483
July, 1964
Derivatives of 6-Aminopenicillanic Acid. V. Synthesis of 6-Aminopenicillanyl Alcohol and Certain Derivatives' Y. G. PERRON, L. B. CRAST,J. 11. ESSERY, R. R. FRASER, J. C. GODFREY, C. T . HOLDREGE, ST;. F. MIXOR,11. E. NEUBERT, R. A. PARTYKA, 4s~) L. C. CHEXEY Reseaich Dzzision, Rristol Labo,atoizes, Divisaon of B ~ i s t o l - M y e r sCompany, S y i a c i ~ s e1 , .\-eta Y o j k
Receiz'ed Socember 29, 1963 iicyl azides of various 5-substituted 6-aminopenicillanic acids have been prepared by treatment of mixed carboxylic-carbonic anhydrides with sodium azide. By a seldom used, yet excellent, method of selective reduction, the acyl azides were converted to the K-substituted 6-aminopenicillanyl alcohols* with sodium borohydride. Direct reduction of a mixed anhydride wit,h sodium borohydride in anhydrous tetrahydrofuran produced the corresponding alcohol, but the azide reduction is preferred. The parent 6-aniinopenicillanyl alcohol was obtained by acid hydrolysis of 6-triphenylmethylaminopenicillanyl alcoliol. Several funrtional derivatives of the N-substituted 6-aminopenicillanyl alcohols have been described.
The purpose of this report is to describe the facile conversion of S-substituted 6-amiiiopeiiicillaiiic acids (1) into the corresponding penicillaiiyl alcohols (4) iia reduction of the acyl azides (3) n-ith sodium borohydride as portrayed in Chart I.
4 Curtius rearrangement
I3 = acylamino, carbobenzoxyamino, phthalimido, and triphenylmethylamino
The possibility of selectively reducing the acyl azides
(3) to the corresponding alcohols (4) by means of' borohydride without attacking the carbonyl function of the p-lactam ring of the penicillin nucleus was suggested by the novel chloramphenicol synthesis of Ehrhart, et aL3 When the reduction was carrjed out on 6-phenylacetamidopenicillanic acid azide, prepared in situ from the mixed anhydride by an adaptation of the elegant Weinstock modification of the Curtius r e a ~ t i o i i ,aiialytically ~ pure G-pheiiglacet~amidopenicillanyl alcohol (4,R = C~HLCH&OSH-)was isolated in 78% yield based on the triethylammoiiium salt of ( 1 ) For paper IV in this series see S. Wolfe, J. C . Godfrey, C. T. Holdrege, and Y. G. Perron. J. A m . Chem. SOC.,85, 6 4 3 (1963). (2) For convenience and simdlicity t h e nomenclature adopted is based on the generally accepted trivial system of J. C. Sheehan. K. R. HeneryLogan, and D. A. Johnson, i b i d . , 76, 3293 (1953). ( 3 ) G. Ehrhart. IV. Sedel, and H. S a h m , Chem. Ber., BO, 2088 (1957j. (4) J. Weinstock, J . Ore. Cham., 26, 3511 (1901).
benzylpenicillin. It was found expedient to conduct the reductioiis without isolation of the labile acid azides, although it was demonstrated that the isolation could be accomplished. For example, successive treatment of 6-phthalimidopenicillaiiic acid (1, R = phthalimido) with triethylamine, ethyl chloroformate, and sodium azide afforded crystalliiie 6-phthalimidopenicillanic acid azide in 81% yield. After storage of the azide for 2 days a t 25" in z " x o , however, it was found that the Curtius rearrangement had proceeded with the formatioii of a quantitative yield of the corresponding isocyanate ( 5 ) . Reaction of the acid azide (3) with benzyl alcohol produced the pure benzyl carbamate (6, 1%= phthalimido) in 91% yield, thus confirming the structural assignment. Aside from the results of Ehrhart and co-workers,3 who expected their reduction product would be an amine, 110 other reduction of an aliphatic acyl azide t o the corresponding primary alcohol has been reported. It is noteworthy that Boyer and Ellzey, Jr.,j isolated a 297, yield of beiizamide as the only identified product obtained from the reduction of benzoyl azide with sodium borohydride in aqueous dioxane. Benzenesulfonyl azide and niethaiiesulfonyl azide were likewise reduced to the corresponding amides under similar conditions. Alternatively, the alcohol function Cali be obtained by direct reduction of the mixed anhydride. For instance, treatment of the mixed anhydride, prepared in situ from the triethylammoiiium salt of benzylpenicillin and ethyl chloroformate in dry tetrahydrofuran, with sodium borohydride gave a 94yG yield of 6pheiiylacetamidopeiiicillaiiyl alcohol whose purity was only slightly inferior to that produced by reduction of the acid azide. Alpparently the reduction of mixed anhydrides to the corresponding alcohols by sodium borohydride has not been described previously. Although uiisymnietrical anhydrides of certain acylamino acids have been reduced to amino alcohols by means of lithium borohydride,b this more powerful reducing agent would probably not be sufficiently selective for use in the present application, as it has been reported to cleave amide bonds.7 The striking effects ( 5 ) J. H. Boyer and J. Ellzey, J r . , ibid.. 23, 127 (1958). ( 6 ) K. Heyns and I \\ itli ~-tc~l~c~ii~siilfoiiie acid riioiioliyd~.atc~lrtl to tlw iholatioii of a 4-47; yield ui' analytically pure amiiir, alcohol i i i the form of its p-tolueiiesuli'oiiatc salt. 'L'IBLE:
I 1
10.
I
I1
111
11\-
I \SI SI1 SI11 \-
\I
S \-I \'I1
Experimentall ' 6-Phthalimidopenicillanic Acid Azide (I).----.\ solutiori iif t11.6 g. (0.10 mole) of ti-pI~tlialiiiiidtipenic.illanic and 1.2 r i l l . (0.10 niole\ of triethylurnine in :HI0 nil. of tetraliytirofuran ( T H F ) cwded t i , -IO" xiiti :i solution uf 10.8 g. (0.10 rnole) of et1 c'hloroforniate in 50 nil. of THF \vas :tdded. T h e resulting ni tiire was stirred at -10' for 1 I r . , and then a solution of 6.5 (0.10 mole) of sodium azide in 30 1111. of water was added duriiig it period of 3 0 niin. The re:tc.ticin inixture was diluted with an equal volurrie of miter and tlie cyvstallir zide thus formed T V ~ S cdltvated hy filtrittiiin, yielding :io I$. (8 ). It was c~linractc~rd tiy its iufr:tred spwtruri\: :tzitle, 2 cui. - ~ :l It lit I i u l iiiiidr , )5, li%,j,:triiI 1710 ?in.-': l?-l:ii,t:mi, 1780 i ' i i l . - - I : :irorti:ttii, ring, 792 aiicl 717 < 111. 6-Phthalimido-2,2-dimethrl-3-11enamyl Isocyanate I1 ).. \ V h m B - ~ h t h : t l i m i d o ~ ~ ~ ~ ~ i i avid r i l l u ~:ui& i i ~ ~ ~ I dried S utidt.r V:ICIIUIII for 2 d:iys :it rnotii temperature, it IVRS wiivertcvl quantitativelr t.o the i.orresyonding crystalline isoc.yitn:ite, TV:LS
(IO) A . Goureviteli. (:, t , i l i i ~ i t .J. , It. Liittinger, ('. 1'. i ' a r n m c k , :rn
