Tucatinib → Tucatinib N-1

HRID 1753780Notes

Reaction equation

HRID 1753780 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]6[O:30][CH2:31][C:32]([CH3:35])([CH3:34])[N:33]=6)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:36])=[CH:6][C:5]=12.C(C1C=C(NC(NC(C)(C)CO)=[S:47])C=CC=1/N=C/N(C)C)#N.N1C=NN2C=CC(OC3C=CC(N)=CC=3C)=CC=12>C(OC(C)C)(=O)C.C(O)(=O)C>[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:33][C:32]([CH3:35])([CH3:34])[CH2:31][OH:30])=[S:47])[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:36])=[CH:6][C:5]=12

Participants

5

Reactant 3

HCID 51039094Tucatinib2×HCID 669370134-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylanilineHCID 178484246HCID 178484246, compound

Product 1

HCID 86731560Tucatinib N-1

Reagents, catalysts & solvents 1

HCID 86731561HCID 86731561, compoundSolvent

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.

Workup

  1. customat 45° C.

Sources & evidence

ORD record
ord-52b5ac2cb92c40bfb83b4c56526a6309
Source dataset
uspto-grants-2015_10
Patent number
US09168254B2

Reaction notes

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