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Preparation method of anidulafungin side chain intermediate

A technology of anidulafungin and an intermediate, which is applied in the field of preparation of anidulafungin side chain intermediates, can solve the problems of uncontrollable reaction conditions, high price, difficult availability, etc., and achieves shortened hydrolysis reaction time, low cost, and low cost. Easy to use effect

Active Publication Date: 2014-02-12
鲁南新时代生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In view of the existing raw material 4-hydroxyl-4'-bromobiphenyl in the prior art, it is expensive and difficult to obtain, and in the bromine-metal lithium exchange reaction, 4'-n-pentyloxy-4-lithium-1,1'- Biphenyl is easy to self-coupling to produce impurities, and the technical problems such as the difficult control of reaction conditions in the process of using butyl lithium reagent to prepare phenylboronic acid. The target compound is prepared by a new synthesis method of 3-step reaction of addition and hydrolysis with borate ester, Suzuki coupling reaction with monophenyl compound, and alkali hydrolysis of terphenylmethyl ester, which achieves simple process operation, low cost, high safety, The purpose of high product purity

Method used

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  • Preparation method of anidulafungin side chain intermediate
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  • Preparation method of anidulafungin side chain intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Example 1 Synthesis of 1,4-benzenediboronic acid

[0041] Under the protection of nitrogen, stirring add 220ml THF, 23.52g (0.98mol) magnesium, 1.0g (0.004mol) I 2 , Slowly add dropwise 315ml THF solution containing 68.4g (0.29mol) 1,4-dibromobenzene, after the dropwise addition, react at 35°C for 3h, cool to -75°C, slowly dropwise add trimethyl borate (123.2ml, 1.13) mol) and 300ml THF mixture, after dripping, react at -75°C for 1.5h, slowly rise to room temperature and stir for 15h. 980ml of 2.5M HCl was added and quickly stirred for 15min, filtered, the filter cake was washed three times with 320ml of n-hexane, and dried in vacuum to obtain 39.7g of white solid with a yield of 82.4%.

Embodiment 2

[0042] Example 2 Synthesis of 1,4-benzenediboronic acid

[0043] Under the protection of nitrogen, add 200ml THF, 15.0g (0.62mol) magnesium, 1.0g (0.004mol) I with stirring 2 , Slowly drop in 300ml THF solution containing 68.4g (0.29mol) 1,4-dibromobenzene, react at 30°C for 3h, cool to -70°C, slowly add trimethyl borate (78.5ml, 0.72 mol) and 300ml THF mixture, after dripping, react at -70°C for 1h, slowly rise to room temperature and stir for 12h. 950ml of 2.5M HCl was added and quickly stirred for 15min, filtered, the filter cake was washed three times with 300ml of n-hexane, and dried under vacuum to obtain 40.7g of white solid with a yield of 84.6%.

Embodiment 3

[0044] Example 3 Synthesis of 4″-n-pentyloxy-1,1′:4′,1″-terphenyl-4-carboxylic acid ethyl ester

[0045] Take 20.0g (120.6mmol) of 1,4-benzenediboronic acid and 13.6g (56.0mmol) of 4-pentyloxy bromobenzene, dissolve in 200ml of dioxane-ethanol (4:1) mixed solvent and 72ml (144.0) mmol) 2M Na 2 CO 3 Solution. The reaction solution was sonicated for 5 minutes and passed N 2 After removing oxygen, add 5.08g (6.99mmol) pd(dppf)cl 2 , In N 2 The reaction was heated under reflux for 5.2h under protection, 25ml of dioxane-ethanol (8:1) solvent containing 11.5g (50.4mmol) of ethyl 4-bromobenzoate was added dropwise, and the reaction was continued under reflux for 4h. Cool, filter, and wash the filter cake with 55ml toluene, 53ml methyl tert-butyl ether, 50ml water, 18ml methyl tert-butyl ether, P 2 O 5 It was dried under vacuum at 40°C to obtain 43.1 g of white solid with a yield of 90.2%.

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Abstract

The invention belongs to the field of medicine synthesis and specifically relates to a preparation method of an anidulafungin side chain intermediate 4'-orthopentyloxy-1,1':4',1'-terphenyl-4-carboxylic acid. The preparation method comprises the following steps: initiating a 1,4-dibromo-benzene material which serves as a starting material to carry out Grignard reagent reaction with magnesium by iodine; then, preparing 1,4-benzene hypoboric acid by virtue of addition and hydrolysis with trimethyl borate; and preparing 4'-orthopentyloxy-1,1':4',1'- terphenyl-ethyl carboxylate by virtue of Suzuki reaction of 1,4-benzene hypoboric acid, 4-pentyloxy bromobenzene and 4-halogenated ethyl benzoate in dioxane-ethanol liquor under catalysis of [1,1'-bis(diphenyl phosphino) ferrocene] palladium dichloride, and then, hydrolyzing to obtain a target product. The preparation method disclosed by the invention can lower process cost, is simple, convenient, safe and reliable to operate, and suitable for industrial production.

Description

Technical field [0001] The invention belongs to the field of medical synthesis, and specifically relates to the preparation of an anidulafungin side chain intermediate. Background technique [0002] Anidulafungin, shown in structural formula 1, is a semi-synthetic antifungal drug of the third generation echinococcus class, and a derivative of amphotericin B. The drug was developed by the American Vicuron Pharmaceutical Company. The FDA accepted the clinical application on May 24, 2004, and was later acquired by Pfizer under the trade name Eraxis. It was listed in the United States in December 2006. This structural change makes Anidungin have a larger volume of distribution and a broader spectrum of antibacterial activity than other echinocandin antifungal drugs. [0003] [0004] Anidulafungin inhibits glucan synthase (an enzyme required by many pathogenic fungi to synthesize the main part of the cell wall, which is not found in mammalian cells), resulting in cell wall damage and ...

Claims

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Application Information

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IPC IPC(8): C07C65/24C07C51/09
CPCC07C51/09C07C67/343C07F5/025C07C65/24C07C69/94
Inventor 苗宇关永霞
Owner 鲁南新时代生物技术有限公司
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