RU2026296C1 - Method of synthesis of nitrogen-containing heterocyclic compounds or their pharmaceutically acceptable salts - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: method involves the synthesis of new heterocyclic nitrogen-containing compounds of the formula (I) where radicals R₁-R₄ have different meanings; X - CH₂ , or their pharmaceutically acceptable salts. Reagent 1: compound of the formula (II) where R - H. Reagent 2: R₂-Y. Synthesized compounds are used in medicine. EFFECT: improved method of synthesis of compounds indicated above. 1 tbl

Description

или

или

или

или

или

где n' - 0,1,2,3; n = 2,1,0, где: Y₃Y₄ - водород низший алкил, Y₅ - фенил-низший алкокси, водород, низший алкокси, при Х - S R₂ - группа

CHY₅ или

или

где Y₃, Y₅ имеют указанные значения;
R₃ - низший алкоксил, низший алкил, водород, галоид, трифторметил, низший алкилсульфонил, R₄ - низший алкоксил или их фармацевтически приемлемых солей.The invention relates to methods for producing new nitrogen-containing compounds of the general formula I
R where R ₁ is hydroxy, lower alkanoyloxy, OCOT ₁ Y ₂ , where: Y ₁ , Y ₂ is hydrogen, lower alkyl at X = CH ₂ ; R ₂ is a group of the formula

or

or

or

or

or

where n 'is 0,1,2,3; n = 2,1,0, where: Y ₃ Y ₄ - lower alkyl hydrogen, Y ₅ - phenyl lower alkoxy, hydrogen, lower alkoxy, when X - SR ₂ - group

CHY ₅ or

or

where Y ₃ , Y ₅ have the indicated meanings;
R ₃ is lower alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfonyl, R ₄ is lower alkoxyl or their pharmaceutically acceptable salts.

 The compounds of formula I and their pharmaceutically acceptable salts act as vasodilating agents that block calcium intake and are particularly useful as antihypertensive agents. When using a composition containing one (or several) substances of the formula I, blood pressure decreases in patients (in a hypertonic mammal). To reduce blood pressure, a single dose is suitable, or the daily dose is divided into two to four portions, providing a dosage of about 0.1-100 mg per 1 kg of body weight per day, preferably from about 1 to 50 mg per 1 kg per day. Preferably, the substances are administered orally, but parenteral methods of administration such as subcutaneous, intramuscular, or intravenous may also be used.

 The substances of this invention can also be used in combination with a beta-adrenergic agent, or an antiarrhythmic agent, diuretin, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, triflaziazide, or benzothiazide, also , furozemide, musolimine, tiamterene bumetenide, amiloride, and spironolactone and salts of such compounds, antiotensin converting enzyme inhibitors such as captopril, zofenopril, fosinopril, en alapril, delapril, pentopril, hinapril, ramipril, lisinopril, and salts of such compounds, thrombolytic agents, such as plasminogen tissue activator (PAt), recombinant PAt, streptokinase, urokinase, prourokinase, and the anisoylated complex of plasminogen streptamine A (PS, AC), Labratoris). In such combination products, if formulated as a fixed dose, the substances of this invention are used within the described dose range, and the other pharmaceutically active agent is used within the approved dosage range.

 The substances of formula I can be formulated for use in lowering blood pressure in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. Substances of formula I can also be administered via a transdermal patch or nasal inhalation solutions. Approximately 10-500 mg of a substance of formula I is combined with a physiologically acceptable carrier, a drug enhancer, a binder, a preservative, a stabilizer, perfume, etc. in a unit dose form as prescribed by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage is obtained in the indicated range.

 The table shows the test results by the following procedure for the claimed compounds.

 Test procedure.

 Tests to study the activity of blocking calcium channels were carried out according to the method, not different from that described in J. Med Chem., 30, 1987, p. 636-640. The studied compounds were tested in the range of 1 nm - 10 μM and evaluated by hemogarithmic increments on the response curves of cumulative concentrations.

The IC ₅₀ value represents the concentration of the test compound in the presence of 50% relaxation for rabbit thoracic aortic contractions induced by KCl in vitro. Then, the least squares method was used to construct curves describing the logarithmic dependence between the concentration and the transformation of the relaxation response.

-

-N

,
(CH₂)_n-

Y

-N

(CH₂)_n

Y

-N

, где n=0,1 Y₄,Y₅-H, низший алкил, Y₆ - алкил; Y₇ - аралкил (1) проявляющие аналогичную активность.Benzothiazepines of formula I are known in which at X = S
R ₄ -H, Hal; alkyl, alkanoyloxy, R ₁ = OY ₃ , Y ₃ -alkanoyl,
R ₃ = H, Hal, R ₂ = - (CH ₂ ) _n -

-

-N

,
(CH ₂ ) _n -

Y

-N

(CH ₂ ) _n

Y

-N

where n = 0.1 Y ₄ , Y ₅ -H, lower alkyl, Y ₆ is alkyl; Y ₇ - aralkyl (1) exhibiting similar activity.

 Compounds are known that contain alkylenecyclic or cyclic residues exhibiting antihypertensive activity in position I of the benzthiazepine ring.

 These inventions allow us to expand the range of benzthiazepine derivatives with antihypertensive activity.

где X, R₃, R₄, R₁ имеют указанные значения, обрабатывают основанием в инертном органическом растворителе с последующей обработкой соединением формулы III R₂Y, где R₂ - имеет указанные значения, Y - отщепляемая группа, с выделением целевого продукта в свободном виде или в виде фармацевтически приемлемой соли.The proposed method for obtaining compounds of formula I or their pharmaceutically acceptable salts, is that the compound of General formula II
R

where X, R ₃ , R ₄ , R ₁ have the indicated meanings, are treated with a base in an inert organic solvent, followed by treatment with a compound of the formula III R ₂ Y, where R ₂ is the indicated meanings, Y is a leaving group, and the desired product is isolated in free as or as a pharmaceutically acceptable salt.

Most preferred are those wherein R ₃ is a 6-trifluoromethyl or 7-methoxy group on a benzazipine nucleus, or an 8-methoxy group on a benzothiazepine nucleus and R ₄ is a methoxy group.

 EXAMPLE 1. [1 (trans), 3a, 4a] -1- [2- (dimethylamino) cyclohexyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3- methyl 6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

To a suspension of 0.3 g of sodium hydride (6.3 mmol, 50% dispersion in oil) in 20 ml of dry dimethylformamide was added 2.0 g of (cis) -1,3,4,5-tetrahydro-4- (4 -methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepin-2-one (5.73 mmol) in a single solid state. The solution was stirred for 45 minutes and then a solution of 1.59 g (6.3 mmol) of (trans) 1-iodo-2- (dimethylamino) cyclohexane in 12 ml of dry dimethylformamide was added dropwise over 15 minutes. This solution was stirred at room temperature for 20 minutes and then heated to 75 ^{° C} for 70 min. Another 0.15 g of sodium hydride and 0.8 g of (trans) -1-iodo-2- (dimethylamino) cyclohexane are added and heating is continued for another 30 minutes. The solution was allowed to cool and dimethylformamide was removed in vacuo. Water was added to the residue, the aqueous solution was extracted twice with ethyl acetate, and the combined organic phases were washed with brine and dried with magnesium sulfate to obtain 3.15 g of a semi-solid.

Chromatography on silica gel with 1% triethylamine with a mixture of 2% methanol in dichloromethane gives 0.74 g of the free base of the title compound as a white foamy solid. This free base is dissolved in diethyl ether and ether saturated with hydrogen chloride is added to give a white precipitate. The solution was evaporated and washed twice with ether to remove excess hydrogen chloride. The remaining white solid was recrystallized from isopropanol-diisopropyl ether to give 0.68 g of the title compound, mp. above 250 ^about C.

 Calculated,%: C 62.51; H 6.77; N, 5.40; Cl 6.83; F 10.99.

C ₂₇ H ₃₄ ClF ₃ N ₂ O ₂ 1,5 H ₂ O
Found,%: C 62.59; H6.84; N, 5.30; Cl, 6.70; F, 10.99.

 PRI me R 2. (cis) -1- [2- (dimethylamino) propyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A, monohydrochloride.

Stirred solution 3.0 g (8.69 mmol) (cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepine- 2-one in 90 ml of 2-butanone is treated with 1.7 g (10.75 mmol) of N, N-dimethyl-2-chloro-1- (methyl) ethylamine and then 3.0 g (2.17 mmol) of powdered carbonate potassium and heated to a boil under reflux. After approximately 2 days of heating, a significant amount of (cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepine-2- is still present it. An additional 1.2 g of N, N-dimethyl-2-chloro-1- (methyl) ethylamine and 2.2 g of potassium carbonate were added, and heating was continued for another day. After cooling, the solids were filtered off, washed with 2-butanone, and the combined filtrates were evaporated. The residue is shaken with 90 ml of ethyl acetate and 30 ml of water, the layers are separated, and the ethyl acetate layer is washed with 30 ml of water and 30 ml of brine, dried with magnesium sulfate and evaporated. The residue was dissolved in diethyl ether, evaporation was repeated and the residue was dried using a pump to obtain 3.86 g of a solid. After two crystallizations from isopropyl ether gave 1.05 g of solid, melting point 154-157 ^C. TLC: major product, R _f 0,51, minor product R _f 0,42 (eluent - 90:10 dichloromethane-methanol ) Main product R _f 0.27; minor product R _f 0.17 (30:70 acetone-hexane).

The indicated material is chromatographed on 40 g of Baker silica gel, eluting with 30: 70 acetone-hexane to give 0.6 g of a single isomer as a colorless solid with mp. 159-161 ^about S.

 Calculated,%: C 66.34; H, 6.73; N, 6.45.

C ₂₄ H ₂₉ F ₃ N ₂ O ₂ .

 Found,%: C 66.50; H 7.02; N, 6.32.

 The residue from the second crystallization from diisopropyl ether and fractions from the described chromatography, which are rich in isomer A, are combined and chromatographed to obtain an additional 0.36 g of identical material.

Both portions are combined (a total of 0.92 g), suspended in 25 ml of methanol, treated with 0.45 ml of a 5N ethanolic solution of hydrogen chloride (the resulting solution), the solvent is evaporated and dried using a pump. This process is repeated to obtain 0.92 g of the title colorless, non-hygroscopic hydrochloride salt, mp. 101-104 ^{° C} (foaming), baked at 88 ° ^C TLC: R _f 0,40 (eluent acetone-hexane, 40:60) R _f 0,25 (eluent - 8: 1 dichloromethane-methanol-acetic acid) .

 Calculated,%: C 60.05; H 6.51; N, 5.84; Cl 7.39.

Found,%: C ₂₄ H ₂₉ F ₃ N ₂ O ₂ ˙HCl 0.5 H ₂ O
Found,%: C 59.93; H 6.87; N 6.04; Cl 7.14.

 PRI me R 3. (cis) -1- [2- (Dimethylamino) propyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer B, monohydrochloride.

 The mother liquors in diisopropyl ether after crystallization of the free base of isomer A from Example 2 are evaporated to give 2.4 g of a waxy precipitate. According to thin layer chromatography (eluent 40:60 acetone-hexane) this material is approximately 40:60 a mixture of isomer A and isomer B.

This mixture was chromatographed over 40 g of Baker silica gel, eluting with 40:60 acetone-hexane to give 0.49 g of the B base isomer as a waxy solid. A solution of this base (0.48 g) in methanol was treated with 0.24 ml of a 5N ethanolic solution of hydrogen chloride and the solvent was evaporated. The residue was triturated under ether, evaporated and dried using a pump. This process was repeated to obtain 0.50 g of a colorless, slightly hygroscopic hydrochloride salt with melting point 83-86 ^{° C} (foaming), baked at 76 ° ^C TLC: R _f 0,22 (eluent - 40:60 acetone- hexane).

 Calculated,%: C 60.05; H 6.71; N, 5.84; Cl, 7.39.

C ₂₄ H ₂₉ F ₃ N ₂ O ₂ ˙ HCl ˙ 0.5 H ₂ O
Found,%: C 60.30; H 7.00; N, 5.62; Cl 7.17.

 PRI me R 4. (cis) -1- [2-amino-1-methylethyl] -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl ) -2H-1-benzazepin-2-one, isomer B, monohydrochloride.

 A) (cis) -1,3,4,5-Tetrahydro-4- (4-methoxyphenyl) -d, 3-dimethyl-2-oxo-6- (trifluoromethyl) -1H-1-benzazepine-1-acetonitrile, more mobile isomer.

To a suspension of 0.22 g of sodium hydride (5.37 mmol, 60% dispersion in oil) in 15 ml of dry dimethylformamide, 1.50 g (4.29 mmol) of (cis) -3-methyl-4- (4 -methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one. The solution was stirred for 15 min at room temperature, cooled ^to 0 ° C and then add exactly 0.42 mL (5.37 mmol) of 2-chloropropionitrile. The solution was stirred at ⁰ ° C for 10 minutes, warmed to room temperature over 15 min and heated to 45 ^{° C} for 90 min. An additional 50 mg of sodium hydride and 0.15 ml chloropropionitrile, the solution was stirred at ⁴⁵ ° C for 20 minutes. The reaction was interrupted by the addition of a 1 M solution of ammonium chloride, dimethyl fluoroformamide was removed under high vacuum with gentle heating. The residue was partitioned between ether and a 1 M solution of ammonium chloride, the organic layer being washed with brine, dried with magnesium sulfate and evaporated to give a brown foamy solid, which was combined with the crude product from a similar reaction mixture, calculated on 1.68 mmol . This crude product consists of two product diastereoisomers designated as the more mobile isomer (BPI, Rf = 0.74, 50% ethyl acetate / hexane). This solid was chromatographed on silica gel (60% ether / hexane) to give 0.90 g of pure BPI as a white solid. Chromatography also gives 0.34 g of an almost pure less mobile isomer (MPI), which is dissolved in hot hexane containing 5% diisopropyl ether. Upon cooling, 0.29 g of pure MPI are obtained in the form of hexagonal prisms with mp 166-168 ^о С. When chromatographing mixed fractions, an additional 0.44 g of pure VPI (total weight 1.34 g) and 0.31 g MPI (total weight 0.60 g) are obtained.

 B) (cis) -1- (2-amino-1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1- benzazepin-2-one, isomer B, monohydrochloride.

A solution of 0.87 g of the more mobile isomer (cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -α, 3-dimethyl-2-oxo- (trifluoromethyl) -1H-1-benzazepine- 1-acetonitrile (2.16 mmol) and 0.87 g of 5% rhodium on alumina in 125 ml of a 1: 1 mixture of methanol: methanol saturated with ammonia is hydrogenated under a pressure of 50 psi (3.5 ati) with hydrogen in for 25 hours. The solution was filtered through Celite, the Celite being washed twice with methanol, the combined fractions were evaporated. The semi-solid residue was dissolved in dichloromethane, filtered through Celite and evaporated to give 0.89 g of a solid as a white foam. To a solution of 0.34 g of this material in ether is added ether saturated with hydrogen chloride. The solution becomes cloudy white, it is evaporated and the residue is dissolved in methanol and evaporated. The residue was dissolved in 1 ml of methanol, 20 ml of ether and then 20 ml of hexane were added, and the solution was frozen. The white solid was filtered and dried to obtain 0.30 g of the title compound as a white solid with melting point 157-162 ^{° C} (foams).

 Calculated,%: C 59.15; H 5.96; N, 6.27; Cl 7.93; F 12.76.

C ₂₂ H ₂₆ ClF ₃ N ₂ O ₂ ˙ 0.21 H ₂ O
Found,%: C 59.15; H 6.10; N, 6.04; Cl 7.84; F 12.78.

 PRI me R 5. (cis) -1- (2-Dimethylamino) -1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- ( trifluoromethyl) -2H-1-benzazepin-2-one, isomer B, monohydrochloride.

Solution 0.62 g (cis) -1- (2-amino-1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H -1-benzazepin-2-one, isomer B, monohydrochloride (1.52 mmol, see example 4) and 1.3 ml of 37% aqueous formaldehyde in 10 ml of acetonitrile are added at one time with stirring, to 0.31 g of solid sodium cyanoborohydride, and then 0.16 ml of acetic acid is added. This solution was stirred for 30 minutes. Ether and 5% potassium carbonate are added, the mixture is separated into layers. The organic layer was washed with brine, dried with magnesium sulfate and evaporated, yielding 0.84 g of a thick oil. Chromatography on silica gel with a mixture of 2% methanol: 1% triethylamine: dichloromethane gives 0.30 g of the pure free base of the title compound. This material is dissolved in ether, ether saturated with hydrogen chloride is added. The white suspension was evaporated and the residue was dissolved twice in methanol and evaporated. Hot diisopropyl ether is added to the glassy solid and hot methanol is added dropwise until the solid is dissolved. The solution is filtered off, hot diisopropyl ether is added until a steady turbidity appears, and the solution is cooled and left in the refrigerator. The waxy precipitate was filtered off and dried in vacuo to give 220 mg of the title white solid having a melting point above 220 ° ^C.

 Calculated,%: C 59.84; H 6.53; N, 5.81; Cl 7.36; F 11.83.

C ₂₄ H ₃₀ ClF ₃ N ₂ O ₂ ˙ 0.60 H ₂ O
Found,%: C 59.84; H 6.52; N, 5.76; Cl 7.27; F 11.93.

 PRI me R 6. (cis) -1- (2- (Dimethylamino)) - 1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6 - (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A, monohydrochloride.

 A) (cis) -1- (2-amino-1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1- benzazepino-2-one.

 A solution of 0.60 g of the less mobile isomer (cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -a, 3-dimethyl-2-oxo-6- (trifluoromethyl) -1H-1- benzazepine-1-acetonitrile (1.49 mmol) and 0.49 g of 5% rhodium on alumina in 125 ml of a 1: 1 methanol mixture: methanol saturated with ammonia is hydrogenated with hydrogen at a pressure of 3.5 atm for 20 hours. The solution was filtered through Celite. The celite was washed twice with methanol and the combined filtrates were evaporated. The semi-solid residue was dissolved in dichloromethane, filtered through Celite and evaporated to give 0.56 g of the title compound as a foamy white solid.

 B) (cis) -1- (2-dimethylamino) -1-methylethyl) -1,3,4,5-tetrahydro-4- (4-hydroxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1 -benzazepin-2-one, isomer A, monohydrochloride.

A solution of 0.56 g of crude (cis) -1- (2-amino-1-methylethyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) - 2H-1-benzazepin-2-one (1.38 mmol) in 10 ml of acetonitrile containing 1.2 ml of 37% formaldehyde, adding 0.28 g of solid sodium cyanoborohydride (4.44 mmol) with stirring and then add 0.145 ml of acetic acid. The solution was stirred for 2 hours, another 0.145 ml of acetic acid was added, and the solution was stirred for 30 minutes. The reaction mixture was partitioned between ether and a 10% aqueous potassium carbonate solution, the organic layer was washed with brine, dried with magnesium sulfate and evaporated to give 0.70 g of an oil. This material was flash chromatographed on silica gel (eluent 1% methanol / 0.5% triethylamine / dichloromethane) to give 0.32 g of pure free base (the title compound) as a white foamy solid. This material was dissolved in ether and ether saturated with hydrogen chloride was added to give a white precipitate. The ether was evaporated, the solid was dissolved in methanol, and the solvent was evaporated. The solid was redissolved in methanol, the solution was filtered through Celite and evaporated. The solid is dissolved in 2 ml of warm methanol and hot diisopropyl ether is added until turbidity begins. The solution was cooled and the solid was collected by filtration to give 0.27 g of the title compound as a crystalline solid with a melting point above 220 ° ^C.

 Calculated,%: C 61.20; H 6.42; N, 5.95; Cl, 7.53; F 12.10.

C ₂₄ H ₃₀ ClF ₃ N ₂ O ₂ ˙HCl.

 Found,%: C 61.15; H 6.52; N, 5.88; Cl 7.71; F 11.78.

 PRI me R 7. (3R- (1 (R *) - 3a; 4a)) - 3- (Acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- ((1-methyl-2-pyrrolidinyl) methyl) -6- (trifluoromethyl) - 2H-1-benzazepin-2-one, monohydrochloride.

 A) R-N- (tert-butoxycarbonyl) -2-pyrrolidinemethanol.

A solution of R-2-pyrrolidinemethanol (5.0 g, 50 mmol) in dry dichloromethane (125 ml) at ⁰ ° C was treated dropwise with a solution of di-tert-butyl dicarbonate (13 g, 59.5 mmol) in 50 mL of dichloromethane for 15 minutes. Immediate release of carbon dioxide. The cooling bath was removed and the mixture was stirred at room temperature for an additional 6 hours. Then, the reaction mixture was concentrated under reduced pressure to obtain the title compound as a pale yellow viscous oil (13 g). This crude material was used in the subsequent reaction without further purification.

 B) R-N-methyl-2-pyrrolidinemethanol.

Lithium aluminum hydride (7.6 g, 200 mmol) was added portionwise to dry tetrahydrofuran (200 ml) cooled to 0-5 ° ^C. is added dropwise a solution of RN- (tert-butoxycarbonyl) -2-pyrrolidinemethanol (13 g crude, 50 mmol) in 100 ml of dry tetrahydrofuran, with thorough stirring for 45 minutes. After 30 min at ⁰ ° C room temperature, the reaction mixture was heated to reflux (reflux) for 16 h. The reaction mixture was cooled ^to 0 ° C, the excess hydride was decomposed by the slow addition of saturated aqueous sodium sulfate solution. The addition continues until all inorganic salts precipitate as a white granular solid. The mixture was diluted with 500 ml of ethyl acetate, dried with magnesium sulfate, filtered and concentrated to give the title compound as a colorless oil (5.7 g). This crude product was used without purification in the next reaction.

 C) R-2- (chloromethyl) -1-methylpyrrolidine, hydrochloride.

To a solution RN-methyl-2-pyrrolidinemethanol (2.0 g, 17.4 mmol) in chloroform (18 mL) at ⁰ ° C was added dropwise thionyl chloride (0.74 g, 52.1 mmol). The reaction mixture was heated to boiling for 2 h and then cooled to room temperature and concentrated under reduced pressure, the residue was subjected to recrystallization from acetone-ether mixture to obtain the title compound as a pale yellow solid (1.14 g).

 D) (3R- (1R *) - 3a, 4a)) - 1 - ((1-methyl-2-pyrrolidinyl) methyl) -3- (hydroxy) -1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

Sodium hydride (0.19 g, 8.1 mmol) is added to the solution of (3-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one ( 1.05 g, 3.0 mmol) in 30 ml of dried dimethylformamide. The mixture was stirred at room temperature for 1 h, after which R-2- (chloromethyl) -1-methylpyrrolidine, hydrochloride (0.78 g, 4.5 mmol) were added, the mixture was heated to 80 ^° C for 1 h. Then the reaction mixture was cooled and the reaction was quenched by the addition of a saturated aqueous solution of potassium bicarbonate and extracted three times with ethyl acetate. The combined extracts were washed with a 10% aqueous lithium chloride solution, dried with magnesium sulfate and concentrated. The crude yellow liquid was chromatographed on a silica gel column and eluted with a mixture of 1-3% methanol in dichloromethane to give the title compound as a viscous liquid (0.24 g).

 E) (3R- (1 (R *), 3 α, 4α)) - 3- (acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1 - ((1-methyl -2-pyrrolidinyl) methyl-6- (trifluoromethyl) - 2H-1-benzazepin-2-one, monohydrochloride.

Solution (3R- (1 (R *), 3 α, 4 α)) - 1 - ((1-methyl-2-pyrrolidinyl) methyl) -3- (hydroxy) -1,3,4,5-tetrahydro -4- (4-methoxyphenyl) -1 - ((1-methyl- 2-pyrrolidinyl) methyl-6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.24 g, 0.54 mmol), acetic anhydride (0.27 g, 2.68 mmol) and 4-dimethylaminopyridine (0.07 g, 1.07 mmol) in dry dichloromethane (6 ml) was stirred at room temperature for 60 hours. The reaction mixture was then taken up with silica gel ( 60-200 mesh), poured onto a silica gel column and eluted with a mixture of 1-3% methanol in dichloromethane to give the title compound as a free base. viscous oil was dissolved in ether and treated with saturated ethereal hydrogen chloride. The white precipitate was recrystallized from toluene-hexane to obtain the title compound as a white solid (0.23 g), m.p. 158-162 ^C. .

[α] _D = +126.8 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 57.31; H 5.92; N, 5.14; Cl 6.51; F 10.46.

C ₂₆ H ₃₀ ClF ₃ N ₂ O ₄ ˙ 1.0 H ₂ O.

 Found,%: C 57.63; H 5.68; N, 5.23; Cl 6.34; F 10.21.

 PRI me R 8. (3R (1 (S *), 3,4)) - 3- (Acetyloxy) -1- (2- (dimethylamino) -3-phenylpropyl) -1.3 4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) S-2- (dimethylamino) -3-phenyl-1-propanol.

 To a solution of S-2-amino-3-phenyl-1-propanol (6.0 g, 4.0 mmol) and 37% aqueous formaldehyde (20 ml) in 200 ml of acetonitrile is added with stirring sodium cyanoborohydride (4.0 g, 64 mmol) in small portions. This mixture was stirred for 30 minutes, after which glacial acetic acid was added dropwise to the solution until it became neutral (according to pH paper). The mixture was stirred at room temperature for 2 hours with periodic addition of glacial acetic acid to maintain a neutral pH of the mixture. Then the reaction mixture was concentrated, and the residual oil was diluted with 2 N. sodium hydroxide solution (250 ml). The mixture was extracted with ethyl acetate three times, and the combined extracts were washed with 1N. potassium hydroxide solution and extracted three times with 1N. aqueous hydrochloric acid. The extracts were combined, dried over anhydrous magnesium sulfate and concentrated to give the title compound as a viscous oil (6.48 g).

 B) S-1-chloro-2- (dimethylamino) -3-phenylpropane, hydrochloride.

K S-2- (dimethylamino) -3-phenyl-1-propanol (3.0 g, 16.7 mmol) in 20 mL of chloroform at ⁰ ° C was added dropwise thionyl chloride (5.97 g, 50.2 mmol ) The reaction mixture was heated (reflux) to a boil for 2 hours and then evaporated to dryness under reduced pressure. The residue was recrystallized from acetone-ether to give the title compound as an off-white solid (2.38 g) with a melting temperature of ^about 167,5-168,5 C.

 C) (3R- (1 (S *), 3α, 4α)) - 3- (hydroxy) -1- (2- (dimethylamino) -3-phenylpropyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

Sodium hydride (0.22 g, 9.0 mmol) is added to the solution of (3R-cis) -3- (hydroxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2- it (1.05 g, 3.0 mmol) in 30 ml of dry dimethylformamide. This mixture was stirred at room temperature for 1 h, after which 0.89 g (4.5 mmol) of (S) -1-chloro-2- (dimethylamino) -3-phenylpropane hydrochloride was added and the mixture was heated to 85 ^about 2 hours. The reaction mixture was cooled, the reaction was quenched by the addition of water and extracted three times with ethyl acetate. The combined extracts were washed with a 10% aqueous solution of lithium chloride, brine and dried over anhydrous magnesium sulfate. After concentration, the crude product is chromatographed on a silica gel column and eluted with 10-30% ethyl acetate in hexane to give the title compound as a white foam (1.16 g).

 D) (3R- (1 (S *), 3α, 4 α)) - 3- (Acetyloxy) -1- (2-dimethylamino) -3-phenylpropyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

Solution (3R- (1 (S *), 3α, 4α)) - 3- (hydroxy) -1- (2- (dimethylamino) -3-phenylpropyl) -1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -6-trifluoromethyl) -2H-1-benzazepin-2-one (1.16 g, 2.26 mmol), acetic anhydride (1.16 g, 11.32 mmol) and 4-dimethylaminopyridine (0 55 g, 4.53 mmol) in dry dichloromethane (25 ml) was stirred at room temperature for 16 hours. The reaction mixture was taken up with silica gel (60-200 mesh), poured onto a silica gel column and eluted with 5-25% ethyl acetate in hexane to give the title compound as a free base (white foam). This free base is dissolved in ether and an excess of ethereal hydrogen chloride solution is added to give the title compound as a white solid (0.96 g), so pl. 144-147 ^about S.

[α] _D = +52.40 ^about (C = 1.0 mmol / l, in methanol).

 Calculated,%: C 61.56; H 5.92; N, 4.63; Cl 5.86; F 9.42.

C ₃₁ H ₃₄ ClF ₃ N ₂ O4 ˙ 0.76 H ₂ O.

 Found,%: C 61.60; H 6.00; N, 4.59; Cl 5.93; F 9.23.

 PRI me R 9. (3R- (1 (R *), 3 α, 4α)) - 3- (Acetyloxy) -1- (2- (dimethylamino) -3-phenylpropyl) -1.3 4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine -2-one, monohydrochloride.

 A) R-2- (dimethylamino) -3-phenyl-1-propanol.

 To a solution of S-2-amino-3-phenyl-1-propanol (6.0 g, 4.0 mmol) and 37% aqueous formaldehyde (20 ml) in 200 ml of acetonitrile is added with stirring sodium cyanoborohydride (4.0 g, 64 mmol) in small portions. This mixture was stirred for 30 minutes, after which glacial acetic acid was added dropwise to the solution until it became neutral (according to pH paper). The mixture was stirred at room temperature for 2 hours with periodic addition of glacial acetic acid to maintain a neutral pH of the mixture. Then the reaction mixture was concentrated, and the residual oil was diluted with 2 N. potassium hydroxide solution (250 ml). The mixture was extracted with ethyl acetate three times and the combined extracts washed with 1 N. potassium hydroxide solution and extracted three times with 1 N. hydrochloric acid solution. The acid extracts are combined, neutralized with solid potassium hydroxide and extracted three times with ethyl acetate. The extracts were combined, dried over anhydrous magnesium sulfate and concentrated to give the title compound as a viscous oil (6.23 g).

 B) R-1-chloro-2- (dimethylamino) -3-phenylpropane, hydrochloride.

To the R-2- (dimethylamino) -3-phenyl-1-propanol (3.0 g, 16.7 mmol) in 20 mL of chloroform at ⁰ ° C was added dropwise thionyl chloride (6.0 g, 50.2 mmol ) The reaction mixture was heated (reflux) to a boil for 2 hours and then evaporated to dryness under reduced pressure. The residue was recrystallized from acetone-ether to give the title compound as an off-white solid (2.27 g), mp. 170-171.5 ^about S.

 C) (3R- (1 (R *), 3α, 4α)) - 3- (hydroxy) -1- (2-dimethylamino) -3-phenylpropyl) -1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

Sodium hydride (0.13 g, 5.4 mmol) is added to the solution of (3R-cis) -3- (hydroxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2- it (0.70 g, 2.0 mmol) in 20 ml of dry dimethylformamide. The mixture was stirred at room temperature for 1 hour, after which 0.60 g (3.0 mmol) of (R) -1-chloro-2- (dimethylamino) -3-phenylpropane, and the mixture was heated to ⁸⁰ ° C for 2.5 hours. The reaction mixture was cooled, the reaction was quenched by the addition of water, and extracted three times with ethyl acetate. The combined extracts were washed with 10% aqueous lithium chloride and brine. Filter, dry over anhydrous magnesium sulfate and concentrate. The crude product is chromatographed on a silica gel column and eluted with 20-50% ethyl acetate in hexanes to give the title compound as a white foam (0.60 g).

 D) (3R- (1 (R *), 3α, 4α)) - 3- (acetyloxy) -1- (2-dimethylamino) -3-phenylpropyl) -1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

Solution (3R- (1 (R *), 3 α, 4 α)) - 3- (hydroxy) -1- (2- (dimethylamino) -3-phenylpropyl) -1,3,4,5-tetrahydro-4 - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.0 g, 1.95 mmol) of acetic anhydride (1.0 g, 9.8 mmol) and 4-dimethylaminopyridine (0.48 g, 3.90 mmol) in dry dichloromethane (20 ml) was stirred at room temperature for 14 hours. The reaction mixture was taken up with silica gel (60-200 mesh), poured onto a silica gel column and eluted with 5-25% mixture ethyl acetate in hexane to give the free base as a white foam. This free base is dissolved in ether and an excess of ethereal hydrogen chloride solution is added to give the title compound as a white solid (0.61 g), so pl. 146-150 ^about C.

[α] _D = +137.3 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 61.93; H 5.89; N 4.66; Cl 5.90; F 9.48.

C ₃₁ H ₃₄ ClF ₃ N ₂ O ₄ ˙ 0.56 H ₂ O.

 Found,%: C 62.02; H 6.21; N 4.67; Cl 5.83; F 9.33.

 PRI me R 10. (3R-cis) -1- (2- (dimethylamino) -2-methylpropyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

Cooking is carried out in an argon atmosphere. A stirred solution of (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (2.5 g, 7.12 mmol) in 75 ml of dimethylformamide is treated with 60% sodium hydride (0.3 g, 7.5 mmol) and stirred for 1 h. Dry toluene solution of 1-chloro-2- (dimethylamino) -2-methylpropane (isolated from 3.75 g (21.8 mmol) of the hydrochloride salt with potassium carbonate in toluene) and the mixture was heated in an oil bath at 71-78 ^{° C} for 1.25 hours. After cooling, dimethylformamide was removed on a rotary weight at a pressure of 0.2 mm Hg .art. The residue is shaken with 125 ml of ethyl acetate and 50 ml of water. The layers were separated and the organic phase was washed 2 times with water (50 ml), brine (25 ml), dried with magnesium sulfate and evaporated. The solid residue is suspended in ether, the evaporation is repeated and the solid is dried by pumping; weight 3.33 g. This amount is combined with 0.64 g of the product from the previous experiment, dissolved in ether, filtered to clear and evaporated. The solid residue (3.94 g) is shaken with 60 ml of ethyl acetate and 40 ml of water containing 17 ml of 1 N. of hydrochloric acid. The layers were separated and the organic layer was extracted with 40 ml of water. The combined aqueous phases are washed with ether (washing is poured), covered with 40 ml of ethyl acetate, 19 ml of 1N are added. sodium hydroxide solution, the mixture is shaken and separated. The aqueous phase is extracted with ethyl acetate (2 times 30 ml), the combined ethyl acetate layers are washed with 20 ml of brine, dried with magnesium sulfate and finally evaporated under a pressure of 0.2 mm to obtain 3.66 g of a solid. Subsequent crystallization from 25 ml of hot isopropanol gives a colorless material (free base of the compound; indicated in the header), weighing 2.36 g, mp 157-159 ^{° C} (sintered at 155 ° ^C).

 Calculated,%: C 63.98; H 6.49; N, 6.22; F 12.65.

C ₂₄ H ₂₉ F ₃ N ₂ O ₃ .

 Found,%: C 64.17; H 6.53; N, 6.08; F 12.93.

This base (2.34 g) in 50 ml of ethyl acetate is treated with 1.2 ml of 5 N. a solution of hydrogen chloride in ethanol, and the solvent is finally evaporated at 0.2 mm Hg The almost solid residue was triturated under a layer of ethyl ether and the evaporation was repeated, after drying after drying by pumping 2.67 g of the title compound as a colorless solid, mp 90-93 ^about C (foaming), sintering at 82 ^about C. [α] _D = +114 ^about (C = 1.00 mol / l, methanol).

 Calculated,%: C 58.12; H 6.30; N, 5.64; Cl 7.15.

C ₂₄ H ₂₉ F ₃ N ₂ O ₃ ˙ HCl ˙ 0.5 H ₂ O.

 Found,%: C 58.06; H 6.53; N, 5.37; Cl 7.00.

 PRI me R 11. (3R-cis) -1- (2-dimethylamino) -1-phenylethyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A, monohydrochloride.

A toluene solution of N, N-dimethyl-2-chloro-2-phenylethylamine is prepared by distributing 3.59 g of a hydrochloride salt (16.3 mmol) between 15 ml of toluene and 100 ml of an aqueous solution of sodium bicarbonate. The aqueous phase is washed with an additional amount (10 ml) of toluene, the combined organic phases are dried with magnesium sulfate and filtered. To a stirred suspension of 0.75 g of sodium hydride (15.6 mmol, 50% dispersion in oil) in 30 ml of dried dimethylformamide was added 5.0 g of (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (14.2 mmol) in one go, as a solid. The solution was stirred for 1 hour at room temperature, heated to ⁷⁰ ° C, and the toluene solution of N, N-dimethyl-2-chloro-2-phenylethylamine was added dropwise over 2 hours. A solution of 1 g of the above hydrochloride salt (4.5 mmol ) and 0.51 g of potassium tert-butoxide (4.5 mmol) are stirred in 5 ml of dimethylformamide for 2 minutes and added to the alkylation reaction mixture. The resulting solution was stirred at 70 ° C. ^for another 2.25 hours, and the reaction was quenched by the addition of an aqueous sodium bicarbonate solution. Solvents are removed under high vacuum with gentle heating. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate, the organic phase was washed with brine, dried with magnesium sulfate, filtered and evaporated to give a pale yellow foamy resin. The crude product was dissolved in 25 ml of ether, seeded with (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one and cooled rapidly to obtain ( after filtration) 0.25 g of isolated (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one. By evaporation of the mother liquor, 7.23 g of a foamy solid are obtained, which is chromatographed on silica gel (eluent: 2% methanol / 0.5% triethylamine / dichloromethane) to obtain 1.90 g of a pure, more mobile isomer (BPI) as a light yellow foamy solid matter. A solution of 0.41 g of pure BPI was dissolved in ether and treated with ether saturated with hydrogen chloride. The white solid is filtered off, washed twice with ether and dried in air to give 0.41 g of a white solid. This material was dissolved in a mixture of 2 ml of isopropanol / 6 ml of diisopropyl ether with heating, and the solution was filtered from a small amount of insoluble material. The filtrate was treated with hexane, and the resulting white solid was collected by filtration and dried, yielding 0.39 g of the title compound, so pl. 136-142 ^about S.

[α] _D = +146.2 ^about (C = 1 mol / l, methanol).

 Calculated,%: C 61.77; H 5.75; N, 5.14; Cl 6.51; F 10.47.

C ₂₈ H ₃₀ ClF ₃ N ₂ O ₃ ˙ 0.52 mol of H ₂ .

 Found,%: C 61.77; H 6.02; N, 5.26; Cl 6.46; F 10.63.

 PRI me R 12. (3R-cis) -1- (2- (dimethylamino) -1-phenylethyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer B, monohydrochloride.

Chromatography of (3R-cis) -1- (2-dimethylamino) -1-phenylethyl) 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H monohydrochloride -1-benzazepin-2-one, isomer A, no fractions containing the less mobile isomer (MPI) were obtained. Fractions containing MPI (contaminated with BPI and (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one) are combined and evaporated to obtain 3, 40 g of crude MPI. This material was rechromatographed on silica gel (eluent: 2% methanol / 0.5% triethylamine / dichloromethane) to give 0.81 g MPI containing trace amounts of BPI and a significant amount of (3R-cis) -3-hydroxy-4- (4 -methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one. (This material is chromatographed on six thin-layer preparative chromatography plates (eluent 5% methanol / dichloromethane), the main strip is removed, extracted twice with 5% methanol (1% triethylamine / dichloromethane, and the combined extracts are evaporated and run three times with carbon tetrachloride, to obtain 0.41 g of pure free base, the title compound This material was dissolved in ether, filtered through Celite to remove turbidity and ether saturated with hydrogen chloride was added. rdoe white substance is filtered, washed 2 times with ether and air dried to give 0.42 g of the title compound as a white solid with mp 165-171 ° ^C. [α] _D = + 221,8 ^about (C = 1 mol / L, methanol).

 Calculated,%: C 61.84; H 5.74; N, 5.15; Cl 6.51; F 0.48.

C ₂₈ H ₃₀ N ₂ O ₃ ClF ₃ ˙ 0.49 ˙ H ₂ O.

 Found,%: C 61.84; H 5.81; N, 5.07; Cl 6.12; F 10.18.

 PRI me R 13. (3R- (1 (S *), 3 α, 4 α)) - 3- (Acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) - 1- (2-pyrrolidinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) S-N- (benzyloxycarbonyl) -2-pyrrolidinemethanol.

Powdered, anhydrous potassium carbonate (41 g, 297 mmol) is added with stirring to a solution of 5-2-pyrrolidinemethanol (6 g, 59.32 mmol) in 20 ml of acetone. The mixture was cooled ^to 0 ° C and added dropwise benzyl chloroformate (6.94 mL, 118.6 mmol). After 40 minutes, the reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic extracts are combined, dried with magnesium sulfate and concentrated. The crude oil was subjected to silica gel column chromatography and eluted with 25% ethyl acetate in hexane to obtain 12.22 g of the title compound as a pale yellow oil.

 B) S-1- (benzyloxycarbonyl) -2- (bromomethyl) pyrrolidine.

 Triphenylphosphine (4.46 g, 17 mmol) and 5.64 g (17 mmol) of carbon tetrabromide are added to a solution of S-N- (benzyloxycarbonyl) -2-pyrrolidinemethanol (2 g, 8.5 mmol) in 100 ml of ether. This mixture was stirred at room temperature for 19 hours, cooled, and the precipitated solids were filtered off. The remaining solids are washed with hexane. The filtrate was concentrated and purified chromatographically on a column of silica gel. Elution with 10-20% ethyl acetate in hexane afforded the title compound (2.11 g) as a colorless oil.

 C) (3R- (1 (S *), 3α, 4α)) - 1- (benzyloxycarbonyl-2-pyrrolidinyl) methyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl ) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

To a suspension of sodium hydride (0.066 g, 2.7 mmol) in dimethylformamide (23 ml) was added (3R-cis) -3- (hydroxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1- benzazepin-2-one (0.8 g, 2.3 mmol). After 1 h at room temperature, 0.97 g (3.4 mmol) of (S) -1- (benzyloxycarbonyl) -2- (bromomethyl) pyrrolidine was added. The reaction mixture was heated at ⁶⁵ ° C for 2.5 h, then additional amount of sodium hydride (0.028 g, 1.14 mmol) and S-1- (benzyloxycarbonyl) -2- (brommetilamino) pyrrole (0.33 g, 1.14 mmol). After a further 1 h at 65 ° ^C, cooled, then diluted with water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with a 10% aqueous lithium chloride solution, dried with anhydrous magnesium sulfate and concentrated. The crude residue was chromatographed on a silica gel column and eluted with 20-40% ethyl acetate in hexane to give the title compound (0.8 g).

 D) (3R (1 (S *), 3 α, 4 α)) - 3-acetoxy-1 - ((1-benzyloxycarbonyl) -2-pyrrolidinyl) methyl) - 1,3,4,5-tetrahydro -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 To a solution of (3R (1 (S *), 3α, 4 α)) - 1 - ((1-benzyloxycarbonyl-2-pyrrolidinyl) methyl) -3-hydroxy-1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.14 g, 1.85 mmol) and acetic anhydride (0.87 g, 9.24 mmol) in dichloromethane (20 ml ) N, N-dimethylaminopyridine (0.45 g, 3.7 mmol) is added. The mixture was stirred at room temperature for 4 days, absorbed with silica gel (60 mesh), and flash chromatographed on a silica gel column. Elution with a mixture of 10-40% ethyl acetate in hexane afforded the title compound as a viscous oil (0.68 g).

 E) (3R- (1 (S *), 3α, 4α)) - 3- (acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (2-pyrrolidinyl) methyl ) -trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

Ammonium formate (0.23 g, 3.64 mmol) is added in one go to a catalyst suspension of 10% palladium on carbon (0.05 g) and (3R- (1 (S *), 3 α, 4 α)) - 3-acetoxy-1 - ((1-benzyloxycarbonyl-2-pyrrolidinyl) methyl) - 1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2 -one (0.48 g, 0.73 mmol) in 10 ml of methanol. The mixture is heated to boiling for 30 minutes, after which it is cooled and filtered through Celite. The remaining solid was washed with ethyl acetate. The filtrate was concentrated to obtain a white foam, which was dissolved in ether and treated with excess ether solution of hydrogen chloride. The solution was concentrated and crystallized from a mixture of toluene and hexane to give the title compound as an off-white solid (0.325 g), so pl. 217-219 ^about S.

[α] _D = +78.7 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 58.06; H 5.37; N, 5.42; Cl 6.86; F 11.02.

C ₂₅ H ₂₇ F ₃ N ₂ O ₄ ˙ HCl ˙ 0.29 H ₂ O
Found,%: C 58.37; H 5.37; N 5.54; Cl 7.05; F 10.58.

 PRI me R 14. (3R- (1 (S *), 3α, 4 α)) - 3- (Acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1 - ((1-methyl-2-pyrrolidinyl) methyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) S-N- (tert-butyloxycarbonyl) -2-pyrrolidinemethanol.

A solution of S-2-pyrrolidinemethanol (10 g, 100 mmol) in dry dichloromethane (250 ml) was treated at ^0-5 ° C was added dropwise a solution of di-tert-butyl dicarbonate (26 g, 119 mmol) in 100 ml of dichloromethane for 30 min After 6 hours at room temperature, the reaction mixture was concentrated to obtain the title compound (23.5 g) as a viscous oil.

 C) S-N-methyl-2-pyrrolidinemethanol.

A solution of crude SN- (tert-butoxycarbonyl) -2-pyrrolidinemethanol (17.5 g, 87 mmol) in dry tetrahydrofuran (100 ml) was added dropwise at 0-5 ^{° C} to a suspension of lithium aluminum hydride (11.4 g, 6.300 mmol) . The mixture was refluxed for 16 hours. It was then cooled in an ice water bath, and the excess hydride was destroyed by adding dropwise a saturated solution of sodium sulfate. The mixture was diluted with ethyl acetate and filtered through anhydrous magnesium sulfate. The solid residue was washed thoroughly with ethyl acetate. The combined filtrate was concentrated under reduced pressure to give a yellow oil which was distilled to obtain the title compound with boiling point ^of 97 C / 50 mmHg

 C) S-2- (chloromethyl) -1-methylpyrrolidine.

Thionyl chloride (3.28 mL, 45 mmol) was added dropwise to a solution of SN-methyl-2-pyrrolidinemethanol (1.73 g, 15 mmol) in 15 mL of chloroform at 0-5 ° ^C. The mixture was heated under reflux for 2 hours and then concentrated. The crude residue was crystallized from a mixture of acetone and ether to give the title compound (1.48 g) as a hydrochloride salt.

 D) (3R- (1 (S *), 3 α, 4 α)) - 1 - ((1-methyl-2-pyrrolidinyl) methyl) -3-hydroxy-1,3,4,5-tetrahydro - 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

To a suspension of sodium hydride (0.13 g, 5.4 mmol) in dimethylformamide (20 ml) was added (3R-cis) -3- (hydroxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H- 1-benzazepin-2-one (0.7 g, 2.0 mmol). The mixture was stirred for 1 hour at room temperature, cooled at ⁰ ° C and added the hydrochloride salt (S) -2- (chloromethyl) -1-methylpyrrolidine (0.52 g, 3 mmol). After stirring at room temperature for 1 h, additional sodium hydride (0.012 g, 0.5 mmol) was added. The mixture was stirred for another 3 hours and then diluted with water and extracted with ethyl acetate. The ethyl acetate extract was washed with a 10% aqueous solution of lithium chloride, dried over anhydrous magnesium sulfate and concentrated. The crude residue was chromatographed on a silica gel column and eluted with a mixture of 2-5% methanol in dichloromethane to give the title compound (0.65 g) as a white foam.

 E) (3R- (1 (S *), 3 α, 4α)) - 3- (Acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1 - ((1-methyl -2-pyrrolidinyl) methyl-6- (trifluoro-methyl) -2H-1-benzazepin-2-one, monohydrochloride.

N, N-Dimethylaminopyridine (0.41 g, 3.34 mmol) is added to the solution of (3R- (1 (S *), 3α, 4 α)) - 1 - ((1-methyl-2-pyrrolidinyl) methyl ) -3- (hydroxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1 - ((1-methyl-2-pyrrolidinyl) methyl-6- (trifluoromethyl) -2H-1- benzazepin-2-one (0.75 g, 1.67 mmol) and acetic anhydride (0.79 ml, 8.4 mmol) in dichloromethane (18 ml). The mixture was stirred at room temperature for 24 hours. coarse silica gel and flash chromatographed on a silica gel column, which was eluted with a mixture of 2-3% methanol in dichloromethane to give the title compound ix as the free base. The free base was dissolved in ether and treated with saturated ethereal hydrogen chloride. An additional 20 mL of ether and the precipitated salt was decanted and dried in vacuo at ⁷⁰ C to give the title compound as a white solid substance (0.536 g), with a mp of 151-154 ^about C.

[α] _D = +80.0 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 58.00; H 5.20; Cl 6.59; F 10.59.

C ₂₆ H ₂₉ F ₃ N ₂ O ₄ ˙ HCl ˙ 0.63 H ₂ O
Found,%: C 57.74; H 5.56; N, 4.93; Cl 7.01; F 10.16.

 PRI me R 15. (3R- (1 (R *), 3 α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- ( 2- pyrrolidinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) R-N- (Benzyloxycarbonyl) -2-pyrrolidinemethanol.

Benzyl ester are added dropwise at ⁰ ° C to the powder suspension of anhydrous potassium carbonate (13.7 g, 99 mmol) and (R) -2-pyrrolidinemethanol (2 g, 19.8 chloroformate (6 ml, 39.5 mmol) mmol) in 100 ml of acetone. After 1 h, the reaction mixture was diluted with water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts are dried with magnesium sulfate, filtered and concentrated. The crude oil is chromatographed on a silica gel column and eluted with 20-60% ethyl acetate in hexane to give the title compound (4.57 g).

 B) R-1- (benzyloxycarbonyl) -2- (bromomethyl) pyrrolidine.

 A solution of RN- (benzyloxycarbonyl) -2-pyrrolidinemethanol (4.55 g, 19.3 mmol, triphenylphosphine (10.2 g, 38.7 mmol) and carbon tetrabromide (12.8 g, 38.7 mmol) in 200 ml ether was stirred at room temperature overnight. The reaction mixture was diluted with hexane and filtered. The filtrate was concentrated and the residue was chromatographed on a silica gel column. Eluting with 5-10% ethyl acetate in hexane gave the title compound as a colorless solid (3.59 g )

 C) (3R- (1 (R *), 3α, 4α) -1- (Benzyloxycarbonyl-2-pyrrolidinyl) methyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methosiphenyl ) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

To a suspension of sodium hydride (0.25 g, 10.5 mmol) in dimethylformamide (70 ml) was added (3R-cis) -3- (hydroxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H- 1-benzazepin-2-one (2.46 g, 7 mmol). The mixture was stirred for 1 h at room temperature and 3 g (10.5 mmol) of (R) -1- (benzyloxycarbonyl) -2- (bromomethyl) pyrrolidine were added. The reaction mixture was heated at ⁸⁰ ° C for 4 h and an additional amount of methanol (0.08 g, 3.5 mmol). After another 2 hours at 80 ° ^C the mixture was cooled and then quenched with water. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with a 10% aqueous solution of lithium chloride, dried with anhydrous magnesium sulfate and concentrated. The crude residue was chromatographed on a silica gel column and eluted with 1% methanol in dichloromethane to give the title compound (4.32 g contaminated with unreacted (3R- (cis) -3- (hydroxy) -4- (methoxyphenyl) -6- ( trifluoromethyl) - 2H) -1-benzazepin-2-one.

 D) (3R- (1- (R *), 3 α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) 2 ) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

Ammonium formate (1.8 g, 28.3 mmol) is added in one go to the catalyst suspension - 10% palladium on coal (1 g and (3R (1 (R *), 3 α, 4 α)) - 1- ( (1-Benzyloxycar - bonyl-2-pyrrolidinyl) methyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2 -one (3.5 g, 5.66 mmol) in 60 ml of methanol. The mixture is refluxed for 90 minutes, cooled and filtered through Celite. The solid residue is washed with chloroform. The combined filtrates are concentrated and the residue is chromatographed on a silica gel column When eluting with a mixture of 3-10% methanol in d chloromethane gives the free base of the title compound. This free base is dissolved in ether and treated with an excess of ethereal hydrogen chloride solution. When the solution is concentrated under reduced pressure and finally under vacuum, the title compound is obtained as an off-white solid (0.21 g ), mp 147-151 ^about C.

[α] _D = +108.5 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 56.50; H 5.77; N, 5.73; Cl 7.25; F 11.66.

C ₂₃ H ₂₅ F ₃ N ₂ O ₃ ˙ HCl ˙ 1.0 H ₂ O
Found,%: C 56.76; H 5.74; N, 5.50; Cl 7.12; F 11.36.

 PRI me R 16. (3R- (1 (S *), 3 α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 1- ( 2- pyrrolidinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (3R- (1 (R *), 3 α, 4 α)) - 1 - ((benzyloxycarbonyl-2-pyrrolidinyl) methyl) -3-hydroxy-1,3,4,5-tetrahydro-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

To a suspension of sodium hydride (0.19 g, 4.8 mmol) in dimethylformamide (40 ml) was added (3R-cis) -3- (hydroxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H- 1-benzazepin-2-one (1.41 g, 4 mmol). After 1 h, added 1.7 g (6 mmol) (S) -1- (Benzyloxycarbonyl) -2- (bromomethyl) pyrrolidine and the mixture heated to ⁸⁰ ° C for 1.5 h. An additional amount of sodium hydride (0, 05 g, 2 mmol) and (3R-cis) -3- (hydroxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.57 g, 2 mmol). The reaction mixture is heated for another 2 hours, cooled, and the reaction is quenched by the addition of water. The mixture was extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with 10% aqueous lithium chloride, dried with magnesium sulfate and concentrated. The crude residue was chromatographed on a silica gel column and eluted with a mixture of 30-50% ethyl acetate in hexane to give the title compound (1.12 g) as a white foam.

 B) (3R- (1 (R *), 3α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

Ammonium formate (0.57 g, 9, mmol) is added to a catalyst suspension of -10% palladium on carbon (0.34 g) and (3R- (1 (S *), 3 α, 4α)) - 1 - (( 1-benzyloxycarbonyl-2-pyrrolidinyl) methyl) -3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine- 2-one (1.12 g, 1.82 mmol) in 40 ml of methanol. The mixture is heated to boiling for 30 minutes, cooled and filtered through anhydrous magnesium sulfate. The remaining solid was washed with ethyl acetate. The combined filtrate was concentrated, then chromatographed on a silica gel column. Elute 2-5% methanol in ethyl acetate and then 10% methanol in dichloromethane to give the title free base (0.72 g). This free base is dissolved in ethyl acetate and treated with excess ether solution of hydrogen chloride. The solution was concentrated and dried in vacuo at ⁷⁰ C to obtain the title compound (0.64 g), m.p. 159-163 ^about S.

[α] _D = +71.3 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 57.56; H 5.67; N, 5.84; Cl 7.39; F 11.88.

C ₂₃ H ₂₅ F ₃ N ₂ O ₃ ˙ HCl ˙ 0.5 H ₂ O
Found,%: C 57.34; H 5.84; N, 5.62; Cl 7.31; F 12.17.

 PRI me R 17. (3R-cis) -3- (acetyloxy) -1- (2- (dimethylamino) -2-methylpropyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl ) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

A stirred solution of 1.9 g (3.9 mmol) of monohydrochloride (3R-cis) -1- (2-methylpropyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one (see example 10). was heated in 50 ml of acetic anhydride, heated to 110-124 ^{° C} (bath temperature) in an oil-bath. Acetylation is relatively slow, and it is necessary to heat the mixture for about 4.25 hours before the starting material disappears (by thin layer chromatography analysis). In parallel, a by-product with a high Rf value is gradually formed during heating. After cooling, the mass of acetic anhydride is removed on a rotary evaporator at a pressure of 0.2 mm RT. Art. and residual oil (3.6 g) was dissolved in 10 ml of ethyl acetate. Since no crystallization occurs, ethyl acetate is evaporated and the oil is triturated under an ether layer to obtain a solid. Most of the ether is decanted off and the material is triturated under fresh ether and cooled overnight.

The colorless solid, which becomes jelly-like, is filtered under argon, washed with ether (hygroscopic), and dried in vacuo. When a solid does not contain a solvent, it loses its hygroscopicity and may be exposed to the atmosphere. Weight 1.23 g, so pl. 88-91 ^about C (bubbles) are sintered at 81 ^about C.

[Α] _D = +104 ^o (c = 1.0 mol / l, in methanol).

 Calculated,%: C 57.09; H 6.26; N, 5.12; Cl 6.48.

C ₂₆ H ₃₁ N ₂ O ₄ ˙HCl ˙H ₂ O
Found,%: C 57.46; H 6.46; N, 4.84; Cl 6.33.

 PRI me R 18. (3R-cis) -1- (1- (dimethylamino) methyl) propyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one, isomer B = monohydrochloride.

 A) (3R-cis) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

To a stirred solution, 10 g of (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (28.5 mmol) and 4.85 mmol of imidazole (71.2 mmol) in 10 ml of dry dimethylformamide at 35 ^o C is added 5.10 g tert-butyldimethylsilyl chloride. The solution was stirred overnight at ³⁵ ° C, cooled to room temperature and partitioned between ether and water. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated, yielding 14.2 g of the title compound as an amorphous solid, mp. 114-116 ^about S.

 B) (3R-cis) -3- (tert-butyldimethylsilyloxy) -1- (1-cyano) propyl) -4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

To a stirred suspension of sodium hydride (0.54 g, 11.2 mmol, 50% dispersion in oil) in dry dimethylformamide (10 ml), 4 g (3R-cis) -3- (tert-butyldimethylsilyloxy) are added in one go -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (8.6 mmol) in solid form. The solution was stirred for 30 minutes, 1.33 g (12.9 mmol) of pure 2-chlorobutyronitrile was added, the solution was heated to 75 ^° C for 1 hour. An additional 0.15 g of sodium hydride and 0.3 g of 2-chlorobutyronitrile were added, and the solution is heated to 75 ^about C for 45 minutes The solution was cooled with a unimolar solution of ammonium chloride, and dimethylformamide was removed in vacuo with gentle heating. The residue was partitioned between ether and a one-molar solution of ammonium chloride, the organic phase was washed with water and brine, dried with magnesium sulfate and evaporated to obtain 4.68 g of a brown gum. It was shown by thin-layer chromatography (eluent 50% ether in hexane) that the product is a 3: 2 mixture of diastereoisomers, the more mobile isomer has Rf = 0.63, and the less mobile isomer Rf = 0.56. Flash chromatography on silica gel (30% ether in hexane) gave the title compound (1.10 g), the more mobile isomer, as a white solid with mp. 54-57 ^about S.

 C) (3R-cis) -1- (1 - ((amino) methyl) propyl) -3- (tert-butyldimethylsilyloxy) - 1- (1-cyano) propyl) -4- (4-methoxyphenyl) -6- (trifluoro-methyl) -2H-1-benzazepin-2-one. A solution of 1.10 g of (3R-cis) -3- (tert-butyldimethylsilyloxy) -1- (1-cyano) propyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2 -one (2.06 mmol) and 0.27 g of the catalyst — rhodium on alumina — are hydrogenated in 100 ml of methanol saturated with ammonia at a pressure of 50 psi (3.5 ati) for 6 hours. 0.10 g of rhodium on alumina, the solution is again saturated with ammonia and hydrogenated at a pressure of 3.5 atm for an additional 2 hours. The solution is filtered through Celite, which is washed 2 times with methanol, and the combined filtrates are evaporated, yielding 1.17 g of a foamy solideschestva. Silica gel flash chromatography (2% methanol / 0.5% triethylamine / dichloromethane) gave the title compound as a gum (0.70 g).

 D) (3R-cis) -1- (1 - ((amino) methyl) propyl) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1 / benzene- zepin-2-one.

To 0.26g of solid sodium cyanoborohydride (4.2 mmol) at ⁰ ° C was added in small portions with stirring, a solution of 0.70 g of (3R-cis) -1- (1 - ((amino) methyl) propyl) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.3 mmol) and 1.2 ml of 37% aqueous formaldehyde in 10 ml of acetonitrile, after which pure acetic acid is added. The ice bath was removed, the solution was stirred for 2 hours and another 0.05 ml of acetic acid was added, and the solution was stirred for another 30 minutes. The solution was partitioned between ether and a 10% aqueous potassium carbonate solution, the ether layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 0.91 g of a thick oil. Silica gel flash chromatography (1% methanol / 0.2% triethylamine / dichloromethane) afforded the title compound as a clear resin (0.49 g).

 E) (3R-cis) -1- (1- (dimethylamino) methyl) propyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H -1-benzazepin-2-one, isomer B, monohydrochloride.

To a solution of 0.49 g of (3R-cis) -1- (1 - ((dimethylamino) methyl) propyl) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) - 2H-1-benzazepin-2-one (0.87 mmol) in 10 ml of dry dimethylformamide add 0.55 g of tetrabutylammonium fluoride trihydrate (1.74 mmol) in one go, as a solid. The solution was stirred for 20 minutes, partitioned between ether and water, and the organic layer was washed with brine, dried with magnesium sulfate and evaporated to give 0.49 g of a semi-solid. Using preparative thin layer chromatography (3 plates, eluent: 5% methanol in dichloromethane), 0.35 g of the title compound is obtained in the form of a free base — white crystals. This free base is suspended in ether, ethyl acetate is added until the substance is dissolved and then ether saturated with hydrogen chloride is added. The resulting white solid was quickly collected by filtration, washed with ether and dried in vacuo to give 0.24 g of the title compound as a white solid with melting point 144-148 ° ^C.

[α] _D = +89.60 ^about (C = 1 mol / l, in methanol).

 Calculated,%: C 56.96; H 6.38; N, 5.45; Cl 7.24; F 11.11.

C ₂₄ H ₃₀ ClF ₃ N ₂ O ₃ ˙1.06 ˙H ₂ O.

 Found,%: C 56.96; H 6.40; N 5.54; Cl 7.00; F 11.26.

 PRI me R 19. (3R-cis) -1- (1- (dimethylamino) methyl) propyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A, monohydrochloride.

 A) (3R-cis) -3- (tert-butyldimethylsilyloxy) -1- (1-cyano) propyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 No pure less mobile isomer (MPI) was obtained by chromatography of the nitrile mixture described for (3R-cis) -1- (1- (dimethylamino) methyl) propyl) -1,3,4,5-tetrahydro-3 - hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride (see example 18). The fractions containing MPI were combined and evaporated to give 1.91 g of a solid. This material was purified by flash chromatography on silica gel (25% ether in hexane) to give 1.21 g of almost pure MPI of the title compound as a white solid.

 B) (3R-cis) -1- (1 - ((amino) methyl) propyl-3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzase-pin -2-he.

 A solution of 1.21 g of (3R-cis) -3- (tert-butyldimethylsilyloxy (-1- (1-cyano) propyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine -2-one (2.27 mmol) and 0.30 g of catalyst — rhodium on alumina — in 75 ml of methanol saturated with ammonia, were hydrogenated at a pressure of 50 psi (3.5 atm) for 5 hours. The solution was filtered through Celite, which was washed 2 times with methanol, and the combined filtrates were evaporated, yielding 1.36 g of a crude solid as a clear gum.

 C) (3R-cis) -1- (1 - ((dimethylamino) methyl) propyl) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine- 2-he.

To 0.46g of solid sodium cyanoborohydride (7.26 mmol) at ⁰ ° C was added in small portions with stirring, a solution of 1.36 g of (3R-cis) -1- (1 - ((amino) methyl) propyl-3- ( tert-butyldimethylsyloxy) - 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (2.27 mmol) and 2.1 ml of 37% aqueous formaldehyde in 20 ml of acetonitrile, then pure acetic acid is added in. The ice bath is removed, the solution is stirred for 2 hours and another 0.15 ml of acetic acid is added, the solution is stirred for another 2 hours. The solution is partitioned between ether and 10% aqueous potassium carbonate solution, the company layer is washed with a 10% aqueous solution of potassium carbonate and brine, dried over anhydrous magnesium sulfate and evaporated, yielding 1.31 g of a clear oil. Flash chromatography on silica gel (1% methanol / 0.5% triethylamine / dichloromethane) gives 1.02 g of a white foamy solid containing the title compound This material was chromatographed on 6 preparative thin-layer plates (eluent 25% ethyl acetate in hexane) and a strip with Rf = 0.52 was cut out and extracted with a mixture of 5% methanol in dichloromethane. The extract was filtered and the filtrate was evaporated, yielding 0.44 g of the title compound as a light brown gum.

 D) (3R-cis) -1- (1- (dimethylamino) methyl) propyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H -1-benzazepin-2-one, isomer A, monohydrochloride.

To a solution of 0.44 g of (3R-cis) -3- (tert-butyldimethylsilyloxy) -1- (1- ((dimethylamino) methyl) propyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) - 2H-1-benzazepin-2-one (0.78 mmol) in 10 ml of dried dimethylformamide is added in one go 0.49 g of tetrabutylammonium fluoride trihydrate (1.56 mmol) in solid form. The solution was stirred for 25 minutes, partitioned between ether and water, the organic phase was washed with brine, dried with magnesium sulfate and evaporated to give 0.45 g of a brown gum. Using preparative thin layer chromatography (on 3 preparative thin layer plates, eluent 2% methanol in dichloromethane), 0.36 g of the free base — the title compound as a white crystalline substance — is obtained. This free base is dissolved in ether, the solution is filtered through Celite and ether saturated with hydrogen chloride is added to the filtrate, the white solid formed is collected by filtration, washed with ether 2 times and dried in vacuo to give 0.35 g of the title compound as white solid substance with so pl. 126-131 ^about S.

[α] _D = +106.8 ^about (C = 1 mol / l, in methanol).

Calculated,%: C 57.54; H 6.35; N 5.59; Cl 7.08; F 11.38
C ₂₄ H ₃₀ ClF ₃ N ₂ O ₃ ˙ 0.78 ˙ H ₂ O
Found,%: C 57.54; H 6.39; N, 5.64; Cl 6.96; F 11.09.

 PRI me R 20. (3R-cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (1-methyl) -2- (methylamino) ethyl ) -6- (trifluoromethyl) - 2H-1-benzazepin-2-one, isomer B monohydrochloride.

 A) (3R-cis) -3- (tert-butyldimethylsilyloxy) -1- (1-cyano) ethyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one .

To a stirred solution of 4 g of (3R-cis) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (8.6 mmol, see Example 18) 380 mg of sodium hydride (9.5 mmol, 60% dispersion in oil) are added in dry dimethylformamide (40 ml). The solution was stirred for 30 minutes at room temperature and 0.68 ml (8.66 mmol) of pure 2-chloropropionitrile was added. The solution was heated ^to 50 ° C for 1 hour. An additional 0.02 g of sodium hydride and 0.07 ml of 2-chloropropionitrile and the solution was heated ^at 50 ° C for 3 hours. The solution was cooled to room temperature, concentrated in vacuo, to remove dimethylformamide and a brown residue partitioned between ethyl acetate and water. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated, and the residue is taken up on a silica gel column. Elution with a mixture of 5% ethyl acetate in hexane gives 1.76 g of the more mobile isomer of the title compound and 1.0 g of the less mobile isomer.

 B) (3R-cis) -1- (1 - ((amino) methyl) ethyl) -3- (tert-butyldimethylsilyloxy) - 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzaz- pin-2-one.

A solution of 0.8 g of (3R-cis) -3- (tert-butyldimethylsilyloxy) -1- (1-cyano) ethyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H) -1-benzene- zepin-2-one (1.5 mmol) in 100 ml of methanol saturated with ammonia at ⁰ ° C for 5 minutes, and added 0.2 g of catalyst - 5% rhodium on alumina. The solution was hydrogenated at a pressure of 45 psi (3.15 ati) for 1.5 hours. An additional 0.10 g of catalyst was added and the solution was again hydrogenated at a pressure of 3.8 ati for an additional 1 hour. The mixture was filtered through a pad. Celite, which was washed with methanol and the combined filtrates, was evaporated, yielding 0.75 g of the title compound.

 C) (3R-cis) -1- (1 - ((trifluoroacetylamino) methyl) ethyl) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine- 2-he.

 To a solution of (3R-cis) -1- (1 - ((amino) methyl) ethyl) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine- 2-one (0.76 g, 1.46 mmol) and pyridine (0.37 ml, 4.66 mmol) in 10 ml of dichloromethane add a solution of trifluoroacetic anhydride (0.41 ml, 2.91 mmol) in 5 ml of dichloromethane for 2 minutes, and the solution was stirred at room temperature overnight. More pyridine (0.37 ml, 4.66 mmol) and trifluoroacetic anhydride (0.41 ml, 2.91 mmol) in 5 ml of dichloromethane were added for 2 minutes, and the solution was stirred for 20 minutes. The solution was extracted with water and brine, dried with magnesium sulfate and evaporated to give 0.77 g of the title compound as a red oil.

 D) (3R-cis) -1- (1 - (((trifluoroacetyl) methylamino) methyl) ethyl)) - 3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H- 1-benzazepin-2-one.

To a solution of (3R-cis) -1- (1 - ((trifluoroacetylamino) methyl) ethyl-3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2 -one (570 mg, 0.94 mmol) in 5 ml of dried dimethylformamide add 44.9 mg of sodium hydride (1.12 mmol, 60% dispersion in oil). The solution is stirred for 30 minutes at room temperature, add 0.07 ml (1.12 mmol) of methyl iodide, and the solution is heated to 50 ° ^C. for 1 hour. An additional 0.02 g of sodium hydride and 0.07 ml of 2-chloropropionitrile are added and the solution is stirred for 2 hours at room temperature. tilatsetatom and water. The organic phase was washed with water and brine, dried with magnesium sulfate and evaporated to give 450 mg of the title compound as a red oil.

 E) (3R-cis) -1- (1 - ((methylamino) methyl) ethyl) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine- 2-he.

 Mixture of (3R-cis) -1- (1 - (((trifluoroacetyl) methylamino) methyl) ethyl) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1 - benzazepin-2-one (450 mg, 0.72 mmol) and sodium carbonate (0.5 g, 4.72 mmol) in 20 ml of methanol are refluxed overnight. The reaction mixture was cooled to room temperature and evaporated, the residue being partitioned between dichloromethane and water, the organic phase was washed with water and brine, dried with magnesium sulfate and evaporated. The residue was purified by preparative thin layer chromatography on 3 silica gel plates which eluted with 5% methanol in dichloromethane. Strips of the product are cut out and extracted with a mixture of 5% methanol: 0.5% triethylamine in dichloromethane. The mixture was filtered through a pad of Celite, which was washed with dichloromethane and the combined filtrates were evaporated. The residue was dispersed with toluene to give 230 mg of the title compound as a yellow oil.

 F) (3R-cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (1-methyl-2- (methylamino) ethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer B monohydrochloride.

To a solution of (3R-cis) -1- (1 - ((methylamino) methyl) ethyl) -3- (tert-butyldimethylsilyloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine- 2-one (1.2 g, 2.24 mmol) in 50 ml of dried dimethylformamide add 1.06 g of tetrabutylammonium fluoride trihydrate (3.36 mmol). The solution was stirred overnight, evaporated and the residue partitioned between dichloromethane and water. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated, yielding 0.86 g of a yellow oil. The residue was purified on 4 preparative silica gel plates, which were eluted with 10% methanol in dichloromethane. Strips of product are cut out and extracted with a mixture of 15% methanol: 0.5% triethylamine in dichloromethane. The substance is dissolved in ether, and ether saturated with hydrogen chloride is added to the solution. The white solid obtained by filtration was washed with ether to give 0.320 g of a pure title compound, mp. 178-180 ^about S.

[α] _D = +63.9 ^about (C = 1 mol / l, in ethanol).

 Calculated,%: C 55.45; H 5.90; N, 5.73; Cl 7.94; F 11.61.

C ₂₂ H ₂₅ F ₃ N ₂ O ₃ ˙ HCl ˙ 0.98 H ₂ O.

 Found,%: C 55.45; H 5.91; N, 5.88; Cl 7.44; F 11.96.

 PRI me R 21. (cis) -1- (2-aminophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl-3-methyl-6- (trifluoromethyl) -2H-1 -benzazepin-2-one, monohydrochloride.

 A) (cis) -1- (2-Nitrophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepine-2- he.

1.0 g (2.86 mmol) (cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) 3-methyl-2-oxo-6- (trifluoromethyl) -2H- are added. 1-benzazepin-2-one to a solution of 125 mg of sodium hydride (3.15 mmol, 60% dispersion in oil) in 5 ml of dry dimethylformamide. The solution was stirred for 35 minutes at room temperature, and 0.32 ml (3.0 mmol) of pure 2-fluoronitrobenzene was added dropwise. The solution was stirred for 105 minutes at room temperature and heated to 45 ^{° C} for 40 min. The solvent was removed under high vacuum with gentle heating and the residue was partitioned between ether and a unimolar solution of ammonium chloride. The organic phase is washed with water (twice) and brine, dried and evaporated to give a yellow solid foam, which is dissolved in 25 ml of ether. After adding 175 ml of hexane and cooling overnight, 780 mg of the title compound A (58%) are obtained as yellow crystals.

 B) (cis) -1- (2-aminophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-methyl-6- (trifluoromethyl) -2H-1-benzazepine-2- he, monohydrochloride.

A solution of 0.73 g (1.55 mmol) of the title A substance and 146 mg of a catalyst — 10% palladium on charcoal in 110 ml of absolute ethanol was hydrogenated for 4.25 hours and filtered through Celite. Celite was washed 2 times with ethanol and the combined filtrates were concentrated. The residue was dissolved twice in carbon tetrachloride and evaporated, yielding 0.73 g of a white solid foam. According to NMR analysis on 1H and C13 nuclei, the product is an almost pure free base. The residue was dissolved in 50 ml of ether and filtered from the turbidity through Celite. After the addition of ethereal hydrogen chloride and incubation for 30 min the white precipitate was collected by filtration, washed 2 times with ether and dried in vacuo at ⁷⁵ ° C for a few days to at-luchit the title compound (0.58 g, 79 %) in the form of a white solid powder with so pl. 165-170 ^about C.

 Calculated,%: C 63.00; H 5.13; N, 5.88; Cl 6.69; F 11.96.

C ₂₅ H ₂₃ F ₃ N ₂ O ₂ ˙ 0.9 HCl ˙ 0.19 H ₂ O.

 Found,%: C 63.00; H 4.87; N, 6.03; Cl 6.55; F 11.79.

 PRI me R 22. (3R-cis) -1- (2-Dimethylamino) phenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-hydroxy-6- (trifluoromethyl ) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (3R-cis) -1- (2-Nitrophenyl) -1,3,4,5-tetrahydro-4- (4-methosiphenyl) -3-hydroxy-6- (trifluoromethyl) -2H-1-benzazepine- 2-he.

 To a solution of 2.0 g (5.69 mmol) (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one in 10 ml dry dimethylformamide was added 230 mg of sodium hydride (5.69 mmol, 60% dispersion in oil). The solution was stirred for 60 minutes at room temperature and a solution of 1.2 ml (11.38 mmol) of pure 1-fluoro-2-nitrobenzene in 5 ml of dimethylformamide was added dropwise for 2 hours. The reaction mixture was stirred overnight at room temperature, concentrated in vacuo to remove dimethylformamide and the residue was partitioned between ethyl acetate and unimolar hydrochloric acid. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated to give a yellow oil. This oil is dissolved in warm ethyl acetate, the yellow solid crystallizing from the solution is filtered off and washed with cold ethyl acetate. 1.68 g (63%) of the title compound A are obtained.

 B) (3R-cis) -1- (2-nitrophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-acetyloxy-6- (trifluoromethyl) -2H-1-benzazepine- 2-he.

 To a stirred solution of the substance from title A (1.68 g, 3.56 mmol) and 4-dimethylaminopyridine (50 mg) in tetrahydrofuran (50 ml) was added pyridine (0.32 ml, 3.92 mmol) and then acetic anhydride ( 0.44 ml, 4.63 mmol). The mixture was stirred at room temperature overnight. The solution was partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (3 times 50 ml). The combined organic phases are washed with water, with a normal sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give 0.85 g (46%) of the title compound B as a yellow solid.

 C) (3R-cis) -1- (2-aminophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-acetyloxy-6- (trifluoromethyl) -2H-1-benzazepine- 2-he.

 To a solution of 0.85 g (1.65 mmol) of the substance indicated in heading B in 100 ml of acetonitrile was added 0.2 g of a catalyst — 10% palladium on charcoal. The solution was hydrogenated under a pressure of 3.5 atm for 3 hours. The mixture was filtered through a pad of Celite. The celite was washed with acetonitrile and the combined filtrates were evaporated, yielding 0.60 g (75%) of the title compound C.

 D) (3R-cis) -1- (2-dimethylaminophenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-acetyloxy-6- (trifluoromethyl) -2H-1-benzaz- pin-2-one, monohydrochloride.

 To a solid sodium cyanoborohydride (62 mg, 0.98 mmol) was added a solution of 120 mg (0.25 mmol) of the compound from heading C and 0.6 ml of 37% formaldehyde in 5 ml of acetonitrile. The reaction mixture was stirred at room temperature for 5 minutes, after which 0.1 ml of acetic acid was added. After 2 hours, another 0.1 ml of acetic acid was added. The solution was partitioned between ethyl acetate and an aqueous solution of potassium carbonate. The organic phase is washed with an aqueous solution of potassium carbonate, water and brine, dried over magnesium sulfate and evaporated. The residue was dissolved in ether and after adding an ethereal solution of hydrogen chloride, a white solid compound was obtained. According to 1H NMR analysis, the acetyl group is partially hydrolyzed.

 E) (3R-cis) -1- (2- (dimethylamino) phenyl) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-hydroxy-6- (trifluoromethyl) -2H-1 -benzase-pin-2-one, monohydrochloride.

A mixture of the title compound D (420 mg, 0.79 mmol) and potassium carbonate (0.5 g, 4.72 mmol) in 30 ml of methanol was refluxed for 5 hours under argon. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue was extracted with dichloromethane. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated. The residue was purified by preparative thin layer chromatography on 4 silica gel plates, which were eluted with a 1: 1 mixture of ethyl acetate and hexane. Strips of product are cut out and extracted with dichloromethane. The combined filtrates were evaporated. The yellow solid was dissolved in ether and ether saturated with hydrogen chloride was added to the solution. A light yellow solid is filtered off and washed with ether to give 302 mg (74%) of the pure title compound, mp. 217-220 ^about C.

[α] _D = +243.4 ^about (C = 1 mol / d, in ethanol).

 Calculated,%: C 60.07; H 5.31; N, 5.38; Cl 6.81; F 10.96.

C ₂₆ H ₂₅ F ₃ N ₂ O ₃ ˙ HCl ˙ 0.72 H ₂ O
Found,%: C 60.07; H 5.27; N, 5.18; Cl 6.89; F 10.62.

 PRI me R 23. (3R-cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-hydroxy-1- (2-pyridinylmethyl) -6- (trifluoromethyl) - 2H-1-benzazepin-2-one, monohydrochloride.

 A stirred solution of 5.0 g (14.2 mmol) (3R-cis) -4- (4-methoxyphenyl) -3-hydroxy-6- (trifluoromethyl) -2H-1-benzazepin-2-one in 150 ml of butanone is treated 2.8 g (17.1 mmol) of 2-chloromethylpyridine hydrochloride and 5.0 g (36.2 mmol) of powdered potassium carbonate and refluxed overnight. According to thin-layer chromatography (95: 5 mixture of methylene chloride: methanol), the reaction is complete. After combining with previous experience in a volume of 0.5 g, the solids are filtered off, washed with butane, and the mass of solvent is removed on a rotary evaporator. The residue is shaken with 150 ml of ethyl acetate and 50 ml of water, the layers are separated and the organic phase is washed with 50 ml of water, 50 ml of brine, dried with magnesium sulfate and the solvent is finally evaporated at a pressure of 0.2 mm Hg. 7.3 g of a light yellow foamy residue are obtained. The residue after aging on Saturday and Sunday is dissolved in ether, filtered to remove insoluble orange material, evaporated and dried by pumping, to obtain 6.9 g of a light yellow brittle foam. According to thin-layer chromatography (TLC) Rf = 0.65 (eluent is a mixture of 95: 5 methylene chloride: methanol).

The specified base in 50 ml of methanol is treated with 3.5 ml of a solution of hydrogen chloride (5 N.) in ethanol and the solvent is finally evaporated at 0.2 mm RT. Art. Partially the solid residue is triturated under an ether layer and evaporation is repeated, yielding 8.3 g of a light yellow solid after drying with pumping. Subsequent crystallization from 90 ml of hot isopropane gives 6.95 g (93%) of a colorless product with so pl. 184-186 ^{° C} (foaming).

[α] _D = +97.0 ^about (C = 1 mol / l, in methanol).

 Calculated,%: C 58.54; H 4.81; N, 5.69; Cl 7.20.

C ₂₄ H ₂₁ F ₃ N ₂ O ₃ HCl ˙ 0.75 H ₂ O.

 Found,%: C 58.46; H 5.15; N, 5.34; Cl 7.24.

 PRI me R 24. (3R-cis) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -3-hydroxy-1- (2-piperidinylmethyl) -6- (trifluoromethyl) - 2H-1-benzazepin-2-one, monohydrochloride, isomer A.

A solution of 3.00 g (6.09 mmol) of the substance indicated in the heading of Example 23 in 200 ml of ethanol is treated with 0.30 g of platinum dioxide and placed for 2 hours in a Parr autoclave under a hydrogen pressure of 3.5 ati, according to TLC in at this point, the restoration of the pyridyl group is completed. The catalyst was filtered off under nitrogen and the solvent was evaporated to give a solid residue. This residue was dissolved in 30 ml of acetonitrile and diluted with 330 ml of ether to give a solid. The mixture was cooled overnight and filtered, yielding 1.29 g (43%) of isomer A with mp. 177-180 ^C. Isomer A was dissolved in 20 ml of hot isopropanol, filtered over a mesh filter (to remove traces of catalyst), cooled overnight and filtered to give 0.72 g of nearly colorless solid, [α] _D = +112 ^o (C = 1 mol / L, in methanol). After recrystallization from 18 ml of hot isopropanol, the weight of the product is 0.63 g (21%), so pl. 177-180 ^о С, [α] _D = +113 ^о (С = 1 mol / L, in methanol), (TLC): Rf = 0.59 (eluent is a mixture of 80:20 methylene chloride: methanol).

 Calculated,%: C 58.89; H 5.87; N, 5.72; Cl 7.24.

C ₂₄ H ₂₇ F ₃ N ₂ O ₃ HCl ˙ 0.25 H ₂ O.

 Found,%: C 58.82; H 5.90; N, 5.68; Cl 7.23.

 (3R-cis) -1,3,4,5-tetrahydro-4- (4-label-siphenyl) -3-hydroxy-1- (2-piperidinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepine- 2-one, monohydrochloride, isomer B.

Upon evaporation of the filtrate obtained during the first crystallization of isomer A, 1.46 g of crude isomer B are obtained. After conversion to the free base, followed by chromatography on a column of 35 g of silica gel (eluent is a 15: 1 mixture of methylene chloride and methanol), 0 48 g of pure isomer 7. This material is dissolved in 5 ml of chloroform and treated with 0.22 ml of an alcoholic 5.1 N solution of hydrogen chloride in 3 ml of chloroform. Removing the solvent in vacuo gave a solid which was triturated with ether to give 0.54 g of a product with mp 130-140 ^о С, [α] _D = +66 ^о (С = 1 mol / l, in methanol).

 Calculated,%: C 56.80; H 6.05; N 5.52; Cl 6.98.

C ₂₄ H ₂₇ F ₃ N ₂ O ₃ ˙HCl ˙1.25 H ₂ O.

 Found,%: C 56.77; H 5.77; N, 5.39; Cl 6.93.

 PRI me R 25. (3R- (1 (R *), 3 α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 1- ( 3- piperidinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

A) (3R- (1 (S *), 3 α, 4 α)) - 1 - ((Benzyl-2-pyrrolidinyl) methyl-3-hydroxy-1,3,4,5-tetrahydro-ro- 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one and
B) (3R- (1 (R *), 3 α, 4 α)) - 1 - ((Benzyl-3-pyrrolidinyl) methyl-3-hydroxy-1,3,4,5-tetra-hydro- 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

Sodium hydride (1.44 g, 59.9 mmol) is added with stirring to a solution of (3R) -cis) -3- (hydroxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one (10 g, 28.5 mmol) in dried dimethylformamide (250 ml). After 1 h at room temperature, the mixture was cooled ^to 0 ° C and added in one portion 7.36 g (30 mmol) (S) -1- (benzyl-2- (chloromethyl) pyrrolidine. The mixture was warmed to room temperature and stirred for 4 hours, The mixture was diluted with saturated aqueous potassium bicarbonate and extracted three times with ethyl acetate.The combined ethyl acetate extracts were washed with 10% aqueous sodium chloride, dried with sodium sulfate, filtered and concentrated. The orange solid was dissolved in a minimum amount of 0.5 n hydrochloric acid and extracted 3 times with ether to remove unreacted (3R-cis) -3- (hydroxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1- benzazepin-2-one. Solid sodium chloride is added and the aqueous layer is extracted 3 times with ethyl acetate. The combined extracts are dried with magnesium sulfate, filtered and concentrated. The crude compounds A and B are obtained, which are indicated in the title, as pale orange solid. Adducts of these compounds A and B cannot be separated at this stage, and they were taken to the next stage without further purification and.

C) (3R- (1 (S *), 3 α, 4α)) - 1 - ((2-pyrrolidinyl) methyl-3-hydroxy-1,3,4,5-tetrahydro-4- (4- methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one and
D) (3R- (1 (R *), 3α, 4α)) - 1 - ((3-piperidinyl) methyl-3-hydroxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 Ammonium formate (9.58 g, 151.9 mmol) is added to a suspension of 10% palladium on carbon (3.7 g) and a mixture of the compounds of headings A and B (18.5 g, 33 mmol) in 350 ml of anhydrous methanol in argon atmosphere. This mixture is refluxed for 5 hours, cooled and filtered through anhydrous magnesium sulfate. The remaining solid is washed with methanol. The filtrate is concentrated, dissolved in a minimum amount of water and washed three times with ether. The aqueous layer is made basic with aqueous potassium bicarbonate and extracted with 3 times with ethyl acetate. rinse with water, dry with magnesium sulfate, filter and concentrate. A mixture of the title compounds C and D is obtained as a light yellow foam (10.89 g, 76%). The isomers of these compounds cannot be separated and they were taken the next step without further purification.

E) (3R- (1 (S *), 3α, 4 α)) - 1- (Benzyloxycarbonyl-2-pyrrolidinyl) methyl-3-hydroxy-1,3, 4,5-tetrahydro-4- (4-methoxyphenyl ) -6- (trifluoromethyl) -2H-1-benzazepin-2-one and
F) (3R- (1 (R *), 3α, 4α)) - 1 - ((Benzyloxycarbonyl-3-piperidinyl) methyl-3-hydroxy-1,3, 4,5-tetrahydro-4- (4-methoxyphenyl ) -6- (trifluoromethyl-2H-1-benzazepin-2-one.

 To a mixture of the compounds of headings C and D (7.07 g, 16.3 mmol) in 1,4-dioxane (80 ml) and a saturated aqueous solution of potassium hydrogen carbonate (30 ml), benzyl chloroformate is added dropwise at room temperature (5 84 g, 32.5 mmol). The reaction mixture was immediately diluted with water and extracted 3 times with ethyl acetate. The combined extract was washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude yellow liquid was chromatographed on a silica gel column and eluted with 15-30% ethyl acetate in hexane to give the title compound E (7.89 g, 85%); Rf = 0.38 (silica gel, 50% ethyl acetate in hexane) and the title compound F (0.87 g, 9.4); Rf = 0.50 (silica gel, 50% ethyl acetate in hexane).

 G) (3R- (1 (R *), 3α, 4 α) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (3-piperidinyl) -6- (trifluoromethyl) -2H-1-benzase-pin-2-one, monohydrochloride.

To a solution of the title compound F (800 mg, 1.41 mmol) in 25 ml of ethyl acetate and 1 ml of trifluoroacetic acid, 160 mg of palladium hydroxide on carbon are added with stirring. The reaction flask was filled with hydrogen from a balloon. This flask is evacuated under reduced pressure and filled with hydrogen (3 times). The mixture was then stirred at room temperature overnight until hydrogen was removed, and anhydrous magnesium sulfate was added. Solids are removed by filtration and washed well with ethyl acetate. The filtrate is washed with an aqueous solution of potassium hydrogen carbonate (3 times). The combined aqueous layers were extracted with ethyl acetate and the organic extracts were combined, dried over magnesium sulfate, filtered and concentrated. The crude residue was triturated with 20 ml of ether and the precipitated free amine was filtered off, collected and dried to obtain 420 mg of a white solid, which was dissolved in 5 ml of methylene chloride and 5 ml of an ethereal HCl solution was added. The solution was concentrated under reduced pressure and finally in vacuo to give the title compound (450 mg, 68%) as a white solid with mp. 183-188 ^about S.

[Α] _D = +102,6 ^o (C = 1 mol / l, in methanol).

 Calculated,%: C 56.51; H 5.77; N, 5.73; Cl 7.25.

C ₂₃ H ₂₅ F ₃ N ₂ O ₃ ˙HCl ˙H ₂ O.

 Found,%: C 56.58; H 5.75; N 5.53; Cl 7.02.

 PRI me R 26. (3R- (1 (R *), 3 α, 4α) -3-acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- ( 3-piperidinyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (3R- (1 (R *), 3 α, 4α)) 1- (benzyloxycarbonyl-3-piperidinyl) -3-acetyloxy-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-1-benzazepin-2-one.

To a solution of the compound of Example 25, F (880 mg, 1.53 mmol) in 20 ml of ethyl acetate, 700 ml of acetyl chloride was added dropwise. The reaction mixture was heated at 70 ° ^C for one day, after which it was cooled, the excess of acetyl chloride were destroyed by the addition of 2 ml of methanol. The mixture was diluted with ethyl acetate and washed 3 times with an aqueous solution of potassium hydrogen carbonate. The combined aqueous wash was extracted 1 time with ethyl acetate. The organic extracts were combined, dried with magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound A (920 mg, 100%) as a white foam.

 B) (3R- (1 (R *), 3α, 4α)) - 3-acetyloxy) -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (3-piperidinyl) -6 - (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

To a solution of the title compound A (920 mg, 1.53 mmol) in 25 ml of ethyl acetate and 1 ml of trifluoroacetic acid, 200 mg of Pearlman catalyst palladium-carbon on carbon are added with stirring. The reaction flask is connected to a cylinder filled with hydrogen. This flask is evacuated under reduced pressure and filled with hydrogen from a balloon (3 times). The mixture was then stirred at room temperature overnight, after which the balloon was removed. Anhydrous magnesium sulfate was added to the reaction mixture and the mixture was filtered through a pad of magnesium sulfate. The solids are washed well with ethyl acetate. The filtrate is washed 3 times with an aqueous solution of potassium hydrogen carbonate. The combined aqueous layers were extracted 2 times with ethyl acetate. The organic extracts are combined, dried with magnesium sulfate, filtered and concentrated. The brown oily residue (770 mg) was chromatographed on a silica gel column (pretreated with 1%) triethylamine and eluted with 5% methanol in ethyl acetate to give 430 ml of the free base as a white foam. This free amine is dissolved in methylene chloride and an excess of ethereal HCl solution is added. The solution was concentrated under reduced pressure to obtain 420 mg of the title compound (65%) as a white solid, mp. 177-180 ^about S.

[Α] _D = +107,9 ^o (C = 1, methanol).

 Calculated,%: C 56.91; H 5.66; N, 5.31; Cl 6.72; F 10.80.

C ₂₅ H ₂₇ F ₃ N ₂ O ₄ ˙ HCl ˙ 0.81 H ₂ O.

 Found,%: C 56.84; H 5.67; N, 5.38; Cl 6.41; F 10.79.

 PRI me R 27. (3R- (1 (S *), 3 α, 4 α)) - 6-Chloro-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxy - phenyl) -1- (2-pyrrolidinylmethyl) -2H-1-benzazepin-2-one.

 A) S-N-tert-butoxycarbonyl-2-pyrrolidinomethanol.

 S-2-pyrrolidinemethanol (15 g, 148.3 mmol) and di-tert-butyl dicarbonate (40 g, 178 mmol) in 500 ml of methylene chloride were stirred for 5 hours at room temperature. The solvent was evaporated under reduced pressure, and the crude product was converted to the next step (B) without further purification.

 B) S-N-tert-butoxycarbonyl- (bromomethyl) pyrrolidine.

 The title compound A (29.8 g, 148.3 mmol), triphenylphosphine (77.8 g, 297 mmol) and carbon tetrabromide (99 g, 297 mmol) in 1000 ml of ether were stirred at room temperature for 18 hours. The solid precipitate was removed by filtration and the solids were washed well with hexane. By concentrating the filtrate, a yellow liquid is obtained, which, after chromatography on a silica gel column and elution with 0-5% ethyl acetate in hexane, gives 17.49 g of the title compound B (45%) as a colorless liquid.

 C) (3R- (1 (S *), 3 a, 4 a)) - 1 - ((tert-butoxycarbonyl-2-pyrrolidinyl) methyl) -3-hydroxy-1,3,4,5-tetrahydro-4 - (4-methoxyphenyl) -6-trifluoromethyl) -2H-1-benzazepin-2-one.

(cis) -6-Chloro-4- (4-methoxyphenyl) -3-hydroxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (3.0 g, 9.44 mmol) is added to a suspension of sodium hydride (0.27 g, 11.33 mmol) in 95 ml of dimethylformamide (aged over 4A molecular sieve) and stirred for 1 hour. The title compound B (3.0 g, 11.33) is added. mmol), the mixture was heated for 3 hours at 80 ° ^C. An additional 0.11 g (4.58 mmol) of sodium hydride and the title compound B (1.25 g, 4.72 mmol). The reaction mixture was heated for 2 hours at 80 ° ^C, cooled and quenched by addition of water and extracted 3 times with ethyl acetate. The combined extract was washed 3 times with a 10% aqueous solution of lithium chloride, dried over magnesium sulfate and concentrated. The crude yellow liquid was chromatographed on a silica gel column, which was eluted with 5-20% ethyl acetate in hexane to isolate the title compound C (0.65 g, 13.7%).

[α] _D = +135.2 ^about (C = 1 mol / l, in methanol).

 D) 3R- (1 (S *), 3α, 4α) -6-chloro-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-pyrrolidinyl-methyl -) - 2H-1-benzazepin-2-one.

A solution of the title compound C (0.67 g, 1.34 mmol) and 1 ml (13.1 mmol) of trifluoroacetic acid in 10 ml of methylene chloride was stirred at room temperature for 6 hours. A saturated aqueous solution of potassium bicarbonate was added to alkalize the reaction mixture, which is then diluted with water and extracted 3 times with ethyl acetate. The combined extract was dried with magnesium sulfate, filtered and concentrated to give a crude product, which was chromatographed on silica gel preparative plates to give 0.28 g of the title compound (52%) as a light yellow foam with mp. 80-84 ^about S.

[α] _D = +148.0 ^about (C = 1 mol / l, in methanol).

 Calculated,%: C 64.70; H 6.38; N, 6.86; Cl 8.68.

C ₂₂ H ₂₅ ClN ₂ O ₃ ˙ 0.42 ˙ H ₂ O.

 Found,%: C 64.96; H 6.34; N, 6.60; Cl 8.78.

 PRI me R 28. (3R- (1 (S *), 3 α, 4α) -3- (acetyloxy) -6-chloro-1,3,4,5-tetrahydro-4- (4-me -toxyphenyl) -1- (2-pyrrolidinylmethyl) -2H-1-benzazepin-2-one.

 A) (3R- (1 (S *), 3α, 4 α) -1 - ((tert-butoxycarbonyl-2-pyrrolidinyl) methyl) -3-acyloxy) - 1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 N, N-Dimethylaminopyridine (0.35 g, 2.88 mmol) was added to a solution of the title compound C) from Example 27 (0.72 g, 1.44 mmol) and acetic anhydride (0.68 g, 7.2 mmol) ) in 20 ml of methylene chloride. The mixture was stirred for 18 hours at room temperature, absorbed with silica gel (60-200 mesh), chromatographed on a silica gel column and eluted with 10-20% ethyl acetate in hexane to give 0.66 g of the title A compound (85%) in in the form of white foam.

 B) (3R (1 (S *), 3α, 4α)) - 3- (acetyloxy) -6-chloro-1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -1- (2- pyrrolidinylmethyl) -2H-1-benzazepin-2-one.

A solution of the title compound A (0.65 g, 1.20 mmol) and trifluoroacetic acid (1.37 ml, 18.0 mmol) in 15 ml of methylene chloride was stirred for 1.5 hours at room temperature. A saturated aqueous solution of potassium hydrogen carbonate was added to the reaction mixture, then water, before being extracted with ethyl acetate (3 times). Dried over magnesium sulfate, filtered and concentrated to give the title compound (0.53 g, 100%) as a white foam, mp. 74-78 ^about C; [α] _D = +130.0 ^about (C = 1, in methanol).

 Calculated,%: C 64.35; H 6.20; N, 6.25; Cl 7.91.

C ₂₄ H ₂₇ ClN ₂ O ₄ ˙ 0.29 ˙ H ₂ O.

 Found,%: C 64.61; H 6.09; N, 5.97; Cl 7.51.

 PRI me R 29. (3R- (1 (2R *), 3 α, 4α)) - 1- (2-dimethylamino) -1-phenylpropyl) -1,3,4,5-tetrahydro 3-hydroxy- 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A.

 A) 1S, 2R-2- (N, N-dimethylamino) -1-phenyl-1-propanol.

 To a suspension of 20 g of 1S, 2R-norephedrine hydrochloride (106 mmol) in 50 ml of ether was added 21 g of a 25% solution of sodium methoxide in 100 ml of methanol. An additional 50 ml of methanol was added and the solution was stirred for several minutes and filtered. The white precipitate was washed several times with ether and the combined filtrates were evaporated, yielding 16.6 g of the free base, 1S, 2R-norephedrine, as a clear oil (100%). This free base is dissolved in 125 ml of acetonitrile and 42 ml of a 37% aqueous formaldehyde solution are added. With periodic cooling in an ice bath, 10.5 g of sodium cyanoborohydride (167 mmol) are added in parts in solid form. Again, with periodic cooling, glacial acetic acid is added dropwise until the pH of the solution drops to 8. The solution is stirred at room temperature for 30 minutes and evaporated. The residue is extracted three times from 2 N. sodium hydroxide solution with ether, and the combined ether extracts are washed with 0.5 N. sodium hydroxide solution and extracted 3 times with 10% hydrochloric acid. The combined acid washes were neutralized with solid sodium hydroxide and extracted 3 times with ether. The combined ether washes were washed with brine, dried over potassium carbonate and evaporated to give 15.6 g (82%) of the title A compound as a white crystalline solid.

 B) 1R, 2R-2- (N, N-dimethylamino) -1-phenyl-1-chloro-propane.

To a solution of the compound from title A (15.2 g, 70.5 mmol) in 100 ml of methylene chloride was added 20.6 ml of thionyl chloride (282 mmol) in 100 ml of methylene chloride, dropwise over an hour. After addition of 200 ml of carbon tetrachloride and cooled to 0 ° ^C is not allocated solid. Methylene chloride was distilled off, and the remaining solution was frozen overnight to obtain a 1: 1 mixture of 1R, 2R and 1S, 2R isomers of the compound from heading B) as a pink solid, which was collected by filtration, washed 3 times with hexane and dried in air . Recrystallization from 150 ml of acetone and 5 ml of methanol gives 0.98 g of the title compound B) (isomer A) as light brown prisms.

[α] _D = -110.9 ^about (C = 1 mol / l, in methanol).

 C) (3R- (1 (2R *), 3 α, 4 α)) - 1- (2-dimethylamino) -1-phenylpropyl) -3- (tert-butyldimethyl-siloxy) - 1,3,4,5 -tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A.

To a suspension of 93 mg of sodium hydride (1.93 mmol, 50% dispersion in oil) in 4 ml of dry dimethylformamide was added 0.75 g of 3-tert-butyldimethylsilyl ether (3R-cis) -3-hydroxy-4- (4 -methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (1.61 mmol). The solution was stirred for 10 minutes, heated to 70 ^° C, and a solution of 0.87 g (3.22 mmol) of the compound from title B and 0.36 g of potassium tert-butylate (3.22 mmol) in 2 ml of dry dimethylformamide was added. Heating and stirring were continued for 70 minutes, another 45 mg of sodium hydride and 0.22 g of the title B compound were added, and the solution was heated for another 90 minutes. The reaction was interrupted by the addition of an aqueous solution of potassium carbonate, dimethylformamide was removed under high vacuum with gentle heating, and the residue was partitioned between ether and aqueous potassium carbonate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated, yielding 1.51 g of a light yellow oil. Flash chromatography on silica gel (eluent 40% ethyl acetate in hexane) gives 0.58 g of the title compound C) as a white solid foam contaminated with approximately 20% of the imidate formed by alkylation of the amide with carbonyl oxygen.

 D) (3R- (1 (2R *) 3 α, 4 α)) - 1- (2-dimethylamino) -1-phenylpropyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4 -methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer A.

To a solution of 0.58 g of the crude title compound C) less than 1.02 mmol) in 25 ml of dried tetrahydrofuran was added 0.68 g of solid tetrabutylammonium fluoride trihydrate (1.56 mmol) in one go. The solution was stirred for 20 minutes and partitioned between ether and water. The aqueous layer was washed with ether, and the combined organic layers were washed with brine, dried with magnesium sulfate and evaporated, yielding 0.51 g of a clear resin. This material is purified on three preparative plates for thin layer chromatography (eluent - 5% methanol: methylene chloride). A strip corresponding to an Rf of 0.48 (10% methanol in methylene chloride) was extracted with a mixture of 10% methanol: 0.5% triethylamine: methylene chloride and the solution was filtered and evaporated to give 0.37 g of the free base indicated in the title compound in the form of a white solid foam. This free base is dissolved in ether, filtered through a pad of Celite and ether saturated with HCl is added. The resulting white precipitate was collected by filtration, washed with ether and dried, yielding 205 mg of the title compound as a white solid foam with mp above 220 ^about C, [α] _D = +180 ^about (C = 1 mol / l, in methanol).

 Calculated,%: C 60.92; H 6.09; N, 4.90; Cl 6.20; F 9.97.

C ₂₂ H ₃₁ F ₃ O ₃ HCl ˙ 1.26 ˙ H ₂ O.

 Found,%: C 60.92; H 6.05; N 4.74; Cl 6.11; F 9.76.

 PRI me R 30. (3R- (1 (2R *), 3 α, 4α)) - 1- (2- (dimethylamino) -1-phenylpropyl) -1,3,4,5-tetrahydro -3- hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride, isomer B.

 A) (3R- (1 (2R *), 3α, 4 α)) - 1- (2-dimethylamino) -1-phenylpropyl) -3- (tert-butyldimethylsiloxy) - 1,3,4,5-tetrahydro 3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) - 2H-1-benzazepin-2-one, isomer B.

To a suspension of 1.08 g of sodium hydride (22.6 mmol of a 50% dispersion in oil) in 10 ml of dried dimethylformamide was added 3.5 g of 3-tert-butyldimethylsilyl ether (3R-cis) -3-hydroxy-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (7.52 mmol). The solution was stirred for 30 minutes, 3.05 g of a 1: 1 mixture of 1R, 2R - and 1S, 2R - (N, N-dimethylamino) -1-phenyl-1-chloropropane (13 mmol, see example 29) was added to solid and the solution is stirred and heated at 65 ° C. ^for 1 hour. The solution is cooled by the addition of an aqueous solution of sodium hydrogen carbonate, dimethylformamide is removed under high vacuum with gentle heating and the residue is partitioned between ether and an aqueous solution of potassium carbonate. The organic layer was washed with brine, dried with magnesium sulfate and evaporated, yielding 6.18 g of a thick brown oil. Flash chromatography on silica gel (eluent 75% ether in hexane and then 75% ethyl acetate in hexane) gives 1.18 g of the crude compound indicated in heading A (Rf = 0.41 in 50% ethyl acetate in hexane) contaminated with a small the amount of the more mobile isomer (compound C) in Example 29 (. Flash chromatography on silica gel (eluent 50% ethyl acetate in hexane) gives 0.84 g of the title A) compound (18%) as a yellow solid foam.

 B) (3R- (1 (2R *), 3α, 4 α)) - 1- (2-dimethylamino) -1-phenylpropyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4 -methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, isomer B, monohydrochloride.

To a solution of 0.84 g of the crude title compound A (1.34 mmol) in 25 ml of dried tetrahydrofuran was added 0.90 g of solid tetrabutylammonium fluoride trihydrate (2.86 mmol) in one go. The solution was stirred for 30 minutes and partitioned between ether and water. The aqueous layer was washed with ether and the combined organic layers washed with brine, dried with magnesium sulfate and evaporated, yielding 0.85 g of a clear resin. This material is purified on four preparative plates for thin layer chromatography (eluent - 75% ethyl acetate in hexane). A strip corresponding to an Rf value of 0.19 (75% ethyl acetate in hexane) was extracted with a mixture of 5% methanol in methylene chloride and the solution was filtered and evaporated to give 0.50 g of the free base of the title compound as a white solid foam. This free base is dissolved in ether, filtered through a pad of Celite and ether saturated with HCl is added. The resulting white precipitate is collected by filtration, washed with ether and dried, but when standing appears hygroscopic. This solid is dissolved in methanol, evaporated, suspended in hot isopropyl ether and methanol added dropwise until dissolution occurs. The solution was cooled, and the resulting white solid was collected by filtration and dried, yielding 0.42 g of the title compound as a white solid powder, mp. 191-192 ^about S.

[α] _D = +242.6 ^about (C = 1.05 mol / l, in methanol).

 Calculated,%: C 62.98; H 5.91; N, 5.06; Cl 6.41; F 10.30.

C ₂₉ H ₃₁ F ₃ N ₂ O ₃ HCl ˙ 0.22 ˙ H ₂ O.

 Found,%: C 62.98; H 5.79; N, 5.04; Cl 6.21; F 10.58.

 PRI me R 31. (3R- (1 (2S *), 3 α, 4α)) - 1- (2- (dimethylamino) -1-phenylpropyl) -1,3,4,5-tetrahydro -3- hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride, isomer B.

 A) 1R-2S-2- (N, N-dimethylamino) -1-phenyl-1-propanol.

To a stirred solution of 1R, norephedrine-25 (25 g, 0.165 mol) and 50 ml of formaldehyde (37% solution in water) in 150 ml of acetonitrile at ⁰ ° C was added 16.3 g of sodium cyanoborohydride (0.26 mol) in several portions. 35 ml of glacial acetic acid are added over 20 minutes. The reaction mixture was stirred at room temperature for 1 h, concentrated to 1/3 of the volume and neutralized to pH 10 with a normal sodium hydroxide solution. The combined organic phases are washed with water and brine, dried over magnesium sulfate and evaporated. The product was recrystallized from a mixture of ethanol and water to give 7.01 g (24%) of the title A compound.

 B) 1R, 2S-2- (N, N-dimethylamino) -1-phenyl-1-chloropropane.

 To a stirred solution of the title A compound (2.19 g, 12.22 mmol) in 25 ml of chloroform was added dropwise a solution of 8.89 ml of titanium chloride (122 mmol) in 15 ml of chloroform over 5 minutes. The reaction mixture was stirred for 15 minutes and evaporated. The dark residue was dispersed with chloroform (2 times 100 ml) and triturated with a 1: 1 mixture of ether with hexane (3 times 100 ml) to obtain 2.28 g (80%) of the title compound B as a yellow solid a substance containing 15% of the 1S, 2S isomer.

 C) (3R- (1- (2S *), 3 α, 4 α)) - 1- (2-dimethylamino) -1-phenylpropyl) -1,3,4,5-tetrahydro-3- (tert-butyldimethylsiloxy ) -4- (4-methoxyphenyl) -6- (trifluoromethyl-2H-1-benzazepin-2-one, isomer B.

To a stirred solution of the title A compound of Example 18 (1.5 g, 3.22 mmol) in 20 ml of dry dimethylformamide was added sodium hydride as a 60% dispersion in oil (0.39 g, 9.67 mmol ) The reaction mixture was stirred for 1 h under argon at room temperature. Was added 0.76 g (3.22 mmol) of neat title substance B and the reaction mixture was stirred ^at 50 ° C overnight. The solution was cooled to room temperature and evaporated. The residue was partitioned between water and methylene chloride, the organic phase was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was purified on a silica gel column, which was eluted with a 1: 1 mixture of ether and hexane to obtain 1.18 g (56%) of the title compound C.

 D) (3R- (1 (2S *), 3α, 4 α)) - 1- (2- (dimethylamino) -1-phenylpropyl) -1,3,4,5-tetrahydro-3-hydroxy-4- ( 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride, isomer B.

To a stirred solution of 1.18 g of the compound from title C) (1.78 mmol) in 20 ml of dried tetrahydrofuran was added 1.12 g of tetrabutylammonium fluoride trihydrate (3.56 mmol). The solution was stirred at room temperature for 1 hour and diluted with ether. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated. The residue was purified on a silica gel column, which was eluted with ether. A solid is obtained which is dissolved in ether. HCl saturated ether was added to give a white precipitate, which was filtered and washed with ether to give 0.47 g of the pure title compound, mp. 148-151 ^about S.

[α] _D = +167.6 ^about (C = 0.75 mol / l, in methanol).

 Calculated,%: C 59.77; H 6.18; N, 4.80; Cl 6.08; F 9.78.

C ₂₉ H ₃₁ F ₃ N ₂ O ₃ HCl˙ 1.87 H ₂ O.

 Found,%: C 59.37; H 5.78; N, 4.90; Cl 6.51; F 9.84.

 PRI me R 32. (3R (1 - ((2S *), 3 α, 4α)) - 1 - (2- (dimethylamino) -1-phenylpropyl) -1,3,4,5-tetrahydro 3-hydroxy- 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride, isomer A.

 A) 1S, 2S-2- (N, N-Dimethylamino) -1-phenyl-1-chloropropane.

 To a stirred solution of the compound indicated in Part A of Example 31 (2.19 g, 12.22 mmol) in 25 ml of chloroform was added dropwise a solution of 8.89 ml of thionyl chloride (122 mmol) in 15 ml of chloroform over 5 minutes. The reaction mixture was stirred for 1 h at room temperature and evaporated. The residue was dispersed with chloroform (3 times 100 ml) and triturated with a 1: 1 mixture of ether and hexane (4 times 100 ml) to obtain a 1: 1 mixture of the 1R, 2S isomer and 1S, 2S isomer as a yellow amorphous solid substances. Recrystallization from acetone affords 0.8 g of the pure compound of Title A.

 B) (3- (1 (2S *), 3 α, 4 α)) - 1- (2-dimethylamino) -1-phenylpropyl) -1,3,4,5-tetrahydro-3- (tert-butyldimethylsiloxy) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride, isomer A.

A mixture of the title A compound (0.4 g, 1.72 mmol), the compound from Part A of Example 18 (0.8 g, 1.42 mmol) and cesium carbonate (16 g, 5.16 mmol) in 10 ml of dry dimethylformamide was heated ^at 55 ° C for 2 hours. The reaction mixture was concentrated in vacuo and the residue was triturated in water. The solid is collected and dissolved in ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated. The residue was purified on a silica gel column, which was eluted with a 1: 1 mixture of ether and hexane to obtain 0.7 g of the pure compound of title B.

 C) (3R- (1 (2S *), 3 α, 4 α)) - 1- (2- (dimethylamino) -1-phenylpropyl-1,3,4,5-tetrahydro-3-hydroxy-4 - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 To a stirred solution of 0.7 g of the title compound B) (1.12 mmol) in 20 ml of dried tetrahydrofuran was added 0.35 g of tetrabutylammonium fluoride trihydrate (1.12 mmol). The solution was stirred for 2 hours at room temperature and evaporated. The residue was dissolved between ethyl acetate and water. The organic phase is washed with water and brine, dried with magnesium sulfate and evaporated. The residue was purified on four preparative silica gel plates which were eluted with methylene chloride.

 Strips of product are cut out and extracted with a mixture of 10% methanol in methylene chloride. The product was dissolved in ether and ether saturated with hydrogen chloride was added. The solution was evaporated and the residue was dispersed with methanol to give a white solid (0.38 g) as indicated in the title.

Mp 233-235 ^about S.

 Calculated,%: C 61.83; H 6.01; N, 4.97; Cl 6.29; F 10.12.

C ₂₉ H ₃₁ F ₃ N ₂ O ₃ HCl ˙ 0.8 H ₂ O.

 Found,%: C 61.77; H 5.81; N, 5.03; Cl 6.54; F 10.00.

 PRI me R 33. (3R- (1 (S *), 3 α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 1- ( 3- pyrrolidinyl) -6- (trifluoromethyl-2H-1-benzazepin-2-one, fumaric acid salt (1: 1).

 A) 3R-1-Benzyl-3- (para-toluenesulfonyloxy) pyrrolidine.

 A mixture of 3R-1-benzyl-3-hydroxypyrrolidine (1 g, 5.6 mmol) and para-toluenesulfonyl chloride (1.6 g, 8.4 mmol) was stirred in 10 ml of pyridine for 4 hours. The reaction mixture was partitioned between aqueous sodium hydrogen carbonate solution and methylene chloride. The organic layer was washed with sodium bicarbonate solution, then brine. Then it is dried with magnesium sulfate and evaporated first under a shallow vacuum and finally with high vacuum pumping to remove traces of pyridine. The resulting yellow residue was purified by flash chromatography on a 5x25 cm silica gel column (eluent mixture 1: 1 ethyl acetate and hexane). Pure fractions were concentrated to give 933 mg of the title A compound as a colorless oil.

 Br (3R- (1 (S *), 3 α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (benzyl-3-pyrrolidinyl) -6- (trifluoromethyl-2H-1-ben-zazepin-2-one.

A mixture of the title compound A (0.9 g, 2.72 mmol), (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2 -one (911 mg, 2.6 mmol) and cesium carbonate (4.23 g, 13 mmol) in 26 ml of distilled methyl ethyl ketone are refluxed for 8 hours and stirred at room temperature for 18 hours. Ethyl acetate (60 ml) is added. and the suspension is filtered. The filtrate was concentrated and the residue was purified by flash chromatography on a 5x25 cm silica gel column using the following elution scheme: 2 L of a 1: 1 mixture of ethyl acetate: hexane: 1 ml of a 3: 1 mixture of ethyl acetate: hexane; 0.5 L of 1% methanol in ethyl acetate. Pure fractions were concentrated to give 1.24 g of an almost white solid. This material was recrystallized from ethyl ether to give 935 mg (71%) of the title compound B as a white crystalline powder, mp. 147-149 ^about S.

 C) (3R- (1 (S *), 3 α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (3-pyrrolidinyl) - 6-trifluoromethyl) -2H-1-benzazepin-2-one.

 A mixture of substance from Part B (865 mg, 1.7 mmol), ammonium formate (552 mg, 8.76 mmol and 10% palladium on carbon (150 mg) is refluxed in 25 ml of a 4: 1 mixture of methanol: acetic acid for 4 hours, then additionally injected 220 mg of ammonium formate (3.5 mmol) and 120 mg of palladium (10 on charcoal). This mixture is boiled for 30 minutes and then the catalyst is filtered off through Celite. The filter cake is washed well with methanol, and the filtrate was concentrated in vacuo and the residue was partitioned between sodium carbonate solution and ethyl acetate.

 The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on a 5x20 cm silica gel column that had been pretreated with a mixture of dichloromethane: methanol and triethylamine, 94: 5: 1. The column is eluted first with 2 L of a mixture of 5% methanol in dichloromethane and then 2 L of 10% methanol in dichloromethane. Pure fractions were concentrated to obtain 60 mg (yield 84% of the title compound C as a colorless foam.

 D) (3R- (1 (S *), 3 α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl-1- (3-pyrrolidinyl-6- (trifluoromethyl-2H-1-benzazepin-2-one, fumaric acid salt (1: 1).

The title compound C (600 mg, 1.43 mmol) was dissolved in 5 ml of methanol and 166 mg (1.43 mmol) of fumaric acid was added as a solution in hot methanol. The solution was concentrated to dryness and the solid residue was crystallized from methanol: ether to give 650 mg (86%) of the title compound as a colorless crystalline solid, mp. 228-231 ^about S.

[α] _D = +57.86 ^o (C = 1.0 mol / L, in acetic acid)
Calculated,%: C 58.20; H 5.07; N, 5.22; F 10.62.

C ₂₂ H ₂₃ F ₃ N ₂ O ₃ ˙C ₄ H ₄ O ₄ .

 Found,%: C 58.09; H 4.81; N, 5.27; F 10.45.

 PRI me R 34. (3R- (1 (R *), 3 α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- ( 3- pyrrolidinyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1).

 A) 3S-1-Benzyl-3- (benzoyloxy) pyrrolidine.

 Diethyl azodicarboxylate (4.8 ml, 30 mmol) is added dropwise to a stirred solution of 3R-1-benzyl-3-hydroxypyrrolidine (3.5 g, 20 mmol, triphenylphosphine (7.86 g, 30 mmol) and benzoic acid (6, 12 g, 50 mmol in 200 ml of tetrahydrofuran at room temperature After stirring for 1.5 h, tetrahydrofuran was removed in vacuo and the residue was partitioned between 1 N hydrochloric acid and ethyl acetate.The organic layer was again extracted with 1 N hydrochloric acid and the combined acid layers alkalinized with solid sodium carbonate. ethyl acetate is washed. The ethyl acetate layer is washed with water, then brine and then dried with magnesium sulfate. The organic layer is evaporated and the residue is purified by flash chromatography on a 5x30 cm silica gel column using a 1: 3 mixture of ethyl acetate and hexane as the mobile phase. Pure fractions are concentrated, to give 3.3 g (59% yield) of the title A compound as a colorless oil.

 C) 3S-1-Benzyl-3-hydroxypyrrolidine.

 A one-normal solution of sodium hydroxide (25 ml, 25 mmol) was added to a solution of the title compound A (3.15 g, 11.2 mmol) in 100 ml of methanol. The reaction mixture immediately becomes cloudy and clears after 30 minutes. After stirring for an additional 30 minutes, methanol was removed in vacuo and the remaining aqueous mixture was extracted with ethyl acetate. The organic phase is washed with water, then brine. After drying over sodium sulfate, ethyl acetate was removed in vacuo to give 1.5 g (77% yield) of the title B compound as a colorless oil.

 C) 3S-1-Benzyl-3- (para-toluenesulfonyloxy) pyrrolidine.

 A mixture of 3R-1-benzyl-3-hydroxypyrrolidine (1.45 g, 8.2 mmol) and para-toluenesulfonyl chloride (2.35 g, 12.3 mmol) was stirred in 16 ml of pyridine for 20 hours. After that, the reaction mixture was partitioned between an aqueous solution of sodium bicarbonate and ethyl ether. The organic layer was washed with sodium bicarbonate solution, water, then brine. After drying with sodium sulfate, the organic layer is evaporated first under a shallow vacuum and finally with high vacuum pumping to remove traces of pyridine. The resulting residue was purified by flash chromatography on a 5x25 cm silica gel column (eluent mixture 1: 3 ethyl acetate and hexane). Pure fractions were concentrated to give 2.31 g (85% yield) of the title compound C as a pale yellow oil.

 D) (3R- (1 (R *), 3α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (benzyl l-3-pyrrolidinyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 A mixture of the title compound C (2.2 g, 6.64 mmol), (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine-2 -one (1.86 g, 5.31 mmol) and cesium carbonate (8.65 g, 26.5 mmol) in 75 ml of methyl ethyl ketone are refluxed for 18 hours. The reaction mixture is cooled, diluted with 150 ml of ethyl ether and filtered through Celite. The filtrate was concentrated, the residue was purified by flash chromatography on a 5x25 cm silica gel column using a 3: 1 mixture of ethyl acetate: hexane as an eluent. Only partial cleaning is achieved on this column. Therefore, the concentrated fractions (2.35 g, 88% purity) are chromatographed repeatedly on a 5x25 cm silica gel column using a mixture of 2.5% methanol in dichloromethane as eluent. Pure fractions were concentrated to give 1.64 g (61% yield) of the title compound D as a white foam.

 E) (3R (1 (R *), 3α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 1- (3-pyrrolidinyl) - 6- ( trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1).

 A solution of the substance from Part D (1.58 g, 3.1 mmol) in 30 ml of glacial acetic acid was hydrogenated over a catalyst of 20% palladium hydroxide on carbon at room temperature for 3 hours using a balloon device. After that, the catalyst is filtered off, and the filter cake is washed with glacial acetic acid (15 ml). The filtrate was diluted with 150 ml of water and the acid mixture was made basic with solid sodium carbonate. This basic mixture was extracted with 150 ml of ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on a 5x25 cm silica gel column, which was pretreated with a mixture of dichloromethane: methanol and triethylamine, 94: 5: 1. The column is eluted first with 2 L of a mixture of 5% methanol in dichloromethane and then 1 L of 10% methanol in dichloromethane. The pure fractions are concentrated to a semi-solid precipitate, which is dissolved in a mixture of 5% methanol in dichloromethane and filtered through Celite. The filtrate was concentrated to obtain 1.173 g (90% yield) of the free base as a white foam.

This free base (1.08 g, 2.57 mmol) was dissolved in methanol and 298 mg (2.57 mmol) of fumaric acid was added as a solution in hot methanol. The solution was concentrated to a white foam, which was crystallized from hot isopropanol. After filtration and drying in vacuo, 925 mg (68% yield) of the title compound are obtained as a white crystalline solid, mp. 228-231 ^about S.

[α] _D = +58.9 ^about (C = 0.50 mol / l, in methanol).

 Calculated,%: C 58.22; H 5.17; N, 5.16; F 10.51.

C ₂₂ H ₂₃ F ₃ N ₂ O ₃ ˙C ₄ H ₄ O ₄ ˙0.1 ˙C ₃ H ₈ O, (isopropanol).

 Found,%: C 58.07; H 5.11; N, 5.26; F 10.44.

 PRI me R 35. (This example is devoted to the compound indicated in the heading of example 16, but differs in the preparation method of the compound in part A of example 16).

 (3R- (1 (S *), 3 α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methosiphenyl) -1- (3-pyrrolidinyl) -6- (trifluoromethyl) - (2H-1-benzase-pin-2-one, monohydrochloride.

 A) S-1- (benzyloxycarbonyl) -2 - ((para-toluenesulfonyloxy) methyl) pyrrolidine.

To S-1- (benzyloxycarbonyl) -2-pyrrolidinemethanol (105.7 g, 449 mmol) in 400 ml of pyridine at ⁰ ° C was slowly added p-toluenesulfonyl chloride (102.8 g, 539 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 20 hours. Half of the pyridine was removed under reduced pressure until the mixture was diluted with water and extracted with ether (3 times). The combined extract is washed with dilute hydrochloric acid - an aqueous solution of copper sulfate (3 times), dried with magnesium sulfate, filtered and concentrated to a crude viscous liquid, which is extracted with warm hexane (3 times). The dark orange viscous liquid (147.7 g, 84%) was slowly solidifies at ⁵ ° C, giving the title A compound as a light purple solid.

 B) (3R- (1 (S *), 3α, 4α)) - 1 - ((1-benzyloxycarbonyl-2-pyrrolidinyl) methyl) -1,3,4,5-tetrahydro-3-hydroxy- 4- (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-1-benzazepin-2-one.

The title compound A (34.6 g, 89.0 mmol) (3R-cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (25 g, 71.2 mmol) and cesium carbonate (34.8 g, 106.7 mmol) in 200 ml of dimethylformamide was heated to 50 ^C. After 8 hours, add another title compound A (2.8 g, 7.2 mmol) and stirring was continued for another 12 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted 3 times with ethyl acetate. The combined extract is washed with a 10% aqueous solution of lithium chloride (3 times), dried with magnesium sulfate, filtered and concentrated. The light yellow solid was triturated with 100 ml of ether for 30 minutes before adding 100 ml of hexane, and stirred for another 30 minutes. Filtration gives 34.5 g of the title compound B as a pale yellow powder.

 C) (3R- (1) S *), 3α, 4α) -1,3,4,5)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1 - (2-pyrrolidinyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A solution of the substance from Part B (35 g, 61.61 mmol) in 700 ml of absolute ethanol and 7 g of palladium hydroxide on charcoal was placed in a shaken-up Parr autoclave and shaken at 3.5 atm hydrogen pressure for 1 h 40 min. After all hydrogen has been pumped out, anhydrous magnesium sulfate is added and the catalyst is filtered off, suctioning the reaction mixture. The solids on the filter are washed well with absolute ethanol. The filtrate was concentrated, the residue was diluted with saturated potassium bicarbonate and extracted 3 times with ethyl acetate. The combined extract was dried with magnesium sulfate, filtered and concentrated to give a light yellow foam, which was dissolved in 350 ml of methanol and filtered. 7.15 g (61.6 mmol) of fumaric acid are added and heated in a steam bath until a homogeneous solution is formed. The solution is allowed to cool and crystallization occurs overnight.

The white crystalline solid was filtered and washed well with ethyl acetate to give 29.76 g (88% yield) of the fumar salt of the title compound. This fumaric salt is converted to the free base by washing with a saturated aqueous solution of potassium bicarbonate and extraction with ether / ethyl acetate (3 times). To the free base dissolved in ether is added an excess of ethereal hydrogen chloride solution. A white precipitate was collected and dried to obtain the title compound (21.6 g, 100% yield from fumarate). Mp 165-167 ^about C, [α] _D = +75.3 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 57.07; H 5.72; N, 5.79; Cl 7.32; F 11.78.

C ₂₃ H ₂₅ F ₃ N ₂ O ₃ ˙ HCl ˙ 0.73 H ₂ O.

 Found,%: C 57.31; H 5.56; N 5.55; Cl 7.42; F 12.03.

 PRI me R 36. (3R- (1 (S *), 3 α, 4α)) - 3- (acetyloxy) -1,3,4,5-tetrahydro-7-methoxymethoxy-4- ( 4-methoxyphenyl) -1- (2-pyrrolidinylmethyl) -2H-1-benzazepin-2-one, monofumarate.

 A) (3R- (1 (S *), 3 α, 4 α)) - 1- (N-benzyloxycarbonyl-2-pyrrolidinyl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 7- (methoxymethoxy) -2H-1-benzazepin-2-one.

Suspension of cis-3-hydroxy-7-methoxymethoxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one (1.5 g, 4.37 mmol), anhydrous cesium carbonate (2.84 g , 8.75 mmol) and the compound of the title a product of eXAMPLE 35 (2.55 g, 6.56 mmol) in 50 ml of dimethylformamide was heated to 58 ^{° C} for 28 hours. The reaction mixture was cooled, diluted with water and extracted 3 times with ethyl acetate. The combined extract was washed with a 10% aqueous solution of lithium chloride, dried with magnesium sulfate, filtered and concentrated to give a crude product. A number of silica gel columns were tested to isolate the desired (+) isomer, the title compound A. The first column was eluted with a mixture of 20% ethyl acetate in dichloromethane to isolate the pure (±) diastereoisomers. The second column is eluted with 1-10% ether in methylene chloride to obtain a more mobile isomer of the title A compound (0.44 g, Rf) 0.64, eluent 50% ether in methylene chloride, [α] _D = + 161.31 ^o (C = 1.0, in methanol)), less mobile isomer (0.08 g, Rf = 0.55, eluent 50% ether in methylene chloride, [α] _D = 81.81 ^o (C = 1.0 in methanol)) and a few mixed fractions (0.57 g). Upon final chromatography of these mixed fractions and elution of 4-10% ether in methylene chloride, an additional amount of the more mobile isomer (0.33 g) is obtained. The total output of BPI was 0.77 g.

 B) (3R- (1S *, 3α, 4 α)) - 1- (1-benzyloxycarbonyl-2-pyrrolidinyl) methyl) -3- (acetyloxy) - 1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -7- (methoxymethoxy) -2H-1-benzazepin-2-one.

 The title compound A (0.70 g, 1.25 mmol), 4-dimethylaminopyridine (0.31 g, 2.5 mmol) and acetic anhydride (0.64 g, 6.24 mmol) were stirred at room temperature in an argon atmosphere for 14 hours. The reaction solution was taken up with silica gel (60-200 mesh) and chromatographed on a silica gel column. Elution with 20-40% ethyl acetate in hexane afforded the title compound B as a white foam (0.74 g).

 C) (3R- (1 (S *), 3α, 4α)) - 3- (acetyloxy) -1,3,4,5-tetrahydro-7-methoxymethoxy-4- (4-methoxyphenyl) -1- (2 -pyrrolidinylmethyl) -2H-1-benzazepinon-2-one, fumaric acid salt (1: 1).

To a solution of the title B compound (0.64 g, 1.06 mmol) in 10 ml of ethyl acetate and 0.4 ml of trifluoroacetic acid, 130 mg of palladium hydroxide on carbon was added with stirring. The reaction vessel is connected to a cylinder filled with hydrogen. The vessel is evacuated under reduced pressure and filled with hydrogen. The mixture was then vigorously stirred at room temperature for 6 hours until hydrogen was removed and anhydrous magnesium sulfate was added. The solids are removed by suction and filtration and washed well with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The organic layer was washed with an aqueous solution of potassium hydrogen carbonate and distributed. The aqueous layer was extracted 2 times with ethyl acetate and the combined organic layers were dried with magnesium sulfate, filtered and concentrated to give the free amine as a light orange foam (0.32 g). This free amine is dissolved in 20 ml of methanol and 79.3 mg (0.68 mmol) of fumaric acid is added and stirred until the solution becomes homogeneous. Upon concentration, the title compound (0.41 g) is obtained in the form of a light yellow foam with mp. 126-130 ^about S.

[α] _D = 89.7 ^about (C = 1 mol / l, in methanol).

 Calculated,%: C 60.50; H 6.30; N 4.71.

C ₂₆ H ₃₂ N ₂ O ₆ ˙ C ₄ H ₄ O ₄ ˙ 0.6 H ₂ O.

 Found,%: C 60.44; H 6.00; N 4.74.

 PRI me R 37. (3R- (1 (2S *, 4R *) - 3α, 4α)) - 1,3,4,5-Tetrahydro-3-hydroxy-4- (4-label-siphenyl) -1 - ((4-phenylmethoxy (-2-pyrrolidinyl) methyl-6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (2S, 4R) -4-hydroxy-1- (tert-butoxycarbonyl) -2-pyrrolidinecarboxylic acid.

A suspension of 20.0 g (0.152 mol) of trans-4-hydroxy-Z-proline and 38.0 g (0.174 mol) of di-tert-butyl dicarbonate in 250 ml of dioxane is gradually treated with 350 ml of a normal solution of sodium hydroxide, then stirred at room temperature for 24 hours. The mixture was concentrated in vacuo to a volume of about 200 ml, then diluted with 150 ml of water. After washing with ethyl acetate, the aqueous layer was acidified with 6-normal hydrochloric acid and saturated with sodium chloride until extraction with ethyl acetate (2 times). The organic solution was washed with water and brine, and evaporated, yielding 30.9 g of the compound indicated in title A as a brown solid, mp. 104-106 ^about S.

 Calculated,%: C 51.94; H 7.40; N, 6.05.

C ₁₀ H ₁₇ NO ₅ .

 Found,%: C 51.31; H 7.55; N, 5.67.

 B) (2S, 4R) -4- (phenylmethoxy) -1- (tert-butosicarbonyl) -2-pyrrolidinecarboxylic acid.

A solution of 7.04 g (0.030 mol) of the title compound A and 5.2 g (0.30 mol) benzyl bromide (also responds well and benzyl chloride) in 70 ml of dimethylformamide (at a bath temperature of -78 ^C. ) are treated with 0.38 g (0.009 mol) of a 60% sodium hydride dispersion and stirred at room temperature for 3 hours, then poured onto ice. The solution was washed with ethyl acetate and acidified to pH 2 using 6 normal hydrochloric acid saturated with sodium chloride. Extraction with ethyl acetate (2 times) gives 7.16 g of oil. Flash chromatography using ethyl acetate gave 4.44 g of the title compound B.

 Calculated,%: C 63.53; H 7.21; N, 4.35.

C ₁₇ H ₂₃ NO ₅ .

 Found,%: C 63.08; H 7.38; N, 4.06.

 C) (2S, 4R) -4- (phenylmethoxy) -1- (tert-butoxycarbonyl) pyrrolidinemethanol.

A solution of 4.40 g (13 mmol) of the compound from heading B) and 1.47 g (13 mmol) of ethyl chloroformate in 65 ml of tetrahydrofuran (151) is treated dropwise with a solution of 1.40 g (13 mol) of triethylamine in 10 ml of tetrahydrofurate. After stirring for 1 h at room temperature, the mixture was filtered directly into a three-necked flask. The stirred solution is treated dropwise with a solution of 0.75 g (20 mmol) of sodium borohydride in 8 ml of water. After 1 h, the solvent was evaporated and the residue in a solution of ethyl acetate was washed with 1N hydrochloric acid, water, 1N. sodium hydroxide solution, water and brine. The dried solution was evaporated, yielding 3.23 g of an oil. Flash chromatography using an eluent - ethyl acetate: hexane 1: 2 yields 2.76 g of the title C, [α] _D = -28,3 ^o (C = 1.86, chloroform).

 D) (2S, 4R) -4- (phenylmethoxy) -1- (tert-butoxycarbonyl) -2-bromomethyl) pyrrolidine.

 A solution of 2.7 g (8.7 mmol) of the compound from heading C), 5.8 g (17.4 mmol) of carbon tetrabromide and 4.5 g (17.4 mmol) of triphenylphosphine in 150 ml of ether are stirred overnight at room temperature. The ether is decanted and the residual solid is washed 2 times with hot hexane. Hexane extracts were combined with ethereal solution and the solvents were evaporated to give a semi-solid material, which was extracted 2 times with boiling hexane. The oily residue after evaporation of hexane is dissolved in ethyl acetate and treated with Baker silica gel (60-200 mesh). The solvent was evaporated, and the resulting powder was placed on a column of the same silica gel and eluted with hexane to remove excess carbon tetrabromide. Elution with 1: 2 ethyl acetate: hexane gave 2.3 g of the title compound D.

[α] _D = -37.9 ^about (C = 2.59, in chloroform).

 E) (3R- (1 (2S *, 4R *), 3a, 4a)) - 1 - ((1- (tert-butoxycarbonyl) -4- (phenylmethoxy) -2-pyrrolidinyl) methyl-3-hydroxy-1 , 3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

A stirred solution of 0.93 g (2.6 mmol) (3-R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one in 10 ml dimethylformamide is treated with 0.13 g (3.3 mmol) of potassium hydride (0.39 ml of a 35% suspension in oil). After 1 hour, a solution of 1.23 g (3.3 mmol) of the compound of the title D in 2 ml of dimethylformamide was gradually added to the reaction mixture, and then heated (oil bath temperature 60 ° ^C) for 18 h. The cooled mixture was diluted with ethyl acetate washed 2 times with water and brine. After drying, the solvent was evaporated, and 2.2 g of a semi-solid material were obtained. This crude product was dissolved in 5 ml of toluene, frozen for 1 h, then filtered to give 0.28 g of the starting material. Flash chromatography of the remaining solution with 400 ml of silica gel using an eluent of 1: 1.5 mixture of ethyl acetate: hexane gives 0.57 g of the title compound E as a glassy solid.

[α] _D = +116.9 ^about (C = 1.95, in chloroform).

 F) (3R- (1 (2S *, 4R *), 3α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1 - ((4-phenylmethoxy ) - (2-pyrrolidinyl) methyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

The compound from Part E) (0.85 g, 14.8 mmol) is dissolved in dichloromethane containing 0.84 g (7.4 mmol) of trifluoroacetic acid. The solution was stirred overnight at room temperature. The solvent was evaporated. The residue was dissolved in toluene and the solvent was evaporated in vacuo to remove excess acid. A solution of the residue in ethyl acetate is washed with 1 N. sodium hydroxide solution, water and brine. The solution was dried and evaporated to give 510 mg of the title compound as an oil
[α] _D = +137.0 ^about (C = 1.0 mol / l, in chloroform).

 Calculated,%: C 66.65; H 5.77; N, 5.18.

C ₃₀ H ₃₁ F ₃ N ₂ O ₄ .

 Found,%: C 65.13; H 5.69; N, 5.04.

The above is dissolved in 15 ml of ether and treated with 1 equivalent of an ethereal HCl solution to obtain 0.42 g of a colorless product with mp. 184-186 ^about S.

[α] _D = +50.4 ^about (C = 1.15 mol / l, in methanol).

 Calculated,%: C 60.55; H 5.93; N, 4.70; Cl 5.95.

C ₃₀ H ₃₁ F ₃ N ₂ O ₄ ˙HCl.

 Found,%: C 60.79; H 5.59; N, 4.43; Cl 6.04.

 PRI me R 38. (3R- (1 (2S *, 4R *), 3α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-1 - ((4-hydroxy -2-pyrrolidinyl) methyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

A suspension of 1.9 g (3.5 mmol) of the title compound of Example 37 in 25 ml of acetic acid was treated with 0.5 g of 10% palladium-carbon catalyst and hydrogenated at atmospheric pressure for 24 hours. According to TLC (eluent 20% methanol in acetic acid) the reaction was completed by about 6%. Another 0.2 g of catalyst was added and hydrogenation was continued for another 48 hours. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated in vacuo ^at 40 ° C, the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. This leads to the formation of a solid product, insoluble in both phases. 1.3 g of this material was dissolved in 7 ml of hot ethanol and filtered through high flow paper (N 50). The solvent is evaporated, the residue is treated with acetonitrile to form 0.77 g of a colorless solid, so pl. 212-214 ^{° C,} [α] _D = +74,1 ^o (C = 0.72 mol / l, in methanol).

The specified product is dissolved in 3 ml of methanol and treated with 1 equivalent of ethereal HCl solution. The solvent is evaporated, the residue is treated with acetonitrile to obtain 0.61 g of a colorless solid, so pl. 217-218 ° C, [α] D = = + 75,2 o (c = 1.0 mol / l, in methanol).

 Calculated,%: C 55.21; H 5.54; N, 5.60; Cl 7.09; F 11.39.

C ₂₃ H ₂₅ F ₃ N ₂ O ₄ ˙ HCl ˙ 0.75 H ₂ O.

 Found,%: C 55.24; H 5.50; N, 5.62; Cl 7.29; F 11.37.

 PRI me R 39. (3R- (1 (2S *, 4S *), 3α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1 - ((4-phenylmethoxy-2-pyrrolidinyl) methyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (2S, 4S) -4-hydroxy-1- (tert-butoxycarbonyl) -2-pyrrolidinecarboxylic acid.

A solution of N-butoxycarbonyl-trans-4-hydroxy-Z-proline (11.55 g, 0.05 mol) and triphenylphosphine (14.4 g, 55 mmol) in 450 ml of dry tetrahydrofuran under argon at ²⁰ ° C was treated with a solution of diisopropylazodicarboxylate (10.9 ml, 0.055 mol) in 50 ml of tetrahydrofuran for 30 minutes, then stirred for an additional 2 hours. The reaction mixture was concentrated in vacuo to a volume of 100 ml, then treated with 100 ml of a normal solution of sodium hydroxide. After stirring for 15 minutes, tetrahydrofuran was removed and the remaining aqueous solution was washed with ethyl acetate (poured). The aqueous layer was acidified to pH 1.5 with hexahydric hydrochloric acid saturated with sodium chloride, and extracted 2 times with ethyl acetate. The organic fractions were washed with brine, dried with magnesium sulfate and concentrated in vacuo to give 13 g of a viscous oil. Trituration with hot diisopropyl ether and cooling gives 10.2 g of the title compound A. M.p. 147-148.5 ^about S.

[α] _D = -47.1 ^about (C = 0.92 mol / l, in ethanol).

 B) (2S, 4S) -4- (phenylmethoxy) -1- (tert-butoxycarbonyl) -2-pyrrolidinecarboxylic acid.

A solution of the title A (10.1 g, 43.8 mmol) and benzyl chloride (5.55 g, 43.8 mmol) in 60 ml of dry dimethylformamide under argon was cooled to ^-78 ° C and treated at once hydride sodium (3.50 g, 87 mmol) (60% in oil). The cooling bath was removed, the reaction mixture was allowed to warm to room temperature, and it was stirred overnight. The mixture was poured onto ice and washed 2 times with ethyl acetate. The basic aqueous solution was acidified to pH 2.0 with hexahydrate hydrochloric acid saturated with sodium chloride, and extracted 2 times with ethyl acetate. The organic fractions are washed with brine, combined and dried with magnesium sulfate. Concentrate in vacuo to give 18.6 g of an oil. Flash chromatography on 1700 ml of silica gel EL-PS-1, eluting with 200: 1 ethyl acetate: acetic acid, affords 9.35 g of the title compound B as a crude solid. Crystallization from isopropyl ether yielded 7.75 g of this compound, with a temperature of 110-111 ^{° C,} [α] _D = -28,8 ^o (C = 0.96, ethanol).

 C) (2S-4S) -4- (phenylmethoxy) -1- (tert-butoxycarbonyl) -2-pyrrolidinemethanol.

A solution of compound from Part B (7.75 g, 24 mmol) of ethyl chloroformate in 150 ml of dry tetrahydrofuran under argon at 15-20 ^{° C} was treated dropwise with a solution of triethylamine (2.44 g, 24 mmol) in 10 ml of tetrahydrofuran for 10-15 minutes After stirring for 2 hours, the solids were filtered off and washed with fresh tetrahydrofuran. The combined filtrate and washings were cooled in a water bath at 15 ^{° C} and treated dropwise with a solution of sodium borohydride (1.36 g, 36 mmol) in 10 mL of water. After stirring at room temperature for 4 hours, the volatiles were removed in vacuo and the residue dissolved in ethyl acetate was washed with 1N. hydrochloric acid, water. 1 n sodium hydroxide solution, water and brine. The dried organic portion of magnesium sulfate was concentrated in vacuo to give 7.2 g of a crude product. Flash chromatography on 1 L of silica gel EL-Es-1, eluting with a mixture of 4 g ethyl acetate: hexane (3: 7) and 2 l of a mixture of ethyl acetate: hexane (1: 1) gives 6.15 g of the compound indicated The title C compound as an oil, [α] _D = -18,5 ^o (C = 1.5, hlororforme).

 D) (2S, 4S) -4- (phenylmethoxy) -1- (tert-butoxycarbonyl) -2- (4-methylphenylsulfonyloxy) methyl) pyrrolidine.

 A solution of the title compound C (3.0 g, 9.6 mmol) in 15 ml of pyridine was treated with toluenesulfonyl chloride (2.05 g, 10.7 mmol) and stirred under argon at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with 1 N hydrochloric acid until the aqueous wash became acidic (3.4 times), then with water, sodium bicarbonate and brine. The dried organic portion of magnesium sulfate was concentrated in vacuo to give 4.55 g of an oil. Flash chromatography on 800 ml of silica gel EP-El-1, eluting with 1: 4 ethyl acetate: hexane, affords 3.9 g of the title compound D.

[α] _D = -8.01 ^about (C = 1.76, in chloroform).

 E) (3R- (1 (2S *, 4S), 3α, 4α)) - 1- (1- (tert-butoxycarbonyl) -4- (phenylmethoxy) -2-pyrroli-dinyl) methyl) -3-hydroxy -1,3,4,5-tetrahydro-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

Solution (3R-cis)) - 3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (2.35 g, 6.7 mmol) and title compound D ) (3.50 g, 7.6 mmol) in 25 ml of dry dimethylformamide under argon was treated with cesium carbonate (3.26 g, 10.05 mmol), then heated ^at 50 ° C overnight. Benzazepine source remains, although tosylate consumed, and the mixture was stirred at ⁶⁰ ° C for an additional 2 days. The reaction mixture diluted with ethyl acetate was washed with water and brine, dried with magnesium sulfate and concentrated in vacuo to give 4.87 g of an oil. Flash chromatography on silica gel 1000 ml E-P-Es-1, eluting with 5: 1 toluene: ethyl acetate to give 3.36 g of the title E, [α] _D = +113,2 ^a (C = 0.87 mol / L, in chloroform).

 F) (3R- (1 (2S *, 4S *), 3α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1 - ((4-phenylmethoxy -2-pyrrolidinyl) methyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 The compound from Part E) (3.1 g, 4.84 mmol) was dissolved in 10 ml of dichloromethane and treated with 7.5 ml (0.1 mol) of trifluoroacetic acid. The mixture is heated at the boiling point for 1 hour. Volatiles are distilled off in vacuo the residue dissolved in ethyl acetate, washed with sodium bicarbonate solution, water and brine. The organic part is dried with magnesium sulfate, concentrated in vacuo, 2.5 g of oil are obtained, flash chromatography on 800 ml of silica gel EPI-1 eluting with ethyl acetate: methanol (93: 7) gives 2.08 g of the title compound as an oil.

[α] _D = +141.1 ^about (C = 0.88 mol / l, in chloroform).

The above free base (700 mg, 1.3 mmol) was dissolved in 15 ml of acetonitrile and treated with excess ethereal HCl. Volatiles are distilled off in vacuo, the residue is triturated with diisopropyl ether to obtain 0.73 g of salt in the form of an off-white powder with a melting point of 120-140 ^about C.

[α] _D = +78.6 ^about (C = 0.90 mol / l, in methanol).

 Calculated,%: C 62.03; H 5.63; N 4.82; Cl 6.10; F 9.81.

C ₃₀ H ₃₁ F ₂ N ₂ O ₄ ˙HCl ˙ 0.2 ˙H ₂ O.

 Found,%: C 61.93; H 5.77; N, 4.92; Cl 6.01; F 9.79.

 PRI me R 40. (3R- (1 (2S *, 4S *), 3 α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-1 - ((4-hydro - si-2-pyrrolidinyl) methyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

A solution of 1.25 g (2.31 mmol) of the title compound of Example 39 in 15 ml of methanol containing 400 mg of 10% palladium-carbon catalyst was treated with 0.73 g (11.6 mmol) of ammonium formate and the mixture refluxed overnight. According to TLC, the reaction did not end. Additionally, 0.2 g of catalyst and 0.3 g of ammonium formate are added and boiling is continued overnight. The catalyst is filtered off through Celite, and the solvent is distilled off in vacuo. The residue was dissolved in ethyl acetate and washed with 1N. sodium hydroxide solution, water and brine. The organic portion is dried with magnesium sulfate, concentrated in vacuo; 0.75 g of oil is obtained. Flash chromatography on 200 ml silica gel EPI-1 (pretreated with 100: 1 methylene chloride: triethylamine), eluting with ethyl acetate: methanol (95: 5), gives 0.50 g of the title compound as foam, [α] _D = +148.9 ^about (C = 0.85 mol / l, in chloroform).

The above free base (480 mg, 1.06 mmol) was dissolved in 10 ml of acetonitrile and treated with excess ethereal HCl solution, which precipitated the salt. This salt was collected, washed with acetonitrile and ether, dried in vacuo over phosphorus pentoxide at ¹⁰⁰ ° C to give 436 mg of product, m.p. 252-255 ^about C. [α] _D = +84.8 ^about (C = 0.56 mol / l, in methanol).

 Calculated,%: C 56.73; H 5.38; N, 5.75; Cl 7.28; F 11.71.

C ₂₃ H ₂₅ F ₃ N ₂ O ₄ ˙HCl ˙0.5 ˙H ₂ O.

 Found,%: C 56.55; H 5.26; N, 5.70; Cl 7.48; F 11.74.

 PRI me R 41. (3R- (1 (3S *, 5S *), 3 α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-1 - ((5- ( hydroxymethyl) -3-pyrrolidinyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monofumarate.

 A) (2S, 4R) -4-hydroxy-2-pyrrolidinecarboxylic acid, methyl ether.

 Acetyl chloride (7.6 ml, 107 mmol) was slowly added to 70 ml of methanol. This reaction is exothermic. 10 g of (2S, 4R) -4-hydroxy-2-pyrrolidinecarboxylic acid (76.2 mmol) are added and the mixture is refluxed for 4 hours. After that, another portion of acetyl chloride (3 ml) in 30 ml of methanol is added. . The mixture was boiled for another 3 hours. The reaction mixture was cooled to room temperature and about 750 ml of diethyl ether was added. The colorless crystals formed are filtered off and dried, yielding 11.89 g of the title compound A.

 B) (2S, 4R) -4-hydroxy-1- (phenylmethyl) -2-pyrrolidindinecarboxylic acid, methyl ether.

 A mixture of the compound from Part A (11.85 g, 65.2 mmol), triethylamine (18.55 ml, 130.04 mmol) and 15 ml of gasoline chloride (130.04 mmol) was refluxed in 60 ml of dichloromethane for 7 h. The resulting suspension is distributed between chloroform and 1 N. sodium hydroxide solution. The organic layer is washed with 1 N. sodium hydroxide, then brine. The organic layer was then dried with sodium sulfate and concentrated. The crude residue was flash chromatographed on a silica gel column (12 x 35 cm), which was eluted as follows: 1) 2 L of dichloromethane; 2) 4 l of a mixture of 3% methanol in dichloromethane and 4 l of a mixture of 5% methanol in dichloromethane. Pure fractions were concentrated to obtain 15.3 g of the title compound B as a colorless oil.

 C) (2S, 4R) -4-hydroxy-1- (phenylmethyl) -2-pyrrolidinemethanol.

A suspension of lithium aluminum hydride (5 g, 126 mmol) in 250 ml of diethyl ether was cooled ^to 0 ° C was added dropwise the compound in the title (9.88 g, 42 mmol) as a solution in 150 ml of diethyl ether. After stirring for 1 h at ⁰ ° C, the reaction was cautiously quenched by the addition of 5 ml of water, 5 ml of 15% sodium hydroxide solution and 15 ml of water. After stirring for 1 h at room temperature, the suspension was filtered through Celite, and the filter cake was washed thoroughly with ether. The filtrate was concentrated and evaporated with toluene (2 times 100 ml) to obtain 7.97 g of the title compound C as a colorless oil.

 D) (2S, 4R) -4-hydroxy-1- (phenylmethyl) -2- (tert-butyldiphenylsilyloxymethyl) pyrrolidine.

tert-butylchlorodiphenylsilane (11.05 mL, 42.5 mmol) was added dropwise to a solution of the title C (7.97 g, 38.5 mmol) in 20 mL of pyridine at 0 ° ^C. After stirring for 1 hour, the reaction mixture was partitioned between ether and water. The organic layer is washed 2 times with water (50 ml each), dried with magnesium sulfate and concentrated. The crude residue was flash chromatographed on a silica gel column (2.5 x 40), which was first eluted with 2 L of methylene chloride and then with a mixture of 5% methanol in methylene chloride (2 L). Pure fractions are combined and mixed fractions are re-chromatographed on a column (5x25 cm) with silica gel, which is eluted with a mixture of 2% methanol in dichloromethane. All pure fractions were concentrated to give 9.88 g of the title compound D).

 E) (2S-4R) -4 - ((4-methylphenylsulfonyloxy) methyl) -1- (phenylmethyl) -2- (tert-butyldiphenylsilyloxymethyl) pyrrolidine.

Para-toluenesulfonyl chloride (3.1 g, 16.3 mmol) was added to a solution of the compound from part D) (4,56 g, 10.9 mmol) in 12 mL of pyridine at 0 ° ^C. After stirring for 1 h at ⁰ ° C and 4 hours at room temperature, the reaction mixture was partitioned between an aqueous sodium hydrogen carbonate solution and ether. The organic layer was dried with magnesium sulfate and evaporated. According to TLC, significant amounts of the compound from D) were not reacted. The residue was redissolved in 12 ml of pyridine and 2 g of para-toluenesulfonyl chloride (11 mmol) was added. The reaction mixture was stirred for an additional 18 hours. After the above treatment, a crude residue (5.8 g) was obtained, which was purified by flash chromatography on a 5x25 cm silica gel column (eluent mixture: 1: 4 ethyl acetate and hexane). Pure fractions were concentrated to obtain 4.44 g of the title compound E as a pale yellow oil.

 F) (3R- (1 (3S *, 5S *), 3α, 4α)) - 1- (5- (tert-butyldiphenylsilyloxymethyl) -1- (phenylmethyl) -3-pyrrolidinyl) -1.3, 4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 A mixture of the title compound E), (3.0 g, 5 mmol), (3R-cis) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- ( trifluoromethyl) -2H-1-benzazepin-2-one (1.58 g, 4.5 mmol) and cesium carbonate (7.34 g, 22.5 mmol) in 45 ml of distilled methyl ethyl ketone are refluxed for 18 hours The reaction mixture was cooled to room temperature, 50 ml of ethyl ether was added, and the suspension was filtered through Celite. The filter cake was washed well with ether, and the filtrate was concentrated to a dark orange oil. The crude product is purified by flash chromatography on a 5x25 cm silica gel column, which is eluted with a mixture of 15% ethyl acetate in hexane. Pure fractions were concentrated to give 2.4 g of the title compound F) as a colorless foam.

 G) (3R- (1 (3S *, 5S *), 3 α, 4 α)) - 1- (5- (hydroxymethyl) -1- (phenylmethyl) -3-pyrrolidinyl) -1,3,4,5 - tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 A solution of tetrabutylammonium fluoride (2.9 g, 9.18 mmol) in 15 ml of tetrahydrofuran is added to a stirred solution of the compound from Part F (3.19 g, 4.17 mmol) in 35 ml of tetrahydrofuran. After stirring for 2 hours, the reaction mixture was diluted with 100 ml of ethyl ether, and the ether layer was washed with 50 ml of water and 50 ml of brine. The organic layer was dried with magnesium sulfate and concentrated. The residue was purified by flash chromatography on a 5x30 cm silica gel column using a mixture of 5% methanol in dichloromethane as the eluent. Pure fractions are combined, and the mixed fractions are chromatographed again on a 5x30 cm silica gel column using the following elution scheme: 1 L of dichloromethane, 1 L of a mixture of 1% methanol in dichloromethane, 1 L of 2% methanol in dichloromethane, 0.5 L of 3% methanol in dichloromethane and 0.5 l of a mixture of 5% methanol in dichloromethane. Pure fractions were concentrated to give 1.788 g of the title G compound as a white foam.

 H) (3R- (1 (3S *, 5S), 3 α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-1 - ((5- (hydroxymethyl) -3-pyrrolidinyl) -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monofumarate.

 A solution of the substance from Part G (1.55 g, 2.87 mmol) in 30 ml of ethyl acetate was hydrogenated over a catalyst of 20% palladium hydroxide on carbon 175 mg) for 24 hours using a balloon device. After this, according to TLC, significant amounts of starting material remained. An additional 175 mg of catalyst was added and hydrogenation was continued for 48 hours. The reaction still did not end, so the reaction mixture was filtered through Celite and the filter cake was washed well with methanol (150 ml). The filtrate was concentrated to a dark residue, which was redissolved in 30 ml of methanol (from a fresh bottle). 370 mg of catalyst was added and the mixture was hydrogenated as indicated for 8 hours. After that, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography on a 5x25 cm silica gel column using the following elution scheme: 2 L of a mixture of dichloromethane: methanol: triethylamine, 94: 5: 1, 1 L of a mixture of dichloromethane: methanol: triethylamine, 89: 10: 1. Pure fractions were concentrated to a gray solid, which, when combined with a mixture of toluene: methanol = 1: 1 (50 ml) and ethyl acetate: methanol = 1: 1 (2 times 50 ml), gives 1.04 g of the title compound .

This free base (972 mg, 2.158 mmol) was dissolved in methanol and 250 mg (2.158 mmol) of fumaric acid was added as a solution in hot methanol. The solution was concentrated to a foam, which was dissolved in a mixture of methanol, isopropanol and ethanol and filtered through Celite. The filtrate was concentrated to a yellow crystalline solid, which was triturated with hot isopropanol to give 1.15 g of the title compound: white crystals, mp. 212-214 ^{° C} (decomposition), 168 ^{° C} (softening) 185 ^{° C} (browning).

TLC: Rf = 0.19 (eluent-dichloromethane: methanol: ammonium hydroxide = 95: 4: 1), free base
[α] _D = + 66.8 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 57.38; H 5.58; N 4.67; F 9.55.

C ₂₃ H ₂₅ F ₃ N ₂ O ₄ ˙C ₄ H ₄ O ₄ ˙0.5 ˙C ₃ H ₈ O.

 Found,%: C 57.33; H 5.59; N, 4.73; F 9.41.

 PRI me R 42. (3R- (1 (3R *, 5S *), 3α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-1 - ((5-hydroxymethyl ) -3- pyrrolidin-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monofumarate.

 F) (2S, 4S) -4- (phenylcarbonyloxy) -1- (phenylmethyl) -2- (tert-butyldiphenylsilyloxymethyl) pyrrolidine.

 Diethyl azodiarboxylate (2.80 ml, 16.3 mmol) was added dropwise over 5 minutes to a stirred solution of the compound from Part D of Example 41 (5 g, 11.2 mmol), triphenylphosphine (4.41 g, 16.8 mmol) and benzoic acid (3.14 g, 28 mmol) in 110 ml of tetrahydrofuran at room temperature. After stirring for 2 hours, the reaction mixture was partitioned between an aqueous sodium hydrogen carbonate solution and ether. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated. The residue was purified twice by flash chromatography on a 5x25 cm silica gel column (eluent: 5:95 ethyl acetate and hexane). The purest fractions are concentrated to give 3.97 g of the title A substance as a pale yellow oil.

 B) (2S, 4S) -4-hydroxy-1- (phenylmethyl) -2- (tert-butyldiphenylsilyloxymethyl) pyrrolidine.

 A mixture of the title compound A (3.95 g, 7.2 mmol), 1N. a solution of sodium hydroxide (72 ml, 72 mmol), 72 ml of tetrahydrofuran and 72 ml of methanol are refluxed for 1 hour. The reaction mixture is partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried with magnesium sulfate and concentrated. The residue was flash chromatographed on a silica gel column (5 x 20 cm), which was eluted with ethyl acetate: hexane (1: 3). Pure fractions were concentrated to give 1.85 g of the title compound B) as a colorless oil.

 C) (2S, 4S) -4 - ((4-methylphenylsulfonyloxy) methyl) -1- (phenylmethyl) -2- (tert-butyldiphenylsilyloxymethyl) pyrrolidine.

 A mixture of para-toluenesulfonyl chloride (1.2 g, 6.25 mmol) and the compound from part B) (1.85 g, 4.15 mmol) in 5 ml of pyridine was stirred for 18 hours at room temperature. The reaction mixture was partitioned between saturated sodium bicarbonate and ethyl ether. The organic layer was washed with brine, dried with magnesium sulfate and evaporated. The residue was purified by flash chromatography on a 5x25 cm silica gel column (eluent mixture 1: 9 ethyl acetate and hexane). Pure fractions were concentrated to obtain 2.3 g of the title compound C as a colorless oil.

 D) (3R- (1 (3E *, 5S *), 3α, 4 α)) - 1- (5- (tert-butyldiphenylsilyloxymethyl) -1- (phenylmethyl) -3-pyrrolidinyl) -1.3, 4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 A mixture of the title compound C), (2.0 g, 3.33 mmol), (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepine -2-one (1.2 g, 3.33 mmol), cesium carbonate (5.4 g, 16.7 mmol) and 30 ml of methyl ethyl ketone are refluxed for 20 hours. The reaction mixture is cooled to room temperature and added 50 ml of ethyl ether. The resulting thick suspension was filtered through Celite, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on a 5x25 cm silica gel column, which was eluted with a mixture of ethyl acetate and hexane (1: 4). Pure fractions were concentrated to give 980 mg of the title compound D. Concentration of the mixed fractions gives 800 mg of impure material, which is rechromatographed on a 5 x 35 cm column using the following elution scheme: 3 L of a mixture of 15% ethyl acetate in hexane, 1 L of 25% ethyl acetate in hexane. Pure fractions were combined with those from the first column to give 1.45 g of the title compound as a colorless oil.

 E) (3R- (1 (3R *, 5S *), 3α, 4α)) - 1- (5- (hydroxymethyl) -1- (phenylmethyl) -3-pyrrolidinyl) - 1,3,4,5 - tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 A normal solution of tetra-n-butylammonium fluoride (3.65 ml, 3.65 mmol) is added to a solution of the compound from Part D (1.395 g, 1.83 mmol) in 20 ml of tetrahydrofuran at room temperature. After stirring for 1 h, the reaction mixture was diluted with 50 ml of ethyl ether and the ether layer was washed with 50 ml of water. After washing with brine and drying with magnesium sulfate, the filtrate was concentrated to a yellow foam. The residue was purified by flash chromatography on a 5x30 cm silica gel column using ethyl acetate: hexane = 3: 1 as an eluent. Pure fractions were concentrated to give 0.85 g of the title compound E as a white foam.

 F) (3R- (1 (3R *, 5S *), 3α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-1 - ((5-hydroxymethyl) -3-pyrrolidinyl) - 4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monofumarate.

 A mixture of a substance from part E (0.80 g, 1.48 mmol) and a catalyst — 20% palladium hydroxide on carbon in 20 ml of acetic acid was hydrogenated for 18 h at room temperature using a balloon device. The catalyst was removed by filtration through Celite, and the filter cake was washed with acetic acid (20 ml). Removing acetic acid in vacuo gave an oil which was partitioned between saturated sodium carbonate and ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated to a white foam. This foam is purified by flash chromatography on a 5x20 cm silica gel column using the following elution scheme: 1 L of a mixture of 5% methanol in dichloromethane, 1 L of 10% methanol in dichloromethane, 2 L of 15% methanol in dichloromethane and 0.5 L of mixture 1: 1 methanol: dichloromethane. Pure fractions were concentrated to give 595 mg of the title compound as a white foam.

This free base (405 mg, 0.9 mmol) was dissolved in 3 ml of methanol and a solution of 104 mg (0.9 mmol) of fumaric acid in hot methanol (2 ml) was added. The resulting solution was concentrated to a solid which was triturated in ether and dried ^at 50 ° C and a pressure of 0.5 mm Hg, yielding 532 mg of the title compound - white powder, m.p. 121-130 ^about C (decomposes).

[α] _D = +68.0 ^about (C = 0.54 mol / l, in methanol).

 Calculated,%: C 54.78; H 5.42; N 4.72; F 9.63.

C ₂₈ H ₂₉ F ₃ N ₂ O ₈ ˙ 1.41 ˙ H ₂ O.

 Found,%: C 55.16; H 5.27; N, 4.79; F 9.24.

 PRI me R 43. (3R-cis) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-4 - (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) 2-Chloromethylimidazoline

To a cooled solution of 2-chloromethylimidazoline hydrochloride (3 g, 19.4 mmol) (preparation is described in Halh.Chim. Acta v. 27, 1773, 1944) in about 5 ml of water was added about 75 ml of anhydrous ethyl ether. An excess of solid potassium carbonate was added to this solution, and the resulting mixture was stirred for 10 minutes. The ether layer was decanted and the remaining suspension was washed 4 times with about 75 ml of anhydrous ethyl ether. The ether layers are combined and dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo afforded 1.89 g of the compound indicated in heading A as a white foam, mp. 63-64 ^about S.

 B) (3R-cis) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl-1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 6-trifluoromethyl) -2H-1-benzazepin-2-one.

Solution (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (4.44 g, 12.6 mmol) and 0.62 g (15.5 mmol) of 60% sodium hydride dispersion in mineral oil in 70 ml of dry dimethylformamide (dried over 4A sieves) was heated at ⁷⁰ ° C, 30 min. Then 2-chloromethylimidazoline (1.08 g, 9.1 mmol) was added. The mixture was allowed to stir for 1 h at 70 ^C. The reaction mixture was washed 2 times with ice water. The organic layers were combined, dried over anhydrous magnesium sulfate and then evaporated in vacuo to give a yellowish residue. This residue was dissolved in ethyl acetate and flash chromatographed (800 ml of silica gel pretreated with a 10: 1: 1 ethyl acetate solution: methanol-triethylamine). Elution with 10: 1: 0.1 ethyl acetate / methanol / triethylamine gives 2.55 g of the title B, [α] _D = +116,5 ^o (C = 1.07, methanol).

 C) (3R-cis) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6-trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

A solution of the compound from Part B (1.02 g, 2.5 mmol) in 30 ml of acetonitrile was treated with excess ethereal HCl. The solvents were removed by evaporation in vacuo and the residue was triturated with anhydrous ethyl ether to give the title compound (1.03 g). This compound (0.96 g, 2.04 mmol) was recrystallized from dichloromethane and diisopropyl ether to give 0.86 g of the title compound, mp. 128-130 ^about C. [α] _D = +90.6 ^about (C = 0.98, methanol).

 Calculated,%: C 53.77; H 5.21; N, 8.55; Cl 7.21; F 11.60.

C ₂₂ H ₂₂ F ₃ N ₃ O ₃ ˙ HCl ˙ 1.2 ˙ H ₂ O.

 Found,%: C 53.77; H 4.91; N, 8.55; Cl 7.14; F 11.38.

 PRI me R 44. cis-1 ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-7- (methoxymethoxy) - 4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, monofumarate.

The title compound was prepared using the procedure described in Example 43, but in step B of this example, (3R-cis) -3-hydroxy-4- (4-methoxyphenyl) -6-trifluoromethyl) -2H-1-benzazepinone- was replaced 2 on cis-3-hydroxy-7-methoxymethoxy-4- (4-methoxyphenyl) -2H-1-benzazepinone-2, mp. 200-210 ^about C (decomposes).

 Calculated,%: C 58.28; H 5.91; N, 7.55.

C ₂₃ H ₂₇ N ₃ O ₅ ˙ C ₄ H ₄ O ₄ ˙ 0.83 ˙ H ₂ O.

 Found,%: C 58.46; H 5.73; N, 7.37.

 PRI me R 45. (3R-cis) -1,3,4,5-tetrahydro-3-hydroxy-1 - ((1H-imidazol-2-yl) methyl) - 4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (3R-cis) -1 - ((1H-3-phenylmethyl-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6 trifluoromethyl) -2H-1-benzazepin-2-one.

 Solution (3R-cis (-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (2.02 g, 5.74 mmol), 1-phenylmethyl- 2-chloromethyl-imidazole hydrochloride (1.67 g, 6.87 mmol) (its preparation is described in IACS, vol. 71, p. 383, 1949) and a 60% dispersion of sodium hydride in mineral oil (0.59 g , 14.8 mmol) are allowed to stir overnight.

The reaction is quenched by the addition of 1 N. hydrochloric acid and then neutralized with a 50% sodium hydroxide solution to a pH of about 11. The reaction mixture was extracted 2 times with ethyl acetate. The organic salts are combined and washed twice (50 ml) with saturated sodium bicarbonate solution, then 2 times (50 ml) with brine. Solvents were removed in vacuo to give a tan oil. Flash chromatography on 800 ml silica gel EP-Es-1, using a 20: 1 mixture of ethyl acetate and methanol gives 1.11 g of the compound indicated in title A, in the form of a solid white foam, [α] _D = +105, 0 ^about (C = 1.01, methanol).

 B) (3R-cis) -1 - ((1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzase-pin-2-one.

 A solution of the compound from title A (1.09 g, 1.95 mmol) in 0.24 g of catalyst — 10% palladium on charcoal in 5 ml of 96% alcohol was hydrogenated at atmospheric pressure overnight.

 The reaction mixture was filtered and the solvents removed in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with 1N. sodium hydroxide solution. The aqueous phase is extracted three times with ethyl acetate. The combined organic layers were dried with magnesium sulfate and concentrated in vacuo to give 666 mg of the compound from title B as a solid white foam.

 C) (3R-cis) -1,3,4,5-tetrahydro-3-hydroxy-1 - ((1H-imidazol-2-yl) methyl) - 4- (methoxyphenyl) -6- (trifluoromethyl) -2H -1-benzase-pin-2-one, monohydrochloride.

A solution of the compound from title B (0.52 g, 1.21 mmol) in acetonitrile was treated with excess hydrogen chloride in an ether solution. Volatiles are removed in vacuo to give a white solid. This was triturated with isopropyl ether and dried in vacuo over phosphorus pentoxide at ¹⁰⁰ ° C, to obtain 0.45 g of the title compound.

Mp 188-191 ^about S.

[α] _D = +101.0 ^about (C = 1.02, methanol).

 Calculated,%: C 56.03; H 4.58; N, 8.91; Cl 7.52; F 12.09.

C ₂₂ H ₂₀ F ₃ N ₃ O ₃ ˙HCl ˙ 0.2 ˙H ₂ O.

 Found,%: C 56.20; H 4.35; N, 8.92; Cl 7.15; F 11.71.

 PRI me R 46. (2R- (2a, 3a, 5 (R *))) - 3- (acetyloxy) -2,3-dihydro-2- (4-methoxyphenyl) - 5- (2-pyrrolidinylmethyl ) -1,5-benzathiazepin-4 (5H) -one, monohydrochloride.

 A) S-1- (tert-butoxycarbonyl) -2 - ((4-methylphenylsulfonyloxy) methyl) pyrrolidone.

 To S-1- (tert-butoxycarbonyl) -2-pyrrolidiniethanol (20.6 g, 102.4 mmol) in 100 ml of pyridine at room temperature in argon, para-toluenesulfonyl chloride (23.4 g, 122.8 mmol) is added with stirring ) After 5 hours, another 9.8 g (51.2 mmol) of para-toluenesulfonyl chloride was added. After total stirring for 23 hours, the reaction mixture was diluted with ethyl acetate and washed with a saturated solution of copper sulfate in water (3 times). The organic layer was dried with magnesium sulfate, filtered and concentrated. The yellow liquid was chromatographed on a silica gel column, which was eluted with 10-30% ethyl acetate in hexane to give 32.1 g of the title compound A as a viscous colorless liquid.

 B) (2S- (2, 3, 5 (R *))) - 2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (1- (tert-butoxycarbonyl) -2-pyrrolidinyl ) methyl) -1,5-benzothiazepin-5- (5H) -one.

(2S-cis) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (3.56 g, 11.81 mmol), cesium carbonate (5.77 g, 17.72 mmol) and the compound of the title a (6.30 g, 17.72 mmol) in 40 ml of dimethylformamide was heated to 50 ^C. After 16 h, the reaction mixture was cooled to room temperature, diluted with water and extracted with ether (3 times). The combined extracts are washed 3 times with a 10% aqueous solution of lithium chloride, dried with magnesium sulfate, filtered and concentrated. The yellow foam is chromatographed on a silica gel column. Elution with 10-25% ethyl acetate in hexane afforded 4.51 g of the title compound B as a yellow foam.

 C) (2S- (2, 3, 5 (R *))) - 2α, 3 α-dihydro-3- (acetyloxy) -2- (4-methoxyphenyl) -5- (1- (tert-butoxycarbonyl) - 2-pyrrolidinyl) methyl) -1,5-benzothiazepin-4- (5H) -one.

 The title compound B (1.0 g, 2.06 mmol) 4-dimethylaminopyridine (0.50 g, 4.13 mmol) and acetic anhydride (1.05 ml, 10.3 mmol) in 20 ml of dichloromethane are stirred at room temperature in argon for 15 hours. The reaction solution was taken up on silica gel (60-200 mesh) and chromatographed on a silica gel column. Elution with 5-20% ethyl acetate in hexane affords the title compound C (0.94 g), a white solid.

 D) (2S- (2α, 3 α, 5 (R *))) - 3- (acetyloxy) -2,3-dihydro-2- (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1.5 -benzothiazepine-4- (5H) -one, monohydrochloride.

The title compound C (0.84 g, 1.60 mmol) in 5 ml of trifluoroacetic acid and 5 ml of dichloromethane was stirred under argon at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, then diluted with an aqueous solution of hydrogen carbonate potassium and extracted 3 times with ethyl acetate. The combined extracts were dried with magnesium sulfate, filtered and concentrated. The yellow foam was dissolved in ethyl acetate and an excess of ethereal HCl was added. Concentration followed by trituration in 50 ml of ether afforded 0.75 g of the title compound as a white foam with mp. 132-135 ^about C, [α] _D = +66.06 ^about (C = 1 methanol).

 Calculated,%: C 58.01; H 6.03; N, 5.88; Cl 7.44; 6.73.

C ₂₃ H ₂₆ N ₂ O ₄ 5 ˙ HCl ˙ 0.73 ˙ H ₂ O
Found,%: C 58.00; H 6.06; N, 5.89; Cl 7.18; 6.48.

 PRI me R 47. (2S- (2 α, 3α, 5 (R *))) - 3-acetyloxy) -2,3-dihydro-8-methoxy-2- (4-methoxyphenyl) - 5- (2-pyrrolidinylmethyl) -1,5-benzothiazepin-4 (5H) -one, monohydrochloride.

The title compound was prepared using the procedure of Example 46, but replaced in Part B of this Example with (2-cis) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) 1,5-benzothiazepine- 4 (5H) -one on cis-2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -8-methoxy-1,5-benzothiazepin-4 (5H) -one, m.p. 147-154 ^about C, [α] _D = +50.0 ^about (C = 1, methanol).

 Calculated,%: C 56.63; H 6.09; N, 5.51; Cl 6.97; S 6.30.

C ₂₄ H ₂₈ N ₂ O ₅ S ˙HCl ˙ 0.89 ˙H ₂ O.

 Found,%: C 56.72; H 5.94; N, 5.42; Cl 7.15; S 6.30.

 PRI me R 48. (2S- (2 α, 3α, 5 (R *))) - 2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1,5-benzothiazepine-4 (5H) -one, monohydrochloride.

 A) (2S- (2α, 3 α, 5 (R *))) - 2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (1- (benzyloxycarbonyl) -2-pyrrolidinyl) methyl) -1,6-benzotiazepine-4 * 5H) -one.

(25-cis) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (1.25 g, 4.15 mmol), cesium carbonate (2.03 g, 6.22 mmol) and 5-1- (benzyloxycarbonyl) -2 - ((4-methylphenylsulfonyloxy) methyl) pyrrolidine (2.02 g, 5.19 mmol) in 20 ml of dimethylformamide are heated to 50 ^about C. After 23 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted 3 times with ether. The combined extract is washed 3 times with a 10% solution of lithium chloride in water, dried with magnesium sulfate, filtered and concentrated. The viscous yellow oil is chromatographed on a silica gel column, which is eluted with 15-30% ethyl acetate in hexane to give the title compound A (1.74 g) as a white solid.

 B) (2S- (2a, 3a, 5 (R *))) - 2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) -1,5-benzothiazepine- 4 (5H) -one, monohydrochloride.

The title compound A (1.2 g, 2.31 mmol), 1.2 g of the catalyst — 10% palladium on carbon (100 wt.%) And ammonium formate (1.2 g, 19.0 mmol) in 40 ml of methanol is heated to a boil. After 5 hours, another 0.6 g of catalyst was added and stirring was continued for another 19 hours. The reaction mixture was cooled to room temperature and anhydrous magnesium sulfate was added before filtration. The solids are washed well with methanol. The filtrate was concentrated, and the residue was diluted with saturated aqueous potassium hydrogen carbonate and extracted 3 times with ethyl acetate. The combined extract was dried with magnesium sulfate, filtered and concentrated to give a pale yellow foam, which was dissolved in dichloromethane. To the solution was added an excess of HC 1 dissolved in ether. Removal of volatile compounds under reduced pressure, followed by trituration of the solid residue in a 2: 1 mixture of ether: dichloromethane, gives the title compound (0.35 g), an amorphous white solid. Mp above 240 ^about C (decomposes).

[α] _D = +91.6 ^about (C = 1, methanol).

 Calculated,%: C 58.26; H 6.06; N, 6.47; Cl 9.01; S 7.41.

C ₂₁ H ₂₄ N ₂ O ₃ S ˙ 1.1 ˙ HCl ˙ 0.46 ˙ H ₂ O.

 Found,%: C 58.45; H 5.76; N, 6.28; Cl 9.35; S 7.41.

 PRI me R 49. (2S- (2a, 3a, 5 (R *)) - 2,3-dihydro-2- (4-methoxyphenyl) -3- (2-methyl-1-oxopropoxy) - 5- (2-pyrrolidinylmethyl) -1,5-benzothiazepin-4 (5H) -one, monohydrochloride.

 A) (2S- (2α, 3 α, 5 (R *))) - 2,3-dihydro-3- (2-methyl-1-oxopropoxy)) - 2- (4-methoxyphenyl) - 5- (1 - (tert-butoxycarbonyl) -2-pyrrolidinyl) methyl) -1,5-benzothiazepine-4 (5H) -one.

 Solution (2S- (2a, 3a, 5 (R *))) - 2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (1- (tert-butoxycarbonyl) -2- (pyrrolidinyl ) methyl) -1,5-benzothiazepine-4 (5H) -one (847 mg, 1.75 mmol), N, N-dimethylaminopyridine (427 mg, 3.5 mmol) and isobutyric acid anhydride (600 mg, 3, 6 mmol) in dichloromethane (25 ml) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residual oil was chromatographed on a silica gel column. Elution with 10-20% ethyl acetate in hexane gave 870 mg of the title compound A as a white foam.

 B) (2S- (2a, 3a, 5 ((R *))) - 2,3-dihydro-2- (4-methoxyphenyl) -3- (2-methyl-1-oxopropoxy) -5- (2- pyrrolidinylmethyl) -1,5-benzothiazepine-4 (5H) -one, monohydrochloride.

The title compound A (1.02 g, 1.84 mmol) in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid was stirred at room temperature for 15 minutes. Then the reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of potassium hydrogen carbonate. The aqueous layer was extracted 3 times with ethyl acetate and the combined organic layers were dried (magnesium sulfate), filtered and concentrated. The yellow solid was chromatographed on a silica gel column (pretreated with 1% triethylamine) and eluted with a mixture of 7% methanol in dichloromethane. The free amine is dissolved in ether and converted to the hydrochloride salt by adding excess ether solution of hydrogen chloride. Upon concentration, a pale yellow foam is obtained, which is triturated thoroughly with ether and filtered. The yield of the title compound was 0.70 g, yellow solid, mp. 197-199 ^about C (decomposes).

[Α] _D = +34,86 ^o (C = 1, methanol).

 Calculated,%: C 60.47; H 6.42; N, 5.64; Cl 7.14; S 6.46.

C ₂₅ H ₃₀ N ₂ O ₄ S ˙HCl ˙ 0.3 ˙H ₂ O.

 Found,%: C 60.32; H 6.38; N, 5.76; Cl 6.80; S 6.55.

 PRI me R 50. (2S- (2a, 3a, 5 (R *))) - 2,3-dihydro-2- (4-methoxyphenyl) -3 - ((methyl-amino) carbonyl) oxy- 5- (2-pyrrolidinylmethyl) - 1,5-benzothiazepin-4 (5H) -one, monohydrochloride.

 A) 2S- (2a, 3a, 5 (R *))) - 2,3-dihydro-3 - (((methylamino) carbonyl) -oxy) -2- (4-methoxyphenyl) -5- (1- ( 1- (tert-butyloxycarbonyl) -2-pyrrolidinyl) methyl) -1,5-benzothiazepin-4 (5H) -one.

To a solution of (2S- (2a, 3a, 5 (R *))) - 2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -5- (1- (tert-butoxycarbonyl) -2-pyrrolidinyl ) -methyl) -1,5-benzotiazepin- 4 (5H) -one (1.0 g, 2.06 mmol) in 15 ml of anhydrous dichloromethane at ⁰ ° C was added with stirring 116 ml (0.82 mmol) and 0 19 g of methyl isocyanate (3.30 mmol). The reaction mixture was allowed to warm to room temperature. After 10 hours, an additional 0.19 g (3.39 mmol) of methyl isocyanate was added, and stirring was continued for another 5 hours. Water was added, the aqueous mixture was extracted 3 times with ethyl acetate. The combined organic extracts are dried with magnesium sulfate, filtered and concentrated. The crude white foam was chromatographed on a silica gel column and eluted with a mixture of 10-20% ethyl acetate in hexane to give 0.89 g of the title compound A as a white foam.

 B) (2S- (2a, 3a, 5 (R *))) - 2,3-dihydro-2- (4-methoxyphenyl) -3 - (((methylamino) carbonyl) oxy) -5- (2-pyrrolidinylmethyl ) -1,5-benzothiazepin-4 (5H) -one, monohydrochloride.

The title compound A (0.89 g, 1.64 mmol) of 5 ml of dichloromethane and 5 ml of trifluoroacetic acid was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the resulting residue was dissolved in ethyl acetate, and washed with a saturated aqueous solution of potassium hydrogen carbonate. The organic layer was separated and the aqueous layer was extracted 2 times with ethyl acetate. The combined organic layers are dried with magnesium sulfate, filtered and concentrated. The free base is dissolved in ether with a minimal addition of ethyl acetate to ensure a homogeneous solution. Excess HCl ethereal solution was added and the volatiles removed under reduced pressure to give 0.66 g of the title compound as a pale yellow solid, mp. 170-177 ^about S.

[α] _D = +37.02 (C = 1, methanol).

 Calculated,%: C 55.70; H 6.10; N, 8.47; Cl 7.15; S 6.46.

C ₂₃ H ₂₇ N ₃ O ₄ S ˙HCl ˙ 1.0 ˙H ₂ O.

 Found,%: C 65.79; H 5.81; N, 8.49; Cl 7.03; S 6.50.

PRI me R 51. (3R- (1 (S), 3α, 4α)) - 3- (acetyloxy) -1,3,4,5-tetrahydro-7-methoxy-4- (4-methoxyphe- nyl) - 1- (2-pyrrolidinylmethyl) -2H-1-benzazepin-2-one, monohydrochloride. The title compound was prepared using the procedures of Example 13 using cis-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, mp. above 250 ^about C.

[α] _D = +92.17 ^o (C = 1.0 mol / L, in methanol).

 Calculated,%: C 62.74; H 6.61; N, 5.86; Cl 7.41.

C ₂₅ H ₃₀ N ₂ O ₅ ˙HCl ˙ 0.2 ˙H ₂ O.

 Found,%: C 62.88; H 6.70; N, 6.04; Cl 7.26.

 PRI me R 52. (2S- (2α, 3α)) - 2,3-dihydro-5- (4,5-dihydro-1H-imidazol-2-yl) methyl) -3-hydroxy-2- (4-methosiphenyl) -1,5-benzothiazepin-4 (5H) -one, monohydrochloride.

The title compound was prepared using the procedures of Example 43 using (2R-cis) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one. The product crystallizes from ethanol. T. pl. 252 ^{° C} (decomposing.).

[α] _D = +94.0 ^about (C = 1.0 mol / l, in methanol).

 0.28 (eluent 18: 1: 1 dichloromethane: methanol: acetic acid).

 Calculated,%: C 55.53; H 5.45; N, 9.71; Cl 8.20; S 7.41.

C ₂₀ H ₂₁ N ₃ O ₃ S ˙HCl ˙ 0.7 ˙ H ₂ O.

 Found,%: C 55.38; H 5.64; N, 9.68; Cl 8.50; S 7.55.

 PRI me R 53. (2S- (2 α, 3α)) - 3-acetyloxy) -2,3-dihydro-2- (4-methoxyphenyl) -5- (2-pyridridinylmethyl) -1.5- benzothiazepine-4 (5H) -one, monohydrochloride.

The title compound was prepared by heating the compound, the title Example 23 with acetic anhydride for 3 hours at 110-115 ^C. The colorless product was crystallized from acetonitrile, m.p. 200-202 ^{° C} (decomposing.).

[α] _D = +137.0 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 57.88; H 5.26; N, 5.63; Cl 7.12; S 6.44.

C ₂₄ H ₂₂ N ₂ O ₄ S ˙HCl ˙1.5 ˙H ₂ O.

 Found,%: C 59.09; H 5.20; N, 5.62; Cl 7.48; S 6.52.

 PRI me R 54. (3R-cis) -3- (acetyloxy) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) - 1,3,4,5-tetrahydro -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (3R-cis) -1 - ((4,5-dihydro-1- (tert-butosicarbonyl) -imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-4 - (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-1-benzazepin-2-one.

A solution of the title compound of Example 43 (3.83 g, 8.84 mmol) in 30 ml of dried methylene chloride was treated with tert-butoxycarbonyl anhydride (2.77 g, 12.7 mmol) (1.4 equiv.) And dimethylaminopyridine (0.11 g, 0.9 mmol). The solution was stirred overnight. The reaction mixture was concentrated to a volume of about 15 ml and flash chromatographed on about 800 ml of El-P-Es-1 silica gel using a 2: 1 mixture of hexane and ethyl acetate as the driving phase. Removal of the solvents in vacuo gave 1.51 g of the compound indicated in title A as a white solid foam, mp. 114-116 ^about S.

 B) (3R-cis) -3- (acetyloxy) -1 - ((4,5-dihydro-1- (tert-butoxycarbonyl) - imidazol-2-yl) methyl) -1,3,4,5-tetrahydro -4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

A solution of the title compound A (1.50 g, 2.8 mmol) in 30 ml of dried dichloromethane was treated with acetic anhydride (1.66 g, 16.2 mmol, 5.8 eq) and dimethylaminopyridine (0.68 g, 5.7 mmol, 2 equiv.). The solution was stirred overnight. The reaction mixture is taken up in approximately 30 ml of Celite and chromatographed on 350 ml of silica gel l-Pi-Es-1-eluent mixture 1.5: 1: 0.1 - hexane: ethyl acetate: methanol). Removing the solvents in vacuo left 0.96 g of the title B compound as a white foam with mp. 105-108 ^about S.

 C) (3R-cis) -3- (acetyloxy) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-4- (4- methoxyphenyl) -6-trifluoromethyl) -2H-1-benzazepin-2-one, monohydrochloride.

A solution of the title compound B (0.87 g, 1.5 mmol) in 10 ml of dried dichloromethane was treated with 10 ml of trifluoroacetic acid. The reaction mixture was stirred for 2 hours at room temperature. The solvents are removed in vacuo, the resulting oil is dissolved in ethyl acetate. The ethyl acetate layer was washed twice with saturated potassium carbonate solution and then with brine. The organic layer was dried over magnesium sulfate and the solvents were removed in vacuo to give 0.77 g of a white foam with mp 109-111 ^about C. A solution of the indicated free base (0.74 g, 1.6 mmol) in ethyl acetate is treated with an excess of a solution of HCl in ether. The resulting solid was collected and washed 4 times with ethyl acetate. The solid was dissolved on the filter with acetonitrile and the solvents removed in vacuo to give 0.42 g (51%) of the title compound as a white solid, mp. 260-261 ^about S.

[α] _D = +84,6 ^o (C = 1.11, methanol).

 Calculated,%: C 53.72; H 5.04; N, 7.83; Cl 10.62; F 6.61.

C ₂₄ H ₂₄ F ₃ N ₃ O ₄ ˙HCl ˙ 1.43 ˙H ₂ O.

 Found,%: C 53.87; H 5.14; N, 7.68; Cl 10.70; F 6.79.

 PRI me R 55. (3R-cis) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-7 methoxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (3R- (3a, 4a, 3S *)) - 3- (2-benzyloxycarbonylaminophenyl) propionyl- 1,3,4,5-tetrahydro-7-methoxy-4- (4-methoxyphenyl) -2H-1 - benzazepin-2-one (7.24 g, 23.1 mmol) in 70 ml of tetrahydrofuran is treated with 2S-N-carbobenzyloxyaminophenylalanine (8.60 g, 28.88 mmol) and then with water-soluble carbodiimide (8.82 g, 46, 2 mmol). After 1 hour, N, N-dimethylaminopyridine (566 mg) was added and the homogeneous solution was stirred at room temperature for 1.5 hours. 250 ml of ether was added to the reaction mixture and it was filtered. The filtrate is washed (250 ml in portions): with a normal aqueous solution of hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column, which was eluted with a mixture of 50-75% ethyl acetate and hexane, then with ethyl acetate, to give 10.5 g of a white foam. This foam is further chromatographed and eluted with 50% ethyl acetate in hexane to give 4.4 g of the diastereomeric (3S-cis) product and 4.6 g of the 3R-cis isomer, the title compound A.

 B) (3R-cis) -1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one.

A stirred suspension of the title compound A (4.6 g, 7.73 mmol) in 85 ml of methanol was treated with a 25% solution of sodium methoxide in methanol (5.52 ml, 23.19 mmol). Within 5-10 minutes, all solids pass into solution. After 30 minutes, the mixture was poured into 250 ml of a normal acid solution and extracted 3 times with ethyl acetate. The ethyl acetate extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was triturated with a 1: 1 mixture of ethyl acetate and hexane, the solid precipitate was filtered off and dried in vacuo to obtain 1.73 g of the title compound. The mother liquor is concentrated and then chromatographed on a silica gel column, which is eluted with a mixture of 50-75% ethyl acetate in hexane to give an additional 350 mg of the product indicated in heading B as a white solid, mp. 171-173 ^{° C,} [α] _D = = ^about 187 (C = 0.55 mol / l, in methanol).

 C) (3R-cis) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4- ( 4-methoxyphenyl) -2H-benzazepin-2-one, monohydrochloride.

Sodium hydride (100 mg, 4.14 mmol) was added with stirring to a solution of the compound indicated in heading B (1.08 g, 3.45 mmol) in 15 ml of dry dimethylformamide. After 30 minutes, 490 mg (4.14 mmol) of 2-chloromethylimidazoline was added. The mixture was stirred at room temperature for 1.5 hours and then quickly cooled by the addition of water. The mixture was extracted 3 times with ethyl acetate. The ethyl acetate extracts are combined and washed 3 times with a 10% aqueous solution of lithium chloride. Then, the ethyl acetate extract was washed with dilute hydrochloric acid and water. The aqueous extracts are combined, alkalinized with solid potassium bicarbonate and extracted 5 times with methylene chloride. The chloromethylene extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated, yielding 1.32 g of the free base compound indicated in the title (white solid). A solution of this free base (1 g) in a mixture of methylene chloride is treated dropwise with an excess of ethereal hydrogen chloride. The precipitated white precipitate was filtered off, washed twice with ethyl acetate and twice with ether, dried in vacuo to give 1.64 g of the title compound, mp 183-188 ^about S.

[α] _D = +155.5 ^about (C = 1 mol / l, in methanol).

 Calculated,%: C 59.78; H 5.98; N, 9.51; Cl 8.02.

C ₂₂ H ₂₅ N ₃ O ₅ ˙HCl ˙ 0.62 ˙H ₂ O.

 Found,%: C 59.36; H 6.14; N, 9.43; Cl 7.92.

 PRI me R 56. (3R-cis) -3- (Acetyloxy) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) - 1,3,4,5- tetrahydro-7-methoxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, hydrochloride.

The title compound was prepared from (3R-cis) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-7-methoxy -4- (4-methoxyphenyl) -2H-benzazepin-2-one, according to the procedure described in example 54, so pl. above 270 ^about C.

[α] _D = +95.0 ^about (C = 1 mol / l, in methanol).

 Calculated,%: C 59.19; H 6.09; N, 8.63; Cl 7.28.

C ₂₄ H ₂₇ N ₃ O ₅ ˙HCl ˙ 0.72 ˙H ₂ O.

 Found,%: C 59.36; H 5.75; N, 8.46; Cl 7.05.

 PRI me R 57. (3R- (1 (S *), 3 α, 4α)) - 1,3,4,5-tetrahydro-3- (hydroxy) -7-methoxy-4- (4- methoxyphenyl) - 1- (2-pyrrolidinylmethyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (3R- (1 (S *), 3 α, 4 α)) - 1,3,4,5-tetrahydro-3- (hydroxy) -7-methoxy-4- (4-methoxyphenyl) - 1 - ((N-benzyloxycarbonyl) pyrrolidin-2-yl) methyl) -2H-1-benzazepin-2-one.

 This compound is prepared from (cis) -1,3,4,5-tetrahydro-3-hydroxy-7-methoxy-4- (4-methoxyphenyl) 2H-1-benzazepin-2-one (part E, example 55) , according to the method described in the preparation of the compounds indicated in the header of part A of example 38.

 B) (3R- (1 (S *), 3 α, 4 α)) - 1,3,4,5-tetrahydro-3- (hydroxy) -7-methoxy-4- (methoxyphenyl) -1- (2 -pyrrolidinylmethyl) -2H-1-benzazepin-2-one, monohydrochloride.

This compound is prepared from (3R- (1 (S *), 3 α, 4α)) - 1,3,4,5-tetrahydro-3- (hydroxy) -7-methoxy-4- (4-methoxyphenyl) -1 - ((N-benzyloxycarbonyl) pyrrolidin-2-yl) methyl) -2H-1-benzazepin-2-one according to the procedure described in the preparation of the compound indicated in the heading of example 16, so pl. 179-181 ^about S.

[α] _D = +109.4 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 62.55; H 5.84; N, 6.35; Cl 8.03.

C ₂₄ H ₂₈ N ₂ O ₃ ˙HCl ˙ 0.48 ˙H ₂ O.

 Found,%: C 62.86; H 6.88; N, 6.04; Cl, 8.23.

 PRI me R 58. (2S- (2α, 3α, 3 (R *))) - 2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxy-phenyl) -5- (2-pyrrolidinylmethyl) -1,5-benzothiazepine-4- (5H) -one, monohydrochloride.

 A) (2S- (2α, 3α, 3 (R *))) - 2,3-dihydro-3- (2-benzyloxycarbonylamino-3-phenyl) propionyl-8-methoxy-2- (4-methoxyphenyl) -1 , 5-benzotiazepin-4- (5H) -one.

 (2-S) -Carbobenzyloxyaminophenylalanine (6.88 g, 22.99 mmol) was added at room temperature with stirring to cis-2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (6.09 g, 18.4 mmol) in dry dimethylformamide (55 ml) in an argon atmosphere. Soluble carbodiimide (7.05 g, 36.7 mmol) was added and then after 1 h dimethylaminopyridine (0.45 g, 3.7 mmol). Mixing lasts 75 minutes, the mixture is diluted with 280 ml of ether, washed with 1 N. hydrochloric acid, saturated sodium bicarbonate solution, saturated brine, dried over magnesium sulfate and concentrated in vacuo. The mixture was purified by chromatography, then reverse phase HPLC to give the title compound A (1.30 g).

 B) (2S-cis) -2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4- (5H) -one.

The title compound A (1.30 g, 2.12 mmol) in 21 ml of methanol and 0.2 ml of water under argon was treated with a 25% solution of sodium methoxide in methanol (1.0 ml, 4.3 mmol). Stirring is continued for 90 minutes, the mixture is diluted with 100 ml of water and stirred for an additional 30 minutes. The colorless product is collected by filtration, so pl. 180-183 ^about C (decomp.).

[α] _D = +85.4 ^about (C = 0.79 mol / l, in dimethylformamide).

 C) (2S- (2 α, 3 α, 3 (R *))) - 2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxyphenyl) -5- (2-pyrrolidinylmethyl) - 1,5-benzothiazepine-4- (5H) -one, monohydrochloride.

 The title compound was prepared using the procedures of Example 64, Parts B and D, from (2R-cis) -2,3-dihydro-3-hydroxy-3-methoxy-2- (4-methoxyphenyl) 1,5-benzothiazepine -4 (5H) -one.

Mp 121-124 ^{° C} (decomposing.).

[α] _D = +62.9 ^about (C = 1.08 mol / l, in methanol).

 Calculated,%: C 53.98; H 6.44; N, 5.72; Cl 7.24; S 6.55.

C ₂₂ H ₂₆ N ₂ O ₄ S ˙HCl ˙2.14 ˙H ₂ O.

 Found,%: C 53.99; H 6.02; N, 5.71; Cl 7.57; S 6.65.

 PRI me R 59. (2S-cis) -5- (4,5-dihydro-1H-imidazol-2-yl) methyl-2,3-dihydro-3-hydroxy-8-methoxy-2- ( 4-methoxyphenyl) -1,5-benzothiazepin-4- (5H) -one, monohydrochloride.

The title compound was prepared from (2S-cis) -2,3-dihydro-3-hydroxy-8-methoxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4- (5H) -one, as described in example 43, so pl. 192-199 ^about S.

[α] _D = +62.9 ^about (C = 1.0 mol / l, in methanol).

 Calculated,%: C 54.30; H 5.30; N, 9.05; Cl 8.40; S 6.90.

C ₂₁ H ₂₂ NO ₄ S ˙ HCl ˙ 0.66 ˙ H ₂ O.

 Found,%: C 54.16; H 5.52; N, 9.19; Cl 8.04; S 6.92.

 PRI me R 60. (25-cis) -3-Acetyloxy-5- (4,5-dihydro-1H-imidazol-2-yl) methyl) -2,3-dihydro-8-methoxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4- (5H) -one, monohydrochloride.

The title compound was prepared from (25-cis) -5- (4,5-dihydro-1-imidazol-2-yl) methyl) -2,3-dihydro-3-hydroxy-8-methoxy-2- (4 methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (the title compound of example 59 (according to procedures described in example 54, m.p. 275 ° ^C.

[Α] _D = +65,19 ^o (C = 1.0).

 Calculated,%: C 54.29; H 5.52; N, 8.26; Cl 6.97; S 6.30.

C ₂₃ H ₂₅ N ₃ ClSO ₅ ˙HCl ˙ 0.93 ˙H ₂ O
Found,%: C 54.68; H 5.32; N, 7.72; Cl 7.42; S 5.95.

 PRI me R 61. (cis) -1 - ((4,5-Dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-7-methylthio -4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, monohydrochloride.

The title compound was prepared from (cis) -1,3,4,5-tetrahydro-3-hydroxy-7-methylthio-4- (4-methoxyphenyl) 2H-1-benzazepin-2-one according to the procedure described in example 43, so pl. 195-198 ^about S.

 Calculated,%: C 57.50; H 5.98; N, 9.15; Cl 7.72; S 6.98.

C ₂₂ H ₂₅ N ₃ O ₃ S ˙HCl ˙ 0.64 ˙H ₂ O.

 Found,%: C 57.60; H 6.19; N, 9.05; Cl 7.63; S 6.84.

 PRI me R 62. (cis -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-7-methylsulfonyl- 4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, monohydrochloride.

 A) (cis) -1,3,4,5-tetrahydro-3-hydroxy-7-methylsulfonyl-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one.

Solution (cis) -1,3,4,5-tetrahydro-3-hydroxy-7-methylthio-4- (4-methoxyphenyl) -2H-1-benzene zepin-2-one (1.0 g, 3.04 mmol) in 30 ml of dry methylene chloride at ⁵ ° C was treated metahlorperoksibenzoynoy acid (0.615 g, 3.04 mmol). After 30 minutes, the reaction was complete and the reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine. Organically, the layer was filtered and concentrated in vacuo to give 1.02 g of a solid residue. After trituration in hot ethyl acetate, cooling and filtration, 600 mg of product are obtained with mp. 214-216 ^about C. The mother liquors are concentrated in vacuo and chromatographed on silica gel "El-Es-1" (eluent methylene chloride / methanol). Product fractions were combined and concentrated in vacuo, the residue being crystallized from ethyl acetate to give an additional 200 mg of product.

 B) (cis) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-7-methylsulfinyl-4- (4- methoxyphenyl) -2H-1-benzazepin-2-one, monohydrochloride.

The compound from heading B is prepared from the substance indicated in heading A using the procedures described in example 43, mp 195-205 ^about S.

 Calculated,%: C 54.21; H 5.91; N, 8.62; S 6.58; Cl 7.23.

C ₂₂ H ₂₆ ClN ₃ O ₄ S˙1.3 ˙H ₂ O.

 Found,%: C 54.48; H 5.77; N, 8.35; S 6.33; Cl 7.62.

 PRI me R 63. (3R- (1- (S *), 3α, 4α) -1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2 - azetidinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1).

 A) S-1 - ((1,1-dimethylethoxy) carbonyl) azetidine-2-carboxylic acid.

 Di-tert-butyl dicarbonate (2.18 g, 9.9 mmol) is added in one step to a stirred mixture of (Z) -azetidine-2-carboxylic acid (1.0 g, 9.9 mmol), triethylamine (2.12 ml, 15.0 mmol), 10 ml of acetone and 10 ml of water. The resulting reaction mixture was stirred for 4 hours at room temperature, after which the mixture was partitioned between 100 ml of ethyl acetate and 100 ml of water. The aqueous layer is acidified to pH 3 with a 10% citric acid solution. The resulting acid mixture was extracted 2 times with 200 ml of ethyl acetate and the combined organic extracts were dried with magnesium sulfate and concentrated to give 2.0 g of the title compound as a colorless oil.

 C) S-1 - ((1,1-dimethylethoxy) carbonyl) -azetidine-2-carboxylic acid methyl ester.

A mixture of (S) -1 - ((1,1-dimethylethoxy) carbonyl) -azetidine-2-carboxylic acid (2.0 g, 9.9 mmol), potassium carbonate (6.9 g, 50.0 mmol) and methyl iodide (6.25 ml, 100 mmol) in 20 ml of dimethylformamide was stirred in argon at room temperature for one day. Excess methyl iodide is pumped into a trap cooled with dry ice, and the remaining mixture is poured into water and extracted with 300 ml of ethyl ether. The organic extract was washed 2 times with 150 ml of brine, dried with magnesium sulfate and concentrated to obtain 1.85 g of the substance indicated in heading (B) as a colorless liquid. [α] _D = -114.8 ^about (C = 2.5 mol / l, in chloroform).

 C) R, S-1 - ((1,1-dimethylethoxy) carbonyl) azetidine-2-carboxylic acid, 1,1-dimethylethyl ether.

 To a solution of S-1 - ((1,1-dimethylethoxy) carbonyl) -azetidine-2-carboxylic acid, methyl ether (1.83 g, 8.5 mmol) in 38 ml of tertbutanol at room temperature, 18.8 g of unimolar a solution of potassium tert-butoxide in tetrahydrofuran. The reaction mixture was stirred for 5 hours, after which it was diluted with ethyl ether (200 ml). The resulting mixture was washed successively with 100 ml portions, brine, 1N hydrochloric acid, saturated sodium hydrogen carbonate solution and brine. The organic extracts were dried with magnesium sulfate and concentrated to give 1.63 g of the title compound (C) as a colorless liquid.

 D) R, S-1 - ((1,1-dimethylethoxy) carbonyl) -azetidine-2-methanol.

Lithium borohydride (0.23 g, 10.5 mmol) is added in one go to a solution of (R, S) -1 - ((1,1-dimethylethoxy) carbonyl) -azetidine-2-carboxylic acid, 1,1-dimethyl ester (1.59 g, 6.19 mmol) in 20 mL of tetrahydrofuran at 0 ^C. The reaction mixture was allowed to warm to room temperature and then stirred for 18 hours and then it was partitioned between brine and ethyl acetate. The organic extracts were washed with monoform hydrochloric acid and brine, dried over magnesium sulfate and concentrated to give 0.92 g of the title compound (D) as a colorless oil.

[α] _D = 0 ^about .

 E) R, S-1 - ((1,1, -dimethylethoxy) carbonyl) azetidine-2-methyl- (4-methylbenzene) sulfonate.

 A mixture of R, S-1 - ((1,1-dimethylethoxy) carbonyl) -azetidine-2-methanol (0.9 g, 4.9 mmol) and p-toluenesulfonyl chloride (1.87 g, 9.8 mmol) in 10 ml of pyridine is stirred for 60 hours at room temperature and at this moment another 0.5 g (2.6 mmol) of p-toluenesulfonyl chloride is added and the reaction mixture is stirred for an additional 2 hours. Then 10 ml of saturated sodium hydrogen carbonate solution are added and the mixture is stirred in for 30 minutes, after which it is distributed between 100 ml of ethyl acetate and 100 ml of a saturated solution of sodium bicarbonate. The organic layer is washed 2 times with 70 ml of 1N hydrochloric acid, 50 ml of a saturated solution of sodium bicarbonate and 50 ml of brine, dried with magnesium sulfate and concentrated. The crude residue was purified by flash chromatography (5 x 12 cm column, eluent 4: 1 hexane: ethyl acetate) to obtain 1.43 g of the title compound (E) as a yellow oil.

 F) (3R- (1 (S *), 3α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (1 - (( 1,1-dimethylethoxy) carbonyl) azetidinyl-2-methyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one and (3R - ((1,1-dimethylethoxy) carbonyl) azetidinyl -2-methyl (-6-trifluoromethyl) -2H-1-benzazepin-2-one.

A mixture of R, S-1 - ((1,1-dimethylethoxy) -carbonyl) -azetidine-2-methyl- (4-methylbenzene) sulfonate (0.492 g, 1.46 mmol), (3R-cis) -1.3 4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one (0.46 g, 1.3 mmol) and cesium carbonate (0.977 g, 30.0 mmol) ) in 4 ml of dimethylformamide is stirred for 18 hours at 60 ^about C, then the reaction mixture is distributed between 100 ml of ethyl acetate and 100 ml of water. The organic extracts are washed with water (2 times 50 ml) and brine (50 ml) and then dried with magnesium sulfate and concentrated. The crude light yellow residue was purified, and the isomers were separated by flash chromatography (5 x 12 cm column, 5 L of a 3: 1 hexane: ethyl acetate mixture and 1 L of a 1: 1 hexane: ethyl acetate mixture), yielding 0.2 g (30%) ( 3R- (1 (S *), 3α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 1- (1 - ((1,1-dimethylethoxy ) carbonyl) azetidinyl-2-methyl) -6-trifluoromethyl) -2H-1-benzazepin-2-one as a white foam, along with 0.232 g (34%) (3R- (1 (R *), 3α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (1 - ((1,1-dimethylethoxy) carbonyl) azetidinyl-2-methyl) -6- (trifluoromethyl) - 2H-1-benzazepin-2-one, also in the form of a white foam, as well as 0.15 g of a mixture fractions.

 G) (3R - ((S *), 3α, 4 α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (2-azetidinylmethyl) - (6 - (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1).

Mixture (3R- (1 (S *), 3 α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) -1- (1- ((1,1 - dimethylethoxy) carbonyl) azetidinyl-2-methyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (0.55 g, 1.06 mmol) and 3.3 ml of trifluoroacetic acid in 3, 3 ml of methyl chloride was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. Toluene was added and the mixture was again concentrated under reduced pressure to give a yellow oil, which was partitioned between ethyl acetate and a normal sodium hydroxide solution. The organic extracts were washed with brine, dried with magnesium sulfate and concentrated to give 0.424 g of crude free base, which was purified by flash chromatography; so pl. 155 ^о С (softens) 162-170 ^о С (decomposes).

[α] _D = +62.8 ^about (C = 0.50 mol / l, in methanol).

 Calculated,%: C 57.26; H 5.17; N, 5.14; F 10.45.

C ₂₂ H ₂₃ N ₂ F ₃ O ₃ ˙C ₄ H ₄ O ₄ ˙0.49 ˙H ₂ O.

 Found,%: C 57.24; H 5.05; N, 5.16; F 10.61.

 PRI me R 64. (3R- (1 (R *), 3α, 4α)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 1- (2 - azetidinylmethyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one, fumaric acid salt (1: 1).

The title compound was prepared from (3R- (1 (R *), 3a, 4a)) - 1,3,4,5-tetrahydro-3-hydroxy-4- (4-methoxyphenyl) - 1- (1- ( (1,1-Dimethylethoxy) carbonyl) azotidinyl-2-methyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one described in part F of example 63 using the procedures described in part G of example 63 T.pl. 112 ^C (softens), 140-146 ^{° C} (decomposes).

[α] _D = +90.2 ^about (C = 0.55 mol / l, in methanol).

 Calculated,%: C 56.33; H 5.27; N, 5.05; F 10.28.

C ₂₂ H ₂₃ N ₂ F ₃ O ₃ ˙C ₄ H ₄ O ₄ ˙0.99 H ₂ O.

 Found,%: C 56.21; H 5.22; N, 5.17; F 10.55.

 PRI me R 65. (3R-cis) -1 - ((methyl-4,5-dihydroimidazol-2-yl) methyl) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

 A) (3R-cis) -1- (cyanomethyl) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one.

To a solution of 0.60 g of sodium hydride (14.9 mmol, 60% dispersion in oil) in 150 ml of dry tetrahydrofuran was added 5.0 g of 3R-cis-3-hydroxy-4- (4-methoxyphenyl) -6- trifluoromethyl-2H-1-benzazepin-2-one. Teechnie solution was stirred 15 minutes, cooled at ⁰ ° C and dropwise added thereto iodoatsetonitrila solution 1.03 ml (14.2 mmol) in 10 ml of dry tetrahydrofuran. The solution was allowed to warm to room temperature for 2 hours, then it was partitioned between water and ether. The aqueous layer was washed with ether and the combined ether extracts washed with brine and dried with magnesium sulfate. The solution was evaporated to about 20 ml, 10 ml of hexane was added, and the solution was quickly frozen, yielding 0.74 g of (3R-cis) -1- (cyanomethyl) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl ) -2H-1-benzazepin-2-one as a pale yellow crystalline solid. The mother liquor gives an additional 2.04 g of product.

 B) (3R-cis) -1 - ((1-methyl-4,5-dihydroimidazol-2-yl) methyl) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1 benzazepin-2-one.

Through a suspension of 1.95 g (3R-cis) -1-cyanomethyl) -3-hydroxy-4- (4-methoxyphenyl) -6- (trifluoromethyl) -2H-1-benzazepin-2-one (5 mmol) 20 ml of ether containing 0.31 ml of absolute ethanol (5.24 mmol) at ⁰ ° C was bubbled hydrogen chloride gas until dissolved solid. This solution was sealed and stored at 5 ^{° C} for 4 days and at ^-20 ° C for 6 days. The ether is decanted from a thick, oily precipitate that has settled and dry ether is added to the residue to give a white solid. The ether is decanted and the white solid is washed with ether. This solid was dissolved in 25 ml of dimethylformamide and dropwise added 12.5 ml of this solution to a solution of 0.33 ml of N-methylethylenediamine (3.75 mmol) in 5 ml of dry dimethylformamide at 0 ° ^C. The solution was stirred at room temperature for 90 min, aqueous potassium carbonate was added and the solution was extracted twice with ether. The combined ether extracts were washed 2 times with water, once with brine, dried with potassium carbonate and evaporated to give 0.77 g of a white solid. This material was dissolved in ether and ether saturated with hydrogen chloride was added to give a white solid. It is filtered off, washed 2 times with ether and dissolved in a homogeneous mixture of aqueous potassium carbonate, ether and dioxane. Ether was added so that the phases separated, the aqueous layer was washed with additional ether and the combined organic extracts washed with brine, dried with potassium carbonate and evaporated to give 0.66 g of a white solid. This material is purified by chromatography, eluting with a mixture of 5% methanol in dichloromethane on three thin layer chromatography plates which have been previously eluted with a mixture of 5% triethylamine in dichloromethane. The main strip was removed and extracted twice with a mixture of 10% methanol in dichloromethane and the combined solutions were evaporated, yielding 0.27 g of a light yellow foamy substance. This solid was dissolved in ethyl acetate and ether saturated with hydrogen chloride was added to obtain a waxy solid. The solution was evaporated and dispersed with ether. The solid is dissolved in a 1: 1 mixture of methanol: isopropyl ether and 150 ml of isopropyl ether are added. The solid was filtered and dried in air to give 235 mg (3R-cis) -1 - ((1-methyl-4,5-dihydroimidazol-2-yl) methyl) -3-hydroxy-4- (4-methoxyphenyl) - 6- (trifluoromethyl) -2H-1-benzazepin-2-one in the form of a light brown solid with so pl. above 240 ^about C.

[α] _D = +98.2 (C = 1 mol / L, in methanol).

 Calculated,%: C 53.68; H 5.56; N, 8.16; F 11.07; Cl 6.689.

C ₂₃ H ₂₅ N ₃ F ₃ Cl ˙1.7 ˙H ₂ O.

 Found,%: C 54.08; H 5.46; N, 7.90; F 10.68; Cl 6.90.

 PRI me R 66. (3R-cis) -1 - ((4,5-dihydro-1H-imidazol-2-yl) methyl) -1,3,4,5-tetrahydro-3-hydroxy-6 -chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, monohydrochloride. A) (cis) -1,3,4,5-Tetrahydro-3 - ((2-carboxyphenyl) -carboxyl) -6-chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one.

A stirred suspension of cis-1,3,4,5-tetrahydro-3-hydroxy-6-chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one, obtained according to the procedure for Example 61, in 100 ml of dichloromethane treated with a solution of 5.55 g (55 mmol) of triethylamine in 50 ml of dichloromethane, then 1.0 g of dimethylaminopyridine and 8.2 g (55 mmol) of phthalic anhydride. The solids quickly dissolve and the resulting solution was stirred for 2 hours at room temperature. The mixture was treated in portions with mono-normal hydrochloric acid (83 ml) to obtain a heavy precipitate. After stirring and cooling for 30 minutes, the product is filtered, washed with 25 ml of water (five times) and dried, obtaining the title product A (22.58 g) so pl. 165-167 ^C. Recrystallization from acetonitrile sample of this material melted at 220-222 ° ^C.

 B) (3R-cis) -1,3,4,5-tetrahydro-3 - ((2-carboxyphenyl) carboxyl) -6-chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one , salt with S-α-methylbenzylamine.

A stirred suspension of (cis) -1,3,4,5-tetrahydro-3 - ((2-carboxyphenyl) carboxy) -6-chloro-4- (4-methoxyphenyl) -2H-1-benzazepin-2-one ( 22.17 g, 47.5 mmol) in 250 ml of methanol and treated with a solution of S-alpha-methylbenzylamine (5.80 g, 47.5 mmol) in 50 ml of methanol. The mixture is heated to boiling (reflux) to give a solution, which then begins to crystallize. After standing overnight at room temperature, the crystalline product is filtered off, washed with methanol (3 times 20 ml) and dried to give the title product B (12.03 g), so pl. 160 ^about S.

[α] _D = -15.5 ^about (C = 1.0, in acetic acid).

 C) (3R-cis) -1,3,4,5-tetrahydro-3-hydroxy-6-chloro-4- (4-methoxyphenyl) - 2H-1-benzazepin-2-one.

To a stirred solution of lithium hydroxide hydrate (3.4 g, 81 mmol) in water (113 ml) was added the title B substance (11.85 g, 20.5 mmol). The resulting solution was treated with 11 ml of methanol and heated to boiling under reflux. A heavy precipitate is separated. This slurry was heated at 60-70 ^{° C} for 1 h, diluted with 100 mL of water, cooled and stirred for 2 hours. The solid was filtered, washed with water and dried to give the title C compound as a colorless solid material (5, 76 g), mp 191-193 ^about S.

Claims (1)

 METHOD FOR PRODUCING NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS OR THEIR PHARMACEUTALLY ACCEPTABLE SALTS. The method of obtaining nitrogen-containing heterocyclic compounds of the General formula

where R ₁ is hydroxy, lower alkanoyloxy, OCONY ₁ Y ₂ , where Y ₁ , Y ₂ is hydrogen, lower alkyl, when X is CH ₂ , R _{2 is a} group of the formula

where n '= 0,1,2,3, n = 2,1,0, where Y ₃ , Y ₄ is hydrogen, lower alkyl, Y ₅ is phenyl, lower alkoxy, hydrogen, lower alkoxy; at X- S, R _{2 is a} group of the formula

where Y ₃ , Y ₅ have the indicated meanings;
R ₃ is lower alkoxyl, lower alkyl, hydrogen, halogen, trifluoromethyl, lower alkylsulfinyl;
R ₄ - lower alkoxyl,
or their pharmaceutically acceptable salts,
characterized in that the compound of the general formula

where X, R ₃ , R ₄ , R ₁ have the indicated meanings,
treated with a base in an inert organic solvent, followed by treatment with a compound of the formula R ₂ Y, where R ₂ is as defined, Y is a leaving group, and the desired product is isolated in the free form or as a pharmaceutically acceptable salt. Featured Priority
06/20/88 at X - CH ₂ ,

n '= 0.1;
05.22.89 with XS, R ₂ - group

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