Potassium Phosphate, Tribasic → 5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

HRID 73795ノート

反応式

HRID 73795 の反応式
[O-]P([O-])([O-])=O.[K+].[K+].[K+].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18][CH:17]=[N:16]1.Br[C:30]1[C:31](N2CC[C@@H](O)C2)=[N:32][CH:33]=[C:34]([CH:49]=1)[C:35]([NH:37]C1C=CC(OC(F)(F)C)=CC=1)=[O:36].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19]([C:30]2[CH:31]=[N:32][CH:33]=[C:34]([CH:49]=2)[C:35]([NH2:37])=[O:36])=[CH:18][CH:17]=[N:16]1

参加物

8

反応物 4

HCID 62657Potassium Phosphate, TribasicHCID 516892Sodium BicarbonateHCID 115872081-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 86702628(R)-5-Bromo-N-(4-(1,1-difluoroethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide

生成物 1

HCID 1317318385-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide

試薬・触媒・溶媒 3

HCID 178418397HCID 178418397、化合物触媒HCID 1140Toluene溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
110 °C

実験手順

K3PO4 (113 mg, 0.532 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (99 mg, 0.355 mmol) and Pd(PPh3)4 (10.24 mg, 8.86 mmol) were added to a solution of (R)-5-bromo-N-(4-(1,1-difluoroethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 30.1, 80 mg, 0.177 mmol) in toluene (1.5 mL) under argon atmosphere. and the RM was stirred at 110° C. for 1 h. The RM was diluted with EtOAc (20 mL) treated with sat. NaHCO3 solution (20 mL). and extracted with EtOAc. The combined extracts were washed with brine (20 mL), dried with Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (Silica gel column, 12 g DCM/EtOH from 97:3 to 95:5) to afford N-(4-(1,1-difluoroethoxy)phenyl)-6-(R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide which (66 mg, 0.129 mmol) was dissolved in DCM (1.5 mL) and treated with TFA (0.546 mL, 7.09 mmol) and stirred for 2 h at RT. The RM was diluted with EtOAc (20 mL), treated with sat. NaHCO3 solution (25 mL) and extracted with EtOAc (20 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 10). Fractions containing pure product were combined, treated with 0.5 g NaHCO3 and the MeCN was evaporated off under reduced pressure. The aq. residue was extracted with DCM to give the title product as a white solid. HPLC (Condition 5) tR=5.42 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=430.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.87 (m, 2H) 1.93 (t, J=13.67 Hz, 3H) 2.94 (d, J=11.71 Hz, 1H) 3.15-3.33 (m, 2H) 3.38-3.48 (m, 1H) 4.19 (br. s, 1H) 6.37 (s, 1H) 7.15 (d, J=9.37 Hz, 2H) 7.65-7.83 (m, J=9.37 Hz, 3H) 8.03 (d, J=2.34 Hz, 1H) 8.73 (d, J=2.34 Hz, 1H).

後処理

  1. extractionand extracted with EtOAc
  2. washThe combined extracts were washed with brine (20 mL)
  3. dry with materialdried with Na2SO4
  4. customthe solvent was evaporated off under reduced pressure
  5. customto give a crude product which
  6. customwas purified by flash chromatography (Silica gel column, 12 g DCM/EtOH from 97:3 to 95:5)

出典と根拠

ORDレコード
ord-c8e126c84600462fb854bf83dde7d6b3
出典データセット
uspto-grants-2014_09
特許番号
US08829195B2

反応ノート

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