Synthesis, phase behavior and absolute configuration of β-adrenoblocker bupranolol and related compounds

Article abstract of DOI:10.1016/j.molstruc.2018.06.079

β-Blocker bupranolol 1, it's hydrochloride and their precursors 1-(2-chloro-5-methylphenoxy)-2,3-epoxypropane 2 and 3-(2-chloro-5-methylphenoxy)propane-1,2-diol 3 were prepared in racemic and single-enantiomer forms. For all the studied compounds phase behavior during crystallization was established on the basis of IR, DSC and X-ray investigations. Absolute configurations were established for compounds 1 and 2. Being conglomerate, racemic oxirane 2 was resolved by direct entrainment procedure. Being anticonglomerate, in the process of recrystallization, almost enantiopure 1·HCl accumulates in the mother liquor, not in the crystalline precipitate.

Full text of DOI:10.1016/j.molstruc.2018.06.079

Journal of Molecular Structure 1173 (2018) 157e165
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis, phase behavior and absolute configuration of b-
adrenoblocker bupranolol and related compounds
Alexander A. Bredikhin*, Zemfira A. Bredikhina, Alexey V. Kurenkov,
Dmitry V. Zakharychev, Aidar T. Gubaidullin
Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of RAS, Arbuzov St., 8, 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:
b
-Blocker bupranolol 1, it’s hydrochloride and their precursors 1-(2-chloro-5-methylphenoxy)-2,3-
Received 30 March 2018
Received in revised form
19 June 2018
Accepted 19 June 2018
Available online 26 June 2018
epoxypropane 2 and 3-(2-chloro-5-methylphenoxy)propane-1,2-diol 3 were prepared in racemic and
single-enantiomer forms. For all the studied compounds phase behavior during crystallization was
established on the basis of IR, DSC and X-ray investigations. Absolute configurations were established for
compounds 1 and 2. Being conglomerate, racemic oxirane 2 was resolved by direct entrainment pro-
cedure. Being anticonglomerate, in the process of recrystallization, almost enantiopure 1·HCl accumu-
lates in the mother liquor, not in the crystalline precipitate.
Keywords:
Chiral drug bupranolol
Phase behavior
© 2018 Elsevier B.V. All rights reserved.
Single crystal X-ray analysis
Conglomerate and anticonglomerate
1. Introduction
well as an antianginal agent [7,8]. Its racemic hydrochloride 1·HCl is
marketed under the trade names Betadran, Betadrenol, Looser and
Since the introduction of propranolol into clinical practice by
James Black in 1964 [1], beta-adrenoblockers from the Ar-O-
CH2CH(OH)CH2NHR family remain the drugs of the first choice in
recommendations for heart failure, coronary artery disease, and
atrial fibrillation as well as in hypertension complicated with heart
failure, angina pectoris, or prior myocardial infarction [2]. Other
Panimit. Racemic bupranolol and its enantiomers show significant
differences in biological activity [9e11], which makes it desirable to
create single enantiomeric dosage forms and opens the possibility
of developing active pharmaceutical ingredients based on each of
the enantiomers.
The information on the physicochemical characteristics of the
enantiomers of bupranolol (free base and/or hydrochloride), as well
as its closest synthetic precursors 1-(2-chloro-5-methylphenoxy)-
substantial non-cardiac uses of
b-blockers include glaucoma,
migraine, situational anxiety, benign essential tremors, and cardiac
symptoms of thyrotoxicosis [3]. It has long been reliably established
that pure enantiomers from this family exhibit different physio-
logical activities, with the S-enantiomers acting as eutomers [4,5].
At the same time, R-enantiomers, being distomers as adrenor-
eceptor blockers, may exhibit other activity and serve as a basis for
active pharmaceutical ingredients (APIs) with other indications. By
way of example, the R-enantiomer of propranolol stimulates the
smooth musculature of the uterus and, hence, can act as a female
contraceptive [6].
2,3-epoxypropane 2
и 3-(2-chloro-5-methylphenoxy)propane-1,2-
diol 3 (Chart 1) is practically absent in the available scientific
literature. This complicates the entrance control of their chemical
and stereoisomeric purity. The lack of physicochemical character-
istics does not allow one to make even preliminary conclusions
about the peculiarities of the phase behavior of compounds 1e3,
that introduces uncertainty into the operation of these compounds.
In this work we present the reliable data, including an information
on the structure and absolute configuration of the compounds
studied. Analysis of the results obtained at this stage made it
possible to reveal some important features of the phase behavior of
bupranolol and related substances. In particular, it has been found
that rac-2 exhibits a tendency to spontaneous resolution during
crystallization. Compounds exhibiting such properties have some
additional advantages as the synthetic precursors of single-
Adrenoreceptor blocker bupranolol (Ophtorenin), 1-t-butyla-
mino-3-(2-chloro-5-methylphenoxy)-2-propanol 1 (Chart 1), is
used in the treatment of hypertension, arrhythmia, glaucoma as
* Corresponding author.
E-mail address: baa@iopc.ru (A.A. Bredikhin).
https://doi.org/10.1016/j.molstruc.2018.06.079
0022-2860/© 2018 Elsevier B.V. All rights reserved.

158
A.A. Bredikhin et al. / Journal of Molecular Structure 1173 (2018) 157e165
mixture of light petroleum ether/CH2Cl2/EtOAc (7:2:1) to give the
CH3
CH3
OH
O
pure rac-2 (4.94 g, 71%); Rf ¼ 0.5, light petroleum/CH2Cl2/
EtOAc ¼ 4:2:1. Mp 42e44 ꢀC (hexane). Anal. Calcd for C10H11ClO2: C,
60.46; H, 5.58; Cl, 17.85. Found: C, 60.24; H, 5.49; Cl, 17.44.
