Diisopropylethylamine → (S)-methyl 3-(2-methoxypyridin-4-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoate

HRID 58799Notes

Reaction equation

HRID 58799 reaction equation
[NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([NH:25][C@@H:26]([CH3:30])[C:27](O)=[O:28])=[O:24])[CH2:18][CH2:17]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][C@H:2]([NH:1][C:27](=[O:28])[C@@H:26]([NH:25][C:23](=[O:24])[CH2:22][N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH3:30])[C:3]([O:5][CH3:6])=[O:4])[CH:13]=[CH:12][N:11]=1

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 117607686(2-morpholinoacetyl)-L-alanineHCID 117608201(S)-methyl 2-amino-3-(2-methoxypyridin-4-yl)propanoate

Product 1

HCID 117608200(S)-methyl 3-(2-methoxypyridin-4-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoateYield 48%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

The crude (S)-methyl 2-amino-3-(2-methoxypyridin-4-yl)propanoate (TFA salt, 7.7 mmol) was dissolved in DMF (10 mL). (S)-2-(2-morpholinoacetamido)propanoic acid (1.7 g, 7.7 mmol), HATU (4.40 g, 11.6 mmol) and DIPEA (1 mL) were added at 0° C. with stirring. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. EtOAc (100 mL) and water (100 mL) was added and two layers were separated. The aqueous phase was extracted with EtOAc (30 mL×3) and the combined organic phases were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH=20:1) to afford (S)-methyl 3-(2-methoxypyridin-4-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoate (1.5 g, 48% yield). (S)-methyl 3-(2-methoxypyridin-4-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoate (800 mg, 2.00 mmol) was treated with a solution of lithium hydroxide-H2O (329 mg, 7.80 mmol) in water/THF (10 mL/10 mL) for 30 min. THF was removed and the aqueous phase was acidified to pH=3-4 with 1N aqueous HCl. The resulting mixture was concentrated to dryness to afford the corresponding acid, which was used directly without further purification.

Workup

  1. stirringstirred for 3 h
  2. customtwo layers were separated
  3. extractionThe aqueous phase was extracted with EtOAc (30 mL×3)
  4. washthe combined organic phases were washed with brine (50 mL×3)
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationconcentrated
  7. customThe residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH=20:1)

Sources & evidence

ORD record
ord-bfd0240aa69f41ec966d7208159f9cfa
Source dataset
uspto-grants-2016_09
Patent number
US09434761B2

Reaction notes

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