p-Toluenesulfonic acid monohydrate → 1-(5-((4-(((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)amino)-5-fluoropyrimidin-2-yl)amino)-2-(2-hydroxyethoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one

HRID 633442Notes

Reaction equation

HRID 633442 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=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>[CH3:44][C:37]1([CH3:45])[CH2:36][C@H:35]([NH:34][C:32]2[C:31]([F:46])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:15][CH2:16][CH2:17][OH:18])=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[CH:7]=3)[N:33]=2)[CH2:43][C@H:42]2[N:38]1[CH2:39][CH2:40][CH2:41]2

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 867045341-(5-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one

Product 1

HCID 718113161-(5-((4-(((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)amino)-5-fluoropyrimidin-2-yl)amino)-2-(2-hydroxyethoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-oneYield 21%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

The general displacement procedure was described herein was used with 1-(5-amino-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (382 mg, 1.1 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (350 mg, 1.1 mmol) and pTsOH.H2O (398 mg, 2.1 mmol) in IPA (10 mL) at reflux to give the product (113 mg, 21% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 95:5) as eluent.

Workup

  1. temperatureat reflux

Sources & evidence

ORD record
ord-bd0ca7208b4146e39a62bb83fb9ec5d0
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

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