NH
O
O
HO
HO
CH3
*
*
*
O
2.2.2. Hydrolytic kinetic resolution of racemic epoxide 2
To
a
solution of (R,R)-salen
Со(II) catalyst (22.8 mg,
Cl
Cl
Cl
0.0378 mmol, 0.005 eq.) in 0.5 ml of CH2Cl2, 24
mL of a glacial AcOH
was added and stirred for 30 min. After concentrating the solution,
rac-epoxide 2 (1.5 g, 7.56 mmol) and 1.1 ml of THF were added to
the thus obtained (R,R)-salen-Co-(III)-OAc. The mixture was cooled
H3C
H3C
H3C
3
2
1
to þ4 ꢀC, then 75
mL (4.16 mmol, 0.55 eq.) of water was added using
a micro syringe and stirred for 1 h at þ4 ꢀC and further about 23 h at
rt. The progress of the reaction was monitored by HPLC (Agilent
Eclipse XDB-C18 column, UV 275 nm, CH3CN/H2O (75:25)). The
reaction mixture was concentrated, and was chromatographed on
silica gel (0.125e0.2 mm) by eluting with a mixture of light petro-
leum ether/EtOAc (9:4) to give (S)-1-(2-Chloro-5-methylphenoxy)-
2,3-epoxypropane, (S)-2 (0.66 g, 44%) as a solid. Rf ¼ 0.5 (light pe-
troleum ether/EtOAc ¼ 6:4); 96% ee [chiral HPLC analysis; Chiralcel
OJ column; eluent: hexane/2-propanol (9:1), 1 ml/min; 25 ꢀC;
tR ¼ 11.8 min (major), tR ¼ 13.1 min (minor)]. After recrystallization
from hexane, 0.51 g of pure (S)-2 was isolated, 99% ee. Mp
Chart 1. Bupranolol 1, 1-(2-chloro-5-methylphenoxy)-2,3-epoxypropane 2, and 3-(2-
chloro-5-methylphenoxy)propane-1,2-diol 3.
enantiomeric target products.
2. Experimental
2.1. Instrumentation
The NMR spectra were recorded on a Bruker Avance-400 (399.9
М
Hz for 1H and 100.5 Hz for 13C) or a Bruker Avance-600
М
20
20
64e65 ꢀC; [
a
]
¼ þ7.8 (c 1, EtOH), [
a
]
¼ þ12.0 (c 1, EtOH),
D
365
(600.1 MHz for 1H and 150.9 MHz for 13C) with the signals of the
solvent as the internal standard. The IR spectra of the poly-
crystalline samples of rac- and scal-compounds under in-
vestigations in KBr pellets were recorded on a Bruker Tensor 27
spectrometer. Optical rotations were measured on a PerkineElmer
model 341 polarimeter (concentration c is given as g/100 ml).
Melting points for general purposes were determined using a
20
20
[a
]
¼ ꢁ0.3 (c 1.0, MTBE), [
a
]
¼ ꢁ15.4 (c 1, MTBE). 1H NMR
D
365
(400 MHz, CDCl3)
d
: 2.31 (s, 3H, CH3), 2.81 (dd, J ¼ 5.0, 2.7 Hz; 1H,
CH2O), 2.90 (dd, J ¼ 5.0, 4.2 Hz; 1H, CH2O), 3.36e3.40 (m, 1H, CHO),
4.04 (dd, J ¼ 11.2, 5.2 Hz; 1H, OCH2), 4.26 (dd, J ¼ 11.2, 3.2 Hz; 1H,
OCH2), 6.73 (d, J ¼ 8.0 Hz, 1H, C4ArH), 6.77 (s, 1H, C6ArH), 7.22 (d,
J ¼ 8.0 Hz, 1H, C3ArH). 13C NMR (150.9 MHz, CDCl3)
d: 21.3 (CH3),
44.6 (CH2), 50.1 (CH), 69.8 (CH2), 115.2 (C6Ar), 120.1 (C2Ar-ipso),
122.8 (C4Ar), 129.9 (C3Ar), 138.0 (C5Ar-ipso), 153.8 (C1Ar-ipso). Anal.
Calcd for C10H11ClO2: C, 60.46; H, 5.58; Cl, 17.85. Found: C, 60.68; H,
5.34; Cl, 17.68.
€
Boetius apparatus and are uncorrected. The melting curves were
measured on a NETZSCH 204 F1 Phoenix DSC differential scanning
calorimeter in sealing aluminum pans with the rate of heating of
5 ꢀC∙minꢁ1. The mass of the samples amounted to approximately
~1 mg and was controlled with Sartorius CPA2P balance. Temper-
ature scale and heat flux were calibrated according standard pro-
cedure and verified by naphthalene sample. The elemental
compositions were determined using a EuroVector EA3000 CHN
analyzer. Thin-layer chromatography was performed on Silufol UV-
254 plates; TLC plates were visualized under UV light or by treat-
ment with iodine vapor. HPLC analyses were performed on a Shi-
madzu LC-20AD system controller, UV monitor 275 nm was used as
detector. The column used, from Daicel Inc., was Chiralpak AD
(0.46 ꢂ 25 cm), Chiralcel OJ (0.46 ꢂ 25 cm) or Chiralpak AD-RH
(0.46 ꢂ 15 cm).
