KR20140107770A - Novel Intermediate of L-Cloperastine and Preparation Method Thereof - Google Patents

Abstract

The present invention relates to a novel intermediate of L-cloperastine, which is a pharmaceutically useful enantiomer, and to a preparing method thereof and, more specifically, to a stereoselective preparing method using an intermediate and enzyme of L-cloperastine having the structure of chemical formula 1. In chemical formula 1, here, R is alkyl group of C1 to C3.

Description

Novel Intermediate of L-Cloperastine and Preparation Method Thereof "

The present invention relates to a novel intermediate of L-cloperastine, a pharmaceutically useful enantiomer, and a process for its preparation.

L-Cloerastine (R) -1- [2- (4-chlorophenyl) -phenyl-methoxy] ethyl] piperidine is a diphenhydramine series central chelator that is an H1-receptor antagonist. It selectively acts directly on the cough center without affecting the afferent and efferent central nervous system, suppresses the cough, and exhibits the vinegar effect.

(2)

For many drugs, it has been found that the two enantiomers have the same biological activity but different degrees of quantitative activity. In addition, cloferastine also exhibits about three times as much therapeutic effect as D-cloferastine when compared with D-clopherastine. When administered in a normal amount, side effects (drowsiness) and adverse effects (excitement) Is significantly less. Therefore, since L-clopherastine alone can be used as a more effective therapeutic agent when administered in the form of a racemic mixture of D-and L-clopherastine at a ratio of 50:50, Several methods for the selective preparation of clopherastine have been developed. L-cloferastine can be easily prepared from (R) -4-chlorobenzhydrol (II) which is a chiral alcohol compound by the following reaction formula, The development of a selective method for the production of chlorobenzhydrol is a key factor in the synthesis of L-clerferastine.

Reaction formula

References [J. Organic Chemistry. vol 69, p3997 (2004) discloses a process for producing (R) -4-chlorobenzhydrol using a chiral ferrocene catalyst, which is described in Organic Letters. (R) -4-chlorobenzhydrol by reacting S - ((1R, 2S) -1-phenyl-2-piperidin- . However, the above-mentioned method using a metal catalyst or chiral oxysulfurate is not suitable for commercial production because it requires a special catalyst such as an expensive catalyst, or a special reaction facility such as avoiding contact with air.

EP 385491 describes a process for purifying (R) -4-chlorobenzhydrol from racemic 4-chlorobenzhydrol. Namely, 4-chlorobenzhydrol-phthalate was prepared by reacting racemic 4-chlorobenzhydrol with anhydrous phthalic acid, followed by recrystallization from brucine or (-) - 1-phenylethylamine salt to obtain each isomer . The salt of the separated (R) -isomer is converted to (R) -4-chlorobenzhydrol by hydrolysis. In addition to the problem of using expensive brucine or (-) - 1-phenylethylamine as a method of separating the salt of the (R) -isomer from the racemic mixture of the salt by recrystallization, In order to obtain an isomeric salt, it is necessary to recrystallize it several times, so the yield is low and the process is complicated, which is not suitable for mass production.

EP 894794 describes the preparation of racemic 4-chlorobenzhydrol-hemisuccinate by reacting racemic 4-chlorobenzhydrol with succinic anhydride and converting it into quinine Followed by recrystallization to separate the (R) -isomeric salt. The salt of the (R) -isomer is converted to (R) -4-chlorobenzhydrol by hydrolysis. This method has a higher purity of the final product and yield of each reaction process than the European Patent No. 385491. However, there is still a problem that expensive quinine should be used, recrystallization must be repeated many times, and the process is complicated.

