Process for the Preparation of N-Monosubstituted beta-Amino Alcohols

Abstract

A process is disclosed for the preparation of a compound of formula

##STR00001##

and/or an addition salt of a proton acid, wherein R.sup.1 and R.sup.2 independently represent alkyl, cycloalkyl, aryl or aralkyl, each aryl or aralkyl being optionally further substituted with alkyl, alkoxy and/or halogen.

Claims

1.-20. (canceled)

21. A process for preparing (S)-(+)-N-methyl-[3-(1-naphthyloxy)-3-(2-thienyl)-propyl]-amine comprising converting a compound of formula I ##STR00016## to (S)-(+)-N-methyl-[3-(1-naphthyloxy)-3-(2-thienyl)-propyl]-amine, wherein R.sup.1 is thienyl and R.sup.2 is methyl.

22. The process of claim 21, wherein the compound of formula I is (S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol.

Description

GENERAL PROCEDURE FOR EXAMPLES 1 TO 8

[0073] A mixture of methyl ketone (1 equivalent (eq)), primary alkyl amine and/or an addition salt thereof (1.1 to 1.5 eq), formaldehyde (1.4 to 1.5 eq), a solvent, optionally in the presence of a proton acid, is heated in an autoclave at a total pressure above 1.5 bar for 5 to 24 hours. Afterwards, the reaction solution is cooled to 20° C. Optionally the reaction solvent can than be removed partly or in whole and a solvent like ethyl acetate or isopropyl alcohol can be added under vigorous stirring, if necessary to facilitate precipitation of the product. The suspension is cooled (0 to 20° C.) and filtered after precipitation (0.5 to 10 hours), optionally washed and dried to afford a slightly yellow to white powder in a yield between 50 and 75%. The product can be recrystallized from isopropyl alcohol and/or ethyl acetate if necessary. If the stability of the free base is sufficient at ambient conditions, extracting with an organic solvent and an aqueous base affords the free base.

GENERAL PROCEDURE FOR COMPARATIVE EXAMPLES 1 TO 6

[0074] A mixture of methyl ketone (1 eq), primary alkyl amine and/or an addition salt thereof (1 to 1.5 eq), formaldehyde (1.0 to 1.5 eq), optionally in the presence of a proton acid, is heated in refluxing solvent for 5 to 24 hours. Afterwards, the mixture is cooled to 20° C. Optionally the reaction solvent can than be removed partly or in whole and a solvent like ethyl acetate or isopropyl alcohol can be added under vigorous stirring, if necessary to facilitate precipitation of the product. The suspension is cooled (0 to 20° C.) and filtered after precipitation (0.5 to 10 hours), optionally washed and dried to afford a slightly yellow to white powder in a yield between 30 and 45%. The product can be recrystallized from isopropyl alcohol and/or ethyl acetate if necessary.

Example 1

3-(Methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=thiophen-2-yl, R.SUP.2.=methyl)

[0075] 2-Acetylthiophene (25.5 g, 200 mmol); methylamine hydrochloride (14.9 g, 220 mmol, 1.1 eq); paraformaldehyde (8.2 g, 280 mmol, 1.4 eq); HCl conc. (1.0 g); ethanol (100 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing of ethanol (50 mL) in vacuo; addition of ethyl acetate (200 mL); ca. 71% yield.

[0076] .sup.1H-NMR δ (DMSO-d.sub.6, 400 MHz): 9.16 (2 H, s, br), 8.07 (1 H, dd, J=5.0, 1.0), 8.01 (1 H, dd, J=3.8, 1.0), 7.29 (1 H, dd, J=5.0, 3.8), 3.49 (2 H, t), 3.20 (2 H, t), 2.56 (3 H, s).

[0077] .sup.13C-NMR δ (DMSO-d.sub.6, 100 MHz): 189.9, 142.7, 135.4, 133.8, 128.8, 43.1, 34.6, 32.4.

Example 2

3-(Methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=thiophen-2-yl, R.SUP.2.=methyl)

[0078] 2-Acetylthiophene (24.9 g, 197 mmol); methylamine hydrochloride (14.8 g, 219 mmol, 1.1 eq); paraformaldehyde (8.3 g, 276 mmol, 1.4 eq); HCl conc. (1.1 g); isopropyl alcohol (100 mL); 110° C. for 8 hours; ca. 2 to 2.5 bar; addition of isopropyl alcohol (50 mL); ca. 65% yield.

Comparative Example 1

3-(Methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=thiophen-2-yl, R.SUP.2.=methyl)

[0079] 2-Acetylthiophene (7.9 g, 300 mmol); methylamine hydrochloride (30.4 g, 450 mmol, 1.5 eq); paraformaldehyde (12.6 g, 420 mmol, 1.4 eq); HCl conc. (1.5 g); isopropyl alcohol (200 mL); heating under reflux (82° C.) for 8 hours; addition of ethyl acetate (200 mL); ca. 43% yield.

Example 3

3-(Ethylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=thiophen-2-yl, R.SUP.2.=ethyl)

[0080] 2-Acetylthiophene (6.3 g, 50 mmol); ethylamine hydrochloride (6.1 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); ethanol (35 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing of ethanol (25 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 73% yield.

[0081] .sup.1H-NMR δ (DMSO-d.sub.6, 400 MHz): 9.3 (2 H, s, br), 8.08 (1 H, dd), 8.00 (1 H, dd), 7.28 (1 H, dd), 3.51 (2 H, t), 3.20 (2 H, t), 2.96 (2 H, q), 1.23 (3 H, t).

Comparative Example 2

3-(Ethylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=thiophen-2-yl, R.SUP.2.=ethyl)

[0082] 2-Acetylthiophene (12.6 g, 100 mmol); ethylamine hydrochloride (12.2 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc. (0.5 g); ethanol (70 mL); heating under reflux (78° C.) for 6 hours; removing of ethanol (25 mL) in vacuo; addition of ethyl acetate (70 mL); ca. 31% yield.

Example 4

3-(Isobutylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=thiophen-2-yl, R.SUP.2.=isobutyl)

[0083] 2-Acetylthiophene (6.3 g, 50 mmol); isobutylamine hydrochloride (8.3 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); ethanol (35 mL); 110° C. for 9 hours; ca. 2 to 2.5 bar; removing of ethanol (35 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 56% yield.

[0084] .sup.1H-NMR δ (DMSO-d.sub.6, 400 MHz): 9.0 (2 H, s, br), 8.08 (1 H, dd), 7.99 (1 H, dd), 7.29 (1 H, dd), 3.55 (2 H, t), 3.22 (2 H, t), 2.78 (2 H, d), 2.03 (1 H, m), 0.96 (6 H, d).

Comparative Example 3

3-(Isobutylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=thiophen-2-yl, R.SUP.2.=isobutyl)

[0085] 2-Acetylthiophene (12.6 g, 100 mmol); isobutylamine hydrochloride (16.5 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for 7 hours; addition of ethyl acetate (100 mL); ca. 40% yield.

Example 5

3-(tert-Butylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=thiophen-2-yl, R.SUP.2.=tent-butyl)

[0086] 2-Acetylthiophene (6.3 g, 50 mmol); tert-butylamine hydrochloride (8.3 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); butanol (35 mL); 117° C. for 9 hours; ca. 2 to 2.5 bar; addition of ethyl acetate (50 mL); ca. 52% yield.

[0087] .sup.1H-NMR δ (DMSO-d.sub.6, 400 MHz): 9.2 (2 H, s, br), 8.08 (1 H, dd), 7.98 (1 H, dd), 7.30 (1 H, dd), 3.54 (2 H, t), 3.19 (2 H, t), 1.34 (9 H, s).

Comparative Example 4

3-(tent-Butylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=thiophen-2-yl, R.SUP.2.=tert-butyl)

[0088] 2-Acetylthiophene (12.6 g, 100 mmol); tert-butylamine hydrochloride (16.5 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl cone. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for 18 hours; addition of ethyl acetate (100 mL); ca. 37% yield.

Example 6

3-(Methylamino)-1-(furan-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=furan-2-yl, R.SUP.2.=methyl)

[0089] 2-Acetylfuran (7.5 g, 68 mmol); methylamine hydrochloride (6.9 g, 102 mmol, 1.5 eq); paraformaldehyde (3.1 g, 102 mmol, 1.5 eq); HCl conc. (1.15 g); ethanol (35 mL); 110° C. for 8 hours; ca. 2 to 2.5 bar; removing of ethanol (30 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 64% yield.

[0090] .sup.1H-NMR δ (DMSO-d.sub.6, 400 MHz): 9.0 (2 H, s, br), 8.05 (1 H, m), 7.53 (1 H, m), 6.77 (1 H, m), 3.34 (2 H, t), 3.2 (2 H, m), 2.57 (3 H, s, br).

Comparative Example 5

3-(Methylamino)-1-(furan-2-yl)propan-1-one hydrochloride (II, R.SUP.1.=furan-2-yl, R.SUP.2.=methyl)

[0091] 2-Acetylfuran (11.0 g, 100 mmol); methylamine hydrochloride (10.1 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl cone. (0.5 g); butanol (70 mL); heating under reflux (108° C.) for 7 hours; addition of ethyl acetate (100 mL); ca. 44% yield.

Example 7

3-(Methylamino)-1-phenylpropan-1-one hydrochloride (II, R.SUP.1.=phenyl, R.SUP.2.=methyl)

[0092] 2-Acetophenone (21.0 g, 175 mmol); methylamine hydrochloride (17.5 g, 263 mmol, 1.5 eq); paraformaldehyde (7.9 g, 263 mmol, 1.5 eq); HCl cone. (1.1 g); ethanol (130 mL); 115° C. for 24 hours; ca. 2 to 2.5 bar; addition of ethyl acetate (170 mL); ca. 52% yield.

[0093] .sup.1H-NMR δ (DMSO-d.sub.6, 400 MHz): 9.2 (2 H, s, br), 8.0 (2 H, m), 7.7 (1 H, m), 7.6 (2 H, m), 3.55 (2 H, t), 3.21 (2 H, t), 2.59 (3 H, s).

Example 8

3-(Methylamino)-1-(2-naphthyl)propan-1-one hydrochloride (II, R.SUP.1.=2-naphthyl, R.SUP.2.=methyl)

[0094] 2-Acetonaphtone (8.5 g, 50 mmol); methylamine hydrochloride (5.1 g, 75 mmol, 1.5 eq); paraformaldehyde (2.1 g, 75 mmol, 1.5 eq); HCl conc. (0.3 g); ethanol (35 mL); 117° C. for 14 hours; ca. 2 to 2.5 bar; removing of ethanol (35 mL) in vacuo; addition of ethyl acetate (50 mL); ca. 60% yield.

[0095] .sup.1H-NMR δ (DMSO-d.sub.6, 400 MHz): 9.3 (2 H, s, br), 8.74 (1 H, s), 8.17 (1 H, d), 8.0 (3 H, m), 7.7 (2 H, m), 3.70 (2 H, t), 3.28 (2 H, m), 2.60 (3 H, s).

Comparative Example 6

3-(Methylamino)-1-(2-naphthyl)propan-1-one hydrochloride (II, R.SUP.1.=2-naphthyl, R.SUP.2.=methyl)

[0096] 2-Acetonaphtone (17.0 g, 100 mmol); methylamine hydrochloride (10.1 g, 150 mmol, 1.5 eq); paraformaldehyde (4.1 g, 140 mmol, 1.4 eq); HCl conc. (0.5 g); ethanol (70 mL); heating under reflux (78° C.) for 5 hours; removing of ethanol (30 mL) in vacuo; addition of ethyl acetate (100 mL); ca. 42% yield.

Example 9

3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol (I, R.SUP.1.=thiophen-2-yl, R.SUP.2.=methyl)

[0097] To a mixture of 3-(methylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (10.3 g, 50 mmol) and ethanol (35 mL) at 4° C. sodium hydroxide (4.0 g of a 50% aqueous solution) was added in about 5 minutes. Afterwards, neat sodium borhydride (0.95 g, 25 mmol, 1.0 eq) was added in several portions in about 30 minutes. At the end of the addition, the suspension was stirred for 4 h at the same temperature, then acetone (10.0 mL) was added dropwise in 5 minutes and the mixture was stirred for 10 additional minutes. Water (20 mL) was then added. Afterwards, the mixture was concentrated about 5 times under vacuum and the residue was extracted with tert-butyl methyl ether (2×20 mL). The collected organic phases were finally concentrated under vacuum affording an orange oil which crystallised spontaneously after a few hours. Finally, an orange solid was obtained (7.2 g, 84% yield). This compound can then be used without further purification.

[0098] .sup.1H-NMR δ (DMSO-d.sub.6, 400 MHz): 7.35 (1 H, dd, J=4.8, 1.0), 6.94 (1 H, dd, J=4.8, 3.6), 6.90 (1 H, dd, J=3.6, 1.0), 4.90 (1 H, t), 3.7 (2 H, m), 2.56 (2 H, m), 2.25 (3 H, s), 1.79 (2 H, q).

[0099] .sup.13C-NMR δ (DMSO-d.sub.6, 100 MHz): 150.9, 126.3, 123.7, 122.3, 67.8, 48.5, 38.7, 36.0.

Example 10

3-(Isobutylamino)-1-(thiophen-2-yl)propan-1-ol (I, R.SUP.1.=thiophen-2-yl, R.SUP.2.=methyl)

[0100] To a mixture of 3-(isobutylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (4.2 g, 19.4 mmol) and ethanol (10 mL) at 4° C. sodium hydroxide (1.6 g of a 50% aqueous solution) was added in about 20 minutes. Afterwards, neat sodium borhydride (0.37 g, 9.7 mmol, 1.0 eq) was added in several portions in about 30 minutes. At the end of the addition, the suspension was stirred for 4 hat the same temperature, then acetone (10.0 mL) was added dropwise in 20 minutes and the mixture was stirred for 10 additional minutes. Afterwards the precipitate was removed by filtration and the mixture was concentrated under vacuum affording an orange oil. The crude product was purified by column chromatography using a 40:10:1 (v:v:v) mixture of methylene chloride/methanol/ammonium hydroxide (25% aqueous solution) affording 3.1 g (76% yield) of product.

[0101] .sup.1H-NMR δ (DMSO-d.sub.6, 400 MHz): 7.20 (1 H, dd, J=4.8, 1.0), 6.98 (1 H, dd), 6.94 (1 H, dd, J=4.8, 3.6), 5.20 (1 H, dd), 4.98 (2 H, br), 3.02 (1 H, m), 2.93 (1 H, m), 2.43 (2H, symm. m), 2.03 (1 H, m), 1.97 (1 H, m), 1.80 (1 H, sept), 0.95 (6 H, d).

[0102] .sup.13C-NMR δ (DMSO-d.sub.6, 100 MHz): 150.9, 126.3, 123.8, 122.5, 72.1, 57.8, 48.5, 37.4, 28.2, 20.8.