DD270071A5 - PROCESS FOR PREPARING BENZAZEPINE INTERMEDIATE PRODUCTS - Google Patents

Abstract

The invention relates to a process for the preparation of compounds of the general formula, where the radicals have the meaning given in the invention claim. These compounds are intermediates for the preparation of drugs with vasodilator effect. Formula

Description

27007ί

Title of the invention:

Process for the preparation of benzazepine intermediates

Field of application of the invention:

The application of the invention is in the field of production of drugs with vasodilator effect.

Characteristic of the known technical solutions:

Publications underlying the present invention as prior art are currently known. not known. 30

Object of the invention:

The aim of the invention is to provide novel intermediates for the preparation of drugs with vasodilator effect

-2- Presentation of the essence of the invention:

It is an object of the present invention to provide novel intermediates for the production of drugs having a vasodilator effect, which are distinguished by their particular pharmaceutical activity in comparison to conventional compounds.

The invention relates to a process for the preparation of the d-cis enantiomer of a compound of general formula I.

(T)

20 25

characterized in that the d-cis enantiomer of a compound of general formula VII

(VII)

30

decarboxylated, wherein

Y represents an alkyl radical;

R and R _{1 are} each hydrogen atoms or alkyl radicals, R is a hydrogenator.i and R is an alkyl, alkenyl, alkynyl, aryl, heceroaryl or cycloalkyl radical, or R and R ₁ together with the carbon atom to which they are bonded, a cycloalkyl radical;

-3-

R.sup.1 and R.sup.2 independently of one another denote hydrogen or halogen atoms, alkyl, alkoxy, aryloxy, arylalkoxy, aryl

O alkyl, hydroxyl, alkanoyloxy, -, -O-C-NX X_, diformormethoxy, trifluoromethyl, -NX-X.-, -S (O) -alkyl or -S (O) -aryl radicals

J 4 m m

mean,

m is 0, 1 or 2;

X ₁ and X _{2 are} each independently hydrogen, alkyl, aryl or heteroaryl or X. and X "together with the nitrogen atom to which they are attached represent a nitrogen-containing heteroaryl radical; and X ₃ and X are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl or carbamoyl.

For the preparation of the end products is a compound of general formula I with a compound of the general formula

Halogen- (CH ₂ J _n -NR ₃ R ₃

and optionally the product is converted into pharmaceutically acceptable salts, wherein R "and R _{3 are} each independently alkyl or cycloalkyl radicals or R and R, together with the nitrogen atom to which they are attached, a pyrrolidinyl, piperidinyl or morpholinyl radical; and η is 2 or 3.

The products obtained (drugs) have the formula

-4-

The definitions of various terms used to describe the compounds obtainable in accordance with the invention are further defined below. These definitions apply to the entire description (unless otherwise limited in specific cases) either individually or as part of a larger code.

The terms "alkyl" and "alkoxy" refer to straight-chain and branched radicals. These radicals preferably have 1 to 10 carbon atoms and in particular 1 to 6 carbon atoms. Methyi is the most preferred.

The term "aryl" refers to phenyl and substituted phenyl. Examples of substituted phenyl radicals are radicals which are 1-, 2- or 3-fold by amino (NH ₉ ), alkylamino, dialkylamino, nitro, halogen, hydroxyl, trifluoromethyl, alkyl (1 to H carbon atoms), alkoxy (1 to 4 carbon atoms), alkanoyloxy, carbamoyl or carboxyl.

The term "alkanoyl" refers to radicals of the formula O.

Il

Alkyl-C-. These alkanoyl radicals preferably have 2 to carbon atoms.

The term "heteroaryl" refers to aromatic heterocyclic ritites having at least one heteroatom in the ring. Preference is given to pyridinyl, pyrrolyl, imidazolyl, furyl, thienyl and thiazolyl.

The term "nitrogen-containing heteroaryl radical" refers to aromatic heterocyclic radicals having at least one nitrogen atom in the ring. Preferred are pyridinyl, pyrrolyl, imidazolyl and thiazolyl.

270 07 i

-5-

The term "cycloalkyl" refers to groups having 3, ¹ , 5, 6 or 7 carbon atoms.

The term "halogen atom ¹¹ means fluorine, chlorine, bromine and iodine.

The terms "alkenyl" and "alkynyl" mean straight-chain or branched radicals. Radicals of 2 to 10 carbon atoms are preferred.

Below is more detail on the preparation of the compounds of formula I.

First, a 2-nitrotoluene of formula II

r ^ Y ^CH3

reacted with a Benzylidentnalonat of formula III 25

(III)

in which Y is an alkyl radical. The reaction can be carried out in a polar aprotic solvent (e.g., dimethylformamide) in the presence of a strong base such as sodium hydride. A product of the formula IV is obtained

(IV)

CH- (C-OY).

By reduction of the compound of formula IV, the corresponding compound of formula V is obtained

The reduction may be carried out by catalytic hydrogenation (e.g., using palladium-on-carbon as a catalyst) or by using a chemical reducing agent (e.g., ferrous sulfate or stannous chloride).

Treatment of an amine of formula V with an alkali metal alkoxide (e.g., sodium methoxide) and an alcohol (e.g., methanol) yields the corresponding benzazepine of formula VI

(VI)

The reaction of a compound of formula VI with a strong base (eg lithium diisopropylamide or potassium hexamethyldisilacid) in an ethereal solvent such as tetrahydrofuran is carried out at reduced temperature. The alkylation by addition of an alkylating agent (eg an ^R gives a compound

R ^ CH-halide)

-τ

of the formula VII

(VII)

In some cases, the alkylation reaction may proceed more completely if the nitrogen atom in the benzazepine trimer of the compound of Formula VI is first protected against participation in the reaction, e.g. by treating a benzazepine of the formula VI with a base such as sodium hydride and subsequent reaction with an alkoxymethyl bromide. After completion of the alkylation reaction, the nitrogen protecting group is removed.

The preparation of a compound of the formula VII from a compound of the formula IV can also be carried out according to a different procedure. The alkylation of a compound of formula IV by treatment with a base such as sodium hydride, followed by reaction with a

Alkylating agent (eg an R gives a

R.J.-CH-halide)

Compound of the formula VIII

(VIII)

CH-R ₁

270 07 ί

By reduction of a compound of formula VIII, the corresponding compound of formula IX is obtained

(IX)

The reduction may be carried out by using a chemical reducing agent (e.g., iron-end D-sulfaL or stannous chloride) or by catalytic hydrogenation (e.g., using palladium-on-charcoal as a catalyst).

Treatment of an amine of formula IX with an alkali metal alkoxide (e.g., sodium methoxide) and an alcohol (e.g., methanol) affords the corresponding benzazepine of formula VII.

The decarboxylation of a compound of the formula VII can be prepared by treatment with excess Lithiunjodid in hot pyridine to form a mixture of isomers of formulas I and I ¹

(I)

ice-isomer

and

υ i - '»' · ' ^f

-9-

(I ¹ )

trans isomer

be achieved. The preferred cis isomer is generally the predominantly formed isomer in the above reaction. By using a few drops of water in the aforementioned reaction mixture, the ratio of cis-iso-

, R Merem increased to trans isomer. The isomers, according to Io

conventional methods, for example by crystallization or chromatography, are separated. Another possibility is to carry out the abovementioned reactions using the diastereomeric mixture (mixture of compounds of the formulas X and XI). The mixture of isomers can then be separated into the individual isomers at any point in the series of reactions.

By treating a compound of formula I or I ¹ with _or . an alkali metal hydro '. d (eg sodium hydride) in an inert solvent such as dimethylformamide or dimethyl sulfoxide and subsequent reaction with a compound of formula XII

Halogen- (CHp) -NRpR- (XII)

⁵

to obtain the relevant compound of formula XIII

Ij ι - · ·.

-10-

(XIII)

or a corresponding trans isomer.

The resolved enantiomers of the compounds of the invention can be prepared by first reacting a compound of formula VI to form the corresponding carboxylic acid of formula XIV

(XIV)

hydrolyzed. The hydrolysis can be carried out, for example, by treating a compound of formula VI with an alkali metal hydroxide in an alcohol (e.g., potassium hydroxide in methanol). A carboxylic acid of formula XIV can be resolved using a chiral amine. Reaction between acid and amine in a suitable solvent gives the diastereomeric salts prepared using conventional methods, e.g. by crystallization, can be separated. The regeneration of the carboxylic acid from the pure diastereomeric salt and subsequent esterification provides the desired non-racemic form of a compound of formula VI. This non-racemic

-11-

Compound can be converted to the non-racemic forms of the intermediates of formulas I and I '. Using the methods described above, the preferred intermediate I can be converted to the corresponding non-racemic final product I.

The following are preferred definitions for the individual substituent groups of the compounds of the formula I: R and R. are hydrogen or R is hydrogen and R is a vinyl or methyl group; R.sup.1 represents a halogen atom or a trifluoromethyl group (in particular 6- or 7-trifluoromethyl); and R ₁ . means a p-methoxy group,

Exemplary embodiments: Example 1 (cis) -7-Chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-

methyl-2H-1-benzazepin -? - on

A) l_ 2- (5-chloro-2-nitrophenyl) -1- (4-methoxyphenyl) ethyl / - malonic acid dimethy ester!

2g A mixture of dimethyl p-methoxybenzylidenemalonate (40 g, 0.16 mol) and a 60 percent dispersion of sodium hydride (9.6 g, 0.24 mol) in 350 mL of anhydrous dimethylformamide was added dropwise with stirring over 2 hours with a solution of 5-chloro-2-nitrotoluene (30 g,

₃ Q 0.176 mol) in 30 ml of dimethylformamide. The reaction mixture was stirred for 6 hours at room temperature and then quenched with glacial acetic acid (15.4 ml, 0.26 mol). The solvent was removed under reduced pressure and the residue was triturated with water. The yellow festivals

27007t

-12-

Materials were filtered and triturated with methanol. This gave 50.3 g of a white solid of mp 1, 28, 5-1, 30, 5 ° C.

B) ^ 2- (2-amino-5-chlorophenyl) -1- (4-methoxyphenyl) -ethyl-7- malonic acid dime! Ester

A mixture of _ / 2- (5-chloro-2-nitrophenyl) -1- (4-methoxyphenyl) ethyl 7-malonic acid dimethyl ester (40 g, 95.0 mmol) and hydrated ferrous sulfate (184 , 5 g, 0.663 mol) was added in a 1:10 solution of methanol / water (1.2 liters) under reflux within 30 minutes with concentrated ammonia (142.5 ml). The reaction mixture was refluxed for 20 minutes and then cooled to room temperature. Ethyl acetate and celite were added and the mixture was filtered through Celite.

The filtrate was partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The product was recrystallized from isopropyl alcohol. This gave 28.22 g of the title compound, mp. 114-116 ° C.

