Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Method for preparing nebivolol racemate hydrochloride

A technology for nebivolol racemate and hydrochloride, applied in the field of preparing nebivolol racemate hydrochloride, can solve the problems of difficult preparation and purification, complex reaction products, difficult purification and the like, and achieves low cost , The effect of easy control of reaction conditions and high conversion rate

Inactive Publication Date: 2012-12-12
JINAN ASIA PHARMA TECH
View PDF3 Cites 12 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is mainly that the reaction raw material I is difficult to prepare and purify, and contains a small amount (1~4%) of isomers, which makes the subsequent reaction products complicated and not easy to purify

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Method for preparing nebivolol racemate hydrochloride
  • Method for preparing nebivolol racemate hydrochloride
  • Method for preparing nebivolol racemate hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] In a dry 1000mL three-necked flask, the DMF (75mL) solution of the compound of formula I (36.6g; purity 99.6%, HPLC method) was added dropwise to the compound containing formula II (30.0g; purity 99.6%, HPLC method), NaBr ( 1.6 g), NaHCO 3 (12.6g) in DMF (75mL) solution, heat up to 35-40°C under stirring; continue to heat and stir for 3 hours until the reaction is complete; then, use an ice-water bath to drop to 0-5°C, and add Add tertiary methyl ether (400mL) and water (200mL), stir for 15min and then stand to separate the layers. The aqueous layer is extracted with tertiary methyl ether (200mL×2). The organic phases were combined, dried with anhydrous sodium sulfate (25.0g) for 1 hour, filtered, and the filtrate was concentrated under reduced pressure to obtain an amber oil; the oil was dissolved in isopropyl ether and crystallized at room temperature for 2 hours. Crystal for 1 hour. After filtering, the filter cake was dried to obtain a light yellow solid, which wa...

Embodiment 2

[0050] In a dry 250 mL three-neck flask, the compound of formula III (30.0 g, IIIa / IIIb=50.2 / 49.8) was added to anhydrous acetonitrile (100 mL, water content: 0.01% KF). Slowly raise the temperature to an internal temperature of 70°C with stirring until the solid is completely dissolved and continue stirring for 15 minutes. Slowly cool down to 60°C, add DBU (2.5g), keep warm and stir for 2 hours; slowly cool down to 50°C, keep warm and stir for 3 hours; continue to slowly cool down to 40°C, keep warm and stir for 5 hours; continue to slowly cool down to 30°C, keep warm Stir for 1 hour; dropwise add glacial acetic acid (0.98g) to neutralize the reaction system to neutrality, then cool down to 25°C, filter, soak the filter cake in anhydrous acetonitrile (25mL×2), drain it, and dry it under reduced pressure to obtain Colorless to pale yellow solid, the compound of formula IIIa. A total of 18.8g (purity 99.2%, HPLC method; IIIa / IIIb=99.4 / 0.6).

Embodiment 3

[0052] N 2 Under protection, in a dry 500mL three-neck flask, NaBH 4 (2.24g) was added to anhydrous THF (100mL), cooled to -15~-20°C; and Ti(OPr-i) was slowly added dropwise 4 (33.0g), maintain the temperature at -10~-15°C, and continue to insulate and stir for 30min after dropping; then, slowly add anhydrous THF solution (90mL) containing the compound of formula IIIa (28.0g) dropwise to the above reaction system, drop After completion, keep the temperature at -10~-15°C for 2 hours; after the reaction is complete, keep the temperature at -10~-15°C and add saturated NH 4 Cl (200mL) solution until the reaction system is clear. The layers were separated, and the aqueous layer was washed with CH 2 Cl 2 (100mL×2) extraction, recover THF and CH respectively 2 Cl 2 , to obtain a colorless to light yellow foam, about 30 g, and heated to 60 ° C with ethanol / water (150 mL, v / v=3 / 1) to dissolve until clear, slowly lowered to room temperature, and stirred for 6 hours to crystallize....

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention discloses a method for preparing nebivolol racemate hydrochloride and belongs to the technical field of pharmaceutical synthesis. The method includes that a formula I compound and a formula II compound are used as raw materials to be subjected to an acyloin condensation to prepare a formula III compound, the formula III compound is subjected to an epimerization reaction to increase the ratio between III a and III b from 1:1 to 9:1, the formula III compound is subjected to a recrystallization purification to obtain a high purity III a, the III a is subjected to a carbonyl reduction to generate a formula IV compound, the formula IV compound is directly subjected to a catalytic hydrogenation to remove a benzyl protecting group to obtain a nebivolol racemate crude product, the nebivolol racemate crude product is directly salified by hydrogen chloride, and the recrystallization is performed to obtain the high purity nebivolol racemate hydrochloride. According to the method, the reaction is easy to control, the postprocessing is easy, and the production efficiency is high.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a method for preparing nebivolol racemate hydrochloride. Background technique [0002] Nebivolol is a long-acting cardioselective epinephrine beta 1 Receptor blocking drug, a 50:50 racemic mixture of 2 enantiomers - D-nebivolol and L-nebivolol, without membrane stability and endogenous sympathomimetic active. [0003] The structure of Nebivolol is as follows. It has four chiral carbon atoms and 10 isomers. Its D-isomer hydrochloride has good β1 receptor blocking properties, while the L-isomer hydrochloride contributes a lot to it. Small, but it has a good effect on controlling the release of NO. Their racemic hydrochloride mixture is used to treat essential hypertension, which can effectively control high blood pressure and maintain left ventricular function. The structural formula of nebivolol hydrochloride is shown below. [0004] [0005] So far, there ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D311/58
CPCY02P20/55
Inventor 彭立增
Owner JINAN ASIA PHARMA TECH
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com