2-Aminobenzophenones

A solution of 2-aminobenzophenone (98 g, 0.50 mol) and methyl 2-(methyl-thio)propanoate (74 g, 0,50 mol) in CH Clj (21) was cooled to —70 C and 95% 7-butyl hypochlorite (56 g, 0.5 mol) was added dropwise at such a rate that the temperature did not rise above — 65 C. One hour after the addition was complete, EtjN was added and the mixture was allowed to come to room temperature. The solution w as mixed with 3 N HCl (800 ml) and stirred for 1 h. The organic layer was separated, dried (Na2S04 ) and filtered. The solution was evaporated in vacuo and the residue triturated with ether. Filtration gave the 3-(methylthio)oxindole intermediate (92 g) in 62% yield. 

The importance of the configuration of the oxime is again demonstrated in the oxidative cyclization of o-aminobenzophenone oximes. The (Z)-oxime with nitrous acid produced 3-phenyl-l,2-benzisoxazole, while the (E)-oxime with similar treatment yielded ben-zotriazine N-oxides (27CB1736). 

Aminobenzophenone [1137-41-3] M 197.2, m 123-124 , pK 2.17. Dissolved in aq acetic acid, filtered and ppted with ammonia. Process repeated several times, then recrystd from aqueous EtOH. 

The detection limits for benzodiazepines, aminobenzophenones and sulfonamides lie in the lower nanogram range. 

When o-aminobenzophenone is heated with formamide in the presence of formic acid at 150°C for 20 min, a quantitative yield of 4-phenylquinazoline is obtained. In the absence of formic acid longer heating is necessary. Although this reaction does not proceed with o-acylamidobenzophenones, its extension to other o-acylanilines with aliphatic amides may prove fruitful. 

Inclusion of fluorine on the pendant aromatic ring and the basic side chain seems to emphasize the anticonvulsant and hypnotic effects of this class of drugs. Thus alkylation of the benzodiazepinone, 24 (prepared from the corresponding substituted aminobenzophenone), with 2-chlorotriethylamine via its sodium salt affords fluazepam. ... 

In an alternate approach to the preparation of compounds containing the additional ring, haloamide, 41 (obtained from the aminobenzophenone and bromoacetylbromide) is alkylated with etha-nolamine to afford 42. Treatment of the amino alcohol in acetic acid affords the carbonyl addition product, 43, at the same time... 

The sulfur analogue of the Hauser ortho-substitution rearrangement provides access to an arylacet-ic NSAID. Reaction of the aminobenzophenone 176 with ethyl methylthioacetate and tert-butyl hypochlorite gives the intermediate 178. The reaction probably proceeds by way of formation of the S-chlorinated sulfonium derivative 177 displacement on sulfur will lead to the salt 178. Treatment with triethylamine leads initially to the betaine 179. Electrocyelic rearrangement of that transient intermediate leads, after rearomatization, to the homoanthranilic acid 180. Internal ester-amine interchange leads then to indolone 181 [45]. The thiomethyl group is then removed with Raney niekel. Saponifieation of intermediate 182 affords bromfenac (183) [46J. 

It has been shown that glyeine amides of aminobenzophenones are readily converted to the corresponding benzodiazepines in vivo. Peptides which terminate in such a moiety should thus serve as a benzodiazepine prodrug after hydrolysis by peptidases. One of the glycine residues in lorzafone (194)is presumably removed metabolicaUy in this manner to give a benzodiazepine precursor which spontaneously cyclizes. Acylation of benzophenone 190 with the trityl protected dipeptide 191, as its acid chloride 192, affords the amide 193. Removal of the trityl protecting group with acid yields lorzafone (194) [50]. 

Antidepressant activity is retained when the two carbon bridge in imipramine is replaced by a larger, more complex, function. Nucleophilic aromatic substitution on chloropyridine 31 by means of p-aminobenzophenone (32) gives the bicyclic intermediate 33. Reduction of the nitro group (34), followed by intramolecular Schiff base formation gives the required heterocyclic ring system 35. Alkylation of the anion from 35 with l-dimethylamino-3-chloropropane leads to tampramine 36 [8]. 

Aminobenzophenone Glycine ethyl ester hydrochloride Nitric acid... 

