Хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених β-метилфенілетиламінів
A synthetic approach has been developed leading to the synthesis of new building blocks – enantiomerically pure fluorine-substituted β-methylphenylethylamines. A methodology of kinetic dynamic enzymatic resolution was employed at key stages. A dual enzymatic purification method was applied to achiev...
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| Дата: | 2024 |
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V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine
2024
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Ukrainica Bioorganica Acta| _version_ | 1871193612044206080 |
|---|---|
| author | Kolodiazhna, Anastasiia O. Faiziiev, Oleh O. Kolodiazhna, Olga O. |
| author_facet | Kolodiazhna, Anastasiia O. Faiziiev, Oleh O. Kolodiazhna, Olga O. |
| author_institution_txt_mv | [
{
"author": "Anastasiia O. Kolodiazhna",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Oleh O. Faiziiev",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
},
{
"author": "Olga O. Kolodiazhna",
"institution": "V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine"
}
] |
| author_sort | Kolodiazhna, Anastasiia O. |
| baseUrl_str | https://bioorganica.com.ua/index.php/journal/oai |
| collection | OJS |
| datestamp_date | 2026-07-19T14:56:55Z |
| description | A synthetic approach has been developed leading to the synthesis of new building blocks – enantiomerically pure fluorine-substituted β-methylphenylethylamines. A methodology of kinetic dynamic enzymatic resolution was employed at key stages. A dual enzymatic purification method was applied to achieve a high degree of optical purity of the obtained products. The resulting amines are promising building blocks for developing new pharmaceuticals and physiologically active compounds |
| doi_str_mv | 10.15407/bioorganica2024.02.003 |
| first_indexed | 2025-07-17T12:20:02Z |
| format | Article |
| fulltext |
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
UDC 547.554
DOI: https://doi.org/10.15407/bioorganica2024.02.003
3
RESEARCH ARTICLE
Chemoenzymatic method for the synthesis of enantiomerically pure
fluorine-substituted β-methylphenylethylamines
Anastasiia O. Kolodiazhna*, Oleh O. Faiziiev, Olga O. Kolodiazhna
V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, Kyiv, Ukraine
Abstract: A synthetic approach has been developed leading to the synthesis of new building blocks – enantiomerically pure fluorine-
substituted β-methylphenylethylamines. A methodology of kinetic dynamic enzymatic resolution was employed at key stages. A dual
enzymatic purification method was applied to achieve a high degree of optical purity of the obtained products. The resulting amines are
promising building blocks for developing new pharmaceuticals and physiologically active compounds.
Keywords: biocatalysis; chiral fluorinated methyl phenylamines; lipase; enzymatic resolution; optical activity.
Introduction
Chiral amines play a crucial role as structural elements in
both natural biologically active compounds and various
pharmaceuticals [1-3]. Among them, amines with a
β-methyl stereogenic center are found in many bioactive
substances and drugs [4-6]. Some examples of such
pharmaceuticals are shown in Figure 1.
Lorcaserin is a commercially available drug for the
treatment of obesity [4]. Biarylpropylsulfonamides, such as
LY-404187, are potent positive allosteric modulators of
AMPA (2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)-pro-
panoic acid) receptors-ionotropic receptors of the CNS
involved in the development of diseases such as
Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis
[5]. NPS-1392 is a potent stereoselective antagonist of
NMDA receptors, which are crucial for signal transmission
in the central nervous system and are implicated in CNS
diseases such as schizophrenia, autism, epilepsy, and stroke
[6].
Received:
Revised:
Accepted:
Published online:
08.08.2024
24.09.2024
30.10.2024
30.12.2024
Corresponding author. Tel.: +380-50-870-4187;
e-mail: nastya_k11@ukr.net (A.O. Kolodiazhna)
ORCID: 0000-0002-7990-7830
Traditional methods for synthesizing β-methyl-
phenylethylamines often involve asymmetric hydrogenation
using Ru- and Rh-based catalysts [7, 8]. However, this
method often has limitations, such as high costs, limited
scalability, and restricted access to both enantiomers.
Alternative approaches, including chiral column resolution,
fractional crystallization, and biocatalysis, have been
explored, yet they frequently result in moderate enantio-
selectivity and chemical yields [9-12].
In the last few decades, the trend towards the use of
chiral pharmaceuticals has significantly increased.
