Nitrogen → HCID 178421849, compound

HRID 1621372Notes

Reaction equation

HRID 1621372 reaction equation
O1CCCCC1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH:16][C:17]2[C:22]([C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4C3CCCCO3)=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:8]1.[C:38]12([CH2:48][S:49]([OH:52])(=[O:51])=[O:50])[C:45]([CH3:47])([CH3:46])[CH:42]([CH2:43][CH2:44]1)[CH2:41][C:39]2=[O:40].N#N>C(Cl)Cl.CO>[C:38]12([CH2:48][S:49]([OH:52])(=[O:50])=[O:51])[C:45]([CH3:47])([CH3:46])[CH:42]([CH2:43][CH2:44]1)[CH2:41][C:39]2=[O:40].[N:31]1[C:23]([C:22]2[C:17]([NH:16][C:13]3[C:14]4[CH:15]=[N:7][NH:8][C:9]=4[CH:10]=[CH:11][CH:12]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:24]2[C:28]([NH:27][CH:26]=[N:25]2)=[N:29][CH:30]=1

Participants

5

Reactant 3

HCID 947NitrogenHCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-3×HCID 60154997HCID 60154997, compound

Product 1

HCID 178421849HCID 178421849, compoundYield 174.5%

Reagents, catalysts & solvents 1

HCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
40 °C

Procedure

A solution of 2-(tetrahydro-2H-pyran-2-yl)-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-2H-indazol-4-amine (34.8 mg, 70 μmol) in DCM/MeOH (4 mL; 1:1) was treated with (+/−)-10-camphorsulfonic acid (8 mg, 0.5 equiv.) and the mixture stirred for 16 h. About 50% monodeprotection was observed in a clean reaction. An additional 20 mg of CSA was added (1.7 equiv. total). After 1 h, virtually complete monodeprotection observed and about 10% dideprotection. After 3 h, about 27% conversion to fully deprotected compound was observed in a clean reaction by LCMS. An additional 8 mg CSA was added (2.2 equiv. total) and the temperature of the reaction mixture was increased to 40° C. After a further 3 h, deprotection was essentially complete by LCMS. The volume of the reaction mixture was reduced by about 50% under a stream of N2 in order to remove DCM, and the solution was triturated with Et2O resulting in the formation of a precipitate which was collected by filtration washing with Et2O and dried under vacuum to give N-(3-(9H-purin-6-yl)pyridin-2-yl)-1H-indazol-4-amine (+/−)-10-camphorsulfonate salt (33.7 mg, 86% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (br. s., 1H); 9.89 (d, 1H); 9.33 (s, 1H); 8.76 (s, 1H); 8.41-8.46 (m, 1H); 8.31 (s, 1H); 8.24 (d, 1H); 7.35 (t, 1H); 7.21 (d, 1H); 7.14 (t, 1H); 2.88 (d, 1H); 2.63-2.73 (m, 1H); 2.34-2.42 (d, 1H); 2.18-2.29 (m, 1H); 1.90-1.97 (m, 1H); 1.74-1.90 (m, 2H); 1.27 (m, 2H); 1.05 (s, 3H); 0.75 (s, 3H). m/z (ESI, +ve) 329.0 (M+H)+.

Workup

  1. customAbout 50% monodeprotection was observed in a clean reaction
  2. waitAfter 1 h
  3. waitAfter 3 h
  4. customabout 27% conversion to fully deprotected compound was observed in a clean reaction by LCMS
  5. waitAfter a further 3 h
  6. customto remove DCM
  7. customthe solution was triturated with Et2O resulting in the formation of a precipitate which
  8. filtrationwas collected by filtration
  9. washwashing with Et2O
  10. customdried under vacuum

Sources & evidence

ORD record
ord-8210bc4975d842d0a044b13959dbba31
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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