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Preparation method of indanone intermediate

A technology for intermediates and indanones, applied in the field of preparation of indanone intermediates, can solve the problems of deadly toxicity, high material cost, and restricting large-scale production.

Inactive Publication Date: 2019-12-31
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 1. Use highly toxic cyanide reagents, whose toxicity is fatal to the human body;
[0007] 2. Use the unobtainable starting material 4-bromo-1-indanone, and the material cost is high
[0008] These limit the possibility of large-scale production and are not conducive to further production and development

Method used

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Examples

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preparation example Construction

[0017] According to one aspect of the present invention, the present invention proposes a kind of preparation method of intermediate 2-(2-cyanobenzyl) dimethyl malonate, comprising the following steps:

[0018] (1) In an organic solvent, under the action of a base and a catalyst, 2-cyanobenzyl bromide or 2-cyanobenzyl chloride reacts with dimethyl malonate at a certain temperature, the reaction is completed, and after post-treatment, to obtain Dimethyl 2-(2-cyanobenzyl)malonate.

[0019] According to one aspect of the present invention, the present invention proposes a kind of preparation method of intermediate 2-(2-cyanobenzyl) malonic acid, comprising the following steps:

[0020] (2) Dimethyl 2-(2-cyanobenzyl)malonate is reacted in an organic solvent under the action of an aqueous alkali solution, and after post-treatment, 2-(2-cyanobenzyl)malonate is obtained.

[0021] In some embodiments, according to one aspect of the present invention, a kind of preparation method of i...

specific Embodiment approach

[0103] Embodiments of the present invention are described in detail below. The embodiments described below are exemplary only for explaining the present invention and should not be construed as limiting the present invention. If no specific technique or condition is indicated in the examples, it shall be carried out according to the technique or condition described in the literature in this field or according to the product specification. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.

[0104] In order to describe the present invention, examples are listed below. However, it should be understood that the present invention is not limited to these examples, but only provides a method of practicing the present invention.

[0105] In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Unless otherwise stated, all reagents and solvents used wer...

Embodiment 1

[0106] Embodiment 1: Preparation 2-(2-cyanobenzyl) dimethyl malonate

[0107] The reaction formula is as follows:

[0108]

[0109] Add 2-cyanobenzyl bromide (20.0g), acetonitrile (200mL), salt of wormwood (28.20g), sodium iodide (3.06g), dimethyl malonate (26.96g) successively in single-necked bottle; Stir at 60°C; after the reaction, cool the system to 30°C, distill under reduced pressure, add 200mL water and 200mL dichloromethane, collect the dichloromethane layer, wash once with water, collect the dichloromethane layer and concentrate to obtain 2-(2-cyano Benzyl) dimethyl malonate 32.62g, purity 80%, yield 100%.

[0110] LC-MS:m / z(ESI):248.20(M+H) + .

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Abstract

The invention provides a preparation method of an indanone intermediate, and belongs to the field of pharmaceutical chemicals. The prepration method comprises the following steps: carrying out condensation reaction, hydrolysis and decarboxylation of 2-cyanobenzyl bromide or 2-cyanobenzyl chloride and dimethyl malonate in an organic solvent to obtain 2-cyanophenylpropionic acid; and reacting the obtained 2-cyanobenzene propionic acid with aluminum trichloride and an assistant agent to obtain 4-cyano-1-indanone. According to the invention, no highly toxic cyaniding reagent is needed, and the method has the advantages of high product purity, good safety, high yield, simple operation and the like. The method provided by the invention can effectively prepare the indanone intermediate, and provides favorable conditions for further preparation of ozanimod.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of an indanone intermediate. Background technique [0002] Ozanimod, CAS No.: 1306760-87-01, is a novel oral, selective sphingosine 1 phosphate receptor (S1P1R) modulator, developed for the treatment of autoimmune diseases. At present, the multiple sclerosis (MS) project of the drug has completed phase III clinical trials. [0003] The chemical structural formula of Ozamod is as follows: [0004] [0005] The compound 4-cyano-1-indanone is an important intermediate for the preparation of Ozamod. In the prior art, the method for preparing intermediate 4-cyano-1-indanone has the following problems: [0006] 1. Use highly toxic cyanide reagents, whose toxicity is fatal to the human body; [0007] 2. The starting material 4-bromo-1-indanone which is not readily available is used, and the material cost is high. [0008] These limit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C253/30C07C255/56
CPCC07C253/30C07C2602/08
Inventor 苏伟许国彬孙国栋王仲清胡燕青罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD
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