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Method for industrial production of tulobuterol

A technology of tulobuterol and oxidant, applied in the field of drug synthesis, can solve the problems of difficult removal of toxic impurities and high content of impurities, and achieve the effects of reduced production costs, low cost of raw materials, and simple steps

Inactive Publication Date: 2019-08-27
ANHUI HEALSTAR PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] It can be seen that the above four synthetic methods of tulobuterol will generate toxic impurities that are difficult to remove, and the impurity content is relatively high

Method used

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  • Method for industrial production of tulobuterol
  • Method for industrial production of tulobuterol
  • Method for industrial production of tulobuterol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] 1. Preparation of Intermediate II

[0030] Put 15.4g (0.1mol) of o-chloroacetophenone, 20mL of DMSO and 6g of iodine into a three-necked flask, raise the temperature to 55-60°C and stir for 1-1.5h, and identify the end point of the reaction by TLC (developing agent: ethyl acetate- Petroleum ether = 1:1), after the reaction was completed, cooled to room temperature, added 5 mL of deionized water, added 10 mL of 10% sodium thiosulfate solution, stirred for 10 min, extracted with isopropyl acetate, washed the organic layer twice with water, and saturated salt Washed twice with water, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain 14.5 g (0.086 mol) of intermediate II with a yield of 86.1%.

[0031] Two, the preparation of compound Ⅰ (tulobuterol crude product)

[0032] Add 14g (0.083mol) of intermediate II, 30mL methanol, 6.6g (0.09mol) tert-butylamine, and 4g sodium borohydride to a dry three-necke...

Embodiment 2

[0036] 1. Preparation of Intermediate II

[0037] Put 154g (1mol) of o-chloroacetophenone, 200mL of DMSO and 60g of iodine into a three-necked flask, raise the temperature to 55-60°C and stir for 1-1.5h, and identify the end point of the reaction by TLC (developing solvent: ethyl acetate-petroleum ether =1:1), after the reaction is completed, cool to room temperature, add 50 mL of deionized water, add 100 mL of 10% sodium thiosulfate solution, stir for 10 min, extract with isopropyl acetate, wash the organic layer twice with water, and wash with saturated saline Twice, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain 153 g (0.91 mol) of intermediate II with a yield of 91.1%.

[0038] Two, the preparation of compound Ⅰ (tulobuterol crude product)

[0039] Add 150g (0.893mol) of intermediate II, 330mL methanol, 6g (0.9mol) tert-butylamine, and 43g sodium borohydride into a dry three-necked flask in sequence...

Embodiment 3

[0043] 1. Preparation of Intermediate II

[0044] Put 154g (1mol) of o-chloroacetophenone, 200mL of DMSO and 60g of iodine into a three-necked flask, raise the temperature to 55-60°C and stir for 1-1.5h, and identify the end point of the reaction by TLC (developing solvent: ethyl acetate-petroleum ether =1:1), after the reaction is completed, cool to room temperature, add 50 mL of deionized water, add 100 mL of 10% sodium thiosulfate solution, stir for 10 min, extract with isopropyl acetate, wash the organic layer twice with water, and wash with saturated saline Twice, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain 147 g (0.88 mol) of intermediate II with a yield of 87.5%.

[0045] Two, the preparation of compound Ⅰ (tulobuterol crude product)

[0046] Add 150g (0.893mol) of intermediate II, 350mL ethanol, 6g (0.9mol) tert-butylamine, and 43g sodium borohydride into a dry three-necked flask in turn, con...

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Abstract

The invention discloses a method for industrial production of tulobuterol. The method comprises the following steps of 1, preparation of an intermediate II, wherein chloroacetophenone and an oxidant containing DMSO are added into a reaction kettle in sequence, a reaction is carried out for 1-1.5 hours under the condition of heat preservation, stirring is conducted until the reaction is completelyfinished, and through quenching, extraction, washing and concentration, the intermediate II is prepared; 2, preparation of a crude tulobuterol product, wherein the intermediate II, tert-butylamine, analcohol solvent and sodium borohydride are added into the reaction kettle in sequence and stirred, the reaction temperature is controlled, stirring is conducted until the reaction is completely finished, after concentration, extraction, washing and drying with a drying agent, filtration is conducted, and a filtrate is concentrated and recrystallized to obtain the crude tulobuterol product I; 3, refining of the tulobuterol, wherein the crude tulobuterol product I, an organic solvent and activated carbon for refinement of injection are recrystallized to obtain the refined tulobuterol. The industrial production method is green in reaction and simple in step and causes little pollution to the environment, the purity of the product is up to 99.95% or above, and the tulobuterol contains few impurities.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for industrial production of tulobuterol. Background technique [0002] Tulobuterol, whose chemical name is 1-(2-chlorophenyl)-2-tert-butylaminoethanol, is a selective β2 receptor agonist developed by Abbot Corporation of Japan. Asthma drugs were approved for marketing and were used to treat chronic obstructive pulmonary disease (COPD) in 1998. Currently, they are mostly used as patches to treat children with asthma. [0003] The method for synthesizing tulobuterol in the prior art mainly contains following four kinds: [0004] 1. Using o-chloroacetophenone as the starting material, it is prepared by bromination, amination and reduction at the alpha position of the carbonyl group, and has the following impurities: [0005] [0006] 2. Using 2-chloroacetophenone as the starting material, it is prepared by selenium dioxide oxidation, reduction, and amination, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/00C07C213/10C07C215/08
CPCC07C45/28C07C213/00C07C213/10C07C215/08C07C49/86
Inventor 刘经星徐奎牛春霞
Owner ANHUI HEALSTAR PHARM CO LTD
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