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 pharmacuetically 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.
Claims12
Process for the preparation of compound (I),
- or pharmaceutically acceptable salt thereof, comprising any of the following steps:
- step 1) compound (III) formation,
- via the reaction of 2,3,4-trifluorophenylacetic acid, compound (II),
- and 1-cloro-4-iodobutane;
- step 2) compound (IVa) formation,
- via chiral resolution of salt formation between a chiral base and compound (III);
- step 3) the formation of (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid, compound (IV),
- via dissociation of the compound (IVa) with acid;
- step 4) the formation of (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoyl chloride, compound (V),
- via acyl chlorination of compound (IV) with chlorinating reagent;
- step 5) the formation of compound (VI),
- via coupling reaction between amino-guanidine and the compound (V);
- Step 6) compound (VII) formation,
- via intramolecular cyclization of compound (VI) in the presence of a base;
- Step 7) compound (I) formation,
- via the Sandmeyer reaction.
Process for the preparation of a compound (IVa),
- via chiral resolution of salt formation between a chiral base and compound (III),
A compound which is compound (IVa);
- (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoate;[(1S)-2-hydroxy-1-phenyl-ethyl]ammonium;
A compound which is compound (IV), (2S)-6-chloro-2-(2,3,4-trifluorophenyl)hexanoic acid, compound (IV),
Dependencies are inferred from the claim text.