Claims:We Claim:
1. An improved process for the preparation of Quizalofop-ethyl having the Formula (I)
Formula (I)
which comprises :
(a). reacting quinoxaline compound of Formula (II)
Formula (II)
wherein Lg is a leaving group with hydroquinone of Formula (III)
Formula (III)
using a base in a solvent to obtain a compound of Formula (IV), and
Formula (IV)

(b). reacting compound of Formula (IV) with a compound of formula (V)
Formula (V)
using a base in a solvent in the presence of phase transfer catalyst to obtain Quizalofop-ethyl of Formula (I).

2. The process as claimed in claim 1, wherein the process relates to preparation of Quizalofop-ethyl having the Formula (I
Formula (I)
which comprises :
(a). reacting quinoxaline compound of Formula (II)
Formula (IIa)
with hydroquinone of formula (III)
Formula (III)
using a base in a solvent to obtain a compound of Formula (IV), and
Formula (IV)

(b). reacting compound of Formula (IV) with a compound of formula (V)
Formula (V)
using a base in a solvent in the presence of phase transfer catalyst to obtain compound of Formula (I).

3. The process as claimed in claims 1 and 2, wherein the process relates to preparation of Quizalofop-ethyl having the Formula (I)
Formula (I)
which comprises :
(a). reacting quinoxaline compound of Formula (II)
Formula (IIa)
with hydroquinone of formula (III)
Formula (III)
using sodium hydroxide in water at a temperature in the range of 60 °C to 120 °C to obtain a compound of Formula (IV), and
Formula (IV)

(b). reacting compound of Formula (IV) with a compound of formula (V)
Formula (V)
using potassium carbonate in acetonitrile and TBAB at a temperature in the range of 60 °C to 120 °C to obtain compound of Formula (I).

4. The process as claimed in claim 1, wherein the leaving group is selected from fluoro, chloro, bromo and iodo, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, nonafluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl) sulfonyloxy, (4-rertbutyl-phenyl)sulfonyloxy and (4-methoxy-phenyl)sulfonyloxy.

5. The process as claimed in claim 4, wherein the leaving group is preferably iodo, bromo, chloro, mesyloxy, tosyloxy.

6. The process as claimed in claims 1 and 2, wherein the base is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate.

7. The process as claimed in claims 1 and 2, wherein the solvent is water, acetonitrile, alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, hydrocarbon solvents such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like, N,N-dimethylformamide..

8. The process as claimed in claims 1 and 2, wherein the phase transfer catalyst (PTC) is selected from benzyltriethylammoinium chloride, tetrabutylammonium chloride, Tetrabutyl ammonium bromide, benzyl trimethyl ammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and hexadecyltributyl phosphonium bromide (TBHDPB).

Dated this Twenty Second (22nd) day of January, 2021

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883
, Description:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PROCESS FOR THE PREPARATION OF QUIZALOFOP-ETHYL

We, COROMANDEL INTERNATIONAL LIMITED,
an Indian company incorporated under Companies Act of 1956, having its principal place of business at Coromandel House, Sardar Patel Road, Secunderabad – 500 003, Telangana, India.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of a herbicide.

The present invention specifically relates to an improved process for the preparation of Quizalofop or its salts or its ester.

The present invention more specifically relates to an improved process for the preparation of Quizalofop-ethyl having the Formula (I).
Formula (I)

BACKGROUND OF THE INVENTION
Quizalofop-ethyl is a chemical compound from the group of aryloxyphenoxypropionic-herbicides (a sub-group of derivatives of phenoxyacetic acid and of quinoxaline). Quizalofop-ethyl is a representative of quizalofop herbicides, structurally the ethyl ester of quizalofop, and the free acid. Chemically Quizalofop-ethyl is known as (RS)-2-[4-(6-Chlorchinoxalin-2-yloxy)phenoxy]propionic acid ethyl ester.

Quizalofop is a selective post-emergence herbicide. Quizalofop appears as two different isomer mixtures: quizalofop-ethyl and quizalofop-p-ethyl. Quizalofop-p-ethyl is composed solely of the pesticidally active isomer, and all quizalofop products currently in the marketplace contain this isomer; there are no pesticide registrations for products containing quizalofop-ethyl (a 50/50 racemic mixture of active and inactive isomers). Both quizalofop-p-ethyl and quizalofop-ethyl are referred to collectively as quizalofop.

Quizalofop-p-ethyl is a selective, post-emergence organic phenoxy herbicide that belongs to a subclass of phenoxy compounds known as Aryloxyphenoxys (fops). Quizalofop-p-ethyl is absorbed by the treated foliage and translocated to the roots and other growing points of the plant.

Quizalofop is a systemic herbicide registered for use to control annual and perennial weeds in various food/feed and non-food/non-feed crops. Quizalofop-ethyl is a 50/50 racemic mixture of R- and S-enantiomers. Quizalofop-p-ethyl is the purified R-enantiomer. The pesticidally active isomer is the R-enantiomer (quizalofop-p-ethyl).

CN106432109A discloses a process for the preparation of Quizalofop-p-ethyl, which is shown in the scheme given below :

CN102584724B discloses a process for the preparation of Cyproconazole intermediate of Formula (I), which is shown in the scheme given below :

WO 1997046538A1 discloses a process for producing D(+)-2-[4-(6-chloro-2- quinoxalyloxy)phenoxy]propionic acid (Quizalofop) which comprises reacting an alkali metal salt of 4-(6-chloro-2-quinoxalyloxy)phenol with an alkali metal salt of L-2- chloropropionic acid in an aromatic hydrocarbon solvent in the presence of an aprotic polar solvent to obtain an alkali metal salt of D(+)-2-[4-(6-chloro-2- quinoxalyloxy)phenoxy]propionic acid, and treating it with an acid. . This application also discloses process for the preparation of D(+)-2-[4-(6-chloro-2-quinoxalyloxy)phenoxy]propionate by using D(+)-2-[4-(6- chloro-2-quinoxalyloxy)phenoxy]propionic acid by treating with diethyl sulfate in the presence of a tertiary amine and a base. The process is shown in the scheme given below :

CN 112028842 disclosed a process for the preparation of Quizalofop-p-ethyl which is characterized by comprising the following steps:
1) reaction: the S-2-ethyl chloropropionate and 4- (6-chloro-2-quinoxalinyloxy) phenol react under the conditions of a non-polar organic solvent, tertiary amine alkali and a phase transfer catalyst to generate quizalofop-p-ethyl,
2) and (3) post-treatment: and (3) after the reaction, washing and acidifying the reaction solution until the pH is about =4, separating the solution to recover a tertiary amine alkali hydrochloride aqueous solution, decoloring and filtering an organic phase by using activated carbon to remove residual 4- (6-chloro-2-quinoxalyloxy) phenol and other impurities, washing the filtrate to be neutral, distilling the organic phase under reduced pressure until the system is in a molten state to recover an organic solvent, adding a polar solvent to cool and crystallize, and filtering to obtain the quizalofop-p-ethyl product. The process is shown in the scheme given below:

The process described in the prior-art involves additional purifications which leads to less yield and hence are not suitable on industrial scale. Further, the process of prior-art involves use of organic solvents.

Accordingly, there is a need to industrially acceptable /scalable process which does not need any further purification to obtain Quizalofop-ethyl of Formula (I) in high yields compared to prior-art processes.

The inventors of the present invention have surprisingly found a simple, cost effective and industrially viable process. The process was designed with consideration like environmental, economical aspects and the optimal duration times of the individual stages were determined. Further, the process of the present invention involves use of water which is economic and does not have impact on environment, acetonitrile for which recovery is high. Hence, the process of the present invention is industrially and economically feasible process and has safe operations.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of a herbicide.

Another objective of the present invention is to provide an improved process for the preparation of Quizalofop or its salts or its ester.

Yet another objective of the present invention is to provide an improved process for the preparation of Quizalofop-ethyl having the Formula (I).
Formula (I)

Still another objective of the present invention is to provide an improved process for the preparation of Quizalofop-ethyl having the Formula (I)
Formula (I)
which is commercially feasible / industrially scalable process resulting in the compound with high purity and is devoid of any purifications.

SUMMARY OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of a herbicide.

The present invention specifically relates to an improved process for the preparation of Quizalofop or its salts or its ester.

The present invention relates to an improved process for the preparation of Quizalofop-ethyl having the Formula (I)
Formula (I)
which comprises :
(a). reacting quinoxaline compound of Formula (II)
Formula (II)
wherein Lg is a leaving group with hydroquinone of formula (III)
Formula (III)
using a base in a solvent to obtain a compound of Formula (IV), and
Formula (IV)

(b). reacting compound of Formula (IV) with a compound of formula (V)
Formula (V)

using a base in a solvent in the presence of phase transfer catalyst to obtain Quizalofop-ethyl of Formula (I).

The present invention specifically relates to an improved process for the preparation of Quizalofop-ethyl having the Formula (I)
Formula (I)
which comprises :
(a). reacting quinoxaline compound of Formula (II)
Formula (IIa)
with hydroquinone of formula (III)
Formula (III)
using a base in a solvent to obtain a compound of Formula (IV), and
Formula (IV)

(b). reacting compound of Formula (IV) with a compound of formula (V)
Formula (V)

using a base in a solvent in the presence of phase transfer catalyst to obtain compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The term Lg leaving group used in this reaction include but not limited to fluoro, chloro, bromo and iodo, mesyloxy, tosyloxy, trifluoromethylsulfonyloxy, nonafluorobutylsulfonyloxy, (4-bromo-phenyl)sulfonyloxy, (4-nitro-phenyl)sulfonyloxy, (2-nitro-phenyl)sulfonyloxy, (4-isopropyl-phenyl)sulfonyloxy, (2,4,6-tri-isopropyl-phenyl)sulfonyloxy, (2,4,6-trimethyl-phenyl) sulfonyloxy, (4-rertbutyl-phenyl)sulfonyloxy and (4-methoxy-phenyl)sulfonyloxy. Preferably, X is selected from the group comprising iodo, bromo, chloro, mesyloxy, tosyloxy, (4-nitro-phenyl)sulfonyloxy and (2-nitro-phenyl)sulfonyloxy.

The base used in this reaction include but not limited to a strong base selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like.
The solvent system used in the reaction medium is one or more selected from water, acetonitrile, alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, hydrocarbon solvents such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like N,N-dimethylformamide.

The phase transfer catalyst (PTC) used in this reaction include but not limited to benzyltriethylammoinium chloride, tetrabutylammonium chloride, Tetrabutyl ammonium bromide, benzyl trimethyl ammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, and hexadecyltributyl phosphonium bromide (TBHDPB) etc. The phase transfer catalyst is preferably tetrabutylammonium bromide

The present invention provides an improved process for the preparation of compound of Formula (IV) which comprises reacting the compound of Formula (II) with hydroquinone of formula (III) using a base in a solvent. The reaction is carried out at a temperature in the range from 60 °C to 120 °C. Duration of the reaction varies from 2 to 5 hours. The progress of the reaction is monitored by HPLC, thereafter the product formed is isolated.

In yet another embodiment the present invention provides an improved process for the preparation of Quizalofop-ethyl of Formula (I) which comprises reacting compound of Formula (IV) with a compound of formula (V) using base in a solvent and a phase transfer catalyst. The reaction is carried out at a temperature in the range from 40°C to 120 °C. Duration of the reaction varies from 1 hour to 10 hours. The progress of the reaction is monitored by HPLC, and the product formed is isolated.

In yet another preferred embodiment, the present invention provides process for the preparation of Quizalofop-ethyl having the Formula (I)
Formula (I)
which comprises :
(a). reacting quinoxaline compound of Formula (II)
Formula (IIa)
with hydroquinone of formula (III)
Formula (III)
using sodium hydroxide in water at a temperature in the range of 60 °C to 120 °C to obtain a compound of Formula (IV), and
Formula (IV)

(b). reacting compound of Formula (IV) with a compound of Formula (V)
Formula (V)

using potassium carbonate in acetonitrile and TBAB at a temperature in the range of 60 °C to 120 °C to obtain compound of Formula (I).

The intermediates formed in the present invention may be isolated or not. Any of the above reactions may be carried out in-situ reactions to obtain compound of Formula (I) or its derivative. The above compounds may be isolated as salts or free bases, if the above compounds are isolated as salts they are converted to their free bases first and used for further reactions.

The advantages of the present invention is that process does not involve any purifications, thereby resulting in pure compound with better yields. The process involves simple bases like sodium hydroxide and potassium carbonate. Further, one step of the process involves water as solvent instead of an organic solvent and another step uses acetonitrile as a solvent for which recovery is high. This make the process economically feasible with minimum load on environment wherein discharge of solvents is minimized.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example-1: Preparation of 4-((6-chloroquinoxalin-2-yl) oxy) phenol (CQP):

Water (200mL), 2,6-dichloroquinoxaline (DCQ) (100.0 g), Hydroquinone (HQN) (80.0 g), were taken into a 4 neck RBF equipped with mechanical stirrer. The reaction mass was heated to 75-80°C and 25% sodium hydroxide solution (40g NaOH in 160 mL water) was added to the above mixture drop wise over a period of 30-45mins. The reaction mass was heated to 95- 100 °C and maintained for 4 hrs. The reaction was monitored by HPLC till the DCQ content is less than 1 % (Area normalization). After the completion of reaction, the reaction mass was cooled to room temperature (25-30°C) and filter product under vacuum. The wet cake was washed with water 3 x 100 mL, collected the wet cake and dried in hot air oven at 95- 100°C for 4-6 hrs to obtain 4-((6-chloroquinoxalin-2-yl) oxy)phenol (CQP) with yield of 93-95% (128-130 g) having purity of 97-99% by HPLC (% Area).

Example-2: Preparation of Quizalofop-Ethyl (QZF):

Acetonitrile (400mL), 4-((6-chloroquinoxalin-2-yl)oxy)phenol (CQP) (100 g), potassium carbonate (52 g), ethyl 2-bromo propanoate (EBP) (72 g) and TBAB (6 g) were taken in a 4 neck RBF equipped with mechanical stirrer. The reaction mixture was heated to 75-80°C and maintained for 1-2 hrs. The reaction was monitored till the CQP content is less than 0.5 % by HPLC (% Area). After completion of reaction, the reaction mass was cooled to 25-30°C and filtered the inorganic salts under vacuum. The wet cake was washed with acetonitrile (100 mL). The filtrate was collected, cooled to 5-10°C and maintained for 1 hr. The solid material was filtered under vacuum and washed the wet cake with (50 mL) chilled acetonitrile. The wet cake was dried in hot air oven at 70-750C for 3-4 hrs to obtain Quizalofop ethyl (QZF) with HPLC purity of 98-99% (w/w) and yield is 95-97% (130- 132g).

Example-3: Preparation of 4-((6-chloroquinoxalin-2-yl) oxy) phenol (CQP):

Methylethylketone (400mL), 2,6-dichloroquinoxaline (DCQ) (100.0 g), Hydroquinone (HQN) (80.0 g) and potassium carbonate were taken into a 4 neck RBF equipped with mechanical stirrer. The reaction mass was heated to 75-80°C. The reaction was monitored by HPLC till the DCQ content is less than 1 % (Area normalization). After the completion of reaction, the reaction mass was cooled to room temperature (25-30°C) and filter the inorganic salts under vacuum. Resulted organic layer concentrated under vacuum to obtain crude 4-((6-chloroquinoxalin-2-yl) oxy)phenol (CQP) with yield of 71-75% (98-103 g) having purity of 96-97% by HPLC (% Area).

Example-4 Preparation of 4-((6-chloroquinoxalin-2-yl) oxy) phenol (CQP):

Dimethylformamide (300mL), 2,6-dichloroquinoxaline (DCQ) (100.0 g), Hydroquinone (HQN) (80.0 g) and potassium carbonate were taken into a 4 neck RBF equipped with mechanical stirrer. The reaction mass was heated to 100-105°C. The reaction was monitored by HPLC till the DCQ content is less than 1 % (Area normalization). After the completion of reaction, the reaction mass was cooled to room temperature (25-30°C) and filter the inorganic salts under vacuum. Resulted organic layer concentrated under vacuum to obtain 4-((6-chloroquinoxalin-2-yl) oxy)phenol (CQP) with yield of 80-82% (110-113 g) having purity of 97-99% by HPLC (% Area).

Example-5: Preparation of Quizalofop-Ethyl (QZF):

Acetone (500mL), 4-((6-chloroquinoxalin-2-yl)oxy)phenol (CQP) (100 g), potassium carbonate (53 g), ethyl 2-bromo propanoate (EBP) (72 g) and TBAB (3 g) were taken in a 4 neck RBF equipped with mechanical stirrer. The reaction mixture was heated to 52-55°C and maintained for 4-5 hrs. The reaction was monitored till the CQP content is less than 0.5 % by HPLC (% Area). After completion of reaction, the reaction mass was cooled to 25-30°C and filtered the inorganic salts under vacuum. The wet cake was washed with chilled acetone (50 mL). The filtrate was collected, cooled to 0-5°C and maintained for 1 hr. The solid material was filtered under vacuum. The wet cake was dried in hot air oven at 70-750C for 3-4 hrs to obtain Quizalofop ethyl (QZF) with HPLC purity of 97-98% (w/w) and yield is 85-90% (116- 123g).

Example-6: Preparation of Quizalofop-Ethyl (QZF):

Toluene (500mL), 4-((6-chloroquinoxalin-2-yl)oxy)phenol (CQP) (100 g), potassium carbonate (53 g), ethyl 2-bromo propanoate (EBP) (72 g) and TBAB (3 g) were taken in a 4 neck RBF equipped with mechanical stirrer. The reaction mixture was heated to 105-110°C and maintained for 8-9 hrs. The reaction was monitored till the CQP content is less than 2 % by HPLC (% Area). After completion of reaction, the reaction mass was cooled to 25-30°C and filtered the inorganic salts under vacuum. The filtrate was collected, cooled to 0-5°C and maintained for 1 hr. The solid material was filtered under vacuum. The wet cake was dried in hot air oven at 70-750C for 3-4 hrs to obtain Quizalofop ethyl (QZF) with HPLC purity of 95-98% (w/w) and yield is 93-95% (128- 130g).

Example-7: Preparation of Quizalofop-Ethyl (QZF):

Toluene (500mL), 4-((6-chloroquinoxalin-2-yl)oxy)phenol (CQP) (100 g), potassium carbonate (53 g), ethyl 2-bromo propanoate (EBP) (72 g) and TEBAC (4 g) were taken in a 4 neck RBF equipped with mechanical stirrer. The reaction mixture was heated to 105-110°C and maintained for 11-12 hrs. The reaction was monitored till the CQP content is less than 2 % by HPLC (% Area). After completion of reaction, the reaction mass was cooled to 25-30°C and filtered the inorganic salts under vacuum. The filtrate was collected, cooled to 0-5°C and maintained for 1 hr. The solid material was filtered under vacuum. The wet cake was dried in hot air oven at 70-750C for 3-4 hrs to obtain Quizalofop ethyl (QZF) with HPLC purity of 95-98% (w/w) and yield is 92-93% (126- 128g).

Example-8: Preparation of Quizalofop-Ethyl (QZF):

Dimethylformamide (300mL), 4-((6-chloroquinoxalin-2-yl)oxy)phenol (CQP) (100 g), potassium carbonate (53 g), ethyl 2-bromo propanoate (EBP) (72 g) and TBAB (4 g) were taken in a 4 neck RBF equipped with mechanical stirrer. The reaction mixture was heated to 85-90°C and maintained for 5-6 hrs. The reaction was monitored till the CQP content is less than 1 % by HPLC (% Area). After completion of reaction, the reaction mass was cooled to 25-30°C and filtered the inorganic salts under vacuum. The filtrate was distilled half volume and resulted mass, cooled to 0-5°C and maintained for 1 hr. The solid material was filtered under vacuum. The wet cake was dried in hot air oven at 70-750C for 3-4 hrs to obtain Quizalofop ethyl (QZF) with HPLC purity of 95-98% (w/w) and yield is 90-92% (123- 126g).