Diisopropylethylamine → 4-(2-(2-(1,1-difluoroethyl)-1H-benzo[d]imidazol-1-yl)-9-methyl-8-((4-(oxetan-3-yl)piperidin-1-yl)methyl)-9H-purin-6-yl)morpholine

HRID 1945981ノート

反応式

HRID 1945981 の反応式
[CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:21][O:20][CH2:19]3)[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([NH:28][C:29]1[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1)=[N:6][C:7]=2[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:36][C:37]([F:42])([CH3:41])[C:38](O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:36][C:37]([C:41]1[N:28]([C:5]2[N:4]=[C:3]3[C:8]([N:9]=[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([CH:18]5[CH2:21][O:20][CH2:19]5)[CH2:16][CH2:17]4)[N:2]3[CH3:1])=[C:7]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:6]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]=1)([F:42])[CH3:38]

参加物

6

反応物 4

HCID 81531DiisopropylethylamineHCID 27828252,2-Difluoropropionic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59605317N-[9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-ylpiperidin-1-ylmethyl)-9H-purin-2-yl]benzene-1,2-diamine

生成物 1

HCID 674927034-(2-(2-(1,1-difluoroethyl)-1H-benzo[d]imidazol-1-yl)-9-methyl-8-((4-(oxetan-3-yl)piperidin-1-yl)methyl)-9H-purin-6-yl)morpholine収率 27%

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒

実験手順

To a mixture of N-[9-methyl-6-morpholin-4-yl-8-(4-oxetan-3-ylpiperidin-1-ylmethyl)-9H-purin-2-yl]benzene-1,2-diamine (0.115 g, 0.24 mmol) and 2,2-difluoropropionic acid (0.028 g, 0.25 mmol) and DIPEA (0.091 mL, 0.53 mL) in DMF (7 mL) was added HATU (0.11 g, 0.29 mmol). The reaction mixture was stirred at room temperature for 24 h, then at 90° C. for 24 h. The reaction mixture was concentrated in vacuo and the residue was loaded in MeOH onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted with 2 M NH3 in MeOH. The solution was concentrated in vacuo, the residue was diluted in acetic acid (15 mL) and the reaction mixture was stirred at 90° C. for 7 h. The reaction mixture was concentrated in vacuo and the resultant residue was purified by flash chromatography (Si—PPC, MeOH:DCM, 0:100 to 10:90) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 459 as a white solid (0.032 g, 27%). LCMS (Method I): RT=3.30 min, [M+H]+ 553.3. 1H NMR (400 MHz, DMSO-d6): δ 7.84-7.81 (m, 1 H); 7.74-7.71 (m, 1 H); 7.43-7.35 (m, 2 H); 4.40-4.15 (m, 4 H); 3.84 (s, 2 H); 3.81 (d, J=4.3 Hz, 2 H); 3.78-3.71 (m, 7 H); 3.37 (t, J=6.9 Hz, 2 H); 3.30-3.18 (m, 2 H); 2.96 (t, J=6.9 Hz, 2 H); 2.34-2.21 (t, J=19.5 Hz, 3 H); 2.20-2.08 (m, 1 H); 1.64 (d, J=12.1 Hz, 1 H); 1.50 (d, J=13.0 Hz, 2 H); 1.06 (td, J=12.1, 4.3 Hz, 2 H)

後処理

  1. waitat 90° C. for 24 h
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. washThe cartridge was washed with MeOH
  4. washthe desired product was eluted with 2 M NH3 in MeOH
  5. concentrationThe solution was concentrated in vacuo
  6. additionthe residue was diluted in acetic acid (15 mL)
  7. stirringthe reaction mixture was stirred at 90° C. for 7 h
  8. concentrationThe reaction mixture was concentrated in vacuo
  9. customthe resultant residue was purified by flash chromatography (Si—PPC, MeOH:DCM, 0:100 to 10:90)

出典と根拠

ORDレコード
ord-1c4b96ca9572464892f6e5f62b6a02e3
出典データセット
uspto-grants-2013_03
特許番号
US08394796B2

反応ノート

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