Claims:CLAIMS
WE CLAIM,

1. An novel process for the preparation of 1-acetyl-3,4-dihydro-3-[(3-pyridinylmethyl) amino] -6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl) ethyl]-2(1H)-quinazolinone of formula (I) comprises:
cyclizing of N-[4-heptafluoropropyl-2- (N-pyridin-3-ylmethylhydrazino methyl) -Phenyl]-acetamide of formula (IX) with a cyclizing agent selected form carbon monoxide, diphosgene, triphosgene, chloroformate, aryl chloroformate in presence of solvent with or without phase transfer catalyst.

2. The novel process as claimed in claim 1, wherein solvent is selected from water, acetone, N,N-Dimethylformamide, acetonitrile, Dimethylsulfoxide, sulfolane; methanol, ethanol, propanol, butanol, methylene chloride, chloroform, monochlorobenzene, ethylene chloride, toluene, xylene, heptane, cyclohexane and hexane.

3. The novel process as claimed in claim 1, wherein phase transfer catalyst is selected from Tetrabuylammonium bromide, Tetrabutyammonium chloride.

4. The novel process as claimed in claim 1, wherein process for the preparation of Formula (IX) comprises the steps of:
a) Reacting 3-bromomethyl pyridine of formula (XIII) with hydrazine hydrate of formula (XV) in presence of solvent selected to obtain Pyridin-3-ylmethyl-hydrazine of formula (XI);

b) reacting N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide of Formula (IV) with Pyridin-3-ylmethyl-hydrazine of Formula (XI) in presence of solvent to form compound of Formula IX.

5. The novel process as claimed in claim 4, wherein solvent is selected from water, acetone, N,N-Dimethylformamide, acetonitrile, Dimethylsulfoxide, sulfolane; methanol, ethanol, propanol, butanol, methylene chloride, chloroform, monochlorobenzene, ethylene chloride, toluene, xylene, heptane, cyclohexane and hexane.

Dated this 22nd day of February 2022

, Description:The instant application is a Divisional Patent Application of earlier filed parent patent
application no. 256/MUM/2015 dated 25/01/2015 and Title: A NOVEL PROCESS FOR THE PREPARATION OF PYRIFLUQUINAZON

FIELD OF THE INVENTION

The present invention relates to a novel process for preparation of 1-acetyl-3, 4-dihydro-3-[(3-pyridinylmethyl) amino]-6-[1, 2, 2, 2-tetrafluoro-1-(trifluoromethyl) ethyl]-2(1H)-quinazolinone of formula I in free form or in agrochemically acceptable salt form useful as a pest control agent.

BACKGROUND OF THE INVENTION

EP1097932 discloses new substituted aminoquinazolinone (thione) derivatives for use as, inter alia, insecticides with activity against Hemiptera and Orthoptera pests, and reveals insecticidal activity of certain compounds falling within the generic aminoquinazolinone (thione) structure against three Hemiptera pests (Myzuspersicae, Nilaparvatalugens and Trialeurodesvaporariorum). Whilst the compound of formula I (1-acetyl-1,2,3,4-tetrahydro-3-[(3-pyridylmethyl)amino]-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]quinazolin-2-one; (pyrifluquinazon) is specifically described in the tables of EP1097932 and discloses the process for producing the aminoquinazolinone (thione) derivative of the general formula (I) or salt thereof are schematically shown below:

Pyrifluquinazon as a compound was first disclosed in US5714492 as substituted aminoquinazolinone (thiol) derivative. The said patent also discloses intermediates thereof and pest controllers and method of using the same.

Czech. Chem. Commn. (Vol. 55), 752 (1990) discloses process for compound of the general formula (II), the process of which is disclosed as follows:

wherein, X may be the same or different and is a bromine atom, an iodine atom; a hydroxyl group; a cyano group; a (C1-6)alkyl group; a halo(C1-10)alkyl group; a (C2-6)alkenyl group; a halo(C2-6)alkenyl group; R4 is a (C1-6)alkyl group, and Hal is a halogen atom.

Czech. Chem. Commn. (Vol. 55), 752 (1990) discloses process for preparation of compound of formula (II) by reacting a compound of the general formula (VIII) with a compound of the general formula (VII) in the presence of an inert solvent and a catalyst. The compound of the general formula (V) is prepared by reducing the compound of the general formula (VI) with a reducing agent or by catalytic reduction in the presence or absence of an inert solvent. As the reducing agent, there can be used, for example, metal hydrides such as, NaBH3CN, LiBH3CN, etc. and reducing agents such as BH3, etc. The compound of the general formula (IV) is prepared by reacting the compound of the general formula (V) with 1, 1’-carbonylbis-1H-imidazole (CDI), an alkoxycarbonyl halide, phosgene or thiophosgen in the presence of an inert solvent and in the presence or absence of a base. The compound of the general formula (II) can be prepared by hydrolyzing the compound of the general formula (IV) under basic condition in the presence of an inert solvent.

US8034931 and IN225063 disclose a process for producing a substituted amino quinazolinone derivative useful as a pest control agent. In addition, the invention relates to intermediates and salts of the derivative, a pest control agent containing any one of them as an active ingredient and its usage.

For the production of a substituted aminoquinazolinone derivative, the processes disclosed in the above prior art references have been disadvantageous in that since by-products are produced by hydrogenolysis; both the selectivity and yield of the desired compound are insufficient. Therefore, there has been a desire for a process that solves this problem and permits industrially efficient production of a substituted aminoquinazolinone derivative.

The present invention is directed to the above drawbacks, the purpose is to provide novel process for the preparation of Pyrifluquinazon of formula I involving mild reaction conditions, simple to operate and the said process is also cost effective.

OBJECTIVES OF THE INVENTION
One of the objectives of the present invention is to provide a novel process for the preparation of 1-acetyl-3,4-dihydro-3-[(3-pyridinylmethyl)amino]-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone (Pyrifluquinazon) of formula (I) in free form or in agrochemically acceptable salt form starting from readily accessible and cheap intermediates which are easy to handle, in a simplified process to prepare Pyrifluquinazon of formula (I).

Still another objective of the present invention is to provide novel process for the preparation of an intermediate, 1-acetyl-6-(heptafluoropropyl)-3-[(E)-(pyridin-3-ylmethylidene)amino]-3,4-dihydroquinazolin-2(1H)-one of formula (VII), which is further used in the synthesis of final compound 1-acetyl-3,4-dihydro-3-[(3-pyridinylmethyl)amino]-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone (Pyrifluquinazon) of formula I in free form or in agrochemically acceptable salt.

Still further objective of the present invention is to provide novel process for the preparation of 1-acetyl-3,4-dihydro-3-[(3-pyridinylmethyl)amino]-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone (Pyrifluquinazon) of formula (I) in free form or in agrochemically acceptable salt which can be further used for formulating into suitable dosage forms.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel process for the preparation of 1-acetyl-3, 4- dihydro-3- [(3-pyridinylmethyl) amino]-6- [1, 2, 2, 2-tetrafluoro-1-(trifluoro methyl) ethyl]-2(1H)-quinazolinone (Pyrifluquinazon) of formula I.

Thus, the invention provides a simple, economically affordable and efficient process for preparing a 1-acetyl-3, 4-dihydro-3-[(3-pyridinylmethyl) amino]-6-[1, 2, 2, 2-tetrafluoro-1-(trifluoromethyl) ethyl]-2(1H)-quinazolinone (Pyrifluquinazon) of formula I.

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated and briefly described as follows.

In one embodiment the present invention provides a novel process for the preparation of N-[4-(heptafluropropyl)-2-methylphenyl]acetamide of formula (III) by acetylating 4-(heptafluoropropyl)-2-methyl aniline of formula (II) using an acetylating agent comprising acetic anhydride or acetyl chloride and sulphuric acid in presence of solvent optionally in presence of a phase transfer catalyst.

The process for the preparation of N-[4-(heptafluropropyl)-2-methylphenyl]acetamide of formula III by acetylation was carried with acetic anhydride wherein the organic solvent used in the above step is methylene chloride, ethylene chloride, chloroform, dimethylformamide or mixtures thereof, with or without sulphuric acid catalyst. In another embodiment acetylation was carried out by acetyl chloride in presence of phase transfer catalyst such as, Tetrabutylammonium bromide, Tetrabutylammonium chloride, and base used is potassium carbonate, sodium carbonate, triethylamine, diethylamine or mixtures thereof.

In another embodiment the present invention provides a novel process for the preparation of N-[2-(bromomethyl)-4-(heptafluoropropyl)phenyl]acetamide of formula (IV) by brominating N-[4-(heptafluropropyl)-2-methylphenyl]acetamide of formula (III) in presence of a brominating agent and radical initiator in an organic solvent optionally in the presence of a catalyst.

The solvents used in step of the bromination are polar aprotic solvents such as acetone, N,N-Dimethylformamide, acetonitrile, Dimethyl Sulfoxide, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane or mixtures thereof.

According to a preferred embodiment of the invention a radical initiator, preferably a peroxide catalyst is added to the reaction mixture, selected from but not limited to azobisisobutyronitrile (AIBN), 2,2'-azobis(2,4-dimethylvaleronitrile), benzoyl peroxide, t-butyl peroxide, t-butyl perbenzoate, hydrogen peroxide or dibenzoyl peroxide.

Brominating agents are selected from but not limited to potassium bromide, Sodium bromide, Bromine, hydrobromic acid, dibromodimethylhydantoin (DBDMH),
N-bromophthalimide, N-bromoacetamide or N-bromosuccinimide (NBS) or mixtures thereof.

In the process of the present invention bromination using sodium bromate is in combination with sodium bisulphate (NaBrO3/NaHSO3) in biphasic medium of water immiscible solvent such as ethyl acetate, n-butyl acetate, isopropyl acetate and water in presence of radical initiator as UV or ordinary light.

In the process of the present invention the bromination is carried out using bromine in biphasic medium comprising water and one of the halogenated solvent such as methylene chloride, chloroform, ethylene chloride, and chloroform in presence of radical initiator as UV or ordinary light.

In the process of the present invention the bromination is carried out using N-bromosuccinamide in combination with radical initiator as AIBN or benzoyl peroxide in an organic solvent such as acetonitrile, ethyl acetate, methylene chloride, chlorobenzene, chloroform.