C) 7-Chloro-1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxy)

o xyphenyl) -2H-1-benzazepin-2-one

A solution of _ / 2- (2-amino-5-chlorophenyl) -1- (4-methoxyphenyl) -äthy_l7-malonic acid dimethyl ester (23.2 g, 59.2 mmol) in methanol (200 ml) became a 25 percent solution of sodium methoxide in methanol (16 mL, 69.97 mmol). The solution was refluxed for 3 hours under argon. The reaction mixture was cooled to room temperature and treated with 200 ml of 1N hydrochloric acid. A white precipitate was filtered off, washed with water and methanol and dried under reduced pressure. 19.5 g of the title compound, melting at 189 to 190.5 ⁰ C. was obtained

D) 7-Chloro-1, 3,4,5-tetrahydro-3- (methoxycarbonyD ^ - ^ - Sö meohoxyphenyl) -3-methyl-2H-1-benzazepin-2-one

25 mmol (3 equivalents) of a freshly prepared solution of lithium diisopropylamide in tetrahydrofuran (prepared by adding 9.6 ml of a 2.6 M solution of n-butyl).

-13-

lithium in hexane to 7.5 ml of freshly distilled diisopropylamine in 50 ml tetrahydrofuran at -78 ° C) were mixed with 3.0 g of 7-chloro-1, 3, ¹ ', S-tetrahydro-S-imethoxycarbonyD-ij -one (8.35 mmol). After stirring at -78 ° C for 1.5 hours, 1.5 mL of hexamethylphosphoric triamide was added along with 5.9 g of iodomethane (41.7 mmol, 5 equivalents). The reaction mixture was stirred for 6 hours at -78 ° C to 20 ⁰ C and then stopped with 50 ml of 1 η hydrochloric acid. Stirring was continued at 50 ⁰ C for another 30 minutes. The phases were separated. The aqueous phase was extracted twice with 50 ml of ethyl acetate each time. The combined organic phase was washed twice with 20 ml of saturated sodium bicarbonate solution and with 20 ml of water, then dried ·· net (magnesium sulfate) and concentrated. The residue was purified on a silica gel column. Elution with 25% ethyl acetate / hexanes to give 1, ¹ I g of 7-chloro-1, 3, 4, 5-tetrahydrc-S-imethoxycarbonyD - ^ - i ^ -methoxyphenyD-S-methyl-2H-1-benzazepin 2-on as a white solid.

20

E) (cis) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-

methyl-2H-1-benzazepin-2-one

A mixture of 800 mg of 7-chloro-1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -3-methyl-2H-1-benzazepine-V 25 2-one (2 , 16 mmol), 1.14 g of lithium iodide (8.56 mmol, 4 equivalents) in 20 ml of pyridine was refluxed for 20 hours. The cooled mixture was diluted with 200 ml of ethyl acetate, then washed 4 times with 30 ml of 1 η hydrochloric acid, 2 times with 30 ml of saturated copper (II) sulfate solution and 30 ml of water. The organic phase was dried (magnesium sulfate) and concentrated. The residue was triturated with ether. 400 mg of (cis) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-2H-1-benzazepin-2-one were obtained as a white solid.

35

, Γ "-. ':''W;t' · -:,). · · J ·· · -.

-14-

F) Further reaction to (ice) -7-chloro-1- [2- (dimethylamino) -ethyl] -1, 3,4, -tetrahydro-4- (4-methoxyphenyD-3-methyl-.

A slurry of hexane-washed sodium hydride (132 mg of 50 percent sodium hydride in mineral oil, 2.74 mmol) in 20 mL of dimethylformamide at 25 ° C was treated with 720 mg (cis) -7-chloro-1, 3,4,5- tetrahydro-4- (4-methoxyphenyl) -3-methyl-2H-1-benzazepin-2-one (2.28 mmol). After stirring at 25 ° C for 1 hour, the solution became clear. 6.7 ml of a 1.7M solution of 2-dimethylaminoethyl chloride (11.4 mmol, 5 equiv.) In toluene was added. The reaction mixture (was stirred öei 80 ° C, then cooled to 25 ⁰ C and quenched with 1 η hydrochloric acid for 3 hours. After this was made alkaline with 1 η sodium hydroxide and extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated. The The residue was diluted with ether and treated with a saturated solution of hydrochloric acid in ether and concentrated The residue was triturated with ether and filtered The solid was washed with ether and dried to give 780 mg of the title compound as a white solid, mp 228- 231 ° C, thin layer chromatography: silica gel; 10 $ methanol / dichloromethane; R _f = 0.48

Analysis: Calculated for C ₂₂ H ₂₈ N ₂ O ₂ Cl. 0.8H ₃ O: C, 60.36; V 25 H 6.82; N 6.40; Cl 16,20

Found: C 60.39; H 6.45; N 6,32; Cl 16,40.

Example 2

(Ice) -T-chloro-S-ethyl-i, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -2H-1-benzazepine-2-one

A) 7-Chloro-3-ethyl-1,3,4,5-tetrahydro-3- (methoxycarbonyl) -

4- (4-methoxyphenyl) -2H-1-benzazepin-2-one

A freshly prepared solution of lithium diisopropylamide in tetrahydrofuran (6 equivalents, prepared by adding 19.2 ml of a 2.6M solution of n-butyl-lithium in hexane to 15 ml of freshly distilled diisopropylamine in 80 ml tetrafluoride).

-15-

hydrofuran) of -78 ⁰ C (with 3.0 g 8.35 mmol) of 7-chloro "1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1 benzazep-2-one (see Example 1 C). After stirring for 1.5 hours at -78 ⁰ C Hexamethylphospnorsäuretriamid 3 ml were added together rr.it 13.6 ml of iodoethane (to remove iodine by alumina filtered). The Gfmisch was stirred at -78 ⁰ C for 30 minutes (under argon) and then for 6 days at -2O ⁰ C (Trookeneis / Tetrachlorkohler.stoff bath). The reaction was quenched with 1N hydrochloric acid (50 ml). The aqueous phase was extracted with ethyl acetate (3 times). The ethyl acetate extracts and the tetrahydrofuran were combined, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried (magnesium sulfate). The solution was concentrated, combined with 0.31 g of previously prepared crude product and subjected to flash chromatography (silica gel / 3: 1-hexane: ethyl acetate). It gives 0.61 g of product. ;

B) 7-chloro-3-ethyl-1,

Lithium iodide (0.65 g, 4.84 mmol) became 7-chloro-3-ethyl-1,3,4, S-tetrahydro-S 1 -methethoxycarbonyD-U-Cil-methoxyphenyl) -2H-1-benzazepine Add 2-one (0.47 g, 1.21 mmol) in pyridine (15 mL) and water (3 drops) and heat at reflux for 33 hours. The mixture was cooled, dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 times). The combined ethyl acetate phases were dried (magnesium sulfate) and concentrated. This gave 0.40 g of raw material.

This material was combined with another batch of crude product (total 0.49 g). Purification by flash chromatography (silica gel / 1: 1 hexane: ethyl acetate) gave 0.38 g of the title compound. C) Further reaction for isomer separation and preparation of (cis) -7-chloro-1- / r- (dimethylamino) ethyl] _: 7-3-ethyl-1,3,4,5-tetrahydro-4- (4 -methoxvDhenvl) -2H-1-benzazeDin ~ 2 ₇ on

monohydrochloride *

A slurry of previously washed (hexane) sodium,

35

-16-

hydride (~50% in mineral oil) (0.064 g, 1.3 μmol, 1.2 equivalents) in anhydrous dimethylformamide (10 ml) was treated with 7-chloro-3-ethyl-1,3,4, S-tetrahydro ^ - ( 4-methoxyphenyl) -2H-1-benzazepin-2-one (370mg, 1.12mmol). After stirring the mixture at 25 ° C for 1 h, 3.2 ml (5.6 mmol) of 1.7 N, N-dimethyl-2-chloroethylamine (in toluene) was added. The solution was heated to 80 ° C for 24 hours. Then the reaction was stopped with 1 η hydrochloric acid. It was then basified with a 50% sodium hydroxide solution, extracted with ethyl acetate (2 times) and dried. (Magnesium sulfate). Removal of the solvent left 0.49 g of a brown oil. This crude product was the flash chromatography (silica gel / 3ί1 HexanrEssigsäureäthylester, then 2: 1 hexane: ethyl acetate, then 1: 1 hexane: ethyl acetate and finally ethyl acetate) subjected. The fractions containing the cis-amine product were dissolved in ether. The salt was precipitated by dropwise addition of a saturated solution of hydrogen chloride in ether.

The resulting white solid was collected by suction. 200 mg of product were obtained. The trans isomer with a lower R value _p of the title compound (10 mg) were well as a cis-trans mixture (50 mg) and unreacted starting material (40 mg).

Analysis: Calculated for C ₂₃ H ₂ 0 _{2 2} qC1N .HC1.0,23H ₂ 0: C, 62.5 ^C; H 6.95; N 6,36; Cl 16.06 Found: C, 62.56; H 6.80; N 6,22; Cl 16.00.

Example 3

(cis) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl ) 3- (2-

propenyl) -2H-1-benzazepin-2-one

A) 7-Chloro-1,3,4,5-tetrahydro-3- (methoxycarbonyl) -1- ( methoxymethyl) -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one A solution of 7 Chloro-1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one (270mg, 0.75mmol, see Example 1C ) in dimethylformamide (10 ml)

  "

-17-

was cooled in an ice / water bath to 0 to 5 ° C and 50% sodium hydride (72 mg, 1.5 mmol) was added. After stirring at 0 to 5 ° C for 15 minutes, methoxymethyl bromide (240 μΐ, 3 mmol) was added dropwise. The reaction mixture was stirred for a further 2 hours at 0 to 5 ° C. The excess sodium hydride was destroyed by the addition of water. The resulting mixture was extracted with ether. The aqueous phase was extracted with ether (3 times). The combined organic phases were dried (magnesium sulfate) and concentrated. The crude residue was subjected to flash chromatography (silica gel / 5-20% ethyl acetate: hexane). This gave 233 mg of the title compound as an oil.

B) 7-Chloro-1,3,4,5-tetrahydro-3- (methoxycarbonyl) -1- (meth)

IQ oxymethyl) -4- (4-methoxyphenyl) -3- (2-propenyl) -2H-1 -

benzazepin-2-one

A ⁰ C cooled suspension of 50-percent sodium hydride (48 mg, 1 mmol) in dimethylformamide (5 ml) at 0 to 5 was added dropwise (with a solution of 7-chloro-1,3,4,5-tetrahydro-3- methoxycarbonyl) -1- (methoxymethyl) -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one (102mg, 0.25mmol) in dimethylformamide (1mL). After 20 minutes of stirring at 0 to 5 ⁰ C allyl bromide (360 μΐ, 4 mmol) was added dropwise, and the reaction mixture was stirred for 2 hours at 0 C to room temperature. Excess sodium hydride was destroyed with water and the mixture was extracted with ether. The aqueous phase was extracted with ether C2mal). The combined organic phases were dried (magnesium sulfate) and concentrated. The raw residue

go was triturated with hexane (20 ml). 93 mg of the white, crystalline title compound were obtained (the mother liquor contained further product).

C) 7-Chloro-1, S ^ S. methoxyphenyl) -3- (2-propenyl) -2H-1 -benzazepin-2-one A suspension of 7-chloro-1,3,4,5-tetrahydro-3 - (methoxycarbonyl) -1- (methoxymethyl) - 4- (4-methoxyphenyl) -3- (2-propenyl) -2H-1-benzazepin-2-one (715mg, 1.61mmol) in methanol

-9 §83-; 513V V / -V

2 t'O 07 1

-18-

(40 ml) was added with concentrated sulfuric acid (6 ml) with stirring. The reaction mixture was heated for 8 hours under reflux (bath temperature 75 to 8O ⁰ C), and then diluted with dichloromethane. The sulfuric acid was carefully neutralized by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 times). The combined extracts were dried over anhydrous magnesium sulfate. The concentrated solution was subjected to flash chromatography (silica gel / 10-30% ethyl acetate: hexane). 700 mg of the title compound were obtained.

D) 7-chloro-1, S ^^ - tetrahydro-fl-Cl-methoxyphenyl) -

3- (2-propenyl) -2H-1-benzazepin-2-one

Lithium iodide (0.90 g, 6.7 mmol) was added to 7-chloro-1,3,4,5-th-trahydro-3- (metoxycarbonyl) J- ¹ I- ( ¹ -methoxyphenyl) -3- (2 -propenyl) -2Ή- • 1-benzazepin-2-one (670 mg, 1.68 mmol) in pyridine (5 mL), 3 drops of water were added and the mixture was stirred at reflux overnight . dissolved ethyl acetate and washed with 1 η hydrochloric acid (3 times), wash the organic phase was dried (magnesium sulfate) and concentrated the crude, brownish solid _f material was dissolved in ethyl acetate and through a silica gel plug (to remove the brown color '). by suction filtration ,

^The silica gel was rinsed several times with ethyl acetate. The organic solution was concentrated and dried under reduced pressure. There remained 0.52 g of the title compound as off-white solid. E) Further reaction for Isomerontrennung and preparing (cis) -7-chloro-W ~ 2- (dimethylamino) -äthyl7-1, 3, ¹ 1,5-tetra- ^'hydro-l l- ^(l l-methoxyphenyl) -3- (2-propenyl) -2H-1-benzazepin

A slurry of washed (hexane) sodium hydride (^ 50% in mineral oil) (0.09 g, 1.83 mmol, 1.2 equiv.) In dimethylformamide (13 mL) was added under stirring with 7-chloro-1,3,4 , ^{5-tetrahydro-1} J- ⁽¹ l-methoxyphenyl) -3- (2-propenyl) -2H-1-benzazepin-2-one (520 mg, 1, 5P. mmol) was added. After 1 hour of stirring at 25 ⁰ C was 1.7 η N, N-dimethyl-2-chloro

2 70 OM

-19- ·

ethylamine (in toluene) (4.5 mL, 7.60 mmol) was added and the mixture was heated for 3 hours with stirring to 8O ⁰ C. Then the reaction was stopped with 1 η hydrochloric acid. The mixture was treated with 50 percent sodium hydroxide solution. made basic, extracted with ethyl acetate (2 times), dried (magnesium sulfate), concentrated and dried under reduced pressure. The crude material was subjected to flash chromatography (silica gel / 1% methanol: dichloromethane, then 2% methanol: dichloromethane). The cis-isomer-containing fractions were combined and concentrated. ~ 400 mg of a semi-solid product was obtained. The residue was coevaporated with ether. 310 mg of a fluffy white solid were obtained. This material was dissolved in ether and treated with ether saturated with hydrogen chloride. The resulting white precipitate was recovered by suction. 200 mg of the title compound were obtained. A cis-trans mixture! and low purity trans product were also obtained from flash chromatography.

Analysis: Calculated for C ^ H ^ CIN Op.HCl:

C 64,14; H 6.73; N 6.23; Cl 15,78; Found: C, 63.92; H 6,72, N 6,13; Cl 15,74.

Example 4

(cis) -1,3,4; 5-Tetrahydro-4- (4-methoxyphenyl) -3-methyl-7- (trifluoromethyl) -2H-1-benzazepin-2-one

A) / ~ 2- (2-nitro-5-trifluoromethylphenyl) -1- (4-methoxyphenyl) -

ethyl / malonic acid dimethyl ester

A 2-liter, 3-necked flask (under nitrogen) was charged with 67.0 g (0.293 mol) of dimethyl p-methoxybenzylidenemalonate and 450 ml of dimethylformamide. The stirred solution was charged with 18.7 g (0.39 mol) of a 50 percent sodium hydride dispersion The mixture was treated dropwise over 1 hour with a solution of 60.5 g (0.253 mol) of 2-nitro-5- (trifluoromethyl) -toluene in 50 ml of dimethylformamide, the temperature at

-μ SH'l * i) i ''' ^{/ fW}

2 7007 Γ ^ν

-20-

28 to 32 ° C was maintained (at the end of the addition, the temperature rose to 38 ^C C and was rapidly cooled to 3O ° C) .This mixture was stirred for 4 hours at room temperature, cooled, treated portionwise with 25 ml of acetic acid treated and 2, 5 liters of ice water poured. The mixture was extracted with 250 ml of dichloromethane (3 times), dried (magnesium sulfate), filtered and the solvent was evaporated. 126 g of a pale brown semisolid product were obtained. This product was dissolved in 2YO ml of methanol, cooled and filtered. 72.8 £ a pale yellow Produ '^ a was obtained, melting at 110-112 ⁰ C, R _f value = 0.74 (1: 1 ethyl acetate-hexane). A sample which had been recrystallized from methanol had a melting point of 111-11 ° C.

B) οι- methyl-2- / 2- (2-nitro-5-trifluoromethylohenyl) -1 - (4-

methoxyphenyl) ethyl 7-malonic acid dimethyl ester

2- (2-Nitro-5-trifluoromethylphenyl) -1- (4-methoxyphenyl!) Ethyl / malonic acid: -e-dimethyl ester (7.00 g, 15.4 mmol) was dissolved in anhydrous dimethylformamide (35 ml) under argon. Prewashed (hexane) 50 percent sodium hydride (0.89 g, 18.4 mmol) was added with stirring. Stirring was continued for 20 minutes, then iodomethane (filtered through alumina) (11.6 g, 5.1 mL, 81.5 mmol, specific gravity 2.24-2.27, 5 equiv) was added dropwise The solution was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic phase was collected and washed again with 1N hydrochloric acid, saturated potassium carbonate solution and saturated sodium chloride solution and dried (magnesium sulfate) The concentrated _x residue became the flash Chromatography (silica gel / 9: 1-hexane: ethyl acetate, then 8: 2-hexane: ethyl acetate) The product was recovered from the appropriate fractions and concentrated to give 6.90 g of the title compound as a viscous oil.

270 place

-21-

C) Ot-methyl- / 2- (2-amino-5-trifluoromethylphenyl) -1- (4-

dimethyl methoxyphenyl) ethyl 7- malonate oC-methyl- / 2- (2-uitro-5-trifluoromethylphenyl) -1- (4-mothoxyphenyl) ethyl 7-malonic acid dimethyl ester (6.80 g, 14.9 mmol) was dissolved in methanol (200 ml) under argon at room temperature. Powdered stannous chloride dihydrate (17.48 g, 77.5 mmol) was added, followed by addition of concentrated hydrochloric acid (19 mL) with stirring. After 1.5 hours, celite, ethyl acetate, and saturated potassium carbonate solution were added with stirring (the potassium carbonate was added portionwise). The suspension was filtered through a celite layer. The layer was then rinsed with ethyl acetate (3 times). The filtrate was concentrated and the resulting white solid was triturated with 10% methanol: water and dried. 6.02 g of the title compound were obtained.

D) 1,3,4,5-Tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -3-methyl-7- (trifluoromethyl) -2H-1-benzazepin-2-one

25 percent (wt%) sodium methoxide in methanol solution (14.2 mL, 625 mmol, 4.6 equivalents, d = 0.945) and methyl-2-5- (2-amino-5-trifluoromethylphenyl) -1 - (4-methoxyphenyl) -äthyl7- malonic acid dimethyl ester (5.96 g, 13.56 mmol) _ ₅ in methanol (30 ml) and anhydrous dimethylformamide (35 ml) was heated overnight under reflux (95 ^ ⁰ C) , 1 η hydrochloric acid was added with stirring, forming a white precipitate, which was filtered with suction, washed with water (3 times) and dried under reduced pressure.

4.88 g of a white solid were obtained, one by ovJ

Had detectable impurity NMR spectroscopy. The contaminant disappeared after leaving the sample overnight.

E) 1,3,4,5-tetrahydro-4- (methoxyphenyl) -3-methyl-7- (trioo

fluoromethyl) -2H-1-benzazepin-2-one

Lithium iodide (5.26 g, 39.3 mmol) was added to 1, 3, ^ι , 5-tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -3-methyl-7- (trifluoro-)

HE, - ^ i

270 07i

-22- ·

methyl) -2H-1-benzazepin-2-one, (4.00 g, 9.82 mmol) in f-bromide (40 mL) (5 drops of water were added) and the mixture was allowed to stir for 8 1/2 hours heated with stirring and reflux. The solution was dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 times). The organic phase was dried (magnesium sulfate) and concentrated. This gave 3.43 g of the title compound as a solid. F) Further reaction for isomer separation and preparation of (cis) -1-/-2- (dimethylamino) -ethyl7-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-7- (trifluoromethyl) -2H-1

benzazepin-2-one monohydrochloride

Γ A solution of 1, 3,4, 5 - * - tetrahydro-4- (methoxyphenyl) -3-methyl-7- (trifluoromethyl) -2H-1-benzazepin ~ 2-one (3.37 g, 9, 65 mmol) in anhydrous dimethylformamide (75 ml) was added with stirring pre-washed (hexane) 50 percent sodium hydride (5.56 g, 11.58 mmol, 1.2 equiv.). After about 20 minutes, 1.7 η (in toluene) of N, Ni-dimethyl-2-chloroethylamine (24.0 mL, 40.8 mmol) was added. The mixture was heated at 85 ° C for 4 hours. The mixture was basified with 50 percent sodium hydride and extracted with ethyl acetate (3 times). The combined organic phases were dried (magnesium sulfate) and concentrated. The dark, oily residue was brought under reduced pressure. The crude material was subjected to flash chromatography (silica gel / 1% methanol: dichloromethane, then 3% methanol: dichloromethane). The acidified (hydrogen chloride saturated ether) product weighed 1.06 g

Analysis: Calculated for C ₂₃ H ₂₇ F ₃ N ₂ O ^ H ₂ CHCl:

C 58.10; H 6,36; N 5.89; Cl 7,46; F 12.0; found: C 58.10; H 5.90; N 5.75; Cl 7,94; F 11.5.

