Water → Tamatinib

HRID 1051978Notes

Reaction equation

Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)[C:5]([F:22])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[NH2:28].O.[OH-].[Na+]>CN1CCCC1=O>[F:22][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:13][C:14]([CH3:21])([CH3:20])[C:15](=[O:19])[NH:16][C:17]=3[N:18]=2)=[N:7][C:2]([NH:28][C:27]2[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:25]([O:24][CH3:23])[CH:26]=2)=[N:3][CH:4]=1

Participants

Conditions

Temperature: 120 °C

Procedure

6-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (Step A) (568 kg, 1.00 mol eq) is mixed with 3,4,5-trimethoxyaniline (402 kg, 1.25 mol eq) in N-methylpyrrolidin-2-one (2835 kg) with stirring under a nitrogen atmosphere. To this is added water (11 kg) and the mixture heated to about 120° C. and stirred for about 10 hours. This is then cooled to about 65° C. and the pH adjusted to pH 8.5 with 4% w/w aqueous sodium hydroxide solution. The resulting slurry is further cooled to about 20° C., stirred for at least 6 hours and then filtered. The filtered solid is washed twice with water (2×1440 kg) then twice with acetone (2×1140 kg) and finally dried under vacuum at about 40° C. to give the title compound (754 kg, 91%) as a colored solid.

Workup

stirringstirred for about 10 hours
temperatureThis is then cooled to about 65° C.
temperatureThe resulting slurry is further cooled to about 20° C.
stirringstirred for at least 6 hours
filtrationfiltered
washThe filtered solid is washed twice with water (2×1440 kg)
dry with materialtwice with acetone (2×1140 kg) and finally dried under vacuum at about 40° C.

Sources & evidence

ORD record: ord-40f3772d079e4fab9a0ba19a088cf0d8
Source dataset: uspto-grants-2016_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09388203B2

Reaction notes

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