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

HRID 633411Notes

Reaction equation

HRID 633411 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.[NH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[C:24]([C:42]([F:45])([F:44])[F:43])[CH:23]=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:21][C:22]3[CH:41]=[CH:40][C:25]([O:26][CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[C:24]([C:42]([F:45])([F:43])[F:44])[CH:23]=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 acid2×HCID 22180984Tert-butyl 4-(4-amino-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylateHCID 86704490(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine

Product 1

HCID 86704506N4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)-5-fluoro-N2-(4-(piperidin-4-yloxy)-3-(trifluoromethyl)phenyl)pyrimidine-2,4-diamineYield 36%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.2 g, 0.95 eq, 0.7 mmol), tert-butyl 4-(4-amino-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (0.25 g, 1.0 eq, 0.7 mmol) and PTSA (0.24 g, 1.8 eq, 1.3 mmol) was taken in iPrOH (50 mL) and heated at 110° C. overnight. After 18 hours of heating, reaction mixture was cooled to room temperature and PTSA (1.0 eq) was added to complete the deprotection of the Boc group. Next, the reaction mixture was heated at 110° C. for 2 hours while stifling and cooled to room temperature. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (100 mL) and partitioned with 1N aqueous NaOH solution (50 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (50 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 as a solid in 36% yield.

Workup

  1. temperatureAfter 18 hours of heating
  2. customreaction mixture
  3. temperaturewas cooled to room temperature
  4. temperatureNext, the reaction mixture was heated at 110° C. for 2 hours while stifling and
  5. temperaturecooled to room temperature
  6. customThe volatiles were removed under vacuum
  7. customto leave a crude solid
  8. custompartitioned with 1N aqueous NaOH solution (50 mL)
  9. customOrganic layers were separated
  10. washthe aqueous layer was washed with EtOAc (50 mL)
  11. dry with materialThe combined organic layers were dried over Na2SO4
  12. concentrationconcentrated under vacuum
  13. customto leave a crude solid
  14. customThe solid was purified by column chromatography on silica gel (ISCO System)

Sources & evidence

ORD record
ord-d1e2d8cdcee040008320493e5db94395
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

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