IE49383B1

IE49383B1 - Benzazepine derivatives

Info

Publication number: IE49383B1
Application number: IE228/80A
Authority: IE
Original assignee: Hoffmann La Roche
Priority date: 1979-02-07
Filing date: 1980-02-06
Publication date: 1985-10-02
Also published as: ATE13420T1; EP0052599B1; NZ192775A; IL59330A0; DE3070688D1; DK49780A; EP0014454A2; CA1128937A; AU5515480A; EP0052599A2; EP0014454B1; ATE1582T1; EP0052599A3; IE800228L; AU534862B2; IL59330A; DE3060864D1; EP0014454A3

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LU, NL, SE Compounds of the general formula see diagramm : EP0052599,P6,F2 wherein X and Y each signify hydrogen, halogen with an atomic number of at most 35 or trifluoromethyl and Z signifies hydroxy, methanesulphonyloxy, toluenesulphonyloxy, bromine or chlorine. 1. Claims for the Contracting State : AT A process for the manufacture of propargyl derivatives of the general formula see diagramm : EP0052599,P6,F1 wherein X and Y each signify hydrogen, halogen with an atomic number of at most 35 or trifluoromethyl and Z signifies hydroxy, methanesulphonyloxy, toluenesulphonyloxy, bromine or chlorine, characterized by reacting a compound of the general formula see diagramm : EP0052599,P6,F3 wherein X and Y have the above significance, with propargyl alcohol in the presence of a palladium (II) salt, an organophosphine, a tertiary or secondary amine and of copper (I) iodide and, if desired, converting the resulting compound of formula I in which Z signifies hydroxy into a compound of formula I in which Z signifies methanesulphonyloxy, toluenesulphonyloxy, bromine or chlorine.

Description

The present general formula invention relates to compounds of the wherein X and Y each are hydrogen, halogen having 5 an atomic number not greater than 35 or trifluoromethyl and n is 0 or 1.

These compounds are useful as intermediates in the production of 2-benzazepines, compounds of pharmacological activity.

More particularly, the present invention relates to a novel process for preparing the compounds of formula I, above, and to novel intermediates for their production.

In accordance with the process aspect of the present invention, the compounds of formula I, above, are prepared by treating a compound of the general formula wherein X and Y are as above and Z represents a hydroxyamino, amino or protected amino group with a mercuric salt under acidic conditions or with a strong acid in the presence of water, if Z is a protected amino group, splitting off the protecting group and, if a compound of formula I wherein n is 0 is obtained, oxidizing this compound, if desired, to a compound of formula I, wherein n is 1.

In its main product aspect, the present invention provides compounds of the general formula II, above, and of the general formula V 49383 wherein X and Y are as above and Z1 represents a hydroxy group or a leaving group.

The compounds of formulae II and III are useful 5 as intermediates in the production of 2-benzazepines, compounds of pharmacological activity.

As used herein, the term halogen or halo means the three forms chloro, bromo or fluoro. The term protected amino group includes acylated amino groups such as phthal10 imido, carbobenzoxyamino, tert, butyloxycarbonylamino, formylamino, acetylamino, trifluoroacetylamino and the like.

The term leaving group includes alkyl and aryl sulfonyloxy groups such as methanesulfonyloxy and toluene15 sulfonyloxy, bromo, chloro and the like.

The present invention is illustrated in more detail by the following Reaction Schemes: Scheme 1 V Scheme 2 la VII wherein X and Y are as above.

Scheme 1 IV ........-) Ilia The compound of formula Ilia can be produced byreacting the compound of formula IV with propargyl alcohol in the presence of a palladium II salt such as palladium chloride or acetate, an organophosphine, for example, triphenylphosphine, cuprous iodide and a tertiary or, preferably, secondary amine, such as, diethylamine or diisopropylamine. The reaction solvent may be the amine itself, e.g., diethylamine, a halogenated hydrocarbon, e.g., methylene chloride, dimethylformamide or an ether solvent. The reaction temperature may range from about 0° C to about 70° C with ambient temperatures as preferred. The presence of cuprous iodide is mandatory if the reaction is carried out at room temperature or below whilst this is not the case if the reaction is carried out with heating.

The presence of the organophosphine is not absolutely necessary but highly advantageous. Instead of the palladium salt plus the organophosphine an appropriate complex such as dichloro bis (triphenylphosphine) palladium II can also be utilized.

The starting material of formula IV may be produced by diazotizing the corresponding known aminobenzophenone using sodium nitrite in sulfuric acid and isolating the salts by precipitating the respective tetrafluoroborate salts which are thereafter slurried in water and treated with aqueous potassium iodide to give the iodobenzophenone. These reactions are carried out utilizing methods known in the art.

