Field of the invention
The present invention relates to a simple, efficient and cost-effective method for esterification of carboxylic acids.
Background of the invention
Esters are encountered without exception in all areas of synthetic organic chemistry. They are useful as end-products, solvents, intermediates for further transformation and for protection and characterization of carboxylic acids. Among the esters, Me and Et esters are the most frequently encountered because of the simplicity of their preparation, their reactivity and cost effectiveness.
The four most important methods for producing Me and Et esters are esterification, acylation, alkylation and transesterification, schematically shown below (for the Me esters).

Methods 2 and 3 are more expensive than 1 and also involve generation of organic /inorganic acids and salts. Neutralization of acid by-products generates salts which are basically undesirable. Moreover RCOCI, used in method 2 is made using the highly polluting thionyl chloride. Also, the alkylating agent used in method 3 is highly toxic and the by-product of the reaction, salt of methyl sulphuric acid is genotoxic. Method 4 is also indirect and Is useful in special cases.

Direct esterification (Fischer esterification) with MeOH or EtOH is the most widely employed strategy for obtaining esters. However, direct esterification being a reversible process, the equilibrium has to be shifted to the right by removing water formed either azeotropically or by employing a dehydration agent. An excess amount of MeOH or EtOH is required in cases where water Is not removed. The major disadvantages of direct esterification reaction include the yields being rarely quantitative and the procedures turning expensive and Inconvenient on scale-up. in contrast, dimethyl carbonate (DMC) and diethyl carbonate (DEC) are green reagents by virtue of their being non-toxic, biodegradable and giving rise to 1 eq. MeOH or EtOH and 1 eq. CO2, which is non-toxic In their reactions with carboxylic acids (Tundo, P. and Selve, M., Accounts of Chemical Research, Vol 35, 2002, Pg 706). Also, they are no longer manufactured from phosgene,
Until the advent of this work, these two carbonates were frequently used under base catalysis, (eg. DMAP) in esterifications. In a BAL2 type mechanism the carbonates, being much less reactive than dialkylsulphates or all^ylhalides necessitated the use of higher temperatures (160-300''C) (US Pat. No. 4513146). An improvement in this consisted in the use of 1 eq. DBU in DMC as solvent at reflux. However, DBU is an expensive base and its use at 1 eq. level and use of DMC as solvent are serious limitations (Shieh, W. C. C, Dell, S. J., Repik, O., J. Org. Chem., Vol. 67, 2002, Pg 2188). Acid catalysis of DMC mediated esterifications have been tried earlier using acidic zeolites and tosic acid (PTS. H2O) but reactions were done at 160-170''C in autoclaves (Heuer, L, Joentgen, W., Klausener, A., Gen Often., 1994, DE 4311424).
Use of conc.H2S04 as a catalyst has not been tried earlier. The innovators found to their surprise that use of conc.H2S04 as a catalyst resulted in lower reaction temperature as well as higher yields and purities of product esters. Also, this removed the need to use DMC as solvent. The limitation of using H2SO4 as a catalyst at 10 mol% level, was overcome by recycling H2SO4 in the same pot several times.

The present invention, thus, is an economical and industrially useful process, which circumvents all the drawbacks of the prior art by providing a cost effective method of esterification using an organic carbonate (for example dimethyl carbonate or diethyl carbonate) and sulphuric acid catalyst, wherein the reaction occurs at mild temperature and does not require high pressure, toxic and/or expensive reagents or large quantities of solvent. Also, the present invention provides a highly chemoselective method for the esterification of hydroxybenzoic acids leading to parabens in the case of p-hydroxy benzoic acid.
Additionally, work-up in the reaction according to the present invention can be non-aqueous or without utilization of solvent, thus slashing down the cost of the process further. The recycling of H2SO4 catalyst makes it possible for the subsequent reaction to proceed in the same vessel, which reduces the environmental burden to a large extent. It may be noted that the amount of H2SO4 can be brought down to about 1 mol% level after 10 repetitions in the same pot. Thus the present invention addresses the long felt need of the chemical industry for the provision of a highly efficient and cost-effective esterification process.
Summary of the invention
The objective of the present invention is to provide an efficient and cost-effective esterification method using dimethyl carbonate and diethyl carbonate as esterification reagents and concentrated sulphuric acid as catalyst.
Further it is an objective of the present invention to provide a method of esterification wherein the catalyst is recyclable and the isolated cnjde yields of esters as well as their purities are high, which eliminates the need of any further purification. The method offers scalability without affecting the yield or purity.
Another objective of the present invention is to minimize the amount of carbonates used, in presence of small amount of MeOH or EtOH so that the process economy is dramatically improved.

