Cyclization of N,N-bis(2-chloroethyl)methylamine in aqueous hydrazine

Full text of DOI:10.1023/B:COHC.0000044584.57277.c2

Chemistry of Heterocyclic Compounds, Vol. 40, No. 7, 2004
CYCLIZATION OF N,N-BIS(2-CHLOROETHYL)-
METHYLAMINE IN AQUEOUS HYDRAZINE
1
1
2
1
P. M. Kushakova , V. A. Kuznetsov , A. N. Chernobroviy , and A. V. Garabadgiu
Keywords: 1-amino-4-methylpiperazine, haloalkylamines, N-(2-chloroethyl)-N-(2-hydrazinoethyl)-
methylamine.
1
-Amino-4-methylpiperazine (1) is widely used as an intermediate in synthesis of medicinal drugs [1].
Several methods for obtaining it are known. A method based on a two-step scheme has been used industrially,
starting from piperazine and followed by its nitrosation and reduction [2, 3].
We have obtained compound 1 for the first time by reaction of N,N-bis(2-chloroethyl)methylamine (2)
with an aqueous solution of hydrazine, and we have also developed an efficient method for its isolation. Analysis
of the literature [3, 4] allowed us to determine the optimum ratio of the reagents when the dihalo derivative is
used as the substrate. In the temperature range 40-50°C, the ratio of the reagents is substrate 1:N H (50%) 1:10.
2
4
1
3
Analysis of the reaction mass using GLC data, chromatography/mass spectrometry, and C NMR
showed that along with the target product 1, a number of impurities are formed which we identified.
CH CH Cl
50% aqueous NH
2
NH
2
+
2
2
Me
Me
N
Me
N
CH CH Cl
CH CH Cl
2 2
2
2
2
N
N NH2
CH CH NHNH
2
2
2
Me
N
1
CH CH Cl
2
2
MeN(CH CH NHNH )
2 2
4
2
2
3
In particular, using chromatography/mass spectrometry, we observed formation of up to 2% N,N-bis(2-
hydrazinoethyl)methylamine (3). For less than 80% conversion of substrate 2, we identified N-(2-chloroethyl)-
N-(2-hydrazinoethyl)methylamine (4) in the reaction mass.
Along with the identified compounds 1, 3, 4, the compounds remaining in the vat after distillation of the
target product 1 evidently can be assigned as quaternary ammonium bases [3, 4].
_
_________________________________________________________________________________________
1
St. Petersburg State Institute of Technology (Technical University), St. Petersburg 190013, Russia;
2
e-mail: gar@sitecs.spb.ru. Olainfarm AO, Riga LV-2114, Latvia; e-mail: alchern@olainfarm.lv. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1111-1112, July, 2004. Original article submitted
May 7, 2004.
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0009-3122/04/4007-0960©2004 Springer Science+Business Media, Inc.

1
-Amino-4-methylpiperazine (1). N,N-bis(2-chloroethyl)methylamine hydrochloride (51.0 g,
.265 mol) was added to a 50% aqueous solution of hydrazine (132 ml, 2.65 mol). The mixture was held for 2 h
at 50°C. The reaction mass was evaporated under vacuum to dryness. A 1 M sodium hydroxide solution
100 ml) was added to the dry residue, and the mixture was stirred for 40 min. The precipitate was filtered out.
0
(
1
3
The filtrate was distilled under vacuum. Yield 26.5 g (87%); bp 128-131°C (13 mm Hg). C NMR spectrum
(
7
D O), δ, ppm: 57.51 (C(2), NCH ); 54.15 (C(3), CH N); 45.01 (C(1), CH ). Mass spectrum (electron impact,
2
2
2
3
+
+
+
+
0 eV), m/z (I , %): 116 [M+1] (5.5), 115 [M] (79.5), 99 [M–NH ] (73.9), 98 [M–NH ] (21.3), 58 [M–
r
e
l
2
3
+
+
CH N(CH ) ] (20.6), 57 [M–NH N(CH ) ] (24.5). Found, %: C 52.58; H 11.21; N 36.39. C H N .
3
2 2
2
2 2
5
13
3
Calculated, %: C 52.14; H 11.38; N 36.48.
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1
2
3
4
.
.
.
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