Title of Invention

A PROCESS OF MANUFACTURING PARA METHOXY BENZOIC ACID OR 4-METHOXY BENZOIC ACID

Abstract The present invention relates to a process of preparation of 4-Methoxy Benzoic Acid also known as p-Anisic Acid comprising the etherification of para Hydroxy Benzoic Acid with Dimethyl Sulfate of a quaternary ammonium salt and various alkali hydroxides.
Full Text S-3/PATENT/GUJARAT ORGANIC/PATENT PAA/03.05.06
FORM 2
THE PATENTS ACT, 1970
{39 OF 1970)
&
THE PATENT RULES, 2003
PROVISIONAL SPECIFICATION [SECTION 10 AND RULE 13]
"AQUEOUS PROCESS TO MANUFACTURE PARA METHOXY BENZOIC ACID"
APPLICANT: GUJARAT ORGANICS LIMITED
NATIONALITY: AN INDIAN COMPANY INCORPORATED UNDER THE COMPANIES
ACT, 1956.
ADDRESS: PLOT NO.127/1, GIDC ESTATE, ANKLESHWAR 393 002,
DIST.BHARUCH, GUJARAT STATE, INDIA.
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION: -

2
>-
The present invention relates to the aqueous process of manufacture of 4-Methoxy Benzoic Acid/ Para Anisic Acid.
In the prior art p- Anisic Acid is prepared by catalytic oxidation of p-Methoxy Toluene ,p-anisole Oxidation, para methyl phenol oxidation and methylation of Para hydroxy benzoic acid.The references shows antituberculostatics and antimycobacterial activity of p-Anisic Acid or 4-Methoxy Benzoic Acid .
The present invention involves the reaction of para Hydroxy Benzoic Acid with Dimethyl Sulfate, using Quaternary ammonium salt at controlled pH The one pot synthesis takes place In following steps.
The Phenolic OH group of p-Hydroxy Benzoic Acid is etherified with Dimethyl Sulfate in presence of alkali hydroxides in the presence of phase transfer catalyst e.g. Tetra butyl ammonium Bromide. The progress of the reaction is monitored on thin layer chromatography till P.H.B.A is absent.
The present invention deals with preparation of pure 4-Methoxy Benzoic Acid or p-Anisic Acid having P.H.B.A contents less than 0.2 %( 2000ppm). This was achieved by reacting p-Hydroxy Benzoic Acid in strong aqueous alkaline solution with Dimethyl Sulfate in presence of a quaternary Ammonium salt The 4-Methoxy Benzoic Acid also contains the impurity of 4-Methoxy Benzoic Acid Methyl Ester The formed ether ester of 4-Methoxy Benzoic Acid Methyl Ester is hydrolyzed in situ by addition of alkali hydroxide and heating the reaction mixture up to 90-96 °C. The 4-Methoxy Benzoic Acid Sodium Salt thus obtained is treated with mineral acid to liberate 4-Methoxy Benzoic Acid as a solid The solid obtained is filtered and washed with water till sulfate free. The solid p-Anisic Acid or 4-Methoxy Benzoic Acid is dried till moisture content less than 5000 ppm.(0.5%). The purity of solid obtained is 99.1% to 99.5%.



OOCH3

COOH

+ (CH3)2S04 + R_OH + TBAB

40 - 50 C
Water

COOH


CH,
o



POOR
Alkali Hydroxide
o
90 - 95 C
F.W. 138 126
COOH
P.H.B.A Di methyl sulphate Alkali Hydroxide
)CH3 P-Anisic Acid Sodum Salt
30%- H2S04
)CH3 p-Anisic Acid

