Preparation of trimethoxybenzoate salts and trimethoxybenzoic acid

A salt of 3,4,5-trimethoxybenzoic acid is prepared by initially reacting hydrolyzable tannin with a methylation agent in an alkaline medium under methylation conditions to form methylated tannin and thereafter hydrolyzing the methylated tannin by reaction thereof with a hydrolysis agent under alkaline hydrolysis conditions. The resulting salt can be neutralized to form 3,4,5-trimethoxybenzoic acid, which can readily be recovered.

BACKGROUND OF THE INVENTION 
This invention relates to a process for preparing 3,4,5-trimethoxybenzoate 
salts from hydrolyzable tannin and to a process for preparing 
3,4,5-trimethoxybenzoic acid via preparation of such salts. 
3,4,5-Trimethoxybenzoic acid (hereinafter sometime referred to as "TMB 
acid") is useful for preparing pharmaceutical compositions, e.g., 
trimethoprim. Heretofore, TMB acid has been prepared by a multiplicity of 
steps including (1) hydrolyzing tannin or a tannin-containing material to 
form gallic acid; (2) isolating the gallic acid; (3) methylating the 
isolated gallic acid to form a mixture of TMB acid and its methyl ester; 
(4) saponifying the acid-ester mixture; (5) acidifying the saponified 
mixture to liberate TMB acid from its salt; and (6) recovering the 
TMB-acid. Steps (1) and (2) involving tannin hydrolysis and gallic acid 
isolation are described in Krueger et al., U.S. Pat. No. 2,723,992, 
Japanese Patent 56-123938 indicates that methylation of gallic acid and 
one or more of the remaining steps are described in Org. Syn. Coll., Vol. 
I, 537, Corriere Favm., 22, 196 (1967). The foregoing highly multiple step 
process suffers a number of drawbacks, including need for isolation of 
gallic acid, high cost, and long reaction time where the tannin is 
hydrolyzed to gallic acid under acid hydrolysis conditions and 
decomposition of gallic acid to pyrogallic acid where such tannin 
hydrolysis is effected under alkaline conditions. Accordingly, there is a 
substantial need in the art for improved processes for preparing TMB acid 
and related TMB compounds. 
It has now been found that TMB acid and salts thereof can be formed by an 
improved process which obviates the need for hydrolyzing tannin to gallic 
acid and isolating intermediates. 
DESCRIPTION OF THE INVENTION 
Generally stated, the present invention provides a process for preparing a 
salt of 3,4,5-trimethoxybenzoic acid, which comprises: 
(a) reacting hydrolyzable tannin with a methylation agent in an alkaline 
medium under methylation conditions to form methylated tannin, and 
(b) hydrolyzing the methylated tannin by reaction thereof with a hydrolysis 
agent under alkaline hydrolysis conditions to form a 
3,4,5-trimethoxybenzoate salt of the hydrolysis agent. 
This invention also provides a process for preparing 
3,4,5-trimethoxybenzoic acid (TMB acid) which comprises: 
(a) reacting hydrolyzable tannin with a methylation agent in an alkaline 
medium under methylation conditions to form methylated tannin, 
(b) hydrolyzing the methylated tannin by reaction thereof with a hydrolysis 
agent under alkaline hydrolysis conditions to form a 
3,4,5-trimethoxybenzoate salt of the hydrolysis agent, and 
(c) neutralizing the trimethoxybenzoate salt to form 
3,4,5-trimethoxybenzoic acid. 
DETAILED DESCRIPTION OF THE INVENTION 
In the first step of the process, hydrolyzable tannin is reacted with a 
methylation agent in an alkaline medium under methylation conditions to 
form methylated tannin. The tannin or tannic acid employed can be any 
hydrolyzable tannin such as that obtained by extraction thereof from such 
tannin-containing materials as tara pods, Chinese nut galls, Aleppo galls, 
sumac leaves, etc. Taratannin (i.e., tannin obtained by extraction from 
tara pods) is preferred. Methods for extracting tannin from 
tannin-containing materials are well known in the art. 
Any suitable methylation agent can be used. Suitable methylation agents 
include, for example, dimethyl sulfate, methyl p-toluene sulfonate, methyl 
iodide, diazomethane etc. Dimethyl sulfate is preferred. 
