p-Toluenesulfonic acid monohydrate → 2-(2-(5-cyclopropyl-1H-tetrazol-1-yl)-4-((4-(((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)ethan-1-ol

HRID 633437Notes

Reaction equation

HRID 633437 reaction equation
[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([N:12]2[C:16]([CH:17]3[CH2:19][CH2:18]3)=[N:15][N:14]=[N:13]2)[CH:3]=1.Cl.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:37][C@H:36]3[N:32]([CH2:33][CH2:34][CH2:35]3)[C:31]([CH3:39])([CH3:38])[CH2:30]2)[C:25]([F:40])=[CH:24][N:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[CH:17]1([C:16]2[N:12]([C:4]3[CH:3]=[C:2]([NH:1][C:22]4[N:27]=[C:26]([NH:28][C@@H:29]5[CH2:37][C@H:36]6[N:32]([CH2:33][CH2:34][CH2:35]6)[C:31]([CH3:38])([CH3:39])[CH2:30]5)[C:25]([F:40])=[CH:24][N:23]=4)[CH:11]=[CH:10][C:5]=3[O:6][CH2:7][CH2:8][OH:9])[N:13]=[N:14][N:15]=2)[CH2:19][CH2:18]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 867045302-(4-amino-2-(5-cyclopropyl-1H-tetrazol-1-yl)phenoxy)ethan-1-ol

Product 1

HCID 718113192-(2-(5-cyclopropyl-1H-tetrazol-1-yl)-4-((4-(((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)ethan-1-olYield 66%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

Similarly, 2-(4-amino-2-(5-cyclopropyl-1H-tetrazol-1-yl)phenoxy)ethan-1-ol (67 mg, 0.26 mmol) was used in a similar displacement reaction using (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (95 mg, 0.28 mmol) and pTsOH.H2O (98 mg, 0.51 mmol) in IPA (5 mL) at reflux to give the product (88 mg, 66% yield) after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 9:1).

Workup

  1. temperatureat reflux

Sources & evidence

ORD record
ord-10628d4edbcb4dc3863687c7ebccc3a0
Source dataset
uspto-grants-2016_04
Patent number
US09321763B2

Reaction notes

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