Patent GB-1480559-A (GB)
Title: 3-fluorobenzodiazepines and processes for their preparation
IPC: C07D243/24
Filed: 1975-12-18
Abstract: 1480559 3-Fluorobenzodiazepine-2-ones their preparation and pharmaceutical compositions MERCK PATENT GmbH 18 Dec 1975 [20 Dec 1974 23 Sept 1975] 51893/75 Heading C2C The invention comprises compounds of Formula I wherein R<SP>1</SP> is H, C 1-4  alkyl, fluorinated C 1-4  alkyl or C 4-8  cycloalkylalkyl; R<SP>2</SP> is phenyl, halophenyl or pyridyl and R<SP>3</SP> is F, Cl, Br or NO 2  and physiologically acceptable acid addition salts thereof which may be prepared by (a) fluorination of a compound of Formula II wherein X=H, OH, esterified OH, Hal, NH 2  or M; M is Na, K, Li, MgHal or Tlf 2 ; Hal is Cl, Br or I and R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are as defined above or a 4-N-oxide of such a compound wherein X=H; (b) reacting a compound of Formula III wherein R<SP>1</SP> and R<SP>3</SP> are as defined above and X<SP>1</SP> is OH, C 1-4  alkoxy, Cl or Br with a compound R<SP>2</SP>-M where R<SP>2</SP> and M are as defined above; (c) oxidizing a compound of Formula V in which X<SP>2</SP> is H or OH or R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are as defined above; (d) reducing a compound of Formula VI in which R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are as defined above; (e) treating a compound of Formula VII in which R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are as defined above, X<SP>3</SP> is OH, functionally modified OH or R<SP>5</SP>SO 2 - and X<SP>4</SP> is H or X<SP>3</SP> and X<SP>4</SP> together form R<SP>4</SP> is H or C 1-4  alkyl and R<SP>5</SP> is C 1-10  alkyl or C 6-10  aryl optionally substituted by 1 to 3 halogen atoms with an agent which splits off X<SP>3</SP>X<SP>4</SP>; (f) thermally decomposing a compound of Formula VIII wherein Q is -CF(CO 2 H), -CF(CO 2 t.C 4 H 9 ) or -CH(OCOF) and R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are as defined above; (g) cyclizing a compound having one of the Formulae IXa-IXd wherein one group E is H and the other is X<SP>5</SP>, X<SP>5</SP> is OH, esterified OH or Hal An<SP>(-)</SP> is the anion of a strong acid and A<SP>1</SP> is C 1-4  alkyl and R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are as defined above; or (h) halogenating or nitrating a compound of Formula X wherein R<SP>1</SP> and R<SP>2</SP> are as defined above optionally followed by conversion to an acid addition salt. 1 - Methyl - 5 - o - chlorophenyl - 7 - chloro- 2,3 - dihydro - 1,H - 1,4 - benzodiazepin - 2 - one 4-N-oxide and the corresponding 3-fluoro-5- phenyl compound are prepared by ring closure of 2 - (α - iodo - N - methyl -acetamido) - 2<SP>1</SP>,5- dichlorobenzophenone oxime and the corresponding (α<SP>1</SP> - iodo - α - fluoro) - 5 - chlorobenzophenone respectively in the presence of pyridine. 3 - Fluoro - 4 - p - toluenesulphonyl - 5- phenyl - 7 - nitro - 2,3,4,5 - tetrahydro - 1,H - 1,4- benzodiazepine - 2 - one is prepared by fluorination of the corresponding influorinated compound with CF 3 OF. 2 - (N - methylfluoroacetamido)- 5 - chlorobenzophenone oxime is prepared by reaction of 2 - methylamino - 5 - chlorobenzophenone oxime with fluoroacetyl chloride. The same process is used to prepare similar compounds wherein the S substituent is NO 2 , wherein the fluoroacetyl chloride is replaced by bromofluoroacetyl chloride, bromofluoroacetylbromide chlorofluoroacetyl chloride or bromide, where the amido nitrogen is unsubstituted and/or where the second benzene ring bears a 2- chloro substituent. 2 - (α - Amino - α - fluoroacetamido) - 5 - chlorobenzophenone is obtained by reacting the corresponding 2 - (α - bromo - α - fluoro) compound with liquid ammonia. 2 - (α - Fluoro - α - phthalimidoacetamido)- 5- chlorobenzophenone is obtained by reaction of the corresponding 2 - (α - chloro - α - fluoro) compound with potassium phthalimide. 2 - (α - Azido - α -fluoro - N - methylacetamido)- 5 - chlorobenzophenone is obtained by reaction of sodium azide with the corresponding 2-(α- chloro-α-fluoro) compound. 1 - Cyclopropylmethyl - 3 - p - toluenesulphonyloxy - 5 - phenyl - 7 - chloro - 2,3 - dihydro - 1,H- 1,4 - benzodiazepin - 2 - one is prepared by tosylation of the corresponding compound. 1 - (2,2,2 - Trifluoroethyl) - 3 - fluoro - 5- phenyl - 7 - chloro - 2,3 - dihydro - 1,H - 1,4- benzodiazepine is obtained by reacting the corresponding 3-OH compound with SOCL 2  followed by AgF. α - Fluoro - α - (2 - amino - 5 - nitrobenzhydrylideneamino)acetic acid ethyl ester is prepared by reacting 2-amino-5-nitro benzopheone with α-fluoro-α-bromoorthoacetic acid triethyl ester to obtain 2-(1-ethoxy-2-fluoro-2- bromoethylideneamino)- 5 - nitrobenzophenone and then reacting with liquid ammonia. 2 - Hydroxy - 3 - fluoro - 5 - phenyl - 7 - chloro- 2,3 - dihydro - 1H - 1,4 - benzodiazepin is prepared by reaction of 2-amino-5-chlorobenzophenone - N - (2,2 - diethoxy - 1 - fluoroethyl)imine with HF. Diazepam is reacted with N-bromosuccinimide to obtain 3-bromodiazepam. 1 -Methyl - 3 -fluoro - 5,7 - dichloro 2,3 - dihydro- 1H - 1,4 - benzodiazepin - 2 - one is obtained by reaction of HF with 1-methyl-2,5-dihydro-lH- 1,4-benzo-diazepin-2,5-dione. 1 - Methyl - 3 - fluoro - 4 - hydroxy - 5 - phenyl- 7 - chloro - 2,3,4,5 - tetrahydro - 1H - 1,4 - benzodiazepin - 2 - one is prepared by reaction of N - {2 - (α - fluoro - α - iodo - N - methylacetamido) - 5 - chloro - benzhydryl}hydroxylamine with 1,5-diazabicyclo[4,3,0]non-5-ene. 5 - Fluoro - 7 - methyl - 10 - chloro - 11b - phenyl 1,2,3,5,6,7,11b - hexahydro - oxazolo[3,2 - d]- 1,4 - benzodiazepin - 6 - one is prepared from 2 - (α - bromo - α - fluoro - N - methylacetamido) - 5 - chlorobenzophenone and aminoethanol. 3 - Fluoro - 5 - o - chlorophenyl - 7 - chloro - 2,3- dihydro - 1H - 1,4 - benzodiazepin - 2 - one - 3- carboxylic acid is obtained from the corresponding unfluorinated acid by reaction with CF 3 OF. 3 - Fluorocarbonyloxy - 5 - phenyl - 7 - chloro- 2,3 - dihydro - 1H - 1,4 - benzodiazepin - 2 - one is obtained by reaction of the corresponding 3-OH compound with FCO 2 CH 3 . 3 - Fluoro - 5 - phenyl - 2,3 - dihydro - 1H- 1,4 - benzodiazepin - 2 - one and the corresponding 1-methyl compound are obtained from their unfluorinated and chlorinated analogues respectively by reaction with AgF. Pharmaceutical compositions having central nervous system activity, particularly central depressant, muscle relaxant, anti-convulsive and anxiolytic activity, for enteral, parenteral or oral application comprise at least one compound of Formula I or a physiologically acceptable acid addition salt thereof and an inert physiologically acceptable carrier.