Preparation method of imidazole aromatic alcohol analog derivative with optical activity

An aromatic alcohol, optically active technology, applied in the directions of organic active ingredients, organic chemistry, pharmaceutical formulations, etc., can solve problems such as no optical activity, and achieve the effects of high yield, low cost and simple synthesis process

Inactive Publication Date: 2006-05-03
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are no reports on optically active α-chlorobenzyloxy-β-(1-imidazolyl)-2,4-difluoroethylbenzene compounds and their antifungal activity

Method used

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  • Preparation method of imidazole aromatic alcohol analog derivative with optical activity
  • Preparation method of imidazole aromatic alcohol analog derivative with optical activity
  • Preparation method of imidazole aromatic alcohol analog derivative with optical activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] (1) 2-chloro-2', the preparation of 4'-difluoroacetophenone (2):

[0024] Add 8.667g (0.065mol) of anhydrous aluminum trichloride and 6.45mL (0.065mol) of m-difluorobenzene into a 250mL three-necked flask. At 30°C to 35°C, 3.98 mL (0.050 mol) of chloroacetyl chloride was added dropwise. After the dropwise addition was completed, the temperature was raised to 50°C to 55°C for 4 hours. After the reaction was completed, the mixture was added into 0.6 mol / L 100 mL ice-water hydrochloric acid solution in a thin stream for acid hydrolysis. Filter and wash the solid with water. Recrystallize with n-hexane to obtain light yellow crystals, 8.648g after drying, yield 90.8%. Determination of mp by capillary melting point method: 47℃~48℃.

[0025] (2) Preparation of 2-chloro-1-(2,4-difluorophenyl)-ethanol (3):

[0026] Add 19.05g (0.1mol) of 2-chloro-2',4'-difluoroacetophenone (3) and 90mL of methanol into a 250mL three-necked flask. In an ice-water bath with stirring, NaBH w...

Embodiment 2

[0036] (1) 2-chloro-2', the preparation of 4'-difluoroacetophenone (2):

[0037] Add 8.010g (0.060mol) of anhydrous aluminum trichloride and 6.45mL (0.065mol) of m-difluorobenzene into a 250mL three-necked flask, and in the At 30°C to 35°C, 3.98 mL (0.050 mol) of chloroacetyl chloride was added dropwise. After the dropwise addition was completed, the temperature was raised to 50°C to 55°C for 4 hours. After the reaction was completed, the mixture was added into 0.6 mol / L 100 mL ice-water hydrochloric acid solution in a thin stream for acid hydrolysis. Filter and wash the solid with water. Recrystallize with n-hexane to obtain light yellow crystals, 8.648g after drying, yield 90.8%. Determination of mp by capillary melting point method: 47℃~48℃.

[0038] (2) Preparation of 2-chloro-1-(2,4-difluorophenyl)-ethanol (3):

[0039] With 19.05g (0.1mol) 2-chloro-2', 4'-difluoroacetophenone (3), 22.20g (0.2mol) CaCl 2 , 90mL of methanol was added into a 250mL three-necked flask. ...

Embodiment 3

[0051] (1) 2-chloro-2', the preparation of 4'-difluoroacetophenone (2):

[0052]Add 8.000g (0.060mol) of anhydrous aluminum trichloride and 6.45mL (0.065mol) of m-difluorobenzene into a 250mL three-necked flask. At 30°C to 35°C, 3.98 mL (0.050 mol) of chloroacetyl chloride was added dropwise. After the dropwise addition was completed, the temperature was raised to 30°C-40°C for 4 hours. After the reaction was completed, the mixture was added into 0.6 mol / L 100 mL ice-water hydrochloric acid solution in a thin stream for acid hydrolysis. Filter and wash the solid with water. Recrystallize with n-hexane to obtain light yellow crystals, 8.954 g after drying, yield 94%. Determination of mp by capillary melting point method: 47℃~48℃.

[0053] (2) Preparation of 2-chloro-1-(2,4-difluorophenyl)-ethanol (3):

[0054] With 19.05g (0.1mol) 2-chloro-2', 4'-difluoroacetophenone (2), 19.00g (0.2mol) MgCl 2 , 90mL of methanol was added into a 250mL three-necked flask. Stir at room te...

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PUM

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Abstract

The invention discloses a preparation method for (R)- and (S)-alpha- alkoxy -beta-(1- imidazolyl)-2ú¼4-difluoroethylbenzenenitrate as optical-active imidazolyl aromatic derivant. Wherein, the synthesis method comprises: using chloracetyl chloride to acylate m-difluorobenzene into alpha- chloro-acetophenone; reducing ketone into alcohol; resolutioning racemic alcohol with organic-phase lipase catalyst to prepare (R)- and (S)- alcohol; on condition phase transferring, optical-active alcohol reacts with imidazole for N-alkylation reaction, then with benzylchlorine for O- alkylation reaction, using salt precipitation with nitric acid to obtain the objective product. The testings show: this product has antibacterial activity function, special the (R)- type, the technique has simple process and high yield.

Description

technical field [0001] The invention relates to a preparation method of optically active imidazole aromatic alcohol derivatives. Background technique [0002] In recent years, with the increasing use of immunosuppressants, adrenocortical hormones, and broad-spectrum antibiotics, the body's resistance to fungi has been reduced; the implementation of major operations such as heart, kidney and other organ transplants and severe damage to the body's immune function The spread of AIDS will damage the body's immune system and lead to an increase in fungal infections, and the morbidity and mortality of deep fungal diseases will increase significantly; coupled with the continuous emergence of drug-resistant strains, the development of high-efficiency, low-toxic, and broad-spectrum antibacterial agents Fungal drugs have important clinical significance and broad market demand. The antifungal drugs that have been discovered are mainly allylamines and benzylamines that act on squalene ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/14A61K31/4164A61K31/4178A61P31/10C07D409/12
Inventor 杨立荣王明慧吴坚平
Owner ZHEJIANG UNIV
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