at described preparation 3-amino-2, in the step of 6-dioxopiperidine, the N-Boc-L-glutamic acid of above-mentioned acquisition is carried out under the existence of condensing agent and catalyzer amino-2, the 6-dioxopiperidines of 3-that intramolecular cyclization obtains the Boc protection shown in formula 4;
(5) preparation 3-amino-2, the step of 6-dioxopiperidine hydrochloride, at described preparation 3-amino-2, in the step of 6-dioxopiperidine hydrochloride, the 3-amino-2 that the Boc of above-mentioned acquisition is protected, 6-dioxopiperidine and hydrochloric acid reaction obtain amino-2, the 6-dioxopiperidine hydrochlorides of 3-shown in formula 5;
(6) preparation 3-(4-nitros-1,3 dihydro-1-oxo-2 hydrogen-isoindole-2-bases)-2, the step of 6-dioxopiperidine, at described preparation 3-(4-nitro-1,3 dihydro-1-oxo-2 hydrogen-isoindole-2-bases)-2, in the step of 6-dioxopiperidine, by the 3-of above-mentioned acquisition amino-2,6-dioxopiperidine and 2-brooethyl-3-nitrobenzene methyl react 3-(the 4-nitro-1 shown in acquisition formula 6 under weak basic condition, 3 dihydro-1-oxo-2 hydrogen-isoindole-2-bases) piperidines-2,6-diketone;
(7) steps preparing Revlimid, prepare in the step of Revlimid described, by 3-(the 4-nitro-1 of above-mentioned acquisition, 3 dihydro-1-oxo-2H-isoindole-2-bases) piperidines-2, the nitro of 6-diketone is reduced into amino in acid condition, obtains the target product Revlimid shown in formula 7.
2. prepare the method for Revlimid as claimed in claim 1, it is characterized in that: in the step of described preparation 2-methyl-3-nitro methyl benzoate, described acylating reagent is selected from thionyl chloride or Acetyl Chloride 98Min.; In the step of described preparation 2-brooethyl-3-nitrobenzene methyl, described bromide reagent is selected from bromo-succinimide or bromine, and activator used in bromination reaction is selected from benzoyl peroxide or Diisopropyl azodicarboxylate; At described preparation 3-amino-2, in the step of 6-dioxopiperidine, the condensing agent of Intra-molecular condensation is selected from the mixture of N, N-carbonyl dimidazoles, dicyclohexyl carbodiimide or 1-hydroxyl-benzotriazole and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, and Intra-molecular condensation catalyzer used is DMAP; In the step of amino-2, the 6-dioxopiperidine hydrochlorides of described preparation 3-, the hydrochloric acid removing Boc protection is concentrated hydrochloric acid, the organic solution that maybe can discharge HCl gas; In the step of described preparation 3-(4-nitro-1,3 dihydro-1-oxo-2 hydrogen-isoindole-2-base) piperidines-2,6-diketone, described weak base is selected from one or more the mixture in triethylamine, saleratus or sodium bicarbonate; Prepare in the step of Revlimid described, reduction nitro is that amino reductive agent is selected from iron powder, zinc powder or zinc granule, and acid used is selected from Glacial acetic acid or hydrochloric acid.
3. prepare the method for Revlimid as claimed in claim 2, it is characterized in that: in the step of described preparation 2-methyl-3-nitro methyl benzoate, the benzoic esterification of 2-methyl-3-nitro solvent used is methyl alcohol; In the step of described preparation 2-brooethyl-3-nitrobenzene methyl, the solvent of bromination reaction is any one or two or more mixtures of water, tetracol phenixin, chloroform, methylene dichloride or 1,2-ethylene dichloride; In the step of amino-2, the 6-dioxopiperidines of described preparation 3-, the solvent of Intra-molecular condensation is any one or two or more mixtures in THF, methylene dichloride or Isosorbide-5-Nitrae-dioxane; In the step of amino-2, the 6-dioxopiperidine hydrochlorides of described preparation 3-, removing Boc, to react the solvent adopted be any one or two or more mixtures in ethyl acetate, methylene dichloride or dioxane; In the step of described preparation 3-(4-nitro-1,3 dihydro-1-oxo-2 hydrogen-isoindole-2-base) piperidines-2,6-diketone, described solvent be selected from acetonitrile, dimethyl formamide, tetrahydrofuran (THF) or acetone any one; Prepare in the step of Revlimid described, any one or a few mixture in the solvent selected from methanol of described reduction nitro, ethanol, tetrahydrofuran (THF) or water.
