N-(2,3-epoxypropyl)-α-pyrrolidone: A new reagent for the synthesis of drugs

Full text of DOI:10.1023/A:1005235527482

Pharmaceutical Chemistry Journal
Vol. 34, No. 8, 2000
N-(2,3-EPOXYPROPYL)-a-PYRROLIDONE: A NEW REAGENT
FOR THE SYNTHESIS OF DRUGS
1
1
2
1
1
F. P. Sidel’kovskaya, A. M. Sakharov, S. Z. Taits, Yu. V. Vol’kenshtein, M. M. Vlasova,
Z. N. Nysenko, and N. S. Yusupov1
1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 34, No. 8, pp. 33 – 34, August, 2000.
Original article submitted December 2, 1999.
The presence of a pyrrolidone ring in the structure of or-
ganic compounds usually is associated with an increase in
the hydrophilicity and ability for complex formation and a
decrease in toxicity, and it favors some other properties use-
ful for pharmacologically active substances [1]. This circum-
stance had an important role in the synthesis of some drugs
containing pyrrolidonyl radicals [2]. However, the set of re-
agents to which these radicals can be added is rather limited,
including primarily N-vinylpyrrolidone [1], N-(b-hydroxy-
ethyl)-, N-(chloroalkyl)-, and N-(mercaptoethyl)-pyrrolido-
nes [3, 4]. In this context, it was of interest to study the prop-
erties of N-(2,3-epoxypropyl)-a-pyrrolidone (NEPP) – a
highly reactive compound [5 – 8] that is a new promising re-
agent for the synthesis of therapeutically active (in particular,
radioprotector) substances [7].
The reaction proceeds even at room temperature, but the
best conditions are provided by heating to 50 – 60°C. The
optimum ratio of pyrrolidone, ECH, and the alkaline agent is
1 : 6 : 1.15. Water formed as a result of this reaction is re-
moved in an azeotropic form with excess ECH at a residual
pressure of 110 – 120 Torr (ECH can be regenerated and
used repeatedly). The reaction duration varies from 60 to
90 min at 50 – 60°C to four days at room temperature. The
final pyrrolidone conversion is about 60%.
Attempts at increasing the reaction temperature and du-
ration lead to the following side reactions:
(a) heterocycle opening with the formation of a potas-
+
sium salt of g-aminobutyric acid NH (CH ) COO–K ,
(b) water addition with glycol formation
2
2 3
O
NEPP was originally synthesized [9, 10] using a reaction
of epichlorohydrin (ECH) with potassium pyrrolidone in an
organic solvent (diethyl ether or methylene chloride). Potas-
sium pyrrolidone was preliminarily prepared by interaction
of pyrrolidone and metallic potassium. Later [11], we devel-
oped a single-stage NEPP synthesis based on the reaction of
a-pyrrolidone with ECH in the presence of an alkaline agent
NCH CH(OH)CH OH ,
2
2
(
c) NEPP interaction with the initial pyrrolidone, leading
to N-(2-hydroxy-3-N-pyrrolidonylpropyl)-2-pyrrolidone
O
O
(
potassium or sodium hydroxides).
The purpose of this work was to study the single-stage
NCH CH(OH)CH N
,
2
2
synthesis of NEPP from a-pyrrolidone and ECH in the pres-
ence of potassium hydroxide in more detail.
(
d) NEPP polymerization in the presence of alkali, lead-
ing to resinification of the reaction mixture.
O
We have attempted to inhibit the resin formation caused
by NEPP polymerization, which probably took place during
the product isolation from the reaction mass, by adding agents
of an acidic character (hydrochloric acid, CoCl , MgSO ,
NH + ClCH CH–CH +KOH
2
2
ECH
O
O
2
4
+
KU-2 resin in H form). However, these additives only
slightly reduced the amount of resinous products. From this
we inferred that polymerization of the reaction mass compo-
nents takes place immediately in the course of syntheses.
We have also studied single-stage synthesis in the pres-
ence of an interphase transfer catalyst, triethylbenzylammo-
nium chloride (TEBAC) and sodium hydroxide. In this case,
N
CH2 CH CH + KCl + H O
2
2
O
NEPP
1
2
Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences,
Moscow, Russia.
Deceased.
428
0
091-150X/00/3408-0428$25.00 © 2001 Plenum Publishing Corporation

