KR101491007B1 - Process for preparing ezetimibe intermediate - Google Patents

Abstract

The present invention relates to a process for preparing a compound represented by the following general formula (4), which is an intermediate used in the production of ezetimibe capable of inhibiting cholesterol absorption, wherein a compound represented by the following general formula (2) According to the production method of the present invention comprising asymmetrically reducing the compound of the formula 3, the compound of the following formula 4 can be produced economically and in a high purity as compared with the conventional method:

(2)

(3)

≪ Formula 4 >

In this formula,

Ph and X are as defined in the specification.

Description

PROCESS FOR PREPARING EZETIMIBE INTERMEDIATE [0002]

The present invention relates to a process for the preparation of intermediates used in the production of ezetimibe capable of inhibiting cholesterol absorption.

Ezetimibe of the following formula (1) is an azetidinone derivative which is not only commercially available as a drug for inhibiting cholesterol absorption in the treatment and prevention of arteriosclerosis but also a drug for inhibiting cholesterol synthesis The compound is also marketed:

Various synthetic methods for the production of ezetimibe have been studied so far.

For example, U.S. Patent No. 6,207,822 discloses a method for preparing ezetimibe by performing as shown in Scheme 1 below:

In the above formula, Ph is a phenyl group and TMS is a trimethylsilyl group.

However, the process disclosed in the above Patent is unsuitable for the asymmetric reduction of the compound of Formula 3 to produce the compound of Formula 4, which is an intermediate of ezetimibe, in the presence of expensive (R) -2-methyl-CBS (Corey-Bakshi-Shibata) There is a disadvantage in that it is necessary to use a zabololyridine catalyst, and there is a problem that the compound of the formula (3) must be added dropwise over a long period of time for asymmetric reduction.

In addition, U.S. Patent No. 7,067,675 discloses that the compound of Formula 3 is reduced using (-) - DIP chloride ((-) -? - chlorodiisopinocamphhenylborane) to prepare the compound of Formula 4 as an intermediate of ezetimibe Method is disclosed. However, this method requires a purification process through column chromatography or the like because a large amount of by-products which are not visible to UV are generated after the reaction, and an intermediate of ezetimibe having a satisfactory purity can not be obtained.

Accordingly, an object of the present invention is to provide a method for producing an intermediate used in the production of ezetimibe at a low cost and in a high purity as compared with the conventional method.

In order to accomplish the above object, the present invention provides a process for preparing a compound represented by the following formula (4), which comprises asymmetrically reducing a compound represented by the following formula (3) using a compound represented by the following formula (2) and a metal salt hydride :

In this formula,

Ph is a phenyl radical,

X is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, halogen or nitro radical.

 According to the method of the present invention, intermediates used for the production of ezetimibe capable of inhibiting cholesterol absorption can be produced at a low cost and high purity as compared with the conventional method.

The method for producing the compound of Chemical Formula 4 used as an intermediate of the ezetimibe according to the present invention is characterized in that the compound of Chemical Formula 3 is asymmetrically reduced using the compound of Formula 2 (TarB-X) and the metal bromide hydride.

The reaction for preparing the compound of formula 4 of the present invention can be carried out as shown in Scheme 2 below:

In this formula,

Ph is a phenyl radical,

X is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, halogen or nitro radical and is preferably hydrogen, 2-nitro, 2-fluoro, 2-trifluoromethoxy , 2-methyl, 2-methoxy, 3-nitro, 3-fluoro, 3- trifluoromethoxy, 3- methyl, 3- methoxy, Methoxy, 4-methyl, 4-methoxy or 4-tert-butyl radical and most preferably hydrogen, 3-nitro, 2-nitro, 3-fluoro or 3-methoxy.

The compound of formula (2), which acts as a chiral Lewis acid, can be prepared using a known method (see Tetrahedron Letters, 2002 , 43 , p3649-3652), for example, Similarly, a boronic acid compound substituted with X of formula (5) can be obtained by reacting a boronic acid compound of formula (5) with a (D) -tartaric acid compound of formula (6) in the presence of a metal hydride:

Wherein X is as defined above.

The metal hydride used in the reaction is preferably calcium hydride, and the reaction is preferably carried out in a temperature range of 40 to 80 DEG C in a solvent selected from, for example, tetrahydrofuran or diethyl ether.

The compound of Formula 2 prepared by the above process may be used in an amount of 1 to 5 molar equivalents, preferably 1.5 to 2.5 molar equivalents based on 1 mol of the compound of Formula 3.

Examples of the metal hydride used in the present invention include lithium borohydride, sodium borohydride or potassium borohydride, preferably sodium borohydride. The metal hydride may be used in an amount of 1 to 3 molar equivalents, preferably 2 molar equivalents based on 1 mol of the compound of the formula (3).

The asymmetric reduction of the present invention can be carried out in an organic solvent in a temperature range of 10 ° C to 50 ° C, preferably 20 ° C to 25 ° C, wherein the organic solvent used is tetrahydrofuran, diethyl ether, Mixtures are preferred.

