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Preparation method of zolpidic acid

A technology of zolpidem acid and butyric acid, which is applied in the field of preparation of pharmaceutical intermediate zolpidem acid, can solve the problems of explosives, inconvenient storage and transportation, and high toxicity, and achieve easy operation, simple process steps, and simple operation Effect

Pending Publication Date: 2018-12-21
烟台万润药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this method does not use methyl iodide and sodium cyanide, the hydrazine hydrate used is still highly toxic and explosive, and it is extremely inconvenient to store and transport

Method used

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  • Preparation method of zolpidic acid
  • Preparation method of zolpidic acid
  • Preparation method of zolpidic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Step 1) Add 9.8g of maleic anhydride, 9.2g of toluene and 200ml of dichloromethane into a 1L three-necked flask, cool down to 0°C in a low-temperature bath under mechanical stirring, and then slowly add 27g of aluminum trichloride into the reaction flask to maintain the temperature 0-10°C, after adding, stir at room temperature and react for more than 4 hours. HPLC detects that the reaction is complete. Pour the reaction solution into 500g of ice water to quench, then extract with 500g of ethyl acetate, remove the solvent, and dry to obtain 16.2g of yellow solid. mp. 120.8-123.1°C; 1H-NMR (400 MHz, CDCl3)δ 8.00 (d, J=15.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H),7.33 (d, J=8.1 Hz , 2H), 6.89 (d, J=15.5 Hz, 1H), 2.45 (s, 3H), yield 85.0%.

[0036] Step 2) Add 19.0g of 4-oxo-4-(4-methylphenyl)-2-butenoic acid, 20.2g of 48% hydrobromic acid and 500g of dichloroethane into a 1000mL reaction flask, and heat up to reflux for reaction. After the addition reaction was completed, let it...

Embodiment 2

[0039] Step 1) Add 19.6g maleic anhydride and 200g toluene to a 1L three-necked flask, cool down to 0°C in a low-temperature bath under mechanical stirring, then slowly add 54g of aluminum trichloride to the reaction flask, keep the temperature at 0-10°C, add After completion, the temperature was raised to room temperature and the reaction was stirred for more than 4 hours. HPLC detected that the reaction was complete. The reaction solution was poured into 500 g of ice water to quench, then extracted with 500 g of ethyl acetate, the solvent was removed, and dried to obtain 30.0 g of a yellow solid, mp. 121.3- 123.2°C; 1H-NMR (400 MHz, CDCl3) δ 8.00(d, J=15.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H),7.33 (d, J=8.1 Hz, 2H), 6.89 (d, J=15.5 Hz, 1H), 2.45 (s, 3H), yield 78.7%.

[0040] Step 2) Add 19.0g of 4-oxo-4-(4-methylphenyl)-2-butenoic acid, 18.3g of 20% hydrogen chloride methanol solution and 500g of toluene into a 1000mL reaction flask, heat up and reflux for reaction, after the re...

Embodiment 3

[0043] Step 1) Add 19.6g of maleic anhydride, 18.4g of toluene and 200ml of dichloroethane into a 1L three-necked flask, cool down to 0°C in a low-temperature bath under mechanical stirring, and then slowly add 27g of aluminum trichloride into the reaction flask, keeping Temperature 0-10°C, after addition, stir at room temperature for more than 4 hours, HPLC detects that the reaction is complete, pour the reaction solution into 500g of ice water to quench, then extract with 500g of ethyl acetate, remove the solvent, and dry to obtain 32.4g of yellow solid , mp. 120.8-123.1°C; 1H-NMR (400 MHz, CDCl3) δ 8.00 (d, J=15.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H),7.33 (d, J=8.1 Hz,2H), 6.89 (d, J=15.5 Hz, 1H), 2.45 (s, 3H), yield 85.0%.

[0044] Step 2) Add 19.0g of 4-oxo-4-(4-methylphenyl)-2-butenoic acid, 27.9g of 50% hydroiodic acid solution and 200g of xylene into a 1000mL reaction flask, and raise the temperature at 110-120 ℃ reaction, after the addition reaction is completed, let stan...

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Abstract

The invention discloses a synthesis method of zolpidic acid. Different from the prior art, the synthesis method disclosed by the invention comprises the following steps: firstly performing a Friedel-Crafts reaction of toluene and maleic anhydride to obtain 4-oxo-4-(4-methylphenyl)-2-butenoic acid, then performing addition with hydrohalogen acid to obtain 3-halogenated-4-oxo-4-(4-methylphenyl)-butyric acid, performing esterification and cyclization to obtain 2-(6-methyl-2-p-methylbenzimidazole[1,2-alpha]pyridine-3-yl)acetate, and performing hydrolysis and acidification to obtain zolpidic acid.The method disclosed by the invention can obtain zolpiotan acid with a high purity, and the whole synthetic route has the advantages of few steps, high yield, low cost and few impurities, and is suitable for industrial production.

Description

technical field [0001] The patent relates to the technical field of chemical synthesis, in particular to a preparation method of zolpidem acid, a pharmaceutical intermediate. Background technique [0002] Zolpidem acid is a key intermediate for the preparation of Zolpidem tartrate (formula below). Zolpidem tartrate, N,N,6-Trimethyl-2-(4-methylphenyl)-imidazo[1,2-α]pyridine-3-acetamide-L(+)-tartrate , is a typical non-benzodiazepine sedative-hypnotics, characterized by fast onset, obvious effect, and less adverse reactions. The drug was developed by the French company Synthelabo and is widely used as a sedative-hypnotics all over the world, and it tends to gradually replace benzodiazepines. In my country, there are also many pharmaceutical companies listing this variety, with good market sales and high recognition. [0003] [0004] The preparation method of zolpidem acid mainly contains following several kinds at present: [0005] 1. The preparation method disclosed i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 马振堂程志新陈龙程振龙张雪孙宝佳易朝辉马志珂
Owner 烟台万润药业有限公司
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