SU613716A3 - Method of obtaining 3-aryloxy-3-phenylpropylamine derivatives or salts thereof - Google Patents

Description

The process is carried out at 110 ° C and elevated pressure.

As the compound of general formula (I), it is preferred to use methylamine.

The target products are isolated in the free form of 1ChN S as salts with inorganic aislotham, such as salt, nitrogen, phosphoric, etc., as well as with organic acids such as block, tartar, almond, etc.

Target products can be isolated near the racemate or with optically active anti-oeoids. The racemate can be separated into individual isomers in the usual way, for example, by the formation of salts with optically active acids with the separation of salts by crystallization.

Example. Getting hydrochloride To methyl-3 (o-methoxyphenoxy) 3-phenylpropylamine.

A mixture containing 1OOO g of chloropropylbenzene, 15OO g of K-bromosuccinimide, 5 g of benzoyl peroxide and 6 l of carbon tetrachloride is placed in a 3-throat 12 Lo round bottom flask equipped with a stirrer and a condenser, stirred and heated until the exothermic reaction starts. . The heat source is removed and the boiling of the mixture is controlled by external cooling after completion of the reaction, as seen by the disappearance of the N-bromide succinimide, the solution is cooled and the crystalline succinimide is collected by filtration. The combined succinimide is washed with tetrachloride carbon. The collected filtrate and lamer water is concentrated in vacuo. A residue containing 3-chloro-1-bromopropylbenoyl was detected by NMR and used without further purification. Quit number output.

A solution of o-methoxyphenol is prepared by dissolving 156 g of sodium hydroxide and 485.6 g of oi-methoxyphenol in 2.5 liters of ethanol. Ethanol is removed by evaporation in vacuo to give a mixture of benzene, which is also removed by evaporation in vacuo. This process is repeated several times in order to dry the final o-methoxyphenol sodium salt. The resulting salt is dissolved, in 3 l of dimethyl sulfoxide, the solution is cooled to, 3X chlorine X-bromopropylbenol is added dropwise over 45 minutes, the reaction temperature rises to 25-G, heated at room temperature overnight and then poured into ice. The resulting aqueous layer was extracted with hexane (.2 L). Hexane extracts are washed with water and dried. After removal of gexane in vacuum, it is obtained as a precipitate (o-methoxyphenoxy propyl benzene, which is distilled under vacuum at 135-145 ° C. The structure of the compound is confirmed by an NMR spectrum.

A mixture containing 2OO ml of methylamine, 225 ml of methanol and 75 g of E-chloro-1- {s-meth oxyphenoxy) propyl benzene, is heated in an autoclave V for 12 hours at 14 ° C, cooled, and the solvent is evaporated. The semi-solid precipitate is mixed with a concentrated aqueous solution of sodium hydroxide, the mixture is extracted several times with ether. Mwtcp 3 (o methoxyphenoxy) 3C) is obtained by enylpropnlamine, which does not dissolve in an alkaline solution and is extracted with ether. The ether extracts are combined, washed with water and dried. The ether is removed in vacuo, the amine is obtained as a dark colored precipitate, which is dissolved in ether and 1 aqua is slowly added. oxalic acid in methanol. The 3-methyl-3- (o-methoxyphenoxy) -3-phenylpropylamine oxalate was isolated as an insoluble precipitate, which was filtered, washed and dried, T. Step. oxalate W-methyl-3-phenylpropylamine 150-152 C. The structure of the compound was confirmed by NMR spectrum.

Oxalate W -methyl-3- (o-methoxyphenoxy) -3-phenylpropylamine solution in a minimum amount of water when heated, is added a concentrated aqueous solution of sodium hydroxide. After cooling, the alkaline solution is extracted several times with ether, the combined ether extracts are washed with water, dried, and the ether is removed in vacuo. N-methyl-3 (o methoxyphenoxy) -3phenylpropylamine is obtained, which is dissolved in ether, the ether solution is saturated with dry gaseous chloride, hydrogen, and the desired hydrochloride is obtained, which is recrystallized from ethyl acetate containing a small amount of methanol, m.p. 129-

131 ° C.

Analogously to Example 1, the following N. were obtained. W-dimethyl or N-methyl-3-substituted phenoxy-3-phenylpropylamines:

N, N -dimethyl-3- (o-chlorophenoxy) -3-phenylpropylamine maleate, so pl. 88-9 ° C (from ethyl acetate-cyclohexane).

Calculated,%: C, 62.14j; H, 5.96; V 3.45; C.t 8.73.

Found,%: C 61.94; H 5.67; W 3.68; From 8.92.

N, N-dimethyl-3- {o-trifluoromethylphenoxy) -3-phenylpropyl shn p-toluenesulfonate, so pl. 134 136 ° C (from ethyl acetate).

Calculated,%: C 60.59; H 5.70; M 2.83, F 11.50; 5 6.47.

Found,%: C 60.36; H 5.52; M 3.12} FH, 80; 66.66. N -methyl 3 phenyl-3- (m-chlorophenoxy) -1f1 pilamine oxalate, t, Ø1 „i77-i79 ° C. Calculated%: C 59.10; H 5.61; W 3.83 ce 9.69. Found,%: C 68.89; H 5.45; C 4.07; : e 9.24. N, N-dimethyl-3-phenyl- {.-Methoxyphenxy) -propylamine oxalate, m.p., 125-128 Calculated,%: C 93.99; H 6.91; W 3.73 Found,%: C 63.93; H 6.90; N 3.59 N, N-dimethyl-3-phenyl-3- (o-allylphenox) -propylamine oxalate, m.p. 159 lGl c. Calculated,%: C 68.55} H 7.06; K 3.63. Naipeno. %: C 68.67; H 7.15; N 3.83. N, N -dimethyl-3-phenyl-3- (fh-chlorophenoxy) propylamine oxalate, mp, 13 141 ° C. Calculated,%: C 60.08; H 5.84; Ы 3.69; C B 9.33 Found,%: C 60.34; H 5.95; H 3.88 Ct 9.61. N, N -dimethyl-3- (o-methoxyphenoxy) -Pphenylpropylamine maleate. m.p. 98-SW C. Calculated,%: C 65.82; And 6.78; N 3.49. Found,%: C 65.83; H 6.52; N 3.63. W, N -dimethyl-3- (t1-methoxyphenoxy) -Ephenylpropylamine maleate, m.p., 101 104 C Calculated,%: C 65.82; H 7.8; K 3.49. Found,%: C 65.96; H 6.50; W 3.68. M-methyl-3- (No.-fluorophenoxy) -3-phenylps pilamine maleate, m.p., 112 I9C. Calculated,%: C, 63.99; H 5.91; M 3.73. Found,%: C 63.77; H 6.19; W 3.9O. N-methyl-3- (p-methoxyphenyl) -3-phenylpropylamine maleate, m.p., 128.5-135 C. Calculated,%: C 65.1O; H 6.50; li 3.62, Found,%: C 64.94; H 6.54; N 3.67. N, N -dimethyl-O- (1 -6 tromphenoxy) -3-phenylpropylamine oxalate, t, mp, 144-146 ° C. Vyloch;%: C 53.79; H 5.23; V 3, DA; BP 18.56. Found,%: C 53.84; H W 3.38; Bf 18.86, N -methyl-3-phenyl-3- (o-allylphenoxy) -pro pilaminoxalate, t, mp, 144-147s (decomp.). Calculated,%: C 67.91; H 6.78; M 3.77. Found,%: C 67.90; H 6.85; W 3.96, N tN-dimethyl-3-phenyl-3- (m-trifluoromethylphenoxy) -propylamine oxalate, t, pl. 163- D65 C. Calculated,%: C 58.11; H 5.36; N 3.39; F 13.79. Found,%: C, 57.89;; H, 5.2O; N 3.41; F 13.69. , N-dimethyl-3-phenyl- (o-tert-butylphenoxy) -propylamine oxalate, t, mp, 146149 ° C. Calculated,%: C 68.88; H 7.78; N 3.49. Found,%: C 68.56; H 8, O4; N 3,69, W -methyl-3-phenyl-3- (p-fluorophenoxy) -propylamine oxalate, so pl. 159-161C, Calculated,%: C, 61.88; H 55.77; N 4.01 | F 5.44. Found,%: C 61.66; H 5.90; fS 3.72; f- 5.70. M-methyl-3-phenyl-3- (o-methoxyphenoxy) proglamine chlorhydrate, t. Pl. 105-108C (from ethyl acetate). Vychnsleno: C 66.33; H 7.20; N 4.55; every 11.52. Found,%: C 66.16; H 7.36; ) t | 4.41; every 11.48. N-methyl-3 phenyl-3- {o-fluorophenoxy) -propylamine oxalate, t, pl. 148-150 ° C. Calculated,%: C, 61.88; H 5.77; N 4.0i; t-5.44. Found,%: C 61.83; H 5.97; K 4D4; F 5.65. C -meth # 3-phenyl-3- (m-methoxyphenoxy) propylamine oxalate, so pl. 140-143 ° C. Calculated,%: C 63.15; H 6.42; C 3.88, Found,%: C 62.91; H 6.60; M 4.17, N, M-dimethyl-3- (o-ethylphenoxy) -3-phenylsheaxamine oxalate, t, mp, 152-154 ° c. Calculated,%: C, 67.54; H 7.29; N 3.75; Found,%: C 67.33; H 7.05; N 3,98, N, and-dimethyl-Z- (O-isopropoxyphenoxy) 3-phenylpropylamine oKi alat, t, pl. 139-142 ° C. Calculated,%: C 68.20; H 7.54; N 3,61; Found,%:, 50; H 7.82; N 3.85. W-methyl-3-phenyl- (p-chlorophenoxy) -pro ilamine oxalate, so pl. 163-165 ° C. Calculated,%: C 59.19; H 5.51; N 3.83 {e 9.69. Found,%: C 59.33; H 58, - N 4.07; E 9.45. M, N -dimesh1-3- {p-fluorophenoxy) -3-fvvd "ilprosh1Laminom maleate, so pl. 103-1 ° C, Calculated,%: C 64.77; H 6.21; M 3,6O. Found,%: C 64.79; H 6.5 O; N. M, V-dimethyl-3- (m-chlorophenoxy) -3-feenyl propylamine oxalate, m.p. pp 15O-152 ° C. Bichlorized,%: C 60, O8; H 5.87; N 3.69; E 9.33. Found,%: C 59.9 O; H 60.08; H 3.42 E 9.60. N, N -dimethyl-3- (1-fluorofenohsk) -3-feilpropylamine chlorine, t, pls 166 68 ° C (from adheton-cyclohexane), Calculated,%: C 65.91; H 6.835 N E 11.99; P8,13. Found,%: C 65.78; H 6.82; M E 11.7 O; F 5.99. N -methyl-3-phenoxy-3-phenyl-2-methylproylamine oxalate, so pl. 158-160 0 (from isopropanol). Calculated,%: C 66, O7; H 6.71; M 4, Ov.

Found,%: C 66.12} H, 6.72; W 4.26.

W -methyl-3-phenoxy-3 phenyl-1 methylpropylamine oxapat, t, mp, 80-100 ° C (decomp. Of ethyladetate).

Calculated,%: C, 66.07 H, 6.71 j N, 4.06. five

Found, -%: C 65.85} H 6.45} A 4.20.

W ,, N-dimethyl 3-phenoxy-3-phenyl-1-fekylpropylamine oxapat, m.p., - 113,116 ° C.

Calculated,%: C, 66.84; H 7.01; N 3.90.

Found,%: C 67.03} H, 7.20; M 4.13. Yu

N, N -dimethyl-3-phenoxy-3g-phenyl-2-methyl-propylamine oxalate, so pl. 13O-134- C.

Calculated,%: C 66.89} H, 7.01; N 3.90.

Found,%: C 66.59} H, 7.08; N 3.96.

N -metalNo-3- (to fluorophenoxy) 3-feiylpro t5 pilamine oxalate, t, pl. 177-179 ° C,

Calculated,%: C 61.87} H 5.77} M 4.01} F 5.44.

Found%: C 62.07} H 6.02} U 4.23} F 5.23.20

N, N-d Imethyl-3- (o-ethoxyphenoxy) -3-phenylpropylamine oceanate, m.p. 101 104 ° C.

Vulgarized,%: C 64.77} H 6.99} C 3.6.

Found,%: C 65.05} H 7.00} W 3.88.

| 5 -dP-H, N-dimethyl-3 phenoxy-3-phenyl-25 -1 methylpropylamine oceanate, m. Pl. 131- 133 ° C.

Vychnseno,%: from 66.89} H 7.01; M 3.90.

Found,%; C 66.64} H 7.00} M 3.77.

Example 2. Getting 3-phenoxy-30 -3-phenylpropylamine.

In g 3, the phenoxy-3-phenndpropyl chloride obtained in Example 1 is heated with 15 O ml of liquid ammonia in a high-pressure reactor at 100 ° C for 2 O h. At the same time, the mixture components are evaporated. The resulting residue, containing 3-phenoxy-3 phenylpropylamine, is dissolved in ethanol and the volatile components are again removed by evaporation. The precipitate obtained is dissolved in a mixture of ether and 5N aqueous hydroxide solution. The ether layer is separated and the alkaline aqueous layer is extracted three times with ether. The ether extracts are combined and washed with water. The ether layer is extracted twice with 2N aqueous hydrochloric acid, the primary amine passes into the acidic acid. The acidic extracts are combined and made alkaline with 5N. aqueous solution of sodium hydroxide. The primary amine, insoluble in alkaline solution, is separated and extracted with ether. The ether extract is separated and the alkaline solution is extracted twice with ether. The ether extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried. By evaporation of the ester in BaKyyivie, 3-phenyl pro pylamine is obtained in the form of an oil. The Okhusalatovy salt of the primary is obtained analogously to the example of mp. 170-173 G

Calculated,%: C 64.34} H 6.04 {, M 4.41.

Found,%: C 64.49} H 5.80; | 4.67.

Example 3. Getting salts

Salts of the free bases are prepared by dissolving the free base in ether and adding an equivalent amount of a suitable non-toxic acid, also in ether. The resulting salts, for example, acetic acid and benzoic, are not soluble in ether and can be isolated by filtration. After that, the amine base can be dissolved in ethanol and the equivalent amounts of acid added as an ethanol solution. In this example, the salts formed are dissolved in a mixture and can be extracted and evaporated by evaporation of the solvent in vacuo. In this way, for example, sulfates, hydrobromides, phosphates, hydrogen phosphates, dihydrogen phosphates, acetates, methanesulfates, succinates, hydrochloric acid salts, citrates, benzoates and p-toluenesulfonates can be obtained.

Claims (1)

Invention Formula The method of obtaining the derivatives of 3-aryloxy-3-phenylproshamkam common. formulas / "3  imTs Sn-Sat-1g {c) 5 I I 1 CD CeUs R I 2 where RjL and R j are hydrogen or methyl | 1, l and R - halogen, trifluoromethyl, C. alkyl, C.-Cd-alkoxy or C-SL-aryonyl I and U - 0.1 or 2, and ft to Wt cannot be simultaneously O when both R, - methyl and both R are hydrogen, ILE of their salts, characterized in that chlorine-1- {substituted phenoxy) propyl "1zol is reacted with an amine of the formula NM (T where I has the indicated value, at 10-14 ° C and increased pressure, followed by isolation of the target product as a free compound or salt.