Diisopropylethylamine → rac-(3S,4R)-{4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester

HRID 527471Notes

Reaction equation

HRID 527471 reaction equation
[CH3:1][C:2]1([C:5]([N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:49]([O:53][C:54](=[O:69])[NH:55][CH:56]1[CH:60]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=2)[CH2:59][NH:58][CH2:57]1)([CH3:52])([CH3:51])[CH3:50]>CN(C=O)C.C(OCC)(=O)C>[C:49]([O:53][C:54](=[O:69])[NH:55][CH:56]1[CH:60]([C:61]2[CH:66]=[CH:65][C:64]([Cl:67])=[C:63]([Cl:68])[CH:62]=2)[CH2:59][N:58]([C:13]([CH:10]2[CH2:9][CH2:8][N:7]([C:5]([C:2]3([CH3:1])[CH2:3][CH2:4]3)=[O:6])[CH2:12][CH2:11]2)=[O:15])[CH2:57]1)([CH3:52])([CH3:50])[CH3:51]

Participants

7

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 594381681-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acidHCID 67237824rac-(3S,4R)-[4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester

Product 1

HCID 67237329rac-(3S,4R)-{4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl esterYield 87%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid (4.48 g, 0.02 mol) in DMF (40 ml) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (9.54 g, 0.03 mol). After stirring for 10 min at ambient temperature N,N-diisopropyl ethyl amine (19.82 ml, 0.116 mol) and a solution of rac-(3S,4R)-[4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (6.39 g, 67% purity, 0.013 mol) in DMF (45 ml) were added and the reaction mixture was stirred for 19 h at this temperature. It was diluted with ethyl acetate (80 mL) and the organic layer was washed with water (80 mL), aqueous sodium carbonate (1M, 40 mL) and brine (40 mL). The aqueous layers were extracted with ethyl acetate (160 mL). the combined organic layers were dried over sodium sulfate and concentrated. Purification by flash chromatography (SiO2, EtOAc/methanol 100:0 to 80:20) afforded 5.84 g (87%) of the title compound as a light brown foam. ES-MS m/e: 524.1 (M+H+).

Workup

  1. washthe organic layer was washed with water (80 mL), aqueous sodium carbonate (1M, 40 mL) and brine (40 mL)
  2. extractionThe aqueous layers were extracted with ethyl acetate (160 mL)
  3. dry with materialthe combined organic layers were dried over sodium sulfate
  4. concentrationconcentrated
  5. customPurification by flash chromatography (SiO2, EtOAc/methanol 100:0 to 80:20)

Sources & evidence

ORD record
ord-36b5dde8f9984041b37805e05272c9b6
Source dataset
uspto-grants-2016_05
Patent number
US09346786B2

Reaction notes

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