WO2006050634A1

WO2006050634A1 - A preparation method of 1-(4-fluorophenyl)-(3r)-[3-(4-fluorophenyl)-(3s)-hydroxypropyl]-(4s)-(4-hydroxyphenyl)-2-azetidinone

Info

Publication number: WO2006050634A1
Application number: PCT/CN2004/001292
Authority: WO
Inventors: Lianquan Gu; Jiwu Ruan; Zhishu Huang
Original assignee: Xiamen Mchem Pharma (Group) Ltd.
Priority date: 2004-11-15
Filing date: 2004-11-15
Publication date: 2006-05-18

Abstract

An improved process for producing 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone, comprising: cyclizing the β-(substituted-amino)amide of formula (I) in the presence of a inert organic solvent, a organic base, a fluoride ion catalyst cyclizing agent and a chiral structure protector while removing the protecting groups, and producing the object compound of formula (II). In particular, the chiral structure protector is chlorotrimethylsilane.

Description

1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-ylpropyl]-(4S)-(4-hydroxyphenyl)-2-propane Method for preparing lactam

TECHNICAL FIELD The present invention relates to a process for preparing 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyl The method of phenyl)-2-propiolactam (Ezet imibe).

Background technique

Ezetimibe (chemical name: 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl) -2-propanol, 1-(4-f luorophenyl) - (3R) - [3- (4-f luorophenyl) - (3S) -hydroxy propyl] - (4S) - (4-hydroxyphenyl) -2- Azet idinone is an important product of a new lipid-lowering drug that inhibits intestinal absorption of cholesterol by Merck and Schering-Plough. It can simultaneously lower low-density lipoprotein cholesterol (LDL-C) and raise high-density fat. Protein cholesterol (HDL-C) levels, and good tolerance. In addition, Ezetimibe and statins are highly complementary, and the combination of the two can not only lower cholesterol, but also reduce the dose of statins, thus reducing the side effects such as rhabdomyolysis caused by statins.

The intermediate β-(substituted amino) amide is usually used in the prior art to prepare Ezetimibe, which is based on the intermediate β-(substituted amino) amide.

1

Confirmation Bis-trimethylsilylacetamide (BSA) was used as the silylation reagent, and after cyclization, the protecting group was removed with an acid to obtain Ezetimibe. The disadvantage of this method is that the silylation reagent BSA is expensive, easy to decompose and shield, and difficult to store. The obtained Ezetimibe product contains more impurities, has a pale yellow color, and is not easy to be purified.

U.S. Patent Application No. 5,854,473 also discloses the preparation of Ezetimibe

Method, the method adopts

As a raw material, Ezetimibe is obtained through a multi-step reaction step of alkylation, oxidation, reduction, debenzylation and the like. However, the Ezetimibe produced is not ideal in terms of yield, purity, color and the like.

Therefore, it is necessary to provide a new preparation method for Ezetimibe to improve the purity of the product and reduce the production cost.

Summary of the invention

The object of the present invention is to provide an improved process for the preparation of Ezetimibe from an intermediate β-(substituted amino)amide. The purified Ezetimibe is white in color, high in purity, and has a low production cost. .

In the process of the present invention, a compound represented by the formula I, that is, a β-(substituted amino)amide, is dissolved in an inert organic solvent in the presence of an organic base, a fluoride ion cyclization catalyst and a chiral structure protecting agent. Cyclization of the β-(substituted amino)amide of formula I and simultaneous removal of the protecting group affords 1-(4-fluorophenyl)-(3R)-[3-(4-fluoro) of formula II Phenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxybenzene Base)- 2-propiolactam:

II

Among them, the β-(substituted amino)amide represented by the formula I is a substance which has been described in the literature and can be obtained by a conventional method. The function of the fluoride ion cyclization catalyst is to catalyze cyclization, so that the β-(substituted amino) amide forms a lactam ring; the organic base acts as a deprotecting group; the chiral structure protecting agent functions to maintain the product.

The chiral structure of Ezetimibe.

The inert organic solvent used in the process of the present invention may be dichlorodecane (CH ₂ C1 ₂ ), dioxane (C ₄ H ₈ 0 ₂ ), trichlorodecane (CHC1 ₃ ), tetrahydrofuran (THF), and / or mercapto tert-butyl ether (t-BuOMe), preferably dichloromethane or dioxane; the organic base used may be triethylamine, diisopropylethylamine and / or pyridine, preferably Triethylamine; the fluoride ion cyclization catalyst may be tetrabutylammonium fluoride trihydrate (TBAF '3H ₂ 0), boron trifluoride diacetic acid (BF ₃ .C ₄ H ₈ 0 ₄ ) and/or hydrogen sulfate Potassium (KHS0 ₄ ) is preferably tetrabutylammonium fluoride trihydrate or potassium hydrogen hydride. The chiral structure protecting agent is preferably trimethyl chlorosilane (TMSC1).

In the reaction system of the above method, the molar ratio of the β-(substituted amino)amide, trimethylsilyl chloride and organic base to which the formula I is added is preferably 1: 1: 1 : 2 : 2, and Addition of β-(substituted amino) of formula I The molar ratio of the amide to the fluoride ion cyclization catalyst is preferably 1: G.00 ⁵ to 1: 0.1. Further, in the method of the present invention, the reaction temperature at which the β-(substituted amino)amide represented by the formula I is cyclized and the protective group is simultaneously removed is preferably controlled between -25 and 50 ° C, more preferably - 5 ~ 30 °C. The reaction time of the above reaction is preferably from 0.5 to 5 hours, more preferably from 1 to 3 hours.

When various reaction materials are added to the above reaction system, the β-(substituted amino)amide represented by the formula I may be added to the inert organic solvent, and the organic base and the fluoride ion cyclization catalyst may be added. Then, a trimethyl chlorosilane is further added; or the intermediate β-(substituted amino) amide represented by the formula I may be first dissolved in an inert organic solvent, then an organic base, a fluoride ion cyclization catalyst, and finally three Mercaptochlorosilane.

The impurities of the product obtained by the process of the present invention can be purified by a conventional method to obtain crystals of Ezetimibe. For example, the process of the present invention may further comprise the subsequent steps of concentrating, recrystallizing, filtering, washing, drying, etc., to obtain crystals of Ezetimibe. The specific operation may be: concentrating and drying the mixture containing the product Ezetimibe obtained after the reaction, adding isopropanol, stirring to dissolve, adding water to the solution, and depositing a large amount of white crystals in the solution, filtering, washing The filter cake was dried in vacuo to give a white Ezetimibe solid. Among them, the concentration is preferably carried out by vacuum drying under reduced pressure. The purpose of adding isopropanol is to dissolve Ezetimibe; the purpose of adding water is to precipitate Ezetimibe from the isopropanol solution to achieve recrystallization. In addition to the addition of isopropanol to dissolve the product, other organic solvents may be added, preferably alcohol solvents. For example, it may be decyl alcohol or ethanol.

The method of the present invention provides a new route for preparing Ezetimibe. The purified product Ezetimibe is white in color, high in purity, low in raw materials used, and simple in operation steps, which not only improves the quality of the product but also reduces the production cost. .

The invention is further illustrated by the following examples, but the invention is not limited to the embodiments, and any modifications or substitutions based on the invention are still within the scope of the invention as claimed. DETAILED DESCRIPTION OF THE INVENTION Example 1 0.1 mol of β-(substituted amino)amide ( I ) was dissolved in 1 L of dichloromethane, followed by the addition of 0.2 g of tetrabutylammonium fluoride trihydrate (TBAF '3H ₂ 0) and 0.15 mol of triethylamine was added dropwise 0.15 mol of trimethyl chlorosilane (TMSC1) under ice-water bath cooling and stirring, and the mixture was dropped in about 30 minutes, and a large amount of white solid was precipitated. After the completion of the dropwise addition, the mixture was continuously stirred at room temperature for 2 hours, and then dried under vacuum under reduced pressure. Add 400 mL of isopropanol, stir to dissolve, and then slowly add 600 mL of H ₂ 0. A large amount of white crystals are precipitated, filtered, and the filter cake is washed with water, and dried under vacuum at 50 ° C for 24 hours to obtain 38 g of a white solid product Ezetimibe ( II ). The rate is 92.7 %. Example 2 0. lmol β-(substituted amino)amide ( I ), 0.2 g of tetrabutylammonium fluoride trihydrate (TBAF '3H ₂ 0), 0.15 mol of triethylamine and 1 L of decyl tert-butyl Ether (t-BuOMe) was added to a 2 L flask to give a suspension. 0.15 mol of trimethyl chlorosilane (TMC1) was added dropwise under ice-water bath cooling and stirring, and the mixture was dropped in about 30 minutes. After the completion of the dropwise addition, the reaction was further stirred at room temperature for 2 h and concentrated to dryness. Add 400 mL of isopropanol, stir to dissolve, and then slowly add 600 mL of H ₂ 0, a large amount of white crystals are precipitated, filtered, and the filter cake is washed with water, and dried under vacuum at 50 ° C for 24 hours to obtain 35 g of a white solid product Ezetimibe ( II ). The yield was 85.4%.

Example 3

0. lmol of β-(substituted amino)amide (I), 0.8 g of potassium hydrogen sulfate, 100 mL of dioxane and 0.15 mol of triethylamine were placed in a 1 L flask and heated to 70. C lh, a suspension is obtained. After the reaction mixture was cooled, 0.15 mol of trimethyl chlorosilane (TMC1) was added dropwise thereto under ice-water bath cooling and stirring, and the mixture was dropped over about 30 minutes. After the completion of the dropwise addition, the reaction was further stirred at room temperature for 2 h and concentrated in vacuo. Add 400 mL of isopropanol, stir to dissolve, and then slowly add 600 mL of H ₂ 0, a large amount of white crystals are precipitated, filtered, and the filter cake is washed with water, and dried under vacuum at 50 ° C for 24 hours to obtain 28 g of a white solid product Ezetimibe ( II ). The yield was 68%.

Claims

Rights request

1. Preparation of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl) a method of 2-propanolactam, which cyclizes a compound of formula I and simultaneously removes a protecting group in the presence of an inert organic solvent, an organic base, a fluoride ion cyclization catalyst, and a chiral structure protecting agent. , 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxybenzene) of formula II is obtained. Base) - 2 -propiolactam:

II

2. The method of claim 1 wherein said chiral structure protecting agent is trimethylchlorosilane.

The method according to claim 1, wherein the fluorine ion cyclization catalyst is tetrabutylammonium fluoride trihydrate, boron trifluoride diacetic acid or potassium hydrogen sulfate.

4. The method of claim 3, wherein said fluorine is separated The subcyclization catalyst is tetrabutylammonium fluoride trihydrate or potassium hydrogen sulfate.

The method according to claim 1, wherein the organic base is triethylamine, diisopropylethylamine or pyridine.

6. The method of claim 5 wherein said organic base is triethylamine.

7. The method of claim 1 wherein said inert organic solvent is methylene chloride, dioxane, chloroform, tetrahydrofuran or decyl tert-butyl ether.

8. The method of claim 7 wherein said inert organic solvent is dichlorodecane or dioxane.

9. The method according to claim 1, wherein the molar ratio of the compound of formula I, trimethylchlorosilane and organic base added in the reaction system is 1: 1 : 1 ~ 1 : 2 : 2.

005〜 1: 0. 2。 The molar ratio of the compound of the formula I and the fluoride ion cyclization catalyst is 1: 0. 005 ~ 1: 0.2.

The method according to claim 1, wherein the conversion of the compound of the formula I to the compound of the formula I I is carried out at a temperature between -25 and 50 °C.

12. The method of claim 1 wherein said method further comprises the steps of concentration, recrystallization, filtration, washing and/or drying.