Title of Invention

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

Abstract

ABSTRACT The present invention relates to a simple two step cost-effective and high yielding process for the preparation of 2-Hydroxy-3-methoxy-5-allyl benzannides of formula-(I) involving the novel synthesis of the Intermediate 2-Hydroxy-3-methoxy-5-allyl benzoic acid of formula (II) Where in 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 cydoalkyl and when taken together with the nitrogen atom form as heterocyclic which may contain another hetero atom, which products possess outstanding choleretic properties (US pat 3,668,238). A Particular compound (I) where R<sub>1</sub> = H, R<sub>2</sub> = CH2CH2OH) is a popular therapeutic agent of this class and is known as Alibendol.

Full Text

(ii)Preparation of the ester of the formula(VI) is not possible without having a method of preparation of the corresponding acid of formula (II). Therefore this data Is inadequate to implement this process (ill) Isolation of Intermediate ester of formula(VI) adds one additional step to the process of preparation of benzamides of formula (I). Hence the Process Is multlstep and there Is a need for simplification 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-benzolc acid of the formula-(II) which is the key intermediate for the preparation of benzamides of the formula-(I). Therefore the main objective of the present invention is to provide an inexpensive method for the preparation of benzamides of the general formula-(I) Another objective of the present invention is to provide an inexpensive method for the preparation of benzamides of the general formula-(I) which is scalable on a commercial scale. Accordingly , the present invention provides an improved process for tine preparation of substituted benzamides of the formula-(I) by acidification with Hydrochloric acid, extraction with toluene and filtration. iii)Esterifying the intermediate of the formula-(II) using alcohol to nivp ocfor of thefornnula (VI). - lv)Insltu annination of the reaction mixture by heating with appropriate amines to get the substituted amides of the formula-(I). The alkalis used in step (i) may be selected from potassium hydroxide, potassium hydrogen carbonate or potassium carbonate, preferably potassium carbonate. The carbon dioxide pressure used in 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 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 II may be effected by dissolution of the salt cake in water, acidification of the aqueous layer extraction with toluene, and filtration of the product. For esterification in step (iii) alcohols such as methanol, ethanol (or) isopropanol ,preferably methanol / with dry HCI may be used . 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 : 190 gms MR : 119-128°C Purity by HPLC : 99% Analysis : C11H12O4 Molecular weight : 208.0 IR : KBR Disc OH : at 3500 cm-1 C= 0 : It 1650 cm-1 CH = CH2 : at 905 and 985 cm-1 U.V spectrum : ethanol λ max at : 210 nm 1HNMR ( DMSO - de) ( 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 6. Monoethanolamine - 0.17 Kg 7. Acetic acid - 0.225 L 8. Cone. Hydrochloric acid - 0.050 Kg 9. Activated Carbon for decolorization - 0.040 Kg Procedure Methyl ester of 2-hydroxy-3-methoxy benzoic acid is prepared by refluxing with methanol for 24-26 hours in dry hydrochloric acid presence. After the completion of reaction methanol is distilled off completely under vacuum and the residue is cooled to room temperature. Then monoethanol amine is added slowly to the residue and the suspension is stirred at room temperature for 1 hour and heated to 120°C for 1 hour. Then excess monoethanol amine is recovered by high vacuum distillation. Then the residue is cooled to room temperature and chloroform is charged, chloroform layer is washed with diluted hydrochloric acid, water, 5% sodium carbonate solution and water thoroughly till TLC showed single spot. Then carbon is charged to chloroform layer and heated to reflux. Filtered off carbon using filter aid. Chloroform distilled completely under vacuum, ^cetic acid is charged to the residue at room temperature. DM water is added slowly to the acetic acid till compound is precipitated out completely. It is filtered and washed with DM water. Dried in oven at 50°C under vacuum for 6-8 hours. Yield : 78 gms MR : 93-95°C 6. Piperidine - 0.200 Kg 7. Isopropyl ether - 0.150 L Procedure Methyl ester of 2-hydroxy-3-methoxy benzoic acid is prepared by refluxing with methanol for 24-26 hours in dry hydrochloric acid presence. After the completion of reaction methanol is distilled off completely under vacuum and the residue is cooled to room temperature. Then piperidine is added and heated to reflux for 3 hours. After the completion of reaction excess piperidine is distilled off under reduced pressure. Then chloroform is charged to the residue, chloroform layer is washed with diluted hydrochloric acid, water, 5% sodium carbonate solution and water thoroughly till TLC showed single spot. Then carbon is charged to chloroform layer and heated to reflux. Carbon is filtered using filter aid. Filtrate is distilled off completely under vacuum. The residue is recrystallized with isopropyl ether- Yield : 80 gms MR : 90-92°C Analysis : C16H21NO3 Molecular weight : 275.33 Procedure We Claim 1. An improved process for the preparation of substituted benzamides of the formula-(I) 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 (ii) Isolating the novel intermediate of the formula-(II) by acidification with hydrochloric acid extraction with toluene and filtration. /

Documents:

934-mas-2002 abstarct duplicate.pdf

934-mas-2002 abstarct.pdf

934-mas-2002 claims duplicate.pdf

934-mas-2002 claims.pdf

934-mas-2002 correspondence others.pdf

934-mas-2002 correspondence po.pdf

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

934-mas-2002 description (complete).pdf

934-mas-2002 form-1.pdf

934-mas-2002 form-19.pdf

934-mas-2002 form-5.pdf