1-Hydroxybenzotriazole → (S)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)-3-(pyridin-2-yl)propanamide

HRID 58914Notes

Reaction equation

HRID 58914 reaction equation
OC(C(F)(F)F)=O.[NH2:8][C@@H:9]([CH3:38])[C:10]([NH:12][C@@H:13]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:14]([NH:16][C@@H:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([C@:20]1([CH3:23])[CH2:22][O:21]1)=[O:19])=[O:15])=[O:11].[O:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46](O)=[O:47])[CH2:41][CH2:40]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][C@:20]1([C:18](=[O:19])[C@@H:17]([NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:46](=[O:47])[CH2:45][N:42]2[CH2:43][CH2:44][O:39][CH2:40][CH2:41]2)[CH3:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][O:21]1

Participants

7

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 4389684-Morpholineacetic acidHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 131737031HCID 131737031, compound

Product 1

HCID 117690788(S)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)-3-(pyridin-2-yl)propanamideYield 37%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To (S)-2-((S)-2-aminopropanamido)-N-((S)-1-((S)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-3-(pyridin-2-yl)propanamide TFA salt (0.601 mmol assumed) was added morpholinoacetic acid (174 mg, 1.20 mmol), HOBt (130 mg, 0.962 mmol), HBTU (365 mg, 0.962 mmol) and DMF (3 mL). The mixture was cooled to 0° C. and DIEA (0.627 mL, 3.61 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated. Purification by column chromatography (3:1 DCM/ethyl acetate+0-15% methanol) provided (S)-N-((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)propanamido)-3-(pyridin-2-yl)propanamide (121 mg, 37%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.39 (ddd, J=4.9, 1.8, 0.9 Hz, 1H), 7.89 (d, J=6.7 Hz, 2H), 7.60 (ddt, J=7.7, 5.6, 1.8, 1.8 Hz, 2H), 7.25-7.09 (m, 5H), 7.09-6.99 (m, 2H), 4.88-4.65 (m, 2H), 4.47 (p, J=7.1, 7.1, 7.0, 7.0 Hz, 1H), 3.88-3.61 (m, 4H), 3.34-3.23 (m, 2H), 3.14 (dd, J=15.2, 6.3 Hz, 1H), 3.08-2.94 (m, 3H), 2.88 (d, J=5.0 Hz, 1H), 2.76 (dd, J=14.1, 7.9 Hz, 1H), 2.66-2.42 (m, 4H), 1.45 (s, 3H), 1.35 (d, J=7.1 Hz, 3H). MS (EI) for C29H37N5O6, found 552.4 (MH+).

Workup

  1. customthen quenched with sodium bicarbonate (sat.)
  2. extractionextracted with ethyl acetate (2×)
  3. dry with materialdried with sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification by column chromatography (3:1 DCM/ethyl acetate+0-15% methanol)

Sources & evidence

ORD record
ord-b124b81aa6704bbf9af75b253609cc1e
Source dataset
uspto-grants-2016_09
Patent number
US09434761B2

Reaction notes

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