Preparation method of gliquidone intermediate

A technology for gliquidone and intermediates, applied in the field of pharmaceutical chemical synthesis, can solve problems such as low product purity, long preparation time, waste of resources, etc., achieve the effects of improving product purity, reducing purification steps, and solving environmental problems

Inactive Publication Date: 2019-09-20
天津药物研究院药业有限责任公司
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  • Abstract
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Problems solved by technology

[0004] There are many problems in the existing synthetic method. Because the reaction process requires two steps, the yield of the product is low, and the preparation time is long, which is very easy to cause waste of resources; in addition, because the first step reaction is a reversible reaction, the reaction process It cannot be carried forward completely, so the purity of the product obtained is not high, and the product is not easy to purify, so the purity of the product obtained is low, and the purification process is complicated; in order to make the first step reaction can proceed forward, you can add hydrogen Sodium aqueous solution makes it positive, but this method will cause a large amount of waste lye to be produced during post-processing. In order to ensure environmental protection and discharge, it is necessary to equip corresponding treatment devices, which is likely to cause environmental problems

Method used

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  • Preparation method of gliquidone intermediate
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  • Preparation method of gliquidone intermediate

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preparation example Construction

[0021] The present invention relates to the preparation method of gliquidone intermediate, its structural formula is shown in formula (1),

[0022]

[0023] This scheme realizes the process of preparing the intermediate of gliquidone through a one-step method, specifically, 7-methoxy-2,4,4-trimethyl-1,3(2H,4H)-isoquinolinedione is used as Raw material, react with sodium hydroxide and 4-(2-aminoethyl)-benzenesulfonamide in xylene solution to prepare 4-(2-(3,4-dihydro-7-methoxy-4, 4'-Dimethyl-1,3-dioxo-2(1H)-isoquinolinyl)ethyl)benzenesulfonamide, the structural formulas of the compound of formula (2) and the compound of formula (3) are as follows,

[0024] Wherein, the structural formula of 7-methoxy-2,4,4-trimethyl-1,3(2H,4H)-isoquinolinedione is shown in formula (2),

[0025]

[0026] 4-(2-aminoethyl)-benzenesulfonamide structural formula is shown in formula (3),

[0027]

[0028] The specific preparation method is: sequentially add 7-methoxy-2,4,4-trimethyl-1,3(2H...

Embodiment 1

[0033] Add 300ml of xylene, 20g of 7-methoxy-2,4,4-trimethyl-1,3(2H,4H)-isoquinolinedione raw material, 0.17g of sodium hydroxide and 15.45 g4-(2-aminoethyl)-benzenesulfonamide raw material, start stirring, control the temperature at 100°C, add 1g of water dropwise, and the dropwise addition is completed in 15 minutes; heat to 140°C and stir for 4h, change to distillation, and distill out the distillate After adding toluene, add 300ml of n-propanol to the reaction system and heat to 80°C to dissolve. Cool down to 0-5°C, stir and crystallize for 3-5h, filter, filter, wash the filter cake, and dry to obtain 4-(2-(3,4-dihydro-7-methoxy-4,4'-di Methyl-1,3-dioxo-2(1H)-isoquinolyl)ethyl)benzenesulfonamide finished product. The melting point of the light yellow reaction product was tested, and the m.p. was 200°C. Compared with 4-(2-(3,4-dihydro-7-methoxy-4,4'-dimethyl- The melting point of 1,3-dioxo-2 (1H)-isoquinolyl) ethyl) benzenesulfonamide is consistent; In addition, the light...

Embodiment 2

[0035] Add 300ml of xylene, 20g of 7-methoxy-2,4,4-trimethyl-1,3(2H,4H)-isoquinolinedione raw material, 0.17g of sodium hydroxide and 16.31 g4-(2-Aminoethyl)-benzenesulfonamide raw material, start stirring, control the temperature at 100°C, add water dropwise, and the dropwise addition is completed in 10-20min; heat to 140°C and stir for 4h, change to distillation, and distill out distillate After adding toluene, add 300ml of n-propanol to the reaction system and heat until dissolved. Cool down to 0-5°C, stir and crystallize for 3-5h, filter, filter, wash the filter cake, and dry to obtain 4-(2-(3,4-dihydro-7-methoxy-4,4'-di Methyl-1,3-dioxo-2(1H)-isoquinolyl)ethyl)benzenesulfonamide finished product.

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Abstract

The invention provides a preparation method of a gliquidone intermediate. A one-step process is employed to replace the traditional two-step process, and the method includes: taking 7-methoxy-2, 4, 4-trimethyl-1, 3(2H, 4H)-isoquinoline dione as the starting raw material for addition with 4-(2-aminoethyl)-benzenesulfonamide in a xylene solution of sodium hydroxide, thus generating 4-(2-(3, 4-dihydro-7-methoxy-4, 4'-dimethyl-1, 3-dioxo-2(1H)-isoquinolyl)ethyl)benzenesulfonamide directly. The method avoids reversible reaction in the two-step process, and significantly improves the product generation rate. In addition, a small dose of sodium hydroxide is added in the reaction process, thereby greatly reducing the output of waste alkali water, and avoiding environmental pollution.

Description

technical field [0001] The invention belongs to the field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of a gliquidone intermediate. Background technique [0002] The existing preparation of gliquidone intermediate 4-(2-(3,4-dihydro-7-methoxy-4,4'-dimethyl-1,3-dioxo-2(1H)- The method of isoquinolinyl) ethyl) benzenesulfonamide mostly adopts formula (2) raw material to be hydrolyzed into formula (4) compound earlier in aqueous sodium hydroxide solution, and then generates 4-(2) with formula (3) raw material -(3,4-Dihydro-7-methoxy-4,4'-dimethyl-1,3-dioxo-2(1H)-isoquinolyl)ethyl)benzenesulfonamide, synthetic route as follows: [0003] [0004] There are many problems in the existing synthetic method. Because the reaction process requires two steps, the yield of the product is low, and the preparation time is long, which is very easy to cause waste of resources; in addition, because the first step reaction is a reversible reaction...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/24
CPCC07D217/24
Inventor 韦越王凯赵钊汪洋赵欣许海涛张智强岳金龙李果
Owner 天津药物研究院药业有限责任公司
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