Original synthesis procedure and route
Multkilogram Scale-Up of a Reductive Alkylation Route to
a Novel PARP Inhibitor
Chemical Research and
Development, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich,
Kent CT13
9NJ, United Kingdom,
Organic Process Research
and Development 2012, Vol 16, 1897−1904
Details of the
publication is here: http://newdrugapprovals.org/2015/06/09/ag-014699-rucaparib/
Optimization
The publication
indicate a poor global yield (2.9%) even if the process is optimized, also the
chosen indolization method seems to be difficult, metal catalyzed reaction
employing boronic acids which are now recognized as mutagenic, reduction with
cyanoborohydride and numerous steps.
The “ideal” route i
have chosen involves a Fisher indolization. Few steps are tricky due to some
functional group fragility, but by designing the process correctly, some side
reactions could be avoided. Even if undesirable reaction occurs significantly,
i have indicated some alternatives which, unfortunately, involve a cost.
The key point of
this route is the indolization, i have evaluated the feasibility by some lectures
and by using the software Hulis (Huckel theory), to roughly make a comparison
between the hydrazone intermediate and intermediates seen in the literature,
especially the trifluoroacetyl one. Starting at 4, it is really more an
exploration, that’s why i have indicated some alternatives.
Lastly, it has 9 steps
instead of 12, with 5 isolations.
Optimized route and process
This starting material
is 200 $/kg cheaper than the protected one by the diethylketal. Depending the
protecting group resistance versus the Fisher indol reaction conditions
(described later which takes in consideration the fragility of this PG), there
is a cheap method to protect the aldehyde by ethanol or ethylene glycol with
Zeolite H-ZMS-5 as acid catalyst (tested on benzaldehyde with methanol).
Conditions: ethanol with
a loop taking the distillate by a pump, pass through a column packed with
anhydrous Na2SO4 and re-injected into the reactor ; or ethylene
glycol + other solvent not absorbed by Zeolite which make an azeotrope with
water ; for both methods heat for water removal.
For this step, i have
chosen an acylation through a Grignard alone or followed by a transmetallation to
give an organocuprate. There is several methods involving Br/Mg exchange with
iPrMgBr.LiCl followed by the exchange with CuCN.LiCl, or a Grignard complex with
the bis[2-(N,N-dimethylamino) ethyl] ether which
is less reactive and could avoid a potential alkylation. Finally there is the
iron-catalyzed cross-coupling of Grignard with acid chloride, it potentially
has my preference, but could has a patent issue (the patent should be checked
in details).
Ideally, and if it works, it could be a
Br/Mg exchange with iPrMgCl-bis[2-(N,N-dimethylamino) ethyl] ether complex,
and make the acylation. It is un-reactive versus halo-aryl, so most probably
not reactive versus halo-alkyl. The doubt of the feasibility is with the alkyl
acyl chloride, because of the +I effect of the alkyl chain on the acyl. On the
contrary, the organo cuprate works with an alkyl acid chloride, but react too
with alkyl iodide, it should be checked if it is un-reactive versus a Cl-C
bond.
Solvent: THF,
temperature: room temp
Demonstrating that
alkyl acyl chloride also works with organocuprate: Efficient Synthesis ofFunctionalized Organozinc Compounds by the Direct Insertion of Zinc intoOrganic Iodides and Bromides, A. Krasovski, V. Malakhov, A. Gavryushin, P.Knochel, Angew. Chem. Int. Ed., 2006, 45, 6040-6044.
By using DMSO at 90°C during 48h and the
appropriate amount of hydrazine (6 eq ?), the conditions lead to the
3-fluoro-5-cyanophenylhydrazine. Solvent and conditions could probably be optimized
through 3 DoE (solvent screening, temperature screening and hydrazine quantity
screening).
The neuralgic point in
this route is the Fisher indol synthesis. There are two major difficulties: the
diethylketal which is sensible to acid and water, and the halo-alkyl moiety
which could react with the amine intermediate to afford a 6 members ring, and
lastly, the alkyl chain could make a too high stabilization by +I effect of the
ene-hydrazine intermediate which could lower the yield or prevent the
cyclization (see reference). On the contrary, the substituent on the aromatic
ring makes the cyclization easier by their electro-withdrawing characteristics.
If there is a too high stabilization, by PG removal, the aldehyde could make also
an electro-withdrawing effect.
The diethylketal is a
major problem only during the hydrazone formation with the formation of water.
The halo-alkyl is a more important one during the cyclization.
To resolve the ketal
problem, an anhydrous mineral salt could be used as MgSO4 or Na2SO4
to trap the water immediately, a catalytic amount of AcOH and a gentle heating
during the hydrazone formation. An intermediate filtration must be done to
eliminate the salts before the cyclization which use Amberlite A15. Lastly, the
reaction maybe couldn’t be conducted in an alcohol due to the potential imidate
ester formation during the cyclization. If despite the precautions, the diethylketal
is removed, use 1,3-dioxolane as PG which is more resistant (more expensive
than the diketal if bought).
To avoid the
alkylation, there are two solutions, acid catalyzed indolization with 1 eq or
more of strong acid, and N-acylation which is also driving the cyclization.
For the reaction
conditions, i would try THF or other polar water-miscible aprotic solvent, AcOH
in a catalytic amount to avoid the PG removal during the hydrazone formation
and a gentle heating to also halt to this intermediate. I will try before
ethanol (or IPA my preference) as solvent considering the PG and indolization
conditions seen in the literature, but i am afraid about the alcoholysis (in a
small amount) of the nitrile because of the cyclization conditions (see Pinner
alcoholysis). Once the first step is complete, filter out the salts, add
Amberlit A15 (to keep the ammonium out of the liquid phase - see reference) and
heat. If N-alkylation is observed, use the TFAA strategy (see reference) which
also drive the cyclization.
Lastly, Fisher
indolization could be conducted with zeolite, an alternative which could possibly
avoid N-alkylation of the amine intermediate. This last solution has my
preference if it works (see reference).
Hydrolysis: PG removal of the aldehyde and
nitrile hydrolysis followed by amide N-alkylation (5 and 6)
Add water to the
precedent mixture, easy PG removal if this is an acyclic diethylketal, more
difficult if this is the 1,3-dioxolane. Once the PG removal is complete, filter
out the amberlite A15 and add the Amberlite A26 for the nitrile hydrolysis and
N-alkylation of the amide, NaI and LiX LiI could help.
The more known
condition (by some “chemist”) is N-methyl formamide with formic acid. I will
add ammonium formate or MgCl2 if the reaction is too slow, but there
are some risks of N-formyl benzamide derivative or traces of Mg2+
which must be removed. Also the required temperature could afford impurities
degradation.
The alternative could
be methylamine in ethanol with triethylorthoformate to remove water, formic
acid as reductive agent and ethanol or IPA as solvent. If the imine doesn’t
tolerate the alcohol in a too large quantity, use methylamine in THF and
acetonitrile as solvent.
The N deformylation
could be tried directly with camphor sulfonic acid which has a pKa of 1.2 in IPA/water, if a
Leuckart with N-methyl formamide is tried, else the treatment designed in the
publication. If IPA is used in the previous step, directly isolate the CSA salt
from the mixture.
The product must be of course
recrystallized.
Costing
This is only a price comparison
of majors starting materials, since the process is subject to modifications.
Initial route (12 steps):
5-Fluoro-2-methylbenzoic
acid (molbase): 550$/kg (84.78$/mol)
Phthalimidoacetaldehyde
diethyl acetal (molbase): 2369$/kg (623.73$/mol)
4-Formylphenylboronic
acid (molbase) : 350 $/kg (52.48$/mol)
Total: 3269 $/kg (760.99$/mol)
Optimized route (9 steps):
4-Bromobenzaldehyde
(molbase): 101$/kg (18.69$/mol)
5-Chlorovaleryl
chloride (molbase): 141 $/kg (21.86$/mol)
3,5-Difluorobenzonitrile
(molbase): 150 $/kg (20.87$/mol)
Total: 392 $/kg (61.42$/mol)
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.
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