1-Methylpiperazin-2-one → (S)-N1-methyl-N1-(2-(4-methyl-3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide

HRID 625474ノート

反応式

HRID 625474 の反応式
[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].[CH3:9][N:10]([CH2:53][CH:54]=O)[C:11](=[O:52])[C:12]1[CH:51]=[CH:50][CH:49]=[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[C:30]2[CH:35]=[C:34]([C:36](=[O:48])[NH:37][C@@H:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)[CH:33]=[CH:32][N:31]=2)=[O:16])[CH:13]=1.[BH3-]C#N.[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[CH3:9][N:10]([CH2:53][CH2:54][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[CH2:4]1)[C:11](=[O:52])[C:12]1[CH:51]=[CH:50][CH:49]=[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:20][C:19]=2[C:30]2[CH:35]=[C:34]([C:36](=[O:48])[NH:37][C@@H:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)[CH:33]=[CH:32][N:31]=2)=[O:16])[CH:13]=1

参加物

7

反応物 3

HCID 43990421-Methylpiperazin-2-one2 回HCID 5003444Sodium cyanoborohydrideHCID 86705967(S)-N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide

生成物 1

HCID 56966143(S)-N1-methyl-N1-(2-(4-methyl-3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide

試薬・触媒・溶媒 3

HCID 176Acetic Acid触媒HCID 702Ethanol溶媒2 回HCID 8857Ethyl Acetate溶媒

実験手順

This compound was prepared according to the procedure described for the synthesis of Example 187 using methylpiperazin-2-one in place of L-proline-tert-butyl ester. Into a 50-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (2 mL). This was followed by the addition of a solution of 1-methylpiperazin-2-one (18 mg, 0.16 mmol, 1.00 equiv) in ethanol (2 mL), two drop of acetic acid. To this was added NaBH3CN (20 mg, 0.32 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 38% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 70 mg product was obtained. This resulted in 70 mg (61%) of (S)—N1-methyl-N1-(2-(4-methyl-3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 728 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.25 (s, 1H), 9.18 (d, J=8.4 Hz, 1H), 8.80 (d, J=5.1 Hz, 1H), 8.29 (d, J=13.8 Hz 2H), 7.99 (t, J=6.9 Hz, 2H), 7.86 (d, J=4.8 Hz, 1H), 7.57-7.67 (m, 3H), 7.10-7.28 (m, 5H), 5.25 (d, J=5.4 Hz, 1H), 3.92-3.85 (m, 4H), 3.30-3.54 (m, 10H), 2.78-2.95 (m, 9H), 1.99 (d, J=3.6 Hz, 2H), 1.72-1.80 (m, 6H), 1.60 (s, 2H).

後処理

  1. customThis compound was prepared
  2. customInto a 50-mL round-bottom flask, was placed
  3. washThe resulting mixture was washed with 2×20 mL of brine
  4. dry with materialThe mixture was dried over anhydrous sodium sulfate
  5. concentrationconcentrated under vacuum
  6. customThe crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3)
  7. waitmobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 38% in 6 min)

出典と根拠

ORDレコード
ord-e18578c4c66244978e7ded2de2bc01bb
出典データセット
uspto-grants-2016_04
特許番号
US09301951B2

反応ノート

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