Process for the preparation of (9S)-2-bromo-9-(2,3,4-trifluorophenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-A]azepine
AssigneeHoffmann-La Roche Inc.
InventorsWeichun Chen, Christian Jenny, Hasane Ratni, Guocai Zhang, Fugui Zhang
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Abstract
The present invention relates to a process for synthesizing large scale a compound of formula (I), or pharmaceutically acceptable salt thereof, which is useful as the key intermediate for the synthesis of compounds for prophylaxis and treatment of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.
Claims2
A process for the preparation of compound (I),
- or a pharmaceutically acceptable salt thereof, the process comprising any of the following:
- a) forming compound (III)
- via reaction of 2,3,4-trifluorophenylacetic acid
- with 1-cloro-4-iodobutane;
- b) forming compound (IVa)
- via chiral resolution of salt formation between (S)-(+)-phenylglycinol and compound (III)
- in the presence of IPAc;
- c) forming (2S)-6-chloro-2-(2,3,4-trifluorophenyl) hexanoic acid, compound (IV),
- via dissociation of compound (IVa) with acid;
- d) forming (2S)-6-chloro-2-(2,3,4-trifluorophenyl) hexanoyl chloride, compound (V),
- via acyl chlorination of compound (IV) with a chlorinating reagent;
- e) forming compound (VI)
- via coupling reaction between amino-guanidine and compound (V);
- f) forming compound (VII)
- via intramolecular cyclization of compound (VI) in the presence of K3PO4/KI in IPA;
- and
- g) forming compound (I)
- via a Sandmeyer reaction in the presence of 1.5 eq t-BuONO/CuBr2.
A compound having the structure of compound (IVa)
- (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoate:[(1S)-2-hydroxy-1-phenyl-ethyl] ammonium.
Dependencies are inferred from the claim text.