Trifluoroacetic acid → Diethyl (4-{[4-{[3-(methylsulfinyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate

HRID 511208Notes

Reaction equation

HRID 511208 reaction equation
Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.Cl.[CH3:14][S:15]([C:17]1[CH:18]=[C:19]([CH2:23][NH2:24])[CH:20]=[CH:21][CH:22]=1)=[O:16].C(N(C(C)C)CC)(C)C.ClC1N=C(NCC2C=CC=C(S(C)=O)C=2)C(C(F)(F)F)=CN=1.ClC1C(C(F)(F)F)=CN=C(NCC2C=CC=C(S(C)=O)C=2)N=1.[NH2:78][C:79]1[CH:93]=[CH:92][C:82]([CH2:83][P:84](=[O:91])([O:88][CH2:89][CH3:90])[O:85][CH2:86][CH3:87])=[CH:81][CH:80]=1.C(O)(C(F)(F)F)=O>C(OCC)(=O)C.CCCCCC>[CH3:14][S:15]([C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][NH:24][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:78][C:79]2[CH:80]=[CH:81][C:82]([CH2:83][P:84](=[O:91])([O:85][CH2:86][CH3:87])[O:88][CH2:89][CH3:90])=[CH:92][CH:93]=2)[N:7]=1)=[O:16]

Participants

10

Reactant 7

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 88358Diethyl p-aminobenzylphosphonateHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 668784001-[3-(Methylsulfinyl)phenyl]methanamine hydrochlorideHCID 866540012-chloro-N-[3-(methylsulfinyl)benzyl]-5-(trifluoromethyl)pyrimidin-4-amineHCID 873263524-chloro-N-[3-(methylsulfinyl)benzyl]-5-(trifluoromethyl)pyrimidin-2-amine

Product 1

HCID 49821673Diethyl (4-{[4-{[3-(methylsulfinyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate

Reagents, catalysts & solvents 2

HCID 8058HexaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

2,4-dichloro-5-(trifluoromethyl)pyrimidine XL was reacted with 1-[3-(methylsulfinyl)phenyl]methanamine hydrochloride (Bioorg. Med. Chem. Lett. 2005, 15, 4136-4142) and diisopropylethylamine at 0° C. overnight to afford a mixture of 2-chloro-N-[3-(methylsulfinyl)benzyl]-5-(trifluoromethyl)pyrimidin-4-amine and 4-chloro-N-[3-(methylsulfinyl)benzyl]-5-(trifluoromethyl)pyrimidin-2-amine XLVa/XLVb. A sample of the pure, desired 4-substituted isomer XLVa was isolated as the non-polar component mixture by chromatography over silica gel eluting with 1:3 hexane:ethyl acetate. Reaction of this latter isomer with anilines such as diethyl (4-aminobenzyl)phosphonate in the presence of TFA and TFE under microwave conditions yields the desired product (e.g. diethyl (4-{[4-{[3-(methylsulfinyl)benzyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate, Ex. 47).

Workup

  1. customto afford

Sources & evidence

ORD record
ord-b0a0f06a819c4c399c301ca7ef88e37f
Source dataset
uspto-grants-2015_08
Patent number
US09096624B2

Reaction notes

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