A new process for the synthesis of nafoxidene as a key intermediate of lasofoxifene

Article abstract of DOI:10.1007/s11164-014-1721-7

Abstract A novel brief process for the synthesis of nafoxidene has been developed. The epoxidation of 6-methoxy-1-{4-[2-(pyrrolin-1-yl)ethoxy)]phenyl}-3,4-dihydronaphthalene by m-CPBA directly gave the ketone 6-methoxy-1-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-3,4-dihydronaphthalen-2(1H)-one, which was subject to phenyl magnesium bromide/cerium chloride and subsequently treated with an acid to yield nafoxidene. In addition, the preparation of the starting naphthalene was also optimized by replacing the aromatic lithium at low temperature with its Grignard reagent at refluxing THF. This mild process, without the use of toxic or noble metals, was more cost-efficient and easily worked up.

Full text of DOI:10.1007/s11164-014-1721-7

Res Chem Intermed
DOI 10.1007/s11164-014-1721-7
A new process for the synthesis of nafoxidene as a key
intermediate of lasofoxifene
Yi Lu
Yanqing Lin
•
Yangwei Huang
•
•
Zhong Chen
•
Xueqing Zhao
Received: 26 March 2014 / Accepted: 20 May 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A novel brief process for the synthesis of nafoxidene has been devel-
oped. The epoxidation of 6-methoxy-1-{4-[2-(pyrrolin-1-yl)ethoxy)]phenyl}-3,4-
dihydronaphthalene by m-CPBA directly gave the ketone 6-methoxy-1-[4-(2-
(
pyrrolidin-1-yl)ethoxy)phenyl]-3,4-dihydronaphthalen-2(1H)-one, which was sub-
ject to phenyl magnesium bromide/cerium chloride and subsequently treated with an
acid to yield nafoxidene. In addition, the preparation of the starting naphthalene was
also optimized by replacing the aromatic lithium at low temperature with its
Grignard reagent at refluxing THF. This mild process, without the use of toxic or
noble metals, was more cost-efficient and easily worked up.
Keywords Lasofoxifene Á Nafoxidene Á Synthesis Á Pinacol rearrangement
Introduction
Lasofoxifene (1), a third-generation selective estrogen receptor modulator for the
prevention and treatment of osteoporosis, was approved in the EU under the brand
name Fablyn by the EMEA in March 2009 [1, 2]. For preparation of lasofoxifene,
the reduction of a double bond of nafoxidene (2), followed by demethylation is an
essential pathway (Scheme 1) [3–6]. As a key intermediate of lasofoxifene,
synthetic exploration for nafoxidene, a non-marketed drug, has attracted the
chemist’s interest again.
Y. Lu Á X. Zhao (&)
Fujian University of Traditional Chinese Medicine, Fujian, China
e-mail: zhaowolfgang@163.com
Y. Huang Á Z. Chen Á Y. Lin
Fujian Institute of Microbiology, Fujian, China
123

Y. Lu et al.
O
N
O
N
a). H /Pd-C
2
b). 48% aq. HBr
c). D-tartaric acid
D-tartaric acid
H CO
3
HO
2
1
Scheme 1 The synthetic route of lasofoxifene D-tartrate from nafoxidene
Among the reported literatures, there are four representative processes:
a) commercially bulky 6-methoxy-1-tetralone (3) for the synthesis of methylno-
(
rethindrone was used as a starting material (Scheme 2), and addition of 4-(2-
pyrrolidin-1-yl-ethoxy)phenyl lithium [ArLi prepared from ArBr (4) and nBuLi] in
the presence of cerium chloride at -78 °C and subsequent acid treatment afforded
compound 5. Bromination of the double bond of 5 and Suzuki coupling with
phenylboronic acid gave nafoxidene [4]; (b) addition of ArLi (Scheme 2) to
6
-methoxy-2-phenyl-1-tetralone, followed by dehydration by treatment of hydro-
chloric acid yielded nafoxidene [3, 7]; (c) five steps starting from 2-bromo-5-
methoxytoluene and 4-benzyloxybenzonitrile were described for the synthesis of
nafoxidene via a key coupling reaction catalyzed by TiCl [5]; (d) recently, a novel
3
procedure was presented via HfCl -mediated three-component coupling reaction to
4
construct the major skeleton of nafoxidene in one pot [6]. Unfortunately, all these
methods are involved in one or more of the following drawbacks: tedious
procedures [4, 6], rare raw materials [3, 5, 7], a noble metal [4, 5], harsh conditions,
or low yield [3–5, 7].
Herein, we present a novel brief process for the synthesis of nafoxidene under
mild conditions without the use of toxic and noble metals: epoxidation and
simultaneous pinacol rearrangement of compound 5 afforded the ketone 6, which
was subject to phenyl magnesium bromide/CeCl and then treated with hydrochloric
3
acid to give nafoxidene in good yields (Scheme 3). The preparation of 5 was also
optimized.
Results and discussion
It is well known that the addition of Grignard or lithium reagents to ketones is
significantly enhanced by cerium trichloride with remarkable suppression of side
reaction, particularly enolization [8–10], but in our case, the application of cerium
chloride to ArMgBr failed to yield the desired product. Referred to the preparation
of similar compounds [11], the Grignard reagent, freshly prepared from 4 and
magnesium turnings was added to refluxing THF solution of 3 to give 5 in a
moderate yield (55.9 %) similar to how the corresponding lithium was used at low
temperature.
1
23

A key intermediate of Lasofoxifene
ArBr (4)
Ar =
O
N
THF, -78oC
n-BuLi
ArLi
Ar
O
1) aq. HCl
H CO
3
o
2) aq. NaOH
57%
H CO
3
THF, CeCl ,-78 C
3
3
5
Scheme 2 The synthetic route of intermediate 5
4
Mg THF
Ar
ArMgBr
O
1) 2N aq. HCl
m-CPBA
3
5
H CO
3
2) aq. NaOH
THF, Reflux
CH Cl , 92.5%
2
2
6
55.9%
Ar
a). PhMgBr/CeCl /THF
3
-
10~-5¡æ
Ar =
O
N
HCl
H CO
3
b). 2N aq. HCl, 82%
2
.HCl
Scheme 3 The synthetic route of nafoxidene hydrochloride
Epoxidation of 5, subsequent addition of PhMgBr in the presence of CuI, and
final acidification were our initial imagination for the synthesis of nafoxidene.
However, epoxidation of 5 by m-CPBA in CH Cl at 0–5 °C failed to give the
2
2
desired epoxide 7 but the ketone 6 in a yield of 92.5 %. It was proposed that after
the formation of the epoxy 7, the epoxy ring was immediately opened and
rearranged to the ketone 6 under the acidic condition (Scheme 4).
With the ketone 6 in hand, the addition of phenyl magnesium bromide/cerium
chloride to 6 at -10 to -5 °C and acidic treatment readily gave 2 HCl (nafoxidene)
in a yield of 82 %.
Conclusions
A novelsynthetic route for nafoxidene has been developed. The oxidation of 6-methoxy-
1
-{4-[2-(pyrrolin-1-yl)ethoxy)]phenyl}-3,4-dihydronaphthalene by m-CPBA readily
gave the ketone 6-methoxy-1-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-3,4-di-
hydronaphthalen-2(1H)-one in a high yield. The subsequent addition of phenyl
123

Y. Lu et al.
O
N
N
N
N
O
O
O
H+
- H+
m-CPBA
O
H
O
H
+
O
2 2
CH Cl
H
3
H CO
H CO
H CO
3
3
H CO
3
5
7
8
6
Scheme 4 Mechanism of the rearrangement
magnesium bromide in the presence of cerium chloride followed by treatment with an
acid yielded nafoxidene in a good yield. The process of starting naphthalene was
optimized 1-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl magnesium bromide in place of its
lithium at low temperature was added to refluxing THF solution of 6-methoxy-1-
tetralone to give an approximate yield. This process was more cost-efficient and easily
worked up.
Experimental
IR spectra were acquired on a Bruker Vector 22 spectrometer and are expressed in
-
1
1
(KBr), HNMR spectra on a Bruker DRX300 (500 MHz) spectrometer,
cm
1
3
CNMR spectra on a Bruker DRX300 (75.5 MHz) spectrometer, and mass spectra
with an automated Finnigan TSQ QuantumUltra AM (Thermal) LC–MS spectrom-
eter. All commercial chemicals (AR grade) were used without further purification.
THF was distilled from Na under nitrogen. m-CPBA: meta-chloroperoxybenzoic
acid.
6
-Methoxy-1-{4-[2-(pyrrolidin-1-yl)ethoxy)]phenyl}-3,4-dihydronaphthalene
(
5)
To the mixture of flame-dried magnesium turnings (5.83 g, 240 mmol) and 50 ml of
absolute THF, a small amount of I was added in a 500-ml three-necked flask, and
2
several minutes later about 0.5 ml of 4 was injected in. After the reaction was
initiated by heat, the rest of 4 (62.1 g, 230 mmol) and THF (350 ml) were added
slowly between 20 and 30 °C to give the Grignard reagent as a gray solution.
To the refluxing solution of 3 (23.9 g, 136 mmol) in absolute THF (120 ml) was
the above Grignard reagent added within 30 min. The resulting mixture continued
to reflux for 30 min, and then cooled down to room temperature and quenched with
aqueous saturated NH Cl (400 ml). The mixture was extracted with ethyl acetate
4
(
dried with anhydrous Na SO , and finally evaporated. The residue was dissolved in
160 ml 9 2), and the combined extracts were washed with water (20 ml 9 2),
2
4
2
M aq. HCl, and extracted with isopropyl ether (120 ml 9 2) (discarded). The
aqueous phase was adjusted to pH 11–12 with 2 M aq. NaOH (21 ml), then
extracted with ethyl acetate (160 ml 9 2). The organic layer was washed with
saturated brine (200 ml) and dried over anhydrous Na SO , and evaporated to leave
2
4
1
23

A key intermediate of Lasofoxifene
1
5
as a brown oil (26.6 g, 55.9 %). H-NMR (500 MHz, CDCl ) d:7.29 (d,
3
J = 5.2 Hz, 2H), 7.02–6.94 (m, 3H), 6.79 (s, 1H), 6.7 (d, J = 7.5 Hz, 1H), 5.94 (t,
J = 2.5 Hz, 1H), 4.18 (t, J = 2.5 Hz, 3H), 3.82 (s, 3H), 2.96 (t, J = 5.1 Hz, 2H),
2
3
7
.83 (t, J = 2.5 Hz, 2H), 2.70 (s, 4H), 2.42–2.37 (m, 2H), 1.86 (s, 4H); IR (KBr):
,463.2, 2,920.8, 2,952.3, 1,608.3, 1,569.2, 1,455.2, 1,356.3, 907.8, 805.4, 790.7,
-
47.3, 647, 557.3 cm (identical to the literature [4]).
1
6
2
-Methoxy-1-[4-(2-(pyrrolidin-1-yl)ethoxy)phenyl]-3,4-dihydronaphthalen-
(1H)-one (6)
To the solution of 5 (25.2 g, 72.1 mmol) in CH Cl (100 ml), a solution of m-CPBA
2
2
(
18.6 g, 108 mmol) in CH Cl (186 ml) was added at 0–5 °C for 1 h and stirred for
2
2
1
.5 h. The reaction was terminated with aqueous solution of Na SO (5.12 g,
2 3
4
0.6 mmol), and basified by 2 M aq. NaOH (21 ml) to pH 10–11. The two layers
were partitioned and the organic layer was washed with brine (50 ml 9 2), dried
over anhydrous Na SO (12.1 g), and evaporated to afford 6 as a white power
2
4
1
(
24.4 g, 92.5 %). H-NMR (500 MHz, CDCl ) Naphthalene–Carbon: abbrev. n–C;
3
1
-phenyl carbon: p–C. d 7.66 (d, J = 5.3 Hz, 1H, n–C7–H), 6.93–6.96 (m, 3H, n–
C5–H; p–C2–H; p–C5–H), 6.82 (d, J = 5.1 Hz, 2H, p–C3–H; p–C4–H), 6.75 (d,
J = 1.2 Hz, 1H, n–C8–H), 4.67 (s, 1H, n–C1–H), 4.18 (t, J = 2.5 Hz, 2H,
OCH CH ), 3.86 (s, 3H, OCH ), 3.02 (t, J = 5.1 Hz, 2H, O=CCH ), 2.79 (m, 7H,
2
2
3
2
3
9 CH of N and 1H of O=CCH CH ), 2.57 (dt, J = 10.1/2.5 Hz, 2H, 1H of
2 2 2
1
3
O=CCH CH ), 1.89 (s, NCH CH CH , 4H); C-NMR (75.5 MHz, CDCl ): d
2
2
2
2
2
3
2
5
1
10.0, 159.6, 158.2, 136.7, 132.7, 130.2, 128.4, 128.2, 114.9, 112.9, 80.2, 66.3,
5.4, 54.4, 33.3, 27.7, 23.5; IR (KBr): 3,035.6, 2,929.4, 1,691.3, 1,605.4, 1,511.5,
-
1
,462.4, 1,421.6, 1,282.6, 1,245.8, 1,172.3, 1,119.1, 829.0 cm
.
6-Methoxy-2-phenyl-1-{4-[2-(pyrrolin-1-yl)ethoxy)]phenyl}-3,4-
dihydronaphthalene hydrochloride (2, nafoxidene hydrochloride)
To a suspension of cerium chloride (12.3 g, 33.0 mmol) in THF (80 ml) was added
a solution of compound 6 (11.0 g, 30.1 mmol) in THF (45 ml) at 0 °C under a
nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at that temperature,
and further cooled down to -10 to -5 °C. A solution of phenyl magnesium
bromide, freshly prepared from bromobenzene (5.21 g, 33.2 mmol) and magnesium
turnings (0.820 g, 33.7 mmol) in THF (40 ml), was added. The mixture was stirred
for 2 h and quenched with aqueous aq. NH Cl (80 ml). Cerium chloride was
4
discarded by suction filtration and the filtrate was extracted with CH Cl
2
2
(
extract was evaporated to leave a yellowish oil, which was treated with 2 M aq. HCl
120 ml 9 2), and the combined organic layers were washed with brine. The
1
to yield 2 HCl as white crystals (10.5 g, 82.0 %). Mp: 164–167 °C. H-NMR
(
J = 8.5 Hz, 2H), 6.80 (m, 4H), 6.63 (dd, J = 8.6/2.7 Hz, 1H), 4.10 (t, J = 6.0 Hz,
500 MHz, CDCl ) d: 7.16–7.12 (t, J = 7.4 Hz, 2H), 7.09–7.03 (m, 3H), 6.99 (d,
3
2H), 3.82 (s, 3H), 2.99–2.95 (m, 2H), 2.92 (t, J = 6.0 Hz, 2H), 2.81 (dd, J = 9.2/
6.3 Hz, 2H), 2.66 (b.s, 4H), 1.87–1.82 (m, 4H) (identical to the literature [4]).
123

Y. Lu et al.
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