Title of Invention

PROCESS FOR THE PREPARATION OF ARYL PROPIONIC ACID

Abstract

The present invention related to a process for the preparation of hydroxyphenyl)-2-h drox 3 (4Y ypropionic acid of the formula (1) 3-(4-benzyloxyphenyl)-2-hydroxyphenyl acid of the formula (4) using chemical method in the presence of trifluoroacetic acid as a solvent at a temperature in the range of 40 to 80°C for a period in the range of 4-16 h to yield pure compound of formula (1) and isolating the compound of formula (1) formed by conventional methods.

Full Text

Field of the invention The present invention relates to a process for the preparation of 3-(4- hydroxyphenyl)-2-hydroxypropionic acid of the formula (1) useful as an intermediate for the preparation of many pharmaceutically active compounds. Background of invention 3-Aryl-2-hydroxy propanoic acid derivatives are also used as sweetening agent (Gries et.al. EP 55,689 (1982)), also in photosensitive materials (Komamura et.al. JP 6022850) and also in liquid crystals (Grey et.al. WO 88/02390). It is also a part of sesquiterpene lactone glycoside isolated from Crepis tectorium (Kisiel Wanda et.al. Phy to chemistry, 2403, 28 (9) (1989)]. It is also part of Aeruginorins 102A and B, a new class of Thrombin inhibitors from the Cyanobacterium Microcystis vindis. α-Hydroxy aryl propionic acid of the formula (1) is prepared by several methods reported in the literature. In our WO publication No. 00/26200 we have described process for preparing the compound of formula (3). The reaction is shown in scheme-2 below: where R1 represents hydrogen or lower alkyl group and R2 represents lower alkyl group. The debenzylation of compound of formula (5) to compound of formula (3) is carried out using Pd/c in solvents such as alcohols like methanol, ethanol or isopropanol. Objectives 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 and chiral purity, which can be practiced economically in industrial scale. Detailed description of the invention Accordingly, the present invention provides a process for the preparation of 3-(4-hydroxyphenyl)-2-hydroxypropionic acid of the formula (1), which comprises: i). debenzylating the 3-(4-benzyloxyphenyl)-2-hydroxypropionic acid of the formula (4) using chemical method in the presence of trifluoroacetic acid as a solvent at a temperature in the range of 40 to 80 °C for a period in the range of 4-16 h to yield pure compound of formula (1) and ii). isolating the compound of formula (1) formed by conventional methods. The debenzylation of the compound of formula (4) may be carried out using thioanisole or anisole in the presence of trifluoroacetic acid. The compound of formula (1) is useful in synthesizing antidiabetic compounds of formula (8) as shown below : The invention is explained in detail in the example given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1 Preparation of 3-(4-hydroxyphenyl)-2(S)-hydroxy propionic acid (3) In a 1L 4-necked round bottom flask provided with mechanical stirred, reflux condenser with guard tube, 3-(4-benzyloxy phenyl)-2(S)-hydroxy propionic acid (24 g) in trifluoroacetic acid (25 ml) and thioanisole (25 ml) were taken and stirred at 55 to 60 °C for 6-8 h. The completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 10 to 15 °C and maintained for 1 h. The precipitated compound was filtered, washed with toluene, petroleum ether and dried to yield the title compound (weighs 13 g, yield 77.6 %). Example 2 Preparation of 3-(4-hydroxyphenyI)-2(S)-hydroxy propionic acid (3) In a 1L 4-necked round bottom flask provided with mechanical stirred, reflux condenser with guard tube, 3-(4-benzyloxy phenyl)-2(S)-hydroxy propionic acid (160 g) in trifluoroacetic acid (240 ml) and thioanisole (240 ml) were taken and stirred at 55 to 60 °C for 6-8 h. The completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 10 to 15 °C and maintained for 1 h. The precipitated compound was filtered, washed with toluene, petroleum ether and dried to yield the title compound (weighs 99.2 g, yield 92.7 %). Example 3 Preparation of 3-(4-hydroxyphenyl)-2(S)-hydroxy propionic acid (3) In a 1L 4-necked round bottom flask provided with mechanical stirred, reflux condenser with guard tube, 3-(4-benzyloxy phenyl)-2(S)-hydroxy propionic acid (75 g) in trifluoroacetic acid (75 ml) and thioanisole (50 ml) were taken and stirred at 55 to 60 °C for 6-8 h. The completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 10 to 15 °C and maintained for 1 h. The precipitated compound was filtered, washed with toluene, petroleum ether and dried to yield the title compound (weighs 23 g, yield 68.7 %). Example 4 Preparation of 3-(4-hydroxyphenyI)-2(S)-hydroxy propionic acid (3) In a 1L 4-necked round bottom flask provided with mechanical stirred, reflux condenser with guard tube, 3-(4-benzyloxy phenyl)-2(S)-hydroxy propionic acid (25 g) in trifluoroacetic acid (37.5 ml) and thioanisole (25 ml) were taken and stirred at 55 to 60 °C for 6-8 h. The completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 10 to 15 °C and maintained for 1 h. Trifluoroacetic acid and thioanisole were completely distilled off and the precipitated compound was filtered, washed with toluene and dried to yield the title compound (weighs 16.3 g, yield 97%). Advantages of the present process: • Expensive metal catalyst such as Pd/C was replaced by commercially available low cost chemicals. • The process is simple, robust and cost effective. • High chemical and chiral purities of the product. • The reaction cycle time is less. • Easy scalability and does not require special equipments like pressure reactors. • The reaction is non hazardous compared to catalytic reduction like Pd/C and hydrogen gas which is highly pyrophoric in nature. We claim: 1. A process for the preparation of 3-(4-hydroxyphenyl)-2-hydroxypropionic acid of the formula (1) which comprises: i). debenzylating the 3-(4-benzyloxyphenyl)-2-hydroxypropionic acid of the formula (4) using chemical method in the presence of trifluoroacetic acid as a solvent at a temperature in the range of 40 to 80 °C for a period in the range of 4-16 h to yield pure compound of formula (1) and ii). isolating the compound of formula (1) formed by conventional methods. The process as claimed in claim 1, wherein the debenzylation is carried out using thioanisole or anisole. A process for the preparation of compound of formula (1) substantially as herein described with reference to the examples.

Documents:

0027-mas-2002 abstract duplicate.pdf

0027-mas-2002 claims duplicate.pdf

0027-mas-2002 description(complete) duplicate.pdf

27-mas-2002-abstract.pdf

27-mas-2002-assignment.pdf

27-mas-2002-claims.pdf

27-mas-2002-correspondence others.pdf

27-mas-2002-correspondence po.pdf

27-mas-2002-description complete.pdf

27-mas-2002-form 1.pdf

27-mas-2002-form 26.pdf

27-mas-2002-form 6.pdf

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