Methyl chloroacetate → methyl 2-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-5-methyl-2-oxopyridin-1(2H)-yl)acetate

HRID 869933Notes

Reaction equation

HRID 869933 reaction equation
[F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([OH:30])=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:31])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:40][C:41]([O:43][CH3:44])=[O:42]>CN(C=O)C>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24](=[O:30])[N:25]([CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:31])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24]([O:30][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[N:25][CH:26]=[C:27]([CH3:29])[CH:28]=5)[C:20]([CH3:31])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1

Participants

6

Reactant 3

HCID 7295Methyl chloroacetateHCID 11430Potassium CarbonateHCID 178430687HCID 178430687, compound

Product 2

HCID 68796713methyl 2-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-5-methyl-2-oxopyridin-1(2H)-yl)acetateYield 59.3%HCID 117640833Methyl 2-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3,5'-dimethyl-2,3'-bipyridin-2'-yloxy)acetateYield 24%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-hydroxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (0.029 g, 0.06556 mmol) in DMF (1 mL) was added K2CO3 (0.091 mg, 0.6556 mmol) and methyl chloroacetate (28.82 μL, 0.3278 mmol). The reaction was stirred at 80° C. for 21 hours to yield a mixture of N-alkylated product and O-alkylated product. The reaction was filtered using ethyl acetate and the solvent was evaporated under reduced pressure. The crude products were separated by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield methyl 2-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-5-methyl-2-oxopyridin-1(2H)-yl)acetate [20 mg, 59.3%; ESI-MS m/z calc. 511.47. found 512.5 (M+1)+, retention time 1.74 minutes] and methyl 2-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3,5′-dimethyl-2,3′-bipyridin-2′-yloxy)acetate [8 mg, 24%; ESI-MS m/z calc. 511.47. found 512.5 (M+1)+, retention time 2.13 minutes].

Workup

  1. customto yield
  2. additiona mixture of N-alkylated product and O-alkylated product
  3. filtrationThe reaction was filtered
  4. customthe solvent was evaporated under reduced pressure
  5. customThe crude products were separated by column chromatography on silica gel (0-100% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-6c90428fe19d49339622bc243e10e8b8
Source dataset
uspto-grants-2015_03
Patent number
US08969386B2

Reaction notes

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