p-Toluenesulfonic acid → 1-(5-((4-(((7R,8aS)-5,5-dimethyloctahydroindolizin-7-yl)amino)-5-fluoropyrimidin-2-yl)amino)-2-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one

HRID 633408Notes

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:23]=[CH:24][C:25]([N:35]2[CH2:40][CH2:39][N:38]([CH:41]3[CH2:44][O:43][CH2:42]3)[CH2:37][CH2:36]2)=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]2)[CH:27]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[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:23]=[CH:24][C:25]([N:35]4[CH2:40][CH2:39][N:38]([CH:41]5[CH2:44][O:43][CH2:42]5)[CH2:37][CH2:36]4)=[C:26]([N:28]4[C:32](=[O:33])[N:31]([CH3:34])[N:30]=[N:29]4)[CH:27]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2

Participants

Conditions

Temperature: 120 °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, 0.7 mmol), 1-(5-amino-2-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-4-methyl-1,4-dihydro-5H-tetrazol-5-one (0.3 g, 1.4 eq, 0.9 mmol), PTSA (0.4 g, 2.0 eq, 1.9 mmol) was taken in iPrOH (50 mL) and heated at 120° C. overnight. The volatiles were removed 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 55% yield.

Workup

customThe volatiles were removed under vacuum
customto leave a crude solid
customThe solid was purified by column chromatography on silica gel (ISCO System)

Sources & evidence

ORD record: ord-ad3189b218d24884a61e07ec631678dc
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09321763B2

Reaction notes

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