Initial synthesis of UK-427,857 (Maraviroc)

Article abstract of DOI:10.1016/j.tetlet.2005.05.082

The initial synthesis of UK-427,857 (Maraviroc) is described including the preparation of 4,4-difluorocyclohexanoic acid and amide coupling utilizing a polymer supported reagent.

Full text of DOI:10.1016/j.tetlet.2005.05.082

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5005–5007
Initial synthesis of UK-427,857 (Maraviroc)
*
David A. Price, Simon Gayton, Matthew D. Selby, Jens Ahman,
Sarah Haycock-Lewandowski, Blanda L. Stammen and Andrew Warren
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT139NJ, UK
Received 27 April 2005; accepted 19 May 2005
Available online 9 June 2005
Abstract—The initial synthesis of UK-427,857 (Maraviroc) is described including the preparation of 4,4-difluorocyclohexanoic acid
and amide coupling utilizing a polymer supported reagent.
Ó 2005 Elsevier Ltd. All rights reserved.
UK-427,857 (Maraviroc) is a potent antagonist of the
CCR5 receptor and is currently progressing through
nucleophilic fluorinating sources. This transformation is
routinely accomplished using diethylaminosulfur trifluo-
ride (DAST) which is commercially available but does
require careful handling due to its well-known thermal
phase III clinical trials as a treatment for HIV (Fig.
1
1
). The structure includes a 4,4-difluorocyclohexyl unit,
4
a phenylpropyl motif with a benzylic stereogenic centre
and an equatorially disposed triazole in a tropane sys-
tem. The synthesis of the required 1,2,4-triazole substi-
instability. In our first attempts to use DAST to pre-
pare the target acid 5, we were disappointed to find that
treatment of ketone 1 with 1.05 equiv of DAST in
dichloromethane at 0 °C resulted in complete consump-
tion of the starting material but gave an inseparable 1:1
mixture of the required difluoro compound 2 and the
vinyl fluoride 3 in 85% yield. The formation of vinyl
fluoride co-products from treatment of ketones with
DAST is known in the literature and appears difficult
2
tuted tropane has been previously described. This
letter focuses on the challenges in preparing the
required 4,4-difluorocyclohexanoic acid and the overall
synthetic route used in the preparation of UK-427,857
(
Maraviroc) to underwrite initial studies.
5
The use of fluorine in molecules of pharmacological
interest can profoundly alter their biological properties
and there has been widespread research into methodol-
to control. Optimisation studies undertaken to influ-
ence the ratio of products including temperature,
reagent stoichiometry and solvents were unsuccessful.
3
ogies for the introduction of this atom. One of the most
commonly used techniques is the conversion of carbon–
oxygen functional groups into carbon–fluorine bonds by
The mixture of 2 and 3 was subjected to Upjohn condi-
6
tions for dihydroxylation and we were delighted to find
that after the reaction overnight the required dif-
luorocyclohexyl ester 2 could then be isolated in high
7
purity by column chromatography. The assumed prod-
O
uct 4 from oxidation of the vinyl fluoride was never iso-
lated and only identified by mass spectral evidence from
the crude reaction mixture. Saponification of 2 gave the
required 4,4-difluorocyclohexyl acid 5 which was recrys-
tallised from cyclohexane to furnish an analytically pure
material (Scheme 1).
F
H
N
F
N
N
N
N
Figure 1. UK-427,857 (Maraviroc).
With suitable quantities of 5 in hand, our attention
turned to preparing multigram quantities of the phenyl-
propyl linker. The starting material was the commer-
cially available chirally pure b-amino ester 6 which
Keywords: Heterocycles; Triazoles; Amide; Tropane; Fluorination.
*
Corresponding author. Tel.: +44 1304 644690; fax: +44 1304
51821; e-mail: david.a.price@pfizer.com
8
6
was protected in high yield. The ester was then reduced
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.082

5006
D. A. Price et al. / Tetrahedron Letters 46 (2005) 5005–5007
O
O
F
F
F
H
a
O
N
O
+
N
N
H
N
H
+
N
8
O
OEt
F
O
OEt
O
OEt
a
1
2
3
R
H
b
N
R=Boc 10
b
N
O
N
F
F
F
N
OH
N
c
R=H 11
+
c
O
O
OH
O
OEt
O
OEt
F
H
N
5
2
4
F
N
N
N
Scheme 1. Reagents and conditions: (a) DAST, 0 °C, CH
2 2
Cl , 85%
N
yield of 1:1 mixture; (b) OsO , NMO, acetone, water, 74% yield based
4
UK-427,857
on 1:1 mixture as starting material; (c) NaOH, THF, water, 65%.
O
N
N
to the required aldehyde using 2 equiv of diisobutylalu-
minium hydride in dichloromethane. Over reduction to
the alcohol is prevented by internal coordination of
the aluminium to the nitrogen forming a six-membered
chelate 9 that breaks up upon aqueous work-up liberat-
ing the aldehyde 8 (Scheme 2).
12
Scheme 3. Reagents: (a) Na(AcO)
3
BH, CH Cl
2
2
3 2
, 75%; (b) CF CO H,
CH Cl , 95%; (c) 5, 12, CH Cl , 48%.
2
2
2
2
0
had been N-(3-dimethylaminopropyl)-N -ethylcarbodi-
The optimised synthesis of the 1,2,4-triazole substituted
tropane has been previously described and reductive
amination with the aldehyde 8 furnished the key tert-but-
yl carbamate protected intermediate 10. The tert-butyl
carbamate was removed in high yield using 25% trifluoro-
acetic acid in dichloromethane to give the precursor
1
imide. However, upon closer examination of the
H
NMR spectra of a number of analogues it was apparent
that trace amounts (typically <2 mol %) of the coupling
reagent and associated adducts were contaminating the
product after purification. This level of impurity was
unacceptable in this synthesis as the material was under-
writing key studies that could be influenced by minor
impurities.
1
1.
Previously in the project, high-throughput chemistry
had been applied to template 11 to optimise rapidly
the amide moiety of the series. The reagent of choice
for performing this coupling with a variety of acids
Alternative coupling agents were screened and the opti-
mal conditions obtained were a slight excess of the acid
5
1
(1.1 equiv) and a polymer bound carbodiimide reagent
9
2 (2.0 equiv) in dichloromethane. Once the reaction
was complete, simple filtration and filtering through a
pad of silica furnished UK-427,857 (Maraviroc) which
was recrystallised to analytical purity from toluene/hex-
ane (Scheme 3).
O
NH2
O
O
NH
O
a
OMe
OMe
In conclusion, we have described the initial synthetic
10
route to UK-427,857 (Maraviroc) that was used to
6
7
underwrite early evaluation. Subsequent synthetic
improvements have been made and will be reported in
further communications.
b
O
Al
O
O
N
O
O
NH
O
OMe
Acknowledgements
H
9
The authors wish to thank Andy Fowler for supplying
and recommending the polymer supported reagent and
Torren Peakman for his assistance with analysis of the
8
Scheme 2. Reagents and conditions: (a) (Boc)
b) DIBAL-H, CH Cl
, ꢀ78 °C, 75%.
2 3
O, aq NaHCO , 90%;
1
(
2
2
H spectra.

D. A. Price et al. / Tetrahedron Letters 46 (2005) 5005–5007
5007
References and notes
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8
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1
2
3
. For a review of recent advances in HIV therapy see: De
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Ò
9
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1
0. The coupling reagent 12 (500 mg, 0.54 mmol) was added
to a stirred solution of the amine 11 (100 mg, 0.27 mmol)
and acid 5 (50 mg, 0.30 mmol) in dichloromethane (5 mL)
at room temperature. After 1 h, the reaction mixture was
filtered through a plug of silica washing with 10%
methanol in dichloromethane (20 mL) to furnish UK-
2
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4
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1
5
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1
mp 197–198 °C; H NMR (400 MHz; CDCl
3
) d = 7.36
(2H, m), 7.23 (3H, m), 6.61–6.48 (1H, br m), 5.15 (1H, dd,
J 6.7 Hz, 6.7 Hz), 4.28 (1H, m), 3.33 (2H, m), 2.86 (1H,
5
6
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m), 2.48 (3H, s), 2.28 (2H, m), 2.18–1.61 (19H, m), 1.39
(
+
6H, d, J 7.0 Hz); LRMS: m/z 514.4, MH ; C29
H
41
F N
2 5
O
requires C, 67.75; H, 8.06; N, 13.54; Found C, 67.77; H,
.00; N, 13.64.
8