WO2003024915A1

WO2003024915A1 - A process for the preparation of 3-aryl-2-hydroxy propanoic acid derivatives

Info

Publication number: WO2003024915A1
Application number: PCT/IB2002/003874
Authority: WO
Inventors: Mahender Rao Siripragada; Loka Appala Purushotham Vanadanapu; Ramabhadra Sarma Mamillapalli; Om Reddy Gaddam
Original assignee: Dr. Reddy's Laboratories Ltd.
Priority date: 2001-09-20
Filing date: 2002-09-19
Publication date: 2003-03-27

Abstract

The present invention relates to an improved process for the preparation of 3-phenyl-2-hydroxy propanoic acid derivatives of the formula (I), where R1 represents hydrogen atom or (C¿1?-C6)alkyl group such as methyl, ethyl, propyl, isopropyl and the like, and R?2¿ represents (C¿1?-C6)alkyl such as methyl, ethyl, propyl, isopropyl and the like, useful as an intermediate for the preparation of several pharmaceutically active compounds.

Description

A PROCESS FOR THE PREPARATION OF 3-ARYL-2-HYDROXY PROPANOIC ACID DERIVATIVES

Field of the invention

The present invention relates to a process for the preparation of 3-phenyl- 2-hydroxy propanoic acid derivatives of the formula (1)

where R represents hydrogen atom or (CrC₆)alkyl group such as methyl, ethyl, propyl, isopropyl and the like, and R represents (CrC₆)alkyl such as methyl, ethyl, propyl, isopropyl and the like, useful as an intermediate for the preparation of several pharmaceutically active compounds.

The compounds of formula (1) are also useful as intermediates for the preparation of many pharmaceutically active compounds. Few representative examples of such compounds are

disclosed in WO 99/62870 and

disclosed in WO 99/16758. The compounds of formulae (Ha) and (lib) are shown to have potent blood glucose lowering, triglyceride lowering, cholesterol lowering and body weight reducing activities. Background of invention

The process for the preparation of 3-aryl-2-hydroxy propanoic acid, its derivatives and analogs exhibiting various pharmacological actives and their use in the treatment of certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with eating such as anorexia ήervosa and disorders associated with overeating such as obesity and anorexia bulimia, have been described in US 5,232,945, US 5,306,726, WO 91/11999, DE 1,948,373, DE. 2,033,959, DE 2,014,479, DE 1,668,938, WO 91/19702, WO 92/0252, WO 96/04260, WO 96/0426, WO 95/17394. In addition, these compounds are considered to be useful for treating

The use of 3-Aryl-2-hydroxy propanoic acid derivatives as sweetening agents (Gries et.al. EP 55,689 (1982)) in photosensitive materials (Komamura et.al. JP 6022850) and also in liquid crystals (Grey et.al. WO 88/02390 have been disclosed in the prior- art. i. , . It is also a part of sesquiterpene lactone glycoside isolated from Crepis tectorium (Kisiel Wanda et.al. Phytochemistry, 2403, 28 (9) (1989)]. It is also part of Aeruginorins 102A and B, a new class of Thrombin inhibitors from the Cyanobacterium Microcystis vindis.

Several methods were prepared in the literature for the synthesis of 3-Aryl- 2-hydroxy propionic in the literature:

Joseph et. al, (J. Amer. Chem. Soc, 122 (2000), 11248-11249) described a process for the preparation of compound of formula (lb) from 4-hydroxyphenyl pyruvic acid by enantioselective reduction employing (+)-B- chlorodiisopinocamphenyl borane. The reaction is shown in scheme 1 below:

Scheme-1 EP 696566 describes the process for the preparation of compound of formula (I), which comprises hydrogenating a phenyl pyruvic acid derivative in the presence of a catalyst.

Hisashi Matrada, et.al, Tet. 52 (46) 14501 (1996) discloses

' ^' (3) (4)

Scheme-2

In our WO publication No. 00/26200 we have described process for preparing the compound of formula (la). The reaction schemes are shown below:

(la) (10) (9)

Scheme-3

In the above synthetic method, the compound of formula (7) is produced as a racemic mixture, which has to be resolved to get the optically pure material.

Scheme-4

In this process too the resolution has to be carried out for the compound of formula (7).

(la)

Scheme-5

All the above processes describe preparation of compound of formula (la) in chiral form.

Objective of present invention

The main objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (1) with high chemical purity.

Detailed description of the invention

Accordingly, the present invention provides a process for the preparation 3-aryl-2-hydroxy propanoic acid derivatives of the formula (1)

where R¹ represents hydrogen atom or (Cι-C₆)alkyl group such as methyl, ethyl, propyl, isopropyl and the like, and R² represents (C C₆)alkyl such as methyl, ethyl, propyl, isopropyl and the like, which comprises:

(i) converting the compound of formula (2) to a compound of formula (15) using acids in the presence of an acid and a solvent, at a temperature and duration in the range of 0 to 60 °C and 2 to 12 h respectively, (ii) reducing the compound of formula (15) using reducing agents in the presence of acetic acid and a solvent for 6 to 12 h, to yield a compound of formula (1) and (iii) isolating the compound of formula (1) by conventional methods.

The process explained' above is shown in scheme-6 below:

Scheme-6

The conversion of compound of formula (2) to a compound of formula

(15) may be carried out in the presence of a solvent such as methanol, ethanol, propanol, isopropanol and the like or mixtures thereof. The reaction may be carried out by using an acid such as HC1, sulfuric acid, acidi© resin and ,the like. The reduction of compound of formula (15) may be carried out using reducing agents such as Rh- Alumina, Nickel, Pt0₂, diborane, Borane-DMS, NaBH₄-TFA, NaBH₄CN, LiAlH₄-AlCl₃ and the like in the presence of a solvent such as methanol, ethanol, propanol, butanol and the like or mixtures thereof, or ethyl acetate, acetonitrile, THF, Toluene and the like or mixtures thereof. The reaction may be carried out 40 to 80 pounds per square inch (psi) pressure.

The invention is described in the examples given below which are provided by way of illustration only and therefore should not construed to limit the scope of the invention. Example 1 step (i)

Preparation of ethyl 2,2-diethoxy 3-(4-hydroxyphenyl)propanoate

Dry HC1 gas was bubbled into a stirred solution of 4-lτydroxy phenyl pyruvic acid (10 g) in absolute ethanol (100 ml) between 10-15 °C for about 3 h and stirred the reaction mass for additional 6 h at room temperature followed by heating the reaction mass between 50-60 °C for 4 h. The progress of the reaction was monitored by TLC. The reaction mass was cooled, water (200 ml) was added and the compound was extracted into toluene. The organic layer wa's washed with water and concentrated to yield the title compound as thick syrup (yield 8.5 g).

Step (ii)

Preparation of ethyl-2-ethoxy 3-(4-hydroxyphenyl)propanoate

A solution of ethyl 2,2-diethoxy 3-(4-hydroxyphenyl)propanoate (5 g) in ethanol (100 ml), acetic acid (catalytic amount) and Rh-Al₂0₃ (250 mg) were added and hydrogenated at 60 PSI of pressure for 12 h. The catalyst was filtered, sodium carbonate (200 mg) was added and concentrated to thick syrup. The product was purified by column chromatography to yield the title compound

(yield 2.3 g).

Advantages of the present invention

• The number of steps involved in the process is less, which makes the process simple and economical.

• The reactants employed are easily available and also cheap and make the process economical.

Claims

We claims

1. A process for the preparation 3-aryl-2-hydroxy propanoic acid derivatives of the formula (1)

wherein R represents hydrogen atom or (d-C₆)alkyl group and R represents

(Cι-C₆)alkyl group which comprises:

(i) converting the compound of formula (2)

to a compound of formula (15)

by using an acid in the presence of a solvent at a temperature in the range of 0 to

60 °C for 2 to 12 h,

(ii) reducing the compound of formula (15) using reducing agents in the presence of acetic acid and a solvent at a pressure in the range of 40 to 80 PSI pressure for 6 to 12 h, to yield compound of formula (1) and

(iii) isolating the compound of formula (1) by conventional methods.

2. The process as claimed in claim 1, where in the solvent used in step (i) is selected from methanol, ethanol, propanol, isopropanol and the like or mixtures thereof.

3. The process as claimed in claims 1 and 2, where in the acid used in step (i) is selected from HC1, sulfuric acid or acidic resin.

4. The process as claimed in claims 1 to 3, where in the reducing agent used in step (ii) is selected, from Rh-Alumina, Nickel, Pt0₂, dibprane, .Borane-DMS, NaBH₄-TFA, NaBH₄CN or LiAlH₄-AlCl₃.

5. The process as claimed in claims 1 to 4, wherein the solvent used in step (ii) is selected from methanol, ethanol, propanol, butanol, ethyl acetate, acetonitrile, THF, toluene or mixtures thereof.

6. The process as claimed in claims 1-5, wherein the reaction in step (ii) is carried out at 60 psi pressure.

7. A process for the preparation of compound of the formula (1) as claimed in claims 1-7, substantially as herein described with reference to example 1.