Triethylamine → 2-(5-methoxy-2-pyridinyl)-1-[2-[(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone

HRID 1913473Notes

Reaction equation

HRID 1913473 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.C(N(CC)CC)C.Cl.Cl.[CH3:34][C:35]1[N:40]=[CH:39][N:38]=[C:37]([C:41]2[CH:42]=[C:43]3[C:47](=[CH:48][CH:49]=2)[CH:46]([N:50]2[CH2:53][C:52]4([CH2:58][CH2:57][NH:56][CH2:55][CH2:54]4)[CH2:51]2)[CH2:45][CH2:44]3)[CH:36]=1.[OH-].[Na+]>ClCCl.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:56]2[CH2:57][CH2:58][C:52]3([CH2:51][N:50]([C@H:46]4[C:47]5[C:43](=[CH:42][C:41]([C:37]6[CH:36]=[C:35]([CH3:34])[N:40]=[CH:39][N:38]=6)=[CH:49][CH:48]=5)[CH2:44][CH2:45]4)[CH2:53]3)[CH2:54][CH2:55]2)=[O:12])=[N:7][CH:8]=1

Participants

9

Reactant 5

HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 682631,1'-CarbonyldiimidazoleHCID 584384902-(5-Methoxypyridin-2-yl)acetic acidHCID 674060892-[5-(6-Methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride

Product 1

HCID 584384602-(5-methoxy-2-pyridinyl)-1-[2-[(1R)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanoneYield 89.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of (5-methoxypyridin-2-yl)acetic acid (SM-1aa, 8.90 g, 53.2 mmol) in dichloromethane (225 mL) was added 1,1′-carbonyldiimidazole (8.63 g, 53.2 mmol) and the reaction was stirred for 2 hours at room temperature. In a separate flask, triethylamine (28.3 mL, 203 mmol) was added to a mixture of 2-[5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-dihydrochloride (3-1g, 22.5 g, 50.7 mmol) in dichloromethane (113 mL). The activated acid was added to the amine solution and the reaction was stirred at room temperature for 2 hours. Aqueous sodium hydroxide (1N, 80 mL) and 100 mL of water were added and mixture was stirred for 10 minutes. The aqueous layer was washed with 150 mL of dichloromethane. The combined organic layers were washed with aqueous NH4Cl (3×) to remove the residual amine starting material. The organic solution was concentrated to a light green-amber oil and was stirred at 50° C. in EtOAc (150 mL) until a solution was obtained. The solution was cooled to room temperature with stirring. A solid formed and the thick slurry was diluted with 50 mL of EtOAc and 50 mL of heptanes. The slurry was stirred for 1 hour and filtered under nitrogen to afford 2-(5-methoxy-pyridin-2-yl)-1-{2-[(R)-5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]non-7-yl}-ethanone (22 g, 89.7%) as an off-white solid. MS (ES+) 484.4 (M+H)+. 1H NMR (CDCl3) δ 1.74 (dt, 4H), 1.95-1.99 (m, 1H), 2.25-2.36 (m, 1H), 2.59 (s, 3H), 2.89-2.99 (m, 1H), 3.11-3.21 (m, 1H), 3.34-3.46 (m, 4H), 3.51-3.61 (m, 4H), 3.83-3.92 (m, 5H), 4.17 (dd, 1H), 7.29 (d, 1H), 7.38 (dd, 1H), 7.53 (d, 1H), 7.88 (s, 1H), 8.00 (d, 1H), 8.06 (s, 1H), 8.16 (d, 1H), 9.02 (s, 1H). [α]D20=+55.0 deg (c=1 mg/mL, MeOH).

Workup

  1. stirringthe reaction was stirred at room temperature for 2 hours
  2. stirringmixture was stirred for 10 minutes
  3. washThe aqueous layer was washed with 150 mL of dichloromethane
  4. washThe combined organic layers were washed with aqueous NH4Cl (3×)
  5. customto remove the residual amine starting material
  6. concentrationThe organic solution was concentrated to a light green-amber oil
  7. stirringwas stirred at 50° C. in EtOAc (150 mL) until a solution
  8. customwas obtained
  9. temperatureThe solution was cooled to room temperature
  10. stirringwith stirring
  11. customA solid formed
  12. stirringThe slurry was stirred for 1 hour
  13. filtrationfiltered under nitrogen

Sources & evidence

ORD record
ord-f7d9f60b3a0d487d95e2578b32e0dcf1
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

Loading…