S-alkyl-&( - )-nicotiniuni iodide, .Y'-alkyl-&( - )-Iiicotiniunm iodide, and S,S'-bisalkyl-S-( - )-nicotinium diiodide which may he separated conveniently by chromatography. The compound. in Table I were eluted with 2T0hIeOH-CsH6 Identification waz accomplished by uv spectrowopy in MeOH and acidified (6 S 11B04)3IeOH.
Preparation of a-Methylhistanline f r o m L-Histidine N.R. ISON'.\NU A . F.C a a ~ Pacitlty of Pharniacy and Pharinacrul ical Sciences, Cniveysit o j d 1b d c i , Ednionton 7 , d lbc ria, C'anarla
Kecc~iz.c.t/.llai,ch , I l , 1970 0c-J tethylhistamine has been shown to possess weak histamine-like agonist acthit,!.? by its pharmacological effects on the blood pressure and gastric secretion of various test snimals and by its stimulation of the contraction of isolated guiritra pig ileum. The synthesis of this compound by :I sequence of steps has been described only once before3 : i d we now report it new and convenient route to the compound using 1.-histidine as the precursor.
Experimental Section
Derivatives of S-(- )-nicotilie which are S' quaternized show great enhancement of the maxinium occurring at around 260 mp in acid solution. The aiialogous S-quarterriized isomers show iieither enhaiicenieiit or shift of the maximum when st,udied under 1 he m i l e coiiditioiis. The hame sitiiatioil ohtains Kith .\',.\'-bis-yualeriiized S-(- )-iiiwtiiiiuni salts. .Y,-Y '-Bisalkyl-S-( - )-nicotinium Diiodides.--hu excess of the appropi'iate alkyl halide nah added to 3.2 g (0.02 mole) of S-alkylS-(- )-iiicotiiiium bromide or iodide. Reaction was continued for 7 2 hr at roorxi temp. Excess alkyl halide was evapd under vacuum at room temp. In instances when alkyl bromides were used iii quateixizatioii the reported diiodide products were obtained by halogeii exchange with KI. The crude product ( 5 g ) was chromatographed o n 50 g of \Toelm Activity Grade I neutral AI&. The conipnuiids i n Table I1 were eluted with 5-lOclL ;\leOH-CtiHti.
R
n' CiH, n-C3H; CH3 C2Ha CH 3 CjHs CH? CH i C - 6 H (-11 1 "
1)Ilecl
LIP,
230-233 220-222 176-178 206-209 235-238 236-239 176-178
H>groScoplcb
So
TO NO XO SO XO NO
Y CC,
r>
205-20X
Ill
106-198 Ye\ ZU('II0 ovel 1 ' 2 0 ,
Melting points were determined on a Thomas-Hoover Tnil l e l t capillary melting poiiit apparatus arid are uncorrected. The ir aiid pmr spectra were all as expected. During the reaction sequence for the preparation of L-hibtidiiiol from L-histidine, the literature method4 was modified during the stage iiivolviiig reduction of S-benzo2ilhistidiiie methyl ester to .~-benzoylhistidiimol; thus, a stirred suapeiisioii (rather than a solution) of L.1H (12 g ) naa used t o reduce 0.1 mole of the ester aiid the Algelfornmedduring the riornial reaction work-up was thoroughly extracted with hot 3IeOH t o obtain ,significant yield5 (ca. 7 3 5 ) of the product. a-Bromomethy1histamine.-L-Histidinol. 2HBr (mp 185-186') (1.80 g ) was dissolved in an aged red-brown solutiori of 32y0 HBr in AcOIl (40 ml) (Eastman Organics) contained in a 200-ml pressure bottle (Fisher Scientific Co.). The sealed vessel was heated a t 110-120' (oil bath) with internal magnetic stirring for 19 hr, the solution cooled and t,he solvent removed i n z~acuo. The semisolid residue was triturated with E t O H to yield a hiiff dihydrobromide product,, (1.86 g), mp 214-215' (EtOH-Et,()). :Inn!. (C6HI3Br2S3)C, H. An experiment using a fresh solution of HBr i n AcOH (strawrolored) afforded only unchanged L-histidinol and it is therefore possible t,hat traces of free Br2 catalyze the reaction. a-Methylhistamine.-a-Bromomet,hylhistanmine 2HBr (0.40 g ) was dissolved iii a solution of SaOAc (0.5 g ) in 10% aq AcOH (25 ml) containing lOy0 Pd-C (0.5 g), and the mixture hydrogeiiated a t room temperature and pressure until gas absorption ceased (18 hr). The suspension v a s filtered via kieselguhr, the solvent removed in uacito and the residual solid extracted with portions of hot EtOH. The organic solution was evaporated t o dryness and the piilk oily residue treated with arihyd Et20 t o yield the crude dihydrobromideproduct (mp 110-11.5') contaminated with KaOXc (pmr evidence). An ammoniacal solution of the product was t,reated with an excess of aq picric acid t o afl'ord the andhydrous dipicrate derivat'ive (0.39 g), nip 182-1 X 3 " iH10) (lit.r, dipirrate monohydrate, 202-204'). Anal. ( C I ~ H I ~ S1 ~ , O J ~ C, H, N. Hydrogenolysis of a-bromomethylhistamiue t o a-niethylhistamine would not proceed when either EtOH or MeOH were iised as the solvent. The product was isolated arid characterized as the dipicrate derivative after rioting the infinite solubility of the free hane in HnO which precluded any easy separation of t'hcb amine base for formation of hydrohalide salts.
Acknowledgment.-The authors thank the Medical Research Council of Canada for financial support. Acknowledgments.-l'hib rebearch and the related pharmacology has beeii generuusly supported by the American Medical Association Education and Research Foundation, Committee for Research on Tobacco and Health and the A. H. Robins Company, Richmond, Virgiiiia. The :iutliot.\ e s p r c ~\iticere gratitude for their aisiit m c e .
(1) .\uthur t u ivliutii inquiries b h U l l h ~l w addressed; Iiresent address: Department of Pharmacology, University of Cambridge. Cambridge. England. ( 2 ) (a) G. A . AlleJ, 31. A . Schull, and B. B. Visegarver. J . Pkarmacol., 7 7 , 54 (1943); (b) 31. I . Grossman, C. Robertson, and C. E. Rosiere, i b i d . . 104, 277 (1952): ( c ) A. Burger, AI. Bernabe, and P. TT-. Collins, J. M e d . Chem.. 19, 33 (1970). (3) G. .I. .\Ilea. S . H . Cliapman. .\. ,J. Tompsett, and E.R . Kisevar\.er. .I. O r y . C h e w . . 2 2 , 2 2 1 (1113T). (4) E. .\damb, H. I%aiier.and 11. T a b o r . Biochem. P r e p . . 4, 4 i (19.53).
