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Lenalidomide intermediate preparation method

A compound and better technology, applied in the field of synthesis of chemical drugs, can solve problems such as large environmental impact, difficulty in labor protection for experimenters, and difficulty in environmentally sound treatment

Active Publication Date: 2016-04-27
SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During synthetic formula (I) compound, what WoonECY etc. adopt is bromine (Br 2 ), has strong oxidizing and rotten candle property; MullerGW etc. use highly toxic carbon tetrachloride (CCl 4 ) as a solvent; JagtapPG etc. have chosen anesthetic dichloromethane (CH 2 Cl 2 ) as solvent, CCl 4 and CH 2 Cl 2 These two solvents are highly toxic solvents, which have a great impact on the environment. Environmentally harmless treatment is very difficult, and the labor protection of the experimenters is also difficult, and the reaction time is relatively long, generally more than 24 hours.

Method used

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preparation example Construction

[0042] The preparation method of the present invention comprises the steps of:

[0043] (i) in the presence of a catalyst, the compound of formula II is reacted with methanol to obtain the compound of formula III;

[0044]

[0045] (ii) in an inert solvent, in the presence of a free radical initiator, the compound of formula III reacts with a brominating reagent to prepare the compound of formula I

[0046]

[0047]In another preferred example, the compound of formula II is suspended in methanol, and thionyl chloride is added dropwise with stirring, and heated to reflux for 2 hours after the dropwise addition is completed. The resulting reactant was poured into water, stirred, and an off-white solid was precipitated. After filtering, the filter cake was washed with water and dried under reduced pressure to obtain methyl 2-methyl-3-nitrobenzoate (III).

[0048]

[0049] In another preferred example, 2-methyl-3-nitrobenzoic acid methyl ester (III), N-bromosuccinimide ...

Embodiment 1

[0065] 1-1. Preparation of compound of formula III

[0066] Suspend the compound of formula II (40.0 g, 0.22 mol) in methanol (500 ml), add thionyl chloride (32.6 ml, 0.44 mol) dropwise under stirring, and heat to reflux for 2 h after the dropwise addition. The obtained reactant was poured into water (500ml), stirred, and an off-white solid was precipitated. After filtering, the filter cake was washed with water and dried under reduced pressure to obtain methyl 2-methyl-3-nitrobenzoate (III) (42 g), mp63-65°C (98% yield, mp61-63°C).

[0067] 1 HNMR (CDCl 3 )δ:2.63(s,3H,CH 3 ),3.95(s,3H,OCH 3 ), 7.39 (t, 1H, J = 7.9Hz, Ph), 7.85 (d, 1H, J = 7.9Hz, Ph), 8.00 (d, 1H, J = 7.9Hz, Ph). EI-MS (m / z): 195 (M+), 178, 165, 89.

[0068] 1-2 Formula I compound preparation

[0069] Add formula III compound (30g, 0.15mol), N-bromosuccinimide (NBS) (48g, 0.27mol) and azobisisobutyl Nitrile (AIBN) (3.1ml, 0.021mol), 1,2-dichloroethane (C 2 h 4 Cl 2 ) (100ml), stir and mix evenly, he...

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Abstract

The present invention provides a lenalidomide intermediate preparation method, namely a preparation process of important intermediate 2-bromomethyl-3-nitro-methyl benzoate of 3-(4-amino-1-oxo-1,3-dihydro- 2H- isoindolyl-2-yl) piperidine-2,6-dione (namely lenalidomide).

Description

technical field [0001] The present invention relates to the field of synthesis of chemical drugs, in particular to a 3-(4-amino-1-oxo-1,3-dihydro-2H-isozainden-2-yl)piperidine-2, The preparation process of the important intermediate 2-bromomethyl-3-nitrobenzoate methyl ester (compound of formula I) of 6-diketone (lenalidomide). Background technique [0002] Multiple myeloma (Multiplemgeloma, MM) is a refractory malignant B-cell disease, in patients with bone marrow malignant cells continue to proliferate, making normal cells unable to function. Myelodysplastic syndrome (myelodysplastic syndrome, MDS) is a clonal hematopoietic neoplasm. Myelodysplastic syndrome occurs when blood cells in the bone marrow are always in the immature stage and cannot perform their necessary functions. The bone marrow is full of these immature cells. Inhibits the development of normal cells. Chemotherapy for MM and MDS began in the 1960s. In the following 30 years, melphalan combined with predni...

Claims

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Application Information

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IPC IPC(8): C07C201/12C07C205/58
CPCC07C201/12C07C205/58C07C205/57
Inventor 李函璞
Owner SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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