2-(3-chloro-4-methoxyphenyl)ethanamine

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 5.00 g of N-methyl-(2-(3-chloro-4-methoxyphenyl)ethylamine, 9.49 g of N-(4-bromobutyl)phthalimide, 4.16 g of anhydrous potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at a room temperature for 14 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated, followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand and filtered to remove insoluble matter. The filtrate was distilled to obtain 3.16 g of the title compound as a colorless oil (yield: 47%). The obtained mixture was extracted with ethyl acetate the ethyl acetate phase was washed with water a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate concentrated followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate The obtained mixture was heated under reflux for 2 hours cooled filtered to remove insoluble matter The filtrate was distilled

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methoxyphenethyl amine (39.4 g, 0.261 mol) was dissolved in water (300 mL) and concentrated HCl(22mL). To this solution was added chlorine gas (20.3 g, 0.287 mol) in glacial acetic acid (300 mL) OVcr a 15 minute period while maintaining the temperature below 35° C. After standing for ten minutes, the volatiles were removed in vacuo and the dark solid residue was dissolved in absolute ethanol (100 mL) and allowed to crystallize at -10° C. The collected precipitate was dissolved in a mixture of saturated sodium bicarbonate (400 mL) and dichloromethane (400 mL). The organic layer was separated and dried over anhydrous sodium sulfate. It was condensed on a rotorevaporator to afford a dark oil which was distilled (115°-116° C./1.75 mm Hg) to give 12.8 g (26.4%) of a clear oil. 1R (neat) 3600-3310 (br,NH2), 1600, 1500, 1250 and 1060 cm-1 ; 1H NMR(CDCl3)δ,d 7.36-6.71 (m, 3H, ArH), 3.85 (S, 3H, OCH3), 3.15-2.48 (m, 4H, (CH2)2), 1.12(S, 2H, NH2). while maintaining the temperature below 35° C After standing for ten minutes the volatiles were removed in vacuo the dark solid residue was dissolved in absolute ethanol (100 mL) to crystallize at -10° C The collected precipitate was dissolved in a mixture of saturated sodium bicarbonate (400 mL) and dichloromethane (400 mL) The organic layer was separated dried over anhydrous sodium sulfate condensed on a rotorevaporator to afford a dark oil which was distilled (115°-116° C./1.75 mm Hg)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methoxyphenethyl amine (39.4 g, 0.261 mol) was dissolved in water (300 mL) and concentrated HCl(22mL). To this solution was added chlorine gas (20.3 g, 0.287 mol) in glacial acetic acid (300 mL) over a 15 minute period while maintaining the temperature below 35° C. After standing for ten minutes, the volatiles were removed in vacuo and the dark solid residue was dissolved in absolute ethanol (100 mL) and allowed to crystallize at -10° C. The collected precipitate was dissolved in a mixture of saturated sodium bicarbonate (400 mL) and dichloromethane (400 mL). The organic layer was separated and dried over anhydrous sodium sulfate. It was condensed on a rotorevaporator to afford a dark oil which was distilled (115°-116° C./1.75 mm Hg) to give 12.8 g(26.4%) of a clear oil. 1R (neat) 3600-3310 (br,NH2), 1600, 1500, 1250 and 1060 cm-1 ; 1H NMR(CDCl3)δ,d 7.36-6.71 (m, 3H, ArH), 3.85 (S, 3H, OCH3), 3.15-2.48 (m, 4H, (CH2)2), 1.12(S, 2H, NH2). while maintaining the temperature below 35° C After standing for ten minutes the volatiles were removed in vacuo the dark solid residue was dissolved in absolute ethanol (100 mL) to crystallize at -10° C The collected precipitate was dissolved in a mixture of saturated sodium bicarbonate (400 mL) and dichloromethane (400 mL) The organic layer was separated dried over anhydrous sodium sulfate condensed on a rotorevaporator to afford a dark oil which was distilled (115°-116° C./1.75 mm Hg)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 5.00 g of N-methyl-(2-(3-chloro-4-methoxyphenyl)ethylamine, 9.49 g of N-(4-bromobutyl)phthalimide, 4.16 g of anhydrous potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at a room temperature for 14 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated, followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand and filtered to remove insoluble matter. The filtrate was distilled to obtain 3.16 g of the title compound as a colorless oil (yield: 47%). The obtained mixture was extracted with ethyl acetate the ethyl acetate phase was washed with water a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate concentrated followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate The obtained mixture was heated under reflux for 2 hours cooled filtered to remove insoluble matter The filtrate was distilled

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 5.00 g of N-methyl-(2-(3-chloro-4-methoxyphenyl)ethylamine, 9.49 g of N-(4-bromobutyl)phthalimide, 4.16 g of anhydrous potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at a room temperature for 14 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated, followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand and filtered to remove insoluble matter. The filtrate was distilled to obtain 3.16 g of the title compound as a colorless oil (yield: 47%). The obtained mixture was extracted with ethyl acetate the ethyl acetate phase was washed with water a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate concentrated followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate The obtained mixture was heated under reflux for 2 hours cooled filtered to remove insoluble matter The filtrate was distilled

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(4-chlorophenyl)cyclobutanecarbonyl chloride (20 g) in ether (50 ml) was added to a stirred mixture of 3-chloro-4-methoxyphenethylamine (16.2 g), triethylamine (13 ml) and ether (100 ml). After one hour, water (50 ml) was added and the mixture extracted with ethyl acetate. The organic layer gave a residue which was recrystallised twice from industrial methylated spirits. A portion of the product (12.6 g) was warmed with polyphosphate ester (70 ml). The resulting solution was heated at 90° C. for 48 hours, cooled and added to a mixture of ice, concentrated ammonia solution and ether. The ether layer was washed, dried and added to sodium borohydride (5 g) in ethanol (200 ml) and the mixture heated under reflux for 90 minutes. The ether evaporated during this time and then the ethanol was removed. Water (200 ml) was added and the resulting mixture extracted with ether. The extract was added to a mixture of 1M aqueous sodium phosphite solution [prepared from phosphorous acid (16.4 g), sodium bicarbonate (16.8 g) and water 200 ml)], 37-40% aqueous formaldehyde solution (130 ml) and methanol (300 ml). The ether was removed by evaporation and methanol (250 ml) added. The mixture was then heated under reflux for 16 hours and then the methanol was removed by evaporation. The residue was basified with aqueous ammonia solution and extracted with ether. The solvent was removed from the extract and the residue dried by azeotropic distillation with industrial methylated spirits and then with propan-2-ol. The dried residue was crystallised from propan-2-ol to give a solid which was further purified by high performance liquid chromatography. A sample of this purified product (1 g) was heated at 110°-115° C. under nitrogen with glacial acetic acid (10 ml) and 48% hydrobromic acid (10 ml) for 6 hours. The reaction mixture was then cooled and partitioned between ether and 50% aqueous potassium carbonate solution. The ether layer yielded 6-chloro-1-[1-(4-chlorophenyl)cyclobutyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (m.p. 168°-171° C.). the mixture extracted with ethyl acetate The organic layer gave a residue which was recrystallised twice from industrial methylated spirits A portion of the product (12.6 g) was warmed with polyphosphate ester (70 ml) cooled added to a mixture of ice, concentrated ammonia solution and ether The ether layer was washed dried added to sodium borohydride (5 g) in ethanol (200 ml) the mixture heated under reflux for 90 minutes The ether evaporated during this time the ethanol was removed Water (200 ml) was added the resulting mixture extracted with ether The extract was added to a mixture of 1M aqueous sodium phosphite solution [ prepared from phosphorous acid (16.4 g), sodium bicarbonate (16.8 g) and water 200 ml)], 37-40% aqueous formaldehyde solution (130 ml) and methanol (300 ml) The ether was removed by evaporation and methanol (250 ml) added The mixture was then heated under reflux for 16 hours the methanol was removed by evaporation extracted with ether The solvent was removed from the extract the residue dried by azeotropic distillation with industrial methylated spirits The dried residue was crystallised from propan-2-ol to give a solid which was further purified by high performance liquid chromatography A sample of this purified product (1 g) was heated at 110°-115° C. under nitrogen with glacial acetic acid (10 ml) and 48% hydrobromic acid (10 ml) for 6 hours The reaction mixture was then cooled partitioned between ether and 50% aqueous potassium carbonate solution

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 5.00 g of N-methyl-(2-(3-chloro-4-methoxyphenyl)ethylamine, 9.49 g of N-(4-bromobutyl)phthalimide, 4.16 g of anhydrous potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at a room temperature for 14 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated, followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand and filtered to remove insoluble matter. The filtrate was distilled to obtain 3.16 g of the title compound as a colorless oil (yield: 47%). The obtained mixture was extracted with ethyl acetate the ethyl acetate phase was washed with water a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate concentrated followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate The obtained mixture was heated under reflux for 2 hours cooled filtered to remove insoluble matter The filtrate was distilled

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 5.00 g of N-methyl-(2-(3-chloro-4-methoxyphenyl)ethylamine, 9.49 g of N-(4-bromobutyl)phthalimide, 4.16 g of anhydrous potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at a room temperature for 14 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated, followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand and filtered to remove insoluble matter. The filtrate was distilled to obtain 3.16 g of the title compound as a colorless oil (yield: 47%). The obtained mixture was extracted with ethyl acetate the ethyl acetate phase was washed with water a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate concentrated followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate The obtained mixture was heated under reflux for 2 hours cooled filtered to remove insoluble matter The filtrate was distilled

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and [2-(3-chloro-4-methoxyphenyl)ethyl]amine in a similar manner as described for Example 24. 1H NMR (500 MHz DMSO-d6): δ 7.55-7.47 (m, 5H), 7.34 (t, 1H), 6.94 (d, 1H), 6.65 (dd, 1H), 6.61 (d, 1H), 4.32 (qt, 1H), 3.78 (s, 3H), 3.03-2.96 (m, 2H), 2.43-2.37 (m, 2H), 1.46 (d, 6H); 13C NMR (125 MHz DMSO-d6): δ 158.7, 153.7, 136.1, 132.4, 131.9, 130.3, 129.4, 128.8, 126.1, 121.3, 113.3, 105.0, 56.7, 47.3, 45.0, 34.4, 20.5; Mass spectrum M+H+ 435

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared from 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and [2-(3-chloro-4-methoxyphenyl)ethyl]amine in a similar manner as described for Example 24. 1H NMR (500 MHz DMSO-d6): δ 7.55-7.47 (m, 5H), 7.34 (t, 1H), 6.94 (d, 1H), 6.65 (dd, 1H), 6.61 (d, 1H), 4.32 (qt, 1H), 3.78 (s, 3H), 3.03-2.96 (m, 2H), 2.43-2.37 (m, 2H), 1.46 (d, 6H); 13C NMR (125 MHz DMSO-d6): δ 158.7, 153.7, 136.1, 132.4, 131.9, 130.3, 129.4, 128.8, 126.1, 121.3, 113.3, 105.0, 56.7, 47.3, 45.0, 34.4, 20.5; Mass spectrum M+H+ 435

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture comprising 5.00 g of N-methyl-(2-(3-chloro-4-methoxyphenyl)ethylamine, 9.49 g of N-(4-bromobutyl)phthalimide, 4.16 g of anhydrous potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at a room temperature for 14 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate and the ethyl acetate phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated, followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 2 hours, cooled by allowing to stand and filtered to remove insoluble matter. The filtrate was distilled to obtain 3.16 g of the title compound as a colorless oil (yield: 47%). The obtained mixture was extracted with ethyl acetate the ethyl acetate phase was washed with water a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate concentrated followed by the addition of 50 ml of ethanol and 1.5 ml of hydrazine monohydrate The obtained mixture was heated under reflux for 2 hours cooled filtered to remove insoluble matter The filtrate was distilled

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methoxyphenethyl amine (39.4 g, 0.261 mol) was dissolved in water (300 mL) and concentrated HCl(22mL). To this solution was added chlorine gas (20.3 g, 0.287 mol) in glacial acetic acid (300 mL) OVcr a 15 minute period while maintaining the temperature below 35° C. After standing for ten minutes, the volatiles were removed in vacuo and the dark solid residue was dissolved in absolute ethanol (100 mL) and allowed to crystallize at -10° C. The collected precipitate was dissolved in a mixture of saturated sodium bicarbonate (400 mL) and dichloromethane (400 mL). The organic layer was separated and dried over anhydrous sodium sulfate. It was condensed on a rotorevaporator to afford a dark oil which was distilled (115°-116° C./1.75 mm Hg) to give 12.8 g (26.4%) of a clear oil. 1R (neat) 3600-3310 (br,NH2), 1600, 1500, 1250 and 1060 cm-1 ; 1H NMR(CDCl3)δ,d 7.36-6.71 (m, 3H, ArH), 3.85 (S, 3H, OCH3), 3.15-2.48 (m, 4H, (CH2)2), 1.12(S, 2H, NH2). while maintaining the temperature below 35° C After standing for ten minutes the volatiles were removed in vacuo the dark solid residue was dissolved in absolute ethanol (100 mL) to crystallize at -10° C The collected precipitate was dissolved in a mixture of saturated sodium bicarbonate (400 mL) and dichloromethane (400 mL) The organic layer was separated dried over anhydrous sodium sulfate condensed on a rotorevaporator to afford a dark oil which was distilled (115°-116° C./1.75 mm Hg)