KR20160116933A - Method for the preparation of Ezetimibe - Google Patents

Abstract

Provided is a manufacturing method of ezetimibe using a novel intermediate product, an isomer thereof, or salts thereof. According to the present invention, the ezetimibe, an isomer thereof, or salts thereof can be produced at a high yield without using an expensive catalyst under moderate reaction conditions. Thus, ezetimibe, an isomer thereof, or salts thereof, can be cost-effectively and efficiently produced in a large quantity.

Description

The present invention relates to a method for preparing ezetimibe,

The present invention relates to a method for producing ezetimibe.

The ezetimibe represented by the following formula (a) is an azetidinone derivative,

It is marketed by Merck / Schering-Plow Pharmaceuticals under the trade name Igrotrol® and approved by the US Food and Drug Administration for use in patients with hypercholesterolemia to reduce LDL cholesterol and total cholesterol. It is also commercially available as a combination with a statin drug that inhibits cholesterol synthesis in the liver.

(A)

Various methods for the preparation of ezetimibe are known, and representative methods of manufacture are described in U.S. Patent No. 6,207,822, International Patent Publication No. 2007/072088 and International Patent Publication No. 2007/120824, U.S. Patent No. 5,856,473 Lt; / RTI >

The method of U.S. Patent No. 6,207,822 can be represented by the following reaction formula A. According to this method, compound f is prepared by asymmetrically reducing compound e under (R) -methyl CBS oxaborolidine catalyst, and the obtained compound f is protected simultaneously with imine compound g, h and reacting the compound h with tetrabutylammonium fluoride / N, O-bis (trimethylsilyl) acetamide to prepare a betalactam compound i, from which an ezetimibe is prepared. However, as a result of conducting the reproducibility test in Korean Patent No. 10-1156588, it has been found that, in the step of adding the acid in the step of producing the compound h, 10 to 20% of the product h as the product is returned to the compound f And it is disadvantageous in that the production cost is high and the process is long in mass production by using expensive asymmetric reducing agent.

[Reaction Scheme A]

The method of WO 2007/072088 and WO 2007/120824 can be represented by the following reaction scheme B, and according to the above method, a method of preparing an ezetimibe by introducing a ketal protecting group from a ketone, There is a disadvantage that the deprotection is not easy and the working days due to the protective process are prolonged. Further, there is a problem in that an asymmetric reduction from compound i-2 to compound i-3 uses an expensive metal catalyst.

[Scheme B]

In the above reaction formula, R1, R2 and R3 are independently -H, phenyl, methyl or isopropyl, and R4 is a silyl group such as tert-butyl-dimethyl-silyl, Butyl-dipheyl-silyl group, and the like.

The process of U.S. Patent No. 5,856,473 can be represented by the following reaction scheme C, and according to the above method, it is necessary to carry out the reaction at a very low temperature of -78 ° C in order to prepare the compound m, And the compound p can not be crystallized. Therefore, it is difficult to purify only by means of column chromatography.

[Scheme C]

In the above reaction scheme B, Bn represents a benzyl group.

As described above, the production method of ezetimibe known so far has a high production cost by using an expensive catalyst, a long manufacturing process by introducing a protecting group, difficulty in production application due to cryogenic temperature and hydrogen reaction, Is lowered. Therefore, there is a demand for development of a method for manufacturing and industrializing ezetimibe through a simpler and more economical process.

U.S. Patent No. 6,207,822 International Patent Publication No. 2007/072088 International Patent Publication No. 2007/120824 U.S. Patent No. 5,856,473

The present invention provides a novel method for producing ezetimibe, an isomer thereof, or a salt thereof.

The present invention

Reacting a compound represented by the formula (I) and a compound represented by the following formula (II) or an isomer thereof to prepare a compound represented by the formula (III) or an isomer thereof; And

There is provided a process for producing an ezetimibe, an isomer thereof or a salt thereof, which comprises the step of producing a compound represented by the formula (IV) or an isomer thereof from the compound represented by the above formula (III) or an isomer thereof.

(I)

≪ RTI ID = 0.0 &

(III)

(IV)

Ac in the formulas (I) to (IV) represents an acetyl group.

The process of the present invention does not require the use of expensive catalysts, does not involve severe reaction conditions such as cryogenic temperatures and does not require a severe reaction condition such as a hydrogen reaction, has a high reaction yield and is excellent in ezetimibe, Or salts thereof can be economically and effectively mass produced.

In the present invention, the compound represented by Formula (III) or an isomer thereof is prepared by reacting the compound represented by Formula (I) and Formula (II) or an isomer thereof.

In the present invention, the step of preparing the compound represented by the formula (III) or an isomer thereof may be carried out in the presence of a Lewis acid, and the Lewis acid may be titanium tetrachloride, titanium isopropoxide, For example, titanium tetrachloride.

In the present invention, the step of preparing the compound represented by the above formula (III) or its isomer can be carried out at -40 ° C to 0 ° C, preferably at -25 ° C to -15 ° C.

In the present invention, the step of preparing the compound represented by the formula (III) or an isomer thereof may be carried out in the presence of a solvent, and the solvent may be dichloromethane, chloroform, tetrahydrofuran, toluene, Lt; RTI ID = 0.0 > dichloromethane. ≪ / RTI >

In the present invention, the step of preparing the compound represented by the above formula (III) or an isomer thereof may be carried out in the presence of a base. The base may be diisopropylethylamine (DIPEA) or triethylamine (TEA), preferably diisopropylethylamine.

In the present invention, a compound represented by the above formula (IV) is prepared from the compound represented by the above formula (III) or an isomer thereof. The compound represented by the formula (III) or an isomer thereof may be reacted under a cyclization catalyst promoting cyclization to prepare a compound represented by the formula (IV) or an isomer thereof.

In the present invention, in the step of producing the compound represented by the above formula (IV) or an isomer thereof, the cyclization catalyst may be tetrabutylammonium fluoride or a hydrate thereof.

In the present invention, the step of preparing the compound represented by the formula (IV) or an isomer thereof may be carried out in the presence of a base. The base may be a base containing a nitrogen atom, and preferably bis (trimethylsilyl) acetamide (BSA).

In the present invention, the step of preparing the compound represented by the formula (IV) or an isomer thereof may be carried out in the presence of both a cyclization catalyst and a base, preferably tetrabutylammonium fluoride or a hydrate thereof and bis Silyl) acetamide. ≪ / RTI >

In the present invention, the step of preparing the compound represented by the formula (IV) or an isomer thereof may be carried out in the presence of a solvent, and the solvent may be toluene, tetrahydrofuran, ethyl acetate or a mixture thereof, May be toluene.

In the present invention, the step of preparing the compound represented by the formula (IV) or the isomer thereof may be carried out at 25 ° C to 100 ° C, preferably 45 ° C to 70 ° C.

In the present invention, the isomers refer to all kinds of isomers, and preferably include stereoisomers such as diastereomers or enantiomers. Also, when the isomer is an enantiomer, it includes not only each enantiomer but also racemates in which the enantiomers are mixed.

In the present invention, the salt is a salt commonly used in the pharmaceutical industry, and may be an inorganic acid salt, an organic acid salt, a sulfonic acid salt, an amino acid salt or an amine salt. For example, the salt may be an inorganic acid salt prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid or sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid Gluconic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanilicic acid, mandelic acid, mucic acid, fucic acid, glutaric acid, malic acid, Sulfonic acid salts such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid or naphthalenesulfonic acid, glycine, arginine or the like, Lysine or the like, or an amine salt prepared by using trimethylamine, triethylamine, ammonia, pyridine, picoline or the like. However, Quot; is not limited to a specific kind of salt.

In the present invention, the method for preparing the ezetimibe, the isomer thereof or the salt thereof may further include a step of deacylating the compound represented by the formula (IV) or an isomer thereof. Ethersitiv, isomers thereof, or salts thereof may be prepared by carrying out a deacylation reaction of the compound of formula (IV) or its isomer.

In the present invention, the deacylation reaction of the compound represented by the formula (IV) or an isomer thereof may be carried out in the presence of a solvent, and the solvent may be an alcohol, toluene, ethyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, Or a mixture thereof, preferably C1 to C4 alcohols, and more preferably ethanol.

In the present invention, the deacylation reaction can be carried out by adding an acid or a base, preferably an acid. The acid may be hydrochloric acid, sulfuric acid, nitric acid or a mixture thereof, preferably sulfuric acid and may be added in the form of an aqueous solution.

In the present invention, the deacylation reaction can be carried out at about 0 ° C to 80 ° C, preferably at 25 ° C to 60 ° C.

For example, the process for preparing ezetimibe according to the present invention can be represented by the following reaction scheme I:

[Reaction Scheme I]

In the scheme I, Ac represents an acetyl group.

