Water → 5-[(3As,4s,6ar)-2-oxohexahydro-1h-thieno[3,4-d]imidazol-4-yl]-n-(4-{[3-[2-(cyclopentylamino)-pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)-pentanamide

HRID 861165Notes

Reaction equation

HRID 861165 reaction equation
[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)=[N:15][N:16]4[C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C1C(=O)N([O:50][C:51]([CH2:53][CH2:54][CH2:55][CH2:56][C@@H:57]2[S:61][CH2:60][C@@H:59]3[NH:62][C:63]([NH:65][C@H:58]23)=[O:64])=O)C(=O)C1.O>CN(C)C=O>[O:64]=[C:63]1[NH:62][C@H:59]2[CH2:60][S:61][C@@H:57]([CH2:56][CH2:55][CH2:54][CH2:53][C:51]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:21]3[N:16]4[N:15]=[C:14]([C:28]5[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=5)[C:13]([C:11]5[CH:10]=[CH:9][N:8]=[C:7]([NH:6][CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[N:12]=5)=[C:17]4[CH:18]=[CH:19][CH:20]=3)=[O:50])[C@H:58]2[NH:65]1

Participants

6

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 6710714Biotin N-hydroxysuccinimide ester2×HCID 10140154N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine

Product 1

HCID 574947285-[(3As,4s,6ar)-2-oxohexahydro-1h-thieno[3,4-d]imidazol-4-yl]-n-(4-{[3-[2-(cyclopentylamino)-pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)-pentanamideYield 51.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a cold (0° C.) solution of N-[3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]butane-1,4-diamine (33 mg, 0.07 mmol) in N,N-dimethylformamide (3 mL) was added triethylamine (0.03 mL, 0.21 mmol) and d-biotin-N-hydroxysuccinimide ester (27 mg, 0.08 mmol). The resultant mixture was warmed to room temperature and stirred for 30 minutes. A subsequent 5 mg of d-biotin-N-hydroxysuccinimide ester was added and the mixture was stirred an additional 30 minutes. Water was added and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and then brine. The aqueous layer was extracted with dichloromethane and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (5% to 8% methanol in dichloromethane) provided 5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]-N-(4-{[3-[2-(cyclopentylamino)-pyrimidin-4-yl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl]amino}butyl)-pentanamide (25 mg, 51%) as a yellow solid. 1H NMR (CDCl3): δ 7.98 (d, 1 H), 7.80 (d, 1 H), 7.58 (d, 2 H), 7.32 (m, 1 H), 7.00 (d, 2 H), 6.60 (s,1 H), 6.39 (m, 1 H), 6.33 (d, 1 H), 6.18 (m, 1 H), 6.02 (m, 1 H), 5.72 (s, 1 H), 5.62 (broad, 1 H), 4.44–4.31 (m, 2 H), 4.19 (m, 1 H), 3.89 (s, 3 H), 3.39 (m, 2 H), 3.28 (m, 2 H), 3.06 (m, 1 H), 2.95 (m, 2 H), 2.77 (dd, 1 H), 2.58 (d, 1 H), 2.20–2.05 (m, 4 H), 1.82–1.54 (m, 12 H), 1.39 (m, 2 H); MS m/z 698 (M+1).

Workup

  1. stirringthe mixture was stirred an additional 30 minutes
  2. customthe layers were separated
  3. washThe organic layer was washed with saturated aqueous sodium bicarbonate
  4. extractionThe aqueous layer was extracted with dichloromethane
  5. dry with materialthe combined organics were dried over sodium sulfate
  6. filtrationFiltration and concentration

Sources & evidence

ORD record
ord-f1866283030c4ddb819d4d99b87ef169
Source dataset
uspto-grants-2006_12
Patent number
US07153855B2

Reaction notes

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