N-(2,3-Epoxypropyl)-a-pyrrolidone
429
TABLE 1. Single-Stage Synthesis of N-(2,3-Epoxypropyl)-a-pyrrolidone (NEPP) Using an Interphase Transfer Catalyst (TEBAC)
Weight of reaction components, g (mole)
Vacuum distillation conditions
Solvent
Experi-
ment
NEPP
Residual
pressure,
Torr
Bottom residue
(
volume,
ml)
yield, %
a-Pyrrolidone
NaOH
ECH
TEBAC
B.p., °C
weight, %
of charge
1
12.8 (0.15)
12.8 (0.15)
76.6 (0.9)
269 (3.16)
50.1 (1.30)
8.4 (0.21)
50.4 (1.26)
177 (4.42)
83.2 (0.90) 0.75 (0.003)
83.2 (0.90) 0.75 (0.003)
250 (2.70) 2.25 (0.01)
–
–
78 – 80
95 – 96
0.02
14.6
8.5
88
90
75
66
2
3
4
0.40
Toluene (210) 103 – 105
115 – 120
1.00 – 1.50
4.00 – 5.00
17.0
34.0
1850 (20.0)
7.9 (0.03)
–
Notes. In experiments 1 and 2, alkali was added in the form of a 50% aqueous solution.
the NEPP yield increases up to 90% and the reaction product
contains virtually no initial pyrrolidone. However, not less
than five impurities appear instead, of which only the major
one (diglycidyl ester) was isolated and identified.
upon prolonged storage. NEPP is soluble in water, alcohols,
acetone, benzene, and chloroform and insoluble in hydrocar-
20
bons; b.p., 101 – 103°C/2.5 Torr, 92 – 93°C/1.5 Torr; nD
,
20
13
.4860; d4 , 1.1362; C NMR spectrum in CDCl (d, ppm):
1
3
2
CH –CHCH Cl + 2NaOH
2CH –CHCH OCH CH–CH +
2
2
2
2
2
2
1
4
74.89 (C-2), 30.31 (C-3), 17.70 (C-4), 44.34 (C-5 + C-6),
9.88 (C-7), 47.99 (C-8).
O
O
O
+
2NaCl + H O
2
REFERENCES
The results of some experiments on NEPP synthesis in
the presence of TEBAC are listed in Table 1.
1. F. P. Sidel’kovskaya, The Chemistry of N-Vinylpyrrolidone and
Related Polymers [in Russian], Nauka, Moscow (1970).
2. U. N. Musaev, A. R. Karimov, N. Kh. Irgasheva, et al., Some
Aspects of the Synthesis of Polymers for Medical Applications
EXPERIMENTAL PART
1
3
[
. M. F. Shostakovskii, F. P. Sidel’kovskaya, E. V. Rogova, et al.,
in Russian], Fan, Tashkent (1978), pp. 22 – 23.
The C NMR spectra were measured on a Bruker
AC-200 spectrometer operated at a working frequency of
3
4
Izv. Akad. Nauk SSSR, Otd. Khim. Nauk, No. 6, 1111 – 1116
(
2
00 MHz, using CDCl as a solvent and TMS as an internal
3
1961).
standard.
N-(2,3-Epoxypropyl)-a-pyrrolidone (NEPP). To a
. M. F. Shostakovskii, F. P. Sidel’kovskaya, E. S. Shapiro, and
T. Ya. Ogibina, Izv. Akad. Nauk SSSR, Otd. Khim. Nauk, No. 8,
1524 – 1527 (1961).
mixture of 34.3 g (0.4 mole) of a-pyrrolidone and 236 g
ECH in a flat-bottom three-neck flask equipped with ther-
mometer, stirrer, capillary, and reflux cooler were added with
intensive stirring 24.8 g of powdered or granulated potas-
sium hydroxide. The mixture exhibited self-heating to
5. A. A. Il’chenko, V. A. Ponomarenko, F. P. Sidel’kovskaya, et
al., Vysokomol. Soedin., Ser. A, 16(12), 2804 – 2809 (1974).
6
. F. P. Sidel’kovskaya, N. A. Raspevina, A. V. Ignatenko, and
V. A. Ponomarenko, Izv. Akad. Nauk SSSR, Ser. Khim., No. 6,
1111 – 1116 (1986).
3
0 – 35°C. The azeotropic water – ECH mixture was dis-
7
8
. B. V. Golomolzin, E. A. Tarakhtii, I. P. Tregubenko, et al.,
Khim.-Farm. Zh., 22(7), 839 – 843 (1988).
tilled off at 60 – 63°C/110 – 120 Torr. The reaction mixture
was filtered, and the residue (containing predominantly po-
tassium chloride) was washed several times with ECH. The
filtrates were combined, and ECH was distilled on a rotary
. F. P. Sidel’kovskaya, V. A. Ponomarenko, N. A. Raspevina, et
al., Khim.-Farm. Zh., 24(5), 67 (1990).
9. F. P. Sidel’kovskaya, N. A. Mukhitdinova, M. G. Zelenskaya,
and V. A. Ponomarenko, USSR Inventor’s Certificate
No. 196,850; Byull. Izobret., No. 12 (1967).
13
evaporator. By the C NMR data, the residual liquid was a
NEPP mixture with the initial reagents. NEPP was purified
1
0. F. P. Sidel’kovskaya, N. A. Mukhitdinova, M. G. Zelenskaya,
and V. A. Ponomarenko, Khim. Geterotsikl. Soedin., No. 2,
by chromatography on a column filled with SiO (L 40/100)
eluted with a chloroform – acetone (5 : 1) mixture; NEPP
yield, 22.6 g (40%).
2
212 – 214 (1968).
1
1. F. P. Sidel’kovskaya, V. A. Ponomarenko, L. F. Oreshkina, and
O. D. Trifonova, USSR Inventor’s Certificate No. 506,181;
Byull. Izobret., No. 48 (1987).
Pure NEPP is a colorless transparent liquid with a slight
characteristic odor, which acquires a slight yellowish tint