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Process for preparing lenalidomide

A compound and selected technology, applied in the field of medicine, can solve the problems of low production safety, difficult industrialized production, complex preparation process, etc., and achieve the effects of high synthesis efficiency, short production cycle and simple preparation process

Inactive Publication Date: 2015-08-05
HUBEI BIO PHARMA IND TECHCAL INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many methods for preparing lenalidomide at present, there are disadvantages such as complex preparation process, low synthesis efficiency, high production cost, low production safety, pollution of the natural environment, and difficulty in industrialized production.
[0005] Therefore, the current method for preparing lenalidomide still needs to be improved

Method used

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  • Process for preparing lenalidomide
  • Process for preparing lenalidomide
  • Process for preparing lenalidomide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Embodiment 1: Esterification reaction

[0056] 3-Amino-2-methylbenzoic acid (100 g, 0.662 mol) and p-toluenesulfonic acid (200 g, 1.162 mol), add 3000 ml of methanol, stir, reflux for 10 hours, add ethyl acetate after cooling to room temperature 3000 ml and 3000 ml of 1M potassium carbonate aqueous solution were stirred, filtered, the filtrate was extracted with ethyl acetate, washed with 1M potassium carbonate aqueous solution and saturated brine, the organic layer was dried and concentrated under reduced pressure to obtain 3-amino-2-methylbenzoic acid Methyl ester (Compound 3, 93.0 g, 0.564 mol), yield 85%. 1 H NMR (CDCl 3 ):δ2.36(s,3H),3.82(s,3H),6.71-6.77(m,1H),6.99-7.01(m,1H),7.16-7.20(m,1H).MS(m / z ):165[M+H] + .

Embodiment 2

[0057] Embodiment 2: Esterification reaction

[0058] 3-amino-2-methylbenzoic acid (100 grams, 0.662 moles) and sulfuric acid (63 milliliters, 1.162 moles), add 3000 milliliters of methanol, stir, reflux reaction for 10 hours, after cooling to room temperature, add 3000 milliliters of ethyl acetate and 3000 ml of 1M potassium carbonate aqueous solution was stirred, filtered, and the filtrate was extracted with ethyl acetate, washed with 1M potassium carbonate aqueous solution and saturated brine, and the organic layer was dried and concentrated under reduced pressure to obtain 3-amino-2-methylbenzoic acid methyl ester ( Compound 3, 79.0 g, 0.483 mol), yield 73%. MS(m / z):165[M+H] + .

Embodiment 3

[0059] Embodiment 3: Amino protection reaction

[0060] Dissolve compound 3 (93.0 g, 0.564 mol) in 1000 ml of dichloromethane, add di-tert-butyl dicarbonate (147.5 g, 0.677 mol), control the temperature at 25 degrees Celsius, stir for 5 hours, extract with dichloromethane, and use Wash with saturated aqueous sodium bicarbonate and saturated brine to obtain methyl 3-tert-butoxyformamide-2-methylbenzoate (compound 4(a), 143.5 g, 0.541 mol), with a yield of 96%. 1 H NMR (CDCl 3 ):δ1.41(s,9H),2.35(s,3H),3.87(s,3H),6.92-6.97(m,1H),7.05-7.11(m,1H),7.56-7.59(m,1H ).MS(m / z):265[M+H] + .

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Abstract

The invention discloses a method for preparing lenalidomide. The method uses 3-amino-2-methylbenzoic acid as a starting material to synthesize lenalidomide. The method for preparing lenalidomide of the present invention can effectively prepare lenalidomide, and the process is simple, the synthesis efficiency is high, and the purity of the prepared lenalidomide is high. In addition, the preparation method also has the advantages of easy availability of starting materials, simple process operation, mild reaction conditions, no need for special reaction equipment, and no difficult-to-separate compounds in the preparation process, so it is more suitable for large-scale and industrial production of lenalidomide .

Description

technical field [0001] The invention relates to the technical field of medicine. In particular, it relates to a process for the preparation of lenalidomide. Background technique [0002] Lenalidomide (Lenalidomide / Revlimid, compound 1), the chemical name is 3-(7-amino-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione, its chemical The structure looks like this: [0003] [0004] Lenalidomide is an immunomodulatory drug with multiple effects such as anti-angiogenesis, immune regulation and direct killing of tumor cells. It was developed by Celgene Corporation of the United States and was approved by the FDA in December 2005 for the treatment of multiple tumors. Myeloma and myelodysplastic syndrome, an enhanced version of thalidomide, used to treat morning sickness that has caused birth defects in thousands of babies, has anticancer potential Fewer adverse reactions, studies have proven that it will not cause birth defects in babies. Although there are many methods for prepar...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04
CPCY02P20/55
Inventor 许勇李莉娥郭涤亮乐洋张绪文杨仲文王磊田华
Owner HUBEI BIO PHARMA IND TECHCAL INST
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