1-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl chloride → Methyl 2-(3-(tert-butoxycarbonyl)phenyl)-6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)nicotinate

HRID 2420929Notes

Reaction equation

HRID 2420929 reaction equation
[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=2)[N:3]=1.[F:25][C:26]1([F:41])[O:30][C:29]2[CH:31]=[CH:32][C:33]([C:35]3([C:38](Cl)=[O:39])[CH2:37][CH2:36]3)=[CH:34][C:28]=2[O:27]1>N1C=CC=CC=1.C(Cl)Cl>[C:21]([O:20][C:18]([C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:1][C:38]([C:35]3([C:33]4[CH:32]=[CH:31][C:29]5[O:30][C:26]([F:41])([F:25])[O:27][C:28]=5[CH:34]=4)[CH2:37][CH2:36]3)=[O:39])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[CH:17]=[CH:16][CH:15]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]

Participants

5

Reactant 2

HCID 575168501-(2,2-Difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl chloride2×HCID 59166112Methyl 6-amino-2-(3-(tert-butoxycarbonyl)phenyl)nicotinate

Product 1

HCID 59166109Methyl 2-(3-(tert-butoxycarbonyl)phenyl)-6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)nicotinateYield 67.9%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of methyl 6-amino-2-(3-(tert-butoxycarbonyl)phenyl)nicotinate (400 mg, 1.2 mmol) and 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (630 mg, 2.4 mmol) in pyridine (12 mL) was stirred at room temperature for 3 days and then at 90° C. for 7 hours. Additional 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (320 mg, 1.2 mmol) was added and the reaction was heated at 90° C. for 12 hours until the amine was completely consumed. The reaction mixture was concentrated and the residue was purified by column chromatography (0-40% ethyl acetate—hexanes). The material obtained was dissolved in CH2Cl2 and was washed with 1N HCl (×3) and saturated aq. NaHCO3 (×3), dried (MgSO4) and concentrated to yield methyl 2-(3-(tert-butoxycarbonyl)phenyl)-6-(1-(2,2-difluorobenzo [d][1,3]dioxol-5-yl)cyclopropanecarboxamido)nicotinate as a cream colored solid (450 mg, 67%). ESI-MS m/z calc. 552.2, found 553.3 (M+1)+. Retention time 2.49 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.24 (d, J=8.7 Hz, 1H), 8.12 (d, J=8.7 Hz, 1H), 7.95-7.91 (m, 2H), 7.64 (d, J=7.9 Hz, 1H), 7.57-7.51 (m, 2H), 7.39 (d, J=8.3 Hz, 1H), 7.34 (dd, J=1.6, 8.3 Hz, 1H), 3.63 (s, 3H), 1.54 (m, 11H), 1.22-1.19 (m, 2H).

Workup

  1. customwas completely consumed
  2. concentrationThe reaction mixture was concentrated
  3. customthe residue was purified by column chromatography (0-40% ethyl acetate—hexanes)
  4. customThe material obtained
  5. washwas washed with 1N HCl (×3) and saturated aq. NaHCO3 (×3)
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-a89940bd0fa74cd69129006961c9df1a
Source dataset
uspto-grants-2011_06
Patent number
US07956052B2

Reaction notes

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