Process for the preparation of 3-aryl-2-hydroxy propanoic acid

Details Process for the preparation of 3-aryl-2-hydroxy propanoic acid Process for the preparation of 3-aryl-2-hydroxy propanoic acid

2001-04-17

2003-05-06

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S055000, C560S060000, C560S075000

Reexamination Certificate

active

06559335

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 3-aryl-2-hydroxy propanoic acid derivatives of the formula (1)
useful as an intermediate for the preparation of many pharmaceutically active compounds.
BACKGROUND OF INVENTION
The process for the preparation of 3-aryl-2-hydroxy propanoic acid, its derivatives and analogs exhibiting various pharmacological actives have been described in U.S. Pat. Nos. 5,232,945, 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 certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with eating such as anorexia nervosa and disorders associated with overeating such as obesity and anorexia bulimia.
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. 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.
3-Aryl-2-hydroxy propionic acid is prepared by several methods reported in the literature.
Hisashi Matruda, et.al., Tet. 52 (46) 14501 (1996)
In our WO publication No. 00/26200 we have described process for preparing the compound of formula (1). The reaction schemes are shown below:
Though it is convergent synthetic method, the compound of formula (7) is produced in racemic mixture, which has to be resolved to get the optically pure material.
In this process too the resolution has to be carried out for compound of formula (7).
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 and chiral purity.
Another objective of the present invention is to produce pure and stable compound of formula (9) acid salt with respect to chemical and chiral purities.
To convert the crude compound of formula (9) (partially racemised) to compound of formula (9) acid and to get pure compound of formula (9) acid, which is back esterified to get pure compound of formula (9).
To overcome the problem of partial racemisation during the conversion of compound of formula (8) to compound of formula (9).
To avoid use of highly reactive, difficult to handle and expensive chemicals such as sodium hydride and ethyl iodide and replaced with simple, inexpensive chemicals such as diethylsulphate and potassium carbonate.
Accordingly, the present invention provides an improved process for the preparation 3-aryl-2-hydroxy propanoic acid derivatives of the formula (1) wherein R
1
represents hydrogen atom or (C
1
-C
6
)alkyl group such as methyl, ethyl, propyl, isopropyl and the like, and R
2
represents (C
1
-C
6
)alkyl group such as methyl, ethyl, propyl, isopropyl and the like which comprises:
(i). selectively benzylating L-tyrosine of the formula (10) using benzyl chloride, CuSO
4
and sodium hydroxide in a solvent to yield a compound of the formula (11),
(ii). diazotising the compound of the formula (11) in the presence of an acidic reagent and an organic solvent to produce compound of the formula (8a),
(iii). simultaneous etherification and esterification of compound of formula (8a) using alkylating agent in the presence of a base and a solvent to obtain crude compound of formula (9a) with ee>90% wherein R
1
represents hydrogen or lower alkyl group and R
2
represents lower alkyl group,
(iv). hydrolysing the crude compound of formula (9a) obtained in step (iii) above in polar solvents using aqueous alkali to produce compound of formula (9b) acid wherein R
1
represents hydrogen or lower alkyl group,
(v). treating the compound of formula (9b) acid where R
1
represents hydrogen and lower alkyl group with chiral base in the presence of solvent to produce chemical and chiral pure (ee>99%) salt of formula (12) where R
1
represents hydrogen or lower alkyl group and X represents chiral bases such as R(+)-&agr;-methylbenzylamine, S(+) phenylglycinol, cinchonidine, ephidrine, N-octylglucaramine, N-methylglucaramine and the like,
(vi). if desired, recrystallising compound of formula (12) obtained above in a solvent to produce highly pure compound of formula (12) where R
1
represents hydrogen or lower alkyl group,
(vii). converting the compound of formula (12) defined above using a solvent and an acid to pure compound of formula (9b) where R
1
represents hydrogen or lower alkyl group,
(viii). esterifying the pure compound of formula (9b) defined above using alkylating agent in the presence of potassium carbonate, hydrochloric acid, sulfuric acid, amberlite or amberlist to produce pure compound of formula (9c) where R
1
represents hydrogen or lower alkyl group and R
2
represents lower alkyl group and
(ix). debenzylating the compound of formula (9c) using aqueous alcohol in the presence of metal catalysts to yield pure compound of formula, (1) where R
1
represents hydrogen or lower alkyl group and R
2
represents lower alkyl group.
The process explained above is shown in scheme-5 below:
The process of the present invention starts with benzylating the compound formula (10) using benzyl halide, CuSO4, sodium hydroxide in the presence of solvents such as aqueous methanol, ethanol and the like to afford compound of the formula (11). Diazotization of the compound of the formula (11) using diazotizing agent such as sodium nitrite, isoamyl nitrite, potassium nitrite, ammonium nitrite and the like under acidic conditions using acids such as sulfuric acid, HCl, acetic acid and the like, in appropriate organic solvent such as CHCl
3
, 1,4-dioxane, THF, acetone and the like, gives the compound of the formula (8a). Simultaneous etherification and esterification of compound of formula (8a) to obtain crude compound of formula (9a) may be carried out using alkyl sulfates such as diethyl sulphate, dimethylsulphate and the like or alkyl halides such as ethyl iodide, methyliodide and the like, in the presence of solvents such as hydrocarbons like toluene, benzene and the like or DMF, DMSO, MIBK and the like, in alkali bases such as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride and the like. Alternatively, the compound of formula (9a) may also be prepared by slow addition of compound of formula (8a) to a solution of DMF, sodium hydride, and alkali halides such as methyl iodide, ethyl iodide and the like at a temperature ranging from 0 to 80° C. The compound of formula (9a) upon hydrolysis in polar solvents such as alcohols such as methanol, ethanol, propanol, isopropanol and the like or ketonic solvents such as acetone, methyl ethyl ketone and the like using aqueous alkali bases such as sodium hydroxide or potassium hydroxide yields compound of formula (9b). The resolution of compound of formula (9b) with chiral bases such as R(+)-&agr;-methylbenzylamine, S(+) phenylglycinol, cinchonidine, ephidrine, N-octylglucaramine, N-methylglucaramine and the like using solvents such as alkyl ester such as methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate and the like or alcohol such as methanol, ethanol, propanol, isopropanol and the like or ketone such as acetone, methyl isobutyl ketone and the like or acetonitrile produces the chemical and chiral pure compound of formula (12) where X represents chiral bases such as R(+)-&agr;-methylbenzylamine, S(+) phenylglycinol, cinchonidine, ephidrin, N-octylglucaramine, N-methylglucaramine and the like. The compound of formula (12) defined above may further purified by recrystallization from solvents such as alkyl ester such as methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate and

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