Tetrahydrofuran → (R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester

HRID 1427724노트

반응식

HRID 1427724 반응식
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:23]2[C:24]([F:29])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=2[Cl:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

참가 물질

7

반응물 5

HCID 8028TetrahydrofuranHCID 11776TriphenylphosphineHCID 27735612-Chloro-3,6-difluorophenolHCID 5363146Diisopropyl azodicarboxylateHCID 58507548(R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester

생성물 1

HCID 66924701(R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester수율 91.5%

시약·촉매·용매 1

HCID 8857Ethyl Acetate용매

실험 절차

A mixture of (R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 g, 36.1 mmol), 2-chloro-3,6-difluorophenol (8.9 g, 54.1 mmol) and PPh3 (9.93 g, 37.8 mmol) in THF (20.5 mL, 252 mmol) was sonicated for several minutes. While sonicating, DIAD (7.5 mL, 37.8 mmol) was slowly added dropwise to the mixture over several minutes and sonicated further for 15 minutes. The mixture was concentrated and then triturated in excess hexanes for 16 hours. The PPh3 oxide precipitate was filtered off and the organic layer was concentrated to yield a yellow oil. The crude mixture was diluted in EtOAc (300 mL), washed with 1N NaOH (2×200 mL) and saturated aqueous NaCl (100 mL). The organic layer was dried with anhydrous MgSO4, filtered, and concentrated. The organic material was purified by silica gel chromatography (330 g column, 20-50% EtOAc in hexanes) to yield 14 g of (R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a yellow oil which was used in the next step without further purification.

후처리

  1. customwas sonicated for several minutes
  2. customWhile sonicating
  3. customsonicated further for 15 minutes
  4. concentrationThe mixture was concentrated
  5. customtriturated in excess hexanes for 16 hours
  6. filtrationThe PPh3 oxide precipitate was filtered off
  7. concentrationthe organic layer was concentrated
  8. customto yield a yellow oil
  9. washwashed with 1N NaOH (2×200 mL) and saturated aqueous NaCl (100 mL)
  10. dry with materialThe organic layer was dried with anhydrous MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe organic material was purified by silica gel chromatography (330 g column, 20-50% EtOAc in hexanes)

출처 및 근거

ORD 기록
ord-43afd11422f644d799745e9919b6179e
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08933249B2

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