Ilia - - > Illb The compound of formula Ilia can be reacted with methanesulfonyl chloride in the presence of a tertiary amine, such as, triethylamine, and in the presence of an organic solvent, such as, a halogenated hydrocarbon, e.g., methylene chloride or toluene or diethyl ether. The reaction can be run between about -78° C and room temperature with about 0° C as preferred. Compounds corresponding to those of formula Illb but which contain a suitable leaving group other than mesyloxy can also be prepared starting from compounds of formula Ilia by methods known per se, e.g., by means of toluenesulfonyl chloride, thionyl chloride, phosphorus tribromide and the like.

Illb-» Ila ——»la The compound of formula Illb or an analog thereof containing a suitable leaving group other than mesyloxy is reacted with hydroxylamine. This is conveniently effected in a to C4 alcohol solvent at a reaction temperature of from about 0° C to room temperature, with about room temperature as preferred. The isolated intermediate compound Ila can thereafter be reacted with a mercuric salt, such as the sulfate, chloride, acetate, trifluoroacetate, a sulfonate (including salts with sul5 fonic acid groups containing ion exchangers) in the presence of an acid such as carboxylic acids or dilute or concentrated mineral acid and expediently in the presence of an inert organic solvent. Thus, the compound of formula Ila can be reacted with a mixture of mercuric sulfate and a C·^ to Cj carboxylic acid, e.g., formic or acetic acid in an inert solvent, such as, a halogenated hydrocarbon, e.g., methylene chloride. The reaction temperature ranges from about -10° C to room temperature with about 0° C to 5° C as preferred. Alternatively, the compound of formula Ila can be treated with a strong acid in the presence of water, e.g., with concentrated sulfuric acid at from about -10° C to room temperature with about 0° C being preferred.

Ia ) V The compound of formula Ia can then be reacted with dimethylformamide dimethylacetal in an inert solvent, such as, a halogenated hydrocarbon, e.g., methylene chloride, or dimethylformamide or high boiling ethers. The reaction temperature may range from about O° C to 100° C with room temperature as preferred.

Scheme 2 IV .....- > lib The compound of formula IV can be reacted with propargyl phthalimide in the presence of palladium chloride, cuprous iodide, an organophosphine, e.g., triphenylphosphine and a secondary amine, such as, diethylamine or diisopropylamine. The solvents and reaction conditions are as previously disclosed for step IV ->IIIa. Compounds corresponding to those of formula lib but which contain a suitable protected amino group other than phthalimido can also be prepared in a similar manner starting from compounds of formula IV by means of e.g. N-carbobenzoxy propargylamine or corresponding N-formyl, N-tert.butoxycarbonyl, N-acetyl or N-trifluoroacetyl compounds. lib — > VI The compound of formula lib or an analog thereof containing a suitable protected amino group other than phthalimido can then be subjected to reaction conditions as described for step Ila·—»Ia, above. Thus it can be reacted with a mixture of mercuric sulfate and a to C5 carboxylic acid, e.g., formic or acetic acid, in the presence of a halogenated hydrocarbon solvent, e.g., methylene chloride, or an inert ether. The reaction temperature may range from about o° C to room temperature with about 0° C as preferred.

Alternatively, the compound of formula lib or an analog thereof containing a suitable protected amino group other than phthalimido can be treated with concentrated sulfuric acid at from about -10° C to room temperature with about 0° C being preferred. The compounds of formula VI and analogs thereof containing a suitable protected amino group other than phthalimido also form part of the present invention. They are useful as intermediates in the production of 2-benzazepines, compounds of pharmacological activity.

VI - ) lb In order to obtain a compound of formula lb, the protecting group is split off from a compound of formula VI or an analog thereof containing a suitable protected amino group other than phthalimido.

A compound of formula VI is expediently reacted with a primary alkyl amine, e.g., methyl or ethylamine in a Cj, to C4 alcohol solvent. The reaction temperature may range from about 0° C to room temperature with room temperature as preferred.

An alternate method to produce the compound of formula lb consists of the reaction of the compound of formula VI with hydrazine in an inert solvent, such as, ethanol, a mixture of ethanol and chloroform, tetrahydrofuran or aqueous ethanol. The reaction temperature may vary from about room temperature to about 100° C with reflux temperature of the selected solvent as preferred.

The product is extracted with dilute mineral acid and thereafter recovered by neutralization.

A third method which may be utilized to produce the compound of formula lb consists of an acid or base hydrolysis of the compound of formula VI. For an acid hydrolysis, a 30% solution of a mineral acid, such as, hydrochloric, hydrobromic, sulfuric or phosphoric acid may be utilized. The reaction is run at or about reflux temperature. For a base hydrolysis, an alkali metal hydroxide, such as, potassium or sodium hydroxide is utilized.

Inert organic solvents, such as those set forth above may be utilized to solubilize the ingredients. The reaction is run at or above reflux temperature of the selected solvent.

