Triethylamine → 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{(3S,5R)-1-[5-chloro-2-(4-hydroxy-piperidin-1-yl)-pyrimidin-4-yl]-5-ethyl-pyrrolidin-3-yl}-amino)-pyrimidin-5-yl]-3-methyl-imidazolidin-2-one

HRID 409499Notes

Reaction equation

HRID 409499 reaction equation
C(O[C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:14]2[N:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][N:22]([CH3:25])[C:21]3=[O:26])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH2:42][CH3:43])=O)(C)(C)C.[ClH:44].CCO[C:48]([CH3:50])=[O:49].FC(F)(F)C1C=[C:55](C=C(C(F)(F)F)C=1)[CH2:56][N:57]([C:65]1[N:70]=[CH:69][C:68](N2CCN(C)C2=O)=C[N:66]=1)[C@@H:58]1CN[C@H](CC)C1.CCN(CC)CC.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(Cl)Cl>[F:36][C:34]([F:35])([F:37])[C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([C:38]([F:40])([F:41])[F:39])[CH:31]=1)[CH2:27][N:13]([C@H:11]1[CH2:10][C@@H:9]([CH2:42][CH3:43])[N:8]([C:6]2[C:68]([Cl:44])=[CH:69][N:70]=[C:65]([N:57]3[CH2:58][CH2:50][CH:48]([OH:49])[CH2:55][CH2:56]3)[N:66]=2)[CH2:12]1)[C:14]1[N:19]=[CH:18][C:17]([N:20]2[CH2:24][CH2:23][N:22]([CH3:25])[C:21]2=[O:26])=[CH:16][N:15]=1

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 516892Sodium BicarbonateHCID 21866389Hydrogen chloride-ethyl acetateHCID 59614381(2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(3-methyl-2-oxo-imidazolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 86648406(2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(3-methyl-2-oxo-imidazolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine

Product 1

HCID 596144061-[2-((3,5-bis-trifluoromethyl-benzyl)-{(3S,5R)-1-[5-chloro-2-(4-hydroxy-piperidin-1-yl)-pyrimidin-4-yl]-5-ethyl-pyrrolidin-3-yl}-amino)-pyrimidin-5-yl]-3-methyl-imidazolidin-2-oneYield 68%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a mixture of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(3-methyl-2-oxo-imidazolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.24 mmol) in EtOAc (1 mL) is added 4N HCl/EtOAc (2.4 mL, 2.44 mmol). After removal of solvent, the mixture is used without further purification. (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(3-methyl-2-oxo-imidazolidin-1-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine is treated with 2,4,5-trichloro-pyrimide (67.1 mg, 0.37 mmol) and Et3N (0.07 mL, 0.49 mmol) in CH2Cl2 (1 mL) at RT for 12 hours. After adding sat. NaHCO3 (aq.), the mixture is extracted with CH2Cl2, washed with brine and dried (MgSO4). Concentration under vacuum and purification with silica gel column chromatography (eluent: n-hexane:EtOAc=1:1) gives 1-[2-((3,5-Bis-trifluoromethyl-benzyl)-{(3S,5R)-1-[5-chloro-2-(4-hydroxy-piperidin-1-yl)-pyrimidin-4-yl]-5-ethyl-pyrrolidin-3-yl}-amino)-pyrimidin-5-yl]-3-methyl-imidazolidin-2-one (110 mg, 68%)

Workup

  1. customAfter removal of solvent
  2. customthe mixture is used without further purification
  3. extractionthe mixture is extracted with CH2Cl2
  4. washwashed with brine
  5. dry with materialdried (MgSO4)
  6. concentrationConcentration
  7. customunder vacuum and purification with silica gel column chromatography (eluent: n-hexane:EtOAc=1:1)

Sources & evidence

ORD record
ord-dabfe4bd116349aa9e5b6ccecc48e049
Source dataset
uspto-grants-2014_06
Patent number
US08759365B2

Reaction notes

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