Title of Invention

A PROCESS FOR THE PRODUCTION OF ACYLATED PRODUCTS BY REDUCTIVE ACYLATION OF NITRO, AZIDO AND CYANO ARENES

Abstract A process for the production of acylated products by reductive acylation of nitro, azido, and cyano arenes The present invention relates to A process for the production of acylated products by reductive acylation of nitro, azido, and cyano arenes. More particularly, this invention relates to an improved process for the preparation of amides and anilides using C3-C7 carboxylic acids as proton source/acylating agents employing Fe3+-montmorillonite as a catalyst. The eco-friendly process for reductive acylation of nitro, azido and cyano arenes uses metal cation exchanged montmorillonite as a catalyst dispensing with the use of stiochiometric amounts of corrosive salts as reagents. The reductive acylated products are important intermediates in the preparation of drugs and pharmaceuticals
Full Text Field of the invention
The present invention relates to a process for the production of acylated products by reductive acylation of nitro, azido, and cyano arenas. More particularly, this invention relates to an improved process for the preparation of amides and anilides using C3-C7 carboxylic acids as proton source/acylating agents employing Fe3+-montmorillonite as a catalyst.
This invention particularly relates to an eco-friendly process for reductive acylation of nitro, azido and cyano arenes using metal cation exchanged montmorillonite as a catalyst dispensing with the use of stiochiometric amounts of corrosive salts as reagents. The reductive acylated products are important intermediates in the preparation of drugs and pharmaceuticals. Background of the invention
Reference is made to Li et al., Journal of American Chemical Society; 726, 124, 2002 wherein enzymes are known to produce and consume hydrogen. The inherent disadvantages in this process are the electrons are supplied by H-clusters. Reference is also made to Cammack, Nature; 214, 397, and 1999 wherein [Fe]-hydrogenase enzyme is known to produce hydrogen, while the [Ni-Fe] -hydrogenase consumes hydrogen. The inherent disadvantages in this process are complex and tedious synthetic protocols. The hydrogenase models are developed to produce hydrogen substoichiometrically.
Reference is made to Nomura, Journal of Molecular Catalysis A., 1, 130, 1998
wherein reduction of nitroarenes is carried out using carbonyl complexes as catalysts
under carbon monoxide pressures. The inherent disadvantage in this process is the use
of non-regenerable expensive carbonyl complexes in stoichiometric quantities or
expensive catalysts with hydrogen or CO pressure. Reference is also made to
Wantanabe et al; Journal of Organic Chemistry 4451, 49, 1984 wherein reductive
acylation of nitrobenzene is carried out by using platinum complexes under carbon
monoxide pressure. The inherent disadvantages in this process are use of expensive
platinum complexes and high CO pressure.
Reference is made to Kamal et al; Tetrahedron Letters, 7743, 41, 2000 wherein azides are reduced to amines by using stiochiometric quantities of FeSO4 in ammonia solution. The major drawback in this process is the reduction of azo compounds induced by non-regenerable stoichiometric hydride reagents.

Objects of the invention
The main object of the present invention is to provide a method for the processing of hydrogen for the reductive acylation of substituted nitro, azido and cyano arenes which obviates the drawbacks detailed above.
It is another object of the present invention to provide a novel and ecofriendly process for the production and consumption of hydrogen for the reductive acylation of substituted nitro, azido and cyano arenes.
It is a further object of the invention to provide a novel, economic and ecofriendly process for the reductive acylation of nitro, azido and cyano compounds.
It is yet another object of the invention to provide a process for the reductive acylation of substituted nitro, azido and cyano arenes which dispenses with the use of corrosive and stiochiometric quantities of non-regenerable expensive carbonyl complexes in stiochiometric quantities or expensive catalysts with hydrogen or CO pressure.
It is yet another object of the invention to provide a process for the reductive acylation of substituted nitro, azido and cyano arenes with good selectivity and yields.
It is yet another object of the invention to provide a process for the reductive acylation of substituted nitro, azido and cyano arenes wherein the catalyst can be recycled without significant loss of activity. Summary of the invention
The novelty of the present invention provides resides in the production of hydrogen and consumption in the reductive acylation of nitro, azido, and cyano compounds using carboxylic acid as a proton source/ acylating agents and iodide anion as electron source by metal exchanged montmoriilonite catalyst under reflux conditions.
Promotive effect of montmoriilonite, a prebiotic material and low redox potential of iron, and abundance of both these materials at cheaper cost prompted its use in the present studies. Higher yields and selectivities are obtained towards amides and anilides, when Fe3+-montmorillonite as synthesized is used in the reductive acylation of nitro, azido and cyano arenes in carboxylic acid solvent. Since anilides and amides are the desired starting materials for the synthesis of drugs, pharmaceuticals, this invention is timely and appropriate. Thus earlier papers, patents fell short of expectations for commercial reality and economics of the process. Thus,this invention offers the best techno-economic route for the synthesis of amides and anilides intermediates for drugs and phannaceuticals.
Accordingly, the present invention provides a method for the processing of hydrogen for reductive acylation of nitro, azido, and cyano arenes comprising reacting nitro, azido and cyano arines with C3-C7 carboxylic acid as an acylating agent/proton source in the ratio of 1:4 to 1:10 and iodide as electron source in presence of metal ion exchanged montmorillonite catalyst in the range of 5 to 20% by weight with respect to the substrate at a temperature in the range of 116-200°C for a period of 0.5 -24 hrs., recovering the catalyst by filtration for reuse and recovering the acylated product.
In an embodiment of the invention, the temperature used for simultaneous production and consumption in the reductive acylation of substituted nitro, azido and cyano arenes is in the range of 25-200°C.
In an embodiment of the invention, the metal ion used for exchange on montmorillonite is selected from the group consisting of Fe3+, Cu2+ Ce3+, Zr4+ and
In an embodiment of the invention, the production and consumption of hydrogen is catalysed by the same catalyst.
In an embodiment of the invention, the production of hydrogen is by the reduction of proton generated from the carboxylic acid.
In another embodiment of the invention, the reduction of proton generated from carboxylic acid is effected at room temperature by Mn+ -montmorillonite where Mn+ is selected from Fe3+, Cu2+ Ce3+, Zr4+ and Al3+
In another embodiment of the invention the nitro, azido or cyano arenes used for the reductive acylation reactions comprise substituted aromatic compounds selected from the group consisting of methyl, ethyl, propyl, halogen, acid, aryl and heteroaryl.
In yet another embodiment of the invention, the quantity of the catalyst is 5 to 20% by weight with respect to the substrate.
In another embodiment of the invention the C3-C7 carboxylic acid is selected from the group consisting of propionic acid to heptanoic acid.
In another embodiment of the invention, the iodide anion used as electron source is sodium iodide.

