Piperidine nucleophilic substitution without solvent: An efficient synthesis of raloxifene

Article abstract of DOI:10.1080/00397911.2014.943348

Mild and high-yielding synthesis is described for raloxifene via piperdine nucleophilic substitution of a new raloxifene intermediate 3-aroyl-2-aryl-substituted benzo[b]thiophenes, which is obtained by acylation of para-substituted benzoyl chlorides and 2-arylbenzo[b]thiophenes. The key step is solvent free and offers valuable advantages, such as low cost, and is suitable for industrial production.

Full text of DOI:10.1080/00397911.2014.943348

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Piperidine Nucleophilic Substitution
Without Solvent: An Efficient Synthesis
of Raloxifene
Yewei Yang a , Tao Zhang a , Wenhai Huang a & Zhenrong Shen a
a Zhejiang Academy of Medical Sciences , Hangzhou , China
Accepted author version posted online: 16 Jul 2014.Published
online: 05 Sep 2014.
To cite this article: Yewei Yang , Tao Zhang , Wenhai Huang & Zhenrong Shen (2014) Piperidine
Nucleophilic Substitution Without Solvent: An Efficient Synthesis of Raloxifene, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
44:22, 3271-3276, DOI: 10.1080/00397911.2014.943348
To link to this article: http://dx.doi.org/10.1080/00397911.2014.943348
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Synthetic Communications1, 44: 3271–3276, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.943348
PIPERIDINE NUCLEOPHILIC SUBSTITUTION WITHOUT
SOLVENT: AN EFFICIENT SYNTHESIS OF RALOXIFENE
Yewei Yang, Tao Zhang, Wenhai Huang, and Zhenrong Shen
Zhejiang Academy of Medical Sciences, Hangzhou, China
GRAPHICAL ABSTRACT
Abstract Mild and high-yielding synthesis is described for raloxifene via piperdine
nucleophilic substitution of a new raloxifene intermediate 3-aroyl-2-aryl-substituted benzo[b]
thiophenes, which is obtained by acylation of para-substituted benzoyl chlorides and
Received May 8, 2014.
Address correspondence to Zhenrong Shen, Zhejiang Academy of Medical Sciences, Hangzhou
310013, China. E-mail: shenzr601@163.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
3271

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Y. YANG ET AL.
2-arylbenzo[b]thiophenes. The key step is solvent free and offers valuable advantages, such
as low cost, and is suitable for industrial production.
Keywords Friedel–Crafts acylation; green chemistry; nucleophiles; raloxifene; SERM
INTRODUCTION
Raloxifene (1) is a selective estrogen receptor modulator (SERM), which acts
in a tissue-specific fashion as estrogen receptor antagonist in some tissues (uterine
and mammary tissues) but as agonist in others (bone and cardiovascular systems).
It was approved in 1997 by the U.S. Food and Drug Administration (FDA) for
the treatment of osteoporosis in postmenopausal women and in 2007 for the chemo-
prevention of breast cancer in postmenopausal women at high risk for invasive
breast cancer.[1,2]
It is currently a large volume product, and the recent work of novel formulations
and drug delivery systems could have increased bulk demand for the drug. Several
manufacturing routes to raloxifene are well developed.[3] Schmid reported the syn-
thesis of raloxifene or its side-chain analogs via nucleophilic aromatic displacement
of aroylbenzohiophenes (Scheme 1, route a). Acylation of substituted p-benzoyl
chlorides with benzothiophene 6 gives aroylbenzohiophene, following nucleophilic
aromatic substitution with oxygen-based nucleophiles to introduce the side
piperdino-ethanol chain.[4–7] Jones and coworkers reported the Friedel–Crafts
Scheme 1. Current manufacturing routes to raloxifene.

EFFICIENT SYNTHESIS OF RALOXIFENE
3273
acylation of benzothiophene 6 with 4-[2-(1-piperidino)ethoxy]benzoly chloride has
been utilized for the raloxifene (route b).[8,9] Generally routes a and b both need
a strong basic condition (NaH, DMF or Cs2CO3, CuI) to introduce the piperdino-
ethanol side chain, generating large aqueous waste streams. Thus an environmentally
friendly route of manufacture would be developed not only to the increase bulk
demand of the drug but also to meet the needs of green chemistry. We report here
that route c, using difunctionalized coumpunds 5 as key intermediate, which incorpo-
rates both in the acylation reaction and piperidine nucleophilic substitution, might
meet this need.
RESULTS
The improved synthesis of raloxifene 1 was accomplished as shown in
Scheme 2. Methyl p-hydroxybenzoate 2, 1-bromo-2-chloroethane, and K2CO3 were
refluxed in acetone, yielding compound 3 in 94% yield. Without prior purification, 3
was hydrolyzed to the corresponding p-substituted benzoyl acids 4 in 100% yield.
The application of general reaction conditions of methanol as solvent and
Scheme 2. Reagents and conditions: (a) K2CO3, 1-bromo-2-chloroethane, acetone, reflux, 91%; (b) HCl,
THF, 100%; (c) SOCl2, CH2Cl2; (d) AlCl3, CH2Cl2, 50 ꢀC, 95% from 3; (e) piperidine, 94%; and (f) AlCl3,
CH2Cl2, 50 ꢀC, 90%.

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Y. YANG ET AL.
hydrochloric as acid would afford the substitution impurity 4-(2-methoxy-
ethoxy)-benzoic acid. To control this impurity during reaction, various solvents such
as alcohol, ethyl acetate, acetone, and tetrahydrofuran (THF) were screened, and
THF gave the best result from the view of impurity formation and yield. Compound
4 is a solid and was easily isolated from THF by adding water. Then 4 was trans-
ferred to acid chlorides 5 and substantially reacted with benzothiophene 6 using
AlCl3 in dichloromethane at 50 ꢀC to afford aroylated benzothiophene 7 in two
steps, with yield of 95% (79% from method A[8] and 65.5% from method B[3]).
With the requisite 7 in hand, we next examined piperidine nucleophilic substi-
tution to produce the desired beno[b]thien-3-yl ketones 8. In general using reaction
conditions A (acetone, NaI, K2CO3, reflux, 70%) and B (acetonitrile, NaI, K2CO3,
reflux, 85%), impurity formation was observed from the beginning of the reaction.
We screened various conditions and were delighted to found that using excess
piperidine at reflux temperature gave negligible impurity formation. Piperidine was
not only reagent but also solvent. The isolated product 8 was stable and was
converted into the desired raloxifene 1 as reported.
In conclusion, we have developed a viable alternative route for the synthesis of
raloxifene. The new synthesis would have been better able to support the increase in
bulk demand for this drug for the chemoprevention of breast cancer and novel for-
mulations. Our synthetic route has several advantages: the use of difunctionalized
coumpunds 5 as key intermediate makes Friedel–Crafts acylation and nucleophilic
substitution highly efficient. The using of piperine as reagent and solvent avoids
the large waste streams derived from neutralization reaction of sodium hydride.
The cost of the new route is less than the current route of manufacture.
EXPERIMENTAL
Melting points are uncorrected. NMR spectra were recorded on AM400
(Bruker) instruments in CDCl3. Chemical shifts were calibrated using a solvent peak
or tetramethylsilane as an internal reference. All reactions were carried out under a
nitrogen atmosphere with dry, freshly distilled solvents under anhydrous conditions.
Dichloromethane (CH2Cl2) was distilled from calcium hydride immediately prior to
use. All chemicals were distilled or recrystallized before use, where necessary.
Preparation of [4-(2-Chloro-ethoxy)-phenyl]-[6-methoxy-2-
(4-methoxy-phenyl)-benzo[b]thiophen-3-yl]-methanone (7)
Under an N2 atmosphere, 5 was added to a mixture of 6 (20.25 g, 75 mmol) and
AlCl3 (13.30 g, 100 mmol) in DCM (2 mL), and the mixture was stirred for 12 h. The
reaction was monitored by TLC (n-hexane/EtOAc, 4:1). After the reaction was
judged complete, the reaction mixture was allowed to cool. The crude mixture was
poured into H2O and extracted with EtOAc. The organic layer was separated and
concentrated. The residue was crystallized from EtOAc to give the product 7
(32.26 g, 95%): yellow solid crystals; mp 119–120 ꢀC; IR (KBr) nmax: 2960, 2835,
1647, 1599, 1472, 1251, 1169, 1032, 830 cmꢁ1;1H NMR (400 MHz, CDCl3) d 7.76
(d, J ¼ 8.8 Hz, 2H), 7.53 (d, J ¼ 8.8 Hz, 1H), 7.32 (d, J ¼ 8.4 Hz, 2H), 7.31 (s, 1H),
6.95 (dd, J ¼ 8.4, 2.4 Hz, 1H), 6.75 (dd, J ¼ 9.2, 7.2 Hz, 4H), 4.20 (t, J ¼ 4.0 Hz,

EFFICIENT SYNTHESIS OF RALOXIFENE
3275
2H), 3.87 (s, 3H), 3.78 (t, J ¼ 6.0 Hz, 2H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 193.1, 162.1, 159.7, 157.6, 142.7, 139.9, 133.8, 132.3, 130.9, 130.2, 130.1, 125.9,
123.9, 114.8, 114.1, 113.9, 104.4, 67.8, 55.6, 55.2, 41.5; MS (EI) m/z (%):452 (Mþ,
100.0), 437 (13.0), 297 (25.0), 183 (39.0), 121 (44.0). HRMS m/z (EI) calcd. for
C25H22ClO4S: (MþH) þ: 453.0927; found: 453.0933.
Preparation of [6-Methoxy-2-(4-methoxy-phenyl)-benzo[b]
thiophen-3-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (8)
Under an N2 atmosphere, a mixture of 7 (8.50 g, 19 mmol) and piperdine
(30 ml) was stirred under reflux for 12 h. The reaction was monitored by TLC (n-hex-
ane/EtOAc, 4:1). After the reaction was judged complete, the reaction mixture was
allowed to cool. The mixture was concentrated for recovery of piperidine. EtOAc
was added and the residue was washed with saturated NaHCO3 aqueous solution.
The organic layer was separated and concentrated to give the product 8 (8.80 g,
94%): yellow viscous oil; IR (KBr) nmax: cmꢁ1 2933, 1645, 1597, 1535, 1501, 1470,
1249, 1164, 1030, 827; 1H NMR (400 MHz, CDCl3) d7.76 (d, J ¼ 8.8 Hz, 2H),
7.52 (d, J ¼ 8.8 Hz, 1H), 7.33 (d, J ¼ 8.8 Hz, 2H), 7.30 (d, J ¼ 2.4 Hz, 1H), 6.94
(dd, J ¼ 8.8, 2.0 Hz, 1H), 6.75 (dd, J ¼ 7.2, 5.2 Hz, 4H), 4.08 (t, J ¼ 6.0 Hz, 2H),
3.86 (s, 3H), 3.73 (s, 3H), 2.71 (t, J ¼ 6.0 Hz, 2H), 2.46 (s, 4H), 1.60–1.54 (m, 4H),
1.43–1.41 (m, 2H).13C NMR (100 MHz, CDCl3) d 193.2, 163.0, 159.7, 157.6,
142.4, 140.1, 133.9, 132.3, 130.6, 130.4, 130.2, 126.0, 124.0, 114.8, 114.2, 114.1,
104.5, 66.3, 57.7, 55.6, 55.2, 55.1, 25.9, 24.1. MS (EI) m/z (%): 501 (Mþ, 100.0),
452 (12.0), 402 (21.0), 297 (24.0), 98 (100.0). HRMS m/z (EI) calcd. for
C30H32NO4S: (MþH) þ: 502.2052; found: 502.2055.
FUNDING
We are grateful to the National Natural Science Foundation of China (Project
No. 81102380), Zhejiang Provincial Natural Science Foundation of China (Y2111012),
and Science Technology Department of Zhejiang Provincial (2012F10005,
2012C23106) for financial support.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
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