Description:Field of the Invention
The present invention relates to an improved process for the preparation of 2-Amino-5-cyano-3,N-dimethylbenzamide of Formula-I, which is an advanced intermediate of Cyantraniliprole.

Background of the Invention
Anthranilamide derivatives are a kind of novel insecticides with high efficacy and safety. 3-Bromo-N-(4-cyano-2-methyl-6-(methylcarbamoyl)phenyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxamide is highly effective against insects, which is commercialized by DuPont, its generic common name is Cyantraniliprole;

There are a number of methods reported for preparing phenylcarboxamides, for example:
WO 2004067528 A1 discloses that 3-halo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acids reacts with substituted anthranilic acids in the presence of methanesulfonyl chloride and pyridine as acid binding agent to give the benzoxazinones in 86%-92% yield. Then the product reacts with Copper(I)cyanide/ Copper iodide in the presence of tetrakis (triphenylphosphine)palladium(0) catalyst followed by reacting with alkylamine to yield the Cyantraniliprole.

WO 2006062978 A1 discloses a process for the preparation of 2-amino-5-cyano-3,N-dimethylbenzamide of Formula-I by reacting compound of Formula-II with Aqueous methylamine in acetic acid to produce 2-amino-3,N-dimethylbenzamide of Formula-III, which undergoes further bromination in the presence of HBr in acetic acid solvent to obtain 2-amino-5-bromo-3,N-dimethylbenzamide of Formula-IV. Further, compound of Formula-IV undergoes further cyanation in the presence of HCN/Activated zinc powder/ Palladium(II)acetate/1,4-bis(diphenylphosphino)butane in DMF/AcOH solvent to obtain 2-amino-5-chloro-3,N-dimethylbenzamide of Formula-I.

The synthetic procedure is illustrated in Scheme-I as below:

SCHEME-I

WO 2012/103436 A1 discloses a process for the preparation of 2-amino-5-cyano-3,N-dimethylbenzamide of Formula-I by reacting compound of Formula-V with carbon monoxide and methyl amine in the presence of Palladium (II) acetate and 1,4-bis(diphenylphosphino)butane to produce compound of Formula-I.

The synthetic procedure is illustrated in Scheme-II as below:

SCHEME-II
WO 2008070158 A1 discloses a process for the preparation of 2-amino-5-cyano-3,N-dimethylbenzamide of Formula-I by cyanation of 2-amino-5-halo-3,N-dimethylbenzamide of Formula-VI in the presence of NaCN or KCN and palladium catalyst in ethers/ nitrile solvents to produce compound of Formula-I.

The synthetic procedure is illustrated in Scheme-III as below:

SCHEME-III
Further, WO 2009006061 A2 discloses a process for the preparation of 2-amino-5-cyano-3,N-dimethylbenzamide of Formula-I by cyanation of 2-amino-5-halo-3,N-dimethylbenzamide of Formula-VI in the presence of KCN and chloronaphthalenyl-bis(triphenylphosphine)nickel catalyst to produce compound of Formula-I.

The synthetic procedure is illustrated in Scheme-IV as below:

SCHEME-IV
WO2009061991A1 discloses a process for the preparation of 2-amino-5-cyano-3,N-dimethylbenzamide of Formula-I by cyanation of 2-amino-5-halo-3,N-dimethylbenzamide of Formula-VI in the presence of NaCN/ Zn and [1,1-bis(diphenylphosphino)-ferrocene][(1,2,5,6)-1,5-cyclooctadiene]nickel catalyst to produce compound of Formula-I.
The synthetic procedure is illustrated in Scheme-V as below:

SCHEME-V
WO 2009085816 A1 discloses a process for the preparation of 2-amino-5-cyano-3,N-dimethylbenzamide of Formula-I by cyanation of 2-amino-5-halo-3,N-dimethylbenzamide of Formula-VI in the presence of powdered NaCN/CuI and 1-methylnaphthalene catalyst in 4-picoline to produce compound of Formula-I.

The synthetic procedure is illustrated in Scheme-VI as below:

SCHEME-VI
WO 2009111553 A1 discloses a process for the preparation of 2-amino-5-cyano-3,N-dimethylbenzamide of Formula-I by cyanation of 2-amino-5-halo-3,N-dimethylbenzamide of Formula-VI in the presence of NaCN/CuI and 1-methylnaphthalene and 1-butyl-1H-imidazole catalyst to produce compound of Formula-I.

The synthetic procedure is illustrated in Scheme-VII as below:

Objective of the Invention
The main objective of the present invention is to provide a simple and cost effective and commercially viable processes for the preparation of 2-Amino-5-cyano-3,N-dimethylbenzamide of Formula-I , which is an advanced intermediate of Cyantraniliprole.

Summary of the Invention:
The present invention provides a process for preparation of 2-Amino-5-cyano-3,N-dimethyl benzamide of Formula-I,

Formula-I
comprising the steps of:
a) reacting 2-Nitro-3-methylbenzoic acid of Formula-VII

Formula-VII
with a chlorinating agent in a suitable solvent to produce compound of Formula-VIII.

Formula-VIII
b) reacting the compound of Formula-VIII in-situ with methylamine in presence of a base in a suitable solvent to produce compound of Formula-IX.

Formula-IX
c) reducing the compound of Formula-IX in presence of Raney nickel catalyst and hydrogen in a suitable solvent to produce compound of Formula-X;

Formula-X
d) brominating the compound of Formula-X with HBr/ H2O2 in presence of a base in a suitable solvent to produce a compound of Formula-XI.

Formula-XI
e) reacting the compound of Formula-XI with copper cyanide and potassium iodide in a suitable solvent to produce compound of Formula-I.

Detailed Description of the Invention
The present invention provides a process for preparation of 2-Amino-5-cyano-3,N-dimethyl benzamide of Formula-I, comprising the steps of:
a) reacting 2-Nitro-3-methylbenzoic acid of Formula-VII with a chlorinating agent in a suitable solvent to produce compound of Formula-VIII,
b) reacting the compound of Formula-VIII in-situ with methylamine in presence of a base in a suitable solvent to produce compound of Formula-IX,
c) reducing the compound of Formula-IX in presence of Raney nickel catalyst and hydrogen in a suitable solvent to produce compound of Formula-X,
d) brominating the compound of Formula-X with HBr/ H2O2 in presence of a base in a suitable solvent to produce a compound of Formula-XI,
e) reacting the compound of Formula-XI with copper cyanide and potassium iodide in a suitable solvent to produce compound of Formula-I.
In step a) of present invention, chlorinating agent is selected from thionyl chloride, oxalyl chloride, PCl3, POCl3.

In step a) of the present invention, a suitable solvent is selected from toluene, acetonitrile, methylene chloride chloroform and xylene mixture thereof. preferably toluene.
In step a) of the present invention, the reaction may be performed usually from 20°C to 100°C for 1 to 5 hours, preferably 30-65°C for 1 to 2 hours. The obtained compound of Formula-VIII can be used in the next reaction without further purification.
In step b) of the present invention, the base is in-organic base comprising sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Preferably sodium carbonate.

In step b) of the present invention, the suitable solvent is selected from water, acetonitrile, N,N-dimethylformamide, toluene, dimethylsulphoxide. Preferably water.

In step b) of the present invention, the reaction may be performed usually from 20°C to 40°C for 1-10 hours, preferably 25-30°C for 1-2 hours. The obtained compound of Formula-IX may be used in next reaction with directly or optionally after further purification.

In step c) of the present invention, suitable solvent is selected from alcohol methanol, ethanol, propanol, isopropanol, n-butanol or mixture thereof. Preferably methanol.

In step c) of the present invention, the reaction may be performed usually from 20°C to 60°C boiling point of the solvent used for 1-10 hours, preferably 40-45°C for 2-3 hours. The compound of formula-X from step c) may be used in next reaction with directly or optionally after further purification.

The suitable solvent used in step d) of present invention is selected from acetonitrile, water, N,N-dimethylformamide, toluene, dimethylsulphoxide. Preferably water.

In step d) of the present invention, the reaction may be performed usually from 0°C to 30°C for 2 to 24 hours, preferably 10-15°C for 3-5 hours. The compound of Formula-XI from step (d) is isolated from reaction mass by distillation of solvent followed by quenching into water in >85% yield with purity > 97.0% by HPLC.

The suitable solvent used in step e) of present invention is organic solvent comprises dimethyl formamide, methanol, ethanol, dichloromethane or mixture thereof.
In step e) of the present invention, the reaction may be performed usually from 20°C to 150°C boiling point of the solvent used for 2 to 24 hours, preferably 140-145°C for 10-15 hours. The compound of Formula-I from step e) is isolated from reaction mass by distillation of solvent followed by quenching into water in >85% yield with purity > 97.0% by HPLC.

Advantages of present invention:
The present invention process involves less expensive and readily available reagents and solvents.
Chlorinating reagents employed in present invention process are thionyl chloride, oxalyl chloride which are very less expensive and readily available.
Solvents used in present invention were less expensive and can be recovered
and reused.
Product of present invention is directly isolated from the reaction mass without involving any laborious work-up processes. Therefore, the process of the present invention is suitable for commercial scale.
Brominating reagents employed in present invention process are hydrobromic acid, hydrogen peroxide which are very less expensive and readily available

The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.

EXAMPLES:
Example-01: Preparation of N,3-dimethyl-2-nitro-benzamide Formula-IX.

Charged 1000.0 ml of toluene lot-I and 500.0 g of 3-Methyl-2-nitro benzoic acid (2.76 moles, Formula-VII) into a 3.0L 4N RB flask at 25-30°C and the resulting suspension was stirred for 5 min, after which N,N-Dimethylformamide (1.5 ml ) was added at 25-30°C and reaction mass (Suspension) was heated at 60-65°C. Thionyl chloride (459.4 g; 3.86 moles) was added to the reaction mass at 60-65°C and stirred for 2h. After completion of the reaction (by TLC), reaction mass was cooled to 25-30°C.
Into another 10.0 L, 4N RB flask charged 500.0 ml of toluene lot-II, 2750.0 ml of DM Water lot-I, 228.2 g of Sodium carbonate (2.15 moles) and 250.2 g of 40% Aqueous Mono methylamine solution (3.23 moles) and stirred the solution at 25-30°C for 10-15 min. The above acid chloride was slowly added to the reaction mass at 25±5°C and stirred for 1h. After completion of the reaction (by TLC), filtered the solid and washed with 500.0 ml of toluene then dried for 6h at 60-65°C to afford N,3-dimethyl-2-nitro-benzamide of Formula-IX as off-white coloured powder.
Weight of the product is 517.0g. (96.5% by theory). Purity by HPLC>99.0%.
Example-02: Preparation of 2-amino-N,3-dimethyl-benzamide of Formula-X.

Charged 2500.0 ml of methanol and 500.0 g (2.57 moles) of Formula-IX into a 5.0 L hydrogenation Kettle at 25-30°C. Charged 100.0 g of Raney Nickel to reaction mass at 25-30°C. Reaction mass was heated at 40-45°C. Applied the hydrogen pressure to 80 psi. After completion of hydrogen consumption, the reaction mass was stirred at 40-45°C for 2h. After completion of the reaction (by TLC), filtered the reaction mass and washed with 500.0 ml of methanol. The solvent was distilled under vacuum at 60-65°C. Product was isolated from water to afford 2-amino-N,3-dimethyl-benzamide of Formula-X as light brown coloured powder. Weight of the product is 393.0g. (93.0% by theory). Purity by HPLC>99.0%.

Example-03: Preparation of 2-amino-5-bromo-N,3-dimethyl-benzamide of Formula-XI.
Charged 250.0 ml of aqueous hydrobromic acid and 100.0 g of Formula-X (0.609 moles) into a 1.0 L 4 N RB flask at 25-30°C. The reaction mass was stirred at 25-30°C for 5-10 min and cooled to 10-15°C. 30% Hydrogen peroxide (91.0g) was added to reaction mass at 10-15°C over a period of 1h and stirred at 10-15°C for 3h. After completion of the reaction (by TLC), reaction mass was filtered, and filtrate was neutralized with sodium carbonate solution. Solid was filtered and washed and dried to afford 2-amino-5-bromo-N,3-dimethyl-benzamide of Formula-XI as pink coloured powder. Weight of the product is 133.0g. (90.0% by theory). Purity by HPLC>99.0%.
Example-04: Preparation of 2-amino-5-cyano-N,3-dimethyl-benzamide of Formula-I.
Charged 70.0 g of Formula-XI (0.287 moles) and 210.0 ml of DMF into a 500 ml 4 N RB flask and stirred at 25-30°C for 5 min (Reaction mass becomes clear solution). Acetic acid (15.4g) was added to the reaction mass at 25-30°C and stirred for 30 min at 25-30°C. Charged 37g of KI, 39.0 g of Copper cyanide and 70 ml of DMF to the reaction mass at 25-30°C. Resulting reaction mass was heated to 140-145°C and stirred for 24 h. After completion of the reaction (by TLC), reaction mass was cooled to 25-35°C. Water (1120.0 ml) was added the reaction mass slowly at 25-30°C and cooled to 20-25°C. Aqueous ammonia solution (140 ml) was slowly added to the reaction mass at 20-25°C and filtered the solid and washed with 700.0 ml of water. Crude compound was recrystallized from Ethyl acetate to afford 2-Amino-5-cyano-N,3-dimethyl benzamide of Formula-I as off-white coloured powder. Weight of the product is 393.0g. (70.0% by theory). Purity by HPLC>98.0%
, Claims:WE CLAIM:
1. A process for preparation of 2-Amino-5-cyano-3,N-dimethyl benzamide of Formula-I,

Formula-I
comprising the steps of:
a) reacting 2-Nitro-3-methylbenzoic acid of Formula-VII

Formula-VII
with a chlorinating agent in a suitable solvent to produce compound of Formula-VIII.

Formula-VIII
b) reacting the compound of Formula-VIII in-situ with methylamine in
presence of a base in a suitable solvent to produce compound of Formula-IX.

Formula-IX
c) reducing the compound of Formula-IX in presence of Raney nickel
catalyst and hydrogen in a suitable solvent to produce compound of Formula-X;

Formula-X
d) brominating the compound of Formula-X with HBr/ H2O2 in presence of a
base in a suitable solvent to produce a compound of Formula-XI.

Formula-XI
e) reacting the compound of Formula-XI with copper cyanide and potassium
iodide in a suitable solvent to produce compound of Formula-I.

2. The process as claimed in claim 1, a suitable solvent used in step a) is selected from toluene, acetonitrile, methylene chloride chloroform and xylene mixture thereof.

3. The process as claimed in claim 1, wherein the base used in step b) is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate.

4. The process as claimed in claim 1, wherein the suitable solvent used in step c) is selected from alcohol methanol, ethanol, propanol, isopropanol, n-butanol or mixture thereof.
5. The process as claimed in claim 1, wherein the suitable solvent used in step-d) is selected from acetonitrile, N,N-dimethylformamide, toluene, dimethylsulphoxide or mixture thereof.

6. The process as claimed in claim 1, wherein the suitable solvent used in step-e) is selected from N,N-dimethylformamide, methanol, ethanol, dichloromethane or mixture thereof.

7. The process as claimed in claim 1, wherein the compound of Formula-I is used in the preparation of Cyantraniliprole.