2-Methyl-3-butyn-2-ol → 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide

HRID 2181448Notes

Reaction equation

HRID 2181448 reaction equation
[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>CCOCC.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:19][C:18]=2[F:24])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]

Participants

5

Reactant 2

HCID 82582-Methyl-3-butyn-2-olHCID 98038913,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)benzamide

Product 1

HCID 102876513,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamideYield 97%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 3283Diethyl EtherSolvent

Procedure

3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)benzamide, which can be prepared according to the procedure in PCT Publication No. WO 00/41505, and 2-methyl-3-butyn-2-ol were reacted in the presence of CuI and (PhP3)2C]2 by the general procedure of Example 1, Step A, and the mixture stirred at RT for 4 h. The reaction mixture was diluted with 50% Et2O/McOH and filtered through Celite®. The filtrate was concentrated under reduced pressure and further purified by flash chromatography on silica (CH2Cl2—10% MeOH/CH2Cl2 gradient elution) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide (97%) as a cream solid; m.p. (CH2Cl2/Hexane) 139-142° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.80 (br s, 1 H), 8.78 (br s, 1 H), 7.46-7.40 (m, 1 H), 7.28-7.19 (m, 2 H), 7.07 (dd, J=8.4, 1.5 Hz, 1 H), 6.79 (ddd, J=8.7, 8.7, 4.7 Hz, 1 H), 5.43 (br s, 1 H), 4.70 (br s, 1 H), 3.86 (t, J=4.7 Hz, 2 H), 3.57 (t, J=4.7 Hz, 2 H), 1.45 (s, 6 H). Anal. Calcd for C20H19F3N2O4: C, 58.8; H, 4.7; N, 6.9. Found C, 58.5; H, 4.8; N, 6.7.

Workup

  1. filtrationfiltered through Celite®
  2. concentrationThe filtrate was concentrated under reduced pressure
  3. customfurther purified by flash chromatography on silica (CH2Cl2—10% MeOH/CH2Cl2 gradient elution)

Sources & evidence

ORD record
ord-1a75abd35c6c4bd9959ecc2e545d8f11
Source dataset
uspto-grants-2005_05
Patent number
US06891066B2

Reaction notes

Loading…