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Synthesis method of lenalidomide metabolite

A synthesis method and technology of lenalidomide are applied in the field of synthesis of lenalidomide metabolites to achieve the effects of reasonable process design, high purity and cost saving

Active Publication Date: 2018-06-22
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The synthesis method of lenalidomide metabolites has not been reported yet. In order to conduct comprehensive analysis and research on lenalidomide clinical, pharmacology, pharmacokinetics, and toxicology, it is necessary to design and develop it on the basis of existing technologies. The preparation method of lenalidomide metabolites provides a reference material for analysis and research for comprehensive analysis of the clinical, pharmacology, pharmacokinetics and toxicology of lenalidomide

Method used

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  • Synthesis method of lenalidomide metabolite

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Experimental program
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Effect test

Embodiment 1

[0017] like figure 1 Shown, the preparation method of lenalidomide metabolite comprises the following steps:

[0018] Preparation of compound 2:

[0019] Dissolve 26 g of methyl 4-hydroxy-2-methylbenzoate in 80 mL of concentrated sulfuric acid, slowly add 15 mL of 65% concentrated nitric acid under ice bath, stir at room temperature for 2 hours, the reaction is complete, a large amount of solids precipitate out, suction filtration, The solid was washed with water, dried in a desiccator, and purified by a chromatographic column to obtain 15.2 g of compound 2 with a yield of 46%.

[0020] MS: 210[M-H - ]; 1H NMR: (400 MHz, DMSO-d6): δ 2.38 (s, 3 H), 3.81 (s, 3H), 6.9 (dd, 1 H), 7.9 (dd, 1 H), 11.8 (brs, 1 H)).

[0021] Preparation of compound 3

[0022] Dissolve 10 g of compound 2 in 120 mL of dimethylformamide, add 26 g of potassium carbonate and 8 g of chloromethyl methyl ether, and react at 65°C for 2 hours. Thin-layer chromatography shows that the reaction is complete. ...

Embodiment 2

[0034] like figure 1 Shown, the preparation method of lenalidomide metabolite comprises the following steps:

[0035] Preparation of Compound 2:

[0036] Dissolve 2.6 g of methyl 4-hydroxy-2-methylbenzoate in 8.0 mL of concentrated sulfuric acid, slowly add 1.5 mL of 95% concentrated nitric acid under ice bath, stir at room temperature for 1 hour, the reaction is complete, and solids are precipitated. After washing with water and drying in a desiccator, the solid was purified by chromatographic column to obtain 1.3 g of compound 2 with a yield of 43%.

[0037] Preparation of compound 3

[0038] Dissolve 1 g of compound 2 in 12 mL of dimethylformamide, add 2.5 g of potassium carbonate and 0.78 g of chloromethyl methyl ether, and react at 65°C for 2 hours. Thin layer chromatography shows that the reaction is complete. Extracted with ethyl acetate, washed with aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain 1 g of compound 3 with a yiel...

Embodiment 3

[0048] like figure 1 Shown, the preparation method of lenalidomide metabolite comprises the following steps:

[0049] Preparation of compound 2:

[0050] Dissolve 13 g of methyl 4-hydroxy-2-methylbenzoate in 50 mL of concentrated sulfuric acid, slowly add 7 mL of 95% concentrated nitric acid under ice bath, stir at room temperature for 2 hours, the reaction is complete, and solids are precipitated, filter with suction 1. The solid was washed with water, dried in a desiccator, and purified with a chromatographic column to obtain 8 g of compound 2, with a yield of 47%. MS: 210[M-H - ]

[0051] Preparation of compound 3

[0052] Dissolve 5 g of compound 2 in 60 mL of dimethylformamide, add 13 g of potassium carbonate and 4 g of chloromethyl methyl ether, and react at 65°C for 2 hours. Thin-layer chromatography shows that the reaction is complete. The reaction solution is poured into water in ice and used Extracted with ethyl acetate, washed with aqueous sodium chloride, drie...

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Abstract

The invention discloses a synthesis method of lenalidomide metabolite, and belongs to the field of medicine synthesis. The technological design is reasonable, the raw material is low in price, and theobtained product is high in purity. With methyl 2-hydroxy-4-methylbenzoate being the raw material, firstly, phenolic hydroxyl is protected, afterwards, the adjacency of hydroxyl is nitrified, a separated product is purified, phenmethyl is brominated, then a substitution reaction is conducted with 2,6-dioxopiperidine-3-ammonium chloride, aminolysis ring closing is conducted, under palladium catalysis, nitro is reduced to amino, and finally, a protecting group is removed to obtain a target molecule. The whole path is reasonable in design, and the target product provides a testing sample for research of the metabolic mechanism of lenalidomide and has important application value.

Description

technical field [0001] The invention belongs to the field of drug synthesis, in particular to a method for synthesizing lenalidomide metabolites. Background technique [0002] The chemical name of Lenalidomide is 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-2,6-piperidinedione, CAS No.: 191732-72-6, trade name: Revlimid. A new type of immunomodulator with anti-angiogenic and anti-tumor properties developed by Celgene Corporation of the United States. It was approved for marketing in the United States for the first time in 2006. It is mainly used to treat myelodysplastic syndrome subtypes and multiple myeloma with deletion of the long arm of chromosome 5. This product is used to treat morning sickness and cause tens of thousands of birth defects in babies. The derivative of thalidomide has more stable chemical properties, stronger angiogenesis inhibition, immune regulation and direct anti-tumor activity, etc. It is safer in clinical application, and its drug effect is abo...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04Y02P20/55
Inventor 陈强蒋纪言崔希林刘春胡永铸
Owner TLC NANJING PHARMA RANDD CO LTD
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