Flow trifluoromethylation of carbonyl compounds by Ruppert-Prakash reagent and its application for pharmaceuticals, efavirenz and HSD-016

Article abstract of DOI:10.1039/c6ra19790f

The Ruppert-Prakash reagent is the most powerful and well-documented reagent for trifluoromethylation. Despite its versatility, no general method exists for its use in a flow system. Here we report the first flow trifluoromethylation of carbonyl compounds

Full text of DOI:10.1039/c6ra19790f

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Flow trifluoromethylation of carbonyl compounds by Ruppert-
Prakash reagent and its application for pharmaceuticals, Efavirenz
and HSD-016
Received 00th January 20xx,
Accepted 00th January 20xx
Satoshi Okusu,a Kazuki Hirano,a Yoshimasa Yasuda,a Etsuko Tokunagaa and Norio Shibata*a
DOI: 10.1039/x0xx00000x
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The Ruppert-Prakash reagent is the most powerful and well- companies such as TOSOH-F TEC INC8 and P&M Invest,9 and
documented reagent for trifluoromethylation. Despite its has become a versatile reagent for industrial use.
versatility, no general method exists for its use in a flow system.
OMe
MeO
Here we report the first flow trifluoromethylation of carbonyl
H
N
compounds and its utility for drug synthesis of Efavirenz and HSD-
016, including preliminary results of enantioselective variants.
O
O
N
OH
CF3
O
N
H
Ph
O
F3
C
OH
CJ-17493
Befloxatone
H2N
F3C
O
S
S
Introduction
N
N
F
O
The introduction of a trifluoromethyl group (CF3) into a drug
candidate can greatly affect its properties, in particular
bioavailability due to the alteration of the lipophilic/lipophobic
balance.1 The improvement of the chemical and physical
stability of drugs by trifluoromethylation to improve oxidative
degradation has also been reported.1 Among these cases,
trifluoromethyl carbinols are very impressive.2 The strong
electron-withdrawing effect of CF3 strengthens the hydrogen-
bonding affinity of carbinols. Consequently, trifluoromethyl
carbinols have been successfully employed as components of
many pharmaceuticals and drug candidates,2 including the NK-
1 receptor antagonist CJ-17493, reversible monoamine oxidase.
A inhibitor Befloxatone, anti-HIV drug Efavirenz,3 and 11β-
hydroxysteroid dehydrogenase type 1 inhibitor HSD-0164 and
HSD-621,5 among others (Figures 1 and 2). One of the most
powerful and efficient methods to prepare trifluoromethyl
carbinols is the direct trifluoromethylation of carbonyl
compounds by (trifluoromethyl)trimethylsilane (CF3SiMe3, or
Ruppert-Prakash reagent).6 This method was reported by
Me
F3C
HSD-621
Figure 1. Examples of pharmaceuticals and drug candidates with trifluoromethyl
carbinols.
The emergence of flow technology in organic synthesis, i.e.,
flow chemistry, has started to become a major contributor to
process chemistry and scale-up in the pharmaceutical and
chemical industries from the perspective of environmental
compatibility.10 Flow chemistry, in particular, micro-flow
reactions, has several advantages over classical batch reaction
systems including the speed of reactions, easy scale-up, safety,
and a reduced size of the plant. Recent advances in synthetic
flow chemical technology have achieved a wide variety of
fundamental batch reactions for flow systems, including
coupling,
photo,
and
asymmetric
reactions.
Trifluoromethylation reactions have also been subjected to
flow chemistry using conditions adapted from common batch
conditions.10d,11 Photochemical trifluoromethylation using
CF3I,11a,b CF3SO2Na,11c,d CF3SO2Cl,11b,e and a trifluoromethyl
aromatic coupling reaction using CF3CO2K11f have been
reported. However, there is no report on trifluoromethylation
using the Ruppert-Prakash reagent, CF3SiMe3 in a flow system
despite its wide versatility in industry. Herein, we disclose the
trifluoromethylation of carbonyl compounds by CF3SiMe3 in a
flow system for the first time. A wide variety of carbonyl
compounds, including aryl ketones, alkyl ketones and
aldehydes, were promptly converted into the corresponding
trifluoromethyl carbinols with CF3SiMe3 in a flow system. A
glass column packed with KOH/Celite was effective for flow
trifluoromethylation eluted with DMF. The method enabled
the flow synthesis of a key precursor of the anti-HIV drug
Efavirenz, and a potent, selective, and efficacious 11β-HSD1
Prakash and co-workers using
a catalytic amount of
tetrabutylammonium fluoride (TBAF) over 20 years ago.7
Nowadays, not only fluoride catalysts but also a wide variety of
catalytic systems, including Lewis bases and inorganic bases,
are known for this transformation. The Ruppert-Prakash
reagent is available in up to ton quantities from chemical
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inhibitor of HSD-016. Enantioselective trifluoromethylation in
this flow system was also employed for the first time using a
cinchona alkaloid/Celite-packed system (Figure 2).
Table 1. Optimization of base and solvent for trifluoromethylation of 1a
Run
1
base
KOH
KOH
KOH
KOH
KOH
KOH
PhOK
LiOAc
CsF
solvent
Solkane®365
toluene
THF
2a Yield (%)a
0
2
0
3
0
4
CH2Cl2
DMSO
DMF
0
5
48
6
95
7
DMF
68
Figure 2. Flow trifluoromethylation of carbonyl compounds by CF3SiMe3 and its
application to pharmaceuticals, Efavirenz and HSD-016, including preliminary attempts
of an enantioselective reaction.
8
DMF
77b (2a/3a=78/22)
75b (2a/3a=72/28)
89b (2a/3a=94/ 6)
80b (2a/3a=59/41)
9
DMF
10
11
KOHc
KOHd
DMF
DMF
Results and discussion
aDetermined by 19F-NMR using a crude mixture with trifluorotoluene as the
We devised a simple Pasteur pipette flow reactor packed with internal standard. b Total yields of 2a and 3a. The ratios of 2a/3a are indicated in
parentheses. c20 mg of KOH was used. d5 mg of KOH was used.
base/Celite for the trifluoromethylation of benzophenone (1a
)
with CF3SiMe3 (Figure 3).
1a, Me3SiCF3 in solvent
Pasteur pipette
(7 Ø X 146 mm)
base/Celite
product 2a
sat. NH4Cl
Figure 3. System diagram of flow reactor for trifluoromethylation.
First, KOH was selected as a packed base in Celite (50 wt.%)
for the flow-trifluoromethylation of 1a by Me3SiCF3, since KOH
is an inexpensive and good initiator of trifluoromethylation in a
greener solvent, Solkane®365 in a common batch system.12
However, the reaction did not take place in Solkane®365 under
flow conditions (run 1, Table 1). Toluene, THF and
dichloromethane were also not suitable (runs 2—4), while
DMSO showed a good result of 48%, yielding trifluoromethyl
carbinol 2a (run 5). We thus attempted the reaction in a polar
aprotic solvent, DMF, and 2a was obtained in 95% yield (run
6). The base was next screened in DMF (runs 7—9). The
reaction proceeded smoothly in DMF with PhOK, LiOAc and
CsF, but the yields were not higher than when KOH was used.
Interestingly, 2a was solely obtained by potassium salts, KOH
and PhOK (runs 6 and 7), while a mixture of 2a and its
trimethylsilyl ether 3a was observed using lithium and cesium
salts (runs 8 and 9). The formation of 3a suggested that a
catalytic process was partially involved in the reaction. We
thus reduced the amount of KOH in Celite for flow
trifluoromethylation (runs 10—11). As expected, the formation
of 3a was dependent upon the amount of KOH, i.e., as the
amount of KOH decreased, the amount of 3a increased, while
the total yields of 2a and 3a remained as the majority.
Scheme 1. Trifluoromethylation of carbonyl compounds 1 by the flow reaction. The
values indicate isolated yield after desilylation and the values in parentheses are 19F-
NMR yields. aLiOAc was used instead of KOH.
With a suitable condition in hand (run 6, Table 1), the
substrate scope for trifluoromethylation in the flow system
was explored (Scheme 1). Diarylketones 1a
converted to the corresponding α-trifluoromethyl alcohols
2a in good to high isolated yields (67%—99%). Aryl methyl
ketones 1d with an enolizable proton and cyclic aliphatic
ketone 1g were also accepted in the flow system to provide
the corresponding trifluoromethylated carbinols 2d in up to
—c were nicely
—c
—f
—g
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91% isolated yields. Chalcone (1h) was transformed exclusively was also successfully performed with a microflow reactor
into 1,2-trifluoromethyalted adduct 2h in 74% yield. We next under similar conditions (KOH/Celite, 50% wt, glass packed
examined the reaction of aldehydes 1i—n. A variety of column) providing Efavirenz intermediate 2p in high yield of
substituents at their aromatic ring of aldehydes such as 91% (Figure 4). Hence, our method can be easily extended to
methyl, and methoxy, nitro cyano were well tolerated to the continuous-flow process which realizes the large scale
provide the corresponding α-trifluoromethyl alcohols 2i
good to high yields, with up to 94% isolated yield. Although the
aldehydes 1m having electron-withdrawing NO2 and CF3
groups decomposed in KOH, this was overcome by using LiOAc
to provide in 60–81% yield as a mixture with its silyl ethers
3m
—
n
in preparation of corresponding trifluoromethyl carbinols.
—
n
2
—n.
We next focused on the synthesis of pharmaceuticals using
our flow trifluoromethylation (Scheme 2). Flow reactions have
long been used for the preparation of simple materials in the
chemical industry, while the technology has just recently
gained special attention by the pharmaceutical industry to
realize the on-demand synthesis of drugs.10e,f, 13 In this context,
we were interested in the flow synthesis of a potent and
efficacious 11β-HSD1 inhibitor, HSD-016.4 HSD-016 was
developed by Pfizer and shows attractive pharmaceutical
profiles in human studies. Although HSD-016 can be prepared
in multigram quantities in batch synthesis, the flow synthesis
of HSD-016 has not been examined. We found that our flow
trifluoromethylation was well-adapted for the synthesis of
HSD-016 from corresponding ketone 1o by Me3SiCF3 under our
flow-system to furnish 2o (HSD-016) in 80% yield as a mixture
of diastereoisomers. The next target was Efavirenz.3 Efavirenz
is an anti-HIV drug, and its production is carried out in a batch
system by Merck14 and Lonza,15 and a flow protocol for the
synthesis of Efavirenz is the next challenge.16 We thus
examined the flow trifluoromethylation of 1-(5-chloro-2-
nitrophenyl)-3-cyclopropylprop-2-yn-1-one (1p) with Me3SiCF3
through our KOH/Celite packed reactor. As expected, the
Figure 4. System diagram of microflow reactor for trifluoromethylation of 1p to
2p.
Finally, enantioselective trifluoromethylation was attempted
under the flow system (Scheme 3). We devised a cinchona
alkaloid/Celite packed Pasteur pipette. DMF was unsuitable for
this flow system due to the high solubility of cinchona alkaloids
packed with Celite in a column. We first attempted the
enantioselective trifluoromethylation of ketones
1 with
Me3SiCF3 using our previously reported batch system, the
combination of ammonium bromide of cinchona alkaloids and
tetramethylammonium fluoride (TMAF),17,18 however, the
method also failed. After many trials, we found that the
system consisting of cinchona alkaloid ammonium phenoxides
packed with Celite and eluted with CH2Cl2/toluene (1/1) was
useful for this transformation. Namely, a mixture of 2-
naphthaldehyde (1i) and Me3SiCF3 in CH2Cl2/toluene (1/1) was
directly eluted through the cinchona alkaloid catalyst
A18a/Celite pack to afford 2i in 52% yield with 36% ee. The
enantioselective flow trifluoromethylation of Efavirenz was
also successful through a cinchona alkaloid catalyst B17a/Celite
pack from alkynyl ketone 1p and 1q with Me3SiCF3 to afford 2p
in 41% yield with 36% ee, and 2q in 47% yield with 30% ee,
respectively. Enantioenriched 2q and 2p can be converted to
Efavirenz by methods described in the literature. These are the
first examples of enantioselective trifluoromethylation in a
flow system.
reaction proceeded rapidly to provide
a
desired
trifluoromethylated carbinol 2p in 88% yield. 1-(2,5-
Dichlorophenyl)-3-cyclopropylprop-2-yn-1-one (1q) was also
nicely converted into trifluoromethylated adduct 2q in 86%
yield in the flow system. Both trifluoromethylated carbinols
2p17 and 2q15 are key intermediates for the synthesis of rac-
Efavirenz.
Scheme 2. Application of flow trifluoromethylation for the preparation of
pharmaceuticals, HSD-016 and Efavirenz. aA mixture of diastereomers was obtained
(the ratio was not determined.) b 19F-NMR yield.
To show the potential of large-scale synthesis of
trifluoromethyl carbinols, the flow trifluoromethylation of 1p
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Scheme 3. Enantioselective trifluoromethylation of 1i, 1p and 1q by a flow system.
aMixtures (R=H and SiMe3) were obtained, and ratios were determined by 19F-NMR.
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Conclusions
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See
the
website
of
P&M-Invest
Ltd,
We have developed
a
flow method for the
http://www.fluorine1.ru/.
trifluoromethylation of carbonyl compounds by the Ruppert-
Prakash reagent. The KOH/Celite packed column is easy to set
up and trifluoromethylation can be performed under air. The
reaction is rapid and can be applied to the synthesis of
pharmaceuticals such as Efavirenz and HSD-016. A microflow
reactor is also useful for this flow trifluoromethylation. We
also devised a cinchona alkaloid ammonium phenoxides/Celite
packed column and disclose preliminary results of
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This research was partially supported by the Aichi Science &
Technology Foundation, JSPS KAKENHI Grant Number JP
16H01142 in Middle Molecular Strategy, the Platform Project
for Supporting in Drug Discovery and Life Science Research
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