Synthesis and crystal structure of (S)-pindolol

Article abstract of DOI:10.1016/j.tetasy.2017.02.009

Racemic 3-(4-indolyloxy)-1,2-propanediol 2 has been effectively resolved into (S)- and (R)-enantiomers by a preferential crystallization procedure. Non-racemic (S)-2 was converted into (S)-4-(2,3-epoxypropoxy)-1H-indole (S)-4 via a Mitsunobu reaction and then into (S)-pindolol (S)-1. The crystalline (S)-1 was studied by single crystal X-ray diffraction. A large number of symmetry independent molecules (Z' = 6) led to a weakening of the system of strong intermolecular hydrogen bonds, which combined with a loose packing (PI = 64.6%), may be the cause of the abnormally low melting point of (S)-1 as compared with rac-1.

Full text of DOI:10.1016/j.tetasy.2017.02.009

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and crystal structure of (S)-pindolol
⇑
Alexander A. Bredikhin , Zemfira A. Bredikhina, Alexey V. Kurenkov, Dmitry B. Krivolapov
A.E. Arbuzov Institute of Organic & Physical Chemistry, Kazan Scientific Centre of the Russian Academy of Sciences, Kazan 420088 Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Racemic 3-(4-indolyloxy)-1,2-propanediol 2 has been effectively resolved into (S)- and (R)-enantiomers
by a preferential crystallization procedure. Non-racemic (S)-2 was converted into (S)-4-(2,3-epoxypro-
poxy)-1H-indole (S)-4 via a Mitsunobu reaction and then into (S)-pindolol (S)-1. The crystalline (S)-1
Received 22 December 2016
Revised 1 February 2017
Accepted 10 February 2017
Available online xxxx
was studied by single crystal X-ray diffraction. A large number of symmetry independent molecules
0
(
Z = 6) led to a weakening of the system of strong intermolecular hydrogen bonds, which combined with
a loose packing (PI = 64.6%), may be the cause of the abnormally low melting point of (S)-1 as compared
with rac-1.
Ó 2017 Elsevier Ltd. All rights reserved.
1
. Introduction
tors precludes the possibility of racemic pindolol resolution into
individual enantiomers using direct methods.
1
-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]-2-propanol
1
Recently, we have shown that one of the possible synthetic pre-
cursors of pindolol, racemic 3-(4-indolyloxy)-1,2-propanediol, rac-
2 (Chart 1) crystallizes as a normal conglomerate and can be
(
Chart 1) is primarily known as a mixed b-adrenergic blocker and
serotonin 5HT1A-receptor antagonist, and as such is widely used
in cardiovascular therapy. Pindolol has been intensively studied
in the treatment of nervous disorders.
racemic form, although it has been demonstrated that its enan-
tiomers possess different activities,
family of beta-blockers.8
1
15
resolved into its enantiomers by a direct entrainment approach.
2–4
Pindolol is used in its
Herein we report the spontaneous resolution of diol 2 and the fea-
tures of the pindolol phase diagram for obtaining active pharma-
ceutical ingredient 1 with high enantiomeric purity.
5–7
which is usual for the entire
,9
14
According to the literature, pindolol is characterized by a
There has been a trend towards replacing racemic active phar-
maceutical ingredients with single enantiomers.9 The main lim-
iting factor to its implementation is whether it is economically and
ecologically justified. Pindolol is sensitive to the action of acidic
reagents, hence the use of chiral acids as resolving agents for the
resolution of rac-1 is problematic. In order to obtain the enantiop-
ure product in a neutral medium, it would be attractive to use
eutecticless phase diagram, but the difference between the melting
,10
f
temperatures of rac-1 (169.7 °C) and scal-1 (92–93 °C),
D
T > 76°, is
extraordinarily high not only for continuous solid solution, but also
for any type of crystalline chiral organic matter. Detailed informa-
tion about the crystalline structure of scal-1 could clarify the cause
of this anomaly. Therefore, our second objective was to study
enantiopure pindolol by single crystal X-ray analysis.
1
1
direct methods without the need for any additional substances.
However, previous investigations on rac-1 by X-ray analysis have
revealed that the substance crystallizes in the non-Sohncke space
2
2
. Results and discussion
1
group P-42 c with a single symmetry independent molecule in
.1. Chemistry
1
2,13
the unit cell.
This means that in the crystalline phase, racemic
pindolol forms a normal racemic compound.
Racemic pindolol is usually prepared via the reaction of 4-
According to the thermochemical data of Neau et al., the pin-
dolol binary phase diagram represents a steep dome with its apex
at ee = 0, and the dome branches rest on the points ee = 1. This
means that pindolol crystallizes as a continuous solid solution with
a pronounced positive deviation.14 The combination of these fac-
hydroxyindole with racemic epichlorohydrin, followed by the
addition of isopropyl amine to the oxirane ring. Applying this
method to the synthesis of (S)-pindolol by using (ꢀ)-epichlorohy-
drin, however, leads to a decrease in the enantiomeric purity due
to a partial attack of the aryloxy anion on the carbon atom C1 of
epichlorohydrin in competition with the epoxide ring-opening.16
Our approach for the synthesis of enantiopure pindolol is shown
in Scheme 1.
⇑
Corresponding author. Tel.: +7 843 2727393; fax: +7 843 2731872.
E-mail address: baa@iopc.ru (A.A. Bredikhin).
http://dx.doi.org/10.1016/j.tetasy.2017.02.009
957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
0
Please cite this article in press as: Bredikhin, A. A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.02.009

2
A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
OH
HO
b = 50.686 Å, c = 11.1038 Å), six independent molecules with an
S)-configuration are present. All of molecules are free of disor-
dered fragments. Figure 1 shows one of the independent (S)-1
molecules (molecule F) and the numbering scheme adopted for
the non-hydrogen atoms.
(
NH
HO
O
O
N
H
N
Although, strictly speaking, pindolol is not classified as a simple
alcohol or vicinal diol, the compound, at least formally, is subject to
H
1
2
1
7
the rule derived in the literature, in which these classes crystal-
lize either in the high symmetry space group with the only inde-
pindolol
3-(4-indolyloxy)-1,2-propanediol
0
Chart 1. Pindolol 1 and its possible synthetic precursor 3-(4-indolyloxy)-1,2-
propanediol 2.
pendent molecule (Z = 1) or in the normal groups (triclinic,
0
monoclinic, or orthorhombic), but with a high Z ꢂ 2. The causes
and consequences of this occurrence in the unit cell of the crystal
0
of several symmetry independent molecules, the case of Z > 1,
The reaction of 4-hydroxyindole 3 with racemic 3-chloro-
propane-1,2-diol leads to racemic diol 2, which, after a slight
enrichment of one enantiomer (ꢁ9% ee), was then subjected to
direct resolution into the individual enantiomers by an entrain-
ment procedure involving crystallization from a saturated solution
in water. This process has some peculiarities worthy of mention.
After seeding with crystals of the predominant enantiomer, an
incubation period is observed during which no crystallization
occurs. In order to induce crystallization, the temperature was
reduced gradually until noticeable crystallization began, after
which the solution was thermostated at this temperature. The
crystallization is very fast, while the period before the separation
of the precipitate takes a rather short time (approx. 40 minutes),
after which the precipitate is filtered. The enantiomeric purity of
the thus obtained scalemic diol (ꢁ80% ee) can be enhanced by
recrystallization from water (see experiment).
