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Preparation method of lenalidomide

A technology of lenalidomide and reaction temperature, applied in the field of preparation of lenalidomide, can solve the problems of high price of L-glutamine, unsuitable for industrial production, difficult purification and the like, and achieves good practicability and application value, The effect of high yield and simple process

Inactive Publication Date: 2018-06-29
JIAXING CITY NO 2 HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] There are many preparation methods for lenalidomide. The patent CN101665484B utilizes 2-bromomethyl-3-nitrobenzoic acid methyl ester and L-glutamine methyl ester to react to form an intermediate, and undergoes 6 steps such as cyclization reaction and racemization reaction. Synthesis of lenalidomide by reaction, but this method has lower yield, difficult purification, more expensive raw materials, and low yield
There are also relevant literature reports to prepare by reacting L-glutamine and 2-bromomethyl-3-nitrobenzoic acid methyl ester, but the price of L-glutamine is still relatively expensive, and it is not suitable for industrialized production

Method used

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  • Preparation method of lenalidomide
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  • Preparation method of lenalidomide

Examples

Experimental program
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Effect test

Embodiment 1

[0036] A kind of preparation method of lenalidomide, concrete steps are as follows:

[0037] (1) Preparation of 2-methyl-3-nitrobenzoic acid methyl ester:

[0038] Add 1.81g (0.01mol) of 2-methyl-3-nitrobenzoic acid into 10ml of anhydrous methanol, add 0.003mol of triphosgene solid, add 3 drops of DMF, reflux for 5h, monitor by TLC, and recover by distillation under reduced pressure after the reaction Methanol was dissolved in ethyl acetate, washed with water, washed with saturated brine, distilled under reduced pressure, and dried to obtain 1.87 g of the product, with a yield of 95.8%;

[0039] (2) Preparation of 2-bromomethyl-3-nitrobenzoic acid methyl ester:

[0040] Add 1.95g (0.01mol) of methyl 2-methyl-3-nitrobenzoate to 10ml of dichloroethane, add 3.54g (0.02mol) of NBS and heat to reflux, add a small amount of BPO, reflux for 8h, add 20ml of water, and separate the liquids , washing the organic phase with water, washing with saturated brine, distillation under reduce...

Embodiment 2

[0050] A kind of preparation method of lenalidomide, concrete steps are as follows:

[0051] (1) Preparation of 2-methyl-3-nitrobenzoic acid methyl ester:

[0052] Add 1.81g (0.01mol) of 2-methyl-3-nitrobenzoic acid into 10ml of anhydrous methanol, add 0.004mol of triphosgene solid, add 5 drops of DMF, reflux for 6h, monitor by TLC, and recover by distillation under reduced pressure after the reaction Methanol was dissolved in ethyl acetate, washed with water, washed with saturated brine, distilled under reduced pressure, and dried to obtain 1.88 g of the product, with a yield of 96.41%;

[0053](2) Preparation of 2-bromomethyl-3-nitrobenzoic acid methyl ester:

[0054] Add 1.95g (0.01mol) of methyl 2-methyl-3-nitrobenzoate to 10ml of chloroform, add 3.54g (0.02mol) of NBS, heat to reflux, add a small amount of BPO, reflux for 12h, add 20ml of water, separate liquid, organic phase Washing with water, washing with saturated brine, distillation under reduced pressure, and recr...

Embodiment 3

[0064] A kind of preparation method of lenalidomide, concrete steps are as follows:

[0065] (1) Preparation of 2-methyl-3-nitrobenzoic acid methyl ester:

[0066] Add 1.81g (0.01mol) of 2-methyl-3-nitrobenzoic acid into 10ml of absolute ethanol, add 0.01mol of thionyl chloride, add 3 drops of DMF, reflux for 5h, monitor by TLC, and distill under reduced pressure after the reaction is completed Methanol was recovered, dissolved in ethyl acetate, washed with water, washed with saturated brine, distilled under reduced pressure, and dried to obtain 1.64 g of the product with a yield of 84.10%;

[0067] (2) Preparation of 2-bromomethyl-3-nitrobenzoic acid methyl ester:

[0068] Add 1.95g (0.01mol) of methyl 2-methyl-3-nitrobenzoate to 10ml of carbon tetrachloride, add 3.54g (0.02mol) of NBS and heat to reflux, add a small amount of BPO, reflux at 60°C for 8h, add 20ml of water, Separation, washing the organic phase with water, washing with saturated brine, distillation under red...

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Abstract

The invention discloses a preparation method of lenalidomide. The preparation method comprises the following specific steps: taking 2-methyl-3-nitrobenzoic acid as a raw material to prepare methyl 2-bromomethyl-3-nitrobenzoate; taking L-glutamic acid as a raw material to prepare N-CBZ-L-glutamic acid; taking N-CBZ-L-glutamic acid as a raw material to prepare 3-amino-2,6-piperidinone hydrochloride;taking methyl 2-methyl-3-nitrobenzoate and 3-amino-2,6-piperidinone hydrochloride as raw materials to prepare 3-(4-nitro-1,3 dihydro-1-oxo-2-hydrogen-isoindole-2-yl) piperidine-2,6-dione; taking the3-(4-nitro-1,3 dihydro-1-oxo-2-hydrogen-isoindole-2-yl) piperidine-2,6-dione as a raw material to prepare the lenalidomide. The preparation method has the advantages of being simple in process, economic in raw materials, less in byproduct, simple to purify, higher in yield, environment-friendly and the like, is simple in post-treatment, has better practicality and application value and also has great industrialization prospect.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of lenalidomide. Background technique [0002] Lenalidomide is a new type of immune preparation, mainly used to treat chronic myeloma and abnormal bone marrow hyperplasia. Clinical studies have found that lenalidomide is 100 times more effective in treating multiple myeloma than thalidomide, and more than half of the The patient's survival period is greatly prolonged, and its pharmacological effects are currently recognized as exerting its effect by inhibiting TNF-α, IL1b, and IL2. Immunological studies have shown that lenalidomide can stimulate the proliferation of primary T cells and the release of cytotoxins, regulate Sexual T cells can also proliferate, and it can be said that its role is powerful and complex. Lenalidomide has not yet been marketed in my country. [0003] The structural formula of lenalidomide is: [0004] There are many pr...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 王琰萍杨毅张晓玲周清河徐从英
Owner JIAXING CITY NO 2 HOSPITAL
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