1,2-Dichloroethane → [(2R)-3-(2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide

HRID 1366549Notes

Reaction equation

HRID 1366549 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH:12]3[C:10]([N:14]([CH3:16])[CH3:15])([CH2:11]3)[CH2:9]2)[C:5]([F:17])=[C:4]([NH:18][NH2:19])[N:3]=1.[CH:20]1([CH2:25][C@H:26]([CH2:30][N:31]([CH:40]=[O:41])[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][NH:19][C:27](=[O:28])[C@H:26]([CH2:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:30][N:31]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:40]=[O:41])[C:5]([F:17])=[C:6]([N:8]2[CH2:13][CH:12]3[C:10]([N:14]([CH3:16])[CH3:15])([CH2:11]3)[CH2:9]2)[N:7]=1

Participants

8

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 181649HOAtHCID 21305218(R)-3-(Benzyloxy-formyl-amino)-2-cyclopentylmethyl-propionic acidHCID 87210194racemic 3-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine

Product 1

HCID 86636983[(2R)-3-(2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamideYield 104.9%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of racemic 3-(2-chloro-5-fluoro-6-hydrazino-4-pyrimidinyl)-N,N-dimethyl-3-azabicyclo[3.1.0]hexan-1-amine (0.3374 g, 1.177 mmol) in DMF (10 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.3257 g, 1.067 mmol), N-methylmorpholine (0.590 mL, 5.366 mmol), 1-hydroxy-7-azabenzotriazole (0.174 g, 1.278 mmol), and EDC (0.245 g, 1.278 mmol). The mixture was stirred overnight, and then diluted with Et2O (100 mL). The mixture was washed with water (2×50 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (50 mL). This organic phase was washed with a fresh portion of water (50 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was diluted with DCM (200 mL), and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo to provide crude [(2R)-3-(2-{2-chloro-6-[1-(dimethylamino)-3-azabicyclo[3.1.0]hex-3-yl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.6428 g, >100% crude yield, mixture of diastereomers) as an orange oil. LCMS: (M+H)+: 574.2.

Workup

  1. washThe mixture was washed with water (2×50 mL)
  2. extractionthe combined aqueous phase was extracted with a fresh portion of Et2O (50 mL)
  3. washThis organic phase was washed with a fresh portion of water (50 mL)
  4. dry with materialthe combined organic phase was dried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. additionThe residue was diluted with DCM (200 mL)
  8. dry with materialdried over anhydrous Na2SO4
  9. filtrationThe mixture was filtered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-4824fedbaf6940f1b546ef77a5bc1330
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

Loading…