Triethylamine → 5-[(1R)-1-{7-[(5-methoxypyridin-2-yl)acetyl]-2,7-diazaspiro[3.5]non-2-yl}-2,3-dihydro-1H-inden-5-yl]pyrazine-2-carboxamide

HRID 1913480Notes

Reaction equation

HRID 1913480 reaction equation
Cl.Cl.[CH2:3]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][N:4]1[C@H:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[N:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39](O)=[O:40])=[N:36][CH:37]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([N:9]2[CH2:10][CH2:11][C:6]3([CH2:5][N:4]([C@H:12]4[C:20]5[C:15](=[CH:16][C:17]([C:21]6[N:22]=[CH:23][C:24]([C:27]([NH2:29])=[O:28])=[N:25][CH:26]=6)=[CH:18][CH:19]=5)[CH2:14][CH2:13]4)[CH2:3]3)[CH2:7][CH2:8]2)=[O:40])=[N:36][CH:37]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 584384902-(5-Methoxypyridin-2-yl)acetic acidHCID 866577265-[(R)-1-(2,7-Diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyrazine-2-carboxylic acid amide dihydrochloride

Product 1

HCID 584384885-[(1R)-1-{7-[(5-methoxypyridin-2-yl)acetyl]-2,7-diazaspiro[3.5]non-2-yl}-2,3-dihydro-1H-inden-5-yl]pyrazine-2-carboxamideYield 29.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 5-[(R)-1-(2,7-diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyrazine-2-carboxylic acid amide (10-1c, 28 mg, 0.08 mmol) in 3 mL of DMF was added (5-methoxy-pyridin-2-yl)-acetic acid (SM-1aa, 13.0 mg, 0.08 mmol), HBTU (33.0 mg, 0.09 mmol) and triethylamine (0.06 mL, 0.46 mmol). The solution was stirred at room temperature overnight. The reaction was concentrated under reduced pressure and coevaporated with toluene. The residue was partitioned between 10 mL of dichloromethane and 10 mL of 1N NaOH solution. The organic layer was washed with saturated brine, dried over Na2SO4 and concentrated. The crude product was purified by Biotage reverse phase column chromatography (Biotage, Inc.) using 100-60% water in acetonitrile to give the desired product 12.0 mg (27%). MS (ES+) 513.4 (M+H)+. 1H NMR (CD3OD) δ 1.56-1.81 (m, 4H), 1.81-2.09 (m, 1H), 2.11-2.35 (m, 1H), 2.93 (d, 1H), 3.12 (d, 1H), 3.20-3.27 (m, 2H), 3.31-3.41 (m, 1H), 3.43-3.66 (m, 4H), 3.69-3.89 (m, 5H), 4.06 (dd, 1H), 4.54-4.81 (m, 2H), 7.25 (d, 1H), 7.34 (dd, 1H), 7.50 (d, 1H), 7.97 (dd, 1H), 8.04 (s, 1H), 8.13 (d, 1H), 9.12 (d, 1H), 9.22 (d, 1H).

Workup

  1. concentrationThe reaction was concentrated under reduced pressure
  2. customThe residue was partitioned between 10 mL of dichloromethane and 10 mL of 1N NaOH solution
  3. washThe organic layer was washed with saturated brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated
  6. customThe crude product was purified by Biotage reverse phase column chromatography (Biotage, Inc.)

Sources & evidence

ORD record
ord-f2941ead5d6f432ca699a2544759d4b3
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

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