Methods for splitting off the protecting group from compounds corresponding to those of formula VI but containing a suitable protected amino group other than phthalimido are readily available to those skilled in the art.

Scheme 3 lib-----9 He In order to obtain a compound of formula lie, the protecting group is split off from a compound of formula lib or an analog thereof containing a suitable protected amino group other than phthalimido under conditions as described for step VI—»lb, above. Thus, a compound of formula lib can be reacted with a primary alkyl amine, e.g., methyl or ethylamine in a water miscible solvent, such as, to alcohols or ethers or dimethylformamide. The reaction 49363 temperature may range from about 0° C to 60° C with about room temperature as preferred. lie ) lb The compound of formula lie can then be subjected to reaction conditions as described for step Ila—^Ia, above. Thus, it may be reacted with a mixture of mercuric sulfate and a to C$ carboxylic acid in the presence of a halogenated hydrocarbon solvent or may be reacted with concentrated sulfuric acid at from about -10° C to room temperature with about 0° C as preferred.

Ib -------> la and VII The compound of formula Ib can be reacted with a peracid, such as, metachloroperbenzoic acid in an inert organic solvent such as a halogenated hydrocarbon, e.g., methylene chloride or an ether. The reaction may be carried out from about 0° C to 40° C with about room temperature as preferred. The mixture of products may thereafter be separated from one another by fractional crystallization. Analysis by thin-layer chromatography indicates the presence of both products. ' 49383 In the above scheme it should be noted that where the term lower alkyl or alkyl is utilized, there is meant a to C? (C^ to preferred) straight or branched aliphatic hydrocarbon chain.

The compound of formula lb is a known intermediate in the art and is useful in the production of various benzazepines which are compounds of pharmacological utility, i.e., as anxiolytics, see, for example, U.S. Patents Nos. 4.028.381; 4.022.800 and 4.022.801.

‘ The present process to produce lb offers an advantage over the prior art in that it involves fewer steps, is cheaper and affords better yields. In a similar way as the compounds of formula Ia, also the compounds of formula lb can be reacted with dimethylformamide dimethylacetal as described for step la -»V.

The compound of formula V which can be prepared from the compound of formula Ia is also a useful intermediate for the production of 2-benzazepines, e.g., pyrimido-2benzazepines of the formula wherein X and Y are as above.

The above compounds of formula VIII can be produced by the reaction of the compound of formula V with a compound of the formula NH NH2 - C ''''' IX nh2 Any inert organic solvent such as methylene chloride, alcohols such as methanol, ethers such as dioxane, tetrahydrofuran or dimethylformamide may be utilized with a reaction temperature ranging from about room temperature to reflux temperature of the chosen solvent with about room temperature as preferred.

The above reaction of V with IX to give VIII does not form a part of the present invention, but is presented for completenesss of disclosure relating to the utility of the compounds of formula Ia. The pyrimido-2-benzazepines of formula VIII exhibit anxiolytic and sedative activities.

The following Examples illustrate the present invention. All temperatures are indicated in degrees centigrade.

Example 1 -Chloro-2-iodobenzophenone A mixture of 76 g (1.1 mole) of sodium nitrite and 450 ml of sulfuric acid was heated on a steam bath to ca 80° C until complete solution was achieved, g The solution was cooled to 30° C and 232 g (KO mole) of 2-amino-5chlorobenzophenone was added in portions keeping the temperature between 30° C and 40° C. The mixture was stirred for 1 hr and then slowly poured into 3 1. of an ice and water mixture. The solution was filtered through Hy-Flo and to the stirred filtrate was added slowly a solution of 200 g (1.83 mole) of sodium fluoborate in 800 ml of water. The resulting precipitate was collected by filtration and washed with water (2x100 ml) to give a moist white solid.

The moist 2-benzoyW-chlorobenzenediazonium fluoborate was slurried in 3 1. of water, and a solution of 332 g (2 moles) of potassium iodide in 1 L of water was added dropwise. The mixture was stirred at room temperature for 4 hr and the resulting precipitate was collected by filtration. The crude product was added to 1 1. of boiling ether, filtered, and dried with anhydrous sodium sulfate. The ether solution was concentrated to 500 ml and the addition of 100 ml of petroleum ether gave the product. A small amount of the material was recrystallized from a mixture of ether and petroleum ether to give fine yellow prisms, mp 80-82° C.

Example 2 -Chloro-2'-fluoro-2-iodobenzophenone The preparation of 5-ehloro-2'-fluoro-2-iodobenzophenone was conducted in the same manner as the preparation of 5-ehloro-2-iodobenzophenone to give light yellow prisms, mp 78-81° C.

