Method for the synthesizing terbutaline intermediates

A synthesis method and technology of terbutaline, applied in the field of medicine and chemical industry, can solve the problems of impurity content, inability to meet quality standard requirements of residue on ignition, insufficient income from input and output, and high price of Bambooterol, so as to avoid high energy The use of consuming operating conditions, the avoidance of the use of large amounts of solvents, the effect of easy degradation

Inactive Publication Date: 2020-01-17
BEIJING INCREASE INNOVATIVE DRUG RESEARCH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has the following disadvantages: hydrolyzed polyphenols are easily oxidized under alkaline conditions; the amount of solvent used in the refining process is large, the purification effect is poor, and the indicators such as impurity content and residue on ignition a...

Method used

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  • Method for the synthesizing terbutaline intermediates
  • Method for the synthesizing terbutaline intermediates

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Add 100 g of the compound of formula I to 10 times (weight to volume ratio) of ethyl acetate, add 25 g of p-toluenesulfonic acid and 64 g of dibromohydantoin, replace with nitrogen for 3 times, and stir at 25°C under normal pressure for 5 hours in the dark. Suction filtration, the suction filtrate is placed in a reaction flask, washed three times, dewatered and dried, the suction filtrate is placed in a reaction flask and distilled under reduced pressure, concentrated to dryness, added 4 times (weight to volume) methanol and stirred for 35min, reduced to 10- Crystallize at 15°C for 1.5 h, and filter with suction to obtain 95 g of white crystalline solid with a yield of 76.76% and a purity of 99.37%.

[0039] 1 HNMR (400MHz, CDCl 3 ): δ (ppm): 4.415 (2H, s), 5.108 (4H, s), 6.878 (1H, m), 7.234-7.237 (2H, m), 7.284-7.469 (10, m).

[0040] 13 CNMR (100MHz, CDCl 3 ): δ (ppm): 31.22, 70.76, 108.09-108.19, 137.91-129.00, 138.50, 138.10, 160.43, 191.17.

Embodiment 2

[0042]Add 100 g of the compound of formula I to 5 times (weight to volume ratio) of ethyl acetate, add 20 g of trifluoroacetic acid and 80 g of dibromohydantoin, replace with nitrogen for 3 times, and stir at 25°C under normal pressure for 4 hours in the dark. Suction filtration, the suction filtrate is placed in a reaction flask, washed three times, dewatered and dried, the suction filtrate is placed in a reaction flask and distilled under reduced pressure, concentrated to dryness, added 5 times (weight to volume ratio) methanol and stirred for 30min, reduced to 10- Crystallize at 15°C for 2 hours, and filter with suction to obtain 89 g of white crystalline solid with a yield of 71.9% and a purity of 99.83%.

Embodiment 3

[0044] Add 100 g of the compound of formula I to 8 times (weight to volume ratio) of dichloromethane, add 18 g of p-toluenesulfonic acid and 70 g of dibromohydantoin, replace with nitrogen for 3 times, and stir for 5 hours at 25°C under normal pressure in the dark. Suction filtration, the suction filtrate is placed in a reaction flask, washed three times, dewatered and dried, the suction filtrate is placed in a reaction flask for vacuum distillation, concentrated to dryness, down to room temperature, add 3 times (weight to volume ratio) methanol and stir for 30min, Decrease to 10-15°C to crystallize for 2 hours, and filter with suction to obtain 93 g of white crystalline solid with a yield of 75.14% and a purity of 99.0%.

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Abstract

The invention provides a method for synthesizing terbutaline intermediates. The method provided by the invention adopts a single solvent for a reaction, the single solvent can be recycled, the processis simplified, and the post-treatment operation is simple. In key steps, dibromohyne is adopted as a brominating reagent, so that the method is green, environment-friendly and pollution-free, and theobtained product is high in purity and considerable in yield.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a method for synthesizing a key intermediate of terbutaline. Background technique [0002] Terbutaline: 5-(1-hydroxy-2-tert-butylaminoethyl)benzene-1,3-diol, CAS 23031-25-6, molecular formula C 12 h 19 NO 3 , the structural formula is as follows: [0003] [0004] Terbutaline is a short-acting β2-receptor agonist COPD drug developed by AstraZeneca, and it is a clinically recommended drug for patients with mild and moderate COPD. Compared with other marketed short-acting β2-receptor agonists, terbutaline inhalation has lower dose-dependent side effects. [0005] The terbutaline compound patent (SE335359) was applied for on October 19, 1966 by the Swedish Draco Company, and there is no Chinese patent of the same family. This patent uses 3,5-dibenzyloxyacetophenone as the starting material to obtain 2-(N-benzyl tert-butylamino)-1-(3,5-dibenzyloxybenz...

Claims

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Application Information

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IPC IPC(8): C07C45/63C07C49/84
CPCC07C45/63C07C49/84
Inventor 张保献胡杰王学元
Owner BEIJING INCREASE INNOVATIVE DRUG RESEARCH CO LTD
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