Field of the invention
The present invention relates to a process for the preparation of antidiabetic compound having the formula (1).

where R represents alkyl group such as ethyl, ethyl, propyl, isopropyl and the like.
The compound of formula (I) is useful in lowering the plasma glucose, triglyceride, total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL).
The compound of formula (I) is also useful in reducing body weight and for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The compound of formula (I) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes).
Background of invention
In our WTO application No. 483/MAS/99 we have described a process for the preparation of antidiabetic compound having the formula (I). The process described therein comprises, directly reacting the compound of formula (II) with L-arginine in a mixture of ethanol and water.
The process is shown in the scheme -1 given below


In our copending application No. 797/MAS/2001, we have described a process for the preparation of formula (1). The process is shown in scheme -1 below :

Recognizing the importance of the new antidiabetic compound, we continued the research to develop a more efficient, simple and commercially viable stereoselective process for the preparation of the said novel compound of the formula (I).
Summary of the invention
The present invention is based on the fact that strong base displaces a weak base from its salts, since L-arginine is a stronger base than phenyl ethylamme due to its guanidine unit. This was applied for our reaction, which results in formation of the product in good yield and purity. Based on this fact, we found that the compound of formula (I) may be obtained in commercial yield and purity when phenyl ethylamine salt is treated with L-arginine.

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 (I) with high chemical and chiral purity.
Detailed description of the invention
Accordingly, the present invention provides a process for the preparation of compounds of the formula (I),

wherein R' represents (C1-C6) alkyl group such as methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, t-butyl and the like, which comprises :
i). converting the compound of formula (II) to a compound of formula (III) by
reacting with phenyl ethylamine in the presence of a solvent at a temperature in the
range of 20 to 50°C,
ii). reacting the compound of formula (III) with L-arginine m the presence of a ,'■
solvent at a temperature in the range of 20 °C to reflux temperature of the solvent,
for a period in the range of 4-24 h, to yield compound of formula (I) where R is as
defined above and
iii). isolating the compound of formula (I) formed by conventional methods.
The process explained above is shown in scheme-2 below:


The conversion of compound of the formula (II) to phenyl ethyl amine salt of compound of formula (III) may be carried out using phenyl ethylamine in the presence of 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, ethers like THF, dioxane, diisopropyl ether and the like or hydrocarbons such as benzene, toluene, xylene, cyclohexane and the like or mixtures thereof at a temperature in the range of range of 20 to 50 °C. The duration of the reaction may range from 2-12 h.
The reaction of compound of formula (III) with L-arginine may be carried out in the presence of solvents like (C1-C6) alcohols such as methanol, ethanol, propanol, isopropanol and the like; acetonitrile, DMF, DMSO, acetone, in 1,4-dioxane and the like or mixture thereof. The reaction may be carried out at a temperature in the range of 20 °C to reflux temperature, for a period in the range of 2-24 h.
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 (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy
propanoic acid phenyl ethylamine salt (III)
To a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (100 g) in ethyl acetate (800 ml) at room temperature, phenyl ethyl amme (PEA) (28 g) was added slowly and stirred for 4-6 h. The precipitated salt was filtered and the salt was washed with ethyl acetate (200 ml), dried and recrystallized from hot ethyl acetate (1.0 L) to yield the title compound (90-95 g).
Step (ii)
Preparation of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy
propanoic acid L-arginine salt
To a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid phenyl ethylamine salt (100 g, 0.238 mol) in methanol (500 ml) at 30-35 °C, L-arginine (41.52 g, 0.238 M) was added in about 5-10 min time and heated under reflux for 30-40 min to get a clear solution. Activated charcoal (2-5 g) was added at 55-60 °C and maintained at same temperature for 15-20 min and passed through filters. To the clear solution, isopropanol (1.5 L) was added at 60-65 °C in about 20-30 min. After complete addition, the reaction mass was heated under reflux until solid starts separating out and then maintained at same temperature for additional 3-4 h. The reaction mass was cooled to 35-45 °C and the product was filtered, washed with isopropanol (300 ml) and dried under vacuum at 70-75 °C for 6-8 h to yield the title compound as white to off white free flowing solid (weighs about 95-99 g, yield 87-90%, purity > 99%).
Example 2 Step (i)

Preparation of (S)-3-[4-[2-(phenoxazin-10-yI)ethoxy]phenyI]-2-ethoxy
propanoic acid phenyl ethylamine salt (III)
To a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yI)ethoxy]phenyl]-2-ethoxy propanoic acid (100 g) in ethyl acetate (800 ml) at room temperature, phenyl ethyl amine (PEA) (28 g) was added slowly and stirred for 4-6 h. The precipitated salt was filtered and the salt was washed with ethyl acetate (200 ml), dried and recrystallized from hot ethyl acetate (1.0 L) to yield the title compound (90-95 g).
Step (ii)
Preparation of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy
propanoic acid L-arginine salt
To a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid phenyl ethylamine salt (50 g, 0.12 mol) in isopropanol (750 ml) at 30-35 °C, and activated charcoal (2 g) was added and heated to 70-75 °C and maintained at same temperature for 15-20 min and passed through filters. To the clear solution L-arginine (20.76 g, 0.12 M) was added and heated under reflux for 6 h. The reaction mass was cooled to 35-45 °C and filtered, washed with isopropanol (150 ml) and dried under vacuum at 70-75 °C for 6-8 h to yield the title compound as white to off white free flowing solid ( weighs about 45 g, yield 90%, purity > 99%).
Advantages
• The process is cheap and cost effective.
• The process involves use of less raw materials.
• The process duration is short and results in high yield.
• The process has less number of steps, at the same time the chiral purity is
improved by direct replacement of PEA.

We claim:
1. A process for the preparation of compound of the formula (I),

wherem R' represents (Ci-C6)alkyl group, which comprises : i). converting the compound of formula (II)

wherein R1 represents (C1-C6)alkyl group to a compound of formula (III)

by reacting with phenyl ethylamine in the presence of a solvent at a temperatvire in
therange of 20 to 50°C,
ii). reacting the compound of formula (III) with L-arginine in the presence of a
solvent at a temperature in the range of 20 °C to reflux temperature of the solvent,
for a period in the range of 4-24 h, to yield compound of formula (I) where R is as
defined above and
111). isolating the compound of formula (I) formed by conventional methods.
2. The process as claimed in claim 1, wherem the solvent used in step (i) is
selected from methyl acetate, ethyl acetate, ethyl propanoate, n-butylacetate,
methanol, ethanol, propanol, isopropanol, acetone, methyl isobutyl ketone,
acetonitrile, THF, dioxane, diisopropyl ether, benzene, toluene, xylene,
cyclohexane or mixtures thereof.

3. The process as claimed m claims 1 to 2, wherein the reaction in step (i) is carried out at a temperature in the range of range of 20 to 50 °C for a period ranging from 2-12 h.
4. The process as claimed in claims 1 to 3, wherein the solvent used in step (ii) is selected from methanol, ethanol, propanol, isopropanol, acetonitrile, DMF, DMSO, acetone, in 1,4-dioxane or mixture thereof
5. The process as claimed in claims 1 to 4, wherein the reaction in step (ii) is carried out at a temperature in the range of 20 °C to reflux temperature of the solvent, for a period in the range of 2-24 h.
6. The process for the preparation of compound of formula (I) substantially as herein described with reference to the examples.