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Preparation method of 2-hydroyxl-2,2-dithienyl-2-polyglycolic acid-1-azabicyclo[2, 2, 2] octyl-3(R)-base ester

A technology of azabicyclo and dithiophene, which is applied in the field of medicinal chemistry and can solve the problems of product racemization, short route, and high cost of raw materials

Inactive Publication Date: 2014-04-30
AVENTIS PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The route is one-step reaction to obtain the target product, the route is short, but the cost of raw materials is high, and in the reaction process, the use of strong base NaH as a catalyst easily leads to racemization of the product

Method used

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  • Preparation method of 2-hydroyxl-2,2-dithienyl-2-polyglycolic acid-1-azabicyclo[2, 2, 2] octyl-3(R)-base ester
  • Preparation method of 2-hydroyxl-2,2-dithienyl-2-polyglycolic acid-1-azabicyclo[2, 2, 2] octyl-3(R)-base ester
  • Preparation method of 2-hydroyxl-2,2-dithienyl-2-polyglycolic acid-1-azabicyclo[2, 2, 2] octyl-3(R)-base ester

Examples

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example 1

[0028] Add 12.5 g (57.6 mmol) R-3-quinine alcohol and 50 mL THF to a 100 mL three-necked flask, stir in an ice bath, and slowly add 5.0 mL (58.2 mmol) oxalyl chloride dropwise. The reaction was stirred for 1 h, and THF was distilled off under reduced pressure. A light yellow solid was obtained, and 50 mL of deionized water was added to make a slurry at room temperature for 0.5 h to obtain 16.6 g of a strong yellow powdery solid. The yield is 93.8%. MS (ESI): 309 m / z (M+H) + .

[0029] (2) Preparation of 2-hydroxy-2,2-dithiophen-2-ylacetic acid-1-azabicyclo[2,2,2]oct-3(R)-yl ester

example 2

[0031] Under the protection of nitrogen, 1.6 g (65.8 mmol) of magnesium chips and 80 mL of anhydrous THF were sequentially added to a 250 mL three-necked flask, and two grains of iodine were added as a catalyst, and 9.5 g (65.5 mmol) of 2-bromothiophene was slowly added dropwise, and the After the addition was complete, the reaction was heated to reflux for 2 h, stirred and cooled to room temperature. Under nitrogen protection, 10 g (32.5 mmol) of bisquinine-3(R)-yl oxalate was dissolved in 100 mL of dry THF, stirred in an ice bath, and a THF solution of 2-thienylmagnesium bromide was slowly added dropwise, After the dropwise addition, the reaction was stirred in an ice bath for 2 h, and 50 mL of saturated ammonium chloride solution was slowly added dropwise, and the quenching temperature was controlled at 5-10 °C. THF was distilled off under reduced pressure, adjusted to pH=7-8 with 1 mol / L sodium hydroxide solution, extracted three times with 200 mL of dichloromethane, conce...

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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a preparation method of 2-hydroyxl-2,2-dithienyl-2-polyglycolic acid-1-azabicyclo[2, 2, 2] octyl-3(R)-base ester. Specifically, the preparation method comprises the following steps: enabling (R)-3-quinuclidinol (II) and oxalic acid or derivatives of the oxalic acid to be subjected to esterification reaction so as to obtain oxalic acid diquinine-3(R)-base ester (III): enabling the compound (III) and bimolecular 2-R base thiophene to be subjected to nucleophilic addition substitution, thus obtaining the target product (I). The preparation method has the advantages that the process route is short, reaction conditions are mild, raw materials are simple and easy to obtain, and the specific reaction routes are as shown in descriptions.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to aclidinium bromide synthesis intermediate 2-hydroxyl-2,2-dithiophen-2-ylacetic acid-1-azabicyclo[2,2,2]octyl-3(R )-based ester preparation process. Background technique [0002] Aclidinium bromide, an inhaled, long-acting, selective muscarinic cholinergic receptor antagonist (M receptor antagonist), is mainly used for the treatment of bronchospasm caused by chronic obstructive pulmonary disease. It is the third anticholinergic bronchodilator on the market after ipratropium bromide and tiotropium bromide. Its onset speed is faster than that of tiotropium bromide, and it is safe, well tolerated, and has fewer adverse reactions. . [0003] 2-Hydroxy-2,2-dithiophen-2-ylacetic acid-1-azabicyclo[2,2,2]oct-3(R)-yl ester is an important intermediate in the synthesis of aclidinium bromide, Patents WO0104118 A2 and CN00812754.9 report their synthetic methods, specifically as follows....

Claims

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Application Information

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IPC IPC(8): C07D453/02
CPCC07D453/02
Inventor 苟远诚王涛黄莉莎侯春徐艳马苏峰
Owner AVENTIS PHARMA HAINAN
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