Water → HCID 66747655, compound

HRID 2402147Notes

Reaction equation

HRID 2402147 reaction equation
[C:1]([C:3]1[C:4]([CH:18]([O:29][CH3:30])[C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[C:5]([C:14]([O:16]C)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].O1CCCC1.[OH-].[Na+].O>CO>[C:1]([C:3]1[C:4]([CH:18]([O:29][CH3:30])[C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[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]

Participants

6

Reactant 4

HCID 962WaterHCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 66747714HCID 66747714, compound

Product 1

HCID 66747655HCID 66747655, compoundYield 96%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To methyl 4-cyano-3-[methoxy(2-naphthyl)methyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (10.56 g, 25 mmol) in a round bottom flask equipped with a stirbar was added tetrahydrofuran (278 mL) and 1.000 M of sodium hydroxide in water (208 mL, 208 mmol). Methanol (139 mL) was added to the mixture, and the resulting yellow mixture was stirred at room temperature for 16 h. The reaction mixture was quenched by the addition of 1N HCl aqueous solution to adjust the pH to 2 and EtOAc was added. The mixture was transferred to a separatory funnel, separated layers, extracted aqueous 2× w/EtOAc, combined organics, washed w/brine, dried over Na2SO4, filtered, added celite, rotavapped, dried on high vacuum for 45 min. The crude material was purified using a dry load on 330 g silica gel ISCO column (gradient elution: 0-20% MeOH/DCM) to obtain the product as an impure beige solid (9.8 g). Took 2 g, redissolved in DCM, added Celite, rotovapped, dried on high vac 45 min. Repurified this portion of product on 120 g ISCO silica gel column (gradient elution: 0-12% MeOH/DCM) to obtain 2.0 g beige foam product (racemate). LC/MS (FA) ES− 407; NMR (400 MHz, DMSO) δ 13.57 (s, 1H), 7.96 (s, 1H), 7.89-7.86 (m, 3H), 7.53-7.46 (m, 3H), 6.68 (s, 1H), 3.73-3.67 (m, 4H), 3.50-3.45 (m, 4H), 3.43 (s, 3H). Enantiomeric separation of the enantiomers was performed by chiral HPLC on CHIRALPAK IC 4.6×250 mm with 85/5/10/0.1% HEX/IPA/ETOH/DEA 10 uL Injection at 1.0 mL/min for 50 min.

Workup

  1. customThe reaction mixture was quenched by the addition of 1N HCl aqueous solution
  2. additionwas added
  3. customThe mixture was transferred to a separatory funnel
  4. customseparated layers
  5. extractionextracted aqueous 2× w/EtOAc
  6. washwashed w/brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. additionadded celite
  10. customdried on high vacuum for 45 min
  11. customThe crude material was purified
  12. washon 330 g silica gel ISCO column (gradient elution: 0-20% MeOH/DCM)

Sources & evidence

ORD record
ord-c3103618ec814fb19a813303c84207c1
Source dataset
uspto-grants-2014_08
Patent number
US08796271B2

Reaction notes

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