In another embodiment of the invention, the ratio of nitro, azido or cyano
compounds to acylating agent is 1:4 to 1:8
In a further embodiment of the invention, the ratio of nitro and azido
compounds to sodium iodide is 1:2 to 1:6
In yet another embodiment of the invention the ratio of cyano compounds to
sodium iodide is 1:3 to 1:6
In another embodiment of the invention, the reaction of nitro and cyano
compounds is effected at a temperature of 160-200°C.
In another embodiment of the invention, the reaction of azido compounds is
effected at a temperature of 116-160°C.
In still another embodiment of the present invention, the reaction is effected
for a period of 0.5 -24 hrs.
Detailed Description of the invention
The invention provides a method for the processing of hydrogen for the
reductive acylation of substituted nitro, azido and cyano arenes, by reacting C3-C?
carboxylic acids as acylating agents/proton sources, iodide ion as electron source,
employing metal cation exchanged montmorillonite as catalyst generally at a
temperature in the range of 116-200°C for a period of 0.5-24h, and recovering the
catalyst by filtration for re-use and the acylated products by conventional methods.
The processing of hydrogen comprises production of hydrogen at room temperature
and consumption of hydrogen at higher temperatures. Generally, both the production
and consumption of hydrogen is catalysed by the same catalyst. Hydrogen is produced
by the reduction of proton generated from carboxylic acid.
The process of the invention dispenses with the use of corrosive and nonregenerable
stoichiometric hydride reagents or under hydrogen pressure in the
presence of expensive catalysts, and non-regenerable expensive carbonyl complexes
in stoichiometric quantities or using expensive catalysts with hydrogen or CO
pressure.
Another object of the present invention is to provide a process for the
preparation of amides and anilides wherein the selectivity and conversions are good
and the work up procedure is simple. The reduction of proton generated from
carboxylic acid is effected at room temperature by Mn+ -montmorillonte catalyst
where M n+ is preferably Fe3+, Cu2+, Ce3+, Zr4+, or A13+. The montmorillonite or metal
exchanged montmorillonite are used as catalysts for the reductive acylation of nitro,
azido, and cyano arenes. The catalyst can be used for several cycles with consistent
activity.
The C3-C7 carboxylic acids used as acylating agents/proton sources are
preferably selected from propionic acid to heptanoic acid. Sodium iodide is a
preferred electron source. In an embodiment of the present invention, the temperature
used for simultaneous production and consumption of hydrogen in the reductive
acylation of substituted nitro, azido and cyano arenes is in the range of 25-200°C. The
nitro, azido, cyano arenes used for the reductive acylation reactions are substituted
aromatic compounds selected from methyl, ethyl, propyl, halogen, acid, aryl and
heteroaryl.
The quantity of the catalyst is 5 to 20% by weight with respect to the substrate.
The ratio of nitro, azido and cyano compounds to acylating agent is preferably 1:4 to
1:8. More particularly, the ratio of nitro and azido compounds to sodium iodide is
preferably 1:2 to 1:6 and the ratio of cyano compounds to sodium iodide is 1:3 to 1:6.
The reaction of nitro and cyano compounds is preferably effected at a temperature of
160-200°C and the reaction of the azido compounds is effected at a temperature of
116-160°C.
The following examples are given by way of illustration of the present
invention and therefore should not be construed to limit the scope of invention.
EXAMPLE 1
Catalyst preparation
a) Metal exchanged-montmorillonite:
K 10-montmorillonite purchased from Fluka chemicals was used as such. To a 1-
litre solution of FeCb chloride (1.0 M), 80g of K 10 montmorillonite was added.
Stirring was maintained for 24 h in order to saturate the exchange capacity of
montmorillonite K 10. The clay suspension was centrifuged and the supernatant
solution was discarded. The clay catalyst was washed each time with fresh
distilled water and centrifuged till the disappearance of chloride ions from the
discarded water. The clay was dried overnight in an oven at 120 degree. C and
finally ground in a mortar.
b) Zn2"1" -exchanged catalyst: It was prepared in the same manner as in example a,
stirring 1M solution of ZnCl2 and 80 g of K10 montmorillonite.
c) Ce3+-exchanged catalyst: It was prepared in the same manner as in example a,
stirring 1M solution of CeCb and 80 g of K10 montmorillonite.
d) Cu2+-exchangedcatalyst: It was prepared in the same manner as in example a,
stirring 1M solution of CuCl2 and 80 g of K10 montmorillonite.
e) Al3+-exchangedcatalyst: It was prepared in the same manner as in example a,
stirring 1M solution of A1C13 and 80 g of K10 montmorillonite.
EXAMPLE 2
A mixture of propionic acid (10 ml), sodium iodide (3.0 g, 20 mmol) and
Fe3+-montmorillonite catalyst (0.5 g) were stirred in a round-bottomed flask at 25° C
for 6 h. The reaction mixture was filtered off to separate- the catalyst. The resultant
filtrate was titrated with 0.1M sodium thiosulphate solution using starch as an
indicator to know the amount of iodine present in the solution. The amount of iodine
liberated in the reaction is 0.998 g (3.7 mmol)
EXAMPLE 3
A mixture of acetic acid 10ml, sodium iodide (20 mmol) and Fe3+-
montmorillonite catalyst (0.5 g) were stirred in a round-bottomed flask (50ml) at
reflux temperature. After obtaining temperature, 2-azido anisole, (10 mmol) were
added slowly drop by drops for ten minutes and continued the reaction. After
completion of the reaction (followed by G.C), the reaction mixture was filtered and to
separate the catalyst. The reaction mixture was taken into ethyl acetate, quenched with
sodium thiosulphate and washed with sodium bicarbonate to remove unreacted acid
and distilled off to obtain the product. Yield: 1.61 g
EXAMPLES 4-7
The procedure was followed as in example 3, with various substrates and
results are shown in Table 1
EXAMPLES
A mixture of propionic acid (40 mmol), sodium iodide (30 mmol) and Fe3+-
montmorillonite catalyst (0.5 g) were stirred in a round-bottomed flask (50ml) at
reflux temperature. After obtaining temperature benzonitrile, (10 mmol) was added
slowly drops by drop for ten minutes and continued the reaction. After completion of
the reaction (followed by G.C), the reaction mixture was filtered to separate the
catalyst. The reaction mixture was taken into ethyl acetate, quenched with sodium
thiosulphate and washed with sodium bicarbonate to remove unreacted acid and
distilled off to obtain crude product. Yield: 1.14 g
EXAMPLES 9-11
The procedure was followed as in example 8, with various substrates and
results are shown in Table 1
EXAMPLE 12
A mixture of propionic acid (10 ml), sodium iodide (20 mmol) and Fe3+-
montmorillonite catalyst (0.5 g) were stirred in a round-bottomed flask (50ml) at
reflux temperature (160°C). After obtaining temperature nitrobenzene (10 mmol) were
added slowly drop by drops for ten minutes and continued the reaction. After
completion of the reaction (followed by G.C), the reaction mixture was filtered off to
separate the catalyst. The reaction mixture was taken into ethyl acetate, quenched with
sodium thiosulphate and washed with sodium bicarbonate to remove unreacted acid
and distilled off to obtain product. Yield: 1.19 g
EXAMPLES 13-21
Procedure was followed as in example 12, with various substrates. Results are
shown in Table 1
The main advantages of the present invention are:
1. A novel and ecofriendly process for the production and consumption of hydrogen.
2. A novel and ecofriendly process for the reductive acylation of nitro, azido and
cyano compounds.
3. The present process dispenses the use of corrosive and stiochiometric quantities of
non-regenerable expensive carbonyl complexes in stiochiometric quantities or
using expensive catalysts with hydrogen or CO pressure.
4. The cheaply and readily available metal exchanged montmorillonite as a catalyst
for the reductive acylation.
5. The selectivity and yields are good.
6. The present process envisages no disposal problem as the catalyst can be used for
several cycles. The catalyst was subjected to many recycles, which displayed
consistent activity
7. The present process is environmentally safe since there is no disposal problem.
8. The process is economical.









