Isopropanol → (S)-isopropyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

HRID 1499286Notes

Reaction equation

HRID 1499286 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.[CH3:47][CH:48](O)[CH3:49]>S(Cl)(Cl)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18][CH:48]([CH3:49])[CH3:47])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH3:40])[CH:34]=3)=[CH:29][C:28]=2[N:41]2[CH:45]=[CH:44][C:43]([CH3:46])=[N:42]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1

Participants

4

Reactant 2

HCID 3776IsopropanolHCID 117947646(3S)-8-[2-amino-6-[(1R)-1-[4-(3,4-dimethylphenyl)-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxylic acid

Product 1

HCID 117952625(S)-isopropyl 8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate

Reagents, catalysts & solvents 1

HCID 24386Thionyl ChlorideCatalyst

Procedure

To a solution of the compound of Example 1m (400 mg, 0.53 mmol) in propan-2-ol (5 mL) was added thionyl chloride (2 drops) at 0° C. The mixture was warmed to RT and then heated to reflux for 2 h. Then the reaction mixture was cooled to RT, concentrated and neutralized with saturated aqueous NaHCO3 solution to pH 7-8. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by flash column (0˜10% MeOH in DCM) on silica gel to afford the title compound as a white solid.

Workup

  1. temperatureheated
  2. temperatureto reflux for 2 h
  3. temperatureThen the reaction mixture was cooled to RT
  4. concentrationconcentrated and neutralized with saturated aqueous NaHCO3 solution to pH 7-8
  5. extractionThe aqueous layer was extracted with CH2Cl2
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. custompurified by flash column (0˜10% MeOH in DCM) on silica gel

Sources & evidence

ORD record
ord-bf33640c127f4e5099d522fcd088eb3e
Source dataset
uspto-grants-2015_12
Patent number
US09199994B2

Reaction notes

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