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A kind of preparation method of anidungin side chain intermediate p-pentyloxyterphenylcarboxylic acid

A technology of p-pentoxy terphenyl formic acid and n-pentyloxy biphenyl is applied in the field of preparation of p-pentyloxy terphenyl acid in the side chain of anidungin, and can solve the problems of complicated operation, difficult control and high risk. , to achieve the effect of simple and safe process operation and low cost

Active Publication Date: 2021-12-24
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the problems of cumbersome operation, difficult control and high risk in the method for preparing boric acid by reacting butyllithium or Grignard reagent in the prior art, and provide a kind of anifungin side chain intermediate p-amyloxy The preparation method of terphenylformic acid

Method used

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  • A kind of preparation method of anidungin side chain intermediate p-pentyloxyterphenylcarboxylic acid
  • A kind of preparation method of anidungin side chain intermediate p-pentyloxyterphenylcarboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0076] Example 1 Synthesis of 4'-bromo-4-n-pentoxybiphenyl

[0077] Add 1450mL of water and 21.2g of sodium hydroxide to a 2L three-necked flask, stir to dissolve, add 120g of 4-hydroxy-4'-bromobiphenyl and 6g of tetrabutylammonium bromide, stir at room temperature for 10min, then add 87.2g dropwise 1-Bromopentane, reflux for 5 hours after the dropwise addition, and filter with suction after the reaction has dropped to room temperature. After filtering and washing the filter cake with 60 mL of n-heptane, the obtained solid was vacuum-dried at 60° C. for 5 hours, and the yield was 87%. 1 H NMR (d 6 DMSO,400MHz)δ8.04-8.02(m,2H),7.85-7.83(m,1H),7.63-7.57(m,3H),7.02-7.00(m,2H),4.01-3.98(m,2H) ,1.75(t,J=8.0Hz,2H),1.41-1.36(m,4H),0.92-0.89(m,3H).

Embodiment 2

[0078] Example 2 Synthesis of 4'-bromo-4-n-pentoxybiphenyl Add 1200mL of water and 17.7g of sodium hydroxide to a 2L three-necked flask, stir to dissolve and add 100g of 4-hydroxy-4'-bromobiphenyl and 5g of tetrabutylammonium bromide, stirred at room temperature for 10min, then added dropwise 72.7g of 1-bromopentane, refluxed for 5h after the dropwise addition, and suction filtered after the reaction was lowered to room temperature, and the filter cake was washed with 300mL of water, and the solid Heat slurry with 320mL n-heptane / water (1:1) mixed solution, filter with suction and wash the filter cake with 60mL n-heptane, and dry the obtained solid under vacuum at 60°C for 5 hours, with a yield of 87%. 1 H NMR (d 6 DMSO,400MHz)δ8.04-8.02(m,2H),7.85-7.83(m,1H),7.63-7.57(m,3H),7.02-7.00(m,2H),4.01-3.98(m,2H) ,1.75(t,J=8.0Hz,2H),1.41-1.36(m,4H),0.92-0.89(m,3H).

Embodiment 3

[0079] Example 3 Synthesis of 4-pentyloxy-4'-biphenylboronic acid Under nitrogen protection, add 5g of 4'-bromo-4-n-pentyloxybiphenyl, 88mg of palladium acetate, 4.6g of potassium acetate into a 100mL three-necked flask, 144mg of tris(o-methylphenyl)phosphine and 15mL of tetrahydrofuran, cooled to 0-10°C in an ice-water bath, 1.84g of tetrahydroxydiboron dissolved in 10mL of methanol and added dropwise to the reaction, stirred at room temperature, and added after the raw materials disappeared Dilute with 30 mL of ethanol, filter with suction, wash the filter cake with 10 mL of ethanol, spin the filtrate, add 80 mL of dichloromethane / water mixed solvent (1:1) for beating at 40°C for 1 hour, cool to room temperature and filter with suction, and filter the cake in turn Wash with 5 mL of water and 5 mL of dichloromethane, and dry in vacuo at 50° C. to obtain 2.84 g of a white solid with a yield of 64%. 1 H NMR (d 6 DMSO,400MHz)δ7.98-7.96(m,2H),7.85-7.83(m,2H),7.62-7.57(m,4H),7.02...

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Abstract

The invention relates to a preparation method of anidulungin side chain intermediate p-amyloxy terbenzoic acid. The method comprises the following steps: S1: 4-hydroxy-4'-bromobiphenyl and 1-bromopentane undergo a nucleophilic substitution reaction to obtain 4'-bromo-4-n-pentyloxybiphenyl; S2: 4'-bromo ‑4‑pentyloxybiphenyl and tetrahydroxydiboron undergo Suzuki coupling reaction to obtain 4‑pentyloxy‑4'‑biphenylboronic acid; S3: 4‑pentyloxy‑4'‑biphenylboronic acid and 4‑ Methyl iodobenzoate undergoes a Suzuki coupling reaction to obtain methyl 4''-(pentyloxy)-[1,1',4',1''-terphenyl]-4-formate; S4: hydrolysis to obtain p- Pentoxy terbenzoic acid. The present invention adopts Suzuki coupling to prepare aryl boronic acid and then prepares the target product through Suzuki coupling and alkali hydrolysis, which has the advantages of low cost, simple and safe process operation.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, more specifically, to a preparation method of anidifungin side chain p-amyloxy terbenzoic acid. [0002] technical background [0003] Anidulafungin (anidulafungin) is a derivative of amphotericin B, which is a third-generation echinomycin semi-synthetic antifungal drug developed by Vicuron Pharmaceutical Company of the United States, with a trade name of Eraxis, which was obtained in the United States in 2006. Listed in batches. Anidifungin has a larger volume of distribution and a broader spectrum of antibacterial activity than other echinocandin antifungals. [0004] Anifungin is a semi-synthetic antifungal agent derived from cyclic peptide antifungal agents prepared by culturing various microorganisms. All of these antifungal agents are structurally characterized by the inclusion of a cyclic hexapeptide core with an amino group of the cyclic amino acid carrying a fatty acyl group form...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C41/16C07C43/225C07F5/02C07C67/343C07C27/02C07C69/76C07C51/09C07C65/24
CPCC07C41/16C07C51/09C07C67/343C07F5/025C07C43/225C07C69/76C07C65/24
Inventor 钱宇刘毅胡文浩
Owner SUN YAT SEN UNIV
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