(2R)-Oxiran-2-ylmethyl butanoate → (R)-4-Fluoro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester

HRID 277821

반응식

HRID 277821 반응식
[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([F:35])([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](OCC4C=CC=CC=4)=O)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:41]([O:46][CH2:47][C@@H:48]1[O:50]C1)(=[O:45])CCC>O1CCCC1>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([F:35])([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][C@H:47]([CH2:48][OH:50])[O:46][C:41]4=[O:45])=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

참가 물질

5

반응물 3

HCID 2724536(2R)-Oxiran-2-ylmethyl butanoateHCID 538510694-Fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl esterHCID 178418339Butyllithium

생성물 1

HCID 54327244(R)-4-Fluoro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

반응 조건

온도
-78 °C

실험 절차

A solution of 4-fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 2, 2.03 g, contaminated with the elimination side product) in dry tetrahydrofuran (21 mL) at −78° C. under N2 is treated with n-butyllithium (2.80 mL, 1.6M in hexanes) dropwise over 5 mins. The resulting mixture is stirred at −78° C. for 1.25 hrs and is then treated with (R)-(−)-glycidyl butyrate (0.63 mL) dropwise. The resulting solution is stirred at −78° C. for 1 hr, warmed to ambient temperature and stirred for an additional 20 hrs, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (10 mL), and the layers are separated. The organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 250 g), eluting with methanol/methylene chloride (3/97). Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent) gives the title compound (contaminated with the elimination side product from the starting material). An analytical sample is prepared by radial chromatography (2000 m silica gel rotor, ethyl acetate/hexane (60/40) eluent), NMR (400 MHz, CDCl3) 7.45, 7.34, 7.18, 5.16, 4.74, 4.17, 3.97, 3.72, 3.22, 2.25 and 1.90δ and HRMS calculated for C23H24F2N2O5: 446.1653. Found: 446.1660.

후처리

  1. customat −78° C.
  2. stirringThe resulting solution is stirred at −78° C. for 1 hr
  3. temperaturewarmed to ambient temperature
  4. stirringstirred for an additional 20 hrs
  5. customafter which the reaction is quenched with saturated aqueous ammonium chloride (10 mL)
  6. additiondiluted with water (10 mL)
  7. customthe layers are separated
  8. washThe organic phase is washed with saline (10 mL)
  9. dry with materialdried over anhydrous magnesium sulfate
  10. concentrationconcentrated under reduced pressure
  11. customto give the crude product which
  12. customis chromatographed on silica gel (230-400 mesh, 250 g)
  13. washeluting with methanol/methylene chloride (3/97)
  14. customPooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent)

출처 및 근거

ORD 기록
ord-e3970cc77ee14b0d8ebc81ccffe5894e
출처 데이터셋
uspto-grants-2002_03
특허 번호
US06358942B1

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