WO2015158518A1 - Process for manufacturing benzoxazinones - Google Patents

Process for manufacturing benzoxazinones Download PDF

Info

Publication number
WO2015158518A1
WO2015158518A1 PCT/EP2015/056541 EP2015056541W WO2015158518A1 WO 2015158518 A1 WO2015158518 A1 WO 2015158518A1 EP 2015056541 W EP2015056541 W EP 2015056541W WO 2015158518 A1 WO2015158518 A1 WO 2015158518A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
amino
acid
process according
alkyl
Prior art date
Application number
PCT/EP2015/056541
Other languages
French (fr)
Inventor
Bernd Wolf
Michael Rack
Volker Maywald
Roland Götz
Timo Frassetto
Original Assignee
Basf Se
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Basf Se filed Critical Basf Se
Publication of WO2015158518A1 publication Critical patent/WO2015158518A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

  • the invention relates to a process for manufacturing benzoxazinones and their use in a process for manufacturing triazinon-benzoxazinones.
  • WO 13/092856 discloses a process for the preparation of benzoxazinones comprising cycliza- tion of a respective amino compound, wherein the acid necessary for the cyciisation is dosed to the respective amino compound.
  • said process has several disadvantages, as purity and yield of the desired product are unsatisfying.
  • One task of the invention is to provide an efficient process for manufacturing benzoxazinones of formula (I).
  • benzoxazinones of formula (I) can be obtained by acid-mediated cyclization of amino compounds of formula (II), wherein the amino compound of formula (II) is added to the acid.
  • R 1 is H or halogen
  • R 2 is halogen
  • R 3 is H or halogen
  • R 4 is H, Hal or NH 2 ;
  • W is O or S; characterized in that amino compounds of formula (II),
  • R 1 , R 2 , R 3 , R 4 and W are defined as in formula (I);
  • R 5 , R 6 are independently of each other d-Ce-alkyl, C 2 -Ce-alkenyl, C 2 -Ce-alkynyl, Ci-Ce-haloalkyl, d-Ce-cyanoalkyl, Ci-C6-nitroalkyl, Ci-C 6 -hydroxyalkyl, d-Ce- alkoxy-d-Ce-alkyl, amino-d-Ce-alkyl, (Ci-C6-alkyl)amino-CrC6-alkyl, di(d- C6-alkyl)amino-Ci-C6-alkyl, d-Ce-cycloalkyl, phenyl or benzyl, wherein the phenyl and the benzyl ring are independently of one another unsubstituted or substituted withl to 5 substituents selected from the group consisting of halo- gen, Ci-C6-alkyl or Ci-C6
  • organic moieties mentioned in the definition of the variables according to the present inven- tion e.g. R 1 to R 6 are - like the term halogen - collective terms for individual enumerations of the individual group members.
  • halogen denotes in each case fluorine, chlorine, bromine or iodine.
  • All hydrocarbon chains, i.e. all alkyl, can be straight-chain or branched, the prefix C n -C m denoting in each case the possible number of carbon atoms in the group.
  • Ci-C 4 -alkyl for example CH 3 , C 2 H 5 , n-propyl, CH(CH 3 ) 2 n-butyl, CH(CH 3 )-C 2 H 5 , CH 2 - CH(CH 3 ) 2 and C(CH 3 ) 3 ;
  • Ci-C4-haloalkyl a Ci-C4-alkyl radical as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoro- methyl, chlorodifluoromethyl, bromomethyl, iodomethyl, 2-fluoroethyl, 2-chloroethyl, 2- bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-
  • Ci-C6-haloalkyl Ci-C4-haloalkyl as mentioned above, and also, for example,
  • 5-fluoropentyl 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl and dodecafluorohexyl;
  • C3-C6-cycloalkyl monocyclic saturated hydrocarbons having 3 to 6 ring members, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
  • C3-C6-alkenyl for example -propenyl, 2-propenyl, -methylethenyl, -butenyl, 2-butenyl,
  • 1 - propenyl 1 ,2-dimethyl-2-propenyl, 1 -ethyl-1 -propenyl, 1 -ethyl-2-propenyl, 1 -hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl-1 -pentenyl, 2-methyl-1 -pentenyl, 3-methyl- 1 -pentenyl, 4-methyl-1 -pentenyl, 1 -methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2- pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,
  • C3-C6-alkynyl for example 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1 - methyl-2-propynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -methyl-2-butynyl, 1 -methyl- 3-butynyl, 2-methyl-3-butynyl, 3-methyl-1 -butynyl, 1 ,1 -dimethyl-2-propynyl, 1 -ethyl-2-propynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1 -methyl-2-pentynyl, 1 -methyl-3- pentynyl, 1 -methyl-4-pentyn
  • C2-C6-alkynyl C3-C6-alkynyl as mentioned above and also ethynyl;
  • Ci-C4-alkoxy for example methoxy, ethoxy, propoxy, 1 -methylethoxy butoxy,
  • Ci-C6-alkoxy Ci-C4-alkoxy as mentioned above, and also, for example, pentoxy, 1 - methylbutoxy, 2-methylbutoxy, 3-methoxylbutoxy, 1 ,1 -dimethylpropoxy, 1 ,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1 -ethylpropoxy, hexoxy, 1 -methylpentoxy, 2-methylpentoxy, 3- methylpentoxy, 4-methylpentoxy, 1 ,1-dimethylbutoxy, 1 ,2-dimethylbutoxy, 1 ,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1 -ethylbutoxy, 2-ethylbutoxy, 1 ,1 ,2- trimethylpropoxy, 1 ,2,2-trimethylpropoxy, 1 -ethyl-1-methylpropoxy and 1 -ethyl-2-methylpropoxy.
  • (Ci-C4-alkyl)amino for example methylamino, ethylamino, propylamino, 1-methylethyl- amino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1 , 1-dimethylethylamino;
  • di(Ci-C4-alkyl)amino for example N,N-dimethylamino, ⁇ , ⁇ -diethylamino, N,N-di(1 - methylethyl)amino, N,N-dipropylamino, ⁇ , ⁇ -dibutylamino, N,N-di(1 -methylpropyl)amino, N,N- di(2-methylpropyl)amino, N,N-di(1 ,1 -dimethylethyl)amino, N-ethyl-N-methylamino, N-methyl-N- propylamino, N-methyl-N-(1-methylethyl)amino, N-butyl-N-methylamino, N-methyl-N-(1- methylpropyl)amino, N-methyl-N-(2-methylpropyl)amino, N-(1 ,1 -dimethyleth
  • a monocyclic, saturated or aromatic cycle having three to six ring members which comprises apart from one nitrogen atom and carbon atoms optionally additionally one to three heteroatoms selected from the group O, S and N, for example:
  • halogen particularly preferred F or CI, especially preferred F
  • R 2 is preferably CI or F, particularly preferred F; is preferably H, CI or F, particularly preferred H or F, especially preferred H;
  • halogen particularly preferred F or CI, especially preferred F
  • halogen is also preferably halogen or NH 2 , particularly preferred halogen
  • H or NH 2 is also preferred H or NH 2 , particularly preferred ⁇ 2 ;
  • W is preferably O
  • the particularly preferred embodiments correspond, either independently of one another or in combination with one another, to those of the variables of R 1 , R 2 , R 3 , R 4 and W of formula (I), or have, either independently of one another or in combination with one another, the following meanings:
  • R 5 and R 6 preferably are independently of each other Ci-C6-alkyl, Ci-C6-cyanoalkyl, C1-C6- hydroxyalkyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-C6-cycloalkyl, phenyl or benzyl,
  • phenyl and the benzyl ring are independently of one another unsubsti- tuted or substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci-C6-alkyl or Ci-C6-alkoxy,
  • R 5 and R 6 together with the N atom which they are attached to, represent a saturated or aromatic 5- to 6-membered ring, optionally containing 1 additional heteroatom from the group O and N, with the ring optionally being substituted with 1 to 2 Ci-C6-alkyl substituents; particularly preferred are independently of each other Ci-C 4 -alkyl, Ci-C4-hydroxyalkyl, Ci- C6-alkoxy-Ci-C4-alkyl or benzyl,
  • benzyl ring is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, Ci-C 4 -alkyl or Ci-C 4 -alkoxy,
  • benzyl ring is unsubstituted
  • R 5 and R 6 together with the N atom which they are attached to, represent a saturated 5- to 6-membered ring, optionally containing 1 additional oxygen atom, with the ring optional- ly being substituted with 1 to 2 Ci-C6-alkyl substituents; also particularly preferred are independently of one another Ci-C6-alkyl.
  • amino compounds of formula (II) are added to an acid to obtain the benzoxazinones of formula (I):
  • the process according to the invention is generally carried out at a temperature in the range of from 0 °C to the boiling point of the solvents, preferably in the range from 25 to 80 °C, especially preferred in the range from 40 to 65 °C.
  • Suitable acids are organic acids or inorganic acids.
  • Suitable organic acids are formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, succinic acid, adipic acid, maleic acid, fumaric acid, citric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, trifluoroacetic acid, benzoic acid, ni- trobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid (triflic acid), bis(trifluoro- methane)sulfonimide (triflimide), camphorsulfonic acid, benzenesulfonic acid, para-toluene- sulfonic acid, nitrobenzenesulfonic acid or dinitrobenzenesulfonic acid.
  • suitable inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, tetrafluoroboric acid, hex- afluorophosphoric acid or hexafluorosilicic acid.
  • the concentration of the acid is below 50%, preferably below 30 %.
  • the concentration of the acid is from 3 to 50%, preferably from 10 to 30 %.
  • Preferred acids are acetic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and nitric acid.
  • Particularly preferred acids are hydrochloric acid, sulfuric acid and acetic acid.
  • Especially preferred acids are hydrochloric acid and sulfuric acid.
  • a more preferred acid is sulfuric acid.
  • the concentration of the sulphuric acid is below 50%, preferably below 30 %.
  • the concentration of the sulphuric acid is from 3 to 50%, preferably from 10 to 30 %.
  • acid as used herein also includes mixtures of two or more, preferably two of the above compounds. Particular preference is given to the use of one acid. Accordingly, in a particularly preferred embodiment one acid is employed.
  • the molar ratio of the amino compound of formula (II) to the acid is generally in the range of 1 :0.5 to 1 :10, preferably 1 :1 to 1 :2, more preferably 1 :1.
  • the process according to the invention is carried out in a solvent.
  • suitable solvents are water, alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, 2-butanol, iso-butanol, tert-butanol, 2-ethyl-hexanol, hexafluoroisopropanol; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, cymene, xylenes, mesitylene, benzotrifluoride; esters such as methyl acetate, ethyl acetate, n-butyl acetate, isobutyl acetate; ethers such as di-n-butyl ether, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), 1 ,4- dioxane, 1 ,2-dimethoxyethane; aliphatic hydrocarbons such as hexa
  • Preferred solvents are alcohols as mentioned above, and water.
  • Preferred solvents include methanol, ethanol, isopropanol, toluene, xylenes and water.
  • More preferred solvents include methanol, toluene and water. More preferred solvents are methanol and toluene.
  • solvent as used herein also includes mixtures of two or more of the above compounds.
  • the acid and a solvent are pre-charged in the reaction vessel and then the mixture is heated to a definite temperature, before the amino compounds of formula (II) are added.
  • the acid and a solvent are pre-charged in the reaction vessel and then a solution of the amino compounds of formula (II) in a solvent are dosed to the pre- charged catalyst/solvent mixture in that way, that the benzoxazinones of formula (I) are formed immediately.
  • the acid and a solvent are pre-charged in the reaction vessel, then a solution of the amino compounds of formula (II) in a solvent are dosed to the pre-charged acid/solvent mixture in that way, that the benzoxazinones of formula (I) are formed immediately and the reaction temperature can be kept constant in a desired range.
  • the respective mixture can be worked up by means of standard techniques. Examples thereof include extraction, filtration, aqueous work-up, distilling off solvents and/or other volatile compounds. These methods can also be combined with each other.
  • the benzoxazinones of formula (I) can also be used without further purification or can be purified using standard techniques, for example precipitation, recrystallization or column chromatography.
  • the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5.
  • the pH of the reaction mixture is adjusted to slightly acidic, preferably a pH from 3 to 7, more preferably from 4 to 5. According to another embodiment of the invention, after completion or partial completion of the cyclization reaction, the pH of the reaction mixture is adjusted to a pH of 4.
  • benzoxazinones of formula (I) are isolated by precipitation.
