METHOD FOR PREPARING SUBSTITUTED 4-AMINOINDANE DERIVATIVES

Abstract

The present invention relates to a method for preparing substituted 4-aminoindane derivatives of the general formula (I) by cyclization,

##STR00001##

in which R, n, R.sup.1, R.sup.2, R.sup.3, R.sup.4, Q.sup.1 and Q.sup.2 have the definitions specified in the description.

Claims

1. Method for preparing substituted 4-aminoindane derivative of formula (I) ##STR00016## in which R is mutually independently halogen, cyano, (C.sub.1-C.sub.12)alkyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.1-C.sub.6)alkylphenyl, aryl, cyano(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkyl having 1-9 identical or different halogen atoms, halo(C.sub.3-C.sub.7)cycloalkyl having 1-9 identical or different halogen atoms, halo(C.sub.1-C.sub.6)alkoxy having 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylsulphanyl, halo(C.sub.1-C.sub.6)alkylsulphanyl having 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkylsulphonyl or halo(C.sub.1-C.sub.6)alkylsulphonyl having 1-9 identical or different halogen atoms, n is an integer from 0 to 3, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are mutually independently hydrogen, (C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.8)cycloalkyl(C.sub.3-C.sub.8)cycloalkyl, (C.sub.1-C.sub.8)alkylphenyl, (C.sub.1-C.sub.8)alkoxy, aryl, cyano(C.sub.1-C.sub.8)alkyl, halo(C.sub.1-C.sub.8)alkyl having 1-9 identical or different halogen atoms, (C.sub.1-C.sub.8)alkoxycarbonyl(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)alkoxy(C.sub.1-C.sub.8)alkyl or halo(C.sub.1-C.sub.8)alkoxy(C.sub.1-C.sub.8)alkyl having 1-9 identical or different halogen atoms, and Q.sup.1 and Q.sup.2 are mutually independently hydrogen, substituted (C.sub.1-C.sub.6)alkylsulphonyl, substituted alkoxycarbonyl(C.sub.1-C.sub.6)alkyl or substituted (C.sub.1-C.sub.6)haloalkyl sulphonyl, comprising reacting one or more alcohols of formulae (IIa), (Ib) or (IIc) ##STR00017## with one or more sulphonic acids.

2. Method according to claim 1, wherein R is mutually independently halogen, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, (C.sub.1-C.sub.4)alkylphenyl, aryl, cyano(C.sub.1-C.sub.4)alkyl, halo(C.sub.1-C.sub.4)alkyl having 1-9 identical or different halogen atoms, (C.sub.1-C.sub.4)alkoxycarbonyl(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl or halo(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl, n is an integer from 0 to 3, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are mutually independently hydrogen, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkylphenyl, (C.sub.1-C.sub.4)alkoxy, aryl, cyano(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl and Q.sup.1 and Q.sup.2 are mutually independently hydrogen, substituted (C.sub.1-C.sub.4)alkylsulphonyl, substituted alkoxycarbonyl(C.sub.1-C.sub.4)alkyl or substituted (C.sub.1-C.sub.4)haloalkylsulphonyl.

3. Method according to claim 1, wherein R is mutually independently fluorine, chlorine, bromine, methyl or trifluoromethyl, n is an integer from 0 to 1, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are mutually independently hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and Q.sup.1 and Q.sup.2 are mutually independently hydrogen, substituted (C.sub.1-C.sub.4)alkylsulphonyl, substituted alkoxycarbonyl(C.sub.1-C.sub.3)alkyl or substituted (C.sub.1-C.sub.3)haloalkylsulphonyl.

4. Method according to claim 1, wherein n is 0 or R is fluorine and n is 1, wherein fluorine is optionally in the 5-, 6- or 7-position, optionally in the 6- or 7-position and optionally in the 7-position of the indane residue, or R is trifluoromethyl and n is 1, wherein trifluoromethyl is optionally in the 5-, 6- or 7-position, optionally in the 6- or 7-position and optionally in the 7-position of the indane residue, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are mutually independently hydrogen, methyl, ethyl, n-propyl, n-butyl, isobutyl or sec-butyl and Q.sup.1 and Q.sup.2 are hydrogen.

5. Method according to claim 1, wherein the sulphonic acid used is methanesulphonic acid or trifluoromethanesulphonic acid.

6. Method according to claim 1, wherein the sulphonic acid used is trifluoromethanesulphonic acid.

Description

PREPARATION EXAMPLES

Example 1: Synthesis of 1,1-dimethyl-3-propylindan-4-amine

[0074] ##STR00010##

[0075] 35.6 g (237 mmol) of trifluoromethanesulphonic acid are initially charged in a 250 mL reaction vessel and cooled to 0 C. Subsequently, 5.0 g (15.8 mmol, 70% purity) of 4-(2-aminophenyl)-2-methylheptan-4-ol are added and the reaction mixture is allowed to warm slowly to room temperature over 1 h. The reaction mixture is again cooled to 0 C. and 25 ml of water are added. The solid which precipitates is filtered off and washed three times with 10 ml of water. The solid is then recrystallized from toluene and the resulting solid is dried. This is then suspended in 50 mL of dichloromethane and 45% aqueous NaOH solution is added until a basic pH is reached. After stirring at room temperature for 30 min, the phases are separated and the aqueous phase is extracted twice with 30 mL of dichloromethane each time. The combined organic phases are washed once with 70 mL of saturated NaCl solution and dried over Na.sub.2SO.sub.4. The solvent is evaporated under reduced pressure and 2.4 g of 1,1-dimethyl-3-propylindan-4-amine (95% yield, 94.0% purity by HPLC) are obtained as a brown oil.

[0076] .sup.1H NMR (CDCl.sub.3) (ppm)=7.0 (t, 1H), 6.6 (d, 1H), 6.5 (d, 1H), 3.6 (br s, 2H), 3.05-3.1 (m, 1H), 2.1 (dd, 1H), 1.85-1.9 (m, 1H), 1.8 (dd, 1H), 1.5-1.55 (m, 1H), 1.35-1.4 (m, 2H), 1.3 (s, 3H), 1.2 (s, 3H), 1.0 (t, 3H).

Comparative Example 1: Synthesis of 1,1-dimethyl-3-propylindan-4-amine

[0077] ##STR00011##

[0078] 153.4 g (791 mmol) of polyphosphoric acid are initially charged in a 1000 mL reaction vessel, 18.5 g (79.0 mmol, 95% purity) of 4-(2-aminophenyl)-2-methylheptan-4-ol are added and the mixture is stirred overnight at 190 C. The reaction mixture is cooled and 300 ml of water are added over 1 h. The reaction mixture is then added dropwise to 200 mL of a cooled 45% aqueous NaOH solution. After stirring at room temperature for 30 min, 300 mL of dichloromethane are added and the mixture is stirred for a further 1.5 h. The phases are separated and the aqueous phase is extracted twice with 200 ml of dichloromethane each time. The combined organic phases are washed once with 500 mL of saturated NaCl solution, dried over Na.sub.2SO.sub.4 and the solvent is evaporated under reduced pressure. The crude product thus obtained is purified firstly by Kugelrohr distillation (100-120 C., 0.4 mbar) and subsequently by column chromatography (cyclohexane:ethyl acetate=9:1). 4.2 g of 1,1-dimethyl-3-propylindan-4-amine (25% yield, 95.8% purity by HPLC) are obtained as a brown oil.

Example 2: Synthesis of 1,1-dimethyl-3-ethylindan-4-amine

[0079] ##STR00012##

[0080] 35.6 g (237 mmol) of trifluoromethanesulphonic acid are initially charged in a 250 mL reaction vessel and cooled to 0 C. Subsequently, 5.0 g (15.8 mmol, 65% purity) of 4-(2-aminophenyl)-2-methylhexan-4-ol are added and the reaction mixture is allowed to warm slowly to room temperature over 1 h. The reaction mixture is again cooled to 0 C. and 25 ml of water are added. The solid which precipitates is filtered off and washed three times with 10 ml of water. The solid is then recrystallized from toluene and the resulting solid is dried. This is then suspended in 50 mL of dichloromethane and 45% aqueous NaOH solution is added until a basic pH is reached. After stirring at room temperature for 30 min, the phases are separated and the aqueous phase is extracted twice with 30 mL of dichloromethane each time. The combined organic phases are washed once with 70 mL of saturated NaCl solution and dried over Na.sub.2SO.sub.4. The solvent is evaporated under reduced pressure and 2.5 g of 1,1-dimethyl-3-ethylindan-4-amine (84% yield, 92.8% purity by HPLC) are obtained as a brown oil.

[0081] .sup.1H NMR (CDCl.sub.3) (ppm)=7.0 (t, 1H), 6.6 (d, 1H), 6.5 (d, 1H), 3.6 (br s, 2H), 3.0-3.1 (m, 1H), 2.1 (dd, 1H), 1.9-2.0 (m, 1H), 1.8 (dd, 1H), 1.4-1.5 (m, 1H), 1.3 (s, 3H), 1.2 (s, 3H), 1.0 (t, 3H).

Example 3: Synthesis of 1,1-dimethyl-3-ethylindan-4-amine

[0082] ##STR00013##

[0083] 14.0 g (145 mmol) of methanesulphonic acid are initially charged in a 100 mL reaction vessel, 2.5 g (10.0 mmol, 80% purity) of 4-(2-aminophenyl)-2-methylhexan-4-ol are added and the reaction mixture is stirred at 120 C. for 2 h. The reaction mixture is cooled to 0 C. and 45% aqueous NaOH solution is added until a basic pH is reached. After stirring at room temperature for 30 min, the phases are separated and the aqueous phase is extracted twice with 30 mL of dichloromethane each time. The combined organic phases are washed once with 50 mL of saturated NaCl solution and dried over Na.sub.2SO.sub.4. The solvent is evaporated under reduced pressure and 3.6 g of 1,1-dimethyl-3-ethylindan-4-amine (52% yield by HPLC) are obtained as crude product.

Comparative Example 2: Synthesis of 1,1-dimethyl-3-ethylindan-4-amine

[0084] ##STR00014##

[0085] 81.4 g (420 mmol) of polyphosphoric acid are initially charged in a 500 mL reaction vessel, 9.4 g (42.0 mmol, 93% purity) of 4-(2-aminophenyl)-2-methylhexan-4-ol are added and the mixture is stirred overnight at 190 C. The reaction mixture is cooled and 140 ml of water are added over 1 h. The reaction mixture is then added dropwise to 100 mL of a cooled 45% aqueous NaOH solution. After stirring at room temperature for 30 min, 150 mL of dichloromethane are added and the mixture is stirred for a further 1.5 h. The phases are separated and the aqueous phase is extracted twice with 100 ml of dichloromethane each time. The combined organic phases are washed once with 250 mL of saturated NaCl solution, dried over Na.sub.2SO.sub.4 and the solvent is evaporated under reduced pressure. The crude product thus obtained is purified by Kugelrohr distillation (85-105 C., 0.4 mbar). 1.8 g of 1,1-dimethyl-3-ethylindan-4-amine (22% yield, 95.6% purity by HPLC) are obtained as a brown oil.

[0086] The cyclizations described above were carried out using trifluoromethanesulphonic acid, methanesulphonic acid or polyphosphoric acid. As is evident from Table 1, cyclization experiments with other Brnsted or Lewis acids were unsuccessful.

TABLE-US-00001 TABLE 1 cyclization experiments of 4-(2-aminophenyl)-2-methylhexan-4-ol to give 1,1-dimethyl-3-ethylindan-4-amine using various Brnsted or Lewis acids: Brnsted or Input Lewis acid Solvent Yield 1 TfOH 84% 2 MsOH 52%* 3 Polyphosphoric 22% acid 4 Diphosphoric acid 0% 5 Trifluoroacetic acid 0% 6 HCl Dioxane 0% 7 HCl Water 0% 8 H.sub.2SO.sub.4 0% 9 p-TsOH 0% 10 AlCl.sub.3 Xylene 0% 11 BF.sub.3OEt.sub.2 0% 12 BF.sub.3OEt.sub.2 Xylene 0% *yield by HPLC

Example 4: Synthesis of 4-(2-aminophenyl)-2-methylheptan-4-ol

[0087] ##STR00015##

[0088] 160 mL (318 mmol, 2M in THF) of n-propylmagnesium chloride solution are initially charged in a baked-out 2 L reaction vessel under argon and the mixture is cooled to 0 C. 15 g (127 mmol) of 2-aminobenzonitrile are dissolved in 150 ml of dry THF and added dropwise at 0 C. over 1 h. After addition has ended, the mixture is stirred at room temperature for 30 min. 320 mL of aqueous HCl (1M) are initially charged in a further reaction vessel and cooled to 0 C. The reaction mixture is slowly added dropwise and subsequently adjusted to pH 4 with concentrated HCl. The phases are separated and the aqueous phase is extracted twice with 200 ml of ethyl acetate each time. The combined organic phases are washed once with 400 mL of saturated NaCl solution, dried over Na.sub.2SO.sub.4 and the solvent is evaporated under reduced pressure.

[0089] The ketone thus obtained is dissolved in 130 mL of dry THF and added dropwise under argon to 100 mL (200 mmol, 2M in THF) of isobutylmagnesium chloride at 0 C. over 1 h. After addition has ended, the mixture is stirred at room temperature for 30 min. 200 mL of aqueous HCl (1M) are initially charged in a further reaction vessel and cooled to 0 C. The reaction mixture is slowly added dropwise and subsequently adjusted to pH 4 with concentrated HCl. The phases are separated and the aqueous phase is extracted twice with 200 ml of ethyl acetate each time. The combined organic phases are washed once with 400 mL of saturated NaCl solution, dried over Na.sub.2SO.sub.4 and the solvent is evaporated under reduced pressure. 18.9 g (65% yield over two stages, 94.6% purity by HPLC) of 4-(2-aminophenyl)-2-methylheptan-4-ol are obtained as a yellow oil.

[0090] .sup.1H NMR (CD.sub.3CN) (ppm)=7.0 (d, 1H), 6.9 (t, 1H), 6.5-6.6 (m, 2H), 4.9 (br s, 2H), 2.9 (s, 1H), 1.8-1.9 (m, 2H), 1.8 (d, 2H), 1.6 (sept, 1H), 1.3-1.4 (m, 2H), 0.9 (t, 3H), 0.9 (d, 3H), 0.8 (d, 3H).