This invention relates to a novel process for the preparation of a 2-nitro, 5-chlorophenylethanoic acid alkyl ester of general formula IV
starting from 1,4-chloronitrobenzene.
2-nitro, 5-chlorophenylethanoic acid alkyl ester is an intermediate in the preparation of 5-chloroxindole which is an important intermediate used in the production of pharmaceuticals including, for/ 1,,3-disubstituted 2-oxoindoles (US patent 4,721,712).
The parent application 297/MAS/93 described and claims a process for the preparation of 5-chloroxindole of Formula I•
I
There are several known processes for preparing 5-chloroxindole. A process starting from 5-chloroindole is described in U.S. Patent No.4,761,485, in which the 5-chloroindole is converted, using pyridine bromide perbromide, into 3,3-dibromo-5-chloro-xindole, which is then converted into 5-chloroxindole by catalytic hydrogentation with palladium or carbon. Disadvantages of this process are that the educt 5-chloroxindole is not readily available and that the yield of 5-chloroxindole is poor.

A process for preparing 5-chloroxindole from 5-ohloroisatin, is
described in US Patent No.4,730,004. In this process, the 5-
chloroisatin is converted with hydrazine hydrate into 5-chloro-3-
hydrazone-2-oxoindole and the latter is then converted into 5-
chloroxindole, by reaction of sodium methanolate. Again, the
educt, 5-chloroxisatin, is not readily available and the yield of
the desired product is poor.
An object of the invention is to provide an economic and simple process for the preparation of 2-nitro, 5-chlorophenylethanoic acid alkyl ester, which produces good yields of the product compound.
Accordingly, the present invention provides a process for the preparation of a 2-nitro, 5-ohlorophenylethanoic acid alkyl ester of general Formula IV:

in which R denotes a branched or unbranched alkyl group of 1-7 carbon atoms, wherein 1,4-chloronitrobenzene of Formula II:

is reacted with a chloroethanoic acid alkyl ester of general
Formula III: 0
N
CI - CH2 - C - OR III

in which R has the aforementioned meaning, in the presence of an alkali amide in liquid ammonia and the product 2-nitro 5-chlorophenylethanoic acid alkyl ester isolated by conventional means.
The preferred chloroethanoic acid alkyl esters of general Formula III are those in which P denotes a methyl, ethyl, propyl, isopropyl, tertiary butyl or tertiary pentyl group, more preferably an ethyl group.

The chloroethanoic acid alkyl ester of general formula III is preferably used in excess with regard to the 1,4-chloronitrobenzene and, more preferably, in an amount of 1.3 to 1.7 moles per mole of 1,4-chloronitrobenzene.
Both of these reagents can be used in Step (1) in a non-polar solvent such as, for example, toluene, diethyl ether, tetrahydrofuran or tertiary butyl methyl ether. Toluene is the preferred solvent.
The preferred base present in Step (1) is an alkali amide or alkali hydroxide. Preferably, the alkali hydroxide is an alkali metal hydroxide, such as sodium or potassium hydroxide, and the alkali amide is an alkali metal amide, such as sodium or potassium amide. ■
In an embodiment, the base used in Step (1) is an alkali amide, preferably sodium amide, in liquid ammonia, which can be formed in situ from the corresponding elemental metal in liquid ammonia, optionally in the presence of a catalyst.
In a particularly preferred embodiment, the alkali amide is formed in situ and is used in the presence of an

alcohol of general formula VI:
R - OH VI
in which R denotes a branched or unbranched alkyl group of 1-7 carbon atoms. Preferred such alcohols include those in which R denotes a methyl, ethyl, propyl, isopropyl, tertiary butyl or teritary pentyl, preferably a tertiary butyl, group. The alcohol reacts with alkali amide to form the corresponding alkali alcoholate which catalysis the reaction.
The alcohol and the alkali amide are preferably used in equimolar quantities.
The step (1) conversion, preferably, is performed at a temperature of -30 to -40°C .
After a preferred reaction time of 0.1 to 2 h, the 2-nitro, 5-chlorophenylethanoic acid alkyl ester of formula IV


can then be isolated in a conventional manner, for example, by the addition of ammnonium chloride.
In Step (2), the 2-nitro, 5-chlorophenylethanoic acid alkyl ester (formula IV) is catalytically hydrogenated to the corresponding amine (formula V) with hydrogen. Noble metal catalysts, noble metal oxide catalysts or Raney catalysts, optionally carried on a suitable support, are the preferred hydrogenation catalysts, with Raney nickel or platinum on carbon being more preferred. In a preferred embodiment, the hydrogentation catalyst used in Step (2) is platinum on carbon, with, preferably, 0.5 to 5 wt.% of platinum on the carbon substrate.
The hydrogenation catalyst can be used in a quantity of
0.1 to 20 wt.%, preferably 5 to 10 wt.%, relative to the
quantity of 2-nitro, 5-chlorophenylethanoic acid alkyl
ester present and, preferably, hydrogenation is carried out under an elevated H2 pressure, of, preferably, 5 to
10 bar.
The catalytic hydrogenation in Step (2) is preferably performed in a non-polar solvent such as toluene, or in a polar solvent, such as an alcohol or an ester. Suitable esters include methyl acetate or ethyl acetate and suitable alcohols include methanol, ethanol or propanol; the preferred alcohol being ethanol.

step (2) is preferably performed at a temperature of 0 to 55oC, more preferably between 10 and 20oC.
After a preferred reaction time of 1 to 20 h, the resulting 2-amino, 5-chlorophenylethanoic acid alkyl ester (formula V) either can be isolated in a conventional manner or, after separation of the catalyst, can be and, preferably, is used directly in Step (3) of the preparation.
In Step (3) the 2-amino, 5-chlorophenylethanoic acid alkyl ester of general formula V is cyclised, in the presence of an acid, to 5-chloroxindole (formula I). The preferred acids include toluene 4-sulphonic acid, methane sulphonic acid and their hydrates; toluene 4-sulphonic acid or a hydrate thereof being most preferred.
Preferably the acid is used in an amount of 0.0005 to 0.1 mole, preferably 0.05 to 0.1 mole, per mole of amine.
Step (3) can be carried out in a solvent which, preferably, is one of the solvents referred to in the foregoing as being useful in Step (2).
The reaction in Step (2) preferably proceeds at a temperature of 50°C up to reflux temperature, more

preferably, from 70oC up to the reflux temperature of the solvent.
After a preferred reaction time of 1 to 20 h, the 5-chloroxindole can be isolated with good yield using conventional techniques.
Example
Production of 5-chloroxindole
(a) Production of 2-nitro, 5-chlorophenylethanoic acid
ethyl ester
(Step (D) 250 ml of NH3 were condensed in a dried and argon flushed
flask (Kryoma temperature -40oC). A small piece of sodium was added causing the solution to turn blue. 250 mg of iron(III) nitrate nonahydrate were added and the solution decolorised. Over 15 minutes, 5.75 g (250 mmoles) of sodium was added in small pieces and the resulting mixture was stirred for 10 minutes. Then, 18.53 g (250 mmoles) of tert. butanol, dissolved in 3 ml of toluene, were added dropwise over 15 minutes and stirred for 35 minutes to leave a grey suspension. Immediately thereafter, a mixture of 15.76 g (100 mmoles) of 1,4-chloronitrobenzene and 18.38 g (150 mmoles) of ethyl chloroacetate, dissolved in 20 ml of toluene, was added dropwise over 15 minutes (reaction mixture became blue).

After this addition, the mixture was stirred for a further hour, then 26.75 g (500 mmoles) of solid ammonium chloride were carefully added. The dry ice cooler was then removed and the suspension heated to 10oC over approx. 30 minutes (removal of NH3). Then, over 20
minutes, 200 ml of toluene (Kryoma temperature: 10oC) were added dropwise. After 30 minutes, the reaction mixture was filtered through a G3 glass Buchner funnel (with Celite). The filtrate was evaporated on the Rotavap at 35°C and 25 mbar and dried under a high vacuum for approx. 30 minutes.
27.14 g of product were obtained, content (HPLC): 78.8%, corresponding to a yield of 87.8% related to the educt used.
(b) Production of 2-amino, 5-chlorophenylethanoic acid ethyl ester (Step (2))
26.73 g of crude product from step (1) were dissolved in 135 ml of ethanol at room temperature. After the addition of 1 g of Pt/C (catalyst), the mixture was placed in an autoclave, which had been flushed with H2 three times, and the pressure was then raised with H2 to 5 bar and the mixture stirred for 7.5 hours at room temperature. The reaction mixture was then filtered off and the filtration

residue washed with 25 ml of ethanol. The filtrate was directly further processed in Step (3).
(c) Production of 5-chloroxindole
(Step (3)) The filtrate from Step (2) was combined with 1.90 g (10 mmoles) of toluene 4-sulphonic acid monohydrate and the mixture was refluxed for 30 minutes. Then, over 4.5 hours, a total of 125 ml of ethanol were distilled off, leaving a suspension which was cooled to room temperature and filtered. The filtration residue was washed with a total of 60 ml of ethanol (3 x 20 ml portions) and then dried for 12 hours at 35°C and 40 mbar.
12.07 g of a pink/violet solid were obtained as the product, content (HPLC): 94.3%, corresponding to a yield of 67.9% related to the 1,4-chloronitrobenzene used in Step (1).

WE CLAIM:
1. A process for the preparation of a 2-nitro, 5-
chlorophenylethanoic acid alkyl ester of general Formula IV:

in which R denotes a branched or unbranched alkyl group of 1-7 carbon atoms, v?herein l,4-chloronitroben2ene of Formula II:

is reacted with a chloroethanoic acid alkyl ester of general
formula III:
0
CI - CH2 - C - OR III
in which R has the aforementioned meaning, in the presence of an alkali amide in liquid ammonia and the product 2-nitro 5-chlorophenylethanoic acid alkyl ester isolated by conventional means.
2. A process as claimed in claim 1, wherein the reaction is
carried out in the presence of an alcohol of general formula VI:
R - OH VI
in which R has the aforementioned meaning, the said alcohol reacting with the said alkali amide to the corresponding alkali alcoholate which catalysis the reaction.

3. A process as claimed in claim 2, wherein the alcohol of
general Formula VI is tertiary butanol the alkali amide is soidum
amide, and the alkali alcoholate formed therefrom is sodium
tertiary butoxide.
4. A process as claimed in any of claims 1 to 3, wherein the
reaction is earned out at a temperature of -30 to -40o0.
5. A process for the preparation of a 2-nitro, 5-
chlorophenylethanoic acid alkyl ester of general Formula IV,
substantially as hereinabove described and exemplified.