Title of Invention

IMPROVED PROCESS FOR THE PREPARATION OF AN INTERMEDIATE FOR THE PREPARATION OF 2-HYDROXY-3- METHOXY-5-ALLYLBENZAMIDES

Abstract This invention relates to an improved method for the preparation of an intermediate useful for the preparation of benzamides. This invention particularly relates to an improved method for the preparation of an intermediate of the formula (I) useful for the preparation of substituted benzamides of the general formula (II) given below wherein R<SUB>1</SUB> and R<SUB>2</SUB> are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl of one to seven carbon atoms, aryl and cycloalkyl and when taken together with the nitrogen atom form a heterocycle which may contain another hetero atom. The substituted benzamides of the general formula (II) are useful as choleretic and antispasmodic agents.
Full Text This invention relates to an improved method for the preparation of an intermediate useful for the preparation of benzamides. This invention particularly relates to an improved method for the preparation of an intermediate of the formula (I) useful for the preparation of substituted benzamides of the general formula (II) given above .

Wherein Ri and R2 are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl of one to seven carbon atoms, aryl and cycloalkyl and when taken together with the nitrogen atom form a heterocycle which may contain another heteroatom, which products possess outstanding choleretic properties.
The substituted benzamides of the general formula (II) are useful as choleretic and antispasmodic agents
Background of the invention
A study of information contained in the US patent no 3668238 on the method of preparation of the substituted benzamides of formula (II) revealed that essentially two routes are available for the preparation
The first route disclosed in the said US patent no 3,668,238 for the preparation of substituted benzamides of the general formula-(I), comprises of following steps as exemplified.

The first route disclosed in the said US patent no 3,668,238 for the preparation of substituted benzamides of the general formula-(I), comprises of following steps as exemplified.
a) Ethyl ester of 2-hydroxy-3-methoxy benzoic acid of formula-(III-A) is
treated with monoethanolamine to yield 2-hydroxy-3-methoxy-N-

b) The compound of the formula IV-A obtained in Step (a) is treated with
allyl bromide to yield allyl ether of the formula IV-B which, insitu is
converted into 2-hydroxy-3-methoxy 5-allyl-N-(p-hydroxy ethyl)-
benzamide of formula-(V) by high temperature Claisen rearrangement
reaction.


This process is beset with the following difficulties
(i) For this process the starting material is 2-Hydroxy-3-methoxy benzoic
acid (o-vanillic acid) of formula (III-B) which is very expensive and
difficult for procurement.
(ii) In step(a) of the process excess ethanolamine has to be used which is not recycled thus making this process expensive
(iii)For step (b) we have noticed that after allylation, the rearrangement step is very exothermic and it can pose serious problems such as an uncontrollable run-away reaction during scale-up trials.
(iv)Yield is not mentioned for the compound obtained in step (b).
The second route described in US Patent no 3,668,238 involves the following process.
Ester of the formula (VI) on condensation with appropriate amines yielded corresponding benzamides of the formula (II) in 58-78% yields.

Though this route is apparently straight forward with better yields when compared to the first route, we found the following draw backs in the method:

(i) Preparation of the compound of the formula (I), (2-Hydroxy-3-methoxy-5-allyl benzoic acid) is not disclosed. Although compound of formula (I) is known in literature, its method of synthesis is not described. In this patent, the reference given for the preparation of compound of formula (II) [ J. Amer. Chem. Soc, 71, 1067 (1949)] discloses only the esterification procedure of compound of formula (II).
(ii)Preparation of the ester of the formula (VI) is not possible without having a method of preparation of the corresponding acid of formula (I). Therefore this data is inadequate to implement this process
Detailed discussion of the present invention
Keeping in view of the difficulties in commercialization of the process disclosed in the above mentioned patent, we aimed our research work to develop a simple and cost-effective process for the preparation of the 2-hydroxy-3-methoxy-5-allyl-benzoic acid of the formula-(I) which is the key intermediate for the preparation of benzamides of the formula-(II).
Therefore the main objective of the present invention is to provide an inexpensive method for an intermediate of the formula (I) useful for the preparation of benzamides of the general formula-(II)
Another objective of the present invention is to provide an inexpensive method for the preparation of the intermediate of the formula (I) useful for the preparation of benzamides of the general formula-(II) which is scalable on a commercial scale.

Another objective of the present invention is to provide an inexpensive method for the preparation of the intermediate of the formula (I) useful for the preparation of benzamides of the general formula-(I) which is economical.
During our sustained research to develop a simple process for the preparation of substituted benzamides of the formula-(I), we observed that a promising approach for such a processes would be to
a) Avoid the use of o-vanillic acid as the key starting material
b) Use eugenol of the formula-(VII) as the key starting material
c) Carboxylation of eugenol employing carbondioxide and anhydrous alkali to give the intermediate of the formula (II).
The present invention has been developed based on our above mentioned findings to achieve the above stated objectives.
Accordingly, the present invention provides an improved process for the preparation of compound of the formula (I) useful for the preparation of substituted benzamides of the formula (II).



