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Binap, (A+-)- → [3-(4-Benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetic acid ethyl ester

HRID 1767694
Notes
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Reaction equation

HRID 1767694 reaction equation
[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8](Cl)[N:7]=1)[CH3:2].[CH2:18]([N:25]1[CH2:32][CH2:31][NH:30][CH2:29][C:26]21[CH2:28][CH2:27]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([N:30]2[CH2:29][C:26]3([CH2:28][CH2:27]3)[N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:32][CH2:31]2)[N:7]=1)[CH3:2]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 634876Binap, (A+-)-HCID 11379685Ethyl 2-(3-chloroisoquinolin-1-yl)acetateHCID 113900664-Benzyl-4,7-diazaspiro[2.5]octaneHCID 23676156Sodium t-butoxide

Product 1

HCID 11327484[3-(4-Benzyl-4,7-diaza-spiro[2.5]oct-7-yl)-isoquinolin-1-yl]-acetic acid ethyl ester

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
85 °C

Procedure

(3-Chloro-isoquinolin-1-yl)-acetic acid ethyl ester (2.50 g, 10.01 mmol), 4-benzyl-4,7-diaza-spiro [2.5]octane (2.23 g, 11.01 mmol), NaOtBu (1.06 g, 11.01 mmol), BINAP (249 mg, 0.40 mmol) and Palladium(II)-acetate (180 mg, 0.80 mmol) are mixed under argon. After addition of degassed, dry dioxane (36 ml), the suspension is heated to 85° C. After 25 minutes at 85° C., HPLC analysis indicates a conversion of 71%. The mixture is cooled to RT, diluted with EtOAc, and washed with H2O and sat. aq. NH4Cl (back extracted). The combined organic layers are dried over Na2SO4, the solvent is removed and the residue purified by FCC (hexane/EtOAc 100:0 to 96:4 to 93:7 to 90:10 to 85:15) to afford the title compound. 1H NMR (DMSO, 400 MHz) δ 0.58 -0.61 (m, 2H), 0.70 -0.73 (m, 2H), 1.18 (t, J=8.8, 3H), 2.98 (t, J =5.5, 2H), 3.39 (s, 2H), 3.49 (t, J=5.5, 2H), 3.86 (s, 2H), 4.12 (s, 2H), 4.12 (q, J=8.8, 2H), 5.59 (s, 1H), 7.14 -7.19 (m, 6H), 7.39 (t, J=8.8, 1H), 7.51 (d, J=9.9, 1H), 7.78 (d, J=9.9, 1H); ES-MS: 417 [M+H]+.

Workup

  1. additionAfter addition
  2. customof degassed
  3. temperatureThe mixture is cooled to RT
  4. additiondiluted with EtOAc
  5. washwashed with H2O and sat. aq. NH4Cl (back extracted)
  6. dry with materialThe combined organic layers are dried over Na2SO4
  7. customthe solvent is removed
  8. customthe residue purified by FCC (hexane/EtOAc 100:0 to 96:4 to 93:7 to 90:10 to 85:15)

Sources & evidence

ORD record
ord-0cc93b0fbe184b91bf758bc8b3cc7289
Source dataset
uspto-grants-2007_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07235555B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes