CN103739537B - New synthesis method of ezetimibe - Google Patents

Abstract

The invention relates to a new synthesis method of ezetimibe. Particularly, a new method for synthesizing ezetimibe (as shown in formula (I)) comprises the steps of addition, closed loop, deprotection and the like by using a compound shown in a formula (II) and having good stability as a starting raw material. The new synthesis method has the advantages of strong stability, simple operation, high yield and the like, and is suitable for large-scale industrial production. The formula (I) is described in the specification.

Description

The novel synthesis of Ezetimibe

Technical field

The present invention relates to pharmaceutical synthesis field, be specifically related to the novel synthesis of Ezetimibe and 1-(4-fluorophenyl)-3 (R)-[3-(4-fluorophenyl)-3 (S)-hydroxypropyl]-4 (S)-(4-hydroxyphenyl)-2-azetidinone.

Background technology

Ezetimibe (Ezetimibe) as shown in the formula (I), another name ezetimibe, Zetia, for the first selectivity cholesterol absorption inhibitor that Schering Plough (Schering-Plough) company and Merck (Merck) company develop jointly, this product is first cholesterol absorption selective depressant class medicine be approved listing by U.S. FDA, trade(brand)name Zetia.This product obtains FDA approval on October 25th, 2002, and goes on the market on November 30th, 2002 in the U.S..At present, the indication that Ezetimibe obtains FDA approval has primary hypercholesterolemia (adult, paediatrics) homozygous familial hypercholesterolemia (adult, paediatrics), homozygous familial Sitosterolemia (adult, paediatrics), mixed type hyperlipidemia (adult).

European patent EP 720599 makes public for the first time the synthetic method of Ezetimibe:

This operational path is longer, employs active metal reagent and precious metal palladium, and gained midbody compound is unfavorable for purifying, and cost is higher, is not suitable for suitability for industrialized production.

Schering Plough company of the U.S. is optimized above-mentioned technique, discloses a kind of method of synthesis Ezetimibe newly in patent WO2000/34240:

This route has carried out larger improvement to technique in early stage: chiral reduction obtains chiral alcohol, protects in next step asymmetric Mannich reaction, and adopt TMSCl to protect one pot process intermediate, then Cheng Huan, deprotection prepare Ezetimibe finished product.But the asymmetric Mannich reaction in route due to intermediate character active, cause byproduct of reaction more, yield is lower, limits its application in suitability for industrialized production.

Summary of the invention

The object of this invention is to provide a kind of simple to operate, yield is high and the novel method of the synthesis Ezetimibe of applicable suitability for industrialized production.

Another object of the present invention is to the method providing a kind of preparation formula (I) compound, it comprises the following steps:

A) formula (III) compound and chlorosilane protect reagent to react under the existence of organic bases, the compound of obtained protected silane, then add formula (II) compound and Lewis acid, react, obtain formula (IV) compound under the existence of Lewis acid and organic bases,

B) formula (IV) compound cyclization under the existence of silane reagent and fluoride ion catalyst, obtains formula V compound,

Wherein, in formula (II), formula (IV) and formula V compound, R is selected from C₁-C₃alkyl, phenyl; Optional, described phenyl can be selected from alkyl further, the substituting group of alkoxyl group replaces;

C) formula V compound removes acyl group and silane protecting group, obtains Ezetimibe as shown in the formula (I),

Preferably, organic bases described in step a) is diisopropylethylamine.

Preferably, described in step b), silane reagent is selected from N, the two trimethylsilyl ethanamide of O-or trimethyl silane.

Preferably, fluoride ion catalyst described in step b) is three hydration tetrabutyl ammonium fluorides.

Preferably, acyl group and protected silane base group employing protonic acid solution is removed described in step c); Preferred, described protonic acid is selected from hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; Be particularly preferably sulfuric acid.

Another object of the present invention is also to provide a kind of such as formula the intermediate preparing Ezetimibe shown in (IV),

Wherein, R is methyl.

Another object of the present invention is also to provide a kind of intermediate preparing Ezetimibe as shown in formula V,

Wherein, R is methyl.

The present invention, by adopting acyl group protection to the alcoholic extract hydroxyl group of formula (II) compound, makes its difficult drop-off in reaction process, the corresponding activity that improve other reactive groups, contributes to the yield improving reaction.In addition, preparation technology of the present invention reacts less demanding, simple to operate, is easy to purifying, such that the preparation of Ezetimibe is more economical, more environmental protection, be more suitable for industrialization.

Embodiment

In order to understand content of the present invention better, below in conjunction with specific embodiment, the invention will be further described, but scope of the present invention is not limited to specific embodiment.

Embodiment 1: the preparation of Ezetimibe intermediate formula (IV) compound

At N₂under, add 150 milliliters of methylene dichloride and 21.5 grams of formula (III) compounds, stir and be cooled to-20 DEG C.Add 30.6 milliliters of diisopropylethylamine (DIPEA); Slow dropping 16.1 milliliters of trimethylchlorosilanes (TMSCl), keep temperature-15 DEG C to stir 1.5 hours.Reaction solution is cooled to-30 DEG C and adds 20.0 grams of formula (II) compounds, stir 10 minutes.Slow dropping 4.1 milliliters of TiCl₄, keep temperature-30 DEG C of stirring reactions 4 hours.Slowly water is added in reaction mixture, cancellation is reacted, add 60 milliliters of 1N aqueous hydrochloric acids, add 200 milliliters of methylene dichloride, stratification after stirring, organic layer is washed, anhydrous sodium sulfate drying, be concentrated into a small amount of solvent, add 15 milliliters of two trimethyl silane yl acetamides, reflux 30 minutes.Enriched mixture, removing methylene dichloride, makes product crystallization in ethyl acetate and normal heptane mixed solvent, and filter, 30 DEG C of vacuum-dryings, obtain product 27.1 grams, yield 79.1%.

Embodiment 2: the preparation of Ezetimibe intermediate formula V compound

Under nitrogen protection, add 300 milliliters of methyl tertiary butyl ethers and 20 grams of formula (II) compounds, add the two trimethylsilyl ethanamide (BSA) of 14.3 milliliters of N, O-, control temperature 10 DEG C.Add 0.48 gram of tetrabutyl ammonium fluoride (three water) (TBAF), stirring reaction 2 hours.Mixture is concentrated into dry, directly enters next step.

Embodiment 3: the preparation of Ezetimibe

In the product in embodiment 2, add 50 milliliters of Virahols and 15 milliliters of 2N sulphuric acid solns, stirred at ambient temperature 2 hours, separate out solid, filter, collect solid, in isopropyl alcohol and water, obtain white solid after recrystallization, target product formula (I) compound 14.54 grams is obtained, yield 93% after drying.

MS(ESI):432.14(M+Na⁺).

¹H-NMR(500MHz,DMSO)δ(ppm):1.761-1.804(m,3H),1.823-1.889(m,1H),3.079-3.101(m,1H),4.514-4.535(m,1H),4.804-4.808(d,1H),5.263-5.272(d,1H),6.772-6.789(d,2H),7.099-7.141(m,4H),7.218-7.249(m,4H),7.306-7.334(m,2H),9.504(s,1H).

Claims (1)

1. a method for preparation formula (I) compound, it comprises the following steps:

a)

At N₂under, add 150 milliliters of methylene dichloride and 21.5 grams of formula (III) compounds, stir and be cooled to-20 DEG C, add 30.6 milliliters of diisopropylethylamine; Slow dropping 16.1 milliliters of trimethylchlorosilanes, keep temperature-15 DEG C to stir 1.5 hours, reaction solution are cooled to-30 DEG C and add 20.0 grams of formula (II) compounds, stir 10 minutes, slowly drip 4.1 milliliters of TiCl₄keep temperature-30 DEG C of stirring reactions 4 hours, in reaction mixture, slowly add water, cancellation is reacted, and adds 60 milliliters of 1N aqueous hydrochloric acids, add 200 milliliters of methylene dichloride, stratification after stirring, organic layer is washed, anhydrous sodium sulfate drying, be concentrated into a small amount of solvent, add 15 milliliters of two trimethyl silane yl acetamides, reflux 30 minutes, enriched mixture, removing methylene dichloride, make product crystallization in ethyl acetate and normal heptane mixed solvent, filter, 30 DEG C of vacuum-dryings, obtain product 27.1 grams, yield 79.1%;

B) under nitrogen protection, add 300 milliliters of methyl tertiary butyl ethers and 20 grams of formula (IV) compounds, add 14.3 milliliters of N, the two trimethylsilyl ethanamide of O-, control temperature 10 DEG C, adds 0.48 gram of three water tetrabutyl ammonium fluoride, stirring reaction 2 hours, mixture is concentrated into dry, directly enters next step;

C) in the product of previous step, 50 milliliters of Virahols and 15 milliliters of 2N sulphuric acid solns are added, stirred at ambient temperature 2 hours, separate out solid, filter, collect solid, in isopropyl alcohol and water, obtain white solid after recrystallization, obtain target product formula (I) compound 14.54 grams after drying, yield 93%;

Wherein, in formula (II), formula (IV) and formula (V) compound, R is methyl.