Process for preparation of ezetimibe and derivatives thereof
A compound, selected technology, applied in chemical instruments and methods, compounds of elements of group 4/14 of the periodic table, drug combination, etc., can solve problems such as low yield
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Publication Date
- 2011-12-21
- Estimated Expiration
- Not applicable · inactive patent
Smart Images
Figure 1 
Figure 2 
Figure 3
Abstract
Description
[0001] This application is a divisional application of a Chinese invention patent application with a filing date of January 24, 2008, an application number of 200880007504.9, and a title of "Preparation Method of Ezetimibe and Its Derivatives". technical field
[0002] The present invention relates to [ruthenium-R based on p-fluoroacetophenone 3 R 4 NSO 2 Preparation of 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl] by asymmetric transfer hydrogenation of -1,2-diamine] - Improved methods of 4(S)-(4-hydroxyphenyl)-2-azetidinones. Said intermediates can be obtained in high yield and purity in a rapid and cost-effective manner. Background technique
[0003] Hypercholesterolemia and high blood or plasma cholesterol are common diseases in moderately affluent countries. Hypercholesterolemia is implicated in atherosclerosis, arteriosclerosis, myocardial infarction, and is one of several conditions that can lead to coronary artery and arterial disease. Risk gro...
Examples
Embodiment 1
[0299] Example 1.3-{(2S, 3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propanoic acid (Vb; Z=CO2 h)
[0300] Process 1 : Hydrolysis with KOH in THF / t-BuOH=1 / 3, small scale
[0301] To methyl 3-{(2S, 3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propane Ester (Vb; Z=CO 2 Me) (1.6 g, 3.7 mmol) in tetrahydrofuran (1 ml) and tert-butanol (3 ml) was added powdered potassium hydroxide (244 mg, 3.7 mmol). The mixture was stirred at room temperature for 1 h, then an additional amount of powdered potassium hydroxide (90 mg, 1.3 mmol) was added and stirring was continued for 1 h. 1M hydrochloric acid (5ml) and ethyl acetate (18ml) were added, the organic layer was washed 3 times with water and dried over sodium sulfate. Concentration in vacuo provided the acid (Vb; Z=CO 2 H) (1.5 g, 95%).
[0302] Process 2 : Hydrolysis with KOH in THF / t-BuOH=1 / 3, larger scale
[0303] To methyl 3-{(2S, 3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-o...
Embodiment 2
[0310] Example 2.3-{(2S,3R)-2-[4-(4-bromobenzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl } Propionic acid (Vc; Z = CO 2 h)
[0311] To methyl 3-{(2S, 3R)-2-[4-(4-bromobenzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidine-3- Base} propionate (Vc; Z=CO 2 Me) (11.5g, 22.4mmol) in tetrahydrofuran (27ml) and tert-butanol (36ml) was added powdered potassium hydroxide (1.75g, 22.4mmol). The mixture was stirred at room temperature for 0.5h, then 1M hydrochloric acid (30ml) and ethyl acetate (100ml) were added. The organic layer was washed 3 times with water and dried over sodium sulfate. Concentration in vacuo provided the acid (Vc; Z=CO 2 H) (9.2 g, 82%).
Embodiment 3
[0312] Example 3.3-{(2S,3R)-2-[4-(4-chlorobenzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidinyl}propionic acid (Vd; Z=CO 2 h)
[0313] To methyl 3-{(2S, 3R)-2-[4-(4-chlorobenzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidine-3- Base} propionate (Vd; Z=CO 2 Me) (12.78g, 27.3mmol) in tetrahydrofuran (30ml) and tert-butanol (90ml) was added powdered potassium hydroxide (1.95g, 34.8mmol). The mixture was stirred at room temperature for 6h, then 1M hydrochloric acid (40ml) and ethyl acetate (100ml) were added. The organic layer was washed with water and dried over sodium sulfate. Concentration in vacuo provided the acid (Vd; Z = CO 2 H) (13.1 g, 96%).