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

HRID 2181449Notes

Reaction equation

HRID 2181449 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:31])([CH2:29][CH3:30])[C:27]#[CH:28]>CCOCC.CO.[Cu]I>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:28]#[C:27][C:26]([OH:31])([CH3:25])[CH2:29][CH3:30])=[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 64943-Methyl-1-pentyn-3-olHCID 98038913,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)benzamide

Product 1

HCID 101270833,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-pentynyl)anilino]-N-(2-hydroxyethoxy)benzamideYield 77%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 21864698Diethyl ether methanolSolvent

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 3-methyl-1-pentyn-3-ol were reacted in the presence of CuI and (PhP3)2PdCl2 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/MeOH 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-pentynyl)anilino]-N-(2-hydroxyethoxy)benzamide (77%) as a white solid; m.p. (CH2Cl2/Hexane) 127-131° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.79 (br s, 1 H), 8.79 (br s, 1 H), 7.45-7.39 (m, 1 H), 7.28-7.18 (m, 2 H), 7.07 (dd, J=8.4, 1.5 Hz, 1 H), 6.79 (ddd, J=8.7, 8.7, 4.6 Hz, 1 H), 5.31 (br s, 1 H), 4.71 (br s, 1 H), 3.86 (t, J=4.7 Hz, 2 H), 3.57 (t, J=4.7 Hz, 2 H), 1.68-1.57 (m, 2 H), 1.40 (s, 3 H), 0.98 (t, J=7.4 Hz, 3 H). Anal. Calcd for C21H21F3N2O4: C, 59.7; H, 5.0; N, 6.6. Found C, 59.9; H, 5.1; N, 6.9.

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-b2d0a1538b6f42a081080918bb461a98
Source dataset
uspto-grants-2005_05
Patent number
US06891066B2

Reaction notes

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