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Preparation method of 7-piperazinyl benzothiophene or salt thereof

A technology based on benzene and piperazine, applied in the field of preparation of 7-piperazinylbenzothiophene or its salt, can solve the problems of high production cost, expensive, low reaction yield, etc.

Inactive Publication Date: 2020-05-05
ZHEJIANG JINGXIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The technical problem to be solved by the present invention is to overcome the disadvantages of using expensive homogeneous palladium catalyst, high production cost and low reaction yield in the existing synthesis process of 7-piperazinylbenzothiophene, and provide a new Preparation method of 7-piperazinylbenzothiophene (compound 9-1 for short) or salt thereof

Method used

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  • Preparation method of 7-piperazinyl benzothiophene or salt thereof
  • Preparation method of 7-piperazinyl benzothiophene or salt thereof
  • Preparation method of 7-piperazinyl benzothiophene or salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056]

[0057] According to the literature method of Synthetic Communications; 2011, 41(20), 2985-2992, under the action of nitrate and trichloroisocyanuric acid, salicylaldehyde was selectively nitrated to obtain 3-nitrosalicylaldehyde (compound 2).

[0058] In a 100ml one-necked flask, 3-nitrosalicylaldehyde (1.67g, 0.01mol), triethylamine (4ml, 0.028mol, 2.8eq), and dichloromethane (40ml) were stirred and dissolved. After cooling in an ice bath to below 10°C, p-toluenesulfonyl chloride (1.90g, 0.01mol, 1eq) was added. After the addition was complete, the temperature was raised naturally, and the reaction was stirred for 4h. Sampling and detection, after the reaction of 3-nitrosalicylaldehyde is complete, pour the reaction solution into ice dilute hydrochloric acid, stir and separate the liquid, extract the water phase with dichloromethane, combine the organic phase, and use saturated sodium bicarbonate aqueous solution, saturated salt Washed with water, dried over anhyd...

Embodiment 2

[0060]

[0061] Combine 3.2 g of the solid obtained in Example 1 (compound 3-1, 0.01 mol), potassium carbonate (1.66 g, 0.012 mol, 1.2 eq), DMF (50 ml) under nitrogen protection, in an ice bath, and stir. After cooling to below 10 °C, methyl thioglycolate (1.17 g, 0.011 mol, 1.1 eq) was added. After the addition, the temperature was raised naturally, and the reaction was stirred for 6h. Sampling and testing, after the raw materials have reacted completely, pour the reaction solution into 150ml of ice water, stir for 15 minutes, a yellow solid precipitates out, filter with suction, rinse the filter cake with ice water, and dry to obtain 7-nitro-benzothiophene-2 Methyl carboxylate (compound 5), 2.3 g of yellow solid.

[0062] 1 H NMR (CDCl 3 )δ: 8.52 (1H, d, J = 8Hz), 8.23 ​​(1H, d, J = 8Hz), 8.19 (1H, s), 7.62 (1H, t, J = 8Hz), 4.00 (3H, s)

[0063]

[0064] 2-Chloro-3-nitro-benzaldehyde (3.7g, 0.02mol), potassium carbonate (3.32g, 0.024mol, 1.2eq), DMF (70ml) were st...

Embodiment 3

[0066]

[0067] Two-step decarboxylation:

[0068] The 7-nitro-benzothiophene-2-carboxylic acid methyl ester (2.37g, 0.01mol) prepared by the preparation method of Example 2 was dissolved in methanol, and 1N aqueous sodium hydroxide solution (20ml, 2eq) was added, and the reaction was stirred for 2h . Sampling and testing showed that the reaction of the raw materials was complete. Spin to dry the solvent, dilute the residue with water, adjust the pH to 1~2 with 1N hydrochloric acid, extract with ethyl acetate, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter with suction, and spin dry to obtain 7-nitro -Benzothiophene-2carboxylic acid, yellow solid 2.3g

[0069] The above-mentioned 7-nitro-benzothiophene-2 ​​carboxylic acid (2.3g), DMF (20ml) and cuprous oxide (0.3g) were mixed and stirred, heated and reacted in an oil bath at 120°C for 2h, sampling was detected, the basic reaction was complete, and the reaction was reduced....

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Abstract

The invention discloses a preparation method of 7-piperazinyl benzothiophene or salt thereof, comprising the following steps: (1) carrying out substitution ring closing reaction on a compound 3 and acompound 4 to obtain a compound 5; (2) carrying out hydrolysis decarboxylation on the compound 5 to obtain a compound 6; (3) performing a nitro reduction reaction on the compound 6 to obtain a compound 7; and (4) carrying out a reaction between the compound 7 and a salt of a compound 8-1 to obtain the product. According to the preparation method, cheap salicylaldehyde can be used as a starting material, and 7-piperazinyl benzothiophene or salt thereof is prepared through multi-step reaction. An expensive homogeneous palladium catalyst is not used in the synthesis route of the preparation method, the production cost is low, the operation is simple and convenient, the reaction conditions are mild, and the total reaction yield is relatively high.

Description

technical field [0001] The invention relates to a preparation method of 7-piperazinylbenzothiophene or a salt thereof. Background technique [0002] A class of cyclohexane derivatives or their stereoisomers or salts is disclosed in CN106518841A, wherein compound I has a strong affinity for dopamine D3 receptors and 5-hydroxytryptamine, but a weak affinity for D2 receptors, showing that it has a strong affinity for D3 receptors. The / D2 receptor has high selectivity, strong anti-schizophrenia symptom effect, only extremely low toxicity and good safety, and can be used for preparing neuropsychiatric disease drugs. [0003] [0004] 7-piperazinylbenzothiophene or its salt is an important synthetic intermediate for the synthesis of the compound I. At present, its synthetic method is by the piperazine of 7-bromobenzothiophene and Boc protection carries out coupling under palladium phosphorus complex, has adopted expensive homogeneous palladium catalyst in the palladium phosph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/54
CPCC07D333/54Y02P20/55
Inventor 徐辉吴茂江
Owner ZHEJIANG JINGXIN PHARMA
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