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WO2004063178A1 - Process for the preparation of antidiabetic phenoxazine compounds - Google Patents

Process for the preparation of antidiabetic phenoxazine compounds Download PDF

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Publication number
WO2004063178A1
WO2004063178A1 PCT/IB2003/000043 IB0300043W WO2004063178A1 WO 2004063178 A1 WO2004063178 A1 WO 2004063178A1 IB 0300043 W IB0300043 W IB 0300043W WO 2004063178 A1 WO2004063178 A1 WO 2004063178A1
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Prior art keywords
compound
formula
preparation
phenyl
solvent
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Ceased
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PCT/IB2003/000043
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French (fr)
Inventor
Om Reddy Gaddam
Mahender Rao Siripragada
Naveen Kumar Reddy Chepyala
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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Priority to AU2003202718A priority Critical patent/AU2003202718A1/en
Priority to PCT/IB2003/000043 priority patent/WO2004063178A1/en
Publication of WO2004063178A1 publication Critical patent/WO2004063178A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings

Definitions

  • the present invention relates to a process for the preparation of an antidiabetic compound having the formula (1).
  • R 1 represents alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl 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 lipoprotem (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).
  • 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 ethylamine 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 ethylamme salt is treated with L-arginine.
  • 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.
  • the present invention provides a process for the preparation of compounds of the formula (I), wherein R 1 represents (C ⁇ -C 6 )alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl and the like, which comprises :
  • the conversion of compound of the formula (2) to phenyl ethyl amine salt of compound of formula (3) may be carried out using phenyl ethylamine in the presence of a solvent 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 a mixture thereof at a temperature range of 20 to 50 °C for a period of 2 to 12 h.
  • a solvent such as alkyl ester such as methyl acetate, e
  • the reaction of compound of formula (3) with L-arginine may be carried out in the presence of a solvent like (C ⁇ -C 6 )alcohols such as methanol, ethanol, propanol, isopropanol and the like; acetonitrile, DMF, DMSO, acetone, 1,4-dioxane, water and the like or mixture thereof.
  • a solvent like (C ⁇ -C 6 )alcohols such as methanol, ethanol, propanol, isopropanol and the like; acetonitrile, DMF, DMSO, acetone, 1,4-dioxane, water and the like or mixture thereof.
  • the reaction may be carried out at a temperature range of 20 °C to reflux temperature, for a period of 2 to 24 h.
  • 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%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

A process for the preparation of compound of the formula (I), wherein R1 represents (C1-C6) alkyl group via a compound of formula (III).

Description

PROCESS FOR THE REPARATION OF ANTIDIABETIC HENOXAZINE COMPOUNDS
Field of the invention
The present invention relates to a process for the preparation of an antidiabetic compound having the formula (1).
Figure imgf000002_0001
where R1 represents alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl 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 lipoprotem (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 international application No. PCT/IB99/00683, we have described a process for the preparation of an antidiabetic compound having the formula (1). The process described therein comprises, directly reacting the compound of formula (2) with L- arginine in a mixture of ethanol and water.
The process is shown in the scheme -1 given below
Figure imgf000002_0002
(2) (1)
Scheme-1 In our co pending international application No. PCT/IB02/03947, we have described a process for the preparation of formula (1). The process is shown in scheme -1 below:
Figure imgf000003_0001
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 (1).
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 ethylamine 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 ethylamme 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),
Figure imgf000004_0001
wherein R1 represents (Cι-C6)alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl and the like, which comprises :
(i) converting the compound of formula (2) to a compound of formula (3) by reacting with phenyl ethylamine in the presence of a solvent at a temperature range of 20 to 50 °C for a period 2 to 12 h.
(ii) reacting the compound of formula (3) with L-arginine in the presence of a solvent at a temperature in the range of 20 °C to reflux temperature, for a period in the range of 4 to 24 h, to yield compound of formula (I) where R1 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:
Figure imgf000004_0002
(I)
Scheme-2
The conversion of compound of the formula (2) to phenyl ethyl amine salt of compound of formula (3) may be carried out using phenyl ethylamine in the presence of a solvent 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 a mixture thereof at a temperature range of 20 to 50 °C for a period of 2 to 12 h.
The reaction of compound of formula (3) with L-arginine may be carried out in the presence of a solvent like (Cι-C6)alcohols such as methanol, ethanol, propanol, isopropanol and the like; acetonitrile, DMF, DMSO, acetone, 1,4-dioxane, water and the like or mixture thereof. The reaction may be carried out at a temperature range of 20 °C to reflux temperature, for a period of 2 to 24 h.
The invention is described in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example 1
Step (i)
Preparation of (25) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid phenyl ethylamine salt (3)
To a stirred solution of (2S) 3-[4-[2-(phenoxazin-10-yl)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 to 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 (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid L-arginine salt (1)
To a stirred solution of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid phenyl ethylamine salt (25 g) in methanol (75 ml) and refluxed. To this was added a solution of L-arginine (7.97 g) in methanol-water (50:12.5) dropwise and continued to reflux for 2 h. Isopropyl alcohol (375 ml) was added and continued further reflux for 5 h. The reaction mixture was concentrated to 170 ml by distilling out the solvent and seeded. Reflux was continued further for 30 minutes when salt formation was observed. Stirring was continued further for 5 h and then cooled to 40 °C and the product was filtered, washed with isopropanol (25 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 21 g, yield 77%, purity > 99%).
Example 2
Step (i)
Preparation of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propanoic acid phenyl ethylamine salt (3)
To a stirred solution of (2S) 3-[4-[2-(phenoxazin-10-yl)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 to 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 (1)
To a stirred solution of (25) 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.

