WO1989005298A1

WO1989005298A1 - Process for preparation of aryl substituted propionate derivatives

Info

Publication number: WO1989005298A1
Application number: PCT/AU1988/000458
Authority: WO
Inventors: Yik Man Fung; Matthew Gredley; William Roy Jackson; Barry Ross Matthews
Original assignee: Ici Australia Operations Proprietary Limited
Priority date: 1987-11-30
Filing date: 1988-11-25
Publication date: 1989-06-15

Abstract

A process for the preparation of a compound of formula (I) wherein Ar is selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl; R is a carboxylic acid or ester or a group capable of being converted to a carboxylic acid or ester group; R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl; and X is halogen; which process comprises reacting a compound of formula (III) wherein R2 is selected from the group consisting of alkyl, aryl, substituted alkyl and substituted aryl, with a compound of formula R3R4R5SiX wherein R3, R4, and R5 are independently chosen from alkyl and aryl.

Description

PROCESS FOR PREPARATION OF ARYL SUBSmITUTED PPOPIONATE DERIVATIVES

This invention relates to chiral aryl substituted propionate derivatives and to enantioselective processes for preparation thereof . In one aspect the invention relates to preparation of propionate derivatives of formula I .

wherein Ar is selected from the group of aryl, heteroaryl, substituted aryl and substituted heteroaryl; R is a carboxylic acid group or ester or a group capable of being converted to a carboxylic group or ester, R¹ is selected from hydrogen, alkyl substituted alkyl, aryl and substituted aryl, and X is halogen. Compounds of formula I are useful intermediates for preparation of biologically active compounds in which the stereochemistry of the final compound is controlled entirely or in part by the configuration of the chiral carbons (marked *). For example, Diltiazem, a benzothiazepine derivative which is well known as a vasodilator. is one of four possible optical isomers. There is a wide variation in biological activity between Diltiazem and its three related optical isomers, Diltiazem, being the isomer of commercial interest as a vasodilator. In a nonstereospecific synthesis of Diltiazem, the desired (2S,3S) isomer can be obtained in at most a 25% yield, and hence workers in the area have concentrated on stereoselective synthetic routes which require the intermediates such as the compound of formula I, to have a high optical purity.

We have now found a highly enantioselective process for preparation of compounds of formula I. In accordance with the invention we therefore provide an enantioselective process for preparation of a compound of formula I.

wherein:

Ar is selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl; R is a carboxylic acid or ester or a group capable of being converted to a carboxylic acid or ester group; R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl and substituted aryl; and X is halogen; which process comprises: reacting a compound of formula III

wherein R is selected from the group consisting of alkyl, aryl, substituted alkyl and substituted aryl, with a compound of formula R 3R4R5SiX wherein R3 , R4 and R are independently chosen from alkyl and aryl .

In the compounds of formula I and III: Ar is preferably selected from the group of formula IV

wherein A is independently selected from the group consisting of halogen, C₁ to C₆ alkyl, C₁ to C₆ alkoxy, C₁ to C₆ alkylthio, and more preferably C- to C₄ alkyl and C₁ to C₄ alkoxy, and n is an integer of from 0 to 3 inclusive and preferably n is 0 or 1.

Most preferred Ar is p-(C₁ to C₆ alkoxy)phenyl, for example p-methoxyphenyl; Preferably R is. selected: from the group

consisting of cyano, thiocarbamoyl,

and CH₂Z, wherein: G is chosen from the group consisting of: hydrogen, hydroxy, mercapto, C₁ to C₁₀ alkoxy, C₁ to C₁₀ haloalkoxy, C₂ to C₁₀ alkenyloxy, C₃ to C₁₀ alkynyloxy, C₃ to C₁₀ alkynylthio, C₃ to C₇ cycloalkoxy, C₃ to C₇ cycloalkoxy substituted with one or two C₁ to C₄ alkyl groups, phenoxy, phenylthio, benzyloxy, benzylthio, the group C₁ to C₆ alkoxy substituted with a substituent chosen from the group consisting of C₁ to C₆ alkoxy, amino, ammonio, cyano, N-(C₁ to C₆ alkyl)amino and N,N,N-tri(C₁ to C₆ alkyl)ammonio, the groups phenoxy, phenylthio, benzyloxy and benzylthio wherein in each group the phenyl ring is substituted with from 1 to 3 substituents chosen from the group consisting of halogen, nitro, cyano, C₁ to C₆ alkyl, C₁ to C₆ haloalkyl and C₁ to C₆ alkoxy, the group - NHSO₂R⁶ wherein R⁶ is chosen from C₁ to C₁₀ alkyl and C₁ to C₆ haloalkyl, the group -NR⁷R⁸ wherein R⁷ and R⁸ are independently chosen from the group consisting of hydrogen, C₁ to C₆ alkyl, phenyl and benzyl or R⁷ and R⁸ together form a heterocyclic ring, and the group -O-N=R⁹ wherein R⁹ is a C₁ to C₁₀ alkylidene group; Z is chosen from the group consisting of halogen, hydroxy, mercapto, C₁ to C₁₀ alkoxy, C₁ to C₁₀ haloalkoxy, C₁ to C₁₀ alkylthio and the group -NR⁷R⁸ wherein R⁷ and R⁸ are as hereinbefore defined.

Preferred R is cyano, the group

wherein

G is selected from hydrogen, hydroxy, C₁ to C₆ alkyl, C₁ to C₆ alkoxy and the group CH₂Z wherein Z is hydroxy, chloro or C₁ to C₆ alkoxy. 0 Particularly preferred R are the group -C-G where G is hydroxy or C₁ to C₆ alkoxy (e.g. methoxy). The compound of formula III may be the cis- or trans- geometrical isomer. Preferably the compound of formula III is predominantly the trans geometrical isomer.

Preferably R¹ is selected from hydrogen, C₁ to C₆ alkyl, phenyl, benzyl and C₁ to C₆ haloalkyl. More preferably R¹ is C₁ to C₆ alkyl and most preferably methyl or ethyl. X is the group halogen and preferably X is chlorine. R², R³, R⁴ and R⁵ are preferably C₁ to C₄ alkyl and most preferably methyl. The reaction is preferably carried out in non-polar solvent such as may be selected from hydrocarbons and chlorinated hydrocarbons. Specific examples of such solvents include chloroform, dichloromethane, pentane, hexane, benzene, toluene and xylene.

Typically the reaction is carried out in the presence of a weak Bronsted-acid which we believe increases the rate of product formation. When used the weak acid need only be present in minor amounts eg. (0.1 to 15 mole percent based on the compound of Formula III) although the amount of the acid is not narrowly critical and larger amounts may be used if desired. Preferably the weak acid is present in an amount of at least 1 mole % based on the compound of formula III. Trisubstituted amine hydrochlorides are the preferred weak acids and a trialkylamine hydrochloride such as triethylamine hydrochloride is convenient. The commercial grades of many chlorinated hydrocarbons such as for example dichloromethane and chloroform contain minor amounts of hydrochloric acid and when using such solvent it may be convenient to generate a weak acid in situ by addition of a trialkylamine.

Typically the reaction is carried' out at a temperature in the range of from -20° to 80°C. Convenient working temperatures may vary depending on the reactants and other conditions however preferably the temperature is in the range of from -5 to 40°C.

In accordance with εtoichiometry of the reaction it is preferred that at least 1 molar equivalent of the chlorosilane compound be present and an excess may be used if desired.

As hereinbefore described the process of the invention proceeds with a high degree of εtereoselectivity. To obtain the maximum advantage from the process of the invention it is preferred that the starting material consist predominantly of a single stereochemistry at the 4- and 5- positions of the dioxolane moiety. That is, preferably the dioxolane. starting material will comprise predominantly, for example, at least 80% and preferably at least 90% of one of the trans- and cis- isomers. In the case of Diltiazem preparation it is the trans isomer which will give the correct configuration.

The process of the invention provides inversion of stereochemistry at the chiral centre bearing the Ar substituent. For example, the trans dioxolane (4R,5S) of formula III (a) is converted with a high degree of enantioεelectivity to the propionic acid derivative of formula I (a) (2R,3R).

The group R¹ and the group OR² are different and hence the 2-position of the dioxalane ring is a chiral centre. However the configuration at the

2-position is not critical as this chiral centre is lost as a result of the chlorination reaction.

Preferably the compound of formula I will comprise at least 80% of one enantioner and more preferably at least 90% of one enantiomer.

Indeed we have found that composition comprising at least 95% of a single enantiomer of the compound of formula I may be prepared from the compound of formula III consisting of essentially one of the trans and cis dioxolane geometrical isomers. In a further embodiment of the invention there is provided a composition of the compound of formula I characterised in that at least 80%

(preferably at least 90% and more preferably at least 95%) of the compound of formula I is in the form of a single enantiomer.

It is preferred that at least 80% (preferably at leaast 90% and more preferably at least 95%) of the compound be in the form of the 2R,3R propionic acid derivative of formula I (a). As hereinbefore described it is preferred that the composition of the compound of formula III consist of a major portion of one of the trans-dioxolane isomer and cis-dioxolane.

Such a composition may be prepared by a variety of techniques including classical resolution methods however we have found that the compound of formula III may be prepared in a stereoselective manner from the diol of formula V which is enriched in a single enantiomer.

Accordingly we provide a process for the preparation of a compound of formula III comprising:- reacting a compound of formula V with a compound of formula VI in the presence of a Bronsted-acid catalyst and where the compound of formula V comprises at least 80%, preferably at least 90%, of a single enantiomer.

In the compounds of formula V and VI the substituents R, R¹, R² and Ar are as hereinbefore defined,

Examples of Bronsted-acid catalyst include sulphuric acid and p-toluene-sulphonic acid.

The conditions under which preparation of the dioxolane are carried out are not narrowly critical. Typically the temperature is in the range -20 to 150°C and temperatures in the range -5 to 40°C are generally the most convenient. The reaction may be carried out neat, for example, by using the compound of formula VI in excess to act as a solvent for the reaction, alternatively the reaction may be carried out in the presence of an inert solvent such as hydrocarbons and halogenated hydrocarbons. The diol of formula V may be prepared by a variety of methods . A preferred enantioselective method of preparation of the diol of formula V is described in our copending application , Australian Patent Application No . PI 4458 and International Application PCT/AU88/00345. We have found that the diol of formula V may be used to prepare the compound of formula I with a high degree of enantioselectivity using the processes hereinbefore described.

The invention is now demonstrated by but in no way limited to the following examples.

Example 1

Preparation of 2-_nethoxy-4-methoxycarbonyl-5-(4¹- methoxyphenyl)-2-methyl-1,3-dioxolane

(i) To a solution of (2R,3S)-methyl 2,3- dihydroxy-3-(4-methoxyphenyl) propionate (1.25 g) in trimethyl orthoacetate (25 ml), p-toluenesulphonic acid (110 mg) was added, and the combined mixture was stirred overnight at room temperature. The volatile components were removed under reduced pressure. The residue was redissolved in ether (50 ml), washed with aqueous triethylamine (40 ml, 4% v/v), and the aqueous laqer was re-extracted twice with ether (2 × 30 ml). The combined organic layers were washed with brine, dried over Na^SO., then evaporated to dryness under reduced pressure to give crude (4R,5S) 2-methoxy-4-methoxycarbonyl- 5-(4 -methoxyphenyl)-2-methyl-1,3-dioxolane as a clear oil in quantitative yield (1.6 g). The dioxolane was further purified by flash chromatography [light petroleum-ethyl acetate (7:3, v/v)] to give 1.3g of pure product. The product was characterised by itε protein Ji.m.r. as follows: 1H-N.m.r. δ (CDCl₃) (90 MHz) 1.71, 1.74, S, S, CH₃, diastereomeric; 3.41, 3.44, S, S, OCH₃, diastereomeric; 3.78, 3.80, S, S, CO₂CH₃, diastereomeric; 3.81, S, p-CH₃PC₆H₄; 4.40, d, J 7.0 Hz, 4.52, d, J 8.4 Hz, H4 diastereomeric; 5.07, d, J 8.4 Hz, 5.33, d, 7.0 Hz, H5, diastereomeric; 6.91, m, m-ArH; 7.27-7.45, m, O-ArH Example 2

