Preparation method of butylphthalide and pharmaceutical intermediate thereof

A technology of intermediates and drugs, which is applied in the field of medicinal chemistry, can solve problems such as unsuitable for large-scale industrial production, unavailable raw materials, and high toxicity of cyanide ketones, so as to facilitate large-scale industrial production, avoid the use of Grignard reagents, The effect of reducing production energy consumption and cost

Active Publication Date: 2018-10-09
QILU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The raw materials of this method are not easy to obtain, the cyclization step uses cyanide ketone, which is highly toxic, the reaction temperature is high (between 140 and 150°C), the operation is cumbersome, the Grignard reaction conditions are harsh, and the safety risk...

Method used

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  • Preparation method of butylphthalide and pharmaceutical intermediate thereof
  • Preparation method of butylphthalide and pharmaceutical intermediate thereof
  • Preparation method of butylphthalide and pharmaceutical intermediate thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0040] The preparation of embodiment 1 2-(methoxycarbonyl) benzoic acid

[0041] Add 500g of phthalic anhydride to a 3L reaction flask, add 2L of methanol to the system, raise the temperature of the system to 60-80°C until the phthalic anhydride disappears, concentrate under reduced pressure to remove methanol, and obtain a wet product at 50°C Vacuum drying for 4-6 hours gave 588 g of 2-(methoxycarbonyl)benzoic acid, with a yield of 96.7%.

Embodiment 2

[0042] Example 2 Preparation of 2-(ethoxycarbonyl)benzoic acid

[0043] Add 500g of phthalic anhydride to a 3L reaction flask, add 2L of ethanol to the system, raise the temperature of the system to 60-80°C until the phthalic anhydride disappears, concentrate under reduced pressure to remove ethanol, and obtain a wet product at 50°C Vacuum drying for 4-6 hours gave 596 g of 2-(ethoxycarbonyl)benzoic acid, with a yield of 91.0%.

Embodiment 3

[0044] Example 3 2-[(2-Methoxycarbonyl)pentanoyl]benzoic acid

[0045] Add 428g of sodium hydride into a 5L reaction flask, add 3.1L of N,N-dimethylformamide, 311g of methyl valerate and 580g of 2-(methoxycarbonyl)benzoic acid to the system at 0-10°C, The temperature of the system rises to 90-100°C, react at this temperature for 4-6 hours, stop heating, lower the system to room temperature, add 4L of purified water and stir until the system is dissolved, adjust the pH of the system to 2-3 with concentrated hydrochloric acid, ethyl acetate After ester extraction, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 646 g of 2-[(2-methoxycarbonyl)pentanoyl]benzoic acid, with a yield of 91.2%. Purity 95.6% (HPLC method);

[0046] 1 HNMR (400MHz, CDCl 3 )7.84(t, 1H), 7.72(d, 1H), 7.63−7.52(m, 2H), 3.78(s, 3H, OCH 3 ), 2.93 (dd, 1H), 2.35–1.73 (m, 2H), 1.34–1.25 (m, 4H), 0.90 (t, 3H). LC-MS for C...

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Abstract

The present invention provides a new pharmaceutical intermediate and a method for preparing butylphthalide by using the new pharmaceutical intermediate. According to the method, o-phthalic acid monoester as a raw material and valerate are subjected to ester condensation, o-pentanoylbenzoic acid is prepared through hydrolysis and decarboxylation, and reducing with sodium borohydride and ring closure are performed to obtain the product. According to the present invention, the method has characteristics of inexpensive and easily-available raw material, mild reaction condition, no high-temperaturereaction, no Grignard reaction, production energy consumption reducing, production cost reducing and operation safety improving.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a drug intermediate of butylphthalide and a preparation method thereof. Background technique [0002] Butylphthalide, the chemical name is 3-n-butyl-1( 3H )-isobenzofuranone, which has a chemical structure shown in formula I, is the main component of celery volatile oil, and is also widely present in other plants. Butylphthalide has strong anti-convulsant, anti-asthma, inhibits prostaglandin F 2x , increase blood flow, anti-tumor and antihypertensive and other pharmacological activities, and is currently mainly used for the treatment of mild and moderate acute ischemic stroke and the improvement of subsequent neurological deficits. [0003] [0004] At present, the main reports on the synthesis of butylphthalide are: (1) In 1990, Li Shaobai of Lanzhou University disclosed that phthalic anhydride was used as the starting raw material, and it was prepar...

Claims

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Application Information

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IPC IPC(8): C07C67/343C07C69/738C07D307/88
CPCC07C67/08C07C67/343C07C69/738C07D307/88
Inventor 齐宪亮高永宏范传文田振平李殿庆
Owner QILU PHARMA
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