Type a reaction class (ex: alkylation) or name (ex: Lossen rearrangement)

Thursday, October 15, 2015

Alternate Synthetic route and process proposal of AZD 3264 an IKK2 Inhibitor

Target

Key words: Aromatic nucleophilic substitution, isoxazole, reduction, diazotation, amino-thiophene, chlorination, cross-coupling, hydrolysis

Complete report here

Original synthesis procedure and route (used for large scale synthesis)



Exploiting the Differential Reactivities of Halogen Atoms: Development of a Scalable Route to IKK2 Inhibitor AZD3264, Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Hebbal, OffBellary Road, Bangalore 560024, India, Org. Process Res. Dev.2014, 18, 646−651

The synthesis is already optimized (chosen route: scheme 4), but there are some drawbacks:

-        The use of boronic derivatives, which are now classified as mutagen, if avoided, should be better.
-        The isoxazole derivatives is expensive (1260 $/kg – molbase price)
-        Cryogenic conditions to prepare the unstable boronic derivative 3 with n-Hexyl lithium.
-        The process described in the patent for the compound 6 (an in house product) use a toxic reagent to prepare the 2-[(aminocarbonyl)amino] : chlorosulfonylisocyanate.

Alternate route proposal:
Cheaper starting materials (1336 $/kg less) but with 2 more steps (thiophene moiety excluded since this is an in-house product). This route avoids a cryogenic stage with n-Hexyl lithium (health and safety and plant capabilities considerations), and optionally avoids the use of boronic derivatives which are now classified as mutagenic.


Sum-up of the modifications:
Modification of the starting material with three possibilities, essentially to introduce the isoxazole moiety: According to some lectures about the VNS of H (reference mentioned later), it maybe possible to use 1-halo-2-nitrobenzene which is cheaper (27$/kg (Cl) 101$/kg (F) – molbase) and 3-chloropentane-2,4-dione (358$/kg), to take advantage of the nitro EWG behavior. It will be reduced later, followed by a diazotation and CuBr/KBr or KI dependently of the method, which will avoid a cryogenic step. Also, to go back to the original route, the diazonium salt could be reacted with B2(OH­)4 which afford the boronic derivative (see reference later)

If doesn’t work, 1-chloro-5-fluoro-2-nitrobenzene probably do, which is unfortunately more expensive than the trihalobenzene (675$/kg – molbase), but the exceeding price of 480$/kg should be absorbed by other starting materials, pentane-2,4-dione (110$/kg - molbase) and hydroxylamine sulfate (25$/kg - molbase).

6 is an in-house product, but to avoid the use of the toxic reagent, i will use in this proposal, the 2-amino-3-cyano-thiophene (450 $/kg – mol base), which is commercially available and treat it with CDI/formamide to obtain the 2-[(aminocarbonyl)amino].

Also if the original compound 6 is used, an exchange could be made with i-PrMgClBis[2-(N,N-dimethylamino)ethyl] Ether Complexes, followed by a treatment with trimethylborate which lead to the boronic acid derivatives (see reference), instead of using the unstable aryl boronic derivative.

Complete report here 

Disclaimer: 
This is some personal works on paper only, i have no responsibility in any way if somebody would try this route and has all sort of troubles, including but not limited to: injuries and money loss. This is for experienced chemists only, and tests must be conducted in a suitable lab only.

But if my work is used to synthesize the targeted molecule described here, please, send a word, even if it fails, chemistry is always an experimental science. This will make me pleased, thank you.

© David Le Borgne, 2015, specialist in chemical process development and optimization.