Diisopropylethylamine → MK-0493 free base

HRID 2415559Notes

Reaction equation

HRID 2415559 reaction equation
C(N(CC)C(C)C)(C)C.Cl.[C:11]([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:17]([C:28](O)=[O:29])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12].Cl.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[C:37]([C@@H:39]([NH:41][C:42](=[O:44])[CH3:43])[CH3:40])[CH:38]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O>[C:11]([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:17]([C:28]([N:48]2[CH2:47][CH2:46][CH:45]([C:36]3[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][C:37]=3[C@@H:39]([NH:41][C:42](=[O:44])[CH3:43])[CH3:40])[CH2:50][CH2:49]2)=[O:29])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67212109(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid hydrochlorideHCID 68520212N-[(1S)-1-(5-chloro-2-piperidin-4ylphenyl)ethyl]acetamide hydrochloride

Product 1

HCID 11642422MK-0493 free baseYield 99.1%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

N,N-diisopropylethylamine (5.86 mL, 33.6 mmol) was added to a stirred suspension of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid hydrochloride (3-9) (3.07 g, 9.61 mmol), N-[(1S)-1-(5-chloro-2-piperidin-4-ylphenyl)ethyl]acetamide hydrochloride (3.05 g, 9.61 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (4.38 g, 11.5 mmol) in N,N-dimethylfoimamide (20 mL) at ambient temperature. After approximately 18 h, the reaction mixture was poured water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) provided 3-10 (5.2 g) as a foam m/z (ES) 546 (MH+).

Workup

  1. extractionextracted three times with ethyl acetate
  2. washThe combined organic extracts were washed with brine
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated in vacuo
  5. customPurification of the residue by flash chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent)

Sources & evidence

ORD record
ord-49eeaa2b4a614b9db44f2795ed66b821
Source dataset
uspto-grants-2004_11
Patent number
US06818658B2

Reaction notes

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