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

HRID 633432Notes

Reaction equation

HRID 633432 reaction equation
[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[C:4]([O:22][CH:23]([F:25])[F:24])[CH:3]=1.Cl.Cl[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:43][C@H:42]3[N:38]([CH2:39][CH2:40][CH2:41]3)[C:37]([CH3:45])([CH3:44])[CH2:36]2)[C:31]([F:46])=[CH:30][N:29]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[F:25][CH:23]([F:24])[O:22][C:4]1[CH:3]=[C:2]([NH:1][C:28]2[N:33]=[C:32]([NH:34][C@@H:35]3[CH2:43][C@H:42]4[N:38]([CH2:39][CH2:40][CH2:41]4)[C:37]([CH3:44])([CH3:45])[CH2:36]3)[C:31]([F:46])=[CH:30][N:29]=2)[CH:21]=[CH:20][C:5]=1[O:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1

Participants

5

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 86704489(7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochlorideHCID 86704526Tert-butyl 4-(4-amino-2-(difluoromethoxy)phenoxy)piperidine-1-carboxylate

Product 1

HCID 86704527N2-(3-(difluoromethoxy)-4-(piperidin-4-yloxy)phenyl)-N4-((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)-5-fluoropyrimidine-2,4-diamineYield 58.3%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

The general displacement procedure described herein was used with tert-butyl 4-(4-amino-2-(difluoromethoxy)phenoxy)piperidine-1-carboxylate (113 mg, 0.3 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (106 mg, 0.3 mmol) and pTsOH.H2O (42 mg, 0.2 mmol) in IPA (3 mL) at reflux to give the product (91 mg, 55% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 85:15) as eluent.

Workup

  1. temperatureat reflux

Sources & evidence

ORD record
ord-680337716c7d486e8b1d2efee691ae06
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

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