3,5-DIMETHYLPIPERIDINE (CIS)

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

Procedure: To cis-3,5-dimethylpiperidine (374 mg.; 3.3 m moles) in 3 ml. of methylene chloride is added 192 mg. (0.66 m moles) of 2,3-dichloro-5-chlorosulfonylbenzoic acid and the mixture heated to reflux for 1.5 hrs. The solvent is removed under reduced pressure, and the residue is partitioned between 25 ml. of 1 N sodium hydroxide solution and diethyl ether. The aqueous layer is separated, acidified with 6 N hydrochloric acid and the resulting precipitated product filtered and dried, 230 mg., m.p. 235°-238° C. Recrystallization from acetonitrile gave the purified product, m.p. 244°-245° C. to reflux for 1.5 hrs The solvent is removed under reduced pressure the residue is partitioned between 25 ml The aqueous layer is separated the resulting precipitated product filtered dried Recrystallization from acetonitrile gave the purified product, m.p. 244°-245° C.

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

Procedure: Starting materials: 6,7-difluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 374) and (3S,5R)-3,5-dimethylpiperidine (HCl Salt).

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

Procedure: Starting materials: 6,7-difluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 374) and (3S,5R)-3,5-dimethylpiperidine (HCl Salt).

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

Procedure: 24.7 g (0.1 mol) of 8-s-butyl-2-chloromethyl-1,4dioxaspiro [4,5] decane and 45.2 g (0.4 mol) of cis-3,5-dimethylpiperidine are stirred at 140° C. for 16 hours and cooled, 200 ml of ethyl acetate are added, the mixture is washed three times with 200 ml of water each time, dried over sodium sulphate and concentrated in vacuo and the residue is purified by chromatography (silica gel; mobile phase: ethyl acetate). 24.3 g (75% of theory) of 8-s-butyl-2-(3,5-dimethylpiperidin-1-ylmethyl) -1,4-dioxaspiro[4,5] decane are obtained as an oil of refractive index nd20 1.4762. cooled the mixture is washed three times with 200 ml of water each time dried over sodium sulphate concentrated in vacuo the residue is purified by chromatography (silica gel; mobile phase: ethyl acetate)

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

Procedure: 24.7 g (0.1 mol) of 8-s-butyl-2-chloromethyl-1,4dioxaspiro [4,5] decane and 45.2 g (0.4 mol) of cis-3,5-dimethylpiperidine are stirred at 140° C. for 16 hours and cooled, 200 ml of ethyl acetate are added, the mixture is washed three times with 200 ml of water each time, dried over sodium sulphate and concentrated in vacuo and the residue is purified by chromatography (silica gel; mobile phase: ethyl acetate). 24.3 g (75% of theory) of 8-s-butyl-2-(3,5-dimethylpiperidin-1-ylmethyl) -1,4-dioxaspiro[4,5] decane are obtained as an oil of refractive index nd20 1.4762. cooled the mixture is washed three times with 200 ml of water each time dried over sodium sulphate concentrated in vacuo the residue is purified by chromatography (silica gel; mobile phase: ethyl acetate)

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

Procedure: To solution of 5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-(1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (320 mg) and triethylamine (265 μL) in dimethoxyethane (1.3 mL) was added 3,5-cis-dimethylpiperidine (189 mg). After 2 h, the reaction solution was concentrated in vacuo and flash chromatographed on silica gel (50% ethyl acetate/hexanes) to afford the title compound of this Example as a colorless solid, 130 mg. MS Calc.:505.3 Found:505.2 the reaction solution was concentrated in vacuo and flash chromatographed on silica gel (50% ethyl acetate/hexanes)

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

Procedure: 16 g (0.044 mole) of 2-bromomethyl-5-[1-(4-chlorophenoxy)-2-methyl-prop-2-yl]-5-methyl-tetrahydrofuran are stirred together with 11 g (0.097 mole) of cis-3,5-dimethylpiperidine at a bath temperature of 140° C. for about 14 hours. The resulting reaction mixture is taken up in ether, washed several times with water, dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography (silica gel 60/ether-petroleum ether 1:1). 7.8 g (45% of theory) of 5-[1-(4-chlorophenoxy)-2-methyl-prop-2-yl-]-2-(cis)(3,5-dimethylpiperidin-1-ylmethyl)-5-methyl-tetrahydrofuran of refractive index nD20 =1.5049 are obtained. The resulting reaction mixture washed several times with water dried over sodium sulphate concentrated in vacuo The oily residue is purified by column chromatography (silica gel 60/ether-petroleum ether 1:1)

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

Procedure: 16 g (0.044 mole) of 2-bromomethyl-5-[1-(4-chlorophenoxy)-2-methyl-prop-2-yl]-5-methyl-tetrahydrofuran are stirred together with 11 g (0.097 mole) of cis-3,5-dimethylpiperidine at a bath temperature of 140° C. for about 14 hours. The resulting reaction mixture is taken up in ether, washed several times with water, dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography (silica gel 60/ether-petroleum ether 1:1). 7.8 g (45% of theory) of 5-[1-(4-chlorophenoxy)-2-methyl-prop-2-yl-]-2-(cis)(3,5-dimethylpiperidin-1-ylmethyl)-5-methyl-tetrahydrofuran of refractive index nD20 =1.5049 are obtained. The resulting reaction mixture washed several times with water dried over sodium sulphate concentrated in vacuo The oily residue is purified by column chromatography (silica gel 60/ether-petroleum ether 1:1)

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

Procedure: Prepared analogously to Example 1.2.c. from (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-chloromethylphenyl)acrylamide and cis-3,5-dimethylpiperidine. Yield: 30 mg (30% of theory); melting point: 217° C.-218° C.; C29H31ClN2O (M=459.03); calc.: molecular ion peak (M+H)+: 459/461; found: molecular ion peak (M+H)+: 459/461. Prepared analogously to Example 1.2.c

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

Procedure: To solution of 5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (320 mg) and triethylamine (265 μL) in dimethoxyethane (1.3 mL) was added 3,5-cis-dimethylpiperidine (189 mg). After 2 h, the reaction solution was concentrated in vacuo and flash chromatographed on silica gel (50% ethyl acetate/hexanes) to afford the title compound of this Example as a colorless solid, 130 mg. MS Calc.:505.3 Found:505.2. the reaction solution was concentrated in vacuo and flash chromatographed on silica gel (50% ethyl acetate/hexanes)

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

Procedure: Starting materials: 6,7-difluoro-3-methylbenzo[d]isoxazole-5-carbaldehyde (Intermediate 374) and (3S,5R)-3,5-dimethylpiperidine (HCl Salt).

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

Procedure: To cis-3,5-dimethylpiperidine (374 mg.; 3.3 m moles) in 3 ml. of methylene chloride is added 192 mg. (0.66 m moles) of 2,3-dichloro-5-chlorosulfonylbenzoic acid and the mixture heated to reflux for 1.5 hrs. The solvent is removed under reduced pressure, and the residue is partitioned between 25 ml. of 1 N sodium hydroxide solution and diethyl ether. The aqueous layer is separated, acidified with 6 N hydrochloric acid and the resulting precipitated product filtered and dried, 230 mg., m.p. 235°-238° C. Recrystallization from acetonitrile gave the purified product, m.p. 244°-245° C. to reflux for 1.5 hrs The solvent is removed under reduced pressure the residue is partitioned between 25 ml The aqueous layer is separated the resulting precipitated product filtered dried Recrystallization from acetonitrile gave the purified product, m.p. 244°-245° C.