  • the precipitated benzoxazinones of formula (I) can be isolated by filtration.
  • the benzoxazinones of formula (I) precipitate upon cooling, preferably to a temperature in the range of from 0 to 30 °C. According to another embodiment of the invention, the benzoxazinones of formula (I) are precipitated by adding water to the reaction mixture.
  • the benzoxazinones of formula (I) precipitate upon cooling, preferably to a temperature in the range of from 0 to 30 °C, and adding water.
  • the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5.
  • the benzoxazinones of formula (I) precipitate upon cooling, preferably to a temperature in the range of from 0 to 30 °C and/or adding water.
  • the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5, and the reaction mixture is cooled, preferably to a temperature in the range of from 0 to 30 °C, to precipitate the benzoxazinones of formula (I).
  • the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5, and water is added to the reaction mixture to precipitate the benzoxa- zinones of formula (I).
  • the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5, water is added to the reaction mixture, and the reaction mixture is cooled, preferably to a temperature in the range of from 0 to 30 °C, to precipitate the benzoxazinones of formula (I).
  • the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5.
  • the benzoxazinones of formula (I) precipitate in a temperature range from 0 to 30 °C. Such embodiment is preferred.
  • benzoxazinones of formula (I) are suitable intermediates for the synthesis of triazinon- benzoxazinones, e.g. as disclosed in WO 2013/092856.
  • Amino compounds of formula (I I) can prepared by known methods, e.g. by reacting nitro compounds of formula (II I) with a reducing agent to obtain the amino compound of formula (I I),
  • R 1 , R 2 , R 3 , R 4 , R 5 - R 6 and W are as defined above;
  • R A is H, Hal, NH 2 or N0 2 .
  • Amino compounds of formula (I I) can also be prepared by adding a nitro compound of formula (I I I) to a reducing agent :
  • the reduction of the nitro compounds of formula (II I) is generally carried out at a temperature in the range of from 0 °C to the boiling point of the solvents, preferably 20 to 80 °C, especially preferred in the range from 35 to 65 °C.
  • Suitable reducing agents and conditions are known from the literature and can be found inter alia in Advanced Organic Chemistry (ed. J. March), 4 th edition, Wiley-lnterscience, NY 1992, p.1216 ff; or Organikum, 22 nd edition, Wiley-VCH, Weinheim 2004, p. 626 ff.
  • reducing agents are molecular hydrogen, hydrazine, formic acid, ammonium formate, borane or borohydrides in combination with a homogeneous or heterogeneous catalyst, for example selected from metal salts of nickel, palladium, platinum, cobalt, rhodium, iridium, ruthenium or copper.
  • catalysts are palladium on charcoal, palladium on alumina, palladium on BaS0 4 , platinum on charcoal, platinum on alumina, platinum(IV) oxide, Raney nickel, rhodium on alumina, ruthenium on alumina.
  • suitable reducing agents are metals in their elemental form such as magnesium, iron, zinc, tin or metal salts such as tin(ll) chloride in combination with an acid such as hydrochloric or acetic acid.
  • Suitable reducing agents are sulfur compounds like sodium hydrosulfite, rongalite, sodium sulfide, sodium hydrogen sulfide and ammonium polysulfide.
  • the reducing agent is molecular hydrogen in combination with a homogeneous or heterogeneous hydrogenation catalyst.
  • Examples for hydrogenation catalysts are catalyst selected from the group consisting of metal salts of nickel, palladium, platinum, cobalt, rhodium, iridium, ruthenium or copper.
  • hydrogenation catalysts include palladium on charcoal, palladium on alu- mina, palladium on BaS0 4 , platinum on charcoal, platinum on alumina, platinum(IV) oxide, Raney nickel, rhodium on alumina, ruthenium on alumina.
  • Preferred reducing agents are molecular hydrogen in combination with palladium on charcoal, palladium on alumina, palladium on BaS0 4 , molecular hydrogen in combination with platinum on charcoal, platinum on alumina.
  • Especially preferred reducing agents are molecular hydrogen in combination with palladium on charcoal or platinum on charcoal.
  • a more preferred reducing agent is molecular hydrogen in combination with palladium on charcoal.
  • a more preferred reducing agent is molecular hydrogen in combination with platinum on charcoal.
  • the term reducing agent as used herein also includes mixtures of two or more, preferably two of the above compounds. Particular preference is given to the use of one reducing agent.
  • one reducing agent is employed in the pro- cess according to the invention.
  • the molar ratio of the nitro compound of formula (III) to the reducing agent is generally in the range of 1 :2 to 1 :15, preferably 1 :2.5 to 1 :10, more preferably 1 :3 to 1 :6.
  • the reducing agent and the solvent are pre-charged in the reaction vessel and then the mixture is heated to a definite temperature, before the nitro compound of formula (III) is added.
  • the reducing agent and the solvent are pre-charged in the reaction vessel and then the nitro compound of formula (III) is dosed to the pre-charged catalyst/solvent mixture in such way, that the nitro compound of formula (III) is reduced immediately, and thus the stationary concentration of nitro compound of formula (III) in the reaction mixture is very low.
  • the catalyst and the solvent are pre-charged in the reaction vessel, the mix- ture is heated to a definite temperature, and then pressurized with hydrogen under stirring before the nitro compound of formula (III) is added.
  • the catalyst and the solvent are pre-charged in the reaction vessel and then a solution of the nitro compound of formula (III) in a solvent is dosed to the pre-charged catalyst/solution mixture in that way, that the nitro compound of formula (III) is reduced immediately.
  • the catalyst and the solvent are pre-charged in the reaction vessel and then a solution of the nitro compound of formula (III) in a solvent is dosed to the pre-charged catalyst/solution mixture in such way, that the nitro compound of formula (III) is reduced immediately, and thus the stationary concentration of nitro compound of formula (III) in the reaction mixture is very low.
  • the catalyst and the solvent are pre-charged in the reaction vessel and then a solution of the nitro compound of formula (III) in a solvent is dosed to the pre-charged catalyst/solvent mixture in that way, that the nitro compound of formula (III) is reduced immediately and the reaction temperature can be kept constant in a desired range.
  • the reducing agent being molecular hydrogen in combination with a catalyst
  • first the mixture of the catalyst and a solvent are stirred at a temperature in the range of from 20 to 80 °C, preferably 40 to 60 °C, in the presence of hydrogen at a pressure in the range of from 0 to 20 bar, preferably 0 to 10 bar; and then the nitro compound of formula (III) is added.
  • the process according to the invention is carried out under an elevated pressure of up to 20 bar, preferably up to 10 bar.
  • the reduction of the nitro compounds of formula (III) is carried out in a solvent.
  • suitable solvents are water, alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, iso-butanol, tert-butanol, 2-ethyl-hexanol, hexafluoroisopropanol; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, cymene, xylenes, mesitylene, benzotrifluoride; esters such as methyl acetate, ethyl acetate, n-butyl acetate, isobutyl acetate; ethers such as di-n-butyl ether, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), 1 ,4- dioxane, 1 ,2-dimethoxyethane; aliphatic hydrocarbons such as hexanes,
  • More preferred solvents include methanol and toluene.
  • solvent as used herein also includes mixtures of two or more of the above solvents. Preference is given to the use of methanol/toluene mixtures or methanol/xylenes mixtures. Particular preference is given to the use of methanol/toluene mixtures.
  • the respective mixture can be worked up by means of standard techniques. Examples thereof include extraction, filtration, aqueous work- up, distilling off solvents and/or other volatile compounds. These methods can also be combined with each other.
  • the hydrogen source is removed and the catalyst is filtered off.
  • reaction mixture is brought to room temperature and the catalyst is filtered off.
  • the solvent is partly or completely distilled off.
  • the product precipitates upon cooling, preferably to a temperature in the range of from 0 to 30 °C and/or adding water.
  • the precipitated amino compound of formula (I) can be isolated by filtration.
  • amino compounds of formula (II) are suitable intermediates for the synthesis of benzoxazi- nones of formula (I).
  • benzoxazinones of formula (I) are prepared by
  • R 1 , R 2 , R 3 , R 5 - R 6 and W are as defined above; and R A is H, Hal, NH 2 or N0 2 ;
  • benzoxazinones of formula (I) are prepared by
  • amino compounds of formula (II) are isolated prior to being used in step (ii).
  • amino compounds of formula (II) are not isolated, and the reaction mixture obtained in step (i) is directly used in step (ii).
  • amino compounds of formula (II) are not isolated, and the reaction mixture obtained in step (i) is directly used in step (ii) under inert conditions, especially under exclusion of oxygen.
  • Such embodiment is especially preferred.
  • the catalyst is filtered off, and the filtrate containing the amino compound of formula (II) used in one or more subsequent reaction step(s).
  • the catalyst is filtered off and the amino compound of formula (II) is not isolated, but the filtrate containing such amino compound of formula (II) is dosed immediately in another reactor to be used in one or more subsequent reaction step(s).
  • such filtration is conducted under inert conditions, especially under exclusion of oxy- gen.
  • the catalyst is filtered of and recycled.
  • the solvent is not exchanged between carrying out steps (i) and (ii).
  • a mixture of nitro compounds of formula (III), the catalyst, and a solvent are stirred at a temperature in the range of from 20 to 60 °C, preferably 40 to 60 °C, in the presence of hydrogen at a pressure in the range of from 0 to 20 bar, preferably 0 to 10 bar.
  • the hydrogen source is removed.
  • the catalyst is optionally filtered off, and the filtrate is subsequently used in step (ii), i.e. is added to the acid.
  • Such reaction mixture is then stirred at a temperature in the range of from 20 to 65 °C, preferably 40 to 65 °C, for 0.5 to 5 h, preferably 0.5 to 2 h.
  • reaction mixture is brought to room temperature and the catalyst is filtered off. Then the filtrate is subsequently used in step (ii), i.e. is added to the acid.
  • the catalyst is filtered off from the reaction mixture in a temperature range of 50 to 60 °C.
  • the filter cake is washed with methanol up to three times. Then the filtrate is subsequently used in step (ii), i.e. is added to the acid.
  • the catalyst is filtered off from the reaction mixture and the filtrate is brought to room temperature. Then the filtrate is subsequently used in step (ii), i.e. is added to the acid.
  • nitro compounds of formula (III) can be prepared by known methods, e.g. as described in WO 2013/092856.
  • the temperature of the reaction mixture was held constantly at 39 - 41 °C by cooling. After completion of the reaction the pressure is released and the catalyst is filtered off through a pressure filter (1 bar nitrogen overpressure).
  • the remaining catalyst was washed with 200 g methanol, which was then filled into the hydro- genation reactor, pressed through the filter cake, and then also piped into the second reactor containing the sulfuric acid reaction mixture. Such reaction mixture was stirred for additional 50 minutes at 60°C. Then NaOH (25% in H2O) was added to the mixture to adjust the pH from 1 .8 to 4. Afterwards 1652.9 g water was added and the suspension was cooled to 15°C.
  • H3PO4 in acetonitrile starting with 10% B, then B rising from 10% to 50% within 10 min, then B rising from 50% to 90% within 20 min, then back to 10% B within 2 min, then 8 min 10% B
  • the temperature of the reaction mixture was held constantly at 39 - 41 °C with cooling.
  • H3PO4 in acetonitrile starting with 10% B, then B rising from 10% to 50% within 10 min, then B rising from 50% to 90% within 20 min, then back to

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention relates to for manufacturing benzoxazinones of formula (I), characterized in that amino compounds of formula (II) are added to an acid; wherein the substituents are defined according to the specification.

Description

Process for manufacturing benzoxazinones
Description The invention relates to a process for manufacturing benzoxazinones and their use in a process for manufacturing triazinon-benzoxazinones.
WO 13/092856 discloses a process for the preparation of benzoxazinones comprising cycliza- tion of a respective amino compound, wherein the acid necessary for the cyciisation is dosed to the respective amino compound. However said process has several disadvantages, as purity and yield of the desired product are unsatisfying.
Hence, there is still room for improvement, specifically in view of economic aspects. One task of the invention is to provide an efficient process for manufacturing benzoxazinones of formula (I).
Surprisingly it has further been found that benzoxazinones of formula (I) can be obtained by acid-mediated cyclization of amino compounds of formula (II), wherein the amino compound of formula (II) is added to the acid.
It is therefore one object of the present invention to provide a process for manufacturing benzoxazinones of formula (I),
Figure imgf000002_0001
H
wherein
R1 is H or halogen;
R2 is halogen;
R3 is H or halogen;
R4 is H, Hal or NH2; and
W is O or S; characterized in that amino compounds of formula (II),
Figure imgf000003_0001
wherein R1, R2, R3, R4 and W, are defined as in formula (I); and
R5, R6 are independently of each other d-Ce-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ci-Ce-haloalkyl, d-Ce-cyanoalkyl, Ci-C6-nitroalkyl, Ci-C6-hydroxyalkyl, d-Ce- alkoxy-d-Ce-alkyl, amino-d-Ce-alkyl, (Ci-C6-alkyl)amino-CrC6-alkyl, di(d- C6-alkyl)amino-Ci-C6-alkyl, d-Ce-cycloalkyl, phenyl or benzyl, wherein the phenyl and the benzyl ring are independently of one another unsubstituted or substituted withl to 5 substituents selected from the group consisting of halo- gen, Ci-C6-alkyl or Ci-C6-alkoxy, or R5 and R6 together with the N atom which they are attached to, represent a saturated or aromatic 3- to 6-membered ring, optionally containing 1 to 3 additional heteroatoms from the group O, S and N, with the ring optionally being substi- tuted with 1 to 3 Ci-C6-alkyl substituents;
is added to an acid.
In a further aspect of the invention there is provided a process for manufacturing benzoxazi- nones of formula (I) from amino compounds of formula (II), wherein such amino compounds of formula (II) are prepared from nitro compounds of formula (III).
The organic moieties mentioned in the definition of the variables according to the present inven- tion, e.g. R1 to R6 are - like the term halogen - collective terms for individual enumerations of the individual group members.
The term halogen denotes in each case fluorine, chlorine, bromine or iodine. All hydrocarbon chains, i.e. all alkyl, can be straight-chain or branched, the prefix Cn-Cm denoting in each case the possible number of carbon atoms in the group.
Examples of such meanings are:
Ci-C4-alkyl: for example CH3, C2H5, n-propyl, CH(CH3)2 n-butyl, CH(CH3)-C2H5, CH2- CH(CH3)2 and C(CH3)3;
Ci-Ce-alkyl and also the d-Ce-alkyl moieties of d-Ce-cyanoalkyl, d-Ce-nitroalkyl, d-Ce- hydroxyalkyi, d-Ce-alkyoxy-d-Ce-alkyl, amino-d-Ce-alkyl, (d-Ce-alky amino-d-Ce-alkyl and di(d-C6-alkyl)amino-d-C6-alkyl: d-C4-alkyl as mentioned above, and also, for example, n- pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1 -ethylpropyl, n-hexyl, 1 .1 - dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 1 ,1-dimethylbutyl, 1 ,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3- dimethylbutyl, 3,3-dimethylbutyl, 1 -ethylbutyl, 2-ethylbutyl, 1 ,1 ,2-trimethylpropyl, 1 ,2,2- trimethylpropyl, 1 -ethyl-1 -methylpropyl or 1 -ethyl-2-methylpropyl, preferably methyl, ethyl, n- propyl, 1-methylethyl, n-butyl, 1 , 1-dimethylethyl, n-pentyl or n-hexyl;
Ci-C4-haloalkyl: a Ci-C4-alkyl radical as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoro- methyl, chlorodifluoromethyl, bromomethyl, iodomethyl, 2-fluoroethyl, 2-chloroethyl, 2- bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-
2.2- difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3- dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, a Ci-C3-haloalkyl radical as mentioned above, and also, for example, 1 -(fluoromethyl)-2-fluoroethyl, 1 -(chloromethyl)-2-chloroethyl, 1 - (bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, nonafluorobutyl, 1 ,1 ,2,2,-tetrafluoroethyl and 1-trifluoromethyl-1 ,2,2,2-tetrafluoroethyl;
Ci-C6-haloalkyl: Ci-C4-haloalkyl as mentioned above, and also, for example,
5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl and dodecafluorohexyl;
C3-C6-cycloalkyl: monocyclic saturated hydrocarbons having 3 to 6 ring members, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
C3-C6-alkenyl: for example -propenyl, 2-propenyl, -methylethenyl, -butenyl, 2-butenyl,
3- butenyl, 1 -methyl-1 -propenyl, 2-methyl-1 -propenyl, 1 -methyl-2-propenyl, 2-methyl-2-propenyl, 1 -pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl-1 -butenyl, 2-methyl-1 -butenyl, 3- methyl-1 -butenyl, 1 -methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1 -methyl-3- butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1 ,1 -dimethyl-2-propenyl, 1 ,2-dimethyl-
1 - propenyl, 1 ,2-dimethyl-2-propenyl, 1 -ethyl-1 -propenyl, 1 -ethyl-2-propenyl, 1 -hexenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl-1 -pentenyl, 2-methyl-1 -pentenyl, 3-methyl- 1 -pentenyl, 4-methyl-1 -pentenyl, 1 -methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2- pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl,
4- methyl-3-pentenyl, 1 -methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl- 4-pentenyl, 1 ,1 -dimethyl-2-butenyl, 1 ,1 -dimethyl-3-butenyl, 1 ,2-dimethyl-1 -butenyl, 1 ,2-dimethyl-
2- butenyl, 1 ,2-dimethyl-3-butenyl, 1 ,3-dimethyl-1 -butenyl, 1 ,3-dimethyl-2-butenyl, 1 ,3-dimethyl- 3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1 -butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-
3- butenyl, 3,3-dimethyl-1 -butenyl, 3,3-dimethyl-2-butenyl, 1 -ethyl-1 -butenyl, 1 -ethyl-2-butenyl, 1 - ethyl-3-butenyl, 2-ethyl-1 -butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1 ,1 ,2-trimethyl-2- propenyl, 1 -ethyl-1 -methyl-2-propenyl, 1 -ethyl-2-methyl-1 -propenyl and 1 -ethyl-2-methyl-2- propenyl;
- C2-C6-alkenyl: C3-C6-alkenyl as mentioned above, and also ethenyl;
C3-C6-alkynyl: for example 1 -propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1 - methyl-2-propynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -methyl-2-butynyl, 1 -methyl- 3-butynyl, 2-methyl-3-butynyl, 3-methyl-1 -butynyl, 1 ,1 -dimethyl-2-propynyl, 1 -ethyl-2-propynyl, 1 -hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1 -methyl-2-pentynyl, 1 -methyl-3- pentynyl, 1 -methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1 -pentynyl, 3- methyl-4-pentynyl, 4-methyl-1 -pentynyl, 4-methyl-2-pentynyl, 1 ,1-dimethyl-2-butynyl, 1 ,1- dimethyl-3-butynyl, 1 ,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1 -butynyl, 1 - ethyl-2-butynyl, 1 -ethyl-3-butynyl, 2-ethyl-3-butynyl and 1 -ethyl-1 -methyl-2-propynyl;
C2-C6-alkynyl: C3-C6-alkynyl as mentioned above and also ethynyl;
Ci-C4-alkoxy: for example methoxy, ethoxy, propoxy, 1 -methylethoxy butoxy,
1 -methylpropoxy, 2-methylpropoxy and 1 ,1 -dimethylethoxy;
Ci-C6-alkoxy: Ci-C4-alkoxy as mentioned above, and also, for example, pentoxy, 1 - methylbutoxy, 2-methylbutoxy, 3-methoxylbutoxy, 1 ,1 -dimethylpropoxy, 1 ,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1 -ethylpropoxy, hexoxy, 1 -methylpentoxy, 2-methylpentoxy, 3- methylpentoxy, 4-methylpentoxy, 1 ,1-dimethylbutoxy, 1 ,2-dimethylbutoxy, 1 ,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1 -ethylbutoxy, 2-ethylbutoxy, 1 ,1 ,2- trimethylpropoxy, 1 ,2,2-trimethylpropoxy, 1 -ethyl-1-methylpropoxy and 1 -ethyl-2-methylpropoxy.
(Ci-C4-alkyl)amino: for example methylamino, ethylamino, propylamino, 1-methylethyl- amino, butylamino, 1-methylpropylamino, 2-methylpropylamino or 1 , 1-dimethylethylamino;
(Ci-C6-alkyl)amino and also the (Ci-C6-alkyl)amino moieties of (Ci-C6-alkyl)amino-Ci-C6- alkyl: (Ci-C4-alkylamino) as mentioned above, and also, for example, pentylamino, 1 - methylbutylamino, 2-methylbutylamino, 3-methylbutylamino, 2,2-dimethylpropylamino, 1 -ethyl- propylamino, hexylamino, 1 ,1 -dimethylpropylamino, 1 ,2-dimethylpropylamino, 1 -methyl- pentylamino, 2-methylpentylamino, 3-methylpentylamino, 4-methylpentylamino, 1 ,1 -dimethyl- butylamino, 1 ,2-dimethylbutylamino, 1 ,3-dimethylbutylamino, 2,2-dimethylbutylamino, 2,3- dimethylbutyl-amino 3,3-dimethylbutylamino, 1 -ethylbutylamino, 2-ethylbutylamino, 1 ,1 ,2- trimethylpropylamino, 1 ,2,2-trimethyl-propylamino, 1 -ethyl-1 -methylpropylamino or 1 -ethyl-2- methylpropylamino;
di(Ci-C4-alkyl)amino: for example N,N-dimethylamino, Ν,Ν-diethylamino, N,N-di(1 - methylethyl)amino, N,N-dipropylamino, Ν,Ν-dibutylamino, N,N-di(1 -methylpropyl)amino, N,N- di(2-methylpropyl)amino, N,N-di(1 ,1 -dimethylethyl)amino, N-ethyl-N-methylamino, N-methyl-N- propylamino, N-methyl-N-(1-methylethyl)amino, N-butyl-N-methylamino, N-methyl-N-(1- methylpropyl)amino, N-methyl-N-(2-methylpropyl)amino, N-(1 ,1 -dimethylethyl)-N-methylamino, N-ethyl-N-propylamino, N-ethyl-N-(1 -methylethyl)amino, N-butyl-N-ethylamino, N-ethyl-N-(1 - methylpropyl)amino, N-ethyl-N-(2-methylpropyl)amino, N-ethyl-N-(1 ,1 -dimethylethyl)amino, N- (l -methylethyl)-N-propylamino, N-butyl-N-propylamino, N-(1 -methylpropyl)-N-propylamino, N-(2- methylpropyl)-N-propylamino, N-(1 ,1 -dimethylethyl)-N-propylamino, N-butyl-N-(1 - methylethyl)amino, N-(1 -methylethyl)-N-(1 -methylpropyl)amino, N-(1 -methylethyl)-N-(2-methyl- propyl)amino, N-(1 ,1 -dimethylethyl)-N-(1 -methylethyl)amino, N-butyl-N-(1 -methylpropyl)amino, N-butyl-N-(2-methylpropyl)amino, N-butyl-N-(1 ,1 -dimethylethyl)amino, N-(1 -methylpropyl)-N-(2- methylpropyl)amino, N-(1 ,1 -dimethylethyl)-N-(1 -methylpropyl)amino or N-(1 ,1 -dimethylethyl)-N- (2-methylpropyl)amino; di(Ci-C6-alkyl)amino and also the di(Ci-C6-alkyl)amino moieties of di(Ci-C6-alkyl)amino- Ci-C6-alkyl: di(Ci-C4-alkyl)amino as mentioned above, and also, for example, N-methyl-N- pentylamino, N-methyl-N-(1 -methylbutyl)amino, N-methyl-N-(2-methylbutyl)amino, N-methyl-N- (3-methylbutyl)amino, N-methyl-N-(2,2-dimethylpropyl)amino, N-methyl-N-(1 -ethylpropyl)amino, N-methyl-N-hexylamino, N-methyl-N-(1 ,1 -dimethylpropyl)amino, N-methyl-N-(1 ,2- dimethylpropyl)amino, N-methyl-N-(1 -methylpentyl)amino, N-methyl-N-(2-methylpentyl)amino, N-methyl-N-(3-methylpentyl)amino, N-methyl-N-(4-methylpentyl)amino, N-methyl-N-(1 ,1 - dimethylbutyl)amino, N-methyl-N-(1 ,2-dimethylbutyl)amino, N-methyl-N-(1 ,3- dimethylbutyl)amino, N-methyl-N-(2,2-dimethylbutyl)amino, N-methyl-N-(2,3- dimethylbutyl)amino, N-methyl-N-(3,3-dimethylbutyl)amino, N-methyl-N- (l -ethylbutyl)amino, N- methyl-N-(2-ethylbutyl)amino, N-methyl-N-(1 ,1 ,2-trimethylpropyl)amino, N-methyl-N- (1 ,2,2- trimethylpropyl)amino, N-methyl-N-(1 -ethyl-1 -methylpropyl)amino, N-methyl-N- (1 -ethyl-2- methylpropyl)amino, N-ethyl-N-pentylamino, N-ethyl-N-(1 -methylbutyl)amino, N-ethyl-N-(2- methylbutyl)amino, N-ethyl-N-(3-methylbutyl)amino, N-ethyl-N-(2,2-dimethylpropyl)amino, N- ethyl-N-(1 -ethylpropyl)amino, N-ethyl-N-hexylamino, N-ethyl-N-(1 ,1 -dimethylpropyl)amino, N- ethyl-N-(1 ,2-dimethylpropyl)amino, N-ethyl-N-(1 -methylpentyl)amino, N-ethyl-N-(2-methyl- pentyl)amino, N-ethyl-N-(3-methylpentyl)amino, N-ethyl-N-(4-methylpentyl)amino, N-ethyl-N- (1 ,1 -dimethylbutyl)amino, N-ethyl-N-(1 ,2-dimethylbutyl)amino, N-ethyl-N-(1 ,3- dimethylbutyl)amino, N-ethyl-N-(2,2-dimethylbutyl)amino, N-ethyl-N-(2,3-dimethylbutyl)amino, N-ethyl-N-(3,3-dimethylbutyl)amino, N-ethyl-N-(1 -ethylbutyl)amino, N-ethyl-N-(2- ethylbutyl)amino, N-ethyl-N-(1 ,1 ,2-trimethylpropyl)amino, N-ethyl-N-(1 ,2,2- trimethylpropyl)amino, N-ethyl-N-(1 -ethyl-1 -methylpropyl)amino, N-ethyl-N-(1 -ethyl-2- methylpropyl)amino, N-propyl-N-pentylamino, N-butyl-N-pentylamino, Ν,Ν-dipentylamino, N- propyl-N-hexylamino, N-butyl-N-hexylamino, N-pentyl-N-hexylamino or N,N-dihexylamino;
- saturated or aromatic 3- to 6-membered ring optionally containing 1 to 3 additional heteroatoms selected from the group O, S and N:
a monocyclic, saturated or aromatic cycle having three to six ring members which comprises apart from one nitrogen atom and carbon atoms optionally additionally one to three heteroatoms selected from the group O, S and N, for example:
1-aziridinyl, 1-azetidinyl; 1-pyrrolidinyl, 2-isothiazolidinyl, 2-isothiazolidinyl, 1-pyrazolidinyl, 3- oxazolidinyl, 3-thiazolidinyl, 1 -imidazolidinyl, 1 ,2,4-triazolidin-1 -yl, 1 ,2,4-oxadiazolidin-2-yl, 1 ,2,4- oxadiazolidin-4-yl, 1 ,2,4-thiadiazolidin-2-yl, 1 ,2,4-thiadiazolidin-4-yl; 1 -pyrrolyl, 1 -pyrazolyl, 1 - imidazolyl, 1 ,2,3-triazol-1 -yl, 1 ,2,4-triazol-1 -yl, 1 -tetrazolyl; 1 -piperidinyl, 1 -hexahydropyridazinyl, 1 -hexahydropyrimidinyl, 1 -piperazinyl, 1 ,3,5-hexahydrotriazin-1 -yl, 1 ,2,4-hexahydrotriazin-1 -yl, tetrahydro-1 ,3-oxazin-1 -yl, 1 -morpholinyl.
The preferred embodiments of the invention mentioned herein below have to be understood as being preferred either independently from each other or in combination with one another. According to a preferred embodiment of the invention preference is also given to the preparation of those benzoxazinones of formula (I), wherein the variables, either independently of one another or in combination with one another, have the following meanings: R1 is preferably H or F; particularly preferred H;
is also preferably halogen, particularly preferred F or CI, especially preferred F;
R2 is preferably CI or F, particularly preferred F; is preferably H, CI or F, particularly preferred H or F, especially preferred H;
is also preferably halogen, particularly preferred F or CI, especially preferred F; is preferably H or halogen, particularly preferred H;
is also preferably halogen or NH2, particularly preferred halogen;
is also preferred H or NH2, particularly preferred ΝΗ2;
W is preferably O,
is also preferably S.
Particular preference is also given to the preparation of benzoxazinones of formula (la), which correspond to benzoxazinones of formula (I) wherein R3 is F:
Figure imgf000007_0001
I
Particular preference is also given to the preparation of benzoxazinones of formula (la.1 ), which correspond to benzoxazinones of formula (I) wherein R3 is F and R4 is NH2:
Figure imgf000007_0002
Particular preference is also given to the preparation of benzoxazinones of formula (la.2), which correspond to benzoxazinones of formula (I) wherein R2 and R3 are F:
Figure imgf000008_0001
Particular preference is also given to the preparation of the benzoxazinone of formula (la.1 .1 ), which corresponds to benzoxazinones of formula (I) wherein R1, R2 and R3 are F, R4 is H2 and W is O:
Figure imgf000008_0002
With respect to the variables within the amino compound of formula (II), the particularly preferred embodiments correspond, either independently of one another or in combination with one another, to those of the variables of R1, R2, R3, R4 and W of formula (I), or have, either independently of one another or in combination with one another, the following meanings:
R5 and R6 preferably are independently of each other Ci-C6-alkyl, Ci-C6-cyanoalkyl, C1-C6- hydroxyalkyl, Ci-C6-alkoxy-Ci-C6-alkyl, C3-C6-cycloalkyl, phenyl or benzyl,
wherein the phenyl and the benzyl ring are independently of one another unsubsti- tuted or substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci-C6-alkyl or Ci-C6-alkoxy,
or R5 and R6 together with the N atom which they are attached to, represent a saturated or aromatic 5- to 6-membered ring, optionally containing 1 additional heteroatom from the group O and N, with the ring optionally being substituted with 1 to 2 Ci-C6-alkyl substituents; particularly preferred are independently of each other Ci-C4-alkyl, Ci-C4-hydroxyalkyl, Ci- C6-alkoxy-Ci-C4-alkyl or benzyl,
wherein the benzyl ring is unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen, Ci-C4-alkyl or Ci-C4-alkoxy,
especially preferred the benzyl ring is unsubstituted,
or R5 and R6 together with the N atom which they are attached to, represent a saturated 5- to 6-membered ring, optionally containing 1 additional oxygen atom, with the ring optional- ly being substituted with 1 to 2 Ci-C6-alkyl substituents; also particularly preferred are independently of one another Ci-C6-alkyl. In the process according to the invention, amino compounds of formula (II) are added to an acid to obtain the benzoxazinones of formula (I):
Figure imgf000009_0001
wherein the substituents are as herein defined.
The process according to the invention is generally carried out at a temperature in the range of from 0 °C to the boiling point of the solvents, preferably in the range from 25 to 80 °C, especially preferred in the range from 40 to 65 °C.
Examples for suitable acids are organic acids or inorganic acids.
Examples of suitable organic acids are formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, succinic acid, adipic acid, maleic acid, fumaric acid, citric acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, trifluoroacetic acid, benzoic acid, ni- trobenzoic acid, methanesulfonic acid, trifluoromethanesulfonic acid (triflic acid), bis(trifluoro- methane)sulfonimide (triflimide), camphorsulfonic acid, benzenesulfonic acid, para-toluene- sulfonic acid, nitrobenzenesulfonic acid or dinitrobenzenesulfonic acid.
Examples of suitable inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, tetrafluoroboric acid, hex- afluorophosphoric acid or hexafluorosilicic acid.
According to a preferred embodiment of the invention, the concentration of the acid is below 50%, preferably below 30 %.
According to another preferred embodiment of the invention, the concentration of the acid is from 3 to 50%, preferably from 10 to 30 %. Preferred acids are acetic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and nitric acid.
Particularly preferred acids are hydrochloric acid, sulfuric acid and acetic acid.
Especially preferred acids are hydrochloric acid and sulfuric acid.
A more preferred acid is sulfuric acid. According to a preferred embodiment of the invention, the concentration of the sulphuric acid is below 50%, preferably below 30 %.
According to another preferred embodiment of the invention, the concentration of the sulphuric acid is from 3 to 50%, preferably from 10 to 30 %.
The term acid as used herein also includes mixtures of two or more, preferably two of the above compounds. Particular preference is given to the use of one acid. Accordingly, in a particularly preferred embodiment one acid is employed.
The molar ratio of the amino compound of formula (II) to the acid is generally in the range of 1 :0.5 to 1 :10, preferably 1 :1 to 1 :2, more preferably 1 :1.
Preferably the process according to the invention is carried out in a solvent.
Examples of suitable solvents are water, alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1 -butanol, 2-butanol, iso-butanol, tert-butanol, 2-ethyl-hexanol, hexafluoroisopropanol; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, cymene, xylenes, mesitylene, benzotrifluoride; esters such as methyl acetate, ethyl acetate, n-butyl acetate, isobutyl acetate; ethers such as di-n-butyl ether, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), 1 ,4- dioxane, 1 ,2-dimethoxyethane; aliphatic hydrocarbons such as hexanes, cyclohexane; dipolar aprotic solvents such as Ν,Ν-dimethylformamide (DMF), Ν,Ν-dibutylformamide, N,N- dimethylacetamide (DMAC), 1 -methyl-2-pyrrolidinone (NMP), 1 ,3-dimethyl-2-imidazolidinone (DMI), Ν,Ν'-dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), sulfolane.
Preferred solvents are alcohols as mentioned above, and water.
Preferred solvents include methanol, ethanol, isopropanol, toluene, xylenes and water.
More preferred solvents include methanol, toluene and water. More preferred solvents are methanol and toluene.
The term solvent as used herein also includes mixtures of two or more of the above compounds.
Particular preference is given to the use of methanol/toluene/water mixtures.
Also particular preference is given to the use of methanol/toluene mixtures.
In a preferred embodiment the acid and a solvent are pre-charged in the reaction vessel and then the mixture is heated to a definite temperature, before the amino compounds of formula (II) are added.
In another preferred embodiment the acid and a solvent are pre-charged in the reaction vessel and then a solution of the amino compounds of formula (II) in a solvent are dosed to the pre- charged catalyst/solvent mixture in that way, that the benzoxazinones of formula (I) are formed immediately.
In another preferred embodiment the acid and a solvent are pre-charged in the reaction vessel, then a solution of the amino compounds of formula (II) in a solvent are dosed to the pre-charged acid/solvent mixture in that way, that the benzoxazinones of formula (I) are formed immediately and the reaction temperature can be kept constant in a desired range.
After completion or partial completion of the cyclization reaction, the respective mixture can be worked up by means of standard techniques. Examples thereof include extraction, filtration, aqueous work-up, distilling off solvents and/or other volatile compounds. These methods can also be combined with each other. The benzoxazinones of formula (I) can also be used without further purification or can be purified using standard techniques, for example precipitation, recrystallization or column chromatography.
According to one embodiment of the invention, after completion or partial completion of the cy- clization reaction, the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5.
According to one embodiment of the invention, after completion or partial completion of the cyclization reaction, the pH of the reaction mixture is adjusted to slightly acidic, preferably a pH from 3 to 7, more preferably from 4 to 5. According to another embodiment of the invention, after completion or partial completion of the cyclization reaction, the pH of the reaction mixture is adjusted to a pH of 4.
In a further embodiment, the benzoxazinones of formula (I) are isolated by precipitation.
The precipitated benzoxazinones of formula (I) can be isolated by filtration.
According to one embodiment of the invention, the benzoxazinones of formula (I) precipitate upon cooling, preferably to a temperature in the range of from 0 to 30 °C. According to another embodiment of the invention, the benzoxazinones of formula (I) are precipitated by adding water to the reaction mixture.
According to another embodiment of the invention, the benzoxazinones of formula (I) precipitate upon cooling, preferably to a temperature in the range of from 0 to 30 °C, and adding water.
According to another embodiment of the invention, after completion or partial completion of the cyclization reaction, the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5. The benzoxazinones of formula (I) precipitate upon cooling, preferably to a temperature in the range of from 0 to 30 °C and/or adding water.
According to another embodiment of the invention, after completion or partial completion of the cyclization reaction, the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5, and the reaction mixture is cooled, preferably to a temperature in the range of from 0 to 30 °C, to precipitate the benzoxazinones of formula (I).
According to another embodiment of the invention, after completion or partial completion of the cyclization reaction, the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5, and water is added to the reaction mixture to precipitate the benzoxa- zinones of formula (I).
According to another embodiment of the invention, after completion or partial completion of the cyclization reaction, the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5, water is added to the reaction mixture, and the reaction mixture is cooled, preferably to a temperature in the range of from 0 to 30 °C, to precipitate the benzoxazinones of formula (I).
According to another embodiment of the invention, after completion or partial completion of the cyclization reaction, the pH of the reaction mixture is adjusted to slightly acidic, preferably 3 to 7, more preferably 4 to 5. After addition of water the benzoxazinones of formula (I) precipitate in a temperature range from 0 to 30 °C. Such embodiment is preferred.
The benzoxazinones of formula (I) are suitable intermediates for the synthesis of triazinon- benzoxazinones, e.g. as disclosed in WO 2013/092856.
Amino compounds of formula (I I) can prepared by known methods, e.g. by reacting nitro compounds of formula (II I) with a reducing agent to obtain the amino compound of formula (I I),
Figure imgf000013_0001
wherein R1 , R2, R3, R4, R5- R6 and W are as defined above; and
RA is H, Hal, NH2 or N02.
Amino compounds of formula (I I) can also be prepared by adding a nitro compound of formula (I I I) to a reducing agent :
reducing agent
Figure imgf000013_0002
( I I )
wherein the substituents are as herein defined.
The reduction of the nitro compounds of formula (II I) is generally carried out at a temperature in the range of from 0 °C to the boiling point of the solvents, preferably 20 to 80 °C, especially preferred in the range from 35 to 65 °C.
Examples of suitable reducing agents and conditions are known from the literature and can be found inter alia in Advanced Organic Chemistry (ed. J. March), 4th edition, Wiley-lnterscience, NY 1992, p.1216 ff; or Organikum, 22nd edition, Wiley-VCH, Weinheim 2004, p. 626 ff. Examples for reducing agents are molecular hydrogen, hydrazine, formic acid, ammonium formate, borane or borohydrides in combination with a homogeneous or heterogeneous catalyst, for example selected from metal salts of nickel, palladium, platinum, cobalt, rhodium, iridium, ruthenium or copper.
Specific examples for catalysts are palladium on charcoal, palladium on alumina, palladium on BaS04, platinum on charcoal, platinum on alumina, platinum(IV) oxide, Raney nickel, rhodium on alumina, ruthenium on alumina. Further examples of suitable reducing agents are metals in their elemental form such as magnesium, iron, zinc, tin or metal salts such as tin(ll) chloride in combination with an acid such as hydrochloric or acetic acid.
Further examples of suitable reducing agents are sulfur compounds like sodium hydrosulfite, rongalite, sodium sulfide, sodium hydrogen sulfide and ammonium polysulfide.
In a preferred embodiment of the process according to the invention the reducing agent is molecular hydrogen in combination with a homogeneous or heterogeneous hydrogenation catalyst.
Examples for hydrogenation catalysts are catalyst selected from the group consisting of metal salts of nickel, palladium, platinum, cobalt, rhodium, iridium, ruthenium or copper.
Specific examples for hydrogenation catalysts include palladium on charcoal, palladium on alu- mina, palladium on BaS04, platinum on charcoal, platinum on alumina, platinum(IV) oxide, Raney nickel, rhodium on alumina, ruthenium on alumina.
Preferred reducing agents are molecular hydrogen in combination with palladium on charcoal, palladium on alumina, palladium on BaS04, molecular hydrogen in combination with platinum on charcoal, platinum on alumina.
Especially preferred reducing agents are molecular hydrogen in combination with palladium on charcoal or platinum on charcoal. A more preferred reducing agent is molecular hydrogen in combination with palladium on charcoal.
Also a more preferred reducing agent is molecular hydrogen in combination with platinum on charcoal. The term reducing agent as used herein also includes mixtures of two or more, preferably two of the above compounds. Particular preference is given to the use of one reducing agent.
Accordingly, in a particularly preferred embodiment one reducing agent is employed in the pro- cess according to the invention.
The molar ratio of the nitro compound of formula (III) to the reducing agent is generally in the range of 1 :2 to 1 :15, preferably 1 :2.5 to 1 :10, more preferably 1 :3 to 1 :6.
In a preferred embodiment the reducing agent and the solvent are pre-charged in the reaction vessel and then the mixture is heated to a definite temperature, before the nitro compound of formula (III) is added.
In another preferred embodiment the reducing agent and the solvent are pre-charged in the reaction vessel and then the nitro compound of formula (III) is dosed to the pre-charged catalyst/solvent mixture in such way, that the nitro compound of formula (III) is reduced immediately, and thus the stationary concentration of nitro compound of formula (III) in the reaction mixture is very low.
In another preferred embodiment with the reducing agent being molecular hydrogen in combination with a catalyst, the catalyst and the solvent are pre-charged in the reaction vessel, the mix- ture is heated to a definite temperature, and then pressurized with hydrogen under stirring before the nitro compound of formula (III) is added.
In another preferred embodiment with the reducing agent being molecular hydrogen in combination with a catalyst, the catalyst and the solvent are pre-charged in the reaction vessel and then a solution of the nitro compound of formula (III) in a solvent is dosed to the pre-charged catalyst/solution mixture in that way, that the nitro compound of formula (III) is reduced immediately.
In another preferred embodiment with the reducing agent being molecular hydrogen in combination with a catalyst, the catalyst and the solvent are pre-charged in the reaction vessel and then a solution of the nitro compound of formula (III) in a solvent is dosed to the pre-charged catalyst/solution mixture in such way, that the nitro compound of formula (III) is reduced immediately, and thus the stationary concentration of nitro compound of formula (III) in the reaction mixture is very low. In another preferred embodiment with the reducing agent being molecular hydrogen in combination with a catalyst, the catalyst and the solvent are pre-charged in the reaction vessel and then a solution of the nitro compound of formula (III) in a solvent is dosed to the pre-charged catalyst/solvent mixture in that way, that the nitro compound of formula (III) is reduced immediately and the reaction temperature can be kept constant in a desired range.
In another preferred embodiment with the reducing agent being molecular hydrogen in combination with a catalyst, first the mixture of the catalyst and a solvent are stirred at a temperature in the range of from 20 to 80 °C, preferably 40 to 60 °C, in the presence of hydrogen at a pressure in the range of from 0 to 20 bar, preferably 0 to 10 bar; and then the nitro compound of formula (III) is added.
The process according to the invention is carried out under an elevated pressure of up to 20 bar, preferably up to 10 bar.
Preferably, the reduction of the nitro compounds of formula (III) is carried out in a solvent.
Examples of suitable solvents are water, alcohols such as methanol, ethanol, 1 -propanol, 2- propanol, 1-butanol, 2-butanol, iso-butanol, tert-butanol, 2-ethyl-hexanol, hexafluoroisopropanol; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, cymene, xylenes, mesitylene, benzotrifluoride; esters such as methyl acetate, ethyl acetate, n-butyl acetate, isobutyl acetate; ethers such as di-n-butyl ether, tert-butyl methyl ether (TBME), tetrahydrofuran (THF), 1 ,4- dioxane, 1 ,2-dimethoxyethane; aliphatic hydrocarbons such as hexanes, cyclohexane; dipolar aprotic solvents such as Ν,Ν-dimethylformamide (DMF), Ν,Ν-dibutylformamide, N,N- dimethylacetamide (DMAC), 1 -methyl-2-pyrrolidinone (NMP), 1 ,3-dimethyl-2-imidazolidinone (DMI), Ν,Ν'-dimethylpropylene urea (DMPU), dimethyl sulfoxide (DMSO), sulfolane. Preferred solvents include methanol, toluene and xylenes.
More preferred solvents include methanol and toluene.
The term solvent as used herein also includes mixtures of two or more of the above solvents. Preference is given to the use of methanol/toluene mixtures or methanol/xylenes mixtures. Particular preference is given to the use of methanol/toluene mixtures.
After completion or partial completion of the reaction, the respective mixture can be worked up by means of standard techniques. Examples thereof include extraction, filtration, aqueous work- up, distilling off solvents and/or other volatile compounds. These methods can also be combined with each other.
In a preferred embodiment the hydrogen source is removed and the catalyst is filtered off.
In another preferred embodiment the reaction mixture is brought to room temperature and the catalyst is filtered off. The solvent is partly or completely distilled off.
The product precipitates upon cooling, preferably to a temperature in the range of from 0 to 30 °C and/or adding water. The precipitated amino compound of formula (I) can be isolated by filtration.
The amino compounds of formula (II) are suitable intermediates for the synthesis of benzoxazi- nones of formula (I).
Accordingly, in a further preferred embodiment of the invention benzoxazinones of formula (I) are prepared by
(i) reacting nitro compounds of formula (III)
Figure imgf000017_0001
wherein R1, R2, R3, R5- R6 and W are as defined above; and RA is H, Hal, NH2 or N02;
with a reducing agent to obtain amino compounds of formula (II); and
(ii) adding such amino compounds of formula (II) to an acid.
In another preferred embodiment of the invention benzoxazinones of formula (I) are prepared by
(i) adding nitro compounds of formula (III) to a reducing agent to obtain amino compounds of formula (II); and
(ii) adding such amino compounds of formula (II) to an acid.
In one embodiment the amino compounds of formula (II) are isolated prior to being used in step (ii).
In another embodiment the amino compounds of formula (II) are not isolated, and the reaction mixture obtained in step (i) is directly used in step (ii).
Such embodiment is preferred. In another embodiment the amino compounds of formula (II) are not isolated, and the reaction mixture obtained in step (i) is directly used in step (ii) under inert conditions, especially under exclusion of oxygen.
Such embodiment is especially preferred.