In the present invention, the compound represented by the above formula (I) can be produced by a method of acetylating a compound represented by the above formula (V).

(V)

In the present invention, the compound represented by formula (I) may be prepared by reacting the compound represented by formula (V) with acetyl chloride, acetyl bromide, acetic anhydride or a mixture thereof, preferably with acetyl chloride .

In the present invention, the preparation of the compound of formula (I) may be carried out in the presence of a solvent, which may be ethyl acetate, dichloromethane, chloroform, toluene or a mixture thereof, preferably dichloromethane .

In the present invention, the preparation of the compound represented by the above formula (I) may be carried out in the presence of a base, and the base may be triethylamine, diisopropylethylamine, pyridine or a mixture thereof, Ethylamine or diisopropylethylamine.

In the present invention, the preparation of the compound represented by the above formula (I) can be carried out at about -10 ° C to 25 ° C, preferably about -10 ° C to 5 ° C.

For example, the process for preparing the compound of formula (I) according to the present invention can be represented by the following reaction formula (II).

[Reaction Scheme II]

In the above Reaction Scheme II, Ac represents an acetyl group.

In the present invention, the compound represented by the formula (II) or an isomer thereof may be prepared from a compound represented by the following formula (VI) or an isomer thereof and acetylation of the compound represented by the formula (VI) A compound to be displayed or an isomer thereof can be produced.

(VI)

In the present invention, the compound represented by the formula (II) or an isomer thereof may be prepared by reacting a compound represented by the formula (VI) or a isomer thereof, preferably reacted with acetyl chloride to obtain a compound represented by the formula (VI), acetyl chloride, acetyl bromide, Acetic anhydride or mixtures thereof.

In the present invention, the compound represented by the formula (II) or an isomer thereof may be carried out in the presence of a solvent, and the solvent may be ethyl acetate, dichloromethane, chloroform, toluene or a mixture thereof, Dichloromethane.

In the present invention, the preparation of the compound represented by the formula (II) or an isomer thereof may be carried out in the presence of a base, and the base may be triethylamine, diisopropylethylamine, pyridine or a mixture thereof, May be diisopropylethylamine.

In the present invention, the preparation of the compound represented by the above formula (II) or an isomer thereof can be carried out in the presence of a catalyst. If the preparation of the compound of formula (II) or the isomer thereof is carried out in the presence of a catalyst, the reaction rate may be increased and the yield may be improved. The catalyst may be dimethylaminopyridine (DMAP). For example, the reaction rate of the step of preparing the compound represented by the formula (II) can be improved by adding the dimethylaminopyridine to a solution containing the compound represented by the formula (VI), the base and the acetyl chloride.

In the present invention, the preparation of the compound represented by the formula (II) or an isomer thereof can be carried out at about -10 ° C to 60 ° C, preferably about 25 ° C to 45 ° C.

For example, the process for preparing the compound of formula (II) according to the present invention may be represented by the following reaction formula (III).

[Reaction Scheme III]

The present invention relates to a process for producing ezetimibe, an isomer thereof or a salt thereof using an acetyl group-protected intermediate, and the process is simple and can be effectively used for mass production applications for industrialization.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following examples should not be construed as limiting the scope of the present invention, but should be construed to facilitate understanding of the present invention.

The reagents and solvents mentioned below were purchased from Sigma-Aldrich Corp. and Purified Gold Co., unless otherwise noted, and ¹ H-NMR was measured with BRUKER AVANCE III 400.

≪ Preparation Example 1 &

Acetic acid 4 - [(4-fluorophenylimino) -methyl] -phenyl ester (compound of formula I)

10 g (46.5 mmol) of 4 - [(4-fluorophenylimino) -methyl] -phenol was introduced into a round bottom flask and 50 ml of dichloromethane was introduced. After 16.2 ml of diisopropylethylamine was poured, it was cooled to 5 캜. 3.5 ml of acetyl chloride was slowly added dropwise thereto, followed by cooling and stirring for 1 hour to prepare a reaction mixture. 50 ml of water was poured into the reaction mixture to separate the organic layer, and the organic layer was washed with 30 ml of saturated brine. After washing, the organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a solid compound. The resulting solid compound was dissolved in 20 mL of ethyl acetate to dissolve the solid compound, and 60 mL of n-hexane was added dropwise to crystallize to obtain 8.2 g (yield: 68.9%) of the title compound as a white solid.

¹ H-NMR (CDCl ₃ , 400 MHz, ppm)? 2.35 (3H, s), 7.05-7.15 (2H, m) 7.18-7.25 (4H, m), 7.90-7.95 , s)

≪ Preparation Example 2 &

 Synthesis of (4S) -3 - [(5S) -5- (4-fluorophenyl) -5-acetyloxy- 1 -oxopentyl] -4-phenyl-2-oxazolidinone

A round bottom flask was charged with 10 g of (4S) -3 - [(5S) -5- (4-fluorophenyl) -5-hydroxy-1-oxopentyl] -4-phenyl-2-oxazolidinone imidazole 28.0 mmol) and 50 ml of dichloromethane (MC). After 9.75 ml of diisopropylethylamine (DIPEA) was injected, 2.7 ml of acetyl chloride (AcCl) was added dropwise. After the temperature was raised to 45 캜, 0.1 g of methylaminopyridine (DMAP) was added, and the mixture was stirred for 1 hour to prepare a reaction mixture. 50 ml of water was poured into the reaction mixture, and the organic layer was separated and washed with saturated brine. After washing, the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 10.9 g (97.4%) of the title compound represented by the above formula on an oil phase.

_{^{1 H-NMR (CDCl 3,}} 400 MHz, ppm) δ 1.5-2.0 (4H, m), 2.05 (3H, s), 2.95 (2H, m), 4.3 (1H, dd), 4.7 (1H, t) , 5.4 (1H, dd), 5.7 (1H, dd), 7.0 (2H, m), 7.2-7.5 (7H,

≪ Example 1 >

(4S) -3 - {(5S) -5- (4-fluorophenyl) -5-acetyloxy- 1 -oxopentyl} -2 - {(S) -4-fluorophenylaminomethyl) - 4-acetyloxyphenyl)}] - 4-phenyl-2-oxazolidinone (compound of formula III)

To a solution of 2.08 g of acetic acid 4 - [(4-fluorophenylimino) -methyl] -phenyl ester synthesized in Preparation Example 1 and Preparation Example 2 and 2.08 g of (4S) -3 - [(5S) -5- Phenyl) -5-acetyloxy-1-oxopentyl] -4-phenyl-2-oxazolidinone was introduced into a round bottom flask and 30 ml of dichloromethane was introduced. After 2.4 ml of diisopropylethylamine (DIPEA) was poured, the mixture was cooled to -30 占 폚 and stirred for 0.5 hour. 11 ml of 1 mol of titanium tetrachloride (dichloromethane solution) was slowly added dropwise over 20 minutes, followed by cooling and stirring for 5 hours to prepare a reaction mixture. After 2 ml of acetic acid was added dropwise, 50 ml of water was slowly added thereto to separate the organic layer. The separated organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a solid. The solid phase was dissolved in dichloromethane to form a solution. A small amount of silica gel was added to the solution, and the mixture was concentrated under reduced pressure to adsorb the compound on silica gel. The compound adsorbed on the silica gel was loaded on a silica gel column packed with n-hexane and packed with a mixed solvent of n-hexane / ethyl acetate = 3: 1, followed by silica gel column chromatography (silica gel 60 (230-400 mesh ASTM , Merck) was performed to obtain a solution of the desired fraction. The solid obtained by concentrating the solution under reduced pressure was dissolved in 5 mL of ethyl acetate to dissolve the solid, and 20 mL of n-hexane was added dropwise to crystallize, (31.8%) of the title compound.

_{^{1 H-NMR (CDCl 3,}} 400 MHz, ppm) δ 1.6-1.9 (4H, m), 1.99 (3H, s), 2.28 (3H, m), 4.22 (1H, m), 4.33 (1H, m) (1H, m), 4.6 (1H, m), 4.8 (1H, m), 4.95 , m)

≪ Example 2 >

3- (4-fluorophenyl) -3-acetyloxy)} - 4-oxoazetidine Di-2-yl] -phenol (compound of formula IV)

(4S) -3 - [{(5S) -5- (4-fluorophenyl) -5-acetyloxy- 1 -oxopentyl} -2 - {(S) -4- Phenylamino) - (4-acetyloxyphenyl)}] - 4-phenyl-2-oxazolidinone was introduced into a round bottom flask and 15 ml of toluene (Tol) was introduced. 0.55 ml of N, O-bistrimethylsilyl acetamide (BSA) was added, and the mixture was stirred for 0.5 hour. The reaction mixture was stirred for 12 hours by injecting tetrabutylammonium fluoride trihydrate (TBAF · 3H ₂ O) 17.5mg and the temperature was raised to 60 ℃ was prepared. After 0.5 ml of methanol was poured into the reaction mixture, 30 ml of water and 30 ml of ethyl acetate were injected to separate the organic layer. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give a solid. The solid phase was dissolved in dichloromethane to form a solution. A small amount of silica gel was added to the solution, and the mixture was concentrated under reduced pressure to adsorb the compound on silica gel. The compound adsorbed on the silica gel was loaded on a silica gel column packed with n-hexane and packed with a mixed solvent of n-hexane / ethyl acetate = 5: 1 to 3: 1, followed by silica gel column chromatography (Silica gel 60 -400 mesh ASTM, Merck) to obtain 0.28 g (56.0%) of a solid compound represented by the above formula in the form of a foam.

_{^{1 H-NMR (CDCl 3,}} 400 MHz, ppm) δ 1.7-2.2 (4H, m), 2.05 (3H, s), 3.05 (1H, t), 4.55 (1H, d), 5.7 (1H, t) , 6.8-7.3 (12H, m)

≪ Example 3 >

Synthesis of Ezetimibe

30 mg of the azetidine compound synthesized in Example 2 was injected into a round bottom flask, and 2 ml of ethanol was injected. Sulfuric acid aqueous solution, and the mixture was stirred at 70 占 폚 for 12 hours to prepare a reaction mixture. The organic layer was separated by injecting water and ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain crude ezetimibe.

¹ H-NMR (CDCl ₃ , 400 MHz, ppm)? 1.7-2.2 (4H, m), 3.05 (1H, t), 4.55 m)

Claims (13)

Reacting a compound represented by the formula (I) and a compound represented by the following formula (II) or an isomer thereof to prepare a compound represented by the formula (III) or an isomer thereof; And
A process for producing an ezetimibe, an isomer thereof or a salt thereof, comprising the step of producing a compound represented by the formula (IV) or an isomer thereof from the compound represented by the formula (III) or an isomer thereof.
(I)

≪ RTI ID = 0.0 &

(III)

(IV)

The method according to claim 1, wherein the step of preparing the compound represented by the formula (III) or an isomer thereof is carried out in the presence of a Lewis acid, an isomer thereof or a salt thereof. 3. The method of claim 2, wherein the Lewis acid is titanium tetrachloride, titanium isopropoxide, or a mixture thereof, or an isomer thereof or a salt thereof. The method according to claim 1, wherein the step of preparing the compound represented by the formula (III) or an isomer thereof is carried out at a temperature of -40 ° C to 0 ° C, an isomer thereof or a salt thereof. The method according to claim 1, wherein the step of preparing the compound represented by the formula (IV) or the isomer thereof is carried out in the presence of tetrabutylammonium fluoride or a hydrate thereof, or an isomer thereof or a salt thereof Way. The method according to claim 1, wherein the step of preparing the compound represented by the formula (IV) or the isomer thereof is carried out at 25 ° C to 100 ° C, an isomer thereof or a salt thereof. The method according to claim 1, which further comprises performing a deacylation reaction on the compound represented by the general formula (IV) or an isomer thereof, wherein the isomer thereof, or a salt thereof. 8. The method according to claim 7, wherein the deacylation reaction is carried out by adding an acid to the compound represented by the formula (IV) or an isomer thereof, or an isomer thereof or a salt thereof. The method according to claim 1, wherein the compound represented by the formula (I) is prepared from a compound represented by the following formula (V), an isomer thereof or a salt thereof.
(V)

10. The compound of claim 9, wherein the compound of formula (I) is prepared by reacting the compound of formula (V) with one selected from the group consisting of acetyl chloride, acetyl bromide, acetic anhydride and mixtures thereof. , An isomer thereof, or a salt thereof. The method according to claim 1, wherein the compound represented by the formula (II) or an isomer thereof is prepared from a compound represented by the following formula (VI) or an isomer thereof, or an isomer thereof or a salt thereof.
(VI)

12. The compound of claim 11, wherein the compound of formula (II) or an isomer thereof is prepared by reacting the compound of formula (VI) with one selected from the group consisting of acetyl chloride, acetyl bromide, acetic anhydride, Ezetimibe, an isomer thereof or a salt thereof. 12. The method according to claim 11, wherein the preparation of the compound represented by the formula (II) or an isomer thereof is carried out in the presence of dimethylaminopyridine (DMAP), an isomer thereof or a salt thereof.