IL41237A - 2-amino-5-alkanoyl-benzophenone derivatives - Google Patents

Description

derivatives SPARAI-!EDICA JUS C» 39094 The present invention ir» concerned with benzophono e derivatives. 1 I The benzophenone derivatives provided by the present' invention can be generically formulated thus: wherein R represents a hydrogen atom, a protecting group or the group -B-£!I-NH2, B represents a methylene or carbonyl group, j represents a hydrogen R4 atom or a lower alkyl group, R2 represents a hydrogen or halogen atom and ^ and each represent a hydrogen atom or a lower alkyl group.

The benzophenone derivatives provided by the invention are useful as starting materials for the manufacture of the corresponding benzodiazepine derivatives which form the subject matter of our copending application No. 34816 The term "lower alkyl" is used in this description and in the accompanying claims to mean both straight-chain and branched-chain C^-C^, preferably C^-C^, hydrocarbon groups such as methyl, ethyl, propyl, isopropyl, butyl and the like. The term "halogen" means chlorine, bromine, fluorine and iodine. Tho term "lower alkanoyl" means the acyl residue of a lower alka-noic acid (e.g. acetyl, propionyl, butyryl, pcntylcarbonyl, isopropionyl , caproyl and the like). When 2 represents a halogen atom, it is preferably joined at the 21 -position of the S-nhenyl ring and preferably represents a fluorine atom Also, when and R^ in formula 1 represent lower alkyl groups, an alkyl group containing up to four carbon atoms is preferred, with methyl being most preferred. Thus, preferred benzophenone derivatives of foi*mula I arc those in represents a hydrogen atom.

In accordance with the present invention compounds of the fonrail; I can be prepared by a process wh ch comprises a) for preparing compounds of the formula R, wherein ^, 2 and ^ have the meaning indicated above and R1 represents protecting group, treating a compound of the general formula I (" wherein ^, 2, Rj and R1 have the meaning indicated above, with an oxidizing agent, or b) for preparing compounds of the formula 0 wherein U^, R2 and R^ have the meaning indicated above, splitting off the pro c) for preparing compounds of the formula wherein R^, R^ ^3 anc' ^ have the meaning indicated above, reacting a compound of the general formula wherein R^, ^3 anc* ^4 have the meaning indicated above and Y represents halogen, lower alkyl sulfonyloxy or phenyl sulfonyloxy, with ammonia,. or reacting a compound corresponding to formula III, but in which Y represents a carbobenzoxyamino group, with a hydrohalic acid in the presence of acetic acid, or reacting a compound corresponding to formula III, but in which Y represents a phthal iinido group, with hydrazine hydrate, or catalytically reducing a compound corresponding to formula III, but in which Y represents an azido group, or d) for preparing compounds of the formula Id wherein R^, ^. ^ «nd R^ have the meaning indicated above, reacting a compound of the general formula wherein R, , R„ , R_ and R. have the meaning indicated above and X represents 1' 2' 3 4 halogen, with ammonia, or reacting a compound corresponding to formula IV, but in which X represents a phthalimido group, with hydrazine hydrate, or hydrolyz-ing a compound corresponding to formula IV, but in which X represents a benz-amido grou . . .

The benzophenone derivatives of formula I wherein R represents a protecting group can be prepared in the following manner: In a first stage, a p- (lower alkyl) -aniline or a N-(lower alkyl) derivative thereof is reacted with a benzoyl halide or a halo-ben zoyl halide, preferably an ortho-halo-benzoyl halide, in the presence of a catalyst such as zinc chloride to give a compound of the general formula wherein R^, R2 and R^ have the significance given earlier.

Preferred benzoyl -hal ides include benzoyl chloride, o_-chlorobcnzoyl chloride, o-fluoi'obenzoyl chloride and the like. The reaction of a benzoyl halide with a p_-(lower alkyl) -aniline in the presence of zinc chloride is suit the reaction at a temperature of above about 130°C. The reaction should be performed in an anhydrous medium. Thus, it can be conducted in the absence of any solvent apart from the reactants themselves or, alternatively, it can be conducted in the presence of an inert organic solvent such as benzene and the like. Suitably, the reaction is effected utilizing the benzoyl halidc as, the reaction medium.

In a second stage, the so-obtained compound of formula V is converted into a corresponding compound bearing a suitable nitrogen-protecting group at the aniline nitrogen atom, i.e. a compound of formula II. This group serves to prevent the nitrogen atom of the 2-amino function from participating in further reactions until it is desired. Nitrogen-protecting groups are v.'ell known and can be represented by lower alkanoyl groups provided by acetic anhydride, acetyl chloride and the like. However, the literature describes a multitude of nitrogen-protecting groups which can be readily used in accordance with the present invention. Suitably, this reaction is effected in the presence of an inert organic solvent such as benzene, ether, a halogenated hydrocarbon such as methylene chloride and the like. Temperature and pressure are not critical to a successful performance of this stage. Thus, the reaction can be effected at room temperature or at elevated temperatures. However, in a preferred aspect, the reaction is conducted under reflux conditions.

In a third stage, compound of formula II is oxidised. In a preferred embodiment, the oxidation is effected utilizing a buffered solution of potassium permanganate as the oxidizing agent. Of course, any oxidizing agent which is capable of converting the lower alkyl group in the 5-position into a lower alkanoyl group can also be conveniently employed. The oxidation with potassium permanganate occurs upon treatment with a dilute aqueous solution (0.1-5%) of potassium permanganate. Suitably, for every mole of the compound to be oxidized, there is present from about 1 to about 4 moles of permanganate in the medium. The oxidation is effected at a temperature of from about 0°C to about 80eC, most preferably from about 50°C to about 70°C. It will be ' medium. However, other suitable solvents can also be utilized as the medium in which' the oxidation may be conducted. While potassium permanganate is mentioned as being the preferred oxidizing agent, it will, or course, be appreciated that other permanganates such as lithium, sodium, calcium and magnesium permanganate can similarly be utilized with equal efficaciousness. This oxidation yields a benzophenone derivative of formula la in which the lower alkanoyl group in. the 5-position contains more than two carbon atoms.

As will be evident from the foregoing, the process just described yields only those derivatives wherein the lower alkanoyl group in the 5-position has two or more carbon atoms. Corresponding 2-amino--5-formylbenzophenones can be obtained by oxidizing an appropriate 2-arnino-5-methyl-benzophenone .

The oxidation of a 2-amino-5-methyl-benzophenone with a eerie salt is preferably effected by adding the 2-amino-5-methyl-benzophenonc to any appropriate inert medium and adding a eerie salt to the resulting medium. As a suitable inert oxidation medium there can be utilized an inert organic solvent such as a C^-C^ saturated fatty acid (e.g. formic acid, acetic acid, propionic acid and the like) or a dilute aqueous mineral acid such as dilute nitric acid. It will be appreciated that all that is required of the inert organic solvent utilized is that the eerie ions formed be stable therein and also that both the eerie salt and the 2-amino-5-methyl-benzophenone be soluble therein. Thus, it will be appreciated that a wide variety of solvents are suitable for the purposes of this oxidation.

Examples of ccric salts which may be used in the foregoing oxidation include eerie ammonium nitrate, eerie nitrate, eerie sulfate or any other suitable eerie salt.

While temperature is not critical to a successful performance of this oxidation, it is preferred to perform the oxidation at a temperature between about 0°C and about 50°C, most preferably at room temperature.

From the foregoing it will be appreciated that the manner of bringing together eerie salt and a 2-amino-5-mcthyl -benzophenone is not of primary «4 In a preferred aspect, the oxidation is carried out in the presence of an inert organic solvent of the type set forth earlier. It will bo appreciated that the use of a solvent will ordinarily allow the oxidation to proceed in a relatively simple manner which avoids the use of extraordinary conditions, extensive equipment and the like.

According to a preferred mode of carrying out this oxidation, either a 2-amino-5-mcthyl -benzophenone is added to an appropriate inert organic solvent, preferably a lower fatty acid such as acetic acid. To the resulting solution there is added a eerie salt, most preferably eerie ammonium nitrate dissolved in water. The resulting mixture is then permitted to stand at room temperature. The 2-amino-5-formyl-beni:ophcnone which results is thereafter isolated.

Where it is desired to prepare a corresponding benzophenone derivative of formula I in which R represents a hydrogen atom, a benzophenone dcr-vative obtained from the third stage is subjected to hydrolysing conditions. Standard hydrolysis procedures can be vised; for example, water miscible solvents such as dioxane, tetrahydrofuran, ethanol and the like in the presence of an acid such as hydrochloric acid or a base such as an alkali metal hydroxide (preferably sodium hydroxide) .

Where it is desired to prepare a corresponding benzophenone derivative of formula I in which R represents the group -CO-CH-MI , a benzophenone derivative of the formula lb can be treated with a compound of the formula Y-CH-CO halogen in which R. and Y have the significance given earlier to yield a compound of the formula III.

Suitable halo-(lower alkanoyl) halides [i.e. halo-(lower alkanoyl) leaving group-containing compounds wherein Y represents a halogen atom, most suitably a chlorine, bromine or iodine stom] arc preferably represented by chloroacetyl chloride, bromoacetyl bromide, bromoacetyl chloride, bromonx'o-pionyl chloride and the like. From the foregoing, it will be appreciated that - sulfonyloxy group are mesyloxyacctyl chloride and tosyloxyacetyl chloride.

Suitably, this treatment is effected in the presence of an inert organic solvent such as benzene, ether, methylene chloride and the like. Temperature and pressure are not. critical to a successfu performance of this treatment. However, in a preferred aspect, this treatment is conducted at elevated temperatures (e.g. at about the reflux temperature of the medium).

A so-obtained compound of formula III is treated with ammonia to yield a benzophenone derivative of fonnula I in which represents the groups R4 2 One mode of carrying out the treatment comprises dissolving a compound of fonnula III in an inert organic solvent such as methylene chloride, carbon tetrachloride, an ether such as tetrahydrofuran, dioxane or diethyl ether, dimethyl sulfoxide, dimcthylforma ide and the like and treating the resulting solution with liquid ammonia to yield a benzophenone derivative of formula I in which R represents the groups -CO-CH-NH-.

Compounds corresponding to formula III, but in which Y represents a carbobenzoxyamino group can be obtained by reacting a 2-amino-benzophenone of fonnula lb with a carbobenzoxy-glycylating agent such as carbobenzoxy-glycine, carbobenzoxy-glycine anhydride or a carbobenzoxy-glycyl halide. The carbobenzoxy-glycylation can be conducted at room temperature or at temperatures above or below room temperature. In one preferred embodiment, the carbobenzoxy-glycylation is effected by condensing carbobenzoxy-glycine v.'ith a 2-amino-benzophenone of formula lb in the presence of an ,N* -disubstituted carbodi-imide. The carbobenzoxy-glycylation can, for example, be carried out 'at a temperature between about. 0°C and about 50°C, preferably at a temperature slightly below room temperature. Advantageously, a solvent is present during the carbobenzoxy-glycylation. Among the solvents which can be used for this purpose there can be mentioned organic solvents such as methylene chloride, chloroform, dioxane tetrahydrofuran, dimcthylformamide, acetonitrile and the like, as well as water and mixtures of the solvents mentioned. acetyl-benzophenonc) can be converted into the corresponding bcnzophenone derivative of formula I in which R represents the group -CO-CH-λΉ by treatment with a hydrohalic acid in the presence of acetic acid. This treatment results in the selective splitting of one of the amide linkages of the carbobenzoxy-glycylamino chain so as to yield said bcnzophenone derivative of formula I.

Preferably, hydrobromic acid is used as the hydrohalic acid. However, other hydrohalic acids such as hydrochloric acid can also be used. The treatment can be performed either in an aqueous or anhydrous medium. It can be conducted at room temperature or at temperatures above or below room temperature.

