DE2325328B2 - PHENYLAETHYLAMINE DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND PRODUCTS CONTAINING THEM - Google Patents

Description

wherein Ri and R2 are a hydrogen atom or a represent straight-chain or branched alkyl radical having 1 to 5 carbon atoms, and A is either a Means sulfur or an oxygen atom, in racemic form or as optical isomers as well their addition salts with pharmaceutically suitable mineral or organic acids.

2. Process for the preparation of the compounds according to claim 1, characterized in that one in a manner known per se a l-phenyl-propanone-2 of the formula (II)

10

15th

(H)

in the presence of formic acid with an amine of the formula (III)

40

HN

(III)

R ₂

converts, the reaction product obtained optionally separates into its isomers and / or into the Transferred addition salt.

3. Pharmaceutical agent, characterized by a content of one of the compounds according to Claim 1 and a conventional carrier.

55

The invention is defined in more detail in the claims.

The manufacturing process uses condensation in the presence of formic acid a large excess of amine (III) carried out, being carried out at an elevated temperature, in general between 160 and 170 ° C, heated and the reaction mixture at this temperature for 10 up to 20 hours, preferably 14 hours. The amine (I) is isolated either in the form of a base or in the form of a salt, such as its hydrochloride.

Phenyl-l-propanone-2 of the formula (II) is prepared by reducing phenyl-l-nitro-2-pro

fts CH - = C

NO,

which in turn by condensation of the corresponding Benzaldehyde can be obtained with nitroethane.

The invention also includes the separation of the amines (I) into their optical antipodes by means which are known per se Procedures included. This separation is preferably carried out by an optically active acid, preferably d-tartaric acid or d-dibenzoyl-tartaric acid

The claimed compounds have appetite suppressant properties, they are the known Fenfluramine are superior.

The examples illustrate the invention.

example 1

(Trifluoromethylthio-3'-phenyl) -1-ethylamino-2-propane

1.85 g (40 mmol) of formic acid are introduced into a 50 ml two-necked flask equipped with an air cooler and a dropping funnel. It is cooled in an ice bath and 2 ml of ethylamine are added drop by drop. The reaction mixture is allowed to rise again to room temperature and 2.85 g (10 mmol) of (trifluoromethylthio-3'-phenyl) -1-propanone-2 are added. Heating the contents of the flask for 14 hours at 160 to 170 ⁰ C, add 2 ml of concentrated hydrochloric acid and 2 ml of water is added and heated for 3 hours at reflux temperature. 2 ml of concentrated hydrochloric acid are added again and the mixture is brought to reflux again for 2 hours. It is allowed to cool, water is added, extracted once with 50 ml of ether, the aqueous phase is made alkaline with soda solution, extracted three times successively with 50 ml of ether, the combined ethereal extracts are washed several times with water, dried over sodium sulfate, filtered and the ether is evaporated Filtrate on a water bath in vacuo. The 1.4 g of the oily residue are dissolved in anhydrous ether and ethereal hydrochloric acid is added until the precipitation has ended.

The (trifluoromethylthio-3'-phenyl) -l -ethylamino-2-propane hydrochloride Recrystallized from ethyl acetate, lies in the form of a white crystallized, water-soluble Compound that melts at 130 ° C. Yield 30%.

Analysis of KJrCi ₂ H ₁₇ ClFjNS (299.8):

Calculated: C 48.07, H 5.71, N 4.67, Cl 11.83%;

found: C 48.19, H 5.67, N 4.66, Cl 11.97%;

C 48.15, H 5.62, -, C! 11.87%.

Example 2

(Trifluoromethoxy-3'-phenyl) -1-ethylamino-2-propane and its hydrochloride

In a 250 ml two-necked flask fitted with a Air cooler and a dropping funnel and immersed in an alcohol-dry ice cooling bath 13 ml (0.2 mol) of ethylamine are introduced and there are

9.65 ml (0.25 mol) of formic acid were added dropwise through the dropping funnel. Allowing the temperature of the mixture to room temperature to return, added 14.15 g (0,065MoI) (3'-trifluoromethoxy-phenyl) -I-propanone-2 added and heated the contents of the flask s for 20 hours at 150 ⁰ C. It is allowed to cool , add 20 ml of water and 20 ml of concentrated hydrochloric acid and reflux this solution for 5 hours. The solution was diluted with a large volume of water, _{extracted) 0} with 100 ml of ether, the aqueous solution basified with sodium carbonate and extracted three times successively with 100 m! Ether. These essential extracts are combined, washed with water, dried over sodium sulfate, filtered and the ether of the Filtrais evaporated in a water bath in vacuo and rectified.

Finally, 8.7 g (yield 70%) (trifluoromethoxy-3'phenyl) - 1-ethylamino-2-propane in the form of a liquid which passes over at 108 to 11 OVl 6 Torr.

Analysis for Ci ₂ Hi ₆ F ₃ NO (247.27):

Calculated: C 58.31, H 6.52, N 5.66%;
found: C 58.58, H 6.67, N 5.59%.