Example 3 2',5-Dichloro-2-io Method A. The preparation of 21, 5-dichloro-2-iodobenzophenone was conducted in the same manner as the preparation of 5-ehIoro-2-iodobenzophenone to give light yellow prisms, mp 64-66° C.

Method B. A solution of 9.0 g (0.13 mole) of sodium nitrite in 30 ml of water was added dropwise to a solution of 27 g (0.1 mole) of 2-amino-2’,5dichlorobenzophenone in 50 ml of acetic acid and 30 ml of sulfuric acid which was cooled to 0’ C. Stirring at 0° C was continued for 1.5 hr followed by the dropwise addition of 33 g (0.2 mole) of potassium iodide in 40 ml of water. The mixture was stirred at 0° C for 2 hr. The mixture was diluted with water, and extracted with ether. The ether solution was washed with 5% aqueous sodium thiosulfate, dried over anhydrous sodium sulfate and concentrated at reduced pressure to a brown oil. Crystallization from cold ether gave the product, mp 63-65° C which was identical in every respect to an authentic sample.

Example 4 2t-Chloro-2-iodobenzophenone The preparation of 2'-chloro-2-iodobenzophenone was conducted in the same manner as 5-chloro-2-iodobenzophenone to give pale yellow prisms, mp 62-64° C.

Example 5 2-Iodobenzophenone The preparation of 2-iodobenzophenone was conducted in the same manner as the preparation of 5-chloro-2-iodobenzophenone to give a brown oil. A small amount was purified by column chromatography to give white prisms, mp 29-31° C.

Example 6 l-[4-Chloro-2-benzoyIphenyl] -3-phthalimidopropyne A mixture of 0.71 g (4.0 mmole) of palladium chloride, 2.1 g (8.0 mmole) of triphenylphosphine, 0.80 g (4.2 mmole) of cuprous iodide, 68.8 g (0.21 mole) of -chloro-2-iodobenzophenone, 200 ml of diethylamine, and 400 ml of methylene chloride was stirred at room temperature under argon until complete solution was obtained. In one portion, 40.0 g (0.22 mole) of N-propargyl-phthalimide was added to the solution and the resulting mixture stirred for 20 hr. The volatiles were removed at reduced pressure and the residue was triturated with 200 ml of isopropanol. The resulting precipitate was collected by filtration to give the crude product mp 130-133° C. Recrystallization from acetone gave cream colored prisms, mp 148-150° C.

Example 7 1- [4-Chloro-2-(2-fluorobenzoyI)phenyl]-3-phthalimidopropyne The preparation of l-[4-chloro-2-(2-fluorobenzoyl)phenyl] -3-phthalimidopyropyne was conducted in the same manner as the preparation of l-[4-ch!oro2- benzoylphenyl] -3-phthalimidopropyne to give eream colored prisms, mp 158161° C.

Example 8 l-(4-Chloro-2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne The preparation of l-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne was conducted in the same manner as the preparation of l-[4-chloro2-benzoylphenyl) -3-phthalimidopropyne to give cream colored prisms, mp 144145° C.

Example 9 l-(2-(2-Chlorobenzoyl)phenyl]-3-phthalimidopropyne The preparation of 142-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne was conducted in the same manner as the preparation of l-[4-chloro-25 benzoylphenyl]-3-phthalimidopropyne to give cream colored prisms, mp 149150° C.

Example 10 l-[2-Benzoylphenyl]-3-phthalimidopropyne The preparation of 142-benzoylphenyl] -3-phthalimidopropyne was eon10 ducted in the same manner as the preparation of l-[4-ehloro-2-benzoylphenyfl 3-phthalimidopropyne to give cream colored prisms, mp 184-165° C.

Example 11 3-Hydroxy-l-[4-ohloro-2-benzoylphenyl]propyne A mixture of 0.17 g (1.0 mmole) of palladium chloride, 0.5 g (2.0 mmole) of triphenylphosphine, 0.1 g (0.5 mmole) of cuprous iodide, 15 g (43 mmole) of 5chloro-2-iodobenzophenone and 60 ml of diethylamine was stirred at room temperature for 20 min. In one portion 6.0 g (107 mmole) of propargyl alcohol was added, and the resulting mixture was stirred for 24 hr. The solvent was removed at reduced pressure and the residue was dissolved in ether. The ether solution was washed with water, (fried with anhydrous sodium sulfate, and concentrated at reduced pressure to give the product as a red oil.

Example 12 3-Hydroxy-l-[4-chloro-2-(2-fluorobenzoyl)phenyl]propyne A mixture of 0.37 g (0.5 mmole) of dichlorobis (triphenylphosphine) palladium Π, 70 mg (0.35 mmole) of cuprous iodide, 36.1 g (0.1 mole) of 5-ciiloro2'-fluoro-2-iodobenzophenone and 12 ml (0.2 mole) of propargyl alcohol in 200 ml of diethylamine was stirred at room temperature for 4 days. The mixture was concentrated at reduced pressure and the residue was partitioned between ether and water. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give the product as an amber oil.

