Diisopropylethylamine → (5S)-2,2-dimethyl-5-((1S)-3-methyl-1-{[(2R)-2-methyl-4-(2-pyridinyl)piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-one

HRID 1677784Notes

Reaction equation

HRID 1677784 reaction equation
[CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[C:4](=[O:15])[O:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ONC(=O)[C@@H](O)[C@@H](C([N:61]1[CH2:66][CH2:65][N:64]([C:67]2[CH:72]=[C:71](C(F)(F)F)[CH:70]=[CH:69][N:68]=2)[CH2:63][C@H:62]1[CH3:77])=O)CC(C)C>CN(C=O)C.O>[CH3:16][C:2]1([CH3:1])[O:3][C:4](=[O:15])[C@H:5]([C@@H:7]([C:8]([N:61]2[CH2:66][CH2:65][N:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=3)[CH2:63][C@H:62]2[CH3:77])=[O:10])[CH2:11][CH:12]([CH3:14])[CH3:13])[O:6]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 63988602-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)-4-methylpentanoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 11517633(2S,3S)-N,2-dihydroxy-5-methyl-3-({(2R)-2-methyl-4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)hexanamide2×

Product 1

HCID 58487968(5S)-2,2-dimethyl-5-((1S)-3-methyl-1-{[(2R)-2-methyl-4-(2-pyridinyl)piperazinyl]carbonyl}butyl)-1,3-dioxolan-4-oneYield 49%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a cold (0° C.) solution of (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid (prepared according to WO 94/0244 or similarly to Seebach et al., 1990, Org. Syntheses, Coll. Vol. III, p 153-159; 7; 755.0 mg; 3.28 mmol; 1.0 eq.) and DIEA (1.18 mL; 6.89 mmol; 2.1 eq.) in DMF (4 mL) was added HATU (1.37 g; 3.61 mmol; 1.1 eq.) and the resulting reaction mixture was stirred for 2 min at 0° C. (3R)-3-methyl-1-pyridin-2-ylpiperazine (Intermediate 3, 639.3 mg; 3.61 mmol; 1.1 eq.) was then added and the resulting reaction mixture was stirred for 14 h at RT. Water was added and the mixture was extracted with Et2O (3×). The combined organic layers were washed with an aqueous saturated solution of NaCl, dried over MgSO4, filtered and evaporated to give an oil. This residue was purified by chromatography (gradient from 33% EtOAc in c-hex up to 50% EtOAc in c-hex in about 30 min) to give the title product as a white solid (625 mg, 49%) as a mixture of 2 diastereoisomers (HPLC (Condition D): Rt major: 13.7 min; Rt minor: 13.8 min; major/minor: 55/45). M+(ESI): 390.3. HPLC (Condition A), Rt: 2.3 min (HPLC purity: 97.4%).

Workup

  1. customthe resulting reaction mixture
  2. additionwas then added
  3. customthe resulting reaction mixture
  4. extractionthe mixture was extracted with Et2O (3×)
  5. washThe combined organic layers were washed with an aqueous saturated solution of NaCl
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customto give an oil
  10. customThis residue was purified by chromatography (gradient from 33% EtOAc in c-hex up to 50% EtOAc in c-hex in about 30 min)

Sources & evidence

ORD record
ord-b95fd74cc2d5416da07dd2914a86760c
Source dataset
uspto-grants-2011_08
Patent number
US08008302B2

Reaction notes

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