Ann.New York Acad. Sc. 50(2) 120-127 May 25,1948.
THE CHEMISTRY OF PIPERAZINE COMPOUNDS IN THE CHEMOTHERAPY OF
By S. Kushner, L. M. Bkancone, R. I. Hewitt,
W. L. McEw en and Y. SubbaRow
Lederle Laboratories Division, American Cyanamid Company,
Pearl River, New York
and H. W. S TEWART , R. J. T URNER , AND J. J. D ENTON Calco Chemical
Division, American Cyanamid Company, Bound Brook, New Jersey
For some time, our laboratory has been actively interested in obtaining an active
filaricide that would be administered orally and still be non- metallic and thus avoid the
usual effects of the heavy metals in body assimilation. Screening experiments against
microfilariae in the cotton rat led us to believe that we might achieve our goal in the
The first compound that showed great promise in the initial screening was 1-
This compound, designated as 180-C, was prepared by reacting ethyl
chlorocarbonate (III) under controlled conditions with piperazine (II) in aqueous solution.
The resulting 1-carbethoxypiperazine (IV), which
is obtained in good yield, can be reacted with methyl tosylate (V) in alcoholic solution to
give 180-C. This method was used by Moore and co-workers 1 in the preparation of the
Subsequent variations of this molecule have led to preparation of more than 60
compounds for chemotherapeutic testing.
In our initial experimentation, the carbethoxy group on the 1 position was kept
constant while different groups were placed in the 4 position.
KUSHNER ET AL.: CHEMISTRY OF PIPERAZINES 121
In TABLE 1, these compounds are listed with a few of their physical properties and
their relative activity in the cotton rat. The first eight compounds listed in this table were
prepared in the same manner as designated for 180-C, with the appropriate changes in
the alkyl tosylate f or compounds 3, 4. 5, and 6.
M.P.of HCl ºC.
Compound R B.P. of base °C. Mm.
1 H 156.5-157 +
2 CH2 97-98 8 168.5-169 ++
3 C2H6 132 28 +
4 n-C2H7 136 16 189-192 +
5 iso-C2H7 138-144 19 +
6 n-C4H9 139-140 8 +
7 sec.-C4H7 139-147 18 218-221 (dec:) +
8 iso-C4H7 139-143 18 —
9 n-C7H15 159-161 4 —
CH2 = CH
10 113-115 6 —
11 CH2CH2OH 175-177 12 —
12 CH2CO2C2H4 123-125 2 —
13 C6H5 61-61.5 (m.p) 197-198 (dec:) —
14 C6H5CH2 218-218.5 —
15 CO2CH5 131-133 3 —
The n-heptyl, allyl, β-hydroxy ethyl, benzyl, and carbethoxymethyl derivatives were
prepared by the use of their corresponding halide in alcoholic solution wit h 1 -
The dicarbethoxypiperazine was prepared by the action in neutral or alkaline
solution with piperazine and ethyl chlorocarbonate. It is usually isolated as the by-product
in the preparation of 1-carbethoxypiperazine, t h e s t a r t i n g m a t er i a l f o r m o st of t h e
compounds in TABLE 1.
The l-carbethoxy-4-phenylpiperazine was prepared by direct reaction of ethyl
chlorocarbonate on 1-phenylpiperazine.
No gain in activity was shown by homologous preparation; rather, activity
decreases with the increasing radical size. Substitution of such solubilizing groups as
the β-hydroxyethyl showed no advantages.
Various compounds similar to 180-C were made, wherein the carbethoxy g r oup
was r eplaced b y lo w er or hig her car balkoxy hom olog ues. T hese
were prepared in the same manner as that outlined for 180-C, with the corresponding
substitution for the alkyl chlorocarbonate. These com- pounds, tabulated in TABLE 2, show
no enhanced activity but rather a decrease in activity.
Compound R1 R2 B.P. of base 0C. Mm. Activity
1 H CH3 112-116 7 -
2 CH2 CH2 116-121 (m.p.) — -
3 CO2CH2 CH2 163 11 -
4 H n-C4H9 141-143 10 -
5 CO2C4H4-n n-C4H9 205-208 10 -
6 H iso-C4H9 138-142 13 -
7 CO2C4H9-iso iso- C4H9 203-205 15 -
Certain 1 -alkylpiperazines have been made by Baltzly2 by the alkylation of 1-
benzylpiperazine in the 4 position with subsequent removal of the benzyl group by
catalytic hydrogenation. A more indirect procedure has been used by Prelog and Stepan3
for the preparation of 1-methyl- piperazine from l-methyl-4-phenylpiperazine. Moore,
Boyle, and Thorn1 obtained 1-ethylpiperazine from the hydrolysis of l-carbethoxy-4-ethyI-
piperazine in concentrated hydrochloric acid. We have used this latter m et hod f or
pr epar ing t he 1 - alk ylpiper a zi nes r epor t ed in T A B L E 3.
R1 R2 B.P.of base °C, Mm. M.P. of base HCl ºC.
1 CH3 H 134-136 760 82.5-83 -
2 CH2 CH. 131-133 760 251.5-253 (dec.) -
3 CH2 — — 262-264
4 C2H5 H 155-158 760 — -
5 iso -C2H7 H — — 274-275 (dec.) -
6 C6H5 H 161-164 — 245-247 -
7 C6H5 CH2 130-131 — 180-182 (dec.) -
KUSHNER ET AL.: CHEMISTRY OF PIPERAZINES 123
The 1,4 dimethylpiperazine was prepared by the reaction of piperazine with
formaldehyde and formic acid. This mode of methylation was also used for large-scale
preparation of 180-C.
The l-methyl-4-β-dimethylaminoethyl piperazine was prepared by the interaction of
methylpiperazine and β-dimethylaminoethyl chloride. None of these compounds
showed appreciable activity.
T AB LE 4
In TABLE 4 are listed several miscellaneous compounds that are combinations of
types represented by the preceding tables.
The bis (l-carbethoxy-4-piperazyl) methane and 1,2-bis (1-carbcthoxy- 4-piperazyl)
ethane were prepared by reacting methylene bromide and ethylene bromide respectively
with 1-carbethoxypiperazine in alcohol, with sodium bicarbonate. The l,l'-sulfonyl-bis(4-
methylpiperazine) was syndiesized by the reaction of sulfuryl chloride and
methylpiperazine in cold chloroform solution.
The 2,3-diphenylpiperazine was prepared by the catalytic reduction of 2,3-
diphenyl-5,6-dihydropyrazine which was prepared by Mason4 by reacting ethylene
diamine with benzil.
The active compound in TABLE 4, 1,4-dicarbethoxy-2-methylpiperazine, was prepared in
the same manner as the non-nuclear substituted com- p o u n d s s h o wn i n T A B L E 1 .
The 2-methylpiperazine was prepared by the reaction of the disodio derivatives of N,N'
ditosyl propylenediamine with ethylene bromide followed by an acid hydrolysis.
* M.p. of sulfate.
Inasmuch as the synthesis of a new and more active filaricide, greater in activity
than 180-C, could not be found in transformations of alkyl and carbalkoxy groups, other
acid derivatives were sought. The compounds listed in TABLE 5 contain these
transformations. l-guanyl-4-carbethoxy- piper azine, which showed some activit y,
was prepared by the interact ion of l -carbethoxypiperazine with methylisothiourea.
The diguanyl piperazi n e 5 was f or m ed by using t he f r ee base in t he sam e
r eact ion.
1-Nitroso-4-carbethoxypiperazine was synthesized by the action of nitrous acid
and 1-carbethoxypiperazine. The nitroso compound could then be further reduced by zinc
and acetic acid to give the corresponding a m i n o c o m p o u n d .
The amides and thioamide were prepared by the action of potassium isocyanate
and thiocyanate, respectively.
Although negative results as regards activity were obtained in the preparation of
these acid derivatives, it was our belief that, if we increased their fat solubility while still
maintaining their water solubility, we would o b t a i n a h i g h l y a c t i v e c o m p o u n d .
Compound B.P. of MP. of Activity
R1 R2 base °C. Mm. HCloC.
1 C2H5OOC- -CON (C2H5)2 163-167 3 —
2 H- -CON (CH3)2 144-146 15
3 H- -CON(C2H5)2 113.5- 3 147- —
4 H- -CON CH 115.5
146 9 151 —
5 H- (CH3)2 2
-CON(n- 158-162 5 —
6 H- C4H9,)2
-CON(i- 200-202 35 —
(C2H5)2NOC- -CON(C2H5)2 174-178 2 55.7-56
This was accomplished by alkylating the amide. In TABLE 6 are listed the carbamyl
derivatives that were inactive. They contain no alkylation in t he 4 posit ion.
These compounds were prepared in the same manner as 1-diethyl- carbamyl-4-
methyIpiperazine. This latter compound (Hetrazan) and l-dimethylcarbamyl-4
methylpiperazine, shown in TABLE 7, are highly active, and the former (Hetrazan) was
clinically tested. Its synthesis is as follows.
Diethylcarbamyl chloride (VI) is treated in a modified Schotten- Baumann manner
with piperazine (H) to give 1-diethylcarbamylpiperazine (VIl). This compound is then
methylated by means of formaldehyde a n d f o r m i c a c i d t o g i ve 1 d i e t h yl c a r b a m yl -
4 - m et h yl p i p e r a z i n e ( V I I I ) .
Compounds 2 and 6 were prepared by the direct reaction of the corresponding
isocyanate with 1-methylpiperazine.
The synthesis of l-benzylcarbamyl-4-methylpiperazine was effected by a
modification of the procedure of James6 wherein the benzoate of phenyl acethydroxamic
acid (IX), when heated with aqueous alkali, gives symmetrical dibenzylurea (XI)
presumably through the intermediate benzyl isocyanate (X). Instead of heating the
benzoate with alkali, 2 moles of l-methylpiperazine are added; 1 mole causes the
intermediate formation of the isocyanate, which immediately reacts with the remaining l-
methylpiperazine to give the desired l-benzylcarbainyl-4-methylpiperazine (XII).
BI B L I O G R AP H Y
1. Moore, T. S., M. Boyle, & V. M. Thorn
1929. N. Substituted derivation of piperazine and ethylenediamine. J. Chem. Soc: 39.
2. Baltzly, R., J, S. Buck, E. Lorz, & W. Schan1944. The preparation of N-
monosubstituted and unsymmetrically substituted piperazines. J. Am. Chem. Soc. 66:
3. Prelog, V., & V. Stepan 1935. A new synthesis of N-monoalkylpiperazines. Chem.
Abstr. 29: 4013.
4. Mason, A. T. 1887. Condensation derivatives of ethylene diamine. Ber. 20: 267.
5. Bischoff, F. 1928. Preparation of some substituted guanidines. J. Biol. Chem. 80:
6. James, L. W.1912. The Beckmann rearrangement of hydroxamic acids. Am. Chem.