3-phenyloxane-2,6-dione

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5.09 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-furanylmethyl)-1H-benzimidazol-2-amine and 54 parts of N,N-dimethylformamide was stirred and heated at 50° C. and there was added dropwise a solution of 2.8 parts of dihydro-3-phenyl-2H-pyran-2,6(3H)dione in 18 parts of N,N-dimethylformamide. Upon completion, stirring was continued overnight at 50° C. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 1.8 parts of N-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]formamide hemihydrate; mp. 125.2° C. (compound 46). Upon completion, stirring The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol The pure fractions were collected the eluent was evaporated The residue was from a mixture of acetonitrile and 2,2'-oxybispropane

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5.09 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-furanylmethyl)-1H-benzimidazol-2-amine and 54 parts of N,N-dimethylformamide was stirred and heated at 50° C. and there was added dropwise a solution of 2.8 parts of dihydro-3-phenyl-2H-pyran-2,6(3H)dione in 18 parts of N,N-dimethylformamide. Upon completion, stirring was continued overnight at 50° C. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 1.8 parts of N-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]formamide hemihydrate; mp. 125.2° C. (compound 46). Upon completion, stirring The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol The pure fractions were collected the eluent was evaporated The residue was from a mixture of acetonitrile and 2,2'-oxybispropane

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 2-phenylglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting solution was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.93 (2H, p); 2.12 (2H, m); 2.18-2.37 (2H, comp. band); 2.42-2.55 (1H, comp. band); 2.74-2.90 (7H, comp. band); 3.48 (2H, t); 3.66/4.38 (1H, t); 6.60/6.62 (1H, d); 7.23-7.39 (5H, comp. band); 7.51/7.55 (1H, d). The resulting solution was purified by HPLC

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

Procedure: The procedure for the preparation of the product of EXAMPLE 8 was repeated using 2-phenylglutaric anhydride (Aldrich) in the place of 3,3-tetramethyleneglutaric anhydride to provide a 55:45 mixture of the title products as a gum. 1H (CD3OD) δ 1.90 (2H, m); 2.15-2.35 (2H, comp. band); 2.32/2.40 (3H, s); 2.42-2.53 (1H, comp. band); 2.69/2.76 (2H, t); 2.85 (1H, m); 2.92-3.04 (4H, comp. band); 3.45 (2H, t); 3.66/4.39, (1H, t); 7.23-7.40 (5H, comp. band), 7.44/7.52 (1H, s). to provide

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

Procedure: 8.3 g (0.0436 mole) of 2-phenylglutaric anhydride and 5.2 g (0.0436 mole) of Schiff base, prepared from benzaldehyde and methylamine, are refluxed at 140° in 50 ml of xylene for 12 hr. After cooling the solid is collected and washed with xylene and ether: 7.6 g of 2,3-diphenyl-1-methyl-piperidin-6-one-3-carboxylic acid, mp 268°-72° (diastereomeric mixture). A solution of 7.3 g (0.0263 mole) of the above compound in 10 ml of THF is treated with diborane generated from 7.5 g of NaBH4 in 150 ml of diglyme and 50.6 ml of BF3 -etherate in 150 ml of diglyme. After completion of the reaction 30 ml of 6N HCl are added very slowly at first. 100 ml of water are added and the THF removed in vacuo. The water solution is adjusted to pH 8-9 with 6N NaOH and extracted with methylenechloride. The gummy residue (6.3 g) is crystallized from ether: 4.2 g (62%) of title compound mp 138°-44° (very likely diastereomeric mixture). After cooling the solid is collected washed with xylene and ether are added very slowly at first the THF removed in vacuo extracted with methylenechloride The gummy residue (6.3 g) is crystallized from ether

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5.09 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-(2-furanylmethyl)-1H-benzimidazol-2-amine and 54 parts of N,N-dimethylformamide was stirred and heated at 50° C. and there was added dropwise a solution of 2.8 parts of dihydro-3-phenyl-2H-pyran-2,6(3H)dione in 18 parts of N,N-dimethylformamide. Upon completion, stirring was continued overnight at 50° C. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 1.8 parts of N-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]formamide hemihydrate; mp. 125.2° C. (compound 46). Upon completion, stirring The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol The pure fractions were collected the eluent was evaporated The residue was from a mixture of acetonitrile and 2,2'-oxybispropane

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

Procedure: 8.3 g (0.0436 mole) of 2-phenylglutaric anhydride and 5.2 g (0.0436 mole) of Schiff base, prepared from benzaldehyde and methylamine, are refluxed at 140° in 50 ml of xylene for 12 hr. After cooling the solid is collected and washed with xylene and ether: 7.6 g of 2,3-diphenyl-1-methyl-piperdin-6-one-3-carboxylic acid, mp 268°-72° (diastereomeric mixture). A solution of 7.3 g (0.0263 mole) of the above compound in 10 ml of THF is treated with diborane generated from 7.5 g of NaBH4 in 150 ml of diglyme and 50.6 ml of BF3 -etherate in 150 ml of diglyme. After completion of the reaction 30 ml of 6N HCl are added very slowly at first. 100 ml of water are added and the THF removed in vacuo. The water solution is adjusted to pH 8-9 with 6N NaOH and extracted with methylenechloride. The gummy residue (6.3 g) is crystallized from ether: 4.2 g (62%) of title compound mp 138°-44° (very likely diastereomeric mixture). After cooling the solid is collected washed with xylene and ether are added very slowly at first the THF removed in vacuo extracted with methylenechloride The gummy residue (6.3 g) is crystallized from ether

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 2-phenylglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting solution was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.93 (2H, p); 2.12 (2H, m); 2.18–2.37 (2H, comp. band); 2.42–2.55 (1H, comp. band); 2.74–2.90 (7H, comp. band); 3.48 (2H, t); 3.66/4.38 (1H, t); 6.60/6.62 (1H, d); 7.23–7.39 (5H, comp. band); 7.51/7.55 (1H, d). The resulting solution was purified by HPLC

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

Procedure: The procedure for the preparation of the product of EXAMPLE 8 was repeated using 2-phenylglutaric anhydride (Aldrich) in the place of 3,3-tetramethyleneglutaric anhydride to provide a 55:45 mixture of the title products as a gum. 1H (CD3OD) δ1.90 (2H, m); 2.15–2.35 (2H, comp. band); 2.32/2.40 (3H, s); 2.42–2.53 (1H, comp. band); 2.69/2.76 (2H, t); 2.85 (1H, m); 2.92–3.04 (4H, comp. band); 3.45 (2H, t); 3.66/4.39, (1H, t); 7.23–7.40 (5H, comp. band), 7.44/7.52 (1H, s). to provide

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of (1Z)-N′-hydroxy-4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butanimidamide (100 mg, WO 99/30709), 2-phenylglutaric anhydride (80 mg, Aldrich) and 1,4-dioxane (2 mL, Aldrich) was heated to 100° C. for 16 hrs. The resulting solution was purified by HPLC to provide the title compound as a gum. 1H (CD3OD) δ 1.93 (2H, p); 2.12 (2H, m); 2.18-2.37 (2H, comp. band); 2.42-2.55 (1H, comp. band); 2.74-2.90 (7H, comp. band); 3.48 (2H, t); 3.66/4.38 (1H, t); 6.60/6.62 (1H, d); 7.23-7.39 (5H, comp. band); 7.51/7.55 (1H, d). The resulting solution was purified by HPLC

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

Procedure: The procedure for the preparation of the product of EXAMPLE 8 was repeated using 2-phenylglutaric anhydride (Aldrich) in the place of 3,3-tetramethyleneglutaric anhydride to provide a 55:45 mixture of the title products as a gum. 1H (CD3OD) δ 1.90 (2H, m); 2.15-2.35 (2H, comp. band); 2.32/2.40 (3H, s); 2.42-2.53 (1H, comp. band); 2.69/2.76 (2H, t); 2.85 (1H, m); 2.92-3.04 (4H, comp. band); 3.45 (2H, t); 3.66/4.39, (1H, t); 7.23-7.40 (5H, comp. band), 7.44/7.52 (1H, s). to provide

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

Procedure: 8.3 g (0.0436 mole) of 2-phenylglutaric anhydride and 5.2 g (0.0436 mole) of Schiff base, prepared from benzaldehyde and methylamine, are refluxed at 140° in 50 ml of xylene for 12 hr. After cooling the solid is collected and washed with xylene and ether: 7.6 g of 2,3-diphenyl-1-methyl-piperidin-6-one-3-carboxylic acid, mp 268°-72° (diastereomeric mixture). A solution of 7.3 g (0.0263 mole) of the above compound in 10 ml of THF is treated with diborane generated from 7.5 g of NaBH4 in 150 ml of diglyme and 50.6 ml of BF3 -etherate in 150 ml of diglyme. After completion of the reaction 30 ml of 6N HCl are added very slowly at first. 100 ml of water are added and the THF removed in vacuo. The water solution is adjusted to pH 8-9 with 6N NaOH and extracted with methylenechloride. The gummy residue (6.3 g) is crystallized from ether: 4.2 g (62%) of title compound mp 138°-44° (very likely diastereomeric mixture). After cooling the solid is collected washed with xylene and ether are added very slowly at first the THF removed in vacuo extracted with methylenechloride The gummy residue (6.3 g) is crystallized from ether