Which comprises solid phase carboxylation of eugenol of the formula (VII) Using carbon dioxide gas and anhydrous alkali at a temperature in the range of 150-250°C and isolating the intermediate of the formula (II) By acidification with hydrochloric acid extraction with toluene and filtration.

The alkalis used may be selected from potassium hydrogen carbonate or potassium carbonate preferably potassium carbonate. The carbon dioxide pressure usedln the carboxylation step may be in the range of 6-12 Kg preferably in the range of 8-10 Kg. The temperature of carboxylation may be in the range of 150-250°C preferably in the range of 190-210°C

This isolation can be carried out by standard extraction, filtration and drying* methods. For example the isolation of the intermediate of the formula(I) may be effected by dissolution of the salt cake in water, acidification of the aqueous layer extraction with toluene, and filtration of the product.
The compound of the formula (I) can be used for the preparation of substituted benzamides of the formula (II) by the reaction scheme shown below.

The process shown in the above scheme has been made the subject matter of a separate application filed simultaneously with this application.
The details of the invention are given in the Examples given below which are provided to illustrate the invention only and therefore they should not be construed to limit the scope of the invention

Illustrative Examples
Example-1
Process for the preparation of 2-Hydroxy-3-methoxy-5-allyl benzoic acid

Raw materials Qty
1. Eugenol - 0.250 Kg
2. Anhydrous potassium carbonate - 1.6 Kg
3. Sodium carbonate - 0.2 Kg
4. Cone. HCI - 2.4 L
5. Carbon dioxide - as required
6. Activated Carbon for decolorization - 0.150 Kg
7. Toluene - 2.5 L
8. Acetic acid - 0.475 L
Procedure :
Commercial potassium carbonate is dried at 100-120°C for 72 hours. Potassium carbonate /Eugenol mixture is prepared by thoroughly mixing eugenol and potassium carbonate at room temperature. All reagents and apparatus are thoroughly dry, but otherwise no special precaution is observed. This material is placed in pressure reactor and carbon dioxide gas

is admitted from a commercial cylinder. The reactor is heated to 190-210°t
Carbon dioxide feeding continue till absorption is ceased (approx. - 24
hours). At the end of the reaction the apparatus is allowed to cool, vented
and removed inlet tubes. Reaction mass is a hard cake having a light yellow
to brown colour. This cake is dissolved in hot water and acidified with cone.
Hydrochloric acid and toluene is charged to this solution. Then separated
mass is filtered and extracted with toluene to remove unreacted eugenol.
Filtered compound is dissolved in 5% sodium carbonate solution and carbon
treatment is given. This filtrate is acidified filtrate with concentrated
hydrochloric acid and the separated pale brown 2-Hydroxy-3-methoxy-5-
allyl benzoic acid is filtered and washed thoroughly. It is dried in oven at
50°C.
Yield : 190 gms
MR : 119-128°C
Purity by HPLC : 99%
Analysis : CnHi204
Molecular weight : 208.0
IR : KBR Disc
OH : at 3500 cm"1
C= O : It 1650 cm1
CH = CH2 : at 905 and 985 cm"1
U.V spectrum ethanol
X max at : 210 nm
XHNMR ( DMSO - d6) ( ppm)
3.3 (m,2H) Ar-CH2
3.8 (s,3H) OCH3
5.15 (m,2H) = CH2
5.95 (m,lH) - CH=
7.0, 7.2 (2d,2H) Ar-H

Example-2
Process for the preparation of 2-Hydroxy-3-methoxy-5-allyl benzoic acid

Raw materials Qty
1. Eugenol - 0.250 Kg
2. Potassium hydrogen carbonate - 2.2 Kg
3. Sodium carbonate - 0.2 Kg
4. Cone. HCI - 2.6 L
5. Carbon dioxide - as required
6. Activated Carbon for decolorization - 0.150 Kg
7. Toluene - 2.5 L
8. Acetic acid - 0.475 L
Procedure :
Commercial potassium carbonate is dried at 100-120°C for 72 hours. Potassium hydrogen carbonate /Eugenol mixture is prepared by thoroughly mixing eugenol and Potassium hydrogen carbonate at room temperature. All reagents and apparatus are thoroughly dry, but otherwise no special precaution is observed. This material is placed in pressure reactor and carbon dioxide gas is admitted from a commercial cylinder. The reactor is

