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Sodium Hydroxide → (5-(Cyano-dimethyl-methyl)-2-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester

HRID 2200051
Notes
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Reaction equation

HRID 2200051 reaction equation
[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:8]=2)[N:5]=[C:4]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])[CH:3]=1.[OH-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]([Cl:38])([Cl:37])[Cl:36])=[O:32]>CCOC(C)=O>[Cl:36][C:35]([Cl:38])([Cl:37])[CH2:34][O:33][C:31](=[O:32])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:8]=2)[N:5]=[C:4]([C:23]([C:24]#[N:25])([CH3:27])[CH3:26])[CH:3]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 870632,2,2-Trichloroethyl chloroformate3×HCID 1177287572-(5-Amino-1-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-1H-pyrazol-3-yl)-2-methyl-propionitrile

Product 1

HCID 117729108(5-(Cyano-dimethyl-methyl)-2-{3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl esterYield 80%

Reagents, catalysts & solvents

1
HCID 8857Ethyl AcetateSolvent

Procedure

Intermediate 20c (317 mg, 0.86 mmol) was dissolved in EtOAc (2.5 mL) and 1M NaOH solution (1.4 mL, 2.14 mmol) and cooled in an ice bath. While stirring, 2,2,2-trichloroethyl chloroformate (227 mg, μL, 1.07 mmol) was then added dropwise, and the ice bath removed. After 30 min, a further 0.65 eq. of 2,2,2-trichloroethyl chloroformate was added, and the reaction continued. After 30 min, a further 0.65 eq. of 2,2,2-trichloroethyl chloroformate was added, and the reaction continued overnight. The reaction was then partitioned between H2O and EtOAc, the organic layer was separated, and the aqueous layer extracted again with EtOAc. The combined organics were dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 5-30% EtOAc in cyclohexane, to afford the title compound as a light yellow oil (375 mg, 80%). LCMS (Method 3): Rt 4.41 min, m/z 567, 569 [M+Na].

Workup

  1. customthe ice bath removed
  2. waitAfter 30 min
  3. customthe reaction continued overnight
  4. customThe reaction was then partitioned between H2O and EtOAc
  5. customthe organic layer was separated
  6. extractionthe aqueous layer extracted again with EtOAc
  7. dry with materialThe combined organics were dried over MgSO4
  8. concentrationconcentrated in vacuo
  9. washeluting with 5-30% EtOAc in cyclohexane

Sources & evidence

ORD record
ord-9876eb4da6cd4002b81635d1c1cc20b6
Source dataset
uspto-grants-2016_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09359354B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes