FI72117B - SOM MELLANPRODUKTER ANVAENDBARA FOERENINGAR VID FRAMSTAELLNINGAV THERAPEUTISKT ANVAENDBARA 4-PHENYL-1,3-BENZODIAZEPINDERI VA - Google Patents

Description

1 72117 Compounds useful in the preparation of therapeutically useful 4-phenyl-1,3-benzodiazepine derivatives as intermediates 5 Separated from patent application No. 793062

The present invention relates to intermediates for the preparation of therapeutically useful 4-phenyl-1,3-benzodiazepine derivatives of formula I

10 X --------! N-R;

W / 1 I

15

wherein R is hydrogen or lower alkyl, R 1 is hydrogen, C 1-6 alkyl, C 2-8 cycloalkyl-C 1-2 alkyl or phenyl-C 1-6 alkyl, X is hydrogen or chlorine, Y is hydrogen, chlorine, fluoro, C 1-4 alkyl 20 or C 1-2 alkyl and n is 1 or 2, and compounds useful in the preparation of their physiologically acceptable salts, which are characterized in that they have the formula II

x — t ^ Ä I1

CH '- CH - N - H

2 i 11 30 wherein R 1, X, Y and n are as defined above and the process for their preparation.

Rodriguez et al., In U.S. Patent No. 3,681,340, which discusses 1,3-benzodiazepines, disclose that compounds of formula 721 1 7 2

OCA

Wherein R 1 is hydrogen, free or etherified OH or SH, an amino or aliphatic, araliphatic or aromatic group; is hydrogen or acyl, an aliphatic, araliphatic or aromatic group; their N-oxides and quaternary compounds and salts have central nervous system calming and coronary dilating effects.

The compounds of formula I have better antidepressant activity than the compounds known from U.S. Pat. No. 3,681,340. The therapeutic properties of the compounds of formula I are described in FI Patent Application No. 793062 (FI Publication No. 69836).

Similarly, the preparation of compounds of formula I from compounds of formula II is described in FI Patent Application No. 793062.

The process according to the invention for the preparation of compounds of formula II is characterized in that the compound of formula _. WELL"

25 x <X

CHP-CH-N-H

6-30 wherein R., X, Y and n are as defined above, are reduced by hydrogenation with a suitable catalyst in a manner known per se.

The preferred reduction process involves hydrogenation with palladium on carbon catalyst or Adams catalyst.

35 Other chemical reduction methods are also useful, such as the use of tin and hydrochloric acid.

li 3 72117

The starting materials used in the process of the invention can be prepared, for example, as follows, wherein R, R 1, X, Y and n are as previously defined unless otherwise stated: a) 2- (2-nitrophenyl) acetophenone of formula III

___. WELL

10 III

CH -C = O 15 is converted to the oxime of formula IV

'<C

CH_ C = NOH IV

6- ·· by any suitable method known in the art. The preferred method involves boiling acetophenone in a mixture of ethyl alcohol, aqueous sodium acetate and hydroxylamine.

b) The compound of formula IV is acylated with acetic anhydride to give the corresponding oxime acetate of formula 30% pH = NOCCH.

δ3 V

—N 4 72117 c) The compound of formula V is carefully reduced to give the corresponding 2-nitro-N-phenylphenethylamine of formula VI (R 1 is hydrogen)

5 x ^ 0C

CH CHNH_ Ö- '· "10 The reducing agent used in this step must be compatible with the phenyl-nitro group. Diborane is preferred. In addition, this reduction is carried out in the presence of a solvent such as tetrahydrofuran and at low temperature at about 0 ° C to about 30 ° C: or ambient temperature.

B. d) The compound of formula VI is converted by any method known in the art to the corresponding amide of the formula 20 x ~ X 2 ° CH--C-NH-C-R 25. n VI1 wherein R1 is hydrogen, CH3 or C2H, -. This conversion is performed with a suitable carboxylic anhydride or halide in the presence of a suitable solvent. In addition, when R 2 is hydrogen, the preferred method is a mixed anhydride method using a mixture of acetic anhydride and formic acid at a temperature of about 0-100 ° C with a suitable solvent such as benzene.

e) The compound of formula VII is reduced according to the method of step c above, wherein

II

s 72117 gives the corresponding N-alkyl-α-phenyl-2-nitrophenylethylamine of the formula 5 x -OC v

ch ^ -ch-n-h VIII

Wherein R 1 is alkyl.

In all of the above reaction steps, the optimum conditions depend on the starting materials, solvents, catalysts, and other reaction components, as will be more apparent from the examples below.

Example 1a a stirred mixture of 43.0 g of 2- (2-nitrophenyl) acetophenone, 200 ml of 95% ethyl alcohol, 31.2 g of sodium acetate and 24.3 g of hydroxylamine hydrochloride 100 ml of water, boil for one hour and its

after which it is allowed to stand for 16 hours. The precipitate is then collected by suction filtration and the filter cake is washed successively with 100 ml of 60% aqueous ethyl alcohol solution, with two 100 ml portions of water, dried and recrystallized from 95% ethyl alcohol to give almost colorless crystals, mp. 119-121 ° C, 2- (2-nitro-phenyl) -acetophenone oxime. The [2- (2-nitrophenyl) acetophenone starting material is described in Chem. Abstr. 63 (1965) 16237 q.J

30b. A stirred solution of 5.0 g of 2- (2-nitrophenyl) acetonophenoxime in 10 ml of potassium hydroxide-dried pyridine is treated with 5 ml of acetic anhydride, which is used in three equal portions. After the entire addition, the solution is heated in a water bath for 35 to 45 minutes, protected from moisture, and then decanted into 50 ml of ice water. An oil separates which turns 72117 solid upon continuous stirring. The solid is then collected by filtration, washed with water, dried in vacuo over potassium hydroxide pills and recrystallized from 95% ethyl alcohol to give 5 as almost colorless crystals, m.p. 63-66 ° C, 2- (2-nitrophenyl) -acetophenone oxime acetate.

c. 150 ml of a 1-molar solution of diborane in tetrahydrofuran are added to a stirred mixture of 9.0 g of 2- (2-nitrophenyl) acetophenone oxime acetate and 150 ml of tetrahydrofuran under cooling for 20 minutes in an ice-water bath. After the entire addition, the reaction mixture is stirred for 48 hours at ambient temperature before 150 ml of 5% hydrochloric acid solution are carefully added with stirring. After complete addition, the tetrahydrofuran is distilled off in vacuo and the residue is extracted three times with 200 ml portions of ether. The aqueous phase is basified with 50% sodium hydroxide and the alkaline phase is extracted three times with 300 ml portions of ether. The combined ether extracts are dried and then concentrated to leave an oil which is converted, in ether, to its hydrochloride salt. The salt is collected by filtration in vacuo and then washed thoroughly with ether. The dried salt is recrystallized from methyl alcohol to give colorless crystals, m.p. 261-263 ° C with decomposition, 2-nitro-O-t-phenyl-2-phenylethylamine hydrochloride.

d. 19.4 g of a 25% (w / w) solution of sodium methylate in methyl alcohol are added to a suspension of 19.6 g of 2-nitro-OC-phenylphenethylamine hydrochloride in 100 ml of ethyl alcohol. After the addition, the mixture is stirred with a water bath while heating before being filtered. The filter cake is washed with 70 ml of 95% ethyl alcohol and the filtrates are combined and then transferred to a 500 ml Parr hydrogenation flask containing 2.0 g of 10% palladium / carbon catalyst. and 20 ml of 95% ethyl alcohol. The mixture 35 is hydrogenated for three hours at a pressure of 345 kPa at ambient temperature. The mixture is then filtered off with suction and the filtrate is evaporated to dryness to leave an orange oil which is dissolved in 100 ml of chloroform. The chloroform solution and washings are extracted twice with 100 ml portions of chloroform. All chloroform solutions are combined and then dried, filtered and the filtrate is evaporated to dryness to leave an ice-orange oil which is diluted with 12 ml of cyclohexane. To this solution is added as a seed a crystalline product obtained from the crude oil previously obtained by crystallizing a sample from a small amount of 10 cyclohexane, stirred vigorously and allowed to stand at 5 ° C for 48 hours. The mother liquor is then decanted off and the crystalline precipitate is comminuted and collected in a Buchner funnel. The filter cake is washed with cyclohexane, dried and recrystallized from cyclohexane to give colorless crystals, m.p. 43-44 ° C, 2-aminophenylphenethylamine.

e. 70 ml of absolute ethyl alcohol saturated with hydrochloric acid are added dropwise to a stirred mixture of 7.0 g of 2-amino-OC-phenylphenethylamine hydrochloride, the salt of step d and 70 ml of triethyl orthoformate. After the whole addition, the reaction mixture is boiled, protected from moisture, for 16 hours and then cooled, diluted with ether and filtered off with suction to give a crystalline substance which is dried in vacuo for 5 hours. The product is recrystallized from methyl alcohol-ether-ether and the resulting crystals are washed with ether and then dried to give colorless crystals, m.p. 185-187 ° C, 4,5-dihydro-4-phenyl-3H-1,3-benzodiazepine hydrochloride.

Analysis for C 1 H 2 N 3 N · HCl:

Calculated: C 69.62 H 5.84 N 10.82%

Found: C 69.71 H 5.84 N 10.83% 8 72117

Example 2a. A mixture of 27.6 g of acetic anhydride and 16.7 ml of formic acid is heated at 50-67 ° C for 15 minutes and then cooled to 10-15 ° C. A solution of 13.8 g of 2-nitro-α-phenylphenethylamine, the free base of Example 1c, in benzene is added at such a rate that the temperature of the reaction mixture is maintained between 10-15 ° C. After the entire addition, the suspension is stirred for 48 hours at 50 ° C and then stirred for a further 48 hours at ambient temperature. The substance is then collected by suction filtration and then rinsed well with ether. The filtrate is evaporated to dryness in vacuo and the solid obtained is combined with the filter cake. The combined solid is dried under vacuum at 40 ° C for two hours and the dried solid is dissolved in methylene chloride and this solution is then washed with 5% hydrochloric acid solution, washed with water, dried, filtered and evaporated to dryness to leave a solid. The solid is recrystallized from ethyl alcohol to give, after drying in vacuo at 90 ° C, as pale yellow crystals, m.p. 151-153 ° C, N-formyl-2-nitro-O-phenylphenethylamine.

b. A solution of 96 ml of a 1-molar solution of diborane in tetrahydrofuran and 50 ml of tetrahydrofuran is added dropwise to an ice-cold suspension of 13 g of N-formyl-2-nitro-O-phenylphenethylamine in 150 ml of tetrahydrofuran. After the effervescence has stopped, 28 ml of 5-norm are added dropwise. hydrochloric acid.

The solvent is then removed in vacuo and the resulting oily mixture is basified with 50% aqueous sodium hydroxide solution. The basified mixture is extracted with several portions of ether and the combined ether extracts are dried, filtered and evaporated to dryness to give an oil, the oil is dissolved in benzene and this solution is treated with ethereal hydrogen chloride solution. The solvent is removed and the resulting material is recrystallized from isopropyl alcohol, li 72117 to give, after drying over xylene for 24 hours, as pale yellow crystals, m.p. 192-196 ° C, N-methyl-2-nitro-N-phenylphenethylamine hydrochloride.

5 c. A solution of 0.5 g of N-methyl-2-nitro-CC-phenylphenethylamine hydrochloride in 20 ml of ethyl alcohol is added to a Parr hydrogenation flask previously charged with 0.2 g of platinum dioxide, Adams 1 in catalyst and 5 g of ml of ethyl alcohol. A hydrogen pressure of 10,345 kPa is applied to this for five minutes, then a pressure of 104 kPa is applied and the Parr1 is placed in a shaker for 30 minutes. The mixture is filtered through a fine sintered glass funnel and the filtrate is evaporated to dryness. The resulting material is recrystallized from isopropyl alcohol to give, after drying, colorless crystals, m.p. 190-191 ° C, 2-amino-N-methyl-Ct-phenylphenethylamine hydrochloride.

d. 40 ml of absolute ethyl alcohol saturated with hydrogen chloride are added dropwise to a stirred mixture of 4.0 g of 2-amino-N-methyl-N-phenylphenethyl-20-amine hydrochloride and 40 ml of triethyl orthoformate. The solution obtained after this addition is boiled for 16 hours, cooled, diluted with ether and filtered off with suction to give a crystalline substance. The material is recrystallized by dissolving in methyl alcohol, filtering and diluting with ether to give, after drying, as colorless crystals, m.p. 251-154 ° C, 4,5-dihydro-3-methyl-4-phenyl-3H-1,3-benzodiazepine hydrochloride.

Analysis for C,, Η, ,, Ν ,. * HCl: 16 16 2

Calculated: C 70.45 H 6.28 N 10.26% 30 Found: C 70.44 H 6.19 N 10.50% 10,721 1 7

Example 3 4,5-Dihydro-7-chloro-2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine hydrochloride In a cooled solution (5 ° C) containing 19.36 g of 2- (5-chloro 2-Nitro-Ofc-phenyl) -1-phenylethanol oxime acetate in 150 ml of tetrahydrofuran is added dropwise under nitrogen with 226 ml of borohydride in tetrahydrofuran (0.24 M). The mixture is stirred overnight. Carefully add 30 ml of acetic acid and then 30 ml of concentrated hydrochloric acid and 60 ml of methanol. The mixture is heated on a steam bath for 0.5 hours, then basified with 10% sodium hydroxide. The solvent is evaporated off and the residue is partitioned between water and ether. The ether extract is collected, dried over anhydrous sodium sulfate and filtered. The product-containing solution is collected, dried over anhydrous sodium sulfate and filtered. The product 5-chloro-2-nitro-Q- (phenylbenzeneethanamine) is precipitated as the hydrochloride salt by adding ethereal hydrogen chloride solution to give 14.6 g of product, mp 222-224 ° C.

Analysis for 3C1N2O2 'HCl:

Calculated: C 53.69 H 4.51 N 8.93%

Found: C 53.89 H 4.63 N 8.93%

A mixture of 9.8 g of 5-chloro-2-nitro-O-phenyl-25-benzeneethanamine and 100 ml of methyl formate is placed in a Parr bomb. The bomb is placed in an oil bath (80 ° C) and kept at this temperature overnight. The mixture is cooled and the solvent is evaporated off to give 11 g of product, 5-chloro-N-formyl-2-nitro-α-phenylbenzene-30-ethanamine. An analytical sample of the product was recrystallized from 95% ethanol, m.p. 128 ° C.

Analysis for C.j-H, j ^ Cl ^ O ^:

Calculated: C 59.12 H 4.30 N 9.19%

Found: C 59.20 H 4.26 N 9.15% 35 11 li 72117 To a cooled solution (5 ° C) of 10.2 g of 5-chloro-N-formyl-2-nitro-dt-phenylbenzeneethanamine In 150 ml of tetrahydrofuran, 132 ml of borohydride in tetrahydrofuran are added dropwise. The mixture is stirred overnight at ambient temperature. The mixture is cooled and 30 ml of 6N hydrochloric acid are carefully added. The mixture is stirred overnight at ambient temperature. The mixture is then basified with 10% sodium hydroxide and the tetrahydrofuran is evaporated off. The residue is partitioned between water and ether. The ether extract is washed with water, dried over anhydrous sodium sulfate and filtered. An ethereal solution of hydrogen chloride is added to the extract, whereupon the product crystallizes to give 10 g of the hydrochloride salt of 5-chloro-N-methyl-2-nitro-c (phenylbenzeneethanamine, mp 255-15256 ° C).

Analysis for the compound, -H.j ..Cl ^ C ^ * HCl:

Calculated: C 55.06 H 4.93 N 8.56%

Found: C 55.23 H 4.99 N 8.41% 20 * To a mixture of 6.09 g of 5-chloro-N-methyl-2-nitro-Ofc-phenylbenzeneethanamine, 95% ethanol, 22 ml water and 11.5 g of iron (reduced electrolytically,

Mallinckroft), concentrated hydrochloric acid is added dropwise until pH 6 is reached, after which the mixture is heated to reflux for 30 minutes. The cooled mixture is mixed with a small amount of celite and filtered. The alcohol is evaporated off. The residue is basified with 10% sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 5.43 g of 2-amino-5-chloro-N-methyl-Ct-phenylbenzeneethanamine.

12,721 1 7

A mixture of 3.2 g of 2-amino-5-chloro-N-methyl-O-phenylbenzeneethanamine, 11.68 g of triethyl orthoacetate and 4.5 ml of acetic acid is heated under reflux for two hours. The solvents are evaporated off and the residue is partitioned between dichloromethane and 10% sodium hydroxide. The dichloromethane extract is washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The resulting oil is dissolved in ether. An ethereal solution of hydrogen chloride is added to the solution, whereupon the product of ot-10 is crystallized (2.8 g), m.p. 288-292 ° C.

Analysis for C1-1H17ClN2-HCl:

Calculated: C 63.56 H 5.65 N 8.72%

Found: C 63.91 H 5.60 N 8.73%

Example 4 2-Amino-N-ethyl-OL-phenylphenethylamine hydrochloride (II) 3.00 g of N-ethyl-2-nitro-O-phenylphenethylamine hydrochloride are treated for 15 minutes with 100 ml of hot 95%: ethanol with 1.10 g of potassium hydroxy-20 dia, after which the mixture is filtered and placed in a Parr flask. 0.15 g of 10% palladium on carbon is added and the mixture is hydrogenated at room temperature and 345 kPa for three hours, after which the catalyst is removed. The ethanol is evaporated off from the filtrate and the yellow oil obtained is poured into 100 ml of water. The biphasic aqueous mixture is extracted with methylene chloride (2 x 100 mL). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride is evaporated to give a colorless oil. The oil is dissolved in 50 ml of ether. An ethereal solution of chlorine-hydrogen (100 ml) is added, whereupon the hydrochloride salt precipitates as an oil. The ethanol is evaporated off and the oil is dissolved by heating in 20 ml of isopropanol. Upon cooling, white crystals precipitated from the solution, m.p. > 248 ° C with decomposition to give 2-amino-N-ethyl-O-phenylphenethylamine-35 dihydrochloride.

Analysis for C., H._N_ * 2 HCl:

Zο Z \) Z

Calculated: C 61.36 H 7.08 N 8.94%

Found: C 61, 25 H 7.11 N 8.95%

II

is 72117

Example 5 2-Amino-OC-phenyl-N-propylphenethylamine dihydrochloride (II) 3.34 g of 2-nitro-ac-phenyl-N-propylphenethylamine-5 hydrochloride are heated for 15 minutes in 100 ml of 95% strength: ethanol with 1.21 g of potassium hydroxide, after which the precipitated sodium chloride is removed by filtration. The ethanol filtrate is placed in a Parr flask containing 0.15 g of 10% palladium on charcoal and hydrogenated at 345 kPa for two hours. The catalyst is then removed and the ethanol is evaporated off. The resulting yellow oil is poured into 100 ml of water and the biphasic aqueous mixture is extracted with methylene chloride (2 x 100 ml). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride is evaporated to give a yellow oil, the oil is dissolved in 50 ml of ethanol. Ethereal hydrogen chloride solution (50 ml) is added to precipitate the hydrochloride salt. The ethanol is evaporated off and the white powder obtained is recrystallized from 20 ml of isopropanol to give 20 g of crystals, m.p. > 243 ° C with decomposition, 2-amino-OC-phenyl-N-propylphenethylamine dihydrochloride.

Analysis for C 17 H 24 N 2 O 2:

Calculated: C 62.39 H 7.39 N 8.56%

Found: C 62.16 H 7.32 N 8.49% Example & 2-Amino-N-cyclohexylmethylene-Ct-phenylphenethylamine dihydrochloride (II) 7.0 g of N-cyclohexylmethylene-2-nitro-O-phenylphenyl -ethylamine hydrochloride is treated for 15 minutes with 30,200 ml of warm 95% ethanol containing 2.07 g of potassium hydroxide, then the mixture is filtered and placed in a Parr flask containing 0.35 g of 10% palladium -puuhiiltä. The mixture is hydrogenated at 345 kPa for two hours. After removal of the catalyst, the ethanol is evaporated off and the biphasic mixture obtained is poured into 200 ml of water.

14 721 1 7

The aqueous mixture is extracted with methylene chloride (2 x 200 mL). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride is evaporated to give a colorless oil, the oil is dissolved in 100 ml of ether. Ethereal hydrogen chloride solution (200 ml) is added and the salt precipitates out of solution. The hydrochloride salt is collected as a resinous powder which is recrystallized from isopropanol to give crystals, m.p. 205 ° C with decomposition, 2-amino-N-cyclohexylmethylene-Ct-phenylphenethylamine dihydrochloride.

Analysis for C21H28N2 * ^ HCl:

Calculated: C 66.14 H 7.93 N 7.35%

Found: C 65.90 H 7.86 N 7.34%

Example 7 2-Amino-N-methyl-OC- (4-methylphenyl) phenethylamine dihydrochloride (II)

To a mixture of 10 g of (X- (4-methylphenyl) -N-methyl-2-nitrophenethylamine and 150 ml of ethanol is added 3.7 g of potassium hydroxide. The mixture is stirred for 15 minutes and the potassium chloride is filtered off. hydrogenate at room temperature for two hours in the presence of 0.5 g of 10% palladium-on-charcoal, filter off the catalyst and add ethereal hydrogen chloride to the ethanolic filtrate, evaporate to dryness and recrystallize the residue from ethanol-25 / ether. 225-222 ° C, 2-amino-N-methyl-OC- (4-methylphenyl) phenethylamine dihydrochloride are obtained as crystals.

Analysis for C_H_nN „-2 HCl: 2ο 2 U 2.

Calculated: C 61.35 H 7.08 N 8.91% 30

Found: C 61.18 H 7.02 N 8.87% h 721 1 7 15

Example 8 2-Amino-N- (4-methoxyphenyl) -N-methylphenethylamine dihydrochloride (II)

A mixture of 10.01 g of α- (4-methoxyphenyl) -N-methyl-2-nitrophenethylamine hydrochloride, 100 ml of dichloromethane and 100 ml of water is treated with an excess of 10% sodium hydroxide solution. The dried (anhydrous sodium sulfate) organic phase is concentrated to give 8.74 g of a yellow oil. A mixture of 10 with oil, 100 ml of absolute ethanol and 0.5 g of 10% palladium on charcoal is hydrogenated at 345 kParn and ambient temperature in a Parr 'apparatus. Filtration and concentration of the filtrate on a rotary evaporator gives 10.33 g of an oil. A solution of the oil and 20 ml of me-15 tanol is treated with an excess of ethereal hydrogen chloride solution. Further dilution with ether gives a resin which solidifies on trituration with fresh ether. Recrystallization from 25 ml of isopropanol gives crystals, m.p. 223-226 ° C with decomposition, 2-amino-20-o- (4-methoxyphenyl) -N-methylphenethylamine dihydrochloride.

Analysis for HCl:

Calculated: C 58.37 H 6.74 N 8.51%

Found: C 58.11 H 6.93 N 8.36% Example 9 N-acetyl-2-amino-oi- (3,4-dimethoxyphenyl) -N-methylphenethylamine (II)

A solution of 3.8 g of N-acetyl-α- (3,4-dimethoxy-phenyl) -N-methyl-2-nitrophenethylamine in 100 ml of ethanol-30 is hydrogenated at room temperature at 345 kPa for about 20 minutes using 0.5 g of 10% palladium on carbon. The catalyst is filtered off and the solvent is evaporated off to give the product. Recrystallization from 95% ethanol gave crystals, m.p. 139-142 ° C, N-acetyl-2-amino-O- (3,4-dimethoxyphenyl) -N-methyl-phen-5-amine.

Analysis for c 18 H 24 N 2 O 3:

Calculated: C 69.53 H 7.37 N 8.53%

Found: C 69.67 H 7.33 N 8.56% Preparation of intermediates: 10 Example 10 1- (4-Fluoro-2-methylphenyl) -2- (2-nitrophenyl) ethanone (III)

To a mixture of 181 g of o-nitrophenylacetic acid in 400 ml of 1,2-dichloroethane is added dropwise 78 ml of thionyl chloride at room temperature. The mixture is heated to about 65 ° C and then allowed to stand overnight at ambient temperature. 133 g of aluminum chloride are added portionwise to 400 ml of m-chlorotoluene, followed by dropwise addition of a solution of acid chloride-20, keeping the temperature between approximately 20 and 25 ° C.

The mixture is gradually heated to 60 ° C and maintained at 60 ° C until gas evolution ceases. The reaction mixture is poured into concentrated hydrochloric acid and ice and allowed to stand over the weekend. Additional methylene chloride is added to the reaction mixture. The organic layer is separated, washed with 5% sodium hydroxide solution and water, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate to dryness gives a black oil. The oil is extracted with boiling isopropyl ether to give 50 products on cooling. Recrystallization from hexane gives crystals, m.p. 72-74 ° C, 1- (4-fluoro-2-methylphenyl) -2- (2-nitrophenyl) ethanone.

Analysis for C 1 H 3 FNO:

Calculated: C 65.93 H 4.43 N 5.13% 35 Found: C 66.01 H 4.47 N 5.10%

It 721 1 7 17

Example 11 1- (4-Chlorophenyl) -2- (2-nitrophenyl) ethanone (III) A mixture of 46 g of 06- (4-chlorobenzoyl) -β-dimethylamino-2-nitrostyrene, 150 ml of dioxane and 50 ml of 5 water, heated to boiling for 18 hours. The solution is concentrated. The residue is extracted with methylene chloride, dried over anhydrous sodium sulfate and evaporated to an oil. the oil is dissolved in a small volume of 95% ethanol and the product crystallizes. Recrystallization from ethanol 10 gives crystals, m.p. 70-72 ° C, 1- (4-chlorophenyl) -2- (2-nitrophenyl) ethanone.

Analysis for ^ CINO ^:

Calculated: C 61.00 H 3.66 N 5.08%

Found: C 60.96 H 3.68 N 5.15% Example 12 1- (4-fluorophenyl) -2- (2-nitrophenyl) ethanone (III) To a mixture of 10 g of nitrophenylacetic acid in 29 ml of fluorobenzene, 4.3 g of thionyl chloride are added dropwise at room temperature. The mixture is heated at 45 ° C for 20 3 1/2 hours. 8.1 g of aluminum chloride are added portionwise to the cooled solution. During the addition, the reaction is slightly exothermic and the temperature rose to 40 ° C. The mixture is heated at 45 ° C for about 1 1/2 hours. The reaction mixture is poured into a mixture of concentrated hydrochloric acid and ice and extracted with ether. The ether extract is washed with 5% sodium hydroxide solution, water, dried over anhydrous sodium sulfate and evaporated to dryness to give a crude solid. Recrystallization from 95% ethanol gives crystals, m.p. 80-81 ° C, 1- (4-fluorophenyl-30) -2- (2-nitrophenyl) ethanone.

Analysis for C 1 H 4 FNO 2:

Calculated: C 64.86 H 3.89 N 5.40%

Found: C 64.64 H 3.94 N 5.31% 18 7211 7

Example 13 1- (4-Methoxyphenyl) -2- (2-nitrophenyl) ethanone oxime acetate (V)

To a stirred solution of 15.0 g of 1- (4-methoxy-5-phenyl) -2- (2-nitrophenyl) ethanone oxime and 30 ml of potassium hydroxide-dried pyridine is added dropwise 15.0 ml of acetic anhydride. After stirring protected from moisture overnight at ambient temperature, the solution is heated for two hours in a water bath. The solution is then decanted into 300 ml of ice water and the resulting biphasic mixture is extracted with a total of 270 ml of methylene chloride. The organic phase is washed once with dilute acetic acid (18 ml of glacial acetic acid diluted with 200 ml of water) and then twice with water. Concentration of the dried (anhydrous sodium sulfate) organic phase gives 21.0 g of a yellow oil. The solution in 125 ml of ether is washed successively with 50 ml portions of 5% hydrochloric acid solution, water, 5% sodium hydrogen carbonate solution and water. The organic phase (dried over anhydrous sodium sulfate) is concentrated to a cloudy yellow oil which is distilled using azeotropic distillation with absolute ethanol. At ambient temperature overnight, small crystal rosettes separate from the solution and one rosette is removed for use as seed. The residue is dissolved in 40 ml of 95% ethanol, cooled slowly until an oil begins to separate and the previously isolated crystals are added as seed. The crystalline precipitate is collected by filtration in vacuo, washed with 95% ethanol and dried in vacuo to give crystals, m.p. 65-68.5 ° C, 1- (4-methoxyphenyl) -2- (2-nitrophenyl) ethanone oxime acetate.

Analysis for C ^ ^ ^ I ^ Oj. :

Calculated: C 62.19 H 4.91%

Found: C 62.16 H 4.85% 11 19 72117

Example 14 1- (4-Methoxyphenyl) -2- (2-nitrophenyl) ethanone oxime (IV)

To a stirred suspension of 46.0 g of 1- (4-methoxy-5-phenyl) -2- (2-nitrophenyl) ethanone and 240 ml of 95% ethanol is added a solution of 22.6 g of hydroxylamine hydrochloride. , 46.3 g of sodium acetate trihydrate and 130 ml of water. The stirred suspension is heated to reflux and 95% ethanol (180 ml) is added. The mixture is heated to reflux for three hours, after which a solution which turns bright yellow is obtained. After stirring the solution overnight at ambient temperature, the excess ethanol is removed on a rotary evaporator and the residue is diluted with approximately one liter of water. An oil separates and 15 crystallizes. The solid is collected, washed with water and dried at 40 ° C overnight in vacuo. Recrystallization from 100 ml of 95% ethanol gives crystals, m.p. 106-110 ° C, 1- (4-methoxyphenyl) -2- (2-nitrophenyl) ethanone oxime.

Analysis for 5Hi 4N2 ° 4:

Calculated: C 62.93 H 4.93%

Found: C 62.95 H 4.93%

Example 15 1- (4-Fluorophenyl) -2- (2-nitrophenyl) ethanone oxy 25 miacetate (V)

To a solution of 72.7 g of 1- (4-fluorophenyl) -2- (2-nitrophenyl) ethanone oxime in 175 ml of pyridine is added dropwise 70 ml of acetic anhydride. The mixture is heated in a water bath for 1 1/2 hours. The reaction mixture is poured into ice water and the solution is slightly acidified with hydrochloric acid. The precipitate is filtered off, dried and recrystallized from 95% ethanol to give crystals, m.p. 74-75 ° C, 1- (4-fluorophenyl) -2- (2-nitrophenyl) ethanone oxime acetate.

20 721 1 7

Analysis for C H FN „0 .: Ίο I J 2 4

Calculated: C 60.76 H 4.14 N 8.86%

Found: G 60.66 H 4.13 N 8.78%

Example 16 1- (4-Fluorophenyl) -2- (2-nitrophenyl) ethanone oxime (IV)

To a solution of 6.62 g of 1- (4-fluorophenyl) -2- (2-nitrophenyl) ethanone in 40 ml of 95% ethanol is added 3.55 g of hydroxylamine hydrochloride in 10 ml of water and 4, 48 g of sodium acetate in 10 ml of water. The mixture is boiled for three hours and allowed to stand overnight. The ethanol is removed in vacuo and the product is extracted with ether, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization from a 95% ethanol-15 list gives crystals, m.p. 39-142 ° C, 1- (4-fluorophenyl) -2- (2-nitrophenyl) ethanone oxime.

Analysis for compound ^:

Calculated: C 61.31 H 4.04 N 10.21%

Found: C 61.15 H 4.08 N 10.27% Example 17 1- (4-Methylphenyl) -2- (2-nitrophenyl) ethanone oxime (IV)

To a mixture of 50 g of 1- (4-methylphenyl) -2- (2-nitrophenyl) ethanone in 200 ml of 95% ethanol is added a solution of 27.8 g of hydroxylamine hydrochloride in 50 ml. water and a solution of 36.1 g of sodium acetate. The reaction mixture is boiled for three hours and allowed to stand overnight at ambient temperature. The product crystallizing from the reaction mixture is filtered off and dried.

Recrystallization from 95% ethanol gives crystals, m.p. 129-132 ° C, 1- (4-methylphenyl) -2- (2-nitrophenyl) ethanone oxime.

Analysis for c 15 H 14 N 2 O 3:

Calculated: C 66.66 H 5.22 N 10.36% 35 Found: C 66.59 H 5.31 N 10.45% li 721 1 7 21

Example 18 1- (4-Methylphenyl) -2- (2-nitrophenyl) ethanone oxime acetate (V)

To a solution of 47.3 g of 1- (4-methylphenyl) -2-5 (2-nitrophenyl) ethanone oxime in 100 ml of pyridine is added dropwise 40 ml of acetic anhydride. The mixture is heated in a water bath (internal temperature about 80 ° C) for one hour. The mixture is poured into water and the crystallized product is filtered off to give crystals, m.p. 95-98 ° C, 1- (4-methyl-10-phenyl) -2- (2-nitrophenyl) ethanone oxime acetate.

Analysis for C17H16N2O4:

Calculated: C 65.38 H 5.20 N 8.97%

Found: C 65.42 H 5.16 N 9.00%

Example 19 1- (3,4-Dimethoxyphenyl) -2- (2-nitrophenyl) ethanone oxime (IV)

A mixture of 154 g of 1- (3,4-dimethoxy) -2- (2-nitrophenyl) ethanone in 600 ml of 95% ethanol, 70.9 g of hydroxylamine hydrochloride in 150 ml of water and 92 g of 20 sodium acetate in 150 ml of water, boil for seven hours. The product, which crystallizes on standing overnight at room temperature, is filtered off and dried to give crystals, m.p. 129-130 ° C, 1- (3,4-dimethoxyphenyl) -2- (2-nitrophenyl) ethanone oxime.

Analysis for compound 0 ^ Η ^ 6Ν20 ^:

Calculated: C 60.75 H 5.10 N 8.85%

Found: C 60.75 H 5.15 N 8.84%

Example 20 1- (3,4-Dimethoxyphenyl) -2- (2-nitrophenyl) ethanone-30-oxime acetate (V)

A mixture of 156 g of 1- (3,4-dimethoxyphenyl) -2- (2-nitrophenyl) ethanone oxime and 100 g of acetic anhydride is heated on a water bath for 30 minutes. The product crystallizes when the mixture is in place overnight at room temperature-35. Trituration with hexane gives crystals, 22 72 1 1 7 m.p. 118-120 ° C, 1- (3,4-dimethoxyphenyl) -2- (2-nitrophenyl) ethanone oxime acetate.

Analysis for c 1 H 18 N 2 O 6:

Calculated: C 60.37 H 5.06 N 7.82%

Found: C 60.14 H 5.11 N 7.78 L

Example 21 1- (2-Fluorophenyl) -2- (2-nitrophenyl) ethanone oxime (IV)

A mixture of 12.3 g of 2'-fluoro-2- (2-nitrophenyl) -10 acetophenone in 80 ml of 95% ethanol, 6.6 g of hydroxylamine hydrochloride in 20 ml of water and 8.53 g of g of sodium acetate in 20 ml of water, boil overnight. The product crystallizes on cooling. Recrystallization from 95% ethanol gives crystals, m.p. 105-109 ° C, 1- (2-fluorophenyl) -2- (2-nitrophenyl) ethanone oxime.

Analysis for -j:

Calculated: C 61.31 H 4.04 N 10.21%

Found: C 61.19 H 4.09 N 10.25%

Example 22 1- (2-Fluorophenyl) -2- (2-nitrophenyl) ethanone oxime acetate (V)

To a solution of 8 g of 1- (2-fluorophenyl) -2- (2-nitrophenyl) ethanone oxime in 20 ml of pyridine is added dropwise 10 ml of acetic anhydride. The mixture is heated (water bath) for 3 1/2 hours, poured into water and extracted with methylene chloride. The methylene chloride extract is washed with 5% hydrochloric acid, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residual oil is distilled under 5 mm vacuum to give 1- (2-fluorophenyl) -2- (2-nitrophenyl) ethanone oxime acetate, b.p. 133-135 ° C.

Analysis for C 16 H 12 FN 2 O 4:

Calculated: C 60.76 H 4.14 N 8.86%

Found: C 60.83 H 4.09 N 9.11%

II

721 1 7 23

Example 23

Oi- (4-methoxyphenyl) -2-nitrophenethylamine hydrochloride (VI) A stirred solution cooled in ice water with 27.8 g of 1- (4-methoxyphenyl) -2- (2-nitrophenyl) ethanone oxime acetate and 250 ml tetrahydrofuran, is treated for 30 minutes with 360 ml of a 0.94 molar solution of borane in tetrahydrofuran (four times the excess boron hydride). After the entire addition, the solution is stirred for 10 hours at ice bath temperature, followed by stirring for four hours at ambient temperature. The solution is then allowed to stand for two days at ambient temperature. The stirred solution is cooled in an ice-water bath and quenched by the dropwise addition of 100 ml of hydrochloric acid.

15 A colorless precipitate separates and the mixture is stirred under cooling for two hours. Glacial acetic acid (15 ml) is added, followed by stirring for two hours and then the mixture is left to stand overnight at ambient temperature. The stirred suspension is then treated with 300 ml of 10% sodium hydroxide solution, after which the excess tetrahydrofuran is removed on a rotary evaporator. The remaining biphasic mixture is extracted three times with 200 ml portions of methylene chloride. The combined organic phase is dried over anhydrous sodium sulfate, filtered in vacuo and evaporated to an orange oil. A solution of the oil and 200 ml of dry ether is treated with a small excess of ethereal hydrogen chloride solution. The precipitate is collected by filtration in vacuo. The filter cake is washed twice with ether and dried under vacuum at 40 ° C on sodium hydroxide pills. Recrystallization of the crude product from 600 ml of 95% ethanol gives slightly yellow crystals, m.p. 240-242 ° C, 16.1 g of <X- (4-methoxyphenyl) -2-nitrophenethylamine hydrochloride.

Analysis for C, cH LO.-HCl: 1 jb 2. j 35 Calculated: C 58.35 H 5.55%

Found: C 58.21 H 5.25% 24 721 1 7

Example 24 ot- (4-Methylphenyl) -2-nitrophenethylamine hydrochloride (VI) To a cooled solution of 48 g of 1- (4-methyl-5-phenyl) -2- (2-nitrophenyl) ethanone oxime acetate in 350 ml tetrahydrofuran under a nitrogen atmosphere, 594 ml of a 1.01 molar solution of borane in tetrahydrofuran are added dropwise. The internal temperature remains between 0 and 20 ° C during the addition. The mixture is stirred for 45 minutes at the temperature of 10 ice baths and then stirred overnight at ambient temperature. The mixture is cooled and the complex is decomposed by carefully adding 6-norm. hydrochloric acid. A precipitate gradually forms and the mixture is stirred overnight. The tetrahydrofuran is evaporated off in vacuo and the residue is taken up in 10% sodium hydroxide solution. The product is extracted with ether and dried over anhydrous sodium sulfate. An ethereal solution of hydrogen chloride is added to the solution and the product precipitates as the hydrochloride salt. Recrystallization from ethanol gives crystals, m.p. 265-269 ° C, <X- (4-methylphenyl) -2-nitrophenethylamine hydrochloride.

Analysis for * HCl:

Calculated: C 61.54 H 5.85 N 9.57%

Found: C 61.57 H 6.00 N 9.44%

Example 25 (X- (3,4-Dimethoxyphenyl) -2-nitrophenethylamine hydrochloride (VI) In a cooled mixture of 92.6 g of 1- (3,4-dimethoxyphenyl) -2- (2-nitrophenyl) ) ethanone oxime acetate in 600 ml of tetrahydrofuran under a nitrogen atmosphere-30 Mana, is added dropwise a solution of 1,019 ml of 0.98 mol of borane tetrahydrofuran solution, the mixture is left overnight at ambient temperature, the mixture is cooled and 250 ml of 5% The solvent is evaporated off under vacuum and the residue is taken up in 10% sodium hydroxide solution and the free amine is extracted with ether, dried over anhydrous

II

25 721 1 7 sodium sulfate and filtered. An ethereal solution of hydrogen chloride is added dropwise to the filtrate and the product precipitates as the hydrochloride salt. Recrystallization from methanol-ether gives crystals, m.p. 229-231 ° C, Of- (3,4-dimethoxy-5-phenyl) -2-nitrophenethylamine hydrochloride.

Analysis for -HCl:

Calculated: C 56.73 H 5.65 N 8.27%

Found: C 56.63 H 5.65 N 8.22%

Example 26 Of- (4-fluorophenyl) -2-nitrophenethylamine hydrochloride (VI) 871 ml of a 0.98 molar solution of borane in tetrahydrofuran are added dropwise to a cooled solution of 69.2 g of 1- (4-fluorophenyl) -2- 15 (2-nitrophenyl) ethanone oxime acetate in 500 ml of tetrahydrofuran. The mixture is allowed to stand for the rest of the week. The mixture is cooled and 200 ml of 5% hydrochloric acid are added dropwise. The tetrahydrofuran is evaporated off and the residue is treated with 10% sodium hydroxide solution. The free amine is extracted with ether and dried over anhydrous sodium sulfate. The ether solution is treated with ethereal hydrogen chloride solution and the product is recrystallized from ethanol to give crystals, m.p. 239-243 ° C, 06- (4-fluorophenyl) -2-nitrophenethylamine hydrochloride.

Analysis for c-j 4H-J * HCl:

Calculated: C 56.67 H 4.76 N 9.44%

Found: C 56.86 H 4.70 N 9.36%

Example 27 A 1 molar solution of N-ethyl-2-nitro-O-phenylphenylamine hydrochloride-30 di (VIII) in a tetrahydrofuran complex of the borane-tetrahydrofuran complex (42 ml) is added dropwise to a stirred, cooled suspension of 6.00 g of N-acetyl- 2-nitro-O-phenylphenethylamine in 60 ml of tetrahydrofuran. At the end of the addition, the mixture is stirred at room temperature for 24 hours, after which the excess 26,721 l of borane are decomposed by successive addition of 20 ml of 5% hydrochloric acid and 2 ml of glacial acetic acid. The mixture is then basified with 20 ml of 50% sodium hydroxide solution. The tetrahydrofuran is evaporated off from the biphasic mixture and the remaining aqueous phase is poured into 100 ml of water. The aqueous mixture is extracted with methylene chloride (2 x 100 mL). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and evaporated to a yellow oil which is dissolved in 50 ml of ether. A solution of hydrogen chloride in ether-10 (100 ml) is added, whereupon the salt precipitates as an oil. The ether is evaporated off and the residual oil is dissolved in 20 ml of 100% ethanol and allowed to crystallize to give crystals, m.p. 216-225 ° C with decomposition, N-ethyl-2-nitro-QC-phenylphenethylamine hydrochloride.

15 Analysis for glS ^ O ^ · Η <31:

Calculated: C 62.64 H 6.24 N 9.13%

Found: C 62.53 H 6.20 N 9.22%

Example 28 2-Nitro-Qe-phenyl-N-propylphenethylamine hydrochloride (VIII) 1 molar borane-tetrahydrofuran complex (42 ml) is added dropwise to a cooled, stirred suspension of 6.00 g of 2-nitro-ot-phenyl -N-propionyl-phenethylamine in 60 ml of tetrahydrofuran. At the end of the addition, the mixture is stirred at room temperature for 24 hours, after which the excess borane is decomposed by successive addition of 20 ml of 5% hydrochloric acid and 2 ml of glacial acetic acid. The acidic mixture is stirred for a further 30 minutes, after which the mixture is basified with 20 ml of 50% sodium hydroxide solution. The mixture is then poured into 100 ml of water and the aqueous phase is extracted with methylene chloride (2 x 100 ml). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride is evaporated to give a yellow oil which is dissolved in 50 ml of ether. An ethereal solution of hydrogen chloride (100 ml) is added, whereupon the hydrochloride salt precipitates as an oil. The ether is evaporated off

II

27 72 1 1 7 and the resin obtained are dissolved in 40 ml of hot isopropanol. Upon cooling, the solution precipitates as white crystals, m.p. 189-192 ° C, 2-nitro-OC-phenyl-N-propylphenethylamine hydrochloride.

5 Analysis for ^ H2QN2O2 · HCl:

Calculated: C 63.65 H 6.60 N 8.75%

Found: C 63.64 H 6.88 N 8.38%

Example 29 N-Benzyl-2-nitro-O-phenylphenylamine hydrochloride (VIII) 1-molar borane-tetrahydrofuran complex (60 ml) is added dropwise to a cooled, stirred solution of 9.00 g of N-benzoyl. -2-nitro-O-phenyl-phenethylamine in 90 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred at room temperature for four hours. To facilitate dissolution of the reagents, additional tetrahydrofuran (100 mL) and 1 molar borane-tetrahydrofuran complex (30 mL) are added. The mixture is stirred at room temperature for 24 hours, after which the excess borane is decomposed by successive addition of 45 ml of 5% hydrochloric acid and 5 ml of acetic acid. The acidic mixture is stirred at room temperature for a further 0.5 hour, after which 25 ml of 50% sodium hydroxide solution are added. The tetrahydrofuran is evaporated off and the remaining aqueous mixture is poured into 125 ml of water. The aqueous phase is extracted with methylene chloride (1 x 150 mL, 1 x 100 mL). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and evaporated to dryness to give a solid which crystallizes from 150 ml of 100% ethanol to give fluffy crystals. The ethanol filtrate is acidified with 100 ml of ethereal hydrogen chloride solution. After a prolonged presence, the hydrochloride salt precipitates out of solution. Recrystallization of the salt from 40 ml of ethanol gives yellow granules, m.p. 215-218 ° C, N-benzyl-2-nitro-Ct-35 phenylphenethylamine hydrochloride.

721 1 7 o ft

Analysis for H 2 N 2 O 2 'HCl:

Calculated: C 68.38 H 5.74 N 7.59%

Found: C 68.11 H 5.58 N 7.66%

Example 30 N-Cyclohexylmethylene-2-nitro-O-phenylphenethylamine hydrochloride (VIII) A 1 molar borane-tetrahydrofuran complex (60 ml) is added dropwise to a stirred, cooled suspension of 9.00 g of N-cyclohexylcarbonyl-2 -10 nitro-O-phenylphenethylamine in 90 ml of tetrahydrofuran. At the end of the addition, the mixture is stirred for four hours. To completely dissolve the ingredients, more borane (30 mL) and tetrahydrofuran (100 mL) are added. The mixture is stirred for another 16 hours. After cooling the mixture, the excess borane is decomposed by successive addition of 45 ml of 5% hydrochloric acid and 4 ml of acetic acid. The mixture is stirred for half an hour before 25 ml of 50% sodium hydroxide solution are added. The tetrahydrofuran is evaporated off and the biphasic mixture obtained is poured into 125 ml of water. The aqueous mixture is extracted with methylene chloride (1 x 150 mL, 1 x 100 mL). The combined methylene chloride extracts are dried over anhydrous magnesium sulfate and the methylene chloride is evaporated to give a yellow oil, the oil is dissolved in 100 ml of ether. A solution of hydrogen chloride in ether-25 (200 ml) is added. When the solution is in place, a white precipitate forms. The ether is evaporated off and the solid is recrystallized from 50 ml of ethanol to give crystals, m.p. 225-228 ° C, N-cyclohexylmethylene-2-nitro-O 2 -phenylamine hydrochloride.

Analysis for C 21 H 26 N 2 O 2 * HCl:

Calculated: C 67.28 H 7.26 N 7.47%

Found: C 67.08 N 7.26 N 7.51% it 721 1 7 29

Example 31 ot- (4-methoxyphenyl) -N-methyl-2-nitrophenethylamine hydrochloride (VIII) A stirred suspension cooled in ice water if 12.3 g of N-formyl-Gfc- (4-methoxyphenyl) -2- nitrophenylamine and 120 ml of tetrahydrofuran, are treated for 20 minutes with 85 ml of a 1.01 molar solution of borane in tetrahydrofuran. At the end of the addition, the solution is stirred for three hours under ice-water cooling and then allowed to stand for two days at ambient temperature, protected from moisture. The stirred solution is cooled and quenched by the dropwise addition of 40 ml of 5% hydrochloric acid and 4 ml of glacial acetic acid. Two hours after the addition is complete, the mixture is made alkaline with 50% sodium hydroxide solution, diluted with 50 ml of water and concentrated on a rotary evaporator to remove tetrahydrofuran. The residual liquid is extracted three times with 70 ml portions of dichloromethane and the combined organic phase is dried over anhydrous sodium sulfate, filtered and concentrated to an oil. A solution of the oil and 100 ml of ether is treated with ethereal hydrogen chloride to give a resin. The ether-resin mixture is evaporated to a yellow amorphous foam which is recrystallized from isopropanol to give almost colorless crystals, m.p. 181-185 ° C, Of- (4-methoxyphenyl) -N-methyl-2-nitro-phenethylamine hydrochloride.

Analysis for gN 2 O 3 · HCl:

Calculated: C 59.54 H 5.93 N 8.68%

Found: C 59.24 H 5.81 N 8.65% Example 32

Ot- (3,4-dimethoxyphenyl) -N-methyl-2-nitrophenethylamine hydrochloride (VIII) In a cooled mixture of 33.6 g of N-formyl-Ot- (4-methoxyphenyl) -2-nitrophenethylamine in 500 ml of tet -35 rahydrofuran, is added dropwise and the internal temperature is kept between 0-10 ° C, 408 ml of 0.98 mol of borohydride / 3 ° 72117 tetrahydrofuran solution. The mixture is allowed to stand overnight at ambient temperature. To the cooled mixture is carefully added 100 ml of 5% hydrochloric acid, followed by 20 ml of glacial acetic acid. The solvent is evaporated off in vacuo and the residue is treated with 10% sodium hydroxide solution. The free base is extracted with ether, dried over anhydrous sodium sulfate and filtered. The product precipitates as the hydrochloride salt upon addition of ethereal hydrogen chloride to the ether extract. Recrystallization from ethanol gives crystals, m.p. 185-187.5 ° C, Oh (3-dimethoxyphenyl) -N-methyl-2-nitrophenethylamine hydrochloride.

Analysis for c 7 H 20 O 2 · HCl:

Calculated: C 57.87 H 6.00 N 7.94% 15 Found: C 57.77 H 6.09 N 7.93%

Example 33 α- (4-Fluorophenyl) -N-methyl-2-nitrophenethylamine hydrochloride (VIII) To a cooled mixture of 31.1 g of N-formyl-Δ 2 - (4-fluorophenyl) -2-nitrothenethylamine in 500 ml in tetrahydrofuran is added dropwise 441 ml of a 0.98 molar solution of borane in tetrahydrofuran. The mixture is allowed to stand for the weekend. The mixture is cooled and 100 ml of 5% hydrochloric acid and 20 ml of glacial acetic acid are carefully added. The solvent is evaporated off in vacuo and the residue is treated with 10% sodium hydroxide solution. The free amine is extracted with ether and dried over anhydrous sodium sulfate and filtered. An ethereal solution of hydrogen chloride is added dropwise to the filtrate and the product precipitates as the hydrochloride salt. Recrystallization from ethanol gives crystals, m.p. 241-243 ° C, 0 (- (4-fluorophenyl) -N-methyl-2-nitrophenethylamine hydrochloride.

Analysis for 5Η ^ 5FN2O2 «HCl:

Calculated: C 57.98 H 4.87 N 9.01% 35 Found: C 57.89 H 5.15 N 9.01% 31 72117

Example 34

Ot- (4-methylphenyl) -N-methyl-2-nitrophenethylamine hydrochloride (VIII) In a cooled solution of 17 g of N-formyl-Qt-5- (4-methylphenyl) -2-nitrophenethylamine in 200 ml of tet -rahydrofuran, is added dropwise, under a nitrogen atmosphere, 122 ml of a 0.98 molar solution of borane in tetrahydrofuran. The temperature did not rise above 10 ° C during the addition. The mixture is stirred at room temperature for four hours. The excess borane is decomposed by adding 50 ml of 5% hydrochloric acid and 10 ml of acetic acid. The mixture is allowed to stand for the weekend. The tetrahydrofuran is evaporated off in vacuo. The residue is treated with 10% sodium hydroxide solution, extracted with ether and the organic phase is dried over anhydrous sodium sulfate and filtered. An ethereal solution of hydrogen chloride is added to the filtrate and the hydrochloride salt precipitates. Recrystallization from ethanol gives crystals, m.p. 235-238 ° C, O- (4-methylphenyl) -N-methyl-2-nitrophenethylamine hydrochloride.

Analysis for C., ,.oN „0„ -HCl: lb I o 2 2

Calculated: C 62.64 H 6.24 N 9.13%

Found: C 62.50 H 6.23 N 9.14%

Example 35 N-Acetyl-2-nitro-phenylphenylamine (VII) A solution of 10.0 g of N-methyl-2-nitro-O (phenylphenethylamine in 75 ml of toluene). is added dropwise to a cooled, stirred solution of 10.2 ml of acetic anhydride in 100 ml of toluene, at the end of which the mixture is left at room temperature for 72-30 hours, after which the precipitate is collected, washed with ether (2 x 50 ml) and dried. Recrystallization from 100% ethanol gives, as crystals, mp 171-172 ° C, N-acetyl-2-nitro-hC-phenylmethylamine.

Analysis for C 16 H 16 N 2 O 3: 35 Calculated: C 67.59 H 5.67 N 9.85%

Found: C 67.50 H 5.61 N 9.95% 72117 32

Example 36 N-Propionyl-2-nitro-OC-phenylphenylamine (VII)

A solution of 10.0 g of N-methyl-2-nitro-O-phenylphenethylamine in 75 ml of toluene is added dropwise to a cooled, stirred solution of 10.5 ml of propionic anhydride in 100 ml of toluene. At the end of the addition, the mixture is allowed to stand at room temperature for 75 hours, after which the precipitate is collected, washed with ether (2 x 50 ml) and dried to give a white powder. Recrystallization from 10% ethanol gives pale yellow needles, m.p. 149-151 ° C, N-propionyl-2-nitro-O-phenylphenylamine.

Analysis for C .-. H. oN_0.:

1 / I o 2 J

Calculated: C 68.44 H 6.08 N 9.39% 15 Found: C 68.30 H 5.94 N 9.26%

Example 37 N-Benzoyl-2-nitro-O-phenylphenylamine Amine (VII)

A solution of 10.0 g of 2-nitro-O-phenylphenethylamine in 75 ml of toluene is added dropwise to a stirred, cooled solution of 24.3 g of benzoic anhydride in 75 ml of toluene. At the end of the addition, the mixture is stirred at room temperature for two hours, after which the precipitate is collected, washed with 300 ml of ether and partially dried. The precipitate is heated in 400 ml of boiling ethanol, cooled and collected to give as white needles, m.p. 185-189 ° C, N-benzoyl-2-nitro-OC-phenylphenethylamine.

Analysis for C 11 H 10 N 2 O 2: 2 I 1 o 2

Calculated: C 72.82 H 5.24 N 8.09% 30 Found: C 72.54 H 5.29 N 8.07%

Example 38 N-Cyclohexanecarbonyl-2-nitro-O-phenylphenylamine (VII)

A solution of 10.0 g of 2-nitro-Oc-phenylphenethyl-35 amine in 75 ml of toluene is added dropwise to a stirred, cooled solution of 14.4 ml of 33 7 21 1 7 cyclohexylcarbonyl chloride in 75 ml of toluene and 25 ml of ml of pyridine. After the addition is complete, the mixture is stirred at room temperature for two hours. The mixture is left to stand overnight, after which the golden-brown precipitate is collected in tal-5 and washed with 100 ml of ether. The precipitate is recrystallized from 350 ml of methanol to give yellow needles, m.p. 210-212 ° C, N-cyclohexanecarbonyl-2-nitro- [trans-phenylphenethylamine.

Analysis for C 21 H 24 N 2 O 3: 10 Calculated: C 71.57 H 6.86 N 7.95%

Found: C 71.36 H 6.92 N 7.99%

Example 39 N-Formyl-α- (4-methoxyphenyl) -2-nitrophenylamine (VII) A suspension of 14.0 g of Qt- (4-methoxyphenyl) -2-nitrophenethylamine hydrochloride and 250 ml of water is treated with 70 ml of 10% sodium hydroxide solution.

The mixture is extracted twice with 200 ml portions of methylene chloride and the combined organic phase is dried over anhydrous sodium sulfate. Filtration in vacuo and concentration gives 12.7 g of a yellow oil. The solution with oil and 200 mL of methyl formate is heated at 80-83 ° C (bath temperature) for three days in a 300 mL Parr stainless steel bomb tube. After cooling the patient to room temperature, the pony is opened and the crystalline precipitate is collected by filtration under vacuum. The filter cake is washed once with methyl formate and dried in vacuo at 40 ° C to give slightly yellowish crystals, m.p. 151-153 ° C, N-formyl-O- (4-methoxyphenyl) -2-30 nitrophenethylamine.

Analysis for C., H., N_0 .: ID ID Z 4

Calculated: C 63.99 H 5.37 N 9.33%

Found: C 63.92 H 5.29 N 9.37% 34 721 1 7

Example 40 N-Formyl-QC- (4-methylphenyl) -2-nitrophenethylamine (VII)

A mixture of 19.6 g of Of- (4-methylphenyl) -2-nitro-5 phenethylamine and 230 ml of methyl formate is placed

To a Parr bombshell at 80 ° C overnight. The reaction mixture is cooled and the solvent is removed in vacuo to give an off-white solid. The product is recrystallized from 95% ethanol to give crystals, m.p. 11 DEG-132 DEG C., N-formyl-O- (4-methylphenyl) -2-nitrophenethylamine.

Analysis for C „, Η.,, N_0_:

Ib Ib λ o

Calculated: C 67.59 H 5.67 N 9.85%

Found: C 67.58 H 5.63 N 9.94% 1 Example 41 N-Formyl-O- (4-fluorophenyl) -2-nitrophenethylamine (VII)

A mixture of 36.6 g of Of- (4-fluorophenyl) -2-nitrophenethylamine and 230 ml of methyl formate is placed in a 20 Parr bombshell in an oil bath at 80 ° C and allowed to stand over the weekend. Upon cooling, a crystalline precipitate separates to give 34.6 g of product. The analytical sample is recrystallized from 95% ethanol to give crystals, m.p. 142-145 ° C, N-formyl-α- (4-fluoro-25-phenyl) -2-nitrophenethylamine.

Analysis for C 12 H 12 FN 2 O 3:

Calculated: C 62.50 H 4.54 N 9.72%

Found: C 62.62 H 4.51 N 9.77%

Example 42 N-Formyl-α- (3,4-dimethoxyphenyl) -2-nitrophenethylamine (VII)

A mixture of 41.7 g of Ofc- (3,4-dimethoxyphenyl) -2-nitrophenethylamine and 250 ml of methyl formate is placed in a Parr bombardment tube at 80 ° C and allowed to stand overnight. The solvent is evaporated off and the residue is recrystallized from 95% ethanol to give crystals,

II

35 72 1 1 7 sp. 35-139 ° C, N-formyl-Ofc- (3,4-dimethoxyphenyl) -2-nitrophenethylamine.

Analysis for Ch _Η. oN_0.-: JJ 171825

Calculated: C 61.81 H 5.49 N 8.48% 5 Found: C 61.67 H 5.27 N 8.42%

Example 43 N-Acetyl-O- (3,4-dimethoxyphenyl) -N-methyl-2-nitrophenethylamine (VII) In a cooled solution of 4.17 g of acetic acid 10 anhydride in 50 ml toluene, a solution of 4.31 g of O - (3,4-dimethoxyphenyl) -N-methyl-2-nitrophenethylamine is added dropwise. The mixture is warmed to room temperature and stirred for two hours. The solvents are evaporated off in vacuo to give crystals, m.p. 113-115 ° C, 15 N-acetyl-OC- (3,4-dimethoxyphenyl) -N-methyl-2-nitrophenethylamine.

Analysis for c 19 H 22 N 2 O 5:

Calculated: C 63.67 H 6.18 N 7.82%

Found: C 63.68 H 6.20 N 7.76%

Claims (2)

1. Compounds which may be used as intermediates in the preparation of therapeutically useful 4-phenyl-1,3-benzodiazepine derivatives of the formula IR Wherein R is hydrogen or lower alkyl, R ^ is hydrogen, C ^^ - alkyl alkyl, C3 6-cycloalkyl-C1_ alkyl alkyl or phenyl C , C 3 -C 3 alkyl or C 3 -C 3 alkoxy and n is 1 or 2, and their physiologically acceptable salt, characterized in that they have the formula II 1 x-h I R, \ I1 CH- - CH - N - H II 2 <Λ where R 2, X, Y and n are as defined above. 2. Process for Preparation of a Compound of Formula II xXX I1 CHO-CH-NH II