Example 13 3-Hydroxy-l-[4-chloro-2-(2-fluorobenzoyI)phenyl] propyne methanesulfonate Dropwise 13 ml (0.17 mole) of methanesulfonyl chloride was added to a solution of 28.9 g (0.1 mole) of 3-hydroxy-l-[4-chloro-2-(2-fluorobenzoyl)phenyl] propyne and 24.4 ml (0.175 mole) of triethylamine in 300 ml of methylene chloride which was cooled to 0° C. The mixture was washed with ice water, cold IN hydrochloric acid, cold saturated aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. Concentration of the methylene chloride solution gave a brown oil which was crystallized from ether to give a yellow solid. Recrystallization from a mixture of ether and petroleum ether gave offwhite prisms, mp 95-96° C.

Example 14 l-[4-ChIoro-2-benzoylphenyl] -3-phthalimidopropan-l-one A mixture of 20 g (50 mmole) of l-[4-chloro-2-benzoylphenyl] -3phthalimidopropyne, LO g (3 mmole) of mercuric sulfate and 55 ml of formic acid in 50 ml of methylene chloride was stirred at room temperature for 30 min. The mixture was poured over ice and extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ’ 49383 ethyl acetate and ether to give a colorless solid. Recrystallization from acetone gave colorless prisms, mp 163-164* C.

Example 15 3-Amino-l-[4-chloro-2-benzoyIphenyl]propyne Method A. A mixture of 72 g (0.18 mole) of l-[4-chloro-2-benzoylphenyl] -3-phthalimidopropyne, 90 ml of 40% aqueous methylamine, and 300 ml of ethanol was stirred at room temperature for 90 min. The mixture was diluted with 300 ml of ether, and the precipitate was removed by filtration. The filtrate was further diluted with 300 ml of ether, washed with water and dried over anhydrous sodium sulfate. Concentration of the ether solution at reduced pressure gave a brown oil, which when triturated with ether gave a yellow solid. Recrystallization from ether gave pale yellow prisms, mp 6869’C.

Method B. A mixture of 4 g (10 mmole) of l-[4-ehloro-2-benzoylphenyl] 3-phthalimidopropyne and 0.6 g (16 mmole) of 85% hydrazine hydrate in 150 ml of 95% ethanol was refluxed for 5.5 hr. The mixture was cooled and the insoluble precipitate removed by filtration. The filtrate was diluted with water, acidified with hydrochloric acid and extracted with ether. The aqueous solution was basified with dilute sodium carbonate and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ether and petroleum ether to give a pale yellow solid, mp 68-69* C which was identical in every respect to an authentic sample.

The hydrochloride salt of 3-amino-l-[4-chloro-2-benzoylphenyl] propyne was prepared by the addition of an excess of 6% methanolic hydrogen chloride to a methanol solution of the product and isolated by precipitating the salt with the addition of ether. Recrystallization from a mixture of methanol and ether gave the hydrochloride as white needles, mp 173-174’C.

Example 16 3-Amino-l-[4-chloro-2-(2-fluorobenzoyl)phenyU propyne Method A. The preparation of 3-amino-l-[4-ehloro-2-(2-fluorobenzoyl)phenyl] propyne was conducted in the same manner (Method A) as the preparation of 3-amino-l-[4-chloro-2-benzoylphenyi] propyne to give yellow prisms, mp 89-91° C.

Method B. A mixture of 50 g of l-[4-ehloro-2-(2-fluorobenzoyl)pheny]] 3-phthalimidopropyne, 50 ml of 40% aqueous methylamine and 150 ml of dimethylformamide was stirred at room temperature for 25 min. Dropwise 500 ml of water was added, and the resulting precipitate was collected by filtration. The precipitate was dissolved in methylene chloride, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give a pale yellow solid. Recrystallization from ether gave pale yellow prisms, mp 89-91’ C which was identical in every respect to an authentic sample.

Method C. A mixture of 400 g (0.96 mole) of l-(4-ehloro-2-{2fluorobenzoyl)phenyl] -3-phthalimidopropyne, 1.3 1 of ethanol and 300 ml of 40% aqueous methylamine was stirred at room temperature for 2 hr. Dropwise 2.8 1 of water was added, and the resulting precipitate was collected by filtration to give a pale yellow solid, mp 79-80’C. Recrystallization from ether gave pale yellow prisms, mp 89-91° C which was identical in every respect to an authentic sample. 4-938 3 Example 17 3-Amino-l-[4-chloro-2-(2-chlorobenzoyl)phenyl] propyne The preparation of 3-amino-l-[4-chloro-2-(2-chIorobenzoyI)phenyflpropyne was conducted in the same manner as the preparation of 3-amino-l-[45 chloro-2-benzoylphenyl] propyne [Method A] to give pale yellow prisms, mp 8182° C.

Example 18 3-Amino-l-[2-(2-chlorobenzoyl)phenyl] propyne The preparation of 3-amino-l-[2-(2-ehlorobenzoyl)phenyl] propyne was 10 conducted in the same manner as the preparation of 3-amino-l-[4-chloro-2benzoylphenyU propyne [Method A] to give an amber oil.

The hydrochloride salt of 3-amino-l-[2-(2-chlorobenzoyl)phenyI] propyne was prepared by the addition of an excess of 8% methanolic hydrogen chloride to a methanol solution of the product and isolated by precipitating the salt by the addition of ether. Recrystallization from a mixture of methanol and ether gave the salt as white needles, mp 160-162° C.

Example 19 3-Amino-l-[2-benzoylphenylI propyne The preparation of 3-amino-l-[2-benzoylphenyl] propyne was conducted 20 in the same manner as the preparation of 3-amino-l-[4-chloro-2-benzoyIphenyi] propyne [Method A] to give an amber oil.

The hydrochloride salt of 3-amino-l-[2-benzoylphenyl] propyne was prepared by the addition of an excess of 6% methanolic hydrogen chloride to a methanol solution of the product and was isolated by precipitating the salt with the addition of ether. Recrystallization from a mixture of methanol and ether gave the salt as white needles, mp 157-158° C.

Example 20 8-Chloro-l"(2-fluoropheny 1)-3,4-dihydro-5H-2-benzazepin-5-one 5 Method A. A solution of 14.4 g (50 mmole) of 3-amino-l-[4-chloro-2-<2fluorobenzoyl)phenyl] propyne in 50 ml of methylene chloride was added to a solution of 3.0 g (10 mmole) of mercuric sulfate in 50 ml of formic acid, which was cooled to 0° C. The mixture was stirred at 0° C for 3 hr, poured over ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a brown oiL The oil was dissolved in 25 ml of isopropanol and 4.8 g (50 mmole) of methanesulfonic acid was added. The resulting precipitate was collected by filtration to give the methanesulfonate salt of the product as off-white crystals. Recrystallization from a mixture of methylene chloride and isopropanol gave the methanesulfonate salt of the product as pale yellow rods, mp 176-177° C.

A sample of the methanesulfonate salt was partitioned between methylene chloride and aqueous saturated sodium bicarbonate. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated at reduced pressure and the residue was crystallized with ether. Recrystallization from ether gave off-white prisms, mp 109-110°C.

Method B. A solution of 200 g (0.69 mole) of 3-amino-l-[4-chloro-2-(2fluorobenzoybphenyl] propyne in 500 ml of methylene chloride was added dropwise to 400 ml of concentrated sulfuric acid, which was cooled to 5° C. The mixture was stirred at 5°C for 3 hr, poured over ice, basified with ammonium 9383 hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a brown oil. The brown oil was dissolved in 350 ml of a 2M methanol solution of methanesulfonic acid and the salt of the product was precipitated by the addition of ether to give the salt as off-white rods. Recrystallization from a mixture of methylene chloride and isopropanol gave the methanesulfonate salt as off-white rods, mp 176-177* C which were identical in every respect to an authentic sample.

Example 21 8-Chloro-l-phenyl-3,4-dihydro-5H-2-benzazepin-5-one The preparation of 8-chloro-l-phenyl-3,4-dihydro-5H-2-benzazepin-5one was conducted in the same manner as the preparation of 8-chloro-l-(2fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one (Method A) to give the methanesulfonate salt as off-white prisms, mp 187-190° C.

Example 22 8-ChIoro-l-(2-chlorophenyl)-3,4-dihydro-5 H-2-benzazepin-5-one The preparation of 8-chloro-l-(2-chlorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one was conducted in the same manner as the preparation of 8-chloro-l(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepm-5-one (Method A) to give the methanesulfonate salt as colorless needles, mp 180-181* C.

Example 23 l-(2-Chlorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one The preparation of l-(2-ehlorophenyl)-3,4-dihydro-5H-2-benzazepin-5one was conducted in the same manner as the preparation of 8-chloro-l-(225 fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one (Method A) to give a pale yellow solid, mp 135-137° C.

Example 24 l-PhenyI-3,4-dihydro-5H-2-benzazepin-5-one The preparation of l-phenyl-3,4-dihydro-5H-2-benzazepin-5-one was 5 conducted in the same manner as the preparation of 8-chloro-l-(2-fluorophenyl)3,4-dihydro-5H-2-benzazepin-5-one (Method A) to give the methanesulfonate salt as off-white prisms, mp 196-198° C.

