Indian Patents. 277876:METHOD FOR ESTERIFICATION

Title of Invention	METHOD FOR ESTERIFICATION
Abstract	The present invention relates to esterification of carboxylic acids using borates, the esterification reaction being catalyzed by acid catalysts and taking place under mild conditions, giving high yield and purity of esters.

Full Text	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: Esterification of acids to yield esters can be performed in a number of ways. The most common method is to heat a carboxylic acid with an alcohol while removing the water that is formed. A mineral acid catalyst is usually needed to make the reaction occur at a useful rate. Generally, an excess amount of alcohol is required in these conventional methods of esterification, which adds up to the cost of the reaction. Fischer esterification, wherein esters are formed by refluxing carboxylic acid and an alcohol in the presence of an acid catalyst has also been used. To obtain esters, direct acylation of alcohols with carboxylic acids is preferred over acylation with anhydrides or acid chlorides. However, the major disadvantage of direct acylation is the unfavorable chemical equilibrium. Since the esterification reaction is reversible, the equilibrium needs to be remedied in order to increase the conversion rate of carboxylic acids. This has generally been done by the use of molecular sieves which are generally very expensive or by the use of excessive amounts of alcohols or constantly removing the product from the reaction system. These methods substantially increase the production cost of carboxylic esters. Organic carbonates such as Dimethyl carbonate (DMC) has also been used in Fischer esterifications. But the by products of DMC include the greenhouse gas CO2 and methanol, which is toxic. Borates, being green reagents have been increasingly used to catalyze esterification reactions. The reactions catalyzed by borates are essentially free of any toxic or harmful by-products. A borate mediated esterification of carboxylic acids in a stoichiometric ratio of 3: 1 for the carboxylic acid and the borate, m refluxing toluene has been reported (Hirao N. and Yabuuchi T., J. Pharm. Soc. Japan., 1954, 1073). Mansoori et al. (Mansoori et al.. Chin. J. Chem., 2007, 1878; Mansoori et al,. Green Chemistry, 2005, 870), report a solvent and catalyst firee borate mediated carboxylic acid esterification, in a stoichiometric ratio of 3: 1 for the carboxylic acid and the borate. However, the yields of the carboxylic acid esters obtained range from about 38% to 82%. It was surprisingly found out by our inventors that the use of acid catalysts in borate mediated esterification reactions resulted in an unexpected reduction of reaction temperatures and time as well as offered very high yield and purity of the reaction products. The recycled acid catalyst makes it possible for the subsequent reaction to proceed in the same vessel, which reduces the environmental burden to a fair degree. The present invention thus is an economical and industrially useful process, which circumvents all the drawbacks of the prior art by providing a solvent free method for borate mediated esterification wherein the yields and purities of the reaction products are more and the reaction occurs at low temperature conditions. 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 efficacious and cost-effective borate mediated esterification method using acid catalysts. Further it is an objective of the present invention to provide a method of esterification wherein the isolated yields of esters as well as their purities are high, which eliminates the need of any further purification step. Detailed description of the invention: The present invention relates to a method of esterification of carboxylic acids using borates under mild conditions of temperature, wherein the method is cost-effective, solvent free and consumes less time. In an embodiment, the process of esterification comprises the following steps: • Reacting the carboxylic acid and borate in presence of acid catalyst. • Isolating the resulting ester. In an embodiment, carboxylic acid and tributyl borate were used in a stoichiometric ratio of about 3 equivalents of carboxylic acid to 1 equivalent of tributyl borate, particularly the ratio of 1 equivalent of carboxylic acid to 1 equivalent of tributyl borate was found useful. Scheme-h Mechanism of esterification of carboxvlic acids bv tributyl borate In an embodiment, aromatic carboxylic acids, for