Notes Department of Chemistry, Stanford University

VOl. 3

Heterocyclic compounds. VI. An improved preparation of n-hydroxysuccinimide

Kung- sung !ang ", Donald N. #rattesani and #oris !einstein$ Department of Chemistry, Stanford University Stanford, California %&3'(
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*e+eived De+em,er -', )%.( Stanford, California %&3'(

N-/ydro0ysu++inimide is an intermediate used in peptide +hemistry to prepare various a+tivated esters of a+ylamino a+ids 1&,(,.,23. he +ompound has ,een 4no5n for many years 16,%,l'3, ,ut has only re+ently ,een o,tained in moderate amounts ,y fusion of su++ini+ anhydride either 5ith hydro0ylamine 1))3 o r hydro0ylamine hydro+hloride, follo5ed ,y fra+tional +rystalli7ation. 8 simple alternative to this later pro+edure e0ists in the addition of su++ini+ anhydride to a solution of hydro0ylamine, then heating in an inert solvent su+h as toluene o r 0ylene to form Nhydro0ysu++inami+ a+id, follo5ed ,y +y+li7ation under for+ed esterifi+ation +onditions to afford the desired produ+t. he prin+ipal advantage to the modified method des+ri,ed here is the a,ility to manipulate large 9uantities 5ithout the need for spe+ial apparatus and temperature +ontrol. :;<:*=>:N 8? 1)-3 N-/ ydro0ysu++inimide. 8 freshly prepared solution o f sodium 1..2' g . , '.-%) g.-atom3 in methanol 1)'' ml.3 5as poured into a stirred suspension of finely- ground hydro0ylamine hydro+hloride 1--.- g . , '.-%) mole3 in methanol 1)'' m l , 3 . he mi0ture 5as reflu0ed on a steam ,ath for ) ( minutes, +hilled in an i+e ,ath for )( minutes, and filtered to remove pre+ipitated sodium +hloride. Su++ini+ anhydride 1-%.) g., '.-%) mole3 5as added in small portions over a several-minute period to the stirred hydro0ylamine filtrate, and the resulting li9uid 5as ,oiled for - hours. :0+ess solvent 5as removed ,y distillation, toluene 1or 0ylene3 1)-'' ml.3 5as mi0ed 5ith the vis+ous NOn leave of a,sen+e from the Department of Chemistry, National ai5an University, aipei, ai5an, *epu,li+ of China $Department of Chemistry, Stanford University
"

@or the previous paper in this series, seeA #. !einstein and . 8. /ylton, etrahedron, -', )2-( 1)%.&3

hydro0ysu++inami+ a+id, and reflu0ing 5as +ontinued for another & hours. During this period, a Dean-Star4 trap 5as used to +olle+t a mi0ture of methanol- toluene-5ater 1-'' ml.3. he hot solvent 5as de+anted, and on standing deposited +rude N-hydro0ysu++inimide, m. p. 6..'-%-.'B. he residual solid in the rea+tion flas4 5as e0tra+ted 5ith a +om,ination of toluene mother li9uor and methyl ethyl 4etone 1)'' m l. 3, and on +on+entration and +ooling afforded a se+ond +rop of produ+t. he analyti+al sample 5as re+rystalli7ed from ethyl a+etate to give )..( g. 1&%B).3 of 5hite fla4es, m.p. %2.'-%6.'B, identi+al 5ith authenti+ materialC infrared +m-BA 3''' 1,road3, )22( 1s3. )2'' 1,road3, )&-' 1 s 3 , )--' 1,road3, )'2' 1 s 3 , and .(( 1 ( 3 . 8+4no5ledgment. his investigation 5as supported ,y funds from the National S+ien+e @oundation, grant D#-(62. National Coun+il o f S+ien+e, *epu,li+ of China, is than4ed for the a5ard of a fello5ship for advan+ed study to one of us 1K- . !ang3. *:@:*:NC:S 1)3 @or the previous paper in this series , seeA #. !einstein and )2-( 1)%.&3. . 8. /ylton, etrahedron, -'. he

1-3 On leave of a,sen+e fr om the Department of Chemistry, National ai5an University, ai5an, *epu,li+ of China. E. 8m. Chem. SOC., 6., )63% 1)%.&3. 133 o 5hom in9uiries +on+erning t hi s paper should ,e dire+ted.

aipei,

1&3 Deorge !. 8nderson, Eoan :. Fimmerman, and @ran+is >. Callahan. 1)%.&3. Eournal of the 8meri+an Chemi+al So+iety. doiA)'.)'-)GHa')'.3a'32, 1(3 Deorge !. 8nderson. 1)%.&3. he use of a+tivated esters in peptide synthesis. >eta,olism. doiA)'.)').Gs''-.-'&%(1.&36''---. 1.3 D. !. 8nderson 8+ta Chim. 8+ad. S+i. /ung. )%.( 123 >. ?I5, ?. Kisfaludy 8+ta Chim. 8+ad. S+i. /ung. )%.( 163 D. :rrera Da77. Chim. =tal. -(, == -( )6%( 1%3 8. Eohnson, Neues Euhr,. >ineral. Deol., =, 6% 1)%'23. 1)'3 D. :. 8mes, . @. Drey )%(( E. Chem. So+, .3) 1)%((3. 1))3 *. !egler, @. Dre5e. and K. >ehlhose, U. S. <atent -,6).,))) 1De+em,er )', )%(23. 1)-3 he melting points are un+orre+ted. he =* spe+trum 5as determined on a <er4in - :lmer >odel &-) spe+trophotometer in a pressed potassium ,romide dis4.