Hydrochloric Acid → Methyl (4R)-1-[(2S)-2-cyclohexyl-2-({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetyl]-4-[(7-methoxy-2-oxo-6-vinyl-1,2-dihydroquinolin-4-yl)oxy]-L-prolinate

HRID 1423376Notes

Reaction equation

HRID 1423376 reaction equation
Cl.[CH3:2][O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([O:15][C@H:16]3[CH2:20][NH:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)=[CH:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH:25]=[CH2:26].[CH:27]1([C@H:33]([NH:37][C:38]([O:40][CH2:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH:44]=[CH2:45])=[O:39])[C:34](O)=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.CCOC(C)=O>[CH:27]1([C@H:33]([NH:37][C:38]([O:40][CH2:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH:44]=[CH2:45])=[O:39])[C:34]([N:19]2[CH2:20][C@H:16]([O:15][C:8]3[C:7]4[C:12](=[CH:13][C:4]([O:3][CH3:2])=[C:5]([CH:25]=[CH2:26])[CH:6]=4)[NH:11][C:10](=[O:14])[CH:9]=3)[CH2:17][C@H:18]2[C:21]([O:23][CH3:24])=[O:22])=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 57617041(2S)-cyclohexyl({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetic acidHCID 86643488Methyl (4R)-4-[(7-methoxy-2-oxo-6-vinyl-1,2-dihydroquinolin-4-yl)oxy]-L-prolinate hydrochloride

Product 1

HCID 59279821Methyl (4R)-1-[(2S)-2-cyclohexyl-2-({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetyl]-4-[(7-methoxy-2-oxo-6-vinyl-1,2-dihydroquinolin-4-yl)oxy]-L-prolinateYield 119.9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of the product from Step 4, methyl (4R)-4-[(7-methoxy-2-oxo-6-vinyl-1,2-dihydroquinolin-4-yl)oxy]-L-prolinate hydrochloride (0.84 g, 2.206 mmol) and linker B20, (2S)-cyclohexyl({[(2,2-dimethylpent-4-en-1-yl)oxy]carbonyl}amino)acetic acid (0.689 g, 2.316 mmol) in DMF (2 mL) was added DIPEA (1.156 mL, 6.62 mmol) and HATU (1.090 g, 2.87 mmol). After 15 min, the reaction was complete and 1 N HCl and EtOAc were added. The organic layer was washed with water and brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified on silica (gradient elution, 0-5% MeOH/DCM) to yield 1.65 g of material which still contained HATU residue. This was removed by extracting the material with EtOAc and 1N HCl (4×), water (1×) and brine (1×). The organic layer was dried over MgSO4 and the solvent was removed in vacuo to yield 1.13 g (82%) of the title compound. LRMS ESI+(M+H)+ 624.6.

Workup

  1. washThe organic layer was washed with water and brine
  2. dry with materialdried over MgSO4
  3. customthe solvent was removed in vacuo
  4. customThe crude product was purified on silica (gradient elution, 0-5% MeOH/DCM)

Sources & evidence

ORD record
ord-1eb36b68168a48e79eb4e63ebbc43a5e
Source dataset
uspto-grants-2015_01
Patent number
US08927569B2

Reaction notes

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