Lithium Hydroxide → Methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid

HRID 79975Notes

Reaction equation

HRID 79975 reaction equation
C[O:2][C:3](=[O:16])[C:4]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Li+].[OH-]>CO>[CH3:15][O:14][C:12]([NH:11][C:4](=[C:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)[C:3]([OH:16])=[O:2])=[O:13]

Participants

4

Reactant 2

HCID 3939Lithium HydroxideHCID 59611496Methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester

Product 1

HCID 59611013Methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid methyl ester (141 mg, 0.62 mmol) in methanol (1.8 mL) was added an aqueous LiOH solution (1M, 1.8 mL, 1.8 mmol). The resulting solution was stirred at room temperature for 16 hours and then washed with ethyl acetate. The ethyl acetate washing was discarded and the aqueous layer was acidified with concentrated HCl. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4), and concentrated to give methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid. To a solution of methoxycarbonylamino-(tetrahydropyran-4-ylidene)-acetic acid (23 mg, 0.11 mmol) in dimethylformamide (0.6 mL) was added HATU (41 mg, 0.11 mmol). After stirring for 5 minutes, a solution of {2-methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloride (50 mg, 0.068 mmol) in dimethylformamide (0.6 mL) was added to the reaction, followed immediately by diisopropylethylamine (85 μL, 0.49 mmol). The reaction was stirred for 1 hour at room temperature then diluted with ethyl acetate. The organic layer was washed successively with saturated aqueous NaHCO3 solution, water and brine, dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield {1-[2-(5-{6-[4-(2-{1-[2-methoxycarbonylamino-2-(tetrahydropyran-4-ylidene)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (28 mg, 50%).

Workup

  1. washwashed with ethyl acetate
  2. extractionThe acidified aqueous layer was extracted twice with ethyl acetate
  3. washThe combined organics were washed with brine
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-f089d598a775476698d6e428fa6d1c21
Source dataset
uspto-grants-2014_09
Patent number
US08841278B2

Reaction notes

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