4. prepare the method for Revlimid as claimed in claim 3, it is characterized in that: in the step of described preparation 2-methyl-3-nitro methyl benzoate, described esterification reaction temperature is the reflux temperature of room temperature to solvent; In the step of described preparation 2-brooethyl-3-nitrobenzene methyl, the temperature of described bromination reaction is the reflux temperature of 0 DEG C-solvent; In the step of amino-2, the 6-dioxopiperidines of described preparation 3-, the temperature of described intramolecular cyclization reaction is the reflux temperature of 0 DEG C-solvent; In the step of amino-2, the 6-dioxopiperidine hydrochlorides of described preparation 3-, the temperature of reaction removing Boc is the reflux temperature of 0 DEG C-solvent; In the step of described preparation 3-(4-nitro-1,3 dihydro-1-oxo-2 hydrogen-isoindole-2-base) piperidines-2,6-diketone, temperature of reaction is the reflux temperature of 0 DEG C-solvent; Prepare in the step of Revlimid described, the temperature of reaction of described reduction nitro is the reflux temperature of 0 DEG C-solvent.
5. as the method preparing Revlimid in claim 1-4 as described in any one, it is characterized in that: in the step of described preparation 2-methyl-3-nitro methyl benzoate, described esterification reaction temperature is the reflux temperature of solvent; In the step of described preparation 2-brooethyl-3-nitrobenzene methyl, the temperature of described bromination reaction is the reflux temperature of solvent; In the step of amino-2, the 6-dioxopiperidines of described preparation 3-, the temperature of described intramolecular cyclization reaction is the reflux temperature of solvent; In the step of amino-2, the 6-dioxopiperidine hydrochlorides of described preparation 3-, the temperature of reaction of acidolysis Boc is room temperature; In the step of described preparation 3-(4-nitro-1,3 dihydro-1-oxo-2 hydrogen-isoindole-2-base) piperidines-2,6-diketone, temperature of reaction is 50 DEG C; Prepare in the step of Revlimid described, the temperature of reaction of described reduction nitro is room temperature.
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| CN105001147A (en) * | 2015-07-01 | 2015-10-28 | 浙江华海药业股份有限公司 | Preparation method of Pregabalin intermediate impurity |
| CN105523939A (en) * | 2015-12-30 | 2016-04-27 | 李函璞 | Lenalidomide intermediate preparation method |
| CN106957299A (en) * | 2017-03-31 | 2017-07-18 | 常州制药厂有限公司 | A kind of lenalidomide preparation method |
| CN107337666A (en) * | 2017-08-30 | 2017-11-10 | 临沂齐泽医药技术有限公司 | A kind of preparation method for being used to treat the lenalidomide of Huppert's disease |
| CN108218833A (en) * | 2016-12-15 | 2018-06-29 | 王琰萍 | A kind of preparation method of lenalidomide |
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| CN109516925A (en) * | 2018-10-31 | 2019-03-26 | 陕西慧康生物科技有限责任公司 | A kind of synthetic method of the glutamic acid -1- methyl esters -5- tert-butyl ester |
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| CN114014761A (en) * | 2021-12-02 | 2022-02-08 | 西安淳甄新材料有限公司 | Method for separating o-nitrobenzoic acid based on esterification |
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| CN105523939A (en) * | 2015-12-30 | 2016-04-27 | 李函璞 | Lenalidomide intermediate preparation method |
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| CN107337666A (en) * | 2017-08-30 | 2017-11-10 | 临沂齐泽医药技术有限公司 | A kind of preparation method for being used to treat the lenalidomide of Huppert's disease |
| CN107337666B (en) * | 2017-08-30 | 2019-06-04 | 上海万巷制药有限公司 | It is a kind of for treating the preparation method of the lenalidomide of Huppert's disease |
| 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 |
| CN109516925A (en) * | 2018-10-31 | 2019-03-26 | 陕西慧康生物科技有限责任公司 | A kind of synthetic method of the glutamic acid -1- methyl esters -5- tert-butyl ester |
| 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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