Preparation of methyl-2(S)-acetoxy-3(R)chloro-3-(4-methoxyphenyl)propionate

(ii) To a solution of (4R, 5S) methoxydioxolane (447 mg) and triethylamine hydrochloride (26 mg) in dry dichloromethane (4 ml) at 4°, chlorotrimethylsilane (485 mg) in dry dichloromethane (3.5 ml) was added. The combined mixture was allowed to stir at 4° under nitrogen for 1.5 h. The volatile components were removed under reduced presεure. The reεidue was dissolved in chloroform (5 ml), washed once with cold aqueous triethylamine (4 ml, 4% v/v) and the aqueous layer was re-extracted with chloroform (4 ml). The combined organic layers were washed with water (5 ml), dried over anh. Na2SO4, then evaporated to dryness under reduced pressure to give methyl-2(s)-acetoxy- 3(R)chloro-3-(4-methoxy phenyl) propionate as a colourless oil in quantitative yield (480 mg). The product was characterised by itsproton n.m.r. as follows:

1H-N.m.r. δ (CDCl₃) (90 MHz) 2.03, S, CH₃CO; 3.62, S, CO₂ CH; 3.72, S, p-CH₃OC₆H₄; 5.28, d, J 5.9 Hz, H3; 5.54, d, J 5.9 Hz, H2; 6.86, m, m-ArH; 7.36, m, o-ArH.

Optical purity of the product was determined by conversion of the chloroacetate to the corresponding thiol adduct in its reaction with the potassium salt of 2-aminothiophenol in DMF. The optical purity of the thiol adduct was determined by ¹H-n.m.r. spectroscopy with Eu(hfc) as chiral shift reagent (0.15-0.25 molar equivalent). Optical purity of the thiol adduct was found to equal that of the starting diol. Example 3

Preparation of trans-2-methoxy-4-methoxycarbonyl-5-phenyl-2-methyl-1,3-dioxolane

Trimethylorthoacetate (0.5ml) and a catalytic amount of benzoic acid were added to a solution of (2R, 3S) -methyl 2,3-dihydroxy-3-phenylpropanaoate (0.45g) in dry benzene (10ml). The combined mixture was heated under reflux for 2h. A small amount of triethylamine (0.5ml) was added to the cooled reaction mixture which was then concentrated under reduced pressure. Kugelrohr distillation of the residue (140°C/0.05 mm Hg) afforded trans-2-methoxy-4-methoxycarbonyl-5-phenyl-2-methyl-1,3-dioxolane as a clear oil (0.44g, 76% (Found: C,62.1;H, 6.4..

C₁₃H₁₆O₅ requires C, 61.9; H, 6.4%) [d}19 +30.6° (C,0.98 in benzene). ¹H-N.m.r. spectrum showed an 80:20 mixture of diastereomers at C2. ¹H-N.m.r. (CDCl₃δ(300 MHz): Major isomer 1.73, s, CH₃; 3.45, S, OCH₃; 3.80, S, CO₂CH₃; 4.54, d, J 8.3 Hz, H2; 5.13, d, J 8.3 Hz, H3; 7.3-7.5, m, ArH; Minor isomer 1.76, s, CH₃; 3.41, S, OH₃; 3.82, S, CO₂CH₃; 4.43, d, J 6.9 Hz; H2; 5.39, d, J 6.9 Hz, H3 ? 7.3-7.5, m, ArH.

Example 4

Preparation of methyl-ervthro-2-acetoxy-3-chloro-3-phenyl-propanoate

Chlorotrimethylsilane (0.2ml) and triethylamine (0.02) were added to a stirred solution of trans -2-methoxy-4-methoxycarbonyl-5-phenyl-2-methyl-1, 3-dioxolane (200 mg) in dichloromethane (5ml). Stirring was continued at room temperature for 3 h, and the mixture was concentrated under reduced pressure. The crude product was purified by preparative t.i.c. (dichloromethane) to give methyl erythro -2-acetoxy-3-chloro-3-phenylpropanoate as an oil (137 mg) contaminated by a small amount of the correεponding 2-chloro-3-acetoxy iεomer. [d]¹⁹ +

22.9° (C, 0.45 in CHCl₃). ¹H-N.m.r.δ (CDCl₃ (300

MHz) 2.08, S, CH₃CO 3.70, S, CO₂CHO₃; 5.29, d, J 6.1

Hz, H3; 5.54, d, J 6.1 Hz, H2; 7.3-7.4, m, ArH.

