FORM 2
The Patent Act 1970,
(39 of 1970)
&
The Patent rule 2003
Complete Specification
(See Section 10 and Rule 13)
1. TITLE OF THE INVENTION
A commercial process for the preparation of Cloquintocet mexyl ester.
2. APPLICANT(S)
(a) NAME : Alchem Technologies
(b) NATIONALITY : Indian
(c) ADDRESS: Alchem Technologies
A/6 Shubhechha C.H.Soc.
S.V. Road
Naupada, Thane (W) -400602.India.
3. PREAMBLE OF THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

A commercial Process for the preparation of Cloquintocet Mexyl ester
Field of the invention:
The present invention relates to a development of commercially viable, simple and robust process for the preparation of Cloquintocet mexyl ester, useful for protecting plants from harmful effects of agrochemicals.
Background and prior art:
Agrochemicals such as herbicides, insecticides are known to have harmful effects on the cultivated plants. These chemicals may damage the cultivated plants depending upon their dosage, method of application, time of exposure, climatic conditions. Various chemicals are added to agrochemical formulations to protect the plants from such adverse effects; such compounds are commonly known as "safener". Herbicide safeners selectively protect the crop plant from herbicide damage without reducing the activity in target weed species. They are used commercially to improve the herbicide selectivity between crops and weed species.
Cloquintocet mexyl ester a quinoline derivative of formula (I) is described in European patent application EP 094,349 as plant protecting agent.

According to EP 094,349 Cloquintocet mexyl is prepared by reacting 8-hydroxyquinoline with bromoacetic acid derivatives in the presence of a base, in an inert solvent at elevated temperature. This process yields the undesirable byproducts which detoriate the quality of the final product.
US patent 6,660,865 describes another method for the preparation of compounds of formula (I) according to which 8-hydroxyquinoline is reacted with
1

chloroacetic acid 1-methylhexyl ester in the presence of base like sodium hydroxide in presence of mixture of solvents comprising at least one solvent which can form an azeotrope with water (like xylene) and at least one aprotic-dipolar solvent (like N-methylpyrolidine). The choice of solvent, azeotropic distillation, difficulties in drying the final product and the undesired impurities generated during reaction makes this process tedious for large-scale preparations.
The aim of the present invention is accordingly to provide a process for the preparation of quinoline derivatives of formula (I), which is high yielding and providing good quality of product.
Another aim of the present invention is to provide a process for the preparation of quinoline derivatives of formula (I), which is suitable for the industrial application and circumvents the disadvantages of the known processes.
Another objective of the present invention is to provide a process for the preparation of quinoline derivatives, which is environmentally benign and produces less or no by-products.
Yet another objective of the present invention is to provide a process, which is cost effective.
Summary of the invention:
Present invention relates to a process for the preparation of Cloquintocet mexyl ester by reacting (5-chloroquinoline-8-yl-oxy)acetic acid methyl ester with 2-heptanol in the presence of acid catalyst in an inert solvent.
Detailed description:
The process according to the invention for the preparation of formula (I)
comprises
a) reacting a commercially available 5-chloro-8-hydroxyquinoline
2


with an alkyl chloroacetate, in the presence of a phase transfer catalyst or catalytic amount of potassium iodide forming a (5-chloroquinoline-8-yloxy)acetic acid alkyl ester of formula CUV

wherein Rl is a lower alkyl group from C1-C2
b) Trans esterifying (5-chloroquinoline-8-yloxy)acetic acid alkyl ester of formula (II) with 2-heptanol in the presence of catalytic amount of acid.
5-Chloro-8-hydroxyquinoline is introduced in suitable solvent with approximately equal amount of base, followed by addition of alkyl chloroacetate. According to a preferred embodiment, the alkyl group of chloroacetyl ester can be selected from lower alkyl groups like methyl, ethyl, propyl, isopropyl, t-butyl etc. More preferably the alkyl group can be methyl or ethyl.
According to a preferred embodiment, the base can be selected from sodium hydroxide, potassium hydroxide, potassium carbonate etc. The base is added either in an equal molar amount of 5-chloro-8-hydroxyquinoline or in slight excess. The preferred amount of base is 1 to 1.5 equivalent of quinoline.
A suitable solvent can be toluene, xylene or methyl isobutylketone.
Alkyl chloroacetate is then added to the above reaction mixture over a period of one hour in an equal amount or in slight excess relative to the amount
3

of 5-chloro-8-hydroxyquinoline, preferably 1.0 to 1.5 equivalents more preferably 1.05-1.25 equivalents of 5-chloro-8-hydroxyquinoline.
The reaction mixture is heated at about 130-150°C till 5-chloro-8-hydroxyquinoline is completely consumed in the reaction mixture. The reaction mixture is then cooled to 55-65°C and then filtered to eliminate inorganics. The organic filtrate containing (5-chloro-quinoline-8-yloxy)acetic acid alkyl ester of formula (II) is concentrated, leaving behind sufficient amount of solvent, which acts as a vehicle for trans-esterification reaction
2-Heptanol is then introduced in the solution containing above alkyl ester of formula (II). The alcohol is added either in an equal amount that of the alkyl ester of formula (II) or in slight excess, preferably 1 to 1.75 equivalents, more preferably 1 to 1.5 equivalents of the alkyl ester of formula (II). Catalytic amount of acid is added to the reaction mixture for trans-esterification. Acid can be selected from p-toluenesulfonic acid (PTSA), sulfuric acid or methanesulfonic acid etc.
The reaction mixture is maintained at temperature of about 110-150°C. Simultaneously the low boiling fraction i.e. methanol is collected. The reaction can be monitored by TLC or GLC for the disappearance (5-chloroquinoline-8-yloxy)acetic acid alkyl ester. After completion of the reaction, the reaction mixture is cooled to room temperature and washed with water. Reaction mixture is then concentrated to recover the solvent and 2-heptanol if any. The residual molten Cloquintocet mexyl ester of formula (I) is crystallized from a suitable solvent.
Following examples are for illustration purpose only and it is a non-limiting disclosure of the invention.
Example 1
To a mixture of 89.75 gms (0.5 mole) of 5-chloro-8-hydroxyquinoline in 1500 ml of xylene, 75.9 gms (0.55 mole) of Potassium carbonate are added in portion. The resulting slurry is then refluxed for one hour, followed by addition of 60 gms (0.55 mole) of methyl chloroacetate in the course of one hour, with stirring and
4

boiling. The resulting reaction mass is then refluxed for 6.5 hours, till 5-chloro-8-hydroxyquinoline is completely consumed. After cooling to 60°C, the mixture is filtered to separate inorganic cake and the filtrate containing (5-chloroquinolin-8-yloxy)acetic acid methyl ester. This organic layer is washed with 50 ml of water and taken for concentration, leaving behind (5-chloroquinolin-8-yloxy)acetic acid methyl ester.
To a solution of (5-chloroquinolin-8-yloxy)acetic acid methyl ester in xylene is added 102 gms of 2-heptanol and 1 gm of p-toluenesulphonic acid and maintained for 6 hours for trans-esterification to complete. Excess 2-heptanol and xylene is then evaporated under vacuum leaving behind oily semisolid residue, which is purified by crystalization from hexane. (5-chloro-quinoline-8-yloxy)acetic acid-1-methyl hexyl ester is obtained in the form of beige-coloured crystals having melting point 66-69 °C.
Example 2
Solution of (5-chloroquinolin-8-yloxy)acetic acid ethyl ester (prepared by analogous procedure as described in example 1) in xylene is trans-esterified with 102 gm of 2-heptanol using 1 gm of p-toluenesulphonic acid as catalyst. After complete trans-esterification, excess of 2-heptanol and xylene are distilled out under vacuum leaving behind crude (5-chloro-quinoline-8-yloxy)acetic acid-1-methyl hexyl ester, which is purified by crystallization from hexane.
5

We Claim:
1. A process for preparation cloquintocet mexyl ester of compound of formula I

by reacting of (5-chloroquinoline-8-yloxy)acetic acid alkyl ester of formula (II)
O^OR,
wherein Rl is a lower alkyl group from C1-C2
with 1 to 1.75 equivalents 2-heptanol in the presence of an acid at temperature
about 110 to 150°C.
2. A process as claimed I claim 1, wherein preferred quantity of 2-heptanol is 1 to 1.5 equivalents to that of compound of formula (II)
3. A process as claimed in claim 1 or 2, wherein the acid can be selected from PTSA, sulfuric acid, methanesulfonic acid
4. A process as claimed in any of 1 or 3 wherein the acid is added in 1 to 2 mol%.
5. A process as claimed in claim 1 wherein the temperature about 130 to 145°C.
6. A process for preparation of cloquintocet mexyl ester of compound of formula (I) as herein described in the accompanying text and example.


Dated 17th day of July 2006
6