Recently, many attempts have been made to resolve racemic mixtures using enzymes. However, the resolution by enzymes depends not only on the type of enzyme but also on the chemical structure of the enzyme substrate, so that the optical purity of the result varies depending on the type of alcohol and the type of enzyme, and the ee (enantiomeric excess) value Also vary from 0 to 100%. For example, U.S. Patent No. 5,928,933 discloses a method for resolving racemic N- (alkoxycarbonyl) -4-keto-D, L-proline alkyl ester using 44 enzymes (lipase, protease, esterase) , Only one kind of enzyme showed 95%% value, and the other enzymes did not react at all or substrate specificity was low. The enzyme-based resolution is advantageous in purification efficiency and purity since the reaction process is shorter than the resolution using the salt of the prior art, and the purification is based on the difference in reactivity, not the difference in solubility. However, Methods for resolving (R) -4-chlorobenzhydrol from chlorobenzhydrol are not yet known.

European Patent No. 385491 European Patent No. 894794 U.S. Patent No. 5,928,933 Patent No. 10-458560

J. Organic Chemistry. vol. 69, p3997 (2004) Organic Letters. vol10, p1235 (2008)

The present invention aims to provide a novel intermediate for the synthesis of L-clopherastine in order to solve the above problems.

It is still another object of the present invention to provide a method for selectively producing the intermediate from racemic 4-chlorobenzhydrol using an enzyme.

In order to accomplish the above object, the present invention relates to an intermediate of L-clopherastine having a structure represented by the following formula (1).

Formula 1

, 이때, R은 C1~C3의 알킬기이다.

, Wherein R is a C1 to C3 alkyl group.

The compound can be stereoselectively prepared by reacting racemic 4-chlorobenzhydrol with RC (= O) O-CH = CH2 by lipase or protease. The reaction may be carried out in the presence of a solvent such as a saturated hydrocarbon such as pentane, hexane, heptane, octane or decane, an ether such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran or 1,4-dioxane, Dichloroethane, carbon tetrachloride, chlorocarbons such as chloroform, and aromatic solvents such as benzene, toluene, p-xylene, o-xylene and m-xylene. According to the preliminary experiment, the stereoselectivity was slightly changed depending on the solvent, but the variation was not large. As can be seen from the examples, the desired reaction could not be obtained in the case of estera, and the stereoselectivity of candida antacidica lipase A and Candida lucosa lipase was excellent in lipase or protease. The stereoselectivity of the esterification reaction in the examples was confirmed by chiral HPLC and the stereostructure of the (R) -, (S) -ester was prepared by reacting the hydrolyzate of the ester produced with (R) or (S) Benzhydrol standards and chiral HPLC.

Using the compound of formula (1) according to the present invention, (A) hydrolyzing the compound of formula (1) to prepare (R) -4-chlorobenzhydrol; (B) Coupling of (R) -4-chlorobenzhydrol with N- (2-chloroethyl) piperidine to produce L-clopherastine can be used to prepare L- have. The hydrolysis of step (A) can be carried out by a conventional hydrolysis method of an ester, and the production of L-clopherastine of step (B) can also be carried out by a method known from the prior art such as Patent No. 10-458560 . As can be seen from the following examples, 4-chlorobenzhydrol prepared from the compound 1 of the present invention which is 90 ee% can be easily purified with 98 e% of the (e)% of (R) by only one recrystallization Respectively.

Since the (R) -type and (S) -type 4-chlorobenzhydrols exist in the racemic mixture at 50:50, if only the (R) -type ester is reacted by the enzyme reaction according to the present invention, the maximum conversion rate 50%. The remaining (S) -4-chlorobenzhydrol is obtained by reversing the stereochemistry of (R) -4-chlorobenzhydrolone by the method described in Patent No. 10-458560 and then used in the production of L-chloroperastine .

As described above, by using an intermediate which can be produced stereoselectively and in high yield from racemic 4-chlorobenzhydrol in a high yield and environmentally friendly manner, L-chloroperastine can be efficiently produced by a simpler process .

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the drawings and the embodiments are only illustrative of the contents and scope of the technical idea of the present invention, and the technical scope of the present invention is not limited or changed. It will be apparent to those skilled in the art that various changes and modifications can be made within the scope of the technical idea of the present invention based on these examples.

