Diisopropylethylamine → HCID 86643335, compound

HRID 1948291Notes

Reaction equation

HRID 1948291 reaction equation
Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:11].Br[C:23]1[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:23]2[S:24][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:27]=2)[CH2:15][C@H:14]1[C:19]([OH:21])=[O:20])=[O:11]

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 2773502Methyl 2-bromothiazole-5-carboxylateHCID 86643336HCID 86643336, compound2×

Product 1

HCID 86643335HCID 86643335, compound

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
55 °C

Procedure

Cis(±)4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidine-3-carboxylic acid hydrochloride (Intermediate 79; 1.84 g) was dissolved in anhydrous DMF (20 ml) under an argon atmosphere in a 100-ml round bottom flask. Methyl 2-bromothiazole-5-carboxylate (1.43 g) was added followed by N,N-diisopropylethylamine (3.6 ml) at room temperature. The reaction was heated to 55° C. for 14 h cooled to room temperature. The reaction mixture was diluted with EtOAc (250 ml) and washed with a saturated aqueous ammonium chloride solution (125 ml), followed by a saturated aqueous sodium chloride solution (100 ml). The EtOAc solution was dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0-10% CH3OH in DCM. The recovered product was recrystallised from EtOAc to further enhance the diastereomeric excess, increasing it from a 90:10 cis:trans mixture to a 96:4 cis:trans mixture (by HPLC analysis). The recrystallised product was carried on to the next reaction (2 g). MS (ES−(M+H)+): 461, 463 for C17H18Cl2N4O5S; NMR: 1.71 (m, 1H), 1.91 (m, 1H), 2.16 (s, 3H), 2.81 (dt, 1H), 3.42 (m, 2H), 3.74 (s, 3H), 3.86 (m, 1H), 4.34 (m, 2H), 7.43 (d, 1H), 7.88 (s, 1H), 8.50 (brs, 1H), 12.06 (s, 1H).

Workup

  1. temperaturecooled to room temperature
  2. washwashed with a saturated aqueous ammonium chloride solution (125 ml)
  3. dry with materialThe EtOAc solution was dried over anhydrous MgSO4
  4. concentrationconcentrated in vacuo
  5. customThe crude product was purified by silica gel chromatography
  6. customThe recovered product was recrystallised from EtOAc
  7. temperatureincreasing it from a 90:10 cis
  8. customThe recrystallised product was carried on to the next reaction (2 g)

Sources & evidence

ORD record
ord-746f26d849664f37aa7da095ac9fe1df
Source dataset
uspto-grants-2013_03
Patent number
US08399489B2

Reaction notes

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