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Method for synthesizing triazole antifungal agent intermediate

An antifungal agent, triazole technology, applied in the field of chemical synthesis, can solve the problems of unsatisfactory product enantioselectivity, long synthetic route, poor leaving ability, etc., and achieve easy industrial expansion synthesis, mild reaction conditions, and reliable good repeatability

Active Publication Date: 2022-04-26
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Kang et al reported the synthesis of chiral intermediate 1 using copper-catalyzed desymmetric asymmetric benzoylation reaction as the key step. The leaving ability of the group is poor, and it needs to be protected by Ms, then the nucleophilic substitution reaction is introduced to triazole, and then the protection of Bz is removed, so the synthetic route is longer
[0008] At present, the preparation methods of chiral intermediate 1 at home and abroad have problems such as unsatisfactory product enantioselectivity and long synthetic routes, so it is necessary to explore new synthetic routes for chiral intermediate 1

Method used

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  • Method for synthesizing triazole antifungal agent intermediate
  • Method for synthesizing triazole antifungal agent intermediate
  • Method for synthesizing triazole antifungal agent intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040]

[0041] Into an oven-dried 10 mL round bottom flask equipped with a stir bar, was charged triol substrate (61.3 mg, 0.3 mmol, 1.0 eq.), cuprous iodide (5.7 mg, 0.03 mmol, 10 mol%), chiral ligand Body L1 (15.1 mg, 0.03 mmol, 10 mol%), silver carbonate (49.6 mg, 0.18 mmol, 0.6 eq.), proton sponge (12.8 mg, 0.06 mmol, 0.2 eq.), and then dry chloroform (3 mL) was added. After stirring at room temperature for 5 minutes, benzenesulfonyl chloride (46 μL, 0.36 mmol, 1.2 eq.) was added. React at room temperature for 1 day, filter with a filter device covered with diatomaceous earth, concentrate the filtrate and dissolve it with acetonitrile (3mL), then add potassium carbonate (82.8mg, 0.6mmol, 2.0eq.) and 1,2,4- Triazole (41.4mg, 0.6mmol, 2.0eq.) was reacted at 60°C for 1 day, the solvent was removed in a rotary evaporator and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 2). A white solid (56.5 mg, yield: 74%, ee: 93%) was obtained.

[0042...

Embodiment 2

[0050]

[0051] A 10 mL round-bottomed flask equipped with a stirring bar and oven-dried was charged with triol substrate (0.3 mmol), cuprous iodide (0.009 mmol, 3 mol%), chiral ligand L2 (0.006 mmol, 2 mol%), Silver carbonate (0.09 mmol), proton sponge (0.020 mmol) and then dry chloroform (3 mL) were added. After stirring at room temperature for 5 minutes, benzenesulfonyl chloride (0.9 mmol, 3 eq.) was added. React at room temperature for 1 day, filter with a filter device covered with diatomaceous earth, concentrate the filtrate and dissolve it with acetonitrile (3mL), then add potassium carbonate (0.9mmol, 3eq.) and 1,2,4-triazole ( 0.9mmol, 3eq.), reacted at 60°C for 1 day, removed the solvent in a rotary evaporator and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 2) to obtain the product (yield: 73%, ee: 83%).

Embodiment 3

[0053]

[0054] Into an oven-dried 10 mL round-bottomed flask equipped with a stirring bar, charge triol substrate (0.3 mmol), cuprous iodide (0.09 mmol, 30 mol%), chiral ligand L3 (0.045 mmol, 15 mol%), Silver carbonate (0.1 mmol), proton sponge (0.10 mmol), and then dry chloroform (4 mL) were added. After stirring at room temperature for 5 minutes, benzenesulfonyl chloride (0.6 mmol, 2 eq.) was added. React at room temperature for 1 day, filter with a filter device covered with diatomaceous earth, concentrate the filtrate and dissolve it with acetonitrile (3mL), then add potassium carbonate (0.3mmol, 1eq.) and 1,2,4-triazole ( 0.3mmol, 1eq.), reacted at 70°C for 1 day, removed the solvent in a rotary evaporator and purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 2) to obtain the product (yield: 70%, ee: 84%).

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Abstract

The invention belongs to the field of chemical synthesis, and discloses a method for synthesizing a triazole antifungal agent intermediate, which comprises the step of preparing a compound B by reacting a compound A with PhSO2Cl by using an L ligand, in which R is selected from phenyl or alkyl, alkoxy, trifluoromethyl, cyano and nitro-substituted phenyl. According to the synthesis method, the synthesis route is remarkably shortened, the yield and ee value are relatively high, the reaction conditions are relatively mild, the repeatability is relatively good, industrial expanded synthesis is easy to carry out, and the method has a very good application prospect.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a method for synthesizing an intermediate of a triazole antifungal agent. Background technique [0002] Azole antifungal agents can be divided into three generations. The first generation, marked by imidazoles such as clotrimazole and econazole, was mainly used to treat superficial fungal infections; the second generation, marked by ketoconazole, was widely used for its broad-spectrum and high-efficiency characteristics. Treatment of deep fungal infections, and now mainly used for superficial fungal infections due to liver toxicity and side effects; the third-generation 1,2,4-triazole compounds are more efficient and broad-spectrum than the first and second generations , low toxicity, such as fluconazole and itraconazole, are widely used in the treatment and prevention of various deep and superficial fungal infections. Triazole compounds have developed into the res...

Claims

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Application Information

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IPC IPC(8): C07D249/08C07C303/28C07C309/73
CPCC07D249/08C07C303/28C07B2200/07C07C309/73Y02A50/30
Inventor 刘心元程永峰鱼章龙
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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