Process for the preparation of ezetimibe
AssigneeMSN Laboratories Limited
InventorsManne Satyanarayana Reddy, Muppa Kishore Kumar, Maram Reddy Sahadeva Reddy
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Abstract
The present invention relates to a cost effective and industrially advantageous process for the preparation of (3R,4S)-1-(4-fluorophenyl)-3-[3(S)-3-(4-fluorophenyl)-3-hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone, referred to here as Ezetimibe and represented by structural formula (I). The process comprises an multi-step reaction sequence that includes a chiral auxiliary-controlled condensation, a silyl-mediated cyclization, a palladium-catalyzed Negishi cross-coupling, and the enantioselective reduction of a ketone to a hydroxyl group.
Claims27
A process for the preparation of (3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone (Ezetimibe) compound of formula (I)
- comprising:
- (a) reacting glutaric anhydride compound of formula (II) with linear or branched chain aliphatic C1-C6 alcohols in presence of a base to give alkyl ester compound of formula (III)
- wherein R is C1-C6 alkyl;
- (b) reacting the compound of formula (III) with pivaloyl chloride in presence of an acid trapping agent, and subsequently reacting the product with a chiral auxiliary compound of formula (IV) to give ester compound of formula (V)
- (c) reacting the ester compound of formula (V) with benzylated imine compound of formula (VI) in presence of a Lewis acid to obtain an amide compound of formula (VII)
- (d) cyclizing the amide compound of formula (VII) with (i) a silylating agent and (ii) a fluoride ion catalyst cyclizing agent in a solvent to obtain the compound of formula (VIII)
- (e) hydrolyzing the ester group of compound of formula (VIII) with a base in a solvent, followed by adjusting the pH of the reaction mixture to 5-7, and followed by extracting the carboxylic acid compound of formula (IX)
- (f) reacting the compound of formula (IX) with oxalyl chloride in a first solvent to form an acid chloride product, followed by reacting the product acid chloride compound in situ with 4-fluorophenyl zinc halide in the presence of palladium(II) acetate in a second solvent, thereby producing the aromatic ketone compound of formula (X)
- (g) reducing the aromatic ketone compound of formula (X) in presence of a chiral reducing agent alone or in combination with a chiral catalyst in a solvent to obtain hydroxy compound of formula (XI), followed by isolating the hydroxy compound of formula (XI) as a solid using an organic solvent,
- (h) debenzylating the compound of formula (XI) with palladium carbon in an alcoholic solvent or dichloromethane or toluene to produce the compound of formula (I)
A process for the preparation of the compound of formula (X) from the compound of formula (IX), comprising:
- reacting the compound of formula (IX)
- with oxalyl chloride in a first solvent, followed by reacting the product acid chloride compound in situ with 4-fluorophenyl zinc halide in the presence of palladium(II) acetate in a second solvent, thereby producing the aromatic ketone compound of formula (X)
Dependencies are inferred from the claim text.