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 872063노트

반응식

HRID 872063 반응식
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

참가 물질

9

반응물 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

생성물 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

시약·촉매·용매 4

HCID 167845palladium(II) acetate촉매HCID 962Water용매HCID 8028Tetrahydrofuran용매HCID 8857Ethyl Acetate용매

반응 조건

온도
100 °C

실험 절차

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.

후처리

  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)

출처 및 근거

ORD 기록
ord-1664dbe00a05400ead197307f6476974
출처 데이터셋
uspto-grants-2015_03
특허 번호
US08975261B2

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