A mixture of 16.8 g of 2-aminobenzophenone, 11.9 g of glycine ethyl ester hydrochloride and 200 cc of pyridine was heated to reflux. After one hour, 20 cc of pyridine was distilled off. The solution was refluxed for 15 hours, then 11.9 g of glycine ethyl ester hydrochloride was added and the refluxing was continued for an additional 4 hours. The reaction mixture was continued for an additional 4 hours. The reaction mixture was concentrated in vacuo, then diluted with ether and water. The reaction product, 5-phenyl-3H-1,4-benzodiazepin-2(1 H)-one, crystallized out, was filtered off, and then recrystallized from acetone in the form of colorless rhombic prisms, MP 182°Cto 183°C. 

Friedel-Crafts alkylations and acylations of N-arylamides also proceed normally. For example, benzoylation of acetanilide (iV-acetylaniline) under Friedel-Crafts conditions gives 4-aminobenzophenone in 80% yield after hydrolysis. 

The action of a-amino acid ethyl ester hydrochlorides on 2-aminobenzophenones in hot pyridine gives benzodiazepinones 4 directly (Method A). Selected examples are given.193194... 

A solution of a 2-aminobenzophenone (0.1 mol) and an z-amino acid ethyl ester hydrochloride (0.15 mol) in pyridine (200 mL) was refluxed. During the first 4h, 20-50 mL of liquid was allowed to distill and was replaced by fresh pyridine. Heating was continued for a further 11 h, the mixture was evaporated under reduced pressure and H20 and Et20 were added. In most cases some of the reaction product remained undissolved and was filtered off. The aqueous layer was separated, made alkaline and extracted with Et20. The comhined F.t20 phases were washed with H20. dried and evaporated and the reaction product was separated from unchanged amino ketone by crystallization. 

A three-stage procedure is more versatile and gives higher yields. In this method (Method B), the 2-aminobenzophenone is treated with an a-haloacetyl halide and the resulting haloacetamide 5 converted into an aminoacetamide 6 by reaction with ammonia. Cyclization to the benzo-diazepinone 7 occurrs readily. In some cases the intermediates 5 and 6 are not isolated selected examples are given.193 94... 

Ice (500 g) and hromoacetyl bromide (26.3 g, 0.13 mol) were added simultaneously in portions to a stirred solution of a 2-aminobenzophenone (0.1 mol) in Et20 (500 mL) at such a rate that the temperature remained at 10-15 C. After 1 — 2 h the Et,0 layer was separated, washed with H20, followed by dil aq NaOH, dried (Na2S04) and evaporated under reduced pressure to give 5. 

A further variant of Method B is the acylation of a 2-aminobenzophenone with a protected a-amino acid chloride, followed by conversion of the product 11 into the 2-(aminoacet-amido)benzophenone 12 by reaction with hydrobromic acid in acetic acid.196... 

In another procedure, 2-aminobenzophenone is acylated with an sc-azido acid in the presence of l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide and the product 23 is converted into a benzodiazepinone by reductive cyclization with propane-1,3-dithiol (Method F).200... 

Hydrobromides 13 of 3//-1,3,4-benzotriazepin-2-amines are formed in the reaction of 2-aminobenzophenone hydrazones 12 with cyanogen bromide. Selected examples are given.356... 

Aminobenzophenone (19.7 g, 0.1 mol) was dissolved in chlorobenzene (250 mL), A1C13 (7.5 g, 56 mmol) was added, and the solution was heated under reflux for 8 h. After cooling, the solution was washed with aq NaOH, and the solvent was removed in vacuo. Recrystallization (CH2Cl2/EtOH) gave pale-yellow prisms yield 12.7 g (71%) mp 191-193 C. 

The oxo function in the 2-aminobenzophenone can also be masked as an imino function,31 32 an example being the reaction of 10. 

Syntheses starting from amides of 2-aminobenzoic acid and 2-aminobenzophenone derivatives are also known.34,35... 

Aminobenzophenones 223,225 2-Amino-5-bromophenyl(pyridin-2-yl)methanone (= ABP) 226, 227 2-Amino-5-chlorobenzophenone (ACB) 226, 227... 

The phthalide 25, obtainable by condensation of 4,4 -bisdimethyl-aminobenzophenone-2-carboxylic acid with 3-dimethylaminoacetanilide and subsequent hydrolysis, was diazotized in sulfuric acid and the resultant diazonium salt treated with copper powder to yield 26. However, better yields are reportedly obtained by carrying out ring closure of the diazonium salt in phosphoric acid.103 A further synthetic route has also been described in which phthalides undergo intramolecular cyclization in the presence of aluminum chloride and urea.104,105 Thus, Crystal Violet lactone (2) has been directly converted into phthalide 26.106... 

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