1,2-Dichloroethane → [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide

HRID 1366417Notes

Reaction equation

HRID 1366417 reaction equation
[CH:1]([OH:4])([CH3:3])C.[F:5][C:6]1[C:7]([N:15]2[CH2:24][CH2:23][N:22]3[C@H:17]([CH2:18][O:19][CH2:20][CH2:21]3)[CH2:16]2)=[N:8][C:9]([CH3:14])=[N:10][C:11]=1[NH:12][NH2:13].CN1[CH2:31][CH2:30][O:29]CC1.ON1[C:37]2N=[CH:39][CH:40]=[CH:41][C:36]=2N=N1.[CH2:42](Cl)[CH2:43]Cl.[CH3:46][N:47]([CH:49]=[O:50])C>CCOCC>[CH:42]1([CH2:43][C@@H:3]([C:1]([NH:13][NH:12][C:11]2[C:6]([F:5])=[C:7]([N:15]3[CH2:24][CH2:23][N:22]4[C@H:17]([CH2:18][O:19][CH2:20][CH2:21]4)[CH2:16]3)[N:8]=[C:9]([CH3:14])[N:10]=2)=[O:4])[CH2:46][N:47]([O:29][CH2:30][C:31]2[CH:37]=[CH:36][CH:41]=[CH:40][CH:39]=2)[CH:49]=[O:50])[CH2:40][CH2:41][CH2:36][CH2:37]1

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 3776IsopropanolHCID 6228DimethylformamideHCID 79724-MethylmorpholineHCID 181649HOAtHCID 66936132(9aS)-8-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine

Product 1

HCID 86636930[(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

To a solution of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid, N,N-diisopropylethylamine salt, isopropanol solvate (33.64 g, 68.0 mmol) in DMF (230 mL) was added (9aS)-8-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine (20.16 g, 71.4 mmol), N-methylmorpholine (30 mL, 273 mmol), 1-hydroxy-7-azabenzotriazole (11.10 g, 81.6 mmol), and EDC (15.64 g, 81.6 mmol). The solution was stirred overnight and then diluted with Et2O (500 mL). The mixture was washed with water (2×200 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (100 mL). This Et2O phase was then washed with water (50 mL). This extraction-wash procedure was repeated 6 times, and the total combined organic phase was then diluted with DCM (250 mL). The organic phase was then dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (42.32 g, >100% crude yield) as a light yellow foam. LCMS: (M+H)+: 570.3.

Workup

  1. washThe mixture was washed with water (2×200 mL)
  2. extractionthe combined aqueous phase was extracted with a fresh portion of Et2O (100 mL)
  3. washThis Et2O phase was then washed with water (50 mL)
  4. additionthe total combined organic phase was then diluted with DCM (250 mL)
  5. dry with materialThe organic phase was then dried over anhydrous Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c2245776b6bf47f8bafe0abeddf3a33c
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

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