Lithium Hydroxide → 2-Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid ethyl ester

HRID 1350448Notes

Reaction equation

HRID 1350448 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[Li+].[OH-].C(O)(C(F)(F)F)=O>CS(C)=O.O.C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:12]([CH3:13])[CH3:14])[S:9][C:10]=1[NH:11][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=[O:5])[CH3:2]

Participants

8

Reactant 4

HCID 3939Lithium HydroxideHCID 6422Trifluoroacetic acidHCID 738951-Fluoro-2-nitrobenzeneHCID 58860584Ethyl 5-amino-2-isopropyl-1,3-thiazole-4-carboxylate

Product 1

HCID 588606132-Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acid ethyl esterYield 91.1%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent

Procedure

Combine a solution of 5-amino-2-isopropyl-thiazole-4-carboxylic acid ethyl ester (8.71 g, 40.6 mmol) and 2-fluoronitrobenzene (4.28 mL, 40.6 mmol) in DMSO (105 mL) and stir at rt under N2 as LiOH (1.95 g, 81.4 mmol, 2.0 eq.) or LiOH monohydrate (2 eq) is added in one portion. The reaction turns dark. Heat the reaction mixture to 55° C. for 3 h until complete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 mL/min). Cool to rt overnight, Cool the reaction to 0–5° C. with stirring as deionized water (315 mL) is added at such a rate to maintain the temperature below 20° C. Precipitate the product and the reaction color changes from brown to rust-orange color. Stir the slurry for 3–4 h at rt, filter by vacuum and rinse with minimal 3:1/H2O: DMSO, dry in a vacuum oven at 60° C. to afford 12.4 g (91%) of the title compound as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ 11.52 (bs, 1H), 8.23 (d, 1H, J=8.05 Hz), 7.80 (m, 2H), 7.21 (m, 1H), 4.36 (q, 2H, J=7.32 Hz, 6.95 Hz), 3.23 (dq, 1H, J=6.95 Hz), 1.34 (m, 9H). 13C NMR (75 MHz, DMSO-d6) δ 163.22, 161.85, 149.08, 136.99, 136.37, 136.10, 126.53, 126.48, 121.94, 117.05, 60.45, 32.47, 22.34(2), 14.24. IR (CHCl3) 2976, 2932, 2867, 1709, 1677, 1611, 1580, 1550, 1512, 1415, 1340 cm−1. HRMS (ES) M/z calculated for C15H17N3O4S 336.1018, found 336.1009.

Workup

  1. additionis added in one portion
  2. temperatureCool
  3. customthe reaction to 0–5° C.
  4. additionis added at such a rate
  5. temperatureto maintain the temperature below 20° C
  6. customPrecipitate the product
  7. filtrationfilter by vacuum
  8. washrinse with minimal 3:1/H2O
  9. dry with materialDMSO, dry in a vacuum oven at 60° C.

Sources & evidence

ORD record
ord-4ec0fc8a79d9425b80ae78ff841533d1
Source dataset
uspto-grants-2007_05
Patent number
US07214673B2

Reaction notes

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