One-step facile synthesis of l-proline ethylamide hydrochloride

Full text of DOI:10.1007/s10593-014-1474-7

Chemistry of Heterocyclic Compounds, Vol. 50, No. 2, May, 2014 (Russian Original Vol. 50, No. 2, February, 2014)
ONE-STEP FACILE SYNTHESIS OF L-PROLINE
ETHYLAMIDE HYDROCHLORIDE
1
1
1
1
*
A. N. Balaev , K. A. Okmanovich , V. N. Osipov , and V. E. Fedorov
Keywords: dichlorodimethylsilane, L-proline ethylamide, large-scale preparation, one-step amidation,
optimization.
L-Proline (1) ethylamide or its hydrochloride (2) are widely used as starting reagents for the synthesis of
biologically active compounds and pharmaceutical substances, such as analogs of LH-releasing hormone
(including buserelin and leuprorelin) [1-3], HCV protease inhibitors [4], kininogenase inhibitors [5], and
inhibitors of pancreatic and leukocyte elastase [6].
A traditional approach to the synthesis of salt 2 from L-proline (1) involves a multi-stage synthesis
including the installation of protecting groups (usually Boc- or Z-group), preparation of the protected L-proline
ethylamide, and finally deprotection [7-12]. No information about a one-step convenient preparative synthesis
of the alkylamides of proline directly from L-proline has been reported in the literature up to now.
Nevertheless, a general approach to solving the problem was developed from work by van Leeuwen et
al. [13]. According to this report, L-phenylalanine was treated with dichlorodimethylsilane in pyridine as
solvent, followed by the addition of primary alkylamines, from which the corresponding amides of
L-phenylalanine could readily be obtained in excellent yields. Dichlorodimethylsilane is a commercially
available low-cost reagent. The proposed mechanism of this reaction involves the formation of an unstable
cyclic silicon intermediate shown in the scheme. It should be noted that in the van Leeuwen work, the reactions
were carried out on a milligram scale and were only successful when L-phenylalanine was utilized as starting
material. In addition, it was necessary to purify the products obtained in this work by chromatography.
We report herein the application of this dichlorodimethylsilane-mediated amidation strategy for the
preparative synthesis of the salt 2.
1) EtNH2
O
Me2SiCl2
O
room temp., 1 h;
N
Si O
Me
N
H
· HCl
Py, 0°C, 2 h
COOH
2) HCl, H2O
N
H
Me
NHEt
1
2
_______
*To whom correspondence should be addressed, e-mail: abalaev@pharm-sintez.ru.
1Pharm-Sintez, 8 Vtoroy Roschinskiy Blvd., Moscow 115419, Russia.
_________________________________________________________________________________________
Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 315-317, February, 2014. Original
article submitted January 5, 2014.
0009-3122/14/5002-0287©2014 Springer Science+Business Media New York
287

During the optimization, it was found that the most significant factors for the success of this reaction are
dryness of the solvent and reagents, amounts of dichlorodimethylsilane and ethylamine, as well as the
temperature of the process (Table 1). Thus, the optimal conditions involve a reaction temperature in the range of
-10 to 0°C and the use of 1.15 equiv. of Me2SiCl2 and 5 equiv. of EtNH2. The crude base of L-proline
ethylamide, obtained by treatment of the evaporated reaction mixture with Na2CO3, was then converted to
hydrochloride 2 by adding aqueous hydrochloric acid. In terms of purification, crude salt 2 was dissolved in
methanol, after which inorganic salts were filtered off and the solvent was removed under reduced pressure;
after addition of diethyl ether, pure salt 2 was obtained as white crystals.
TABLE 1. Yield of L-Proline Ethylamide Hydrochloride (2) under
Different Conditions
Entry Equivalents of Me2SiCl2 Equivalents of EtNH2
Temp, °C
Isolated yield, %
1
2
3
4
5
6
7
8
1.15
1.15
1.15
1.15
1.15
1.00
1.30
1.45
1.15
1.15
1.15
4
4
4
4
4
4
4
4
2
3
5
-10
0
10
20
30
0
0
0
0
0
84
83
78
71
59
75
84
84
<15
62
87
9
10
11
0
We are of the opinion that the newly developed method of one-step synthesis for the preparation of
L-proline ethylamide hydrochloride from L-proline could be useful not only in the laboratory but also for large-
scale preparation of pharmaceutical substances. Reaction was performed on an over 100 gram scale and the pure
L-proline ethylamide hydrochloride was isolated without any need for column chromatography. Furthermore, a
preliminary study of the reaction of L-proline with other amines (isobutylamine, methylamine, benzylamine,
and pyrrolidine) revealed that the corresponding amides can be prepared in yields up to 80% (detected by
HPLC).
1
13
The IR spectrum was recorded on a Nicolet 6700 instrument in KBr pellets. H and C NMR spectra
were recorded on a Bruker AM-360 spectrometer (360 and 90 MHz, respectively) in CDCl3 (1H NMR
spectrum) and D2O (13C NMR spectrum). Elemental analysis was carried out with a Perkin Elmer 2400 CHN
analyzer. The melting point was determined using a Melting Point M-565 (BUCHI) apparatus. The optical
rotation was measured on an OTAGO AP-300 automatic polarimeter. HPLC-MS analysis was conducted on an
Agilent LC/MS 1200 with electrospray ionization at atmospheric pressure. The purity of the obtained compound
2 was monitored by a liquid chromatography Shimadzu 20A series apparatus, Grom-Sil 12J ODS-4HE column
(4.6×250 mm), temperature 23°C, linear AB gradient 0-20 min from 95:5 (v/v) to 0:100 (v/v), eluent A: 0.001%
TFA in H2O, eluent B: 0.001% TFA in MeCN, flow rate 1 ml/min.
L-Proline Ethylamide Hydrochloride (2). Me2SiCl2 (148.4 g, 1.15 mol) was added dropwise to a
suspension of L-proline (1) (115.1 g, 1.00 mol) in dry pyridine (500 ml) at 0°C under argon atmosphere. The
reaction mixture was stirred at 0°C for 2 h and then dry EtNH2 (180.3 g, 4.00 mol) was added at the same
temperature. The reaction mixture was subsequently stirred at room temperature for 1 h. The residue
precipitated during the process was separated from the solution by filtration, and the solvent was removed under
low pressure. The viscous residue was then dissolved in 5% Na2CO3 solution (300 ml), and the resulting
solution was washed with Et2O–hexane (1:1, 400 ml). The water layer was concentrated under low pressure,
17% HCl (200 ml) was added to the obtained residue of crude L-proline ethylamide, and the resulting mixture
288

was evaporated again in vacuo. MeOH (400 ml) was added to the residue, after which the inorganic salts were
filtered off and the solvent was removed under low pressure. After adding Et2O (500 ml) and stirring for 1 h,
pure hydrochloride 2 was separated from the solution by filtration. Yield 148.4 g (83.1%), white crystals, mp
98-100°C (mp 97°C [14]). Purity 99.24% (HPLC). [α]D27 -52.48 (c 0.3, H2O). IR spectrum, ν, cm-1: 3509, 3453,
2971, 2927, 2593, 2471, 1686, 1577, 1471, 1396, 1290, 1259, 1147, 1055, 816, 565. 1H NMR spectrum, δ, ppm
(J, Hz): 1.16 (3H, t, J = 7.2, CH2CH3); 1.96-2.11 (3H, m, 3-CHA, 4-CH2); 2.50-2.64 (1H, m, 3-CHB); 3.19-3.35
(2H, m, 5-CH2); 3.43-3.52 (2H, m, CH2CH3); 4.62-4.71 (1H, m, 2-CH); 7.89 (1H, br. s, N+H); 10.46 (1H, br. s,
N+H); 8.68 (1H, t, J = 7.1, CONH). 13C NMR spectrum, δ, ppm: 12.9; 23.3; 29.2; 34.3; 46.1; 59.4; 168.4. Mass
spectrum, m/z (Irel, %): 143 [M–Cl]+ (100). Found, %: C 47.13; H 8.55; N 15.81. C7H15ClN2O. Calculated, %:
C 47.06; H 8.46; N 15.68.
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