Example 25 8-Chloro-l-(2-fluorophenyl)-3,4-dihydro-4-Kdimethylamino)methyIeneI-5H10 2-benzazepin-5-one Method A. A mixture of 7.2 g (25 mmole) of 8-chloro-l-{2fluorophenyl)-3,4-dihydro-5H-2~benzazepin-5-one and 50 ml of dimethylformamide dimethyl acetal was refluxed for 1 hr. The mixture was concentrated at reduced pressure to give tan crystals. Recrystallization from ether gave yellow prisms, mp 228-233’ C.

Method B. A mixture of 10 g (35 mmole) of crude 8-chloro-3,4-dihydrol-(2-fluorophenyl)-5H-2-benzazepin-5-one and 10 g (84 mmole) of dimethylformamide dimethyl acetal in 10 ml of dimethylformamide was stirred at room temperature for 12 hr. The resulting precipitate was collected by filtration, and washed successively with ethanol and ether to give tan crystals which were identical in every respect to an authentic sample.

Method C. A solution of 100 g (0.35 mole) of 3-amino-l- [4-chloro-2-(2fluorobenzoy])phenyU propyne in 200 ml of methylene chloride was added dropwise to 210 ml of 95% sulfuric acid, which was cooled to 5°C. The mixture 4-9383 was stirred at 5°C for 3.5 hr. The dark, syrupy mixture was poured over 2.5 1 of crushed ice, basified with 525 ml of concentrated ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a brown oil containing 8-chloro-l-(2-fluorophenyl)-3,4dihydro-5H-2-benzazepin-5-one.

The oil was dissolved in 200 ml of dimethylformamide dimethyl acetal and heated on a steam bath for 15 min. The mixture was cooled and the resulting precipitate was collected by filtration and washed successively with ethanol and ether. The product was air dried to give light tan crystals which were identical in every respect to an authentic sample.

Example 26 8-Chloro-I-phenyl-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin5-one The preparation of 8-chloro-l-phenyl-3,4-dihydro-4-[(dimethylamino)methylene] -5H-2-benzazepin-5-one was conducted in the same manner as the preparation of 8-chloro-l-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene] -5H-2-benzazepin-5-one (Method A) to give yellow prisms, mp 180183° C.

Example 27 8-ChIoro-l-(2-chloropheny 1)-3,4-dihydro-4-[(dimethylamino)methyIene] -5 H2-benzazepin-5-one A mixture of 18.6 g (61 mmole) of 8-chloro-l-(2-chlorophenyl)-3,4dihydro-5H-2-benzazepin-5-one and 149 ml of dimethylformamide dimethyl acetal was gently heated (ca 50° C) for 12 hr. The mixture was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ether and methylene chloride to give a yellow solid, mp 170-171° C. Reerystallization from ether gave yellow prisms, mp 170-171° C.

Example 28 l-(2-Chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methyIene]-5H-2-benzazepin5-one A mixture of 3.4 g (12.5 mmole) of l-(2-ehlorophenyl)-3,4-dihydro-5H-2benzazepin-5-one and 28 ml of dimethylformamide dimethyl acetal was refluxed for 2 hr. The mixture was concentrated at reduced pressure and the resulting solid was triturated with ether to give a tan solid, mp 155-157° C. Recyrstallization from a mixture of methylene chloride and ether gave yellow prisms, mp 158-159° C.

Example 29 3,4-Dihydro-4-[(dimethylamino)methylene]-5H-2-ben2azepin-5-one A mixture of 5.2 g (22 mmole) of 3,4-dihydro-l-phenyl-5H-2-benzazepin5-one and 43 ml of dimethylformamide dimethyl acetal was refluxed for 4 hr. The mixture was concentrated at reduced pressure to dryness. The residue was crystallized with ether to give a yellow solid, mp 131-133° C. Recrystallization from ether gave yellow prisms, mp 131-132° C.

Example 30 8-Chloro-l-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide Method A. A mixture of 6.4 g (22 mmole) of 8-cWoro-l-{2fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 6.4 g (34 mmole) of mehloroperbenzoic acid in 350 ml of methylene chloride was stirred at room temperature for 2 hr. The methylene chloride solution was washed with saturated aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. The oil was crystallized from a mixture of ether and petroleum ether to give off-white prisms, mp 166-168° C. Recrystailization from a mixture of ether and methylene chloride gave colorless prisms, mp 168-170* C.

Method B. A mixture of 5.8 g (16 mmole) of 3-hydroxy-l-[4-chloro-2-{2fluorohenzoyl)phenyl] propyne methanesulfonate and 50 ml of methanolic solution of hydroxylamine (from 6.1 g, 88 mmole of hydroxylamine hydrochloride) in 50 ml of tetrahydrofuran was stirred at room temperature for 13 hr. The mixture was concentrated at reduced pressure and the residue was partitioned between methylene chloride and water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an amber oil containing 3-hydroxyamino-l-[4-chloro-2-(2-fluorobenzoyl)phenyl] propyne.