3
SUMMARY OF THE INVENTION
The present invention relates to an aqueous process to prepare 4-methoxy Benzoic Acid comprising the steps of i) etherification of phenolic OH group and ii) hydrolysis of the resultant at step i) using an alkali hydroxide.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of 4-Methoxy Benzoic Acid or p-Anisic Acid comprising the steps of: a) Etherification of Phenolic OH group using Dimethyl Sulfate and alkali hydroxide, b) Hydrolysis of the formed impurity (ether ester) using alkali hydroxide. The p-Hydroxy Benzoic Acid Phenolic -OH group is etherified on reaction with Dimethyl sulfate in the presence of alkali hydroxide pH range 9.0 to 13 in the presence of a quaternary ammonium salt in aqueous medium at temperature ranges between 30 to 55 °C. The reaction is monitored on thin layer chromatography till (p-Hydroxy Benzoic Acid is absent.) Hydrolysis of the 4-Methoxy Benzoic Acid Methyl ester at 90 to 96 °C to 4-Methoxy Benzoic Acid Sodium salt till ether ester absent by TLC. Cool the contents to 28 to 30 °C and add Mineral acid /organic acid continuously to make it acidic to congo red (pH range 2.0-3.0). The solid 4-Methoxy Benzoic Acid or p-Anisic Acid thus obtained is filtered /centrifuged, washed with water till sulfate free (less than 2000ppm) The solid obtained is dried till moisture content less than 2000ppm(parts per million)
The preferred alkali hydroxide is either Sodium Hydroxide, potassium Hydroxide or lithium Hydroxide.
The preferred quaternary ammonium salt is tetra butyl ammonium bromide or Benzyl tri ethyl ammonium chloride.
The quaternary ammonium salt is preferably generated in situ, using Benzyl chloride and triethyl amine.
The methylating agent used is Dimethyl Sulfate.
The present invention will now be described with reference to the following examples. However, the examples are only illustrative and in no way limit the scope of the invention:
EXPERIMENTAL SECTION:
EXPERIMENT ONE:
Charge p-Hydroxy Benzoic Acid (1.0 kg) in water (1.5 Kg). Charge Sodium Hydroxide (0.580kg+0.200 kg) followed by addition of Dimethyl Sulfate (2.8 kg) at 30-55°C. The Dimethyl Sulfate addition is done at pH 9.0 to 13. The contents are stirred at 30-55°C for 18 hrs and pH is kept -9.0 to 13. The contents are stirred at 30-55 °C for 18 hrs and pH is kept'-9.0 to 13 by adding alkali hydroxide solution till p-Hydroxy Benzoic Acid is absent on T.L.C.When reaction is complete at 30-55°C, contents are hydrolyzed by addition of 0.3 kg Sodium hydroxide water solution and 0.3 litre of water followed by heating of the contents at 90-95 °C. The contents are then cooled to 28-30 °C. The pH of the contents is adjusted by acidifying it to pH 2.5-3.0 at 28-40°C. Then stir the contents for 1.0 hr at 28-40°C followed by the filtration of the solid The filtered solid is washed with water till sulfate free(less than 500 parts per million). The solid is unloaded and dried till LOD less than 0.2 %( 2000ppm).

*fery weight of 4-Methoxy Benzoic Acid = 1.03 kg
% yield =93.6% (theory)
Purity (H.P.L.C) =99.5%
Moisture Content =2000 ppm
Ether Ester impurity = not detected
MP = 180-184 °C
EXPERIMENT TWO
Charge p-Hydroxy Benzoic Acid (1.0 kg) in water (1.5 Kg). Charge Potassium Hydroxide (0.812 kg+0.280 kg) and Tetra butyl ammonium bromide 0.04 kg followed by addition of Dimethyl Sulfate (2.8 kg) at 30-55°C. The DimethylSulfate addition is done at pH 9.0 to 13. The contents are stirred at 30-55°C for 18 hrs and pH is kept -9.0 to 13. The contents are stirred at 30-55 °C for 18 hrs and pH is kept'-9.0 to 13 by adding potassium hydroxide solution till p-Hydroxy Benzoic Acid is absent on T.L.C.When reaction is complete at 30-55°C, contents are hydrolyzed by addition of 0.420 kg potassium hydroxide and 0.4litre of water followed by heating of the contents at 90-95 °C. The contents are then cooled to 28-30 °C.The pH of the contents is adjusted by acidifying it to pH 2.5-3.0 at 28-40°C Then stir the contents for 1.0 hr at 28-40°C followed by the filtration of the solid The filtered solid is washed with water till sulfate free(less than 500 parts per million) Then solid is unloaded and dried till LOD less than 0.2 %(2000ppm).
Dry weight of 4-Methoxy Benzoic Acid = 1.05 kg
% yield =95.40% (theory)
Purity (H.P.L.C) =99.6%
Moisture Content =2000 ppm
Ether Ester impurity = not detected
M.P = 180-184 °C
EXPERIMENT THREE:
Charge p-Hydroxy Benzoic Acid (1.0 kg) in water (1.5 Kg). Charge Lithium Hydroxide (0.348kg+0.120 kg) and Benzyl Triethyl ammonium chloride 0.04 kg generated insitu using benzyl chloride and tri ethyl amine followed by addition of Dimethyl Sulfate (2.8 kg) at 30-55 C. The Dimethyl Sulfate addition is done at pH 9.0 to 13. The contents are stirred at 30-55°C for 18 hrs and pH is kept -9.0 to 13. The contents are stirred at 30-55 °C for 18 hrs and pH is kept'-9.0 to 13 by adding lithium hydroxide solution till p-Hydroxy Benzoic Acid is absent on T.L.C.When reaction is complete at 30-55°C, contents are hydrolyzed by addition of 0.18 kg lithium hydroxide and 0.18 litre of water followed by heating of the contents at 90-95 °C. Then contents are cooled to 28-30 °C.The pH of the contents is adjusted by acidifying it to pH 2.5-3.0 at 28-40°C Then stir the contents for 1.0 hr at 28-40°C followed by the filtration of the solid The filtered solid is washed with water till sulfate free(less than 500 parts per million). The solid is unloaded and dried till LOD less than 0.2 %( 2000ppm).
Dry weight of 4-Methoxy Benzoic Acid = 1.02 kg
% yield =92.70% (theory)
Purity (H.P.L.C) =99.5%
Moisture Content =2000 ppm
Ether Ester impurity = not detected
M.P = 180-184 °C

EXPERIMENT FOUR:
>-
Charge p-Hydroxy Benzoic Acid (1.0 kg) in water (1.5 Kg). Charge Sodium Hydroxide (0.580kg+0.200 kg) and tetra butyl ammonium iodideO.04 kg followed by addition of Dimethyl Sulfate (2.8 kg) at 30-55°C. The Dimethyl Sulfate addition is done at pH 9.0 to 13. The contents are stirred at 30-55°C for 18 hrs and pH is kept -9.0 to 13. The contents are stirred at 30-55 °C for 18 hrs and pH is kept'-9.0 to 13 by adding alkali hydroxide solution till p-Hydroxy Benzoic Acid is absent on T.L.C.When reaction is complete at 30-55°C, contents are hydrolyzed by addition of 0.3 kg alkali hydroxide and 0.3 litre of water followed by heating of the contents at 90-95 °C. Then contents are cooled to 28-30 °C. The pH of the contents is adjusted by acidifying it to pH 2.5-3.0 at 28-40°C Then stir the contents for 1.0 hr at 28-40°C followed by the filtration of the solid .The filtered solid is washed with water till sulfate free(less than 500 parts per million) The solid is unloaded and dried till LOD less than 0.2 %(2000ppm).
Dry weight of 4-Methoxy Benzoic Acid = 1.05 kg
% yield =95.4% (theory)
Purity (H.P.L.C) =99.6%
Moisture Content =2000 ppm
Ether Ester impurity = not detected
MP = 180-184 0C
EXPERIMENT FIVE:
Charge p-Hydroxy Benzoic Acid (1.0 kg) in water (1.5 Kg). Charge Potassium Hydroxide (0.812kg+0.280 kg) and tetra butyl ammonium hydrogen sulphate 0.04 kg followed by addition of Dimethyl Sulfate (2.8 kg) at 30-55°C. The Dimethyl Sulfate addition is done at pH 9.0 to 13. The contents are stirred at 30-55°C for 18 hrs and pH is kept -9.0 to 13. The contents are stirred at 30-55 °C for 18 hrs and pH is kept'~9.0 to 13 by adding potassium hydroxide solution till p-Hydroxy Benzoic Acid is absent on T.L.C.When reaction is complete at 30-55°C, contents are hydrolyzed by addition of 0.42kg alkali hydroxide and 0.42 litre of water followed by heating of the contents at 90-95 °C. The contents are cooled to 28-30 °C.The pH of the contents is adjusted by acidifying it to pH 2.5-3.0 at 28-40°C Then stir the contents for 1.0 hr at 28-40°C followed by the filtration of the solid The filtered solid is washed with water till sulfate free (less than 500 parts per million) The solid is unloaded and dried till LOD less than 0.2 %(2000ppm).
Dry weight of 4-Methoxy Benzoic Acid = 1.03 kg
% yield =93.6% (theory)
Purity (H.P.L.C) =99.5%
Moisture Content =2000 ppm
Ether Ester impurity = not detected
MP = 182-184 °C

6 ADVANTAGES:
(1) Present invention produces 4-Methoxy Benzoic Acid or p-Anisic Acid free from p-Hydroxy Benzoic Acid in 92.7 to 95.4 % yield based on theory.
(2) The present invention is an economical method for manufacturing of 4-Methoxy Benzoic Acid or p-Anisic Acid.
Dated this jT_ day of May 2006
Himanshu Wasudeo Kane Applicants' Patent Agent
TO
The Controller of Patents The PATENT OFFICE, MUMBAI 400037

Documents:

718-MUM-2006-ABSTRACT(3-5-2007).pdf

718-MUM-2006-ABSTRACT(GRANTED)-(6-5-2011).pdf

718-MUM-2006-CANCELLED PAGES(13-4-2011).pdf

718-MUM-2006-CANCELLED PAGES(5-5-2010).pdf

718-MUM-2006-CLAIMS(3-5-2007).pdf

718-MUM-2006-CLAIMS(AMENDED)-(13-4-2011).pdf

718-MUM-2006-CLAIMS(AMENDED)-(5-5-2010).pdf

718-MUM-2006-CLAIMS(GRANTED)-(6-5-2011).pdf

718-mum-2006-correspondance-received.pdf

718-MUM-2006-CORRESPONDENCE(04-05-2009).pdf

718-MUM-2006-CORRESPONDENCE(19-6-2007).pdf

718-MUM-2006-CORRESPONDENCE(IPO)-(6-5-2011).pdf

718-mum-2006-description (provisional).pdf

718-MUM-2006-DESCRIPTION(COMPLETE)-(3-5-2007).pdf

718-MUM-2006-DESCRIPTION(GRANTED)-(6-5-2011).pdf

718-MUM-2006-FORM 18(19-6-2007).pdf

718-MUM-2006-FORM 2(COMPLETE)-(3-5-2007).pdf

718-MUM-2006-FORM 2(GRANTED)-(6-5-2011).pdf

718-MUM-2006-FORM 2(TITLE PAGE)-(5-5-2010).pdf

718-MUM-2006-FORM 2(TITLE PAGE)-(COMPLETE)-(3-5-2007).pdf

718-MUM-2006-FORM 2(TITLE PAGE)-(GRANTED)-(6-5-2011).pdf

718-MUM-2006-FORM 2(TITLE PAGE)-(PROVISIONAL)-(9-5-2006).pdf

718-MUM-2006-FORM 5(3-5-2007).pdf

718-mum-2006-form-1.pdf

718-mum-2006-form-2.doc

718-mum-2006-form-2.pdf

718-mum-2006-form-3.pdf

718-MUM-2006-GENERAL POWER OF ATTORNEY(5-5-2010).pdf

718-MUM-2006-REPLY TO EXAMINATION REPORT(5-5-2010).pdf

718-MUM-2006-REPLY TO HEARING(13-4-2011).pdf

718-MUM-2006-SPECIFICATION(AMENDED)-(5-5-2010).pdf


Patent Number 247718
Indian Patent Application Number 718/MUM/2006
PG Journal Number 19/2011
Publication Date 13-May-2011
Grant Date 06-May-2011
Date of Filing 09-May-2006
Name of Patentee GUJARAT ORGANICS LTD.
Applicant Address PLOT NO. 127/1, GIDC ESTATE, ANKLESHWAR 393 002, DIST. BHARUCH,
Inventors:
# Inventor's Name Inventor's Address
1 PATHAK RAJESH KUMAR PLOT NO. 127/1, GIDC ESTATE, ANKLESHWAR 393 002, DIST. BHARUCH,
PCT International Classification Number A61K31/015
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA