Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
  • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
  • C07C211/54—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings
  • C07C211/56—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to two or three six-membered aromatic rings the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/40—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/42—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to carbon atoms of at least one six-membered aromatic ring and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
• • 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
  • C07C233/12—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 halogen atoms or by nitro or nitroso groups
  • C07C233/15—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 halogen atoms or by nitro or nitroso 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
  • C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/32—Oxygen atoms
  • C07D209/34—Oxygen atoms in position 2
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

• the present invention relates to processes for the production of 2-phenylamino-5-alkylphenyl acetic acids (the compounds of formula I given below), intermediates therefor and pharmaceutically acceptable salts thereof and pharmaceutically acceptable prodrug esters thereof;
• the invention provides a process for the production of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable and physiology cleavable prodrug ester thereof, comprising cleaving a lactam of formula II
• the above processes may include, if desired, temporarily protecting any interfering reactive groups and then isolating the resulting compound of the invention; and, if desired, converting the free carboxylic acid of the compound of formula I into a pharmaceutically acceptable ester derivative thereof; and/or if desired, converting the free acid of formula I into a salt or a resulting salt into the free acid or into another salt.
• the above processes may be carried out under conditions known in the art for the hydrolytic cleavage of lactams, preferably with a strong base, such as aqueous sodium hydroxide (e.g. a 30% aqueous solution of NaOH), optionally in the presence of a water miscible organic solvent such as ethanol or methanol, preferably at elevated temperature, e.g. at a temperature in the range from about 50° to 100° C., (for instance as generally described in U.S. Pat. No. 3,558,690).
• the resultant reaction mixture is conveniently neutralised with an acid, e.g. a mineral acid such as hydrochloric acid to give the free acid product of formula I, which may be recovered by crystallisation, e.g. on cooling of the reaction mixture to ambient temperature, and filtration.
• a strong base such as aqueous sodium hydroxide (e.g. a 30% aqueous solution of NaOH)
• a water miscible organic solvent such as ethanol or methanol
• prodrug esters are ester derivatives which are convertible by solvolysis or under physiological conditions to the free carboxylic acids of formula I.
• esters are e.g. lower alkyl esters (such as the methyl or ethyl ester), carboxy-lower alkyl esters such as the carboxymethyl ester, nitrooxy-lower alkyl esters (such as the 4-nitrooxybutyl ester), and the like.
• Pharmaceutically acceptable salts represent metal salts, such as alkaline metal salts, e.g. sodium, potassium magnesium or calcium salts, as well as ammonium salts, which are formed e.g. with ammonia and mono- or di-alkylamines, such as diethylammonium salts, and with amino acids such as arginine and histidine salts.
• alkaline metal salts e.g. sodium, potassium magnesium or calcium salts
• ammonium salts which are formed e.g. with ammonia and mono- or di-alkylamines, such as diethylammonium salts, and with amino acids such as arginine and histidine salts.
• Preferred compounds of formula I which may be prepared according to the present invention include:
• Particularly preferred compounds of formula I which may be prepared according to the present invention include:
• the processes of the invention may be used to prepare compounds of formula I in which R is methyl or ethyl; R 1 , is chloro or fluoro; R 2 is hydrogen; R 3 is hydrogen, fluoro, chloro, methyl or hydroxy, R 4 is hydrogen; R 5 is chloro, fluoro or methyl; or a pharmaceutically acceptable salt or a pharmaceutically acceptable prodrug ester thereof.
• the lactam of formula I may be prepared by oxidation of a lactam of formula III
• Standard mild oxidation conditions may be used, such as heating with catalytical amounts of palladium on charcoal in a proper solvent, e.g. xylene.
• the lactam of formula III may be prepared by coupling an aniline derivative of formula IV
• R is ethyl or methyl and R′ is lower alkyl or similar.
• Coupling of IV with Va and Vb typically involves elimination of water or the secondary amine, HNR′ 2 , e.g. under acidic conditions.
• Vb may be prepared by reaction of the amino substitutes cyclohexene derivative of formula Vb′
• Vb may be converted to Va by hydrolysis, for instance as hereinafter described in the Examples.
• the cyclisation process is conveniently carried out under Friedel-Crafts alkylation conditions, e.g. in the presence of a Friedel-Crafts catalyst such as aluminium chloride or ethyl aluminium dichloride, preferably at elevated temperature, e.g. a temperature in the range from about 100° to about 180° C.
• a Friedel-Crafts catalyst such as aluminium chloride or ethyl aluminium dichloride
• elevated temperature e.g. a temperature in the range from about 100° to about 180° C.
• the cyclisation reaction may be carried out in the presence of an inert solvent such as dichlorobenzene, or preferably a melt of the compound of formula VII is heated with the Friedel-Crafts catalyst.
• the compound of formula VII is prepared by N-acylation of a diphenylamine of formula VII
• the compound of formula VIII is heated e.g. to about 80° C., with chloroacetylchloride.
• the product may be recovered by diluting the reaction mixture with solvent, e.g. 2-propanol, and crystallisation.
• the compound of formula VIII may be obtained by rearrangement and hydrolysis of a compound of formula IX.
• the compound of formula IX is treated with an organic base, e.g. an alkali metal alkoxide such as sodium methoxide, preferably with beating, e.g. to a temperature of at least about 75° C.
• an organic base e.g. an alkali metal alkoxide such as sodium methoxide
• beating e.g. to a temperature of at least about 75° C.
• diphenylamine compound of formula VIII may be obtained by coupling of the corresponding halobenzene derivative of formula XI
• X is a halogen, e.g. I or Br, and the other symbols are as defined above with p-toluidine or 4-ethyl aniline.
• Such a coupling reaction may be carded out by use of Buchwald chemistry.
• the compound of formula XI and the p-toluidine or 4-ethyl aniline are mixed with an organic base, e.g. sodium tertiary butylate, and an appropriate ligand, e.g. BINAP, in an organic solvent such as toluene; a palladium compound or catalyst precursor such as Pd(dba) 2 is added and the reaction mixture is heated.
• acid e.g. HCl
• the diphenylamine product of formula VIII may be recovered from the organic phase of the reaction mixture.
• diphenylamine compound of formula VIII may be obtained by coupling of the corresponding aniline derivative of formula IV
• the compound of formula IV and the 4-bromotoluene or 1-ethyl-4-bromobenzene are mixed with an organic base, e.g. sodium tertiary butylate in an organic solvent such as toluene; a palladium compound or catalyst precursor e.g. Pd(dba) 2 , and a ligand, e.g. P(tBu) 3 , or BINAP, are added to this reaction mixture which is then stirred at elevated temperature, e.g. 110° C., until completion of the reaction, e.g. overnight.
• the diphenylamine product of formula VIII may be recovered from the organic phase of the reaction mixture, for instance after cooling and treatment with acid, e.g. HCl.
• the compound of formula IX may be prepared by alkylation of the corresponding phenol derivative of formula XII
• 2-chloro-N-(4-methylphenyl)acetamide and 2-chloro-N-(4-ethylphenyl)acetamide may be prepared, e.g. in situ, by reaction of 4-methyl- or 4-ethylaniline with chloroacetyl chloride.
• the compound of formula IX may be recovered from the reaction mixture if desired.
• the compound of formula IX is not isolated but is converted to the compound of formula VIII, by rearrangement and hydrolysis as described above carried out on the product reaction mixture resulting from the alkylation of the compound of formula XII.
• diphenylamine of formula VIII may be prepared by oxidation of the corresponding compound of formula XIII (or tautomer thereof)
• the dehydrogenation reaction may be carried out by classical methods, for instance by treatment with iodine, e.g. 12 in THF/AcOH.
• the compound of formula XII may be prepared by coupling of 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexa-1,4-diene with an aniline derivative of formula IV as defined above.
• This coupling reaction may be carried out in the presence of a catalyst such as TiCl 4 in organic solvents e.g. THF and chlorobenzene, preferably with cooling, e.g. at about ⁇ 40° C.
• a catalyst such as TiCl 4 in organic solvents e.g. THF and chlorobenzene, preferably with cooling, e.g. at about ⁇ 40° C.
• 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-1,4-diene may be prepared by partial reduction of 4-methylanisole or 4-ethylanisole by Birch reduction, e.g. by treatment with Na in liquid ammonia, for instance as described by Subba Rao et al., Australian Journal of Chemistry 1992, 45, p. 187-203.
• the compound of formula XIII is not isolated, but the coupling reaction between the compound of formula IV and the 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexa-1,4-diene, is followed by oxidation to give the diphenylamine derivative of formula VIII.
• hydroxy protecting groups are those that can be converted under mild conditions into free amino, hydroxy and carboxyl groups without other undesirable side reactions taking place.
• hydroxy protecting groups are preferably benzyl or substituted benzyl groups.
• the invention includes a process selected from
• a process for the formation of a compound of formula X which comprises rearrangement of a compound of formula IX j) A process for the production of a compound of formula IX which comprises alkylation of a compound of formula XII with 2-chloro-N-(4-methylphenyl)acetamide or 2 chloro-N-(4-ethylphenyl)acetamide k) A process for the production of a compound of formula VIII which comprises alkylation of a compound of formula XII with 2-chloro-N-(4-methylphenyl)acetamide or 2 chloro-N-(4-ethylphenyl)acetamide followed by rearrangement and cleavage of the intermediate compound of formula IX; l) A process for the production of a compound of formula VIE coming oxidation of the corresponding compound of formula MM (or tautomer thereof)
• One or more of the processes a) to n) above may be used in appropriate sequence (see the scheme given above) in the preparation of the compound of formula I.
• the invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable prodrug ester thereof, when prepared by a process which comprises one or more of processes a) to n) as defined above, preferably with a process according to the first aspect of the invention.
• the invention provides a compound selected from:
• Compounds of formula XII in which at one of R 1 or R 6 is chlorine and the other is fluorine may be prepared by methods known in the art of chlorination of phenols, preferably in the presence of catalytic amounts of a secondary amine, e.g. diisopropylamine.
• the chlorination reaction comprises simultaneous addition of chlorine and phenol to the reaction mixture, preferably using hexane fraction as the solvent. It has been found that simultaneous addition of at least part, preferably the majority, of the chlorine and the phenol to the reaction mixture gives rise to high productivity and selectivity in production of the desired product as compared with the unwanted side products. Furthermore use of hexane fractions permits isolation of the desired phenol product in high purity (e.g. 99%) by crystallisation.
• N,N-Bis-p-tolyl-2,3,4,6-tetrafluoroaniline is isolated as a byproduct, nip: 94.96° C.
• the mixture is filtered and the filtrate is separated into its phases.
• the organic phase is washed three times with water, dried using magnesium sulfate and evaporated to dryness.
• the residue can be used as such in the following step or purified by flash chromatography on silica using toluene as the eluent affording 1.13 g of N-(2′,3′,6′-trifluorophenyl)-4-ethylanilin.
• N-2′,3′,5′,6′-tetrafluorophenyl)-4-ethylanilin (2.05 g) and chloro acetylchloride (1.99 g) is mixed without solvent and heated with stirring to 90° C. under nitrogen for 20 h.
• Tetrahydrofurane (10 ml) and aqueous sodium bicarbonate are added after cooling and stirring is continued for about 1 hour.
• the organic phase is diluted with toluene and washed with water three times and dried over magnesium sulfate.
• N-(2′-Chloro-6′-methylphenyl)-N-4-ethylaniline (4.95 g, 20 mmol) is treated with chloro acetylchloride (3.23 g, 28.5 mmol) and the mixture is heated with stirring under nitrogen at 95° C. for 40 minutes. After adding 2-propanol (5 ml) and cooling to room temperature, the mixture is diluted with toluene and extracted with aqu. sodium bicarbonate. The organic phase is washed with water and evaporated to dryness. Flash chromatography on silica (55 g) using toluene as the eluent affords 5.66 g (17.6 mmol. 88%) of N-(2′-chloro-6′-methylphenyl)-N-chloroacetyl-4-ethylaniline as a viscous liquid.
• N-(2′,4′Dichloro-6′-methylphenyl)-4-ethylaniline (4.83 g as a mixture with the byproduct N,N-di-(4-ethylphenyl)-2′,4′-dichloro-6′-methylaniline) is dissolved in 4.18 g of chloro acetylchloride and heated to 100° C. for 1.5 h. The mixture is cooled, diluted with toluene (50 ml) and extracted with aqu. sodium bicarbonate.
• compounds of Formula VIII may be prepared by a procedure involving coupling of 1-methoxy-4-methylcyclohexa-1,4-diene or 1-methoxy-4-ethylcyclohexa-1,4-diene with an anile derivative of formula IV as defined above to give an intermediate compound of Formula XIII (or tautomer thereof)
• the water phase is extracted with ethyl acetate (1 ⁇ 200 ml and 2 ⁇ 100 ml), the ethyl acetate phases are unified and washed with 100 ml of water.
• the organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to yield 11.44 g of a dark slurry.
• the slurry was dissolved in hexane/t-butyl-methylether and the solution was filtered over silica gel to obtain, after evaporation of the solvent, 5.75 g of crude product.
• the product can be used directly in the next step. Alternatively, it can be purified e.g. by column chromatography on silica gel with hexane/t-butyl-methylether (9:1) as eluent to yield pure N-(2′,6′-Dichlorophenyl)-4-methylaniline.
• the aqueous phase is extracted with ethyl acetate (1 ⁇ 200 ml and 2 ⁇ 100 ml), the ethyl acetate phases are unified and washed with 100 ml of water.
• the organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellow viscous liquid.
• the liquid was dissolved in hexane/t-butyl-methylether and the solution was filtered over silica gel to obtain, after evaporation of the solvent, 4.33 g of crude product.
• the product can be used directly in the next step. Alternatively, it can be purified e.g. by column chromatography on silica gel with hexane/t-butyl-methylether (9:1) as eluent to yield pure N-(2-Chloro-6′-fluoro-phenyl)-4-methylaniline.
• a solution of 8.06 g of iodine ⁇ 16.4 ml of tetrahydrofuran and 1.8 ml of acetic acid is added to the reaction mixture and the temperature is allowed to warm up to 0° C.
• the mixture is stirred for 30 minutes at 0° C. and 2 hours at 25° C.
• 2.68 g of iodine is added to the reaction mixture and stirring is continued for additional 24 hours at 25° C.
• 2.68 g of iodine is added and stirring is continued for additional 72 hours at 25° C.
• the reaction is finally quench by pouring the reaction mixture onto a mixture of 250 ml of aqueous sodium bisulfite (38-40%) and 450 ml of saturated aqueous sodium carbonate.
• the water phase is extracted with ethyl acetate (1 ⁇ 200 ml and 2 ⁇ 100 ml, the ethyl acetate phases are unified and washed with 100 ml of brine.
• the organic phase was dried over anhydrous sodium sulfate and evaporated in vacuo to give a dark viscous liquid.
• the liquid was dissolved in heptane/toluene and the solution was filtered over silica gel to obtain, after evaporation of the solvent, 2.0 g of crude product.
• the product can be used directly in the next step. Alternatively, it can be purified e.g. by column chromatography on silica gel with heptane I toluene (7:3) as eluent to yield pure N-(2′-Chloro-6′-methyl-phenyl)-4-ethylaniline.
• Example 4 The 1-Methoxy 4-methylcyclohexa-1,4-diene and 1-Methoxy-4-ethylcyclohexa-1,4-diene starting materials for Example 4 are prepared according to a known literature procedure.
• Compound 4 was prepared according to the same literature procedure given above for 1-methoxy-4-methylcyclohexa-1,4-diene.
• N-(2′,6′-Dichlorophenyl methylaniline (4.86 g) is reacted with chloroacetylchloride (3.92 g) at 90° C. for 2 h. After dilution with toluene, the mixture is washed with aqueous sodium carbonate twice, 40% aqu. sodium bisulfite and water. The organic phase is dried (MgSO4) and evaporated. The residue is recrystallised from ethanol (12 g) to obtain N-(2′,6′-Dichlorophenyl)-N-chloroacetyl-4-methylaniline in (2.83 g), mp: 129.5-130° C.
• This oil is heated to 90° C. and treated with 6.5 ml of chloroacetylchloride. After 2 h the mixture is diluted with 60 ml of 2-propanol, cooled to about 20° C. and seeded. The precipitated suspension is cooled to 0° C. The crystals are isolated by filtration, washed with cold 2-propanol and dried to obtain N-(2′,6′-dichloro-4′-methylphenyl)-N-chloroacetyl-4-methylamine. Mp: 140-141° C.
• N-(2′-chloro-6′-methylphenyl-N-chloroacetyl-4-ethylaniline (2.08 g) are mixed with aluminium trichloride (1.16 g) and the mixture is flushed with nitrogen.
• the flask is introduced into an oil bath (155-160° C.) and the mixture is stirred under a stream of nitrogen for 4.5 hours.
• the mixture is slightly cooled to about 100° C., treated with toluene (30 ml) and 1N HO (20 ml) and stirred for 30 minutes while the temperature decreases gradually.
• the organic phase is washed with 1N HCl and water, dried (magnesium sulfate) and evaporated.
• the residue is chromatographed on silica (86 g) using toluene containing 5-20% isopropyl acetate as eluent affording the title product.
• lactams of Formula II are prepared by oxidation of an unsaturated lactam of Formula III
• Example 8 which may be prepared, for instance as described in Example 8.
• IR film: strong absorptions at 2960, 1710, 1624, 1609, 1191, 1156 and 1120 cm ⁇ 1 .
• An analytical sample of the crude product can be purified by chromatography on silica gel using toluene/ethyl acetate (9:1) as eluent to yield pure 1-(2-Chloro-6-methyl-phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one.
• 1-(2-Chloro-6-methyl-phenyl)-5-ethyl-1,4,5,6-tetrahydro-indol-2-one can be oxidized by classical methods, e.g. with 10% Pd—C in refluxing xylene to yield N-(2-Chloro-6-methyl-phenyl)-5-ethyl-oxindole.
• Lactams of Formula II as defined above are converted to compounds of Formula I as defined above, for instance as described in Example 9 below.
• a mixture of 1.5 g of N-(2′,6′-dichloro-4′-methylphenyl)-5-methyloxindole, 18 ml of ethanol and 1 ml of water is heated to reflux. 1.9 g of a 30% sodium hydroxide solution is slowly added and reflux is continued for 45 h. The solution is cooled to about 40° C. and treated slowly with a solution of 1.5 g of concentrated hydrochloric acid in 12 nm of water up to a pH of 3-4. The obtained suspension is cooled to 20° C. The crystals are collected by filtration, washed with water and dried giving 5-Methyl-2-(2′,6′-dichloro-4′-methylanilino)phenylacetic acid.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Rheumatology (AREA)
• Pharmacology & Pharmacy (AREA)
• Pain & Pain Management (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• General Chemical & Material Sciences (AREA)
• Veterinary Medicine (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Hydrogenated Pyridines (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Indole Compounds (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Priority Applications (2)

Applications Claiming Priority (5)

Related Parent Applications (2)

Related Child Applications (1)

Publications (1)

Family

ID=10861676

Family Applications (2)

Family Applications After (1)

Country Status (33)

Cited By (1)

Families Citing this family (12)

Citations (1)

Family Cites Families (19)

• 1999
  • 1999-09-27 GB GBGB9922830.6A patent/GB9922830D0/en not_active Ceased
• 2000
  • 2000-09-25 NZ NZ517461A patent/NZ517461A/en not_active IP Right Cessation
  • 2000-09-25 PT PT00969292T patent/PT1216226E/pt unknown
  • 2000-09-25 SK SK414-2002A patent/SK287241B6/sk not_active IP Right Cessation
  • 2000-09-25 IL IL14833000A patent/IL148330A0/xx active IP Right Grant
  • 2000-09-25 TR TR2002/00745T patent/TR200200745T2/xx unknown
  • 2000-09-25 PE PE2000001007A patent/PE20010644A1/es not_active Application Discontinuation
  • 2000-09-25 CZ CZ20021027A patent/CZ20021027A3/cs unknown
  • 2000-09-25 EP EP00969292A patent/EP1216226B1/en not_active Expired - Lifetime
  • 2000-09-25 HU HU0202728A patent/HUP0202728A3/hu unknown
  • 2000-09-25 AR ARP000105014A patent/AR031529A1/es active IP Right Grant
  • 2000-09-25 DE DE60043261T patent/DE60043261D1/de not_active Expired - Lifetime
  • 2000-09-25 PL PL365994A patent/PL207777B1/pl unknown
  • 2000-09-25 BR BR0014314-6A patent/BR0014314A/pt not_active IP Right Cessation
  • 2000-09-25 ES ES00969292T patent/ES2338209T3/es not_active Expired - Lifetime
  • 2000-09-25 AU AU79067/00A patent/AU775416B2/en not_active Ceased
  • 2000-09-25 SI SI200031050T patent/SI1216226T1/sl unknown
  • 2000-09-25 DK DK00969292.2T patent/DK1216226T3/da active
  • 2000-09-25 WO PCT/EP2000/009346 patent/WO2001023346A2/en active IP Right Grant
  • 2000-09-25 EP EP09171648A patent/EP2275403A1/en not_active Withdrawn
  • 2000-09-25 JP JP2001526501A patent/JP2003510303A/ja active Pending
  • 2000-09-25 CN CNB008133972A patent/CN100412053C/zh not_active Expired - Fee Related
  • 2000-09-25 AT AT00969292T patent/ATE447547T1/de active
  • 2000-09-25 KR KR1020027003901A patent/KR100745341B1/ko not_active Expired - Fee Related
  • 2000-09-25 EC EC2000003680A patent/ECSP003680A/es unknown
  • 2000-09-25 CA CA2379553A patent/CA2379553C/en not_active Expired - Fee Related
  • 2000-09-25 RU RU2002109239/04A patent/RU2273628C2/ru not_active IP Right Cessation
  • 2000-09-26 MY MYPI20004481 patent/MY125201A/en unknown
  • 2000-09-27 CO CO00073348A patent/CO5210865A1/es not_active Application Discontinuation
  • 2000-09-27 TW TWPROCESSFA patent/TWI270540B/zh not_active IP Right Cessation
• 2002
  • 2002-02-21 IL IL148330A patent/IL148330A/en not_active IP Right Cessation
  • 2002-03-19 NO NO20021368A patent/NO327912B1/no not_active IP Right Cessation
  • 2002-03-25 ZA ZA200202367A patent/ZA200202367B/en unknown
• 2003
  • 2003-01-10 AR ARP030100070A patent/AR042404A2/es unknown
• 2007
  • 2007-08-16 US US11/893,481 patent/US20080249318A1/en not_active Abandoned
• 2009
  • 2009-01-13 EC EC2009003680A patent/ECSP093680A/es unknown
  • 2009-05-07 US US12/436,991 patent/US7906677B2/en not_active Expired - Fee Related
• 2010
  • 2010-02-03 CY CY20101100105T patent/CY1110539T1/el unknown

Patent Citations (1)

Also Published As

Similar Documents

Legal Events