Title of Invention

A PROCESS FOR THE PREPARATION OF ETHYL 3-ETHOXY-4-ETHOXYCARBONYL-PHENYLACETATE

Abstract A process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyI-phenylacetate The present invention relates to a process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate having formula 1. Ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate (1) is an important key intermediate for the synthesis of repaglinide (2) an oral hypoglycemic agent. The process steps are; reacting 4-methylsalicylic acid with diethyl sulfate in presence of potassium carbonate in polar organic solvent to obtain ethyl-2-ethoxy-4-methylbenzoate, brominating ethyl-2-ethoxy-4-methylbenzoate with a brominating agent in organic solvent to obtain ethyl-4-bromomethyl-2-ethoxy benzoate, reacting ethyl-4-bromomethyl-2-ethoxy benzoate with CO in ethyl alcohol in the presence of a palladium catalyst, to obtain ethyl 3-ethoxy-4-ethoxycarbonyI-phenylacetate of formula 1.
Full Text Field of the invention
The present invention relates to a process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate having formula 1.
(Formula removed)

Ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate (1) is an important key intermediate for the synthesis of repaglinide (2) an oral hypoglycemic agent.
(Formula removed)

Background of the Invention
Repaglinide (+) 2 ethoxy-4[N-{l-(2-piperidinophenyl)3-methyll-butyl} aminocarbonyl methyl] benzoicacid having formula 2 is from a class of hypoglycemic agents for type II non insulin dependant diabetes mellitus.
Hitherto known process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate having formula 1 involves two methods as shown below Route 1 (J. Med. Chem. 1998, 41, 5219)
1. Alkylation of 4-methylsalicylic acid with ethyl bromide at 150°C for 30 hrs in autoclave to give ethyl 2-ethoxy-4-methyl benzoate of formula 3.
(Formula removed)

(Formula Removed)
2.
Formula 3
2. Bromination of ethyl 2-ethoxy-4-methyl benzoate of Formula 3 with N-bromo succinamide to give ethyl 4-bromomethyl-2-ethoxybenzoate of formula 4.
(Formula Removed)

o •• Formula 4
3. Cyanation of compound of formula 4 with sodium cyanide to give ethyl-4-cyanomethyl-2-ethoxybenzoate of formula 5.
(Formula Removed)

Formula 5
3. Treatment of gaseous HCL with ethyl-4-cyanomethyl-2-ethoxybenzoate in ethyl alcohol to give ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate of formula 1.

(Formula Removed)

Route 2 (PCT WO 01/3590, 2001)
1. Alkylation of 4-methylsalicylic acid with ethyl bromide in dimethyl sulfoxide to yield ethyl-2-ethoxy-4-methylbenzoate of formula 3.
(Formula Removed)

Formula 3
2. Carbonylation of ethyl-2-ethoxy-4-methylbenzoate with lithium diisopropyl amide and carbon dioxide at -80°C in presence of HMPA gave 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid of formula 6.
(Formula removed)

The prior art processes have following drawbacks.
a. The alkylation of 4-methylsalicylic acid involves the use of ethyl bromide which
is low boiling reagent, inconvenient for industrial handling.
b. The alkylation of 4-methylsalicylic acid requires dimethylsulfoxide solvent
which is not safe for industrial scale.
c. The alkylation reaction requires high pressure and long duration.
d. The use of with lithium diisopropylamide reaction is not easier to handle on
industrial scale.
Objects of the invention
The main object of the present invention is to provide a new process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate of formula 1 which obviates the drawbacks of the prior art processes and use cheaper and easily available chemicals. Summary of Invention
Accordingly the present invention provide a new process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate of formula 1 which comprises a. reacting 4-methylsalicylic acid with diethyl sulfate in presence of potassium carbonate in polar organic solvent at a temperature in the range of 50-80°C for a
time period in the range of 6-12 hrs, filtering the product obtained, removing the organic solvent by evaporation and distilling the residue to obtain ethyl-2-ethoxy-4-methylbenzoate of formula 3,
(Formula removed)

b. brominating ethyl-2-ethoxy-4-methylbenzoate of formula 3 with a brominating
agent in organic solvent at temperature in the range of 40-60°C to obtain ethyl-4-
bromomethyl-2-ethoxy benzoate of formula 4,
(Formula removed)

c. Reacting ethyl-4-brornomethyl-2-ethoxy benzoate with CO in ethyl alcohol at a
temperature in the range of 30-50°C for the period in the range of 14-24 hrs, in the
presence of a palladium catalyst, removing the solvent by evaporation to obtain
ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate of formula 1
(Formula removed)

In one embodiment of the invention the organic solvent used in step (a) for the reaction is selected from the group consisting of acetonitrile, acetone and dioxane.
In another embodiment of the invention the brominating agent used in step (b) is selected from l,3-dibromo-5,4-dimethylhydantoin and N-bromosuccinamide.


In another embodiment of the invention the palladium catalyst used is selected from dichlorobis (1,2,5-triphenylphosphole) palladium and dichlorobis-(triphenylphosphine) palladium. Detailed description of the invention
the present invention provide a new process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate of formula 1 which comprises
a. reacting 4-methylsalicylic acid with diethyl sulfate in presence of potassium
carbonate in polar organic solvent at a temperature in the range of 50-80°C for a
time period in the range of 6-12 hrs, filtering the product obtained, removing the
organic solvent by evaporation and distilling the residue to obtain ethyl-2-ethoxy-
4-methylbenzoate of formula 3.
b. brominating ethyl-2-ethoxy-4-methylbenzoate of formula 3 with a brominating
agent in organic solvent at temperature in the range of 40-60°C to obtain ethyl-4-
bromomethyl-2-ethoxy benzoate of formula 4.
c. reacting ethyl-4-bromomethyl-2-ethoxy benzoate with CO in ethyl alcohol at a
temperature in the range of 30-50°C for the period in the range of 14-24 hrs, in the
presence of a palladium catalyst, removing the solvent by evaporation to obtain
ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate of formula 1
The organic solvent used in step (a) for the reaction is selected from the group consisting of acetonitrile, acetone and dioxane. The brominating agent used in step (b) is selected from l,3-dibromo-5,4-dimethylhydantoin and N-bromosuccinamide. The palladium catalyst used is selected from dichlorobis (1,2,5-triphenylphosphole) palladium and dichlorobis-(triphenylphosphine) palladium prepared by procedure reported in literature [B.M. Choudhary & N. Prabhakar Reddy, Polyhydron, 5, 911 (1986); T. Okano, I. Uchida, T. Nakagaki, H. Konishi, /. Molecular catalysis, 54, 65 (1989)].
The process of the present invention is described herein below with reference to the following examples which are illustrative and should not be construed as limiting the scope of the present invention in any manner. Example 1
4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15g, 0.132 mole) were mixed thoroughly in dry acetonitrile and mixture was refluxed for 12 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum.
Residue was purified by fractional distillation at 0.5mm vacuum. 1st fraction distilled
at 48-51°C (oil bath temperature 80°C). Product (ethyl-2-ethoxy-4-methylbenzoate) 3
distilled at 90-93°C (oil bath temperature 120°C) Yield = 6 g (87%).
'HNMR CDC13 (Spectrum 1) 1.35(t, 3H), 1.45(1, 3H), 2.35(s, 3H), 4.07(q, 2H),
4.34(q, 2H), 6.75(s, 1H), 6.77(d, 1H), 7.70(d, 1H)
GC conditions
Column : HP1
Temperature : 100-200°C,
Diethyl sulphate : 0.48 RT
Product 3 : 4.09 RT
Example 2
4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) and anhydrous potassium carbonate (18.15g, 0.132 mole) were mixed thoroughly in dry dioxane and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction distilled at 48-51°C (oil bath temperature 80°C). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93°C (oil bath temperature 120°C) Yield = 5.8 g (84%). Example 3.
4-Methyl salicylic acid (5 g, 32.89 mmol), diethyl sulfate (20.26 g, 0.131 mole) 'and anhydrous potassium carbonate (18.15g, 0.132 mole) were mixed thoroughly in dry acetone and mixture was refluxed for 16 hr. Reaction mixture was cooled and filtered through Celite bed. Filtrate was concentrated under vacuum. Residue was purified by fractional distillation at 0.5 mm vacuum. 1st fraction distilled at 48-51°C (oil bath temperature 80°C). Product (ethyl-2-ethoxy-4-methylbenzoate) 3 distilled at 90-93°C (oil bath temperature 120°C) Yield = 5.2 g (75%) Example 4
Ethyl-2-ethoxy-4-methylbenzoate (3, 5g, 24 mmol), freshly recrystallized N-bromosuccinimide (4.7 g, 26.4 mmol), AIBN (30 mg) were mixed in dry carbon tetrachloride (25 ml). Mixture was irradiated with light using 500 W lamp and was refluxed for 12 hr. Reaction mixture was cooled to room temperature and filtered to remove succinimide. Filtrate was washed with water followed by brine wash, dried

on anhydrous sodium sulfate and solvent was removed under vacuum. Residue
solidifies on keeping. It was dissolved in petroleum, ether (10 ml) by refluxing.
Solution was kept at room temperature for 6 hr. Product ethyl 4-bromomethyl-2-
ethoxy-benzoate (4) crystallized out as yellow crystals. Cooled in ice bath and
filtered. Crystals were washed with ice-cold pet. ether. Dried in air. Yield = 3.5 g
(50.9%).
'HNMR CDC13: (Spectrum 2) 1.45(m,6H), 4.12(q, 2H), 4.34(q, 2H), 4.46(s, 2H),
6.97(s, 1H), 6.98(d, 1H), 7.72(d, 1H)
MS: (Spectrum 3) 287(12%), 286(10%), 208(14%), 161(47%), 147(24%),
134(100%), 119(16%), 105(28%)
Example 5.
A mixture ethyl 4-bromomethyl-2-ethoxy-benzoate (4, 1 gm, 3.5 mmol), dichlorobis-(triphenylphosphine)palladuim catalyst (0.1 gm), ethyl alcohol (5 ml) was heated to 50°C with CO for 6-15 hrs. Catalyst was filtered and solvent was removed to yield the product ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate (1, 0.75 gm, 2.6 mmol, 76%).
'HNMR CDC13 1.26(t, 3H), 1.44(t, 3H), 3.60(s, 2H), 4.18(q, 2H), 4.35(m, 4H), 6.82(d, 1H), 6.90(s, 1H), 7.81(d, 1H). Example 6
A mixture of ethyl 4-bromomethyl-2-ethoxy-benzoate (4, 1 gm, 3.5 mmol), dichlorobis (l,2,5-triphenylphosphole)-palladium catalyst (0.1 gm), ethyl alcohol (5 ml) was heated to 50°C with CO for 6-15 hrs. Catalyst was filtered and solvent was removed to yield the product ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate (1, 0.87 gm, 3.1 mmol, 88%).






We claim:
1. A process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate of formula 1 which comprises
(Formula removed)

a. reacting 4-methylsalicylic acid with diethyl sulfate in presence of
potassium carbonate in polar organic solvent at a temperature in
the range of 50 to 80°C and for a time period in the range of 6 to 12
hours, filtering, removing the organic solvent by evaporation and
distilling to obtain ethyl-2-ethoxy-4-methylbenzoate of formula 3.
(Formula removed)

b. brominating ethyl-2-ethoxy-4-methylbenzoate of formula 3 with
brominating agent selected from dibromo dimethylhydantoin or N-
bromosuccinimide. in organic solvent at a temperature in the range
of 40 to 60°C to yield ethyl-4-bromomethyl-2-ethoxy benzoate of
formula 4.
(Formula removed)

c. reacting ethyl-4-bromomethyl-2-ethoxy benzoate with CO in ethyl
alcohol in presence of palladium catalyst at a temperature in the
range of 30 to 50°C and for a time period in the range of 14 to 24
hours, removing the solvent by evaporation to obtain ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate of formula 1
2. A process claimed in claim 1, wherein the polar organic solvent used in step (a) is
selected from the group consisting of acetonitrile, acetone and dioxane.
3. A process claimed in claim 1, wherein CO is used for the extension one carbon
unit.
4. A process claimed in claim 1, wherein the palladium catalyst used is selected from
dichlorobis (l,2,5-triphenylphosphole)-palladium or dichlorobis-
(triphenylphosphine) palladium.
5. A process as claimed in claim 1, wherein the solvent used in step (b) comprises
carbon tetrachloride.
6. A process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyI-phenylacetate
of formula 1 substantially as herein describe with reference to examples
accompanying this specification.

Documents:

643-del-2004-Abstract-(24-12-2009).pdf

643-del-2004-abstract.pdf

643-del-2004-Claims-(24-12-2009).pdf

643-del-2004-claims.pdf

643-DEL-2004-Correspondence-Others-(12-03-2010).pdf

643-DEL-2004-Correspondence-Others-(23-03-2010).pdf

643-del-2004-Correspondence-Others-(24-12-2009).pdf

643-del-2004-correspondence.pdf

643-DEL-2004-Correspondesce-Others.pdf

643-DEL-2004-Correspondesce-po.pdf

643-del-2004-Description (Complete)-(24-12-2009).pdf

643-DEL-2004-Description (Complete).pdf

643-del-2004-description.pdf

643-del-2004-Form-1-(24-12-2009).pdf

643-DEL-2004-Form-1.pdf

643-DEL-2004-Form-18.pdf

643-del-2004-Form-2-(24-12-2009).pdf

643-DEL-2004-Form-2.pdf

643-del-2004-Form-3-(24-12-2009).pdf

643-DEL-2004-Form-3.pdf

643-DEL-2004-Form-5.pdf

643-del-2004-form1.pdf

643-del-2004-form2.pdf

643-del-2004-form3.pdf

643-del-2004-form5.pdf

643-DEL-2004-Petition 137-(12-03-2010).pdf

643-DEL-2004-Petition 137-(23-03-2010).pdf

abstract.jpg


Patent Number 239893
Indian Patent Application Number 643/DEL/2004
PG Journal Number 15/2010
Publication Date 09-Apr-2010
Grant Date 07-Apr-2010
Date of Filing 31-Mar-2004
Name of Patentee COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 UTTAM RAMRAO KALKOTE NATIONAL CHEMICAL LABORATORY, PUNE, INDIA.
2 MUKUND KESHAO GURJAR NATIONAL CHEMICAL LABORATORY, PUNE, INDIA.
3 SHREERANG VIDYADHAR JOSHI NATIONAL CHEMICAL LABORATORY, PUNE, INDIA.
4 SURESH MAHADEV KADAM NATIONAL CHEMICAL LABORATORY, PUNE, INDIA.
5 SANJAY JANARDHAN NAIK NATIONAL CHEMICAL LABORATORY, PUNE, INDIA.
PCT International Classification Number C07C 229/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA