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

HRID 1913471Notes

Reaction equation

HRID 1913471 reaction equation
Cl.Cl.[CH2:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([N:20]2[CH2:23][C:22]4([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21]2)[CH2:15][CH2:14]3)=[N:9][CH:10]=1)[CH3:4].[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38](O)=[O:39])=[N:35][CH:36]=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)C=O>[CH2:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([N:20]2[CH2:23][C:22]4([CH2:28][CH2:27][N:26]([C:38](=[O:39])[CH2:37][C:34]5[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:36][N:35]=5)[CH2:25][CH2:24]4)[CH2:21]2)[CH2:15][CH2:14]3)=[N:9][CH:10]=1)[CH3:4]

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 674091552-[(1R)-5-(5-Ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride

Product 1

HCID 584384872-[(1R)-5-(5-Ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-7-[(5-methoxypyridin-2-yl)acetyl]-2,7-diazaspiro[3.5]nonaneYield 80.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-[(1R)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane dihydrochloride (3-1c, 630 mg, 1.38 mmol) in dimethylformamide (5 mL) was added (5-methoxypyridin-2-yl)acetic acid (SM-1aa, 230 mg, 1.38 mmol), HBTU (523 mg, 1.38 mmol) and triethylamine (1.20 mL, 8.5 mmol). The solution was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the residual DMF was azeotroped with toluene. The residue was partitioned between 50 mL of ethyl acetate and 50 mL 1N NaOH solution. The organic layer was collected, washed with saturated brine, dried over Na2SO4 and concentrated. The crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column (1-10% MeOH in CH2Cl2 in 20 minutes) to afford the desired product (554 mg, 79.4%) as an off-white foam. The solid was stirred in 50 mL of refluxing diisopropyl ether for 6 hours and filtered to afford a light-grey powder (490 mg, 71%). MS (ES+) 498.5 (M+H)+. 1H NMR (CDCl3) δ 1.28 (t, 3H), 1.53-1.77 (m, 4H), 1.77-2.01 (m, 1H), 2.03-2.22 (m, 1H), 2.65 (q, 2H), 2.76-2.94 (m, 1H), 2.95-3.18 (m, 5H), 3.30-3.54 (m, 4H), 3.69-3.86 (m, 5H), 3.88-4.04 (m, 1H), 7.14 (dd, 1H), 7.19-7.26 (m, 1H), 7.33 (d, 1H), 8.13-8.29 (m, 3H), 8.60 (s, 2H). [α]D20=+40.0 deg (c=10 mg/mL, MeOH).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customthe residual DMF was azeotroped with toluene
  3. customThe residue was partitioned between 50 mL of ethyl acetate and 50 mL 1N NaOH solution
  4. customThe organic layer was collected
  5. washwashed with saturated brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customThe crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column (1-10% MeOH in CH2Cl2 in 20 minutes)

Sources & evidence

ORD record
ord-5401baf33ffb47628a561fbe49cfc9ad
Source dataset
uspto-grants-2013_12
Patent number
US08609680B2

Reaction notes

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