WO1993019065A1 - Process and intermediates 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

Process and intermediates 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 Download PDF

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WO1993019065A1
WO1993019065A1 PCT/EP1993/000598 EP9300598W WO9319065A1 WO 1993019065 A1 WO1993019065 A1 WO 1993019065A1 EP 9300598 W EP9300598 W EP 9300598W WO 9319065 A1 WO9319065 A1 WO 9319065A1
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general formula
hydrogen
optionally
acid
alkyl
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PCT/EP1993/000598
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French (fr)
Inventor
Michael Ganzer
Reinhold Puttner
Hartmut Seba
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Schering Aktiengesellschaft
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Priority to EP93906536A priority Critical patent/EP0631579A1/en
Priority to JP5516237A priority patent/JPH07504671A/en
Publication of WO1993019065A1 publication Critical patent/WO1993019065A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/58—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • This invention relates to a process and intermediates for the preparation of substituted D,L-2-(7-fluoro- 3,4-dihydro-3-oxo-2H-l,4-benzoxazin-6-yl)perhydro- imidazo[l,5-a]pyridine-l,3-diones of general formula I
  • R 1 is C ⁇ Cg-al yl, C 2 -C 6 -alkenyl or C 3 -C 6 -alkynyl.
  • the compounds of formula I have herbicidal activity against a broad spectrum of monocotyledonous and dicotyledonous weeds in agricultural crops. Their preparation and use are described in EP 311 135.
  • 6-amino-2H-l,4-benzoxazin-3 (4H)-one is not very soluble in a number of solvents, so that the compound, which is obtained by an environmentally damaging catalytic hydrogenation, can be separated from the catalyst only under great difficulty.
  • This process has the further disadvantage that the synthesis goes via an isocyanate intermediate, whose preparation on the one hand involves phosgene or triphosgene and on the other hand the presence of further reactive groups in the molecule is only very limited.
  • This has the consequence that the introduction of the sometimes very expensive group R 1 must be introduced before the isocyanate step which make the preparation of the end product considerably more expensive. From the industrial viewpoint this process is therefore not particularly suitable for a large scale production.
  • the object of the present invention is to provide a new process which allows preparation of compounds of general formula I without any problems on an industrial scale, and under mild reaction conditions, whilst avoiding the stated disadvantages.
  • acetyl chloride or acetic anhydride is reacted with acetyl chloride or acetic anhydride, in the presence of an acid binding agent, optionally in a suitable solvent.
  • R 4 is hydrogen or C 1 -C 4 -alkyl and Y is halogen, methanesulfonyloxy or p-toluenesulfonyloxy,
  • phenoxyacetic acid, so formed, of general formula V is nitrated with nitric acid, or an organic or inorganic derivative thereof, optionally in a suitable solvent,
  • H is hydrogenated with hydrogen, in the presence of a suitable catalyst in an inert solvent, or reduced with a chemical reducing agent in the presence of an inert solvent,
  • X is halogen, nitro or cyano and n is an integer of 0 to 5, in a suitable inert solvent, optionally with the addition of an organic or inorganic acid binding agent,
  • R 2 is hydrogen, methyl or ethyl, in an inert solvent, optionally with the addition of an organic or inorganic acid binding agent,
  • R- - XIII in which R 1 has the meaning given in formula I and W is chlorine, bromine, iodine, p-toluenesulfonyloxy or methanesulfonyloxy, optionally with the addition of a base in a suitable solvent.
  • Process step a) is generally carried out by reacting the starting materials with or without a solvent, optionally with the addition of an inorganic or organic base at a temperature between 0 and 150°C.
  • the reaction also can optionally be carried out in a two phase mixture, for example water-methyl isobutyl ketone.
  • Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic amines, as well as heterocyclic bases. Examples include sodium and potassium hydroxide, sodium and potassium carbonate, sodium and potassium hydrogen carbonate, triethyla ine and 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, and nitriles, such as acetonitrile, and also two phase mixtures with water.
  • 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
  • nitriles such as acetonitrile
  • Process step b) is generally carried out by reacting the starting materials in an inert solvent, optionally with the addition of an inorganic or organic base at a temperature between 0 and 150°C, preferably at the boiling point of the solvent.
  • Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic amines, as well as heterocyclic bases. Examples include sodium and potassium hydroxide, sodium and potassium carbonate, sodium and potassium hydrogen carbonate, triethylamine and 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, and nitriles, such as acetonitrile.
  • 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
  • Two phase mixtures with water and a water immiscible organic solvent can be used with the addition of a phase transfer catalyst.
  • Process step c) can generally be carried out according to known processes for nitration of phenyl ethers, as described for example in Houben- eyl, Vol. X/l, page 566 ff. Nitration of the aro atics in sulfuric acid solution by adding sulfuric acid/nitric acid mixtures with cooling has been proved.
  • Process stage d) is generally carried out according to known processes for reduction of an aromatic nitro group, for example as described in Houben-Weyl, Vol. XI/1, page 360 ff.
  • Hydrogenation with hydrogen in a suitable solvent in the presence of catalyst is particularly preferred.
  • 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, esters such as ethyl acetate, or also carboxamides, such as dimethylformamide.
  • 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
  • esters such as ethyl acetate
  • carboxamides such as dimethyl
  • catalysts there can be used known hydrogenation catalysts. Examples are Raney-nickel, palladium or platinum oxide.
  • the process can be carried out over a wide temperature range from 0 to 150°C, preferably from 20°C to 100°C.
  • the reaction can be carried out under normal pressure but higher pressures can be used.
  • the reduction may also be 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-fluoro- phenoxy)acetic acid derivatives are new.
  • Process step e) is generally carried out by reacting the starting materials in a suitable solvent, optionally with the addition of an inorganic or organic base at a temperature between 0 and 50°C.
  • the reaction can also optionally be carried out in a two phase mixture with water and a water immiscible organic solvent optionally with the addition of a phase transfer catalyst.
  • Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic amines as well as heterocyclic bases. Examples include sodium and potassium hydroxide, sodium and potassium hydrogen carbonate, 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.
  • 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.
  • Process step f) is generally carried out by reacting the starting materials in a suitable solvent, at a temperature between 20 and 130°C, optionally with the addition of an inorganic or organic base.
  • the reaction time is from 0.5 to 10 hours.
  • Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic and aromatic amines as well as heterocyclic bases. Examples include sodium and potassium hydroxide, potassium tert.-butanolate, sodium and potassium hydrogen carbonate, 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.
  • 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
  • nitriles such as acetonitrile.
  • hydantoin can be formed from ⁇ -aminocarboxylic acid esters and isocyanates, see for example EP 0 272 594.
  • the disadvantage is -that the preparation of the corresponding isocyanate involves phosgene or triphosgene. Further in the known processes the presence of further reactive groups in the molecule is not possible since the corresponding isocyanate cannot be prepared.
  • the process of the invention allows the preparation of hydantoins with further functional groups, as contained in compounds of general formula XI, where also the use of phosgene or triphosgene can be avoided.
  • Process step g) is generally carried out by reacting the starting materials in a suitable inert solvent, optionally with the addition of an inorganic or organic acid at a temperature between 20 and 150°C, preferably at the boiling point of the solvent. It can also however be carried out in the absence of additional solvent, in a process in which for example, the starting materials are dissolved directly in the appropriate acid or their mixtures.
  • inorganic acids are hydrochloric acid and sulfuric acid and of organic acids are acetic acid or p-toluenesulfonic acid.
  • Suitable solvents include hydrocarbons such as hexane, cyclohexane, toluene or xylene, and chlorinated hydrocarbons, such as methylene chloride or 1,2-dichloroethane.
  • Process step h) is generally carried out by reacting the starting materials in a suitable solvent, optionally with the addition of an inorganic or organic base at a temperature between -10 and 150°C.
  • the reaction can also be carried out in a two phase system with water using a phase transfer catalyst.
  • Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic amines as well as heterocyclic bases. Examples include sodium and potassium hydroxide, sodium and potassium hydrogen carbonate, 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.
  • 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
  • nitriles such as acetonitrile.
  • the compounds of general formulae I, XI and XII are optically active.
  • the compounds can optionally be present as pure enantiomers or as their mixtures.

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

PROCESS AND INTERMEDIATES FOR THE PREPARATION OF SUBSTITUTED D,L-2-(7-FLUORO-3, -DIHYDRO-3-OXO-2H-1,^-BENZOXAZIN-6-YL)- PERHYDROIMIDAZO l,5-A/PYRIDINE-l, 3-DIONES
This invention relates to a process and intermediates for the preparation of substituted D,L-2-(7-fluoro- 3,4-dihydro-3-oxo-2H-l,4-benzoxazin-6-yl)perhydro- imidazo[l,5-a]pyridine-l,3-diones of general formula I
Figure imgf000003_0001
in which R1 is C^Cg-al yl, C2-C6-alkenyl or C3-C6-alkynyl.
The compounds of formula I have herbicidal activity against a broad spectrum of monocotyledonous and dicotyledonous weeds in agricultural crops. Their preparation and use are described in EP 311 135.
The known syntheses starting from 2-nitro-5-fluorophenol give, over 6 stages, a total yield of 26% of I. These go via the highly insoluble 7-fluoro-2H-benzoxazin-3 (4H)-one derivatives. For example the intermediate 7-fluoro-
6-amino-2H-l,4-benzoxazin-3 (4H)-one is not very soluble in a number of solvents, so that the compound, which is obtained by an environmentally damaging catalytic hydrogenation, can be separated from the catalyst only under great difficulty. This process has the further disadvantage that the synthesis goes via an isocyanate intermediate, whose preparation on the one hand involves phosgene or triphosgene and on the other hand the presence of further reactive groups in the molecule is only very limited. This has the consequence that the introduction of the sometimes very expensive group R1 must be introduced before the isocyanate step which make the preparation of the end product considerably more expensive. From the industrial viewpoint this process is therefore not particularly suitable for a large scale production.
The known process is as follows
phosgene/toluene
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
The object of the present invention is to provide a new process which allows preparation of compounds of general formula I without any problems on an industrial scale, and under mild reaction conditions, whilst avoiding the stated disadvantages.
This object is solved by a process in which a) 2-amino-5-fluorophenol of formula II
is reacted with acetyl chloride or acetic anhydride, in the presence of an acid binding agent, optionally in a suitable solvent.
b) the acetanilide, so formed, of formula III
Figure imgf000005_0002
H
is reacted with a compound of general formula IV
0
R4^0 ^Y IV
in which R4 is hydrogen or C1-C4-alkyl and Y is halogen, methanesulfonyloxy or p-toluenesulfonyloxy,
c) the phenoxyacetic acid, so formed, of general formula V
Figure imgf000006_0001
is nitrated with nitric acid, or an organic or inorganic derivative thereof, optionally in a suitable solvent,
d) the phenoxyacetic acid, so formed, of general formula VI
O
Figure imgf000006_0002
H is hydrogenated with hydrogen, in the presence of a suitable catalyst in an inert solvent, or reduced with a chemical reducing agent in the presence of an inert solvent,
e) the phenoxyacetic acid, so formed, of general formula VII
O
Figure imgf000006_0003
is reacted with a compound of general formula VIII
Figure imgf000006_0004
in which X is halogen, nitro or cyano and n is an integer of 0 to 5, in a suitable inert solvent, optionally with the addition of an organic or inorganic acid binding agent,
f) the phenoxyacetic acid, so formed, of general formula IX
Figure imgf000007_0001
is reacted with a piperidine-2-carboxylic acid derivative of general formula X
Figure imgf000007_0002
in which R2 is hydrogen, methyl or ethyl, in an inert solvent, optionally with the addition of an organic or inorganic acid binding agent,
g) the hydantoin, so formed, of general formula XI O
Figure imgf000007_0003
is cyclised to the benzoxazinone, optionally in the presence of an acid or base, with simultaneous cleavage of the acetyl group, and finally h) the hydantoin, so formed, of general formula XII
Figure imgf000008_0001
is reacted with a compound of general formula XIII
R- - XIII in which R1 has the meaning given in formula I and W is chlorine, bromine, iodine, p-toluenesulfonyloxy or methanesulfonyloxy, optionally with the addition of a base in a suitable solvent.
Although the process of the invention requires 8 process steps, which is two more than in the known process, surprisingly there is .double the overall yield in relation to the known process.
Process step a) is generally carried out by reacting the starting materials with or without a solvent, optionally with the addition of an inorganic or organic base at a temperature between 0 and 150°C. The reaction also can optionally be carried out in a two phase mixture, for example water-methyl isobutyl ketone.
Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic amines, as well as heterocyclic bases. Examples include sodium and potassium hydroxide, sodium and potassium carbonate, sodium and potassium hydrogen carbonate, triethyla ine and 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, and nitriles, such as acetonitrile, and also two phase mixtures with water.
Process step b) is generally carried out by reacting the starting materials in an inert solvent, optionally with the addition of an inorganic or organic base at a temperature between 0 and 150°C, preferably at the boiling point of the solvent.
Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic amines, as well as heterocyclic bases. Examples include sodium and potassium hydroxide, sodium and potassium carbonate, sodium and potassium hydrogen carbonate, triethylamine and 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, and nitriles, such as acetonitrile. Two phase mixtures with water and a water immiscible organic solvent can be used with the addition of a phase transfer catalyst.
The resulting 2-(2-acetamido-5-fluorophenoxy) acetic acid derivatives are new.
Process step c) can generally be carried out according to known processes for nitration of phenyl ethers, as described for example in Houben- eyl, Vol. X/l, page 566 ff. Nitration of the aro atics in sulfuric acid solution by adding sulfuric acid/nitric acid mixtures with cooling has been proved.
The resulting 2-(2-acetamido-5-fluoro-4-nitrophenoxy) - acetic acid derivatives are new.
Process stage d) is generally carried out according to known processes for reduction of an aromatic nitro group, for example as described in Houben-Weyl, Vol. XI/1, page 360 ff.
Hydrogenation with hydrogen in a suitable solvent in the presence of catalyst is particularly preferred.
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, esters such as ethyl acetate, or also carboxamides, such as dimethylformamide.
As catalysts there can be used known hydrogenation catalysts. Examples are Raney-nickel, palladium or platinum oxide.
The process can be carried out over a wide temperature range from 0 to 150°C, preferably from 20°C to 100°C. The reaction can be carried out under normal pressure but higher pressures can be used.
The reduction may also be 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-fluoro- phenoxy)acetic acid derivatives are new.
Process step e) is generally carried out by reacting the starting materials in a suitable solvent, optionally with the addition of an inorganic or organic base at a temperature between 0 and 50°C. The reaction can also optionally be carried out in a two phase mixture with water and a water immiscible organic solvent optionally with the addition of a phase transfer catalyst.
Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic amines as well as heterocyclic bases. Examples include sodium and potassium hydroxide, sodium and potassium hydrogen carbonate, 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-phenoxycarbonyl- aminophenoxy)acetic acid derivatives are new.
Process step f) is generally carried out by reacting the starting materials in a suitable solvent, at a temperature between 20 and 130°C, optionally with the addition of an inorganic or organic base. The reaction time is from 0.5 to 10 hours.
Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic and aromatic amines as well as heterocyclic bases. Examples include sodium and potassium hydroxide, potassium tert.-butanolate, sodium and potassium hydrogen carbonate, 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.
It is known, that hydantoin can be formed from α-aminocarboxylic acid esters and isocyanates, see for example EP 0 272 594. The disadvantage is -that the preparation of the corresponding isocyanate involves phosgene or triphosgene. Further in the known processes the presence of further reactive groups in the molecule is not possible since the corresponding isocyanate cannot be prepared.
The process of the invention allows the preparation of hydantoins with further functional groups, as contained in compounds of general formula XI, where also the use of phosgene or triphosgene can be avoided.
The resulting 2-(5-acetamido-4-carbonylmethoxy-2-fluoro- phenyl)perhydroimidazo[1,5-a]pyridine-l,3-dione derivatives are new.
Process step g) is generally carried out by reacting the starting materials in a suitable inert solvent, optionally with the addition of an inorganic or organic acid at a temperature between 20 and 150°C, preferably at the boiling point of the solvent. It can also however be carried out in the absence of additional solvent, in a process in which for example, the starting materials are dissolved directly in the appropriate acid or their mixtures.
Examples of inorganic acids are hydrochloric acid and sulfuric acid and of organic acids are acetic acid or p-toluenesulfonic acid.
Suitable solvents include hydrocarbons such as hexane, cyclohexane, toluene or xylene, and chlorinated hydrocarbons, such as methylene chloride or 1,2-dichloroethane.
Process step h) is generally carried out by reacting the starting materials in a suitable solvent, optionally with the addition of an inorganic or organic base at a temperature between -10 and 150°C. The reaction can also be carried out in a two phase system with water using a phase transfer catalyst.
Suitable bases are alkali and alkaline earth metal hydroxides, carbonates and/or hydrogen carbonates, tertiary aliphatic amines as well as heterocyclic bases. Examples include sodium and potassium hydroxide, sodium and potassium hydrogen carbonate, 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 general formulae I, XI and XII are optically active. The compounds can optionally be present as pure enantiomers or as their mixtures.
The following illustrate by way of examples, the preparation processes of the invention.
Process stage a)
N-(4-Fluoro-2-_Lydroxyphenyl)acetamide
97 g 5-Fluoro-2-aminophenol was dissolved in 500 ml ethanol and 84 g acetic anhydride added dropwise. The mixture was stirred for 1 hour at room temperature, when the product partially crystallised. The crystals were suction-filtered and the residue concentrated .in vacuo. The residue was washed with hexane and dried in vacuo.
Yield: 115 g = 89% of theory m.p. : 174 - 176°C
Process stage b)
Ethyl 2-(2-acetamido-5-fluoropttenoxy) cetate
80 g N-(4-Fluoro-2-hydroxyphenyl) acetamide was dissolved in 2 1 methyl isobutyl ketone and 80 g potassium carbonate and 71 g ethyl chloroacetate added. The mixture was heated under reflux for 3 hours and cooled to room temperature. The precipitated salts were suction-filtered. The filtrate was concentrated __n vacuo. The oily residue was stirred with warm hexane. The crystals were suction-filtered and dried in vacuo.
Yield: 119 g = 99% of theory m.p.: 71°C Process stage c)
Ethyl 2- (2-acetamido-5-fluoro-4-nitrophenoxy) cetate
300 g Ethyl 2-(2-acetamido-5-fluorophenoxy) acetate was dissolved in 1200 g concentrated sulfuric acid (96%) at 10 - 15°C. The solution was cooled to 0°C and a mixture of 120 g concentrated nitric acid (65 %) and 240 g concentrated sulfuric acid (96%) slowly added dropwise. The mixture was stirred for 60 minutes at 0°C and then poured into 3 1 ice/water. It was extracted several times with dichloromethane, the combined organic phases washed, with aqueous sodium hydrogen carbonate until neutral and the solvent removed i_n vacuo. The residue was triturated at 50°C with methyl tert.-butyl ether.
Yield: 331 g = 94% of theory m.p.: 114 °C
Process stage d) Ethyl 2- (2-acetamido-4-amino-5-fluorophenoxy) acetate
100 g Ethyl 2-(2-acetamido-5-fluoro-4-nitrophenoxy) acetate was dissolved in 660 ml ethyl acetate and 5 g palladium on active charcoal added. The mixture was hydrogenated for 7 hours at 40°C and 50 mbar hydrogen, until no more hydrogen was taken up. The catalyst was suction-filtered and the solvent removed __n vacuo.
Yield: 89 g = 99% of theory m.p.: 95°C Process stage e)
Ethyl 2-(2-acetamido-5-fluoro-4-phenoxycarbonylamino- phenoxy) cetate
0.6 g Magnesium oxide was added to 120 ml water and 60 ml dichloromethane and 5.0 g ethyl 2-(2-acetamido-4-amino- 5-fluorophenoxy)acetate added. A solution of 2.9 g phenyl chloroformate in 10 ml dichloromethane was added dropwise at room temperature over 20 minutes. The mixture was stirred for 4 hours at room temperature and then allowed to stand overnight. It was diluted with 150 ml water, die phases separated and shaken 3 times with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated j-n vacuo. the solid material was triturated with diisopropyl ether.
Yield: 6.2 g = 86% of theory m.p.: 128-130°C
Process stage f)
D/L-2-(5-Acetamido-4-ethoxycarbonylmethyloxy-2-fluoro¬ phenyl)perhydroimida2o[l,5-a]pyridine-l,3-dione
2.1 g Potassium carbonate was added to 30 ml tetrahydrofuran and 5.8 g ethyl 2-(2-acetamido- 5-fluoro-4-phenoxycarbonylaminophenoxy)acetate added. At 60°C, a solution of 2.9 g ethyl piperidine-2-carboxylate in 10 ml tetrahydrofuran was added dropwise over one hour and the mixture stirred for one hour. The reaction mixture was cooled and added to
30 ml 2N hydrochloric acid, the phases separated and the aqueous phase extracted 3 times with ethyl acetate. The combined organic phases were washed twice with water, dried over magnesium sulfate and concentrated. The residue was recrystallised from diisopropyl ether. Yield: 5.1 g = 84 % of theory m.p. : 177 - 179°C
Process stage g) D/L-2-(7-fluoro-3,4-dihydro-3-oxo-2H-l,4-benzoxazin-6-yl) perhydroimidazo[l,5-a]pyridine-l 3-dione
2.5 g D,L-2-(5-Acetamido-4-ethoxycarbonylmethyloxy- 2-fluorophenyl)perhydroimidazo[l,5-a]pyridine-l,3-dione was dissolved in 20 ml acetic acid and 6 ml 20% sulfuric acid added. The mixture was heated under reflux for 2 hours. After cooling, it was poured into 50 ml ice-water and extracted 3 times with ethyl acetate. The combined organic phases were washed twice with water, dried over magnesium sulfate and concentrated. The residue was recrystallised from diisopropyl ether.
Yield: 1.9 g = 98% of theory m.p. : 220 - 222°C
Process stage h)
D,L-2- (7-Fluoro-3, -dihydro-3-oxo-4-(2-propynyl) -
2H-l,4-benzoxazin-6-yl)perhydroimidazo[l,5-a]pyridine-
1,3-dione
A mixture of 1.0 g D,L-2-(7-fluoro-3 ,4-dihydro-3-oxo- 2H-1,4-benzoxazin-6-yl)perhydroimidazo[l,5-a]pyridine- 1,3-dione, 0.4 g potassium carbonate and 0.5 g 3-bromo- propyne in 20 ml dimethylformamide was heated for 5 hours at 60°C. The solvent was distilled iri vacuo and the residue taken up in 30 ml 2N aqueous hydrochloric acid, extracted 3 times with ethyl acetate. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallised from ethanol. Yield: l.o g 90% of theory m.p. : 204°C

Claims

1. A process for the preparation of substituted
D,L-2-(7-fluoro- ,4-dihydro-3-oxo-2H-l,4-benzoxazin- 6-yl)perhydroi idazo[1,5-a]pyridine-1,3-diones of general formula I
Figure imgf000019_0001
in which
R1 is C^Cg-alkyl, C2-C6-alkenyl or C3-C6-alkynyl, characterised in that a) 2-amino-5-fluorophenol of formula II
Figure imgf000019_0002
is reacted with acetyl chloride or acetic anhydride, in the presence of an acid binding agent, optionally in a suitable solvent.
b) the acetanilide, so formed, of formula III
Figure imgf000019_0003
H
is reacted with a compound of general formula IV 0
Figure imgf000020_0001
in which R4 is hydrogen or C1-c4-alkyl and Y is halogen, methanesulfonyloxy or p-toluenesulfonyloxy,
c) the phenoxyacetic acid, so formed, of general formula
Figure imgf000020_0002
H is nitrated with nitric acid, or an organic or inorganic derivative thereof optionally in the presence of a suitable solvent,
d) the phenoxyacetic acid, so formed, of general formula
Figure imgf000020_0003
is hydrogenated with hydrogen, in the presence of a suitable catalyst in an inert solvent, or reduced with a chemical reducing agent in the presence of an inert solvent,
e) the phenoxyacetic acid, so formed, of general formula VII
Figure imgf000020_0004
is reacted with a compound of general formula VIII
Figure imgf000021_0001
in which X is halogen, nitro or cyano and n is an integer of 0 to 5, in a suitable inert solvent, optionally with the addition of an organic or inorganic acid binding agent,
f) the phenoxyacetic acid, so formed, of general formula
IX
O
Figure imgf000021_0002
is reacted with a piperidine-2-carboxylic acid derivative of general formula X
Figure imgf000021_0003
in which R2 is hydrogen, methyl or ethyl, in an inert solvent, optionally with the addition of an organic or inorganic acid binding agent,
g) the hydantoin, so formed, of general formula XI
Figure imgf000021_0004
is cyclised to the benzoxazinone optionally in the presence of an acid or base with simultaneous cleavage of the acetyl group, and finally
h) the hydantoin, so formed, of general formula XII
Figure imgf000022_0001
is reacted with a compound of general formula XIII
Figure imgf000022_0002
in which R1 has the meaning given in formula I and W is chlorine, bromine, iodine, p-toluenesulfonyloxy or methanesulfonyloxy optionally with the addition of a base in a suitable solvent.
2. 2-(2-Acetamido-5-fluorophenoxy)acetic acid derivatives of general formula
Figure imgf000022_0003
in which R4 is hydrogen or C1-C4-alkyl.
3. 2-(2-Acetamido-5-fluoro-4-nitrophenoxy)acetic acid derivatives of general formula
Figure imgf000022_0004
in which R4 is hydrogen or C1-C4-alkyl.
4. 2-(2-Acetamido-4-amino-5-fluorophenoxy)acetic acid derivatives of general formula
Figure imgf000023_0001
in which R4 is hydrogen or C1-C4-alkyl.
5. 2-(2-Acetamido-5-fluoro-4-phenoxycarbonylamino- phenoxy)acetic acid derivatives of general formula
Figure imgf000023_0002
in which R4 is hydrogen or C1-C4-alkyl .
6. 2- (5-Acetamido-4-carbonylmethoxy-2-f luorophenyl) - perhydroimidazo [ l , 5-a] pyridine-l , 3-dione derivatives of general formula
O
Figure imgf000023_0003
in which R4 is hydrogen or C--C4-alkyl ,
PCT/EP1993/000598 1992-03-17 1993-03-10 Process and intermediates 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 WO1993019065A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP93906536A EP0631579A1 (en) 1992-03-17 1993-03-10 Process and intermediates 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
JP5516237A JPH07504671A (en) 1992-03-17 1993-03-10 Substituted D,L-2-(7-fluoro-3,4-dihydro-3-oxo-2H-1,4-benzoxazin-6-yl)-perhydroimidazo[1,5-a]pyridine- Method for producing 1,3-dione and its intermediates

Applications Claiming Priority (2)

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DEP4208778.3 1992-03-17
DE4208778A DE4208778C1 (en) 1992-03-17 1992-03-17

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IL (1) IL104810A0 (en)
TW (1) TW213915B (en)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012041789A1 (en) 2010-10-01 2012-04-05 Basf Se Herbicidal benzoxazinones

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Publication number Priority date Publication date Assignee Title
BR0111457A (en) * 2000-06-09 2003-06-24 Aventis Pharma Deustschland Gm Acylphenylurea derivatives, processes for their preparation and their application as medicines

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0311135A2 (en) * 1987-10-09 1989-04-12 Schering Aktiengesellschaft Heterocyclic substituted azoles and azines, process for their preparation and their use as an agent with herbicide activity

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0311135A2 (en) * 1987-10-09 1989-04-12 Schering Aktiengesellschaft Heterocyclic substituted azoles and azines, process for their preparation and their use as an agent with herbicide activity

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012041789A1 (en) 2010-10-01 2012-04-05 Basf Se Herbicidal benzoxazinones

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IL104810A0 (en) 1993-06-10
EP0631579A1 (en) 1995-01-04
DE4208778C1 (en) 1993-09-23
HUT68172A (en) 1995-05-29
HU211068B (en) 1995-10-30
TW213915B (en) 1993-10-01
HU9402674D0 (en) 1994-12-28

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