Diisopropylethylamine → tert-Butyl 5-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)isoindoline-2-carboxylate

HRID 1808379Notes

Reaction equation

HRID 1808379 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[N:55]1[CH:60]=[CH:59][C:58]([N:61]2[CH2:66][CH2:65][C:64]3([CH2:71][CH2:70][NH:69][CH2:68][CH2:67]3)[CH2:63][CH2:62]2)=[CH:57][CH:56]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:55]1[CH:56]=[CH:57][C:58]([N:61]2[CH2:66][CH2:65][C:64]3([CH2:67][CH2:68][N:69]([C:17]([C:13]4[CH:14]=[C:15]5[C:10](=[CH:11][CH:12]=4)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:16]5)=[O:19])[CH2:70][CH2:71]3)[CH2:63][CH2:62]2)=[CH:59][CH:60]=1

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 27960291-Hydroxybenzotriazole hydrateHCID 164501432-(tert-Butoxycarbonyl)-2,3-dihydro-1H-isoindole-5-carboxylic acidHCID 66701057HCID 66701057, compound

Product 1

HCID 59483841tert-Butyl 5-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)isoindoline-2-carboxylate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

2-(tert-Butoxycarbonyl)isoindoline-5-carboxylic acid (0.5 g, 0.0019 mol) ([CAS: 149353-71-9] available commercially from Milestone, for example), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.6 g, 0.0019 mol) and 1-hydroxybenzotriazole hydrate (0.26 g, 0.0019 mol) were dissolved in tetrahydrofuran, under protecting gas, and stirred for 30 min at RT. A solution of 3-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane dihydrochloride (F-09) (0.5 g, 0.0019 mol) and diisopropylethylamine (DIPEA) (0.86 g, 0.066 mol) in tetrahydrofuran was added, and the reaction mixture was stirred for 15 h at RT. Tetrahydrofuran was then removed in vacuo, the residue was taken up in ethyl acetate and sat. sodium hydrogen carbonate solution, and the phases were separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were in turn washed with sat. sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/methanol 10:1+1% ammonia solution (25% aq.)). Yield: 0.85 g (94%)

Workup

  1. stirringthe reaction mixture was stirred for 15 h at RT
  2. customTetrahydrofuran was then removed in vacuo
  3. customsat. sodium hydrogen carbonate solution, and the phases were separated
  4. extractionThe aqueous phase was extracted with ethyl acetate
  5. washwashed with sat. sodium chloride solution
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by column chromatography (ethyl acetate/methanol 10:1+1% ammonia solution (25% aq.))

Sources & evidence

ORD record
ord-d2c55a0fbad74c79a941b6797d505c6a
Source dataset
uspto-grants-2013_01
Patent number
US08357717B2

Reaction notes

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