N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide → N-(3-fluoro-4-(2-(3-(4-(hydroxymethyl)piperidin-1-yl)-3-methylbut-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 1676309Notes

Reaction equation

HRID 1676309 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]1)([C:38]#[CH:39])[CH3:37]>>[F:1][C:2]1[CH:3]=[C:4]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:20]([C:22]2([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]2)=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:39]#[C:38][C:36]([N:40]3[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]3)([CH3:37])[CH3:35])[S:17][C:10]=12

Participants

3

Reactant 2

HCID 67347909N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideHCID 86614650(1-(2-Methylbut-3-yn-2-yl)piperidin-4-yl)methanol

Product 1

HCID 67345514N-(3-fluoro-4-(2-(3-(4-(hydroxymethyl)piperidin-1-yl)-3-methylbut-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 23%

Procedure

Prepared from N-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Example 12, Step A, 20 mg, 0.0338 mmol) and (1-(2-methylbut-3-yn-2-yl)piperidin-4-yl)methanol (12.3 mg, 0.0676 mmol) using the procedure described for Example 6, Step B. The crude was purified by preparative TLC (1 mm thickness, Rf=0.63) eluting with 20% MeOH/DCM. The compound required a second purification by preparative TLC (0.5 mm thickness, Rf=0.11), eluting with 15% MeOH in EtOAc, to obtain product of adequate purity. The product was obtained as a beige powder (5 mg, 23%). HPLC: 99% purity (254 nm); LCMS (APCI−): 100% purity, 220 nm, m/z 643 (M−1) detected; 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.49 (d, J=5 Hz, 1H), 8.23 (s, 1H), 7.78 (m, 1H), 7.56 (s, 1H), 7.45 (m, 2H), 7.27 (m, 2H), 7.07 (t, J=9 Hz, 2H), 6.53 (d, J=5 Hz, 1H), 3.53 (d, J=6 Hz, 2H), 3.22 (br s, 2H), 2.31 (br s, 2H), 1.82 (m, 4H), 1.62 (m, 10H), 1.36 (m, 2H).

Workup

  1. customThe crude was purified by preparative TLC (1 mm thickness, Rf=0.63)
  2. washeluting with 20% MeOH/DCM
  3. customa second purification by preparative TLC (0.5 mm thickness, Rf=0.11)
  4. washeluting with 15% MeOH in EtOAc
  5. customto obtain product of adequate purity

Sources & evidence

ORD record
ord-56951795818047c7b361657ca2eadce4
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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