Preparation method of terbutaline derivatives

A technology for terbutaline derivatives, applied in the field of preparation of terbutaline derivatives, to achieve the effects of high product purity, good environmental protection effect, and reasonable process design

Pending Publication Date: 2020-07-24
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the control of impurity levels has been paid more and more attention by medical workers in the process of drug development and research, but the synthesis method of terbutaline series derivatives has not been reported yet.

Method used

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  • Preparation method of terbutaline derivatives
  • Preparation method of terbutaline derivatives
  • Preparation method of terbutaline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Such as figure 1 Shown, the preparation method of terbutaline derivative A comprises the following steps:

[0038] (1) Dissolve 20 g of terbutaline in 200 ml of acetonitrile, add 30 g of pyridine and 54 g of tert-butyldimethylchlorosilane to react at room temperature for two hours, concentrate, dilute with dichloromethane, wash with water, and concentrate to obtain 40 g of intermediate 1 , yield 85%;

[0039] (2) Dissolve 20g of intermediate 1 in dimethyl sulfoxide, add 10g of sodium bicarbonate and 9g of benzyl chloride, react at 40°C for 3 hours, add 300ml of water to dilute, extract with ethyl acetate, concentrate, and purify by column chromatography After obtaining about 14g of intermediate 2, the yield is 65%;

[0040] (3) Dissolve 7g of intermediate 2 in 70ml of tetrahydrofuran, add 20ml of dilute hydrochloric acid with a concentration of 4mol / L to reflux for 4 hours, adjust the pH to 7-8 with sodium hydroxide, extract with dichloromethane, and then purify by co...

Embodiment 2

[0042] Such as figure 1 Shown, the preparation method of terbutaline derivative A comprises the following steps:

[0043] (1) Dissolve 20 g of terbutaline in 200 ml of dimethyl sulfoxide, add 30 g of pyridine and 54 g of tert-butyldimethylchlorosilane to react at room temperature for two hours, concentrate, dilute with dichloromethane, wash with water, and concentrate to obtain 38g intermediate 1, yield 81%;

[0044] (2) Dissolve 20g of intermediate 1 in dimethyl sulfoxide, add 10g of sodium bicarbonate and 9g of benzyl chloride, react at 60°C for 2 hours, add 300ml of water to dilute, extract with ethyl acetate, concentrate, and purify by column chromatography After obtaining about 15g of intermediate 2, the yield is 61%;

[0045](3) Dissolve 14g of intermediate 2 in 150ml of tetrahydrofuran, add 40ml of dilute hydrochloric acid with a concentration of 4mol / L to reflux for 4 hours, adjust the pH to 7-8 with sodium hydroxide, extract with dichloromethane, and then purify by ...

Embodiment 3

[0047] Such as figure 1 Shown, the preparation method of terbutaline derivative B comprises the following steps:

[0048] (1) Dissolve 60g of raw material 3 in 500ml of acetonitrile, add 100g of potassium carbonate and 67g of benzyl bromide to react at 40°C for 3 hours, add 600ml of water to dilute, extract with ethyl acetate, concentrate, and obtain about 80g of intermediate after purification by column chromatography 4. The yield is 84%;

[0049] (2) Dissolve 55g of intermediate 4 in 550ml of acetonitrile, add 51g of pyridine and 51g of tert-butyldimethylchlorosilane to react at room temperature for two hours, concentrate, dilute with dichloromethane, wash with water and concentrate to obtain 70g of intermediate 5, Yield 86%;

[0050] (3) Dissolve 70g of intermediate 5 in 700ml of acetonitrile, add 100g of N-bromosuccinimide, react at 60°C for 4 hours, concentrate and purify by column chromatography to obtain 70g of intermediate 6, with a yield of 82%;

[0051] (4) 25g of...

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Abstract

The invention discloses a preparation method of terbutaline derivatives, belongs to the field of compound preparation, and provides a synthesis method of a novel drug molecule acotiamide derivative, which is reasonable in process design, high in yield and convenient and controllable in operation process. The invention provides a preparation method of three terbutaline derivatives. The preparationmethod provided by the invention has the advantages of reasonable process design, strong operability, mild reaction conditions and high yield, and can realize industrial production. The series of terbutaline derivatives prepared by the method provide important basis for scientific evaluation of quality, safety and efficiency of the series of terbutaline derivatives, and have important applicationvalue.

Description

technical field [0001] The invention belongs to the field of compound preparation, in particular to a preparation method of terbutaline derivatives. Background technique [0002] The structural formula of terbutaline (5-(1-hydroxy-2-tert-butylaminoethyl)benzene-1,3-diol) is: [0003] [0004] It has a bronchodilator effect, is highly selective to bronchial smooth muscle, has little stimulating effect on the heart, and has no central effect. It is used for bronchial asthma, asthmatic bronchitis, obstructive emphysema and other pulmonary diseases with bronchospasm It has a high selectivity for airway β2 receptors, and its bronchodilator effect is similar to that of salbutamol, and its effect on the heart is only 1 / 100 of that of isoproterenol, especially suitable for cardiovascular diseases such as hypertension and coronary heart disease of asthmatic patients. This product replaces the catechol ring with the m-hydroxyphenol ring, and replaces the hydrogen atom of the amin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/06C07C215/52C07C221/00C07C225/16
CPCC07F7/0834C07C213/06C07C221/00C07C231/02C07C213/00C07C215/52C07C225/16C07C235/34C07C217/60
Inventor 马富胡永铸崔希林
Owner TLC NANJING PHARMA RANDD CO LTD
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