WO1989005291A1

WO1989005291A1 - Enantioselective preparation of substituted aminothiophenol derivatives

Info

Publication number: WO1989005291A1
Application number: PCT/AU1988/000459
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 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 group or ester or a group capable of being converted to a carboxylic acid or ester; Q1 is selected from the group consisting of hydrogen, alkylsulfonyl, substituted alkylsulfonyl, arylsulfonyl, substituted arylsulfonyl, and the group of formula (a), wherein R1 is selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl; Q2 is selected from the group consisting of hydrogen, alkyl and substituted alkyl; B is selected from the group consisting of halogen, alkyl and haloalkyl; and m is an integer from 0 to 3 inclusive; which process comprises: reacting a compound of formula (II) with a compound of formula (III), wherein X is halogen and Z is an organic or inorganic cation.

Description

Enanti osel ective preparati on of substi tuted ami nothi ophenol derivatives

This invention concerns preparation of compounds of formula I

wherein Ar is selected from 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 acid or ester; Q¹ is selected from hydrogen, alkylεulfonyl, substituted alkylsulfonyl, aryl sulfonyl, substituted aryl

sulfonyl, and the group where R¹

is selected from alkyl, substituted alkyl, aryl and substituted aryl; Q² is selected from hydrogen, alkyl and substituted alkyl; B is selected from halogen, alkyl and haloalkyl and m is an integer from 0 to 3.

Compounds of formula I are useful as intermediates to biologically active compounds and in particular Diltiazem, a drug well known as a coronary vasodilator.

The activity of biologically active compounds is in many cases stereospecific, for example for Diltiazems vasodilatory activity is stereospecific to the d-cis-isomer. Hence to maximise the yield of a synthetic approach to such compounds it is important to use a stereoselective process to control the configuration of the chiral carbons (marked *) of the intermediates.

Japanese Patent Publication No. 82-01773 describes a non-stereoselective synthetic approach to 2,3-dihydro-1,5-benzothiazepin-4(5H)one derivatives from racemic 2-acetoxy-3-halo-3-(4-methoxyphenyl) propionic acid, however the optimum yield of a single enantiomer which can be achieved by such an approach is 50%. Furthermore, reaction of the propionate with 2N-(2-dimethyl-aminoethyl) aminothiophenol is carried out under relatively severe conditions which would tend to induce racemization.

We have now developed a method of preparation of compounds of formula I which allows the use of mild conditions and enables a high degree of enantioselectivity to be attained.

Accordingly we provide a process for preparation of a compound of formula I

wherein Ar is selected from 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 acid or ester; Q¹ is selected from hydrogen, alkylsulfonyl, substituted alkylεulfonyl, arylsulfonyl, substituted aryl

sulfonyl, and the group

where R¹ is selected from the group consisting of alkyl, substituted alkyl, aryl and substituted aryl; R² is selected from hydrogen, alkyl and substituted alkyl; B is selected from halogen, alkyl and haloalkyl and m is an integer from 0 to 3; which process comprises:reacting a compound of formula II with a compound of formula III

wherein X is halogen and Z is an organic or inorganic cation.

In the compounds of formula I and II: Ar is preferably selected from the group of formula IV wherein A is independently selected from the Group consisting of halogen, C1 to C, alkyl, C₁ to C₆ alkoxy, C₁ to C₆ alkylthio, and more preferably C₁ to C₄ alkyl and C₁ to C₄ alkoxy, and n is zero or an integer of from 1 to 3 inclusive and preferably n is 0 or 1.

Most preferred Ar is p-(C₁ to C₆ alkoxy) phenyl, for example p-methoxyphenyl; Most preferred Ar is p-(C₁ to C₆ alkoxy) phenyl, for example p-methoxyphenyl;

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 CH₂J, wherein: G is chosen from the group consisting of: hydrogen hydroxy, mercapto, C₁ to C₁₀ alkoxy, C₁ to C₁₀ haloalkoxy, C₂ to C₁₀ alkenyloxy, C₂ to C₁₀ alkynyloxy, C₁ 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 -

NHSO₂R³ wherein R³ is chosen from C₁ to C₁₀ alkyl and C₁ to C₆ haloalkyl, the group -NR⁴R⁵ wherein R⁴ and R⁵ are independently chosen from the group consisting of hydrogen, C₁ to C₆ alkyl, phenyl and benzyl or R⁴ and R⁵ together form a heterocyclic ring, and the group -O-N=R⁶ wherein R⁶ is a C₁ to C₁₀ alkylidene group; J 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 -NR⁴R⁵ wherein R⁴ and R⁵ 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 CH₂J wherein J is hydroxy, chloro or C₁ to C₆ alkoxy.

Preferred Q¹ include hydrogen, and the group

C R¹ where R¹ is selected from the group consisting of C₁ to C₅ alkyl and C₁ to C₅ haloalkyl. Most preferably Q¹ is methyl. Preferred Q² include hydrogen, C₁ to C₆ alkyl, C₁ to C₆ amino-alkyl, N-(C₁ to C₄ alkyl) amino(C₁ to C₆ alkyl) and H,N-di(C₁ to C₄ alkyl)amino (C₁ to C₆ alkyl). More preferred Q² include hydrogen and 2(N,N-dimethyl- amino)ethyl.

In the compound of formula II X is preferably chlorine.

In the compound of formula III the group Z is an organic or inorganic cation. Examples of inorganic cations include the cations of the alkali and alkaline earth metals and preferably sodium, potassium and calcium and most preferably sodium and potassium. Examples of organic cations include ammonium ions such as R⁶R⁷R⁸R⁹

wherein R⁶,R⁷,R⁸,R⁹ are independently selected from the group consisting of hydrogen, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl wherein the alkyl group is substituted with a substituent selected from the group consisting of hydroxy, halogen and C₁ to C₆ alkoxy, phenyl and benzyl. Preferred organic cations include tetra(C₁ to C₆ alkyl)ammonium ions. Where the group B is present in the compounds of formula I and III preferred B include halogen such as chlorine and bromine and haloalkyl such tichloromethyl. The integer m is preferably 0 or 1 and most preferably 0, that is, most preferably there is no B substituent.

The process of the invention is generally carried out in the presence of a solvent. Preferably the compound of formula III is soluble in the solvent under reaction conditions. Preferred solvents are polar aprotic solvents such as dimethylformamide, dimethylsulphoxide, acetonitrile, tetrahydrofuran and dioxan.

Generally it is preferred that the reaction temperature is in the range of from -20° to 80°C and more preferably in the range of from -5 to 40°C. In order to minimise racemization during the reaction it is preferred that high temperatures, for example over 100ºC, not be used. As hereinbefore stated the process of the invention enables a high degree of enantioselectively to be attained by using a compound of formula II which is enriched in a single enantiomer. Preferably the compound of formula II will comprise at least 80% of a single enantiomer and more preferably 90%. Using such starting material we have found that the process of the invention proceeds with no appreciable loss of optical purity. In a further embodiment of the invention there is therefore provided a composition comprising a compound of formula I wherein at least 80% (preferably 90%) of said compound is in the form of a single enantiomer.

By using a single enantiomer of starting material of formula II we have found that a product comprising well over 95% of a single enantiomer is typically produced.

In preparation of Diltiazem it is the 2S, 3S propionate iεomer of formula I which provides the required stereochemistry, such as in the compound of formula I (a) (i).

The compound of formula II may be prepared with high enantioselectivity from the chiral diol of formula V as described in our copending Australian Patent application No PI 5673, Enantio-selective preparation of the diol of formula V from the olefin of formula VI is described in our copending application Australian Patent Application PI 4458.

The process hereinbefore disclosed together with our copending applications thus provides the complete process shown in the following scheme.

The starting material of formula II may be prepared by reacting a compound of formula VII with a compound of formula J¹J²J³Six wherein J¹,J² and J³ are independently chosen from alkyl and aryl and preferably C₁ to C₆ alkyl.

The compound of formula VII may in turn be prepared from the compound of formula V by reaction thereof with a compound of formula VIII.

The preparation of the compound of formula VII is described in our copending Australian Patent Application No PI 5673 the text of which is incorporated herein by reference.

The compound of formula V may be prepared from the compound of formula VI by reaction thereof with no more than 20 mole percent (preferably no more than 5 mole percent) of osmium tetroxide in the presence of an optically active nitrogen containing compound, such as dihydroquinidine esters and dihydroquinine esters, and an oxidant such as N-methylmorpholine-N-oxide. The preparation of compounds of formula V is disclosed in our copending International Patent Application No

PCT/AU88/00345 the text of which is incorporated herein by reference. This scheme, as described in this and our copending applications, provides a process for the preparation of a key intermediate to biologically active compounds such as Diltiazem from relatively simple starting materials and with a high degree of enantioselectivity.

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

Example 1

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

The chloropropionate was prepared according to our copending Australian application No PI 5673 as follows

(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 waε 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 No. 2SO4, then evaporated to dryness under reduced pressure to give crude (4R, 4S)

2-methoxy-4-methoxycarbonyl- 5- (4¹-methoxy- phenyl)-2-methyl 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.

(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 pressure. The residue 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 preεεure to give methyl 2(S)-acetoxy-3(R)chloro-3-(4-methoxy phenyl) propionate as a colourless oil in quantitative yield (480 mg).

Example 2

Preparation of 2S 3S methyl-2-acetoxy-3-(2-amino phenylthio)-3-(4-methoxyphenyl)proρionate

To a solution of potasεium o-aminothio- phenoxide (152 mg) in dry dimethylformamide (1 ml), the 2(S)acetoxy-3(R)-chloro propionate (204 mg) in dry dimethylformamide (1 ml) waε added. The combined mixture waε allowed to stir overnight at room temperature under nitrogen. Water (10 ml) was added to the mixure and the resulting solution waε extracted three times with chloroform ( 10 ml & 2 × 5 ml). The combined chloroform extracts were washed five timeε with water (5 × 15 ml), dried over anh. Na2SO4, then evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography [light peroleum-ethyl acetate (7:3, v/v] to give methyl (2S, 3S)-2- acetoxy-3-(2-amino phenylthio)-3-(4-methoxy- phenyl)-propionate (56 mg) as a yellowish oil;

1H-N.m.r. δ (CDCl₃) (300MHz) 2.15, S, CH₃CO;

3.56, S, CO₂CH₃; 3.78, S, p-CH₃OC₆H₄; 4.3, b, NH2; 4.49, d, J 5.16 Hz, H2 ; 5.36, d, J 5.14 Hz, H3; 6.55, dd, J 7, 7.6 Hz, H 5; 6.66. d, J 8 Hz, H 3; 6.79, dd, J 2, 6.7Hz, m-ArH; 7.08, ddd, J 1.4, 7, 8 Hz, H 4; 7.14, dd . J 1.4, 7.6 Hz, H 6; 7.23, dd, J 2, 6.7 Hz, O-ArH.

Optical purity of the thiol adduct was determined by 300MHz H-N.m.r. spectroscopy with Eu(hfc), aε chiral shift reagent (0.15-0.25 molar equivalent). Optical purity of the product was found to equal that of the starting diol.

Claims

1. A 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 group or ester or a group capable of being converted to a carboxylic acid or ester; Q¹ is selected from the group consisting of hydrogen, alkylsulfonyl, substituted alkylsulfonyl, arylsulfonyl, substituted

arylsulfonyl, and the group of formula C R¹ wherein

R¹ is selected from the group consisting of alkyl, subεtituted alkyl, aryl and substituted aryl; Q² is selected from the group consisting of hydrogen, alkyl and substituted alkyl; B is selected from the group consisting of halogen, alkyl and haloalkyl; and m is an integer from 0 to 3 inclusive;

which process comprises: reacting a compound of formula II with a compound of formula III

wherein X is halogen and Z is an organic or inorganic cation.

2. A process according to claim 1 wherein the reaction is carried out in the preεence of a solvent in which the compound of formula III is soluble under reaction conditions.

3. A process according to claim 1 or claim 2 wherein the reaction temperature is in the range of from -20° to 80°C.

4. A process according to any one of claims 1 to

3 wherein the compound of formula II compriεes at least 80% of a single enantiomer.

5. A process according to any one of claims 1 to

4 wherein the compound of formula II comprises at least 90% of a single enantiomer.

6. A procesε according to any one of claims 1 to

5 wherein the compounds of formula II:

Ar is the group of formula IV

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

Preferably R is selected from the group

0 consisting of cyano, thiocarbamoyl, -C-G and CH₂J, wherein: G is chosen from the group consisting of: hydrogen, hydroxy, mercapto, C₁ to C₁₀ alkoxy, C₁ to C₁₀ haloalkoxy, C₂ to C₁₀ alkenyloxy, C₂ to C₁₀ alkynyloxy, C₁ to C₁₀ alkynylthio, C₃ to C₇ cycloalkoxy, C₃ to C₇ cycloalkyoxy substituted with one or two C₁ to C₄ alkyl groupε, phenoxy, phenylthio, benzyloxy, benzylthio, the group C. 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 substituentε choεen from the group conεiεting of halogen, nitro, cyano, C₁ to C₆ alkyl, C₁ to C₆ haloalkyl and C₁ to C₆ alkoxy, the group - NHSO₂R³ wherein R³ is chosen from C₁ to C₁₀ alkyl and C₁ to C₆ haloalkyl, the group -NR⁴R⁵ wherein R⁴ and R⁵ are independently chosen from the group consiεting of hydrogen, C₁ to C₆ alkyl, phenyl and benzyl or R⁴ and R⁵ together form a heterocyclic ring, and the group -O-N=R wherein R⁶ is a C₁ to

C₁₀ alkylidene group; J 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 -NR⁴R⁵ wherein R⁴ and R⁵ are as hereinbefore defined;

Q¹ is εelected from the group conεiεting of

hydrogen, and the group of formula

where R¹ is εelected from the group conεiεting of C₁ to C₅ alkyl and C₁ to C₅ haloalkyl and X is halogen. A process according to claim 6 wherein in the compounds of formula I and II: Ar is the group of formula IV wherein A is independently selected fromC₁ to C₄ alkyl and C₁ to C₄ alkoxy and n is selected from zero and 1;

R is selected from the group consisting of cyanc;

the group

wherein G is selected from hydrogen, hydroxy and C₁ to C₆ alkyl; and the group CH₂J where J is hydroxy, chloro or C₁ to C₆ alkoxy; R¹ is C₁ to C₆ alkanoyl;

8. A process according to claim 6 wherein in the compounds of formula I and II the group Ar is p-(C₁ to C₆ alkoxy)phenyl;

R is the group

wherein G is selected from the group consiεting of hydroxy and C₁ to C₆ alkoxy; R¹ is acetyl; and X is chlorine.

9. A proceεε according to any one of claimε 1 to 8 inclεuive wherein in the compound of formula III:

R² is selected from the group conεisting of hydrogen, C₁ to C₆ alkyl, amino (C₁ to C₆ alkyl), N-(C₁ to C₄ alkyl) amino (C₁ to C₆ alkyl) and N,N-di(C₁ to C₄ alkyl)amino (C₁ to C₄ alkyl); Z is selected from the group consisting of alkali earth metals, alkaline earth metals, ammonium ions of formula R⁶R⁷R⁸R⁹N wherein R⁶, R⁷, R⁸ and R⁹ are independently selected from the group consiεting of hydrogen, C₁ to C₆ alkyl, phenyl, benzyl, and substituted C₁ to C₆ alkyl wherein the alkyl group is substituted with a substituent selected from the group consisting of hydroxy, halogen and C₁ to C₆ alkoxy; B when present is independently selected from halogen and haloalkyl and m is zero or 1.

10. A process according to claim 9 wherein in the compound of formula III: Q² is selected from the group conεiεting of hydrogen and 2-(N,

N-dimethylamino)ethyl; Z iε εelected from the group consisting of potassium ion, calcium ion, sodium ion and tetra (C₁ to C₆ alkyl) ammonium ions; and M is zero.

11. A process for the preparation of a compound of formula I comprising the following steps in sequence:

(a) reacting a compound formula VII with a compound of formula J¹J²J³SiX wherein J¹, J² and J³ are independently selected from C₁ to

C₆ alkyl and X is halogen to form a compound of formula 11(a) (the compound of formula II

where Q is

and optionally hydrolysing the compound of formula 11(a) to provide a compound of formula II wherein Q¹ is hydrogen; and

(b) reacting the compound of formula II according to the procesε of claim 1 to provide the compound of formula I.

12. A process for the preparation of a compound of formula I comprising the following steps in sequence:

(a) reacting a compound of formula VI with no more than 5 mole percent in the presence of an optically active nitrogen-containing compound selected from the group consisting of esters of dihydroquinidine and esters of dihydroquinine and N-methylmorpholine-N-oxide to form a compound of formula V;

(b) Reacting the compound of formula V with a compound of formula VIII in the presence of a Bronεted-acid catalyεt

to provide a compound of formula VII;

(c) Reacting the compound of formula VII with a compound of formula J¹J²J³SiX wherein J¹ , J² and J³ are independently selected from C₁ to

C₆ alkyl and X is halogen to provide a compound of formula 11(a) (the compound of

0 formula II wherein Q ¹ is -C" RIjNand optionally hydrolysing the compound of formula II(a) to provide a compound of formula II wherein Q¹is hydrogen; and (d) Reacting the compound of formula II with a compound of formula III in according to claim 1 to provide a compound of formula I.

13. A process according to claim 1 wherein the compound of formula III comprises at least 85% of the trans isomer.

14. A composition comprising the compound of formula I wherein at least 80% of said compound is in the form of a single enantiomer.