Process for synthesis of ezetimibe and intermediates used in said process

A preparation method for a compound of formula I,

• wherein the method comprises the following steps:
• (a) subjecting a compound of formula 1 and p-fluoro aniline to an allyl amination reaction in the presence of a base to prepare a compound of formula 2;
• (b) subjecting the compound of formula 2 and a compound of formula 3 to an addition reaction under the action of a base to prepare the compound of formula I having a structure shown in formula 4A;
• and optionally,
• (c) removing an ester group at the β position of ketone carbonyl from the compound of formula I having a structure shown in formula 4A to form the compound of formula I having a structure shown in formula 5A,
• wherein P is a hydrogen, an acetyl, a propionyl, a t-butyloxycarbonyl, a benzyl, a carbobenzoxy, a trityl, a trimethylsilyl, a tert-butyldimethylsilyl, a tert-butyldiphenylsilyl or diphenylmethylsilyl;
• X is H or CO2R2;
• R1 and R2 are independently selected from the group consisting of:
• a hydrogen, a methyl, an ethyl, an isopropyl, an n-butyl, a tert-butyl, a benzyl, an allyl and an adamantyl;
• and
• LG is selected from the group consisting of an acetyl, a t-butyloxycarbonyl, a methoxycarbonyl, and a di(ethoxy)phosphinyl.

A preparation method for a compound of formula 6A, wherein the method includes the step of subjecting the compound of formula I to a cyclization reaction under the action of a base to form the compound of formula 6A,

• wherein P is a hydrogen, an acetyl, a propionyl, a t-butyloxycarbonyl, a benzyl, a carbobenzoxy, a trityl, a trimethylsilyl, a tert-butyldimethylsilyl or a diphenylmethylsilyl;
• R1 is a hydrogen, a methyl, an ethyl, an isopropyl, an n-butyl, a tert-butyl, a benzyl, an allyl or an adamantyl;
• and
• X is H.

A preparation method for Ezetimibe, which is a compound of formula 8, wherein the method includes the following steps:

• (i) subjecting a compound of formula 5 to a cyclization reaction under the action of a base to form a compound of formula 6;
• (ii) subjecting the compound of formula 6 to an asymmetric reduction reaction at the position of ketone carbonyl in an organic solvent to obtain a compound of formula 7;
• and
• (iii) removing a protecting group from the compound of formula 7 to obtain Ezetimibe, the compound of formula 8,
• wherein P is a hydrogen, an acetyl, a propionyl, a t-butyloxycarbonyl, a benzyl, a carbobenzoxy, a trityl, a trimethylsilyl, a tert-butyldimethylsilyl or a diphenylmethylsilyl;
• and
• R1 is a hydrogen, a methyl, an ethyl, an isopropyl, an n-butyl, a tert-butyl, a benzyl, an allyl or an adamantyl.