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

HRID 1096179

Reaktionsgleichung

Reaktionsgleichung von HRID 1096179
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.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[OH-].[Na+].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.[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

Komponenten

7

Edukt 5

HCID 5892NadideHCID 14798Sodium HydroxideHCID 439153NadhHCID 5360315Magnesium ChlorideHCID 667827836-Benzyl-6-aza-spiro[2.5]octan-4-one hydrochloride

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 3776IsopropanolLösungsmittel2×

Reaktionsbedingungen

Temperatur
35 °C

Versuchsvorschrift

A mixture of 300 mg of 6-benzyl-6-aza-spiro[2.5]octan-4-one hydrochloride (1.19 mmol, 1 eq.), 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 □-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 KRED-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 NaCl (9 g), EtOAc (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 EtOAc. 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.

Aufarbeitung

  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 NaCl (9 g), EtOAc (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 EtOAc
  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

Quellen und Nachweise

ORD-Eintrag
ord-00be0b1b42aa4243ae7722298b4f6737
Quelldatensatz
uspto-grants-2012_03
Patentnummer
US08138175B2

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