Hydrochloric Acid → N2-(3-chloro-4-(((3S,4S)-3-fluoropiperidin-4-yl)oxy)phenyl)-N4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)-5-fluoropyrimidine-2,4-diamine

HRID 633423Notes

Reaction equation

HRID 633423 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:42]=[CH:41][C:25]([O:26][C@H:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][C@@H:28]2[F:40])=[C:24]([Cl:43])[CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.Cl>CC(O)C.O1CCOCC1>[Cl:43][C:24]1[CH:23]=[C:22]([NH:21][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]3[CH2:17][C@H:16]4[N:12]([CH2:13][CH2:14][CH2:15]4)[C:11]([CH3:19])([CH3:18])[CH2:10]3)[C:5]([F:20])=[CH:4][N:3]=2)[CH:42]=[CH:41][C:25]=1[O:26][C@H:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[F:40]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 6101p-Toluenesulfonic acid2×HCID 86704490(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amineHCID 86704517tert-butyl (3S,4S)-4-(4-amino-2-chlorophenoxy)-3-fluoropiperidine-1-carboxylate

Product 1

HCID 86704518N2-(3-chloro-4-(((3S,4S)-3-fluoropiperidin-4-yl)oxy)phenyl)-N4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)-5-fluoropyrimidine-2,4-diamineYield 50%

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.2 g, 1.0 eq, 0.6 mmol), tert-butyl (3S,4S)-4-(4-amino-2-chlorophenoxy)-3-fluoropiperidine-1-carboxylate (0.2 g, 1.0 eq, 0.64 mmol) and PTSA (0.1 g, 0.9 eq, 0.6 mmol) was taken in iPrOH (10 mL) and heated at 100° C. for over night. 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. Then the reaction mixture was heated at 100° C. for 3 hours while stifling and cooled to room temperature. The volatiles were removed under vacuum to leave a crude solid. 4N HCl in dioxane (5 mL) was added to the crude mixture to ensure complete dprotection of the Boc group and the mixture was concentrated to dryness. Work-up and purification conditions used were the same as in Example 89 above for Compound 119, and gave the product as a solid in 50% yield.

Workup

  1. temperatureAfter 18 hours of heating
  2. customreaction mixture
  3. temperaturewas cooled to room temperature
  4. temperatureThen the reaction mixture was heated at 100° C. for 3 hours while stifling and
  5. temperaturecooled to room temperature
  6. customThe volatiles were removed under vacuum
  7. customto leave a crude solid
  8. concentrationthe mixture was concentrated to dryness
  9. custompurification conditions

Sources & evidence

ORD record
ord-4b257267e2964b55891167106575c4b2
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

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