Nadide → (S)-6-benzyl-6-aza-spiro[2,5]octan-4-ol

HRID 559339

반응식

HRID 559339 반응식
Cl.[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:14][CH2:13]2)[C:11](=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[OH-].[Na+].[Cl-].[Mg+2].[Cl-]>CC(O)C>[CH2:2]([N:9]1[CH2:16][CH2:15][C:12]2([CH2:13][CH2:14]2)[C@H:11]([OH:17])[CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1

참가 물질

6

반응물 4

HCID 5892Nadide2회HCID 14798Sodium HydroxideHCID 5360315Magnesium ChlorideHCID 667827836-Benzyl-6-aza-spiro[2.5]octan-4-one hydrochloride

생성물 1

HCID 25204267(S)-6-benzyl-6-aza-spiro[2,5]octan-4-ol

시약·촉매·용매 1

HCID 3776Isopropanol용매2회

반응 조건

온도
35 °C

실험 절차

A mixture of 300 mg of 6-benzyl-6-aza-spiro[2.5]octan-4-one hydrochloride (1.19 mmol, 1 equiv.), 1.5 ml of 2-propanol and 28 ml of 30 mM aq. TRIS-HCl buffer (pH 8.1) was heated to 35° C. The pH was re-adjusted to 8.0. The reaction was started by adding β-NAD (1 mg; free acid; Roche Diagnostics Cat. No. 10 004 626) and ketoreductase KRED-NADH-117 (29.3 mg; Codexis [ex. Biocatalytics]). The suspension was stirred at 35° C. keeping the pH constant at 8.0 by the controlled addition (pH-stat) of 1.0 M aq. sodium hydroxide solution. After roughly 80 area % conversion and 1 d, further 2-propanol (0.3 ml), β-NAD (3 mg; free acid; Roche Diagnostics Cat. No. 10 004 626), ketoreductase K RED-NADH-117 (30 mg; Codexis [ex. Biocatalytics]) and magnesium chloride (12.7 mg) were added. After 4 d, 98.5 area % conversion and 5.9 ml consumption of 1.0 M aq. sodium hydroxide solution the reaction mixture was stopped by the addition of sodium chloride (9 g), ethyl acetate (30 ml) and filter aid (1 g Dicalite Speedex). The mixture was stirred 30 min. and filtered. The filtrate was extracted 3 times with 30 ml ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the crude product in over 99.9% e.e. Purification by flash chromatography provided the title compound as a colorless oil.

후처리

  1. custom98.5 area % conversion and 5.9 ml consumption of 1.0 M aq. sodium hydroxide solution the reaction mixture
  2. additionwas stopped by the addition of sodium chloride (9 g), ethyl acetate (30 ml)
  3. filtrationfilter aid (1 g Dicalite Speedex)
  4. stirringThe mixture was stirred 30 min.
  5. filtrationfiltered
  6. extractionThe filtrate was extracted 3 times with 30 ml ethyl acetate
  7. dry with materialThe combined organic phases were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customto provide the crude product in over 99.9% e.e
  11. customPurification by flash chromatography

출처 및 근거

ORD 기록
ord-e9f52ceace994cb7b9f2c309f3a179be
출처 데이터셋
uspto-grants-2011_11
특허 번호
US08063042B2

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