In the process of the present invention the bromination agent is added to a solution of a compound of Formula (III) in a solvent. During the addition of the bromination agent the mixture is preferably kept at a temperature within the range of from room temperature to reflux temperature. After the addition of the bromination agent is completed the reaction mixture is preferably stirred for an additional time period of few minutes to 10 hours maintaining temperature between 20°C to 60°C. The crude product N-[2-(bromomethyl)-4-(heptafluoropropyl)phenyl]acetamide of formula (IV) is purified optimally by recrystallization in presence of ether class of organic solvent such as diethylether, di-isopropylether, methyl tert-butyl ether or mixture thereof.

In a preferred embodiment, the invention provides a novel process for the synthesis of N-[4-(heptafluoropropyl)-(hydrazinylmethyl) phenyl) acetamide of formula (V), which comprises reacting N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide formula (IV) with hydrazine hydrate in presence of solvent. The reaction mixture is refluxed for few hours to obtain N-[4-(heptafluoropropyl)-(hydrazinylmethyl) phenyl) acetamide of formula (V). After completion of the reaction, the remaining hydrazine hydrate and the solvent were removed from the reaction mixture by distillation under reduced pressure to obtain a crude product. There after crude product was recrystallized from methanol to obtain pure N-[4-(heptafluoropropyl)-(hydrazinylmethyl) phenyl) acetamide of formula (V).

Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, N, N-Dimethylformamide, acetonitrile, Dimethyl sulfoxide, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene and ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.

In a preferred embodiment, the invention provides a novel process for the synthesis of N-(4-heptafluoropropyl)-2-{[N-(pyridine-3-ylmethylene)hydrazinomethyl]-phenyl] acetamide of formula (VI), which comprises reacting N-[4-(heptafluoropropyl)-(hydrazinylmethyl) phenyl) acetamide of formula (V) with pyridine-3-carbaldehyde of formula (XII) in presence solvent and optionally in presences of acid.

The pyridine 3-carbaldehyde of formula (XII) in reaction acts both as a protective group as well as part of the end structure to ensure desired regioselectivity during cyclization.

Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, N,N-Dimethylformamide, acetonitrile, dimethyl sulfoxide, sulfolane; alcohols such as methanol, ethanol, propanol, butanol;chloro solvents like methylene chloride, chloroform, monochlorobenzene, ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.

In a preferred embodiment, the invention provides a novel process for the synthesis of N-[4-Heptafluoropropyl-2-(N'-pyridin-3-ylmethylene-hydrazinomethyl)-phenyl]-acetamide of formula (VI), which comprises reacting N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide formula (IV) with Pyridin-3-yl-methylene-hydrazine of formula (X) in presence of solvent. Solvent is selected from Dimethyl Sulfoxide, N,N-Dimethylformamide, Acetonitrile, Toluene, Xylene and the like. Copper halide catalysts are Copper bromide, Copper chloride, copper iodide and the like. After completion of reaction solvent is recovered and crude is recrystallized in alcohols solvent selected from ethanol, methanol, isopropyl alcohol, butanol .

In a preferred embodiment, the invention provides a novel process for the preparation of 1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one of formula VII, by cyclizing N-(4-heptafluoropropyl)-2-(N(pyridine-3-ylmethylene) hydrazinomethyl]-phenyl] acetamide of formula (VI) with cyclizing agent selected from carbon monoxide, phosgene, diphosgene, triphosgene, alkyl chloroformate, aryl chloroformate in presence of solvent with or without phase transfer catalyst such as,Tetrabutylammonium bromide, Tetrabutyammonium chloride and the like.

Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, N,N-Dimethylformamide, acetonitrile, Dimethyl sulfoxide, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.

Compound of formula VII may alternatively be prepared in a 2-step reaction as per the route below:
1-acetyl-3-amino-6-(heptafluoropropyl)-3,4-dihydroquinazolin-2-(1H)-one of formula (VIII) is prepared by cyclizing N-[4-(heptafluoropropyl)-(hydrazinylmethyl) phenyl) acetamide of formula (V) with cyclizing agent selected form carbon monoxide, phosgene, diphosgene, triphosgene, alkyl chloroformate, aryl chloroformate in presence of solvent with or without phase transfer catalyst such as, Tetrabutylammonium bromide, Tetrabutylammonium chloride and the like.

Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, N,N-Dimethylformamide, acetonitrile, Dimethyl sulfoxide, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane.

In the further next step, preparation of 1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one of formula VII is carried out by reacting 1-acetyl-3-amino-6-(heptafluoropropyl)-3,4-dihydroquinazolin-2-(1H)-one of formula VIII with pyridine-3-carbaldehyde of formula (XII) made institutively as described earlier in presence of solvent and optionally in presences of acid.

Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, N,N-Dimethylformamide, acetonitrile, Dimethyl sulfoxide, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane.

Suitable acid is inorganic or organic acids. Inorganic acids include mineral acids such as hydrohalic acids, such as hydrobromic and hydrochloric acids, sulfuric acids, phosphoric acids and nitric acids. organic acids include all pharmaceutically or veterinary acceptable aliphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acids tricarboxylic acids, aliphatic carboxylic acids, aromatic carboxylic acids, carbonic acid, formic acid, fumaric acid, acetic acid, propionic acid, isopropionic acid, valeric acid, alphahydroxy acids, glycolic acid and lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid, salicylic acid, oxalic acid, malic acid, succinic acid, tataric acid maleic acid, tricarboxylic acid, citric acid, butyric acid, isobutyric acid, sec-butyric acid, lauric acid, palmitic acid .

In one of preferred embodiment, the invention provides a novel process for the synthesis of Pyridine -3-carbaldehyde of Formula (XII) from 3-cyanopyridin of formula (XV) by hydrogenation in presence of Nickel catalyst .The catalyst is removed by filtration and recycled in number of times. The filtrate is neutralized with alkali and the filtrate containing Pyridine-3-carbaldehyde is used immediately in next reaction.

In the final stage of the invention, novel process for the preparation of 1-acetyl-3,4-dihydro-3-[(3-pyridinylmethyl)amino]-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone (Pyrifluquinazon) of formula I is completed by reducing1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one of formula VII prepared by either of the above two routes in presence of catalyst and solvent.

The reducing catalyst is metal compound selected form Palladium, Platinum, Raney Nickel, Rhodium or Ammonium formate or Trialkylammonium Formate wherein Ammonium formate or Trialkylammonium Formate is prepared by reacting formic acid with triethylamine in presence of solvent wherein Formate is Triethylammonium Formate.

Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, N,N-Dimethylformamide, acetonitrile, Dimethyl sulfoxide, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane.

In one of the preferred embodiment, the invention provides a novel process for the synthesis of Pyridin-3-ylmethyl-hydrazine of formula (XI) by reacting 3-Bromomethyl-pyridine of formula (XIII) with hydrazine hydrate of formula (XV) in presence of catalyst like Copper halide. After completion of reaction the product is recrystallized in suitable solvent to get the pure product.

In one of the preferred embodiment, the invention provides a novel process for the synthesis of N-[4-heptafluoropropyl-2-(N-pyridin-3-ylmethylhydrazinomethyl)-Phenyl]-acetamide of formula (IX) by reacting N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide of formula (IV) with Pyridin-3-ylmethyl-hydrazine of formula (XI) in presence of solvent and Copper halide as catalyst. After completion of reaction solvent is removed by distillation and recrystallized from alcohols such as methanol, ethanol, isopropyl alcohol, butanol to get pure compound of the formula (IX).

Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, N,N-Dimethylformamide, acetonitrile, Dimethyl sulfoxide, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane.

In the final stage of the invention, novel process for the preparation of 1-acetyl-3,4-dihydro-3-[(3-pyridinylmethyl)amino]-6-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2(1H)-quinazolinone (Pyrifluquinazon) of formula I is completed by cyclizing N-[4-heptafluoropropyl-2-(N-pyridin-3-ylmethylhydrazinomethyl)-Phenyl]-acetamide of formula (IX) with cyclizing agent selected from carbon monoxide, phosgene, diphosgene, triphosgene, alkyl chloroformate, aryl chloroformate and the like in presence of solvent with or without phase transfer catalyst such as, tetrabutylammonium bromide, tetrabutylammonium chloride and the like.

Suitable solvent is selected from but not limited to water, alcohols, ketones, diols, triols, esters, amides, ethers, hydrocarbons, polar aprotic solvents, polar solvents, chloro solvents, nitriles or mixtures thereof. Polar aprotic solvents such as acetone, N,N-Dimethylformamide, acetonitrile, Dimethylsulfoxide, sulfolane; alcohols such as methanol, ethanol, propanol, butanol; chloro solvents like methylene chloride, chloroform, monochlorobenzene, ethylene chloride; hydrocarbon solvents like toluene, xylene, heptane, cyclohexane and hexane, more preferably toluene.

The above process can be represented stepwise as shown below:

The process of the invention is illustrated with reference to the following Examples and is not intended to limit the scope of the invention. Any permutations and modifications in the process are possible without limiting the scope of the invention.

Example 1:
Preparation of N-[4-(heptafluropropyl)-2-methylphenyl] acetamide of formula III:
Process: A

4-(heptafluoropropyl)-2-methylaniline (276gm 1.0 mole) was charged in Methylene chloride (300ml). Acetylating Mixture was prepared by mixing acetic anhydride (104gm, 1.02 moles) and H2SO4 (0.2gm) to the above mixture. This acetylating mixture was added in the above reaction mixture at 40°C & maintained at 40°C for about 1 hr. After completion of reaction, reaction mass was neutralized using 20% sodium hydroxide solution by adjusting pH between 6.5 to 8.5. Product was extracted in methylene chloride and solvent was distilled out under reduced pressure.
% Purity = 95 %
Yield = 94%

Process: B

4-(heptafluoropropyl)-2-methylaniline (276gm, 1.0 mole) was charged in Methylene chloride (300ml). Acetylating Mixture was prepared by mixing acetic anhydride (104gm1.02 mole) and H2SO4 (0.2gm) to the above mixture. This acetylating mixture was added in the above reaction mixture at 40°C and maintained at 50°C for 1.0 hr. After completion of reaction, reaction mass neutralized by using 20% sodium hydroxide solution and pH was adjusted between 6.5 to 8.5. Product was extracted in methylene chloride and solvent was distilled out under reduced pressure.
% Purity = 97%
Yield = 93%

Process: C

4-(heptafluoropropyl)-2-methylaniline (276gm, 1.0 mole) and potassium carbonate (200gm) were charged in methylene chloride & dimethylformamide mixture (300ml). Phase transfer catalyst Tetrabutylammonium bromide (1gm) was added to the above reaction mixture. Acetyl chloride (118gm, 1.50 moles) was added at 40°C within 2 hours in the reaction mixture. Reaction was maintained at 50°C for about 1 hr. After the completion of reaction (as indicated by the disappearance of starting material on TLC), water (200gm) was added to the mixture. The separated solid was filtered, washed with water (2x 10 ml) and dried. The crude product on recrystallization from isopropyl alcohol gave pure N-[4-(heptafluropropyl)-2-methylphenyl] acetamide.
% Purity = 97% ; Yield = 92.37 %
Example 2:
Preparation of N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl]acetamide of formula (IV)
Process A:

N-[4-(heptafluropropyl)-2-methylphenyl]acetamide(318gm,1.0 mole ) was dissolved in acetonitrile (500ml).To the solution was added N-bromoacetamide or N-bromosuccinimide (NBS) (180gm,1.02 mole ) and azobisisobutyronitrile (AIBN) (2.5gm) at room temperature. The reaction mass was heated to 40°C for about 12 hrs. After completion of reaction acetonitrile was removed under reduced pressure. The crude product obtained was dissolved in methylene chloride and stirred to get clear solution. The solution was washed with water. The solvent was recovered by atmospheric distillation. Crude product obtained was crystallized in hexane and cooled to 0°C. It was then filtered to get pure N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide.
% Purity=95% ;
% Yield =91%

Process B:

Sodium bromate (152 gm, 1.01 mole) was dissolved in 500 ml water. To the clear solution was added solution of N-[4-(heptafluropropyl)-2-methylphenyl]acetamide (318 gm1.0 mole ) in ethyl acetate and stirred at room temperature. To the biphasic solution was added a solution of sodium bisulphate (75gm) in water (340ml) and maintaining temperature between 30 to 40°C over a period of 15 min. The reaction mass was stirred for about 8 hours at room temperature while it is exposed to UV light. Organic layer was separated and washed with 10% aqueous sodium bisulphate solution (2*100 ml) followed by water. It was dried and concentrated to remove ethyl acetate. The crude product obtained was purified by recrystallized in hexane to obtain N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide as solid having purity more than 95%.
% Yield = 84%

Process C:

N-[4-(heptafluropropyl)-2-methylphenyl] acetamide (318gm1.01 mole) was dissolved in 900 ml Methylene chloride and to this solution was added Bromine solution (90gm) and stirred at room temperature. The reaction mass was exposed to UV light. Organic layer was separated and washed with 10% aqueous sodium bisulphate solution (2*250 ml) followed by water (500 ml). It was dried and concentrated to remove methylene chloride. The crude product obtained was purified by recrystallization in Cyclohexane or heptanes to obtain obtain N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide as solid having purity more than 95%.
% Yield = 83.7%
Process D:

N-[4-(heptafluropropyl)-2-methylphenyl]acetamide (318gm,1.01 mole) was dissolved in 900 ml Methylene chloride and to this solution was added potassium bromide (130gm,1.09 mole ) in 150 ml water followed by hydrogen peroxide (30% 227 gm 2.0 mole ) at room temperature. To the reaction mixture was added concentrated sulphuric acid (140gm) over a period of 30 minutes at 20°C. The reaction mixture was stirred for 12 hrs. at 20°C while it was exposed to UV light. Organic layer was separated and washed with 10% aqueous sodium bisulphate (2*300 ml) solution followed by 500 ml water. The crude product was dried and concentrated to remove methylene chloride. The crude product obtained was purified by recrystallization in hexane to obtain N-[2-(bromomethyl)-4-(heptafluoropropyl)phenyl]acetamide as solid having purity more than 95% ; % Yield = 85%
Example 3:
Preparation of N-[4-(heptafluoropropyl)-(hydrazinylmethyl) phenyl) acetamide of formula (V)

Process: A
N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide (396gm 1.0 mole) was dissolved in 800ml Ethylene chloride, to which was charged 6.0 gm sodium iodide and to this solution was added hydrazine hydrate (75 gm, 1.5 mole ) within 1 hour with stirring followed by reflux for 3 to 4 hours. After completion of the reaction, the remaining hydrazine hydrate and the solvent were removed from the reaction mixture by distillation under reduced pressure to obtain a crude product. The resulting crude product was recrystallized from ethanol to obtain N-[4-(heptafluoropropyl)-2-(hydrazinylmethyl) phenyl]acetamide having purity more than 97% .
Yield: 94%.

Process: B
N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide (396 gm, 1.0 mole) was dissolved in 500 ml acetonitrile and to this solution was added (75 gm1.5 mole) of hydrazine hydrate within 1 hour with stirring. The reaction mass was maintained at 82°C for 12 hours. After completion of the reaction, the remaining hydrazine hydrate and the solvent were removed from the reaction mixture by distillation under reduced pressure to obtain a crude product. The resulting crude product was recrystallized from ethanol to obtain N-[4-(heptafluoropropyl)-2-(hydrazinylmethyl) phenyl] acetamide having purity greater than 97%.
Yield: 92%.

Example 4:
Preparation of N-(4-heptafluoropropyl)-2-(N-(pyridin-3-ylmethylene)
Hydrazinomethyl) -phenyl] acetamide (VI)

Process: A
N-[4-(heptafluoropropyl)-(hydrazinylmethyl) phenyl) acetamide (348gm,1.0 mole) was dissolved in 600 ml toluene and to this solution was added pyridine-3-carbaldehyde (202.28 gm,2.0 mole ) and heated to 65° to70°C to reflux for 10 hours under vacuum to remove water completely. Solvent was removed by vacuum distillation under vacuum form the reaction mixture. After completion of reaction, the resulting crude product was isolated by filtration to obtain N-(4-heptafluoropropyl)-2-(N-(pyridin-3-ylmethylene) Hydrazinomethyl) -phenyl] acetamide.
% Purity of the product = 97 %
% Yield = 98 %

Process: B
N-[4-(heptafluoropropyl)-(hydrazinylmethyl) phenyl) acetamide (348gm, 1.0 mole) was dissolved in 900 ml Methanol and to this solution was added pyridine-3-carbaldehyde (129gm, 1.2 mole) and sulphuric acid (0.5 gm). Reaction mixture was heated at 60°C for 8 hours. After completion of reaction, the resulting crude product was isolated by filtration to obtain N-(4-heptafluoropropyl)-2-(N-(pyridin-3-ylmethylene) Hydrazinomethyl) -phenyl] acetamide.
% Purity of the product = 96 %
% Yield = 90 %

Example 5:
Preparation of 1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one of formula (VII)

Process: A
N-(4-heptafluoropropyl)-2-(N-(pyridin-3-ylmethylene) Hydrazinomethyl) -phenyl] acetamide (437gm, 1.0 mole ) was dissolved in 1500 ml di-isopropyl ether and to this solution was added triethylamine (132gm,1.30 mole ) and then reaction mass was cooled to 10°C. To the above solution was charged methyl chloroformate solution (95gm) drop wise at 10°C to 20°C. After completion of addition temperature was slowly raised to 40°C. Reaction mixture was maintained at 40°C for 2 hours. After completion of reaction 1500 ml water was added. The product was extracted in di-isopropyl ether (3*500 ml). Organic layer was separated and washed with 500ml water. Finally organic layer was dried over anhydrous sodium sulphate. Solvent was removed by distillation under vacuum under reduced pressure. The resulting crude product was recrystallized in ethanol to obtain 1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one having purity of 95%.
% Yield= 87%
Process: B
N-(4-heptafluoropropyl)-2-{[(2E)-2-(pyridine-3-ylmethylidene) hydrazinyl] methyl} phenyl] acetamide (437gm,1.0 mole ) was dissolved in 1500ml toluene and to this solution was added triphosgene solution in Toluene (119gm in 119gm Toluene 0.40 mole) at 90°C within 3 hrs. After completion of reaction it was treated with water (1500 ml). The product was extracted in ethyl acetate (3*500 ml). Organic layer was separated and washed with saturated sodium chloride 500ml followed by water 500ml. Finally organic layer was dried over anhydrous sodium sulphate. Solvent was removed by distillation under vacuum under reduced pressure The resulting crude product recrystallized in methanol to obtain 1-acetyl-6- (heptafluoropropyl) - [(E)- (pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one having purity of 92% .
Wt. of the product = 422 gm.
% Yield= 91 %
Example 6:
Preparation of 1-acetyl-3-amino-6-(heptafluoropropyl)-3, 4-dihydroquinazolin-2-(1H)-one of formula (VIII)
Process: A

N-(4-heptafluoropropyl)-2-(hydrazinylmethyl) phenyl] acetamide (348 gm1.0 mole ) was dissolved in 1500 ml Toluene and to this solution was added Triphosgene solution in Toluene (119gm in 119gm Toluene, 0.40 mole ) at 90°C within 3 hrs. After completion of reaction, reaction mass was charged with 150ml methanol and lower boiling fraction was removed by isotropic distillation. The resulting crude product was recrystallized in methanol to obtain 1-acetyl-3-amino-6-(heptafluoropropyl)-3, 4-dihydroquinazolin-2-(1H)-one having purity of 95%.
% Yield= 90 %

Process: B

N-(4-heptafluoropropyl)-2-(hydrazinylmethyl) phenyl] acetamide (348gm, 1.0 mole) was dissolved in 1500 ml Di-isopropyl ether and to this solution was added triethylamine (121.10 gm, 1.20 mole) and then reaction mass was cooled to 0°C. To the above solution methyl chloroformate solution (95gm) was charged drop wise at 5 to 15°C. After completion of addition temperature was slowly raised to room temperature and reaction mass was maintained at room temperature for 3 hours. After completion of reaction, was added 1500 ml water. The product was extracted in ethyl acetate (3*500 ml). Organic layer was separated and washed with saturated sodium chloride 500 ml followed by washing with water 500 ml. Finally organic layer was dried over anhydrous sodium sulphate. Solvent was removed by distillation under vacuum under reduced pressure .The resulting crude product recrystallized in Methanol to obtain 1-acetyl-3-amino-6-(heptafluoropropyl)-3,4-dihydroquinazolin-2-(1H)-one having purity greater than 95% .
% Yield= 90 %

Example 7
Preparation of pyridine-3-carbaldehyde

3-cyanopyridine (150gm) was dissolved in water (540gm) and acetic acid (150gm) are mixed together in a stirring autoclave and to this solution was added moist Nickel catalyst (30 gm) in water (90 gm). Hydrogenation was carried out at under a constant hydrogen pressure of 2 bars. When consumption of hydrogen was ceased, the stirrer is switched off and the reaction mixture was neutralized by sodium hydroxide solution and pH of reaction mass was adjusted between 6.0 to 9.0. Catalyst was recovered by filtration and recycled no. of times. Aqueous layer 720 gm solution contains 20% Pyridin-3-Carbaldehyde and is taken as such for next reaction .This represents a yield of 93 % of theory.
Example 8:
Preparation of 1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one of formula (VII)
Process: A

1-acetyl-3-amino-6-(heptafluoropropyl)-3,4-dihydroquinazolin-2-(1H)-one (373 gm,1.0 mole) was dissolved in 900 ml toluene and to this solution was added pyridine-3-carbaldehyde (108gm1.07 mole ). Reaction mixture was heated to 70 °C for 3 hours to remove water completely under vacuum. Solvent was removed by vacuum distillation under vacuum. After completion of reaction, 1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one was isolated by filtration.
% Purity of the product = 97 %
% Yield = 95 %

Process: B
1-acetyl-3-amino-6-(heptafluoropropyl)-3, 4-dihydroquinazolin-2-(1H)-one (373gm 1.0 mole) was dissolved in 900 ml Methanol and to this solution was added pyridine-3-carbaldehyde (108 gm1.07 mole) and sulphuric acid (0.5 gm). Reaction mixture was heated up to reflux for 3 hours. After completion of reaction, 1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one was isolated by filtration. % Purity of the product = 97 %
% Yield = 90 %

Example 9:
Preparation of 1-acetyl-3, 4- dihydro -3- [(3-pyridinylmethyl) amino] -6- [1, 2, 2, 2-tetrafluoro-1-(trifluoromethyl) ethyl] -2(1H)-quinazolinone (Pyrifluquinazon) of formula (I)
Process A

1-acetyl-6-(heptafluoropropyl)- [(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin -2 (1H)-one (463gm,1.0 mole) was dissolved in 1300 ml of acetic acid and to this solution was added of 5% palladium charcoal (25gm) and potassium iodide (0.5gm). Hydrogenation was carried out at 4 to5 kg/cm3. After absorption of theoretical amount of hydrogen, the catalyst was filtered and recycled. Solvent was removed by distillation under reduced pressure. Resulting product was neutralized by adding 20% sodium hydroxide solution and extracted in Methylene Dichloride (3*100 ml). Separated organic layer was washed with saturated sodium chloride (500ml) followed by water (500 ml). Finally organic layer was dried over anhydrous sodium sulphate. Solvent was removed by distillation under reduced pressure. The resulting crude product was recrystallized in methanol to obtain 1-acetyl-3, 4-dihydro -3- [(3-pyridinylmethyl)amino] -6- [1,2,2,2-tetrafluoro-1-(trifluoromethyl) ethyl] -2(1H)-quinazolinone (Pyrifluquinazon) having purity greater than 95% .
% Yield = 88%.

Process B

Triethyl Ammonium formate was first prepared by charging 250 ml Toluene in Reactor and Formic acid (56 gm) in Toluene was added with stirring. Then Triethylamine (130 gm) was slowly added with Stirring for 0.5 hrs. and water was removed azeotropically.

1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one (463 gm, 1.0 mole) was charged into above prepared catalyst solution. Reaction mixture was refluxed until the component 1-acetyl-6-(heptafluoropropyl)-[(E)-(pyridine-3-ylmethylidene) amino]-3, 4-dihydroquinazolin-2(1H)-one is below 0.5%. Organic layer was washed with saturated sodium chloride 500 ml followed by water 500 ml. Finally organic layer was dried over anhydrous sodium sulphate. Solvent was removed by distillation under reduced pressure. The resulting crude product was recrystallized in Methanol to obtain 1-acetyl-3, 4-dihydro -3- [(3-pyridinylmethyl)amino] -6- [1,2,2,2-tetrafluoro-1-(trifluoromethyl) ethyl] -2(1H)-quinazolinone (Pyrifluquinazon) having purity greater than 95% .
% Yield = 89 %.

Example 10:
Preparation of N-(4-heptafluoropropyl)-2-(N-(pyridin-3-ylmethylene)
Hydrazinomethyl) -phenyl] acetamide (VI)

Process A
Acetonitrile 200 gm was charged in reaction flask at room temperature. To this was charged (133 gm 1.1 mole) Pyridin-3-yl-methylene-hydrazine at room temperature. CuI 2.0 gm was charged in the above reaction flask under stirring. N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide (396gm 1.0 mole) was charged in the above reaction at 40 °C within 2 to 3 hours and reaction was maintained at 80°C for 24 hours .After completion of reaction solvent was recovered under vaccum and product was recrystallized in methanol to get N-(4-heptafluoropropyl)-2-(N-(pyridin-3-ylmethylene)Hydrazinomethyl)-phenyl] acetamide.
having purity greater than 97%.
% Yield = 84%

Example 11:
Preparation of Pyridin-3-ylmethyl-hydrazine from 3-bromomethyl-pyridine of formula (XIII)

Process A
3-bromomethyl-pyridine (173 gm 1.0 mole) was reacted with 99% Hydrazine hydrate (100 gm 2.0 mole) in presence of Dimethyl sulfoxide (200 gm) and CuI (2.0 gm) in reaction flask under stirring at 40 to 45°C for about 2 to 3 hours and the reaction was maintained at 80°C for about 24 hours After completion of reaction solvent was recovered under vacuum and product was recrystallized in water to get Pyridin-3-ylmethyl-hydrazine having purity greater than 97%.
% Yield = 85%
Process B
N, N-Dimethylformamide 200 gm was charged in reaction flask at room temperature. To this was charged (100 gm 2.0 mole) 99% Hydrazine hydrate at room temperature. Copper iodide 2.0 gm was charged in reaction flask under stirring. 3-bromomethyl-pyridine (208gm 1.20 mole) was charged in the above reaction at 40 to 45°C within 2 to 3 hours and reaction was maintained at 80°C for 24 hours .After completion of reaction solvent was recovered under vacuum and product was recrystallized in water to get Pyridin-3-ylmethyl-hydrazine having purity of about 97%.
% Yield = 86 %
Example 12:
Preparation of N-[4-heptafluoropropyl-2-(N-pyridin-3-ylmethylhydrazinomethyl)-
Phenyl]-acetamide of formula (IX)

Process: A
N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide (396gm 1.0 mole) was dissolved in 800ml methylene chloride. To this was charged 2.0 gm copper chloride and to this solution was added pyridine-3-ylmethyl-hydrazine (154 gm, 1.25 mole) within 1 hour with stirring. Reaction mass was refluxed for 3 to 4 hours. After completion of the reaction, the solvent were removed from the reaction mixture by distillation to obtain a crude product. The resulting crude product was recrystallized from ethanol to obtain N-[4-heptafluoropropyl-2-(N-pyridin-3-ylmethylhydrazinomethyl)-
Phenyl]-acetamide having purity of about 97.5 %.
Yield: 88 %.
Process: B
N-[2-(bromomethyl)-4-(heptafluoropropyl) phenyl] acetamide (396gm 1.0 mole) was dissolved in 600ml Acetonitrile. To this was charged 2.0 gm copper chloride and to this solution was added pyridine-3-ylmethyl-hydrazine (154 gm, 1.25 mole) within 1 hour with stirring. Reaction mass was maintained at 50°C for 10 hours. After completion of the reaction, the solvent were removed from the reaction mixture by distillation under reduced pressure to obtain a crude product. The resulting crude product was recrystallized from methanol to obtain N-[4-heptafluoropropyl-2-(N-pyridin-3-ylmethylhydrazinomethyl)-Phenyl]-acetamide having purity 98.5%.
Yield: 80 %.

Example 13:
Preparation of 1-acetyl-3, 4- dihydro -3- [(3-pyridinylmethyl) amino] -6- [1, 2, 2, 2-tetrafluoro-1-(trifluoromethyl) ethyl] -2(1H)-quinazolinone (Pyrifluquinazon) of formula (I)
Process: A

N-[4-heptafluoropropyl-2-(N-pyridin-3-ylmethylhydrazinomethyl)-Phenyl]-acetamide (438 gm1.0 mole ) was dissolved in 1100 ml Toluene and to this solution was added Triphosgene solution in Toluene (178 gm in Toluene,0.60 mole ) at 90°C within 3 hrs. After completion of reaction, reaction mass was charged 300 ml methanol and lower boiling fraction was removed by isotropic distillation. The resulting crude product was recrystallized in methanol to obtain 1-acetyl-3, 4- dihydro -3- [(3-pyridinylmethyl) amino] -6- [1, 2, 2, 2-tetrafluoro-1-(trifluoromethyl) ethyl] -2(1H)-quinazolinone (Pyrifluquinazon) having purity of about 95%.
% Yield= 88 %

Process: B

N-[4-heptafluoropropyl-2-(N-pyridin-3-ylmethylhydrazinomethyl)-Phenyl]-acetamide (438 gm1.0 mole) was dissolved in 1200 ml 2-methyl tetrahydrofuran and to this solution was added triethylamine (121 gm, 1.20 mole) and then reaction mass was cooled to 10°C. To the above solution methyl carbonochloridate solution (95gm) was charged drop wise at 10 ° to15°C. After completion of addition temperature was slowly raised to 45° to50°C and reaction mass was maintained at room temperature for 3 hours. After completion of reaction, it was treated with water (1000ml).The product was extracted in butyl acetate (3*500 ml). Organic layer was washed with 500ml water. Finally organic layer was dried over anhydrous sodium sulphate. Solvent was removed by distillation under vacuum under reduced pressure. The resulting crude product recrystallized in ethanol to obtain 1-acetyl-3, 4- dihydro -3- [(3-pyridinylmethyl) amino] -6- [1, 2, 2, 2-tetrafluoro-1-(trifluoromethyl) ethyl] -2(1H)-quinazolinone (Pyrifluquinazon) having purity of about 96%.
% Yield= 87 %