Triethylamine → 4-(4-fluoro-3-(4-hydroxy-4-methylpiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one

HRID 1091755ノート

反応式

HRID 1091755 の反応式
F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.C(N(CC)CC)C.Cl.[CH3:55][C:56]1([OH:62])[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C)C=O.C(Cl)Cl>[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([N:59]1[CH2:60][CH2:61][C:56]([OH:62])([CH3:55])[CH2:57][CH2:58]1)=[O:30]

参加物

7

反応物 4

HCID 8471Triethylamine2 回HCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 219492954-Methylpiperidin-4-ol hydrochlorideHCID 248117402-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid

生成物 1

HCID 577917664-(4-fluoro-3-(4-hydroxy-4-methylpiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one収率 23.63%

試薬・触媒・溶媒 2

HCID 6228Dimethylformamide溶媒2 回HCID 6344Dichloromethane溶媒

反応条件

温度
25 °C

実験手順

O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (572 mg, 1.51 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (300 mg, 1.01 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (3 mL) at 25° C. under an air atmosphere. The resulting solution was stirred at 25° C. for 10 minutes. A solution of 4-methylpiperidin-4-ol hydrochloride (154 mg, 1.02 mmol) and triethylamine (0.308 mL, 2.21 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the resulting solution stirred at 25° C. for 2 hours. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with water (3×50 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a gum (94 mg, 23.63% yield); 1H NMR (400.132 MHz, DMSO) δ 1.13 (3H, s), 1.29-1.47 (4H, m), 3.20-3.28 (4H, m), 4.32 (2H, s), 4.41 (1H, s), 7.19 (1H, d), 7.31 (1H, dd), 7.38-7.42 (1H, m), 7.83 (1H, td), 7.88 (1H, td), 7.96 (1H, d), 8.27 (1H, dd), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=1.45 (M+H 396.4).

後処理

  1. stirringthe resulting solution stirred at 25° C. for 2 hours
  2. washwashed sequentially with water (3×50 mL) and saturated brine (20 mL)
  3. dry with materialThe organic layer was dried over MgSO4
  4. filtrationfiltered
  5. customevaporated
  6. customto afford crude product, which
  7. customwas purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length)
  8. additionFractions containing the desired compound
  9. customwere evaporated to dryness

出典と根拠

ORDレコード
ord-3aba7beadd7f4730aa53bedce98b448e
出典データセット
uspto-grants-2012_03
特許番号
US08129380B2

反応ノート

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