HU211068B - Process for the preparation of substituted d,l-2-(7-fluoro-3,4-dihydro-3-oxo-2h-1,4-benzoxazin-6-yl)-perhydroimidazo[1,5-a]pyridine-1,3-diones - Google Patents

Abstract

Process for the preparation of compounds of formula (I), in which R1 is alkyl, alkenyl or alkynyl, via formulas (II), (III), (V), (VI), (VII), (IX), (XI) and (XII). New intermediates of formulas (V), (VI), (VII), (IX) and (XI).

Description

Scope of the description: 10 pages (including 5 sheets)

HU 211 068 B

The present invention relates to substituted D, L-2- (7-fluoro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) perhydroimidazo [I, 5-a] pyridine-1,3-dione derivatives

R ¹ is C 1-6 alkyl, C 2-6 alkenyl or C 3-6 alkynyl.

The compounds of formula I have a broad spectrum herbicidal activity against monocotyledonous and dicotyledonous weeds in agricultural crops. Their preparation and use are described in EP 311 135.

Known syntheses from 2-nitro-5-fluorophenol yielded the compounds of formula I in 6 steps with a final yield of 26%. These syntheses lead through the highly insoluble 7-fluoro-2H-benzoxazin-3 (4H) -one derivatives. For example, the intermediate 7-fluoro-6-amino-2H-1,4-benzoxazin-3 (4H) -one is poorly soluble in many solvents so that this material, which is obtained by catalytic hydrogenation harmful to the environment, can only be separated at great difficulty from the catalyst. A further disadvantage of this process is that the synthesis takes place via an isocyanate intermediate, the preparation of which requires phosgene or triphosgene on the one hand, and further reactive groups on the molecule may be only very limited. The consequence is that the sometimes very costly R ¹ group must be introduced before the isocyanate step, which significantly increases the final product. Therefore, from an industrial point of view, this process is not very suitable for large scale production.

The known procedures are illustrated in Scheme A below.

It is an object of the present invention to provide a novel process which allows the compounds of formula (I) to be prepared without any difficulty on an industrial scale and under mild reaction conditions while avoiding the above disadvantages.

This objective is achieved by a method. during which:

i) reacting 2-amino-5-fluorophenol of formula (II) with acetyl chloride or acetic anhydride in the presence of an acid acceptor in a suitable solvent, and (ii) reacting the resulting anilide of formula (III) with a compound of formula (IV). wherein R ⁴ is hydrogen or C 1-4 alkyl, Y is halogen, methanesulfonyl oxy or p-toluenesulfonyloxy, and iii) the compound of formula V thus obtained in formula R ⁴ the above mentioned nitric acid or its inorganic or organic derivative is nitrated in a suitable solvent, and iv) hydrogenation of the resulting phenoxyacetic acid of formula VI, wherein R ⁴ is hydrogen, is carried out with hydrogen in the presence of a suitable catalyst in an inert solvent or reducing with a chemical reducing agent in the presence of an inert solvent, and

v) reacting the resulting phenoxyacetic acid of formula VII wherein R ⁴ is as defined above with a compound of formula Vili wherein X is halogen, nitro or cyano, n is an integer from 0 to 5; - a suitable inert solvent, by addition of an organic or inorganic acid binding agent, and vi) the resulting phenoxyacetic acid of formula IX wherein R ⁴ , X and n are as defined above, is piperidine-2 of formula X; reacting with a carboxylic acid derivative, wherein R ² is hydrogen, methyl or ethyl in an inert solvent, optionally by adding an organic or inorganic acid binding agent, and vii) the hydantoin of formula XI in the formula wherein R ⁴ is as defined above for ring closure. , optionally in the presence of an acid or base, by simultaneously cleaving the acetyl group, and finally viii) the corresponding benzoxazinone of formula (XII) is reacted with a compound of formula (XIII) wherein R ¹ is as defined above, W is chloro, bromo, iodo, p-toluenesulfonyl-oxy or methanesulfonyloxy; , optionally by adding a base in a suitable solvent.

Although the process according to the invention requires 8 steps, two more than its known methods, surprisingly, the final yield is twice the known method.

The reaction step (i) is generally carried out by reacting the starting materials with or without a solvent, optionally by adding an organic or inorganic base at a temperature of from 0 to 150 ° C. The reaction is preferably carried out in a biphasic mixture, for example water-methyl isobutyl ketone.

Suitable bases include alkali metal or alkaline earth metal hydroxides, carbonates and / or hydrogen carbonates, tertiary aliphatic amines, and heterocyclic bases. Examples include sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, triethylamine or pyridine.

Suitable solvents include hydrocarbons such as toluene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether or tetrahydrofuran, alcohols such as methanol or ethanol, ketones such as acetone, butanone or methyl isobutyl ketone, or nitriles. such as acetonitrile and biphasic mixtures with water.

Generally, step ii) is carried out by reacting the starting materials in an inert solvent, optionally by adding an inorganic or organic base at 0-150 ° C, preferably at the boiling point of the solvent.

Suitable bases include alkali metal or alkaline earth metal hydroxides, carbonates and / or hydrogen carbonates, tertiary aliphatic amines, and heterocyclic bases. Examples include sodium or potassium hydroxide, sodium or potassium carbonate, sodium or potassium bicarbonate, triethylamine or pyridine.

Suitable solvents include water,

Hydrocarbons such as toluene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether or tetrahydrofuran, alcohols such as methanol, ethanol or isopropanol, ketones such as acetone, butanone or methyl isobutyl ketone, or nitriles such as acetonitrile. Biphasic mixtures of water and a water-immiscible solvent may also be used using a phase transition catalyst.

The resulting 2- (2-acetamido-5-fluorophenoxy) acetic acid derivatives are novel compounds.

Generally, step (iii) can be carried out according to known procedures for the nitration of phenyl ethers, such as, for example, Houben-Weyl, X / l. Volume 566, p.

Nitration of aromatic compounds in sulfuric acid, with sulfuric acid / nitric acid mixtures, has proven to be applicable during cooling.

The resulting 2- (2-acetamido-5-fluoro-4-nitrophenoxy) acetic acid derivatives are novel compounds.

Process step iv) is generally carried out by methods known in the art for reducing aromatic nitro groups, as described, for example, in Houben-Weyl, XI / 1. Volume 360, p.

It is particularly preferred to carry out the hydrogenation using hydrogen in a suitable solvent in the presence of a catalyst

Suitable solvents include water, hydrocarbons such as toluene, xylene or hexane, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether, diisopropyl ether, dioxane or tetrahydrofuran, alcohols such as methanol, ethanol or isopropanol. , ethers such as ethyl acetate or carboxamides such as dimethylformamide.

Known hydrogenation catalysts are known as catalysts. Examples include Raney nickel, palladium or platinum oxide

The process can be carried out at a wide temperature range of ΟΙ50 'C, preferably 20-100 ′ C. The reaction can be carried out under normal pressure, but elevated pressure may be employed.

The reduction may also be carried out under liquid conditions, for example using iron powder in dilute acetic acid, in the presence of glacial acetic acid and ethyl acetate.

The resulting 2- (2-acetamido-4-amino-5-fluorophenoxy) acetic acid derivatives are novel.

Process step v) is generally carried out by reacting the starting materials in a suitable solvent, optionally by adding an inorganic or organic base at 0-50 ° C. The reaction is preferably carried out in a biphasic mixture consisting of water and a water-immiscible organic solvent, optionally in the presence of a phase transition catalyst.

Suitable bases include alkali metal or alkaline earth metal hydroxides, carbonates and / or hydrogen carbonates, tertiary aliphatic amines, and heterocyclic bases. These include, for example, sodium or potassium hydroxide, sodium or potassium bicarbonate, calcium carbonate, magnesium oxide, triethylamine and pyridine.

Suitable solvents include hydrocarbons such as toluene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether or tetrahydrofuran, and ketones such as acetone, butanone or methyl isobutyl ketone.

The resulting 2- [2-acetamido-5-fluoro-4- (phenoxycarbonylamino) phenoxy] acetic acid derivatives are novel.

Process step vi) is generally carried out by reacting the starting materials in a suitable solvent at 20-130 ° C, optionally with an inorganic or organic base.

Suitable bases include alkali metal or alkaline earth metal hydroxides, carbonates and / or hydrogen carbonates, tertiary aliphatic and aromatic amines, and heterocyclic bases. Examples of these include sodium or potassium hydroxide, potassium t-butanolate, sodium or potassium bicarbonate, triethylamine and pyridine.

Suitable solvents include hydrocarbons such as toluene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether or tetrahydrofuran, ketones such as acetone, butanone or methyl isobutyl ketone, and nitriles such as acetonitrile.

The resulting 2- [2-acetamido-5-fluoro-4- (phenoxycarbonylamino) phenoxy] acetic acid derivatives are novel

It is known, for example, from EP 272 594, that hydantoin can be prepared from α-aminocarboxylic acid esters and isocyanates. The disadvantage of this process is that phosgene or triphosgene should be used to prepare the corresponding isocyanate. Furthermore, in the known methods there can be no further reactive groups in the molecule since the corresponding isocyanate cannot be produced.

The process of the present invention also allows the preparation of hydantoins having additional functional groups, such as compounds of formula XI, to avoid the use of phosgene or triphosgene.

The resulting 2- [5-acetamido-4- (carbonylmethoxy) -2-fluorophenyl] -perhydroimidazo [1,5-a] pyridine-1,3-dione derivatives are novel.

Process step vii) is generally carried out by reacting the starting materials in a suitable inert solvent, optionally by adding an inorganic or organic acid at a temperature of 20-150 ° C, preferably at the boiling point of the solvent. However, the reaction can also be carried out without the use of an additional separate solvent in a process in which, for example, the starting materials are directly dissolved in the appropriate acid or in a mixture thereof.

The inorganic acid may be hydrochloric acid or sulfuric acid, the organic acid may be acetic acid or p-toluenesulfonic acid.

Suitable solvents include a hydrocarbon such as hexane, cyclohexane, toluene or xylene, or a chlorinated hydrocarbon such as methylene chloride or 1,2-dichloroethane.

Process step viii) is generally carried out by treating the starting materials in a suitable solvent, optionally an inorganic or organic base.

The solution was dissolved in 20 ml of acetic acid and 6 ml of 20% sulfuric acid solution was added. The mixture was refluxed for 2 hours. After cooling, it is poured into 50 ml of ice water and extracted three times with ethyl acetate. The combined organic phases are washed twice with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from diisopropyl ether.

Yield: 1.9 g (98%).

Melting point: 220-222'C. viii) a procedural step

D, L-2- (7-Fluoro-3,4-dihydro-3-oxo-4- (2-propynyl) 2H-1,4-benzoxazin-6-yl) perhydroimidazo [1,5a] pyridine-1 , 3-dione

1.0 g of D, L-2- (7-fluoro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) perhydroimidazo [1,5-a] pyridine-1,3-dione A mixture of 0.4 g of potassium carbonate and 0.5 g of 3-bromopropine in 20 ml of dimethylformamide was heated to 60 ° C for 5 hours. The solvent was removed in vacuo and the residue was taken up in 30 ml of 2N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined organic phases are washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol.

Yield: 1.0 g (90%).

Melting point: 204 ° C.

Claims (2)

PATIENT PERSONALITY Procedure for Substituted D, L-2- (7-Fluoro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) perhydroimidazo [1,5-a] pyridine-1 For the preparation of 3-dione derivatives in the formula R ¹ is C 1-6 alkyl, C 2-6 alkenyl or C 3-6 alkynyl, characterized in that i) reacting 2-amino-5-fluorophenol of formula (II) with acetyl chloride or acetic anhydride in the presence of an acid acceptor in a suitable solvent, and (ii) reacting the resulting anilide of formula (III) with a compound of formula (IV); wherein ^R4 is hydrogen or C1-4 alkyl, Y is a halogen atom, a methane sulfonyl oxivagy p-toluene sulfonyloxy group, and iii) the compound thus obtained (V) wherein R ⁴ is as defined above - with nitric acid or nitrating organic derivative thereof, optionally in a suitable solvent, and iv) reacting (VI) phenoxyacetic acid of the formula: - wherein R ⁴ is hydrogenated as described above with hydrogen in an inert suitable catalyst in a solvent or a chemical reducing agent is reduced in an inert solvent in the presence of, and v) reacting the resulting phenoxyacetic acid of formula VII wherein R ⁴ is as defined above with a compound of formula VIII wherein X is halogen, nitro or cyano, n is from 0 to 5; an integer in an appropriate inert solvent, optionally by addition of an organic or inorganic acid binding agent; and vi) the resulting phenoxyacetic acid of formula IX wherein R ⁴ , X and n are as defined above, is a piperidine of formula X Reacting with a 2-carboxylic acid derivative wherein R ² is hydrogen, methyl or ethyl in an inert solvent, optionally by adding an organic or inorganic acid binding agent, and vii) the hydantoin of formula XI thus obtained in the formula R ⁴ is as defined above. - subjecting to ring closure, optionally in the presence of an acid or base, the acetyl group is simultaneously cleaved and (viii) reacting the corresponding benzoxazinone of formula (XII) with a compound of formula (XIII) wherein R ¹ is as defined in the formula, W is chloro, bromo, iodo, p-toluenesulfonyl- oxy or methanesulfonyloxy, optionally by adding a base in a suitable solvent. HU 211 068 Β is reacted at -10 ° C to 150 ° C. The reaction may also be carried out in an aqueous two-phase system using a phase transition catalyst. Suitable bases include alkali metal or alkaline earth metal hydroxides, carbonates and / or hydrogen carbonates, tertiary aliphatic amines, and heterocyclic bases. These include, for example, sodium or potassium hydroxide, sodium or potassium bicarbonate, sodium hydride, triethylamine and pyridine. Suitable solvents include hydrocarbons such as toluene, chlorinated hydrocarbons such as methylene chloride or chloroform, ethers such as diethyl ether or tetrahydrofuran, ketones such as acetone, butanone or methyl isobutyl ketone, carboxamides such as dimethylformamide and nitriles. such as acetonitrile. The compounds of formulas (I), (XI) and (XII) are optically active. Preferably, the compounds may be present as pure enantiomers or mixtures thereof. The invention is illustrated by the following non-limiting examples. i) a procedural step N- (4-Fluoro-2-hydroxyphenyl) acetamide g 5-Fluoro-2-aminophenol was dissolved in 500 ml of ethanol and 84 g of acetic anhydride was added dropwise. The mixture was stirred for 1 hour at room temperature, when the product partially crystallized. The crystals were filtered, suction filtered and the residue concentrated in vacuo. The residue was then washed with hexane and dried in vacuo. Yield: 115 g (89%). Melting point: 174-176 ° C. ii) a procedural step Ethyl 2- (2-acetamido-5-fluorophenoxy) acetic acid g N- (4-Fluoro-2-hydroxyphenyl) acetamide is dissolved in 2 L of methyl isobutyl ketone and 80 g of potassium carbonate and 71 g of ethyl chloroacetic acid were added. The mixture was refluxed for 3 hours and then cooled to room temperature. The precipitated salts were filtered and suction filtered, and the filtrate was concentrated in vacuo and the oily residue was stirred with warm hexane. The crystals were filtered, suction filtered and dried under vacuum. Yield: 119 g (99%). Melting point: 71 'C. iii) a procedural step 2- (2-acetamido-5-fluoro-4-nitro-phenoxy) -acetic acid ethyl ester 300 g of ethyl 2- (2-acetamido-5-fluorophenoxy) acetic acid were dissolved in 1200 g of 96% concentrated sulfuric acid at 10-15 ° C. The solution was cooled to 0 ° C and a mixture of 120 g of concentrated nitric acid (65%) and 240 g of concentrated sulfuric acid (96%) was slowly added. The mixture was stirred for 60 minutes at 0 ° C and then poured into 3 L of ice water. Extract several times with dichloromethane, wash the combined organic phases with neutral sodium bicarbonate solution and remove the solvent in vacuo. The residue was triturated with 50 ° C of methyl t-butyl ether. Yield: 331 g (94%). Melting point: 114 ° C. iv) a procedural step 2- (2-acetamido-4-amino-5-fluoro-phenoxy) -acetic acid ethyl ester 100 g of ethyl 2- (2-acetamido-5-fluoro-4-nitrophenoxy) acetic acid were dissolved in 660 ml of ethyl acetate and 5 g of palladium on carbon was added. The mixture was hydrogenated for 7 hours at 40 ° C under 50 mbar hydrogen until no more hydrogen was added. The catalyst was filtered off, filtered off and the solvent removed in vacuo. Yield: 89 g (99%). 95 ° C. v) a procedural step 2- [2-Acetamido-5-fluoro-4- (phenoxycarbonylamino) phenoxy] acetic acid ethyl ester To a mixture of 120 ml of water and 60 ml of dichloromethane was added 0.6 g of magnesium oxide and 50.0 g of ethyl 2- (2-acetamido-4-amino-5-fluorophenoxy) acetic acid. A solution of 2.9 g of phenyl chloroformate in dichloromethane (10 ml) was added dropwise over 20 minutes at room temperature. The mixture was stirred for 4 hours at room temperature and allowed to stand overnight. Dilute with 150 ml of water, separate the phases and extract three times with dichloromethane. The combined organic phases are washed with water, dried over magnesium sulfate and concentrated in vacuo. The solid was triturated with diisopropyl ether. Yield: 6.2 g (86%). Melting point: 12-130 ° C. vi) a procedural step D, L-2- [5-acetamido-4- (ethoxycarbonylmethoxy) -2-fluorophenyl] perhydroimidazo [1,5-a] pyridine-1,3-dione in 30 ml of tetrahydrofuran 2.1 g of potassium 5,8 g of ethyl 2- [2-acetamido-5-fluoro-4- (phenoxycarbonylamino) phenoxy] acetic acid are added. A solution of 2.9 g of piperidine-2-carboxylic acid ethyl ester in 10 ml of tetralofofuran was added dropwise over 1 hour and the mixture was stirred for 1 hour. The reaction mixture was cooled and added to 30 ml of 2N hydrochloric acid, the phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases are washed twice with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from diisopropyl ether. Yield: 5.1 g (84%). Melting point: 177-179'C. vii) procedural step D, L-2- (7-Fluoro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl) perhydroimidazo [1,5-a] pyridine-1,3-dione 2 , 5 g of D, L-2- [5-acetamido-4- (ethoxycarbonylmethoxy) -2-fluorophenyl / perhydroimidazo [1,5-a] pyridin-1,3-di4 I) REACTION SCHEME f / h / toluene hno ₃ / h ₂ so ₄ 89% NqHCO 75% ^r / NoH / DMf 80% EN 211 068 Int. Cl. ⁶ : C 07 D 471/04 THE REACTION SCHEDULE / CONTINUATION / (II) EN 211 068 Int Cl. ⁶ : C 07 D 471/04 (III) H A (IV) ^{1 0} R ⁴ NH (VI) EN 211 068 Int Cl. ⁶ : C 07 D 471/04 (VII) (VIII) (jx) (X) EN 211 068 Int Cl. ⁶ : C 07 D 471/04 (XI) (XII) R ¹ - W I Χ1Π) Published by the National Inventory Office, Budapest Responsible for release: Gyurcsekné Philipp Clarisse Head of Division ARCANUM Databases - BUDAPEST