Preparation method of lenalidomide

A technology of oxo and dihydroisoindole, which is applied in the field of preparation of lenalidomide (piperidine-2,6-dione), can solve the problems of long reaction time of catalytic reaction reflux, labor protection difficulties, production difficulties, etc. , to achieve the effect of novel process route, less three wastes and low production cost

Active Publication Date: 2016-03-30
HANGZHOU HEZE PHARMA TECH
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AI Technical Summary

Problems solved by technology

Under the irradiation of ultraviolet light, the reflux reaction time of the catalytic reaction is long, the yield is low, it is difficult to industrialize large-scale production, and it is difficult for workers to protect themselves from the ultraviolet light generated by the catalytic light source mercury lamp during labor.

Method used

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  • Preparation method of lenalidomide
  • Preparation method of lenalidomide
  • Preparation method of lenalidomide

Examples

Experimental program
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Effect test

Embodiment 1

[0048] (1) Preparation of methyl 2-bromomethyl-3-nitrobenzoate

[0049] 15g of methyl 2-methyl-3-nitrobenzoate, 19g of NBS, 1.89g of AIBN, 100mL of water were stirred, the temperature was kept at 80℃, and the reaction was kept at low speed for 1 hour. The organic layer was separated and crystallized in ethanol to obtain The yellow solid was filtered and dried to obtain 18 g of the product with a yield of 90.2%.

[0050] 1 HNMR(500MHz,CDCl3)δ8.12(dd,J=7.5,2.0Hz,1H),8.00(dd,J=7.4,1.9Hz,1H), 7.51(t,J=7.5Hz,1H), 4.46( s, 2H), 3.94 (s, 3H).

[0051] (2) Preparation of dimethyl 3-(7-nitro-1-oxo-1,3-dihydroisoindol-2-yl)glutarate

[0052] 2-bromomethyl-3-nitrobenzoic acid methyl ester 10.03g, D,L-glutamate dimethyl ester 7.78g, sodium carbonate 9.82g, stirred in DMF80mL, reacted at 45℃ for 16 hours, add water 100mL, It was extracted with EA (100 mL*3), concentrated and recrystallized with ethanol to obtain 10.62 g of a yellow solid product with a yield of 86.3%.

[0053] 1 HNMR(500MHz,CDCl3...

Embodiment 2

[0064] (1) Preparation of 2-chloromethyl-3-nitrobenzoic acid methyl ester

[0065] Methyl 2-methyl-3-nitrobenzoate 15g, NCS14.25g, AIBN1.89g, 100mL of water, stir, and keep the temperature at 80℃, keep stirring at low speed for 1 hour, separate the organic layer and crystallize in ethanol A yellow solid was obtained, filtered, and dried to obtain 15.12 g of the product with a yield of 86.2%.

[0066] 1 HNMR(500MHz,CDCl3)δ8.09(dd,J=7.5,2.0Hz,1H), 8.04(dd,J=7.5,2.0Hz,1H), 7.51(t,J=7.5Hz,1H), 4.64( s, 2H), 3.94 (s, 3H).

[0067] (2) Preparation of dimethyl 3-(7-nitro-1-oxo-1,3-dihydroisoindol-2-yl)glutarate

[0068] 8.43g methyl 2-chloromethyl-3-nitrobenzoate, 7.82g D,L-glutamate dimethyl, 9.77g sodium carbonate, stirred in DMF80mL, reacted at 45°C for 16 hours, added water 100mL, It was extracted with EA (100 mL*3), concentrated and recrystallized with ethanol to obtain 9.16 g of a yellow solid product with a yield of 74.4%.

[0069] 1 HNMR(500MHz,CDCl3)δ8.41(dd,J=7.4,1.9Hz,1H), 8.31(d...

Embodiment 3

[0072] (1) Preparation of methyl 2-bromomethyl-3-nitrobenzoate

[0073] 15g of methyl 2-methyl-3-nitrobenzoate, 19g of NBS, 2.11g of azobisisoheptanitrile, 100mL of chloroform, stir, keep stirring and reflux for 8 hours, cool to room temperature, add 200ml of water, stir, separate The organic layer was washed with 20 ml of saturated sodium bicarbonate, the organic layer was separated and dried over anhydrous sodium sulfate, concentrated and crystallized in ethanol to obtain a yellow solid, which was filtered and dried to obtain 13.86 g of the product with a yield of 69.5%.

[0074] (2) Preparation of dimethyl 3-(7-nitro-1-oxo-1,3-dihydroisoindol-2-yl)glutarate

[0075] 2-bromomethyl-3-nitrobenzoic acid methyl ester 10.03g, D,L-glutamate dimethyl ester 7.78g, potassium carbonate 10.63g, stirred in DMAC 80mL, reacted at 45°C for 16 hours, add water 100mL, It was extracted with EA (100 mL*3), concentrated and recrystallized with ethanol to obtain 10.94 g of a yellow solid product with ...

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Abstract

A preparation method of lenalidomide comprises the following steps: 1, reacting a raw material methyl 2-methyl-3-nitro-benzoate with a halogenating reagent to obtain methyl 2-halomethyl-3-nitro-benzoate represented by formula (I); 2, reacting the methyl 2-halomethyl-3-nitro-benzoate with dimethyl D,L-glutamate hydrochloride in the presence of an alkaline compound to obtain dimethyl 3-(7-nitro-1-oxo-1,3-dihydroisoindole-2-yl)glutarate represented by formula (II); 3, hydrolyzing the above compound of formula (II) to obtain 3-(7-nitro-1-oxo-1,3-dihydroisoindole-2-yl)glutaric acid represented by formula (III); 4, reducing the above compound of formula (III) to obtain 3-(7-amino-1-oxo-1,3-dihydroisoindole-2-yl)glutaric acid represented by formula (IV); and 5, carrying out ring closure on the above compound of formula (IV) to obtain lenalidomide represented by formula (V). The method has the advantages of simple process, high safety, cheap and easily available raw materials, good quality of the above product, and suitableness for industrial production.

Description

Technical field [0001] The present invention relates to a kind of lenalidomide (chemical name: 3-(7-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione) Preparation. technical background [0002] The Chinese chemical name of lenalidomide is 3-(7-amino-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione, produced by American cells A drug developed by Celgene to treat fatal blood diseases and cancer. This product is an enhanced version of thalidomide (thalidomide) used to treat morning sickness that has caused thousands of infant birth defects, and has anti-cancer potential. Compared with thalidomide, it has fewer adverse reactions, and studies have shown that it does not cause birth defects in babies. [0003] In December 2005, the U.S. Food and Drug Administration (FDA) approved Celgene's lenalidomide for the treatment of myelodysplastic syndromes under the trade name Revlimid, which is an oral preparation. In June 2007, the European Medicines Agency accepted Revlimid's m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 倪晟陈鸿翔姜维斌汤建拓华波
Owner HANGZHOU HEZE PHARMA TECH
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