Synthetic methods of chiral aryloxy propanol amine compounds and salts thereof

An aryloxypropanolamine and a synthesis method technology are applied in the preparation of organic compounds, chemical instruments and methods, preparation of aminohydroxy compounds, etc., can solve the problems of high toxic and side effects, low efficacy, poor selectivity, etc. Simple, high product yield, good optical purity

Inactive Publication Date: 2008-12-17
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As a result, the racemate has the disadvantages of large drug dosage, low drug efficacy, poor selectivity, and high toxic and side effects compared with its single configuration enantiomer.

Method used

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  • Synthetic methods of chiral aryloxy propanol amine compounds and salts thereof
  • Synthetic methods of chiral aryloxy propanol amine compounds and salts thereof
  • Synthetic methods of chiral aryloxy propanol amine compounds and salts thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Embodiment 1: the preparation of S configuration carteolol hydrochloride

[0040] The synthetic route of S-configuration carteolol hydrochloride is attached figure 1 .

[0041] Step 1, etherification reaction: In the reactor, add 1.85g of (R) 3-chloro-1,2-epoxypropylene (compound A in the general formula), 1.63g of 5-hydroxyl-3,4- Dihydroquinolone (compound B in the general formula), 3.6 mL of water, 2.3 mL of N,N-dimethylformamide, stirred at room temperature for 5 minutes. An aqueous solution containing 0.8 g of sodium hydroxide was added, crystals were precipitated in the reaction solution, and the reaction was continued to stir at room temperature for 24 hours, and the reaction was stopped. The solid product was collected by filtration and recrystallized with acetone to obtain (S-configuration) intermediate 1 (compound C in the general formula), which was dried and weighed 1.75g, with a yield of 80% and an optical purity e.e. value of 99.5%.

[0042] Step 2, amin...

Embodiment 2

[0044] Embodiment 2: Preparation of S configuration bisoprolol fumarate

[0045] The synthetic route of S configuration bisoprolol fumarate is attached figure 2 .

[0046] Step 1, etherification reaction: In the reactor, add 1.80g of intermediate 2 (compound B in the general formula), 2.0mL of dimethyl sulfoxide, 2.00g of potassium hydroxide powder, and stir at room temperature for 5 minutes . Slowly add 1.85 g of (R) 3-chloro-1,2-propylene oxide (compound A in the general formula) dropwise, stir at room temperature for about 5 hours, and stop the reaction. 50 mL of water was added to the reaction liquid, and then extracted three times with 30 mL of dichloromethane, the organic phases were combined, and the solvent was recovered under reduced pressure to obtain a crude product. The crude product was recrystallized from acetone to obtain (S-configuration) intermediate 3 (compound C in the general formula), which was dried and weighed 1.98g with a yield of 84.0% and an optic...

Embodiment 3

[0049] Embodiment 3: the preparation of R configuration pindolol

[0050] The synthetic route of R configuration pindolol is attached image 3 .

[0051] Step 1, etherification reaction: In the reactor, 13.3g 4-oxindole (compound B in the general formula) was added to 15.5mL (S)-3-chloro-1,2-epoxypropane (general formula In the mixed solution of compound A) and 50.0 mL of ethanol, slowly add an aqueous solution containing 2.70 g of potassium carbonate dropwise at room temperature, and react for 6 hours under temperature control at 30-40° C. after the dropping is completed. Add 50.0 mL of water, adjust the pH to neutral with hydrochloric acid, recover ethanol to precipitate solids, filter, wash with water, and dry to obtain 15.56 g (R-configuration) of intermediate 4 (compound C in the general formula), with a yield of 82.3%. The purity e.e. value is 98.5%.

[0052] Step 2, amination reaction: In a reactor, add 10.00 g (R-configuration) of intermediate 4 (compound C in the g...

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Abstract

The invention relates to a synthesis method of chiral aryloxy propanol amine compound and salts thereof, which pertains to chemical pharmacy field. The method of the invention takes chiral source (R or S) halogenated propylene oxide and phenol compound as initial raw materials, (R or S) aryloxy propanol amine compound of high optical purity is obtained through etherification reaction and amination reaction, and the method of the invention can be applied to the preparation of various salts or compounds through salt forming reaction. The products of the invention usually has the characteristics of retarder of beta adrenoceptor and can be used as medicaments for curing diseases such as high blood pressure, angina pectoris, cardiac neurosis, arrhythmia and glaucoma, etc.

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and relates to a synthesis method of chiral aryloxypropanolamine compounds and salts thereof. Background technique [0002] Aryloxypropanolamine compounds have various biological activities in pharmacology, and these compounds are widely used clinically as antiadrenergic drugs. Anti-adrenaline drugs can block adrenergic receptors, known as adrenergic receptor blockers, they have the effect of blocking α receptor effects (peripheral vasoconstriction, etc.) and β receptor effects (cardiac contraction, increased heart rate , bronchial smooth muscle relaxation, etc.). Anti-adrenaline drugs are usually effective in the treatment of hypertension, angina pectoris, cardiac neurosis, arrhythmia, glaucoma and other diseases. Common aryloxypropanolamines are: Propranolol, Metoprolol, Atenolol, Bisoprolol, Labetalol, Oxprenolol, Sotalol, Pindolol, Carteolol, Betaxolol, Esmolol, etc. [0003]...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/04C07C217/04C07C233/25C07D215/20C07D209/43C07D209/88
Inventor 姚军宋伟朱江玲
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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