Cyclopentylamine → N4-Cyclopentyl-6-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-1H-indazole-3,4-diamine

HRID 2367570Notes

Reaction equation

HRID 2367570 reaction equation
[CH2:1]([C@@H:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([C:17]2[CH:24]=[C:23](F)[C:20]([C:21]#[N:22])=[C:19](F)[CH:18]=2)[CH:10]=1)[CH3:2].[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1.[NH2:33][NH2:34].CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O.CN(C=O)C>[CH:27]1([NH:32][C:23]2[C:20]3[C:21]([NH2:22])=[N:33][NH:34][C:19]=3[CH:18]=[C:17]([C:11]3[CH:10]=[C:9]([N:4]4[CH2:5][CH2:6][O:7][CH2:8][C@H:3]4[CH2:1][CH3:2])[N:14]=[C:13]([NH:15][CH3:16])[N:12]=3)[CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1

Participants

8

Reactant 4

HCID 2906CyclopentylamineHCID 9321HydrazineHCID 81531DiisopropylethylamineHCID 585044754-[6-[(3R)-3-Ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile

Product 1

HCID 58504752N4-Cyclopentyl-6-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-1H-indazole-3,4-diamineYield 19%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a 4 mL vial was added 4-[6-[(3R)-3-ethyl-4-morpholinyl]-2-(methylamino)-4-pyrimidinyl]-2,6-difluorobenzonitrile (100 mg, 0.278 mmol), DMF (1 mL), and cyclopentyl amine (23.7 mg, 0.28 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was poured into EtOAc (10 mL) and the aqueous was extracted with EtOAc (2×). The organics were then dried over Na2SO4 and concentrated to afford a yellow oil that was taken up in CH3CN (1.5 mL) and added to a 5 mL microwave vial followed by the addition of hydrazine (0.035 mL, 1.113 mmol) and Hunig's base (0.39 mL, 2.23 mmol). The reaction was irradiated at 150° C. for 90 minutes. The reaction mixture was then concentrated and purified via reverse phase HPLC (20-40% CH3CN/H2O, 0.1% TFA). Fractions were combined and diluted with EtOAc. The organics were washed with saturated NaHCO3 solution that was back extracted with EtOAc. The organics were combined and dried over Na2SO4. The product was taken up in 2 mL H2O and lyophilized to afford the title compound (23 mg). LC-MS (ES) m/z=437 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.89 (s, 3H), 1.53-1.82 (m, 8H), 2.00-2.09 (m, 2H), 2.79-2.85 (m, 3H), 3.03-3.13 (m, 1H), 3.39-3.48 (m, 1H), 3.49-3.55 (m, 1H), 3.82-3.86 (m, 1H), 3.87-3.92 (m, 1H), 4.11-4.19 (m, 1H), 4.20-4.28 (m, 1H), 5.03 (s, 2H), 5.32-5.37 (m, 1H), 6.35 (bs, 1H), 6.46 (bs, 1H), 6.55 (bs, 1H), 7.11 (bs, 1H), 11.38 (bs, 1H).

Workup

  1. extractionthe aqueous was extracted with EtOAc (2×)
  2. dry with materialThe organics were then dried over Na2SO4
  3. concentrationconcentrated
  4. customto afford a yellow oil that
  5. additionadded to a 5 mL microwave vial
  6. customThe reaction was irradiated at 150° C. for 90 minutes
  7. concentrationThe reaction mixture was then concentrated
  8. custompurified via reverse phase HPLC (20-40% CH3CN/H2O, 0.1% TFA)
  9. additiondiluted with EtOAc
  10. washThe organics were washed with saturated NaHCO3 solution that
  11. extractionwas back extracted with EtOAc
  12. dry with materialdried over Na2SO4

Sources & evidence

ORD record
ord-e5b31d460f944be68cb2956bf49016a7
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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