The first enantiomerically pure synthesis of (S)- And (R)-naftopidil utilizing hydrolytic kinetic resolution of (±)-(α-Naphthyl) glycidyl ether

Article abstract of DOI:10.1246/cl.2004.1212

Hydrolytic Kinetic Resolution (HKR) of (±)-(α-Naphthyl) glycidyl ether with (R,R)-salen Co(III) OAc complex provided enatiomerically pure (S)-naphthyl glycidyl ether and (R)-1-naphthyl glycerol; opening of the corresponding pure terminal epoxide with 1-(2-methoxyphenyl)piperizine gave the enantiomerically pure (S)- and (R)-Naftopidil.

Full text of DOI:10.1246/cl.2004.1212

1212
Chemistry Letters Vol.33, No.9 (2004)
The First Enantiomerically Pure Synthesis of (S)- and (R)-Naftopidil Utilizing Hydrolytic
Kinetic Resolution of (Æ)-(ꢀ-Naphthyl) Glycidyl Ether
Kiran Kumar Kothakondaꢀy;yy and D. Subhas Boseyy
yDepartment of Chemistry, University of Montreal, Montreal, QC, Canada, H3C 3J7
yyFine Chemical Laboratory, Indian Institute of Chemical Technology, Hyderabad, India
(Received April 30, 2004; CL-040492)
Hydrolytic Kinetic Resolution (HKR) of (ꢁ)-(ꢀ-Naphthyl)
most versatile C3-chiral synthons with neumorous applications
for ꢁ-blockers, MAO inhibitors, alkyl glycerophospholipids
and other pharmaceuticals as well as in organic synthesis.4
glycidyl ether with (R,R)-salen Co(III) OAc complex provided
enatiomerically pure (S)-naphthyl glycidyl ether and (R)-1-naph-
thyl glycerol; opening of the corresponding pure terminal epox-
ide with 1-(2-methoxyphenyl)piperizine gave the enantiomeri-
cally pure (S)- and (R)-Naftopidil.
O
N
OH
N
H3CO
Naftopidil
The importance of chirality in the context of biological func-
tion has been fully appreciated and the R and S forms of most
drugs are metabolized by different biochemical paths and at dif-
ferent rates. For example, (R)-thalidomide is an effective seda-
tive where as the (S)-enantiomer is highly teratogenic and causes
fetal abnormalities.1
Naftopidil (BM-15275)5 is a vasodilator from the piperizine
derivative series. Pharmacologically, naftopidil is a novel
ꢀ1-adrenoceptor antagonist (ꢀ1-blocker), renal urologic drug,
used for the treatment of arterial hypertension. Asahi Chemicals
has launched naftopidil (Flivas[R]) in Japan, where it is indicat-
ed for the treatment of dysuria of men with benign prostatic hy-
pertrophy as racemic mixture. In the investigations of the safety
of naftopidil in racemic form, it was found that urine and electro-
lyte excretion was slightly reduced at doses active on blood pres-
sure, with some other sedative properties,6 and also found that
the drug affects on phenylephrine-induced increases in prostatic
and blood pressure in anesthetized dogs.7 All these information
necessitate preparation of optically pure (S)- and (R)-naftopidil
and investigation of their pharmacokinetics as individual molec-
ular entities.
H
H
N N
Co
O O
O
Ac
(R,R)- Salen Co (III) OAc Complex (1)
O
O
OH
O
O
O
OH
H
OH
a
b
R
R
R
H
+
0.5 mol% 1
+
2
3
4
5
O
OH
O
HO
0.55 equiv. H2O
Scheme 2. a) Epichlorohydrin, K2CO3, acetone, reflux, 12 h,
90%; b) 0.5 mol % 1, water (0.55%), rt, 24 h.
>99%ee
>99%ee
Scheme 1.
The truly fascinating Hydrolytic Kinetic Resolution of rac-
emic glycidyl ethers8 promoted us to undertake the synthesis
of optically pure (S)- and (R)-naftopidil. ꢀ-Naphthol (2) was
treated with racemic epichlorohydrine to afford racemic (ꢀ-
naphthyl) glycidyl ether (3). Compound 3, catalyst salen com-
plex (1) and 0.55 equiv. of water stirred for 24 h at room temper-
ature (Scheme 2). Chromatographic purification of the reaction
mixture gave (S)-1-(ꢀ-naphthyl) glycidyl ether (4) in 45% yield
{½ꢀꢂD ¼ þ30:1ꢃ (c ¼ 1:5, MeOH); lit.9 ½ꢀꢂD ¼ þ31:4ꢃ (c ¼
1:5, MeOH)} and (R)-1-(ꢀ-naphthyl) glycerol (5) in 45% yield
{½ꢀꢂD ¼ ꢄ5:2ꢃ (c ¼ 0:7, EtOH); lit.10 ½ꢀꢂD ¼ ꢄ4:9ꢃ (c ¼ 0:7,
EtOH)} as a light yellow solid (mp 108 ꢃC, lit.10 108–109 ꢃC).
Piperizine derivative, 1-(2-methoxyphenyl)piperizine (8)
was obtained from the coupling of O-anisidine and bis(2-chloro-
ethyl) amine hydrochloride (7), which was prepared from dieth-
anolamine (6) (Scheme 3). (S)-epoxide (4) was treated with pi-
Terminal epoxides are versatile starting materials for the
preparation of bioactive molecules;2 it is pertinent to mention
the different methods to obtain enantiomerically pure epoxides,
which include classical optical resolution via diastereomers,
chromatographic separation, enzymatic resolution, chemical ki-
netic resolution, and asymmetric synthesis. However, the recent-
ly reported technique of Hydrolytic Kinetic Resolution (HKR) of
terminal epoxide by Jacobsen3 has been unexplored for prepara-
tion of chiral building blocks. This process uses water as the only
reagent without solvent and low loading of a recyclable chiral
(R,R)-salen cobalt(III) OAc catalyst (1) affords highly valuable
terminal epoxides and 1,2-diols in high yields with high enantio-
meric enrichment (Scheme 1). This method is also extremely
simple to work with compared to other approaches for chiral gly-
cidyl ethers. Chiral glycidyl derivatives are perhaps one of the
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.9 (2004)
1213
sized utilizing Jacobsen’s HKR method for the resolution of rac-
emic (ꢀ-naphthyl) glycidyl ether. This will promote the investi-
gation of their pharmacokinetics as individual molecular entities
and will be reported soon.
OCH3
NH
N
a
b
Cl
Cl
HO
HO
NH.HCl
NH
8
References and Notes
7
6
1
2
S. J. Fabro, Biochem. Basis Chem. Teratog., 1981, 159.
H. C. Kolb, M. S. Van Nieuwenhze, and K. B. Sharpless,
Chem. Rev., 94, 2483 (1994).
O
N
OH
N
3
a) M. Tokunaga, J. F. Larrow, F. Kakiuchi, and E. N.
Jacobsen, Science, 277, 936 (1997). b) B. D. Brandes and
E. N. Jacobsen, Tetrahedron: Asymmetry, 8, 3927 (1997).
c) M. E. Furrow, S. E. Sehaus, and E. N. Jacobsen, The
Nucleus, 2, 26 (1998).
c
H3CO
9
Scheme 3. a) SOCl2, benzene, reflux, 5 h, 74%; b) O-Anisidine,
aq. NaHCO3, 100 ꢃC, 24 h, 85%; c) 5, iPrOH, reflux, 30 h, 93%.
4
5
6
7
8
M. Bulliard, Manuf. Chem., 4, 25 (1996).
Drugs Future, 12, 31 (1987).
Drugs Future, 25, 93 (2000).
L. Ikegi, Jpn. J. Pharmacol., 1, 79 (1999).
a) S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunanga,
K. B. Hansen, A. E. Gould, M. E. Furrow, and E. N.
Jacobsen, J. Am. Chem. Soc., 124, 1307 (2002), and
references cited therein. b) M. K. Gurjar, K. Sadalapure, S.
Adhikari, B. V. N. B. S. Sarma, A. Talukdar, and M.
Chorghade, Heterocycles, 48, 1471 (1998).
O
O
N
O
OH
O
OH
OH
N
a
b
H3CO
5
10
11
Scheme 4. a) DEAD, TPP, benzene, reflux, 24 h, 87%; b) 8,
iPrOH, reflux, 30 h, 90%.
9
H. S. Bevinakatti and A. A. Banerji, J. Org. Chem., 56, 3710
(1991).
perizine derivative (8) in iPrOH under reflux condition to afford
the (S)-naftopidil (9) in 93% yield {½ꢀꢂD ¼ þ3:8ꢃ (c ¼ 1:5,
MeOH)} as a light yellow solid (mp 127 ꢃC).11
Subsequently, diol (5) was subjected to Mitsunobu invertion
with DEAD and Ph3P in bezene under reflux to afford the (R)-
1-(naphthyl) glycidyl ether (10) {½ꢀꢂD ¼ ꢄ33:2ꢃ (c ¼ 1:5,
MeOH); lit.9 ½ꢀꢂD ¼ ꢄ33:9ꢃ (c ¼ 1:55, MeOH)}. (R)-epoxide
on treatment with piperizine derivative (8) in iPrOH under reflux
gave the (R)-naftopidil (11) in 90% yield {½ꢀꢂD ¼ ꢄ3:94ꢃ
(c ¼ 1:5, MeOH)} as a light yellow solid (mp 127–128 ꢃC)
(Scheme 4).
The pharmacokinetic findings suggest that in ten patients
(9M/1F) with severe hepatic impairment or evidence for marked
changes in hepatic blood flow the dose of naftopidil may require
adjustment to the lower end of the therapeutic range and/or may
be limited to once daily.12 In conclusion, it is pertinent to men-
tion that first optically pure (S)- and (R)-naftopidil was synthe-
10 a) M. J. Klunder, S. Y. Ko, and K. B. Sharpless, J. Org.
Chem., 51, 3710 (1986). b) L. Salajar, J. L. Bermudez, C.
Ramirez, E. F. Llama, and J. V. Sinisterra, Tetrahedron:
Asymmetry, 10, 3507 (1999).
11 (S)-Naftopidil (9), mp: 127 ꢃC. ½ꢀꢂD ¼ þ3:8ꢃ (c ¼ 1:5,
MeOH). IR: 3450, 3020, 2980, 2920, 1230 cmꢄ1. H NMR
1
(CDCl3, 400 MHz): ꢂ 8.22–8.18 (dd, J ¼ 2:3, 7.1 Hz, 1H);
7.8–7.74 (dd, J ¼ 2:3, 7.1 Hz, 1H); 7.5–6.74 (m, 9H);
4.22–4.03 (m, 5H); 3.9 (s, 3H); 3.58–3.17 (m, 9H). 13C NMR
(CDCl3, 400 MHz): ꢂ 154.51; 154.33; 138.19; 134.36;
127.33; 126.26; 125.74; 125.49; 125.29; 125.05; 124.06;
121.85; 121.1; 120.36; 111.79; 104.8; 70.12; 68.38; 61.73;
57.99; 55.31; 51.26; 44.58; 42.51. EIMS: 329 (Mþ).
12 M. J. Farthing, E. M. Alstead, S. M. Abrams, G. Haug, A.
Johnston, R. Hermann, G. Niebch, P. Runs, K. H. Molz,
and P. Turner, Postgrad. Med. J., 70, 363 (1994).
Published on the web (Advance View) August 21, 2004; DOI 10.1246/cl.2004.1212