Hydrochloric Acid → (2R,4S)-Methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate

HRID 1963474노트

반응식

HRID 1963474 반응식
C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[CH3:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O>[CH3:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]

참가 물질

7

반응물 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730430cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate

생성물 1

HCID 86646612(2R,4S)-Methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate수율 55.1%

시약·촉매·용매 2

HCID 887Methanol용매HCID 962Water용매

반응 조건

온도
-40 °C

실험 절차

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (6.28 g, 15.12 mmol) was dissolved in MeOH (60 mL) and cooled to −40° C. 3.8 M NaOH (3.98 mL, 15.12 mmol) was dissolved in water (6 mL) and added to the mixture and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.926 mL, 15.12 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. warm solution of 6 M HCl (76 mL, 453.53 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified in two runs by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (3.2 g, 55%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.81-1.93 (m, 2H), 2.21-2.42 (m, 2H), 2.44 (s, 3H), 3.03-3.13 (m, 1H), 3.59 (s, 3H), 3.63-3.75 (m, 1H), 4.12-4.20 (m, 1H), 5.02 (dd, 1H), 5.65 (s, 1H), 7.30 (d, 1H), 7.37-7.44 (m, 2H). MS m/z 383 (M−H)−

후처리

  1. additionadded to the mixture
  2. stirringstirring
  3. waitcontinued for 3.5 h at −40° C
  4. additionThe reaction mixture was then added to a preheated 80° C.
  5. stirringstirred for 20 min
  6. customThe reaction mixture was partitioned between water and DCM
  7. extractionThe aqueous phase was extracted twice with DCM
  8. customthe combined organic phase was dried
  9. customevaporated
  10. customThe compound was purified in two runs by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  11. custombuffer over 30 minutes

출처 및 근거

ORD 기록
ord-c1eeb03b5b6f4af98dc92972b60d694f
출처 데이터셋
uspto-grants-2013_04
특허 번호
US08415378B2

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