Example 5

(Ice) -1,3,4,5-Tetrahydro-4- (4-methoxyphenyl) -3- (2-propenyl) -7-t-ri f 1 n-1-methyl , ) -2H-1-ben7.a7.epin -2-on.

-23-

Method I

A) _ / ~ 2- (2-Amino-5-brifluoromethylphenyl) -1- (4-mebhoxyphenyl) -ethylt-malonic acid -dimethyl-ethyl __

A suspension of 25.0 g (0.055 mol) of _f 2- (2-nibro-5-brifluoromethylphenyl) -1- (U-mebhGxyphenyl) -dibutyl-7-malonic acid dimebyeesber (compare Example ¹ I rt) in 200 ml Mebhanol was treated with a calf suspension of 2.5 g of 5% palladium on carbon in 50 ml of methanol (not Sbicksboff) and placed in a Parr apparatus at a water pressure of 4.08 bar (58 lb). The bheorebic amount of hydrogen was consumed in about 30 minuets. This mixture was then heated for 1 second at 50-55 ° C to ensure that the whole Sbicksboff compound went into solution. The mixture was removed from the Parr apparatus and allowed to settle on ambient room temperature. The flask was heated to dissolve the crystallizable product. The hot solution was washed by Celibe (not Stick3boff) and hot Mebhanol mibhanol. The colorless filbrab was concentrated on a Robabionsverdampfer to formation of 22.2 g of a nearly colorless Fesbsboffs eingengb. The Fesbsboff was triturated with 100 ml of hexane and then with 50 ml of hexane. The solution was decolorated. The disrupted solution mibble was removed on a Robabionsverdampfer. One obtains 21.3 g of product from the

F. 124-! 27 ⁰ G. A sample of this Maberials melted by Krisballisabion from Mebhanol at 125-127 ⁰ C.

B) 1,3,4,5-Tebrahydro-3- (mebhoxycarbonyr) -4- (mebhoxyp'aenyl) -7- (brifluoromethyl) -2H-1-benzazepin-2-one

A stirred solution of / 2- (2-amino-5-brifluoromethylphenyl) -1- (4-mebhoxyphenyl) -dibutyl-T-malonic acid dimebuthylesber (20.0 g, 0.047 mol) in 200 ml of methanol was added to an argon atmosphere 13.3 ml of 25 percent Nabriummebhoxide in Mebhanol treated and no reflux erwärmb. After heating to 2.75% of boiling point, the mixture was cooled in ice-water and made to precipitate the product mib 1 η hydrochloric acid. Then it was stirred in an ice water bath, then filbrierb, mib washed water and

ι · ¹ O "/ ''

27007t

-24-.

dried in the air. 19.0 g of product were obtained. The product was suspended in 30 ml of isopropanol, allowed to stand for 1 hour, filtered and washed with isopropanol and hexane. 13.64 g of the title compound, melting at 161-163 ⁰ C. This gave

C) 1, S 1 S-tetrahydro-S-dethoxycarbonyD-i-dinethoxymethyD-

A suspension of sodium hydride (360 mg, 7.5 mmol, 50% oil dispersion / prewashed several times with dry ether) in anhydrous dimethylformamide (30 ml) was added

Cooled to 0 ° to 5 ° C. and added dropwise with stirring to a solution of 1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (mehroxyphenyl) -7- (trifluoromethyl) -2H-1-benzazepine-2- on (1.9 g, 5 mmol ¹ 'in anhydrous dimethylformamide (15 ml).

The mixture was stirred for a further 20 minutes at 0 to 5 C, followed by the dropwise addition of bromomethyl methyl ether (800 μl, 10 mmol) and stirring at this temperature

Continued for an additional 1 hour, excess sodium hydride was destroyed by the addition of water. The mixture was diluted with ether and washed with water. The aqueous phase was extracted with ether (3 times) and the combined extracts were dried (magnesium sulfate) and concentrated. The crude oily residue was subjected to flash chromatography (silica gel / 5-25% ethyl acetate: hexane). This gave 1.67 g of the title compound as an oil.

D ^ 1,3,4,5-Tetrahydro-3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) -3- (2-propenyl) -7- (trifluoromethyl) -2H-1- benzazepine-2 -one

A suspension of sodium hydride (384mg, 8mmol, 50% oil dispersion) in anhydrous dimethylformamide (35mL) was cooled in an ice / water bath and added dropwise with stirring to a solution of 1,3,4-tetrahydro. (Me thoxycarbonyl) -1- (methoxymethyl) -4- (me thoxyphenyl) - 7- (trifluoromethyl) -2H-1-benzazepin-2-one (917mg, 21mmol) in dimethylformamide (8mL). After stirring for 30 minutes at 0 to 5 ^° C., allyl bromide (1.5 ml) was added in one portion. The mixture was left for a further 3 hours

Ϊ -Jt-

-25-

at 0 to 5 ⁰ C, after which excess hydride was destroyed by the addition of water. The mixture was diluted with ether and washed with water. The aqueous phase was extracted with ether (3 times). The combined ether extracts were dried (magnesium sulfate) and concentrated. The crude residue was subjected to flash chromatography (silica gel / 5-20% ethyl acetate: hexane). 905 mg of the title compound were obtained in crystalline form.

E) 1,3,4,5-Tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -

3- (2-propenyl) -7- (trifluoromethyl) -2H-1-benzazepin-2-one Concentrated sulfuric acid (8 ml) and anhydrous lithium bromide (720 mg, 8 mmol) were added to a stirred suspension of 1, 3,4,5-Tetrahydro-3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) -3- (2-propenyl) -7- (trifluoromethyl) -2H-1-benzazepine-2 on (905 mg, 1.9 mmol) in methanol (40 ml). The reaction mixture was heated at reflux (bath temperature = 80-85 ° C) for 9 hours and then allowed to stand at room temperature overnight. The acid was carefully neutralized by adding saturated sodium bicarbonate solution. It was then extracted with ethyl acetate (3 times). The combined organic phases were dried (magnesium sulfate) and concentrated. 858 mg of the title compound were obtained as a solid.

F) 1, 3,4,5-tetrahydro-4- (methoxyphenyl) -3- (2-propenyl) -7-

( trifluoromethyl) -2H-1-benzazepin-2-one

Lithium iodide (1.08 g, 8.04 mmol). was added to 1,4,4-tetrahydro-(methoxycarbonyl) -4- (me thoxy-phenyl) -3- (2-propenyl) -7- (trifluoromethyl) -2H-1-benzazepin-2-one (870 mg, 2.01 mmol) in pyridine (14 ml). After adding 3 drops of water, the mixture was stirred at reflux for 6.5 hours. The solution was dissolved in ethyl acetate and washed with 1N hydrochloric acid (3 times). The organic phase was dried (magnesium sulfate) and concentrated. This gave 0.79 g of solid. The raw material was used as such in the next step.

-26-

G) Further reaction to separate isomers and preparation of (c.is) -1-_ / ~ 2- (dimethylamino) -ethyl7-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2 propenyl) -7- (trifluoromethyl) -

2H-1-benzazepin-2-one monohydrochloride d

A slurry of washed (hexane) sodium hydride (<50% in mineral oil) (0.10 g, 2.11 mmol) in dimethylformamide (13 mL) was added under stirring with 1,3,4,5-tetrahydro-4- ( methoxyphenyl) -3- (2-propenyl) -7- (trifluoromethyl) -2H-1-benzazepin-2-one (660mg, 1.76mmol). After 1 hour at 25 ⁰ C (8.80 mmol 5.2 mL,) was 1.7 η N, N-dimethyl-2-chloroethylamine (in toluene) was added. The mixture was heated to 8O ⁰ C with stirring overnight. The mixture was quenched with 1N hydrochloric acid, basified with 50% sodium hydroxide solution, extracted with ethyl acetate (2 times) and dried (magnesium sulfate) .The concentrated crude mixture weighed 0.77 g, the solid was subjected to flash chromatography (silica gel 1% methanol: dichloromethane, then 2% methanol: dichloromethane, then 3% methanol: dichloromethane.) Corresponding fractions contained the desired cis-free amine product which was collected (fractions concentrated by rotary evaporation) and dissolved in ether A small amount of ether insoluble material (presumably silica gel) was filtered off, and the filtrate was treated with ether saturated with hydrogen chloride, The resulting low-sulfur precipitate was collected by suction filtration and rinsed with ether, The title compound weighed 190 mg. A mixture of cis / trans product and pure trans product were also obtained by flash chromatography

Analysis: Calculated for C ₂₅ H ₉₉ F ₃ N ₂ O ₂ .HCl.0,4MH ₂ O: C, 61.17; H 6,34; N ~ 5.71; Cl 7,22; F, 11.61; Found: C 61.17; H 6.07; N, 5.58; Cl 6,98; F 11,32.

Method II

A) o <- (2-Propenyl) - / 2- (2-nitro-5-trifluoromethylphenyl) -1- (M-methoxyphenyl) -ethyl 7-malonyl acid dimethyl ester Γ ~ 2- (2-nitro-5- trifluoromethylphenyl) -1- (4-methoxyphenyl) -ethyl-T-malonic acid dimethyl ester (46.54 g, 0.102 mol, yg, Example 1 A) was dissolved in anhydrous dimethylformamide under argon.

_27-

formamide (290 ml). 50 percent sodium hydride (5) 89 g> 0.123 mol, prewashed with hexane) was added with stirring. Stirring was continued for 20 minutes. Then, allyl bromide (44 ml, 61.7 g, 0.510 mmol, d = 1.398, 5 equivalents) was added dropwise. After 6 hours and 40 minutes, the reaction was quenched with Γη hydrochloric acid. The solution was extracted with ethyl acetate (2 times). The extract was washed with 1N hydrochloric acid (2 times), saturated sodium carbonate solution (2 times) and saturated sodium chloride solution, and dried (magnesium sulfate). The concentrated solution (viscous oil) became the

(Flash chromatography (silica gel / 9: 1-hexane: ethyl acetate, then 8: 2-hexane: ethyl acetate) in 2 portions, then dried overnight under reduced pressure to give 54.77 g of product as a yellow , viscous oil. The product was used as such directly in the next stage. *

B) <y- (2-propenyl) -jf ~ 2- (2-amino-5-trifluoromethylphenyl) -1- ( 4-methoxyphenyl) ethyl 7-malonoic acid dimethyl ester

Ethyl (2-propenyl) - 2- (2-nitro-5-trifluoromethylphenyl) -1- (4-methoxyphenyl) ethyl 7-malonic acid dimethyl ester (50.49 g, 0.102 mol) was added at room temperature under argon Dissolve methanol (350 mL). Powdered tin (II) -chlo-V 25 chloride dihydrate (119.67 g, 0, ^κ 3 moles, 5.2 equivalents) was added, followed by an addition of concentrated hydrochloric acid (155 ml) under stirring. Celite, ethyl acetate and saturated potassium carbonate solution were added with stirring (the potassium carbonate was added portionwise). The suspension was filtered through a celite pad (rinsed 3 times with ethyl acetate), subjected to rotary evaporation and filtered by suction. The recovered white solid was rinsed with 10% methanol: water and then dried. This gave 51.97 l of the title compound.

