A novel and efficient asymmetric synthesis of anti-HIV drug maraviroc

Article abstract of DOI:10.1080/00397911.2019.1607875

A novel and efficient route to asymmetric synthesis of Maraviroc by using (S)-tert-butanesulfinamide as chiral auxiliary is described. Two interesting impurities of the process are isolated and identified. The synthesis was concise, mild, and easy to oper

Full text of DOI:10.1080/00397911.2019.1607875

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
A novel and efficient asymmetric synthesis of anti-
HIV drug maraviroc
Yijun Zhu, Hongyan Li, Kuaile Lin, Bing Wang & Weicheng Zhou
To cite this article: Yijun Zhu, Hongyan Li, Kuaile Lin, Bing Wang & Weicheng Zhou (2019) A
novel and efficient asymmetric synthesis of anti-HIV drug maraviroc, Synthetic Communications,
49:13, 1721-1728, DOI: 10.1080/00397911.2019.1607875
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SYNTHETIC COMMUNICATIONSV
2019, VOL. 49, NO. 13, 1721–1728
https://doi.org/10.1080/00397911.2019.1607875
A novel and efficient asymmetric synthesis of anti-HIV
drug maraviroc
Yijun Zhua, Hongyan Lib, Kuaile Linb, Bing Wanga, and Weicheng Zhoub
b
aChangzhou Pharmaceutical Factory, Changzhou, China; State Key Laboratory of New Drug &
Pharmaceutical Process, Shanghai Key Laboratory of Anti-Infectives, State Institute of Pharmaceutical
Industry, Shanghai, China
ABSTRACT
ARTICLE HISTORY
Received 1 February 2019
A novel and efficient route to asymmetric synthesis of Maraviroc by
using (S)-tert-butanesulfinamide as chiral auxiliary is described. Two
interesting impurities of the process are isolated and identified. The
synthesis was concise, mild, and easy to operate. The overall yield
and stereoselectivity were excellent.
KEYWORDS
Asymmetric synthesis;
impurity; maraviroc;
stereoselectivity; (S)-tert-
butanesulfinamide
GRAPHICAL ABSTRACT
Introduction
Human immunodeficiency virus (HIV) is a pandemic virus, which seriously threatens
the health of 35.3 million people worldwide.[1] Although many anti-HIV drugs have
been approved for clinical treatment since Zidovudine was launched,[2] drug side effects,
viral escape, and compliance issues continued to drive the discovery of novel target
drugs. Chemokine receptor type 5 (CCR5) emerged as a necessary passway for HIV-1
infection and blockade of CCR5 was a new mechanism of the HIV-1 treatment regi-
men.[3] Pfizer’s Maraviroc (1, UK-427857) was the first small-molecule CCR5 receptor
antagonist approved by the FDA in 2007 for the therapy of HIV-1 infection
(Figure 1).[4]
CONTACT Weicheng Zhou
zhouweicheng58@163.com
State Key Lab of New Drug & Pharmaceutical Process,
Shanghai Key Lab of Anti-Infectives, State Institute of Pharmaceutical Industry, No. 285, Gebaini Rd, Shanghai
201203, China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

1722
Y. ZHU ET AL.
F
F
O
NH
N
N
N
N
Figure 1. Maraviroc (1).
The asymmetric synthesis of Maraviroc has attracted great attention. So far the syn-
thesis was based on two main synthetic strategies. Both medicinal chemistry[5] and pro-
cess synthesis[6,7] of Maraviroc by Pfizer utilized the key intermediate (methyl S-3-
amino-3-phenylpropionate) as a chiral source, which was produced by enantiomeric
resolution to couple with 4,4-difluorocyclohexane-1-carboxylic acid and triazole-substi-
tuted tropane.[8] The other methods were based on the chiral catalyst-controlled asym-
metric C–H amination to establish the absolute configuration of the stereocenter.[9–11]
However, some of these methods were undermined by low enantioselectivity, complex
synthetic procedures, and expensive chiral catalysts.
Chiral auxiliary tert-butanesulfinamide, developed by Ellman, has been proven to be
a broadly useful reagent for the preparation of chiral amines through the intermediate
of chiral N-tert-butanesulfinyl imines.[12,13] Due to its high diastereoselectivity and con-
venient cleavage of the N-tert-butanesulfinyl group, it has become an excellent chiral
auxiliary in the synthesis of chiral amine compounds.[14,15] In this paper, we shall report
a novel and efficient synthetic route for Maraviroc (1), which involve the enantioselec-
tive construction the amino group with S-configuration from 3-(3-(3-isopropyl-5-
methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-1-phenylpropan-1-one
(4)
through the chiral auxiliary (S)-tert-butanesulfinamide.
Results and discussion
The synthetic strategy herein is to stereoselectively prepare, (1S)-3-(3-(3-isopropyl-5-
methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-1-phenylpropan-1-amine (7),
followed by the acylation to get the target compound, illustrated in Scheme 1.
The ketone 4 was synthesized for the first time from two commercially available
materials 3-chloro-1-phenylpropan-1-one (2) and triazole-substituted tropane (3) by
simple nucleophilic substitution. Then, the imine formation with (S)-tert-butanesulfina-
mide (SM) in the presence of Ti(OEt)4 was further optimized (Table 1).
According to the similar imine formation conditions,[14] compound 4 reacted with
(S)-tert-butanesulfinamide in the presence of Ti(OEt)4, but it was found that the reac-
tion was difficult to reach completion if it was carried out in THF or 2-MeTHF, (even
after 24 h more than 50% of 4 remained, Table 1, entries 1 and 2). In order to drive the
imine formation, the reaction was conducted in toluene at elevated temperature and

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1723
O
O
S
Cl
O
N
SM
t-Bu
O
S
t-Bu
N
2
K2CO3,KI
N
H2N
CH3CN
N
N
N
N
N
N
Ti(OEt)4,DIPEA
reflux,3h
N
N
toluene,100oC,10h
HN
N
5
4
90% yield
3
O
S
NH2
8
F
HN
t-Bu
N
COCl
N
1)HCl/EtOH, 15oC,2h
2)NaOH aq/DCM
F
DIBAl-H
toluene
N
pyridine,DCM
0~15oC, 2~3h
N
N
N
N
N
-70~0 oC,3h
7
6
90% yield
60%, two step overall yield
de 99.72%
F
F
O
NH
N
N
N
N
1
70% yield
ee 99.94%
Scheme 1. Synthetic process for Maraviroc 1.
Table 1. Optimization of sulfinylimine formationa.
Entry
Condensation agent
Solvent
Temperature (oC)
Time (h)
ratio 4:5:5’:5”b
1
2
3
4
5
6
7
Ti(OEt)4(4 Eq.)
Ti(OEt)4(4 Eq.)
Ti(OEt)4(4 Eq.)
Ti(OEt)4(3 Eq.)
Ti(OEt)4(2 Eq.)
Ti(OEt)4(2 Eq.)
Ti(OEt)4(3 Eq.)
DIPEA(0.5 Eq.)
Ti(OEt)4(3 Eq.)
DIPEA(1.2 Eq.)
Ti(OEt)4(3 Eq.)
DIPEA(1.8 Eq.)
THF
65
80
100
100
100
reflux
100
36
24
10
10
20
24
10
51:28:2:4
46:12:4:12
3:52:9:22
2:75:11:4
41:38:1:12
35:55:7:4
2:79:6:5
2-MeTHF
toluene
toluene
toluene
toluene
toluene
8
9
toluene
toluene
100
100
10
10
1:86:5:1
2:75:10:4
aThe ratio of 4:(S)-tert-butanesulfinamide was 1:1.2 in reactions; bmeasured by HPLC.
HPLC analysis showed that 4 was nearly consumed up after 10 h (Table 1, entry 3). The
data of entries 4–6 of Table 1 indicated that 3 Eq. of Ti(OEt)4 were sufficient. However,
HPLC also indicated that the reaction generated two impurities. After purification
through column chromatography, their structures were identified as (S)-2-methyl-N-(1-
phenylallylidene)propane-2-sulfinamide(5’) and 8-((2,6-diphenylpyridin-3-yl)methyl)-3-
(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane(5”) (Scheme 2).
The byproduct 5’ might be formed by Hoffman elimination of 5 in the presence of
Lewis acid Ti(OEt)4, and then 5 further reacted with 5’ by Michael addition, cyclization,

1724
Y. ZHU ET AL.
O
O
N
Ti(OEt)4
N
S
O
O
N
N
Ti(OEt)3
N
N
N
4
Elimination
O
N
Ti(OEt)4
N
N
Cyclization
-EtOH
HN
S
S
N
N
Michael Addition
N
O
N
5'
O
S
OTi(OEt)3
[O]
- H2
N
N
N
N
N
N
N
N
N
N
5''
Scheme 2. Plausible mechanism for the formation of impurity 5”.
Table 2. Condition for the reduction of sulfinylimine 5.
O
S
O
S
O
S
HN
t-Bu
HN
t-Bu
N
N
t-Bu
N
reduction
N
N
N
N
N
N
N
N
5
N
6'
6:6’a
6
N
Entry
reductant
solvent
temperature(oC)
time (h)
de(%)
1
2
3
4
5
6
7
8
NaBH4(1 Eq.)
LiBH4(1 Eq.)
KBH4(2 Eq.)
NaBH(OAc)3(3 Eq.)
NaBH3CN(1 Eq.)
BH3(1 Eq.)
DIBAlH(4 Eq.)
DIBAlH(4 Eq.)
DIBAlH(3 Eq.)
DIBAlH(3 Eq.)
DIBAlH(3 Eq.)
THF
THF
THF
THF
THF
THF
THF
toluene
toluene
toluene
toluene
ꢀ5
ꢀ10
5
3
3
12
12
2
3
3
6
2
52:48
60:40
75:25
4
20
50
0
25
15
NRb
NR
ꢀ15
No desired product
87:13
95:5
95:5
95:5
96:4
ꢀ70
74
90
90
90
92
ꢀ70
9c
10
11d
ꢀ70
ꢀ70 ꢁ 10
ꢀ70 ꢁ 10
3
aThe ratio was determined by HPLC; bno reaction; compound 5 was not consumed up; done-pot synthesis of imine for-
c
mation and reduction.
elimination, and oxidation to obtain 5” (The plausible mechanism was proposed in
Scheme 2). Hence the key optimization of this step was to control the generation of 5’.
It was supposed that the formation of 5’ was related to the acidic condition, so DIPEA
as a basic additive was tried. Pleasantly, the employment of 1.2 Eq. of DIPEA led to the
optimal results in which 5 was obtained in 86% ratio (Table 1, entries 7–9). Based on
the optimized condition of entry 8 of Table 1, this step was carried out on a 50 g scale.
The diastereoselective reduction of imine 5 was the key step in this route, so various
conditions were screened and the results were listed in Table 2.
Various boron reducing reagents were screened based on the previous work of our
group.[15] However, unsatisfactory results were obtained (Table 2, entries 1–3), even no

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SYNTHETIC COMMUNICATIONSV
1725
reaction (Table 2, entries 4 and 5) or no desired product (Table 2, entry 6). Fortunately,
when diisobutyl aluminum hydride (DIBAl-H) was used as the reductant,[16] the dia-
stereoisomeric excess (de) of the product was improved to 74% (Table 2, entry 7).
Then, extensive optimization based on DIBAl-H was perfomed (Table 2, entries 8–10).
It was found that the reduction was well conducted in toluene at about 10 ꢂC after add-
ition of the reductant at ꢀ70 ꢂC (Table 2, entry 10). With the best conditions for sul-
finyl imine formation and reduction identified, the one-pot procedure was implemented
to yield crude 6 in 92% de (Table 2, entry 11). After recrystallization from MTBE, com-
pound 6 was obtained in 60.1% yield (two steps) with 99.72% de.
Exposure of purified 6 to HCl in methanol at 15 ꢂC resulted in cleavage of the chiral
auxiliary group and basification with 2 N NaOH gave the primary amine 7 in 90% yield.
The optical rotation value of 7 was consistent with that in the original patent.[17]
Finally, Maraviroc 1 was obtained by acylation of 7 with 4,4-difluorocyclohexanecar-
bonyl chloride (8) in the presence of pyridine in about 70% yield. After recrystallization
from ethyl acetate, both of the purity (99.71%) and enantiopurity (99.94% ee) of
Maraviroc were excellent. The characterization and the optical rotation value of com-
pound 1 were consistent with that previously reported.[10]
Conclusion
In summary, a novel and stereoselective synthesis of Maraviroc based on the Ellman
auxiliary (S)-tert-butanesulfinamide was developed in five steps in overall 34% yield
with a chemical purity of 99.71% and a chiral purity of 99.94%. Two impurities were
isolated and identified in the sulfinyl imine formation to guide the reaction improve-
ments. The new route was concise, mild, and easy to operate.
Experimental
All solvents and reagents were reagent grade pure and used without further purification.
1H and 13C NMR spectra were measured using a Bruker 400 MHz spectrometer
(Bruker, MA, USA) with TMS as an internal standard in CDCl3 or DMSO-d6. HPLC
analyses were recorded with on a Dionex Ultimate 3000 chromatograph (Dionex
Corporation, CA, USA) and chiral HPLC analyses were recorded with Agilent 1100
Series chromatography (Agilent, CA, USA). The HRMS data were obtained using Q-
TOF micro mass spectrometry. The melting point was measured by Buchi Melting
R
Point M-565. The optical rotations were measured by AutopolVIV Automatic
Polarimeter.
3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-1-
phenylpropan-1-one (4)
To the solution of 3-chloro-1-phenylpropan-1-one 2 (71.2 g, 384 mmol, 1.1 Eq.) and 3-
(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane 3 (90 g, 422 mmol,
1 Eq.) dissolved in CH3CN (1300 ml) K2CO3 (106 g, 768 mmol, 2 Eq.) and KI (63.7 g,
384 mmol, 1 Eq.) were added, respectively and charged with N2. The mixture was

1726
Y. ZHU ET AL.
stirred at 80 ꢂC for 3 h and TLC showed 2 was consumed up. The mixture was cooled
down, filtered, and the filtrate cake was washed with 200 ml DCM. The combined fil-
trate was concentrated, and the residue was dissolved in 500 ml DCM, extracted with
4 N HCl (aq) (400 ml ꢃ 2). The combined aqueous layer was washed with DCM
(150 ml ꢃ 2). The pH of the aqueous layer was adjusted with 4 N NaOH (aq) to 13 and
white solid was precipitated out. The suspension was stirred overnight and filtered, and
the filtrated cake was slurried with water (1 L ꢃ 2), The precipitate was filtered again
and dried at 70 ꢂC for 6 h to yield about 126.7 g white solid. (90% yield) m.p. 90–91 ꢂC;
1H-NMR (CDCl3, 400 MHz): d7.91 (d, 2H); 7.49 (t, 1H); 7.41–7.26 (m, 2H); 4.21–4.14
(m, 1H); 3.34 (s, 2H); 3.11 (t, 2H); 2.90–2.88 (m, 2H); 2.79 (t, 2H); 2.36 (s, 3H);
2.13–2.03 (m, 4H); 1.58–1.56 (m, 4H); 1.28–1.27 (d, 6H). 13C-NMR (CDCl3, 100 MHz):
d199.59, 159.10, 150.71, 136.96, 133.17, 128.61, 128.01, 59.52, 47.80, 47.07, 38.18, 36.36,
26.34, 25.63, 21.61, 12.89. HRMS (ESI): m/z calcd. for C22H31N4O [M þ H]þ: 367.2532,
found 367.2517.
(S)-N-((1S)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]
octan-8-yl)-1-phenylpropyl)-2-methylpropane-2-sulfinamide (6)
To the above toluene solution, 1.5 M DIBAl-H (272.9 ml, 409 mmol, 3 Eq.) was added
dropwise at about ꢀ70 to ꢀ78 ꢂC. After addition, the dark gray mixture was warmed to
room temperature (ca 10 ꢂC, for about 1 h), then stirred for 4 ꢁ 6 h, TLC showed 5 was
disappeared. The mixture was quenched with 500 ml saturated NaCl, stirred for 1 h, and
filtered. The filtrate cake was washed with toluene (250 ml ꢃ 2). The combined filtrate
was separated, and the aqueous layer was extracted with DCM (500 ml). The combined
organic phase was dried over MgSO4, and was concentrated to afford about 60.2 g car-
dinal crude oil. The residue was recrystallized from MTBE (500 ml) to yield 38.7 g paꢂle-
D
yellow solid (60.1% yield of two steps). de 99.72%, m.p. 154–156 ꢂC; [a]23 ¼ 22.2 (c
1
1,CHCl3). H-NMR (CDCl3, 400 MHz)：d7.39–7.30 (m, 4H); 4.68–4.64 (m, 1H); 4.40
(s, 1H); 4.34–4.25 (m, 1H); 3.39 (d, 2H); 3.00 (m, 1H); 2.50 (s, 3H); 2.38 (s, 2H);
2.16–2.13 (m, 3H); 2.04–1.95 (m, 3H); 1.66–1.62 (m, 4H); 1.42–1.40 (d, 6H); 1.22 (s,
9H). 13C-NMR (CDCl3, 100 MHz): d159.07, 150.66, 142.33, 128.68, 127.74, 127.13,
59.17, 58.72, 56.22, 56.01, 48.21, 47.14, 35.91, 35.81, 35.35, 26.31, 25.77, 22.71, 21.66,
13.06. HRMS (ESI): m/z calcd. for C26H42N5OS [M þ H]þ: 472.3110, found 472.3094.
(1S)-3-(3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl)-
1-phenylpropan-1-amine (7)
To the solution of 6 (10 g, 21.2 mmol, 1 Eq.) in 30 ml methanol 3 ml HCl/MeOH (aq) at
about 0 ꢁ 10 ꢂC was added. After addition, the mixture was stirred at room temperature
for 2 h, TLC showed 6 was consumed up. To the concentrated mixture, 15 ml DCM
and 4 ml 2 N NaOH (aq) were added, the pH of the solution was adjusted to 12. The
mixture was separated, and the aqueous layer was extracted with 15 ml DCM. The com-
bined organic phase washed with water and brine, dried over Na2SO4, and concentrated
ꢂ
D
to yield 7.4 g pale-yellow oil (90% yield). [a]15 ¼ 14 (c 0.1, MeOH)[17] 1H-NMR
(CDCl3, 400 MHz): d7.36–7.26(m, 4H); 7.25–7.23(m, 1H); 4.28–4.25(m, 1H);

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SYNTHETIC COMMUNICATIONSV
1727
4.11(s, 1H); 3.39(d, 2H); 3.00(m, 1H); 2.45 (s, 3H); 2.38 (s, 2H); 2.22–2.19 (m, 2H);
2.06–2.03 (m, 2H); 1.93–1.84 (m, 2H); 1.64–1.60 (m, 4H); 1.37–1.36 (d, 6H). 13C-NMR
(CDCl3, 100 MHz): d159.09, 150.65, 145.97, 128.51, 127.05, 126.24, 58.83, 58.50, 55.06,
49.24, 47.36, 37.77, 36.01, 26.54, 26.36, 25.74, 21.58, 12.95. HRMS (ESI): m/z calcd. for
C22H34N5 [M þ H]þ: 368.2814, found 368.2815.
Maraviroc (1)
The preparation of 4,4-difluorocyclohexanecarbonyl chloride (8)
To the solution of 4,4-difluorocyclohexanecarboxylic acid (3 g, 18.3 mmol, 1 Eq.) dis-
solved in 7.5 ml toluene SOCl2 (6.6 ml, 5 Eq.) was added. The mixture was refluxed and
stirred for 2 ꢁ 3 h. TLC showed the acid was consumed up, cooled, concentrated to
yield about 2.5 g dryness oil (100% yield).
Then to the solution of 7 (3.6 g, 10 mmol, 1 Eq.) in 12 ml DCM was added pyridine
(2.4 ml, 3 Eq.). The mixture was cooled to 0 ꢁ 10 ꢂC and acyl chloride (2.2 g, 1.2 Eq.)
was added dropwise. After addition, the mixture was stirred for 2 h and TLC showed 7
was consumed up. To the mixture, 10 ml water and 10 ml DCM were added. The mix-
ture was separated, and the aqueous layer was extracted with 10 ml DCM. The com-
bined organic phase was washed with 2 N NaOH (aq) (10 ml), water, and brine
respectively, dried over Na2SO4, and concentrated to yield 4 g crude oil. The residue
was recrystallized from ethyl acetate (15 ml) to afford 3.5 g 1 as white solid (70% yield).
ꢂ
ꢂ
D
D
chiral HPLC: 99.94% ee; [a]25 ¼ ꢀ32.8 (c ¼ 1, CHCl3) (literature[10]: [a]25 ¼ ꢀ27.4 ,
1
96% ee); m.p. 195–196.2 ꢂC. H-NMR (CDCl3, 400 MHz): d8.27(d, 1H); 7.34–7.31(m,
4H); 7.23(m, 1H); 4.96–4.94(m, 1H); 4.21(m, 1H); 3.39 (s, 2H); 3.13 (m, 2H); 2.50 (s,
3H); 2.38 (m, 3H); 2.10–2.07 (m, 4H); 1.90 (m, 2H); 1.89–1.84 (m, 2H); 1.82 (m, 4H);
1.72 (m, 2H); 1.68–1.66 (m, 2H); 1.58–1.55 (m, 2H); 1.26–1.246 (d, 6H). 13C-NMR
(CDCl3, 100 MHz): d173.60, 159.14, 150.57, 142.31, 128.61, 127.27, 126.53, 122.72, 58.82,
58.40, 51.86, 48.12, 47.34, 42.53, 35.69, 35.57, 35.05, 32.82, 32.78, 26.71, 25.98, 25.78,
21.65, 13.10. HRMS (ESI): m/z calcd.for C29H41N5OF2Na [M þ Na]þ: 536.3177,
found 536.3155.
Experimental procedures and NMR and HRMS data of 1, 4, 5, 6, 7, 5’ and 5”, and
chiral HPLC of 1 and 6. This material can be found via the “Supplementary Material”
section of this article’s webpage.
Funding
This work was funded by the Jiangsu Province "innovation and entrepreneurship program" in
2017 & 2018 and Jiangsu Planned Projects for Postdoctoral Research Funds [2018K264C].
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