In a further aspect, compounds corresponding to formula III, but in which Y represents a phthalimido group can be obtained by condensing a 2-amino-benzophenonc of foi-mula lb with a phthalimido acetyl halide (preferably the bromide or chloride) or an ct-(lower alkyl) derivative thereof in the presence or in the absence of an alkaline hydrogen halide binder. The condensation is carried out in a suitable inert solvent such as a halogenatcd hydrocarbon (e.g., chloroform or methylene chloride), pyridine or the like. Λ preferred temperature range for effecting the condensation is from about room temperature to about the reflux temperature of the solvent utilized, A compound corresponding to formula III, but in which Y represents a phthalimido group can also be obtained by treating a compound of formula III with an alkali metal salt of phthalimide (e.g. phthalimide potassium).

A so-obtained compound corresponding to formula III, but in which Y represents a phthalimido group can be converted into a corresponding benzo-phenone derivative of formula I in which R represents the group -CO-CH-NH- by treatment with hydrazine hydrate. Suitably, this treatment is effected in an inert organic solvent. Preferably, one or more molar equivalents of hydrazine hydrate is present in the mixture for every molar equivalent of a compound corresponding to formula III, but in which Y represents a phthalimido group.

Temperature and pressure are not critical to a successful performance of this treatment. However, elevated temperatures, preferably at about the reflux as a lower alkanol (e.g., ethanol) . I n proceeding accordingly, a benzophenone derivative of formula I in which R represents the group -CO-^H-Kl l is obtained.

A compound corresponding to formula I I I , but in which Y represents an azide group can be obtained by treating a compound of formula I I I with an azide-generating reagent to yield a corresponding azide. Examples of azide-generating reagents (i.e. azide group-providing agents) are alkali metal azides such as sodium azide, potassium azide, lithium azide and alkaline earth metal azides such as calcium azide, ammonium aside and the like (preferably sodium azide). In this procedure, a compound of formula I I I aforesaid is added to an appropriate organic solvent such as an alkanol (e.g. methanol), an ether (e.g., dioxane or tetrahydrofuran) or the like. To the resulting solution there is added the azide -generating reagent and the mixture is then heated at a temperature from slightly above room temperature to about the reflux temperature of the medium.

The so-obtained azide can then selectively be reduced by catalytic hydrogenation utilizing any conveniently available reducing system which may include catalysts such as RANEY-nickel and noble metal catalysts (e.g. palladium, platinum and the like) to yield a corresponding benzophenone derivative of formula I in which R represents the group -CO-CH-N'iL. The catalytic hydro- genation is suitably effected in the presence of an inert organic solvent such as an ether (e.g., tetrahydrofuran).

In still another alternative, the azide just mentioned can be prepared directly from a compound of formula lb by reaction with a compound of the formula N-CHC0C1 in which R. has the significance given earlier (e.g. azido- acetyl chloride) at a temperature of from about 10°C to about 50°C in the presence of an inert organic solvent such as chloroform.

Benzophenone derivatives of formula I in which R represents the groxip -CM -CH-NH^ can be obtained by treating a 2-amino-benzophenone of formula 4 " lb with an ethylene dihalide and subsequently with ammonia in analogy to the procedure described earlier with respect to the corresponding benzophenone deri Furthermore, 2-amino-benzoohcnones of formula lb can be reacted' with a phthalimidoethyl halide to produce a corresponding 2-phthalimidocthyl-amino-benzophenonc which, in turn, can be treated with hydrazine hydrate to yield a benzophenone derivative of formula I in which R represents the group -C1VCH-NJL.

R4 A still further method consists in reacting a 2-amino-benzophenone of formula lb with a benzamidoethyl halide and treating the 2-benzamidocthyl-a ino-benzophenone obtained with hydrochloric acid to give a benzophenone derivative of fo'mula I in which R represents the group -CH -CH- M . k4 The following Examples illustrate the manner in which the benzophenone derivatives provided by the invention can be prepared.

