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thus we sought the incorporation of a more labile protecting group.
The mild and selective cleavage of isopropyl aryl ethers in the pres-
ence of methyl aryl ethers22 led to the investigation of the isopro-
poxy unit as an alternative protecting group strategy within our
system.
the reaction time or using a larger excess of alkylating reagent in-
creased by-product formation, as determined by HPLC and 1H NMR
analysis. An analytically-pure sample of product 12 could be ob-
tained chromatographically, but such purification proved impracti-
cal on multigram scale due to the near-identical retention factors
of the product and unreacted N,N-diethylbromoacetamide. At-
tempts to purify oil 12 by vacuum distillation led to degradation
of the mixture, thus we decided to explore the possibility of carry-
ing crude 12 through to the following step; the condensation of b-
cyanoketone 12 with hydrazine hydrate to generate the pyrazole
nucleus of 13. Subjecting chromatographically-purified 12 to this
reaction cleanly produced the desired product, and doping the
reaction with N,N-diethylbromoacetamide had no effect on the
yield. Thus, subjecting a sample of crude 12 (containing small
quantities of 11 and N,N-diethylbromoacetamide) to this reaction
produced desired aminopyrazole 13, while 11 was converted into
heterocycle 14. Isolation of a small quantity of 14 by chromatogra-
phy allowed exploration of solubility differences between 13 and
14, and these differences were exploited in the work-up of the bulk
reaction product. Thus, the crude reaction product was dissolved in
aqueous hydrochloric acid and the salt of 13 was precipitated by
the addition of Et2O with vigorous swirling, allowing 14 to be re-
moved by simple filtration. Liberation of free base 13 followed by
recrystallization from toluene gave analytically pure material in
71% yield over two steps, allowing the preparation of more than
20 g of 13 in a single run.
The synthesis of 8 via an improved route is shown in Scheme 2.
The first step of this sequence is the alkylation of 4-hydroxybenzo-
ate methyl ester (9) with 2-bromopropane to give methyl 4-isopro-
poxybenzoate 10 in 100% yield. Although 10 is commercially
available, its in-house preparation was deemed more economically
feasible due to the required quantities, affordability of reactants
and reagents, and ease of synthesis. Initially, this alkylation was
performed under standard conditions in DMF, however, complete
removal of DMF proved problematic. The use of acetone as a sol-
vent for this reaction extended the completion time, but allowed
the quantitative isolation of 10 following work-up, with no purifi-
cation required. This reaction provided 10 of >99% purity by HPLC
(see Supplementary data) on scales of up to 150 mmol. It is feasible
that the reaction time may be reduced by phase-transfer catalysis,
however, this has not been explored.
Toluene containing two equivalents of sodium hydride was
slowly treated with an excess23 of acetonitrile to generate the con-
jugate base. Addition of ester 10 to this mixture produced cyano-
acetophenone 11, which was subsequently deprotonated by the
additional equivalent of acetonitrile conjugate base. The resultant
enolate precipitated from the reaction mixture and was easily fil-
tered. Aqueous dissolution and acidification of this enolate allowed
11 of good purity to be easily isolated. Analytical purity was
achieved by recrystallization from isopropanol–petroleum spirit
(40–60 °C), and consistently provided 11 of >99% purity by HPLC,
in good yield (67%), up to the 130 mmol scale.
Condensation of almost 50 g of aminopyrazole 13 with a stoi-
chiometric quantity of 2,4-pentadione cleanly generated the pyraz-
olopyrimidine core of 15. Evaporation of the solvent and
recrystallization of the crude product from isopropanol provided
15 of >99% purity by HPLC, in 91% yield.
Previous attempts to synthesize intermediate 6 (Scheme 1)
As expected, cleavage of the relatively labile isopropyl ether of
15 with aluminum chloride proceeded more cleanly than the
aforementioned demethylation strategies for 1. The reaction was
quenched by the addition of saturated aqueous ammonium chlo-
ride solution with the free phenol 8 eluted through a short plug
of silica to hydrolyze any complexed product species and trap
remaining aluminum. Simple trituration of this crude material
with diethyl ether provided 8 (92% yield) of suitable purity for sub-
sequent alkylation. Recrystallization of 8 from isopropanol pro-
vided material of >97% purity by HPLC.
Each reaction has been performed several times by multiple
operators, confirming the robust and reproducible nature of the se-
quence. Excluding step (f), each reaction has been performed with
approximately 100 mmol or more of starting material, providing a
stockpile of tens of grams of 15 in a single run. Phenol 8, the com-
mon precursor for the generation of the DPA class of TSPO ligands,
has been synthesized on multigram scale in 40% yield over six
steps without column chromatography.
The synthesis of 1–4 and other alkyl aryl ether derivatives of 8
has been achieved using both classical alkylation conditions and
the Mitsunobu reaction.14,15,20,21 Reported alkylation conditions
have employed sodium hydride as the base in THF or DMF at ambi-
ent temperatures or reflux, with microwave irradiation conferring
no significant improvement to the yield.14,15,20,21 Of these methods,
the yields reportedly obtained from classical alkylation are compa-
rable to those of the Mitsunobu procedure (57–80% and 39–90%,
respectively).14,15,20,21 In our hands, both methods have produced
various members of the DPA class of TSPO ligands in acceptable, al-
beit variable yields, and necessitated chromatographic purification
of the products due to the formation of multiple by-products. It
was envisaged that the alkylation of 8 using conditions analogous
to those used in the formation of 10 might provide a cleaner reac-
tion, however, 8 was found to possess poor solubility in acetone.
Retaining potassium carbonate as the base, 8 was dissolved in
DMF and treated with 2-fluoroethyl bromide at ambient tempera-
have employed N,N-diethylchloroacetamide,
a relatively poor
alkylating reagent, and an excess of iodide to expedite the reaction.
The multiple by-products from this process necessitate careful and
laborious chromatographic isolation of oil 6 from the crude reac-
tion mixture. Other approaches include the use of an appropriate
2-haloacetic acid, such as iodoacetic acid, to give a carboxylic acid
that is carried through the synthesis with late-stage formation of
the required amide.24 However, while the solid carboxylic acid
products are typically isolated without resort to chromatography,
the yields (ꢀ30%) are lower than those employing haloacetamides
(up to 80%).
The synthesis of 12 was attempted using a range of alkylation
conditions. The choice of base used to generate the enolate of 11
proved essentially arbitrary, and was typically governed by solvent
choice. The use of polar protic solvents, such as alcohols or aqueous
alcohol mixtures, appeared to attenuate the nucleophilicity of the
enolate. THF proved an ideal solvent, but the low temperatures re-
quired for the use of alkyllithium bases caused extensive precipita-
tion of the enolate intermediate and precluded complete
deprotonation, an issue easily resolved by using sodium hydride
as the base. N,N-Diethylbromoacetamide offered greater reactivity
than N,N-diethylchloroacetamide, and produced more cleanly the
desired alkylated product. Thus, alkylation of cyanoacetophenone
11 was achieved by preforming the enolate in THF with an excess
of sodium hydride and treating this with a slight excess of N,N-
diethylbromoacetamide. Unfortunately, despite the relatively
clean formation of the desired product, the reaction consistently
failed to proceed to completion. Analysis of the crude material iso-
lated from the reaction, using 1H NMR spectroscopy, typically indi-
cated the desired product in the majority (ꢀ80–85%), along with
smaller amounts of starting material 11 (ꢀ10–15%), unreacted
N,N-diethylbromoacetamide, and the unidentified products of side
reactions (likely resulting from further alkylation of 12). Attempts
to force complete conversion of the starting material by extending