HRP930129A2 - N-subutituted derivatives of n-methyl-3-(p-trifluoromethylphenoxy) -3-phenylpropilamine and the process for the preparation thereof - Google Patents

Description

The technical field to which the invention belongs

Int. spike. C07C 93/08, A61K 31/135

The invention relates to N-alkyl-, N-aryl- and N-alkoxycarbonyl derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine as well as to the process for their preparation.

The most similar known compounds are N,N-dimethyl- and alkyl N-carboxylate derivatives of N-methyl-3-(p-trifluoromethylphenoxy) 3-phenylpropylamine. The N,N-dimethyl derivative was prepared by condensation of N,N-dimethyl-3-phenyl-3-chloropropylamine and p-trifluoromethylphenol [US Pat. 4,018,895(1977)], and alkyl N-carboxylate derivatives were prepared by the reaction of alkyl M-methyl-3-phenyl-3-methylsulfonyl-oxypropylamine-N-carboxylate and p-trifluoromethylphenol [Sp. pat. 556 009(1986)]. N,N-dimethyl and alkyl N-methyl-N-carboxylate derivatives are used as intermediates in the synthesis of pharmacologically very important N-methyl-3-(p-trifluoro-methylphenoxy)-3-phenylpropylamine (fluoxetine).

The subject of this invention is the process of preparing N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenyl propylamine of the general formula I,

[image]

where the radical R has the meaning of aryl, alkylaryl and alkyl residue with C1 to C4 atoms, and n can be 0 and 1.

A further subject of this invention are the compounds of the general formula I, where the radical R has the meaning of an aryl and alkylaryl radical, and n has the aforementioned meaning. It was found that the compounds of the general formula I, where the radical R has the meaning of a benzyl and p-nitrobenzyl radical, and n 0, can be prepared easily and in high yield by condensation of N-substituted derivatives of N-methyl-3-phenyl-3-hydroxypropylamine of the general formula II,

[image]

where the radical R has the meaning of a benzyl and p-nitrobenzyl radical, and n 0, and p-trifluoromethylchlorobenzene of formula III,

[image]

in N,N-dimethylacetamide with sodium hydride at a temperature of 90-160°C. The obtained N-substituted derivatives of the general formula I, where the radical R has the meaning of a benzyl and p-nitrobenzyl radical, and n is 0, undergo a reaction with esters of chloroformic acid of the general formula IV,

[image]

where the radical R has the aforementioned meaning, in an aprotic solvent such as, for example, methylene chloride, toluene, xylene, at a temperature of 20-115°C. Evaporation of the organic solvent after the completed reaction and washing with water and crystallization of the residue from a suitable solvent such as petroleum ether, lower alcohols, or chromatography on a silica gel column give compounds of the general formula I, where the radical R has the aforementioned meaning, and n is 1 It was also found that the reaction of N,N-dimethyl derivatives and esters of chloroformic acid sometimes gives very stable quaternary ammonium salts as the main reaction product, and not the corresponding N-methyl-N-alkoxycarbonyl derivatives (M. Matzner, R. P. Kurkjy and R. J. Cotter, Chem .Rew., 64 (1964) 645; B. J. Calvert and J. D. Hobson, J. Chem. Soc., 1965, 2723).

According to the present invention, it follows that N-benzyl- and N-p-nitrobenzyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamines are much more suitable substrates for the preparation of N-methyl-N-alkoxycarbonyl derivatives than the corresponding N,N -dimethyl derivative.

Example 1

N-benzyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine

A solution of N-benzyl-N-methyl-3-phenyl-3-hydroxypropylamine (2.55 g, 0.01 mol) in N,N-dimethylacetamide (8 ml) was added dropwise to a suspension of sodium hydride (0.43 g of 60% dispersion in oil, 0.011 mol) in N,N-dimethylacetamide (6 ml) and heated for 5-10 min at 70-75°C. p-trifluoromethylchlorobenzene (2.1 g, 0.0115 mol) was added to the resulting mixture and the resulting reaction mixture was heated for 6 hours at a temperature of 130-135°C, then evaporated in a vacuum and the residue was dissolved in toluene (12 ml). The solution is washed with water (4x5 ml), the organic layer is filtered, then 2N hydrochloric acid (12 ml) is added dropwise with stirring and cooled for 2 to 3 hours at 5-10°C. The secreted white crystals are filtered off with suction and washed first with water (10 ml) and then with toluene (10 ml). 3.92 g of product are obtained in the form of hydrochloride, m.p. 155-156°C. The resulting hydrochloride was stirred in 1N sodium hydroxide (20 ml) for 10 min. at a temperature of 60-70°C, extract with toluene (25 ml), wash the organic layer with water (4 x 10 ml), filter and evaporate in a vacuum. 3.59 g (90.0%) of N-benzyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine m.p. 42-44°C.

IR (KBr): 2970w, 1620m, 1520m, 1460m, 1330vs, 1250s, 1210vs, 1175s, 1070s, 835m, 700s, cm-1;

300 MHz 1H NMR (CDCl3) δ: 1.96-2.05 (2H, m, CH2), 2.22(3H, s, NMe), 2.39-2.48 and 2.57-2 .64 (2 H, m, CH2), 3.47 and 3.51 (2 H, 2d, J 12 Hz, CH2Ph), 5.32 (1 H, dd, CH), 6.86 (2 H, d, J 8.6 Hz, arom.), 7.22-7.30 (10 H, m, 2 C6H5),

7.41 (2 H, d, J 8.6 Hz, arom.);

Anal. C24H24F3NO (399.46)

calculated: C 72.16; H 6.06; N 3.51 %

found: C 72,18; H 6.34; N 3.54 %

Example 2

Methyl N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine-N-carboxylate

A solution of N-benzyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropyl-amine (4.0 g, 0.01 mol) and methyl chloroformate (1.45 g 98% alcohol, 0.015 mol) in of toluene (50 ml) is heated for 4 hours in a sealed tube at a temperature of 110-115°C. After cooling, the reaction solution is washed first with 0.1N hydrochloric acid (4 x 10 ml) and then with 0.1N sodium hydroxide. (4 x 10 ml). Finally, the organic layer is washed with water (4 x 10 ml), evaporated in a vacuum and the residue recrystallized from petroleum ether (12 ml). 3.3 g of 90%) methyl N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine-N-carboxylate m.p. 72-74°C.

IR (KBr): 2960w, 1710vs, 1620s, 1490m, 1410m, 1375m, 1340vs, 1275vs, 1165vs, 1070s, 845vs, 700s cm-1;

300 MHz 1H NMR (CDCl3)6: 2.09-2.10 (2H, br, CH2), 2.94 (3H, s, NMe), 3.48-3.65 (5H, br, CO2Me and CH2), 5.13-5.19 (1 H, br, CH), 6.9 (2 H, d, J 8.6 Hz, arom.), 7.25-7.35 (5 H , m, C6H5), 7.4 (2 H, d, J 8.6 Hz, arom.);

Anal.: C19H20F3NO3 (367.36)

calculated: C 62.11; H 5.49; N 3.81 %

found: C 62.33; H 5.63; N 3.79 %

Example 3

Phenyl N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine-N-carboxylate

A solution of N-benzyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine (4.0 g, 0.01 mol) and phenyl chloroformate (1.76 g 98%, 0.011 mol) in methylene chloride ( 50 ml) was stirred for 3 hours at room temperature and the reaction solution was then treated analogously to the procedure described in example 2. 3.71 g (86.5%, i-propanol) of pure phenyl N-methyl-3-(p- trifluoromethylphenoxy)-3-phenylpropyl-amine-N-carboxylate m.p. 83-84°C.

IR(KBr): 2940w, 1715vs, 1620s, 1580m, 1410vs, 1340vs, 1260vs, 1190vs, 1110vs, 1050vs, 947s, 835s, 700s cm-1;

300 MHz 1H NMR (CDCl3)5: 2.16-2.35 (2 H. m, CH2), 3.02 and 3.09 (3 H, 2s, NMe), 3.49-3.69 and 3.78-3 .85 (2 H, 2m, CH2), 5.23-5.26 (1 H, no. CH), 6.84 (2 H, d, J 10.5 Hz, arom.), 6.90-7.35 ( 10 H, m, 2 C 6 H 5 ), 7.42 (2 H, d, J 10.5 Hz, arom.);

Anal. C24H22F3NO3 (429.42)

calculated: C 67.12; H 5.16; N 3.26 %

found: C 67.38; H 5.36; N 3.38 %

Example 4

p-Nitrophenyl N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine-N-carboxylate

Analogous to the procedure described in example 2 from N-benzyl-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine (4.0 g, 0.01 mol) and p-nitrophenyl chloroformate (2.37 g 97%- tni, 0.011 mol) in methylene chloride (50 ml) gives 4.36 g (92%, i-amyl alcohol) p-nitrophenyl N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamino-N-carboxylate m.p. 96-97°C.

IR (KBr): 2970w, 1720vs, 1620m, 1520s, 1410m, 1350s, 1320s, 1260s, 1210s, 1160s, 1110s, 840s, 750m cm-1;

300 MHz 1H NMR (CDCl3)8: 2.14-2.35 (2 H, br, CH2), 3.05 and 3.11 (3 H, 2s, NMe), 3.49-3.60, 364 -3.74 and 3.82-3.92 (2 H, 3m, CH2), 5.21-5.29 (1 H, m, CH), 6.86 (2 H, d, J 8.7 Hz, arom), 6.91 and 6.98 (2 H, 2d, J 9 and 9 Hz, arom), 7.14-7.39 (5 H, m, C6H5), 7.43 (2 H. d. J 8.7 Hz, aroma) ,8.12 and 8.19 (2 H, 2d, J 9 and 9 Hz, aroma);

Anal.: C24H21F3N2O5 (474.42)

calculated: C 60.76; H 4.46; N 5.91 %

found: C 61.03; H 4.37; N 6.20 %

Example 5

Benzyl N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine-N-carboxylate

A solution of N-methyl-N-p-nitrobenzyl-3-(p-trifluoromethylphenoxy)-3-phenylpropyl amine (4.43 g, 0.01 mol) and benzyl chloroformate (1.98 g 95%, 0.011 mol) in methylene chloride (50 ml) is heated for 5 hours at the boiling temperature of the solution and then processed analogously to the procedure described in example 2. The residue after evaporation of the toluene layer is chromatographed on a silica gel column eluting with a solvent mixture of chloroform-benzene (1:1). 3.77 g (85%, Rf=0.47) of benzyl N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine-N-carboxylate are isolated in the form of an oil.

IR (KBr): 2965w, 1710vs, 1620s, 1460m, 1410m, 1335vs, 1255vs, 1165vs, 1115vs, 1075s, 840s, 700s cm-1

300 MHz 1H NMR (CDCl3): 2.06-2.22 (2H, br, CH2), 2.93 (3H, s, NMe), 3.44-3.57 (2H, br, CH2 ), 4.86-5.19 (3 H, br, CH and CO2CH2Ph), 6.80-7.14 (14 H, m, arom);

Anal. C25H24F3NO3 (443.45)

calculated: C 67.70; H 5.46; N3.16%

found: C 67.45; H 5.68; N 3.05 %

Example 6

N,N-dimethyl-N-benzyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylammonium chloride

A solution of N,N-dimethyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine (3.23 g, 0.01 mol) and benzyl chloroformate (1.98 g 98%, 0.011 mol) in toluene (20 mL) ) is heated for 4 hours at the boiling temperature of the mixture and then cooled for 15 hours at 0-5 °C. The secreted crystals are filtered off with suction and recrystallized from toluene (20 ml). 3.46 g (77%) of N,N-dimethyl-N-benzyl-3-(p-trifluoro-methylphenoxy)-3-phenylpropylammonium chloride m.p. 154-155 °C.

IR (KBr): 3020w, 2980w, 1620s, 1525s, 1340vs, 1255vs, 1160vs, 1025vs, 1070vs, 835vs, 735s, 705s cm-1;

300 MHz 1H NMR (CDCl3): δ 2.70-2.81 (2H, m, CH2), 3.56 (6H, s, NMe2), 3.91-3.97 and 4.18-4 .24 (2 H, 2m, CH2), 5.16 and 5.27 (2 H, 2d, J 12.6 and 12.6 Hz, CH2Ph), 5.73 (1 H, dd, CH, 7, 13-7.83 (14 H, m, arom);

Anal. C25H27ClF3NO (449.93)

calculated: C 66.73; H 6.03; N 3.11; Cl 7.88 %

found: C 67.02; H 6.15; N 3.06; Cl 8.08 %

Claims (8)

1. Process for the preparation of N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine of the general formula I [image] where when n=0 R has the meaning of a benzyl or p-nitrobenzyl group, and when n=1 R represents an aryl, alkylaryl or alkyl group with C1-C4 atoms, indicated by the condensation of N-substituted derivatives of N-methyl- 3-phenyl-3-hydroxypropylamine of the general formula II, [image] where the radical R has the meaning of a benzyl and p-nitrobenzyl radical, and n 0 and p-trifluoromethylchlorobenzene of formula III, [image] preparations N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine of the general formula I, where the radical R has the meaning of bezil and p-nitrobenzyl residues, and n is 0, which are then reacted with esters of chloroformic acid of the general formula IV, ClCOOR IV where the radical R has the above-mentioned meaning, translates into a compound of the general formula I, where the radical R has the above-mentioned meaning, and n is 1. 2. N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenyl-propylamine of general formula I, characterized by the fact that when n=0, R represents benzyl or p-nitrobenzyl, and when n=1 , R represents aryl or alkyl. 3. The compound according to claim 2, characterized in that the radical R is benzyl and n is 0. 4. The compound according to claim 2, characterized in that the radical R is p-nitrobenzyl and n is 0. 5. The compound according to claim 2, characterized in that the radical R is phenyl and n is 1. 6. Compound according to claim 2, characterized in that the radical R is p-nitrophenyl and n is 1. 7. Compound according to claim 2, characterized in that the radical R is benzyl and n is 1. 8. The compound according to claim 2, characterized in that the radical R is p-nitrobenzyl and n is 1.