-a

-28-

Ο 1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -

3- (2-propenyl ) -1- (trifluoromethyl) -2H-1-benzazepin-2-one ctf - (2-propenyl]) - - - / 2- (2-amino-5-trifluoromethylphenyl) -1- Dimethyl (4-methoxyphenyl) ethyl 7-> malonate (47.47 g, 0.102 mol) and a 25 weight percent solution of sodium methoxide in methanol (107 ml, 0.469 mol, d = 0.945, 4.6 equivalents) in methanol ( 200 ml) and anhydrous dimethylformamide (200 ml) was refluxed overnight (rv95 ° C.) 1 N hydrochloric acid was added with stirring to give a precipitate which was filtered off with suction and triturated with water (2 times) wur-

Slurried in carbon tetrachloride and evaporated on a rotary evaporator. After drying under reduced pressure, 42.99 g of crude product were obtained. 15

D) 1,3,4,5-Tetrahydro-4- (4-methoxyphenyl) -3- (2-propenyl) -7- (trifluoromethyl) -2H-1-benzazepin-2-one ι '

Lithium iodide (13.75 g, 10.1.6 mmol) was added to 1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -3- (2-propenyl) -7- (trifluoromethyl) - Add 2H-1-benzazepin-2-one (42, <4 g, 99 mmol) in pyridine (300 mL). A few drops of water were added. The mixture was stirred at reflux for 2 days. Then, pyridine was distilled off under vacuum, and the almost dry residue was dissolved in chloroform and washed with 1N hydrochloric acid (4 times) and saturated sodium chloride solution, and dried (magnesium sulfate). The organic solution was concentrated and dried under reduced pressure overnight. 35.12 g of reddish crude product were obtained. This material was triturated with methanol.

This gave 19.87 g of the title compound as a solid.

E) Further isomer separation reaction and preparation of (cis) -1-/-2- (dimethylamino) ethyl, 7-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2 -propenyl) -7-trifluoromethyl) -2H -1-benzazepin-2-one monohydrochloride , -. ,

A slurry of prewashed sodium hydride (320 mg 60 percent sodium hydride in mineral oil) in 30 ml of dimethylformamide was mixed at 25 ° C with 2.5 g of 1,3,4,5-tetrahydro-4- (4-, me thoxy-phenyl) -3- (2-propenyl) -7- (trifluorooctyl) -2H-1-benz-

2 70 0 7 ί

-29-

azepin-2-one added. After stirring for 1 hour at 25 ⁰ C. 4.65 ml of a 2.15 M solution of 2-Dimethylaminoäthylohlorid (9.99 mmol, 1.5 equivalents) of n ^ toluene. The reaction mixture was stirred for 3 hours at 8O ⁰ C, then cooled to 25 ° C, quenched with 1 η hydrochloric acid, made alkaline with 1 ^N sodium hydroxide and extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated. The residue was subjected to flash chromatography on a prewashed silica gel column. The appropriate fractions were combined, concentrated and dried under reduced pressure over power. This gave 1.92 g of free amine product. This material was dissolved in ether and treated with ether saturated with hydrogen chloride. 2.08 g of the title compound were obtained.

Analysis: Calculated for C ₂₅ H ₂₉ F ₃ N ₂ O ₂ .HCl.0.22H ₂ O:

"C 6.1,66; H 6,30: N 5,75; Cl 7,28; F 11,70; \ found: C 61,66; H ö, 15; N 5,73; Cl 7,17; F 11.46.

Example 6

(cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl ¹⁾ -3-propyl-I- (7-trifluoromethyl) -2H-1-benzazepin-2-one

A) 1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-propyl-7

(Trifluoromethyl) -2H-1-benzazepin-2-one

1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2-propyl) -7- (trifluoromethyl) -2H-1-benzazepin-2-one (3.50 g, 9.32 mmol, see Example 5, Method II, Section D) was dissolved in glacial acetic acid (100 ml) and trifluoroacetic acid (50 ml). Palladium on activated carbon (0.71 g) was added to the degassed solution. The mixture was placed in a Parr apparatus for 4 hours and the solution was filtered through a celite pad The celite was rinsed several times with ethyl acetate The concentrated mixture was dried under reduced pressure to give 3.53 g of the Title compound as a solid.

270 07 j

-30-

B) Further isomer separation and preparation of (ice) »1- / 2- (dimethylamino) -ethyl 7-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-propyl-7 (trifluoromethyl) -2H-l-

benzazepin-2-one monohydroohlorid

Potassium hydrogencarbonate (1.86 g, 18.5 mmol), 1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-propyl-7- (trifluoromethyl) -2H-1-benzazepine-2 -one (3.50 g, 9.27 cmol) and potassium iodide (catalytic amount) were suspended in methyl ethyl ketone (55 ml). 2-Dimethylaminoethylchloride (5.5 mL of a 2.15 M solution in toluene, 11.9 mmol) was added with stirring and the mixture was heated at reflux for 1 hour.

An additional 5.5 ml of 2-dimethylaminoethylchloride was added and the reflux process was continued for 2 hours. Dirnethylformamide (10 ml) was added. After a further 4 hours of heating at reflux, the solution was evaporated on a rotary evaporator and the dimethylformamide was removed by means of a high vacuum pump. The residue was partitioned between ethyl acetate / water and the organic phase was dried (magnesium sulfate) and concentrated. The crude free amine of the title compound (4.29 g) was subjected to flash chromatography using 0.1% -2.0% methanol-dichloromethane. One received 2, äd g product. This product was converted to the title hydrochloride hydrochloride salt using hydrogen chloride saturated ether. F. 233.5-235 ° C.

Analysis: Calculated for C ₃ H ₃₁ F ^ N ₂ O ₃ .HCl:

C 61.91; H, 6.65; N 5.78; Cl 7,31; F 11,75; Found: C 61.79; H, 6.31; N 5.73; Cl 7.05; F 11,71.

Example 7

(Cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2-propenyD-

6- (trifluoromethyl) -2H-1-benzazepin-2-one

A) / ~ 2- (2-nitro-6-trifluoromethylphenyl) -1- (4-methoxyphenyl) -

ethyl-t-malonic acid-dlmethylester ·

To a dry 2 liter 3-necked flask was added 52.7 g (0.21 mol) of p-methoxybenzylidene malonate and 350 ml of dimethylformamide. This solution was

-31-

Cloth), treated with 11.0 g (0.27 mol) of a 60 percent sodium hydride dispersion, and the slurry was added dropwise over 30 minutes to a solution of 43.0 g (0.21 mol) of 2-nitro-6 - (Trifluoromethyl) -toluene treated in 50 ml of dimethylformamide, the temperature was maintained at 28-3O ⁰ C. The mixture was stirred at room temperature for 6 hours, allowed to stand at room temperature overnight, cooled and treated portionwise with 20 ml of acetic acid. The slurry was poured into 2 liters of ice-water and extracted with 500 ml of dichloromethane. The aqueous phase was extracted with 250 ml of dichloromethane and then with 100 ml of dichloride than (2 times); The organic phases were combined, extracted (3 times) with 500 ml of water, dried (magnesium sulfate) and filtered, the solvent was evaporated to give 99.1 g of a granular solid, which solid was triturated with 150 ml of hot methanol The suspension was brought to room temperature, cooled overnight, filtered, washed with cold methanol and dried.

This gave 78.3 g of a solid, mp 117-119 ° C.

B) o <- (2-propenyl) - / 2- (2-nitro-6 "trifluoromethylphenyl) -1-

Dimethyl (4-methoxyphenyl) ethyl, t -n-1-ylacetic acid dimethyl ester / f ~ 2- (2-nitro-6-trifluoromethylphenyl) -1- (4-methoxyphenyl) -V ^ 25-ethyl-t-malonic acid dimethyl ester (14, 55 g, 31.96 mmol) were dissolved in anhydrous dimethylformamide (90 ml) under argon. Prewashed 50 percent sodium hydride (1.85 g, 38.5 mmol) was added with stirring and stirring was continued for 20 minutes, after which time allyl bromide (19.33 g, 159.8 mmol, 13.8 mL, d = 1.398, 5 equivalents) was added dropwise. The mixture was stopped after a few minutes reaction time (1 η hydrochloric acid) and with. Essigsäureäthylester (2 times) extracted. The organic phase was washed with saturated potassium carbonate solution (2 times) and saturated sodium chloride solution and dried (magnesium sulfate). The solution was concentrated by means of a high vacuum pump. This gave 23.0 g of material. This material was subjected to flash chromatography (silica gel / 9: 1 hexane: acetic acid).

-i, y

   ; '. - ·. -32-. '.

acid ethyl ester). The appropriate fractions were combined and concentrated. 15.45 g of the title compound were obtained as an oil.

C) d - (2-Propenyl) - / 2- (2-amino-6-trifluoromethylphenyl) -1-

(4-Methoxyphenyl) ethyl 7-ijoalonic acid dimethyl ester _

(X- (2-Propenyl) - / 2- (2-nitro-6-trifluoromethylphenyl) -1- (U-methoxyphenyl) -ethyl 7-malonic acid dimethyl ester (15.42 g, 31.12 mmol) was added under argon Dissolved at room temperature in methanol (110 ml) Powdered stannous chloride dihydrate (36.52 g, 161.8 mmol, 5.2 equiv) and then concentrated hydrochloric acid (50 ml) were added with stirring Celite, ethyl acetate and a saturated potassium carbonate solution were added with stirring (the potassium carbonate solution was added portionwise) for about 1.5 hours, the suspension was filtered and the solid was rinsed with ethyl acetate (3 times) The washings were concentrated and dried under reduced pressure to give about 16 g of a yellow oil The solids (tin salts, celite, potassium bicarbonate and the like) which had been filtered off from the reaction mixture became .in acetone (more rubbed through a celite layer.

