Triethylamine → tert-butyl (2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidine-1-carboxylate

HRID 74728

Reaction equation

HRID 74728 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:22]1([CH2:28][C@@H:29]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)[NH2:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:20][O:19][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:14]([CH3:18])[C:15](=[O:17])[NH:30][C@H:29]([C:31]1[S:32][CH:33]=[CH:34][N:35]=1)[CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 11033491(2R,3R)-3-((2S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanoic acidHCID 13586794DiethylphosphorylcyanideHCID 91971232(S)-2-phenyl-1-(thiazol-2-yl)ethanaMine hydrochloride

Product 1

HCID 14753401tert-butyl (2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]amino]propyl]pyrrolidine-1-carboxylateYield 81.1%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 21584019Toluene ethylacetateSolvent

Procedure

To a solution of #11 (280 mg, 0.974 mmol, 1 eq.) and #15 (460 mg, 1.44 mmol, 1.48 eq.) in N,N-dimethylformamide (3 mL, 0.32 M) at 0° C. was added diethylphosphoryl cyanide (DEPC) (93% purity, 212 μL, 1.30 mmol, 1.34 eq.), followed by triethylamine (367 μL, 2.63 mmol, 2.7 eq.). After 2 hours at 0° C., the reaction mixture was warmed to room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate:toluene (2:1, 30 mL) and was washed successively with 1 M aqueous sodium bisulfate solution (35 mL) and 50% saturated aqueous sodium bicarbonate solution (4×25 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (12% to 100% ethyl acetate in heptane) to give #16 as a light amber oil (374 mg, 81%). LC-MS: m/z 474.4 [M+H+], 374.4 [(M−2-methylprop-1-ene)+H+] retention time=3.63 minutes; 1H NMR (400 MHz, DMSO-d6), characteristic signals: δ 8.66 (d, J=8.5 Hz, 1H), 7.78 (d, J=3.3 Hz, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.21-7.31 (m, 4H), 7.14-7.20 (m, 1H), 5.40 (ddd, J=11.4, 8.5, 4.0 Hz, 1H), 3.23 (br s, 3H), 2.18 (dq, J=9.7, 6.7 Hz, 1H), 1.06 (d, J=6.6 Hz, 3H).

Workup

  1. washwas washed successively with 1 M aqueous sodium bisulfate solution (35 mL) and 50% saturated aqueous sodium bicarbonate solution (4×25 mL)
  2. dry with materialThe organic layer was dried over sodium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. custompurified by silica gel chromatography (12% to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-5f756295f1714914b38cda81bbb1997d
Source dataset
uspto-grants-2014_09
Patent number
US08828401B2

Linked notes

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