p-Toluenesulfonic acid monohydrate → Ammonia methanol

HRID 710223Notes

Reaction equation

Cl.Cl[C:3]1[N:8]=[C:7]([NH:9][CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:18])[C:12]([CH3:20])([CH3:19])[CH2:11]2)[C:6]([F:21])=[CH:5][N:4]=1.[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH2:36])=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1.[OH2:38].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[NH3:4].[CH3:3][OH:38].[CH:22]1([C:25]2[C:30]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][C:28]([NH:36][C:3]3[N:8]=[C:7]([NH:9][CH:10]4[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:18])[C:12]([CH3:20])([CH3:19])[CH2:11]4)[C:6]([F:21])=[CH:5][N:4]=3)=[C:27]([F:37])[CH:26]=2)[CH2:24][CH2:23]1

Participants

Conditions

Temperature: 100 °C

Procedure

A mixture of 2-chloro-5-fluoro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidin-4-amine hydrochloride (0.196 g, 0.58 mmol, 1 equiv), 4-cyclopropyl-2-fluoro-5-(1H-tetrazol-1-yl)benzenamine (0.140 g, 0.64 mmol, 1.1 equiv), and para-toluenesulfonic acid monohydrate (0.090 g, 0.47 mmol, 0.8 equiv) in IPA (15 mL) were heated to 100° C. overnight. After cooling to ambient temperature, the crude mixture was quenched with 2M NH3/MeOH followed by concentrating to dryness and repeating once. The crude product was purified by flash chromatography and eluted with DCM:2M NH3/MeOH (100:0 to 95:5 using 1% 2M NH3/MeOH increments) to provide the desired product which was titurated with DCM/Hexane to give the title compound (0.100 g, in 36% yield) as a solid.

Workup

temperatureAfter cooling to ambient temperature
customthe crude mixture was quenched with 2M NH3/MeOH
concentrationby concentrating to dryness
customThe crude product was purified by flash chromatography
washeluted with DCM

Sources & evidence

ORD record: ord-d2b8e5e4a02f49bfae8a79b2548b4b91
Source dataset: uspto-grants-2015_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09181222B2

Reaction notes

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