Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → N-(3-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-1H-indazol-4-amine

HRID 1621428Notes

Reaction equation

HRID 1621428 reaction equation
[CH3:1][C:2]1[N:7]=[C:6]2[N:8](C3CCCCO3)[N:9]=[CH:10][C:5]2=[C:4]([C:17]2[C:18]([NH:23][C:24]3[C:25]4[C:29]([CH:30]=[CH:31][CH:32]=3)=[N:28][N:27](C3CCCCO3)[CH:26]=4)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl.CO>[CH3:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([C:17]2[C:18]([NH:23][C:24]3[C:25]4[CH:26]=[N:27][NH:28][C:29]=4[CH:30]=[CH:31][CH:32]=3)=[N:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1

Participants

5

Reactant 2

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-2×HCID 66611204HCID 66611204, compound

Product 1

HCID 49785829N-(3-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-1H-indazol-4-amineYield 92.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of N-(3-(6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (56.9 mg, 111 μmol) in DCM (1 mL) and MeOH (2 mL) was treated with (+/−)-10-camphorsulfonic acid (57 mg, 2.2 equiv.) and stirred for 16 h. LCMS indicated clean monodeprotection with only a small amount of the fully deprotected compound. Additional (+/−)-10-camphorsulfonic acid (57 mg, 2.2 equiv.) was added and the solution stirred at 60° C. for 1 h after which time reaction was complete. The mixture was concentrated and purified by SCX ion exchange chromatography washing with MeOH and eluting off with 2N NH3/MeOH to give N-(3-(6-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-1H-indazol-4-amine (35 mg, 87% yield) as a brown solid. 1H NMR of free base thus obtained gives broad signals, so a small amount was converted to the HCl salt for better 1H NMR analysis by dissolving in MeOH containing 2 drops 2 M aqueous HCl followed by concentration to dryness. HCl salt: 1H NMR (400 MHz, d6-DMSO) δ 14.18 (br. s., 1H); 11.38 (s, 1H); 10.43 (s, 1H); 9.76 (s, 1H); 9.42 (d, 1H); 9.04 (s, 1H); 8.64 (d, 1H); 8.46 (s, 1H); 7.85-7.98 (m, 2H); 7.69 (d, J=9.54 Hz, 1H); 2.14 (s, 3H). m/z (ESI, +ve) 343.0 (M+H)+.

Workup

  1. stirringthe solution stirred at 60° C. for 1 h
  2. customafter which time reaction
  3. concentrationThe mixture was concentrated
  4. custompurified by SCX ion exchange chromatography
  5. washwashing with MeOH
  6. washeluting off with 2N NH3/MeOH

Sources & evidence

ORD record
ord-63911f3c407143c8a7db99c850b58a22
Source dataset
uspto-grants-2014_07
Patent number
US08772480B2

Reaction notes

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