Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → N-{trans-2-[5-Chloro-2-(1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclopentyl}-methanesulfonamide

HRID 1040860Notes

Reaction equation

HRID 1040860 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=2[C:22]=1[O:35][CH3:36].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=3[C:22]=2[O:35][CH3:36])=[N:3][CH:4]=1

Participants

5

Reactant 3

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 672642417-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-oneHCID 86633888N-[trans-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentyl]-methanesulfonamide

Product 1

HCID 66830105N-{trans-2-[5-Chloro-2-(1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclopentyl}-methanesulfonamideYield 40.3%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
120 °C

Procedure

N-[trans-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentyl]-methanesulfonamide (60 mg, 0.185 mmol), 7-amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (43 mg, 0.185 mmol) and camphorsulfonic acid (64 mg, 0.278 mmol) were combined in 3 mL isopropanol and heated at 120° C. in microwave for a total of 110 min. The reaction was concentrated to be taken up in dichloromethane and washed with saturated sodium bicarbonate solution (2×30 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was chromatographed on a 4 g amine capped ISCO flash column from 0-100% ethyl acetate in hexanes. The product was collected as a foam after concentrating to afford 39 mg (40%) of a white foam. Compound 4: mp 141° C.; MS (ES+ calculated—523; found—524 M+H). 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=8, 1H), 8.01 (s, 1H), 7.37 (s, 1H), 7.01 (d, J=8, 1H), 6.11 (s, 1H), 5.46 (d, 1H), 4.25 (m, 1H), 3.82 (s, 3H), 2.89 (m, 1H), 2.89 (s, 4H), 2.32 (br s, 6H), 1.89 (m, 2H), 1.73 (m, 1H), 1.59 (s, 3H), 1.15 (t, J=7, 4H) ppm.

Workup

  1. concentrationThe reaction was concentrated
  2. washwashed with saturated sodium bicarbonate solution (2×30 mL)
  3. dry with materialThe organic layer was dried over MgSO4
  4. filtrationfiltered
  5. customThe filtrate was chromatographed on a 4 g amine capped ISCO flash column from 0-100% ethyl acetate in hexanes
  6. customThe product was collected as a foam
  7. concentrationafter concentrating

Sources & evidence

ORD record
ord-e435e255bfbf4161bbc2081d943f53c7
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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