FIELD OF INVENTION
The present invention relates to the process for the preparation 5-(2-Chloroethyl)-6-chloro-oxindole. The present invention is specifically relates to an improved process for the preparation of 5-(2-Chloroethyl)-6-chloro-oxindole, which is an intermediate of Ziprasidone and depicted as Figure (1). The present invention is more specifically relates to the cost effective synthesis of 5-(2-Chloroethyl)-6-chloro-oxindole, which is more useful for the synthesis of Ziprasidone.

Figure (1)
The marketed form of Ziprasidone is Ziprasidone hydrochloride monohydrate, which is
therapeutically used as Anti-psychotic.
BACKGROUND OF INVENTION
5-(2-Chloroethyl)-6-chloro-oxindole is one of the crucial starting materials for the
preparation of 5-(2-(4-(l,2-benzisothiozole-3yl)-piperazinyl) ethyl) - 6- chloro-1, 3
dihydro-2H-indole-2-one, which is generically known as Ziprasidone. The said
intermediate is widely used in the preparation of other advanced intermediates and their
derivatives to prepare Active Pharma Ingredients (API).
USP 4,831,031 discloses the process for preparation of 5-(2-Chloro ethyl)-6-chloro
oxindole by reacting the 5-(2-Chloro acetyl)-6-chloro oxindole with trifluoroacetic acid

and triethyl silane, farther it also discloses the process for preparation of 5-(2-(4-(l,2-benzisothiozole-3yl)-piperazinyl) ethyl) - 6- chloro-1, 3 dihydro-2H-indole-2-one hydrochloride (Ziprasidone hydrochloride).
The patent claims Ziprasidone and its derivatives along with their pharmaceutical acceptable salts, composition and method of treatment using these compounds. Ziprasdione and its related salts are useful in the treatment psychiatric diseases, hence it is an important to have a cost effective process. The prior art process for the preparation of Ziprasidone is high cost process as it involves the usage of costly and hazardous raw materials such as trifluoro acetic acid and triethyl silane in the preparation of an intermediate 5-(2-ChJoro ethyl)-6-chloro oxindole.
There is a need to select an alternate process for the preparation of 5-(2-Chloro ethyl)-6-chloro oxindole, which is an essential raw material for the preparation of Ziprasidone to have a cost-effective process.
Hence, the present invention provides cost-effective and eco-friendly process for the synthesis of 5-(2-Chloro ethyl)-6-chloro oxindole. The process of the present invention is well suited for commercial production. SUMMARY OF INVENTION
The objective of the present invention is to prepare 5-(2-Chloroethyl)-6-chloro-oxindole of Figure (1), which is a key intermediate of Ziprasidone.
The present invention is more specifically relates to the cost-effective process for the preparation of 5-(2-Chloroethyl)-6-chloro-oxindole. The process of the present invention comprises, the reduction of 5-(2-Chloroacetyl)-6-chloro-oxindole with sodium

borohydride in tetrahydrofuran using sulfuric acid by avoiding the use of very costly and
highly corrosive reagents like triethyl silane and trifluoroacetic acid.
The process of the present invention can be schematically depicted as follows:

DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to an improved process for the preparation of 5-(2-Chloroethyl)-6-chloro-oxindole of Figure (1).
Accordingly, an improved process for the preparation of 5-(2-Chloroethyl)-6-chloro-oxindole of the present invention comprises,
a) suspending 5-(2-Chloroacetyl)-6-chloro-oxindole in ether solvents such as
diethyl ether, di isobutyl ether, ditertiary butyl ether, 1,4-dioxane or
tetrahydrofiiran, preferably tetrahydrofiiran;
b) cooling the mass to a temperature of-40 to +20°C, preferably to -20 to +10°C,
more preferably to -15° to 0°C;
c) adding metal borohydrates such as Lithium borohydride, Zinc borohydride or
Sodium borohydride, preferably Sodium borohydride to the reaction mass under
nitrogen atmosphere at a temperature of -40 to +20°C, preferably at -15 to 0°C;
d) stirring the reaction suspension for 10 - 60 minutes, preferably 30-60 minutes;
e) further adding strong dehydrating agents such as sulfuric acid or methane
sulfonic acid, preferably sulfuric acid;
f) stirring the reaction mass till reaction substantially completes;

g) decomposing the mass into crushed ice at a temperature of 0-3 0°C, preferably
10-20°C; h) filtering the isolated compound by conventional techniques; i) suspending the wet material of step (h) in water and further adjusting the PH of the mass with inorganic bases or its aqueous solutions such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, preferably saturated sodium bicarbonate solution to 6.0 - 7.5; j) filtering the resulting desired compound accompanied by washing with cyclic or acyclic hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, preferably n-hexane; k) drying the obtained solid at a temperature of 50-90°C, preferably 60-80°C to afford the 5-(2-Chloroethyl)-6-chloro-oxindole. Thus, the present invention provides an improved process for the preparation of 5-(2-Chloroethyl)-6-chloro-oxindole compared to the prior art process. The present invention does not involve the usage of very costly, highly corrosive and flammable reagents like triethyl silane and trifluoroacetic acid. The present invention instead uses the cheap, safe and readily available reducing agent like sodiumborohydride and sulfuric acid.
Hence the present invention is guided through a safer, cheaper route compared to the prior art process.

Thus, the improved process for the preparation of 5-(2- Chloroethyl)-6-chloro-
oxindole of the present invention is safe, cost effective, eco friendly and commercially
viable process.
The following examples illustrate the invention but do not limit it any way.
EXAMPLES:
Reference example:
Preparation of 5-(2-chloroacetyl)-6-chloro-oxindole:
The mixture of 6-chloro oxindole (100 grams), chloroacetyl chloride (107.3 grams)
and aluminum chloride (318 grams) were refluxed in methylene chloride (500 ml) till
the reaction was substantially completes, which was confirmed by TLC. Then the
reaction mass was poured into crushed ice (1800 grams) and stirred for 15-30 minutes
to crystallize the solid mass. The solid mass was filtered, washed with water (2000 ml)
and dried at the temperature of 60-70°C to afford the 5-(2-chloroacetyl)-6-chloro-
oxindole (Weight: 141 grams, 96.8%.)
Example 1:
5-(2-Chloro acetyl)-6-chloro oxindole (25 grams, 0.10 moles) (prepared as per the
reference example) was suspended in tetrahydrofiiran (125 ml) and cooled the mass to
a temperature of-10 to 0° C. Sodium borohydride (11.6 grams, 0.30 moles) was
added to the reaction mass under nitrogen atmosphere and stirred for 30-60 minutes.
Then sulphuric acid (375 ml) was added very slowly at a temperature of -10 to 0°C in
over a period of 1-2 hours. The reaction mass was stirred at a temperature of 0 - 10°C
till the reaction completes and the reaction completion was confirmed by TLC method.
Further, the reaction mass was poured into crushed ice (3750 grams) and stirred for 30

- 60 minutes to crystallize the solid mass. The solid mass was filtered and the wet material was suspended in water (250 ml), the PH of the reaction mass was adjusted to 6-7 with saturated sodium bicarbonate solution (80 ml). The solid was filtered, washed with water (50 ml) followed by n-hexane (50 ml) and dried at the temperature of 60-70°C to a constant weight to afford 5-(2-Chloroethyl)-6-chloro-oxindole. (Weight: 19.0 grams, 80.6%.) Example 2:
5-(2-Chloro acetyl)-6-chloro oxindole (5.0 grams, 0.02 moles) (prepared as per the reference example) was taken in sulphuric acid (75 ml) and cooled to a temperature of -10 to 0° C. Sodium borohydride (3.9 grams) was added slowly in over a period of 30 minutes to the resulting reaction solution under nitrogen atmosphere. The reaction mass was stirred at a temperature of 0-3 5°C till the reaction completes and reaction completion was confirmed by TLC method. Then, the reaction mass was poured into crushed ice (750 grams) and stirred for 30 minutes to crystallize the solid mass. The solid mass was filtered and the wet material was suspended in water (250 ml), the P of the reaction mass was adjusted to 6-7 with saturated sodium bicarbonate solution (15 ml). The solid was filtered, washed with water (20 ml) followed by n-hexane (20 ml) and dried at the temperature of 60-70°C to a constant weight to afford 5-(2-Chloroethyl)-6-chloro-oxindole. (Weight: 3.8 grams, 80.6%)

We claim:
1. An improved process for the preparation of 5-(2-Chloroethyl)-6-chloro-oxindole which comprises;
a) suspending 5-(2-Chloroacetyl)-6-chloro-oxindole in ether solvents such as diethyl ether, di isobutyl ether, ditertiary butyl ether, 1,4-dioxane or tetrahydrofiiran, preferably tetrahydrofuran;
b) cooling the mass to a temperature of -40 to +20°C, preferably to -20 to +10°C, more preferably to -15 to 0°C;
c) adding metal borohydrides such as lithium borohydride, zinc borohydride or sodiumborohydride, preferably sodium borohydride to the reaction mass under nitrogen atmosphere;
d) stirring the reaction suspension for 10 - 60 minutes, preferably 30-60 minutes;
e) further adding strong dehydrating agents such as sulphuric acid or methane sulfonic acid, preferably sulphuric acid;
f) stirring the mass till reaction substantially completes;
g) decomposing the mass into crushed ice at a temperature of 0-30 C, preferably 10-20°C;
h) filtering the isolated compound by conventional techniques;
i) suspending the wet material of step (h) in water and further adjusting the PH of the mass with inorganic bases or its aqueous solutions such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium

carbonate, sodium bicarbonate or potassium bicarbonate, preferably
saturated sodium bicarbonate solution to 6.0 - 7.5; j) filtering the resulting desired compound accompanied by washing with
cyclic or acyclic hydrocarbon solvents such as n-pentane, n-hexane, n-
heptane, n-octane, cyclohexane, preferably n-hexane; k) drying the obtained solid at a temperature of 50-90°C, preferably 60-
80°C to afford the 5-(2-Chloroethyl)-6-chloro-oxindole.
2) The process as claimed in claim (1) of step (a), wherein the ether solvent is
tetrahydrofuran.
3) The process as claimed in claim (1) of step (c), wherein the reducing agent is
Sodiumborohydride.
4) The process as claimed in claim (1), wherein the reaction temperature is -15 to 0°C.
5) The process as claimed in claim (1) of step (e), wherein the strong dehydrating agent
is sulphuric acid.
6) The process as claimed in claim (1) of step (i), wherein the aqueous inorganic base
solution is saturated sodium bicarbonate solution.
7) The process as claimed in claim (1) of step (j), wherein the acyclic hydrocarbon
solvent is n-hexane.