Ethyl chloroformate → ethyl 4-[4-[[methyl(1,2,3,4-tetrahydro-1-naphthalenyl)amino]carbonyl]-2-thiazolyl]-alpha-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-beta-oxo-1-piperidinepropanoate

HRID 660044Notes

Reaction equation

HRID 660044 reaction equation
[CH3:1][N:2]([CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH2:17][N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[N:19]3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4].C([N-]C(C)C)(C)C.[Li+].Cl[C:48]([O:50][CH2:51][CH3:52])=[O:49]>O1CCCC1>[CH3:1][N:2]([CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)[C:3]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:28])[CH:17]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:26])([F:25])[F:27])=[N:19]3)[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:12][CH2:11]2)[S:8][CH:9]=1)=[O:4]

Participants

5

Reactant 3

HCID 10928Ethyl chloroformateHCID 2724682Lithium diisopropylamideHCID 58242735N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-4-thiazolecarboxamide2×

Product 1

HCID 68525704ethyl 4-[4-[[methyl(1,2,3,4-tetrahydro-1-naphthalenyl)amino]carbonyl]-2-thiazolyl]-alpha-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-beta-oxo-1-piperidinepropanoate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-(1,2,3,4-tetrahydro-1-naphthalenyl)-4-thiazolecarboxamide (120 mg, 0.23 mmol) (i.e. the product of Example 2, Step E) in tetrahydrofuran (5 mL) at −78° C. was added a solution of lithium diisopropylamide in tetrahydrofuran (0.5 M, 2.0 mL, 1 mmol). After stirring at −78° C. for 30 minutes, a solution of ethyl chloroformate (100 μL) in tetrahydrofuran (2 mL) was added. The reaction mixture was stirred at −78° C. for 30 minutes more and then at 0° C. for 30 minutes. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure, and the residue was purified by medium-pressure liquid chromatography using 75-100% of ethyl acetate in hexanes as eluant to provide 4 mg of the title product, a compound of the present invention.

Workup

  1. stirringThe reaction mixture was stirred at −78° C. for 30 minutes more
  2. waitat 0° C. for 30 minutes
  3. customThe reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution
  4. extractionthe mixture was extracted with ethyl acetate
  5. dry with materialThe organic layer was dried (MgSO4)
  6. concentrationconcentrated under reduced pressure
  7. customthe residue was purified by medium-pressure liquid chromatography

Sources & evidence

ORD record
ord-6a1f0863fa7d44e4a7dc401e98adc84a
Source dataset
uspto-grants-2011_12
Patent number
US08084468B2

Reaction notes

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