N,N,N',N'-Tetramethylethylenediamine → N,beta,beta-trimethyl-L-phenylalanyl-N1-[(1S,2E)-1-isopropyl-3-methyl-4-oxo-4-(1,3-thiazol-2-yl)but-2-enyl]-N1,3-dimethyl-L-valinamide

HRID 1865725Notes

Reaction equation

HRID 1865725 reaction equation
[S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CN(CCN(C)C)C.[Li]CCCC.[CH3:19][NH:20][C@H:21]([C:31]([NH:33][C@H:34]([C:39]([N:41]([C@@H:43]([CH:53]([CH3:55])[CH3:54])/[CH:44]=[C:45](\[CH3:52])/[C:46](N(OC)C)=[O:47])[CH3:42])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])[C:22]([CH3:30])([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:19][NH:20][C@H:21]([C:31]([NH:33][C@H:34]([C:39]([N:41]([C@@H:43]([CH:53]([CH3:55])[CH3:54])/[CH:44]=[C:45](\[CH3:52])/[C:46](=[O:47])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:42])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])[C:22]([CH3:30])([CH3:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1

Participants

6

Reactant 4

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 9256ThiazoleHCID 11656496N,beta,beta-trimethyl-L-phenylalanyl-N1-{(1S,2E)-1-isopropyl-4-[methoxy(methyl)-amino]-3-methyl-4-oxobut-2-enyl}-N1,3-dimethyl-L-valinamideHCID 178418339Butyllithium

Product 1

HCID 11613574N,beta,beta-trimethyl-L-phenylalanyl-N1-[(1S,2E)-1-isopropyl-3-methyl-4-oxo-4-(1,3-thiazol-2-yl)but-2-enyl]-N1,3-dimethyl-L-valinamideYield 86%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-60 °C

Procedure

To a solution of thiazole (0.035 mL, 0.5 mmol) and TMEDA (0.068 mL, 0.45 mmol) in anhydrous THF (1.0 mL) cooled to −60° C. is added n-BuLi (0.17 mL, 0.43 mmol). After stirring for 20 min at −60° C., a solution of N,β,β-trimethyl-L-phenylalanyl-N1-{(1S,2E)-1-isopropyl-4-[methoxy(methyl)-amino]-3-methyl-4-oxobut-2-enyl}-N1,3-dimethyl-L-valinamide (52 mg, 0.1 mmol, from Example 52, in anhydrous THF (0.5 mL) is added. The purple reaction mixture is stirred for 2 h from −60° C. to room temperature, quenched with saturated aqueous ammonium chloride (1.5 mL). The reaction mixture is extracted with ethyl acetate three times. The combined organic layers are dried (Na2SO4), filtered and concentrated. The residue is purified by reversal phase HPLC (mobile phase A: 0.1% TFA/5% acetonitrile/H2O, mobile phase B: 100% acetonitrile) to give 56 mg (86%) of desired product as a yellow solid. HRMS (ESI) calcd for C30H44N4O3S [M+H] 541.3207, found 541.3203.

Workup

  1. stirringThe purple reaction mixture is stirred for 2 h from −60° C. to room temperature
  2. customquenched with saturated aqueous ammonium chloride (1.5 mL)
  3. extractionThe reaction mixture is extracted with ethyl acetate three times
  4. dry with materialThe combined organic layers are dried (Na2SO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue is purified by reversal phase HPLC (mobile phase A: 0.1% TFA/5% acetonitrile/H2O, mobile phase B: 100% acetonitrile)

Sources & evidence

ORD record
ord-1b31f0e48a294ed5afbdc68d31c2bac6
Source dataset
uspto-grants-2009_12
Patent number
US07626023B2

Reaction notes

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