Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → cis-2-[5-Chloro-2-(3-dimethylcarbamoylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclopentanecarboxylic acid methylamide

HRID 1040861Notes

Reaction equation

HRID 1040861 reaction equation
[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[N:12]=1)=[O:4].[NH2:19][C:20]1[C:36]([O:37][CH3:38])=[CH:35][C:23]2[CH2:24][CH2:25][N:26]([CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:27][CH2:28][C:22]=2[CH:21]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[CH3:1][NH:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:19][C:20]2[C:36]([O:37][CH3:38])=[CH:35][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][C:30](=[O:31])[N:32]([CH3:33])[CH3:34])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:12]=1)=[O:4]

Participants

5

Reactant 3

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 672635242-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethylacetamideHCID 86633889cis-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentanecarboxylic acid methylamide

Product 1

HCID 66830324cis-2-[5-Chloro-2-(3-dimethylcarbamoylmethyl-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclopentanecarboxylic acid methylamideYield 51%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
120 °C

Procedure

cis-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclopentanecarboxylic acid methylamide (46 mg, 0.160 mmol), 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (44 mg, 0.160 mmol) and camphorsulfonic acid (56 mg, 0.240 mmol) were combined in 3 mL isopropanol and heated at 120° C. in microwave for a total of 90 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 43 mg (51%) of a white foam. Compound 5: mp 240° C.; MS (ES+ calculated—529; found—530 M+H). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 6.65 (s, 1H), 6.14 (d, J=7 Hz, 1H), 5.57 (br s, 1H), 4.61 (t, J=7 Hz, 1H), 3.88 (s, 3H), 3.29 (s, 2H), 3.15 (s, 3H), 2.99 (s, 3H), 2.89 (s, 4H), 2.71 (d, J=4 Hz, 6H), 2.17 (m, 1H), 2.08 (m, 1H), 1.98 (br s, 2H), 1.65 (m, 1H) 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-e26b5a4fade44f1fb6363ec5c51dca20
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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