Example 1 To a solution of 41.7 g (0.36 moles) of zinc chloride in 175 ml (1.52 moles) of benzoyl chloride maintained at 140°C, 29.1 g (0.24 moles) of P-ethylaniline were added portionwise (from a beaker) with stirring. The mixture was heated under reflux at 210° - 220C'C for 1 hour. The temperature was then lowered to 140°C and the excess benzoyl chloride was removed by distillation at water aspirator pressure.. Without letting the mixture cool, 100 ml of 6-N hydrochloric acid were added carefully at about 140°C and the mixture was stirred and heated under reflux at 140° - 160°C for 20 hours. The mixture was partially cooled. Methylene chloride (about 300 ml) was added followed by about 300 ml of water. The mixture was stirred until all solids dissolved.

The aqueous layer was extracted twice with methylene chloride. The combined methylene chloride layers were washed thoroughly, in sequence, with 3-N hydrochloric acid, 3-N' sodium hydroxide and water. After drying over anhydrous sodium sulfate and evaporation of the metlivlene chloride, a dark gum of 2-amino-5-ethylbcnzophenone was obtained.

The gum was chromatographed on a column of 500 g of activity I alumina. Elution with 10¾ ether in benzene gave 2-a ino-S-ethylbenzophenone as a gum (single spot on tic). Crystallization from petroleum ether gave pale ° ° To solution of 90,0 g (0.4 moles) of 2-amino-5-ethyl benzophenone in 400 ml of benzene were added 84 ml (91.0 g, 0.8 moles) of acetic anhydride and the mixture was heated under reflux for 45 minutes.

After cooling, the mixture was concentrated i_n vacuo , to yield a semi-solid. Repeated solution in ethyl acetate followed by evaporation of the solvent gave a deep brown solid. After one recrystalllzation from ethanol, 2-acetamido-5 -ethyl benzophenone in a pale brown amorphous form was obtained, m.p. 109° - 110.5°C. Repeated recrystal ligation from ethanol gave colourless needles, m.p. 112° - 113.5^ A three-necked 3 litre flask was charged with 5.0 g (125 mmoles) of magnesium oxide, 170 ml (250 mraoles) of concentrated nitric acid and 2 litres of water. To this solution were added 13.3 g (50 mmoles) of 2-acetamido-5-ethyl -benzophenone and 19.5 g (125 mmoles) of potassium permanganate. The mixture was heated with stirring at 60°C t 2°C for 5 hours.

The mixture was chilled in ice. Manganese dioxide was dissolved by reduction with a stream of gaseous sulfur dioxide. The remaining pale yellow solid was collected and washed with water. After two recrystallizations from ethanol, 2-acctamido-5-acetylbenzophenone was obtained as colourless needles, m.p. 115° - 116°C.

Example 2 To a solution of 5.6 g (20 mmoles) of 2-acetamido-5-acetylbenzo-phenone in 100 ml of ethanol were added 100 ml (0.2 mole) of 2- -sodium hydroxide and the mixture was heated under reflux for 3 hours. On cooling, pale yellow crystals of 5-acetyl-2-aminobenzophenone precipitated. The crystals were collected and washed with ethanol. After recrystallization from benzene/ (petroleum ether), 5-acetyl-2-amino-benzophenonc was obtained as yellow prisms, m.p. 153° - 154.5°C.

Example 3 To a solution of 7,2 g (30 mmoles) of 2-amino-S-acctyl benzophenone in 100 ml of benzene were added 12.06 g (60 mmoles) of bromoacetyl bromide and N ■ sulfate and evaporated in vacuo to yield a buff coloured solid. On recrystallization" from benzene/ (petroleum ether), S-acetyl-2-(2-bromoacctamido)benzo-phenone was obtained as a buff coloured amorphous acid, m.p. 118° - 120°C. A portion of this material on further recrystallization yielded red hexagonal prisms .

In a similar manner, by reacting 2- mino-5-acctylbcnzophenone with mesyloxyacetyl chloride there can be obtained 5-acetyl-2-(2-mesyloxyacetamido) benzophenone .

Also, in a similar manner, by reacting 2-amino-S-acetylbcn∑:ophenone with: tosyloxyacetyl chloride there can be obtained 5-acetyl-2- (2-tosyloxy-acetamido)benzophenone .

To a solution of 3.0 g (8.4 mmoles) of 5-acetyl-2-(2-bromoace†.amido) benzophenone in 120 ml of methanol, were added 1.08 g (16.8 mmoles) of sodium azide in one portion. The mixture was heated on a steam-bath for 15 minutes. On cooling, 5-acetyl-2-(2-azidoacetamido)benzophenone precipitated as pale pink microprisms. Upon recrystallization from ethanol, pink microprisins were obtained, m.p. 144° - 145°C. - In a similar manner, upon the treatment of 5-acetyl-2~(2~tosyloxy-acetamido)benzophenone or 5-acetyl-2~ (2-mesyloxyacetamido) benzophenone with sodium azide, there can be obtained 5-acetyl-2-(2-azidoacetamido)benzophenone.

To a solution of 2.0 g (6.2 mmoles) of S-acetyl -2- (2-azidoacetamido) benzophenone in 125 ml of tetrahydrofuran were added 350 g of 10% palladium on carbon. The mixture was hydrogenated at one atmosphere for 2 houi's and yielded 5-acetyl-2-glycylaminobenzophenone.

Example 4 A solution of 2.4 g (6.8 mmoles) of 5-acetyl -2- (2-bromoacetamido) benzophenone in 10 ml of methylene chloride was added to 25 ml of liquid ammonia at minus 78°C and the mixture was chilled in a dry ice-acetone bath to give 5-acetyl-2-glycylamjnobenzoy>henone. After stirring for 2 hours, the dry ice-acetone bath was removed and the liquid ammonia allowed to evaporate. The 2-g1ycy1aminobcnzophenone .

Ex mple J>_ Starting with p_-fluorobenzoyl chloride and p-ethylaniline, 5-acetyl-2-amino-2' -fluorobenzophenone was obtained in the manner described in Examples 1 and 2.

Example 6 To a solution of 30 mmoles of 2-amino-5-acetyl-21 -fluorobenzophenone in 100 ml of benzene were added 60 mmoles of bromoacetyl bromide and the mixture was heated under reflux for 3 hours. On cooling, the mixture was washed with ice-cold dilute alkali and water, dried over anhydrous sodium sulfate and evaporated in vacuo to yield a buff coloured solid. On recrystallization from benzene/ (petroleum ether) , 5-acetyl-2- (2-bromoacetamido) -21 -fluorobenzophenone w s obtained.

A solution of 2. g (6.8 mmoles) of 5 -acetyl -2- (2-bromoacetamido) -21 -fluorobenzophenone in 10 ml of methylene chloride was added to 25 ml of liquid ammonia at minus 7S°C and the mixture was chilled in a dry ice-acetone bath to give 5-acetyl-2-glycylamino-2' -fluorobenzophenone. After stirring for 2 hours, the dry ice-acetone bath was removed and the liquid ammonia was allowed to evaporate. The methylene chloride layer was washed with water, dried over "anhydrous sodium sulfate and evaporated to dryness to give an oily residue containing 5-acetyl-2-glycylamino- 2* -fluorobenzophenone.

Example 7 To a solution of 2.3 g of 5-acetyl-2-aminobenzophenone and 2.1 g of carbobenzoxyglycine in 25 ml of tetrahydrofuran were added 2.2 g of Ν,Ν'- r dicyclohexylcarbodiimide . After stirring for several minutes, dicyclohex lurea began to crystallize. Stirring was continued for 2 hours and dicyclohexylurea was then filtered off. The filtrate was then treated with 2 ml of acetic acid to decompose any excess Ν, ' -dicyclohexylcarbodiimide. After 15 minutes, additional solid was removed by filtration. The filtrate was taken to dryness in vacuo and the residue was dissolved in benzene and washed successively with 1-N-hydrochloric acid, water and 5% sodium bicarbonate and then dried over i . On seeding, (4 -acetyl - -benzoylphenylcarbamoylmethyl) carbamic acid/ester crystallized. Λ solution of 4.5 g of (4-acetyl-2-benzoylphenylcarbamoyl!nethyl) carbamic acid benzyl ester in 45 ml of 20% hydrobromic acid in acetic acid was stirred for 30 minutes at room temperature. Anhydrous ether (175 ml) was then carefully added. After pouring off the supernatant, the residue was stirred with water and ether, cooled in an ice-bath and made slightly alkaline with ammonia. The ether layer was dried over sodium sulfate, filtered, some benzene added and the resulting solution concentrated in vacuo to a small volume. On addition of hexane to the residue, 5-acetyl-2-glycylaminobenzophenone was obtained.

Example 8 To 125 ml of a chloroform solution of phthalimidoacetyl chloride JO there were added *5 g of 5-acetyl-2-aminobenzophenone . After refluxing for 3 hours, the mixture was allowed to stand for 48 hours at room temperature.

Removal of the solvent in vacuo left crystalline 2-phthalimidoacetamido-5- acetylbenzophenone.

A solution of 2-phthalimidoacetamido-5-acetylbenzophenone (0.5 mg) in 95% ethanol (25 ml) containing hydrazine hydrate (0.17 g) was^heated under reflux for two hours. About 10 ml of ethanol were then distilled off to give a mixture containing 5-acetyl-2-glycylaminobenzophenone.

Example 9 ^ A 500 ml three necked flask was charged with a solution of 41.0 g (0,3 moles) of zinc chloride in 175 ml (1.25 moles) of benzoyl chloride. The solution was heated to 150°C, and 29.8 g (0.2 moles) of p_-n-butylaniline were added portionwise with vigorous stirring, the temperature being maintained at 150°C. The temperature was then raised to 210° - 220°C and the mixture .was heated under reflux for 0.75 hour until most of the gaseous hydrogen chloride was expelled.

The mixture was cooled to 140°C, the excess benzoyl chloride was distilled off at aspirator pressure without letting the mixture cool, 100 ml of reflux for 20 hours.

The hot resinous materials were .partitioned between water and methylene chloride until all the solids had dissolved. The aqueous phase was extracted a further twice with methylene chloride, the combined organic layers were 'washed- twice, in sequence, with 250 ml portions of 3-N hydrochloric acid, podium hydroxide and water, dried over anhydrous sodium sulfate and evaporated in vacuo to yield a greenish yellow oil. The oil was .essentially 2-amino-5-butylbenzophenone. ' » To 2.53 g (0.01 mole) of 2--amino--5-butylbpnzophenone> the oil obtained in the preceding paragraph, in 15 ml of benzene, were added 3,0 ml (0.03 v · . · moles) of acetic anhydride and the mixture was stirred at room temperature for 2 hours .

The solvent was then evaporated in_ vacuo_,- the dark solid obtained was dissolved in 10 ml of dim.ethylformamide and treated with water to yield a light brown solid (76° - 77eC) . After recrystallization from ether/pentane, 2-acetamido-5-butylbenzophenone was obtained in a light y¾llow amorphous form, .p. 79.5° - Sl.S'C.

A 250 ml 3-necked flask was charged with a solution of 290 mg (7.2 mmoles) of magnesium oxide in 150 ml of water, 1,0 ml' (15 mmoles) of concentrated nitric acid, 1.00 g (3.6 mmoles) of 2-acetamido-5-butylbenzophcnone and 1.10 g (7.2 mmoles) of potassium permanganate. The mixture was heated with stirring for 8 hours at 60°C i 2°C. On Gooling, gaseous sulfur was passed through the dark brown mixture to dissolve the manganese dioxide. The remaining pale yellow solid was collected and washed with water. This solid was dissolved in methylene chloride and Abashed with aqueous sodium bicarbonate. The methylene chloride layer was dried over anhydrous sodium sulfate and evaporated to dryness. Trituration of the residual solid followed by chilling gave 2-acetamido-5-butyrylbenzophenone as colourless needles, m.p. 125° -126.5eC.

