Method of synthesizing landiolol hydrochloride

A technique for the synthesis of landyrolol hydrochloride and a synthetic method, which is applied in the field of synthesis of landylol hydrochloride, can solve problems such as unfavorable industrial production, increase reaction cost, and reduce product yield, so as to be beneficial to industrial production and reduce synthesis cost , the effect of increasing the reaction yield

Inactive Publication Date: 2009-07-01
BEIJING UNIV OF CHEM TECH
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  • Abstract
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AI Technical Summary

Problems solved by technology

[0021] 1) In the reaction [A], because the raw material II is too active, it is easily decomposed in dimethyl sulfoxide, which reduces the product yield. At the same time, the product I needs to be separated by column chromatography, thus increasing the reaction cost and not conducive to Industrial production; in reaction [D], one molecule product III reacts easily with two molecule product II, obtains the by-product of bistructural effect, reduces the yield of product; Use methanol as solvent in reaction [E], will decomposes product IV
[0022] 2) In the reaction [C], the raw material IV is used, which is expensive and highly toxic, and it will remain in the product III, which will affect the use of the final product landisolol hydrochloride

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  • Method of synthesizing landiolol hydrochloride
  • Method of synthesizing landiolol hydrochloride
  • Method of synthesizing landiolol hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] (1) Add 8.00ml S(+)-epichlorohydrin to 40.0ml acetone, slowly add 1.0ml boron trifluoride ether catalyst, and react at 40°C for 6 hours to obtain colorless and transparent (2,2 - Dimethyl-1,3-dioxolane-4S) methyl chloride liquid (product 1) 16.46 g, the yield is 95.5%.

[0062] (2) Dissolve 8.30g of p-hydroxyphenylpropionic acid in 30.0ml of dimethyl sulfoxide, add 2.50g of potassium hydroxide and 8.20g of potassium carbonate, add 14.46g of product 1 dropwise into the reaction system, and react at 120°C 12 hours, be cooled to room temperature, filter, with the mixed solution of ethyl acetate and sherwood oil (V 乙酸乙酯 :V 石油醚 =1:5) extraction, washed with saturated sodium bicarbonate and sodium chloride, dried over magnesium sulfate and concentrated to separate 3-(4-hydroxyphenyl)propionic acid (2,2-dimethyl-1,3-di Oxolane-4S) methyl ester (product 2) 11.79g, its yield is 84.2%

[0063] (3) Dissolve 5.6g of product 2 in 40.0ml of acetone, add 6.8g of anhydrous potassium...

Embodiment 2

[0068] In step (1), the reaction temperature was 45° C., and the weight of product 1 was 16.58 g, and the yield was 96.2%. Other steps are with embodiment 1.

Embodiment 3

[0070] In step (2), add 2.75g potassium hydroxide, with the mixed solution of ethyl acetate and sherwood oil (V 乙酸乙酯 :V 石油醚 =1:8) extraction, the weight of the precipitated product 2 was 12.35g, and the yield was 88.2%. Other steps are with embodiment 1.

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Abstract

The present invention relates to an organic synthesis method, in particular to a synthesis method of landisolol hydrochloride. The method uses S(+)-epichlorohydrin to replace 3-chloro-1,2-propanediol as a raw material, and optimizes the reaction conditions of condensation, esterification and etherification to obtain 3-[4-(2S,3- Glycidyloxy) phenyl] propanoic acid (2,2-dimethyl-1,3-dioxolane-4S) methyl ester; then N-(2- Aminoethyl) morpholine carboxamide oxalate undergoes a ring-opening reaction in isopropanol aqueous solution to obtain landisolol, and obtains the target product landisolol hydrochloride by a direct salt-forming method. The synthesis method is simple in operation, high in product yield, reduces the cost of raw materials, optimizes the reaction route, and also reduces the requirement on reaction conditions, and is beneficial to industrial production.

Description

technical field [0001] The present invention relates to an organic synthesis method, in particular to a synthesis method of landisolol hydrochloride. Background technique [0002] The chemical name of Landisolol Hydrochloride is 3-{4-[2S-Hydroxy-[3-(2-morpholinecarboxamido)ethyl]-aminopropoxy]-phenyl}propionic acid (2,2 -Dimethyl-1,3-dioxolane-4S) methyl ester hydrochloride, the English name is (2,2-dimethyl-1,3-dioxolan-4S-yl)methyl-3-{4- [2S-hydroxy-3-(2-morpholinocarbonyl-aminoethyl-)aminopropoxy]phenyl}propionate hydrochloride. The structural formula is: [0003] [0004] (landiolol hydrochloride, landiolol hydrochloride) was developed by Japan's Ono Pharmaceutical Co., Ltd. (Ono), and its tachycardia arrhythmia (atrial fibrillation, atrial flutter and sinus tachycardia) treatment drug during surgery Ono-act injection was approved by the Ministry of Health and Welfare on July 5, 2002, and was first launched in Japan in September 2002. [0005] This product is selec...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/24C07D413/12
Inventor 马润宇熊毅乔仁忠尤雅
Owner BEIJING UNIV OF CHEM TECH
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