Synthesis of new (arylcarbonyloxy)aminopropanol derivatives and the determination of their physico-chemical properties

Article abstract of DOI:10.2478/s11532-013-0302-8

Eight hydrochlorides of 3-{2-[(2/4-fluorophenoxy)-ethylamino]}-2- hydroxypropyl-4-alkoxybenzoates and four hydrochlorides of 3-tert-butylamino-2- hydroxypropyl-4-butoxybenzoates were prepared as potential antagonists of the β₁-adrenergic receptor (beta-blockers). A multistep synthesis of these compounds is described as well as their detailed analytical characterization. The pharmacokinetic properties of these weak base compounds are significantly influenced by their acid-base dissociation constant, pK _a. The knowledge of this value is crucial for new drug development. This paper is aimed at developing a methodology that utilizes pH-dependent ¹H NMR spectroscopy for its routine analysis. The selected predicted physico-chemical parameters of the new (arylcarbonyloxy)aminopropanols (i.e., aryloxyaminopropanol derivatives) were compared with the model drugs esmolol and flestolol. [Figure not available: see fulltext.]

Full text of DOI:10.2478/s11532-013-0302-8

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Central European Journal of Chemistry
Synthesis of new (arylcarbonyloxy)aminopropanol
derivatives and the determination
of their physico-chemical properties
Research Article
Jan Tengler1,2*, Iva Kapustíková1ꢀꢁ2QGāHMꢁ6WURSQLFNĘ1,
3HWUꢁ0RNUĘ1, Michal Oravec3, Jozef Csöllei1, Josef Jampílek1
1'HSDUWPHQWꢀRIꢀ&KHPLFDOꢀ'UXJVꢂꢀ)DFXOW\ꢀRIꢀ3KDUPDF\ꢂꢀ
8QLYHUVLW\ꢀRIꢀ9HWHULQDU\ꢀDQGꢀ3KDUPDFHXWLFDOꢀVFLHQFHVꢀ%UQRꢂꢀ
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Received 21 February 2013; Accepted 25 June 2013
Abstract:ꢀ
(LJKWꢀK\GURFKORULGHVꢀRIꢀꢁꢂ^ꢃꢂ>ꢄꢃꢅꢆꢂĠXRURSKHQR[\ꢇꢂHWK\ODPLQR@`ꢂꢃꢂK\GUR[\SURS\OꢂꢆꢂDONR[\EHQ]RDWHVꢀDQGꢀIRXUꢀK\GURFKORULGHVꢀRIꢀꢁꢂtert-
EXW\ODPLQRꢂꢃꢂK\GUR[\SURS\OꢂꢆꢂEXWR[\EHQ]RDWHVꢀZHUHꢀSUHSDUHGꢀDVꢀSRWHQWLDOꢀDQWDJRQLVWVꢀRIꢀWKHꢀȕ1ꢂDGUHQHUJLFꢀUHFHSWRUꢀꢄEHWDꢂEORFNHUVꢇꢈꢀ
$ꢀ PXOWLVWHSꢀ V\QWKHVLVꢀ RIꢀ WKHVHꢀ FRPSRXQGVꢀ LVꢀ GHVFULEHGꢀ DVꢀ ZHOOꢀ DVꢀ WKHLUꢀ GHWDLOHGꢀ DQDO\WLFDOꢀ FKDUDFWHUL]DWLRQꢈꢀ 7KHꢀ SKDUPDFRNLQHWLFꢀ
SURSHUWLHVꢀRIꢀWKHVHꢀZHDNꢀEDVHꢀFRPSRXQGVꢀDUHꢀVLJQLğFDQWO\ꢀLQĠXHQFHGꢀE\ꢀWKHLUꢀDFLGꢂEDVHꢀGLVVRFLDWLRQꢀFRQVWDQWꢉꢀSKDꢈꢀ7KHꢀNQRZOHGJHꢀ
RIꢀWKLVꢀYDOXHꢀLVꢀFUXFLDOꢀIRUꢀQHZꢀGUXJꢀGHYHORSPHQWꢈꢀ7KLVꢀSDSHUꢀLVꢀDLPHGꢀDWꢀGHYHORSLQJꢀDꢀPHWKRGRORJ\ꢀWKDWꢀXWLOL]HVꢀS+ꢂGHSHQGHQWꢀ1+ꢀ105ꢀ
VSHFWURVFRS\ꢀIRUꢀLWVꢀURXWLQHꢀDQDO\VLVꢈꢀ7KHꢀVHOHFWHGꢀSUHGLFWHGꢀSK\VLFRꢂFKHPLFDOꢀSDUDPHWHUVꢀRIꢀWKHꢀQHZꢀꢄDU\OFDUERQ\OR[\ꢇDPLQRSURSDQROVꢀ
(i.eꢈꢉꢀDU\OR[\DPLQRSURSDQROꢀGHULYDWLYHVꢇꢀZHUHꢀFRPSDUHGꢀZLWKꢀWKHꢀPRGHOꢀGUXJVꢀHVPROROꢀDQGꢀĠHVWROROꢈ
Keywords: $U\OR[\DPLQRSURSDQROꢀľꢀ%HWDꢁEORFNHUVꢀľꢀ$FLGꢀGLVVRFLDWLRQꢀFRQVWDQWꢀľꢀ1+ꢀ105ꢀVSHFWURVFRS\ꢀľꢀ8OWUDVKRUWꢀHIIHFW
© Versita Sp. z o.o.
whose cleavage, by tissue and plasma esterases,
could lead to potential ultrashort effect [7,8].
1. Introduction
a
$OWKRXJKꢀ DQWDJRQLVWVꢀ RIꢀ ȕ1-adrenergic receptors (beta-
blockers)areamongtheoldestcardiovasculardrugs, they
have an irreplaceable role in the treatment of diseases
such as arterial hypertension, ischemic heart disease,
cardiac arrhythmias, chronic heart failure and glaucoma
[1-3]. Newer beta-blockers have added features, mainly
increased vasodilatory activity. This may be caused by
WKHLUꢀ DELOLW\ꢀ WRꢀ UHOHDVHꢀ 12ꢀ ꢁQHELYROROꢂꢃꢀ ȕ2-adrenoceptor
Chemically, they are described as hydrochlorides of
ꢅꢆ^ꢇꢆ>ꢁꢇꢈꢉꢆÀXRURSKHQR[\ꢂꢆHWK\ODPLQR@`ꢆꢇꢆK\GUR[\SURS\Oꢆ
ꢉꢆDONR[\EHQ]RDWHVꢃꢀZKHUHꢀWKHꢀDONR[\ꢀJURXSꢀLVꢀSUHVHQWHGꢀ
by methyl to butyl homology series. For a comparison of
WKHꢀLQÀXHQFHꢀRIꢀEDVLFꢀVXEVWLWXWLRQꢃꢀIRXUꢀVLPSOHꢀtert-butyl
analogues have also been prepared (Scheme 1). None
of the prepared substances have been published so far,
H[FHSWꢀIRUꢀFRPSRXQGꢀ10cꢀꢁDVꢀDQꢀR[DODWHꢀVDOWꢂꢀSXEOLVKHGꢀ
DJRQLVWꢀDFWLYLW\ꢀꢁFHOLSUROROꢂꢀRUꢀĮ1-adrenoceptor blockade by Kam et al. [9] Nevertheless, this compound was
(carvedilol) [4-6]. Substances prepared in our department prepared by a different synthetic method and its acid-
FDQꢀEHꢀFODVVL¿HGꢀDPRQJꢀWKHꢀODWWHUꢄꢀ$ꢀSKHQR[\HWK\ODPLQRꢀ base properties were not discussed.
moiety in their structure could be potentially responsible
Physico-chemical
properties,
described
by
for this dual activity. They also contain an ester group WKHUPRG\QDPLFꢀ HTXLOLEULXPꢀ FRQVWDQWVꢃꢀ LQÀXHQFHꢀ WKHꢀ
* E-mail: jan.tengler82@gmail.com
1757

Synthesis of new (arylcarbonyloxy)aminopropanol derivatives
and the determination of their physico-chemical properties
bioavailability of drugs and the general pharmacokinetics by reversed-phase TLC glass plates DC Fertigplatten
RIꢀGUXJVꢀLQꢀWKHꢀERG\ꢄꢀ7KHꢀLRQL]DWLRQꢀFRQVWDQWꢀLVꢀRQHꢀRIꢀ Merck RP-8 F254 S (both Merck, Germany). The plates
the most fundamental and important parameters. The were illuminated under UV (254 nm). The melting
LRQL]DWLRQꢀ FRQVWDQWꢀ ꢁRUꢀ DFLGꢀ GLVVRFLDWLRQꢀ FRQVWDQWꢂꢃꢀ SRLQWVꢀZHUHꢀGHWHUPLQHGꢀE\ꢀDꢀ.RÀHUꢀKRWꢆSODWHꢀDSSDUDWXVꢀ
Kaꢃꢀ LVꢀ XVHGꢀ WRꢀ FKDUDFWHUL]Hꢀ WKHꢀ DFLG±EDVHꢀ EDODQFHꢀ RIꢀ +0.ꢀ ꢁ)UDQ]ꢀ .XVWQHUꢀ 1DFKWꢀ .*ꢃꢀ *HUPDQ\ꢂꢀ DQGꢀ DUHꢀ
Dꢀ PROHFXOHꢀ DQGꢀ LVꢀ JHQHUDOO\ꢀ H[SUHVVHGꢀ DVꢀ Dꢀ QHJDWLYHꢀ uncorrected. Infrared spectra were recorded on a Nicolet
logarithm, -log Ka = pKa. In medicinal chemistry, it is ,PSDFWꢀ ꢉꢊꢋꢀ )7ꢆ,5ꢀ 6SHFWURPHWHUꢀ ꢁ7KHUPRꢀ 6FLHQWL¿Fꢃꢀ
1
common to use pKa for both acids and bases. Drugs are USA) in the region of 4000-600 cm-1. H and 13C NMR
multifunctional compounds, especially the discussed spectra were recorded on a Bruker Avance 500 FT-NMR
EHWDꢆEORFNHUVꢃꢀ ZKLFKꢀ FRQWDLQꢀ WZRꢀ RUꢀ PRUHꢀ LRQL]DEOHꢀ VSHFWURPHWHUꢀꢁꢌꢋꢋꢀ0+]ꢀIRUꢀ1+ꢀDQGꢀꢊꢇꢌꢀ0+]ꢀIRUꢀ13C) and
IXQFWLRQDOꢀ PRLHWLHVꢄꢀ 7KXVꢃꢀ WKH\ꢀ FDQꢀ H[LVWꢀ LQꢀ GLIIHUHQWꢀ %UXNHUꢀ$YDQFHꢀꢉꢋꢋꢀ)7ꢆ105ꢀVSHFWURPHWHUꢀꢁꢉꢋꢋꢀ0+]ꢀIRUꢀ
LRQL]HGꢀꢁFKDUJHGꢀ±ꢀVDOWꢀRUꢀXQFKDUJHGꢀ±ꢀIUHHꢀEDVHꢂꢀVWDWHVꢀ 1+ꢀDQGꢀꢊꢋꢋꢀ0+]ꢀIRUꢀ13C, both Bruker Comp., Germany).
depending on their acid or base strength, and the pH 13C spectra were measured using APT pulse sequence.
values of the individual body compartments. As only &KHPLFDOꢀVKLIWVꢀDUHꢀUHSRUWHGꢀLQꢀSSPꢀꢁįꢂꢃꢀDQGꢀDUHꢀUHIHUUHGꢀ
QRQꢆLRQL]HGꢀ IRUPVꢀ DUHꢀ DEOHꢀ WRꢀ SDVVꢀ WKURXJKꢀ ELRORJLFDOꢀ to internal TMS, coupling constants (JꢂꢀDUHꢀJLYHQꢀLQꢀ+]ꢄꢀ
membranes, it is necessary to determine pKa in order FT-NMR spectrometer Gemini 2000 (Varian, USA) with
to predict the behavior of developed substances in the WKHꢀRSHUDWLQJꢀIUHTXHQF\ꢀRIꢀꢇꢋꢋꢀ0+]ꢀIRUꢀ1H was used for
body; pKa YDOXHVꢀLQÀXHQFHꢀELRDYDLODELOLW\ꢄꢀ7KHꢀYDOXHꢀRIꢀ pKa determination. Mass spectra were measured using
pKa is used to correct values for lipophilicity, distribution a LTQ Orbitrap Hybrid Mass Spectrometer (Thermo
volume, the biological correlations in QSAR studies, and Electron Corporation, USA) with direct injection
IRUꢀWKHꢀRSWLPL]DWLRQꢀRIꢀDQDO\WLFDOꢀPHWKRGVꢀ[10-12].
into an APCI source (400 °C) in the negative mode.
There are several ways to determine pKa, whose Elemental analyses were performed using a Vario EL
principles are based on measuring the changes in ,,,ꢀ 8QLYHUVDOꢀ &+126ꢀ (OHPHQWDOꢀ $QDO\]HUꢀ ꢁ(OHPHQWDUꢀ
physical, chemical and spectral properties in response Analysensysteme, Germany). The purity of compounds
to changes in pH. The most common methods include 8a-d and 9a-d were checked by RP-HPLC. An HPLC
SRWHQWLRPHWULFꢀ WLWUDWLRQꢃꢀ FDSLOODU\ꢀ ]RQHꢀ HOHFWURSKRUHVLVꢃꢀ separation module Waters Alliance 2695 XE, Waters
UV-VIS spectrometry and NMR (1H, 13C, 15N, deuterium) Photodiode Array Detector 2996 and chromatographic
spectroscopy[13-16].Also,manypredictionprogrammes column Symmetry C18ꢀ ꢌꢀ ȝPꢃꢀ ꢉꢄꢍîꢇꢌꢋꢀ PPꢀ ꢁ:DWHUVꢀ
are commercially available, but their results are rather Corp., USA) were used. This detector was also used
tentative and dependent on the algorithms used.
WRꢀREWDLQꢀ89ꢀVSHFWUDꢀꢁȜꢃꢀQPꢂꢄꢀ7KHꢀPRELOHꢀSKDVHꢀPL[WXUHꢀ
7KLVꢀSDSHUꢀLVꢀDLPHGꢀDWꢀSUHSDULQJꢀDQGꢀFKDUDFWHUL]LQJꢀ was MeOH:H2O (55:45, v/v).
twelve hydrochloride salts of N-substituted 3-amino-2-
K\GUR[\SURS\OꢀꢉꢆDONR[\EHQ]RDWHꢃꢀWDUJHWꢀFRPSRXQGVꢀWKDWꢀ 2.2. Synthesis
can act as potential cardiovascular agents. A method for ꢀꢁꢀꢁꢂꢁꢃ6\QWKHVLVꢃꢃRIꢃꢀꢄꢅꢀꢄꢆꢇꢄĠXRURSKHQR[\ꢈHWK\ODPLQHVꢃꢃ
1
pKa determination of measuring the H nuclei chemical ꢃꢃꢃꢃꢃꢃꢃꢃꢃꢃꢅꢉꢄꢊꢈ
shift depending on a variable pH has been chosen. 1.6 M NaOH aqueous solution (125 mL) was added
Based on pKa values and other calculated molecular GURSꢆZLVHꢀWRꢀDꢀPL[WXUHꢀRIꢀꢊꢃꢇꢆGLEURPRHWKDQHꢀꢁꢋꢄꢉꢀPROꢂꢀ
descriptors, potential intestinal absorption is discussed. DQGꢀꢇꢆꢃꢀRUꢀꢉꢆÀXRURSKHQROꢀꢁꢋꢄꢇꢀPROꢂꢃꢀUHVSHFWLYHO\ꢄꢀ$IWHUꢀDꢀ
ꢎꢀKRXUꢀUHÀX[ꢃꢀWKHꢀFRROHGꢀUHDFWLRQꢀPL[WXUHꢀZDVꢀWDNHQꢀXSꢀ
LQꢀFKORURIRUPꢀꢁꢅꢌꢋꢀP/ꢂꢀDQGꢀWKHꢀXQUHDFWHGꢀÀXRURSKHQROVꢀ
were removed by thoroughly washing with 1.9 M NaOH
solution (250 mL) and water (250 mL). The organic
2. Experimental procedure
2.1. Instrumentation and chemicals
phase was dried (Na2SO4) and evaporated to give
intermediates 1, 2ꢄꢀ$ꢀPL[WXUHꢀRIꢀDU\OR[\HWK\OꢀEURPLGHꢀ1
or 2 (0.18 mol) and potassium phthalimide (0.18 mol) in
dimethylformamide (100 mL) was heated for 2 hours.
Intermediates 3, 4ꢀFU\VWDOOL]HGꢀDIWHUꢀSRXULQJꢀFROGꢀZDWHUꢀ
LQWRꢀWKHꢀUHDFWLRQꢀPL[WXUHꢄꢀ7KHꢀSUHFLSLWDWHꢀZDVꢀ¿OWHUHGꢀDQGꢀ
UHFU\VWDOOL]HGꢀIURPꢀSURSDQꢆꢇꢆROꢄꢀ3UHSDUHGꢀSKWKDOLPLGHVꢀ
ꢁꢋꢄꢊꢀPROꢂꢀZHUHꢀDGGHGꢀWRꢀDꢀVROXWLRQꢀRIꢀK\GUD]LQHꢀK\GUDWHꢀ
ꢁꢋꢄꢇꢀPROꢂꢀꢀLQꢀHWKDQROꢀꢁꢊꢌꢋꢀP/ꢂꢀDQGꢀUHÀX[HGꢀIRUꢀꢊꢀKRXUꢄꢀ
$IWHUꢀ FRROLQJꢃꢀ WKHꢀ SUHFLSLWDWHꢀ ZDVꢀ ¿OWHUHGꢀ RIIꢃꢀ HWKDQROꢀ
was removed, and the residue was dissolved in diethyl
All reagents were purchased from Sigma-Aldrich
ꢁ*HUPDQ\ꢂꢀZLWKꢀVXI¿FLHQWꢀSXULW\ꢃꢀDVꢀZHOOꢀDVꢀPHWKDQROꢆd4,
DMSO-d6, tetramethylsilane (TMS) and sodium
2,2-dimethyl-2-silapentane-5-sulfonate
(DSS).
'HXWHULXPꢀ R[LGHꢀ ꢁ'2O) was purchased from Merck
ꢁ*HUPDQ\ꢂꢃꢀ WULÀXRURDFHWLFꢀ DFLGꢀ IURPꢀ )OXNDꢀ ꢁ*HUPDQ\ꢂꢃꢀ
DQGꢀ VRGLXPꢀ K\GUR[LGHꢀ DQGꢀ VROYHQWVꢀ IRUꢀ V\QWKHVLVꢀ
IURPꢀ /DFKꢆ1HUꢀ ꢁ&]HFKꢀ 5HSXEOLFꢂꢄꢀ 7KHꢀ UHDFWLRQVꢀ ZHUHꢀ
monitored with TLC alumina-backed silica gel 60 F254
plates and retardation factors RF(rev) were determined
1758

J. Tengler et al.
ether. This was then treated with a saturated ethereal CH2CH3, COOCH2), 3.34-3.30 (m, 1H, CHꢆR[LUDQꢂꢃꢀ
+&Oꢀ VROXWLRQꢄꢀ 2EWDLQHGꢀ VDOWVꢀ ZHUHꢀ UHFU\VWDOOL]HGꢀ IURPꢀ 2.83 (dd, 1H, 2J=4.9, 3J=4.3, CH2ꢆR[LUDQꢂꢃꢀꢇꢄꢎꢇꢀꢁGGꢃꢀꢊ+ꢃꢀ
3
ethanol, suspended in chloroform and transferred back 2J=4.9, J=2.6, CH2ꢆR[LUDQꢂꢃꢀ ꢊꢄꢅꢉꢀ ꢁWꢃꢀ ꢅ+ꢃꢀ 3J=7.0, CH3).
to bases 5, 6 by adding 3% ammonia solution.
13&ꢀ105ꢀꢁꢌꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢊꢍꢌꢄꢋꢃꢀꢊꢍꢉꢄꢌꢃꢀꢊꢅꢊꢄꢇꢃꢀ
121.3, 114.3, 64.8, 63.4, 48.9, 43.7, 14.3.
1H spectra are in accordance with literature [17].
ꢀꢁꢂꢀꢁÀXRURSKHQR[\ꢃHWK\ODPLQH (5). Yield 82%.
2[LUDQꢁꢀꢁ\OPHWK\Oꢅ ꢄꢁSURSR[\EHQ]RDWHꢅ (7c).
1
RF: 0.38 (Acetone). +ꢀ105ꢀꢁꢇꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀ Yield 48%. RF: 0.65 (Acetone/toluene 1:2). 1H NMR
7.29-7.10 (m, 2H, Ar), 7.04-6.93 (m, 2H, Ar), 4.28 (t, ꢁꢇꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢎꢄꢑꢇꢀꢁGꢃꢀꢇ+ꢃꢀ3J=8.8, ArCOO),
3
3
2H, J=5.2, CH2O), 3.14 (t, 2H, J=5.2, CH2N), 1.91 (s, 7.04 (d, 2H, 3J=8.8, ArO), 4.60 (dd, 1H, 2J=12.4, 3J=2.7,
2H, NH2). 13&ꢀ105ꢀ ꢁꢌꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢊꢌꢊꢄꢐꢀ ꢁGꢃꢀ COOCH2), 4.04 (dd, 1H, 2J=12.4, 3J=6.4, COOCH2),
1JC-F=244.2), 145.7 (d, JC-F=10.5), 124.8 (d, JC-F=3.8), 4.00 (t, 2H, J=6.5, OCH2CH2), 3.36-3.28 (m, 1H, CH-
2
4
3
121.8 (d, JC-F=6.9), 116.1 (d, JC-F=17.9), 115.7, 65.6, R[LUDQꢂꢃꢀꢇꢄꢐꢅꢀꢁGGꢃꢀꢊ+ꢃꢀ2J=5.0, J=4.3, CH2ꢆR[LUDQꢂꢃꢀꢇꢄꢎꢇꢀ
3
2
3
2
3
38.1.
(dd, 1H, J=5.0, J=2.7, CH2ꢆR[LUDQꢂꢃꢀꢊꢄꢐꢅꢆꢊꢄꢍꢌꢀꢁPꢃꢀꢇ+ꢃꢀ
ꢀꢁꢂꢄꢁÀXRURSKHQR[\ꢃHWK\ODPLQH (6). Yield 79%. CH2CH3), 0.97 (t, 3H, J=7.4, CH3). 13&ꢀ105ꢀꢁꢌꢋꢀ0+]ꢃꢀ
3
1
RF: 0.39 (Acetone). +ꢀ105ꢀꢁꢇꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀ DMSO-d6ꢂꢃꢀįꢏꢀꢊꢍꢌꢄꢋꢃꢀꢊꢍꢇꢄꢎꢃꢀꢊꢅꢊꢄꢇꢃꢀꢊꢇꢊꢄꢅꢃꢀꢊꢊꢉꢄꢉꢃꢀꢍꢑꢄꢇꢃꢀ
7.17-7.04 (m, 2H, ArF), 6.99-6.88 (m, 2H, ArO), 3.87 (t, 64.9, 49.0, 43.7, 21.8, 10.1.
2H, 3J=5.8, OCH2), 2.85 (t, 2H, 3J=5.8, CH2N), 1.97 (bs,
2[LUDQꢁꢀꢁ\OPHWK\Oꢅ ꢄꢁEXWR[\EHQ]RDWHꢅ (7d). Yield
2H, NH2). 13&ꢀ105ꢀꢁꢌꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢊꢌꢍꢄꢅꢀꢁGꢃꢀ1JC- 67%. RF: 0.67 (Acetone/toluene 1:2). M.p. 33-35°C
F=235.5), 155.0 (d, 4JC-F=1.8), 115.6 (d, 3JC-F=8.1), 115.6 (propan-2-ol). +ꢀ 105ꢀ ꢁꢇꢋꢋꢀ 0+]ꢃꢀ '062ꢆd6ꢂꢃꢀ įꢏꢀ ꢎꢄꢋꢌꢀ
1
(d, 2JC-F=22.9), 70.8, 40.9.
(d, 2H, 3J=8.9, ArO), 4.60 (dd, 1H, 2J=12.4, 3J=2.7,
COOCH2), 4.09-3.99 (m, 3H, CH2CH2, COOCH2), 3.36-
3
ꢀꢁꢀꢁꢀꢁꢃ6\QWKHVLVꢃRIꢃR[LUDQꢄꢀꢄ\OPHWK\OꢃꢇꢄDONR[\EHQ]RDWHVꢃꢃꢃ 3.28 (m, 1H, CHꢆR[LUDQꢂꢃꢀꢇꢄꢐꢅꢀꢁGGꢃꢀꢊ+ꢃꢀ2J=4.9, J=4.4,
3
ꢃꢃꢃꢃꢃꢃꢃꢃꢃꢃꢅꢋDꢄGꢈ
CH2ꢆR[LUDQꢂꢃꢀꢇꢄꢎꢇꢀꢁGGꢃꢀꢊ+ꢃꢀ2J=4.9, J=2.7, CH2ꢆR[LUDQꢂꢃꢀ
$ꢀPL[WXUHꢀRIꢀLQGLYLGXDOꢀꢉꢆDONR[\EHQ]RLFꢀDFLGꢀꢁꢋꢄꢋꢋꢑꢀPROꢂꢀ 1.79-1.65 (m, 2H, CH2CH2), 1.53-1.34 (m, 2H, CH2CH3),
and PCl5 (0.01 mol) in toluene (40 mL) was heated for 0.93 (t, 3H, 3J=7.3, CH3), 13&ꢀ105ꢀꢁꢌꢋꢀ0+]ꢃꢀ'062ꢆd6),
4 hours to give appropriate acyl chlorides. The toluene įꢏꢀꢊꢍꢌꢄꢋꢃꢀꢊꢍꢇꢄꢍꢃꢀꢊꢅꢊꢄꢇꢃꢀꢊꢇꢊꢄꢅꢃꢀꢊꢊꢉꢄꢉꢃꢀꢍꢎꢄꢌꢃꢀꢍꢉꢄꢐꢃꢀꢉꢐꢄꢑꢃꢀ
was removed and crude intermediates reacted directly 43.7, 30.4, 18.5, 13.4.
LQꢀWKHꢀQH[WꢀVWHSꢄꢀ7KHꢀPL[WXUHꢀRIꢀꢇꢃꢅꢆHSR[\SURSDQꢆꢊꢆROꢀ
(0.01mol)andtriethylamine(0.01mol)indichlormethane 2.2.3.
6\QWKHVLVꢃ
RIꢃ
ꢌꢄDPLQRꢄꢀꢄK\GUR[\SURS\Oꢃ
(20 mL) under argon was cooled to 0°C and the acyl
ꢇꢄDONR[\EHQ]RDWHꢃGHULYDWLYHVꢃꢅꢍDꢄGꢎꢃꢏDꢄGꢎꢃꢂꢐDꢄGꢈ
chloride (0.01 mol) dissolved in dichlormethane (20 mL) Intermediate 7a-d (0,01 mol) was added to a solution
was added dropwise. After 4 hours, a formed precipitate of corresponding amine 5, or tert-butylamine
6
ZDVꢀ ¿OWHUHGꢀ RIIꢀ DQGꢀ WKHꢀ VROYHQWꢀ ZDVꢀ HYDSRUDWHGꢄꢀ (0,012 mol) in propan-2-ol (50 mL). The reaction was
%HQ]RDWHVꢀ 7a, 7b and 7dꢀ ZHUHꢀ UHFU\VWDOOL]HGꢀ IURPꢀ WKHQꢀ UHÀX[HGꢀ IRUꢀ ꢊꢀ KRXUꢀ DQGꢀ VWLUUHGꢀ IRUꢀ ꢎꢇꢀ KRXUVꢀ DWꢀ
SURSDQꢆꢇꢆROꢃꢀEHQ]RDWHꢀ7c was dissolved in acetone and URRPꢀ WHPSHUDWXUHꢄꢀ 7KHꢀ PL[WXUHꢀ ZDVꢀ HYDSRUDWHGꢃꢀ DQGꢀ
UHÀX[HGꢀZLWKꢀFKDUFRDOꢄꢀ$FHWRQHꢀZDVꢀUHPRYHGꢀDQGꢀWKHꢀ the crude, basic product was dissolved in ethyl acetate
residual oily product was washed with petroleum ether. and transformed to hydrochloric salt by the addition of
NMR spectra of 7a are in accordance with literature [18]. saturated ethereal HCl. The resulting white precipitate
2[LUDQꢁꢀꢁ\OPHWK\OꢅꢄꢁPHWKR[\EHQ]RDWH (7a). Yield ZDVꢀ FROOHFWHGꢀ E\ꢀ ¿OWUDWLRQꢀ DQGꢀ UHFU\VWDOOL]HGꢀ IURP
55%. RF: 0.61 (Acetone/toluene 1:2). M.p. 34-37°C propan-2-ol.
(propan-2-ol). 1+ꢀ105ꢀꢁꢇꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢎꢄꢑꢉꢀꢁGꢃꢀ
2H, 3J=8.9, ArCOO), 7.06 (d, 2H, 3J=8.9, ArO), 4.60 (dd, K\GUR[\SURS\Oꢅ ꢄꢁPHWKR[\EHQ]RDWHꢅ K\GURFKORULGH
ꢆ ꢁ > ꢀ ꢁ ꢂ ꢀ ꢁ I O X R U R S K H Q R [ \ ꢃ H W K \ O D P L Q R @ ꢁ ꢀ ꢁ
2
3
2
1H, J=12.4, J=2.7, COOCH2), 4.05 (dd, 1H, J=12.4, (8a). Yield 48%. RF: 0.57 (methanol). RF(rev): 0.58
3J=6.4, COOCH2), 3.84 (s, 3H, OCH3), 3.29-3.35 (m, 1H, (Acetone/0.1 M HCl 2:3). M.p. 137-138°C (propan-2-ol).
CHꢆR[LUDQꢂꢃꢀ ꢇꢄꢐꢅꢀ ꢁGGꢃꢀ ꢊ+ꢃꢀ 2J=4.9, J=4.4, CH2ꢆR[LUDQꢂꢃꢀ +3/&ꢀSXULW\ꢀꢑꢐꢄꢇꢐꢒꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 258. IR (Zn/Se ATR,
3
2.72 (dd, 1H, 2J=4.9, 3J=2.6, CH2ꢆR[LUDQꢂꢄꢀ 13C NMR cm-1ꢂꢏꢀ ꢅꢉꢍꢌꢀ ꢁȣꢀ 2+ꢂꢃꢀ ꢇꢑꢌꢉꢀ ꢁȣꢀ &+ꢂꢃꢀ ꢇꢎꢊꢅꢀ ꢁȣꢀ 1+ꢂꢃꢀ ꢊꢍꢐꢊꢀ
ꢁꢌꢋꢀ 0+]ꢃꢀ '062ꢆd6ꢂꢃꢀ įꢏꢀ ꢊꢍꢌꢄꢋꢃꢀ ꢊꢍꢅꢄꢇꢃꢀ ꢊꢅꢊꢄꢇꢃꢀ ꢊꢇꢊꢄꢌꢃꢀ ꢁȣꢀ& 2ꢂꢃꢀꢊꢍꢋꢐꢀꢁȣringꢀ& &ꢂꢃꢀꢊꢇꢌꢍꢀꢁȣasꢀ&ꢆ2ꢆ&ꢂꢃꢀꢊꢊꢊꢌꢀꢁȣs
114.0, 64.9, 55.4, 49.0, 43.7.
C-O-C). 1+ꢀ105ꢀꢁꢉꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢑꢄꢌꢊꢀꢁEVꢃꢀꢊ+ꢃꢀ
3
2[LUDQꢁꢀꢁ\OPHWK\Oꢅ ꢄꢁHWKR[\EHQ]RDWHꢅ (7b). Yield NH), 9.17 (bs, 1H, NH), 7.97 (d, 2H, J=8.9, ArCOO),
68%. RF: 0.64 (Acetone/toluene 1:2). M.p. 46-47°C 7.26-7.13 (m, 3H, ArF), 7.05-6.97 (m, 1H, ArF), 7.03 (d,
1
(propan-2-ol). +ꢀ 105ꢀ ꢁꢇꢋꢋꢀ 0+]ꢃꢀ '062ꢆd6ꢂꢃꢀ įꢏꢀ ꢎꢄꢑꢇꢀ 2H, 3J=8.9, ArO), 6.00 (d, 1H, 3J=3.1, OH), 4.42 (t, 2H,
(d, 2H, 3J=8.9, ArCOO), 7.04 (d, 2H, 3J=8.9, ArO), 4.60 3J=6.1, CH2O), 4.28-4.23 (m, 3H, CH2CH, CHOH), 3.83
2
3
(dd, 1H, J=12.4, J=2.6, COOCH2), 4.16-3.99 (m, 3H, (s, 3H, CH3), 3.46-3.42 (m, 2H, NCH2), 3.37-3.30 (m, 1H
1759

Synthesis of new (arylcarbonyloxy)aminopropanol derivatives
and the determination of their physico-chemical properties
CH2N), 3.16-3.11 (m, 1H, CH2N). 13&ꢀ105ꢀꢁꢊꢋꢋꢀ0+]ꢃꢀ
ꢆ ꢁ > ꢀ ꢁ ꢂ ꢀ ꢁ I O X R U R S K H Q R [ \ ꢃ H W K \ O D P L Q R @ ꢁ ꢀ ꢁ
DMSO-d6ꢂꢃꢀįꢏꢀꢊꢍꢌꢄꢇꢃꢀꢊꢍꢅꢄꢇꢃꢀꢊꢌꢊꢄꢐꢀꢁGꢃꢀ1JC-F=244.0), 145.6 K\GUR[\SURS\Oꢅ ꢄꢁEXWR[\EHQ]RDWHꢅ K\GURFKORULGH
(d, 2JC-F=10.5), 131.5, 124.9 (d, 4JC-F=3.8), 121.9 (d, 3JC- (8d). Yield 34%. RF: 0.61 (methanol). RF(rev): 0.37
2
F=6.8), 121.7, 116.2 (d, JC-F=17.8), 115.4, 113.9, 65.9, (Acetone/0.1 M HCl 2:3). M.p. 118-120°C (propan-2-
64.6, 64.5, 55.6, 49.9, 46.0. Anal. calc. for C19H23ClFNO5 ROꢂꢄꢀ+3/&ꢀSXULW\ꢀꢑꢐꢄꢉꢌꢒꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 259. IR (Zn/Se
(399.84): 57.07% C, 5.80% H, 3.50% N; found 57.13% ATR, cm-1ꢂꢏꢀ ꢅꢉꢍꢎꢀ ꢁȣꢀ 2+ꢂꢃꢀ ꢇꢑꢌꢎꢀ ꢁȣꢀ &+ꢂꢃꢀ ꢇꢎꢅꢅꢀ ꢁȣꢀ 1+ꢂꢃꢀ
C, 5.86% H, 3.45% N. HR-MS: for C19H23ClFNO5ꢀ>0±+@- ꢊꢍꢐꢇꢀꢁȣꢀ& 2ꢂꢃꢀꢊꢍꢋꢌꢀꢁȣringꢀ& &ꢂꢃꢀꢊꢇꢌꢋꢀꢁȣas C-O-C), 1117
calc. 398.1176 m/z, found 398.1178 m/z.
ꢁȣs C-O-C). 1+ꢀ 105ꢀ ꢁꢉꢋꢋꢀ 0+]ꢃꢀ '062ꢆd6ꢂꢃꢀ įꢏꢀ ꢑꢄꢉꢍꢀ
3
ꢆ ꢁ > ꢀ ꢁ ꢂ ꢀ ꢁ I O X R U R S K H Q R [ \ ꢃ H W K \ O D P L Q R @ ꢁ ꢀ ꢁ (bs, 1H, NH), 9.17 (bs, 1H, NH), 7.95 (d, 2H, J=8.9,
3
K\GUR[\SURS\Oꢅ ꢄꢁHWKR[\EHQ]RDWHꢅ K\GURFKORULGH ArCOO), 7.26-7.14 (m, 3H, ArF), 7.02 (d, 2H, J=8.9,
(8b). Yield 43%. RF: 0.58 (methanol). RF(rev): 0.51 ArO), 7.01-6.97 (m, 1H, ArF), 5.99 (d, 1H, 3J=4.7,
(Acetone/0.1 M HCl 2:3). M.p. 121-122°C (propan-2-ol). OH), 4.46-4.38 (m, 2H, CH2O), 4.29-4.22 (m, 3H,
3
+3/&ꢀSXULW\ꢀꢑꢐꢄꢊꢑꢒꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 259. IR (Zn/Se ATR, CH2CH, CHOH), 4.05 (t, 2H, J=6.5, CH2CH2), 3.44 (t,
cm-1ꢂꢏꢀ ꢅꢉꢍꢉꢀ ꢁȣꢀ 2+ꢂꢃꢀ ꢇꢑꢎꢑꢀ ꢁȣꢀ &+ꢂꢃꢀ ꢇꢍꢉꢍꢀ ꢁȣꢀ 1+ꢂꢃꢀ ꢊꢍꢐꢊꢀ 2H, J=5.0, NCH2), 3.36-3.29 (m, 1H CH2N), 3.16-3.10
ꢁȣꢀ& 2ꢂꢃꢀꢊꢍꢋꢎꢀꢁȣringꢀ& &ꢂꢃꢀꢊꢇꢌꢌꢀꢁȣasꢀ&ꢆ2ꢆ&ꢂꢃꢀꢊꢊꢊꢉꢀꢁȣs (m, 1H CH2N), 1.74-1.67 (m, 2H, CH2CH2), 1.48-1.39
&ꢆ2ꢆ&ꢂꢄꢀ+ꢀ105ꢀꢁꢉꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢑꢄꢉꢐꢀꢁEVꢃꢀꢊ+ꢃꢀ (m, 2H, CH2CH3), 0.93 (t, 3H, J=7.4, CH3). 13C NMR
3
NH), 9.17 (bs, 1H, NH), 7.95 (d, 2H, J=8.9, ArCOO), ꢁꢊꢋꢋꢀ 0+]ꢃꢀ '062ꢆd6ꢂꢃꢀ įꢏꢀ ꢊꢍꢌꢄꢇꢃꢀ ꢊꢍꢇꢄꢎꢃꢀ ꢊꢌꢊꢄꢎꢀ ꢁGꢃꢀ 1JC-
2
4
7.26-7.14 (m, 3H, ArF), 7.02-6.97 (m, 1H, ArF), 7.01 F=244.0), 145.6 (d, JC-F=10.5), 131.4, 124.9 (d, JC-
3
3
(d, 2H, J=8.9, ArO), 5.99 (d, 1H, J=3.1, OH), 4.42 (t, F=3.7), 124.9 (d, 3JC-F=3.7), 121.5, 116.2 (d, 2JC-F=17.8),
3
2H, J=6.1, CH2O), 4.28-4.22 (m, 3H, CH2CH, CHOH), 115.4, 114.3, 67.6, 65.9, 64.6, 64.5, 49.9, 46.0, 30.6,
4.11 (q, 2H, 3J=7.0, CH2CH3), 3.44 (t, 2H, J=4.8, NCH2), 18.7, 13.7. Anal. calc. for C22H29ClFNO5 (441.92):
3.36-3.30 (m, 1H CH2N), 3.16-3.10 (m, 1H, CH2N), 1.34 59.79% C, 6.61% H, 3.17% N; found 59.85% C, 6.68%
3
(t, 3H, J=7.0, CH3). 13&ꢀ 105ꢀ ꢁꢊꢋꢋꢀ 0+]ꢃꢀ '062ꢆd6), H, 3.13% N. HR-MS: for C22H29ClFNO5ꢀ >0±+@- calc.
įꢏꢀ ꢊꢍꢌꢄꢇꢃꢀ ꢊꢍꢇꢄꢌꢃꢀ ꢊꢌꢊꢄꢎꢀ ꢁGꢃꢀ 1JC-F=243.9), 145.6 (d, JC- 440.1646 m/z; found 440.1645 m/z.
2
F=10.6), 131.5, 124.9 (d, 4JC-F=3.8), 121.9 (d, 3JC-F=6.8),
ꢆ ꢁ > ꢀ ꢁ ꢂ ꢄ ꢁ I O X R U R S K H Q R [ \ ꢃ H W K \ O D P L Q R @ ꢁ ꢀ ꢁ
2
121.5, 116.2 (d, JC-F=17.9), 115.4, 114.3, 65.9, 64.6, K\GUR[\SURS\Oꢅ ꢄꢁPHWKR[\EHQ]RDWHꢅ K\GURFKORULGH
64.5, 63.6, 49.9, 46.0, 14.5. Anal. calc. for C20H25ClFNO5 (9a). Yield 45%. RF: 0.55 (methanol). RF(rev): 0.56
(413.87): 58.04% C, 6.09% H, 3.38% N; found 58.10% (Acetone/0.1 M HCl 2:3). M.p. 166-168°C (propan-2-ol).
C, 6.12% H, 3.33% N. HR-MS: for C20H25ClFNO5ꢀ>0±+@- +3/&ꢀSXULW\ꢀꢑꢐꢄꢇꢍꢒꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 258. IR (Zn/Se ATR,
calc. 412.1133 m/z; found 412.1335 m/z.
cm-1ꢂꢏꢀ ꢅꢅꢍꢋꢀ ꢁȣꢀ 2+ꢂꢃꢀ ꢇꢑꢍꢅꢀ ꢁȣꢀ &+ꢂꢃꢀ ꢇꢎꢎꢐꢀ ꢁȣꢀ 1+ꢂꢃꢀ ꢊꢎꢊꢌꢀ
ꢆ ꢁ > ꢀ ꢁ ꢂ ꢀ ꢁ I O X R U R S K H Q R [ \ ꢃ H W K \ O D P L Q R @ ꢁ ꢀ ꢁ ꢁȣꢀ& 2ꢂꢃꢀꢊꢍꢋꢉꢀꢁȣringꢀ& &ꢂꢃꢀꢊꢇꢉꢊꢀꢁȣasꢀ&ꢆ2ꢆ&ꢂꢃꢀꢊꢋꢑꢌꢀꢁȣs
K\GUR[\SURS\Oꢅ ꢄꢁSURSR[\EHQ]RDWHꢅ K\GURFKORULGH C-O-C). 1+ꢀ105ꢀꢁꢌꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢑꢄꢅꢋꢀꢁEVꢃꢀꢊ+ꢃꢀ
3
(8c). Yield 43%. RF: 0.60 (methanol). RF(rev): 0.44 NH), 9.09 (bs, 1H, NH), 7.96 (d, 2H, J=8.9, ArCOO),
(Acetone/0.1 M HCl 2:3). M.p. 113-115°C (propan-2-ol). 7.16-7.13 (m, 2H, ArF), 7.04 (d, 2H, 3J=8.9, ArO), 7.02-
+3/&ꢀSXULW\ꢀꢑꢐꢄꢅꢍꢒꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 259. IR (Zn/Se ATR, 6.99 (m, 2H, OArF), 5.96 (d, 1H, 3J=4.7, OH), 4.32-4.23
cm-1ꢂꢏꢀ ꢅꢉꢍꢑꢀ ꢁȣꢀ 2+ꢂꢃꢀ ꢇꢑꢌꢎꢀ ꢁȣꢀ &+ꢂꢃꢀ ꢇꢎꢅꢋꢀ ꢁȣꢀ 1+ꢂꢃꢀ ꢊꢍꢐꢇꢀ (m, 5H, CHOH, CH2O, CH2CH), 3.84 (s, 3H, CH3), 3.40
3
ꢁȣꢀ& 2ꢂꢃꢀꢊꢍꢋꢌꢀꢁȣringꢀ& &ꢂꢃꢀꢊꢇꢌꢉꢀꢁȣasꢀ&ꢆ2ꢆ&ꢂꢃꢀꢊꢊꢊꢍꢀꢁȣs (t, 2H, J=5.0, NCH2), 3.29-3.26 (m, 1H, CH2N), 3.13-
C-O-C). 1+ꢀ105ꢀꢁꢉꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢑꢄꢉꢍꢀꢁEVꢃꢀꢊ+ꢃꢀ 3.07 (m, 1H, CH2N). 13&ꢀ 105ꢀ ꢁꢊꢇꢌꢀ 0+]ꢃꢀ '062ꢆd6),
3
4
NH), 9.18 (bs, 1H, NH), 7.95 (d, 2H, J=8.8, ArCOO), įꢏꢀꢊꢍꢌꢄꢊꢃꢀꢊꢍꢅꢄꢇꢃꢀꢊꢌꢍꢄꢐꢀꢁGꢃꢀ1JC-F=236.5), 154.04 (d, JC-
7.26-7.13 (m, 3H, ArF), 7.02 (d, 2H, 3J=8.9, ArO), 7.01- F=1.8), 131.4, 121.6, 116.0 (d, JC-F=8.2), 115.9 (d,
3
6.97 (m, 1H, ArF), 6.00 (d, 1H, J=4.6, OH), 4.45-4.38 2JC-F=23.1), 113.9, 65.9, 64.4, 63.9, 55.5, 49.7, 46.1.
3
(m, 2H, CH2O), 4.30-4.22 (m, 3H, CH2CH, CHOH), Anal. calc. for C19H23ClFNO5 (399.84): 57.07% C, 5.80%
4.00 (t, 2H, 3J=6.5, CH2CH2), 3.44 (t, 2H, J=4.9, NCH2), H, 3.50% N; found 57.12% C, 5.87% H, 3.44% N. HR-
3.37-3.30 (m, 1H CH2N), 3.16-3.10 (m, 1H CH2N), 1.79- MS: for C19H23ClFNO5ꢀ>0±+@- calc. 398.1176 m/z; found
3
1.70 (m, 2H, CH2CH3), 0.98 (t, 3H, J=7.4, CH3). 13C 398.1173 m/z.ꢅ
105ꢀꢁꢊꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢊꢍꢌꢄꢇꢃꢀꢊꢍꢇꢄꢎꢃꢀꢊꢌꢊꢄꢎꢀꢁGꢃꢀ
ꢆ ꢁ > ꢀ ꢁ ꢂ ꢄ ꢁ I O X R U R S K H Q R [ \ ꢃ H W K \ O D P L Q R @ ꢁ ꢀ ꢁ
1JC-F=244.0), 145.6 (d, JC-F=10.8), 131.5, 124.9 (d, JC- K\GUR[\SURS\Oꢅ ꢄꢁHWKR[\EHQ]RDWHꢅ K\GURFKORULGH
F=3.8), 121.9 (d, 3JC-F=6.9), 121.5, 116.2 (d, 2JC-F=18.0), (9b). Yield 63%. RF: 0.56 (methanol). RF(rev): 0.49
115.4, 114.3, 69.3, 64.6, 64.5, 63.6, 49.9, 46.0, 21.9, (Acetone/0.1 M HCl 2:3). M.p. 169-171°C (propan-2-ol).
10.3. Anal. calc. for C21H27ClFNO5 (427.89): 58.95% C, +3/&ꢀSXULW\ꢀꢑꢐꢄꢐꢇꢒꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 259. IR (Zn/Se ATR,
6.36% H, 3.27% N; found 59.02% C, 6.39% H, 3.22% cm-1ꢂꢏꢀ ꢅꢅꢑꢎꢀ ꢁȣꢀ 2+ꢂꢃꢀ ꢇꢑꢐꢋꢀ ꢁȣꢀ &+ꢂꢃꢀ ꢇꢎꢐꢌꢀ ꢁȣꢀ 1+ꢂꢃꢀ ꢊꢎꢊꢉꢀ
N. HR-MS: for C21H27ClFNO5ꢀ>0±+@- calc. 426.1489 m/z; ꢁȣꢀ& 2ꢂꢃꢀꢊꢍꢋꢉꢀꢁȣringꢀ& &ꢂꢃꢀꢊꢇꢉꢑꢀꢁȣasꢀ&ꢆ2ꢆ&ꢂꢃꢀꢊꢋꢑꢎꢀꢁȣs
2
4
found 426.1490 m/z.
C-O-C). 1+ꢀ105ꢀꢁꢌꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢑꢄꢇꢑꢀꢁEVꢃꢀꢊ+ꢃꢀ
1760

J. Tengler et al.
3
NH), 9.07 (bs, 1H, NH), 7.96 (d, 2H, J=8.9, ArCOO), 67.5, 65.8, 64.4, 63.9, 49.7, 46.1, 30.5, 18.6, 13.6. Anal.
7.18-7.13 (m, 2H, ArF), 7.04-7.0 (m, 4H, ArF, ArO), 5.96 calc. for C22H29ClFNO5 (441.92): 59.79% C, 6.61% H,
3
(d, 1H, J=4.6, OH), 4.31-4.24 (m, 5H, CHOH, CH2O, 3.17% N; found 59.87% C, 6.67% H, 3.11% N. HR-
CH2CH), 4.12 (q, 2H, 3J=7.0, OCH2), 3.41 (t, 2H, 3J=4.9, MS: for C22H29ClFNO5ꢀ>0±+@- calc. 440.1646 m/z; found
NCH2), 3.30-3.27 (m, 1H, CH2N), 3.13-3.08 (m, 1H, 440.1646 m/z.
3
CH2N), 1.37 (t, 3H, J=7.0, CH3). 13&ꢀ105ꢀꢁꢊꢇꢌꢀ0+]ꢃꢀ
ꢆ ꢁ W H U W ꢁ E X W \ O D P L Q R ꢁ ꢀ ꢁ K \ G U R [ \ S U R S \ Oꢅ
1
DMSO-d6ꢂꢃꢀ įꢏꢀ ꢊꢍꢌꢄꢊꢃꢀ ꢊꢍꢇꢄꢌꢃꢀ ꢊꢌꢍꢄꢐꢋꢀ ꢁGꢃꢀ JC-F=236.5), ꢄꢁPHWKR[\EHQ]RDWHꢅ K\GURFKORULGH (10a). Yield
154.04 (d, JC-F=1.8), 131.5, 121.4, 116.0 (d, JC-F=8.1), 81%. RF: 0.48 (methanol). RF(rev): 0.44 (Acetone/0.1
115.9 (d, JC-F=23.1), 114.3, 65.8, 64.4, 63.9, 63.5, M HCl 2:3). M.p. 168-170°C (propan-2-ol). UV (nm),
49.7, 46.1, 14.4. Anal. calc. for C20H25ClFNO5 (413.87):
4
3
2
Ȝ
PD[: 260. IR (Zn/Se ATR, cm-1ꢂꢏꢀꢅꢇꢅꢉꢀꢁȣꢀ2+ꢂꢃꢀꢇꢑꢐꢋꢀꢁȣꢀ
58.04% C, 6.09% H, 3.38% N; found 58.08% C, 6.11% &+ꢂꢃꢀꢇꢎꢑꢐꢀꢁȣꢀ1ꢆ+ꢂꢃꢀꢊꢎꢊꢇꢀꢁȣꢀ& 2ꢂꢃꢀꢊꢍꢋꢅꢀꢁȣring CAr=CAr),
H, 3.34% N. HR-MS: for C20H25ClFNO5ꢀ >0±+@- calc. ꢊꢇꢍꢇꢀꢁȣasꢀ&ꢆ2ꢆ&ꢂꢃꢀꢊꢊꢇꢉꢀꢁȣs C-O-C). 1+ꢀ105ꢀꢁꢉꢋꢋꢀ0+]ꢃꢀ
412.1133 m/z; found 412.1334 m/z.
DMSO-d6ꢂꢃꢀįꢏꢀꢑꢄꢅꢅꢀꢁEVꢃꢀꢊ+ꢃꢀ1H), 8.66 (bs, 1H, NH), 7.98
ꢆ ꢁ > ꢀ ꢁ ꢂ ꢄ ꢁ I O X R U R S K H Q R [ \ ꢃ H W K \ O D P L Q R @ ꢁ ꢀ ꢁ (d, 2H, 3J=8.9, ArCOO), 7.05 (d, 2H, 3J=8.9, ArO), 5.96
K\GUR[\SURS\Oꢅ ꢄꢁSURSR[\EHQ]RDWHꢅ K\GURFKORULGH (d, 1H, 3J=4.0, OH), 4.28-4.19 (m, 3H, CH2CH, CHOH),
(9c). Yield 42%. RF: 0.57 (methanol). RF(rev): 0.41 3.83 (s, 3H, CH3), 3.15-3.09 (m, 1H, CH2N), 2.92-2.90
(Acetone/0.1 M HCl 2:3). M.p. 160-162°C (propan-2- (m, 1H, CH2N), 1.32 (s, 9H, CH3). 13&ꢀ105ꢀꢁꢊꢋꢋꢀ0+]ꢃꢀ
ROꢂꢄꢀ+3/&ꢀSXULW\ꢀꢑꢐꢄꢅꢐꢒꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 259. IR (Zn/Se DMSO-d6ꢂꢃꢀįꢏꢀꢊꢍꢌꢄꢇꢃꢀꢊꢍꢅꢄꢇꢃꢀꢊꢅꢊꢄꢌꢃꢀꢊꢇꢊꢄꢎꢃꢀꢊꢊꢉꢄꢋꢃꢀꢍꢍꢄꢋꢃꢀ
ATR, cm-1ꢂꢏꢀ ꢅꢅꢑꢌꢀ ꢁȣꢀ 2+ꢂꢃꢀ ꢇꢑꢍꢊꢀ ꢁȣꢀ &+ꢂꢃꢀ ꢇꢎꢐꢉꢀ ꢁȣꢀ 1+ꢂꢃꢀ 65.1, 56.3, 55.5, 44.1, 25.0. Anal. calc. for C15H24ClNO4
ꢊꢎꢊꢅꢀꢁȣꢀ& 2ꢂꢃꢀꢊꢍꢋꢇꢀꢁȣringꢀ& &ꢂꢃꢀꢊꢇꢉꢑꢀꢁȣas C-O-C), 1094 (317.81): 56.69% C, 7.61% H, 4.41% N; found 56.73%
ꢁȣs C-O-C). 1+ꢀ 105ꢀ ꢁꢌꢋꢋꢀ 0+]ꢃꢀ '062ꢆd6ꢂꢃꢀ įꢏꢀ ꢑꢄꢅꢊꢀ C, 7.67% H, 4.35% N. HR-MS: for C15H24ClNO4ꢀ>0±+@-
3
(bs, 1H, NH), 9.09 (bs, 1H, NH), 7.95 (d, 2H, J=8.9, calc. 316.1321 m/z; found 316.1321 m/z.
ArCOO), 7.17-7.12 (m, 2H, ArF), 7.04-6.98 (m, 2H,
OArF), 7.02 (d, 2H, J=8.9, ArO), 5.96 (d, 1H, J=4.7, ꢄꢁHWKR[\EHQ]RDWHꢅ K\GURFKORULGH (10b). Yield 83%.
ꢆ ꢁ W H U W ꢁ E X W \ O D P L Q R ꢁ ꢀ ꢁ K \ G U R [ \ S U R S \ Oꢅ
3
3
OH), 4.31-4.23 (m, 5H, CHOH, CH2O, CH2CH), 4.01 (t, RF: 0.48 (methanol). RF(rev): 0.33 (Acetone/0.1 M HCl
3
3
2H, J=6.5, CH2CH2), 3.40 (t, 2H, J=5.0, NCH2), 3.28- ꢇꢏꢅꢂꢄꢀ0ꢄSꢄꢀꢊꢎꢉꢆꢊꢎꢌƒ&ꢀꢁSURSDQꢆꢇꢆROꢂꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 260.
3.26 (m, 1H, CH2N), 3.12-3.07 (m, 1H, CH2N), 1.75 IR (Zn/Se ATR, cm-1ꢂꢏꢀꢅꢇꢉꢇꢀꢁȣꢀ2ꢆ+ꢂꢃꢀꢇꢑꢐꢊꢀꢁȣꢀ&+ꢂꢃꢀꢇꢐꢊꢅꢀ
3
(m, 2H, CH2CH3), 0.98 (t, 3H, J=7.4, CH3). 13C NMR ꢁȣꢀ 1ꢆ+ꢂꢃꢀ ꢊꢎꢊꢅꢀ ꢁȣꢀ & 2ꢂꢃꢀ ꢊꢍꢋꢅꢀ ꢁȣring CAr=CArꢂꢃꢀ ꢊꢇꢉꢎꢀ ꢁȣas
ꢁꢊꢇꢌꢀ 0+]ꢃꢀ '062ꢆd6ꢂꢃꢀ įꢏꢀ ꢊꢍꢌꢄꢊꢃꢀ ꢊꢍꢇꢄꢎꢃꢀ ꢊꢌꢍꢄꢐꢀ ꢁGꢃꢀ &ꢆ2ꢆ&ꢂꢃꢀꢊꢊꢊꢇꢀꢁȣs C-O-C). 1+ꢀ105ꢀꢁꢉꢋꢋꢀ0+]ꢃꢀ'062ꢆd6),
1JC-F=236.5), 154.0 (d, 4JC-F=1.8), 131.4, 121.4, 116.0 (d, įꢏꢀꢑꢄꢅꢇꢀꢁEVꢃꢀꢊ+ꢃꢀ1H), 8.66 (bs, 1H, NH), 7.96 (d, 2H,
3JC-F=8.2), 115.9 (d, 2JC-F=23.0), 114.3, 69.3, 65.8, 64.4, 3J=8.9, ArCOO), 7.03 (d, 2H, 3J=8.9, ArO), 5.96 (d, 1H,
63.9, 49.7, 46.1, 21.8, 10.3. Anal. calc. for C21H27ClFNO5 3J=4.0, OH), 4.28-4.19 (m, 3H, CH2CH, CHOH), 4.10 (q,
3
(427.89): 58.95% C, 6.36% H, 3.27% N; found 58.99% 2H, J=7.0, CH2CH3), 3.14-3.09 (m, 1H, CH2N), 2.92-
C, 6.41% H, 3.23% N. HR-MS: for C21H27ClFNO5ꢀ>0±+@- 2.89 (m, 1H, CH2N), 1.34 (t, 3H, 3J=7.0, CH2CH3), 1.32
calc. 426.1489 m/z; found 426.1496 m/z.
(s, 9H, CH3). 13&ꢀ105ꢀꢁꢊꢋꢋꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢊꢍꢌꢄꢇꢃꢀ
ꢆ ꢁ > ꢀ ꢁ ꢂ ꢄ ꢁ I O X R U R S K H Q R [ \ ꢃ H W K \ O D P L Q R @ ꢁ ꢀ ꢁ 162.5, 131.5, 121.5, 114.3, 66.0, 65.1, 63.5, 56.3, 44.1,
K\GUR[\SURS\Oꢅ ꢄꢁEXWR[\EHQ]RDWHꢅ K\GURFKORULGH 24.9, 14.5. Anal. calc. for C16H26ClNO4 (331.84): 57.91%
(9d). Yield 47%. RF: 0.58 (methanol). RF(rev): 0.34 C, 7.90% H, 4.22% N; found 58.07% C, 7.98% H, 4.16%
(Acetone/0.1 M HCl 2:3). M.p. 148-150°C (propan-2- N. HR-MS: for C16H26ClNO4ꢀ>0±+@- calc. 330.1478 m/z;
ROꢂꢄꢀ+3/&ꢀSXULW\ꢀꢑꢐꢄꢅꢐꢒꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 260. IR (Zn/Se found 330.1478 m/z.
ATR, cm-1ꢂꢏꢀ ꢅꢅꢍꢉꢀ ꢁȣꢀ 2+ꢂꢃꢀ ꢇꢑꢅꢌꢀ ꢁȣꢀ &+ꢂꢃꢀ ꢇꢎꢉꢐꢀ ꢁȣꢀ 1+ꢂꢃꢀ
ꢆ ꢁ W H U W ꢁ E X W \ O D P L Q R ꢁ ꢀ ꢁ K \ G U R [ \ S U R S \ Oꢅ
ꢊꢎꢋꢅꢀꢁȣꢀ& 2ꢂꢃꢀꢊꢍꢋꢅꢀꢁȣringꢀ& &ꢂꢃꢀꢊꢇꢉꢐꢀꢁȣas C-O-C), 1093 ꢄꢁSURSR[\EHQ]RDWHꢅK\GURFKORULGH (10c). Yield 63%.
ꢁȣs C-O-C). 1+ꢀ 105ꢀ ꢁꢌꢋꢋꢀ 0+]ꢃꢀ '062ꢆd6ꢂꢃꢀ įꢏꢀ ꢑꢄꢇꢎꢀ RF: 0.49 (methanol). RF(rev): 0.21 (Acetone/0.1 M HCl
3
(bs, 1H, NH), 9.14 (bs, 1H, NH), 7.94 (d, 2H, J=8.9, ꢇꢏꢅꢂꢄꢀꢀ0ꢄSꢄꢀꢊꢌꢌꢆꢊꢌꢍƒ&ꢀꢁSURSDQꢆꢇꢆROꢂꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 260.
ArCOO), 7.17-7.12 (m, 2H, ArF), , 7.04-6.98 (m, 2H, IR (Zn/Se ATR, cm-1ꢂꢏꢀꢅꢇꢉꢌꢀꢁȣꢀ2ꢆ+ꢂꢃꢀꢇꢑꢎꢑꢀꢁȣꢀ&+ꢂꢃꢀꢇꢐꢋꢇꢀ
3
3
OArF), 7.02 (d, 2H, J=8.9, ArO), 5.96 (d, 1H, J=4.8, ꢁȣꢀ 1ꢆ+ꢂꢃꢀ ꢊꢎꢊꢇꢀ ꢁȣꢀ & 2ꢂꢃꢀ ꢊꢍꢋꢊꢀ ꢁȣring CAr=CArꢂꢃꢀ ꢊꢇꢉꢑꢀ ꢁȣas
OH), 4.32-4.23 (m, 5H, CHOH, CH2O, CH2CH), 4.05 (t, &ꢆ2ꢆ&ꢂꢃꢀꢊꢊꢊꢋꢀꢁȣs C-O-C). 1+ꢀ105ꢀꢁꢉꢋꢋꢀ0+]ꢃꢀ'062ꢆd6),
3
3
2H, J=6.5, CH2CH2), 3.40 (t, 2H, J=5.1, NCH2), 3.29- įꢏꢀꢑꢄꢅꢇꢀꢁEVꢃꢀꢊ+ꢃꢀ1H), 8.66 (bs, 1H, NH), 7.96 (d, 2H,
3.26 (m, 1H, CH2N), 3.12-3.07 (m, 1H, CH2N), 1.71 (m, 3J=8.9, ArCOO), 7.04 (d, 2H, 3J=8.9, ArO), 5.96 (d, 1H,
2H, CH2CH2), 1.48-1.40 (m, 2H, CH2CH3), 0.93 (t, 3H, 3J=4.01, OH), 4.28-4.19 (m, 3H, CH2CH, CHOH), 4.20
3J=7.4, CH3). 13&ꢀ105ꢀꢁꢊꢇꢌꢀ0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢊꢍꢌꢄꢊꢃꢀ (t, 2H, 3J=6.5,CH2CH3), 3.14-3.09 (m, 1H, CH2N), 2.94-
162.7, 156.8 (d, 1JC-F=236.5), 154.0 (d, 4JC-F=1.8), 131.4, 2.87 (m, 1H, CH2N), 1.78-1.69 (m, 2H, CH2CH3), 1.32
121.4, 116.0 (d, JC-F=8.2), 115.9 (d, JC-F=23.1), 114.3, (s, 9H, CH3), 0.97 (t, 3H, J=7.4, CH3). 13C NMR (100
3
2
3
1761

Synthesis of new (arylcarbonyloxy)aminopropanol derivatives
and the determination of their physico-chemical properties
0+]ꢃꢀ'062ꢆd6ꢂꢃꢀįꢏꢀꢊꢍꢌꢄꢇꢃꢀꢊꢍꢇꢄꢎꢃꢀꢊꢅꢊꢄꢌꢃꢀꢊꢇꢊꢄꢌꢃꢀꢊꢊꢉꢄꢉꢃꢀ Calculator 4.6 (U.S. Environmental protection Agency,
69.3, 66.0, 65.1, 56.3, 44.1, 24.9, 21.9, 10.3. Anal. calc. 86$ꢂꢃꢀ0DUYLQ6NHWFKꢀꢌꢄꢑꢄꢉꢀꢁ&KHP$[RQꢀ.IWꢄꢃꢀ+XQJDU\ꢂꢄ
for C17H28ClNO4 (345.86): 59.04% C, 8.16% H, 4.05%
N; found: 59.12% C, 8.23% H, 4.01% N. HR-MS: for
C17H28ClNO4ꢀ>0±+@- calc. 344.1634 m/z; found 344.1633 3. Results and discussion
m/z.
ꢆ ꢁ W H U W ꢁ E X W \ O D P L Q R ꢁ ꢀ ꢁ K \ G U R [ \ S U R S \ Oꢅ
ꢄꢁEXWR[\EHQ]RDWHꢅ K\GURFKORULGH (10d). Yield 57%.
RF: 0.50 (methanol). RF(rev): 0.14 (Acetone/0.1 M HCl
ꢇꢏꢅꢂꢄꢀ0ꢄSꢄꢀꢊꢉꢅꢆꢊꢉꢌƒ&ꢀꢁSURSDQꢆꢇꢆROꢂꢄꢀ89ꢀꢁQPꢂꢃꢀȜPD[: 260.
IR (Zn/Se ATR, cm-1ꢂꢏꢀꢅꢇꢅꢑꢀꢁȣꢀ2ꢆ+ꢂꢃꢀꢇꢑꢍꢌꢀꢁȣꢀ&+ꢂꢃꢀꢇꢎꢑꢌꢀ
ꢁȣꢀ 1ꢆ+ꢂꢃꢀ ꢊꢎꢊꢊꢀ ꢁȣꢀ & 2ꢂꢃꢀ ꢊꢍꢋꢇꢀ ꢁȣring CAr=CArꢂꢃꢀ ꢊꢇꢉꢎꢀ ꢁȣas
&ꢆ2ꢆ&ꢂꢃꢀꢊꢊꢊꢋꢀꢁȣs C-O-C). 1+ꢀ105ꢀꢁꢉꢋꢋꢀ0+]ꢃꢀ'062ꢆd6),
įꢏꢀꢑꢄꢅꢊꢀꢁEVꢃꢀꢊ+ꢃꢀ1H), 8.65 (bs, 1H, NH), 7.96 (d, 2H,
3J=8.7, ArCOO), 7.04 (d, 2H, 3J=8.7, ArO), 5.96 (d, 1H,
3J=3.3, OH), 4.28-4.19 (m, 3H, CH2CH, CHOH), 4.04 (t,
3.1. Chemical synthesis
7KHꢀ¿QDOꢀFRPSRXQGVꢀ8a-d, 9a-d, 10a-dwerepreparedby
multistep synthesis according to Scheme 1. Fluorinated
amines 5, 6 were prepared by Gabriel synthesis [19].
$SSURSULDWHꢀSKHQR[\HWK\OꢀEURPLGHVꢀ1, 2 were obtained
E\ꢀ :LOOLDPVRQꢀ HWKHUL¿FDWLRQꢀ IURPꢀ ꢊꢃꢇꢆGLEURPRHWKDQHꢀ
and ortho- or paraꢆÀXRURSKHQROVꢃꢀ UHVSHFWLYHO\ꢃꢀ DVꢀ
described by Augstein et al. [20@ꢀ,QꢀWKHꢀQH[WꢀVWHSꢀRIꢀWKHꢀ
amines’ synthesis, the bromine atom of compounds 1, 2
was substituted with the potassium salt of phthalimide
to obtain the intermediates 3, 4, performed according
WRꢀ PHWKRGꢀ E\ꢀ 5H]QLNꢀ et al. [21]. Primary amines 5, 6
SUHSDUHGꢀ E\ꢀ K\GUD]LQRO\VLVꢀ RIꢀ 3, 4, were transformed
WRꢀ K\GURFKORULGHꢀ VDOWVꢃꢀ UHFU\VWDOOL]HGꢀ IURPꢀ HWKDQROꢀ DQGꢀ
transferred back to bases by 3% ammonia solution. The
yield of all three steps was 46%, or 51%, respectively.
%HQ]RDWHVꢀ 7a-d were prepared according to
Dꢀ PRGL¿HGꢀ PHWKRGꢀ SXEOLVKHGꢀ E\ꢀ 0RNU\ꢀ et al. [22]
$SSURSULDWHꢀ ꢉꢆDONR[\EHQ]RLFꢀ DFLGꢀ ZDVꢀ FRQYHUWHGꢀ LQWRꢀ
the acyl chloride. Phosphorus pentachloride was used
instead of thionyl chloride in this step. These reactive
3
2H, J=6.4, OCH2CH2), 3.14-3.09 (m, 1H, CH2N), 2.92-
2.89 (m, 1H, CH2N), 1.74-1.67 (m, 2H, OCH2CH2), 1.47-
1.38 (m, 2H, CH2CH3), 1.32 (s, 9H, CH3), 0.92 (t, 3H,
3J=7.4, CH3). 13&ꢀ105ꢀꢁꢊꢋꢋꢀ0+]ꢃꢀ'062ꢆd6), įꢏꢀꢊꢍꢌꢄꢇꢃꢀ
162.7, 131.5, 121.5, 114.4, 67.6, 66.0, 65.1, 56.3,
44.1, 30.6, 24.9, 18.7, 137. Anal. calc. for C18H30ClNO4
(359.89): 60.07% C, 8.40% H, 3.89% N; found 60.12%
C, 8.47% H, 3.82% N. HR-MS: for C18H30ClNO4ꢀ>0±+@-
calc. 358.1791 m/z; found 358.1790 m/z.
2.3. pKa determination
ꢊꢋꢀPJꢀIURPꢀDOOꢀWKHꢀVDPSOHVꢀZHUHꢀGLVVROYHGꢀLQꢀDꢀPL[WXUHꢀ intermediates were directly used in reaction with
of solvents (CD3OD:D2O, v/v) with sodium 2,2-dimethyl- ꢇꢃꢅꢆHSR[\SURSDQꢆꢇꢆROꢀWRꢀJLYHꢀUHTXLUHGꢀEHQ]RDWHV 7a-d.
2-silapentane-5-sulfonate (DSS) as the water soluble According to Stamatov et al. [18], dichloromethane was
internal standard (0 ppm). A CF3COOH titration solution used as a solvent.
was used at a concentration of c = 0.7 mL mL-1 from
WKHꢀ VROYHQWVꢀ PL[WXUHꢀ DQGꢀ 1D2+ꢀ DWꢀ Dꢀ FRQFHQWUDWLRQꢀ RIꢀ
c = 5 mg mL-1ꢀIURPꢀWKHꢀVROYHQWVꢀPL[WXUHꢄꢀ6ROYHQWꢀPL[WXUHꢀ
composition differed according to the method used.
NMR spectra for pKa determination were recorded by a
Gemini-2000 NMR spectrometer (Varian, USA) with an
RSHUDWLQJꢀIUHTXHQF\ꢀRIꢀꢇꢋꢋꢀ0+]ꢀꢁ1H) at a temperature of
21.5°C. The following parameters were used: 90° pulse,
UHOD[DWLRQꢀWLPHꢀꢊꢀVꢃꢀDFTXLVLWLRQꢀWLPHꢀꢊꢄꢑꢑꢑꢐꢀVꢃꢀZLWKꢀWKHꢀ
Addition of amines 5, 6ꢀ WRꢀ WKHꢀ R[LUDQHꢀ ULQJꢀ RIꢀ
DSSURSULDWHꢀEHQ]RDWHVꢀ7a-dꢀJDYHꢀEDVHVꢀRIꢀ¿QDOꢀSURGXFWVꢀ
8a-d and 9a-d. In the case of products 10a-d, prepared
amines were replaced by tert-butylamine. The obtained
bases were transformed to its hydrochloride salts with
increased water solubility.
3.2. Determination of pKa and prediction of
physico-chemical parameters
number of scans from 16 to 128. The pH was measured For determination of pKa values, a method of measuring
1
using an electrode IS-FET Microelectrode PH46-SS the H nuclei chemical shift depending on a variable
(3.8 mm diameter), calibrated by three-point calibration pH has been chosen. During these changes, electron
using WTW Trace buffers with pH values of 4.01, 6.87 density in the vicinity of the dissociable group, magnetic
DQGꢀꢑꢄꢊꢐꢃꢀFRQQHFWHGꢀWRꢀDQꢀ,4ꢇꢉꢋꢀS+ꢀPHWHUꢀꢁ,4ꢀ6FLHQWL¿Fꢀ shielding and the consequent changes in the chemical
,QVWUXPHQWVꢃꢀ86$ꢂꢄꢀ&KDQJHVꢀ RIꢀ SSPꢀLQꢀ S+ꢀUDQJHꢀ ꢇꢀ±ꢀ shift of the observed protons are affected [23-25]. The
13 were recorded. MestReNova 7.1.2. (Mestrelab resulting pKaꢀ YDOXHꢀ OLHVꢀ LQꢀ WKHꢀ LQÀHFWLRQꢀ SRLQWꢀ RIꢀ WKHꢀ
Research, Spain) software was used for interpreting arising sigmoid curve. In general, the need to use binary
the obtained NMR spectras. Ppm and pH values were DQGꢀWHUQDU\ꢀPL[WXUHVꢀRIꢀVROYHQWVꢀGXHꢀWRꢀWKHꢀORZꢀZDWHUꢀ
evaluated by SigmaPlot 11.0. (San Rafael, USA). solubility of the measured samples (or conjugate bases)
Predicted pKa values were calculated by ACD/Percepta is one of disadvantages of this method, as well as a
need to use these samples in concentrated form due to
the relatively lower sensitivity of NMR spectroscopy. It
VRIWZDUHꢀ ±ꢀ SKa Classic values, ver. 2012 (Advanced
Chemistry Developement Inc., Canada), SPARC On-line
1762

J. Tengler et al.
Synthesis of the studied compounds. Reagents and conditions: a) 1,2-dibromoethane, NaOH; b) potassium phthalimide, DMF;
c) NH2NH2.H2O, ethanol; d) toluene, PCl5; e) CH2Cl2ꢀꢁꢂꢀꢃꢄHSR[\SURSDQꢄꢅꢄROꢀꢁ7($ꢆꢁIꢇꢁꢂꢄꢈꢂꢄꢉꢊꢄĠXRURSKHQR[\ꢇHWK\ODPLQHꢁ5 resp. 6,
propan-2-ol; g) HCl, Et2O; h) tert-butylamine, propan-2-ol; i) HCl, Et2O.
Scheme 1.
is then necessary to correlate the results to an aqueous
The dependence curve of the chemical shift of
HQYLURQPHQWꢄꢀ,QꢀSUHYLRXVꢀVWXGLHVꢃꢀWHUQDU\ꢀPL[WXUHVꢀZLWKꢀ hydrogens H1, 2 and H3, 4 on the pH of compound 8a is
methanol and DMSO were used and the possibilities of shown in Fig. 1. Both curves gave very similar results,
their recalculations were given [24,26-29]. The use of so only H3, 4 values are used in all of the tables. In
deuterated solvents also should be taken into account the case of compounds 8a-d and 9a-d, the observed
[30]ꢄꢀ $OWKRXJKꢀ WKLVꢀ PHWKRGꢀ ꢁRUꢀ LWVꢀ PRGL¿FDWLRQVꢂꢀ ZDVꢀ signals were evaluated as triplets, although it should
used to determine the pKa of some alkaloids, amino be theoretically considered as multiplet. In the case of
sugars, antibiotics, polyprotic bases, proteins or compounds 10a-d, the chemical shift of the tert-butyl
glycolipids, no work describing the pKa determination hydrogens singlet was observed. Values obtained from
s
of small molecules affecting the sympathetic nervous WKHꢀLQÀHFWLRQꢀSRLQWꢀꢁ pK *) have been recalculated to a
system has been published so far [24,31-34].
w
a
water environment by two possible methods.
$OOꢀWKHꢀDERYHꢀGHVFULEHGꢀ¿QDOꢀFRPSRXQGVꢀZHUHꢀXVHGꢀ
7KHꢀ ¿UVWꢀ SURFHGXUHꢀ ꢁPHWKRGꢀ $ꢂꢀ ZDVꢀ EDVHGꢀ RQꢀ
as hydrochlorides and in the form of the racemate. Due to UHODWLRQVKLSVꢀ IRUꢀ WKHꢀ ZDWHUꢀ ±ꢀ PHWKDQROꢀ UHFDOFXODWLRQꢃꢀ
WKHꢀSRRUꢀZDWHUꢀVROXELOLW\ꢀRIꢀFRQMXJDWHGꢀEDVHVꢃꢀDꢀPL[WXUHꢀ SUHYLRXVO\ꢀ GH¿QHGꢀ LQꢀ OLWHUDWXUHꢄꢀ )LUVWO\ꢃꢀ SKa values
s
pK *) were transferred by equation Eq. 1 to a pK
w a
a
RIꢀVROYHQWVꢀKDGꢀWRꢀEHꢀXVHGꢄꢀ,QꢀRXUꢀFDVHꢃꢀLWꢀZDVꢀDꢀPL[WXUHꢀ
(
of CD3OD and D2O in a ratio of 10:3. Consequently, the YDOXHꢀUHÀHFWLQJꢀWKHꢀDFWLYLW\ꢀRIꢀPHWKDQROꢀFRQWDLQHGꢀLQꢀWKHꢀ
obtained values had to be converted into an aqueous PL[WXUHꢀRIꢀVROYHQWVꢄ
environment. Two possible recalculation approaches
s
s
were used and their results were compared.
pK * = pK ꢓꢀ±ꢀį
(1)
s
a
w
a
First, the sample solution was titrated by
a
CF3COOH solution to acidic pH. In each subsequent
3DUDPHWHUꢀ įꢀ LVꢀ GHSHQGHQWꢀ RQꢀ WKHꢀ FRQWHQWꢀ RIꢀ
VWHSꢃꢀꢊꢋꢀ±ꢀꢌꢋꢀȝ/ꢀRIꢀ1D2+ꢀVROXWLRQꢀZDVꢀDGGHGꢀGLUHFWO\ꢀ PHWKDQROꢀLQꢀWKHꢀPL[WXUHꢃꢀDQGꢀZDVꢀFDOFXODWHGꢀDFFRUGLQJꢀ
to the standard NMR tube (5 mm diameter), and pH to an empirical relationship Eq. 2ꢃꢀZKHUHꢀijꢀLVꢀWKHꢀYROXPHꢀ
was measured by an electrode in the tube. Thereafter, IUDFWLRQꢀRIꢀPHWKDQROꢀLQꢀWKHꢀPL[WXUHꢀ[35].
1
the H NMR spectrum was obtained. Deprotonation of
the secondary amine occurred with an increasing pH, įꢀ ꢀꢁꢋꢃꢋꢑijꢀ±ꢀꢋꢃꢊꢊij2ꢂꢀꢈꢀꢁꢊꢀ±ꢀꢅꢃꢊꢌij + 3,51ij2ꢀ±ꢀꢊꢃꢅꢌij3) (2)
magnetic shielding grew and chemical shift of protons
of vicinal groups moved into lower values. At the end
Then, pKa values corresponding to the aqueous
RIꢀWKHꢀH[SHULPHQWꢃꢀWKHꢀFRPSRXQGVꢀH[LVWHGꢀLQꢀWKHꢀIRUPꢀ HQYLURQPHQWꢀRIꢀWKHꢀVROYHQWꢀPL[WXUHVꢀZHUHꢀFDOFXODWHGꢀE\ꢀ
of the base only. Fifteen repetitions of this step were linear relationship Eq. 3 [36,27].
XVXDOO\ꢀVXI¿FLHQWꢀWRꢀREWDLQꢀDꢀFXUYHꢀRIꢀFKHPLFDOꢀVKLIWꢀ±ꢀS+ꢀ
s
w
pK * + b
dependence. In the case of compounds 8a-d and 9a-d,
the chemical shift of protons of methylene groups of the
SKHQR[\HWK\ODPLQHꢀPRLHW\ꢀZDVꢀREVHUYHGꢀꢁ+1, 2 and H3, 4),
and both groups provided comparable pKa values.
pK * = a
s
a
s w
a
s
(3)
Directive as = 0.96436, and the regression constant
bs = -0.57692 are dependent on the composition of a
1763

Synthesis of new (arylcarbonyloxy)aminopropanol derivatives
and the determination of their physico-chemical properties
Figure 1. pH dependence of 1H NMR shifts for compound 8a.
PL[WXUHꢀ DQGꢀ WKHꢀ IDFWRUVꢀ RIꢀ SUHIHUHQWLDOꢀ VROYDWLRQꢀ RIꢀ 0DUYLQ6NHWFKꢂꢀRIꢀWKHꢀQHZO\ꢀV\QWKHVL]HGꢀFRPSRXQGVꢀDUHꢀ
functional groups in the studied molecule. They were shown in Table 1.
calculated according to the relations Eqs. 4 and 5
The measured pKa values are slightly higher than
derived for protonated amines, where w is the content of the calculated values. Changes in the chemical shift
PHWKDQROꢀLQꢀWKHꢀPL[WXUHꢃꢀDQGꢀLVꢀH[SUHVVHGꢀDVꢀDꢀZHLJKWꢀ of protons H1,2 directly adjacent to the amino group,
percentage [28].
ZKRVHꢀ LRQL]DELOLW\ꢀ ZDVꢀ VWXGLHGꢃꢀ KDGꢀ ZLGHUꢀ UDQJHVꢀ
than changes in the further H3,4 protons, but they
as = (1 -0,077w + 0,245w2) / (1 + 0,019w + 0,188w2) (4) gave comparable results. Compared to the aliphatic
substitution of tertꢆEXW\Oꢃꢀ WKHꢀ SKHQ\OR[\HWK\ODPLQHꢀ
bs = (-0,577w + 0,608w2ꢂꢈꢁꢊꢀ±ꢀꢊꢃꢌꢐꢐw + 0,615w2)
(5) fragment causes a decrease of electronic density and
consequently of pKa by its electron-withdrawing I and
The conversion for the real environment from M effect. Basicity descends in order 10a-d > 9a-d >
deuterated solvents was performed using Eq.
relationship [30].
6
8a-d. ACD/Percepta calculated values of electronic
VXEVWLWXHQWꢀ FRQVWDQWVꢀ IRUꢀ ꢇꢆ)ꢆSKHQ\OR[\HWK\ODPLQHꢀ
fragment (compounds 8a-d, pKaꢀ§ꢀꢎꢄꢎꢂꢀDVꢀIROORZVꢏꢀıꢁ,ꢂꢀ
w
w
pK * + 0,41
pK
= 0,929
(6) ꢀ ꢋꢄꢋꢍꢃꢀ ıꢁ0ꢂꢀ ꢀ ꢆꢋꢄꢊꢉꢃꢀ IRUꢀ ꢉꢆ)ꢆSKHQ\OR[\HWK\ODPLQHꢀ
fragment (compounds 9a-d, pKaꢀ §ꢀ ꢐꢄꢎꢂꢀ DVꢀ IROORZVꢀ
a(A)
w
a
W
The second recalculation procedure (method B) ıꢁ,ꢂ ꢀꢆꢋꢄꢋꢊꢃꢀıꢁ0ꢂ ꢀꢆꢋꢄꢊꢍꢀDQGꢀIRUꢀtert-butyl (compounds
came from constructing a calibration curve given by 10a-d, pKaꢀ§ꢀꢑꢄꢉꢂꢀDVꢀIROORZVꢀıꢁ,ꢂ ꢀꢆꢋꢄꢋꢊꢃꢀıꢁ0ꢂ ꢀꢆꢋꢄꢊꢐꢄꢀ
the decreasing portion of methanol-d4 in a solvent 7KHVHꢀFRPSXWHGꢀUHVXOWVꢀPHWꢀWKHꢀH[SHULPHQW¶VꢀUHVXOWVꢃꢀ
PL[WXUHꢄꢀ7KHꢀSKa of compound 10aꢀZDVꢀ¿UVWꢀPHDVXUHGꢀ ZKLFKꢀ FRQ¿UPHGꢀ WKDWꢀ ÀXRULQHꢀ VXEVWLWXWLRQꢀ LQꢀ WKHꢀ para-
LQꢀDꢀPL[WXUHꢀRIꢀFRPSRVLWLRQꢀPHWKDQROꢆd4:D2O in a 12:1 position increased basicity only moderately (average
proportion, and subsequently 11:2, 10:3, 9:4, 8:5, 7:6, 0.34 pH degrees) compared with the ortho-position of
1:1 and 6:7. The resulting linear dependence led to ÀXRULQHꢀVXEVWLWXWLRQꢄꢀ$OOꢀWKHꢀSURJUDPPHVꢀXVHGꢀQHJOHFWHGꢀ
equation Eq. 7 where direction aw is -1.373 and the pKa DQ\ꢀ LQÀXHQFHꢀ RIꢀ WKHꢀ HORQJDWLQJꢀ DONR[\ꢀ FKDLQꢃꢀ EXWꢀ
w
(
pK
of the tested compound corresponding to H[SHULPHQWDOO\ꢀREWDLQHGꢀGDWDꢀGLIIHUꢀIURPꢀHYHU\ꢀLQGLYLGXDOꢀ
a(B))
W
the environment theoretically having no methanol-d4 compound from the homology series. Therefore, it can
was calculated. This relationship was used for pKa EHꢀVWDWHGꢀWKDWꢀH[SHULPHQWDOO\ꢀGHWHUPLQHGꢀSKa data can
recalculations of other samples with an aliphatic base VSHFLI\ꢀLRQL]DELOLW\ꢀZLWKLQꢀDOOꢀWKHꢀVHULHVꢀRIꢀWKHꢀGLVFXVVHGꢀ
part of the molecule (10a-d). For compounds 8a-d and compounds. The results calculated by method A
9a-dꢀZLWKꢀSKHQ\OR[\HWK\ODPLQHꢀPRLHW\ꢀLQꢀWKHꢀEDVHꢀSDUWꢀ correlates more closely with predicted values. It could
of the molecule, a direction aw -1.509 was used.
EHꢀH[SHFWHGꢃꢀWKDWꢀDOOꢀWKHꢀQHZꢀVXEVWDQFHVꢀZLOOꢀH[LVWꢀDVꢀ
cations at physiological pH. Titration was not performed
(7) under argon or nitrogen, so the results could be affected
by CO2 absorption.
w
pK
= a . + bw
w X(%MeOH)
a(B)
W
The measured, recalculated and predicted values
$GGLWLRQDOO\ꢃꢀEDVHGꢀRQꢀWKHꢀH[SHULPHQWDOO\ꢀGHWHUPLQHGꢀ
(by chemical programmes ACD/Percepta, SPARC and pKa values (Table 1) and selected calculated physico-
1764

J. Tengler et al.
s
w
Table 1. The pK ꢁYDOXHVꢁDWꢁWKHꢁLQĠHFWLRQꢁSRLQWꢁꢈ pK ꢋꢇꢀꢁğQDOꢁFRUUHFWHGꢁYDOXHVꢁRIꢁSK ( pK ) and calculated values of original compounds.
a(A/B)
w
a
w
a
a
H1
O
H3
H4
O
N
H
O
R2
H2
. HCl
R1
OH
O
pK
s
w
w
w
w
w
pK
W
R1
R2
w
a
)
a(A)
a(B)
a
a
a
Comp.
*
pK
pK
pK
pK
W
W
W
W
(H3,4
(H3,4
)
(H3,4
)
(ACD Percepta)
(SPARC)
(Marvin)
8a
8b
8c
8d
9a
9b
9c
9d
CH3
C2H5
C3H7
C4H9
CH3
2-F
2-F
2-F
2-F
4-F
4-F
4-F
4-F
7.96
7.75
7.59
7.91
8.12
8.13
8.15
8.22
8.53
8.33
8.18
8.49
8.69
8.70
8.72
8.78
8.88
8.68
8.54
8.84
9.03
9.04
9.06
9.12
7.69
7.68
7.68
7.69
8.65
8.65
8.65
8.65
7.54
7.54
7.54
7.54
7.65
7.65
7.65
7.65
8.91
8.91
8.91
8.91
8.98
8.98
8.98
8.98
C2H5
C3H7
C4H9
O
N
O
. HCl
H
R1
OH
9.86
O
10a
10b
10c
10d
CH3
C2H5
C3H7
C4H9
-
-
-
-
9.12
9.08
9.10
9.11
9.65
9.61
9.63
9.64
9.40
9.40
9.40
9.40
9.08
9.08
9.08
9.08
9.96
9.96
9.96
9.96
9.83
9.85
9.86
chemical parameters (see Table 2), it is possible to Table 2.
compare the passive permeation through membranes
in the body of the discussed compounds with the
permeation of the model drugs esmolol [7@ꢀDQGꢀÀHVWROROꢀ
[8] (see Fig. 2). Based on the data listed in Table 2, it can
be stated that lipophilicity of the prepared compounds,
Selected
predicted
physico-chemical
parameters
LQĠXHQFLQJꢁ SDVVLYHꢁ SHUPHDWLRQꢁ WKURXJKꢁ PHPEUDQHVꢁ DWꢁ
the physiological pH 7.4 of the discussed compounds
8-10ꢁLQꢁFRPSDULVRQꢁZLWKꢁHVPROROꢁDQGꢁĠHVWROROꢌꢁGLVWULEXWLRQꢁ
FRHIğFLHQWꢁꢈORJꢁD7.4), solubility (log S), ionizability (pKa) and
permeability (Pe [cm/s]). Calculated by ACD/Percepta ver.
2012.
H[SUHVVHGꢀDVꢀGLVWULEXWLRQꢀFRHI¿FLHQWꢀꢁORJꢀD7.4), is higher
forderivatives8a-9d, 10cand10dthanlogD7.4 ofesmolol
DQGꢀÀHVWROROꢃꢀZKLOHꢀHVWHUVꢀ10a and 10b have similar log
D7.4 as both drugs. This fact is in accordance with the
VROXELOLW\ꢀ GDWDꢀ H[SUHVVHGꢀ DVꢀ ORJꢀ S, and compounds
10a-d showed similarity with the models. Compounds
9a-d and 10a-dꢀH[SUHVVHGꢀKLJKHUꢀLRQL]DELOLW\ꢀꢁSKa) than
ÀHVWROROꢀRUꢀHVPROROꢄꢀ7KHꢀLQÀXHQFHꢀRIꢀDꢀVLGHꢀFKDLQꢀꢁ51
VXEVWLWXWLRQꢂꢀRQꢀSHUPHDELOLW\ꢀLVꢀXQH[SHFWHGꢔꢀSHUPHDELOLW\ꢀ
increases from methyl to propyl chain within individual
series, while the permeation of butyl derivatives is
VLJQL¿FDQWO\ꢀ ORZHUꢄꢀ %DVHGꢀ RQꢀ WKHVHꢀ REVHUYDWLRQVꢀ
from in silico primary screening, it can be concluded
that the discussed compounds 10a and 10b can be
considered as promising agents for subsequent design
and development of novel potential beta blockers with
supposed ultrashort effect.
Comp.
log D7.4
log S
pKa
Pe [cm s-1
]
esmolol
ĠHVWRORO
8a
0.3
0.2
2.8
3.1
3.5
4.4
1.7
2.1
2.4
3.6
0.3
0.5
0.9
2.8
0.2
-1.9
-2.8
-3.2
-3.5
-4.1
-1.9
-2.3
-2.6
-3.2
0.0
9.10
8.40
7.69
7.68
7.68
7.69
8.65
8.65
8.65
8.65
9.40
9.40
9.40
9.40
29×10-6
0.7×10-6
167×10-6
175×10-6
176×10-6
106×10-6
92×10-6
106×10-6
110×10-6
41×10-6
34×10-6
41×10-6
56×10-6
44×10-6
8b
8c
8d
9a
9b
9c
9d
10a
10b
10c
10d
-0.3
-0.7
-1.3
1765

Synthesis of new (arylcarbonyloxy)aminopropanol derivatives
and the determination of their physico-chemical properties
NMR spectroscopy was used to determine their acid-
EDVHꢀ SURSHUWLHVꢄꢀ ([SHULPHQWꢆGHWHUPLQHGꢀ SKa values
were compared with various software-calculated data.
%DVHGꢀ RQꢀ WKHVHꢀ H[SHULPHQWDOꢀ GDWDꢀ DQGꢀ WKHꢀ SUHGLFWLRQꢀ
of other fundamental physico-chemical properties,
it can be concluded that the prepared compounds
10a and 10b can be considered as promising agents
for subsequent design and development of novel
potential beta-blockers with supposed ultrashort
effect.
Figure 2. 6WUXFWXUHVꢁRIꢁHVPROROꢁDQGꢁĠHVWROROꢍ
Acknowledgements
4. Conclusions
ThisworkwassupportedbygrantsfromtheInternalGrant
Agency of University of Veterinary and Pharmaceutical
In conclusion, twelve compounds have been prepared Sciences Brno No. IGA VFU 224/2009/FaF, IGA VFU
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