A solution of 3.4 g of the amber oil in 70 ml of methylene chloride was added dropwise to a mixture of 0.7 g (2.3 mmole) of mercuric sulfate and 17 ml of formic acid which was cooled to 0° C. The resulting mixture was stirred at room temperature overnight, poured over ice and basified with ammonium hydroxide. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. Purification by column chromatography (silica gel, 50 g; 3:1 methylene chloride and ether, eluent) gave tan crystals, mp 165-167* C. Recrystailization from a mixture of ether and methylene chloride gave pale yellow prisms, mp 167-170° C which were identical in every respect to an authentic sample.

Example 31 8-Chloro-l-(2-chlorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide The preparation of 8-chloro-l-(2-chlorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide was conducted in the same manner as the preparation of 85 chloro-l-(2-fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one-2-oxide (Method A) to give yellow prisms, mp 184-187° C.

Example 32 8-Chloro-l-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H2-benzazepin-5-one-2-oxide A mixture of 3.4 g (11 mmole) of 8-ehloro-l-(2-fluorophenyl)-3,4-dihydro5H-2-benzazepin-5-one-2-oxide and 26 ml of dimethylformamide dimethyl acetal was stirred at room temperature for 12 hr. The mixture was diluted with ether and the precipitate collected to give a yellow solid, mp 175-178° G. Recrystallization from a mixture of ether and ethyl acetate gave yellow needles, mp 193-194° C.

Example 33 8-Chloro-l-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene3-5H2-benzazepin-5-one-2-oxide The preparation of 8-chloro-l-(2-chlorophenyl)-3,4-dihydro-4-[(di20 methylamino)methylene]-5H-2-benzazepin-5-one-2-oxide was prepared in the same manner as the preparation of 8-chloro-l-(2-fluorophenyl)-3,4-dihydro-4Kdimethylamino)methylene]-5H-2-benzazepin-5-one-2-oxide to give yellow prisms, mp 196-198° C.

Example 34 8-Chloro-l-phenyl-3,4-dihydro-5H-2-benzazepin-5-one A mixture of 2.1 g (5 mmole) of I-[4-chIoro-2-benzoylphenyl]-3phthalimidopropan-l-one and 10 ml of 40% aqueous methylamine in 25 ml of ethanol was stirred at room temperature for 45 min. The mixture was poured into water and extracted with ether. The ether layer was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue (1.4 g) was purified by plug filtration (silica gel; eluent, methylene chloride). The resulting oil was treated with a 1M solution of methanolic methanesulfonic acid to give the methanesulfonate salt of the product, mp 187-190° C., which was identical in every respect to an authentic sample.

Claims

Claims:

1. A process for general formula the preparation of compounds of the wherein x and Y each are hydrogen, halogen having 5 an atomic number not greater than 35 or trifluoromethyl and n is 0 or 1, which comprises treating a compound of the general formula SC—CHg—Z X· II *9383 wherein X and Y are as above and Z represents a hydroxyamino, amino or protected amino group with a mercuric salt under acidic conditions or with a strong acid in the presence of water, if Z is a protected amino group, splitting off the protecting group and, if a compound of formula I wherein n is 0 is obtained, oxidizing this compound, if desired, to a compound of formula I, wherein n is 1.

2. A process as claimed in Claim 1 wherein Z is a hydroxyamino, amino or phthalimido group and wherein, respectively, (a) if Z is hydroxyamino, the compound of formula II is reacted with a mixture of mercuric sulfate and a to carboxylic acid in an inert solvent, (b) if Z is amino, the compound of formula II is reacted with a mixture of mercuric sulfate and a to carboxylic acid in the presence of a halogenated hydrocarbon solvent or with concentrated sulfuric acid, or (c) if z is phthalimido, the compound of formula II is reacted with a mixture of mercuric sulfate and a to C 4 carboxylic acid in the presence of a halogenated hydrocarbon solvent whereupon the product thus obtained is reacted with a 4 938 3 primary alkyl amine or hydrazine in a water miscible solvent, and wherein the optional oxidation of a compound of formula I wherein n is 0 is effected by means 5 of a peracid in an inert organic solvent.

3. A compound of the general formula wherein X, Y and Z are as defined in Claim 1.

4. A compound as claimed in Claim 3 wherein Z is a phthalimido group.

5. A process as claimed in Claim 1, substantially as herein described.

6. Compounds of the general formula I as defined in Claim 1, whenever prepared by the process claimed in 15 a preceding claim or by an obvious chemical equivalent thereof.