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New preparation method of hydrochloride landiolol

A technique for landisolol hydrochloride and intermediates, which is applied in a new preparation field and can solve problems such as many reaction steps, unfavorable industrial production, unfavorable large-scale production, etc.

Active Publication Date: 2013-11-06
KUNMING JIDA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] (1), used the separation method of column chromatography in the synthetic process, has improved the cost of reaction, and is unfavorable for industrialized large-scale production
[0012] (2), there are many reaction steps, which is not conducive to actual operation
[0018] (1) The catalyst boron trifluoride diethyl ether used in the synthesis has relatively high reactivity and high toxicity, which is not conducive to industrial production
[0019] (2), used the separation method of column chromatography in the synthesis, not only time-consuming but also improved the cost of reaction, is unfavorable for suitability for industrialized production
[0020] (3), the activity of S(+)-epichlorohydrin is relatively low, and the reaction takes time

Method used

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  • New preparation method of hydrochloride landiolol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] (1) Synthesis of N-(2-aminoethyl)morpholine formamide (intermediate II)

[0051] Take 70 g of N-(2-aminoethyl) morpholine formamide oxalate and add it into a 2 L three-necked flask, add 1 L of 95% ethanol, and stir. Ice-water bath, add sodium hydroxide 18.9g to the three-neck flask in batches. After addition, stir for 7-18 hours. Add anhydrous sodium sulfate to dry. Filter and dry the filtrate under reduced pressure below 40°C. The oil was dissolved in 300ml of dichloromethane, and dried by adding anhydrous sodium sulfate. Filter and dry the filtrate under reduced pressure below 40°C. The oil was placed at low temperature to obtain 38.2 g of solid. Yield = 68.7%

[0052] (2) 3-{4-[2S-Hydroxy-[3-(2-morpholinecarboxamido)ethyl]-aminopropoxy]-phenyl}propanoic acid (2,2-dimethyl- Synthesis of 1,3-dioxolane-4S)methyl ester (Intermediate III).

[0053] Take 22.4g of raw material II and 80ml of dimethyl sulfoxide into a 250L three-neck flask respectively, stir, and add...

Embodiment 2

[0062] (1) Synthesis of N-(2-aminoethyl)morpholine formamide (intermediate II)

[0063] Add 70 g of N-(2-aminoethyl) morpholine formamide oxalate into a 2 L three-necked flask, add 1 L of methanol, and stir. Ice-water bath, add sodium hydroxide 18.9g to the three-neck flask in batches. After addition, stir for 7-8 hours. Add anhydrous sodium sulfate to dry.

[0064] Filter and dry the filtrate under reduced pressure below 40°C. The oil was dissolved in 300ml of dichloromethane, and dried by adding anhydrous sodium sulfate. Filter and dry the filtrate under reduced pressure below 40°C. The oil was placed at low temperature to obtain 37.8 g of solid. Yield = 68.0%

[0065] (2) 3-{4-[2S-Hydroxy-[3-(2-morpholinecarboxamido)ethyl]-aminopropoxy]-phenyl}propanoic acid (2,2-dimethyl- Synthesis of 1,3-dioxolane-4S)methyl ester (Intermediate III).

[0066] Take 22.4g of raw material II and 80ml of dimethyl sulfoxide into a 250L three-neck flask respectively, stir, and add 3.5g o...

Embodiment 3

[0075] (1) Synthesis of N-(2-aminoethyl)morpholine formamide (intermediate II)

[0076] Take 70 g of N-(2-aminoethyl) morpholine formamide oxalate and add it to a 2 L three-necked flask, add 1 L of isopropanol, and stir. Ice-water bath, add sodium hydroxide 18.9g to the three-neck flask in batches. After addition, stir for 7-8 hours. Add anhydrous sodium sulfate to dry. Filter and dry the filtrate under reduced pressure below 40°C. The oil was dissolved in 300ml of dichloromethane, and dried by adding anhydrous sodium sulfate.

[0077] Filter and dry the filtrate under reduced pressure below 40°C. The oil was placed at low temperature to obtain 37.5 g of solid. Yield = 67.5%

[0078] (2) 3-{4-[2S-Hydroxy-[3-(2-morpholinecarboxamido)ethyl]-aminopropoxy]-phenyl}propanoic acid (2,2-dimethyl- Synthesis of 1,3-dioxolane-4S)methyl ester (Intermediate III).

[0079] Take 22.4g of raw material II and 80ml of dimethyl sulfoxide into a 250L three-neck flask respectively, stir, a...

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Abstract

The invention discloses a new preparation method of hydrochloride landiolol; the route has simple operation, environmental-protection, is suitable for organic synthesis method of the industrial mass production, and can realize industrialization. The hydrochloride landiolol is selective beat1 receptor blocker, mainly antagonizes the beat1 receptor existing in the heart, and improves tachycardia arrhythmia through inhibiting the increase of heart rate caused by catecholamine.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis technology, in particular to an organic synthesis method which is simple in operation, environmentally friendly and suitable for industrialized large-scale production, and specifically relates to a new preparation method of landisolol hydrochloride. Background technique [0002] The chemical name of Landisolol hydrochloride is 3-{4-[2 S-hydroxyl-[3-(2-morpholine carboxamido)ethyl]-aminopropoxy]-phenyl}propionic acid (2,2 -Dimethyl-1,3-dioxolane-4S) methyl ester hydrochloride is a kind of therapeutic drug for tachycardia arrhythmia, and its structural formula is: [0003] [0004] Landisolol hydrochloride is a selective β1 receptor blocker, which mainly antagonizes the β1 receptors present in the heart, and improves tachyarrhythmia by inhibiting the increase in heart rate caused by catecholamines. Landisolol hydrochloride 2002 It was listed in Japan for the first time in Septem...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/24A61P9/06
Inventor 严洁李庆锋黄欣
Owner KUNMING JIDA PHARMA
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