NOTES
September 1968
1091
TABLE I 1,4-DISUBSTlTUTED PIPERAZINES
n
RN NX U Yield, NO.
A
1 2 3 4
%
Reaction time,c Recrystnd 1 1 ~" C , ~ Procedureb hr solvent 0.76 124-125 A (acet) C-D E 95-96 Be 0.75 F-H. 1 : 3 233-234 dec A (acet) 0.25 , . . n 216-217 g 111-114 A (ale) 1st: 1-3 1.5 2nd: C-D 2 E 105-107 A (acet) 225 dec A (acet) 1.5 I- J K-L 180-182 h ... E 3 95-97 B (acet) 11 ... 150-152 j K-D 99-102 5 A (ale) I: 2 103.5-107 A (ale) C E 94 5-96 5 B (ether) 1
5
CHzCHOHCH20H CON(CzHs)z C H K ( B r ) = C H ? . 2HC1 CSNHCoHs CHnCONHCONHCHa
44 33 50 69 33
6 7 8 9 10 11 12 13
CHzCONHC6Hs CHzCONHCOSHCnH5 P-SO~C~H~NH~ CON ( C Z H I ) ~ CON(CnHs)z' HCI CHzCONHCONHCHa CH2CONHCONHCHs CON(C6Hs)i
41 78 60 67 62 43 55 85
P
62
256-257dec
A (acet)
CH?CONHCONHCH, CON ( C ? H ~ ) Z " ~ H ~ S O I
30 38
108-110 130-132
A (ale) m
57
39.5-40.5
14
CaHsCHn
'2HCI. 0.5H20
CH>
15 16 17 18
COC(Br) (CHdz' HBr
39
19
CHzCONHCONHCHa
41
75-77
20
CHaCHCOXHCONHCHa
34
107-109
6
1
Analyses C, H , N C , H, N Br, N J,
x
C , H, N C, H , N C , H. E;
s. s
C, H , C1, N C, H , C . H, C, H , C.iH!tCl!S?
0.5H?O
N N S
N
C, H , CI, x, H20
B (ether)
188-190dec
B (ether) A (ale)
B (acet)
RIelting points are uncorrected and were taken wit.h a Fisher-Johns apparatus. * These procedures are described in Experimental Unless otherwise specified, the reacSection. The acet and alc refer to the acetone or alcohol solvents used in the reaction mixture. tions were conducted a t reflux temperatures. d C, ethyl acetate; D, petroleum ether (bp 30-80"); E, petroleum ether (bp 65-110"); F, absolute methyl alcohol; H, dioxane; I, ethyl alcohol; J, water; K, benzene; L, carbon tetrachloride; AI, acetone; N, hexane. ePreThe crude pared from 10% molar excess of benzhydryl chloride plus N,N-diethylcarbamoylpiperazine; temperature kept under 90". product, precipitated out as a dihydrochloride salt when it was dissolved in 10% hydrochloric acid solution. 0 Prepared from equimolar amounts of 1-(diphenylmethy1)piperazine plus phenyl isothiocyanate in anhydrous ether at room temperature. ', Pee Experimental Section for synthesis. New compound. Made by mixing equimolar amounts of 2-chloropropionyl chloride plus methylurea. Product recrystallized from EtOH; yield 40%, mp 139-141". Anal. Calcd for C6HgC1N2O2: N,17.02; C1, 21.54. Found: N, 17.11; C1, 20.59. k 5 hr at 35' plus 2 hr a t 50". 1 Immediate reaction, but left standj Isolated from the same reaction mixture from which 9 was made. ing overnight a t room temperature. m See Experimental Section for preparation. n Dropwise addition of ethereal solution of 2-chlorobenzoxazole to methylpiperazine in ether at room temperature. 0 Reaction run in ice bath; 2-bromoisobutyryl bromide added dropwise to benzylpiperazine. a
showed maximum stimulation at 256 (128% difference from control group), but was lethal at 300 mg/kg PO. Compound 20 was a feeble psychomotor stimulant in mice at 300 mg/kg P O . These compounds were also tested for such other physiological responses or possible uses as hexobarbital potentiation, anthelmintic, schistosomacidal, antibacterial, analgetic, antiinflammatory, and antihypertensive activities. Experimental Section4 The chemicals were purchased either from Eastman or Aldrich Chemical Co. Microanalyses were run at the Sterling-Winthrop Research Institute. The compounds of types I and I1 wereprepared by first making the 1-aralkylpiperazines or l-diethylcarbamoylpiperazines and then alkylating them according to the procedures described below. The following compounds were made by literature methods: a-chloroacetaniIide,5 l-methy1-3-chloroacetyl~rea,~1-(4-chlorodiphenylmethyl)pipera~ine,~ 1-(2-chlorodiphenylmethyl)piper(4) Where analyses are indicated only by symbols of the elements or functions. analytical results obtained for these elements or functions were within 5 0 . 4 % of the theoretical values. (5) P. J. Meyer, Ber., 8 , 1153 (1875). (6) H . Aspelund, F i n s k a Kemistsamfundets Medd., 49, 49 (1940); Chem. Abstr., 36, 2144 (1941). (7) K. Fujii, K. Tomino, and H. Watanabe, J . P h a r m . Soc. J a p a n , 74, 1049 (1954); Chem. Abstr., 49, 11666 (1955).
azine,s 1-phenethylpiperazine dihydrochloride,g 1-S,X-diethylcarbamoylpiperazine,'O 1-benzylpiperazine dihydrochloride, 11 and 1-diphenylmethylpiperazine.12 1,4-Disubstituted Piperazines (Table I). Procedure A.-The stirred reaction mixture, which contained the alkyl halide in 10% molar excess to the monoalkylpiperazine or its hydrochloride, plus HzO, RleQCO, or EtOH, and sufficient XaHC03, was heated in the period of time indicated in Table I. The solvent was then removed by reduced pressure distillation, and the residue "as dissolved in dilute HC1, filtered and made alkaline (NaOH). The products were collected and recrystallized from the solvents shown in Table I. Procedure B.-Two parts of the appropriate nionosubstit,uted piperazine was treated with one part of either the appropriate alkyl chloride or acid halide in the indicated solvent shown in the procedure column of the table. When the reaction was ended, (8) H . G . Morren, R. Denayer, R . Linz, I
