SOREPINEPHRTXE-DEPLETING AGESTS, P-HTnROXI'PHEn'ETHYJ,GU.4NI~INE
November 1967
1007
TABLE I SPRCCTLXEs OF TIIE C:I'.lNIDINES
Ri
Compd
R? H
I I1
H IJ
( 1-11 ( - )-TI
I1
€€
II C1 ('1 IT
IT IT C1 JI
+
111 I \.
H
.IND
T I I E IEFFECT3 ~~ IX
Ra
x
Z
H H H I1 11 TI C1
H OH OH 011 0TI
€1
H 11 I1
011
I1
JhCE
Effect on heart norepinephrinea 1 mg/kgc 10 mg/kgc
++ +++ ++ +++ ++
+ ++ + +++
I1
0 0 0 0
0
Extent of ptosis' 100 mg/kgc +d
+ + + 0 0
++
0 I1 TI 0 or IT1 ir 11 011 11 I1 0 11 JT 011 H II H H OH CHI 0 H H II 0 OH a Percentage depletion: 0 (70'Z0). On this scale, guanethidine was rated (eyes one-quarter to one-half closed), (eyes greater than ( 1 mg/kg) and (10 mg/kg). * 0 (eyes one-quarter closed), Injected subcutaneously t o groups of six mice. Ptosis rating is at one-half closed). On this scale guanethidine was rated 50 mg/kg, since most of the mice died a t 100 mg/kg.
1TI VI1 ( - )-TI1 TI11
OTI
++ ++ ++ +
+ +
+
+++
++ + +.
+
+++
+
++
++
TABLEI1 THEPROPERTIES .IND ASALYSESOF C'ompil
11p, OC"
I I< ( +)-IId ( - )-IId I11 IT-
224-226 227-228 228 242 234-236 245-247 136-138 248 239-241 186-187
Crystn solventh
+W +W +W +W W B +E R A +W A +E
A A A W A
THE
GUANIDINE S.\LTS
r--C> Calcd
Formula
%-Found
7-H, Calcd
%-Found
--N, Calcd
%--I~oitnd
(CgHI3N30)z. TT~SOI
47.36 47.34 6.10 6.18 18.41 lS.31 ( C ~ H ~ Z N ~ O ) ~ . H Z S O47.36 ~ 47.24 6.10 6.08 18.41 18.36 (CgHi3?;,0)2.HzSOa 47.36 47.07 6.10 6.15 18.41 18.17 (CgH1zClN30)z.H2SOa 41.16 41.16 4.99 5.00 16.00 15.90 (C9HliClzN30)z.H2S04 36.37 36.51 4.07 4.29 14.14 14.00 J. (C9HizCl?r'30)2.I-I2SOI 41.16 41.48 4.99 4.99 16.00 16.48 VI CioHiJX302.HNOs 44.11 44.05 5.92 6.07 20.58 20.67 1-11 (CloH16~3O)Z ' H2SO4 49.58 49.39 6.66 6.54 17.35 17.61 ( - )-TIId (CioHijpi30)z~HzS04 49.58 49.77 6.66 6.87 17.35 17.14 VI11 CiiHi7S30.HI 39.41 39.52 5.41 5.78 12.54 12.39 Previously described as the hya Most of the compounds melted with decomposit,ion. b A = EtOH, E = Et'OAc, W = Hz0. driodide [H. C. Bhatnagar, N. K.Chopra, K. S. Xarang, and J. S . Ray, J . Indian Chem. SOC.,14,344 (1937)l and hydrobromide [D. E. Optical rotations were determined a t approximately 5 Heitmeier, E. E. Spinner, and A. P. Gray, J . Org. Chem., 26, 4419 (196l)l. mg/ml in 50% HzO-EtOH using an ETL-XPL automatic polarimeter, Type 143A (Ericsson Telephones Ltd.): (+)-I& [ a I z 3 D +33.4"; (-)-II, [ a I z 3 D -34.1'; (-)-IrII, [a]*'D -35.0".
phenethylamines were obtained by lithium aluminum hydride reduction of appropriate benzoyl cyanides8 or phenylglyoxal aldoximes. S-Xethyl-P-hydroxyphenethylamine, from methylamine and styrene oxide, was resolved with (+)-tartaric acid in ethanol.10
Experimental Section" Resolution of @-Hydroxyphenethy1amine.-@-Hydroxyphenethylamine (500 g, 3.65 moles) was added with stirring to (+)tartaric acid (550 g, 3.65 moles) in boiling HzO ( 1 1.). The yellow solution was boiled with charcoal, filtered, and allowed to cool to room temperature.12 I t was then preferably seeded and stored a t 0-4" for several days. The viscous supernatant liquid was (8) A. Burger and E. D. Hornbaker, J . A m . Chem. Soe., 74, 5514 (1952). (9) N. B. Chapman and D. J. Triggle, J. Chem. Soc., 1385 (1963). (10) G. P. Menshikovand G. 11.Borodina, J . Gen. Chem. V S S R , 17, 1569 (1947); Chem. Abstr., 42, 2245 (1948). (11) Melting points were recorded using an "Electrothermal" melting point apparatus (an electrically heated block and a thermometer calibrated for exposed stem). (12) Sometimes a t this stage the product crystallized in white needles which gave an amine with about half the desired rotation. When this happened, the product was redissolved by heating and the solution was allowed t o cool again. A similar phenomenon was noted by A. Auk [J. Chem. Educ., 42, 269 (1965) I in the resolution of 1-phenylethylamine with (+)-tartaric acid.
decanted, and the chunky crystalline mass rinsed with ice-water, filtered, and dried; yield 150-250 g, [ a I z 3 D -10 to -13" in 5OGC aqueous MeOH. A solution of the tartrate in the minimum of HzO was made alkaline with NaOH, and the free base was extracted with CHC13. The CHCL solution was dried (JlgSOI), and evaporated giving ( - )-P-hydroxyphenethylamine as a yellow oil which quickly solidified. It was converted into the guanidine without further purification. The ( - )-@-hydroxyphenethylguanidine sulfate obtained from several different batches of amine had [aIz3n -31 to - 3 3 " , compared with -34" for the guanidine obtained using ( - )-@-hydroxyphenethylamine prepared by synthesis from pure (-)-mandelic acid. p-HydroxyphenethylguanidineSulfate.-P-Hydroxyphenethylamine (100 g, 0.73 mole), 2-methyl-2-thiopseudourea sulfate (101 g, 0.73 mole), and H 2 0 (200 ml) were heated on a water bath. Methyl mercaptan, which was absorbed in a charcoal-cupric chloride trap,l3 began to be evolved about 60". The temperature was raised to 100' during 1 hr and maintained a t 100" for a further 1 hr. When cooled, the product crystallized. The @hydroxyphenethylgiianidine sulfate was filtered, sucked partly dry, and recrystallized twice from aqueous ethanol; yield 106 g, mp 224-226'. Other guanidine sulfates of Table I1 were similarly prepared. @-Hydroxy:p-methoxyphenethylguanidine Nitrate.-The sulfate salt of this guanidine failed to give a satisfactory analysis. This sulfate ( 1 g) in H 2 0 ( 5 ml), mixed with KHC03 (0.4 g) in HzO (2 ml), gave, on standing at 0' for 2 days, a crystalline hi(13) H. AI. Hill and hl. L. Wolfrom, J . Am. Chem. Soc.. 69, 1539 (1947).
