Patent EA-001935-B1 (EA)
Title: SYNTHESIS OF alpha-CHLORO OR FLUORO KETONES
Inventor: DOLLING ULF H
IPC: C07C45/45
Filed: 1996-09-11
Abstract: 1. A process of making an α-chloro or fluoroketone of the formula I   wherein Y is chloro or fluoro and A is a carbon nucleophile, which is optionally subtstituted phenyl, 3,4-dimethoxyphenyl, benzofuranyl, furanyl, imidazolyl, indolyl, isothiozolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, triazolyl, thienyl, C1-10 alkyl, C2-3alkenyl, C2-3alkynyl comprising: (a) reacting an organometallic reagent of formula II A-M                           (II) wherein M is Li or Mg, with a compound of formula III   wherein X is -NR(OR<1>), R and R<1> are each independently linear or branched C1-3-alkyl, C3-6-cycloalkyl, or optionally substituted with C1-3-alkoxy, phenyl, subtstituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl in an organic aprotic solvent, and (b) reacting, without further purification, the product of step (a) with an aqueous solution of acid G, to yield an organic aprotic solvent phase, comprising the compound of formula I is and aqueous phase of the solvent, comprising the compound of formula III' HNR(OR<1>)xG               III'   2. A process according Claim 1 wherein Y is chloro and G acid is selected from the group, consisting of hydrochloric acid, hydrobromic, sulphuric acid, methanesulfonic, toluenesulfonic, phosphoric acid. 3. A process according Claim 1 wherein an organic aprotic solvent is selected from the group, consisting of diethyl ether, di-n-butyl and diisopentyl ether, anisole, cyclic ethers, such as tetrahydropyran, 4-methyl-1,3-dioxane, tetrahydrofurfurylmethyl ether, ethylic ether, furan and tetrahydrofuran or the mixture thereof. 4. A process according Claim 1 wherein the carbon nucleophile is an optionally substituted phenyl, 3,4-dimethoxyphenyl, benzofuranyl, thienyl, C1-10-alkyl, C2-3-alkenyl, C2-3-alkynyl, wherein the substitutent is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio and C1-3-alkyl. 5. A process according Claim 1 wherein R and R<1> are each independently linear or branched C1-3-alkyl, C3-6-cycloalkyl, or optionally substituted with C1-3-alkoxy, phenyl, substituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and C1-3-alkyl. 6. A process according Claim 1 wherein the compound of formula I is   the compound of formula II is   and X is -NCH3(OCH3). 7. A process for obtaining of the compound of formula III   wherein X is -NR(OR<1>), Y is chloro or fluoro and R and R<1> are each independently linear or branched C1-3-alkyl, C3-6-cycloalkyl, or optionally substituted with C1-3-alkoxy, phenyl, substituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and C1-3-alkyl, comprising acylating HNR(OR<1>) hydrochloride with chloroacetylchloride in a two phase mixture of aqueous base and a non-reactive water insoluble organic solvent to yield a compound of formula III. 8. A process according to Claim 7 wherein Y is chloro and the base is selected from the group consisting of pyridine, tri-C1-3-alkylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. 9. A process according to Claim 7 wherein R and R<1> are each independently linear or branched C1-3-alkyl, C3-6-cycloalkyl, or optionally substituted with C1-3-alkoxy, phenyl, substituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and C1-3-alkyl. 10. A process according to Claim 7 wherein non-reactive water insoluble organic solvent comprises toluene, methyl-tert-butyl ether, hexane, heptane, methylene chloride, dichlorethane, dichlorobenzene, monochlorobenzene or the mixture thereof, but is not limited by them. 11. A process for obtaining of the compound of formula III   wherein X is -NR(OR<1>), Y is chloro or fluoro and R and R<1> are each independently linear or branched C1-3-alkyl, C3-6-cycloalkyl, or optionally substituted with C1-3-alkoxy, phenyl, subtstituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and C1-3-alkyl, comprising separating from the product of reaction step (b) the aqueous solvent phase according to Claim 1, said aqueous solvent phase comprising a compound of formula III' HNR(OR<1>)xG                 (III') wherein G is an acid, and reacting, without further purification, the aqueous solvent phase with chloroacetylchloride in a bi-phasic mixture of aqueous K2CO3 and MTBE or toluene, to yield compound of formula III. 12. A process according Claim 1 wherein Y is chloro and G acid is selected from the group, consisting of hydrochloric acid, hydrobromic, sulphuric acid, methanesulfonic, toluenesulfonic, phosphoric acid. 13. A process according Claim 11 wherein R and R<1> are each independently linear or branched C1-3-alkyl, C3-6-cycloalkyl, or optionally substituted with C1-3-alkoxy, phenyl, substituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and C1-3-alkyl. 14. A process of making an α-chloro or fluoroketone of the formula I   wherein Y is chloro or fluoro and A is a carbon nucleophile, which is optionally substituted phenyl, 3,4-dimethoxyphenyl, benzofuranyl, furanyl, imidazolyl, indolyl, isothiazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolyl, triazolyl, thienyl, C1-10-alkyl, C2-3-alkenyl, C2-3-alkynyl comprising: (a) reacting an organometallic reagent of formula II A-M                           (II) wherein M is Li or Mg, with a compound of formula III   wherein X is -NR(OR<1>), R and R<1> are each independently linear or branched C1-3-alkyl, C3-6-cycloalkyl, or optionally substituted with C1-3-alkoxy, phenyl, subtstituted phenyl, wherein the substituent on the phenyl is selected from F, Cl, Br, methylthio, -OH, methoxy, aminothio, and C1-3-alkyl, in an organic aprotic solvent, and (b) reacting, without further purification, the product of step (a) with an aqueous solution of acid G, to yield an organic aprotic solvent phase, comprising the compound of formula I is and aqueous phase of the solvent, comprising the compound of formula III' HNR(OR<1>)xG               III' separating the organic phase with obtaining the compound of formula I and acylation of aqueous solvent phase comprising HNR(OR<1>) hydrochloride, with chloroacetylchloride in a bi-phasic mixture of aqueous base and non-reactive water insoluble organic solvent to yield compound of formula III wherein the bi-phasic mixture is separated and reacting with the compound of formula II is carried out in order to repeat continuously the obtaining of the compound of formula I.