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Preparation method and anti-asthma application of levo(-)terbutaline

A terbutaline and reaction technology, which is applied in the field of chemical resolution of β2 receptor agonists, can solve problems such as difficulty in chiral resolution

Pending Publication Date: 2019-08-23
KEY PHARMA BIOMEDICAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, obtaining drugs with high optical purity, especially ee values ​​greater than 99% or 99.5%, through synthetic methods has always been a difficult problem in chiral resolution.
So far, there has been no report of highly optically pure levorotatory (-) terbutaline

Method used

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  • Preparation method and anti-asthma application of levo(-)terbutaline
  • Preparation method and anti-asthma application of levo(-)terbutaline
  • Preparation method and anti-asthma application of levo(-)terbutaline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Dissolve racemic terbutaline sulfate (5.0g, 9.12mmol) and anhydrous potassium carbonate (1.3g, 9.42mmol) in 31.5ml methanol, reflux and react at 70°C for about 2h. After the reaction is complete, stop heating and stir. Cool to room temperature, filter with suction, and collect the filtrate.

[0043] D-(+)-DTTA (7.0g, 18.1mmol) was added to the filtrate, placed at 80°C for recrystallization, added with dichloromethane about 10ml, refluxed for 2h, allowed to stand at room temperature for 24h to crystallize, and filtered to obtain levorotatory ( -) Crude terbutaline tartrate, repeat this operation three times to obtain about 2.6 g of L-(-) terbutaline tartrate, the optical purity of which is 99.8%, and the yield is 47%.

[0044] Take 2g of L-(-)terbutaline tartrate and add 10% K 2 CO 3 The solution is about 10ml, extracted four times with 30ml ethyl acetate, combined the organic phases, dried over anhydrous magnesium sulfate, spin-dried the solvent, dissolve the solid powder wi...

Embodiment 2

[0046] Dissolve racemic terbutaline sulfate (5.0g, 9.12mmol) and anhydrous potassium carbonate (1.3g, 9.42mmol) in 31.5ml methanol, reflux and react at 70°C for about 2h. After the reaction is complete, stop heating and stir. Cool to room temperature, filter with suction, and collect the filtrate.

[0047] D-(+)-DTTA (7.0g, 18.1mmol) was added to the filtrate, placed at 80°C for recrystallization, added with dichloromethane about 15ml, refluxed for 2h, allowed to stand at room temperature for 24h to crystallize, and filtered to obtain levorotatory ( -) Crude terbutaline tartrate. Repeat this operation three times to obtain about 2.7 g of L-(-) terbutaline tartrate. The optical purity is 99.8% and the yield is 47%.

[0048] Dissolve 2g of L-(-)terbutaline tartrate in 10ml of water, add about 1ml of ammonia solution, extract four times with 40ml of ethyl acetate, combine the organic phases, dry with anhydrous magnesium sulfate, spin dry the solvent, and use the solid powder Dissolve...

Embodiment 3

[0050] Dissolve racemic terbutaline sulfate (10.0g, 18.24mmol) and anhydrous potassium carbonate (2.6g, 18.84mmol) in 63ml methanol, reflux for about 2h at 70°C, stop heating, stir and cool To room temperature, suction filtration, and collect the filtrate.

[0051] D-(+)-DTTA (14.0g, 36.2mmol) was added to the filtrate, placed at 80°C for recrystallization, added with dichloromethane about 30ml, refluxed for 2h, allowed to stand at room temperature for 24h to crystallize, and filtered to obtain levorotatory ( -) Crude terbutaline tartrate. Repeat this operation three times to obtain about 5.6 g of L-(-) terbutaline tartrate. The optical purity is 99.8% and the yield is 50%.

[0052] Take 2g of L-(-) terbutaline tartrate and add saturated K 2 CO 3 The solution solution is about 10ml, extracted four times with 40ml of isopropanol: dichloromethane (1:3), the organic phases are combined, dried over anhydrous magnesium sulfate, spin-dried to dry the solvent, and the solid powder is diss...

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Abstract

The invention relates to a preparation method of high optical purity and high chemical purity levo(-)terbutaline. The method provided by the invention has the advantages of cheap and easily availablebulk drugs, simple operation and short reaction period, is suitable for industrial production, improves the total yield, and at the same time can acquire high optical purity and high chemical purity product. The high optical purity and high chemical purity levo(-)terbutaline provided by the invention is applied to drug efficacy study of resistance to asthma and obstructive pulmonary disease. The result indicates that compared with the commercially available despinners, the levo(-)terbutaline can improve the anti-asthma efficacy manyfold, and proves a new obtains products with high chemicalpurity and optical purity. The anti-asthma and pulmonary obstruction effects of levo-terbutaline with high optical purity and high chemical purity in the present invention were studied. The results show that levoterbutaline in the invention can double the antiasthmatic efficacy compared with racemates sold in the market, and provides a new optimal treatment scheme for asthma related diseases.

Description

Technical field [0001] The present invention relates to a beta 2 The chemical resolution method of receptor agonists, in particular, relates to a preparation method of L-(-)terbutaline and its pharmaceutically salt and its anti-asthma application. Background technique [0002] Terbutaline is a medicine mainly used to treat bronchial asthma, asthmatic bronchus and bronchospasm in chronic obstructive pulmonary disease. Chemical name (±)α-[(tert-butylamino)methyl]-3,5-dihydroxybenzyl alcohol, molecular formula C 12 H 19 NO 3 , The molecular weight is 225, and the structural formula is as follows: The drug is a short-acting adrenal receptor agonist that can selectively activate β 2 Receptors, and relax bronchial smooth muscle, inhibit the release of endogenous spasm-causing substances, improve bronchial mucosal ciliary epithelial clearance, and can also relax uterine smooth muscle. There is a chiral C atom in the drug, and the drugs currently on the market at home and abroad are all ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/08C07C215/60C07C51/41C07C59/255A61K31/137A61P11/06A61P11/00
CPCA61K31/137C07B2200/07C07C51/412C07C213/08C07C215/60C07C59/255
Inventor 崩慧敏徐玲胡军华谭律雅
Owner KEY PHARMA BIOMEDICAL INC
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