Diisopropylethylamine → HCID 118046285, compound

HRID 595833Notes

Reaction equation

HRID 595833 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]([O:15][C:16](C)(C)C)=O)[C@H:10](CO)[CH2:9]2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:40])[NH:29][C@@H:30]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH2:31][OH:32])=[C:24]([F:41])[CH:23]=1.CCN(C(C)C)C(C)C.C(C1NC=CN=1)(C1NC=CN=1)=[S:52]>C(#N)C.CN(C=O)C>[NH2:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:29][C@@H:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH2:31][OH:32])=[O:40])=[C:24]([F:41])[CH:23]=2)=[CH:4][C:5]([C@@H:8]2[CH2:12][N:11]3[C:13](=[S:52])[O:15][CH2:16][C@@H:10]3[CH2:9]2)=[CH:6][N:7]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 11412697Thiocarbonyl diimidazoleHCID 118047036HCID 118047036, compound

Product 1

HCID 118046285HCID 118046285, compoundYield 11%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Procedure

To a solution of (2S,4R)-tert-butyl 4-(6-amino-5-(4-(((S)-1-(3-chlorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyridin-3-yl)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (45 mg, 0.063 mmol) (see Example 7) in acetonitrile (0.75 mL) and DMF (0.5 mL) was added DIEA (42 μL, 0.240 mmol) and thiocarbonyl diimidazole (15.6 mg, 0.088 mmol). After 2 h, the reaction was quenched with 1 N aqueous solution. NaOH (1 mL) and stirred vigorously to effect decomposition of a mixed thiocarbamate byproduct. The reaction was then diluted with ethyl acetate (10 mL), washed with water (5 mL) and brine (5 mL), then dried over sodium sulfate and concentrated. The crude material was purified by reverse phase prep HPLC yielding 4-(2-amino-5-((6R,7aS)-3-thioxohexahydropyrrolo[1,2-c]oxazol-6-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (3.2 mg, 11% yield). LCMS (m/z): 527.3, 529.3 (MH+), 0.67 min; 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (dd, J=3.91, 7.04 Hz, 1H), 7.85 (d, J=1.96 Hz, 2H), 7.83-7.77 (m, 3H), 7.39-7.32 (m, 5H), 7.30-7.26 (m, 3H), 7.25-7.19 (m, 2H), 5.15-5.07 (m, 2H), 4.73-4.69 (m, 2H), 4.45-4.35 (m, 3H), 3.85-3.65 (m, 8H), 2.38 (td, J=5.58, 11.54 Hz, 2H), 1.80-1.70 (m, 1H).

Workup

  1. customthe reaction was quenched with 1 N aqueous solution
  2. additionThe reaction was then diluted with ethyl acetate (10 mL)
  3. washwashed with water (5 mL) and brine (5 mL)
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated
  6. customThe crude material was purified by reverse phase prep HPLC

Sources & evidence

ORD record
ord-7b29edbae62149d4828c9190b8f4ecf2
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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