4-Methylmorpholine → [(2R)-3-{2-[6-chloro-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide

HRID 1366381Notes

Reaction equation

HRID 1366381 reaction equation
[Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][NH2:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH:13]1([CH2:18][C@H:19]([CH2:23][N:24]([CH:32]=[O:33])[O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:20](O)=[O:21])[CH2:17][CH2:16][CH2:15][CH2:14]1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[N:5]=[C:6]([NH:9][NH:10][C:20](=[O:21])[C@H:19]([CH2:18][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:23][N:24]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH:32]=[O:33])[C:7]=1[F:8]

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 181649HOAtHCID 57937086(2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acidHCID 866369144-Chloro-5-fluoro-6-hydrazino-2-(methylthio)pyrimidine

Product 1

HCID 58000667[(2R)-3-{2-[6-chloro-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamideYield 56.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 4-chloro-5-fluoro-6-hydrazino-2-(methylthio)pyrimidine (9.70 g, 46.5 mmol), (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (19.9 g, 46.5 mmol), HOAt (6.96 g, 51.2 mmol), EDCI (9.82 g, 51.2 mmol) and N-methyl morpholine (25.6 mL, 232.5 mmol) in DMF (300 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate/hexanes (3:2, 1 L) and washed with water (3×500 mL), and the organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by Gilson RP-HPLC (35-95% acetonitrile/water, 8 min gradient time) to afford [(2R)-3-{2-[6-chloro-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide as a red glass (12.89 g, 56.0%). LCMS: (M+H)+: 490.4.

Workup

  1. washwashed with water (3×500 mL)
  2. dry with materialthe organics were dried (Na2SO4)
  3. concentrationconcentrated in vacuo
  4. customThe residue was purified by Gilson RP-HPLC (35-95% acetonitrile/water, 8 min gradient time)

Sources & evidence

ORD record
ord-11c120884d154d3f93fc3c93193e8167
Source dataset
uspto-grants-2011_02
Patent number
US07893056B2

Reaction notes

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