According to another embodiment of the invention, the catalyst is filtered off, and the filtrate containing the amino compound of formula (II) used in one or more subsequent reaction step(s). In another preferred embodiment the catalyst is filtered off and the amino compound of formula (II) is not isolated, but the filtrate containing such amino compound of formula (II) is dosed immediately in another reactor to be used in one or more subsequent reaction step(s).
Preferably such filtration is conducted under inert conditions, especially under exclusion of oxy- gen.
According to another embodiment of the invention, the catalyst is filtered of and recycled.
In another particular embodiment, the solvent is not exchanged between carrying out steps (i) and (ii).
In another preferred embodiment with the reducing agent being molecular hydrogen in combination with a catalyst, a mixture of nitro compounds of formula (III), the catalyst, and a solvent are stirred at a temperature in the range of from 20 to 60 °C, preferably 40 to 60 °C, in the presence of hydrogen at a pressure in the range of from 0 to 20 bar, preferably 0 to 10 bar. After completion or partial completion of step (i), the hydrogen source is removed. The catalyst is optionally filtered off, and the filtrate is subsequently used in step (ii), i.e. is added to the acid. Such reaction mixture is then stirred at a temperature in the range of from 20 to 65 °C, preferably 40 to 65 °C, for 0.5 to 5 h, preferably 0.5 to 2 h.
In another embodiment the reaction mixture is brought to room temperature and the catalyst is filtered off. Then the filtrate is subsequently used in step (ii), i.e. is added to the acid.
In another embodiment the catalyst is filtered off from the reaction mixture in a temperature range of 50 to 60 °C. The filter cake is washed with methanol up to three times. Then the filtrate is subsequently used in step (ii), i.e. is added to the acid. In another embodiment the catalyst is filtered off from the reaction mixture and the filtrate is brought to room temperature. Then the filtrate is subsequently used in step (ii), i.e. is added to the acid.
The nitro compounds of formula (III) can be prepared by known methods, e.g. as described in WO 2013/092856.
The invention is illustrated by the following examples without being limited thereto or thereby. 1 . Preparation of benzoxazinones of formula (I)
Synthesis of 6-amino-2,2,7-trifluoro-4H-benzo-[1 ,4]-oxazin-3-one from 2,2-difluoro-2-(2,4-dinitro- 5-fluoro-phenoxy)]-N,N-dimethyl-acetamide
Figure imgf000019_0001
Example 1.1 :
29.45 g (0.0005 mol) Pt on charcoal (0.8% Pt in dry catalyst; 58.6% water content) and 827.7 g methanol were placed in the reaction vessel.
The mixture was heated to 40°C and then pressurized with 2 bar H2 under vigorous stirring. A solution of 323.2 g (1.00 mol) 2,2-difluoro-2-(2,4-dinitro-5-fluoro-phenoxy)-N,N-dimethyl- acetamide in 1292.8 g toluene was dosed within 3 hours. The transfer pipe was purged with 82.9 g toluene.
The temperature of the reaction mixture was held constantly at 39 - 41 °C by cooling. After completion of the reaction the pressure is released and the catalyst is filtered off through a pressure filter (1 bar nitrogen overpressure).
Then the filtrate (containing the respective amino compound (III) intermediate) was piped into a second reactor and there at 60°C dosed to 376.0 g (1.15 mol) pre-charged sulfuric acid (30% in water).
The remaining catalyst was washed with 200 g methanol, which was then filled into the hydro- genation reactor, pressed through the filter cake, and then also piped into the second reactor containing the sulfuric acid reaction mixture. Such reaction mixture was stirred for additional 50 minutes at 60°C. Then NaOH (25% in H2O) was added to the mixture to adjust the pH from 1 .8 to 4. Afterwards 1652.9 g water was added and the suspension was cooled to 15°C. The precipitated solid was filtered off, washed three times with 142.9 g water in each case and dried under reduced pressure at 50°C resulting in 21 1.4 g of the desired product having 98% purity determined by quanti- tative HPLC method as described below (t.R = 12.73 min; corresponding chemical yield 95%).
Chromatographic conditions:
Column: Symmetry C18 5 μηη 250 x 4.6 mm from Waters
Wavelength: 210 nm
Eluent: gradient of A (0.1 % by volume of H3PO4 in H20) and B (0.1 % by volume of
H3PO4 in acetonitrile); starting with 10% B, then B rising from 10% to 50% within 10 min, then B rising from 50% to 90% within 20 min, then back to 10% B within 2 min, then 8 min 10% B
Flow rate: 1 ml/min
Pressure: approx. 160 bar
1H NMR (DMSO-de, 500 MHz): δ (ppm) = 11 .9 (bs, 1 H); 7.15 (d, 1 H); 6.55 (d, 1 H); 5.28 (bs, 2 H).
Comparative Example 1 .2 (WO 13/092856, example 1 .1 )
To a solution of 2,2-difluoro-2-(2,4-dinitro-5-fluoro-phenoxy)-/V,/V-dimethyl-acetamide (60.0 g, 186 mmol) in toluene (432 g) was added Pd on charcoal (5% Pd, 50% water content,
1 .1 mmol). Thereafter methanol (492 g) was added and the mixture was stirred under an atmosphere of hydrogen (over pressure 0.1 bar) at 45 °C for 2 h. After completion of the reaction the pressure was released, concentrated HCI (36.5%, 22 g, 220 mmol) added and the reaction mixture heated to reflux for further 1 h. The catalyst was filtered off, the pH adjusted with NaOH to 9 and the methanol distilled off under reduced pressure. After addition of water (200 g) and stirring for 1 h the precipitate was filtered off, washed twice with water (100 g) and dried at 50 °C under reduced pressure. The product was obtained as a tan solid (38.9 g, 90% pure by NMR, 160 mmol, 86% yield).
1H NMR (DMSO-de, 500 MHz): δ (ppm) = 1 1.9 (bs, 1 H); 7.15 (d, J = 1 1.0 Hz, 1 H); 6.55 (d, J = 8.5 Hz, 1 H); 5.28 (bs, 2 H).
13C NMR (DMSO-de, 125 MHz): δ (ppm) = 153.7 (t, J = 38 Hz); 146.1 (d, J = 235 Hz); 133.9 (d, J = 15 Hz); 127.3 (d, J = 1 1 Hz); 120.9 (d, J = 3 Hz); 1 13.1 (t, J = 260 Hz); 104.9 (d, J = 24 Hz); 102.4 (d, J = 5 Hz).
2. Preparation of amino compounds of formula (II) Synthesis of 2,2-Difluoro-2-(2,4-diamino-5-fluoro-phenoxy)-N,N-dimethyl-acetamide
Figure imgf000021_0001
Example 2.1 :
29.8 g (0.007 mol) Pd/C (5% Pd in dry catalyst; 50% water content) and 579.4 g methanol were placed in the reaction vessel. The mixture was heated to 40°C and then pressurized with 2 bar H2 under vigorous stirring.
A solution of 226.3 g (0.7 mol) 2,2-difluoro-2-(2,4-dinitro-5-fluoro-phenoxy)-N,N-dimethyl- acetamide in 895.7 g toluene was dosed within 3 hours. The transfer pipe was purged with 58 g toluene.
The temperature of the reaction mixture was held constantly at 39 - 41 °C with cooling.
After completion of the reaction the pressure was released and the catalyst was filtered off through a pressure filter (1 bar nitrogen overpressure). The remaining catalyst was washed with 140 g methanol. The filtrate and wash methanol were combined and evaporated to dryness.
193.7 g of the desired product have been obtained having 90% purity determined by quantitative HPLC method as described below (t.R = 8.02 min; corresponding chemical yield 94% yield). Chromatographic conditions:
Column: Symmetry C18 5 μηη 250 x 4.6 mm from Waters
Wavelength: 210 nm
Eluent: gradient of A (0.1 % by volume of H3PO4 in H20) and B (0.1 % by volume of
H3PO4 in acetonitrile); starting with 10% B, then B rising from 10% to 50% within 10 min, then B rising from 50% to 90% within 20 min, then back to
10% B within 2 min, then 8 min 10% B
Flow rate: 1 ml/min
Pressure: approx. 160 bar
1H NMR (DMSO-d6, 400 MHz): δ (ppm) = 6.79 (d, 1 H); 6.16 (d, 1 H); 4.95 (bs, 2 H); 4.60 (bs, 2 H); 3.19 (s, 3 H); 2.95 (s, 3 H).
Comparative example 1.2 (WO 13/092856, example 3.1 ):
To a solution of 2,2-difluoro-2-(2,4-dinitro-5-fluoro-phenoxy)-A/,A/-dimethyl-acetamide (22.0 g, 68.1 mmol) in toluene (200 g) Pd/C (10% Pd, dry catalyst, 0.7 g, 0.7 mmol) was added. Thereafter, methanol (80 g) was added and the mixture was stirred under an atmosphere of hydrogen (pressure of 0.1 bar) at 45 °C for 90 min. After completion of the reaction the pressure was released, the catalyst was filtered off and the filtrate was evaporated to dryness.
The product (17.3 g, 84% pure by NMR, 55.2 mmol, 81 % yield) was obtained as an off-white solid. If desired, the purity can be increased by chromatography (S1O2, cyclohexane/EtOAc mix- tures).
H NMR (DMSO-de, 500 MHz): δ (ppm) = 6.79 (d, J = 1 1.0 Hz, 1 H); 6.16 (d, J = 8.5 Hz, 1 H); 4.95 (bs, 2 H); 4.60 (bs, 2 H); 3.19 (s, 3 H); 2.96 (bs, 3 H).
3C NMR (DMSO-de, 125 MHz): δ (ppm) = 158.3 (t, J = 35 Hz); 141.7 (d, J = 278 Hz); 137.6; 134.9 (d, J = 14 Hz); 123.9 (d, J = 9 Hz); 1 15.8 (t, J = 272 Hz); 109.2 (d, J = 22 Hz); 102.0 (d, J = 4 Hz); 36.9; 36.2.

