Methanol → 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylic acid

HRID 2401852Notes

Reaction equation

HRID 2401852 reaction equation
[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([O:22]CC)=[O:21])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].CO>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:11]([C:12]#[N:13])=[C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)[S:9][C:8]=2[C:20]([OH:22])=[O:21])=[CH:4][CH:3]=1

Participants

5

Reactant 4

HCID 887MethanolHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 66747497ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate

Product 1

HCID 667476833-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylic acidYield 63%

Procedure

To a round bottom flask containing ethyl 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate (43.0 mg, 0.111 mmol) were added tetrahydrofuran (1.23 mL, 15.2 mmol), sodium hydroxide (1.0N in water, 0.925 mL, 0.925 mmol), and methanol (0.617 mL, 15.2 mmol). The mixture was stirred at room temperature overnight. Reaction was quenched via addition of 1N HCl in water (2 mL), then diluted with EtOAc and transferred to reparatory funnel. The layers were separated, and the aqueous layer was extracted 2× with EtOAc. Combined organics were washed with brine, dried over Na2SO4, and filtered, at adsorbed to Celite (10 mL). Column chromatography (40 g ISCO column, gradient elution 0-8% MeOH/DCM afforded 3-(4-chlorobenzyl)-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylic acid (95) (25 mg, 63%) as a white solid. LC/MS: (FA) ES− 358, 360; 1H NMR (400 MHz, DMSO) δ 14.04 (br s, 1H), 7.33 (d, J=8.5, 2H), 7.26 (d, J=8.5, 2H), 6.64 (s, 1H), 4.43 (s, 2H), 4.24 (d, J=2.9, 2H), 3.79 (dd, J=5.4, 5.4, 2H), 3.32 (br s, 2H).

Workup

  1. customReaction
  2. customwas quenched via addition of 1N HCl in water (2 mL)
  3. additiondiluted with EtOAc
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted 2× with EtOAc
  6. washCombined organics were washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. washColumn chromatography (40 g ISCO column, gradient elution 0-8% MeOH/DCM

Sources & evidence

ORD record
ord-fcbb52038ce643f38006e21b307a7c7f
Source dataset
uspto-grants-2014_08
Patent number
US08796268B2

Reaction notes

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