Methanesulfonyl chloride → HCID 68515156, compound

HRID 2241196Notes

Reaction equation

HRID 2241196 reaction equation
[CH3:1][O:2][C:3]1[CH:45]=[CH:44][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)[C:25]([C:27]5([C:30]([NH2:32])=[O:31])[CH2:29][CH2:28]5)=[O:26])=[CH:20][C:19]=4[F:40])=[C:11]3[C:10]([CH2:41][CH2:42]O)=[N:9]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[CH3:60][N:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>C(Cl)(Cl)Cl>[F:40][C:19]1[CH:20]=[C:21]([N:24]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[C:25]([C:27]2([C:30]([NH2:32])=[O:31])[CH2:28][CH2:29]2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:45][CH:44]=3)[N:9]=[C:10]([CH2:41][CH2:42][N:64]3[CH2:65][CH2:66][N:61]([CH3:60])[CH2:62][CH2:63]3)[C:11]=12

Participants

6

Reactant 4

HCID 31297Methanesulfonyl chlorideHCID 531671-MethylpiperazineHCID 81531DiisopropylethylamineHCID 68516867HCID 68516867, compound

Product 1

HCID 68515156HCID 68515156, compound

Reagents, catalysts & solvents 1

HCID 6212ChloroformSolvent

Procedure

To a stirred mixture of N-(4-(1-(4-methoxybenzyl)-3-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg, 0.16 mmol; prepared as in Example 8, Step C), DIEA (0.057 mL, 0.33 mmol), and chloroform (5 mL), cooled in an ice bath under N2 was added methanesulfonyl chloride (0.0189 mL, 0.244 mmol). The reaction was allowed to warm to room temperature slowly as the ice melted. The solution was stirred for 30 minutes at room temperature. A portion of the reaction mixture (1.25 mL) was transferred to a second flask and concentrated in vacuo. To the residue was added 1-methylpiperazine (0.023 mL, 0.20 mmol). The neat reaction mixture was heated to 100° C. for 1 hour. The crude was partitioned between DCM (2 mL) and a 1:1 saturated aqueous NaHCO3/water mixture (2 mL). The phases were separated, and the organic phase was dried (Na2SO4) and loaded directly on to a preparative TLC plate, eluting with 10% MeOH (containing 7N NH3) in CHCl3. Yield: 4 mg, 12%. 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.36 (s, 1H), 8.28 (d, J=6 Hz, 1H), 7.76 (m, 1H), 7.47 (m, 2H), 7.30 (d, J=9 Hz, 2H), 7.26 (m, 1H, overlaps chloroform), 7.18 (t, J=9 Hz, 1H), 7.06 (t, J=9 Hz, 2H), 6.82 (d, J=9 Hz, 2H), 6.18 (d, J=6 Hz, 1H), 5.57 (s, 2H), 3.76 (s, 3H), 3.29 (m, 2H), 2.93 (m, 2H), 2.5-2.8 (m, 8H), 2.42 (s, 3H), 1.82 (m, 2H), 1.64 (m, 2H).

Workup

  1. temperaturecooled in an ice bath under N2
  2. concentrationconcentrated in vacuo
  3. temperatureThe neat reaction mixture was heated to 100° C. for 1 hour
  4. customThe crude was partitioned between DCM (2 mL)
  5. customThe phases were separated
  6. dry with materialthe organic phase was dried (Na2SO4)
  7. washeluting with 10% MeOH (containing 7N NH3) in CHCl3

Sources & evidence

ORD record
ord-73b43ce80bf342688076f758a98ca71a
Source dataset
uspto-grants-2010_05
Patent number
US07723330B2

Reaction notes

Loading…