Any suitable alkaline medium can be employed for the methylation reaction. 
The alkaline medium includes a liquid solvent or dispersant such as water, 
ethyl acetate, methyl isobutyl ketone, acetone, etc. and an alkaline agent 
such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium 
hydroxide, organic amines (e.g., triethylamine), etc. Aqueous sodium 
hydroxide is preferred for the alkaline medium. 
The methylation reaction is effected, for example, by initially forming a 
reaction mixture of the tannin, methylation agent (e.g., dimethyl 
sulfate), alkaline agent or base (e.g., sodium hydroxide), and the liquid 
solvent or dispersant (e.g., water). The methylation reaction may then be 
effected under any suitable methylation conditions, including for example 
heating with agitation at a temperature of about 15.degree. to about 
80.degree. C. for a period of about 2 to about 8 hours. 
The methylation agent is preferably employed in an amount at least equal to 
the stoichiometric amount required for conversion of all the hydroxyl 
groups of the tannin to methoxy groups. More preferably, a stoichiometric 
excess of the methylation agent is employed. The alkaline agent must be 
included in a sufficient amount such that the reaction mixture is above 7 
pH, preferably at least 8 pH and more preferably at least 10 pH. 
Where the tannin is taratannin and the methylation agent is dimethyl 
sulfate, the amount of dimethyl sulfate may be from 2.5 to about 5.0 parts 
by weight per one part by weight of taratannin. Corresponding molar ratios 
of other methylation agents can be employed for methylation of taratannin 
or other tannins. The amount of sodium hydroxide may be from about 1.25 to 
about 2.25 parts by weight of NaOH per one part by weight of taratannin. 
Corresponding molar ratios of other alkaline agents can be employed for 
taratannin or other tannins. As a general preference the base is employed 
as a 50% aqueous solution. Thus, for example, from about 2.5 to about 4.5 
parts by weight of 50% aqueous sodium hydroxide may be employed per one 
part by weight of taratannin. 
Any suitable concentration of tannin may be employed in the reaction 
mixture. Advantageously, the concentration of tannin is from about 0.5 to 
about 10 lbs. of tannin per gallon of solvent, preferably from about 2 to 
about 8 lbs./gal., and more preferably from about 3 to about 6 lbs./gal. 
All the methylation agent and the alkaline agent can be added initially and 
simultaneously or in any sequence. Alternatively, these agents can be 
added incrementally with heating and agitation of the reaction mixture. 
In a preferred embodiment, the methylation agent and alkaline agent are 
added simultaneously and incrementally over a period of from about 4 to 
about 10 hours at a reaction temperature of from about 20.degree. to about 
60.degree. C. (Optionally, the reaction mixture can be agitated for an 
additional period, e.g., from about 2 to about 6 hours, at a reaction 
temperature of about 20.degree. to about 60.degree. C., to aid in 
maximizing the extent of methylation). 
With or without such additional agitation, hydrolysis of the resulting 
methylated tannin is thereafter effected by heating with agitation under 
hydrolysis conditions, e.g., maintenance of a reaction temperature of 
about 60.degree. to about 110.degree. C. for about 0.5 to about 6 hours. 
Heating with agitation can be effected advantageously by refluxing the 
reaction mixture. Preferred hydrolysis conditions include maintenance of a 
reaction temperature of about 80.degree. to about 105.degree. C. for about 
1 hour to about 4 hours. (Optionally, at this stage, the reaction mixture 
is cooled and any precipitated side products are removed by filtration, 
centrifuging or the like.) 
The above-described hydrolysis involves reaction of the methylated tannin 
with a hydrolysis agent under alkaline hydrolysis conditions to form a 
salt of TMB acid and the hydrolysis agent. Suitable hydrolysis agents 
include, for example, sodium hydroxide, potassium hydroxide, calcium 
hydroxide, ammonium hydroxide, organic amines (e.g., triethylamine), etc. 
The same material can serve as both the alkaline agent in the methylation 
step and as the hydrolysis agent in the hydrolysis step. Sodium hydroxide 
is preferred for use as both the alkaline agent and the hydrolysis agent. 
The amount of sodium hydroxide required for hydrolysis may be added to the 
reaction mixture prior to, during, or after the methylation reaction. 
The above given amounts of sodium hydroxide generally will suffice to serve 
both the alkaline agent and hydrolysis agent functions. If desired an 
additional amount of sodium hydroxide or other hydrolysis agent may be 
added after methylation to aid in maximizing hydrolysis of the methylated 
tannin. 
Advantageously, hydrolysis of the methylated tannin can be effected without 
isolation thereof from the reaction mixture. 
Preferably, both the methylation step and the hydrolysis step are carried 
out under an inert atmosphere, preferably nitrogen, and in the presence of 
an oxygen scavenger, preferably sodium bisulfite. 
After completion of the hydrolysis, TMB acid can be formed by neutralizing 
the 3,4,5-trimethoxybenzoate salt contained in the reaction mixture by 
acidifying with any suitable acid. Preferably, the reaction mixture is 
cooled, e.g., to about 15.degree. to about 45.degree. C., prior to 
neutralization. Suitable acids include, for example, hydrochloric acid, 
sulfuric acid, phosphoric acid, etc. The acid employed is admixed with the 
reaction mixture, preferably by slowly adding the acid to the reaction 
mixture. The acid is added in an amount sufficient to acidify the mixture 
to a pH in the acid range, desirably from about 1 pH to about 6 pH, and 
preferably from about 3 pH to about 5 pH. Hydrochloric acid is preferred 
as the neutralizing agent. The acid may be employed as an aqueous solution 
or in the form of a solution thereof in an organic solvent, e.g., 
methanol, chloroform, etc. 
Practice of the present invention is illustrated by the following 
non-limiting examples. All parts and percentages given throughout this 
disclosure, including the claims which follow, are by weight unless 
otherwise indicated.

EXAMPLE 1 
Preparation of 3,4,5-Trimethoxybenzoic Acid from Aqueous Taratannin 
To 250 ml of aqueous taratannin (gallic acid content approximately 102 
grams, 0.6 mole) are added 192 grams of 50% NaOH and 240 grams of Dimethyl 
sulfate in portions at 20.degree.-40.degree. C. over a 3-6 hour period. 
The reaction mixture is refluxed for 1-3 hours with 48 grams of 50% NaOH. 
Upon cooling to 30.degree.-60.degree. C., 48 grams of 50% NaOH and 120 
grams of dimethyl sulfate are added in portions over a 2-4 hour period. 
After treating with an additional 48 grams of 50% NaOH, the reaction 
mixture is refluxed for 1-3 hours. At the end of hydrolysis, the reaction 
mixture is cooled and acidified with concentrated hydrochloric acid to 
precipitate 3,4,5-trimethoxybenzoic acid (TMB acid). The precipitated 
product is isolated and dried to give 107-112 grams of TMB in 84-87% 
yield. 
EXAMPLE 2 
Preparation of 3,4,5-Trimethoxybenzoic Acid from Aqueous Taratannin 
To a 50 gallon reactor containing 108 lbs. of aqueous taratannin (gallic 
acid content approximately 34.6 lbs), charge 72 lb of 50% NaOH and 90 lbs 
of dimethyl sulfate in portions over a 2-6 hour period while maintaining a 
temperature of 20.degree.-40.degree. C. Then, the reaction mixture is 
refluxed for 2-4 hours with 21 lbs of 50% NaOH. Upon cooling to 
30.degree.-60.degree. C., the reaction mixture is treated with 45 lbs of 
dimethyl sulfate and 18 lbs of 50% NaOH over a 2-4 hour period. Then, 
after the addition of an additional 27 lbs of caustic, the reaction 
solution is refluxed for 2-4 hours. Upon completion of hydrolysis, the 
reaction mixture is cooled, acidified to 3-5 pH with concentrated 
hydrochloric acid to yield 36-37 lbs. of dried 3,4,5-trimethoxybenzoic 
acid in 84-86% yield. 
BEST MODE CONTEMPLATED 
The best mode contemplated for carrying out this invention has been set 
forth in the above description, for example, by way of setting forth 
preferred materials and operating conditions, including but not limited to 
preferred ranges and values of amounts and other nonobvious variables 
material to successfully practicing the invention in the best way 
contemplated at the time of executing this patent application. 
It is understood that the foregoing detailed description is given merely by 
way of illustration and that many modifications may be made therein 
without departing from the spirit or scope of the prsent invention.