The aforementioned 2-acetamido-5-butyrylber.zophenone can be converted into 5-butyryl -2-glycylaminobenzophenonc via 2-amino-5-butyrylbenzophenone c(;di>res described in Examples 2 and 3, Hx mpl_e_10 Λ solution of 0.50 nsniolc of 2-acetamido-S-cthylbcnzophenone in 4 ml of glacial acetic acid was mixed with a solution of 2.0 mmoles of eerie ammonium nitrate in 4 ml of water. The mixture, a clear solution, was allowed to stand at room temperature. After 1 day, the mixture was diluted with 50 ml of water and extracted twice with equal volumes of methylene chloride. The combined methylene chloride layers were washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residual yellow solid was washed with water. After recrystallization from cthanol, 2-acetamido-5-acctylbertzophenone was obtained as colourless needles, .p. 115° - 116C'C.

Example 11 In a similar manner to that described in Example 10, 2-acetamido-5-butylbenzophenone can be treated with eerie air-nonium nitrate to give 2-aceta-mido-5-butyrylbenzophenone, m.p. 125° - 126.5°C.

Claims (1)

1. CLAIMS i A process for the preparation derivatives of the general formula wherein represents a hydrogen a protecting group the group represents a methylene or represents a hydrogen or a lower represents hydrogen or halogen atom and and represent a hydrogen atom or a lower alkyl which comprises for compounds of the wherein and have the meaning indicated above and represents a protecting treating a compound of the general formula wherein have the indicated with an or for of the wherein and the meaning indicated splitting off the protecting group of a compound of the formula or for preparing compounds of the and have the meaning indicated reacting a compound of the general formula wherein and have the meaning indicated and Y represents lower or phenyl with or reacting a compound corresponding to but in which Y represents a with a hydrohalic acid in the presence of acetic or reacting a compound corresponding to but in which Y represents a phthaliinido with hydrazine or ly ducing a compound corresponding to formula but in whic Y represents an azido or for preparing compounds of the formula wherein have the meaning indicated reacting a pound of the general formula wherein and have the meaning indicated above and X represents with or reacting a compound corresponding to formula but in which X represents a i ido with hydrazine or h o Λ process as in Claim wherein is lower alkano A process as in Claim 1 or 2 which comprises treating a compound of formula II in Claim wherein is with a eerie Λ process as claimed in Claim 1 or 2 which comprises treating a compound of formula II in Claim wherein is lower with a ganate or with a eerie Λ process as claimed in Claim 1 or which comprises treating a compound of formula II in Claim with ccric ammonium nitrate or eerie Λ process as claimed in Claim wherein is hydrogen or halogen joined at the of the phenyl Λ process as claimed in Claim wherein R2 is A process as claimed in Claim wherein is A process as claimed in Claim wherein is A process as claimed in im 8 or wherein is Benzonhcnone derivatives of the general formula wherein R represent a hydrogen a protecting group or the group B represents methylene or carbonyl represents a hydrogen atom or each represent a hydrogen aton or a lower derivatives ns claimed in Claim wherein sents a lower alkanoyl Benzophenonc derivatives as in Claim wherein R sents a hydrogen Bcnzophenonc derivatives as claimed in Claim wherein sents a or a halogen in the Bcnzophenonc derivatives as claimed in Claim wherein 2 a fluorine derivatives as in Claim 13 or wherein represents the methyl Bcnzophenonc derivatives as claimed in Claim 13 or wherein represents the methyl according to Claim according to Claim according to Claim according to Claim according to Claim Benzophenonc derivatives as claimed in Claim wherein R the group I Benzoohenonc derivatives as claimed in Claim wherein sents a hydrogen Benzophenonc derivatives as claimed in Claim wherein B scnts a roup and represents a atom or a halogen atom in th derivatives a claimed in Claim wherein sents a fluorine i derivatives as in Claim 25 or wherein represents the methyl Benzophenone derivatives as in Claim 25 or wherein represents the methyl according to Claim according to 11 according to For the Applicants insufficientOCRQuality