Detailed description of the invention
The present invention relates to a method of esterification of carboxylic acids using DMC and DEC under mild conditions of temperature and pressure, wherein the method is cost-effective and solvent free.
In an embodiment, the process of esterification comprises the following steps:
1. Reacting the carboxylic acid and organic carbonate in presence of concentrated sulphuric acid.
2. Isolating the resulting ester after recovering the excess DMC or DEC present.
In an embodiment, carboxylic acids were esterified with about 1.0 eq to about 2.5 eq DMC, particularly from about 1.2 eq to about 2.0 eq DMC, more particularly from about 1.4 eq to about 1.9 eq DMC, under catalysis by cone. H2S04from about 0.01 eq to about 0,2 eq, particularly from about 0.02 eq to about 0.15 eq, more particularly from about 0.05 eq to about 0.10 eq (Scheme-1).
Scheme-I: Esterification of carboxylic acids by DMC
0 HjSO^
f^^^ "^ s. A / " RCqWe + CO; +MeOH
^O' ^O'
In another embodiment, monocarboxylic acids were esterified under catalysis by cone. H2S04 from about 0.01 eq to about 0.5 eq, particularly from about 0.02 eq to about 0.35 eq, more particularly from about 0,05 eq to about 0.20 eq.
In yet another embodiment, dicarboxylic acids were esterified with about 2.0 eq to about 5.0 eq DMC, particularly from about 2.5 eq to about 4.5 eq DMC, more particularly from about 3.0 eq to about 3.8 eq DMC.

In an embodiment, Nitrogen containing acids were esterified under catalysis by cone. H2S04from about 0.5 eq to about 2.0 eq, particularly from about 0.7 eq to about 1.7 eq, more particularly from about 1.0 eq to about 1.5 eq.
The temperature of the reaction according to the present invention can be in the range from about 70X to about 150X, for example about 75°C to about 100X, particularly from about 80°C to about 85X (In the case of DMC).
Reaction of carboxylic acid with organic carbonate may be carried out approximately at atmospheric pressure. Usually the reaction is carried out under ambient or atmospheric pressure. However, pressure may be applied during the reaction,
The reaction time generally ranges from about 30 minutes to about 25 hours.
In an embodiment, the hydroxybenzoic adds gave exclusively the methyl esters at 80-85°C with DMC and the ethyl esters at 120'C with DEC.
The esterification reaction according to the present invention is applicable to aromatic, aralkyl, aliphatic, or unsaturated acids as well as N-containing nicotinic, amino benzoic acids.
In an embodiment, PTSA at 0.2 eq levels was found as effective as sulphuric acid under reflux conditions.
In another embodiment, triflic acid and the Lewis acid trimethyl silyl triflate were found effective as a catalyst for the esterification of carboxylic acids.
In another embodiment, the carboxylic acid, MeOH or EtOH and DMC or DEC are used in 3:1:2 ratio. This makes the method the cheapest esterification method available.
Examples
The following examples are included to illustrate certain aspects of the invention in greater detail but are not intended to limit the scope of the invention in any way. Various examples as well as alternate embodiments will be evident to a person skilled

in the art upon reference to the description and are presumed to be within the scope of the invention.
All products are characterized by IR and NMR spectra and purities were checked by HPLC or GC after work-up. Reaction monitoring was done by TLC on silica gel plates.
EXAMPLE-1
Method-A: Methvl o-toluate
A mixture of o-toluic acid (50 g, 0.367 mole), DMC (55.6 ml, 0.661 mole) and cone. H2S04 (1.9 ml, 0.037 mole) was heated under stimng at 80-85" for 8.5 h. TLC (20% EtOAc in hexane) showed only traces of unreacted acid. On cooling the homogeneous solution to 20°C, a small volume of a brown layer separated out. The reaction mixture was poured into 10% aq. NaHCOa (30.8 g in 300 ml water), under stirring. Product was extracted into a solvent (EtOAc or CH2CI2) and the extract was washed with brine, dried (Na2S04) and stripped of solvent (excess DMC can be recovered at this stage or before quenching), to give a pale yellow liquid, 52 g (94.3%) with a purity of 99.14% (by HPLC). IR and NMR spectra were in accordance with the structure.
EXAMPLE- 2
Recycling of the H2SO4 catalyst (Methyl m-toluate)
After the reaction (as above) (5 g scale) was over, the reaction mixture was cooled to room temperature and m-toluic acid (5 g) was added followed by 1 eq. DMC. Heating at 80-85° for 8-9 h completed the reaction. The sequence was repeated another 3 times. After the 3"^ cycle, reaction took 12 h for completion. So, 0.05 eq

H2SO4 was added and the reaction time restored to 9 h. Work up gave the ester in 82% yield (99% purity) from a total of 25 g of m- toluic acid.
EXAMPLE- 3
Method-B: Dimethylphthalate
0.006 mole) was heated under stirring at 80-85X (water bath) for 6 h. TLC (10% MeOH in CHCI3) showed only traces of the starting acid. Work up was done as in Method-A; Et20 or CH2CI2 was used for extraction. Crude dimethyl phthalate was obtained as a very pale yellow liquid, 5.7 g (97.6%) with a purity of 98.87% (by HPLC)
EXAMPLE- 4
Method-C: Methvl 4-aminobenzoate
A mixture of 4-aminobenzoic acid (5 g, 0.036 mole), DMC (10.95 ml, 0.131 mole, 3.64 eq.) and cone. H2SO4 (2.72 ml, 0.06 mole, 1.39 eq.) was refluxed for 16 h TLC (10% MeOH in CHCI3). Work up was done as in Method-A but using aq. NaHCOa (8.6 g in 86 ml water) gave yield 89.64% and a purity of 99.09% (by HPLC).
EXAMPLE- 5
A mixture of p-naphthol (100 g, 0.694 mole), DMC (112.47 g, 1.249 mole), con. H2SO4 (6.79 g. 0.0694 mole) and glacial AcOH (4.162 g, 0.0694 mole) was heated to 90°C for 20 h. Excess DMC (along with MeOH) was distilled off at ~50°C under vacuum. 15% aq. NaOH (250 ml) was added to the residue and the mixture stirred and solid filtered, washed and dried. The yield was determined to be 86.6 g (78.9%) and the purity was found to be 99.79%. The product was obtained as a white solid, having a m.p. 69°Cto7rC.

Representative examples showing the yields obtained using different types of carboxylic acids are illustrated in Table 1.
EXAMPLE- 6
Method-D: Ethyl 3.5-dihvdroxv benzoate
A mixture of 3,5-dihydroxybenzoic acid (5 g, 0.032 mole) DEC (20.69 g, 0.175 mole) cone. H2SO4 (0.95 g, 0.0097 mole) and acetic acid (0.58 g, 0.0097 mole) was heated at 120° for 3 h The reaction mixture was added to aq. NaHCOs and extracted with EtOAc. After washing the extract with aq. NaHCOa and water and drying (NaaSO*), the solvent was removed giving a white solid, 6.2 g. This crude material was stirred in hexane for 20 min, filtered and dried, wt. 5.26 g (off white solid) mp. 127-129X. The purity was detennined to be 99.46% by HPLC. Representative examples showing the yields obtained using different types of carboxylic acids with DEC are illustrated in Table 2.
EXAMPLE- 7
Method-E: Ethvlo-hvdroxvbenzoate fusing synergistic combination of EtOH / Diethyl carbonate)
A mixture of p-hydroxybenzoic acid (3 g, 0.0217 mole) DEC (1,71 g, 0.0144 mole) EtOH (3ml) and cone. H2SO4 (0.071g, 0.000717 mole) was heated at 100° for 20-24h. The reaction mixture was added to aq. NaHCOs and extracted with EtOAc. After washing the extract with aq. NaHCOa and water and drying (NaaSOA), the solvent was removed giving a white solid, 3.60 g yield - 97.22 %. m.p. -113.7-115. rC. The purity was determined to be 99,46% by HPLC.

What is claimed is:
1. A sulphuric acid catalyzed, method of esterification of carboxylic acids using
organic carbonates.
2. The method of claim 1, wherein the carboxylic acid is aromatic, aliphatic, aralkyl, nicotinic, amino benzoic or unsaturated carboxylic acid.
3. The method of claim 1, wherein the said reaction is conducted at a temperature in the range of from about 70X to about 150X.
4. The method of claim 1, wherein the said reaction is conducted at atmospheric
pressure.
5. The method of claim 1, wherein the organic carbonate is dimethyl carbonate or
diethyl carbonate.