heated to 190-210°C Carbon dioxide feeding continue till absorption is
ceased (approx. - 24 hours). At the end of the reaction the apparatus is
allowed to cool, vented and removed inlet tubes. Reaction mass is a hard
cake having a light yellow to brown colour. This cake is dissolved in hot
water and acidified with cone. Hydrochloric acid and toluene is charged to
this solution. Then separated mass is filtered and extracted with toluene to
remove unreacted eugenol. Filtered compound is dissolved in 5% sodium
carbonate solution and carbon treatment is given. This filtrate is acidified
filtrate with concentrated hydrochloric acid and the separated pale brown
2-Hydroxy-3-methoxy-5-allyl benzoic acid is filtered and washed
thoroughly. It is dried in oven at 50°C.
Yield : 150 gms
MR : 119-120°C
Purity by HPLC : 99%
Analysis : C11H12O4
Molecular weight : 208.0
IR : KBR Disc
OH : at 3500 cm-1
C= O : It 1650 cm"1
CH = CH2 : at 905 and 985 cm"1
U.V spectrum : ethanol
X max at : 210 nm
JHNMR ( DMSO - d6) ( ppm)
3.3 (m,2H) Ar- CH2
3.8 (s,3H) OCH3
5.15 (m,2H) = CH2
5.95 (m,lH) -O-L
7.0, 7.2 (2d,2H) Ar-H

Advantages of the present invention
• The process is Scalable on a commercial scale
• The process results in an overall yield of 60-65% for compounds of formula (II).
• The process is safe & simple
• The process is economical


We Claim
An improved process for the preparation of 2-Hydroxy-3-methoxy-5-allyl benzoic acid of the formula (I) useful for the preparation of substituted benzamides of the formula (II) Wherein R1 and R2 are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl of one to seven carbon atoms, aryl and cycloalkyl and when taken together with the nitrogen atom form a heterocycle which may contain another hetero atom.

which comprises
(i) Solid phase carboxylation of eugenol of the formula-(VII)

Using carbon dioxide gas and anhydrous alkali at a temperature in the range of 150-250°C and isolating the intermediate of the formula-(I)


by acidification with hydrochloric acid extraction with toluene and filtration.
2. An improved process as claimed in claim 1 wherein the alkali used is selected from potassium hydrogen carbonate or potassium carbonate, preferably potassium carbonate.
3. An improved process as claimed in claims 1 & 2 wherein the carbon dioxide pressure used in the carboxylation step is in the range of 6-12 Kg preferably in the range of 8-10 Kg.
4. An improved process as claimed in claims 1 to 3 wherein the temperature of carboxylation is preferably in the range of 190-210°C
5. An improved process as claimed in claims 1 to 4 wherein the isolation is carried out by extraction with toluene, filtration and drying
6. An improved process as claimed in claims 1 to 5 wherein the isolation of the intermediate of the formula II may be effected by acidification with hydrochloric acid
7. An improved process as claimed in claims 1 to 6 wherein the
carboxylation reaction is to be done for 20-24 hours.

Documents:

933-mas-2002 abstract duplicate.pdf

933-mas-2002 abstract.jpg

933-mas-2002 abstract.pdf

933-mas-2002 claims duplicate.pdf

933-mas-2002 claims.pdf

933-mas-2002 correspondence others.pdf

933-mas-2002 correspondence po.pdf

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

933-mas-2002 description (complete).pdf

933-mas-2002 form-1.pdf

933-mas-2002 form-19.pdf

933-mas-2002 form-5.pdf


Patent Number 221868
Indian Patent Application Number 933/MAS/2002
PG Journal Number 37/2008
Publication Date 12-Sep-2008
Grant Date 08-Jul-2008
Date of Filing 16-Dec-2002
Name of Patentee NATCO PHARMA LIMITED
Applicant Address NACTO HOUSE, ROAD NO 2, BANJARA HILLS HYDERABAD - 500 033,
Inventors:
# Inventor's Name Inventor's Address
1 AMALA KOMPELLA NATCO PHRAMA LTD, NATCO HOUSE, ROAD NO 2, BANJARA HILLS, HYDERABAD - 500 033,
2 VENKATA RAMANA KONDEPATI NATCO PHRAMA LTD, NATCO HOUSE, ROAD NO 2, BANJARA HILLS HYDERABAD - 500 033,
3 KALI SATYA BHUJANGA RAO ADIBHATLA NATCO PHRAMA LTD, NATCO HOUSE, ROAD NO 2, BANJARA HILLS HYDERABAD - 500 033,
4 VENKAIAH CHOWDARY NANNAPANENI NATCO PHRAMA LTD, NATCO HOUSE, ROAD NO 2, BANJARA HILLS HYDERABAD - 500 033,
PCT International Classification Number C 01 C 271/22
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA