Application of Isayama–Mukaiyama cobalt catalyzed hydroperoxysilylation for the preparation of ritonavir hydroperoxide

Article abstract of DOI:10.1016/j.tetlet.2016.10.022

We report the preparation of thiazol-5-ylmethyl ((2S,3S,5S)-5-((S)-2-(3-((2-(2-hydroperoxypropan-2-yl)thiazol-4-yl)methyl)-3-methylureido)-3-methylbutanamido)-3-hydroxy-1,6-diphenylhexan-2-yl)carbamate, a hydroperoxide impurity of ritonavir also known as

Full text of DOI:10.1016/j.tetlet.2016.10.022

Tetrahedron Letters 57 (2016) 5099–5102
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Application of Isayama–Mukaiyama cobalt catalyzed
hydroperoxysilylation for the preparation of ritonavir hydroperoxide
Sharon Gazal a, Priya Gupta b, Siva Ramakrishna Gunturu b, Matthew Isherwood b, Matthew E. Voss b,
⇑
a Analytical Technologies Unit, Teva Pharmaceutical Industries, Eli Hurvitz 18, Kfar Saba 44102, Israel
b Medicinal Chemistry Department, Albany Molecular Research Singapore Research Center Pte. Ltd, 61 Science Park Road, #05-01 The Galen, Singapore Science Park III,
Singapore 117525, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
We report the preparation of thiazol-5-ylmethyl ((2S,3S,5S)-5-((S)-2-(3-((2-(2-hydroperoxypropan-2-yl)
thiazol-4-yl)methyl)-3-methylureido)-3-methylbutanamido)-3-hydroxy-1,6-diphenylhexan-2-yl)carba-
mate, a hydroperoxide impurity of ritonavir also known as ritonavir USP impurity G. Due to the complex-
ity of ritonavir’s structure and abundance of oxidation susceptible functional groups, forced degradation
was found to be a non-selective and inadequate tactic. Therefore, a multistep synthesis was applied. The
overall strategy involved initial introduction of a propenyl moiety to the terminal thiazole which enabled
selective oxidation using Co(thd)2 (0.1 equiv)/O2 (Isayama–Mukaiyama cobalt catalyzed hydroperoxysi-
lylation) following structural assembly.
Received 10 August 2016
Revised 3 October 2016
Accepted 7 October 2016
Available online 10 October 2016
Keywords:
Ritonavir hydroperoxide
Isayama–Mukaiyama hydroperoxysilylation
TES stoichiometry
Ó 2016 Published by Elsevier Ltd.
Late stage oxidation
Cobalt
Introduction
instances, a considerable amount (multigram) of the impurity is
required and is not always available by implementation of non-
Ritonavir is an HIV aspartic protease inhibitor and potent Cyto-
chrome P450 (CYP) inhibitor which is used in the clinic as part of
fixed dose combinations mostly due to its CYP inhibitory effect.
Inhibition of CYPs assists in elevating blood levels of other HIV
inhibitors introduced in fixed combination products.1,2
Impurities in drugs are of major concern in terms of quality and
safety. Example impurity sources are remnants of starting materi-
als, intermediates, and reagents from the synthesis of the active
pharmaceutical ingredient (API), degradation of the API,3 and reac-
tion of the API with excipients4 or their contaminants.5
selective, low yielding forced degradation. An additional obstacle
is met when forced degradation is not able to replicate the slow
constant degradation pathway that an API undergoes in a given
formulation during long periods of storage. In other occasions,
the molecule contains several functional groups which are sensi-
tive to the applied conditions. For example, molecules such as
dabigatran etexilate6, sofosbuvir,7 and tenofovir disoproxyl8 com-
prise more than one reactive site which can be cleaved by simple
hydrolytic conditions.
When forced degradation is not effective, there is a need for
synthesis of the desired impurity. Herein, we describe the prepara-
tion of ritonavir hydroperoxide. Although this compound is known
and defined in the USP, a literature search, including SciFinder, did
not reveal any published total synthesis.
In order to be able to identify, quantify and to assess their tox-
icity potential, impurity standards and markers are required. Nev-
ertheless, they are not always commercially available and there is a
continuous pursuit for new sources.
On many occasions, preparation, isolation, and characterization
are possible simply by applying the same conditions that led to the
formation of the desired impurity (forced degradation). However,
in some circumstances, forced degradation is not possible or not
effective. In many cases, impurities form only in formulated low
dosage drug products (approximately 1 mg per dose) and exhaus-
tive preparative isolation is not practical. In some cases, there is a
need for toxicological studies or testing in the Ames assay. In these
Results and discussion
Initial attempts at forced degradation synthesis focused on the
base promoted oxidation of ritonavir. It was reasoned that the
methine hydrogen of the isopropyl group adjacent to the 2-thia-
zole group might be sufficiently labile to enable deprotonation
and subsequent functionalization under an oxygen atmosphere.9,10
Ritonavir was treated with excess KOt-Bu (5 equiv) under an oxy-
gen atmosphere in THF at room temperature (Scheme 1). However,
this first attempt resulted in rapid intramolecular cyclization of
⇑
Corresponding author. Tel.: +65 6398 5500; fax: +65 6398 5511.
E-mail address: matthew.voss@amriglobal.com (M.E. Voss).
http://dx.doi.org/10.1016/j.tetlet.2016.10.022
0040-4039/Ó 2016 Published by Elsevier Ltd.

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S. Gazal et al. / Tetrahedron Letters 57 (2016) 5099–5102
ritonavir to form oxazolidone derivative 2. To eliminate the possi-
bility of cyclization, the 3-hydroxyl group of ritonavir was first pro-
tected as tert-butyldimethylsilyl ether derivative 3 under standard
conditions in 72% yield. This substrate was subjected to the KOt-
Bu/O2 degradation conditions in both THF and DMF at tempera-
tures ranging from room temperature to 60 °C. Unfortunately these
conditions produced only complex reaction mixtures with no
clearly isolable hydroperoxide product.
With the failure of the direct degradation of ritonavir, we
turned our attention to a total synthesis approach and targeted
the peroxidation of a simplified 2-isopropylthiazole fragment
which could be used as a key intermediate in the synthesis of 1.
Boc-protected intermediate 8 (Scheme 2) appeared to be a suitable
substrate to apply the base promoted oxygenation reaction since it
lacked the protic functional group present in ritonavir. Compound
8 was synthesized from commercially available 2-bromothiazole-
4-carbaldehyde 4 in four steps. Reductive amination followed by
Boc-protection afforded 2-bromothiazole derivative 6 in 62% over-
all yield. The key step to introduce the isopropyl group utilized a
Suzuki reaction to first synthesize the isopropylene derivative 7
in 68% yield, which was subsequently hydrogenated to afford 8
in 56% yield.
Compound 8 was subjected to the base promoted oxidation
protocol using KOtBu/O2 in various solvents (THF, tert-butanol,
and DMF) at room temperature. THF and tert-butanol gave poor
results with only trace amounts of 9a observed by LCMS along with
other unidentified side-products. The use of DMF afforded an
improved conversion, however, attempts to isolate 9a by reverse
phase chromatography yielded only trace quantities of the prod-
uct. In order to facilitate isolation of the peroxide, a stepwise O-
silyl protection method was employed. Addition of TBDMSCl to
the reaction mixture after 2 h formed the O-tert-butyldimethylsilyl
peroxide 9b which was isolated by reverse phase chromatography
in 19% yield. Attempts to increase the yield of 9b by elevating the
reaction temperature to 60 °C in the oxidation step resulted in a
complex reaction mixture and decomposition of 9a. Limited by
the low yield of the base promoted oxidation, we considered alter-
native oxidative methods.
The cobalt catalyzed hydroperoxysilylation of alkenes, first
reported by Isayama and Mukaiyama,9 represents a convenient
and mild procedure for the regioselective conversion of alkenes
into the corresponding triethylsilylperoxide derivatives in good
yields. This protocol has been utilized in the synthesis of various
peroxide derivatives11 and peroxide containing natural
products.12–14 It was considered that 2-isopropylene-thiazole
intermediate 7 might serve as a suitable substrate for catalyzed
hydroperoxysilylation and given the success in isolating O-silyl
derivative 9b, this approach appeared appealing. A trial reaction
of
a-methylstyrene using Co(accac)2 (0.1 equiv), O2 (1 atm.), and
triethylsilane (1.0 equiv), for 3 h at room temperature in 1,2-
dichloroethane afforded the expected OTES-protected tertiary
hydroperoxide in 82% yield after chromatography. However, initial
application of these conditions to intermediate 7 failed to afford
the desired peroxide 9c even after a prolonged reaction time of
O2, Et3SiH (5 eq.)
Co(thd)2 (0.1 eq.)
S
S
N
Boc
N
Boc
N
O
O
1,2-DCE, rt, 3 h
38%
N
SET
7
9c
Scheme 3. Cobalt catalyzed OTES peroxidation of 7.
S
KOt-Bu, O2
S
N
O
OH
S
H
H
O
OH
S
N
HOO
H
H
N
N
N
O
N
N
N
N
N
O
N
N
H
THF, rt
O
O
H
O
O
Ritonavir
1
1. KOt-Bu, O2
THF or DMF
rt to 60 °C
TBDMSCl
Hunig's base, cat DMAP
DMF, rt, 16 h, 72%
2. 1.25 M HCl
MeOH
O
S
O
O
H
NH
N
N
N
N
S
Si
H
O
O
S
O
H
H
N
N
N
N
O
N
N
2
H
O
O
3
Scheme 1. Attempted base promoted forced degradation of ritonavir.
S
S
S
S
a
b
c
Boc
N
Boc
N
Br
Br
H
N
Br
93%
67%
68%
N
N
N
N
CHO
4
5
6
7
S
N
S
d
e or f
Boc
N
Boc
N
ROO
56%
N
8
9a, R = H (condition e) - trace
9b, R = OTBS (condition f) - 19%
Scheme 2. Synthesis of intermediate 8. Reagents and conditions: (a) (i) CH3NH2 (33% in EtOH), Ti(OiPr)4, rt, 16 h (ii) NaBH4, rt, 4 h; (b) Boc2O, Et3N, CH2Cl2, rt, 8 h; (c) 4,4,5,5-
tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane, 2M NaHCO3, DMF, 90 °C, 4 h; (d) H2 (1 atm), Pd/C (10 wt%), MeOH, rt, 8 h; (e) KOtBu, O2, rt, 2 h; (f) (i) KOtBu, O2, rt, 2 h,
(ii) TBDMSCl, rt, 3 h. Note: all yields are unoptimized.

S. Gazal et al. / Tetrahedron Letters 57 (2016) 5099–5102
5101
a
c
S
b
S
N
S
S
N
Boc
N
O
O
H
N
H
N
H
N
N
N
23%
N
83%
N
76%
OCH3
OH
12
10
11
O
O
7
OH
S
H
N
N
O
H2N
O
13
S
N
e
O
OH
S
H
N
H
N
N
N
O
39%
N
d, 57%
H
O
O
14
f
S
N
S
N
O
OH
S
O
OH
S
O
O
H
H
HOO
H
N
H
N
N
N
N
N
O
N
N
O
TES
50%
N
N
H
H
O
O
O
O
1
15
Scheme 4. Synthesis of 1. Reagents and conditions. (a) 4 M HCl in 1,4-dioxane; (b) (i) triphosgene, Hünig’s base, THF, À10 °C, 2 h (ii) N-Val-OCH3, Hünig’s base, THF, À10 °C to
rt, 2 h; (c) 2M NaOH, MeOH, rt, 4 h; (d) EDCI, HOBt, Hünig’s base, DMF, rt, 16 h; (e) Co(thd)2 (0.1 equiv), O2 (1 atm.), Et3SiH (5 equiv), 1,2-DCE, rt, 30 h; (f) 0.05% TFA(aq.), rt,
2 h. Note: yields are unoptimized.
16 h. Subsequently, small modifications were made to the reaction
conditions, firstly changing the cobalt complex to the more steri-
cally hindered bis(2,2,6,6-tetramethyl-3,5-heptanedionato)cobalt
(II) Co(thd)2 which has been reported as a superior catalyst for
the transformation.15 Upon substituting this catalyst in place of
Co(accac)2, we were disappointed to see no improvement in the
conversion of 7 to 9c. The effect of the stoichiometry of the tri-
ethylsilane reductant was examined, showing that employing an
excess of triethylsilane reductant had a significant benefit to the
reaction yield. Using the modified conditions of Co(thd)2
(0.1 equiv), O2 (1 atm.), and triethylsilane (5.0 equiv) in 1,2-
dichloroethane for 3 h at room temperature afforded 9c in 38% iso-
lated yield (Scheme 3).
This result confirmed that the Isayama–Mukaiyama peroxida-
tion could be utilized for heterocyclic substrates such as 7. More-
over, the TES-group served the added utility as a protecting
group for the presumably chemically sensitive hydroperoxide.
Despite this we doubted the ability of the OTES group to remain
intact during the subsequent transformations required to synthe-
size the final product 1. To increase the chances of success, we pos-
tulated that the critical hydroperoxysilylation step might be
performed at a later stage in the synthesis, ideally as the penulti-
mate step (Scheme 4). The key intermediate for this approach
was the isopropenyl derivative of ritonavir, compound 14. The
overall synthetic strategy toward 14 involved transformation of
isopropenyl intermediate 7 to valine derivative 12 and subsequent
peptide coupling with amine fragment 13. Compound 7 was sub-
jected to Boc deprotection to afford free amine 10 in high yield. Ini-
tial attempts to convert 10 to urea derivative 11 utilizing CDI/DBU
conditions failed. Eventually compound 10 was converted to the N-
carbamoyl chloride derivative by treatment with triphosgene/
TFA. The crude hydroperoxide was purified by reverse chromatog-
raphy to afford 1 in 50% yield.
Conclusion
A concise and practical synthesis of a ritonavir-hydroperoxide
derivative 1 has been developed. The synthesis employs a late
stage application of the Isayama–Mukaiyama cobalt catalyzed
hydroperoxysilylation reaction to an alkene derivative of ritonavir
and demonstrates the utility of the reaction for the synthesis of
complex hydroperoxide containing products. A crucial modifica-
tion to the reaction conditions involved the use of excess triethyl-
silane reductant, which appeared to be beneficial to enable the
transformation to be carried out in the presence of heterocycles
and complex structural functional groups.
Supplementary data
Supplementary data (synthetic procedures, characterization
data, copies of ESI-MS data and 1H NMR spectrum of products)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2016.10.022.
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