Claims

Claims
1. A process for manufacturing benzoxazinones of formula (I),
Figure imgf000023_0001
wherein
R1 is H or halogen;
R2 is halogen;
R3 is H or halogen;
R4 is H, Hal or NH2; and
W is O or S; characterized in that amino compounds of formula (II)
Figure imgf000023_0002
wherein R1, R2, R3, R4 and W are defined as in formula (I);
R5, R6 are independently of each other Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, d-Ce-haloalkyl, d-Ce-cyanoalkyl, d-Ce-nitroalkyl, d-Ce-hydroxyalkyl, d-Ce- alkoxy-d-Ce-alkyl, amino-d-Ce-alkyl, (d-Ce-alky amino-d-Ce-alkyl, di(d- C6-alkyl)amino-Ci-C6-alkyl, Cs-Ce-cycloalkyl, phenyl or benzyl, wherein the phenyl and the benzyl ring are independently of one another unsubstituted or substituted withl to 5 substituents selected from the group consisting of halogen, d-C6-alkyl or d-di-alkoxy, or R5 and R6 together with the N atom which they are attached to, represent a saturated or aromatic 3- to 6-membered ring, optionally containing 1 to 3 additional heteroatoms from the group O, S and N, with the ring optionally being substituted with 1 to 3 d-C6-alkyl substituents; are added to an acid.
The process according to claim 1 , wherein R1 and R3 are halogen.
3. The process according to claims 1 or 2, wherein R4 is NH2. The process according to claims 1 to 3, wherein R5 and R6 are independently of one another Ci-C6-alkyl.
5. The process according to claims 1 to 4 wherein the acid is selected from hydrochloric acid and sulfuric acid.
6. The process according to claims 1 to 5, wherein the process is carried out in a solvent selected from methanol/toluene mixtures. 7. The process according to claims 1 to 6, wherein the acid and a solvent are pre-charged in the reaction vessel and then a solution of the amino compounds of formula (II) in a solvent are dosed to the pre-charged catalyst/solvent mixture in that way, that the benzoxazi- nones of formula (I) are formed immediately. 8. The process according to claims 1 to 7, wherein after completion or partial completion of the cyclization reaction, the pH of the reaction mixture is adjusted to a pH from 3 to 7. 9. The process according to claims 1 to 8, wherein the benzoxazinones of formula (I) are precipitated by adding water to the reaction mixture.
10. The process according to claims 1 to 9 comprising the following steps:
(i) reacting nitro compounds of formula (III)
Figure imgf000024_0001
wherein R1 , R2, R3, R5- R6 and W are as defined above; and RA is H, Hal, NH2 or N02; with a reducing agent to obtain amino compounds of formula (II); and (ii) adding such amino compounds of formula (II) to an acid.
1 1 The process according to claiml O, wherein in step (i) the nitro compounds of formula (II) are added to the reducing agent.
12 The process according to claims 10 or 1 1 wherein the reducing agent is molecular hydrogen in combination with a homogeneous or heterogeneous hydrogenation catalyst.
13. The process according to claim12, wherein the catalyst is filtered off and the filtrate containing the amino compound of formula (II) used in step (ii).
14. The process according to any of claims 10 to 13, wherein the reducing agent and the sol- vent are pre-charged in the reaction vessel and then the nitro compound of formula (III) is dosed to the pre-charged catalyst/solvent mixture in such way, that the nitro compound of formula (III) is reduced immediately.
15. The process according to any of claims 10 to 14, wherein the amino compounds of formula (III) are not isolated, and the reaction mixture obtained in step (i) is directly used in step (ii).
PCT/EP2015/056541 2014-04-16 2015-03-26 Process for manufacturing benzoxazinones WO2015158518A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP14164944 2014-04-16
EP14164944.2 2014-04-16

Publications (1)

Publication Number Publication Date
WO2015158518A1 true WO2015158518A1 (en) 2015-10-22

Family

ID=50479119

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2015/056541 WO2015158518A1 (en) 2014-04-16 2015-03-26 Process for manufacturing benzoxazinones

Country Status (1)

Country Link
WO (1) WO2015158518A1 (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3184515A1 (en) 2015-12-22 2017-06-28 Basf Se Process for manufacturing 1,4-benzoxazinones
US10023590B2 (en) 2014-04-17 2018-07-17 Basf Se Substituted pyridine compounds having herbicidal activity
US10053436B2 (en) 2014-07-08 2018-08-21 BASF Agro B.V. Process for the preparation of substituted oxiranes and triazoles
US10093634B2 (en) 2013-12-18 2018-10-09 BASF Agro B.V. Process for the preparation of substituted phenoxyphenyl ketones
US10167297B2 (en) 2014-10-24 2019-01-01 Basf Se Substituted pyridine compounds having herbicidal activity
US10344008B2 (en) 2015-05-08 2019-07-09 BASF Agro B.V. Process for the preparation of terpinolene epoxide
US10538470B2 (en) 2015-05-08 2020-01-21 BASF Agro B.V. Process for the preparation of limonene-4-ol
US10640477B2 (en) 2016-06-15 2020-05-05 BASF Agro B.V. Process for the epoxidation of a tetrasubstituted alkene
US11072593B2 (en) 2016-06-15 2021-07-27 BASF Agro B.V. Process for the epoxidation of a tetrasubstituted alkene

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013092859A1 (en) * 2011-12-23 2013-06-27 Basf Se Process for manufacturing 4-substituted amino-benzoxazinones
WO2013092858A1 (en) * 2011-12-23 2013-06-27 Basf Se Process for manufacturing triazinon-benzoxazinones
WO2013092856A1 (en) * 2011-12-23 2013-06-27 Basf Se Process for manufacturing benzoxazinones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013092859A1 (en) * 2011-12-23 2013-06-27 Basf Se Process for manufacturing 4-substituted amino-benzoxazinones
WO2013092858A1 (en) * 2011-12-23 2013-06-27 Basf Se Process for manufacturing triazinon-benzoxazinones
WO2013092856A1 (en) * 2011-12-23 2013-06-27 Basf Se Process for manufacturing benzoxazinones

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D. A. JOHNSON ET AL: "Nonenzymatic Conversion of Penicillins to 6-Aminopenicillanic Acid", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 31, no. 8, 1 August 1966 (1966-08-01), pages 2560 - 2564, XP055028090, ISSN: 0022-3263, DOI: 10.1021/jo01346a027 *
HENRI TÉCHER ET AL: "Amides tertiaires de l'acide oxo-3-dihydro-2,3 benzoxazine-1,4 carboxylique-2", COMPTES RENDUS DES SEANCES DE L'ACADEMIE DES SCIENCES, SERIE C: SCIENCES CHIMIQUES, 1970 , VOL. 270, P. 107 - 110, vol. 270, 1 January 1970 (1970-01-01), pages 107 - 110, XP055026720 *
KLEIN W ET AL: "POTENTIELLE ANALGETIKA, 5. MITT", ARCHIV DER PHARMAZIE, WILEY VERLAG, WEINHEIM, vol. 308, no. 12, 1 January 1975 (1975-01-01), pages 910 - 916, XP002471345, ISSN: 0365-6233, DOI: 10.1002/ARDP.19753081203 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10093634B2 (en) 2013-12-18 2018-10-09 BASF Agro B.V. Process for the preparation of substituted phenoxyphenyl ketones
US10023590B2 (en) 2014-04-17 2018-07-17 Basf Se Substituted pyridine compounds having herbicidal activity
US10053436B2 (en) 2014-07-08 2018-08-21 BASF Agro B.V. Process for the preparation of substituted oxiranes and triazoles
US10167297B2 (en) 2014-10-24 2019-01-01 Basf Se Substituted pyridine compounds having herbicidal activity
US10344008B2 (en) 2015-05-08 2019-07-09 BASF Agro B.V. Process for the preparation of terpinolene epoxide
US10538470B2 (en) 2015-05-08 2020-01-21 BASF Agro B.V. Process for the preparation of limonene-4-ol
EP3184515A1 (en) 2015-12-22 2017-06-28 Basf Se Process for manufacturing 1,4-benzoxazinones
US10640477B2 (en) 2016-06-15 2020-05-05 BASF Agro B.V. Process for the epoxidation of a tetrasubstituted alkene
US11072593B2 (en) 2016-06-15 2021-07-27 BASF Agro B.V. Process for the epoxidation of a tetrasubstituted alkene

Similar Documents

Publication Publication Date Title
WO2015158518A1 (en) Process for manufacturing benzoxazinones
WO2013092856A1 (en) Process for manufacturing benzoxazinones
US9546130B2 (en) Process for manufacturing haloacetamides
AU2013304167B2 (en) Process for manufacturing benzoxazinones
DK2885281T3 (en) CARBAMATE BENZOXAZINONES USED FOR THE PREPARATION OF TRIAZIN-BENZOXAZINONES
EP2794579A1 (en) Process for manufacturing 4-substituted amino-benzoxazinones
EP2794599A1 (en) Process for manufacturing triazinon-benzoxazinones
WO2014012811A1 (en) Process for manufacturing fluoroaromatics
EP2885272A1 (en) Carbamates
DK2794554T3 (en) Method of producing aryloxyacetamider
JP5555426B2 (en) Method for producing sulfonamides
EP2933242A1 (en) Process for manufacturing amino compounds
EP3184515A1 (en) Process for manufacturing 1,4-benzoxazinones
Maciejewska et al. Development of highly active anti-Pneumocystis benzamidines: Insight into the influence of selected substituents on the in vitro activity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15712148

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15712148

Country of ref document: EP

Kind code of ref document: A1