Potassium Phosphate, Tribasic → Tert-butyl 5-(2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)-3,6-dihydropyridine-1 (2H)-carboxylate

HRID 872063ノート

反応式

HRID 872063 の反応式
Br[C:2]1[C:3]([O:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.CC1(C)C(C)(C)OB([C:33]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][CH:34]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:15]2[CH2:16][C@@H:14]2[CH2:13][O:12][C:3]2[C:2]([C:35]3[CH2:36][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38][CH2:33][CH:34]=3)=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][N:9]=3)[N:4]=2)=[N:18][CH:19]=1

参加物

9

反応物 4

HCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 49835909Tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 1176891283-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine

生成物 1

HCID 71062764Tert-butyl 5-(2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridin-3-yl)-3,6-dihydropyridine-1 (2H)-carboxylate

試薬・触媒・溶媒 4

HCID 167845palladium(II) acetate触媒HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
100 °C

実験手順

A mixture of 3-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine (LL2) (50 mg, 0.13 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (52 mg, 0.17 mmol), tripotassium phosphate (55 mg, 0.26 mmol), S-Phos (5.3 mg, 0.01 mmol), and Pd(OAc)2 (1.5 mg, 0.006 mmol) in THF (0.6 mL) and water (0.1 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (5 mL), washed with sodium bicarbonate (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier) to afford the title compound. 1H NMR (500 MHz, DMSO): δ 8.79 (dd, J=4.3, 1.6 Hz, 1 H), 8.18-8.06 (m, 3 H), 7.66 (dd, J=8.4, 4.2 Hz, 1 H), 7.24 (s, 2 H), 6.26 (s, 1 H), 4.54 (m, 1 H), 4.44 (m, 1 H), 4.26 (brs, 2 H), 3.77 (s, 3 H), 3.49-3.40 (m, 2 H), 2.27 (s, 2 H), 2.24-2.19 (m, 1 H), 1.80 (s, 1 H), 1.41 (s, 9 H), 1.23-1.15 (m, 2 H), 1.08 (dt, J=8.7, 4.6 Hz, 1 H); HRMS m/z (M+H) 489.2486 found, 489.2496 required.

後処理

  1. temperatureto cool to room temperature
  2. washwashed with sodium bicarbonate (1 mL) and brine (1 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe resulting residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier)

出典と根拠

ORDレコード
ord-1664dbe00a05400ead197307f6476974
出典データセット
uspto-grants-2015_03
特許番号
US08975261B2

反応ノート

読み込み中…