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A synthesis process, ezetimibe technology, applied in the field of synthesis of small molecule cardiovascular drugs, can solve the problems of low purity of hand-reduced products and unsuitability for industrial production, and achieve high product content and optical purity, easy operation and reaction conditions Gentle and manageable effect
Inactive Publication Date: 2021-03-05
SHIJIAZHUANG HUAXIN PHARMA
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The metal palladium catalyst is used in the process, and the purity of the hand-shaped reduction product is low, and...
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Embodiment 1
[0035] 1. Preparation of Intermediate 2 (INT2)
[0036] In the reaction kettle, dichloromethane (1 L), SM1 (200 g), SM2 (180 g) were added successively, and the reaction was stirred under nitrogen protection. Cool down to -10~0°C, add DIPEA (290g), continue to cool down to -20~-10°C, slowly add TMSCl (183g) dropwise, control the temperature of the dripping liquid not to exceed 0°C, the solids in the system gradually dissolve until completely dissolved , as a pale yellow solution. After dropping, control the liquid temperature to -10-0°C for reaction, and detect with TLC (developing solvent: PE / EA=2 / 1) until the SM1 reaction is complete.
[0037] Cool the reaction system to -20~-10°C, add titanium tetrachloride (128g) and 600ml dichloromethane dropwise under stirring, control the liquid temperature not to exceed -20°C, after the addition, slowly add tetraisopropyl titanate dropwise For ester (64g), control the liquid temperature not to exceed -20°C. After the drop is complete...
Embodiment 2
[0049] 1. Preparation of Intermediate 2 (INT2)
[0050] In the reaction kettle, dichloromethane (5L), SM1 (1.00kg), SM2 (903g) were added sequentially, and the reaction was stirred under nitrogen protection. Cool down to -10-0°C, add DIPEA (1.45kg), continue to cool down to -20--10°C, slowly add TMSCl (912g) dropwise, control the temperature of the dripping solution not to exceed 0°C, and gradually dissolve the solids in the system until completely dissolved as a light yellow solution. After dropping, control the liquid temperature to -10-0°C for reaction, and detect with TLC (developing solvent: PE / EA=2 / 1) until the SM1 reaction is complete.
[0051] Cool the reaction system to -20~-10°C, add titanium tetrachloride (637g) and 3L dichloromethane mixture dropwise under stirring, control the liquid temperature not to exceed -20°C, after the addition is complete, slowly add tetraisopropyl titanate dropwise For ester (318g), control the liquid temperature not to exceed -20°C. Af...
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Abstract
The invention discloses a synthesis process of an ezetimibe bulk drug, belonging to the field of synthesis of small-molecular cardiovascular drugs. The synthesis process comprises the following steps:(1) preparation of INT2: namely subjecting (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxyl-1-oxoamyl]-4-phenyl-2-oxazolidinone (SM1) and 4-[[(4-fluorophenyl)imine]methyl]-phenol (SM2) to reacting with trimethylchlorosilane (TMSCl) under the condition of an alkali reagent, respectively adding TMS protecting groups to hydroxyl groups of above compounds, conducting condensation under the action of Lewisacid so as to obtain INT1, and removing the TMS protecting groups to obtain the INT2; and (2) preparation of a finished product: firstly subjecting the INT2 to reacting with BSA, adding the TMS protecting group to the hydroxyl group, then performing cyclization under the action of a cyclization reagent TBAF.3H2O to obtain INT3, and finally removing the TMS protecting group to obtain ezetimibe (API). The synthesis process provided by the invention has the advantages of usage of easily available raw materials, mild and easily controllable reaction conditions, safety, environmental protection, convenient operation, continuous reaction steps, continuous reaction of an intermediate in the process, a shortened reaction period, high overall reaction yield, high product content and high optical purity, and is suitable for industrial production.
Description
technical field [0001] The invention relates to the field of synthesis of small-molecule cardiovascular drugs, in particular to a synthesis process of ezetimibe bulk drug. Background technique [0002] Ezetimibe, trade name Zetia, is the first selective cholesterol absorption inhibitor jointly developed by Schering-Plough and Merck. In October 2002, it was approved by the FDA of the United States, and in November of the same year, it was launched in Germany. In April 2007, it was approved by the Japanese PMDA, and in December 2013, it was launched in my country. [0003] [0004] The approved indications for ezetimibe include primary hypercholesterolemia, homozygous familial hypercholesterolemia, homozygous familial sitosterolemia, and mixed hyperlipidemia. Ezetimibe can be combined with medium and low-intensity statins, which can simultaneously inhibit the absorption and synthesis of cholesterol. The two mechanisms are complementary and synergistic, and the range of LDL...
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