Non-racemic diol (S)-2, obtained via intramolecular Mitsunobu
etherification, was converted into glycidyl ester (S)-4. After open-
ing the oxirane ring with isopropylamine and purification of the
product by column chromatography, the target (S)-pindolol was
isolated with an enantiomeric excess of 95.7%. In order to increase
the enantiomeric purity of pindolol, the features of its phase dia-
gram should be taken into account, namely, that during recrystal-
lization of pindolol of any enantiomeric purity ee < 100%, the
enantiomeric purity of the precipitate is less than that of the start-
ing material. At the same time, the mother liquor is enriched with
the dominating enantiomer. Thus, during crystallization of the
are actively being discussed in the literature; the current state of
this subject is covered in the Kirsty and Jonathan Steed review.18
According to this source, the share of crystalline structures with
0
Z > 1 in different works is estimated at 9–11% of the total number
0
of investigated crystals. At the same time, the structures with Z > 4
are encountered a hundred times more rarely and make up only
0.07% of the same array.
By itself, a rare occurrence of such crystals may indicate their
relative instability. In the case of pindolol as an argument the pack-
ing density of racemic and enantiopure crystals can serve in favor
of such an interpretation. By using known crystallographic,13 we
evaluated the packing index for rac-1: PI = 66.0%. According to
our data, the PI value for (S)-1 is 64.6%. Normal values of the PI
for molecular crystals, as well as for dense packings of ellipsoids
and spheres, are in the range 65–77%. By this criterion, the magni-
tude of PI for rac-1 fits into the normal range of values, and for (S)-1
is close to the lower limit of existence of crystalline matter (ꢁ60%).
Simultaneously, a large number of independent molecules explic-
itly weakens the network of strong intermolecular hydrogen bonds
with OH and NH group participation in (S)-1 crystals as compared
with a similar highly symmetrical intermolecular hydrogen bond
system within rac-1 crystals. To quantify the effect, rigorous calcu-
lations are required, which goes far beyond the scope of this paper.
We confined ourselves to the qualitative arguments below.
In crystals of rac-1 each pindolol molecule acts as the donor of
0
0
two intermolecular H-bonds: O2AH2ꢃ ꢃ ꢃN2 [d (O2ꢃ ꢃ ꢃN2 ) = 2.758 Å,
0
0
\OAHꢃ ꢃ ꢃN = 176°] and N1AH1ꢃ ꢃ ꢃO2 [d (N1ꢃ ꢃ ꢃO2 ) = 2.875 Å,
\NAHꢃ ꢃ ꢃO = 151°]. Thus, for every six molecules in crystals of
rac-1, there are six intermolecular hydrogen bonds with OH bond
participation close to ideal parameters. There are six intermolecu-
lar hydrogen bonds involving NH bonds, the parameters of which
can be considered in the best case as satisfactory. It is understood
that each molecule simultaneously acts as a recipient (acceptor) of
two H-bonds with adjacent molecules, whose contribution to the
total energy of the intermolecular hydrogen bond system is auto-
matically taken into account when listing donors.
6 6 3
sample ee = 95.5% from C H /CH OH mixture, a small amount of
crystals with a higher melting temperature (138–173 °C) were pre-
cipitated. The total enantiomeric purity of the crystalline crop was
approximately ee = 37%. After the separation of this solid from the
residual mother liquor, the crystalline pindolol was obtained with
ee > 99.9%. These crystals were used for the X-ray analysis of (S)-1.
2
.2. Single crystal X-ray analysis
As noted above, rac-1 crystallizes in the tetragonal non-Sohncke
In crystals of (S)-1, each independent molecule is represented in
the common intermolecular hydrogen bond network differently. In
general, for these 6 molecules there are 6 intermolecular hydrogen
bonds involving OAH bonds (for A, C, D and F molecules these are
1
space group P-42 c with a single symmetry independent molecule
1
2,13
in the unit cell.