Example 1: Determination of stereospecificity of enzyme for esterification reaction

1) Esterification reaction with vinyl acetate

5% by weight of 4-chlorobenzhydrol (Aldrich), 20% by weight of vinyl acetate (Aldrich) and 1% by weight of enzyme (Roche or Aldrich) were added to 1 ml of 1,4-dioxane, And reacted at 30 ° C for 14 hours. After completion of the reaction, 30 μl of the reaction solution was diluted with 300 μl of ethanol, filtered, and analyzed by chiral HPLC (Chiral HPLC). The results are shown in Table 1 below. HPLC was carried out using a Kromasil 100-10-TBB, and the mobile phase of hexane: isopropanol (99: 1) mixture was flowed at a flow rate of 0.8 ml / min and detected with a UV detector set at 254 nm.

2) Esterification reaction with vinyl propionate

The reaction and analysis were carried out in the same manner as in 1) except that vinyl propionate (Aldrich) was used instead of vinyl acetate. Candida antacidica lipase A was used as an enzyme. As a result, 92% ee of R-4-chlorobenzhydrol-propionate was obtained as a reaction product, and the conversion efficiency was 48%.

Example 2 Synthesis of L-Cloferastine

1) Preparation of R-4-chlorobenzhydrol-acetate

20% by weight of 4-chlorobenzhydrol, 40% by weight of vinyl acetate and 0.2% by weight of Candida antacidica lipase A were placed in 200 ml of toluene and reacted for 20 hours while maintaining the temperature at 10 ° C. Analysis of the reaction mixture by chiral Echipiel revealed that it contained 90% ee R-4-chlorobenzhydryl-acetate and 98% ee S-4-chlorobenzhydrol (conversion efficiency 52%). The reaction solution was filtered to recover the enzyme, and the filtrate was distilled under reduced pressure to recover 42 g of concentrated residue. The concentrated residue was dissolved in ethyl acetate and purified by silica gel column chromatography (ethyl acetate: hexane 1: 4 (v / v)) to recover 24 g of 90% ee R-4-chlorobenzhydrylacetate.

2) Preparation of R-4-chlorobenzhydrolone

4 g of R-4-chlorobenzhydrol-acetate obtained in 1) was dissolved in 40 ml of ethanol. A solution of 8 g of sodium hydroxide in 20 ml of distilled water was added thereto, followed by stirring at room temperature for 3 hours. 20 ml of distilled water was further added, followed by extraction twice with an equal volume of ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered, and the organic solvent was concentrated to obtain 20 g of concentrated residue. The residue was recrystallized in 800 ml of hexane to prepare 18 g of R-4-chlorobenzhydrol (98% ee).

3) Preparation of L-chloroperastine

16 g of the R-chlorobenzhydrol prepared in 2) was dissolved in 100 ml of dichloromethane, 27 g of N- (2-chloroethyl) piperidine hydrochloride (Aldrich) and 0.5 g of sodium iodide (NaI) 1 g of butylammonium bromide and 50 ml of a 30% sodium hydroxide solution were added and the mixture was stirred at 25 占 폚 for 12 hours. After confirming that the reaction was completed with TLC (ethyl acetate: hexane 1: 1 (v / v)), distilled water was added and the layer was separated. The aqueous layer was extracted once more with dichloromethane, the organic layers were combined, dried over magnesium sulfate and filtered. The dried organic layer was distilled under reduced pressure to remove the organic layer and unreacted N- (2-chloroethyl) piperidine, and 21 g of L-chloroperastine was prepared (98% ee).

Claims (4)

A compound having the structure of the following formula (1), which is an intermediate of L-clopherastine.
Formula 1

, Wherein R is a C1 to C3 alkyl group.
Characterized in that the racemic 4-chlorobenzhydrol and RC (= O) O-CH = CH2 are stereoselectively prepared by reacting with lipase or protease.
3. The method of claim 2,
Wherein the lipase or protease is candida antacidica lipase A or Candida lucosa lipase.
(A) hydrolyzing the compound of formula (I) to produce (R) -4-chlorobenzhydrol;
(B) coupling of (R) -4-chlorobenzhydrol with N- (2-chloroethyl) piperidine to prepare L-chloroperastine;
≪ / RTI >