Dimethylformamide → 3-(3-{(5-Fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid

HRID 1161591Notes

Reaction equation

HRID 1161591 reaction equation
CN(C=O)C.CO[C:8](=[O:40])[N:9]=[C:10](SC)[C:11]([C:25]1[C:26]([F:37])=[C:27]2[C:32](=[C:33]([O:35][CH3:36])[CH:34]=1)[O:31][CH2:30][CH2:29][CH2:28]2)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.C[O:42][C:43]([C:45]1[S:46][CH:47]=[CH:48][C:49]=1[NH:50][NH2:51])=[O:44]>C(N(CC)CC)C>[F:37][C:26]1[C:25]([CH:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)[C:10]2[NH:9][C:8](=[O:40])[N:50]([C:49]3[CH:48]=[CH:47][S:46][C:45]=3[C:43]([OH:44])=[O:42])[N:51]=2)=[CH:34][C:33]([O:35][CH3:36])=[C:32]2[C:27]=1[CH2:28][CH2:29][CH2:30][O:31]2

Participants

5

Reactant 3

HCID 6228DimethylformamideHCID 2777595Methyl 3-Hydrazinothiophene-2-CarboxylateHCID 72312734[2-(5-Fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester

Product 1

HCID 1363892953-(3-{(5-Fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid

Reagents, catalysts & solvents 1

HCID 8471TriethylamineSolvent

Conditions

Temperature
85 °C

Procedure

To 1 ml of a DMF solution containing 100 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (33d)), 35 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 0.028 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 12 hours under a nitrogen atmosphere and then concentrated. The residue was dissolved in 1.5 ml of methanol, 1.5 ml of THF, and 0.1 ml of acetic acid, and 100 mg of sodium cyanotrihydroborate was further added thereto. The mixture was stirred at room temperature for 3 hours, and 1 ml of a 5 N sodium hydroxide aqueous solution was added thereto. The mixture was stirred at room temperature overnight. Acetic acid (0.3 ml) was added to the reaction mixture, and the resulting mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give a crude product of 3-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid.

Workup

  1. additionwere added
  2. concentrationconcentrated
  3. dissolutionThe residue was dissolved in 1.5 ml of methanol
  4. addition1.5 ml of THF, and 0.1 ml of acetic acid, and 100 mg of sodium cyanotrihydroborate was further added
  5. stirringThe mixture was stirred at room temperature for 3 hours
  6. addition1 ml of a 5 N sodium hydroxide aqueous solution was added
  7. stirringThe mixture was stirred at room temperature overnight
  8. additionAcetic acid (0.3 ml) was added to the reaction mixture
  9. customthe resulting mixture was crudely purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid)

Sources & evidence

ORD record
ord-991305e259d54d9188b1e2109f1096fd
Source dataset
uspto-grants-2010_10
Patent number
US07816522B2

Reaction notes

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