N-piperidin-3-ylacetamide

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This compound was synthesized from 6-chloronicotinonitrile and 3-acetamidopiperidine as described for example 51 step 1 (850 mg, yield 96%) as white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=2.2 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.82-7.79 (dd, J=9.0 Hz, 2.4 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 4.20-4.14 (dd, J=12.7 Hz, 3.1 Hz, 1H), 4.08-4.02 (dd, J=13.2 Hz, 3.9 Hz, 1H), 3.62 (m, 1H), 3.22-3.14 (m, 1H), 3.01-2.93 (dd, J=12.9 Hz, 9.2 Hz, 1H), 1.87-1.71 (m, 2H), 1.78 (s, 3H), 1.53-1.41 (m, 2H). MS (ESI) m/z: Calculated for C13H16N4O: 244.13. found: 245.2 (M+H)+

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(566 mg), 3-acetamidopiperidine (300 mg), triethylamine (220 mg) and dimethylsulfoxide (10 ml) was heated at 100° C. for 2 hours with stirring. Thereafter the mixture was cooled to room temperature and ice water was added thereto. The precipitated crystalline was filtered off andwashed with methanol-ether to give 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (540 mg) (m.p. 280°-282° C., recrystallized from methanol). The product (405 mg) obtained in the above manner was suspended in 6N hydrochloric acid (5 ml) and heated at 100° C. for 2.5 hours with stirring. The reaction mixture was further processed in a similar manner to step (b) of Example 1 to afford hydrochloride of 7-(3-aminopiperidinly-1)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. The physical properties of this product were identical with those of the compound provided in Example 1. Thereafter the mixture was cooled to room temperature The precipitated crystalline was filtered off andwashed with methanol-ether

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(566 mg), 3-acetamidopiperidine (300 mg), triethylamine (220 mg) and dimethylsulfoxide (10 ml) was heated at 100° C. for 2 hours with stirring. Thereafter the mixture was cooled to room temperature and ice water was added thereto. The precipitated crystalline was filtered off andwashed with methanol-ether to give 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (540 mg) (m.p. 280°-282° C., recrystallized from methanol). The product (405 mg) obtained in the above manner was suspended in 6N hydrochloric acid (5 ml) and heated at 100° C. for 2.5 hours with stirring. The reaction mixture was further processed in a similar manner to step (b) of Example 1 to afford hydrochloride of 7-(3-aminopiperidinly-1)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. The physical properties of this product were identical with those of the compound provided in Example 1. Thereafter the mixture was cooled to room temperature The precipitated crystalline was filtered off andwashed with methanol-ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (c)Preparation of (R)—N-piperidin-3-ylacetamide Dibenzyol tartarate salt: In a RBF charged 500 ml of Methanol, 50 gm of N-piperidin-3-ylacetamide & 138 gm of L (+)-Dibenzoyl tartaric acid. The reaction was maintained for about 90 mins at room temperature and then heated to reflux. The reaction mass was maintained for about an hour at reflux and then cooled and maintained at room temperature for about 12.0 hours. Then, the product was filtered and washed with 100 ml methanol. Again charged the obtained wet cake in 800 ml methanol, heated to reflux and maintained reaction mass for 1.0 hr to get a clear solution. Cooled the reaction mass to room temperature and maintained for 12.0 hrs. The product was filtered and washed with 100 ml methanol. The product was dried at about 45-50° C. under vacuum. Unwanted S-isomer NMT 1.5% Dry Wt-20. Gm. heated to reflux The reaction mass was maintained for about an hour at reflux cooled maintained at room temperature for about 12.0 hours Then, the product was filtered washed with 100 ml methanol Again charged the obtained wet cake in 800 ml methanol heated to reflux maintained reaction mass for 1.0 hr to get a clear solution Cooled the reaction mass to room temperature maintained for 12.0 hrs The product was filtered washed with 100 ml methanol The product was dried at about 45-50° C. under vacuum Unwanted S-isomer NMT 1.5% Dry Wt-20

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (c)Preparation of (R)—N-piperidin-3-ylacetamide Dibenzyol tartarate salt: In a RBF charged 500 ml of Methanol, 50 gm of N-piperidin-3-ylacetamide & 138 gm of L (+)-Dibenzoyl tartaric acid. The reaction was maintained for about 90 mins at room temperature and then heated to reflux. The reaction mass was maintained for about an hour at reflux and then cooled and maintained at room temperature for about 12.0 hours. Then, the product was filtered and washed with 100 ml methanol. Again charged the obtained wet cake in 800 ml methanol, heated to reflux and maintained reaction mass for 1.0 hr to get a clear solution. Cooled the reaction mass to room temperature and maintained for 12.0 hrs. The product was filtered and washed with 100 ml methanol. The product was dried at about 45-50° C. under vacuum. Unwanted S-isomer NMT 1.5% Dry Wt-20. Gm. heated to reflux The reaction mass was maintained for about an hour at reflux cooled maintained at room temperature for about 12.0 hours Then, the product was filtered washed with 100 ml methanol Again charged the obtained wet cake in 800 ml methanol heated to reflux maintained reaction mass for 1.0 hr to get a clear solution Cooled the reaction mass to room temperature maintained for 12.0 hrs The product was filtered washed with 100 ml methanol The product was dried at about 45-50° C. under vacuum Unwanted S-isomer NMT 1.5% Dry Wt-20

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This compound was synthesized from 6-chloronicotinonitrile and 3-acetamidopiperidine as described for example 51 step 1 (850 mg, yield 96%) as white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=2.2 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.82-7.79 (dd, J=9.0 Hz, 2.4 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 4.20-4.14 (dd, J=12.7 Hz, 3.1 Hz, 1H), 4.08-4.02 (dd, J=13.2 Hz, 3.9 Hz, 1H), 3.62 (m, 1H), 3.22-3.14 (m, 1H), 3.01-2.93 (dd, J=12.9 Hz, 9.2 Hz, 1H), 1.87-1.71 (m, 2H), 1.78 (s, 3H), 1.53-1.41 (m, 2H). MS (ESI) m/z: Calculated for C13H16N4O: 244.13. found: 245.2 (M+H)+

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(566 mg), 3-acetamidopiperidine (300 mg), triethylamine (220 mg) and dimethylsulfoxide (10 ml) was heated at 100° C. for 2 hours with stirring. Thereafter the mixture was cooled to room temperature and ice water was added thereto. The precipitated crystalline was filtered off andwashed with methanol-ether to give 7-(3-acetamidopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (540 mg) (m.p. 280°-282° C., recrystallized from methanol). The product (405 mg) obtained in the above manner was suspended in 6N hydrochloric acid (5 ml) and heated at 100° C. for 2.5 hours with stirring. The reaction mixture was further processed in a similar manner to step (b) of Example 1 to afford hydrochloride of 7-(3-aminopiperidinly-1)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. The physical properties of this product were identical with those of the compound provided in Example 1. Thereafter the mixture was cooled to room temperature The precipitated crystalline was filtered off andwashed with methanol-ether

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (c)Preparation of (R)—N-piperidin-3-ylacetamide Dibenzyol tartarate salt: In a RBF charged 500 ml of Methanol, 50 gm of N-piperidin-3-ylacetamide & 138 gm of L (+)-Dibenzoyl tartaric acid. The reaction was maintained for about 90 mins at room temperature and then heated to reflux. The reaction mass was maintained for about an hour at reflux and then cooled and maintained at room temperature for about 12.0 hours. Then, the product was filtered and washed with 100 ml methanol. Again charged the obtained wet cake in 800 ml methanol, heated to reflux and maintained reaction mass for 1.0 hr to get a clear solution. Cooled the reaction mass to room temperature and maintained for 12.0 hrs. The product was filtered and washed with 100 ml methanol. The product was dried at about 45-50° C. under vacuum. Unwanted S-isomer NMT 1.5% Dry Wt-20. Gm. heated to reflux The reaction mass was maintained for about an hour at reflux cooled maintained at room temperature for about 12.0 hours Then, the product was filtered washed with 100 ml methanol Again charged the obtained wet cake in 800 ml methanol heated to reflux maintained reaction mass for 1.0 hr to get a clear solution Cooled the reaction mass to room temperature maintained for 12.0 hrs The product was filtered washed with 100 ml methanol The product was dried at about 45-50° C. under vacuum Unwanted S-isomer NMT 1.5% Dry Wt-20