On further elution with a mixture of light petroleum ether/ethyl
acetate (1:1) (R)-3-(2-chloro-5-methylphenoxy)propane-1,2-diol,
(R)-3 was obtained (0.82 g, 50%). Rf ¼ 0.1 (light petroleum ether/
EtOAc ¼ 6:4); 92% ee [chiral HPLC analysis; Chiralpak AD column;
eluent: hexane/2-propanol (95:5), 1 ml/min; 25 ꢀC; tR ¼ 21.5 min
(major), tR ¼ 24.2 min (minor)]. After recrystallization from light
petroleum ether/EtOAc, 0.6 g of pure (R)-3 was isolated, 99% ee. Mp
20
20
73e74 ꢀC; [
a]
¼ þ2.7 (c 1, MeOH), [
a
]
¼ þ8.4 (c 1.0, MeOH),
D
365
20
20
[a
]
¼ þ9.3 (c 1, MTBE), [
a]
¼ þ30.9 (c 1, MTBE). 1H NMR
D
365
(400 MHz, CDCl3) d: 2.30 (s, 3H, CH3), 3.08 (s, 2H, OH), 3.79 (dd,
J ¼ 11.6, 4.9 Hz; 1H, CH2OH), 3.86 (dd, J ¼ 11.6, 3.7 Hz; 1H, CH2OH),
4.05 (dd, J ¼ 9.2, 6.1 Hz; 1H, OCH2), 4.08e4.14 (m, 2H, OCH2, CHOH),
6.71 (d, J ¼ 8.0 Hz, 1H, C4ArH), 6.74 (s, 1H, C6ArH), 7.20 (d, J ¼ 8.0 Hz,
1H, C3ArH). 13C NMR (100.5 MHz, CDCl3)
d: 21.3 (CH3), 63.7 (CH2),
2.2. Materials
70.2 (CH), 70.8 (OCH2), 114.8 (C6Ar), 119.8 (C2Ar-ipso), 122.8 (C4Ar),
129.8 (C3Ar), 138.1 (C5Ar-ipso), 153.6 (C1Ar-ipso). Anal. Calcd for
Racemic epichlorohydrin and 3-chloropropane-1,2-diol (99%),
2-chloro-5-methylphenol (99%) and tert-butylamine (99%) were
purchased from Acros Organics. Diisopropyl azodicarboxylate (94%)
and triphenylphosphine (99þ%) were purchased from Alfa Aesar.
C10H13ClO3: C, 55.44; H, 6.05; Cl, 16.36. Found: C, 54.89; H, 6.23; Cl,
16.00.
(R,R)-salen-С
о
(II) catalyst, (R,R)-N,N0-bis(3,5-di-tert-butylsalicyli-
2.2.3. rac-3-(2-Chloro-5-methylphenoxy)propane-1,2-diol, rac-3
To a solution of 2-chloro-5-methylphenol 2 (1.07 g, 7.5 mmol) in
ethanol (5 ml), a solution of NaOH (0.38 g, 9.4 mmol) in water (3 ml)
was added and the resulting mixture was stirred and heated under
reflux for 3 h. A solution of rac-3-chloropropane-1,2-diol (1 g,
9.1 mmol) in ethanol (5 ml) was then added dropwise and the
mixture was further stirred and heated at reflux for 16 h. After
cooling, the volume of the resulting mixture was reduced to about
one third followed by the addition water (5 ml) and extraction with
EtOAc (4 ꢂ 40 ml). The combined organic layers were dried over
MgSO4 and the solvent was removed. The crude diol rac-3 was
purified by recrystallization from light petroleum ether/EtOAc
20
dene)cyclohexane-1,2-diamino cobalt(II), [
CH2Cl2), was synthesized by us earlier [12].
a
]
¼ ꢁ1100 (c 0.01,
D
2.2.1. rac-1-(2-Chloro-5-methylphenoxy)-2,3-epoxypropane, rac-2
A mixture of 2-chloro-5-methylphenol (5.0 g, 35.1 mmol), 2N
aqueous sodium hydroxide (25 ml) and rac-epichlorohydrin (9.74 g,
105.3 mmol) was stirred for 5 h at 50ꢀС. The reaction mixture was
diluted with water (25 ml) and extracted with CH2Cl2 (3 ꢂ 50 ml).
The organic extract was dried over MgSO4. The solvent was evap-
orated to afford the crude product, which was purified by column
chromatography (silica gel 0.125e0.2 mm) by eluting with a

A.A. Bredikhin et al. / Journal of Molecular Structure 1173 (2018) 157e165
159
(5:1). Yield 1.35 g, 83%; mp 73e75 ꢀC (light petroleum ether/EtOAc)
{lit. [13]: mp 59 ꢀC}; Rf ¼ 0.1 (hexane/EtOAc ¼ 6:4).
2.2.5.2. rac-1-t-Butylamino-3-(2-chloro-5-methylphenoxy)-2-
propanol, rac-bupranolol, rac-1 was prepared similarly from rac-2.
Yield 0.67 g, 99%, solidified oil; mp 71e74 ꢀC. 1H NMR (400 MHz,
CDCl3)
d
: 1.12 (s, 9H, CH3), 2.29 (s, 3H, CH3), 2.78 (dd, J ¼ 11.7, 6.0 Hz,
2.2.4. (R)-1-(2-Chloro-5-methylphenoxy)-2,3-epoxypropane (R)-2
To a stirred solution of diol (R)-3 (0.6 g, 2.77 mmol) and tri-
phenylphosphine (0.87 g, 3.33 mmol) in dry THF (4 ml) a solution of
diisopropyl azodicarboxylate (0.67 g, 3.33 mmol) in THF (8 ml) was
added dropwise for 5 min at 4 ꢀC. The resulting solution was
refluxed for 25 h in an argon atmosphere. The solvent was removed
in vacuum. The residue was purified by column chromatography
1H, CH2NH), 2.90 (dd, J ¼ 11.7, 3.9 Hz, 1H, CH2NH), 3.07 (br. s, 2H,
OH, NH), 4.02 (s, 3H, OCH2, CHOH), 6.69 (d, J ¼ 8.0 Hz, 1H, C4ArH),
6.75 (s, 1H, C6ArH), 7.19 (d, J ¼ 8.0 Hz, 1H, C3ArH). Anal. Calcd for
C14H22ClNO2: C, 61.87; H, 8.16; N, 5.15; Cl, 13.04. Found: C, 61.68; H,
8.10; N, 4.79; Cl, 13.31. rac-Bupranolol hydrochloride, rac-1·HCl was
obtained analogously from rac-1 as described for (S)-1·HCl. Mp
221e223 ꢀC {lit. [14]: mp 220e222 ꢀC}.