Claims

We claim:
1. A process for the preparation of compound of the formula (I),
Figure imgf000007_0001
wherein R1 represents (Cι-C6)alkyl group like methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, which comprises : (i) converting the compound of formula (2)
Figure imgf000007_0002
wherein R1 represents (Cι-C6)alkyl group to a compound of formula (3)
Figure imgf000007_0003
by reacting with phenyl ethylamine in the presence of a solvent at a temperature range of
20 to 50 °C and for a period of 2 to 12h.
(ii) reacting the compound of fonnula (3) with L-arginine in the presence of a solvent at a temperature in the range of 20 °C to reflux temperature, for a period in the range of 4-
24 h, to yield compound of formula (1) where R is as defined above and
(iii) isolating the compound of formula (I) formed by conventional methods.
2. The process as claimed in claim 1, wherein 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, cyclohexanc or a mixture thereof.
3. The process as claimed in claim 1, wherein the solvent used in step (ii) is selected from methanol, ethanol, propanol, isopropanol, acetonitrile, DMF, DMSO, acetone, 1,4- dioxane, water or a mixture thereof.
4. The process for the preparation of compound of formula (I) substantially as herein described with reference to the examples.
PCT/IB2003/000043 2003-01-10 2003-01-10 Process for the preparation of antidiabetic phenoxazine compounds Ceased WO2004063178A1 (en)

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PCT/IB2003/000043 WO2004063178A1 (en) 2003-01-10 2003-01-10 Process for the preparation of antidiabetic phenoxazine compounds

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026200A1 (en) * 1998-10-29 2000-05-11 Dr. Reddy's Research Foundation An improved process for the preparation of new antidiabetic agents
WO2000050414A1 (en) * 1999-02-24 2000-08-31 Dr.Reddy's Research Foundation Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical composition containing them
WO2000063189A1 (en) * 1999-04-16 2000-10-26 Novo Nordisk A/S Crystalline r- guanidines, arginine or (l) -arginine (2s) -2- ethoxy -3-{4- [2-(10h -phenoxazin -10-yl)ethoxy]phenyl}propanoate
WO2002062772A1 (en) * 2001-02-05 2002-08-15 Dr. Reddy's Research Foundation Salts of 3-4(4-(2-phenoxazin- or phenothiazin-10-yl)alkoxy)phenyl)-2-alkoxypropanoic acid derivatives with ppar activity for the treatment of hyperlipimedia and type ii diabetes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000026200A1 (en) * 1998-10-29 2000-05-11 Dr. Reddy's Research Foundation An improved process for the preparation of new antidiabetic agents
WO2000050414A1 (en) * 1999-02-24 2000-08-31 Dr.Reddy's Research Foundation Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical composition containing them
WO2000063189A1 (en) * 1999-04-16 2000-10-26 Novo Nordisk A/S Crystalline r- guanidines, arginine or (l) -arginine (2s) -2- ethoxy -3-{4- [2-(10h -phenoxazin -10-yl)ethoxy]phenyl}propanoate
WO2002062772A1 (en) * 2001-02-05 2002-08-15 Dr. Reddy's Research Foundation Salts of 3-4(4-(2-phenoxazin- or phenothiazin-10-yl)alkoxy)phenyl)-2-alkoxypropanoic acid derivatives with ppar activity for the treatment of hyperlipimedia and type ii diabetes

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