Improved synthesis of (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one, a building block for γ-secretase inhibitors

Tetrahedron Letters

Volumn 50, Issue 46, 2009, Pages 6380-6382

  Hoffmann Emery, Fabienne ^a   Jakob Roetne, Roland ^a   Flohr, Alexander ^a   Bliss, Fritz ^a   Reents, Reinhard ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

Aminodibenzoazepinone; Diastereoselective crystallization; Epimerization; Menthylcarbamate; Resolution

Indexed keywords

7 AMINO 5H,7H DIBENZO[B,D]AZEPIN 6 ONE; CARBAMIC ACID DERIVATIVE; DIBENZAZEPINE DERIVATIVE; GAMMA SECRETASE INHIBITOR; LACTAM; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL STRUCTURE; CRYSTAL STRUCTURE; EPIMERIZATION; STAUDINGER REACTION; SYNTHESIS;

EID: 70349628860     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2009.08.090     Document Type: Article

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10. Optically active acids used were: l-(+)-tartaric acid, (-)-dibenzoyl-l-tartaric acid, (+)-dipivaloyl-d-tartaric acid, (S)-(+)-mandelic acid, (S)-(-)-pyroglutamic acid, d-(-)-quinic acid, (S)-(-)-N-(1-phenylethyl)phthalamic acid, (+)-mono-(1S)-(+)-menthyl phthalate, (-)-N-acetyl-l-glutamic acid, (1R,3S)-(+)-camphoric acid, (1S)-(+)-camphorsulfonic acid, (R)-(+)-2-(4-hydroxyphenoxy)propionic acid, and (S)-(+)-4-isobutyl-α-methylphenylacetic acid.
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12. +, 100), 389 (34), 345 (49).
13. +, 100).
14. Representative procedure of the racemization of 9 and isolation of 8: A solution of 32.3 g mother liquor concentrate (61 mmol, dr = 10.1:89.9) in 130 mL THF was cooled to -15 °C and 92 mL LDA (2 M solution in THF/heptane/methylbenzene, 184 mmol, 3 equiv) were added over 30 min so that the temperature did not exceed -10 °C. The dropping funnel was rinsed with 7 mL THF and the reaction mixture was stirred at 0 °C for 3 h. Fourteen millilitres of EtOH were added dropwise at 0-10 °C and stirring was continued for 30 min. 44 mL EtOAc were added to the clear solution and after cooling to -15 °C, 50 mL aq 25% HCl (385 mmol, 6.3 equiv) were added bringing the aqueous phase to pH 1-2. After separating the phases, the organic layer was washed with 44 mL aq 3 N HCl and twice with 105 mL water. The organic phase was concentrated under reduced pressure and the residue was taken up in 65 mL THF. To this orange suspension, 224 mL n-heptane were added dropwise at 30-40 °C and the suspension was further stirred at room temperature for 1 h. The precipitate was filtered, washed with three portions of 44 mL n-heptane, and dried under reduced pressure at 50 °C affording 12.2 g (38%) 8 as yellow-white crystals of dr = >99.9:0.1.