NO811671L - Benzazepine. - Google Patents

Abstract

3-H-2-benzazepines and and 4,5-dihydro-3H-2-benzazepines of formula. where X is hydrogen, chlorine or bromine, Y is hydrogen, fluorine or chlorine, the broken line indicates any bond, n is zero or 1 and R 1 is hydrogen, bromine, chlorine, iodine, a residue or a residue with which is hydrogen , lower alkyl, hydroxy, amino. monoalkylamino or dialkylamino and R 1 are hydroxy or amino with the proviso that (i) X and Y may not both be hydrogen, and (ii) when R The compounds have anticonvulsant, sedative, antianxiety, antidepressant and muscle relaxant effects or may be intermediates for compounds having such effects. New intermediates and methods for preparing the above benzase epines are also described.

Description

The present invention relates to 3H-'2-benzazepines with the general formula R

where X is hydrogen, chlorine or bromine, Y is hydrogen, fluorine

• or chlorine, the broken line denotes a possible bond, n is zero or 1 and R, is hydrogen, bromine, chlorine, iodine, a|

remainder with formula

or a remainder with a formula

where R 2 is hydrogen, lower alkyl, hydroxy, amino, monoalkylamino or dialkylamino and R 2 is hydroxy or amino with the proviso that

(i) X and Y cannot both be hydrogen, and

(ii) where or when R^ is different from hydrogen, the bond indicated by the broken line must be present,

and

pharmaceutically acceptable salts thereof.

IN

3H-2benzazepines where R=Y=X=H has been previously described, see

Tetrahedron Letters No. 1, pages 33-36, 1974, Pergamon Press. However, these compounds have been shown to be inactive during testing. However, the compounds according to the present invention show good psychotropic activity even though they are structurally related to the inactive compound.

According to the present invention, the compounds of formula I and pharmaceutically acceptable salts thereof can be prepared by

a) to cyclize a compound of the general formula

where X and Y have the meaning indicated above and the broken one

line indicates any binding,

or

b) to oxidize a compound of the general formula

where X and Y have the meanings given above, R^^ is hydrogen, bromine, chlorine or iodine and the broken line indicates a possible j bond with the proviso that R^ is different from hydrogen, the bond indicated by the broken line must be present, or c) to dehydrohalogenate a compound of the general formula

where X and Y have the above meaning and R12 is chlorine, bromine or iodine,

or,

d) to react a compound with the general formula

where X, Y, R12°9n have the meanings given above,

with a compound of the general formula

where R21 is hydrogen, lower alkyl, hydroxy, mono-lower alkylamino or di-lower alkylamino

in the presence of a palladium salt, copper (I) iodide, an organic phosphine or a secondary or tertiary amine,

or!

e) the phthaloyl group(s) from a compound of the general formula in :

where X, Y and n have the meanings given above and Phth is phthalimido,

or

f) transferring a compound of formula I in a pharmaceutically acceptable salt.

The above-mentioned process embodiments for the preparation of the compounds of formula I and the preparation of the starting materials for these are illustrated by the following reaction core where X, Y, R12'n and<p>hth have the above-mentioned meaning and R.-,- is hydrogen, phthalimido, lower alkyl, hydroxy, amino, monoalkylamino or dialkylamino, R^-^ is hydroxy, phthalimido or amino and R^ is lower alkoxy: The compounds of formulas II, III, V, VI, VIII and IX also form part of the present invention.

The compounds of formula VII and X do not form part of the present invention, but examples 34 - 45 in the present description indicate methods for preparing these compounds.

The compounds of formula VII can generally be prepared by diazotizing the corresponding known aminobenzophenones using sodium nitrite in sulfuric acid and isolating the salts by precipitation of the respective tetrafluoroborate salts which are then slurried in water and treated with aqueous potassium iodide to give iodobenzophenone. These turnovers are carried out using methods that are previously known. Then the iodobenzophenone is treated with propargylphthalimide in the presence of a mixture of

palladium chloride, an organophosphine, copper (I) iodide and a secondary amine in a suitable solvent to form the phthalimidopropyne of formula VII.

VII— » VIII

The compound of formula VII is hydrogenated using a transition metal catalyst such as Raney nickel or platinum oxide at from approx. atmospheric pressure to 3.4 atm, atmospheric pressure being preferred. Solvents that can be used include C.-Cr alcohols, tetrahydrofuran, dioxane and toluene.

16

VIII » Ia' and IX Ia"

The compounds of formula VIII and IX can be reacted with an aqueous solution of a lower alkylamine, e.g. methylamine.

A C 1 - alcohol can be used as solvent, ethanol being preferred. The reaction is preferably carried out at around room temperature. The first formed open amine is not isolated, but undergoes spontaneous cyclization to the compound of formula. Ia and Ia".

An alternative method of preparing the compounds of the formulas Ia' and Ia" consists in the reaction of the compounds of the formulas VIII and IX with hydrazine in an inert solvent, such as ethanol, tetrahydrofuran, aqueous ethanol or a mixture of ethanol and chloroform. The reaction temperature can vary from about room temperature to about 100°C, below which the reflux temperature of the selected solvent is preferred.The product is extracted with dilute mineral acid and then recovered and neutralized.

A third method that can be used to prepare the compounds of formulas Ia and Ia" consists of a base followed by an acid hydrolysis of the compounds of formulas VIII and IX. For the basic part of the hydrolysis, an alkali metal hydroxide such as potassium or sodium hydroxide is used. For the acidic part of the hydrolysis, a 10% solution of a mineral acid can be used

such as hydrochloric acid, hydrochloride, hydrobromide, sulfuric acid or phosphoric acid are used. The hydrolyses are carried out at or around room temperature to reflux temperature, below which reflux temperature is preferred. Organic solvents such as C1~C4 alcohols or tetrahydrofuran can be used to solubilize the components.

VII IX.

The compounds of formula VII are hydrogenated using a Lindlar catalyst (pre-hydrogenated 10% palladium or barium sulfate) at approx. atmospheric pressure and approx. room temperature. Suitable solvents for the reaction include c^~cg alcohols, tetrahydrofuran, dioxane or toluene.

VII X.

The compound of formula VII can be reacted with a primary lower alkylamine, e.g. methyl or ethylamine or with hydrazine in a water-miscible solvent, such as C1 .-C6 .I alcohols, ethers or dimethylformamide. The reaction temperature can range from approx. 0°C - 60°C, below which around room temperature is preferred.

Another method that can be used to prepare the compound of formula X consists of a basic followed by an acid hydrolysis of the compound of formula VII. For the basic part of the hydrolysis, an alkali metal hydroxide such as potassium or sodium hydroxide is used. For the acidic part of the hydrolysis, a 10% solution of a mineral acid such as hydrochloric acid, hydrogen bromide, sulfuric acid or phosphoric acid can be used. The hydrolyses are carried out at or around room temperature to reflux temperature, below which reflux temperature is preferred. • Organic solvents such as C-^-C^ alcohols or tetrahydrofuran. can be used to dissolve the components.

X Ia".

The compound of formula X can be converted to a compound of formula Ia" using the reactant and reaction parameters of VII MX. The first formed open amine is not isolated, but undergoes spontaneous cyclization to the compound of formula Ia".

X Ia'

The compound of formula X can be hydrogenated using ay Raney nickel as a catalyst at from atmospheric pressure to 3.4 atm. below which atmospheric pressure is preferred. The reaction is carried out at around room temperature. Suitable solvents for the reaction include c-j_~cg alcohols, tetrahydrofuran, dioxane and toluene. The first formed open amine is not isolated, but undergoes spontaneous ring closure to. the compound of formula Ia<1>.

Ia' —-► Ic and Ia" Id and Ib' —- » Ib"

The compounds of formulas Ia' and Ia" and Ib' can be reacted with a suitable oxidizing agent such as methachloroperbenzoic acid in an inert organic solvent such as ethylene chloride. t '<:>i The reaction can be carried out at between 0°C to the reflux temperature of the solvent, room temperature being preferred .

Ia" —- » III '

The compound of formula Ia" can be halogenated using a halogenating agent such as elemental chlorine, bromine or iodine in a halogenated hydrocarbon such as methylene chloride or chloroform. The reaction is carried out at from about 0°C to about room temperature, with room temperature being preferred.

III Ib'

The compound of formula III can be dehydrohalogenated using an alkali metal, e.g. sodium or potassium, hydroxide, carbonates or alkoxide. Suitable solvents include C - Cg alcohols, tetrahydrofuran, dioxane. and dimethylformamide. When a C,-C, alcohol is used as a solvent in the bven-16 .

said reaction, a final product mixture of compound: with formula Ib<1> and XI is produced. The reaction temperature can vary from 0° to the reflux temperature of the chosen solvent, room temperature being preferred.

Ib — » XII or XIII

The compounds of formula Ib can be reacted with a mono-substituted acetylene of formula H=C-CH2-R22, where R22 is hydrogen, phthalimido, lower alkyl, hydroxy, mono-lower alkylamino or di-lower alkylamino. Examples of the above are propargyl alcohol, propargylphthalimide, N-methylpropargylamine, propyne or N,N-dimethylpropargylamine. The reaction is carried out in the presence of palladium chloride, copper (I) iodide, triphenylphosphine and a di- or trialkylamine, such as di- or triethylamine. Suitable solvents are halogenated hydrocarbons, e.g. methylene chloride or chloroform and dimethylformamide. The reaction temperature can vary from approx. 0°C to return temperature, room temperature being preferred.

It has been found that shorter reaction times and the use of mono- or di-alkyl amino substituted acetylenes tend to give compounds of formula XII, while longer reaction times and the use of hydroxy and phthalimido substituted acetylenes tend to form compounds of formula XIII.

To get to and R^ as amino, one can remove the phthaloyl substituent on °9^ 21 me(^ an acid eHer base hydrolysis or by reaction with an aqueous monoalkyl amine or hydrazine as in step VII X.

As used herein, the term "lower alkyl" or "alkyl" shall mean a C₁-C₂ wherein C₁-C₂ is preferably a straight or branched hydrocarbon chain, e.g. methyl, ethyl, propyl etc.

A suitable pharmaceutical dosage unit can contain from approx.

1 - 500 mg of the benzazepine end products, including a dosage range from approx. 1 mg - 100 mg is preferred as oral administration and a dosage range from approx. 1 mg - 50 mg is preferred for parenteral administration. For any particular purpose, however, the specific dosage should be adjusted depending on the individual need and the professional judgment of the person administering or supervising the administration of the aforementioned compounds. It should be clear that the dosage ranges given here are only examples and that they do not in any way limit the scope or practice of the present invention.

The term "dosage unit" as used herein means pharmaceutical defined units suitable as single doses for mammals each containing a predetermined amount of active material intended to produce the desired therapeutic effect in combination with the necessary pharmaceutical diluent, carrier or excipient.

3H-2-benzazepines of formula I are useful as pharmaceuticals and are characterized by action particularly as sedatives and anxiolytics. These compounds can be used in the form of conventional pharmaceutical preparations, e.g. the aforementioned compounds can be mixed with conventional organic or inorganic inert pharmaceutical carriers suitable for parenteral or enteral administration such as e.g. water, gelatin, lactose, starch, magnesium stearate,

talc, vegetable oil, rubber, polyalkylene glycols, petroleum jelly or the like. They can be given in conventional pharmaceutical forms, e.g. solid forms, e.g. tablets, dragees, capsules, suppositories or the like in liquid form, e.g. solutions, suspensions or emulsions. Furthermore, the pharmaceutical mixtures containing compounds according to the present invention can be subjected to usual pharmaceutical treatments such as sterilization, and can contain conventional pharmaceutical diluents and preservatives, stabilizers, wetting agents, emulsifiers, salts for adjusting osmotic pressure or buffers. The mixtures may also contain other therapeutically active materials.

An example of the effects of the compounds according to the present invention is illustrated through the results of the metrasol experiment with several compounds from the present invention.

A metrazole standardization experiment precedes the measurement to determine the amount of metrazole given to control mice sufficient to induce convulsive reactions in all animals. It is normally 125 mg/kg. In the antimetrazole experiment, a compound is given orally to groups of 4 mice at different dosage levels. One hour later, metrazol (in a predetermined dosage in the standardization test) is given subcutaneously

in and the animals are considered with regard to protection against convulsive reactions. The results are recorded as the number of animals protected against convulsions. The dose at which 50% of the animals are protected against convulsive reactions is expressed as EDj-q For active compounds, 8 animals are used per dosage group. ED^q is calculated by the Miller-Tainter method (Proc.Soc. Exp.Med.and Bio., 57, 261, 1944).

8-chloro-5-(1-amino-2-propyn-3-yl)-1-phenyl-3H-2-benzazepine dihydrochloride

8-chloro-5-(1-amino-2-propyn-3-yl)-1-(2-fluorophenyl)-3H-2 benzazepine dihydrochloride 8-chloro-1-phenyl-3H-2-benzazepine-2-oxide 8-chloro-5-(1-dimethylamino-2-propyn-3-yl)-1-(2-fluorophenyl)-3H-2-benzazepine dihydrochloride

The compounds - according to the present invention where R. is hydrogen, bromine, chlorine and iodine are also intermediates in the production of other active benzazepines, e.g. pyrimidobenza-sepines.

Preferred are the compounds of formula

where X' is chlorine, Y' is hydrogen, fluorine or chlorine and

R,, is a residue of formula

or a residue of the formula where R 22 is amino, monoalkylamino or dialkylamino and R 2 is amino. Particularly preferred are compounds of the above formula Ia where R^^ is a residue of formula

where R 22 is amino, monoalkylamino or dialkylamino.

Particularly preferred compounds of the above formula Ia are: 8-chloro-5-(1-amino-2-propyn-3-yl)-1-phenyl-3H-2-benzazepine;

and

8-chloro-5-(1-amino-2-propyn-3-yl)-1-(2-fluorophenyl)-3H-2-benzazepine.

The above compounds of formula I show antidepressant activity as illustrated in the imipramine binding assay described below.

Male rats (180 g) are opened and the brains are immediately placed on ice. The cortex is dissected and homogenized in 8 volumes of 0.25 M sucrose. The homogenate is centrifuged at 2900 rpm (1000 x g). The supernatant is poured off and polytronized for 60 sec. Dilutions of imipramine hydrochloride are made in ethanol

(1:5) Each measuring sample contains: 1.8 ml Krebs Ringer buffer,

20 ul imipramine or other drugs and 20 ul<3>H-imipramine

-3

(0.1 mM). Imipramine (10 M) is used to define non-specific binding. The incubation is for 15 min. at room temperature. Samples are then placed in an ice bath for 5 min. Each sample is filtered. The filter paper is placed in 13 ml of aquasol and shaken for 2 hours, the radioactivity captured on the filter is determined by:

liquid scintillation spectrometry.

The term "pharmaceutically acceptable salts" is used to include salts with both inorganic and organic pharmaceutically acceptable acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, tartaric acid, metalsulfonic acid, paratoluenesulfonic acid and the like. Such salts can easily be prepared by a person skilled in the art. According to previously known methods and taking into account the properties of the compound to be transferred in salt form.

The following examples are illustrative, but not limiting, of this invention. All temperatures are given in degrees Celsius, unless otherwise stated.

EXAMPLES

. Example 1

1-[ 4- chloro- 2- benzoylphenyl]- 3- phthalimidopropane

A mixture of 2 g (5 mmol) 1-[4-chloro-2^-benzoylphenyl]-3-phthalimidopropyne and 1/2 teaspoon Raney nickel in 25 ml tetrahydrofuran hydrogenated at room temperature and atmospheric pressure. When 240 ml of hydrogen had been absorbed, the catalyst was separated by filtration and the filtrate concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of ether and petroleum ether and gave a crude product as a brown solid,

mp 94-97°. Recrystallization from ether gave pale yellow prisms, mp 98-99°.

Example 2

1- [ 4- chloro- 2- ( 2- fluorobenzoyl). phenyl]-3-phthalimidopropane

A mixture of 9.6 g (23 mmol) of 1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopropyne and 1 teaspoon of Raney nickel in 70 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure. When 1.05 liters of hydrogen had been absorbed, the catalyst was separated by filtration and the filtrate was concentrated to dryness under reduced pressure. The residue crystallized from a mixture of ether and petroleum ether to a product which was a brown solid, mp 98-99°.

Example 3

8- chloro- 4, 5- dihydro- l- phenyl- 3H- 2- benzazepine hydrochloride

A solution of 5.1 g (12.6 mmol) of 1-[4-chloro-2-benzoylphenyl]-3-phthalimido-propane in 100 ml of ethanol and 20 ml of 3N sodium hydroxide was refluxed for 2 hours. The solution was diluted with 60 ml of 3N hydrochloric acid and refluxed for 12 hours. The mixture was diluted with water and extracted with ether. The aqueous layer was separated, made alkaline with dilute sodium hydroxide and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was purified by plug filtration (silica gel 10 g; eluent methylene chloride) and the eluent was acidified with methanolic hydrogen chloride. The solution was concentrated under reduced pressure to dryness and the residue was crystallized from a mixture of isopropanyl and ether to a colorless solid, mp 234-235°. Recrystallization from a mixture of methylene chloride and ether gave colorless needles,

mp 234-235° (decomposition).

Example 4

8- chloro- 4, 5- dihydro- 1-( 2- fluorophenyl)- 3H- 2- benzazepine hydrochloride

Method A

A mixture of 2.9 g (10 mmol) of 3-amino-1-[4-chloro-2-(2-fluorobenzoyl)phenyl]propyne and 1/4 teaspoon of Raney nickel in 50 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure. When 430 ml of hydrogen had been absorbed, the catalyst was removed by filtration and the filtrate was concentrated to dryness under reduced pressure. A solution of the residue in an excess of methanolic hydrogen chloride was diluted with ether and the final product mp 176-177° (dec) was collected by filtration. Recrystallization from a mixture of methanol and ether gave pale yellow plates, mp 209-215° (decomposition).

Method B

A solution of 5.9 g (14 mmol) of 1-[4-chloro-2-(2-fluorobenzoyl)phenyl-3-phthalimidopropane in a mixture of 100 ml of ethanol and 20 ml of 3N sodium hydroxide at reflux for 2 hours, diluted with 60 ml of 3N hydrochloric acid and refluxed for 12 hours. The reaction mixture was poured into water and extracted with ether. The aqueous acidic layer was separated, made alkaline with dilute sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by plug filtration (alumina Woelm I, 50g; eluent, methylene chloride) gave an oil which was diluted with an excess of methanolic hydrogen chloride and concentrated under reduced pressure to dryness. The residue was crystallized from a mixture of methanol from ether to a product identical in every respect to an authentic sample.

Example 5

1-[ 4- chloro- 2- benzoylphenyl]- 3- phthalimidopropene

A mixture of 2.0 g (5 mmol) 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne and 0.1 g prehydrogenated 10% palladium on barium sulfate in 50 ml tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure until 85 ml hydrogen was absorbed. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to dryness. The residue was crystallized from ether to a white solid, mp 70-72°. Recrystallization from ether gave colorless prisms, mp 70-72°.

Example 6

1-[ 4- chloro- 2-( 2- fluorobenzoyl) phenyl]- 3- phthalimidopropene

The preparation of 1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopropene was carried out in the same way as the preparation of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropene and gave colorless needles, mp 117°.

Example 7

8- chloro- 1- phenyl- 3H- 2- benzasepiri hydrochloride

Method A

A mixture of 0.1 g of prehydrogenated 10% palladium on barium sulfate and 27 g (0.1 mol) of 3-amino-1-[2-benzoyl-4-chlorophenyl]propyne in 100 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure up to 2 .4 liters (approx. 0.1 mol) of hydrogen had been absorbed. The catalyst was removed by filtration. The filtrate was diluted with an excess of methanolic hydrogen chloride and 100 ml of isopropanol and concentrated under reduced pressure to a crystalline residue. Trituration with a mixture of ether and methanol gave a brown solid, mp 224-226° (decomposition). Recrystallization from a mixture of methanol and ether gave cream-colored prisms, mp 227-228° (dec.).

Method B

A mixture of 6 g (15 mmol) 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropene, 0.9 g (18 mmol) 85% hydrazine hydrate and 70 ml 95% ethanol was refluxed for 2.5 hours. The insoluble precipitate that formed was separated by filtration. The filtrate was acidified with ice-cold dilute hydrochloric acid and extracted with ether.

The aqueous layer was separated, made alkaline with dilute sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate, acidified with methanolic hydrogen chloride, diluted with isopropanol and concentrated under reduced pressure to a small volume. The crude product was collected by filtration and gave brown prisms, mp 223-225° (decomposition) which were in all respects identical to an authentic sample.

Example 8

8-chloro-1-(2-fluorophenyl)-3H-2-benzazepine hydrochloride

Preparation of 8-chloro-1-(2-fluorophenyl)-3H-2-benzazepine

.hydrochloride was carried out in the same way as the preparation of 8-chloro-l-phenyl-3H-2-benzazepine hydrochloride and gave a product (Method A) and (Method B) as grey-white prisms, mp 210-212°

(fission).

Example 9

8-chloro-1-(2-chlorophenyl)-3H-2-benzazepine

A mixture of 4.6 g (15 mmol) of 3-amino-1-[2-(2-chlorobenzoyl)-4-chlorophenyl]profyn and 0.1 g of prehydrogenated palladium and barium sulfate in 30 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure until 355 ml of hydrogen had been absorbed. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure. The residue was crystallized from ether to give a cream-colored solid, mp 113-115°. Recrystallization from ether gave cream-colored prisms, mp 117-118°.

The methanesulfonate salt of 8-chloro-1-(2-chlorophenyl)-3H-2-benzazepine was prepared by adding an excess of 1M methanolic solution of methanesulfonic acid to a methanolic solution of the above compound and isolated by precipitation of the salt by addition of ether. Recrystallization from a mixture of ethanol and ether gave the methanesulfonate salt as colorless plates, m.p. 201-202°.

Example 10

1-(2-chlorophenyl)-3H-2-benzazepine hydrochloride

The preparation of 1-(2-chlorophenyl)-3H-benzazepine hydrochloride was carried out in the same way (Method A) as the preparation of 8-chloro-1-phenyl-3H-2-benzazepine hydrochloride and gave brown needles, mp 201-202° .

Example 11

8- chloro- 4, 5- dihydro- l- phenyl- 3H- 2- benzazepine- 2- oxide

A mixture of 1.4 g (5.5 mmol) 8-chloro-4,5-dihydro-1-phenyl-3H-2-benzazepine and 1.4 g (7 mmol) 85% m-chloroperbenzoic acid in 50 ml methylene chloride was stirred for 18 hours at room temperature. The reaction mixture was washed with dilute aqueous sodium hydroxide and the organic layer separated, dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. The residue was crystallized from ether and gave a colorless solid, mp 120-125°. Recrystallization from ether gas gave

colorless prisms, mp 142-143°.

Example 12

8-chloro-1-phenyl-3H-2-benzazepine-2-oxide

A mixture of 10.7 g (42 mmol) 8-chloro-1-phenyl-3H-2-benzazepine 10.7 g (53 mmol) 85% metachloroperbenzoic acid and 100 ml methylene chloride was stirred at room temperature for 16 hours. The mixture was washed with cold dilute aqueous sodium hydroxide and brine. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was crystallized with ether to a crude product, mp 130-131°. Recrystallization from ether gave brown prisms, mp 122-123°.

Example 13

8-chloro-1-[2-fluorophenyl]-3H-2-benzazepine-2-oxide

Preparation of 8-chloro-1-(2-fluorophenyl)-3H-2-benzazepine-2-oxide was carried out in the same manner as the preparation of 8-chloro-1-phenyl-3H-2-benzazepine-2-oxide and gave colorless prisms,

mp 138-139°.

Example 14

8-chloro-1-(2-chlorophenyl)-3H-2-benzazepine-2-oxide

Preparation of 8-chloro-1-(2-chlorophenyl)-3H-2-benzazepine-2-oxide was carried out in the same manner as the preparation of 8-chloro-1-phenyl-3H-2-benzazepine-2-oxide and gave cream colored prisms, mp 196-197°.

Example 15

1-(2-chlorophenyl)-3H-2-benzazepine-2-oxide

Preparation of 1-(2-chlorophenyl)-3H-2-benzazepine-2-oxide was carried out in the same manner as the preparation of 8-chloro-1-phenyl-3H-2-benzazepine-2-oxide and gave cream colored rods , mp 115-116°.

Example 16

8-chloro-4,5-dibromo-4,5-dih. ydro-l-phenyl-3H-benzazepine

200 ml (0.18 mol) of a 5% bromine solution in methylene chloride was added dropwise to 26.5 g (0.1 mol) of 8-chloro-1-phenyl-3H-2-benzazepine in 300 ml of methylene chloride. The mixture was stirred at room temperature for 1 hour, diluted with an excess of saturated aqueous sodium carbonate and stirred at room temperature for 15 min. The methylene chloride solution was separated, dried over anhydrous sodium sulfate and diluted with an excess of methanolic hydrogen chloride. The acidic solution was concentrated to a small volume under reduced pressure and the salt precipitated by addition of ether, which gave the salt as a colorless solid, mp 164-165°. Recrystallization from methylene chloride gave colorless crystals, mp 164-165° (decomposition). The compound is found to have a second melting point of 172-173° (decomposition).

A methanol solution of salts was neutralized with dilute aqueous sodium hydroxide and the resulting crystals collected by filtration. Recrystallization from methanol gave the final product as colorless prisms, mp 113-115°.

Example 17

8- chloro- 4, 5- dibromo- 4, 5- dihydro- 1-( 2- fluorophenyl)- 3H- 2- benzazepine

Preparation of 8-chloro-4,5-dibromo-4,5-dihydro-1-(2-fluorophenyl)-3H-2-benzazepine. was carried out in the same manner as the preparation of 8-chloro-4,5-dibromo-4,5-dihydro-1-phenyl-3H-2-benzazepine and gave the hydrochloride salt as a colorless solid, mp 158-159° (dec. ) and.end product as colorless prisms,

.mpg 102 -•103°. Example 18 8-chloro-4,5-dibromo-4,5-dihydro-1-(2-chlorophenyl)-3H-2-benzazepine Preparation of 8-chloro-4,5-dibromo-4,5-dihydro-1 -(2-chlorophenyl)-3H-2-benzazepine was carried out in the same manner as the preparation of 8-chloro-4,5-dibromo-4,5-dihydro-l-phenyl-3H-2-benzazepine and gave pale yellow prisms, mp 139° (decomposition).

Example 19

8- chloro- 5- bromo- l- phenyl- 3H- 2- benzazepine hydrochloride and 8- chloro- 3- methoxy- l- phenyl- 3H- 2- benzazepine methanesulfonate

A solution of 24 g (53 mmol) of 8-chloro-4,5-dibromo-4,5-dihydro-1-phenyl-3H-2-benzazepine hydrochloride in 1 liter of methanol and 180 ml of 10% aqueous sodium hydroxide was stirred at room temperature in 45 hours. The mixture was stirred in vacuo to a small volume and the residue was extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate, diluted with an excess of methanolic hydrogen chloride and concentrated in vacuo to dryness. The residue crystallized from a mixture of isopropanol and ether to give an off-white solid, mp 229-230°. Recrystallization from methylene chloride gave the hydrochloride of the bromine compound as colorless prisms, mp 230-235° (decomposition).

The crude mother liquors were basified with dilute aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by column chromatography (silica gel; eluent methylene chloride, then ether) gave, after concentration of the ether fractions, a colorless oil. The oil was dissolved in a methanol solution of methanesulfonic acid and the salt was precipitated by the addition of ether. Recrystallization from a mixture of methanol and ether gave off-white prisms, mp 139-140°.

Example 20

8- chloro- 5- bromo- 1-( 2- fluorophenyl)- 3H- 2- benzazepine hydrochloride

A mixture of 21 g (45 mmol) of 8-chloro-4,5-dibromo-4,5-dihydro-1-(2-fluorophenyl)-3H-2-benzazepine hydrochloride, 40 ml of dioxane,

360 ml of methanol and 40 ml of 10% aqueous sodium hydroxide were stirred at room temperature for 5 hours and then concentrated under reduced pressure to a small volume. The concentrate was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate, diluted with isopropanol and an excess of methanolic hydrogen chloride. The mixture was concentrated under reduced pressure to a small volume to give the hydrochloride salt as a colorless solid, mp 231-232°. Recrystallization from a mixture of methylene chloride and ether gave the salt as colorless crystals, mp 233-234°

(fission). The methanesulfonate salt of the byproduct (8-chloro-3-methoxy-1-(2-fluorophenyl)-3H-2-benzazepine) was not isolated.

Example 21

8-chloro-5-bromo-1-(2-chlorophenyl)-3H-2-benzazepine and 8-^chloro-3-methoxy-1-(2-chlorophenyl)-3H-2-benzazepine

A mixture of 60.0 g (0.134 mol) 8-chloro-4,5-dibromo-4,5-dihydro-1-(2-chlorophenyl)-3H-2-benzazepine and 75 ml 40%

aqueous sodium hydroxide in a mixture of 300 ml of dioxane and 900 ml of methanol was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo to a small volume and the residue was extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate, diluted with an excess of methanolic hydrogen chloride and isopropanol and concentrated in vacuo to dryness. The residue crystallized from a mixture of isopropanol and ether to give a white solid. The white solid was partitioned between ethylene chloride and aqueous sodium bicarbonate. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to an amber oil. Purification by column chromatography

(silica gel, 250 g; eluent, methylene chloride) gave the bromine compound as colorless prisms, mp 125-127°.

The crude mother liquors were partitioned between methylene chloride and aqueous ammonium hydroxide. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Trituration with a mixture of ether and petroleum ether gave the methoxy compound as a brown solid. Recrystallization from. a mixture of ether and petroleum ether gave cream colored prisms,

m.p. 83-85°.

Example 22

8- chloro- 5- bromo- 1- phenyl- 3H- 2- benzazepine- 2- oxide

A solution of 6.9 g (20.7 mmol) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine and 6 g (29 mmol) of 85% m-chloroperbenzoic acid in 100 ml of methylene chloride was stirred at room temperature for 1 hour. The mixture was washed with cold dilute sodium hydroxide, dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was crystallized from ether and gave a white solid, mp 184-185°. Recrystallization from ether gave colorless prisms, mp 185-186° (decomposition).

Example 23

8- chloro- 5-( 1- dimethylamino- 2- propyn- 3- yl)- 1- phenyl- 3H- 2- benzazepine dihydrochloride 1/ 4 molar hydrate

A mixture of 120 ml 98% diethylamine, 88.6 mg (0.5 mmol) palladium chloride, 262.4 mg (1 mmol) triphenylphosphine, 95.2 mg (0.5 mmol) cupric iodide, 8.7 g (26 mmol) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine and 25 g (0.3 mol) of 1-dimethylamino-2-propyne were stirred under argon for 24 hours. The mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methylene chloride and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by column chromatography (silica gel 50 g; eluent, methylene chloride then ether) gave an oil. The oil was dissolved in ethanol and diluted with an excess of ethanolic hydrogen chloride to give the hydrochloride salt as a colorless solid, mp 193-195° (decomposition). Recrystallization from methylene chloride gave the salt as colorless crystals, mp 198-199° (decomposition).

Example 24

8- chloro- 5-( 1- dimethylamino- 2- propyn- 3- yl)- 1-( 2- fluorophenyl)- 3H-2- benzazepine dihydrochloride

A mixture of 40 ml 98% diethylamine, 44.3 mg (0.25 mmol) palladium chloride, 131.2 mg (0.5 mmol) triphenylphosphine, 47.6

mg (0.25 mmol) cupric iodide, 3.5 g (9.4 mmol) 8-chloro-5-bromo-1-(2-fluorophenyl)-3H-2-benzazepine and 16 ml 1-dimethylamino-2- propyne was stirred under nitrogen at room temperature for 23 h. The mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methylene chloride, washed with water and dried over anhydrous sodium sulfate. The methylene chloride solution was diluted with an excess of methanolic hydrogen chloride and concentrated in vacuo to dryness. The residue crystallized from a mixture of ethanol and isopropanol to give the dihydrochloride as a yellow solid, mp 155-156°. Recrystallization from a mixture of ethanol and ether gave the salt as pale yellow rods, mp 194-195° (decomposition).

Example 2 5

8-chloro-(1-dimethylamino-2-propyn-3-yl)-1-phenyl-3H-2^-benzazepine-2-oxide

A mixture of 3.5 g (10 mmol) 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine-2-oxide, 40 ml 98% diethylamine, 40 ml dimethylformamide, 44.3 mg (0 .25 mmol) palladium chloride, 131.2 mg (0.5 mmol) triphenylphosphine, 47.6 mg (0.25 mmol) cupric iodide and 16 ml 1-dimethylamino-2-propyne were stirred at room temperature under nitrogen for 24 hours . The mixture was concentrated under reduced pressure to dryness. An ether solution of the residue containing petroleum ether was washed with water followed by dilute cold hydrochloric acid. The aqueous solution was separated, made alkaline with dilute cold sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue crystallized from a mixture of ether and petroleum ether to give a brown solid, mp 121-123°. Recrystallization from ether gave brown prisms, mp 124-125°.

Example 2 6

8- chloro- 5-( l- hydroxy- 2- propyn- 3- yl)- 1- phenyl- 3H- 2- benzazepine hydrochloride

A mixture of 40 ml 98% diethylamine, 44.3 mg (0.25 mmol) palladium chloride, 131.2 mg (0.5 mmol) triphenylphosphine, 47.6 mg (0.25 mmol) cupric iodide, 3.5 g (10.5 mmol) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine and 5 ml of propargyl alcohol were stirred at room temperature under nitrogen for 7 hours. The mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methylene chloride and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by column chromatography (silica gel 20 g; eluent 20% ether in methylene chloride) gave a colorless oil. The oil was dissolved in an excess of methanolic hydrogen chloride and concentrated under reduced pressure to dryness. The residue crystallized from a mixture of methanol and ether to give a brown solid, mp 228-229° (dec.).

Example 27

8- chloro- 5-( 1, 6- dihydroxy- 2- hexen- 4- yn- 3- yl)- 1- phenyl- 1- 3H- 2-benzazepine

A mixture of 40 ml 98% diethylamine, 44.3 mg (0.25 mmol) palladium chloride, 131 mg (0.5 mmol) triphenyl phosphine, 47.6 mg (0.25 mmol) cupric iodide, 3.5 g (10.5 mmol) of 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine and 5 ml of propargyl alcohol were stirred at room temperature under nitrogen for 24 hours. The mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methylene chloride and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by column chromatography (20 g silica gel; eluent, 20% ether in methylene chloride) gave an oil which crystallized from a mixture of tetrahydrofuran and ether as brown prisms, mp 210-211°

(fission).

The hydrochloride salt was prepared by dissolving the final product

in an excess of methanolic hydrogen chloride and isolated by precipitation of the salt by addition of ether. Recrystallization from a mixture of methanol and ether gave the hydrochloride salt as cream-colored plates, mp 290°.

Example 28

8- chloro- 5-( 1- propynyl)- 1- phenyl- 3H- 2- benzazepine hydrochloride

A stirred mixture of 180 mL 98% diethylamine (degassed with nitrogen), 7.2 g (21.6 mmol) 8-chloro-5-bromo-l-phenyl-3H-2-benzazepine, 0.4 g(0, 6 mmol) of dichlorobis(triphenylphosphine)palladium (II), 0.1 g (0.5 mmol) of copper (I) iodide was saturated with propyne and stirred under an atmosphere of propyne for 23 hours. The mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methylene chloride and washed first with dilute sodium carbonate and water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under pressure to dryness to an oil. A methylene chloride solution of the oil was diluted with an excess of ethanolic hydrogen chloride, concentrated under reduced pressure and crystallized from a mixture of ethanol and isopropanol to the hydrochloride salt as a yellow solid, mp 206-207° (dec.). Recrystallization from a mixture of ethanol and ether gave the salt as pale yellow. prisms, mp 210-211°.

Example 29

8- chloro- 5-( l- phthalimido- 2- propyn- 3- yl)- 1- phenyl- 3H- 2- benzazepine and 8- chloro- 5-( 1, 6- duphthalimido- 2- hexen- 4- yne - 3-yl)-1-phenyl

- benzazepine

A mixture of 600 ml 98% diethylamine, 600 ml methylene chloride,

24 g (65 mmol) 8-chloro-5-bromo-l-phenyl-3H-2-benzazepine hydrochloride, 7.2 g (10 mmol) dichlorobis(triphenylphosphine)palladium (11), 1.8 g (9.5 mmol) cupric (1) iodide and 20 g (0.11 mol) propargyl phthalimide were stirred at room temperature under nitrogen for 5.5 hours. The mixture was concentrated under reduced pressure to dryness and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by column chromatography (silica gel, 450 g; eluent, methylene chloride gradient to 10% ether in methylene chloride) gave as the first product the bound propyn-3-yl compound as a brown solid, m.p. 177^178°. Recrystallization from a mixture of methylene chloride gave brown prisms, mp 185^186°.

A second product bond gave hexen-4-yn-3-yl. the connection

as a grey-white solid, mp 185-190°. Recrystallization from acetonitrile gave gray needles, mp 196-198°.'

Example 3 0

8- chloro-1-(2-fluorophenyl)-5-(1-phthalimido-2-propyn-3-y3)-3H-2-benzazepine

A mixture of 40 ml of 98% diethylamine, 50 ml of methylene chloride,

0.6 g (0.9 mmol) dichlorbis(triphenylphosphine) palladium (II),

0.15 g (0.8 mmol) cupric (I) iodide, 3.8 g (10.8 mmol) 8-chloro-5-bromo-1-(2-fluorophenyl)-3H-2-benzazepine and 3 g (16 mmol) of propargyl phthalimide was stirred under nitrogen at room temperature for 24 hours. The mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methylene chloride and

washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification of the residue by column chromatography (silica gel 50 g; eluent, methylene chloride gradient to 5% ether in methylene chloride) gave a colorless solid as the main fraction. Recrystallization from ether gave colorless needles, mp 164-165°^

Example 31

8- chloro- 5-( N- methyl- 1- 1- amino- 2- propyn- 3- yl)- 1- phenyl- 3H- 2- benzazepine dihydrochloride

A mixture of 3.7 g (10 mmol) 8-chloro-5-bromo-1-phenyl-3H-2-benzazepine hydrochloride, 0.4 g (0.6 mmol) dichlorobis(triphenylphosphine) palladium (II), 0 .2 g (1 mmol) cupric (I) iodide and 2 ml (leftover) 97% N-methylpropargylamine in 50 ml 98% diethylamine and 100 ml methylene chloride were stirred at room temperature under nitrogen for 24 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methylene chloride and extracted with dilute ice-cold hydrochloric acid. The acidic extract was made alkaline with dilute ice-cold sodium carbonate and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. Purification of the residue by column chromatography (silica gel 20 g; eluent, 20% ether in methylene chloride followed by 10% methanol in methylene chloride) gave an amber oil from the last eluent. The oil was dissolved in an excess of methanolic hydrogen chloride and concentrated under reduced pressure to dryness. The residue crystallized from isopropanol and gave the final product which was then recrystallized from isopropanol to brown crystals, mp 169-175° (decomposition).

Example 32

8- chloro- 5-( l- amino- 2- propyn- 3- yl)- 1- phenyl- 3H- 2- benzazepine dihydrochloride

A mixture of 5 g (11.4 mmol) 8-chloro-5-(l-phthalimido-2-propyn-3-yl)-1-phenyl-3H-2-benzazepine, 100 ml ethanol and 20 ml 40% aq. methylamine was stirred at room temperature for 1 hour, poured into ice water and extracted with ether. The ether solution was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in an excess of methanolic hydrogen chloride and concentrated under reduced pressure to dryness. The residue crystallized from a mixture of ethanol and isopropanol to give a brown solid, mp 247-248°. Recrystallization from a mixture of ethanol and ether gave brown prisms, mp 247-248°.

Example 33

8- chloro- 5-( l- amino- 2- propyn- 3- yl)- 1-( 2- fluorophenyl)- 3H- 2-benzazepine dihydrochloride

A mixture of 1.3 g (2.9 mmol) 8-chloro-5-(1-phthalimido-2-propyn-3-yl)-1-(2-fluorophenyl)-3H-2-benzazepine, 50 ml ethanol and 10 ml of 40% aqueous methylamine was stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with ether. The ether mixture was dried over aqueous sodium sulfate and concentrated under reduced pressure to dryness. The residue was dissolved in an excess of ethanolic hydrogen chloride and the resulting salt precipitated by addition of ether which gave a grey-white solid, mp 211-216°. Recrystallization from a mixture of methanol and ether gave gray needles, mp 216-218°.

(fission).

Example 34

5-chloro-2-iodobenzophenone

A mixture of 76 g (1.1 mol) of sodium nitrite and 450 ml of sulfuric acid was. heated in a steam bath to approx. 80° until complete dissolution was obtained. The solution was cooled to 30° and 232 g (1.0 mol) of 2-amino-5-chlorobenzophenone was added in portions to maintain the temperature between 30° and 40°. The mixture was stirred for 1 hour and then poured into 3 liters of a mixture of ice and water. The solution was filtered through Hy-Flo and the stirred filtrate was slowly added to a solution of 200 g (1.83 mol) sodium fluoroborate 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-benzoyl-4-chlorobenzenediazonium fluoroborate was slurried in 3 liters of water and a solution of 332 g (2 moles) of potassium iodide in 1 liter of water was added dropwise. The mixture was stirred at room temperature for 4 hours and the resulting precipitate collected by filtration. The crude product was added to 1 liter of boiling ether, filtered and dried with anhydrous sodium sulfate. The ether solution was concentrated to 500 ml and addition of 100 ml petroleum ether gave the final product. A small amount of the final product was recrystallized from a mixture of ether and petroleum ether to give pale yellow prisms, mp 8o-82°.

Example 35

5-chloro-2'-fluoro-2-iodobenzophenone

The preparation of 5-chloro-2'-fluoro-2-iodobenzophenone was carried out in the same way as the preparation of 5-chloro-2-iodobenzophenone which gave the final product as pale yellow prisms, mp 78-81°.

Example 36

2', 5-dichloro-2-iodobenzophenone

Preparation of 2<1->5-dichloro-2-iodobenzophenone was carried out in the same way as the preparation of 5-chloro-2-iodobenzophenone, which gave the end product as pale yellow prisms, mp 64-66°.

Example 37

2'-chloro-2-iodobenzophenone

Preparation of 2'-chloro-2-iodobenzophenone was carried out in the same manner as 5-chloro-2-iodobenzophenone and gave the final product as pale yellow prisms, mp 62-64°.

Example 38

1-[ 4- chloro- 2- benzoylphenyl]- 3- phthalimidopropyne

A mixture of 0.71 g (4.0 mmol) palladium chloride, 2.1 g

(8.0 mmol) triphenylphosphine, 0.80 g (4.2 mmol) cupric (I) iodide 68.8 g (0.20 mol) 5-chloro-2-iodobenzophenone, 200 ml diethylamine and 400 ml ethylene chloride were stirred at room temperature under argon until complete dissolution...In one portion, 40.0 g (0.22 mol) of N-propargyl phthalimide was added to the solution and the resulting mixture was stirred for 20 hours. The volatile components were removed under reduced pressure and the residue was triturated with 200 ml of isopropanol. The resulting precipitate was collected by filtration to give crude final product. Recrystallization. lization from acetone gave cream-colored. prisms, mp 148-150°.

Example 3 9

1-[ 4- chloro- 2-( 2- fluorobenzoyl) phenyl]- 3- phthalimidopropyne

The preparation of 1-(4-chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopyropyrene was carried out in a similar manner to the preparation of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne and gave cream colored prisms, mp 158-161°.

Example 4 0

1-[ 4- chloro- 2-( 2- chlorobenzoyl) phenyl]- 3- phthalimidopropyne

Preparation of 1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne was carried out in the same manner as preparation

of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne and gave cream-colored prisms, m.p. 144-145°.

Example 41

1- [ 2-( 2- chlorobenzoyl) phenyl]- 3- phthalimidopropyne

Preparation of 1-(2-chlorobenzoyl)phenyl]-3-phthalimidopropyne

was carried out in the same manner as the preparation of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne and gave cream colored prisms, mp 149-150°.

Example 42

3-amino-1-[2-benzoyl-4-chlorophenyl]propyne

Method A

A mixture of 72 g (0.18 mol) 1-[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 is further diluted with 300 ml of ether, washed with water and dried over anhydrous sodium sulfate. Concentration of the ether solution under reduced pressure gave a brown oil, which after trituration with ether gave a yellow solid. Recrystallization from ether gave pale yellow prisms, mp 68-69°.

Method B

A mixture of 4 g (10 mmol) 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne and 0.6 g (16 mmol) 85% hydrazine hydrate in 150 ml 95% ethanol was refluxed for 5.5 hours . The mixture was cooled and its 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 under reduced pressure to dryness. The residue was recrystallized from a mixture of ether and petroleum ether to give a pale yellow solid, mp 68-69° which was identical in all respects to an authentic sample.

The hydrochloride salt of 3-amino-1-[4-chloro-2-benzoylphenyl]propyne was prepared by adding an excess of 6% methanolic hydrogen chloride to a methanolic solution of the product and isolated by precipitation of the salt by addition of ether. Recrystallization from a mixture of methanol and ether gave the hydrochloride as white needles, mp 173-174°.

Example 43

3-amino-1-[4-chloro-2-(2-fluorobenzoyl)phenylpropyne

Method A

Preparation of 3-amino-1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-propyne was carried out in the same way (Method A) as the preparation of 3-amino-1-[4-chloro-2-benzoylphenyl ]propyne and gave yellow prisms, mp 89-91°.

Method B

A mixture of 50 g of 1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-3-phthalimidopropyne, 50 ml of 40% aqueous methylamine and 150 ml of dimethylformamide was stirred at room temperature for 25 min. 500 ml of water was added dropwise and the resulting precipitate was collected by filtration. The precipitate was dissolved in methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to a pale yellow substance. Recrystallization from ether gave pale yellow prisms, mp 89-91°, which were identical in all respects to an authentic sample.

Method C

A mixture of 400 g (0.96 mol) of 1-[4-chloro-2-(2-fluorobenzoyl)-phenyl]-3-phthalimidopropyne, 1.3 liters of ethanol and 300 ml of 40% aqueous methylamine was stirred at room temperature for 2 hours. 2.8 L of water was added dropwise and the resulting precipitate was collected by filtration to give a pale yellow solid, mp 79-80°. Recrystallization from ether gave pale yellow prisms,

mp 89-91° which were identical in every respect to an authentic sample.

Example 44

3-amino-1-[1-chloro-2-(2-chlorobenzoyl)phenyl]propyne

Preparation of 3-amino-1-[4-chloro-2-(2-chlorobenzoyl)phenyl]propyne was carried out in the same manner as the preparation of 3-amino-1-[4-chloro-2-benzoyl-phenyl]propyne ( Method A) and gave pale yellow prisms, mp 81-82°.

Example 4 5

3-amino-1-[2-(2-chlorobenzoyl)phenyl]propyne

Preparation of 3-amino-1-[2-(2-chlorobenzoyl)phenyl]propyne was carried out in the same way as the preparation of 3-amino-1-[4-chloro-2-benzoyl)phenyl]propyne (method A) and gave an amber colored oil.

The hydrochloride salt of 3-amino-1-[2-(2-chlorobenzoyl)phenyl]propyne was prepared by adding an excess of 6% methanolic hydrogen chloride to a methanol solution of the product and isolated by precipitation of the salt by addition of ether. Recrystallization from a mixture of methanol and ether gave the salt as white needles, mp 160-162°.

Claims (10)

1. Procedure for the production of 3H-2-benzazepines with the general formula where X is hydrogen, chlorine or bromine, Y is hydrogen, fluorine or chlorine, the broken line denotes a possible bond, n is 0 or 1 and R-^ is hydrogen, bromine, chlorine, iodine, a residue of formula or a remainder with a formula where R2 is hydrogen, lower alkyl, hydroxy, amino, monoalkylamino or dialkylamino and R^ is hydroxy or amino with the proviso that (1) X and Y cannot both be hydrogen, and (ii) where R, is different from hydrogen, the bond indicated by the broken line must be present, and of pharmaceutically acceptable salts thereof, characterized in that mana) cyclizes a compound of the general formula where X and Y have the meaning stated above and the broken line indicates a possible bond, orb) oxidizes a compound of the general formula where X and Y have the meaning given above, is hydrogen, bromine or iodine and the broken line indicates a possible bond with the proviso that when R-^ is different from hydrogen, the bond indicated by the broken line must be present, orc) dehydrohalogenates a compound with the general compound where X and Y have the above meaning and are chlorine, bromine or iodine, ord) reacts a compound with the general formula where X, Y, R-j 2 ° 9 n have the meaning indicated above, with a compound of the general formula where is hydrogen, lower alkyl, hydroxy, mono-lower alkylamino or di-lower alkylamino, in the presence of a palladium salt, copper (I) iodide, an organic phosphine or a secondary or tertiary amine, or) removes the phthaloyl group(s) from a compound of the general formula where X, Y and n have the meaning given above and Phth is phtalimido, or f) transferring a compound of formula I in a pharmaceutically acceptable salt. 2. Method according to claim 1, characterized in that a compound is produced with that gene real formula where X<1> is chlorine, Y" is hydrogen, fluorine or chlorine and R,^ is a residue of formula or a remainder with a formula where R 1 is amino, monoalkylamino or dialkylamino and R 2 is amino. 3. Method according to claim 2, characterized in that one prepares compounds of the general formula le which is stated in claim 2, where R^ is a residue of formula where R~_. is SOm defined in requirement 2. 4. Method according to claim 3 in the preparation of 8-chloro-5-(1-amino-2-propyn-3-yl)-1-(2-fluorophenyl)-3H-2-benzazepine, characterized in that correspondingly substituted starting materials. 5. Process according to claim 3 for the production of 8-chloro-5-(1-amino-2-propyn-3-yl)-1-phenyl-3H-2-benzazepine, characterized in that correspondingly substituted starting materials are used. 6. Process according to claim 3 in the preparation of 8-chloro-5-(1-dimethylamino-2-propyn-3-yl)-1-(2-fluorophenyl)-3H-2-benzazepine, characterized in that correspondingly substituted starting materials. 7. Process according to claim 1 in the production of 8-chloro-1-phenyl-3H-2-benzazepine-2-oxide, characterized in that correspondingly substituted starting materials are used. 8. Compounds characterized by the formula where X is hydrogen, chlorine or bromine, Y is hydrogen, fluorine or chlorine with the proviso that X and Y cannot both be hydrogen, Z is amino or phthalimido, and where the broken line denotes a possible bond. 9. Connections characterized by the formula where X is hydrogen, chlorine is bromine and Y is hydrogen, fluorine or chlorine with the proviso that X and Y cannot both be hydrogen and R, ~ is chlorine, bromine or iodine. 10. Connections characterized by the formula where X is hydrogen, chlorine or bromine and Y is hydrogen, fluorine or chlorine with the proviso that X and Y cannot both be hydrogen, n is zero or 1 and Phth is phthalimido.