Effective synthesis of non-racemic prenalterol based on spontaneous resolution of 3-(4-hydroxyphenoxy)propane-1,2-diol

Article abstract of DOI:10.1016/j.mencom.2019.03.028

Spontaneous resolution of rac-3-(4-hydroxyphenoxy)propane-1,2-diol has been successfully used in the synthesis of both enantiomers of chiral drug prenalterol.

Full text of DOI:10.1016/j.mencom.2019.03.028

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 198–199
Effective synthesis of non-racemic prenalterol based on spontaneous
resolution of 3-(4-hydroxyphenoxy)propane-1,2-diol
Zemfira A. Bredikhina, Alexey V. Kurenkov and Alexander A. Bredikhin*
A. E. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of the Russian
Academy of Sciences, 420088 Kazan, Russian Federation. Fax: +7 843 273 1872; e-mail: baa@iopc.ru
DOI: 10.1016/j.mencom.2019.03.028
NHPri
NHPri
HO
HO
(S)
(R)
Spontaneous resolution of rac-3-(4-hydroxyphenoxy)propane-
1,2-diol has been successfully used in the synthesis of both
enantiomers of chiral drug prenalterol.
spontaneous resolution
O
O
HO
O
*
OH
rac
OH
OH
OH
Access to enantiomerically pure intermediates is essential for
obtaining pharmaceutically active products.1 Stereoselective crys-
tallization is increasingly employed in the preparation of enantio-
pure organic compounds2–4 since it offers particular practical
benefits.5 A good example among such preparations can be the
prenalterol 1 [(S)-1-(4-hydroxyphenoxy)-3-(2-propylamino)-
propan-2-ol],6 a partial adrenergic agonist with functional b1-
receptor specificity.7,8 It is effective in the treatment of acute
cardiac failure, postmyocardial infarction low-output syndrome,
shock, and is useful in the treatment of b-blocker overdosage.8,9
In this study, we used O-protected diol 2, 3-(4-methoxy-
phenoxy)propane-1,2-diol 3, whose synthesis was previously
described.19 Removal of the protective O-methyl group was
performed according to the patent data,20 by hydrolysis with
concentrated HBr. In this manner, rac-2 required for further work,
as well as its enantiomers (used then as crystalline seeds), were
obtained in overall yields of ~65%.
As already mentioned, rac-2 was resolved by the entrainment
approach when crystallization of the enantiomer from super-
saturated solutions of racemate was provoked by introducing the
enantiopure crystalline seed. Diol 2 is highly soluble in methanol,
slightly worse in acetone and poorly soluble in chloroform,
dichloromethane, benzene, diethyl ether and ethyl acetate. We
have found water to be the most convenient solvent for the
separation of diol 2 enantiomers. Quantitatively, the solubility of
rac-2 at 23.5°C in water was 25 mg ml–1, and at 45.5°C these
values for rac-2 and (R)-2 were 81 and 27 mg ml–1, respectively.
Varying initial concentration, temperature gap and crystallization
time, we have adopted the conditions for the satisfactory resolution
of rac-2 (Table 1). The separation process was monitored by
chiral HPLC (Figure S1, Online Supplementary Materials).
The first resolution run provided moderate results (see Table 1)
when enantiomeric excess for the crystalline R-precipitate was
~39% and that for the (S)-2 mother liquor was ~3.8%. In sub-
sequent cycles, the mother liquors were enriched with the opposite
enantiomer (after the last completed run the mother liquor ee was
10.5%, see Figure S1), the enantiomeric excess of the crystalline
precipitate rose to ~80%. At the same time, the one-time crop of
the enantiomer also increased from 7.5 to ~23%. Obviously, the
enantiomeric purity of non-racemic samples can be improved
by recrystallization. In total, for three cycles (6 runs) from 5.28 g
of rac-2, 1.03 g (19.4%) of (S)-2 and 0.87 g (16.5%) of (R)-2
were obtained, counting on pure enantiomers.† If necessary,
the procedure can be continued until the racemic feedstock is
consumed.
OH
OH
*
*
HO
O
NHPri
HO
O
OH
1
2
In the available literature for the synthesis of compound 1,
the natural raw materials (Chiral Pool) are reported as primary
sources of chirality. With this, the synthetic schemes are multi-
step and involve the use of protective groups.10–13 Investigating
the phase behavior of chiral aromatic glycerol ethers, we found
that the members of this chemotype often prone to spontaneous
resolution during crystallization.5,14 In particular, we have shown
that an ortho-substituted analogue of diol 2 crystallizes from a
racemic substrate as a conglomerate, a mechanical mixture of
enantiopure crystals.15 In turn, compound 2 can serve as a
precursor of potential drug 1.
Preliminary information on the crystallization nature of a
chiral compound can be obtained from comparison between
the melting points of its enantiopure and racemic samples.14
According to the published data, the melting point of amino
alcohol rac-1 is higher than that of the enantiomer by 29°C.13,16
In contrast, diol rac-2 melts 21°C below the enantiopure
sample.12,17 Judging from these data, prenalterol itself should
form a racemic compound in the crystalline state. However, in
the case of diol 2 the formation of conglomerate may be
anticipated. Comparison of vibrational spectra and X-ray powder
diffraction patterns of racemic and enantiomeric crystalline
samples of diol 2 has revealed that this compound can form
racemic conglomerate in the solid phase.18 Here we proved this
hypothesis by direct resolution of rac-2 into individual enantio-
mers using the entrainment method.
†
(S)-3-(4-Hydroxyphenoxy)propane-1,2-diol (S)-2. Mp 150–151 °C
(EtOAc), [a]D20 +8.0 (c 1, MeOH) {lit.,12 149.5–151°C (MeOH–CHCl3),
[a]D20 +8.01 (c 1.0, MeOH)}, 99% ee (HPLC).
(R)-3-(4-Hydroxyphenoxy)propane-1,2-diol (R)-2. Mp 149–151 °C
(EtOAc), [a]D20 –8.1 (c 1.0, MeOH), 98% ee (HPLC).
For experimental details, see Online Supplementary Materials.
© 2019 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2019, 29, 198–199
Table 1 Resolution by entrainment of rac-3-(4-hydroxyphenoxy)propane-1,2-diol (rac-2) in water (50 ml, 8 mg of crystal seeds on every run).
Operation amount
of enantiomers/g
Amount
of rac-2
added/g
Mother
liquor
ee (%)
(R)-2 and (S)-2 obtained
Resolution
time/min
Run
T/°C
(R)-2
(S)-2
Yield/g
eea (%)
YEb/g
YEc (%)
1
2
3
4
5
6
3.000
0.302
0.512
0.508
0.442
0.512
1.500
1.444
1.588
1.401
1.586
1.393
1.500
1.556
1.413
1.600
1.414
1.608
150
215
390
305
480
350
23–24
27
27–28
27–28
26–27
27
(R) 0.310
(S) 0.519
(R) 0.516
(S) 0.451
(R) 0.519
(S) 0.445
39
57
74
84
76
84
0.113
0.288
0.374
0.371
0.386
0.366
7.5
18.5
23.6
23.2
24.3
22.8
3.8 (S)
7.7 (R)
8.4 (S)
9.8 (R)
9.4 (S)
10.4 (R)
a ee is enantiomeric excess (HPLC). bYE is the yield of enantiomer. YE (g) = [Yield (g) × ee (%)]/100 – 0.008 (seed weight). cYE (%) = [YE (g) × 100]/
Operation amount of (R)-2 or (S)-2 (g).
quinone occurs in a low yield (23%) and is accompanied by
contamination of the product.
O
H
Thus, both enantiomers of chiral drug prenalterol were obtained
based on spontaneous resolution of racemic 3-(4-hydroxyphen-
oxy)propane-1,2-diol upon crystallization from water. The proposed
scheme favorably competes with the ‘Chiral Pool’ concept due to
smaller number of stages and the use of racemic raw materials.
O
v
iv
(S)-1
(S)-2
OH
O
HO
i
OH
*
OH
ii
iii
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.03.028.
rac-2
(S)-4
O
OMe
H
References
OMe
rac-3
v
O
iv
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OH
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Scheme 1 Reagents and conditions: i, rac-ClCH2CH(OH)CH2OH, NaOH,
EtOH, reflux; ii, HBr (45% aq.), 50°C; iii, resolution by entrainment; iv, PPh3,
DEAD, THF, reflux; v, PriNH2, reflux.
Based on successful spontaneous resolution of compound 2
as a source of chirality, we suggest a new original scheme for the
preparation of enantiopure prenalterol 1 (Scheme 1), in which
the direct resolution of the racemic diol 2 by an entrainment
procedure was the key step. Conversion of thus obtained enantio-
mers of diol 2 into the target compounds 1 has been carried in
two steps. Initially, the intramolecular Mitsunobu etherification
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isopropylamine in the presence of minimum water.§
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of rac-4 by the reaction between epichlorohydrin and hydro-
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‡
(S)-4-(2,3-Epoxypropoxy)phenol (S)-4. Yield 97%, mp 81–83.5°C
(hexane–EtOAc), [a]D20 +12.8 (c 1.0, MeOH), 93% ee (HPLC).
(R)-4-(2,3-Epoxypropoxy)phenol (R)-4. Yield 95%, mp 81–84°C
(hexane–EtOAc), [a]D20 –13.5 (c 1.0, MeOH), 92% ee (HPLC).
§
(S)-1-(4-Hydroxyphenoxy)-3-isopropylaminopropan-2-ol (S)-1. Yield
89%, mp 125–127°C (EtOAc), [a]D20 –1.9 (c 1.0, MeOH), [a]D20 –21.0
(c 1.0, 0.1 n HCl) {lit.,6 mp 127–128°C (EtOAc), [a]D20 = –1 1 (c 0.94,
MeOH); lit.,13 [a]D25 –20.67 (c 1.0, 0.1 n HCl)}, 98% ee (HPLC).
(R)-1-(4-Hydroxyphenoxy)-3-isopropylaminopropan-2-ol (R)-1. Yield
94%, mp 124–126°C (EtOAc), [a]D20 +2.4 (c 1.0, MeOH), [a]D20 = +18.4
(c 1.0, 0.1 n HCl) {lit.,13 mp 126–127°C (acetone), [a]D25 = +20.85 (c 1.0,
0.1 n HCl)}, 95% ee (HPLC).
22 J. J. Baldwin and D. E. McClure, Patent EU 0006614 A2, 1980.
Received: 18th October 2018; Com. 18/5721
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