We claim:
1. A process for the production of acylated products by reductive acylation of nitro, azido, and cyano arenes, said process comprising steps of reacting nitro, azido and cyano arenes characterized in that with C3-C7 carboxylic acid as an acylating agent/proton source in the ratio of 1:4 to 1:10 and iodide as electron source in presence of metal ion exchanged Mn+ -montmorillonite catalyst where Mn+ is selected from Fe3+, Cu2+, Ce3+, Zr4+ and Al3+ wherein the temperature used for simultaneous production and consumption of hydrogen in the reductive acylation of nitro, azido and cyano arenes is in the range of 25-200°C and is catalysed by the same catalyst, catalyst is in the range of 5 to 20% by weight with respect to the substrate and reaction is carried out at a temperature in the range of 116-200°C for a period of 0.5 -24 hrs., recovering the catalyst by filtration for reuse and recovering the acylated product amides and anilides.
2. A process as claimed in claim 1, wherein the nitro, azido or cyano arenes used for the reductive acylation reactions comprise substituted aromatic compounds selected from the group consisting of methyl, ethyl, propyl, halo, acid, aryl and heteroaryl.
3. A process as claimed in claim 1, wherein the C3-C7 carboxylic acid is selected from the group consisting of propionic acid to heptanoic acid.
4. A process as claimed in claim 1, wherein the electron source is sodium iodide.
5. A method as claimed in claim 1, wherein the ratio of nitro and azido compounds to sodium iodide is 1:2 to 1:6
6. A process as claimed in claim 1, wherein the ratio of cyano compounds to sodium iodide is 1:3 to 1:6.
7. A process as claimed in claim 1, wherein the reaction of nitro and cyano compounds is effected at a temperature of 160-200°C.
8. A process as claimed in claim 1, wherein the reaction of azido compounds is effected at a temperature of 116-160°C.
9. A process as claimed in claim 1, wherein the nitro compound is nitrobenzene.
10. A process as claimed in claim 9, wherein the ratio of nitrobenzene to sodium iodide is 1:2 to 1:4.
11. A process as claimed in claim 6, wherein the cyano compound is a nitrile.
12. A method as claimed in claim 11, wherein the ratio of the nitrile compound to the sodium iodide is 1:3 to 1:6.

13. A process as claimed in claim 1, wherein the azido compound is an azide.
14. A method as claimed in claim 13, wherein the ratio of the azide compound to the sodium iodide is 1:2 to 1:4.
15. A process for the production of acylated products by reductive acylation of nitro, azido, and cyano arenes substantially as herein describe with reference to examples accompanying this specification.

Documents:

498-DEL-2003-Abstract-(15-05-2009).pdf

498-DEL-2003-Abstract-(24-03-2009).pdf

498-del-2003-abstract.pdf

498-DEL-2003-Claims-(15-05-2009).pdf

498-DEL-2003-Claims-(24-03-2009).pdf

498-del-2003-claims.pdf

498-DEL-2003-Correspondence-Others-(15-05-2009).pdf

498-DEL-2003-Correspondence-Others-(24-03-2009).pdf

498-del-2003-correspondence-others.pdf

498-del-2003-correspondence-po.pdf

498-DEL-2003-Description (Complete)-(15-05-2009).pdf

498-DEL-2003-Description (Complete)-(24-03-2009).pdf

498-del-2003-description (complete).pdf

498-DEL-2003-Form-1-(24-03-2009).pdf

498-del-2003-form-1.pdf

498-del-2003-form-13.pdf

498-del-2003-form-18.pdf

498-DEL-2003-Form-2-(24-03-2009).pdf

498-del-2003-form-2.pdf

498-DEL-2003-Form-3-(24-03-2009).pdf

498-del-2003-form-3.pdf

498-DEL-2003-Petition-137-(24-03-2009).pdf


Patent Number 234667
Indian Patent Application Number 498/DEL/2003
PG Journal Number 28/2009
Publication Date 10-Jul-2009
Grant Date 10-Jun-2009
Date of Filing 27-Mar-2003
Name of Patentee COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 BOYAPATI MANORANJAN CHOUDARY INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD-500 007, ANDHRA PRADESH, INDIA.
2 KALLURI VENKATA SRI RANGANATH INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD-500 007, ANDHRA PRADESH, INDIA.
3 MANNEPALLI LAKSHMI KANTAM INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD-500 007, ANDHRA PRADESH, INDIA.
PCT International Classification Number C09K 3/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA