Acetic Acid → HCID 66748087, compound

HRID 2401866Notes

Reaction equation

HRID 2401866 reaction equation
[C:1]([C:3]1[C:4](I)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].O1CCCC1.C1([Li])C=CC=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[N:38]/[S:39]([C:41]([CH3:44])([CH3:43])[CH3:42])=[O:40])=[CH:33][CH:32]=1.CO.C(O)(=O)C>>[C:41]([S:39]([NH:38][CH:37]([C:34]1[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][CH:35]=1)[C:4]1[C:3]([C:1]#[N:2])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][C:5]=1[C:14]([OH:16])=[O:15])=[O:40])([CH3:44])([CH3:42])[CH3:43]

Participants

7

Reactant 6

HCID 176Acetic AcidHCID 887MethanolHCID 8028Tetrahydrofuran2×HCID 12171905HCID 12171905, compoundHCID 42609111HCID 42609111, compoundHCID 178506676HCID 178506676, compound

Product 1

HCID 66748087HCID 66748087, compoundYield 62.2%

Procedure

4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylic acid (1.44 g, 3.96 mmol, prepared as in WO2009/154741) was suspended in anhydrous tetrahydrofuran (80.0 mL, 986 mmol), sonicated under nitrogen atmosphere for 10 min, and cooled in an acetone-dry ice bath for 10 minutes. Phenyllithium (1.8M in n-butyl ether, 8.81 mL, 15.9 mmol) was added dropwise over 7 minutes. The suspension was stirred with cooling for 5 minutes, at which point the cooling bath was removed and the suspension was stirred without cooling for 7 minutes. Reaction mixture was recooled in an acetone-dry ice bath for 10 minutes, at which point a solution of N—[(E)-(4-chlorophenyl)methylene]-2-methylpropane-2-sulfinamide (2.91 g, 11.9 mmol) in anhydrous tetrahydrofuran (20.0 mL, 246 mmol) was added dropwise over 8 minutes, and the mixture was stirred with cooling for 30 minutes. The mixture was quenched with methanol (5.0 mL, 120 mmol) and then acetic acid (1.0 mL, 18 mmol), and allowed to warm to room temperature. The volatiles were removed in vacuo, and the residue was diluted with water and EtOAc. The layers were separated, and the aqueous layer was extracted with 2×EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification via column chromatography (gradient elution: AcOH/MeOH/DCM, 0/0/100 to 0.5/4.5/95) afforded 3-{[(tert-butylsulfinyl)amino](4-chlorophenyl)methyl}-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a mixture of diastereomers. Major diastereomer: 1.19 g, yield 62.2%. (FA) ES+ 482; ES− 480; 1H NMR (400 MHz, CDCl3) δ 7.31-7.33 (m, 2H), 7.15-7.17 (m, 2H), 6.14 (br s, 2H), 3.87-3.89 (m, 4H), 3.60-3.63 (m, 4H), 1.21 (s, 9H). Minor diastereomer: (0.292 g, yield 15.3%). (FA) ES+ 482; ES− 480; 1H NMR (400 MHz, CDCl3) δ 7.26-7.34 (m, 4H), 6.29-6.38 (m, br, 2H), 3.84-3.86 (m, 4H), 3.56-3.60 (m, 4H), 1.35 (s, 9H).

Workup

  1. customsonicated under nitrogen atmosphere for 10 min
  2. temperaturecooled in an acetone-dry ice bath for 10 minutes
  3. temperaturewith cooling for 5 minutes, at which point the cooling bath
  4. customwas removed
  5. stirringthe suspension was stirred
  6. temperaturewithout cooling for 7 minutes
  7. customReaction mixture
  8. stirringthe mixture was stirred
  9. temperaturewith cooling for 30 minutes
  10. customThe volatiles were removed in vacuo
  11. additionthe residue was diluted with water and EtOAc
  12. customThe layers were separated
  13. extractionthe aqueous layer was extracted with 2×EtOAc
  14. washThe combined organic layers were washed with water and brine
  15. dry with materialdried over Na2SO4
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo
  18. customPurification
  19. washvia column chromatography (gradient elution: AcOH/MeOH/DCM, 0/0/100 to 0.5/4.5/95)

Sources & evidence

ORD record
ord-e1f55d3da5b14c52bc05942671d418a3
Source dataset
uspto-grants-2014_08
Patent number
US08796268B2

Reaction notes

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