Requirements regarding this matter were published by the
U.S. Food and Drug Administration (FDA) back in 1992 in
a document titled "Development of New Stereoisomeric
Drugs" [13, 14]. Following these requirements, there has
been a significant shift toward the development of
enantiomerically pure pharmaceuticals. As a result, the
demand for enantiomerically pure drugs is increasing
annually by 13-15% [15, 16]. Given the increasing demand
for enantiomerically pure drugs, our research aims to
develop efficient methods for producing optically pure
β-methylphenylethylamines. Using enzymatic kinetic
resolution and innovative synthetic routes, we aim to
achieve high enantioselectivity and yield, meeting modern
requirements for pharmaceutical intermediates.
Results and Discussion
Biocatalytic synthesis reactions are among the most
economically advantageous transformations in synthetic
© Kolodiazhna A.O. et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Ukrainica Bioorganica Acta
www.bi oorgan ica .org .ua
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
4
Figure 1. Examples of pharmaceuticals and physiologically active compounds containing a β-methylethylamine fragment.
Figure 2. Retrosynthesis of β-methylphenylethylamines.
№ Compound R
1 2a 2-F
2 2b 4-F
3 2c 3-CF3
Figure 3. Synthesis of racemic esters of 3-arylbutanoic acids.
organic chemistry, offering benefits for the total synthesis
of complex natural products or pharmaceuticals. This is
because starting materials are typically produced on a large
scale from inexpensive sources or are commercially
available at low cost. Another advantage of this method for
obtaining enantiomerically pure compounds is the use of
water as a solvent for these reactions. Water is one of the
most environmentally friendly, inexpensive, and readily
available solvents. Additionally, biocatalysts themselves,
particularly enzymes, are of biological origin, with sources
including bacteria, fungi, and living cells. Thus, combining
these concepts provides significant synthetic advantages.
The conditions for enzymatic reactions are typically mild
and environmentally friendly, which is why such
approaches are considered "green chemistry" [17].
Thus, in our work, we employed this approach to obtain
enantiomerically pure fluorine-containing β-methyl-
phenylethylamines. To achieve this goal, a multistep
synthetic scheme was developed, incorporating enzymatic
hydrolysis of racemic 3-arylbutanoic acids at the key stage.
The retrosynthetic scheme is shown in Figure 2.
Racemic esters of 3-arylbutanoic acids 2a-c were
synthesized using the method described by us earlier [18],
according to the two-step procedure outlined in Figure 3
below.
In the first stage of the synthesis, esters of unsaturated
arylcarboxylic acids were obtained using the Horner-Wittig
reaction. Ethyl-2-(diethoxyphosphoryl)acetate was added
dropwise to a suspension of sodium hydride in absolute
tetrahydrofuran (THF) while cooling to 0 °C. The mixture
was stirred for 30 minutes at the same temperature, after
which fluorine-containing acetophenone was added. The
reaction mixture was stirred for 16 hours at 60 °C and then
neutralized with a saturated ammonium chloride solution.
After the usual work-up of the reaction mixture, ethyl (E)-3-
arylbut-2-enoate obtained in 88-90% yield, which was used
in the next stage. To the obtained solution of ethyl (E)-3-
phenylbut-2-enoate in methanol, palladium hydroxide was
A.O. Kolodiazhna et al.
5
added. The mixture was vacuumed and connected to a
hydrogen source at 1 atm. As a result, ethyl-3-
arylbutanoates 2a-c were obtained with a yield of 90%,
which were used in further transformations without
additional purification.
Enzymes are biological catalysts that operate in aqueous
solution, typically at room temperature, and neutral pH
(approximately pH 7). Enzymes demonstrate high chemo-,
regio-, enantio-, and stereoselectivity in reactions.
Hydrolases are enzymes that catalyze hydrolysis reactions
directly in water, aqueous buffers, or even in biphasic
systems of organic solvent/water. Hydrolysis is most
commonly facilitated by esterases, proteases, and certain
lipases.
Lipases have an active site consisting of a triad of amino
acids: serine (Ser), histidine (His), and aspartic acid (Asp).
It is at this site that catalysis occurs. The arylcarboxylic acid
or its ester binds to the enzyme's active site through
hydrophobic interactions (due to the aromatic ring) and
hydrogen bonds. The lipase recognizes one of the
enantiomers thanks to specific pockets in its active site,
which depend on the spatial geometry of the substrate. The
serine residue in the lipase active site acts as a nucleophile
and attacks the carbonyl carbon of the arylcarboxylic acid
ester, forming a tetrahedral transition state, after which
hydrolysis occurs. Histidine in the active site acts as a base,
abstracting a proton from water, polarizing its molecule,
and facilitating the formation of a nucleophilic hydroxide
ion. This ion then attacks the carbonyl carbon in the ester,
creating a new tetrahedral transition state. After this state
breaks down, arylcarboxylic acid (the hydrolysis product)
and the corresponding alcohol are formed.
The substrates presented in this article are racemic esters.
The resolution of racemic esters through enantioselective
hydrolysis, catalyzed by hydrolases, is an effective and
practical method for obtaining pharmaceutical intermediates
(Figure 4). Among the biocatalysts, some of the most
effective esterases and hydrolases (lipases from
Burkholderia cepacia, Pseudomonas cepacia, and Candida
antarctica B) were selected, as they combine broad
substrate specificity with high regio- and enantioselectivity.
After a series of experiments conducted by us, the best
biocatalyst for the enzymatic hydrolysis of fluorine-
containing β-methylphenylpropanoic acids was found to be
Amano PS (lipase from Burkholderia cepacia).
Enzymatic hydrolysis of the racemic ester of
arylcarboxylic acid was carried out in a phosphate buffer at
pH 7.0 with Amano PS lipase [18-20]. The mixture was
stirred for 16 hours at room temperature, and then filtered;
the filtrate was acidified with 2 M HCl to pH 2 and
extracted with methyl tert-butyl ether (MTBE). Carbonic
acid esters 5a-e were obtained with 50-80% yields and
enantioselectivity of 93-100% ee. The aqueous solution
after extraction with the organic solvent was acidified with
2 M HCl to pH 2 and washed with MTBE. The obtained
extract was washed with a sodium chloride solution, dried
over sodium sulfate, and the solvent was removed under
vacuum. As a result, arylcarboxylic acids 3a-c were
obtained with yields of 52-60% and enantiomeric purity of
77-99% (Figure 4).
In the case of moderate optical purity of the obtained
products, to increase the enantiomeric purity of the
arylcarboxylic acids, an additional (double) enzymatic
deracemization was used (Figure 5) [18].
Thionyl chloride was added to a solution of
enantiomerically enriched arylcarboxylic acids 3a-c in
ethanol at 0 °C. The mixture was stirred for 16 hours at
room temperature and then evaporated in vacuo. The
residue was dissolved in water and neutralized with an
aqueous potassium carbonate to pH > 9. The obtained ester
2a-c was added to a suspension of Amano PS in methyl
tert-butyl ether (MTBE) solution with the addition of
5 equivalents of water. The reaction mixture was stirred for
16 hours at 40 °C. After the work-up procedure described
earlier, the target arylcarboxylic acids (R)- and (S)-3a-c
were obtained with a high level of enantiomeric purity -
>95%.
In the next stage of our work, the obtained
enantiomerically pure arylcarboxylic acids were conver-
ted into chiral, optically pure amines via the Curtius
rearrangement, followed by hydrogenation of the
Compd (R)-Ester (S)-Acid Ea
R Yield,% ee, % Yield,% ee, %
2a 2-F 48 95 27 77 >100
2b 4-F 45 95 47 94 >100
2c 3-CF3 20 92 30 70 >100
Figure 4. Scheme of biocatalytic enantioselective resolution of arylcarboxylic acid esters.
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
6
Figure 5. Scheme of double enzymatic deracemization of arylcarboxylic acids.
Figure 6. Scheme of synthesis of fluorine-substituted β-methylphenylethylamines.
intermediate Cbz-amine. Thus, to acid 3a-c in the toluene
solution, DPPA (Diphenylphosphoryl azide) and
triethylamine were added. The reaction mixture was
allowed to be stirred overnight at room temperature. Next,
benzyl alcohol was added dropwise to the mixture and
heated at 110 °C overnight. Afterward, toluene was
evaporated on a rotary evaporator under vacuum. The
residue was dissolved in ethyl acetate, and the solution was
washed with saturated aqueous potassium carbonate and
sodium chloride solutions. The combined organic extracts
were dried over sodium sulfate, and the solvent was
evaporated. The excess benzyl alcohol was removed by
distillation. All Cbz-amines 4a-c were obtained for the first
time and characterized by 1H NMR spectroscopy. They
were used in further reactions without additional
purification.
In the next stage, Cbz-amine 4a-c was dissolved in
methanol, and Pd/C (5%) was added. The flask, equipped
with a reflux condenser and valve, was vacuumed, and a
hydrogen chamber was connected. The mixture was stirred
overnight at room temperature. Then, the reaction mixture
was filtered through silica gel, which was washed 2-3 times
with methanol. The combined methanol fractions were
evaporated under vacuum. The residue was dissolved in
MTBE, and with stirring, dioxane hydrochloride was added
dropwise until the pH indicator strip indicated an acidic
reaction. The resulting precipitate was filtered and washed
several times with MTBE on the filter. The precipitate was
then dried. As a result, the hydrochlorides of the amines
5a-c were obtained (Figure 6).
The absolute configurations of the obtained products
were determined by comparing the optical rotation values
with data from open sources. It was demonstrated that all
amines were obtained with the retention of the absolute
configuration of the stereogenic center. All optically active
β-methylphenylethylamines were described and published
for the first time, with high chemical yields, optical purity
<95%, and retention of the absolute configuration of the
chiral center. They were described and characterized using
modern physicochemical methods, such as NMR, HPLC,
LC-MS, elemental analysis, and optical rotation
measurements.
Conclusions
In this work, we obtained and described all optical
isomers of fluorine-containing β-methylphenylpropanoic
acids. For this purpose, we applied the methodology of
enzymatic kinetic resolution using various lipases, such as
Burkholderia cepacia lipase, Pseudomonas cepacia lipase,
and Candida antarctica B lipase. The best and most
effective lipase for the enzymatic hydrolysis of fluorine-
containing β-methylphenylpropanoic acids was identified as
Amano PS lipase. To achieve the highest level of
enantiomeric purity, a method of double biocatalytic
deracemization was applied. The obtained β-methyl-
phenylpropanoic acids were then converted into optically
pure fluorine-containing β-methylphenylethylamines using
the Curtius rearrangement as a key step. All optically active
β-methylphenylethylamines were synthesized for the first
A.O. Kolodiazhna et al.
7
time, with high chemical yields, optical purity >95%, and
retention of the absolute configuration of the chiral center.
They were described and characterized using modern
physicochemical methods. Thus, all enantiomers of
fluorine-containing β-methylphenylethylamines were
obtained, which serve as promising building blocks for the
synthesis of potential pharmaceutical compounds and
biologically active substances.
Notes
Acknowledgments and finances. We would like to
thank Enamine Ltd. for the material and technical support
for the synthetic part of this work. The authors thank all the
brave defenders of Ukraine that stood against the russian
full-scale invasion and made this publication possible.
The authors declare no conflict of interest.
Experimental section
All solvents were purified according to standard
procedures. All starting materials were obtained from
Enamine LTD. or other commercial sources. Melting points
were measured using the MPA 100 OptiMelt, an automated
melting point determination system. 1H and 13C NMR
spectra were recorded in CDCl3 on a "Bruker Avance III"
500 MHz spectrometer (Germany) at ambient temperature.
Chemical shifts (δ) are given in parts per million relative to
tetramethylsilane (TMS) as the internal standard. Signal
multiplicity is shown as s (singlet), d (doublet), dd (doublet
of doublets), t (triplet), m (multiplet), br (broad signal), q
(quartet). Spin-spin coupling constants (J) are given in
Hertz. Chiral HPLC analysis was carried out on an "Agilent
1100" chromatographic system equipped with a Chiralpak
OD-3 column or Chiracel analytical columns (“Chiral
Technologies”) with a cellulose-based stationary phase. All
reagents and solvents were used without further
purification. Column chromatography was performed on
silica gel 60 (70-230 mesh). Optical rotation was measured
using a "Perkin-Elmer" polarimeter model 241 (sodium D
line at 20 °C). Melting temperatures were not corrected. All
reactions were carried out in glassware that was dried by
flame or in a drying oven. Burkholderia cepacia lipase
(Amano PS), Pseudomonas cepacia lipase from "Amano
Pharmaceutical" (Japan), and Candida antarctica B lipase
from “Novozymes A/S” (Denmark) were used. The
progress of reactions was monitored by analytical thin-layer
chromatography (TLC) on silica gel 60F254 plates
(“Merck”, Germany), and products were visualized using
anisaldehyde or UV light. The purity of all compounds was
determined using TLC and NMR measurements.
Synthesis
General method for the synthesis of fluorosubstituted
β-methylphenylethylamines (5a-c).
To the acid 3a-c (0.033 mol, 1 eq) in toluene (150 ml),
DPPA (0.0396 mol, 1.2 eq) and triethylamine (0.0396 mol,
1.2 eq) were added. The reaction mixture was stirred
overnight at room temperature. Then, benzyl alcohol (0.164
mol, 5 eq) was added, and the mixture was heated at
110 °C. After that, toluene was evaporated under vacuum
using a rotary evaporator. The residue was dissolved in
ethyl acetate, and this solution was washed with saturated
aqueous potassium carbonate (50 ml) and saturated sodium
chloride solution (50 ml). The combined organic extracts
were dried over sodium sulfate, and the solvent was
evaporated under vacuum. Excess benzyl alcohol was
distilled off. The obtained Cbz-amines 4a-c were used in
further reactions without additional purification. The Cbz-
amines 4a-c were dissolved in methanol (100 ml) and Pd/C
5% (10 mol%) was added. The flask, equipped with a
vacuum adapter and valve, was connected to a
hydrogenation chamber. The mixture was stirred overnight
at room temperature in the presence of hydrogen. The
reaction mixture was then filtered through silica gel,
washed 2-3 times with methanol (30 ml), and the combined
methanol fractions were evaporated under vacuum. The
residue was dissolved in MTBE (100 ml), and hydrochloric
acid in dioxane was added dropwise while stirring until an
acidic reaction was observed using an indicator strip. The
precipitate formed was filtered and washed several times
with MTBE on the filter. The precipitate was then dried.
The amine hydrochlorides were obtained as a white powder.
(2S)-Benzyl-2-(2-fluorophenyl)propylcarbamate (S-4a).
Yellow liquid; Yield 8.66 g, 91.74%. 1H NMR (СDCl3,
500 MHz, 25 °C): 7.37-7.30 (m, 5H), 7.22-7.18 (m, 2H),
7.09 (t, J = 7.0 Hz, 1H), 7.01 (t, J = 9.0 Hz, 1H), 5.06 (s,
2H), 4.71 (br.s, NH), 3.52-3.47 (m, 1H), 3.38-3.33 (m, 1H),
3.31-3.27 (m, 1H), 1.28-1.27 (d, J = 7.0 Hz, 3H).
(2R)-Benzyl-2-(2-fluorophenyl)propylcarbamate (R-4а).
Yellow liquid; Yield 8.6 g, 91.5%. 1H NMR (СDCl3, 500
MHz, 25 °C): 7.37-7.30 (m, 5H), 7.22-7.18 (m, 2H), 7.09
(t, J = 7.0 Hz, 1H), 7.01 (t, J = 9.0 Hz, 1H), 5.06 (s, 2H),
4.71 (br.s, NH), 3.52-3.47 (m, 1H), 3.38-3.33 (m, 1H), 3.31-
3.27 (m, 1H), 1.28-1.27 (d, J = 7.0 Hz, 3H).
(2S)-Benzyl-2-(4-fluorophenyl)propylcarbamate (S-4b).
Yellow liquid; Yield 7.8 g, 81.43%. 1H NMR (СDCl3,
500 MHz, 25 °C): 7.36-7.30 (m, 5H), 7.13 (t, J = 6.0 Hz,
2H), 6.98 (t, J = 8.5 Hz, 2H), 5.06 (s, 2H), 4.64 (br.s, NH),
3.47-3.42 (m, 1H), 3.26-3.20 (m, 1H), 2.95-2.90 (m, 1H),
1.25-1.24 (d, J = 7.0 Hz, 3H).
(2R)-Benzyl-2-(4-fluorophenyl)propylcarbamate (R-4b).
Yellow liquid; Yield 8.0 g, 84.5%. 1H NMR (СDCl3, 500
MHz, 25 °C): 7.36-7.30 (m, 5H), 7.13 (t, J = 6.0 Hz, 2H),
6.98 (t, J = 8.5, 2H), 5.06 (s, 2H), 4.64 (br.s, NH), 3.47-3.42
(m, 1H), 3.26-3.20 (m, 1H), 2.95-2.90 (m, 1H), 1.25-1.24
(d, J = 7.0 Hz, 3H).
(2S)-Benzyl-2-(3-(trifluoromethyl)phenyl)propylcarba-
mate (S-4c).
Yellow liquid; Yield 10.12 g, 90.9%. 1H NMR (СDCl3,
500 MHz, 25 °C): 7.52-7.32 (m, 9H), 5.09 (s, 2H), 4.67
ISSN 1814-9758. Ukr. Bioorg. Acta, 2024, Vol. 19, N 2
8
(br.s, NH), 3.54-3.47 (m, 1H), 3.35-3.28 (m, 1H), 3.10-3.01
(m, 1H), 1.32-1.30 (d, J = 9.0 Hz, 3H).
(2R)-Benzyl-2-(3-(trifluoromethyl)phenyl)propylcarba-
mate (R-4c).
Yellow liquid; Yield 10.27 g, 92.3%. 1H NMR (СDCl3,
500 MHz, 25 °C): 7.52-7.32 (m, 9H), 5.09 (s, 2H), 4.67
(br.s, NH), 3.54-3.47 (m, 1H), 3.35-3.28 (m, 1H), 3.10-3.01
(m, 1H), 1.32-1.30 (d, J = 9.0 Hz, 3H).
(2R)-2-(2-fluorophenyl)propan-1-amine hydrochloride
(R-5a).
Wight solid; Yield 5.7 g, 85.46%; mр 147 °C.
[]D
20 = +21.97 (C = 0.5, CH3OH), 98% ee. 1H NMR
(DMSO-d6, 500 MHz, 25 °C): 8.18 (br.s, NH2), 7.39-7.36
(t, J = 8.0 Hz, 1H), 7.31-7.27 (dd, J = 7.5, 6.0 Hz, 1H),
7.19-7.14 (q, J = 7.5 Hz, 2H), 3.38-3.31 (m, 1H), 3.03-2.95
(m, 2H), 1.26-1.25 (d, J = 7.0 Hz, 3H). 19F NMR (DMSO-
d6, 376 MHz, 25 °C): -119.06; LCMS: M 154 (M+H+) (M
153.12) (R); Enantiomeric ratio: 98%, determined by
HPLC: tR 10.35, Column: Chiralcel OJ-H (250x4.6 mm,
5 mkm)-OJH0CE-UF008-3 Mobile Phase: Hexane: IPA,
90:10 Flow Rate: 0.6 ml/min.
(2S)-2-(2-fluorophenyl)propan-1-amine hydrochloride
(S-5a).
Wight solid; Yield 5.5 g, 82.46%; mр 147 °C.
[]D
20 = 21.89 (C = 0.5, CH3OH), 99% ee. 1H NMR
(DMSO-d6, 500 MHz, 25 °C): 8.18 (br.s, NH2), 7.39-7.36
(t, J = 8.0 Hz, 1H), 7.31-7.27 (dd, J = 7.5, 6.0 Hz, 1H),
7.19-7.14 (q, J = 7.5 Hz, 2H), 3.38-3.31 (m, 1H), 3.03-2.95
(m, 2H), 1.26-1.25 (d, J = 7.0 Hz, 3H). 19F NMR (DMSO-
d6, 376 MHz, 25 °C): -119.06; LCMS: M 154 (M+H+) (M
153.12) (S); Enantiomeric ratio: 99%, determined by
HPLC: tR 12.07, Column: Chiralcel OJ-H (250x4.6 mm,
5 mkm)-OJH0CE-UF008-3 Mobile Phase: Hexane: IPA,
90:10 Flow Rate: 0.6 ml/min
(2R)-2-(4-fluorophenyl)propan-1-amine hydrochloride
(R-5b).
Wight solid; Yield 5.8 g, 87.32%; mр 149 °C.
[]D
20 = +23.26 (C = 0.5, CH3OH), 100% ее. 1H NMR
(DMSO, 500 MHz, 25 °C): 8.07 (br.s, NH2), 7.34-7.31
(dd, J = 8.5, 3.0 Hz, 2H), 7.16-7.12 (t, J = 8.5 Hz, 2H),
3.11-3.04 (m, 1H), 2.89-2.96 (q, J = 9.5, 7.0 Hz, 2H), 1.23-
1.22 (d, J = 7.0, 3H). 19F NMR (DMSO-d6, 376 MHz,
25 °C): -116.66; LCMS: M 154 (M+H+) (M 153.12) (R);
Enantiomeric ratio: 100%, determined by HPLC: tR 8.015,
Column: Chiralcel OJ-H (250x4.6 mm, 5 mkm)-
173WE001-DC181-1 Mobile Phase: Hexane(0.1% EDA):
IPA:MeOH, 80:10:10 Flow Rate: 0.6 ml/min.
(2S)-2-(4-fluorophenyl)propan-1-amine hydrochloride
(S-5b).
Wight solid; Yield 5.7 g, 86.1%; mр 149 °C.
[]D
20 = -23.97 (C = 0.5, CH3OH), 97% ее . 1H NMR
DMSO, 500 MHz, 25 °C): 8.07 (br.s, NH2), 7.34-7.3 (dd,
J = 8.5, 3.0 Hz, 2H), 7.16-7.12 (t, J = 8.5, 2H), 3.11-3.04
(m, 1H), 2.89-2.96 (q, J = 9.5, 7.0 Hz, 2H), 1.23-1.22 (d,
J = 7.0 Hz, 3H).19F NMR (DMSO-d6, 376 MHz, 25 °C):
-116.66; LCMS: M 154 (M+H+) (M 153.12) (S); Enantio-
meric ratio: 97%, determined by HPLC: tS 8.42, Column:
Chiralcel OJ-H (250x4.6 mm, 5 mkm)-173WE001-DC181-
1 Mobile Phase: Hexane(0.1% EDA): IPA: MeOH,
80:10:10 Flow Rate: 0.6 ml/min.
(2R)-2-[3-(trifluoromethyl)phenyl]propan-1-amine hyd-
rochloride (R-5c).
Wight solid; Yield 6.45 g, 88.47%; mр 174 °C.
[]D
20 = +16.44 (C = 0.5, CH3OH), 99% ее. 1H NMR
(DMSO, 500 MHz, 25 °C): 8.06 (br.s, NH2), 7.64-7.55
(m, 4H), 3.22-3.15 (m, 1H), 3.05-2.99 (dd, J = 12.0, 7.5 Hz,
2H), 1.27-1.26 (d, J = 7.0 Hz, 3H). 19F NMR (DMSO-d6,
376 MHz, 25 °C): -61.35; LCMS: M 204 (M+H+)
(M 203.12) (R); Enantiomeric ratio: 99%, determined
by HPLC: tR 26.147, Column: Chiralpak AD-H
(250x4.6 mm, 5 mkm)-ADH0CE-BO020-12 Mobile Phase:
Hexane:IPA:MeOH, 95:2.5:2.5 Flow Rate: 0.6 ml/min.
(2S)-2-[3-(trifluoromethyl)phenyl]propan-1-amine hyd-
rochloride (S-5c).
Wight solid; Yield 6.6 g, 90.5% mр 174 °C.
[]D
20 = -16.07 (C = 0.5, CH3OH), 100% ее . 1H NMR
(DMSO-d6, 500 MHz, 25 °C): 8.06 (br. s, NH2), 7.64-7.55
(m, 4H), 3.22-3.15 (m, 1H), 3.05-2.99 (dd, J = 12.0, 7.5 Hz,
2H), 1.27-1.26 (d, J = 7.0 Hz, 3H). 19F NMR (DMSO-d6,
376 MHz, 25 °C): -61.35; LCMS: M 204 (M+H+) (M
203.12) (S); Enantiomeric ratio: 100%, determined
by HPLC: tS 24.44, Column: Chiralpak AD-H
(250 x 4.6 mm, 5 mkm)-ADH0CE-BO020-12 Mobile
Phase: Hexane:IPA:MeOH, 95:2.5:2.5 Flow Rate: 0.6
ml/min
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Хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених
β-метилфенілетиламінів
А.О. Колодяжна*, О.О. Фазієв, О.О. Колодяжна
Інститут біоорганічної хімії та нафтохімії ім. В.П. Кухаря НАН України, Київ, Україна
Резюме: Розроблено синтетичний підхід, що веде до синтезу нових будівельних блоків – енантіомерно чистих флуорозаміщених β-метил-
фенілетиламінів. На ключових етапах використовувалася методологія кінетико-динамічного ферментативного розділення. Для досягнення
високого ступеня оптичної чистоти отриманих продуктів застосовували подвійний ферментативний метод очищення. Отримані аміни є
перспективними будівельними блоками для розробки нових флуорованих фармацевтичних препаратів і фізіологічно активних сполук.
Ключові слова: біокаталіз; хіральні флуоровані метилфеніламіни; ліпаза; ферментативна роздільність; оптична активність.
https://www.fda.gov/regulatory-information/search-fda-guidancedo-cuments/development-new-stereoisomeric-drugs
https://www.fda.gov/regulatory-information/search-fda-guidancedo-cuments/development-new-stereoisomeric-drugs
https://www.ema.europa.eu/en/documents/scientificguideline/investigation-chiral-active-substances_en.pdf
https://www.ema.europa.eu/en/documents/scientificguideline/investigation-chiral-active-substances_en.pdf
|
| id | oai:ojs2.bioorganica.com.ua:article-86 |
| institution | Ukrainica Bioorganica Acta |
| keywords_txt_mv | keywords |
| language | English |
| last_indexed | 2026-07-20T01:01:28Z |
| publishDate | 2024 |
| publisher | V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine |
| record_format | ojs |
| resource_txt_mv | bioorganicacomua/70/262ab6d9a4c4b809e6bfa80a2a06c770.pdf |
| spelling | oai:ojs2.bioorganica.com.ua:article-862026-07-19T14:56:55Z Chemoenzymatic method for the synthesis of enantiomerically pure fluorine-substituted β-methylphenylethylamines Хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених β-метилфенілетиламінів Kolodiazhna, Anastasiia O. Faiziiev, Oleh O. Kolodiazhna, Olga O. biocatalysis chiral fluorinated methylphenylamines lipase enzymatic resolution optical activity біокаталіз хіральні фторовані метилфеніламіни ліпаза ферментативне розділення оптична активність A synthetic approach has been developed leading to the synthesis of new building blocks – enantiomerically pure fluorine-substituted β-methylphenylethylamines. A methodology of kinetic dynamic enzymatic resolution was employed at key stages. A dual enzymatic purification method was applied to achieve a high degree of optical purity of the obtained products. The resulting amines are promising building blocks for developing new pharmaceuticals and physiologically active compounds Розроблено синтетичний підхід, що веде до синтезу нових будівельних блоків – енантіомерно чистих флуорозаміщених β-метил-фенілетиламінів. На ключових етапах використовувалася методологія кінетико-динамічного ферментативного розділення. Для досягнення високого ступеня оптичної чистоти отриманих продуктів застосовували подвійний ферментативний метод очищення. Отримані аміни є перспективними будівельними блоками для розробки нових флуорованих фармацевтичних препаратів і фізіологічно активних сполук &nbsp; V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine 2024-12-30 Article Article application/pdf https://bioorganica.com.ua/index.php/journal/article/view/86 10.15407/bioorganica2024.02.003 Ukrainica Bioorganica Acta; Vol. 19 No. 2 (2024): Ukrainica Bioorganica Acta; 3-9 Ukrainica Bioorganica Acta; Том 19 № 2 (2024): Ukrainica Bioorganica Acta; 3-9 1814-9766 1814-9758 10.15407/bioorganica2024.02 en https://bioorganica.com.ua/index.php/journal/article/view/86/84 Copyright (c) 2024 Anastasiia O. Kolodiazhna, Oleh O. Faiziiev, Olga O. Kolodiazhna https://creativecommons.org/licenses/by/4.0 |
| spellingShingle | біокаталіз хіральні фторовані метилфеніламіни ліпаза ферментативне розділення оптична активність Kolodiazhna, Anastasiia O. Faiziiev, Oleh O. Kolodiazhna, Olga O. Хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених β-метилфенілетиламінів |
| title | Хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених β-метилфенілетиламінів |
| title_alt | Chemoenzymatic method for the synthesis of enantiomerically pure fluorine-substituted β-methylphenylethylamines |
| title_full | Хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених β-метилфенілетиламінів |
| title_fullStr | Хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених β-метилфенілетиламінів |
| title_full_unstemmed | Хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених β-метилфенілетиламінів |
| title_short | Хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених β-метилфенілетиламінів |
| title_sort | хемоферментативний метод синтезу енантіомерно чистих флуорозаміщених β-метилфенілетиламінів |
| topic | біокаталіз хіральні фторовані метилфеніламіни ліпаза ферментативне розділення оптична активність |
| topic_facet | biocatalysis chiral fluorinated methylphenylamines lipase enzymatic resolution optical activity біокаталіз хіральні фторовані метилфеніламіни ліпаза ферментативне розділення оптична активність |
| url | https://bioorganica.com.ua/index.php/journal/article/view/86 |
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