Sodium Carbonate → tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate

HRID 2207480Notes

Reaction equation

HRID 2207480 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10](I)[C:3]=12.OC[C@H]1CCCN1C(OC(C)(C)C)=O.[F:39][C:40]1[CH:41]=[C:42]([CH:59]=[CH:60][CH:61]=1)[O:43][C:44]1[CH:49]=[CH:48][C:47](B2OC(C)(C)C(C)(C)O2)=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.COCCOC>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[N:9]=[C:10]([C:47]3[CH:46]=[CH:45][C:44]([O:43][C:42]4[CH:59]=[CH:60][CH:61]=[C:40]([F:39])[CH:41]=4)=[CH:49][CH:48]=3)[C:3]=12

Participants

8

Reactant 4

HCID 10340Sodium CarbonateHCID 688279N-(tert-Butoxycarbonyl)-D-prolinolHCID 710152102-(4-(3-Fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneHCID 86714463tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate

Product 1

HCID 86714462tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylateYield 79%

Reagents, catalysts & solvents 3

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

Into a 100-mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (300 mg, 0.68 mmol, 1.00 equiv), prepared as described in Example 1 except in the Mitsunobu reaction using (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate instead of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate, 2-[4-(3-fluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (254 mg, 0.81 mmol, 1.20 equiv), tetrakis(triphenylphosphane) palladium (47 mg, 0.04 mmol, 0.06 equiv), ethylene glycol dimethyl ether (50 mL), sodium carbonate (180 mg, 1.70 mmol, 2.50 equiv), water (10 mL). The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with dichloromethane and the organic layers combined, dried and concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane/methanol (50/1) to give 0.27 g (79%) of tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a brown solid.

Workup

  1. customInto a 100-mL 3-necked round-bottom flask purged
  2. temperaturemaintained under an inert atmosphere of nitrogen
  3. customprepared
  4. customas described in Example 1 except in the Mitsunobu reaction
  5. concentrationThe resulting mixture was concentrated under vacuum
  6. extractionThe resulting solution was extracted with dichloromethane
  7. customdried
  8. concentrationconcentrated under vacuum
  9. washeluted with dichloromethane/methanol (50/1)

Sources & evidence

ORD record
ord-01b1d7fa6fc9467c9ec57f150705ea98
Source dataset
uspto-grants-2016_06
Patent number
US09376438B2

Reaction notes

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