Title of Invention

NOVEL PROCESS FOR THE SYNTHESIS OF 4-[2-(5-ETHYI-2-PYRIDINY)-ARYI DERIVATIVES

Abstract The present invention relates to a novel process for the synthesis of 4-[2-(S-ethyl-2-pyridinyl) ethoxy]-aryl derivatives of formula I where G1 is selected from one or more of the following groups NO2, NH2, NHR1, COOH or COOR2; Rl is acetyl or trifluoro acetyl group and R2 is an alkyl group.
Full Text Novel process for the synthesis of 4-[2-(5-ethyl-2-pyridinyl)ethoxy]-aryl derivatives
FIELD OF THE INVENTION
The present invention relates to a novel process for the synthesis of 4-[2-(5-ethyl-2-pyriclinyl) ethoxy]-aryl derivatives.
BACKGROUND OF THE INVENTION
The instant invention relates to a new and industrially advantageous process for the preparation of 4-[2-(5-ethyl-2-pyrldinyl)ethoxy] aryl derivatives of formula I

Formula I where G1 is selected from one or more of the following groups NO2, NH2, NHR1, COOH or COOR2; Ri is acetyl or trifluoro acetyl group and R2 is an alkyl group.
This compound is the key intermediate for the synthesis of the thiazolidinediones, oral hypoglycemic agents.

Previously Known methods for the synthesis of some of the 4-[2-(5-ethyl-2-pyrldlnyl) ethoxy]-aryl derivatives were reported in EP 0 139 256, EP 0 257 781, WO 93/13095, EP 0 816 340.
EP 0 193 256, WO 93/13095 disclosed a reaction of 4-fluoronitroaryl compounds with 2-(5-ethyl-2-pyridinyl) ethanol to produce 4-[2-(5-ethyl-2-pyridlnyl)ethoxy] nitro aryl.
EP 0 257 781 disclosed a reaction of 4-hydroxybenzaldehyde with 2-(5-ethyl-2-pyridinyl)ethanol, or Its derivatives to produce 4-[2-(5-ethyl-2-pyrldlnyl)ethoxy] benzaldehyde. It also disclosed a reaction of 4-cyanophenol with 2-(5-ethyl-2-pyridinyl) ethanol, or Its derivatives to produce 4-[2-(5-ethyl-2-pyrldlnyl)ethoxy] cyan aryl compounds.
EP 0 816 340 disclosed a reaction of 4-hydroxybenzaldehyde with 2-(5-ethyl-2-pyrldlnyl)ethanol, or Its derivatives to produce 4-[2-(5-ethyl-2-pyrldlnyl)ethoxy] benzaldehyde.
The above mentioned methods described in the prior art for the manufacture of compound of formula I or It"s derivatives suffers from the limitation that they use sodium hydride for the reaction, which is a hazardous chemical with potential fire hazard.
The present Invention provides solution to this problem by using non-hazardous reagents.

Also, the present process discloses use of novel starting materials and reagents for the production of 4-[2-(5-ethyl-2-pyridinyl)ethoxy] aryl derivatives.
SUMMARY OF THE INVENTION
The process for preparing of 4-[2-(5-ethyl-2-pyridinyl)ethoxy] aryl derivatives which is a useful intermediate for the synthesis of thiazolidinedione derivatives; comprise of reacting a compound of formula II, where G2 is selected from H, mesyl or tosyl; with a compound of formula III, where G1 is selected from one or more of the following groups NO2, NH2, NHRi, COOH or COOR2; Ri is acetyl or trifluoro acetyl group and R2 is an alkyl group to give the title compound of formula I.
The advantages of the present invention as discussed in the present application over other reported methods include:
(!) Use of non-hazardous reagents.
(ii) Readily available and cheap raw materials.
(ill) Economic and industrially viable process.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for the synthesis of 4-[2-(5-ethyl-2-pyridinyl) ethoxy]-aryl derivatives of formula I

Formula I where G1 is selected from one or more of the following groups NO2, NH2, NHRi, COOH or COOR2; R1 is acetyl or trifluoro acetyl group and R2 is an alkyl group.
The synthesis compounds of formula I comprises of reacting a compound of formula II with a compound of formula III

Formula II Formula III
where G2 is selected from H, mesyl or tosyl; where Gi is selected from one or more of the following groups NO2, NH2, NHRi, COOH or COOR2; Ri is acetyl or trifluoro acetyl group and R2 is an alkyl group.

The reaction is carried out in halogenated hydrocarbon, alcohols, dimethylformamide or acetonitrile.
The halogenated hydrocarbon is selected from dichloromethane or ethylene dichloride.
The alcohol is selected from iso-propanol or ethanol.
When G2 is H the reaction is carried out in the presence of PhsP-diisopropyl axodicarboxylate or LiOH-AbOs.
When G2 is mesyl or tosyl the reaction is carried out in the presence of KOH, K2CO3, LiOH-AlzOs or NaOH.
The invention is further illustrated with examples below, which are not intended to be limiting.
EXAMPLE 1
5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: A stirred
suspension of potassium carbonate (91 g, 0.66 mol) in isopropyl alcohol (400 mL) was heated to 40-45 ° C and p-nitrophenol (64 g, 0.46 mol) was added. After stirring for 1 h at 40-45 ° C, a solution of 2-(5-ethylpyridin-2-yl)ethyl methanesulfonate (100 g, 0.44 mol) in isopropyl alcohol (400 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 18 h maintaining the temperature

between 60-70 ° C. The reaction mixture was filtered and concentrated, diluted with water (1 L), and extracted using ethyl acetate (3 x 500 mL). The combined extract was washed with water (500 mL), brine (500 mL) and concentrated. The residue was stirred with petroleum ether (150 mL) and filtered. Yield: 85 g (71 %).
EXAMPLE 2
5-ethyh2-[2-(4-nitrophenoxy)ethyl]pyridine: A stirred
suspension of potassium hydroxide (37 g, 0.66 mol) in isopropyl alcohol (400 mL) was heated to 40-45 ° C and p-nltrophenol (64 g, 0.46 mol) was added. After stirring for 1 h at 40-45 °C, a solution of 2-(5-ethylpyridin-2-yi)ethyl methanesulfonate (100 g, 0.44 mol) In isopropyl alcohol (400 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 18 h maintaining the temperature between 60-70 ° C. The reaction mixture was filtered and concentrated, diluted with water (1 L), and extracted using ethyl acetate (3 x 500 mL). The combined extract was washed with water (500 mL), brine (500 mL) and concentrated. The residue was stirred with petroleum ether (150 mL) and filtered. Yield: 65 g (55 %).
EXAMPLE 3
5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: To A stirred suspension of p-nitrophenol (32 g, 0.23 mol) and 2-(5-ethylpyridin-2-yl)ethanol (35 g, 0.23 mol) in dichioromethane (200 mL), triphenyl phosphine (63 g, 0.24 mol) and diisopropyl azodicarboxylate (48.5 g.

0.24 mol) were added and stirred for 24 h at ambient temperature. The reaction mixture was filtered, washed with water (250 mL), brine (250 mL) and concentrated. The residue was stirred with petroleum ether (75 mL) and filtered. Yield: 35 g (56 %).
EXAMPLE 4
5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: To A stirred suspension of p-nitrophenol (32 g, 0.23 mol) and 2-(5-ethylpyridin-2-yl)ethanol (35 g, 0.23 mol) In acetonltrile (200 mL), LiOH-AbOa (15 g LiOH adsorbed on 90 g AI2O3) was added and stirred for 24 h at 70-80 °C. The reaction mixture was filtered, diluted with water (250 mL) and extracted using ethyl acetate (3 x 250 mL). The combined extract was washed with water (250 mL), brine (250 mL) and concentrated. The residue was stirred with petroleum ether (75 mL) and filtered. Yield: 32 g (51 %).
EXAMPLE 5
5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: A stirred
suspension of potassium carbonate (68 g, 0.49 mol) in isopropyl alcohol (300 mL) was heated to 40-45 ° C and p-nitrophenol (48 g, 0.34 mol) was added. After stirring for 1 h at 40-45 ° C, a solution of 2-(5-ethylpyridln-2-yl)ethyl 4-methylarylsulfonate (100 g, 0.32 mol) In Isopropyl alcohol (300 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 16 h maintaining the temperature between 60-70 ° C. The reaction mixture was filtered

and concentrated, diluted with water (750 mL), and extracted using ethyl acetate (3 x 300 mL). The combined extract was washed with water (300 mL), brine (300 mL) and concentrated. The residue was stirred with petroleum ether (100 mL) and filtered. Yield: 52 g (60
%).
EXAMPLE 6
5-ethyl-2-[2-(4-nitrophenoxy)ethyl]pyridine: A stirred
suspension of potassium hydroxide (27.5 g, 0.49 mol) In isopropyl alcohol (300 mL) was heated to 40-45 ° C and p-nitrophenol (48 g, 0.34 mol) was added. After stirring for 1 h at 40-45 ° C, a solution of 2-(5-ethylpyridin-2-yl)ethyl 4-methylarylsulfonate (100 g, 0.32 mol) in isopropyl alcohol (300 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 18 h maintaining the temperature between 60-70 ° C. The reaction mixture was filtered and concentrated, diluted with water (750 mL), and extracted using ethyl acetate (3 x 300 mL). The combined extract was washed with water (300 mL), brine (300 mL) and concentrated. The residue was stirred with petroleum ether (100 mL) and filtered. Yield: 45 g (51 %).
EXAMPLE 7
N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl}acetamide:
A stirred suspension of potassium carbonate (91 g, 0.66 mol) in

isopropyl alcohol (400 mL) was heated to 40-45 ° C and /V-(4-hydroxyphenyl)acetamide (70 g, 0.46 mol) was added. After stirring for 1 h at 40-45 ° C, a solution of 2-(5-ethylpyridin-2-yl)ethyl methanesulfonate (100 g, 0.44 mol) in isopropyl alcohol (400 mL) was added to the reaction mixture drop-wise. The mixture was stirred for 18 h maintaining the temperature between 60-70 ° C. The reaction mixture was filtered and concentrated, diluted with water (1 L), and extracted using ethyl acetate (3 x 500 mL). The combined extract was washed with water (500 mL), brine (500 mL) and concentrated. The residue was stirred with petroleum ether (250 mL) and filtered. Yield: 88 g (70 %).


WE CLAIM:
We claim:
1. A process for the synthesis of compounds of formuia I

Formuia I where G1 is selected from one or more of the following groups NO2,NH2, NHR1, COOH or COOR2; Ri is acetyl or tri-fluoro acetyl group and R2 Is an alkyl group
comprising of reacting a compound of formula II with a compound of formula III in the presence of an organic solvent

Formula II Formula III
where G2 Is selected from H, mesyl or tosyl; G1 Is selected from one or more of the following groups NO2, NH2, NHR1, COOH or

COOR2; R1 is acetyl or trifluoro acetyl group and R2 is an alkyl group.
2. The process as claimed in claim 1, wherein said organic solvent includes halogenated hydrocarbon, alcohols, dimethyl formamide or acetonitrile.
3. The process as claimed in claim 2, wherein the halogenated hydrocarbon is selected from dichloromethane or ethylene dichloride.
4. The process as claimed in claim 2, wherein the alcohol is selected from iso-propanol or ethanol.
5. The process as claimed in claim 1, when G2 is H the reaction is carried out in the presence of Ph3P-diisopropyl azodicarboxalate or LiOH-Al2Os.
6. The process as claimed in claim 1, when G2 is mesyl or tosyl the reaction is carried out in the presence of KOH, K2CO3, LiOH-AI2O3 or NaOH.

7. A process for the synthesis of compounds of formula I substantially as herein described with reference to the foregoing examples.

Documents:

369-mas-2002 others document.pdf

369-mas-2002 abstract duplicate.pdf

369-mas-2002 abstract.pdf

369-mas-2002 claims duplicate.pdf

369-mas-2002 claims.pdf

369-mas-2002 correspondence others.pdf

369-mas-2002 correspondence po.pdf

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

369-mas-2002 description (complete).pdf

369-mas-2002 form-1.pdf

369-mas-2002 form-13.pdf

369-mas-2002 form-19.pdf

369-mas-2002 form-26.pdf

369-mas-2002 form-3.pdf

369.jpg


Patent Number 198938
Indian Patent Application Number 369/MAS/2002
PG Journal Number 23/2006
Publication Date 09-Jun-2006
Grant Date 27-Feb-2006
Date of Filing 17-May-2002
Name of Patentee M/S. BIOCON LIMITED
Applicant Address 20th KM HOSUR ROAD, HEBBAGODI 561 229, BANGALORE
Inventors:
# Inventor's Name Inventor's Address
1 POORNAPRAJNA ACHARYA BIOCON LIMITED, 20th KM HOSUR ROAD, HEBBAGODI 561 229, BANGALORE
2 UJIRE SANDHYA BIOCON LIMITED, 20th KM HOSUR ROAD, HEBBAGODI 561 229, BANGALORE
3 VEERANNA VIJAYA KUMAR BIOCON LIMITED, 20th KM HOSUR ROAD, HEBBAGODI 561 229, BANGALORE
4 SRIDHARAN MADHAVAN BIOCON LIMITED, 20th KM HOSUR ROAD, HEBBAGODI 561 229, BANGALORE
5 GANESH SAMBASIVAM BIOCON LIMITED, 20th KM HOSUR ROAD, HEBBAGODI 561 229, BANGALORE
6 PUTHIAPARAMPIL TOM THOMAS BIOCON LIMITED, 20th KM HOSUR ROAD, HEBBAGODI 561 229, BANGALORE
PCT International Classification Number C07D 213/30
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA