FIELD OF THE INVENTION

The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of 3-forrnylmethyl-benzoic acid derivatives, which are useful intermediates in the preparation of benzofurancarboxamide derivatives having gastrointestinal motility stimulating properties, preferably prucalopride.

BACKGROUND OF THE INVENTION U.S.

Patent No. 5,854,260 discloses a novel benzamide derivative, 4-amino-5-chloro-2,3-dihydro-N-[l-(3-methoxypropyl)-4-piperidinyl]-7-benzofurancarboxamide, also known as prucalopride, and pharmaceutically acceptable salts and hydrates thereof, processes for the preparation, pharmaceutical compositions, and method of use thereof. Prucalopride is a gastroprokinetic agent acting as a selective serotonin 5-HT4 receptor agonist which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements. Prucalopride and its pharmaceutically acceptable salts and hydrates thereof show superior enterokinetic properties and are used in the treatment of conditions involving an impaired motility of the intestine, especially of the colon. Prucalopride is represented by the following structural formula I:

Prucalopride was approved by the EMEA for use in Europe for the treatment of chronic constipation and it is sold under the trade name RESOLOR™. It is orally administered as tablets containing 1 mg and 2 mg of prucalopride (as prucalopride succinate salt).

Various processes for the preparation of benzofurancarboxamide derivatives having gastrointestinal motility stimulating properties, preferably prucalopride, and their intermediates, and pharmaceutically acceptable salts and hydrates thereof, are disclosed in U.S. Patent Nos. 5,854,260; 5,374,637; 5,262,418; 5,459,161; 8,063,069; and Chemical and Pharmaceutical Bulletin 46(1), 42-52, 1998; and Journal of Heterocyclic Chemistry 17,1333-1335 (1980).

One of the useful intermediates in the synthesis of benzofurancarboxamide derivatives having gastrointestinal motility stimulating properties, preferably prucalopride, is the 3-formylmethyl-benzoic acid derivative of formula II:

or a salt thereof, wherein R is hydrogen or an alkyl group; R' is hydrogen or a nitrogen protecting group P; R" is hydrogen or a halogen atom, wherein the halogen atom is F, Cl, Br or I, preferably the halogen atom is Cl; and R'" is hydrogen, or an alkali or alkaline earth metal ion.

In the preparation of prucalopride, methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate of formula IIa:
is a key intermediate.

U.S. Patent No. 5,854,260 (hereinafter referred to as the '260 patent) describes several synthetic routes for preparing prucalopride. According to one synthetic process, prucalopride is prepared by the condensation of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid with l-(3-methoxypropyl)-4-piperidinamine in the presence of ethyl chloroformate and N,N-diethylethanamine in trichloromethane to produce a reaction mass, followed by usual work-up and subsequent treatment with isopropanolic-HCl solution to produce prucalopride monohydrochloride salt.

According to another synthetic process as described in the '260 patent, prucalopride is prepared by reacting 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzorurancarboxamide with l-chloro-3-methoxypropane (or its sulfonyloxy analog) in a reaction inert solvent such as a dipolar aprotic solvent, e.g. N,N-dimethylformamide in the presence of an appropriate base such as potassium iodide or triethylamine to produce a reaction mass, followed by usual work-up and subsequent column chromatographic purification over silica gel to produce prucalopride, which is then converted into its hydrochloride salt by treating with isopropanolic-HCl solution.

According to another synthetic process as described in the '260 patent, prucalopride is prepared by the condensation of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid with l-(3-methoxypropyl)-4-piperidinamine in the presence of l,l'-carbonylbis-lH-imidazole in tetrahydrofuran solvent to produce a reaction mass, followed by usual work-up to produce prucalopride free base as a residue, which is then stirred with water and then dried to yield prucalopride monohydrate (melting point: 90.7°C).

Chemical and Pharmaceutical Bulletin 46(1), 42-52 (hereinafter referred to as the 'CPB Journal') discloses a process for the preparation of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid. The synthesis is depicted in scheme l:

Scheme-1:

As per the process reported in the CPB Journal, the 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid intermediate is prepared by oxidizing methyl 4-acetylamino-2-hydroxy-3-propenylbenzoate with osmium tetroxide in diethyl ether and water, followed by stirring the mixture for 10 minutes at 20-25°C and then adding sodium periodate. The resulting mixture is stirred for 12 hours at 20-25°C and the resulting precipitate is collected by filtration to produce a mixture of methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate and methyl 4-acetylamino-2,3-dihydro-2-hydroxybenzo[b]furan-7-carboxylate (melting point: 179-180°C). The resulting mixture is subjected to reduction with sodium borohydride to produce methyl 4-acetylamino-2-hydroxy-3-(2-hydroxyethyl)benzoate, followed by cyclization using diethyl azodicarboxylate (DEAD) and triphenylphosphine by the dehydration reaction to produce methyl 4-acetylamino-2,3-dihydrobenzo[b]furan-7-carboxylate, which is then subjected to chlorination with N-chlorosuccinimide and subsequent alkaline hydrolysis to produce 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid.

The starting material "methyl 4-acetylamino-2-hydroxy-3-propenylbenzoate" is prepared by the processes described in the prior art, for example, as per the processes described in the CPB Journal.

The process for the preparation of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid intermediate described in the aforementioned prior art suffer from disadvantages such as the use of highly expensive and hazardous reagents; use of tedious and cumbersome procedures like prolonged reaction time periods, column chromatographic purifications, multiple isolations/ re-crystallizations, and thus resulting in a poor product yield and quality. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.

The major drawback of the process for the preparation of 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylic acid described in the aforementioned prior art is that the process involves the use of highly expensive and highly hazardous oxidizing agent osmium tetroxide for the oxidation of methyl 4-acetylamino-2-hydroxy-3-propenylbenzoate to produce methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate. Use of the highly expensive and highly hazardous osmium tetroxide is not advisable in commercial scale operations. Moreover, the purity of the resulting oxidized compound, methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate, is very low.

Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of 3-formylmethyl-2-hydroxybenzoic acid derivatives at lab scale and in commercial scale operations.

A need remains for an improved, commercially viable and environmentally friendly process of preparing 3-formylmethyl-2-hydroxybenzoic acid derivatives with high yield and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced cost, greater simplicity, increased purity, and increased yield of the product, thereby enabling the production of benzofurancarboxamide derivatives having gastrointestinal motility stimulating properties, preferably prucalopride, in high purity and with high yield.

SUMMARY OF THE INVENTION

The present inventors have surprisingly found that the 3-formylmethyl-benzoic acid derivatives can be prepared in high purity and with high yield, by oxidizing 3-allyl-benzoic acid derivatives with an oxidizing agent such as potassium permanganate to produce a diol intermediate, which is then reacted with a glycol cleavage agent such as sodium periodate to produce 3-formylmethyl-benzoic acid derivatives, which are useful intermediates in the preparation of benzofurancarboxamide derivatives having gastrointestinal motility stimulating properties, preferably prucalopride.

In one aspect, provided herein is an efficient, industrially advantageous and environmentally friendly process for the preparation of 3-formylmethyl-benzoic acid derivatives, in high yield and with high purity, using novel intermediates. The process disclosed herein avoids the tedious and cumbersome procedures of the prior processes, thereby resolving the problems associated with the processes described in the prior art, which is more convenient to operate at lab scale and in commercial scale operations.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, there is provided an improved process for the preparation of a 3-formylmethyl-benzoic acid derivative of formula II:

or a salt thereof,
wherein R is hydrogen or an alkyl group; R' is hydrogen or a nitrogen protecting group P;
R" is hydrogen or a halogen atom; and R'" is hydrogen, or an alkali or alkaline earth metal ion;
which comprises:
a) oxidizing a 3-allyl-benzoic acid derivative of formula III:

or a salt thereof, wherein R, R', R" and R'" are as defined above, and optionally purifying the compound of formula IV using a suitable solvent or a mixture of suitable solvents; and b) reacting the compound of formula IV with a glycol cleavage agent to produce the 3-formylmethyl-benzoic acid derivative of formula II or a salt thereof, and optionally purifying the compound of formula II using a suitable solvent or a mixture of suitable solvents.

In one embodiment, the compounds of formulae II, III and IV, wherein R is an alkyl group, R' is a nitrogen protecting group P, R" is hydrogen, and R"' is hydrogen.

The term "alkyl", as used herein, denotes an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. Specific alkyl groups are methyl and ethyl; and most specifically methyl.

Exemplary nitrogen protecting groups 'P' include, but are not limited to, acetyl, pyrrolidinylmethyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl, benzyloxymethyl, pivaloyloxymethyl (POM), trichloroethoxycarbonyl, l-adamantyloxycarbonyl, allyl, allyloxycarbonyl, trimethylsilyl, tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl, trimethylsilylethoxymethyl, t-butoxycarbonyl (BOC), t-butyl, l-methyl-l,l-dimethylbenzyl and pivaloyl.

Specifically, the nitrogen protecting group 'P' in the compounds of formulae II, III and IV is acetyl.

In another embodiment, the compounds of formulae II, III and IV, wherein R" is a halogen atom selected from F, Cl, Br and I, and specifically C1.

In another embodiment, the compounds of formulae II, III and IV, wherein R'" is an alkali or alkaline earth metal ion, wherein the alkali metal ion is selected from the group consisting of Na+, K+ and Li+, and wherein the alkaline earth metal ion is Ca2+ or Mg2+,

In one embodiment, a specific 3-formylmethyl-benzoic acid derivative of formula II prepared by the process described herein is methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate of formula IIa (formula II, wherein R is methyl, R' is acetyl, and R" and R"' are hydrogen):
or a salt thereof.

In another embodiment, a specific 3-(2,3-dihydroxypropyI)-benzoic acid derivative of formula IV prepared by the process described herein is methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate of formula IVa (formula IV, wherein R is methyl, R' is acetyl, and R" and R'" are hydrogen):
or a salt thereof.

Salts of the compounds of formulae II, III and IV as used herein include, each independently, acid addition salts and base addition salts. The acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, di-p-toluoyl-L-(+)-tartaric acid, malic acid, ascorbic acid, and the like.

The base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium; and organic amines such as ethylamine, tert-butylamine, diethylamine, diisopropylamine, and the like.

Exemplary salts of the compounds of formulae II, III and IV include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, sodium salt, potassium salt, magnesium salt, and calcium salt.

The reaction in step-(a) and step-(b) can be carried out in the presence or absence of a reaction inert solvent. In one embodiment, the process steps-(a) and (b) are, each independently, carried out in the presence of a solvent or a mixture of solvents.

Exemplary solvents used in step-(a) include, but are not limited to, water, a halogenated hydrocarbon solvent, an ester, a ketone, a cyclic ether, an aliphatic ether, a hydrocarbon, and mixtures thereof.

Specifically, the solvent used in step-(a) is selected from the group consisting of water, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, and mixtures thereof.

In one embodiment, the solvent used in step-(a) is selected from the group consisting of water, a halogenated hydrocarbon solvent, and mixtures thereof; and most specifically a mixture of water and dichloromethane.

Exemplary oxidizing agents used in step-(a) include, but are not limited to, potassium permanganate, sodium permanganate, calcium permanganate, hydrogen peroxide, barium peroxide, calcium peroxide, sodium peroxide, potassium peroxide, and the like. A most specific oxidizing agent is potassium permanganate.

In one embodiment, the oxidizing agent in step-(a) is used in a ratio of about 0.5 to 5 equivalents, specifically about 1 to 1.5 equivalents, with respect to the 3-allyl-benzoic acid derivative of formula III in order to ensure a proper course of the reaction.

In another embodiment, the oxidation reaction in step-(a) is carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base.

Exemplary organic bases include, but are not limited to, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine and l-alkylimidazole.

Exemplary inorganic bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals. Specific inorganic bases are sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert- butoxide, sodium isopropoxide and potassium tert-butoxide; and most specifically sodium hydroxide and potassium hydroxide.

In one embodiment, the base is used in a ratio of about 0.5 to 4 equivalents, specifically about 1.0 to 1.5 equivalents, with respect to the 3-allyl-benzoic acid derivative of formula III in order to ensure a proper course of the reaction.

In another embodiment, the oxidation reaction in step-(a) is carried out in the presence of a phase transfer catalyst. A "phase transfer catalyst" refers to a catalyst or agent which is added to a reaction mixture of components, to transfer one or more of the reacting components to a location where it can conveniently and rapidly react with another reacting component.

Exemplary phase transfer catalysts for use herein include, but are not limited to, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexyl ammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride, benzylmethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetrabutylphosphonium chloride, 1-dodecanyl pyridinium chloride, and the like.

Specific phase transfer catalysts are tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride and tetrabutylammonium hydrogen sulfate; and more specifically tetrabutylammonium bromide.

In another embodiment, the amount of the phase transfer catalyst employed is 0.2% w/w to about 3% w/w, specifically from about 0.3% w/w to about 0.7% w/w.

The reaction temperature and time period for oxidation will ordinarily depend on the starting compound and the solvent employed in the reaction.

In one embodiment, the oxidation reaction in step-(a) is carried out at a temperature of about 0°C to about 40°C, specifically at a temperature of about 5°C to about 35°C, and more specifically at a temperature of about 10°C to about 20°C. The reaction time may vary from about 5 minutes to about 2 hours, specifically from about 10 minutes to about 1 hour, and more specifically from about 15 minutes to about 30 minutes.

The reaction mass containing the 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV obtained in step-(a) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, a decolorization, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula II, or the compound of formula IV may be isolated and/or recrystallized and then used in the next step.

In one embodiment, the 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV is isolated and/or recrystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.

The solvent used for isolating and/or recrystallizing the pure 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

In one embodiment, the solvent used for isolating the compound of formula IV is a mixture of water and an ether solvent, and most specifically a mixture of water and diisopropyl ether.

In another embodiment, the solvent used for recrystallizing the compound of formula IV is a mixture of an alcohol and an ester solvent, and most specifically a mixture of isopropyl alcohol and ethyl acetate.

Exemplary solvents used in step-(b) include, but are not limited to, water, a halogenated hydrocarbon solvent, an ester, a ketone, a cyclic ether, an aliphatic ether, a hydrocarbon, an alcohol, and mixtures thereof.

In one embodiment, the solvent used in step-(b) is selected from the group consisting of water, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, and mixtures thereof.

Specifically, the solvent used in step-(b) is selected from the group consisting of water, an ether solvent, and mixtures thereof; and most specifically a mixture of water and diisopropyl ether.

Exemplary glycol cleavage agents used in step-(b) include, but are not limited to, sodium periodate, potassium periodate, lead tetraacetate, and the like. A most specific glycol cleavage agent is sodium periodate.

In one embodiment, the glycol cleavage agent in step-(b) is used in a ratio of about 1 to 4 equivalents, specifically about 1.5 to 2.5 equivalents, with respect to the 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV in order to ensure a proper course of the reaction.

In one embodiment, the reaction in step-(b) is carried out at a temperature of about 0°C to about 50°C, specifically at a temperature of about 5°C to about 35°C, and more specifically at a temperature of about 20°C to about 30°C. The reaction time may vary from about 15 minutes to about 4 hours, specifically from about 20 minutes to about 2 hours, and more specifically from about 30 minutes to about 1 hour 30 minutes.

The reaction mass containing the 3-formylmethyl-benzoic acid derivative of formula II obtained in step-(b) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, or a combination thereof.

In one embodiment, the 3-formylmethyl-benzoic acid derivative of formula II is isolated and/or recrystallized from a suitable solvent by conventional methods as described above.

The solvent used for isolating and/or recrystallizing the pure 3-formylmethyl-benzoic acid derivative of formula II is selected from the group as described above.

Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

The solid obtained in the above process steps may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.

The use of potassium permanganate as an oxidizing agent for the oxidation process disclosed herein allows the product to be easily isolated and purified, thereby producing a product with high overall yield and purity.

The 3-formylmethyl-benzoic acid derivative of formula II or a salt thereof, preferably methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate of formula Ha, obtained by the process disclosed herein may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents.

In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 80°C.

The 3-formylmethyl-benzoic acid derivative of formula II or a salt thereof, preferably methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate of formula Ha, obtained by the process disclosed herein has a purity of greater than about 90%, specifically greater than about 95%, more specifically greater than about 98%, and most specifically greater than about 99% as measured by HPLC.

According to another aspect, there is provided a process for the preparation of 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV:

or a salt thereof, wherein R is hydrogen or an alkyl group; R' is hydrogen or a nitrogen protecting group P; R" is hydrogen or a halogen atom; and R'" is hydrogen, or an alkali or alkaline earth metal ion; which comprises oxidizing a 3-allyl-benzoic acid derivative of formula III:

or a salt thereof, wherein R, R', R" and R" are as defined above;

with a suitable oxidizing agent in the presence or absence of a base, optionally in the presence of a phase transfer catalyst, to produce a 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV or a salt thereof, and optionally purifying the compound of formula IV using a suitable solvent or a mixture of suitable solvents.

In one embodiment, the oxidizing agents, solvents, bases, phase transfer catalysts and the reaction conditions employed in the oxidation process are as defined above.

According to one aspect, there is provided an improved process for the preparation of a 3-formylmethyl-benzoic acid derivative of formula II:

or a salt thereof, wherein R is hydrogen or an alkyl group; R' is hydrogen or a nitrogen protecting group P; R" is hydrogen or a halogen atom; and R'" is hydrogen, or an alkali or alkaline earth metal ion; which comprises reacting 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV:

or a salt thereof, wherein R, R', R" and R'" are as defined above;

with a glycol cleavage agent to produce the 3-formylmethyl-benzoic acid derivative of formula II or a salt thereof, and optionally purifying the compound of formula II using a suitable solvent or a mixture of suitable solvents.

The 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV or a salt thereof, preferably methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate of formula IVa, obtained by the process disclosed herein has a purity of greater than about 90%, specifically greater than about 95%, more specifically greater than about 98%, and most specifically greater than about 99% as measured by HPLC.

According to another aspect, there is provided a 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV:

or a salt thereof, wherein R is hydrogen or an alkyl group; R' is hydrogen or a nitrogen protecting group P; R" is hydrogen or a halogen atom; and R'" is hydrogen, or an alkali or alkaline earth metal ion.

In one embodiment, a specific compound of formula IV is methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate of formula IVa:
or a salt thereof.

The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES Example 1 Preparation of Methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate Method-I:

Methyl 4-acetylamino-2-hydroxy-3-propenylbenzoate (100 g) was taken into a reaction flask, followed by the addition of dichloromethane (1000 ml), a solution of potassium hydroxide (30 g) in water (1000 ml) and tetra-n-butylammonium bromide (43 g) at room temperature (25-30°C). The resulting mixture was stirred for 10 minutes at room temperature and then cooled to below 10°C, followed by the portion wise addition of potassium permanganate powder while maintaining the temperature at 10-15°C. After complete addition of potassium permanganate, the resulting mass was stirred for 15 minutes, followed by the addition of saturated sodium bisulfite solution (250 g) for decolorization. The resulting mass was filtered to remove unwanted salts and the cake was washed with dichloromethane (100 ml). The mother liquors were taken, followed by the separation of the bottom organic layer and extracting the resulting aqueous layer two times with dichloromethane (200 ml x 2). The organic layers were combined and then distilled off the solvent under vacuum to obtain a residue. Diisopropyl ether (500 ml) and water (500 ml) were added to the residue and then stirred for 15 minutes at 25-30°C. The separated solid was filtered, washed with diisopropyl ether (100 ml) and then dried at 55-60°C to yield 110 g of methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate (Yield: 96.7%; Purity by HPLC: 97%). Method-II:

Methyl 4-acetylamino-2-hydroxy-3-propenylbenzoate (100 g) was taken into a reaction flask, followed by the addition of dichloromethane (1000 ml), water (1000 ml) and tetra-n-butylammonium bromide (43 g) at room temperature (25-30°C). The resulting mixture was stirred for 10 minutes at room temperature and then cooled to below 10°C, followed by the portion wise addition of potassium permanganate powder while maintaining the temperature at 10-15°C. After complete addition of potassium permanganate, the resulting mass was stirred for 15 minutes, followed by the addition of saturated sodium bisulfite solution (250 g) for decolorization. The resulting mass was filtered to remove unwanted salts and the cake was washed with dichloromethane (100 ml). The mother liquors were taken, followed by the separation of the bottom organic layer and extracting the resulting aqueous layer two times with dichloromethane (200 ml x 2). The organic layers were combined and then distilled off the solvent under vacuum to obtain a residue. Diisopropyl ether (500 ml) and water (500 ml) were added to the residue and then stirred for 15 minutes at 25-30°C. The separated solid was filtered, washed with diisopropyl ether (100 ml) and then dried at 55-60°C to yield 108 g of methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate (Yield: 95%; Purity by HPLC: 95%). Purification of Methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate Methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate (25 g, Purity by HPLC: 95%) was dissolved in a mixture of ethyl acetate and isopropyl alcohol (5:1) at reflux temperature (70°C). The resulting solution was subjected to carbon treatment by adding activated carbon (1 g), followed by filtration at reflux temperature. The resulting filtrate was cooled to 0-5°C for 1 hour and the separated solid was filtered and then dried at 55-60°C to produce 20 g of the pure methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate (Yield: 80%; Purity by HPLC: 99.2%).

Infra red (FT-IR) spectrum (KBr Pellets): Main bands at about 3260, 1679, 1658, 1595, 1532, 1439, 1418, 1373,1336, 1293, 1258, 1196,1163, 1147, 1095, 1064,1037, 939, 884, 788, 759, 710 and 663 cm"1.

Example 2 Preparation of Methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate Method-I:
Water (350 ml) was added to the pure methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate (50 g, obtained in example 1) and then stirred for 10 minutes at 25-30°C, followed by the addition of sodium periodate (75 g) while maintaining the temperature at 20-25°C and then stirring the mass for 30 minutes to 1 hour. The separated solid was filtered, washed with water (50 ml) and then dried at 60°C to produce 44 g of methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate (Yield: 98%; Purity by HPLC: 95%).

Method-II:

Diisopropyl ether (350 ml) and Water (350 ml) were added to the pure methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate (50 g, obtained in example 1) and then stirred for 10 minutes at 25-30°C, followed by the addition of sodium periodate (75 g) while maintaining the temperature at 20-25°C and then stirring the mass for 30 minutes to 1 hour. The separated solid was filtered, washed with water (50 ml) and then dried at 60°C to produce 44 g of methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate (Yield: 98%; Purity by HPLC: 97%).

Example 3 Preparation of Methyl 4-Acetylamino-3-formylmethyl-2-hydroxybenzoate

After Methyl 4-acetylamino-2-hydroxy-3-propenylbenzoate (100 g) was taken into a reaction flask, followed by the addition of dichloromethane (1000 ml), a solution of potassium hydroxide (30 g) in water (1000 ml) and tetra-n-butylammonium bromide (43 g) at room temperature (25-30°C). The resulting mixture was stirred for 10 minutes at room temperature and then cooled to below 10°C, followed by the portion wise addition of potassium permanganate powder while maintaining the temperature at 10-15°C. After complete addition of potassium permanganate, the resulting mass was stirred for 15 minutes, followed by the addition of saturated sodium bisulfite solution (250 g) for decolorization. The resulting mass was filtered to remove unwanted salts and the cake was washed with dichloromethane (100 ml). The mother liquors were taken, followed by the separation of the bottom organic layer and extracting the resulting aqueous layer two times with dichloromethane (200 ml x 2). The organic layers were combined and then distilled off the solvent under vacuum to obtain a residue. Water (350 ml) was added to the residue and then stirred for 15 minutes at 25-3 0°C, followed by the addition of sodium periodate (150 g) while maintaining the temperature at 20-25°C and then stirring the mass for 30 minutes to 1 hour. The separated solid was filtered, washed with water (100 ml) and then dried at 60°C to produce 114 g of methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate (Yield: 98%; Purity by HPLC: 98%).

We claim:

1. A process for the preparation of a 3-formylmethyl-benzoic acid derivative of formula II:

or a salt thereof,

wherein R is hydrogen or an alkyl group; R' is hydrogen or a nitrogen protecting group
P; R" is hydrogen or a halogen atom; and R'" is hydrogen, or an alkali or alkaline earth
metal ion;

which comprises:

a) oxidizing a 3-allyl-benzoic acid derivative of formula III:

or a salt thereof, wherein R, R', R" and R'" are as defined in formula II; with a suitable oxidizing agent in the presence or absence of a base, optionally in the presence of a phase transfer catalyst, to produce a 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV:

or a salt thereof, wherein R, R', R" and R'" are as defined above, and optionally purifying the compound of formula IV using a suitable solvent or a mixture of suitable solvents; and

b) reacting the compound of formula IV with a glycol cleavage agent to produce the 3-formylmethyl-benzoic acid derivative of formula II or a salt thereof, and optionally purifying the compound of formula II using a suitable solvent or a mixture of suitable solvents.

2. The process of claim 1, wherein, in the compounds of formulae II, III and IV, R is an alkyl group, R' is a nitrogen protecting group P, R" is hydrogen, and R'" is hydrogen.

3. The process of claim 2, wherein the alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl; and wherein the nitrogen protecting group P is selected from the group consisting of acetyl, pyrrolidinylmethyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl, benzyloxymethyl, pivaloyloxymethyl (POM), trichloroethxoycarbonyl, l-adamantyloxycarbonyl, allyl, allyloxycarbonyl, trimethylsilyl, tert-butyldimethylsilyl, triethylsilyl, triisopropylsilyl,trimethylsilylethoxymethyl, t-butoxycarbonyl (BOC), t-butyl, l-methyl-l,1-dimethylbenzyl and pivaloyl.

4. The process of claim 3, wherein the alkyl group is methyl; and wherein the nitrogen protecting group P is acetyl.

5. The process of claim 1, wherein R" in the compounds of formulae II, III and IV is a halogen atom selected from F, Cl, Br and I; and wherein R'" in the compounds of formulae II, III and IV is an alkali or alkaline earth metal ion.

6. The process of claim 5, wherein R" is Cl; and wherein the alkali metal ion is selected from the group consisting of Na+, K+ and Li+, and wherein the alkaline earth metal ion is Ca2+ or Mg2+.

7. The process of claim 1, wherein the specific 3-formylmethyl-benzoic acid derivative of formula II obtained is methyl 4-acetylamino-3-formylmethyl-2-hydroxybenzoate of formula IIa (formula II, wherein R is methyl, R' is acetyl, and R" and R'" are hydrogen):

or a salt thereof;

and wherein the specific 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula
IV obtained is methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate of
formula IVa (formula IV, wherein R is methyl, R' is acetyl, and R" and R'" are
hydrogen):

or a salt thereof.

8. The process of claim 1, wherein the process steps-(a) and (b) are, each independently, carried out in the presence of a solvent or a mixture of solvents.

9. The process of claim 8, wherein the solvent used in step-(a) is selected from the group consisting of water, a halogenated hydrocarbon solvent, an ester, a ketone, a cyclic ether, an aliphatic ether, a hydrocarbon, and mixtures thereof; and wherein the solvent used in step-(b) is selected from the group consisting of water, a halogenated hydrocarbon, an ester, a ketone, a cyclic ether, an aliphatic ether, a hydrocarbon, an alcohol, and mixtures thereof.

10. The process of claim 9, wherein the solvent used in step-(a) is selected from the group consisting of water, a halogenated hydrocarbon solvent, and mixtures thereof; and wherein the solvent used in step-(b) is selected from the group consisting of water, an ether solvent, and mixtures thereof.

11. The process of claim 1, wherein the oxidizing agent used in step-(a) is selected from the group consisting of potassium permanganate, sodium permanganate, calcium permanganate, hydrogen peroxide, barium peroxide, calcium peroxide, sodium peroxide and potassium peroxide; and wherein the glycol cleavage agent used in step-(b) is selected from the group consisting of sodium periodate, potassium periodate and lead tetraacetate.

12. The process of claim 11, wherein the oxidizing agent used in step-(a) is potassium permanganate; and wherein the glycol cleavage agent used in step-(b) is sodium periodate.

13. The process of claim 1, wherein the oxidation reaction in step-(a) is carried out in the presence of a base, wherein the base is an organic or inorganic base; and wherein the oxidation reaction in step-(a) is carried out in the presence of a phase transfer catalyst.

14. The process of claim 13, wherein the organic base is selected from the group consisting of trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine and l-alkylimidazole; wherein the inorganic base is selected from the group consisting of sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride and tetrabutylammonium hydrogen sulfate.

15. The process of claim 1, wherein the 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV obtained in step-(a) is isolated and/or recrystallized from a solvent selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; and wherein the 3-formylmethyl-benzoic acid derivative of formula II obtained in step-(b) is isolated and/or recrystallized from a solvent selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

16. The process of claim 15, wherein the 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV obtained in step-(a) is isolated from a solvent mixture of water and an ether solvent.

17. A process for the preparation of 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV:

or a salt thereof, wherein R is hydrogen or an alkyl group;

R' is hydrogen or a nitrogen protecting group P;

R" is hydrogen or a halogen atom; and

R'" is hydrogen, or an alkali or alkaline earth metal ion; comprising oxidizing a 3-allyl-benzoic acid derivative of formula III:

or a salt thereof, wherein R, R', R" and R'" are as defined above; with a suitable oxidizing agent in the presence or absence of a base, optionally in the presence of a phase transfer catalyst, to produce the 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula IV or a salt thereof, and optionally purifying the compound of formula IV using a suitable solvent or a mixture of suitable solvents.

18. A process for the preparation of a 3-formylmethyl-benzoic acid derivative of formula II:

or a salt thereof, wherein R is hydrogen or an alkyl group; R' is hydrogen or a nitrogen
protecting group P; R" is hydrogen or a halogen atom; and R'" is hydrogen, or an alkali
or alkaline earth metal ion;

which comprises reacting 3-(2,3-dihydroxypropyl)-benzoic acid derivative of formula
IV:

or a salt thereof, wherein R, R', R" and R'" are as defined above; with a glycol cleavage agent to produce the 3-formylmethyl-benzoic acid derivative of formula II or a salt thereof, and optionally purifying the compound of formula II using a suitable solvent or a mixture of suitable solvents. 19. A 3-(2,3-Dihydroxypropyl)-benzoic acid derivative of formula IV:

or a salt thereof, wherein R is hydrogen or an alkyl group; R' is hydrogen or a nitrogen protecting group P; R" is hydrogen or a halogen atom; and R"' is hydrogen, or an alkali or alkaline earth metal ion. 20. The compound of claim 19, wherein the compound of formula IV is methyl 4-acetylamino-3-(2,3-dihydroxypropyl)-2-hydroxy-benzoate of formula IVa:

or a salt thereof.