Claims

1. A process for the preparation of a compound of formula I

wherein: Ar is selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl; R is a carboxylic acid or ester or a group capable of being converted to a carboxylic acid or ester group; R¹ is selected form the group consisting of hydrogen, alkyl, susbtituted alkyl, aryl and substituted aryl; and X is halogen; which process comprises reacting a compound of formula III wherein R² is selected from the group consisting of alkyl, aryl, substituted alkyl and substituted aryl, with a compound of formula R³R⁴R⁵Six wherein R³, R⁴, and R⁵ are independently chosen from alkyl and aryl.

2. A process according to claim 1 wherein the process is carried out in a non-polar solvent.

3. A process according to claim 2 wherein the non-polar solvent is selected from hydrocarbons and chlorinated hydrocarbons.

4. A process according to claim 1 wherein the reaction is carried out in the presence of a trisubstituted amine hydrochloride.

5. A process according to claim 4 wherein the reaction is carried out in the presence of a trialkylamine hydrochloride.

6. A process according to claim 1 wherein the compound of formula III comprises at least 80% of one of the trans- and cis- geometrical isomers.

7. A process according to claim 6 wherein the compound of formula III comprises at least 90% of the trans-isomer.

8. A process according to claim 1 wherein the compound of formula I compriseε at least 80% of one enantiomer.

9. A procesε according to claim 1 wherein: in the compoundε of formula III and formula I

Ar is selected from the group of formula IV.

wherein A is independently selected from the group consisting of halogen, C₁ to C₆ alkyl, C₁ to C₆ alkoxy and C₁ to C₆ alkylthio and n is from zero to 3; R is selected from the group consisting of cyano,

thiocarbamoyl,

and CH₂Z, wherein: G is chosen from the group consisting of: hydrogen, hydroxy, mercapto, C₁ to C₁₀ alkoxy, C₁ to C₁₀ haloalkoxy, C₂ to C₁₀ alkenyloxy, C₃ to C₁₀ alkynyloxy, C₃ to C₁₀ alkynylthio, to C₁₀ alkoxy, C₁ to C₁₀ haloalkoxy, C₂ to C₁₀- alkenyloxy, C₃ to C₁₀ alkynyloxy, C₃ to C₁₀ alkynylthio,

C₃ to C₇ cycloalkoxy, C₃ to C₇ cycloalkoxy substituted with one or two C₁ to C₄ alkyl groups, phenoxy, phenylthio, benzyloxy, benzylthio, the group C₁ to C₆ alkoxy substituted with a substituent choεen from the group conεiεting of C₁ to C₆ alkoxy, amino, ammonio, cyano, N-(C₁ to C₆ alkyl)amino and N,N,N-tri (C₁ to C₆ alkyl)ammonio, the groups phenoxy, phenylthio, benzyloxy and benzylthio wherein in each group the phenyl ring is substituted with from 1 to 3 substituents chosen from the group consisting of halogen, nitro, cyano, C₁ to C₆ alkyl, C₁ to C₆ haloalkyl and C₁ to C₆ alkoxy, the group

NHSO₂R⁶ wherein R⁶ is chosen from C₁ to C₁₀ alkyl and C₁ to C₆ haloalkyl, the group -NR⁷R⁸ wherein R⁷ and R⁸ are independently chosen from the group consisting of hydrogen, C₁ to C₆ alkyl, phenyl and benzyl or R⁷ and R⁸ together form a heterocyclic ring, and the group -0-N=R wherein R⁹ is a C₁ to C₁₀ alkylidene group; Z is chosen from the group consisting of halogen, hydroxy, mercapto, C₁ to C₁₀ alkoxy, C₁ to C₁₀ haloalkoxy, C₁ to C₁₀ alkylthio and the group -NR⁷R⁸ wherein R⁷ and R⁸ are as hereinbefore defined; R¹ and R² are C₁ to C₄ alkyl R¹ and R² are C₁ to C₄ alkyl;

X is the group halogen; and in the compound of formula R³R⁴R⁵SiX and R³, R⁴ and R⁵ are independently selected from C₁ to C₄ alkyl and X is halogen.

10. A process according to claim 9 wherein:

Ar is selected from p-(C₁ to C₆ alkoxy) phenyl;

R is selected from the group consisting of cyano,

the group

wherein G is selected from hydrogen, hydroxy, C₁ to C₆ alkyl and C₁ to C₆ alkoxy, and the groups CH₂Z wherein Z is selected from the group consisting of hydroxy, Chloro and C₁ to C₆ alkoxy; R¹ is