The acetone filtrate was concentrated and the residual residue was partitioned between chloroform and water. The chloroform phase was dried (magnesium sulfate) and concentrated. 9.06 g of the title compound were obtained as a solid. It was assumed that the remaining product was in the aforementioned yellow oil of about 16 g in weight.

The yellow oil was used as such in the next step as well as the 9.06 g of solid.

D) 1,3,4,5-Tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -3- (2-propenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one cC - ( 2-propenyl) -V 2- (2-amino-6-trifluoromethylphenyl) -1- (4-methoxyphenyl) ethyl 7-malonic acid dimethyl ester (9.03g, 19.4mmol) and a 25% w / w solution of N / A-

in-

-33-

methoxide in methanol (20.5 ml; 89.5 mmol, d = 0.945, 4.6 equivalents) .wurden 4 hours in methanol (100 ml) and anhydrous dimethylformamide (100 ml) at reflux (/ ^ 95 ⁰ C.) , With stirring, 1 η hydrochloric acid was added; The resulting precipitate was filtered off with suction, washed with water (3 times) and dried under reduced pressure to give about 10 g of the title compound as a solid. This raw material was used directly.

E) 1,3,4,5-tetrahydro-4- (methoxyphenyl) -3- (2-propenyl) -6-

(Trifluoromethyl) -2H-1-benzazepin-2-one

Lithium iodide (11.98 g, 89.44 mmol) was added to 1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -3- (2-propenyl) -6- (trifluoromethyl ) -2H-1-benzazepin-2-one (9.69 g, 22.36 mmol) in pyridine (40 mL) and water (a few drops). The mixture was stirred at reflux for 11 hours. The pyridine was distilled off under reduced pressure, and the residue was dissolved in methanol, washed with 1N hydrochloric acid (3 times) and saturated sodium chloride solution, and dried (magnesium sulfate). The concentrated residue was black, indicating that some decomposition had occurred. The 9167 g of this black residue were subjected to flash chromatography (silica gel / 3: 1-hexane: ethyl acetate, then 1: 1 hexane / ethyl acetate). The appropriate fractions were combined and concentrated. 5.87 g of the title compound were obtained as a solid.

F) Further reaction for isomer separation and preparation of (cis) -1- / ~ 2- (dimethylamino) -äthy_l7-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2-propenyl) -6- (trifluoromethyl) -2H- 1-benzazepine-2-one

1, 5 S fluoromethyldHi-benz-bisphenone -on (3.40 g, 9.05 mmol), potassium bicarbonate (1.81 g, 18.1 mmol) and potassium iodide (catalytic amount) were dissolved in methyl ethyl ketone (55 ml) and treated with a 2.15 m solution of 2-dimethyl-aminoethyl chloride (5.1 ml, 10.9 mmol) in toluene with stirring. After about 30 minutes of heating under reflux

An additional 5.1 ml of the amine was added and an additional 1.81 g of potassium bicarbonate was added after 1.5 hours of refluxing. After refluxing for 6 hours, the mixture was evaporated on a rotary evaporator and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried (magnesium sulfate) and concentrated. 4.07 g of the viscous, oily free amine of the title compound were obtained. This material was subjected to flash chromatography (silica gel / O, 5% -3% gradient of methanol-dichloromethane) and the fractions containing the cis-compound were combined and concentrated, dissolved in ether;

washed with 1 η sodium bicarbonate solution, dried (magnesium sulfate) and acidified with ether saturated with hydrogen chloride. The mixture was concentrated and the white solid triturated with ether. The solid product was recovered by suction. This gave 1.89 g of the title compound, mp 226-228 ° C. Analysis calculated for: C ₂₅ H ₃₀ N ₂ ClF ₃ O ₂ .0.23H ₂ O:

C, 61.63; H 6,30; N 5.75; F 11.70; Cl 7:28; found: C, 61.63; H 6,26; N 5.62; F 11.60; Cl 7,53-

Example 8

(cis) -1,3,4,5-Tetrahydro-4- (4-methoxyphenyl) -3-propyl-6- (trifluoromethyl) -2H-1-benzazepin-2-one.

A) 1 ^, ^, Sq fluoromethyl) -2H-1-benzazepin-2-one

(cis) -W.sup.-2- (dimethylaminoj-ethyl-7-1,3,4, S-tetrahydro-ii.-methoxyphenyl) -3- (2-propenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2 -one (U, 25 g, 11.3 mmol) were dissolved in ethyl acetate (65 ml). The degassed solution was added with palladium-on-charcoal (0.86 g). The mixture was browned for 4 hours in a Parr apparatus. The material was filtered through a pad of celite and concentrated to 4.3 g of a crystalline solid. "

«• μ t \ U- 5137Λ- * '

27 0 07 i

'-. · -. ''-35-. · ^; ; , B) Further implementation too

(ice) -1 -_ / ~ 2- (Dimethylamino) ethyl7-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-propyl-6- (tribromo-methyl) -2H- 1-benz-

azepin-2-pn monohydrochloride , ,

1,3,4,5-Tetrahydro-3,4-methoxyphenyl-S-propyl-6-itrifluoromethyl) -2H-1-benzazepin-2-one (4.23 g, 11.21 mmol), potassium bicarbonate (4.49 g, 44.8 mmol, 4 equiv) and potassium iodide (catalytic amount) were suspended in methyl ethyl ketone (70 ml) and washed with a 2.15 m solution of 2-dimethylaminoethyl chloride (12.6 ml, 27.0 mmol, 2.4 Equivalents) in toluene with stirring. The mixture was refluxed for 10.5 hours and then concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic phase was dried (magnesium sulfate) and concentrated. The residue was subjected to flash chromatography (silica gel column / O, 5% methanol-dichloromethane, then 2.0% methanol / dichloromethane). The corresponding Fraktir - were pooled (ind concentrated and the residue was dissolved in it and, mixed with ether, which was saturated with hydrogen chloride..

The mixture was concentrated and evaporated several times together with ether. The residue was partitioned between ether and 1N sodium bicarbonate. The ether phase was dried (magnesium sulfate) and concentrated. After standing overnight, the solid residue in ether was found to be substantially less soluble. The solid was triturated in ether. The mixture was centrifuged. A solid was obtained. Conversion of the hydrochloride salt using ether saturated with hydrogen chloride afforded the title compound, mp 180.5-182.5 ° C.

Analysis: Calculated for _25313222

C, 60.94; H 6.71; N 5.69; Cl.7,20; F 11.57; Found: C, 60.94; H, 6.56; N, 5.65; Cl 7,38; F 11,32.

Example 9

3δ V

-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2-propenyl) 6-trifluoromethyl-2H-1-benzazepin-2-one

.-μ 5

J.

i- I, ι.

(S- ¹ V

27 0 07

· ·::. ~ ³⁶ - '. ν '':. ''

1''A) / ~ 2- (2-amino-6-trifluoromethyl-phenyl) -1- (4-methoxyphenyl) -

ethyl t-malonic acid dimethyl ester -..- "- · ·

A suspension of 40.4 g (0.088 mol) / ~ 2- (2-nitro-6-trifluoromethylphenyl) -1- (4-methoxyphenyl) ethyl 7-malonic acid dimethyiester (see Example 7A) in methanol was treated with a cold suspension of 5% palladium on charcoal in methanol (under nitrogen) and placed in a Parr precursor with a hydrogen pressure of 4.08 bar (58 psi). The mixture was heated at 50 to 55 ° C for 1 hour to ensure that all starting material was dissolved. The mixture was removed from the Parr apparatus and allowed to stand at room temperature overnight. The flask was heated to dissolve the crystallized product. The hot solution was filtered through celite (under nitrogen) and washed with hot methanol. The colorless filtrate was concentrated on a rotary evaporator. 36.9 g of the title compound, melting at 111-113 ⁰ C to obtain a <sample melted at 112-11U ° C.

mp 111-113 ° C. One crystallized from methanol

20

E) 1, 3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -

6- ( trifluoromethyl) -2H-1-benzazepin-2-or -

To a dry 2 liter 3-necked flask was added 34.5 g (0.081 mol) / ~ 2- (2-amino-6-trifluoromethylphenyl) -1- (4-methoxyphenyl) -ethyl-7-malonic acid, and 350 ml of methanol. The suspension was heated to 45 ⁰ C, and the resulting solution was cooled to 30 C and treated with 23 ml of a 25 percent solution of sodium methoxide in methanol. The mixture was heated and refluxed for 1 hour. The slurry was cooled to 15 ° C and treated with a solution of 30 ml of 6N hydrochloric acid in 350 ml of water. After stirring for 2 hours in an ice bath, the pale gray solid was filtered off and dried. This gave 30.8 g of product, mp 214-216 ⁰ C.

A kristailisierte sample from methanol melted at 218-22O ⁰ C.

C) 3-carboxy-1,3,4,5-tetrahydro-4- (methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one

A warm solution of 58.0 g (0.88 mol) of potassium hydroxide (85%) in 500 mL of methanol was added portionwise while stirring with 81.7 g (0.21 mol) of 1,3,4,5-tetrahydro-3-. (methoxycarbonyl) -4- (methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, whereby most of the solid dissolved. The mixture was diluted with 100 ml of dioxane. The resulting solution was refluxed for 6 hours. After standing at room temperature overnight, about 50% of the solvent was removed on a rotary evaporator. The residue was diluted with 4 liters of cold water. The insoluble material was filtered off and dried (10 g). The filtrate was cooled and treated portionwise with 270 ml of acetic acid. A colorless, granular solid was obtained. This solid was filtered off, washed with cold water and dried in a desiccator. This gave 69.0 g of product, mp 179r 181 ° C (S-128 ° C). : \

D) (d-trans) -3-carboxy-1,3,4,5-tetrahydro-4- (methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one - (-) - c ^ methylbenzyl

amine salt

A mixture of 67.0 g (0.176 mol) of 3-carboxy-1,3,4,5-tetrahydro-4- (methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one and 1 liter of ethanol was heated. The resulting solution C25 (52 ° C) was treated with a solution of 21.4 g (0.176 mol) of (-) - <^ - methylbenzylamine in 100 ml of ethanol. The solution was inoculated and left undisturbed for 24 hours at room temperature. The product separated in the form of well-formed crystals on the bulb wall. The mother liquor was decanted from the solid. The solid was suspended in 70 ml of ethanol, filtered and washed with fresh ethanol. This gave 34.6 g of a colorless solid of mp 156 ⁰ C (decomposition) :. / V_7 _D -10.3 ° (c, 1% methanol). '".:.

'35 ,. -. , .:. ; : ·. '':' /, '' ** .. E) (d-trans) -3-carboxy-1,3,4,5-tetrahydro-4H {tr-ethoxyphenyl) -6- (trifluoromethyl) -2H-1 benzazepin-2-one

-4 5RU-B1'3 / "v-r -

2 to

(D-trans) -3-Carboxy-1,3,4,5-tebrahydro-M- (methoxyphenyl) -6- (trifluorraefchyl) -2H-1-behzazepin-2-one - (-) - iX-methylbenzylamine £ 1 L (3 H, 0 g, 67.9 mmol) was stirred in dichloromethane (780 mL) and water (390 mL) and treated with 1 N hydrochloric acid (78 mL). Methanol (195 ml) was added gradually to accelerate solvation. After two clear layers were obtained (15 to 20 minutes), the organic layer was separated. The aqueous layer was extracted with dichloromethane (2 times) and the combined organic slides were washed with water (200 ml).

washed. The organic layer was dried (magnesium sulfate) and concentrated, and the residue was evaporated with acetone (3 times) to give 27.1 g of crude product.

F) (d-trans) -1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -6- (trifluoromethyl) -2H-1-denzazepin-2-one (d - trans) 3-Carboxy-1,3,4,5-t-rahydro-4- (methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (25.75 g, 67.87 mmol ) was dissolved in acetone (200 ml) and stirred at room temperature with 1,8-diazabicyclo / 5.4.07undec-7-ene (10.54 g, 10.4 ml, 69.22 mmol, 1.01 equiv. d = 1.018). (After less than 1 minute a white low

impact). Methyl iodide (43 mL, 96.3 g, specific gravity 2.24-2.26, 678.7 mmol, 10 equiv.) Was added, and the mixture was warmed to about 45 ° C (after about 1 min the mixture was stirred for 15 minutes and then concentrated The residue was partitioned between chloroform and saturated potassium bisulfate solution The aqueous phase was extracted with chloroform (4 times) The combined organic phases were dried (magnesium sulfate) and concentrated 51.74 g of a yellow viscous oil. was obtained. by evaporation of the residue together ^mi ether to give a light yellow solid. This material was preabsorbed on Kieselgei of 60-200 mesh and on a column packed with Ki-eselgel (height 10 cm) column 1: 1 hexane: ethyl acetate was used to wash out the product from the column, with baseline contamination ai beginning

27007f

-39-

remained. The filtrate was dried (magnesium sulfate, concentrated with ether (2 times) and dried under reduced pressure to give 24.78 g of the title compound.

G) (d-trans) -1,3,4,5-tetrahydro-3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) -6- (trifluoromethyl) -2H-

1-benzazepine-2-one

Following the procedure of Example 5, Method I, Section C, using (d-trans) -1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -6- (trifluoromefyl) -? H-1-benzazepin-2-one (10.87 g, 27.63 mmol), freshly distilled methoxymethylbromide (2.5 mL, 3.8 g, 30.39 mol, d - 1.531, 1.1 equiv Prewashed (ether) sodium hydride (0.86 g, 35.92 mmol, 1.3 equiv.) and dimethylformamide (110 mL) the crude title compound (15.83 g). The crude material was subjected to flash chromatography using a gradient of 10% ethyl acetate / hexane to 20% ethyl acetate / hexane. The yield of pure product was 4.23 g. Further, 4.44 g of the starting product mixture and 1.98 g of pure recovered starting material were obtained.

H) (d) - i, 3,4 _l 5-Tetrahydro-3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) -3- (2-propenyl) -6 - (', rifluoromethyl ) -

2H-1-benzazepine-2-one

Following the procedure of Example 5, Method I, Section D, using (d-trans) -1,3,4,5-tetrahydro-3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl ) 6- (trifluoromethyl) -2H-1-benzazepin-2-one (10.39 g, 23.7 mmol), allyl bromide (4.1 mL, 5.75 g, 47.5 mmol, d = 1.398,

2 equivalents), 50% sodium hydride (2.28 g, 47.5 mmol,

2 equivalents) and anhydrous dimethylformamide (110 ml), the crude title compound (17.84 g) as a yellow oil. The oil solidified on co-evaporation with ether.

--μ-fifth H3 ".

-40-

I) (d) -1, S 1 -S, tetrahydro-S-ethethoxycarbonyD-il-dethoxyphenyl) -3- (2-propenyl) -6- (trifluoromethyl) -2H-1-benzazepine

2-ron -

Following the procedure of Example 5, Method I, Section E, using (d) -1, 3,4,5-tetrahydro-3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) - 3- (2-propenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (11.27 g, 23.62 mmol), methanol (2 ¹ JO ml), sulfuric acid (UO ml) and dry lithium bromide (8.65 g, 99.6 mmol), the crude title compound as a yellow oily residue. The residue was dissolved in ethyl acetate and filtered with suction through a / silica gel layer. The clear yellow filtrate was concentrated to give a light yellow semi-solid product

 15

J) (d-cis) -1, S ^ jS-tetrahydro ^ -dnethoxyphenyD ^ - ^ -2H-1-benzazepin-2-one

According to the method of Example 5, Method I, part F, was obtained by using (d) -1,3,4,5-Teträhydro-3- (methoxycarbonyl) - ⁱ l (methoxyphenyl) -3- (2- propenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (10.20 g, 23.53 mmol), lithium iodide (12.60 g, 94.12 mmol, 4 equiv), pyridine ( 210 ml) and water (4 ml) 8.95 g crude title compound. K) Further implementation too

(cis) -1- / 2- (dimethylamino) -ethyl 7-1,3'-tetrahydro-H- (4-methoxyphenyl) -3-propyl-6- (trifluoromethyl) -2H-1-benz-

azepin-2-one monohydrochloride. __.

Following the procedure of Example 5, Method I, Section G, using (d-cis) -1,3,4,5-tetrahydro-4- (methoxyphenyl) -3- (2-j-> i ^> openyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (8.79 g, 23.42 mmol), potassium iodide (catalytic amount), potassium bicarbonate (9.47 g, 93.68 mmol), methyl ethyl ketone (105 mL) and 2.15 M N, N-dimethyl-2-chloroethylamine in toluene (27.2 mL, 58.55 mmol), the crude title compound. Recrystallization (hexene) of the crude product followed by trituration of the precipitate with hexane gave the pure cis material, which was dissolved in ether and treated with hydrochloric acid. The

f r \ * i /

'. , Λ 6.Bi-: öi.3 / Wi

Ζ:. , - ⁴¹ - · -.- ''. - 'Retained hydrochloride salt was recrystallized from ethyl acetate. This gave 3.55 g of the title compound, mp 225-227 ° C (Zers.). Π * _7 _Ό + 96.7 °.

Analysis: Calculated for C ₂₅ H ₂₉ F ₃ N ₂ O.HCl. 1.8H ₃ O: C, 58.28; H 6,57; N 5.43; Cl 6,88; F .11.06 ';

Found: C, 58.25; H 6,15; N 5.39; Cl 6.70; F 11.00.

Example 10

(d-cis) -1, a ^. S itrif luqrmethyl) -2H-1-benzazepin-2-one

A) Cd) -1,3, ^l l, 5-tetrahydro-3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) -3-ethyl-6- (trifluoromethyl) -2H-1

benzazepin-2-one

A suspension of 1.2 g of sodium hydride (25 mmol, 50% oil dispersion prewashed with ether) in 50 ml of dimethylformamide was cooled to 0-5 ° C. in an ice / water bath and stirred in small portions of 5, 2 g of crude solid (d-trans) -1,3,1,5-tetrshydro-3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine 2-on (see Example 9 G). The reaction mixture was stirred at 0 to 5 ° C for 20 minutes, after which 2 ml of iodoethane (25 mmol, 2 equiv.) Was added dropwise. The reaction mixture was allowed to stand for 2 hours at ⁰ ° C to room temperature whereupon excess hydride was destroyed by careful addition of water. The reaction mixture was diluted with ether and washed with water. The combined aqueous phase was extracted once with ether. The ether phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude yellow residue was chromatographed on a silica gel column and eluted with 5-20% ethyl acetate in hexane. This gave 5.01 g of the title compound as an oil.

2 70 07 Γ

-42-

B) (d j-1,3-4,5-tebrahydro-3- (mebhoxycarbonyl) -4- (mebhoxy- phenyl) -3-dibutyl-6- (trifluorobutyl) -2H-i-benzazepine-2-one A solution of U, 85 g (10.7 mmol) of (d) -1,3,4,5-tebrahydro-3- (mebhoxycarbonyl) -1- (mebhoxymebhyl) -4- (mebhoxyphenyl) -3-ethyl-6 (Brifluoromethyl) -2H-1-benzazepin-2-one in 100 ml of methanol was cooled in an ice / water bath and 20 ml of concentrated sulfuric acid were added dropwise, this solution being prepared with 2.7 g of anhydrous libium bromide was enbfernb, and the reaction mixture was pnter reflux (Badbemperabur 8O ⁰ C) erwärmb. the heating was forbgesebzb 2 1/2 Sbunden, after which the Reakbionsgemisch gekühlb (ice / water bath) and MIB water was verdünnb. the formation of a white precipitate The acid was carefully reconstituted by the addition of solid bicarbonate of bicarbonate The reaction mixture was thoroughly distilled from acetic acid ethyl ester (4 times) Esberexbrakb was washed with triglycerin brine, dried over anhydrous magnesium sulphate, and concentrated to a non-degrading pressure. The crude backbone was chromatographed on a silica gel column and chromatographed 20-50% acetic acid ethyl ester in hexane. One erhielb 4.36 g of white krisballines Produkb mp 77-81 ⁰ C.

/; 25 ^c ) Cd-cis) -1,3,1,5-tetrahydro-4- (methoxyphenyl) -3-ethyl-6-

(Brifluormebhyl) -2H-1-benzazepin-2-one

Libium iodide (3.96 g, 29.6 mmol) was added to (d) -1,3,4,5-tebrahydro-S-imebhoxycarbonyD-II-imebhoxyphenyD-S-ethyl-o- (brifluoromethyl) -2H-1. Benzazepin-2-one (3.12 g, 7, ¹ I mmol) in 40 ml of pyridine and 3 ml of water. The mixture was heated to reflux for 4 1/2 hours at 133 ° C. White ^ ps libium iodide (1.00 g) and dimebnylformamide (10 ml) were added and the refluxing process was followed by reboiling. The mixture was cooled and distilled between Kbher and 1N hydrochloric acid. The aqueous phase was extracted several times with fither. The combined organic phases were dried (magnesium sulfate) and concentrated. The crude, dark oily residue became flash chrome

(iitt · o13V ^; \ ".