(silica
gel,
eluent:
light
petroleum
ether/CH2Cl2/
EtOAc ¼ 6:1:0.5e4:1:0.5) to afford epoxide (R)-2 (95% ee) as a
2.3. X-ray analysis
colorless oil, which gradually crystallizes. Yield 0.52 g, 95%. Rf ¼ 0.5
(light petroleum ether/CH2Cl2/EtOAc ¼ 4:2:1). Mp 64e65 ꢀC (hex-
20
Single crystals for XRD experiments were grown from the above
described samples by slow evaporation of their solutions: (S)-1 in a
mixture light petroleum/ethyl acetate, (S)-2 in a mixture EtOН/
CHCl3/MTBE, rac-2 in cyclohexane.
ane); [
a]
¼ ꢁ8.1 (c 1, EtOH); 99.4% ee [chiral HPLC analysis;
D
Chiralcel OJ column; eluent: hexane/2-propanol (9:1), 1 ml/min;
20 ꢀC; tR ¼ 12.2 min (minor), tR ¼ 13.6 min (major)].
The X-ray diffraction data of the investigated crystals were
collected on a Bruker AXS Smart Apex II CCD diffractometer in the
2.2.5. (S)-1-t-Butylamino-3-(2-chloro-5-methylphenoxy)-2-
propanol, (S)-Bupranolol, (S)-1
A mixture of 1-(2-chloro-5-methylphenoxy)-2,3-epoxypropane
(S)-2 (0.5 g, 2.5 mmol) and tert-butylamine (0.46 g, 6.3 mmol) in
5 ml of ethanol was refluxed for 6 h. Excess of amine was removed
u
-scan and 4-scan modes using graphite monochromated Mo Ka (l
0.71073 Å) radiation at 296(2) K. Data were corrected for the ab-
sorption effect using SADABS program [15]. The structures were
solved by direct method using SHELXS [16] and refined by the full
matrix least-squares using SHELXL-2014 [17] and WinGX [18]
programs. All non-hydrogen atoms were refined anisotropically. All
hydrogen atoms were inserted at calculated positions and refined
as riding atoms except the hydrogen atoms of OH and NH2 groups
which were located from difference maps and refined isotropically.
During data collections the images were indexed, integrated, and
scaled using the APEX2 data reduction package [19]. The principal
crystal data are given in Table 1; full crystal data, data collection,
and the refinement parameters are given in Table 1.
under reduced pressure to afford 1 as a solid. Yield 0.67 g, 99%, mp
20
84e86 ꢀC (light petroleum ether/EtOAc); [
a
]
D
¼ ꢁ9.6 (c 1, MeOH),
20
[
a]
¼ ꢁ21.0 (c 1, MeOH); 98.5% ee [chiral HPLC analysis; Chir-
365
alpak AD-RH column; eluent: borate buffer/acetonitrile (6:4),
0.5 ml/min; tR ¼ 17.8 min (minor), tR ¼ 20.2 min (major)]. 1H NMR
(400 MHz, CD3OD) d: 1.16 (s, 9H, CH3), 2.33 (s, 3H, CH3), 2.75 (dd,
J ¼ 11.5, 7.7 Hz, 1H, CH2NH), 2.88 (dd, J ¼ 11.5, 3.9 Hz, 1H, CH2NH),
3.99 (m, J ¼ 7.7, 3.4 Hz, 1H, OCH2), 4.03e4.10 (m, 2H, OCH2, CHOH),
6.75 (d, J ¼ 8.0 Hz, 1H, C4ArH), 6.92 (s, 1H, C6ArH), 7.21 (d, J ¼ 8.0 Hz,
1H, C3ArH). 13C NMR (100.5 MHz, CD3OD)
d: 19.9 (CH3), 27.4 (CH3, t-
Crystallographic data for (S)-1 and (S)-2 has been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 1589716 and 1589715, respectively.
Bu), 45.3 (CH2NH), 50.0 (C-ipso, t-Bu), 68.9 (CHOH), 71.6 (OCH2),
114.4 (C6Ar), 119.4 (C2Ar-ipso), 122.0 (C4Ar), 129.3 (C3Ar), 138.1 (C5
-
Ar
ipso), 154.0 (C1Ar-ipso). Anal. Calcd for C14H22ClNO2: C, 61.87; H,
8.16; N, 5.15; Cl, 13.04. Found: C, 61.68; H, 8.10; N, 4.89; Cl, 13.31.
Treatment of the free base (0.28 g) in benzene solution (7 ml)
with dry hydrogen chloride yields the hydrochloride salt, (S)-
Bupranolol hydrochloride (S)-1·HCl: Yield 0.313 g, 99%. Mp
Table 1
Crystallographic data for (S)-Bupranolol (S)-1 and (S)-1-(2-ahloro-5-
methylphenoxy)-2,3-epoxypropane (S)-2.
20
20
146e149 ꢀC; [
a
]
¼ ꢁ24.2 (c 1, MeOH), [
a
]
¼ ꢁ75.0 (c 1, MeOH);
D
365
ꢃ99% ee [chiral HPLC analysis; Chiralpak AD-RH column; eluent:
borate buffer 18 mM, pH 9/acetonitrile (6:4), 0.5 ml/min;
tR ¼ 12.7 min (minor), tR ¼ 15.5 min (major)]. 1H NMR (400 MHz,
Compound, sample
Formula
M (g/mol)
Temperature, K
Crystal class
Space group
Crystal size (mm3)
Z, Z0
(S)-(-)-1
14H22NClO2
271.77
296(2)
Monoclinic
P21
(S)-(þ)-2
C10H11ClO2
198.64
296(2)
Monoclinic
P21
C
DMSO‑d6) d: 1.32 (s, 9H, CH3), 2.30 (s, 3H, CH3), 2.94e3.01 (m, 1H,
CH2NH), 3.16e3.20 (m, 1H, CH2NH), 4.06 (dd, J ¼ 10.0, 5.5 Hz, 1H,
OCH2), 4.14 (dd, J ¼ 10.0, 5.0 Hz, 1H, OCH2), 4.22e4.32 (m, 1H,
CHOH), 5.93 (s, 1H, OH), 6.79 (d, J ¼ 8.0 Hz, C4ArH), 7.03 (s, 1H,
C6ArH), 7.28 (d, J ¼ 8.0 Hz, 1H, C3ArH), 8.71 (br. s, 1H, NHþ2 ), 9.14 (br. s,
0.29 ꢂ 0.43 ꢂ 0.60 0.24 ꢂ 0.45 ꢂ 0.75 mm3
2, 1
4, 2
Cell parameters
a ¼ 9.3538(5)
b ¼ 7.0311(4)
c ¼ 11.9712(7)
a ¼ 8.2705(10) Å,
b ¼ 4.4603(6) Å,
c ¼ 26.654(3) Å
1H, NHþ2 ). 13C NMR (150.9 MHz, DMSO‑d6)
d: 21.3 (CH3), 25.4 (CH3, t-
Bu), 44.7 (CH2N), 56.9 (C-ipso, t-Bu), 65.9 (CHOH), 71.0 (OCH2),
b
¼ 109.313(3)
b
¼ 90.051(4)ꢀ
115.5 (C6Ar), 118.9 (C2Ar-ipso), 122.9 (C4Ar), 129.9 (C3Ar), 138.7 (C5
-
Ar
V, Ǻ3
743.01(7)
292
1.215
983.2(2)
416
1.342
ipso), 153.8 (C1Ar-ipso). Anal. Calcd for C14H22ClNO2·HCl: C, 54.55;
F(000)
rcalc g/cm3
H, 7.52; N, 4.54; Cl, 23.00. Found: C, 54.13; H, 7.50; N, 4.22; Cl, 22.76.
m
, mmꢁ1
0.252
0.352
q
range, deg
3.366e33.818
25954
0.764e33.697
22116
2.2.5.1. (R)-1-t-Butylamino-3-(2-chloro-5-methylphenoxy)-2-
Reflections measured
propanol, (R)-Bupranolol, (R)-1 was prepared similarly from (R)-1-
Independent reflections/R(int)
Number of parameters/restraints 178/1
5950/0.0255
7005/0.0247
237/1
4731
0.0395/0.0956
0.0688/0.1081
1.035
0.152/ꢁ0.169
ꢁ0.01(2)
ꢁ0.01(2)
(2-chloro-5-methylphenoxy)-2,3-epoxypropane (R)-2. Yield 0.67 g,
20
Reflections [I > 2
s(I)]
4204
99%, mp 83e86 ꢀC (light petroleum ether/EtOAc); [
a
]
D
¼ þ9.4 (c 1,
R1/wR2 [I > 2 (I)]
s
0.0433/0.1138
0.0706/0.1284
1.015
0.386/ꢁ0.284
ꢁ0.017(17)
ꢁ0.026(17)
MeOH). Anal. Calcd for C14H22ClNO2: C, 61.87; H, 8.16; N, 5.15; Cl,
13.04. Found: C, 62.09; H, 8.08; N, 4.71; Cl, 12.84. NMR spectra were
identical with those cited above for (S)-1. (R)-Bupranolol hydro-
R1/wR2 (all reflections)
Goodness-of-fit on F2
rmax
/
rmin (eǺꢁ3
)
Flack parameter
Hooft parameter
chloride, (R)-1·HCl was obtained analogously from (R)-1 as
20
described for (S)-1·HCl. Mp 147e150 ꢀC; [
a
]
¼ þ24.2 (c 1, MeOH).
D

160
A.A. Bredikhin et al. / Journal of Molecular Structure 1173 (2018) 157e165
Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: þ44-(0)
1223e336033 or e-mail: deposit@ccdc.cam.ac.uk).
3.2. Phase behavior of the compounds studied
Crystallization is the main method of isolation and purification
of organic compounds. The results of crystallization are described
(and can be predicted) on the basis of the phase diagram of the
melting (solubility) of the substance. For a chemist practitioner,
working with chiral compounds, the characteristics of the phase
diagram (especially the enantiomeric composition of the eutectic
eeeu [31]) are of special importance, since his task is to isolate not
only the pure (free of impurities of other substances) but also the
enantiopure (free of impurity of the opposite enantiomer) of the
desired product.
Preliminary information on the nature of the phase diagram can
be obtained by comparing the vibrational spectra of solid samples
of the racemate and the scalemate. Typically, modern representa-
tion of a spectrum is a two-dimensional digital array (Ai,ni), where
ni stands for the vibrational frequency (usually expressed in wave
numbers in increments of 1 cmꢁ1), and Ai corresponds to the
3. Results and discussion
3.1. Synthesis of enantiomeric bupranolol and related compounds
Adrenoblockers from the Ar-O-CH2CH(OH)CH2NHR family are
easily obtainable by reaction of the corresponding aryl glycidyl
ethers (AGEs) and amines [20e23]. Racemic AGEs are readily
obtainable from cheap racemic epichlorohydrin and a suitable
phenol. Since its invention, the method of kinetically controlled
hydrolysis of racemic epoxides (Jakobsen hydrolytic kinetic reso-
lution, HKR) [24] is often used to produce scalemic AGEs from the
corresponding racemates [12,25]. However, the “by-product” of
such a kinetic splitting, 3-aryloxypropane-1,2-diol with the oppo-
site configuration, usually does not find an application. Arylox-
ypropanediols themselves can act as precursors of adrenoblockers,
although they must be activated for transformation to amino al-
cohols by conversion to cyclic sulfites [12,26] or oxiranes [27]. A
reliable method for the preparation of oxiranes from vicinal diols is
Mitsunobu intramolecular etherification [28e30]. We have used
the combination of HKR and Mitsunobu intramolecular ether-
ification for obtaining both enantiomers of the desired bupranolol
enantiomers from the common racemic precursor (Scheme 1).
The products of HKR of the oxirane rac-2, when using catalyst
(R,R)-salen Co(III) (0.5 mol %) and water (0.55 eq), were (S)-oxirane
(S)-2 (44%, 96% ee) and (R)-diol (R)-3 (50%, 92% ее). According to
Scheme 1, (R)-3 through intramolecular Mitsunobu etherification
was converted to (R)-oxirane (R)-2 in good yield (95%) with a
minimal loss of enantiomeric purity (from 99 to 95% ee) and
retaining of the configuration of chiral center. The enantiomeric
excess of the oxiranes is increased up to ꢃ99% ee during recrys-
tallization from hexane. The individual enantiomers of bupranolol
(S)-1 and (R)-1 were obtained by boiling epoxides (S)-2 and (R)-2,
respectively, with an excess of tert-butylamine in ethanol. At the
final stage, the amino alcohols 1 were converted to hydrochlorides
by passing gaseous HCl through base solutions in benzene. All the
isolated compounds, as well as the synthetic procedures, are
described in detail in the Experimental Section.
extinction at this wave number. If the
n value for the two arrays
{Ariac} and {Asical} (here superscripts denote racemic and scalemic
samples) changes with the same step, the standard Pearson cor-
relation coefficient R can be used for their quantitative comparison
[32]. Further, for a more descriptive comparison of the spectra we
proposed to use a graphical representation of the correlation be-
tween the two spectra, i.e., visual display them in the coordinates
Ariac vs. Asical [33]. Features of this approach are thoroughly com-
mented on by us [33,34].
The results of such a comparison are quantitatively (Pearson’s
coefficients R) and in a visual way (correlative trajectories; for
identical spectra they degenerate into a straight line on the main
diagonal) for rac.vs.scal pairs of compounds 1, 1$HCl, 2 and 3 are
shown in Fig. 1. As follows from Fig. 1c, the practical identity of IR
spectra points to the crystallization of epoxide 2 in the form of a
conglomerate. The crystalline organization of 1, 1$HCl and 3 is
significantly different for racemic and scalemic samples
(Fig. 1a,b,d), which indicates the formation of a solid racemic
compound in all three cases.
More detailed information on the phase behavior of a chiral
substance is possible to obtain by differential scanning calorimetry.
Fig. 2 shows the experimental DSC traces of the compounds studied
by us. Traditionally, the blue curves correspond to the fusion of
enantiopure samples, the red curves correspond to the melting of
the racemates, and the green curves characterize the melting of the
O
Me
Me
Cl
*
iv
H
O
Me
O
H
NH-But
OH
O
i
Cl
2
3
(S)-
ii
Cl
Cl
Cl
O
O
(S)-bupranolol,
OH
Me
O
1
(S)-
2
rac-
H
OH
(R)-
iii
Me
Cl
O
H
cat.:
t-Bu
H
H
N
N
Co
iv
H
O
Me
NH-But
OH
O
O
O
t-Bu
OAc
t-Bu t-Bu
2
(R)-
Cl
(R,R)-salen-Co(III)-OAc
(R)-bupranolol,
1
(R)-
Scheme 1. Preparation of enantiomeric bupranolols from the common racemic precursor. Reagents and conditions: (i) 2-chloro-5-methylphenol, base; (ii) cat., water, rt; (iii) PPh3,
DIAD, THF, reflux; (iv) But-NH2, EtOH, reflux.

A.A. Bredikhin et al. / Journal of Molecular Structure 1173 (2018) 157e165
161
Fig. 2. Experimental DSC traces of compounds 1 (a), 1∙HCl (b), 2 (c) and 3 (d). Blue and
red curves correspond to the melting, respectively, of enantiopure and racemic sam-
ples. Green curves characterize the melting of samples in which the mole fraction x of
the predominant enantiomer is: x ¼ 0.82 for 1; x ¼ 0.79 for 1∙HCl; x ¼ 0.6, 0.76, 0.81,
0.91 and 0.95 (in order of increasing melting point temperatures) for 2; x ¼ 0.73 for 3.
Table 2
Thermochemical characteristics of rac- and scal-1-3.
Tf ,oC
rac-
D
Hf ,kJ$moleꢁ1
Tfeu,oC
xeu,
a
Comp
scal-
rac-
scal-
1
75.0
223.4
41.7
75.5
84.7
149.0
64.5
74.3
38.3
50.9
22.2
31.8
39.1
30.1
24.8
29.0
37.6
148.0
40.0
67.3
0.66
0.997
0.5
1·HCl
2
3
0.82
a
Values of the eutectic composition (mole fraction of individual enantiomer)
calculated as the intersection of the branches of the phase diagrams calculated ac-
€
cording the Prigogine-Defay and Schroder-Van Laar equations.
Fig. 1. Fragments of IR spectra (on the left) and correlation trajectories (right) for
racemic (red) and scalemic (blue) samples of compounds 1 (a), 1· HCl (b), 2 (c) and 3
(d).
compounds in the solid state form racemic compounds (Fig. 3a,b,d),
of which rac-1$HCl is exceptionally stable. The simultaneous solu-
€
tion of the Schroder-Van Laar and Prigogine-Defay equations allows
samples of the controlled intermediate enantiomeric composition.
one to quantify the enantiomeric composition of the eutectic of the
compounds studied. The values found are shown in Table 2. Again,
we draw the reader’s attention to the unique magnitude of eeeu
99% (!) for 1$HCl. This fact should be taken into account when
purifying this registered API by the recrystallization method, since
for the samples, even possessing a sufficiently high initial enan-
tiomeric purity, the crystalline yield will approach the racemate,
but in the mother liquor the practically pure enantiomer will
accumulate.
Table 2 lists the temperature (Tf ) and the enthalpy (DHf ) of
melting of the studied racemic and scalemic samples. Here, under
the term “scalemic”, the samples with the maximum enantiomeric
purity are understood.
>
Based on these data, preliminary conclusions can be drawn
about the type of phase behavior of chiral compounds 1e3. Thus, a
significant depression of the melting temperature in the scal / rac
transition (oxirane 2) indicates that the substance crystallizes as a
conglomerate of enantiomorphic homochiral crystals, hence the
eutectic enantiomeric composition eeeu ¼ 0. Conversely, a signifi-
cant expression of the melting point in the same direction (1·HCl)
indicates that the substance belongs to the class of anticonglom-
erates where the eeeu ~ 1. An implicit evidence for the latter
assumption is the unusually large value of the enthalpy of melting
of the racemic sample 1$HCl.
3.3. Single-crystal X-ray investigations
Previously among the derivatives of bupranolol and its synthetic
precursors, only the hydrochloride [36] and picrate [37] of racemic
1 have been studied by single crystal X-ray diffraction. The fact that
rac-1·HCl crystallizes in the “non-Sohncke” Pca21 space group with
the single symmetry independent molecule in the asymmetric unit
fully agrees with the above conclusion on the formation of a solid
racemic compound by this substance.
Initially, by X-ray diffraction, we investigated a single crystal of
oxirane 2, randomly selected from a racemic sample. The unit cell of
the investigated crystal belonged to the Sohncke group P21, and the
asymmetric unit contained two independent molecules (Z’ ¼ 2).
Both of these molecules had a common configuration. The general
configuration of independent molecules and the Sohncke group are
A schematic picture of the binary phase diagrams of a chiral
substance can be obtained by using the data on the temperatures
and enthalpies of melting of its enantiopure and/or racemic sam-
ples. Theoretical liquidus lines on such diagrams can be recon-
structed by substituting the experimental values of Tf and
DHf
€
(Table 2) into the well-known Schroder-Van Laar and Prigogine-
Defay equations [35]. The phase diagrams obtained on this basis,
with the experimental points plotted on them, are shown in Fig. 3.
As can be seen from Fig. 3c, the diagram for oxirane 2 charac-
terizes this compound as
a conglomerate. The remaining

162
A.A. Bredikhin et al. / Journal of Molecular Structure 1173 (2018) 157e165
Fig. 5. Fragment of packing of molecules in the (S)-(þ)-2 crystal. (a) Two adjacent one-
dimensional columns along the 0a axis. Blue dotted lines represent the non-classical
H-bonds. (b) M-helix, formed by
hydrogen bonds.
a sequence of atoms bound by covalent and
Fig. 3. Binary melting phase diagrams for compounds 1 (a), 1$HCl (b), 2 (c) and 3 (d).
sufficient proof of the homochirality of the investigated crystal [38],
which finally confirms the ability of rac-2 to spontaneous
resolution.
Enantiopure (þ)-2 sample, as the rac-2 investigated in the first
stage, crystallizes in the P21 group with two independent A and B
molecules in an asymmetric unit (Table 1, Fig. 4).
sequence is highlighted by “spacefill” style. It can be seen from the
figure that such a sequence, actually representing a supramolecular
motif in oxirane 2 crystals, turns out (in the case of (S)-2) a left-
handed M-helix.
In general, the scal-2 packing is sufficiently dense (PI ¼ 67.8%) to
successfully compete with the packing of the potential racemic
compound.
Enantiopure bupranolol (-)-1 crystallizes in the P21 group with a
single independent molecule in the asymmetric unit (Table 1,
Fig. 6).
Fig. 7 shows two neighboring molecules bound in a crystal by
the classical intermolecular hydrogen bond O1eH1/N01. This
classical H-bond is characterized by good geometric parameters
(:OHN’ ¼ 174ꢀ, d (O/ N0) ¼ 2.798 Å) and creates a characteristic
supramolecular motif, namely 1D column organized around the
screw axis 21 parallel to the shortest unit cell edge 0b. Two such
columns are shown in Fig. 8a. In another representation of the same
figure (Fig. 8b), one more peculiarity of the crystal structure of
enantiopure bupranolol becomes evident: it is permeated with
continuous channeled voids, which leads to a decrease in the
There are no classical intermolecular hydrogen bonds in com-
pound 2 crystals. The only pronounced short contact, obviously
having a bonding character, is the nonclassical hydrogen bond
С9BeH9B/O1A (:CHO ¼ 161ꢀ, d (C/O) ¼ 2.587 Å). Due to such
contacts, symmetry independent molecules are sequentially con-
nected to 1D columns elongated along the 0a axis (Fig. 5a).
In crystals of chiral compounds, one-dimensional homochiral
supramolecular motifs are formed, as a rule, around screw axes and
represent internally chiral helixes, the configuration of which is
rigidly related to the configuration of the molecules from which
they consist. In the case of oxirane 2, the axes around which one-
dimensional columns are formed are not symmetry axes. Never-
theless, one can follow the nonclassical hydrogen bonds, which link
the 1D column, while simultaneously taking into account the
covalently bonded atoms, which form the shortest path between
the donor and acceptor centers for these H-bonds. In Fig. 5b, this
Fig. 4. Asymmetric unit, partial numbering scheme, and principal short contacts in the
(S)-(þ)-2 crystal.
Fig. 6. Partial numbering scheme for symmetry independent molecule in the (S)-(-)-1
crystal.

A.A. Bredikhin et al. / Journal of Molecular Structure 1173 (2018) 157e165
163
formed during the crystallization of rac-1.
Concluding this section, we will stay on one more result ob-
tained. The configurations of all nonracemic compounds isolated
during the work were originally attributed according to literature
data on the stereochemistry of the chemical transformations. This
approach is quite credible, but it has a network character, and one
error in a long chain of branching correlations can lead to a
distortion of a significant array of general information [39]. To
reduce the risk of such distortions, it is necessary to check the ac-
curacy of the correlated configurations as often as possible using
reliable independent methods. Reliable information on the
configuration of the chiral compound can be obtained by studying
the anomalous X-ray scattering by an enantiopure single crystal.
Therefore, in the present work, in order to verify configurational
attributions, single crystals of enantiomeric epoxide (þ)-2 (isolated
as a result of HKR) and of enantiopure bupranolol (-)-1 were
studied by this method.
Fig. 7. Two adjacent molecules of (S)-(-)-1 in the crystal. The intermolecular H-bond is
indicated by a red dashed line.
Both molecules 1 and 2 contain a “heavy” chlorine atom. This
factor and the quality of the obtained crystals allowed us to
determine the absolute configuration using the Flack [40,41] and
the Hooft [42] parameters. Both approaches (see Table 1) in com-
bination with the chiroptic characteristics of the compounds
completely confirm the correctness of all the configurational as-
signments made in the work.
3.4. Beneficial consequences of spontaneous resolution of rac-2
First of all, the crystallization of the synthetic precursor bupra-
nolol, racemic epoxypropane 2 in the form of a conglomerate
makes it possible to separate it into individual enantiomers by
direct methods [34,43]. Preliminary tests showed that at room
temperature rac-2 is essentially unlimited soluble in ethyl acetate,
methylene chloride, chloroform, in lower alcohols, and benzene,
poorly soluble in water and moderately soluble in hydrocarbons.
Quantitatively, the solubility of rac-2 at 25 ꢀC was 40.0 and
31.5 mg.mlꢁ1 in hexane and nonane, respectively. For the demon-
stration experiment, we used a less volatile nonane.
Thus, racemic oxirane rac-2 (1 g) was dissolved in 33 ml of
nonane at 35 ꢀC. The solution was cooled to 15 ꢀC and then seeded
with finely pulverized (R)-2 (10 mg). After stirring the mixture for
90 min with a gradual decrease in temperature to 12.5 ꢀC, precipi-
tated (R)-2 was collected by filtration (52 mg after drying; ee 70%).
At this takes place, the mother liquor turns out slightly enriched
with the opposite enantiomer (S)-2, ее ~ 3%. The extra portions of
rac-2 (42 mg) were then dissolved in the mother liquor at 35 ꢀC; the
resulting solution was cooled to 14 ꢀC. After the addition of (S)-2
(10 mg) as seed crystals and stirring the mixture for 90 min at 12-
11 ꢀC, (S)-2 (80 mg after drying; 72% ee) was collected by filtration.
The mother liquor turns out slightly enriched with (R)-2, ее ~ 3%.
Thus, we have shown experimentally that the resolution of rac-2
epoxide is indeed possible without the use of any non-racemic
auxiliaries. Optimization of the process, which requires special
experiments, was not part of the task of this study.
The phase behavior of the compounds studied, described in
Section 3.2, makes enantiomeric enrichment of the 1·HCl samples
practically impossible with standard crystallization. For bupranolol
1 and its precursor diol 3, this possibility appears only for samples
whose initial enantiomeric purity is higher than eeeu (Table 2). In
this respect, oxirane 2 is advantageous in that it can be purified by
crystallization to any desired degree of enantiomeric purity starting
virtually from any enantiomeric composition. For example, a
portion of (R)-2 (455 mg, 81.3% ee) was dissolved when heated in
hexane. After cooling the solution to 25 ꢀC 371 mg of (R)-2, 91.2% ee
was collected. Similarly, 217 mg of (S)-2 (43% ее) was dissolved in
nonane (8.7 ml) at 30 ꢀC. Slow crystallization with a gradual
Fig. 8. Two adjacent 1D columns of molecules bound by intermolecular H-bonds in
(S)-(-)-1 crystal; (a) “Ball-and-Stick» representation, (b) “Spacefill” representation.
packing density (PI ¼ 66.0%). It is obvious that the packing of the
racemic compound is free from this drawback, and it is this that is

164
A.A. Bredikhin et al. / Journal of Molecular Structure 1173 (2018) 157e165
decrease in temperature to 9 ꢀC makes it possible to obtain 51 mg of
(S)-2 with a purity of 89% ee.
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conglomerate. The remaining compounds in the solid state form
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experiment data in combination with the chiroptic characteristics
of the compounds completely confirm the correctness of all the
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Acknowledgments
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors. The
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