Water → Tucatinib

HRID 1753781Notes

Reaction equation

HRID 1753781 reaction equation
[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([NH:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=S)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>O1CCCC1>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]6[O:34][CH2:33][C:32]([CH3:36])([CH3:35])[N:31]=6)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:37])=[CH:6][C:5]=12

Participants

6

Reactant 4

HCID 962WaterHCID 73974-Toluenesulfonyl chlorideHCID 14798Sodium HydroxideHCID 86731560Tucatinib N-1

Product 1

HCID 51039094Tucatinib

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

The synthesis of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described in WO 2007/059257. Generally, N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine may be prepared by coupling (E)-N′-(2-cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido)phenyl)-N,N-dimethylformimidamide with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in isopropyl acetate:acetic acid (65:35 v/v) at 45° C. to yield 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea. The 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea may then be agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the addition of p-toluenesulfonyl chloride. Water may then be charged to yield N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine as a mixture of polymorphs (generally a mixture containing one or more of Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P). The final crystallizations or isolations will determine the polymorphic form, which are further detailed in the Examples section.

Sources & evidence

ORD record
ord-b90d836b69f24e67a2b77a8d3a093d54
Source dataset
uspto-grants-2015_10
Patent number
US09168254B2

Reaction notes

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