Title of Invention


Abstract A catalyst system wherein iridium-xyliphos ligands are immobilized on alumina and heteropolyacid is provided. Also a process for the hydrogenation of imines with hydrogen under elevated pressure in the presence of catalysts system containing iridium-xyliphos ligands And, additionally, the use of hydrogenated imine for preparation of chloroacetamide herbicide, S-Metalachlor is described.
Full Text FORM 2
(39 Of 1970)
(See Section 10, rule 13)
Hydrogenation of imines
A company registered under Indian Company's Act 1956 , having its registered office at 3 - 11, Gidc, Vapi - 396 195, State of Gujarat, India and having its office at Uniphos House, 11th road , C. D. Marg, Khar (West), Mumbai - 400 052 , Maharashtra, India, Indian.
The following specification describes the invention:

The present invention relates to a hydrogenation of imines. The present invention further relates to hydrogenation of imines to asymmetric amines. The present invention also relates to hydrogenation of imines to asymmetric amines using immobilized iridium-xyliphos catalyst. This invention particularly relates to preparation of the novel immobilized iridium-xyliphos catalyst for hydrogenation of imines to amines. The invention further relates to a process for manufacture of chloroacetanilide herbicide, more particularly 2-chloro-N-(2-ethyl-6-methylphenyl)-N- [(1 S)-2-methoxy-1 -methylethyl] acetamide, (Formula (I)), rich in S isomer, known as (S)-Metolachlor, using novel heterogeneous / immobilized catalyst prepared in one embodiment of the present invention.
Back ground and prior art:
Processes for the catalytic hydrogenation of imines with homogeneous iridium catalysts have been known for a relatively long time. Among the various homogeneous catalysts, iridium-xyliphos catalyst has been found most successful commercially in preparation of 2-chloro-N-(2-ethyl-6-methylphenyl)-N- [(1 S)-2-methoxy-1 -methylethyl] acetamide [Hans-Ulrich Blaser, Advanced Synthesis and Catalysis, 2002, 344,17-31. Patents describing hydrogenation of imines by homogeneous catalysts are [WO 97/05094], [US 5,011,995], [US 5886225] and [US 6,822,118]. Of these the last one is described below, to make the further work on heterogenisation of homogenous catalysts easy to follow.
US 6822118 describes in general a process for the hydrogenation of imines with hydrogen under elevated pressure in the presence of homogeneous iridium catalysts with appropriate ligand and with or without an inert solvent, wherein the reaction mixture contains an ammonium or metal chloride, bromide or iodide and additionally an acid.. This patent also describes use of this process in hydrogenating (at 50 °C under 80 bar hydrogen pressure), methyl-ethyl-aniline(MEA)imine of the Formula (II) to (S)-N-(2'-methyl-6'-ethyl-phen-1-yl) -N-(l-methoxymethyl)ethylamine of the Formula (III) with about 78 % enatiomeric excess(ee),using {Ir(l,5-cyclooctadiene)-({(R)-l-{(S)-2-
diphenylphosphino)ferrocenyl]}ethyl-di(3,5-dimethylphenyl)phosphine)Cl] Known of Formula (IV) as Ir Xyliphos catalyst, with acetic acid and toluene; [ Formula (IV) taken

from Romano Dorta et al.. Chemistry - A European Journal. 2004.10. 267-278. - Fie. 9 on page 269] and conversion of the hydrogenated product of Formula (III) to 2-chloro-N-(2-ethyl-6-methylphenyl)-N-[(lS)-2-methoxy-l-methylethyl]acetamide of Formula (I),
The catalysts in these homogeneous processes cannot be recovered or can be recovered only with expensive separation methods, which is always associated with undesirable losses. Homogenous catalysts have been immobilized by bonding them on to support materials. Silica supported catalysts gave selectivity (79% ee) close to that of the homogeneous system. However the TON was only 120,000 for the supported catalyst, compared to 1000,000 for the homogenous system. [Thomas. J. Colacot, Chemical Reviews, 200,103(8). 3115] Following patents describe such supported immobilized catalysts and catalytic hydrogenations of imines using such supported catalysts.
WO9702232 describes a process for the hydrogenation of imines with hydrogen at increased pressure in the presence of iridium-diphosphine [XIrYZ] catalysts immobilized on a support material (organic polymers, inorganic metal oxides), a halide and an acid. X is two olefin ligands or one diene ligand. Y is a ditertiary diene phosphine. Of the various diolefins cyclooctadiene is a preferred amongst some others.
The diphosphine Y contains at least one chiral atom, and the diphosphine is particularly preferably an optically pure stereo-isomer (enantiomer or diastereomer), or a diastereomer pair, since optical inductions are achieved in assymetric hydrogenations with catalysts, which contain these ligands. Ferrocenyldiphosphines are preferred ligands for fixing them to an inorganic support material like silica. The diphosphine Y is preferably bonded via silyl group to an inorganic support material T which is chosen from the group consistmg of silicates, semimetal or metal oxides, glasses or mixtures thereof. The solid support material T is preferably a powder having average particle diameters of 10 nm to 2000 urn, preferably 10 nm to 1000 urn, particularly preferably 10 nm to 500 um. The support can be either compact or porous particles. Porous particles preferably have high internal surface areas (determined by BET method), for example 1 to 1200 m , preferably 30 to 600 m2.

Many support materials organic and inorganic have been suggested. Examples of the oxides of and silicates are SiO2 TiO2, ZrO2, MgO, NiO, W03, A1203, La203, silica gels clays and zeolites. Preferred support materials are silica gels, aluminium oxide, titanium oxide or glass and mixtures thereof.
The said patent discloses the process for preparation of 2-chloro-N-(2-ethyl-6-methylphenyl)-N-[(lS)-2-methoxy-l-methylethyl]-acetamide from the imines using these immobilized catalysts.
However, there is no detail information on bonding of metal ligand complex to inorganic supports other than silica.
US 6,005,148 describes a supported catalyst comprising a support an anchoring agent such as a heteropoly acid or anion and a metal complex which is useful in a wide variety on organic reactions, especially hydrogenation of substituted a,b unsaturated acids and esters and a- or |b- keto esters or lactones. Various methods of preparing the supported catalyst of the present invention are also disclosed. Methods for preparing Rh(DIPAMP)/PTA/Al203 catalyst where gamma alumina is support material, anchoring agent phosphotungstic acid (PTA) is heteropoly acid and Rh(COD)(DIPAMP)BF 4 is metal complex catalyst. In brief, to the support material in methanol, PTA in methanol was added, and to this mixture was added metal complex catalyst in methanol, all under inert gas, and providing time for taking in solvent and completion of reaction at each step, all done at room temperature.
One of the main thrusts in homogeneous catalysis today is to immobilize the catalysts on a support. The major forces behind this developing technology are to minimize the metal leaching into products, recycle the expensive ligands, and make the process more environmentally friendly.
Thus there is a need for reusable catalysts which can easily be separated off, the activity of which and in particular the selectivity of which are largely retained during repeated use, especially in respect of large-scale industrial hydrogenation processes and there is a need for use of such catalyst in preparation of amine which in turn is an important intermediate for the preparation of 2-chloro-A'-(2-ethyl-6-methylphenyl)-N-[(l,S)-2-methoxy-l-methylethyl acetamide, S-Metolachlor (I)

(I) (S-Metolachlor)
2-chloro-N-(2-ethyl-6-methylphenyl)-Ar-[(15)-2-methoxy-l-methylethyl] acetamide
Therefore, the main object of the present invention is to develop a new immobilization
method for the iridium-xyliphos catalyst used for hydrogenation of imines.
Another object is to develop a process for asymmetric hydrogenation of imines to amines
using the catalyst developed.
Yet another object of the present invention is to develop a process for manufacture of
chloroacetanilide herbicide, more particularly 2-chloro-N-(2-ethyl-6-methylphenyl)-N-
[(lS)-2-methoxy-l-methylethyl] acetamide Formula (I) using the catalyst that is
Accordingly, the present invention provides an immobilized iridium-xyliphos catalyst [Ir( 1,5-cyclooctadiene)-( {(R)-1 - {(S)-2-diphenylphosphino)ferrocenyl]} ethyl-di(3,5-dimethylphenyl)phosphine)Cl] supported on alumina and anchoring agent hetero poly acid, useful for stereospecific hydrogenation of imines.
The imines are preferably ketimines, tertiary imines like those of Formula (II).
The present invention provides a method of hydrogenation of imines by using the catalysts
of the present invention.
Another embodiment of the invention provides a process for the large scale production of
commercially feasible 2-chloro-N-(2-ethyl-6-methylphenyl)-N-[(l S)-2-methoxy-1 -
methylethyl] acetamide of Formula (I) known as herbicide (S)-Metolachlor.

Detailed description of the invention:
The immobilized iridium-xyliphos catalyst of the present invention is prepared as follows: [IrCODCl]2 solution in methanol is taken in a round bottom flask and the ligand Xyliphos is added to it and the mixture is stirred at about 30 °C until the solution becomes clear. Alumina and phosphotungstic acid hydrate are then added to the clear solution, and the mixture is stirred for about 3 hours under nitrogen atmosphere to form the catalyst. The mass is filtered under nitrogen and the residue on the filter is dried in vacuum thoroughly.
Hydrogenation of Imine using heterogeneous catalyst prepared as above is as follows:
The method for hydrogenation of imines comprises adding the catalyst to the imine
solution in acetic acid in an autoclave and flushing it with nitrogen; followed by flushing
with hydrogen and raising the hydrogen pressure to about 80 bar, temperature about 50 °C
and keeping the mass under stirring.
On completion of the reaction the reaction mass is filtered to get the hydrogenated product
in the filtrate; and catalyst as residue on the filter.
The acetic acid is distilling off by adding toluene, under vacuum at 60 °C followed by
distilling the hydrogenated product remaining in the still under high vacuum at 70 C to get
the pure product;
The catalyst from the residue on the filter is recovered by washing with methanol and
drying in high vacuum.
This recovered catalyst is reusable several times and has the activity and selectivity as that
of the original.
In another embodiment of the invention is described a process of preparing 2-chloro-N-(2-
ethyl-6-methylphenyl)-N-[(lS)-2-methoxy-l-methylethyl] acetamide of Formula (I)
comprising step i hydrogenation of methyl-ethyl-aniline(MEA)imine of Formula (II) to
(S)-N-(2'-methyl-6'-ethyl-phen-r-yl) -N-(l-methoxymethyl)ethylamine of the Formula
(III) using the catalyst of the present invention and step ii. reacting the hydrogenated
product obtained with chloroacetyl chloride in toluene and a base, at temperature 0 - 5 °C
followed by the recovery of the product by washing the reaction mass free of base; drying
it free of water and separating the organic layer and distilling off the solvent under

The invention will now be illustrated with the help of examples. The inventions are for
illustration only and not for restricting the scope of the invention.
Raw materials used in the examples are given below:
Ir-catalyst: [IrCODCl]2: Bis(l,5-cyclooctadiene) diiridium(I)dichloride
Ligand: Xyliphos: (R)-l-[(S)-2(Diphenylphosphino) ferrocenyl] ethydi (3,5-xylyl)-
Support Material: alumina: Aluminium oxide (Merck)
Anchoring Agent: HP A (heteropolyacid): phosphotungstic acid hydrate (Fluka)
2-Methyl-6-ethyl aniline (FLUKA/ALDRICH)
Methoxyacetone (MANALIPETROCHEM)
Example 1: Preparation of Heterogeneous Catalyst:
In l00mL round bottom flask, a solution of [IrCODCl]2 (10mg, 1.4 x 10"5 mole) and ligand (Xyliphos) (18mga, 2.96 x 10-5 mole) were stirred for 6hr at 30 °C under nitrogen atmosphere in methanol till it became clear with no [IrCODCl]2 in the solid form. Alumina (1.2gm) and HPA (0.24gm) were added and the mixture was stirred at 30 °C under nitrogen atmosphere for 3hr.
The heterogeneous catalyst thus formed was filtered under nitrogen atmosphere and dried in vacuum thoroughly. Catalyst Yield 1.42 g.
Example 2: Preparation of S-Metolachlor
In-process samples in this example were analyzed by GLC using DB17 column with programmed temperature and F.I. Detector facilities, using microlitre syringe.

(i) Preparation of 2-methyl-6-ethylphenyl-r-methyl-2'-methoxyethylimine (referred hereafter as "MEA-imine" was prepared in the following manner by using known methods in the literature.
2-Methyl-6-ethyl aniline (540gm, 4Mole) was taken in a 2L round bottom flask, to this was added methoxy acetone (1056gm, 12Mole). The reaction mixture was heated to 110°C and water thus formed was continuously removed by Dean-Stark assembly. The MEA-imine of Formula (II), (N-(2'-methyl-6'-ethylphenyl-l'- yl) -N-(l-methoxymethyl) ethy-1-yl-ideneamine obtained was 803.6gm and was further purified by distillation to give 98% yield of the MEA-imine of Formula (II) with 99.7% purity by GLC.

2-Methyl-6-ethyl aniline Methoxy acetone (II) (N-(2'-methyl-6'-ethylphenyl-l'-yl)
-N-( 1 -methoxymethyl)ethy-1 -yl-ideneamine
(ii) Hydrogenation of inline using heterogeneous catalyst prepared in Example 1:
In a 100ml SS autoclave, methyl-ethyl-aniline(MEA)-imine of Formula (II) (2.0g, 9.75 x 10"3 mole) was diluted with acetic acid (30ml) and the heterogenous / immobilized catalyst (50mg) prepared in Example 1 was added to this solution. The autoclave containing solution was flushed with nitrogen. After sealing the autoclave, it was flushed once with nitrogen followed by twice with hydrogen. The autoclave was pressurized to 80 bar by hydrogen gas and the temperature was raised to 50 °C. It was stirred at 800 rpm. After 24hr when MEA-imine of Formula (II) was found to be absent on checking on GLC, when the reaction was complete The reaction mass was filtered and to the filtrate was added 25 ml toluene; next toluene and acetic acid were distilled off at 60 C and the hydrogenated MEA-imine-of-Formula-(II), i.e. (S)-N-(2'-methyl-6'-ethyl-phen-l'-yl) -N-

(1-methoxymethyl) ethylamine of the Formula (III) was distilled at 70 °C under one to two Torr vacuum.
The solid catalyst was recovered from the residue on the filter and used for the next cycle of hydrogenation, after washing with methanol (10ml) and vacuum drying.

(N-(2'-methyl-6'-ethylphenyl-l'- (III) (S)-N-(2'-methyl-6'-ethyl-phen-l '-yl)
yl)-N-( 1 -methoxymethyl)ethy-1 -yl- -N-( 1 -methoxymethyl)ethylamine
(Hi) Synthesis of 2-chloro-N-(2-ethyl-6-methylphenyl)-N-[(lS)-2-methoxy-l-
methylethyl] acetamide of Formula (I):
(S)-N-(2'-methy-6'-ethyl-phen-l'-yl)-N-( 1-methoxymethyl) ethylamine of Formula (III)
(4g, 0,192Mole) was taken in toluene (10ml), to this was added sodium hydroxide (0.92g,
0.23Mole). The reaction was stirred for 30mins and cooled to
0 °C. Chloroacetylchloride (CAC) (2.3g, 0.2Mole) in 10ml toluene was added drop wise in
30mins, not allowing the temperature to rise above 5 °C.
The temperature was gradually allowed to come to room temperature and maintained for
After completion the reaction, monitored by GLC, the reaction mixture was washed with
50ml sodium bicarbonate solution (10%w/v), followed by washing with 50ml of
hydrochloric acid solution(l 0%W/v) and finally with water (50ml, twice). The organic
layer was separated and dried over sodium sulphate and toluene was distilled under
vacuum. The quantitative product, 2-chloro-N-(2-ethyl-6-methylphenyl)-N-[(lS)-2-
methoxy-1-methylethyl] acetamide, [Formula (I)] was obtained in 95% yield and having

90% S-isomer (80% ee) when examined by HPLC method using chiral chromatographic "CHIRACEL ODH" column and UV detector at 220 nm using n-hexane, 2- propanol HPLC grade solvents. This gave a product with 80% S- Metolachlor.

(S)-N-(2'-methyl-6'-ethyl-phen-l ‘-yl) (I) 2-chloro-N-(2-ethyl-6-methylphenyl)-N--N-( 1 -methoxymethyl) ethylamine [(1 S)-2-methoxy-1 -methylethyl] acetamide
Advantages of the present invention
• It was surprisingly found that the catalyst activity had been increased when the catalyst is prepared by using heteropoly acid, more particularly phosphotungstic acid and alumina support along with iridium-xyliphos mixture.
• It has also been found, that when asymmetric catalyst, prepared as per the present invention, when used, the enantioselectivity is high, even at reaction temperatures of more than 50 °C.
• Furthermore, the catalysts can easily be separated off and reused without substantial loss in activity, which renders their use in large-scale industrial processes particularly advantageous and economical.







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Patent Number 254278
Indian Patent Application Number 1363/MUM/2007
PG Journal Number 42/2012
Publication Date 19-Oct-2012
Grant Date 16-Oct-2012
Date of Filing 16-Jul-2007
Applicant Address 3-11, GIDC, VAPI-396195, UNIPHOS HOUSE, 11TH ROAD C.D MARG, KHAR (WEST) MUMBAI.
# Inventor's Name Inventor's Address
PCT International Classification Number CO7L209/52
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA