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
Details of the
publication here : http://newdrugapprovals.org/2015/05/15/azd-3264-an-ikk2-inhibitor-from-astra-zeneca/
The synthesis is already
optimized (chosen route: scheme 4), but there are some drawbacks:
- The use of boronic derivatives, which are now classified as mutagenic, 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 mutagen.
Cheaper starting materials (1336 $/kg less) but with 2 more steps (thiophene moiety excluded since this is an in-house product). This route avoids a cryogenic stage with n-Hexyl lithium (health and safety and plant capabilities considerations), and optionally avoids the use of boronic derivatives which are now classified as mutagen.
Sum-up of the modifications:
Modification of the
starting material with three possibilities, essentially to introduce the
isoxazole moiety: According to some lectures about the VNS of H (reference mentioned
later), it maybe possible to use 1-halo-2-nitrobenzene which is cheaper (27$/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.
Making the orientation
into para position need a thermodynamic control with a weak base (K2CO3),
a polar solvent like NMP or DMSO, if necessary a PTC, and an appropriate
reaction temperature. The cited reference indicates a very good selectivity
into para position for a thermodynamic control.
Most probably, by
adding the hydroxylamine sulfate on the precedent mixture, the cyclization
occurs. If the end of reaction is slightly “asthmatic”, the reaction could be
driven to completion by water removal (anhydrous Na2SO4),
which is also needed if it is chained with the next step.
At the end of the
reaction, by removing inorganic solids (KHCO3/K2CO3/Na2SO4),
the mixture is ready for the next step.
Most probably, by
using the conditions mentioned in the original route, it should work. Also if a
one-pot is considered, the ArSNX in cited references below is made
in a polar solvent (MeTHF or tBuOH). Probably by using NMP with tBuOK as base,
it works.
The reduction could
probably be done in a mix water / non-miscible organic solvent to prepare the
next step by washing the organic layer by water to remove remaining dithionite
and bisulfite, followed by an acid extraction with AcOH to avoid the N-Boc
deprotection at a suitable molarity to prepare the next step.
To the aqueous mixture
add NaNO2, adjust AcOH quantity for the diazotation. If the diazonium
salt is unstable, an exchange could be done with TsO- or BF4-
via a resin exchange (but add cost) and add KI to prepare the iodo derivatives.
Since there is a N-Boc protective group, HCl or p-TsOH are not suitable.
As mentioned earlier,
by making a Sandmeyer borylation with B2(OH)4, the route
go back to the original designed one.
References for a draft
procedure:
(This one should be
taken with precautions...)
Sandmeyer with CuBr
cat/KBr:
Sandmeyer borylation:
Instead of using a
toxic reagent, i am pretty sure that a treatment of 2-amino-3-cyano-thiophene with
carbonyl diimidazole followed by addition of formamide afford the “protected”
2-[(aminocarbonyl)amino].
An interesting
publication use NCS with FeCl3 in acetonitrile for the
chlorination. Since Fe(acac)3 or FeCl3 could be used in a
catalyzed cross-coupling reaction in the next step, a feasibility test and
solvent screening (with and without catalyst since there is potentially a
dimerization) should be made to afford the use of the solution with a pre-treatment
to remove the succinimide.
In the publication,
thiophene was used with FeCl3 and only polymerization was observed.
Since the 2-position is substitued, there is maybe a dimerization. Due to the
substituent effects on the ring, it should be tested to see if there is
chlorination or not in these conditions.
If doesn’t work,
instead of using ammonium nitrate (which is slightly “petatoire” in french),
use the procedure in the patent WO 2001058890 A1 in DMF.
Lastly, the standard
procedure is NCS/AcOH.
If the choice is made
to prepare the boronic derivative, NBS must be used.
For the boronic
derivative:
As mentioned earlier, there are several avenues:
1 – Coupling reaction
with the aryl boronic derivative obtained from the diazonium salt
2 – Coupling reaction
with the thiophenyl boronic derivative
The method for case 1
and 2 above is already developed in the publication, the third case is through
a Grignard complex, followed by a cross coupling with FeCl3 or
Fe(acac)3. This third case is purely exploratory and need to be
tested.
The Grignard must be
made on the aryl derivative. The substituent in ortho-position increase the
electronic density on the ring which make the exchange more difficult (that’s
why i have chosen I as halide), but with the EWG group on the thiophene
derivative, these reagents configuration increase the probability of a coupling
with an iron catalyst. Also, since the Grignard reagent is deactivated, maybe
the homo-coupling is avoided like with R-Cu(CN)MgX.
An attention should be
taken about the N-formyl group and the quantity of Grignard needed.
Also, the haloalkane from the exchange must be removed brfore the cross-coupling reaction by a distillation at a reduced pressure (if the stabilized Grignard is unstable above room temp), and at a constant volume with a co-solvent or the reaction solvent.
Also, the haloalkane from the exchange must be removed brfore the cross-coupling reaction by a distillation at a reduced pressure (if the stabilized Grignard is unstable above room temp), and at a constant volume with a co-solvent or the reaction solvent.
Acid hydrolysis of
nitrile to amide is a bit rough (concentrated H2SO4), but
could afford the targeted molecule by N-Formyl removal, N-Boc removal and
nitrile hydrolysis. The last step of N-Boc deprotection use IPA/aqueous HCl.
This condition could also remove the N-formyl, CN hydrolysis must be tested
over a longer reaction time.
Else, a basic
hydrolysis could be used with Amberlyst A26 in IPA/water, followed by a
filtration to remove the resin, and adding aqueous HCl and make the N-Formyl and
N-Boc deprotection.
Costing
This is only a
comparison of major starting material and reagent cost (solvent excluded) between
the two routes (molbase prices):
Original synthesis
Trihalo benzene: 195
$/kg
Isoxazole: 1260 $/kg
n-hexyl lithium: 311
$/kg
Total: 1766 $/kg
Alternate route
1-Chloro-2-nitrobenzene:
27$/kg
1-Chloropentane-2,4-dione:
358 $/kg
Hydroxylamine: 25$/kg
Sodium Dithionite:
10$/kg
Sodium nitrite: <
10$/kg
Total: 430 $/kg
Maximum additional fixed
charges for alternate route to 2 supplementary steps: 1336 $/kg and a minimum
global yield of 57%
Lastly, the cryogenic
step involving the use of n-hexyl lithium is avoided which is a health and safety
concern, and there is a possibility to avoid the use of boronic derivatives
which are now recognized as mutagen.
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.
Update about (14) : add "Also, the haloalkane from the exchange must be removed before the cross-coupling reaction by a distillation at a reduced pressure (if the stabilized Grignard is unstable above room temp), and at a constant volume with a co-solvent or the reaction solvent."
ReplyDeleteIf some have this reference: Iron Catalysis in Organic Synthesis, Ingmar Bauer and Hans-Joachim Knölker*, Chem. Rev., 2015, 115 (9), pp 3170–3387, (DOI http://dx.doi.org/10.1021/cr500425u), please contact me through comment on this page or LinkedIn, i have no access to this publication, and the content seems to be VERY interesting, thank you per advance.
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