Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → 2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide

HRID 1688043Notes

Reaction equation

HRID 1688043 reaction equation
[NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([C:11](=[O:13])[CH3:12])[CH2:7][CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=2[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[C:11]([N:6]1[C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:25]=4[C:26]([NH:28][CH2:29][C:30]#[CH:31])=[O:27])[C:20]([Cl:37])=[CH:19][N:18]=3)=[CH:3][C:4]=2[O:10][CH2:9][CH2:8][CH2:7]1)(=[O:13])[CH3:12]

Participants

6

Reactant 4

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 19660Carbonate IonHCID 672635641-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanoneHCID 866339022-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide

Product 1

HCID 866340672-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamideYield 60.2%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

1-(3-Amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone (97 mg, 0.47 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide (167 mg, 0.494 mmol), and 10-Camphorsulfonic acid (16 mg, 0.070 mmol) in Isopropyl alcohol (4 mL) was irradiated in a CEM microwave (120° C., 30 min). The mixture was neutralized with MP-carbonate (0.3 mmol) and purified on silica gel (ISCO, 2×12 g, 0-100% EtOAc:Hex) to afford 2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide as a light brown foam (144 mg, 60%). MP=196-199° C.; LCMS: 509 (M+H); 1H-NMR (DMSO): 9.50 (s, 1H), 9.21 (s, 1H), 8.99 (m, 1H), 8.20 (s, 1H), 7.49 (m, 3H), 7.34 (s, 1H), 7.16 (m, 1H), 7.06 (m, 1H), 4.55 (m, 1H), 4.34 (m, 1H), 4.01 (d, 2H, J=2.3 Hz), 3.55 (m, 1H), 3.11 (t, 1H, J=2.3 Hz), 2.62 (m, 1H), 1.95 (m, 1H), 1.72 (m, 4H).

Workup

  1. custompurified on silica gel (ISCO, 2×12 g, 0-100% EtOAc:Hex)

Sources & evidence

ORD record
ord-6f008867e85f4a7f9067918845e73d09
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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