Formamide → 2-Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid amide

HRID 131362Notes

Reaction equation

HRID 131362 reaction equation
C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:21]([CH3:23])[CH3:22])[S:9][C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])=O)C.C([NH2:26])=O.C[O-].[Na+].CO.C(O)(C(F)(F)F)=O.[NH4+].[Cl-]>CN(C=O)C.O.C(#N)C>[CH:21]([C:8]1[S:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])=[C:6]([C:4]([NH2:26])=[O:3])[N:7]=1)([CH3:23])[CH3:22]

Participants

10

Reactant 6

HCID 713FormamideHCID 887MethanolHCID 6422Trifluoroacetic acidHCID 25517Ammonium ChlorideHCID 10942334Sodium MethoxideHCID 588606132-Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid ethyl ester

Product 1

HCID 588605762-Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid amideYield 84.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
2.5 °C

Procedure

Stir 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid ethyl ester (68.6 g, 204 mmol) at rt under N2 as a slurry in DMF (205 mL). Add formamide (32.4 mL, 816 mmol, 4.0 eq.) in one portion, and heat the thick red slurry to 100° C.; a dark red/purple solution is formed. Add dropwise over 20-30 min, 25% NaOMe in MeOH (32.6 mL, 143 mmol, 0.7 eq.) Increase the temperature 120° C. and stir the dark solution was stirred at 120° C. overnight until complete (<2% Me ester+SM) by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 mL/min). After cooling the reaction to rt, add aqueous 5% NH4Cl (410 mL) at such a rate as to maintain the temperature below 35° C. with no external cooling. Precipitate the product, cool the slurry to 0-5° C., filter by vacuum filtration and dry in a vacuum oven at 60° C. to afford 52.7 g (84% yield) crude title compound as a purple solid that was used without further purification. An aqueous workup may result in bad emulsions/slow separations: 1H NMR (300 MHz, DMSO-d6) δ 12.22 (bs, 1H), 8.21 (d, 1H, J=7.69 Hz), 7.78 (m, 2H), 7.59 (bs, 1H), 7.53 (bs, 1H), 7.15 (m, 1H), 3.23 (dq, 1H, J=6.95 Hz), 1.35 (d, 6H, J=6.95 Hz): 13C NMR (75 MHz, DMSO-d6) δ 165.53, 161.44, 144.58, 137.12, 136.31, 135.72, 128.90, 126.58, 121.08, 116.28, 32.32, 22.35(2): IR (CHCl3) 3520, 3400, 3004, 2967, 2925, 2866, 1658, 1611, 1578, 1513, 1427, 1342 cm−1: HRMS (ES) M/z calculated for C13H14N4O3S1 329.0684, found 329.0667.

Workup

  1. customa dark red/purple solution is formed
  2. additionAdd dropwise over 20-30 min
  3. temperatureAfter cooling
  4. customthe reaction to rt
  5. temperatureto maintain the temperature below 35° C. with no external cooling
  6. filtrationfilter by vacuum filtration
  7. customdry in a vacuum oven at 60° C.

Sources & evidence

ORD record
ord-2dcd310726ed4d9cb528569e68d638ff
Source dataset
uspto-grants-2008_06
Patent number
US07384934B2

Reaction notes

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