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


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 

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.