Triethylamine → 5-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl ester

HRID 1161530Notes

Reaction equation

HRID 1161530 reaction equation
Cl.Cl.[CH2:3]([O:5][C:6]([C:8]1[C:9]([NH:13][NH2:14])=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].C[O:16][C:17](=O)[N:18]=[C:19](SC)[C:20]([C:34]1[CH:43]=[C:42]([O:44][CH3:45])[C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[C:35]=1[F:46])=[N:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:32]=[C:31]([CH3:33])[O:30][N:29]=2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1[CH:12]=[N:11][NH:10][C:9]=1[N:13]1[C:17](=[O:16])[NH:18][C:19]([CH:20]([C:34]2[CH:43]=[C:42]([O:44][CH3:45])[C:37]3[O:38][CH2:39][CH2:40][O:41][C:36]=3[C:35]=2[F:46])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]=[C:31]([CH3:33])[O:30][N:29]=3)=[CH:24][CH:23]=2)=[N:14]1)=[O:7])[CH3:4]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 72312813[2-(5-Fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl esterHCID 178469938HCID 178469938, compound

Product 1

HCID 1359821585-(3-{(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl esterYield 54.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 62 mg of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)), 106 mg of [2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 41d) and 88 μl of triethylamine in 5 ml of DMF was heated at 85° C. for 15 hours under a nitrogen atmosphere with stirring. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure. The residue was dissolved in 8 ml of methanol, and then 133 mg of sodium cyanotrihydroborate, 49 μl of acetic acid and 0.5 g of MS3A were added and the mixture was stirred at room temperature for 20 hours. Next, 100 ml of ethyl acetate and 50 ml of water were added, and the organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (68 mg) as a light green solid.

Workup

  1. customthe solvent was removed under reduced pressure
  2. dissolutionThe residue was dissolved in 8 ml of methanol
  3. addition133 mg of sodium cyanotrihydroborate, 49 μl of acetic acid and 0.5 g of MS3A were added
  4. stirringthe mixture was stirred at room temperature for 20 hours
  5. additionNext, 100 ml of ethyl acetate and 50 ml of water were added
  6. washthe organic layer was washed with 50 ml of water and 50 ml of saturated brine in that order
  7. dry with materialdried over anhydrous magnesium sulfate
  8. filtrationThe desiccating agent was filtered off
  9. concentrationthe filtrate was concentrated under reduced pressure
  10. customthe residue was purified by silica gel column chromatography (ethyl acetate-methanol)

Sources & evidence

ORD record
ord-ef3480177f254eb9bd0349ca73db6920
Source dataset
uspto-grants-2010_10
Patent number
US07816522B2

Reaction notes

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