The hydrochloride of (trifluoromethoxy-3'-phenyI) -I-ethylamino-2-propane is produced by dissolving the aforementioned base in anhydrous ether and through Addition of essential hydrochloric acid until the precipitation is complete. Melting point 132 ° C.

Analysis for C12H17F3CINO (283.77): ^{} 0}

Calculated: C 50.80, H 6.04, Cl 12.49%;
found: C 50.83, H 5.77, Cl 12.52%.

Example 3

(Trifluoromethylthio-3'-phenyl) -l-amino-2-propane and its hydrochloride

Into a 250 ml two-necked flask fitted with an air cooler and a dropping funnel and from is cooled outside by a dry ice-alcohol bath, 3.5 g (0.2 mol) of liquid ammonia are added. 9.7 ml (0.25 mol) of formic acid are introduced dropwise through the dropping funnel. The mixture is left on Return to room temperature, add 15.1 g (0.065 mol) of (trifluoromethylthio-3'-phenyl) -l-propanone-2 and this mixture is heated to 155 to 160 ° C. for 23 hours. Allow to cool, add 30ml concentrated Hydrochloric acid is added and this solution is refluxed for 7 hours. Man dilute the reaction mixture with a large volume of water, extract it with 100 ml of ether, alkalize the aqueous layer with soda lye, extract three times successively with 100 ml of ether, combine them essential extracts, washes them several times with water, dries them over sodium sulfate, filtered and evaporates the solvent from the filtrate on a water bath in vacuo.

Finally, 8 g (yield 52%) of (trifluoromethylthio-3'-phenyl) -l-amino-2-propane are obtained in the form of a slightly yellowish oil.

Analysis for Ci ₀ Hi ₂ F ₃ NS (235.27):

Calculated: C 51.05, H 5.14, F 24.23, N 5.95, S 13.63%;

found:

C 51.12, H 5.03, F 24.75, N 6.04, S 13.29%.

The hydrochloride of (trifluoromethylthio-3'-phenyl) -l-amino-2-propane is obtained by dissolving the base described above in anhydrous ether and by the addition of ethereal hydrochloric acid until the precipitation is complete.

Analysis for C10H13CIF3NS (271.73):

Calculated:

C 44.20, H 4.82, Cl 13.05, F 20.98, N 5.18, S 11.80%; found:

C 44.17, H 4.90, Cl 12.92, F 21.30, N 5.00, S 12.02%.

Example 4

(Trifluoromethylthio-3'-phenyl) -1-n-propyl-amino-2-propane and its hydrochloride

Into a 250 ml two-necked flask equipped with an air cooler and a dropping funnel, 9.25 g (0.2 mol) of formic acid are added. It is cooled to 0 ° C. in an ice bath and passed through the 11.8 g (0.2 mol) of n-propylamine are added dropwise over 30 minutes to the dropping funnel. The reaction mixture is allowed to return to room temperature and is added Add 14.25 g (0.06 mol) of (trifluoromethylthio-3'-phenyl) -1-propanone-2. The contents of the vessel are heated for 14 Hours to 160 ° C (internal temperature of the mixture), add 10 ml of concentrated hydrochloric acid and Add 10 ml of water and heat to reflux temperature for 3 hours. Another 10 ml concentrated Add hydrochloric acid and reflux the mixture again for 10 hours. It is allowed to cool and 250 ml of water and 250 ml of ether are added. The precipitate is filtered off and slurried put it in water, add soda to this suspension, extract the separated oil with ether, wash the essential solution with water, dries the dried fraction, evaporates the solvent and rectified the residue.

In this way, 5.6 g (yield 33%) (trifluoromethylthio-3'-phenyl) -ln-propylamino-2-propane are obtained in the form of a colorless liquid which passes over at 88 to 90 ° C./0.5 torr . Refractive index η »= 1.478.

The hydrochloride of this base is prepared in anhydrous ether and recrystallized from ethyl acetate. Fixed point 152 ° C.

Analysis for C ₁₃ H ₁₉ ClF ₃ NS (313.81):

Calculated: C 49.77, H 6.10, N 4.66%;
Found: C 49.69, H 6.55, N 4.47%.

Example 5

(Trifluoromethylthio-3'-phenyl) -1-isopropylamino-2-propane and its hydrochloride

In a 250 ml two-necked flask equipped with an air cooler and a dropping funnel, 9.25 g (0.2 mol) of formic acid is introduced. The mixture is cooled to 0 ° C. using an ice bath and 11.8 g (0.2 mol) of isopropylamine are added dropwise. The reaction mixture is allowed to return to room temperature and 14.5 g (0.06 mol) of (trifluoromethylthio-3'-phenyl) -l-propanone-2 are added. The contents of the vessel are heated to 165 ^° C. (internal temperature of the mixture) for 20 hours, 10 ml of concentrated hydrochloric acid and 10 ml of water are added and the mixture is heated to reflux temperature for 3 hours. Another 10 ml of concentrated hydrochloric acid is added and the mixture is brought back to normal

Reflux for 4 hours. Allow to cool, extract the separated oil with water, this solution neutralized with sodium hydrogen carbonate, extracted with ether and dry the essential solution over sodium sulfate. It is filtered and introduced into the filtrate A stream of hydrochloric acid until the precipitation is complete. The hydrochloride which has been separated off is filtered off and recrystallized it from ethyl acetate.

2 g (yield 20%) of the hydrochloride are obtained in this way of (Triruormethylthio-3'-phenyI) -1-isopropylamino-2-propane, which melts at 126 ° C.

Analysis for CuH ,, CIF ₃ NS (313.81):

Calculated: C 49.77, H 6.10, N 4.46%;
Found: C 49.78, H 6.22, N 4.43%.

Example 6

(Trifluoromethylthio-3'-phenyl) -l-n-amylamino-2 propane and its hydrochloride

9.25 g (0.2 mol) of formic acid are placed in a 250 ml two-necked flask equipped with an air cooler and a dropping funnel. It is cooled to 0 ° C. in an ice bath and 17.4 g (0.2 mol) of n-amylamine are added dropwise through the dropping funnel over 30 minutes. The reaction mixture is allowed to return to room temperature and 14.25 g (0.06 mol) of (trifluoromethylthio-3'-phenyl) -1-propanone-2 are added. Heating the contents of the vessel during 10 hours at 160 ⁰ C, 10 ml of concentrated hydrochloric acid and 10 ml of water is added and heated for 3 hours at reflux temperature. Another 10 ml of concentrated hydrochloric acid is added and the mixture is brought to reflux again for 2 hours. The hot flask contents are poured into 250 ml of water, allowed to cool, the precipitate is filtered, the fine crystals are crushed in 200 ml of ether, filtered and carefully washed with ether. It is recrystallized from 250 ml of ethyl acetate. Obtained in this way 9.7 g (yield 46.5%) of the hydrochloride of (Trif luormethyIthio-3'-phenyl) -1-n-amylamino-2-propane, melting at 161 ⁰ C.

Analysis of WrCi ₅ H ₂₃ F ₃ ClNS (341.87):

Calculated: C 52.70, H 6.78, Cl 1038, N <, 10%;
Found: C 52.72, H 6.80, Cl 10.38, N 4.09%.

Example 7

1- (3'-Trifluoromethylthio-phenyl) -2-isobutylamino-propane and its hydrochloride

Charge a 250 ml two-necked flask fitted with an air cooler, a dropping funnel, and a mechanical stirrer is equipped with 9.5 g (0.2 mol) of formic acid. It is cooled to 0 ° C. with an ice bath and add dropwise via the dropping funnel while stirring 14.6 g (0.2 mol) of isobulylamine are added. The temperature of the reaction mixture is allowed to rise to room temperature and sets 14.25 g (0.06MuI) 1- (3'-trinuomethylthio-phenyl) -propanon-2 to. The contents of the flask are heated to 160 ° to 165 ° C. for 14 hours Add 10 ml of concentrated hydrochloric acid and 10 ml of water and heat up for 3 hours

ίο reflux temperature. Then add another 10 ml concentrated hydrochloric acid and heated the Mix again to the reflux temperature for 2 hours. Then let it cool down, decant the organic phase, rub it in with ether and

recrystallizes it from ethyl acetate.

In this way, 4 g (yield = 22%) of the hydrochloride of 1- (3'-Trinuormethylthio-phenyl) -2-isobutylamino-propane, which is obtained Melts from 139 to 140 ° C.

, ₀ analysis WrC ₁₄ H ₂₁ ClF ₃ NS (3273):

Calculated: C 5132. H 6.46, N 437, Cl 10.82%;
found: C 51.22, H 6.34, N 4.08, Cl 11.12%.

Example 8

1 (3'-trifluoromethylthio-phenyl) -

2-methylamino-propane and its hydrochloride

A 250 ml two-necked flask fitted with an air condenser is charged with 113 g (0.2 mol) N-methylformamide, 2.5 g (0.05 mol) formic acid and 9.25 g (0.2 mol) 1 - (3'-triiluomethylithio-phenyl) -propanone. This mixture is heated to 165 ° C. for 15 hours, and the excess formic acid is driven off and the N-methylformamide on the water bath and in vacuo, the residue is treated with 50 ml of 50% strength Hydrochloric acid and refluxed for 8 hours. Then you cool down, dilute the contents of the flask with 100 ml of water, the aqueous solution washes with 50 ml of benzene, filtered through Vegetable activated charcoal, makes the filtrate alkaline with ammonia and extracts five times in a row 50 ml of ether. The ether extracts are combined, dried over sodium sulphate, filtered and the ether expelled of the filtrate, dilute the oily base with anhydrous ether and add it to the end of the precipitation Ether added to hydrogen chloride gas.

The hydrochloride thus formed is filtered off with suction and it crystallizes from an ethyl acetate / isopropyl ether mixture (1/4) around. Melting point = 92 ° C.

Yield = 31%.

Analysis _{WrC 11} H ₁₅ NF ₃ ClS (285.5):

Calculated: C 4630, H 531. N 430, Cl 12.40%;
found: C 46.29, H5A, N 4.27, Cl 12.75%.

Claims (1)

Patent claims:
1. Phenylethylamine derivatives of the formula (I) pen the formula CH, CH ₁ -CH-N CH ₃ (D