794
Derivatives of 6-Aminopenicillanic Acid. VI. Synthesis of Some Derivatives of 6-Aminothiopenicillanic Acid'
Alixed alkosyforriiic atihydridea (11) of vitrioris peiiic~illiiis( I j have I x x i i c ~ i i v e r t e di i i i o the cwrresputidiiig N arglated 6-arninothioperiirillanic. acids (111)4 by t reairmelit with SaSII, These penicillin i hioxids have beeii oxidized to the correspoiiding amorphous bis(acg1) disrdfides ( I Y ) by meaiis of iodine, aiid otic represeiitativcb disulfide has beeii described. In general, the penicillin t.hioacids and their wrrespoiidiiig disulfides we poteiil antimicrobial agents.
Several thiol esters of beiizyl~~ctiic~illiti hnve heen [)repared in satisfactory yields by the interactioii of thiols wit'h benzyl~~eiiicillinicethoxyforinic anhydride."." Treatment' of this inixed anhydride with H2S in thc) presence of 1 equiv. of triethylamine, however, gave only int'ractable products instead of the expected thioacid.' When t'he amount of triethylamine used in the reaction was reduced to a few drops, the only product isolated was a 69% yield of the c:orrespoiidirig cryst:illine henzylpenici,llinic thioa~ihydride.~In 1956, Johlison and Sheehan were successful iii obtaining benzylpenicillin thioacids by passing H,S into a solution of benzylpenicillinic ethoxyforniic anhydridc in the absence of free organic base. Subsequent.ly, the i t i t eresting antimicrobial properties of berizylpenicilliri thio:wid (Table I, 5 ) prompted us to convert R variety of the penicillinsg of therapeutic interest into the correspotiding thioacids'O i n order to ascertain the effects of sidechain alteratioiis on the microbiological activities of t'he penicillin thioacids. In this communication is described an iinproved procedure of general applicatioii for preparing 6-acylaiiiitiothiopeiiicillanic acid derivatives as pictured in Scheme I. Thus, a solution of the appropriate 1)enidliti (I) i i i the form of the free acid in pure dry diniethylformaniidc (DMF) cooled below 0" was treated with exactly 1 ocluiv. of 2,fi-lutidine or triethylamine. Then ethyl or isobutyl (ahloroformate was a,dded a i d the reactioti mixture was stirred at, 0" or below for 10-20 i n i t i . 'fhc resulting mixed anhydride (IT) was t heii t reated w i t h purified XaSH dissolved i n D l I P and added i i i oiic portion. After stirring for 10-43 iiiiri., t,hc mixture was ( I ) 1;or gaper V in this series see Y,G . Perron, I,. 11. ('rast. .I. 31. I < s s r r > . I l I F . The solution was cooled to 0" arid 3.3 g. (0.030 mole) of ethyl chloroformate was added and stirred for 10 min. A solution of 6.7 g. (0.06 mole) of purified N a S H (Fisher) in iS nil. of DXIF was added all at oiice and the stirring was continued for 0.5 hr. The D l I F solution was poured into 1.1 1. of ice water and acidified with 6 .V H?S04to pH 2 . The mixture was extracted three times with 500 nil. of ether. T h e ether extracts were washed with water, dried (Na2S04)!and treated with 12 ml. (0.03 mole) of 505; potassium 2-ethylhexanoate ( K E H ) i n ether. The crystals were collected, washed with acetone, and dried (P205)for 1 hr. a t 1 mni. t o obtain 7 g. of product. See Table I for analysis and properties. The infrared spectrum ( K B r ) showed absorptions ( i n cni.-') at 3325 (amide NH), 1780 with a shoulder at 1763 (8-lactarn carbonyl), 1661 (amide carbonyl), 1540 (thiocarboxyla t e ) , and 741 and 690 (monosubstituted phenyl). T h e n.ni.r. spectrum of a 1120 solution had absorptions which were assigned as follows: a singlet a t 6 7.32 due t o the 5 aromatic protons, a doublet of spacing 4.5 c.p.5. at 5.66 due t o the C-6 proton coupled to the C-5 proton, a correspoiiding doublet ( J = 4.5 c.p.s.) a t 5.51 due to the C-5 proton, a singlet a t 4.60 from the C-3 proton, a singlet at 3.77 due to the methylene protons, and a singlet a t 1.53 from the 6 protons of the gem-dimethyl groups. It was not uiiconinioii for the alkali salts of the thioacids t o resist crystallizatioii. 111 such cases a 0.5 molar equiv. of XJ'diheiizylethyleiiedianiiiie ( 11BEU) diacetate was dissolved in water and added t o a n aqueous solution of t,he thiopenicillariate. T h e resulting mixture was adjusted t o p H 6 b y the addition of glacial acetic acid. The thioacid salt was collected and recrystallized as indicated in Table I. I n Table I compounds 3, 4, and 14 were riot obtained in crystalline form b u t were purified b y trituration with the appropriate solvent. Potassium 6 4Phenylmercaptoacetamido )penicilIanate.This biosynthetic penicillinI5 was prepared in 62y0 yield by the procedure (method A ) outlined b y Perron, et al.,'8 using phenylmercaptoacetyl chloride and 6-aminopenicillanic acid; n1.p. 220-221" dec. (12) More complete microbiological aspects will be presented in a fortlicoming paper by J. A . IJach, T . Pursiano, A . Gourevitcii, and J. Lein. (13) All decomposition points are uncorrected and uere determined as indicated in Table I. T h e infrared spectra were recorded on a Beckman I R 9 spectrometer. The n.m.r. spectra were obtained in deuterium oxide o r deuteriocliloroform solution with tetramethslsilane as a. reference using a Varian -4-60 spectrometer. Optical rotations aerr determined on a R ~ d d i ~polarimeter. li (14j Described helow. ( 1 5 ) 0. IC. Behrens, R . G. Jones, Q. F. Soper, and ,J. W . Corse, U. S. Patent 2,623,876 (1952): Chem. Abstr., 47, 2914 (1953). (16) T.G. Perron, W.F. Minor, C. T . Holdrege, W. J. Gottstein, J. C . Godfres, L. 13. Crast, R. E. 13abe1, and L. C. Clieney, J . A m . Chew&. So