-43-

(Silica gel); 1% -10% pyridine-hexane). 2.65 g of crude (d- * cis) -1,3,4,5-tetrahydro-4- (methoxyphenyl) -3-ethyl-6- (trifluoromethyl) -2H-1-benzazepin-1-one ( about 80:20 cis-trans mixture was obtained).

g D) Further implementation

to (d-cis) -1- / ~ 2- (dimethylamino) ethyl 7-1,3,4,5-tetrahydro- ^l - ( ^ι l-methcxyphenyl) -3-ethyl-6- (trifluoromethyl) -2H -1-benzazepine

2-one monohydrochloride

Prewashed (hexane) sodium hydride (0.26 g, 10.7 mmol) and (d-cis) -1,3,4,5-tetrahydro-4- (methoxyphenyl) -3-ethyl-6- '. (Trifluoromethyl) -2H-1-benzazepin-1-one (2.60g, 7.15mmol) was stirred for 35 minutes in 50ml of anhydrous dimethylformamide. "A 2.15M toluene solution of N, N-dimethyl-2- Chloroethylamine (13.3 mL, 28.6 mmol) was then added and the mixture was heated to 80 ° C. with stirring for 1 1/2 hours The reaction was quenched with ¹ N hydrochloric acid and made alkaline with 50 percent matrium hydroxide solution and ethyl acetate / water, and the aqueous phase was extracted with ethyl acetate.

^D i- ^e combined organic phases were dried (magnesium sulfate) and concentrated. The free amine was recrystallized from hot hexane (3 times), dissolved in ethyl acetate and washed with 1 N sodium bicarbonate solution. The ethyl acetate phase was dried (magnesium sulfate) and then treated with saturated chlorofiber solution in ether. The concentrated mixture was dried under reduced pressure overnight. 0.52 g of a white solid product of mp 162-164 ° C was obtained. / "6" _n 112 ° (the mother liquor contained further product).

Analysis: Calculated for C ₂₄ H ₂₉ N ₂ O ₂ F ₃ .HCl.0,95H ₂ O:

C 59.07; H 6,59; N 5.7 ¹ IJ F 11.67; Cl 7,26; Found: C 59.07; H 6.71; N 5 , 76; F 11,89; Cl, 7.51 ;

3K Example 11 ·

(d-cis) -1 ;; 3 _l 4 ' _l 5 ^ Tetrahydro-4' - (4-methoxyphenyl) -3-mejbhy _> 1-6 (trifluoromethyl) -2H-1-be, nzazepine-2 -one

H 5. II 8 -

270 07 ί

-44-

IA) (d) -1,3,4,5-tetrahydro-3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) -3 · methyl-6- (trifluoromethyl) -2H-

1-benzazepin-2-one _____ '

A suspension of 1.2 g of sodium hydride (25 mmol) in 50 ml of anhydrous dimethylformamide was cooled in one ice / water bath and added with 5.2 g of (d-trans) -1,3,4,5-tetrahydro- 3- (methoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (12 mmol, crude product, see Example 9 G) in small portions. After 20 minutes of stirring at 0 to 5 ° C 1.6 ml of iodomethane (25 mmol} was added rapidly. One Hess the reaction mixture for 3 hours at 0 ⁰ C to be room temperature, after which excess hydride was destroyed by careful addition of water. The The reaction mixture was diluted with ether and washed with water The aqueous phase was extracted with ether The combined ether extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure The crude yellow oil was chromatographed on silica gel and eluted with 5-20% ethyl acetate in hexane 4.68 g of the title compound were obtained.

B) (d) -1,3,4,5-Tetrahydro-3- (methoxycarbonyl) -4- (methoxy- phenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazep in-2-one A solution of 4.37 g of (d) -1,3,4,5-tetrahydro-3 (mathoxycarbonyl) -1- (methoxymethyl) -4- (methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H- 1-Benzazepin-2-one (9.7 mMcl) in 100 ml of methanol was cooled in an ice / water bath and 2.7 g of anhydrous lithium bromide were added, after which 20 ml of concentrated sulfuric acid were added dropwise. The cooling bath was removed and the reaction mixture was heated at reflux (bath temperature 8O-85 ° C) for 4 hours. The reaction mixture was cooled and diluted with ice-cold water. The acid was neutralized by careful addition of solid sodium bicarbonate followed by extraction with ethyl acetate. The combined organic extract was washed once with brine and dried over anhydrous magnesium sulfate. After concentration under

27 Ö O 7 \

_45_

minderten! Pressure gave a yellow oily residue, which was chromatographed on a silica gel. The

Elution was carried out with 5-25% ethyl acetate in hexane. 1.6 g of the desired white crystalline product, mp 71-76 ⁰ C were obtained:

C) (d-cis) -1,3,4,5-tetrahydro-4- (methoxyphenyl) -3-methyl

6- (trifluoromethyl) -2H-1-benzazepin-2-one

A solution of 1.5 g of (d) -1,3,4,5-tetrahydro-3- (methoxycarbonyl) -4- (methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepine-2 -on (4 mmol) in 12 ml of dimethylformamide was added with stirring 2 g of anhydrous lithium bromide and 920 mg of p-aminothiophenol (8 mmol). The reaction mixture was placed in an oil bath and heated to 135 ° C under an argon atmosphere for 5 hours. It was then cooled and diluted with ice water. The reaction mixture was extracted with ether (3 times) and the combined extract of the extract was extracted with water, 1N aqueous hydrochloric acid solution (2 times) and finally with saturated sodium chloride solution. The ether phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This gave 1.3 g of a pale yellow viscous oil. The NMR spectrum of the crude product gave a cis / trans ratio of about 20: 1.

D) Further implementation

to (d-cis) -1 / ~ 2- (dimethylamino) -ethyl 7-1, 3, ^1, 1.5 · i> etrahydro- ¹ L- ( ^ί J -methoxyphenyl) -3-methyl-6- (trifluoromethyl ) -2iJ-1-benz-

azepin-2-one monohydrochloride

A slurry of washed (ether) sodium hydride (0> 13 g, 5.58 mmol) in anhydrous dimethylformamide (15 mL) was treated with (d-cis) -1, 3,4,5-tetrahydro-4- (methoxyphenyl) - Added 3-methyl-6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.27 g, 3.64 mmol). The mixture was stirred for 35 minutes at room temperature, after which a 2.15 m toluene solution of N, N-dimethyl-2-chloroethylamine (5.2 ml, 11.2 mmol) was added. The solution was heated to 80 C for 6 hours. The reaction was stopped with 1N hydrochloric acid. It then became alkaline with 50% sodium hydroxide solution

5.8 a -

270Ö?

extracted, extracted with ethyl acetate (3 times) and dried over magnesium sulfate. The concentrated residue was co-evaporated with hexane (3 times) and left under reduced pressure overnight. The crude material was purified by preparative plate chromatography (silica gel, 5% methanol: dichloromethane, evolution 3 times), dissolved in ethyl acetate, washed with 1 N sodium bicarbonate and dried (magnesium sulfate). The solution was treated with a solution of hydrogen chloride in ether, concentrated, co-evaporated with ether (4 times) and dried under reduced pressure. This gave 870 mg of a white solid product, mp 146-148 ⁰ CjTo (JZ _n + 104 ° (methanol)

Analysis: Calculated for C ₂₃ H ₂₇ N ₂ O ₃ F ₃ O .HCl.1,91H:

C 56,23; H 6,53; N 5.70; Cl 11.60; F 7,22; found: C 56.44; .H 6.69; N 5.83; Cl 11, 62; F 7.04. ,

'·. ^; I

The following are examples of other compounds of the invention: (cis) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-isopropyl-2H-1-benzazepin-2-one,

(Cis) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-butyl-2H-1-benzazepin-2-one,

(cis) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-iso- ^2- butyl-2H-1-benzazepin-2-one,

(Cis) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-cyclohexylmethy1-2H-1-benzazepin-2-one,

(cis) -7-chloro-1,3,4,5-tetrahydro _r 4- (4-methoxyphenyl) -3-cyclopeniylmethyl-2H-1-benzazepin-2-one, (cis) -7-Ghlor-1, 3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-phenylmethyl-2H-1-benzazepin-2-one, (iso) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-allyl-

2H-1-benzazepin-2-one,

(ice) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2-butenyl) -2H-1-benzazepin-2-one, ·

-47-

(Cis) -7-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2-

propynyl) -2H-1-benzazepin-2-one, • (cis) -7-chloro-I ', 3,4,5-tetrahydro-4- (4-methoxyphenyl) -3 - [(2-furanyl) - methyl] -2H-1-benzazepin-2-one,

(cis) -7-chloro-1. 3, 4,5-tetrahydro-4- (4-methoxyphenyl) -3- [(2-pyridyl) -methyl] - 2H-1-benzazepin-2-one,

(Ice) -7-Chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3 - [( 2- pyrrolyl) -methyl] -2H-1-benzazepin-2-one, (cis ) -7-methoxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-2H-1-benzazepin-2-one,

(Ice) -7- (trifluoromethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-isopropyl-2H-1-benzazepin-2-one, (ice) -7- (trifluoromethyl ) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-thy 1,2-H-1-benzazepine-2-one,

(cis) -6- (trifluoromethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-ethyl-2H-1-benzazepin-2-one,

(Ice) -7- (trifluoromethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (phenylmethyl) -2H-1-benzazepin-2-one, (ice) -6- (Trifluoromethyl) -1, 3, 4, 5-tetrahydro-4- (4-m-jthoxyphenyl) -3- (phenylmethyl) -2H-1-benzazepin-2-one,

(Ice) -7- (trifluoromethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2-butenyl) -2H-1-benzazepin-2-one, (ice) - 6- (trifluoromethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-ε (2-furanyl) -methyl] -2H-1-benzazepin-2-one,

(cis) -6- (trifluoromethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2-propynyl) -2H-1-benzazepine-2-one And (cis) - 7- (trifluoromethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- (2-propynyl) -2H-1-benzazepin-2-one.

30

35

»4 r .r

Claims (1)

-48- Invention claim: Process for the preparation of the d-cis enantiomer of a compound of formula I (I) characterized in that the d-cis enantiomer of a compound of general formula VII R- 4 - decarboxylated, wherein Y represents an alkyl radical; (VII) R and R each represent hydrogen atoms or alkyl radicals, R represents a hydrogen atom and R represents an alkyl, alkenyl, alkynyl, aryl, heteroaryl or cycloalkyl radical, or R and R together with the carbon atom to which they are attached form a Cycloalkyl radical; 270 07 t -49- R and R _{5 are} each independently hydrogen or halogen, alkyl, alkoxy, aryloxy, arylalkoxy, aryl Il all.yl, hydroxyl, alkanoyloxy, -OC-NX.X, difluoromethoxy, trifluoromethyl, -NX ₃ X ₄ , -S (O) _m alkyl or -S (O) _m aryl radicals mean, m has the value d, 1 or 2; each of i and X "independently of one another denotes hydrogen atoms, alkyl, aryl or heteroaryl radicals or X. and X" together with the nitrogen atom to which they are attached denote a nitrogen-containing heteroaryl radical; and X ₃ and X are each independently hydrogen, alkyl, alkanoyl, arylcarbonyl, heteroarylcarbonyl or carbamoyl. -VS. Ho-