The compound of Formula 4, which is an intermediate of the ezetimibe produced according to the preparation method of the present invention, can be easily recovered after the reaction and can be produced at a high purity at a lower cost than the conventional method.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Example

Example 1 : Preparation of 3 - [(5S) -5- (4-fluorophenyl) -5-hydroxy-1-oxopentyl] -4-phenyl-2-oxazolidinone

0.94 g (5.6 mmol) of 3-nitrophenylboronic acid, 1.65 g (11 mmol) of (R) -tartaric acid and 0.94 g (23 mmol) of calcium hydride were charged into the flask and purged with nitrogen. 10 ml of anhydrous tetrahydrofuran solvent was added thereto, and the mixture was heated under reflux for 1 hour. The temperature of the reaction was lowered to room temperature, and the reaction product was filtered to obtain a solution of TarB-X (X = 3-NO ₂ , compound of formula (II)).

(5.63 mmol) of 3- [5- (4-fluorophenyl) -1,5-dioxopentyl] -4-phenyl-2-oxazolidinone (compound of Formula 3) was dissolved in anhydrous tetrahydrofuran And then the solution was slowly and carefully dropped into the solution of TarB-X (X = 3-NO ₂ , compound of formula (II)) in nitrogen. After the mixture was stirred at room temperature for 30 minutes, lithium borohydride (11.3 mmol) was slowly added dropwise to the mixture with gentle stirring for 10 minutes and stirred for 30 minutes. To the reaction mixture, 5 ml of water and 3 ml of 6N hydrochloric acid were slowly added dropwise to terminate the reaction, and triethylamine was slowly added dropwise until the pH reached 9 or higher. The water layer was extracted with ethyl acetate and washed with saturated brine. The obtained organic substance was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by distillation under reduced pressure to obtain 1.93 g of the title compound having the purity and yield shown in the following Table 1.

_{^{1 H NMR (300MHz, CDCl 3}} ): δ 7.38~7.26 (7H, m), 7.00 (2H, t), 5.40 (1H, dd), 4.71~4.55 (2H, m), 4.27 (1H, dd), 2.95 (2H, t), 1.72-1.56 (4H, m).

Examples 2 to 5

The compound of formula (IV) having the purity and yield shown in the following Table 1 was obtained in the same manner as in Example 1 using TarB-X (compound of formula (2)) and reducing agent shown in the following Table 1.

Example X substituent (TarB-X) reducing agent ee% yield(%) One 3-NO ₂ LiBH ₄ 98.8 96 2 3-NO ₂ NaBH ₄ 98.7 95 3 3-NO ₂ KBH ₄ 97.0 95 4 3-F NaBH ₄ 91.4 93 5 H NaBH ₄ 92.1 95

As can be seen from the above Table 1, the asymmetric reduction reaction was carried out using the TarB-X compound of Chemical Formula 2 and the metal bromide to produce an intermediate of ezetimibe, which is economical and has a high purity An intermediate of thymine can be obtained.

Claims (10)

A process for preparing a compound represented by the following formula (4), which comprises asymmetrically reducing a compound represented by the following formula (3) using a compound represented by the following formula (2) and a metal salt hydride: (2)

(3)

≪ Formula 4 >

In this formula, Ph is a phenyl radical, X is hydrogen, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, halogen or nitro radical. The method according to claim 1, Wherein X is selected from the group consisting of hydrogen, 2-nitro, 2-fluoro, 2-trifluoromethoxy, 2-methyl, 2-methoxy, 3-nitro, 3-fluoro, 3- trifluoromethoxy , 3-methyl, 3-methoxy, 4-nitro, 4-fluoro, 4-trifluoromethoxy, 4-methyl, 4-methoxy or 4-tert-butyl radical. 3. The method of claim 2, Wherein X is hydrogen, 3-nitro, 2-nitro, 3-fluoro or 3-methoxy. The method according to claim 1, Wherein the compound of formula 2 is obtained by reacting a compound of formula 5 with a compound of formula 6 in the presence of a metal hydride. (2)

≪ Formula 5 >

(6)

Wherein X is as defined in claim 1. 5. The method of claim 4, Wherein the metal hydride is calcium hydride. The method according to claim 1, Wherein the compound of formula (2) is used in an amount of 1 to 5 molar equivalents based on 1 mol of the compound of formula (3). The method according to claim 1, Wherein the metal hydride is lithium borohydride, sodium borohydride or potassium borohydride. The method according to claim 1, Wherein the metal hydride is used in an amount of 1 to 3 molar equivalents based on 1 mol of the compound of the formula (III). The method according to claim 1, Wherein said asymmetric reduction is carried out in an organic solvent at a temperature ranging from 10 캜 to 50 캜. 10. The method of claim 9, Wherein the organic solvent is tetrahydrofuran, diethyl ether or a mixture thereof.