As expected, highly enantiopure (S)-pindolol
2. In the
crystallizes in the Sohncke space group, namely P2
1 1
2
0
asymmetric unit of the orthorhombic unit cell (a = 14.948 Å,
O2AH2ꢃ ꢃ ꢃN2 H-bonds, and for molecules B and E these are
H
OH
O
NH
OH
O
O
4
4
a
5
6
i
ii
iii
iv
3
rac-2
(S)-2
2
N
H
2
N
H
7a
N
H
{
+ (R)-
}
7
3
(S)-4
(S)-1
Scheme 1. Reagents and conditions: (i) K
2
CO
3
2 2 3 3 2
, rac-ClH CCH(OH)CH OH, CH CN, reflux, 16 h; (ii) resolution by entrainment; (iii) PPh , DEAD, THF, reflux, 24 h; (iv) i-PrNH ,
MeOH. The above atom numbering for the indole moiety is used in the description of the experimental NMR spectra.
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A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
of the opposite enantiomer promotes pindolol crystallization, but
prevents the crystallographic symmetry elements of the second
kind, and hence induces the formation of a solid solution. In the
limiting case of racemic feed material, the symmetry ban is lifted
and a normal racemic compound is formed during crystallization.
3
. Conclusion
Herein we have reported a method of producing a popular
active pharmaceutical ingredient pindolol 1 with a high degree of
enantiomeric purity. The key steps in this are the direct resolution
of the enantiomers of racemic 3-(4-indolyloxy)-1,2-propanediol
rac-2 by an entrainment procedure and the conversion of the thus
obtained (S)-2 into (S)-glycidyl 4-hydroxyindole ether (S)-4 via
Mitsunobu reaction. (S)-Pindolol is obtained after oxirane ring
opening by isopropylamine and is characterized by an enan-
tiomeric excess of 95–96%. The enantiomeric excess of (S)-1 can
be increased to 99.9% through a type of recrystallization in which
the crystalline precipitate is discarded and the enantiopure target
product is isolated from the mother liquor.
Single-crystal X-ray structure analysis of highly enantiomeri-
cally enriched pindolol has revealed that scal-1 belongs to a very
rare category of crystals of simple organic compounds, in which
the unit cell contains six symmetry independent molecules. The
crystal packing of scal-1 is characterized by a low packing index
64.6%. A large number of symmetry independent molecules signif-
icantly weakens the system of strong intermolecular hydrogen
bonds in crystals of (S)-1. This effect, coupled with the loose pack-
ing, is responsible for the abnormally low melting point of (S)-1 as
compared with rac-1.
Figure 1. The structure of one of the independent molecules (F) in the crystals of
(S)-1 and accepted numbering for nonhydrogen atoms.
0
O2AH2ꢃ ꢃ ꢃO2 H-bonds). At the same time the average distance
between the donor and acceptor heavy atoms varies from
2
.769 Å to 3.032 Å and an average of dav (Dꢃ ꢃ ꢃA) = 2.876 Å. Angle
DAHꢃ ꢃ ꢃA varies from 160° to 175° with an average of \av
DAHꢃ ꢃ ꢃA = 167°. Both parameters are significantly worse com-
pared to rac-1. The situation appears even more clearly with inter-
molecular hydrogen bonds involving the N1AH1 moiety of indole
cycle. Instead of six H-bonds in the racemate crystals, there are
0
only four, namely intermolecular hydrogen bond N1AH1ꢃ ꢃ ꢃO2
0
[
d
a
v (N1ꢃ ꢃ ꢃO2 ) = 2.963 Å, \av NAHꢃ ꢃ ꢃO = 164°] for molecules E
0
0
and
F
and N1AH1ꢃ ꢃ ꢃN2
[dav (N1ꢃ ꢃ ꢃN2 ) = 2.952 Å,
\
av
NAHꢃ ꢃ ꢃN = 160°] in molecules A and D. The indole moiety in mole-
cules B and C is not involved in the intermolecular hydrogen
bonding.
