Triethylamine → 7-[(5-methoxypyridin-2-yl)acetyl]-2-[(1R)-5-(4-methyl-1H-pyrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane

HRID 1913479Notes

Reaction equation

HRID 1913479 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=O)=[N:7][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[CH3:27][C:28]1[CH:29]=[N:30][N:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[C@H:38]([N:42]2[CH2:45][C:44]4([CH2:50][CH2:49][NH:48][CH2:47][CH2:46]4)[CH2:43]2)[CH2:37][CH2:36]3)[CH:32]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:48]2[CH2:49][CH2:50][C:44]3([CH2:43][N:42]([C@H:38]4[C:39]5[C:35](=[CH:34][C:33]([N:31]6[CH:32]=[C:28]([CH3:27])[CH:29]=[N:30]6)=[CH:41][CH:40]=5)[CH2:36][CH2:37]4)[CH2:45]3)[CH2:46][CH2:47]2)=[O:12])=[N:7][CH:8]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 682631,1'-CarbonyldiimidazoleHCID 584384902-(5-Methoxypyridin-2-yl)acetic acidHCID 674053182-((R)-5-(4-methyl-1H-pyrazol-1-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane dihydrochloride

Product 1

HCID 584384627-[(5-methoxypyridin-2-yl)acetyl]-2-[(1R)-5-(4-methyl-1H-pyrazol-1-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonaneYield 36.8%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a mixture of (5-methoxypyridin-2-yl)acetic acid (SM-1aa, 25.9 mg, 0.16 mmol) in dichloromethane (5 mL) was added 1,1′-carbonyldiimidazole (25.9 mg, 0.16 mmol) and the reaction was stirred overnight at room temperature. In a separate flask, to a mixture of 2-((R)-5-(4-methyl-1H-pyrazol-1-yl)-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane dihydrochloride (8-1b, 60.0 mg, 0.15 mmol) in dichloromethane (10 mL) was added triethylamine (0.31 mL, 0.23 mmol). The activated acid was then added to the amine solution and the resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated and purified on an ISCO (Teledyne Isco Inc., Lincoln Nebr.) 12 g silica column eluting with 50-100% MeOH in ethyl acetate gradient to give 26 mg (36%) of the title compound (8A) as a gum. MS (ES+) 472.9 (M+H)+. 1H NMR (CD3OD) δ 1.62-1.75 (m, 4H), 1.85-1.97 (m, 1H), 2.13 (s, 3H), 2.17-2.31 (m, 1H), 2.80-2.92 (m, 1H), 3.03-3.15 (m, 1H), 3.20-3.27 (m, 2H), 3.32 (d, 2H), 3.48-3.56 (m, 4H), 3.84 (s, 3H), 3.85 (s, 2H), 4.03 (dd, 1H), 7.22-7.28 (m, 1H), 7.35 (dd, 1H), 7.38-7.44 (m, 1H), 7.44-7.51 (m, 2H), 7.55 (s, 1H), 7.94 (s, 1H), 8.13 (d, 1H).

Workup

  1. stirringthe resulting mixture was stirred at room temperature for 2 hours
  2. concentrationThe reaction was concentrated
  3. custompurified on an ISCO (Teledyne Isco Inc., Lincoln Nebr.) 12 g silica column
  4. washeluting with 50-100% MeOH in ethyl acetate gradient

Sources & evidence

ORD record
ord-358c5aac27744f789013c874790813cb
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

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