tert-Butyl 1-oxa-6-azaspiro(2.5)octane-6-carboxylate → tert-butyl 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-hydroxy-1-piperidinecarboxylate

HRID 897643Notes

Reaction equation

HRID 897643 reaction equation
[NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[O:28]1[C:30]2([CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH2:29]1>C(O)(C)C>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH2:29][C:30]4([OH:28])[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12

Participants

4

Reactant 2

HCID 22135564tert-Butyl 1-oxa-6-azaspiro(2.5)octane-6-carboxylate3×HCID 223471371-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Product 1

HCID 22346913tert-butyl 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-hydroxy-1-piperidinecarboxylateYield 38.6%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

To a mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.4 g, 0.0011 mol) in isopropanol (40 mL) was added tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.27 g, 0.0013 mol) at room temperature under an atmosphere of nitrogen. The mixture was stirred at 80° C. for three and a half hours. Additional tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.13 g, 0.00061 mol) was added and the mixture was stirred at 80° C. for seven hours. Furthermore, tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.13 g, 0.00061 mol) was added and the mixture was stirred at 60° C. for 18 hours, then 80° C. for eight hours. The solvent was removed under reduced pressure. The residue was suspended in water (50 mL) and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (1×50 mL) and brine (1×50 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (5:95) followed by methanol/dichloromethane (10:90) as mobile phase to yield tert-butyl 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-hydroxy-1-piperidinecarboxylate (0.243 g, 0.000425 mol).

Workup

  1. stirringthe mixture was stirred at 80° C. for seven hours
  2. stirringthe mixture was stirred at 60° C. for 18 hours
  3. customThe solvent was removed under reduced pressure
  4. extractionthe aqueous phase was extracted with ethyl acetate (2×50 mL)
  5. washThe combined organic extracts were washed with water (1×50 mL) and brine (1×50 mL)
  6. dry with materialdried over magnesium sulfate
  7. customThe solvent was removed under reduced pressure
  8. customThe residue was purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-7c0c3f6b5a8645c090ce4ba4cdd4271f
Source dataset
uspto-grants-2005_07
Patent number
US06921763B2

Reaction notes

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