Chlorotrimethylsilane → (S)-2-Chloro-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[(2-tetrahydropyranyl)oxy]pyridinepropanoic Acid Methyl Ester

HRID 2119290노트

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HRID 2119290 반응식
BrCCBr.C[Si]([Cl:9])(C)C.[CH3:10][O:11][C:12](=[O:24])[C@H:13]([CH2:22]I)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].I[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.[CH2:32]1C[O:35][CH2:34][CH2:33]1.[CH3:37][C:38](N(C)C)=[O:39]>C1COCC1.[Zn].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:11][C:12](=[O:24])[CH:13]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:22][C@:26]1([Cl:9])[C:31]([O:35][CH:34]2[CH2:33][CH2:32][CH2:37][CH2:38][O:39]2)=[CH:30][CH:29]=[CH:28][NH:27]1

참가 물질

9

반응물 5

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 2211262-IodopyridineHCID 10903591methyl (2R)-2-(((tert-butoxy)carbonyl)amino)-3-iodopropanoateHCID 69293768tetrahydrofuran N,N-dimethylacetamide2회

생성물 1

HCID 86759327(S)-2-Chloro-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-3-[(2-tetrahydropyranyl)oxy]pyridinepropanoic Acid Methyl Ester수율 60%

시약·촉매·용매 3

HCID 23994Zinc촉매HCID 178418476HCID 178418476, 화합물촉매HCID 8028Tetrahydrofuran용매2회

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온도
30 °C

실험 절차

To an amberized flask containing activated Zn dust (0.349 g, 5.51 mmol) under Ar is added THF (2 mL) and 1,2-dibromoethane (0.018 mL, 0.21 mmol). The suspension is brought to reflux for several minutes, cooled to approximately 30° C., and TMSCl (0.17 mL of a 1 M solution in THF) is added. The reaction mixture is stirred at 40±5° C. for 30 min and then is cooled to below rt. A solution of N-[(1,1-dimethylethoxy)carbonyl]-3-iodo-L-alanine methyl ester [93267-04-0] (1.81 g, 5.50 mmol) in 11:7 dimethylacetamide/THF (9.0 mL) is added, and the resulting reaction mixture is stirred at 45° C. for 5 h. The reaction mixture is cooled to below rt, and solid PdCl2(PPh3)2 (0.192 g) is added, followed immediately by addition of a degassed solution of the iodopyridine (0.936 g, 2.76 mmol) in 1:1 THF/dimethylacetamide (5.6 mL). This reaction mixture is stirred for 4 h at 45° C. It is cooled to 0° C., quenched with sat'd aq NH4Cl, and extracted with EtOAc. The combined EtOAc portions are washed with sat'd aq NH4Cl and brine. The EtOAc solution is dried, filtered and concentrated to give a green-yellow colored foam, that upon purification by silica flash chromatography (7:3 hexanes/EtOAc) gives 0.879 g (1.85 mmol, 60%) of the title product: TLC (7:3 hexanes/EtOAc) Rf 0.21; 1H NMR (CDCl3, 300 MHz) d 7.39 (1H), 7.00 (1H), 5.46 (1H), 4.61 (1H), 4.13 (1H), 3.80 (3H), 3.62 (1H), 3.20 (1H), 2.13-1.53 (6H), 1.42 (9H).

후처리

  1. temperatureto reflux for several minutes
  2. temperatureis cooled to below rt
  3. customthe resulting reaction mixture
  4. stirringis stirred at 45° C. for 5 h
  5. temperatureThe reaction mixture is cooled to below rt
  6. stirringThis reaction mixture is stirred for 4 h at 45° C
  7. temperatureIt is cooled to 0° C.
  8. customquenched with sat'd aq NH4Cl
  9. extractionextracted with EtOAc
  10. washThe combined EtOAc portions are washed with sat'd aq NH4Cl and brine
  11. dry with materialThe EtOAc solution is dried
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customto give a green-yellow colored foam, that
  15. customupon purification by silica flash chromatography (7:3 hexanes/EtOAc)

출처 및 근거

ORD 기록
ord-e4ae1396d2ee4936a64710fca94ea73c
출처 데이터셋
uspto-grants-2004_02
특허 번호
US06685617B1

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