Malonate Ion → 2-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrile

HRID 2387177Notes

Reaction equation

HRID 2387177 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)([OH:20])[CH2:16][C:17](O)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]([C:11]#[N:12])([CH3:10])[CH3:9].C1N=CN(C(N2C=NC=C2)=O)C=1.C([O-])(=O)[CH2:39][C:40]([O-])=[O:41]>C(C(C(OC(C)(C)C)=O)C(OC)=O)C.CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:16][C:17](=[O:18])[CH2:39][C:40](=[O:41])[O:20]2)[CH:5]=[CH:6][C:7]=1[C:8]([CH3:10])([CH3:9])[C:11]#[N:12]

Participants

7

Reactant 3

HCID 9084Malonate IonHCID 682631,1'-CarbonyldiimidazoleHCID 690589925-[3-Chloro-4-(cyano-dimethyl-methyl)-phenyl]-3-cyclopentyl-3-hydroxy-pent-4-enoic acid

Product 1

HCID 498714082-{2-Chloro-4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-phenyl}-2-methyl-propionitrileYield 90%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 8028TetrahydrofuranSolventHCID 86605377Methyl tert-butyl ethylmalonateSolvent

Conditions

Temperature
42 °C

Procedure

5-[3-Chloro-4-(cyano-dimethyl-methyl)-phenyl]-3-cyclopentyl-3-hydroxy-pent-4-enoic acid, from step 1 above, was dissolved in methyl tert-butyl ethylmalonate (3 mL). 4-DMAP (0.16 g, 0.13 mmol) and CDI (0.27 g, 1.68 mmol) were added and the reaction mixture was stirred under argon for 2 hours. In a separate flask was placed magnesium-bis-monoethyl malonate (0.74 g, 2.58 mmol) was suspended in THF (3 mL) and the mixture was heated to 42° C. The acylimidazole solution was added via cannula to the malonate mixture and the reaction was heated to 42° C. for 2 hours. The solvent was removed in vacuo to give a residue that was partitioned between 1N HCl and EtOAc. The organic layer was dried over MgSO4 and concentrated to a clear oil (0.56 g, 100%). The oil was dissolved in a 0.3 M NaOH solution in MeOH/H2O 1:1 (6 mL), and stirred overnight at room temperature. The reaction mixture was partitioned between H2O and IPE. The aqueous layer was made acidic with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to give the product (0.45 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 1.39-1.71 (m, 8H), 1.81-1.87 (m, 8H), 2.10-2.15 (m, 1H), 2.59-2.68 (m, 2H), 3.51 (s, 2H), 3.75 (s, 2H), 7.11 (dd, J=8.1 Hz, 1.8), 7.27 (d, J=1.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H). ESIMS (MH+): 388.

Workup

  1. customIn a separate flask was placed
  2. temperaturethe reaction was heated to 42° C. for 2 hours
  3. customThe solvent was removed in vacuo
  4. customto give a residue that
  5. customwas partitioned between 1N HCl and EtOAc
  6. dry with materialThe organic layer was dried over MgSO4
  7. concentrationconcentrated to a clear oil (0.56 g, 100%)
  8. dissolutionThe oil was dissolved in a 0.3 M NaOH solution in MeOH/H2O 1:1 (6 mL)
  9. stirringstirred overnight at room temperature
  10. customThe reaction mixture was partitioned between H2O and IPE
  11. extractionextracted with EtOAc
  12. washThe organic layers were washed with brine
  13. dry with materialdried over Na2SO4
  14. concentrationconcentrated

Sources & evidence

ORD record
ord-71862bd5491f49f796091106d372475d
Source dataset
uspto-grants-2012_09
Patent number
US08268835B2

Reaction notes

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