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

HRID 2387177노트

반응식

HRID 2387177 반응식
[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]

참가 물질

7

반응물 3

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

생성물 1

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

시약·촉매·용매 3

HCID 142844-(Dimethylamino)pyridine촉매HCID 8028Tetrahydrofuran용매HCID 86605377Methyl tert-butyl ethylmalonate용매

반응 조건

온도
42 °C

실험 절차

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.

후처리

  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

출처 및 근거

ORD 기록
ord-71862bd5491f49f796091106d372475d
출처 데이터셋
uspto-grants-2012_09
특허 번호
US08268835B2

반응 노트

불러오는 중…