IL25829A - Omega-alkoxy-omega-trifluoromethylphenyl-alkylamines - Google Patents

Description

C O H E N Z E D E K & S P I S B A C H REGD. PATENT ATTORNEYS 24, LEVONTIN STR., P. O. B. 1169 TE L - AVI V P A T E N T S & D E S I G N S O R D I N A N C E I54 2/66 SPECIFICATION ώ -ALKOXY OgpaTITUTISD TRIFLUOROMBTHYIiPHElJYL ■ ALKYIAMI ES MELVILLE SAHYUN, a citizen of the U.S.A., doing business as SAHYUN LABORATORIES, of 316 Castillo Street, Santa Barbara, State of California, U.S. A., HEREBY DECLARE the nature of this invention and in what manner the same is to be performed to be particularly described and ascertained in and by the following statement: As used herein the terms "lower- alkyl" and "lowers alkoxy" refer respectively, to alkyl and alkoxy groups containing from one to eight carbon atoms, preferably less than five carbon atoms, which can be straight- chain or branched. Representative alkyl radicals are methyl, ethyl, propyl, isopropyl, n-butyl and sec-butyl, amyl, isoamyl, hexyl, heptyl and octyl. Representativ lower-alkoxy radicals are methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, and sec-butoxy, amyloxy and octyloxy.

Racemic mixtures are obtained as the carbon atom which bears the ether s bstituent and which is attached to the benzene ring is asymmetric.

Also, when a carbon atom in the methylene chain is asymmetric, a further race mate mixture is possible. Racemate pairs can be separated by fractional crystallization of an acid addition salt and each d and 1 isomer can be separate from the racemate in the conventional manner.

The compounds of this invention comprise the acid addition salts . When the tangible embodiments of the invention are employed for their pharma-cologicai effect, they ordinarily will be used in the form of their non-toxic acic addition salts, i.e. , pharmaceutically acceptable salts. However, any acid addition salt comes within the scope of this invention as they are all useful, e. g. , for purifying the free base or for separating racemate mixtures .

Suitable non-toxic, i. e. , pharmaceutically acceptable, acid addition salts are those formed from mineral acids, e. g. , hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid and sulfuric acid, and organic acids, e. g. , acetic acid, citric acid, tartaric acid, lactic acid, and the like, which provide the hydrochloride, hydrobromide, hydro-iodide, nitrate, phosphate or acid phosphate, sulfate or bisulfate, acetate, Equivalents of the compounds of this invention are those of the above formula bearing additional simple substituents on the benzene ring of th molecule, e . g. , one, two or more of lower- alkyl, aryl, alkaryl, halo, including chloro and bromo, trifluoromethyl, hydroxy, nitro, etc . , in the 2, 4, 5, or 6-position.

Preferred of the compounds of this invention are those wherein the N-lower-alkyl group is methyl or ethyl, the lower- alkoxy group is methoxy or ethoxy, and the methylene bridge contains one or at most two carbon atoms, i. e . , the alpha- unsubstituted and alpha- methyl-phenethyl compounds, and those having combinations of these preferred groups, e . g. , Ν, ^-di-methyl-beta-methoxy-m-trifluoromethylphenethylamine, N-methyl-beta-m.ethoxy-m-trifluoromethylphenethylamine, N-methyl-beta-ethoxy-m-trifluoromethyl-phenet ylamine, N-ethyl-beta-methoxy-m-trifluoromethylphenethylamine, and N-ethyl-beta-ethoxy-m-trifluoromethylphenethylamine .

The following is the manner and process of making and using the invention and the best mode contemplated of carrying out the invention.

The compounds of this invention can be prepared by first convertin a trifluoromethyl substituted phenyl bromide to the corresponding Grignard reagent.

The magnesium Grignard reagent is then reacted with a lower-alkyl G , liT -dihalo-lower-alkyl ether to form a trifluoromethylph¾alkyl halide bearing a lower-alkoxy group on the carbon atom alpha to the phenyl ring. Displacement of the halogen atom by reaction with a primary amine produces the compounds of this invention.

These reactions can be illustrated by the following formulae : and refluxing was continued for one hour after the addition. The cooled solution was poured over iced hydrochloric acid and the ether layer was separated, washed with water, dried and distilled to yield 15. 6 g. (55 percent) of S-methoxy- /3 -(2-trifluorcmethyl)phenethyl bromide, b.p. 71-75° (0. 5 mm. ) (b) N- Methyl- fa -methoxy- , - (2r-trifluoromethyl)phenethyl- amine Hydrochloride : A solution cf 11. 8 g. (0. 042 mole) of - (2-triiluoromethyi)phenethyl bromide in 75 ml. of isopropyl alcohol, containing 16 g. (0. 5 mole) of methylarnine was heated, in a pressure bottle, at 65° for 44 hours. The cooled solution was distilled to remove the excess methylaminej and isopropyl alcohol and the residue was . partitioned between dilute hydrochloric acid and ether. The aqueous solution was made alkaline and the liberated base was extracted with ether and distilled. Yield, 3.3 g. (34 perce of N-methyl- β -methoxy- β -(2-trifiuoromethyl)phenethylamine, b.p. 113-115° (22 mm. ).

Analysis: Calculated for CuHMFsNO: N, 6.01 Neut. Equiv. , 233 Found: N, 5.68 Neut. Equiv. , 235 The hydrochloride, prepared in ether with ethereal hydrogen chloride, melted at 257-258° after recrystallization from methanol-ether.

Analysis: Calculated for CuH14FsN0 · HQ: N, 5.19 Cl~, 13.15 Found: N, 4.80 Q-, 13.40 Example 3. N- Methyl- 3 -methoxy- β -(4-trifluoromethyl)phenethylamine Hydrochloride (a) 3-Methoxy- 3 -(4-trifluoromethyl)phenyl bromide: This compound was prepared in the same manner as the corresponding 2-trifluoro-m th c m o n - - (b) N- Methyl- β -methoxy- β -(4-trifluoromethyl)phenethylamine Hydrochloride: A heterogeneous mixture of 16.8 g. (0.06 mole) of the bromo compound of Example 2(a) and 92 g. (1.2 mole) of 40 percent aqueous methyl - amine was heated at 50-55° in a pressure bottle, for 64 hours. The excess methyiamine was removed by distillation, and the residue was partitioned between dilute hydrochloric acid and ethe . The aqueous solution was made alkaline, and the liberated base was extracted with ether and distilled. Yield, 3.4 g. (24 percent) of N- methyl- β -methoxy- β -(4-trifluoromethyl)phenethyl-| amine, b. p. 120-122° (20 mm. ) .

The hydrochloride, prepared in ether with ethereal hydrogen chloride, melted at 233-234° after recrystallization from a mixture of ethanol and ether.

Analysis: ' Calculated for C^K^NG · HCl: N, 5.19 Cl~, 13.15 Found: N, 4.66 CI", 12.92 Example 4. N- Methyl- V-rnethoxy- y -(3-trifluoromethylphenyl)propyl- amine Hydrochloride . n- (a) c(, Y -Dichloro-j»-propyl methyl ether: Hydrogen chloride was passed through a stirred mixture of 23 g. (0.41 mole) of acrolein and 13.1 s (0.41 mole) of methanol at 0° until 32 g. had been absorbed. After an additiona 20 minutes the layers were separated and the lower layer was dried over calcium chloride and distilled. Yield, 38 g. (64 percent) of Q , "y'-dichloro-p propyl methyl ether, b.p. 48-51° (16 mm. ). Reported: b.p. 45° (12 mm. ); C. A. 18 , 815. (b) V-Methoxy- * * -(3-trifluoromethyl)phenylpropyl . chloride: To the stirred Grignard reagent, prepared from 27 g. (0.12 mole) of m-brom benzotrifluoride and 2.9 g. (0.12 g. at. ) of magnesium in ether, there was added dropwise an ether solution of the above dichloro compound. Stirring a refluxing were continued iQ one hour after the addition, after which the mixture was poured over iced hydrochloric acid. The ether layer was separated, dried and fractionally distilled to yield 17. 3 g. (57 percent) of ^methoxy-(S-tri iuoromethyl)phenylpropyl . chloride, b. p. 82-85° (0. 5 mm . ) . (c) N- Methyl y-met oxy- ^ - (3-trifluoron ethylphenyl)propyl-amine hydrochloride: An autoclave was charged with 175 ml. of isopropyl alco ol containing 31 g. (1 mole) of methylamine and 17. 3 g. (0.068 mole) of the above chloro -ether. The temperature of the mixture was maintained at 95-100° for 14 hours, after which the solution was distilled to remove the excess methylamine and the solvent. The residue was partitioned between dilute hydrochloric acid and ether, and the aqueous solution was rendered alkaline . The liberated base was isolated by ether extraction and distilled. Yield, 9 g. (54 percent) of N-methyl -methoxy- ^-(3-trifluoromethyl-phenyl)propylamine, b.p. 126-128° (20 mm . ) . .

Analysis: Calculated for C12H16FsNO: N, 5. 67 Neut. Equiv. , 247 Found: N, 5. 32 Neut. Equiv. , 238 The hydrochloride, prepared in ether with hydrogen chloride, melted at 111-112° after recrystallizaiion from a mixture of ethanol and ether. Analysis: Calculated for C12H1SF3N0 · HC1: N, 4.94 CI*", 12.45 Found: N, 4. 81 CI ~, 12.71 Following the procedure of Example 1, the following compounds were prepared by substituting the appropriate amine for the methylamine in the alkylation reaction.

Ex. A R b.p. (base) m.p. (. HC1) C3¾ CH2 C2¾ 122-4/ 20 mm 189-1901 6 C¾ CH2 145-7/ 20 mm 138-1392 7 ν-Ίϊ3 CH2 CH(CEs)a — 155-1571 8 CH3 CH2 CH2CH=CH2 — 146-1473 9 ' CH2 CHgCHjjOH — 152-1533 CH2 cyclohexyl 106-9/0.25 mm . 140-141 2 11 CH2 . benzyl 135-7/ 0.3 mm 165-167 12 , £ί3 C¾ phenethyl — -170-171 3 13 CH2 — 142-144d2 14 CA CH2 CH2CE2OH 134-5/0.2mm — CH2 CH3 134-8/ 20 mm 128-1293 16 CE(CHs) c¾ 119-20/ 23mm 165-1661 1recryst. isopropyl alcohol-ether 2recryst. acetone-ether 3 ecryst. acetone 4 recryst. ethanol-ether A related invention are the primary amines otherwise corresponding to the secondary, amines described herein, i. e. , those represented by as intermediates in the production of the corresponding secondary amines of this invention by alkylation with an appropriate hydrocarbon halide or with ethylene oxide. The following example is representative of the manner of producing these primary amines by the reaction of the corresponding lower- alkoxy-trifluoromethylphenalkyl halide with ammonia. β -Methoxy- β -(m-trifluoromethyl)phenethylamine Hydrochloride Twenty-two grams (0.078 moles) of -(m-trifluoro-methyl)phenethyl bromide was combined with 400 ml. of methanol which had been saturated with ammonia at 10°. The solution, contained in an autoclave, was heated to 80-90° for 5 hours and cooled. The alcohol was removed by distillation and the residue was partitioned between dilute sodium hydroxide and ether. The ether solution was washed, dried and distilled to yield 13.2 g. (77 percent) of ^-methoxy-yQ-(m-trifluoromethyl)phenethylamine; b.p. 110-118 (22 mm. ). The hydrochloride, prepared in ether and recrystallized from iso propyl alcohol-ether, melted at 168-169°.

Analysis: Calculated for C^H^NO · HC1: N, 5.48 Cl~, 13.88 Found: N, 5.46 CI", 13.94 '

Claims (4)

P.A. 25839/1 WHAT IS CLAIMED IS t

1. A compound o the formulae lkyl wherein A is an alkylene having one to three earbon atoms bridge containing from one to eight earbon atoms, R is hydroxyethyl or a hydrocarbon group containing from one to eight carbon atoms, or hydrogen, wherein "lower alkyl* means alkyl of 1 to 8 carbon atoms.

2. A compound of Claim 1 wherein the -CF«j group is metal*

3· A compound of the formula wherein A* is a methylene bridge containing from one to two carbon atoms.

4. A compound of the formula alkyl -lower-aIkyl - 5 - N- Lower- alkyl- β -methoxy-m-trifluoromethylphenethylamine . - 6 - N- Methyl- β -methoxy-m-trifluoromethylphenethylamine . - 7 - A compound of the formula wherein A is a one to three carbon atom bridge containing from one to eight - 8 - A compound of Claim 7 wherein the -CF3 group is meta. - 9 - A compound of the formula wherein A is a one to three carbon atom bridge containing from one to eight carbon atoms. DATED SHIS 22nd day of May, 1 6