Thus, the system of strong hydrogen bonds, which make a sub-
stantial contribution to the stability of the crystal lattice in (S)-1
crystals, appear considerably weaker, compared with rac-1 crys-
tals. It can be assumed that this effect is reflected in a decrease
in the enthalpy of fusion for this pair from 57.9 to 25.7 kJ/mol,
and as a result, lowering the melting temperature of the enantiop-
ure sample compared to a racemic sample.
Half of the symmetry independent pindolol molecules in the
crystals of (S)-1 have conformations close to the conformation of
(S)-1 molecules in rac-1 crystals. The other half of independent
molecules has the structure close to (R)-1 molecules in rac-1 crys-
tals. We believe that such a distribution of crystallographic sites
contributes to the formation of continuous solid solution of enan-
tiomers of 1 in the samples of intermediate enantiomeric purity.
1
4
In our opinion, the X-ray analysis data shed light on the cause of
pindolol enantiomers continuous solid solution formation. The
conformation of the main chain of pindolol molecules can be
4. Experimental
described by serial listing of torsion angles
s
1
(C13C12N2C1),
(C2C3O1C4) and
(C3O1C4C11). According to the literature, the conformation
s
2
4.1. General
(
3 4 5
C12N2C1C2), s (N2C1C2C3), s (C1C2C3O1), s
1
3
s
6
The NMR spectra were recorded on a Bruker Avance-400 spec-
trometer (399.9 MHz for H and 100.5 MHz for C) or a Bruker
1
13
of molecule 1 in the crystals of rac-1 can be described as ap, ap,
ap, ap, ap, ap where the deviation of torsion angles from
the ideal value 180° does not exceed 20° modulo, but for molecules
of different enantiomers these deviations have opposite signs.
According to our data, the independent molecules B, E and F in
1
13
s
1
–s
6
Avance-600 (600.1 MHz for H and 150.9 MHz for C) in CDCl3
with the signals of the solvent as the internal standard. Optical
rotations were measured on a Perkin–Elmer model 341 polarime-
ter (concentration c is given as g/100 ml). Melting points for gen-
eral purposes were determined using a Boëtius apparatus and are
uncorrected. Thin-layer chromatography was performed on Silufol
UV-254 plates; TLC plates were visualized under UV irradiation or
by treatment with iodine vapor. HPLC analyses were performed on
a Shimadzu LC-20AD system controller, UV monitor 275 nm was
used as detector. The columns used, from Daicel Inc., were Chiral-
cel OD-RH or Chiralpak AD-RH (0.46 ꢄ 25 cm). For the determina-
tion of enantiomeric compositions of compounds 1 and 2, the
columns were calibrated against the corresponding racemic
compounds.
(S)-1 crystals also exist in the all-trans conformation. At the same
time in the molecules A, C and D, with the total transoid structure
for the remaining fragments, conformations of C2C3O1C4 fragment
(
5
torsion angle s ) differ significantly. If in molecules B, E and F the
s
5
torsion angle values are equal to ꢀ163.2°, ꢀ159.8° and ꢀ161.9°
respectively, then in molecules A, C and D these values are signif-
icantly different in magnitude and sign and are respectively 110.0°,
1
40.4° and 78.1°.
Thus, six independent sites existing in (S)-1 crystals are sepa-
rated into two equal in number of members groups, the first of
which is structurally close to the site of (S)-enantiomer in the race-
mate crystals and is markedly different from the second one.
Apparently, it is this second group of sites that can be readily
replaced by the opposite enantiomer, if it is present in the feed
material. The form of the pindolol phase diagram implies that a
decrease in the enantiomeric excess of the solid is accompanied
by a decrease of its solubility. Therefore, the partial substitution
4.2. Compounds
Racemic pindolol (mp 167–171 °C) was purchased from Sigma
Aldrich. Isopropyl amine (99%) was purchased from Acros Organ-
ics. Diethyl azodicarboxylate (97%) and triphenyl phosphine
(99%) were purchased from Alfa Aesar.
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4
A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4
.2.1. Racemic 3-(4-indolyloxy)-1,2-propanediol rac-2, crystal
(2.5 ml, 1.725 g, 29.2 mmol) at 10 °C. The reaction mixture was
seeds of (S)-2 and (R)-2
stirred for 10 h at room temperature and then for 7 h at 36 °C.
The progress of the reaction was monitored by TLC (light petro-
leum ether/MeOH/EtOAc = 9:1:5). The solvent and excess of amine
were removed in vacuum. The residue was purified by column
All compounds were obtained according to the published
1
5
method rac-2: mp 96.5–97.5 °C (H
ether/acetone = 1:1); (R)-2: mp 121–122 °C (H
HPLC analysis; Chiralpak AD-RH column; 40 °C; eluent: 2-propa-
nol/water (1:3), 0.5 ml/min; t = 9.1 min]; R = 0.2; (S)-2: mp
O); 99.6% ee [chiral HPLC analysis, t = 12.0 min)].
2
O); R
f
= 0.2 (light petroleum
2
O); 98% ee [chiral
chromatography (silica gel 40/100, eluent: CH
1:1) to afford pindolol (S)-1 as a semisolid. Yield 0.212 g (73.4 %,
95.7% ee); R = 0.05 (CH Cl /MeOH = 9:1). Crystallization from a
2 2
Cl /MeOH = 9:1–
R
f
1
22 °C (H
2
R
f
2
2
mixture benzene/methanol afforded colorless crystals with mp
4
.2.2. Resolution of racemic 3-(4-indolyloxy)-1,2-propanediol
138–173 °C, 37% ee. By concentrating the mother liquor a portion
2
0
rac-2 by preferential crystallization (entrainment)
of crystals was separated with mp 93–95 °C, [
a
]
D
= ꢀ11.8 (c 1.0,
2
0
21
Racemic diol rac-2 (1.8 g) and (S)-2 (0.18 g) were dissolved in
EtOH);
[
a
]
365 = ꢀ28.5 (c 1.0, EtOH) {lit.
mp 94–95 °C,
2
5
7
2 ml of water at 60 °C. The solution was cooled to 25 °C and then
[a]
D
= ꢀ12.0 (c 1.0, EtOH); 99% ee}; 99.9% ee [chiral HPLC analysis,
Chiralcel OD-RH column; column temperature 24 °C; flow rate
0.5 ml/min; eluent: 0.06 M KPF aq (pH 2.3):CH CN (58:42);
= 6.5 min (minor), t = 12.2 min (major)]. H NMR (400 MHz,
CDCl ) d: 1.08 (d, J = 6.2 Hz, 6H, 2CH ), 2.77–2.87 (m, 2H, CH
CHNH), 2.93 (dd, J = 12.2, 3.4 Hz, 1H, CH ), 3.04 (br s, 2H, OH,
NH), 4.05–4.17 (m, 3H, OCH , CH), 6.48 (d, J = 7.4 Hz, 1H, H-3),
6.60 (d, J = 2.8 Hz, 1H, H-5), 6.98 (d, J = 8.1 Hz, 1H, H-7), 7.02–
seeded with finely pulverized (S)-2 (0.01 g). The solution was grad-
ually cooled to a temperature where crystallization was pro-
nounced. The solution was then thermostated and stirred at this
temperature. During the course of crystallization, aliquots (10
of the mother liquor were collected at regular intervals. The ali-
6
3
1
t
R
R
l
l)
3
3
2
,
2
i
quots were mixed with 1 ml of Pr OH, and portions of 20
the solutions were analyzed with the Chiralpak AD-RH column
ll of
2
1
3
[
40 °C; eluent: 2-propanol/water (2:5), 0.35 ml/min; t
R
= 8.2 min
7.07 (m, 2H, H-2, 6), 8.44 (br s, 1H, CArHN). C NMR (100.5 MHz,
CDCl ) d: 22.7 (CH ), 22.8 (CH ), 49.1 (CHN), 49.5 (CH N), 68.4
(CH), 70.7 (OCH ), 99.7 (C-3), 100.9 (C-7), 104.9 (C-5), 118.8 (C-
(R)-2), t = 9.7 min (S)-2)]. After changing the enantiomeric compo-
R
3
3
3
2
sition of the mother liquor from the initial value (ee ꢁ 9% with the
predominance of (S)-2) to a value of ee ꢁ 8% with the predomi-
nance of (R)-2 (it takes about 40 min at 24 °C), precipitated (S)-2
was collected by filtration (run 1, 0.35 g after drying; 84% ee).
The extra portion of rac-2 (0.34 g) was then dissolved in the
mother liquor at 60 °C; the resulting solution was cooled to
2
4a), 122.7 (C-2), 122.8 (C-6), 137.4 (C-7a), 152.3 (C-4).
4.3. X-ray analysis
The X-ray diffraction data of the investigated (S)-1 crystals were
2
5 °C. After the addition of (R)-2 (0.01 g) as seed crystals to the
solution, and stirring the mixture for 40 min at 24 °C, (R)-2
0.32 g after drying; 79% ee) was collected by filtration (run 2). Fur-
collected on a Bruker AXS Smart Apex II CCD diffractometer in the
x
a
-scan modes using graphite monochromated MoK (k 0.71073 Å)
(
radiation. The crystal data, data collection, and the refinement
parameters are given in Table 1. Data were corrected for the
ther resolution was carried out at 23–25 °C by adding amended
amounts of rac-2 to the filtrate in a manner similar to that
described above. A double recrystallization of the combined crystal
crop of each of the enantiomers from water enhances the enan-
tiomeric excess to 96–99%: (S)-2: mp 119 °C (DSC), [
1
2
2
absorption effect using SADABS program. The structures were
2
3
solved by direct method using SHELXS and refined by the full
2
4
25
matrix least-squares using SHELXL-2014 and WinGX programs.
All non-hydrogen atoms were refined anisotropically. All hydrogen
atoms were inserted at calculated positions and refined as riding
2
0
a]
D
= +5.3 (c
20
.5, MeOH), 99.1% ee; (R)-2: [a]
D
= ꢀ4.6 (c 1.5, MeOH), 96.4% ee.
2
atoms except the hydrogen atoms of OH and NH groups which
4
.2.3. (S)-4-(2,3-Epoxypropoxy)-1H-indole (S)-4
To a stirred solution of triphenyl phosphine (1.11 g, 4.24 mmol)
were located from difference maps and refined isotropically. Dur-
ing data collections the images were indexed, integrated, and
scaled using the APEX2 data reduction package.
2
6
in dry THF (10 ml) under an argon atmosphere, a solution of
diethyl azodicarboxylate (0.74 g, 4.24 mmol) in THF (10 ml) was
added dropwise for 10 min at +4 °C. A solution of diol (S)-2
(
+
0.73 g, 3.53 mmol) in THF (15 ml) was then added for 10 min at
4 °C. The resulting solution was refluxed for 24 h under an argon
Table 1
Crystallographic data for (S)-pindolol
atmosphere. The solvent was removed in vacuum. The residue was
purified by column chromatography (silica gel 40/100; eluent:
light petroleum ether/MeOH/EtOAc = 16:1:5–12:1:5) to afford
epoxide (S)-4 as a yellowish oil. Yield 0.33 g (50 %); R
petroleum ether/MeOH/EtOAc = 9:1:5). Epoxide was crystallized
Compound, sample
Formula
M (g/mol)
Temperature, K
Crystal class
Space group
Pindolol, (S)-1
C H N O
14 20 2 2
248.32
296(2)
f
= 0.37 (light
Orthorhombic
P2
from Et
2
O to afford analytical sample of (S)-4: mp 76–78 °C,
1 1
2 2
3
2
0
20
19
Crystal size (mm )
0.28 ꢄ 0.16 ꢄ 0.14
[a
]
D
= +24.6 (c 1.0, MeOH); [
a
]
D
= +6.0 (c 1.0, CHCl
3
). {Lit. mp
0
2
0
20
20
Z, Z
24, 6
7
7–78 °C, [
a
]
D
= +25.6 (c 0.99, MeOH); lit. for (R)-4 [
)}. H NMR (600 MHz, CDCl
a]
D
= ꢀ6.4
Cell parameters
a = 14.948(2) Å
b = 50.686(8) Å
c = 11.1038(18) Å
8413(2)
3216
1.176
0.079
1.582–25.998
16,525
150,949/0.0536
1057/0
1
(c 1.6, CHCl
3
3
) d: 2.85 (dd, J = 5.0,
O), 3.47–3.49
CH), 4.39 (dd,
CH), 6.56 (d, J = 7.5 Hz, 1H, H-3), 6.72–
.74 (m, 1H, H-5), 7.05 (d, J = 8.2 Hz, 1H, H-7), 7.11–7.14 (m, 2H,
2
(
.7 Hz, 1H, CH O), 2.96 (dd, J = 5.0, 4.2 Hz, 1H, CH
2
2
V, Å3
m, 1H, CHO), 4.18 (dd, J = 11.2, 5.5 Hz, 1H, OCH
2
F(000)
J = 11.2, 3.2 Hz, 1H, OCH
6
2
q
l
calc g/cm3
, mm
ꢀ1
1
3
H-2, 6), 8.24 (br s, 1H, NH). C NMR (150.9 MHz, CDCl
CH ), 50.5 (CH), 68.9 (OCH ), 99.9 (C-3), 101.0 (C-7), 105.1 (C-5),
18.9 (C-4a), 122.7 (C-2), 122.9 (C-6), 137.5 (C-7a), 152.3 (C-4).
3
) d: 44.9
h range, deg
Reflections measured
Independent reflections/R(int)
Number of parameters/restraints
(
1
2
2
Reflections [I > 2
r
(I)]
12287
4
.2.4. (S)-(ꢀ)-1-(1H-Indol-4-yloxy)-3-[(1-methylethyl)amino]-2-
R
R
1
/wR
/wR
2
[I > 2
(all reflections)
r
(I)]
0.0514/0.0699
0.0773/0.0717
2.475
0.034/ꢀ0.449
propanol, (S)-pindolol (S)-1
1
2
2
Goodness-of-fit on F
To a solution of epoxide (S)-4 (0.22 g, 1.16 mmol) in MeOH
ꢀ
3
q
max
/
qmin (eÅ
)
(
4 ml) under an argon atmosphere, was added isopropyl amine
Please cite this article in press as: Bredikhin, A. A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.02.009

A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
Crystallographic data for (S)-1 have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cation number CCDC 1507190. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: deposit@
ccdc.cam.ac.uk).
6. Fornal, C. A.; Martin, F. J.; Metzler, C. W.; Jacobs, B. L. J. Pharmacol. Exp. Ther.
999, 291, 229–238.
1
7.
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Kaumann, A. J. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2003, 368, 496–503.
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Chiral Drugs: Chemistry and Biological Action; Lin, G.-Q., You, Q.-D., Cheng, J.-F.,
Eds.; John Wiley Sons Inc: Hoboken, New Jersey, 2011; p 472.
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Acknowledgments
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The work was supported by the Russian Fund of Basic Research
and the Government of the Republic of Tatarstan in the framework
of the research project No. 15-43-02238. We also wish to thank Dr.
A.V. Pashagin for valuable assistance with chiral HPLC analysis and
Prof. A.T. Gubaidullin for valuable help with the X-ray data.
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Please cite this article in press as: Bredikhin, A. A.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.02.009