p-Toluenesulfonic acid → N4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)-5-fluoro-N2-(4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine

HRID 633414Notes

Reaction equation

HRID 633414 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[O:21]1[CH2:24][CH:23]([N:25]2[CH2:30][CH2:29][CH:28]([O:31][C:32]3[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=3[C:39]([F:42])([F:41])[F:40])[CH2:27][CH2:26]2)[CH2:22]1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C.CCOC(C)=O>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([O:31][CH:28]4[CH2:27][CH2:26][N:25]([CH:23]5[CH2:24][O:21][CH2:22]5)[CH2:30][CH2:29]4)=[C:33]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2

Participants

6

Reactant 3

HCID 6101p-Toluenesulfonic acidHCID 86704490(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amineHCID 867045084-((1-(Oxetan-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)aniline

Product 1

HCID 71811682N4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)-5-fluoro-N2-(4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)pyrimidine-2,4-diamineYield 70%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.25 g, 1.0 eq, 0.8 mmol), 4-((1-(oxetan-3-yl)piperidin-4-yl)oxy)-3-(trifluoromethyl)aniline (0.3 g, 1.2 eq, 1.0 mmol), PTSA (0.14 g, 0.9 eq, 0.8 mmol) was taken in iPrOH (20 mL) and heated at 100° C. overnight. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (50 mL) and partitioned with 1N aqueous NaOH solution (25 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (2×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to leave a crude solid. The solid was purified by column chromatography on silica gel (ISCO System) using 2M NH3 in MeOH/CH2Cl2 (gradient system from 0:1 to 2:8) as eluent to give the product in 70% yield.

Workup

  1. customThe volatiles were removed under vacuum
  2. customto leave a crude solid
  3. custompartitioned with 1N aqueous NaOH solution (25 mL)
  4. customOrganic layers were separated
  5. washthe aqueous layer was washed with EtOAc (2×20 mL)
  6. dry with materialThe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated under vacuum
  8. customto leave a crude solid
  9. customThe solid was purified by column chromatography on silica gel (ISCO System)
  10. customto give the product in 70% yield

Sources & evidence

ORD record
ord-0f5c1aee74ad4e48a85f0044dbf7280a
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

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