Retrosynthetic analysis of a highly potent, selective, and orally bioavailable factor Xa inhibitor originally made by BristolMyers Squibb (BMS). The disconnection approach uses an amide to break the molecule into two halves, each of which contains two aromatic systems. These aromatic systems include heterocycles – a pyrazole, an imidazole, and a benzisoxazole. The retrosynthesis will construct the pyrazole and benisoxazole using common disconnections, but taking care to account for regioselectivity challenges. For the construction of the pyrazole, a furan ring can be used as a masking group (protecting group) for a carboxylic acid to help differentiate a 1,3dicarbonyl on chemoselectivity (electrophilicity) arguments when a hydrazine is required to be a nucleophile.

BMS Medicinal Chemistry route and original paper that this video is based on:
J. Med. Chem. 2005, 48, 6, 1729
https://doi.org/10.1021/jm0497949

Other key steps in the organic chemistry synthesis include an Ullman coupling between two aromatic rings. This is useful in the medicinal chemistry approach as it makes analogue synthesis more easy and convergent. The benzisoxazole is synthesised from and SNAr nucleophilic substitution step of a hydroxylamine; intramolecular attack on to a nearby nitrile group completes the heterocycle synthesis.

More retrosynthesis videos:
   • Retrosynthesis  

More heterocyclic chemistry videos:
   • Heterocyclic Chemistry  

Chemistry used in this video includes:
SNAr (Nucleophilic Aromatic Substitution)
Furan oxidation
Lithiation of imidazole
Reductive amination
Ullman coupling (Ullman reaction)
Dehydration of amides
FriedelCrafts
Iodination of benzene
Bromination of benzene
Grignard reagents
Heterocycle formation
Isoxazole formation
Pyrazole construction
Regioselectivity for reactions on benzene rings
Amide formation from acid chlorides
Use of copper salts in organic chemistry
Aromatisation reactions

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