example m- toluic acid were esterified with tributyl borate from about 1 eq to about 5 eq, more particularly from about 0.33 eq to about 1 eq, under catalysis by cone. H2SO4 from about 0.01 eq to about 0.5 eq, particularly from about 0.02 eq to about 0.2 eq, more particularly from about 0.05 eq to about 0.1 eq. In 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 another embodiment, aliphatic carboxylic acids, for example phenyl propionic acid were esterified with tributyl borate from about 1 eq to about 5 eq, more particularly from about 0.33 eq to about 1 eq, under catalysis by cone. H2SO4 from about 0.01 eq to about 0,5 eq, particularly from about 0.02 eq to about 0.2 eq. more particularly from about 0.05 eq to about 0.1 eq. In yet another embodiment, heterocyclic carboxylic acids, for example nicotinic acid and iso-nicotinic were esterified with tributyl borate from about 1 eq to about 5 eq, more particularly from about 0.33 eq to about 1 eq, under catalysis by cone. H2SO4 from about 0.01 eq to about 0.5 eq, particularly from about 0.02 eq to about 0.2 eq, more particularly from about 0.05 eq to about 0.1 eq. The temperature of the reaction according to the present invention can be in the range from about 60°C to about 120°C, particularly from about 80°C to about 100°C. Representative borates which may be used in the context of the present invention include but are not limited to tributyl borate, trimethyl borate, triethyl borate, tri-isopropyl borate and the like. The acid catalysts used in the context of the present invention include but are not limited to sulphuric acid, sulfamic acid, PTSA, Triflic acid, Trimethyl silyl triflate and the like. Cone. H2SO4 from about 0.0 i eq to about 2,0 eq, particularly from about 0.02 eq to about 1.5 eq, more particularly from about 0.05 eq to about 1.4 eq was found useful as a catalyst in the context of the present invention (Scheme-1). The reaction time generally ranges from about 30 minutes to about 25 hours. The esterification reaction according to the present invention is applicable to aromatic acids, aliphatic acids, heterocyclic acids including but not limited to unsaturated acids and the like. Examples The following example is included to illustrate certain aspects of the invention in greater detail but is not intended to limit the scope of the invention m 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, Mass 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; Preparation of Butyl benzoate A mixture of benzoic acid (5 g, 0.040 mol), tributyl borate (9.42 g 0.040 mol) and H2SO4 (0.40 g, 0.0040 mole) was heated at 100°C for 7 h (TLC/Si02 30% EtOAc in hexane). After quenching into 10% aq. NaHC03 (50-70 ml) the product is isolated by extraction into ethyl acetate. 7.0 g of butyl benzoate was obtained with 97.59% purity. The purity was determined by HPLC. The yield of the compound was 96.15%, Representative examples showing the reaction times and yields obtained using different types of carboxylic acids are illustrated in Table 1. Table 1: Esterification of ArCOOH with tributyl borate (leq) at 100*'C using cone. H2SO4 (0.1 eq) 1. Same yield and purity at 80-85 °C 2. Solubility problem ; 2 eq borate was used to facilitate stirring 3. 2 eq. borate used 4. 2 eq borate, 1.4 eq H2SO4, substrate dissolves as the reaction progresses 5. As in 4). Product is dark coloured 6. Brown solid Melting range 47-51.4 °C 7. Diester is obtained 8. Separated by chromatography; diester is not obtained very pure (some mono is present) claims 1. A process of esterification of carboxylic acids comprises the steps of: • reacting the carboxylic acid and borate in presence of acid catalyst; and • isolating the resulting ester. 2. The process as claimed in claim 1, wherein the carboxylic acid is aromatic, aliphatic, heterocyclic or unsaturated carboxylic acid. 3. The process as claimed in claim 1, wherein the esterification is catalyzed with an acid selected from sulphuric acid, sulfamic acid, PTSA, Triflic acid, Trimethyl silyl triflate and the like 4. The process as claimed in claim 1, wherein the preferable acid is sulfuric acid 5. The process as claimed in claim 1, wherein the said reaction is conducted at a temperature in the range of from about 60°C to about 120°C. 6. The process as claimed in claim 6, wherein the preferable temperature is from about 80°C to about 100°C. 7. The process as claimed in claim 1, wherein the borate is tributyl borate, trimethyl borate, triethyl borate or tri-isopropyl borate.

Full Text

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:

Esterification of acids to yield esters can be performed in a number of ways. The most common method is to heat a carboxylic acid with an alcohol while removing the water that is formed. A mineral acid catalyst is usually needed to make the reaction occur at a useful rate. Generally, an excess amount of alcohol is required in these conventional methods of esterification, which adds up to the cost of the reaction.

Fischer esterification, wherein esters are formed by refluxing carboxylic acid and an alcohol in the presence of an acid catalyst has also been used. To obtain esters, direct acylation of alcohols with carboxylic acids is preferred over acylation with anhydrides or acid chlorides. However, the major disadvantage of direct acylation is the unfavorable chemical equilibrium. Since the esterification reaction is reversible, the equilibrium needs to be remedied in order to increase the conversion rate of carboxylic acids. This has generally been done by the use of molecular sieves which are generally very expensive or by the use of excessive amounts of alcohols or constantly removing the product from the reaction system. These methods substantially increase the production cost of carboxylic esters. Organic carbonates such as Dimethyl carbonate (DMC) has also been used in Fischer esterifications. But the by products of DMC include the greenhouse gas CO2 and methanol, which is toxic.

Borates, being green reagents have been increasingly used to catalyze esterification reactions. The reactions catalyzed by borates are essentially free of any toxic or harmful by-products. A borate mediated esterification of carboxylic acids in a stoichiometric ratio of 3: 1 for the carboxylic acid and the borate, m refluxing toluene has been reported (Hirao N. and Yabuuchi T., J. Pharm. Soc. Japan., 1954, 1073). Mansoori et al. (Mansoori et al.. Chin. J. Chem., 2007, 1878; Mansoori et al,. Green Chemistry, 2005, 870), report a solvent and catalyst firee borate mediated carboxylic acid esterification, in a stoichiometric ratio of 3: 1 for the carboxylic acid and the borate. However, the yields of the carboxylic acid esters obtained range from about 38% to 82%. It was surprisingly found out by our inventors that the use of acid catalysts in borate mediated esterification reactions resulted in an unexpected reduction of reaction temperatures and time as well as offered very high yield and purity of the reaction products. The recycled acid catalyst makes it possible for the subsequent reaction to proceed in the same vessel, which reduces the environmental burden to a fair degree.

The present invention thus is an economical and industrially useful process, which circumvents all the drawbacks of the prior art by providing a solvent free method for borate mediated esterification wherein the yields and purities of the reaction products are more and the reaction occurs at low temperature conditions. 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 efficacious and cost-effective borate mediated esterification method using acid catalysts.

Further it is an objective of the present invention to provide a method of esterification wherein the isolated yields of esters as well as their purities are high, which eliminates the need of any further purification step.

Detailed description of the invention:

The present invention relates to a method of esterification of carboxylic acids using borates under mild conditions of temperature, wherein the method is cost-effective, solvent free and consumes less time.

In an embodiment, the process of esterification comprises the following steps:

• Reacting the carboxylic acid and borate in presence of acid catalyst.

• Isolating the resulting ester.

In an embodiment, carboxylic acid and tributyl borate were used in a stoichiometric ratio of about 3 equivalents of carboxylic acid to 1 equivalent of tributyl borate, particularly the ratio of 1 equivalent of carboxylic acid to 1 equivalent of tributyl borate was found useful.

Scheme-h Mechanism of esterification of carboxvlic acids bv tributyl borate

In an embodiment, aromatic carboxylic acids, for example m- toluic acid were esterified with tributyl borate from about 1 eq to about 5 eq, more particularly from about 0.33 eq to about 1 eq, under catalysis by cone. H2SO4 from about 0.01 eq to about 0.5 eq, particularly from about 0.02 eq to about 0.2 eq, more particularly from about 0.05 eq to about 0.1 eq.

In 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 another embodiment, aliphatic carboxylic acids, for example phenyl propionic acid were esterified with tributyl borate from about 1 eq to about 5 eq, more particularly from about 0.33 eq to about 1 eq, under catalysis by cone. H2SO4 from about 0.01 eq to about 0,5 eq, particularly from about 0.02 eq to about 0.2 eq. more particularly from about 0.05 eq to about 0.1 eq.

In yet another embodiment, heterocyclic carboxylic acids, for example nicotinic acid and iso-nicotinic were esterified with tributyl borate from about 1 eq to about 5 eq, more particularly from about 0.33 eq to about 1 eq, under catalysis by cone. H2SO4 from about 0.01 eq to about 0.5 eq, particularly from about 0.02 eq to about 0.2 eq, more particularly from about 0.05 eq to about 0.1 eq.

The temperature of the reaction according to the present invention can be in the range from about 60°C to about 120°C, particularly from about 80°C to about 100°C.

Representative borates which may be used in the context of the present invention include but are not limited to tributyl borate, trimethyl borate, triethyl borate, tri-isopropyl borate and the like.

The acid catalysts used in the context of the present invention include but are not limited to sulphuric acid, sulfamic acid, PTSA, Triflic acid, Trimethyl silyl triflate and the like.

Cone. H2SO4 from about 0.0 i eq to about 2,0 eq, particularly from about 0.02 eq to about 1.5 eq, more particularly from about 0.05 eq to about 1.4 eq was found useful as a catalyst in the context of the present invention (Scheme-1).

The reaction time generally ranges from about 30 minutes to about 25 hours.

The esterification reaction according to the present invention is applicable to aromatic acids, aliphatic acids, heterocyclic acids including but not limited to unsaturated acids and the like.

Examples

The following example is included to illustrate certain aspects of the invention in greater detail but is not intended to limit the scope of the invention m 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, Mass 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; Preparation of Butyl benzoate

A mixture of benzoic acid (5 g, 0.040 mol), tributyl borate (9.42 g 0.040 mol) and H2SO4 (0.40 g, 0.0040 mole) was heated at 100°C for 7 h (TLC/Si02 30% EtOAc in hexane). After quenching into 10% aq. NaHC03 (50-70 ml) the product is isolated by extraction into ethyl acetate. 7.0 g of butyl benzoate was obtained with 97.59% purity. The purity was determined by HPLC. The yield of the compound was 96.15%,

Representative examples showing the reaction times and yields obtained using different types of carboxylic acids are illustrated in Table 1.

Table 1: Esterification of ArCOOH with tributyl borate (leq) at 100*'C using cone. H2SO4 (0.1 eq)

1. Same yield and purity at 80-85 °C

2. Solubility problem ; 2 eq borate was used to facilitate stirring

3. 2 eq. borate used

4. 2 eq borate, 1.4 eq H2SO4, substrate dissolves as the reaction progresses

5. As in 4). Product is dark coloured

6. Brown solid Melting range 47-51.4 °C

7. Diester is obtained

8. Separated by chromatography; diester is not obtained very pure (some mono is present)

claims

1. A process of esterification of carboxylic acids comprises the steps of:

• reacting the carboxylic acid and borate in presence of acid catalyst; and

• isolating the resulting ester.

2. The process as claimed in claim 1, wherein the carboxylic acid is aromatic, aliphatic, heterocyclic or unsaturated carboxylic acid.

3. The process as claimed in claim 1, wherein the esterification is catalyzed with an acid selected from sulphuric acid, sulfamic acid, PTSA, Triflic acid, Trimethyl silyl triflate and the like

4. The process as claimed in claim 1, wherein the preferable acid is sulfuric acid

5. The process as claimed in claim 1, wherein the said reaction is conducted at a temperature in the range of from about 60°C to about 120°C.

6. The process as claimed in claim 6, wherein the preferable temperature is from about 80°C to about 100°C.

7. The process as claimed in claim 1, wherein the borate is tributyl borate, trimethyl borate, triethyl borate or tri-isopropyl borate.

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Patent Number

277876

Indian Patent Application Number

92/CHE/2009

PG Journal Number

51/2016

Publication Date

09-Dec-2016

Grant Date

02-Dec-2016

Date of Filing

12-Jan-2009

Name of Patentee

LAURUS LABS PVT LTD

Applicant Address

2ND FLOOR SERENE CHAMBERS ROAD #7 BANJARA HILLS HYDERABAD 500034

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. CASUKHELA SOMESWARA RAO	2ND FLOOR, SERENE CHAMBERS, ROAD NO. 7, BANJARA HILLS, HYDERABAD - 500 034
2	DR. GOTTUMUKKALA VENKATA SUBBARAJU	APTUIT LAURUS PRIVATE LIMITED 2ND FLOOR, SERENE CHAMBERS, ROAD NO. 7, BANJARA HILLS, HYDERABAD - 500 034
3	DR. CHAVA SATYANARAYANA	APTUIT LAURUS PRIVATE LIMITED 2ND FLOOR, SERENE CHAMBERS, ROAD NO. 7, BANJARA HILLS, HYDERABAD - 500 034
4	DR. RATNAMALA ANNAPRAGADA	APTUIT LAURUS PRIVATE LIMITED 2ND FLOOR, SERENE CHAMBERS, ROAD NO. 7, BANJARA HILLS, HYDERABAD - 500 034

PCT International Classification Number

C07C67/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA