Note: Descriptions are shown in the official language in which they were submitted.
8~
~W ~n~'l~ROCYCI~tC ACE~Ia ~CID DERIVA~IV~`S A~D A :EROC:E~SS FO:R
P~`PARAr~ION ~HE~R:EOF
rrhe i~v~ntion rela ~es to new he terocyclic acetic acid
dexivativos of tha gene:ral foxmula (I)
y~ y2H :H
~ CEI COOH
H3C C _r 2
whexairL
yl arld y2 îorm together a removable carbonyl pro~ec~ ; group~
preIerably a ke tal group or a ~hioanalo~ e thereo~
and
R is a remov3ble amido protecting ~;roup~ pre~erably a benzyl
group bearing o~e or more Gi L~. alko~y ~ubstitue~ts or a
phenyl group b~ari~g optionally one or more Cl ~, alko~y
~ub~ti~ue~ts
The~e compound~ carl ba co~verted in'Go thierlan~yGi~
and relatad compoux~fl~ 6~ ;o a~ show~n on Scheme ~A~,
~661~-67 ,
-- 2 --
sch9m~ (A) }-
~2C003~
.
~CH2C~OH
ed (l~ ~ i sn
~ - CH2~0()H 2.esterif~cation
_~
0~ I R ~ C~)O
malon~c ~cid ~ Nl I
semiester sal~ 2
~o 0~
~s ~ ~2~0C~2~
v ~ - , ~-~ C~O~X
~ C) `R ~
c3 ~NH
3~slllfc nic acid ~
. ~ Qn
. . azlde Hl
t H ~ ~c~
N~C(~ L3
f n
~ m cllsrl iC a~i d
O \~ . 5ellrlie5tel' 5alt
O~NH
9c ~
c~c~
:~89~
- 2a -
Scheme ~A~ contlnueJ
~3
H~G~2
~NH
~h~ salt
H
~N~C ICIQ
O- ~yl~ti~
mercaptan
rm~
~3
- ~
D
~ 5
3 ~
In the formulae shown on Schema ~A) yl~ y2 and R ars
as definad above 9
X is a selectively r~movable esterifyi~g group~
Q is a Cl 5 alkyl g~roup or a substituted benzyl group~
Q9 is a Cl 5 alkyl group9 a substi~uted benzyl group9 hydro-
ge~ atom or an al~ali metal ion~ and
R" is a benzyl, aminoe~hyl or .~-acyl~aminoebhyl group
~hienamyci~9 a~ antibiotic o~ broad spectrum o~
activity, wa~s prepared firs~ on microbiological way (US patsnk
specification No~ 399509375) and later on by ch~mical syn~hesis
(German Qffenlsgungsschrift NoO 2~751~597)~
Qur aim was to provide a new route for the synthesis
o~ thianamyci~ and its analogues, wherain bhe azethidi~o~e
skelston and the ~-hydroxyethyl side chain, or a sida chain
which can be conver~ed easily into ~-hydroxy~hyl group~ are
~ormed simultaneously at the aarly stage of th~ sy~thesis,
and the resulting key intermediate is conve.rted then i~o the
desired end~produc~
It has been foun~ tb.a~ whe~ a dialkyl (protecbed
a~ino~malo~ate is acylated with diketene and ~he resulbing
acylated product i5 reactad wi~h iodine and an alk~li me~al
alcoholate7 an azethldi~one compound. o~ the g~naral ~oxmula
(VI)i 0
H3C - C ~ ~ (Cz)2
/ ~ ~VI)
0 \ R
containing an ~-ace~yl side chain7 is ob~ain~da which can be
u~ilized as key inte~mediata in the synthasi~O
In the above ~ormula -R has the same maaning as givan
30 abov~ and Z i9 a Cl_5 al~y~ g~oupO
_ L~ ~
The in~ermediates o~ the general formula (VI) and
'their preparation are dsscribed in detail in our
Hu~garian patent ~o. 181,186. The preparation of these
intermediat~s is also described in the examples of the
present application.
It has also been observed that7 prior to converting
the intermediate of the general formula ~VI) into thiena~
mycin or an analogue thereof~ i~ is prefera~le to protect the
keto group of the ~-C-a~etyl side chain with a group9
particularly a ketal group or a thioanalogue th~reof, which
can be removed at a later stags of the synShe~is~ Ethylene
glycol or a thioanaloguo thereof, such as mercapto-ethanol,
can be applied particularly preferably to ~orm the ethylene-
~etal or hemithioketal pro~ecting groupO The resulting com5 pound of the general,formula (V),
l y2
H3C - C ~ (cooz)2
~ _ ~ N (V)
O ~R
20 wherein R, Z9 -~1 and y2 are as dofined above9 is raacted
then with an alkali metal halide in pyridine or a related
solvent or in aqueous dimethyl sulfoxida to obtain a compou~d
of the gen~ral formula (I~) 9
~1 ~ H
25H3C - C -'- t ~ cooz
' 0 ~ N R (IY~
wherein R9 yl7 y2 and Z are as dafined above~
' 'llhe resul~ing oompound of the general formula (IV) is
a ~ ture o~ cis and trans iso~ersO '~he isomers can ba
-- 5 --
~eparated from each other by chromatography or on the basis of
their different solubilities. The separated trans isomer of
the genexal formula (IVa)
y\l~ COO~ ,
~ ¦IVa) ,
ca~ be converted into the trans carboxylic acid of the ~eneral
~ormula (III)
yl y2 H H
H3C ~ r COOH
~ ~ (III)
\ R
by hydrolysis~ It i8 ~ore preferable, however~ to subject ths
isomeric mixture itself to hydrolysis, since the raac~ion is
sslective, i.e. only the trans ester convert~ into the
respective carboxylic acid.
Some of the compounds of the general formulae ~V~,
(IV) and (IVa) are described in our previous Hungarian patent
No. 180,608, whereas t.~e other representatives of
these compounds and the compounds of the general formula (III)
are de~cribed in our co-pending pa~ent application~ D The pra-
parat~on of the compound~ of the general formulae ~VI) to
(III) is also described in the examples of the present applica-
~ion.
The separated trans carboxylic acid of the gsneral
formula (III) is reacted first wi~h an activator for the carb-
oxy group and then with diazomethana~ and the resulting com-
pound of the general formula (II) 7 wherein R, yl and ~ are
as defined above~
-- 6
yl y2 X H
COC~2
,L
i~ subjected to diazoketione exchange (Wolf~ rearraxlge~
ment) i~ the presance o~ water~ In bhis lat~Gex stap ~he desired
products o:~ the gen~ral formula (I) a~e ob~ai~d"
The compnunds o.~ l;he general ~ormulac ~I) bo (VI~
ar~ racemic mix~uresO
Based on ~he abov6~ the inve~tion rela~os ~o a proc8
î or the prapara ~io~ oi a ~ew compound of ~he ge~ral ~ormula
( I) ~ wherein
yl a~d y2 ~orm ~ogether a removable carbo~yl protecting group~
preIexably a ketal group or a ~hioanalogue thereo
and
R is a removable amido pro~ectiDg gro~lp~ prefarab~y a be~z~l
group beaxing o~ or more C1_L~ alko~y substi~uen~ ox
pb~nyl group bearing optio~ally on~ or more C~ ox~
~ub~tu~ J0 ln 3uoh a w~y ~h3t
a compou~d o~ the general ~ormula (III) 3 wherai~ R~
~1 and y2 are a~ defined above~ is ac~iv~ted o~ ~he carbox~
group and the~ reacted with diazoma~han~ wh~reaf~0r the
rasultl~g compou~d o~ the genaral ~ormula ~ 3 wherei~ R~ Y~
and ~ are a9 defi~ed abova~ is ~ubjec~0d to diazoketo~a
exchan~a in the presenca o~ ~a~er~ or
a compou~d o~ the ge~eral ~ormula ~ wherein R~ Y~
and y2 ars a~ de~ined above~ is ~ubjec~ed to diazoketone
exch~nye in th~ pr~sance o.~' water~
~O and the resul~ing produo~ o~ ~he general ~ormula (I~
8~86
7 --
is s0para tedD
'~he prepara~ion of the starting substances of the
general forlllula (III) is described in detail in the exampl~sO
The azethidin~carbo~ylic acid of the general formula
~IlI) is activated fîrst o~ the carbo~y group~ Any activati~g
agsnt compatible ~ith the ~lacta'm ring can be a,pplied for
this purposa~ I~ is pre.ferred to activat~ ~he carboxy group as
a mixed anhydride~ fo.r which purpose ethyl chloroformata pxovad
~o be a parti.cularly suitabla reactant~ ~he mi~d a~hydxide
is formed in the presence of an acid binding agent, preferably
a ~ertiary amine~ The sal~ of the tertiary amine which
separates from the reaction mixturs can be removed aasily~
The activated form of the compound of formula (III) is
reac~ed ~hen with diazomethane~ Diazomathane is prepa.red pre~
~erably from N~methyl-N-nitroso-urea and i.s added to the re-
action mixtuxe pref0rably as an etheral solu~ion~ Whe~ the
.ga~ evolution ceases; the excoss of diazomet'hane is d0compo~ed
pre.~arably with acetic acid, and the rasulting compound o~
tha ~en~ral foxmula (II) is ssparated from the react~on m
tureO I~ necessary~ this product can be purifi~d ~Og~ by
co'lum~ chromatography~
Thereafter the resulting com~?ound o~ the general
~ormula (II~ is subjected ~o Wolff rearrangement, whereupon
~he ~~diazoketona side chai~ converts first in~o ketane by
nitrogen slimina~ion~ and ~hen i~ reacts with wa~er to ~orm
the dasired product of the genaral formu'La (I)~
Wolff rearrangement can be promoted with a cataly~
b~J ixradiati-~g the mixture with ultraviolet 'Light 3 by ther~al
treakment~ and an~ combi,nation thereo~ Irradiation with ultra
violet li~,ht -~ro~red to be pa:rticularl~J pre~erable~ I:rradi.ation
~ 8 -
can be per~ormod e g. in a photor~actor, pre~arably under inert
gas atmosphere, in the presenca of water and optionally a~
inert organic solventO
The resul~ing product can be separa~ed from the roacO
tion mixt~rs by evaporatioll and/or phase trans~er msthods~
and ca~ be puri~ied e~g~ by recrystallization, if nacessaI~O
The i~ven~ion is elucidated in detail by the aid of
the ~ollowing non-limiting ~`xamples~
~r ~ ~ ~
A mi~ture of 2025 g (6 mmoles~ of tra~s-4~-tdiazoacetyl)-
1-(2 9 L~dimethoxybenzyl)-3-(2-methyl 1,3-dioxolan~2~yl)-2~az~
ethidino~o~ 100 ml of paroxide-Lree tetrahydrofuran and 50 ml
of water is irradiatod ~or about 4 hours with a high~pr~ssure
mercury lamp ~EIPK 125~5 immersed into the reac~ion vessel mad~
o~ pyrex glass~ under argon atmosphere~ rl`he solution is
evaporated in ~acuo to a final volume of 50 ml, and the con-
centxate ls dilutod with water to 1~0 mlO 2~4 ml of a lO~o
aqueous sodium hydroxid~ solution are added to the aqueous
mixture~ and the alkaline mixture- is washed thrice with 20 ~1
o~ dichlorom~thane, each. ~hereafter the aqueous phaso is
acidified to pH - 2 with concentrated aqueous hydrochloric
acid. The acidic solution is extracted khrice with 20 ~1 o~
dichlorome~hane, each9 ~he ex~racts are combined~ dried over
magnesium sulfate3 Yiltered, and the iiltrate is eva-poraked
to dryness~ ~he rasidue is crystallized with ather~ 1~82 g
~83 %) of th~ aimed compound are obtained as a whiteg
cx~y~talIine substance~ mOpO~ 124C (ether)0
IR (KBr): 3500-23009 ?9001 1730~ 1700 cm 1,
~ g _
Analysis:
calculated for C18H23N07 (365~37):
C0 59.17 ~0~ H: 6~34 %, N: ~.8~ %~
~ound: C: 59.22 (~0, H: 6.49 %, N: 4~07 %O
~he staxting substancs can b~ prepared as ~ollows:
a) A mix~ure of 10907 g (0~66 mola) of 2~dimethoxy~
banzaldehyde9 72 ml (0366 mole) of banzylamine and 660 ml of
methanol is stirred at room temperature for 20 minute~3 where~
upon a claar solu~ion is obtained from the susp~nsion~ The
solution is cooled with ice water9 and 1302 g (0O33 mole)
of sodi.um borohydride are added to i~ in small portionsO
rrhe progress of the reaction is moni~orad by thi~
laysr chromato$raphy (Kieselgel G according to Stahl; develop~
ing solvsnt: a 9.1 mixture of benzene and ace~one)~ and at
tha end of the reaction the mixture is e~aporated to dryne~
in vacuoO ~he residue is admixed with 300 ml of watar~ a~d
the aqueous mixture is extracted with 500 ml, 200 ml and 200 ml
portions of eth0rO The ether~al solutions ars combined~ dxied
ovax magnesium sulfata~ filtered, and then 112 ml (0066 mole3
o~ diathyl bromomalonat~ and 9~ ml (0.66 mole) of ~riethyl
amine are added to the filtrate9 rrhe raac~ion mixture i.s
stirred at room temparature for 2-3 days. rrhe separatad kri~
ethyl ammonium bromide is filtersd off and washed with etherO
'rhe mother liquor is evaporated, and the residue is re~
cr~stallized from 150 ml o~ ethanolO The resulting 210 g o~
crude product ~e recrystallized again from 400 ml of ethanol
to obtain 197 g (72 'Y0) of diethyl ~-benzyl_~(2~4-dimethoxy-
benzyl)-amino-malonate; m.p~: 62-6~C (ekhanol)O
IR (~3r)o 1750/1725 cm 1 9 d,
~O b) 61~7 g (00149 mole3 Or diethyl N-benzyl~N~(2~4~di
8~iS
-- 10 --
m~thoxybe~zyl)~ami~o~malo~ate3 pr~pared as describad i~ point
a) abov~ are hydrog~natad in 500 m.l o~ et~lanol under atmo
sph~xic p.r~ssure in tho presenc~ of about 20 g o~ p~ dium~
o~charcoal ca~alystO The catalyst -ls ~ilt~red of~ a~d tha
.~iltrato is ~vaporatsd~ ~701 ~ (97 %) of di~thyl ~2~4-dime~h~
o~ybenzylamino)-malonata aro obtainsdO ~ho product can b~
converted into i~s hydrochlor~.de by r~acting it wi~h hy~ro~
chloric ~cid~ The hydrochlorid~ malts at 122-124C a~r
crys~allizatio~ ~rom ethyl acetate~
~nalysis:
calculatad for C16H2L~ClM06 (361082)
C: 53011 %3 H~ 6~69 %9 Cl: 9~80 %, N: 3~B7 %a
~ound~ C: 52~51 %9 H: 6.77 %~ Cl: 10030 %9 ~ 4~09 %o
IR (~ilm): ~250~ 2900, 2850, 1730~ 1720 cm 1,
H ~ (CDC13? ~ = 1.3 (s~ 6H)~ 3~7~ (s~ 3H)~ 3082
(87 3H) L~-21 (q~ L~H)~ 6~20 (sg 2~I) D 6~L~6~6 ~m~ 2~) ~ 7~3-7055
(m~ lH)~ 797 (broad s) lH) ppm~
c) ~ mixtura o~ 3906 g (00122 mola) of diethyl l2
dimethoxybenzylamino)-r~ lona~e~ prepared as describ~d in poi~
2Q b) above; 80 ml o~ ~lacial ac,etic acid and 1203 g (11~2 ml~
00146 mole) of dikotene i5 boiled for 005 hour~ Glacial acetiG
acid is dis~illed of.~ in vacuo over watar b~h~ and the oily
r6sidu~ is triturated wi~h 150 ml of watera Th~ re~ulting
crgstalline substancc is di.ssolved in 60 ml of ~thyl acetat~
and pxecipitated with petrolaum ethorO 29,6 g ~60 ~ of di~
athyl N ~2~4 dimethoxybanzyl) 3-hydroxy~3~methy~ 5~0~0~2g2
pyrrolidine-dicarboxylate and/or its tautomor are obtai~d~
m O p.: 106~107C.
Analys~s:
calculat~d r~ C20H2.7~J8 (~ 9 3
~1 -
58967 %~ H: 60G~ %9 N: 33~2 %~
~ound~ C. 58079 %~ H~ Go~ %~ N. 303~ %0
IR (I~Br): 3~009 2950~ 2850~ 1730 (1740~ sh)~ 1710 cm
~ NMR (C~13): ~- lol (~ 3H) 9 1017 (~, 3H) 9 1~52
f s~v3H) 7 208 (~ Ool ~) 9 2065 (broad 93 2H) 3 3075 (s~ 6E)~
~8~4015 (m, 4H) 3 6~7 (bxoad s~ 2H) 9 6~25-6045 (m) ~ 74~7~25
~m~ 3H) ppm~
d3 20o5 g (50 mmol~s~ o.~ th3 product pxapared as de~
scribsd in point c) abov~ ar~ suspo~dsd i~ 50 ml o~ dr~ ~hex~
a~d a solutio~ o~ 3045 g (150 mmol~s) o~' m~allic sodium i~
100 ml o~ dry othanol and a solution of 1207 g (50 mmolos) o~
iodins in 150 ml o~ dry ~her aro added simul~an00usl~ ~rom
~wo dropping ~u~nels~ to the vigorously stirrad su~pensio~
under cooling with ice water~ ~h~rea~ter 5 g o~' sodium hydxo~
sulfite3 dissolved in 200 ml of a saturatad a~u~ous sodium
chloride solutio~9 are added to the stirred mixture. Th~ mix~
~ure is fillod i~to a separating funnel and 60 ml of water ar0
added to dissolve the ~oparated inorga~ic ~alks. ~he oxganlc
pha3e is removod, dri~d over magr~esi.um ~ulfato1 .~ilter~d~ and
~0 the ~lltra~e ~3 evaporatedO '~he oily re~idue7 w~ighin~ 1805 g~
i~ cry~tallized from ~0 ml o~ 2-propanol3 10~9 g (5~ %) sf
die~hyl 3-ac~tyl~ 29L~dim3~hoxyb~zyl~4~0~0~292~aze~hidIne~
~icarboxylate are obtain3d~ m.pD 84~85~ ~2~propa~01~3
A~aly~iso
calcula~ed for C20H25N0~ (407041~:
c: 58~96 %9 H, 6~19 %9 N~ 3~ %9
~ound: a: 58099 %9 E: 6~04 %~ N. 3057 %p
lH NMR (GDC13): ~- 1012 (t, 3~) 9 1.21 ~t/ 3H)~ 2031
(~ 3H)~ 3~76 (s) 6H), 3.8~3.~ (rn~ 4H) 7 4~53 (d, lH) a 4~63
(d, l~f)~ 4069 (s~ lH)~ 6~3~60L~ (rn7 2H) * 7,07 (d~ lH) ppm~
~9~5
~ 12
e~ 179 ml ~206 g9 1~452 molq~ o~ boro~ trifluor~de
diath-gl e~herate axa added dropwis3 to a v1gorous~y stirrecl
solu~-io~ o:E -179 g (00484 mole) of diethyl 3~ac~tyl~ 294~di~
me~hoxybenzyl)-4-oxo-292-azethidine~dicarbo~yLate a~d 107 ml
( 120 g~ 10936 moles) of ethylene glycol in 500 ml of dry di~
oxane undar cooliDg~ wi.~h ice wa terO '~h~ reaction mi~t~re i~
allowfld to stand at room t0mperature ~or ox~ day~ dllring l;his
period th~ mixt~re is occasionally stirr~dO '~hsrea:Eter
415 g ( 10452 mole~ of Na2C03,10H2o are
added ~lowly ~o the stirred mixtur3 und~r cooli~g with ~ce
water3 and the mixtur0 is stirred for 15 mi~u~es~ '~hereaft~r
1 litre of e ther and 1 litre o~ water are added~ and th~
phases are separated from ear,h otherO The aqueous phas
sha~e~ twice with 500 ml of diethyl ether; eachO ~he e~heral
phase is dri~d over magnesium sulfate~ filtered~ and ~he
filtrate is evaporated.u 33~9 g (0058 mol~) of sodium chlorid~S
170~ ml (0.968 mole) of water and ~20 ml o~ dimethyl sulfoxide
are added to the residue, and tha mix~ure is ~tirred on a~
oîl bath at 180C. The progras~ of the rsaction i~ monitorad
by thin layer chrom~to~raphy (adsorben~: ~leselgel G accordi~g
to Stahl.; developing solv0nt~ a 6:4 mixture of ben~c~e a~d
eth~l acetate)~ At ~he and of the reaction~ iOe~ a~ter about
15 hours, the mixture is pour~d into 1100 ml of saturatcd
aqueous sodium chloride solutio~ and th~ resulting mixture
i9 shakan with 1000 ml and then twice with 500 ml of diethyl
ather~ eachO ~he etherea'solut`ions ara combinad9 dacolou~i~ed
wi~h charcoal~ driad over magnesium sulfata 3 and tha filtrata
is evapora ted to a final volume of cca, 200 mlO Thi~ con-
cerltra~ed solution is coolod with ice water to obtain 59 g
(35 %3 of trans -ethyl 1-(2 7 ll~dimethox;yb~næyl) - 3-~2~methyl~13 3-
9~s
dioxola~2~yl)~4-oxo-2~azethidine-carboxyla~e; mOp.~ 95C.
~) A mixture o~ 0~5 g ~102 mmoles~ of diethyl 3~ace~y1
1~2~4~di~lethoxybenzyl1~4-oxo-2,2~azethidine-dicarboxyl~e~
prepared as desc:Libed in point d) above, 3 ml of dry te~ra~
~y~ro~uran and 0053 g (306 mmole~) of mercapto~etha~ol is ~oiled
:~or 4 hours, and then 10 ml of' water and 10 ml o~ chloroform
are added to the reaction mixture. The organic pha~e is
separatad) washed with a 5% aqueous sodium ~ydrocarbo~ak~ solu~
tion9 dried over magnesium sulfa~e, filtered9 and the pxoduct
is separated ~rom the ~ rate by prepaxatî~e ~hin layer
chroma~ography (adsorbent: Kieselgel 60 PF254~366, de~eloping
solvellt: a 8:2 mix~ure o.~ toluene and ac~tono). 0.30 g (53 %)
of diothyl 1-~2~4-dimethoxybenzyl)-3-(2 methyl~l73~oxathiolan~
2~yl)~4-oxo-292-az6~hidine-dicarboxylate are obtain~dO
lX NMR (CDC13): G~ = 0 8~1055 (m~ 6H) 9 1072 ~ 1.77 (d9
3H); 209-304 ~m~ 2H); 3~75 (s~ 6H), 400-500 (m, 9E)~ 6~4 (m9
2H) ~ 701 (d, lH) ppm~
g) h solution of' 5421 g (0.130 mole) o~ sodi.um hydx~
oxide in 60 ~1 of water is added to a suspension of 4102 g
(OolO9 mole) o~ tran~s~ethyl 1~(2~4~dimethoxyb~nzyl~-3~(2~m~thyl~
1~3-dioxolan 2-yl)-r4-oxo~2-azethidine-carboxylate 9 prapared
as described in poin~ e) above, i~ 50 ml o~ ethanol u~der
stirring and coolir~ with ice water3 and stirring is con~
tinued until a clear solution is obtained (about 20 ~inut~)0
100 ml of wa~er are add~d then to the solution; and the mix~
ture i5 shakerl with 100 ml of etherO ~he aqusous phase is
acidi~ied ko pH = 1 with concentrated a~ueous hydrochloric
acid9 and then shaken quickl~ wi~h 100 ml and twice with 50 ml
0~ diChloro~De~hane 9 each. ~'he dichloromethane solutions are
~0 co~sl'Dine~, dried over magnesium .sulfate; filtex~d7 and the
-- l L~ 9 ~, 5i
filtrate is evaporated3 Thfl oily residue is cr~y3tallizec1 from
a mixture of toluene and petroleum ether to obtai~ 35 g (92 %)
of trans~ 2~4~dimetho.xybenzyl)-3 (2-methyl-1 3 3-dioxolan~2
yl)~L~oxo~2 azethidirle-carbo~ylic acid~ mOpo 117-118C
(t~luene)0
Analy~is:
c~lculated for C17H21N07 (351~35)
C ~ 58 oll %~ H 6 ~03 %~ N~ 3 ~99 %;
fou~d: C: 58017 %9 H: 6~30 %~ N- 4n24 %~
IR ~I~Br3: 3500-2500~ 29009 17609 1720 cm`l~
lH NMR (CDCl~)o ~ = 1039 (Sg 3H)~ 3O50 (d, lHg a = 2~5
Ez), 3~77 (s~ 3H), 3079 ~s~ 3H) ~ 3~86 (d, lI-I~ J = 205 Hz) 7 3a96
(m, 4H) ~ 4,21 * 4~56 (d~ 2H~ JAB= 15 Hz) 9 6044 (m~ 2H) ~ 7015
(d~ lH~ J = 10 ~z)~ 7~58 (broad s, lH) ppm~
h~ 7~ ml (52~5 mmoles) of triethyl'amine are added to
a solutio~ of 17~6 g (50 mmoles) of ~rans-1-(2,L~di.methoxy-
benzyl) 3~2 methyl;l93-dioxolan-2-yl)-4 oxo~2~azethidine-carb~
oxylic acid9 prepared as described in poi~t g) above, i~
150 ml of d~'t~tra~ydrofuran, and then 500 ml (52~5 m~oles)
2~ of ethyl chloroformate ar3 added to tha mixture undqr cooli~g
with ice~ The mixture is cooled to -15C, sti.rred at this
temperature f'or 20 minutes, and the separated triethyl amine
salt is f'il~ered off at the same temperature under axgon atmo~
sphareO A solution of 150 mmolss o~ diazomethan6 in 230 ml of
cold diethyl ~t'nor is addad ~o the ~iltrateO ~he mixtuxe i5
stirr~d9 al'lowed to warm to room t~mperaturo~ a~d a~ter 2 hours
o~ stirring i~ is evapoxated to drynessO ~'he bro~ thick
residue is disso].ved in 20 ml o~ ~anzene, and khe produck is
separated by column chromatography (adsorbent: 150 g o~ Kiesal-
~0 gel 60, ~ = 0006~0~200 ~, eluting agent: a 7~2 mixture o~
~39~5
5 ~
benxene and ac0t;0ne)0 12~0 g (64 %) of trans~(diazoac~tyl3~~ 4 dimethoxybenzyl)~3-(2-methyl 193-dioxola~-2~yl)~2~az~
ekhidinone are o~tainedO
Ana ly5i 5:
5calculated for C18H;~lN306 (375037): C: 57~59 %, H~ 5064 %~
~ound: C 57078 ~ H. 5~9 %3
IR (KBr): 29009 ~1103 1760 cm 1,
Exam~
10 ~aL=~oxo-2-a z~cid
3 . 3 g ( 0~ 01 mole) o~ trans-~(diazoacetyl)~3~(2-m~thyl~
193~dioxolan-2-yl3-1~(4-methoxyphenyl)-2~azethid~none are di~-
solved in a mixturo o~ 50 ml o~ wator and 100 ml Or tetr~
hydro~uranO ~he mixtura is irradiated with a high pxe~sur0
mercury lamp in a photoreactor under nitrogan atmosphare a~
room temperat~e~ and the progrsss of' ~he reacbion is monitoraa
by thin layer chromatography (adsorbent- Kieselgel G according
~o Stahl~ dev~lopi~g solvent: a 7:1 mixture o~ benzene and
acetorlo)" When kh~ reaction is ove:r~ t~trahyaxof`uran is
20 distill~d o~f in vacuo, I;he residue is rendcred alka~ nc with
20% aclueous ~30dium hydroxide solution, and ~h~ ~olutio~ is
washod twice wi~h 15 ml of dichlorom~tharle ~ oachO ~hc aqueous
ph3~e is acidiîied ~o pH 1 2 with conc~ntrat~d aqlleous hydro-
chloxic acid and ~he~ extracted thrice with 20 ml of dichloro~
25 me thane ~ oach~ ~he orgarlic phasas a~e combins~ driod over
magnesium sulfate3 îilteroda and th~ îiltrat~ is ~vaporal.0dO
106 g (50 %) o~ the eimed compound are obtai~ed3
Ana lys is:
calculated ~or C16H19N06 ~321~33
C: 59080 %, H: 5b96 %, N: ~36 %~
865
found- C: 59060 %~ H: 5076 %~ N: 4v08 ~0
IR (film): 3500-2500~ 1760-1700 cm ~0
~'he starting substance can be prepared as ~ollows~
a) A mixture of 24-o6 g tl~ mole~ o:E 4- methoxyanilino
and 23"9 g (17 ml, 0.1 mole~ of diethyl bromomalonate is
stirred at room temperature for 2 days,, The resul~i~g mass i5
triturated with 100 ~nl o.f` diethyl ether9 the separated L~meth~
oxy-anisidin~ hydrobromide is filtered off and wash0d with a
small amoun~ of die~hyl e~herO The mothar li~uor is ~vapoxat~
0d and the r6sidue is crystallized from diluta acetic ~lcido
1302 g (47 ~o) of diethyl (4-mc~hoxyf~nilino)-malonate ar~ ob~
tained~ mOpO: 64~65C (ethanol).
Analysis:
calculatod for C14H19~5 (281-31
15C: 59077 %) lI: 6.~1 %7 ~: 4~,99 %~
~ound- C: 59099 %, H: 61~97 %~ N: 5025 %"
Bx): 3300, 17757 1725 cm lo
LH NDqR (CDC13): ~- 1.23 (t~ 6H, J = 7-2 H~z~ 9 3-~7
(s, 3II), 402 (c, /~H~ J = '7~.2 Hz)~ 4O62 (s~ lH~, 401_L~o5 (broad
s, lH~ 6055 (2H) ~ 6073 t2H9 AA'BB9~ J = 9 Hz) ppmO
b) A mixture of' 1102 g (0004 mol~ of dieth~l (L~meth~
o~yani:lino)-malonate~ prepared as described in point a) abo~r03
15 ml of glacial acetic acid and 4 g (3.7 ml~ 0~,048 mol~) o~
diketena is boiled for 0~5 hour~ The solution is evaporatad
25 ~n ~acuo, the oily residue is tril~urated wit;h diethyl other3
and the solid is Liltered of:~. 10~5 ~ (72 %) OI diathyl
1~(4~methoxyphen~ hydroxy~3~methyl-5~oxow2,2-pyrrolidine~
dicarboxyla ta and/or it~ tautomar are obtain~d, m"p,,~
1~6~137C (~thyl aceta~o~.
3~ IR ~KBr3~ 3600-3C00~ 176(), 1740~ :L685 cm 1.
17
Anal~sis.
calculated f 017 Cl~H23~07 (365~38):
C 59~17 %, H: 60~9 %, N. 3~83 %7
found. C0 5~3098 %~ H: 6090 v~? N: L~oO4 ~0O
lH N~ (C~Cl~ 0? (t, ~Hg J = 7~2 Hz)~ 1028 (~
3H9 J = 702 Hz~9 1~58 (S9 3H)~ 2~76 (s~ 2H)7 306~ (S9 l~I)9
3~76 [S9 3H), 401 (q~ 2~9 J = 7~2 H~)~ 4~27 (q~ 2H7 J = 702 Hz~ 9
607 ~2H~ ~ 7~0 (2H, AA9~B9) J = 9 Hz) ppm~
c) 901 g (0.025 mole) of diethyl 1-(4~mathox~phsnyl)-~
3~hydro.xy~-mathyl-5-oxo-272~pyrrolidi.ne-dicaxbo.~-,ylat~ pr0-
pared as described in point b) aboveS are suspended .in 50 ml
of dry diethyl ether) and a solution of 1.72 g of metallic
sodium in 30 ml o~ dry etha~ol and a solution of 6335 g (03025
molo) of iodine in 50 ml of dry diethyl ekher ar~ simul-
tan00usly dropped inko the suspension under vigorous stirring
and cooli~g with ice~ rrhereafte.r the mix~ure is poured into
100 ml o~' a sa~u.rated aqueous sod-ium chloride solution~ and
2 g o~ sodium hydrosul~ite and 2 ml of glacial acetic acid are
addedO rrhH ethexeal phase is separa~ed, and ~he aqueous phasa
is e~xtracked khrice with 50 ml of diethyl ether9 each3 r~h~
~there~ phases ara combined, drisd over magnesium sul~at~
filtared7 and ~he ~ilkrate is evaporat~dJ The oily residu~
i~ txi~urated with 2-propanol to obtain 6~2 g ~68 %~ o~
crys~alli~e die~hyl 3-ace~yl~ methoxyphenyl)-4 oxo 2~2
azethidina dicarboxylate; m~pO- 70-71~ (e~hanol)~
Analysis:
calculated ~or C18H21~07 (363.38):
C: 59050 %, H- 5~82 %, N: 3085 %~
~ourld~ C~ 59004 %, H: 5084 %, N- 4.08 %.
IR (KBr): 17607 17~5 7 1720 cm 1,
891~S
8 _
H NMR (CDC13)~ ~= 1.20 ~t, 3Hg J - 7~2 Hz3~ 1022
(~ 3H~ J - 702 Hz)~ 2.~3 (59 3H)~ 3~7 ~9 3H) 9 4017 (q~ 2H~
J = 7.2 Hz)~ 4~19 ~q9 2H3 J = 702 Hz), 407 (~ lH)g 6~7 ~2.
7~1 (2H9 AA'~B' 3 J = 9 EIz) ppm,
d) 6 g ~000155 mole) o~ diethyl 3-acetyl~ (4wm~ho~y~
ph~3~1)-L~o~o-~g2-aæet:~hidin~3-dicarbo~ylal:i~J 9 pr~par~d ~
de~cribed i~ poi~t c~ abovs~ are dissolved in 20 ml o~ d~y di~
o~ane and 4~1 g (3075 ml, 01066 mole) o.~ ethyl~ne glyCO~-D
701 g ~6~3 ml~ 0~05 mole) o~ boron trifluoride--diathyl ether2te
complex are added dropwise to the stirred solu~ion under iC3
coolingg and the rsaction mi~ture is stirred fo.r addi~.onal
2 hours at room temper~ureO The solution is rendered alkaline
with saturat~d aqueous sodium hydrocarbonate solution~ thsre~
af~er 100 ml o~ water are added~ and the mixture is axtracked
thrice with 50 ml oî die thyl e ther, each i Th~ organic phases
~re combined3 dried over magnesium sulfate9 f'ilterod., ~nd ~h~
. ~iltra~e is ~vapora~ed~ Tho oily rasidue is triturated wi~
die thyl o thar to ob tairl 6 g ( 89 %) o:E cxys ta llinc die l;h~T1
3- (2~m~thyl~1 j3~di.o}~olar:l-2~ (L~me~ho~ph~ ? ~4~oxo~2~2~
aze~hidin~Ddicarbo~yla~e; m.p.~ 82~83~C (ethanol~0
lysis:
, . calcula~ad ~or C20H25N0~3 (L~07043)-
C: 58396 %j H: 6.18 %9 No 3044 %"
~ound: C: 58~70 %9 H: 5~68 ~9 N~ 3363 %0
IR (KBr): 1740 cm 1 (broad)
H NMR ~CDC~33 ~= 1.17 ~'l;7 3~I~ J -- 7-~ Hz) ~ 6
(~ 3H3 J = 702 Hz), 105 ~s~ 3H) 9 307 (~ 3H) 9 3~9 ~m, 4H~
~92 ~m7 5H) ~ 6~67 (2H) ~ 7034 (2Ha, AA9~:B9 7 J ~ 9 Hz) ppmO
~)~11 g (0~0245 mole~ o.f di~thyl 3~(2~m~1;hyl~133~di~-
oxolan-2-;7l)~l-(4-me~hox,~pher1yl)-4~oxo~2~2-azethidin~dicarb~
1365~
- 19 -
oxylate~ pr~pared as dflscri~ed in point d) ~bova~ aro dis~
solved in 20 ml of dimethyl su~ oxide 9 1D72 g ~0~0295 mole~
o~ sodium chloride and 0.9 ml ~0~049 mole) o~ water are added~
a~d the mix~ure is stirred at 175C ~mtil a complete reaction
i~ obtaîned~ r~he progrsss of the reaction i.5 monitored by
thin layar chromabography (adsorb~nt: Kicselga:l G according
to Stahl~ dev~lopi.~g solvent: a 6 4 mixtura of b~n~fl~e and
ethyl acetate)0
~he mixturo is cooled~ poured into 150 ml of a ~at~ra~
ed a~ueous sodium chloride solution, a~d oxtractod thrice with
50 ml o~ diethyl cthqr, each~ ~he orgallic phases a.rfl comhi.ned~
dried over maOrnesium sulfate, filtered, and the filtra~e i9
evaporated. The resulting oily residue 9 wsi.ghi~g 6 g9 iS dis~
solvad in 25 ml of 96% ethanol~ and a so;lutio~ of 0072 g (0~018
mole) o~ sodium hydroxide in 10 ml o~ water is added to bhc
alcoholic mix~ure u~der cooii~l~ with ice water~ ~he mi~ture
is stirred fox 005 hour, then dilutod with 50 ml of water and
~ashed twice with 25 ml o~ dlchloromethane 9 sach~ The aquoous
~ ~phase is acidi.~ied bo pH = 1 with concentrated aquaous hydro~
chlorlc acid, and then sxtract~d thricfl with 25 ml o~ dichloro
m~tha~o, each. The organic phases are combined7 ~xiad over
magnesium sul~ate~ fil~ered, and ths fi.ltrate is avaporatsd~
The oily residue is crys~allized with benzene. 4 g (54 %~ o~
trans;-3~(2-methyl-1,3-dio~olan~2~yl)~1-(L~methox~phanyl)~L~oxo~
2-azsthidine~carbo~ylic acid axe obtained~
Analysis~
calculat9d ~or C15H17~ 6 ~3 7~3
C 5~o6~ %~ ~ 5~57 %, N: L~56 %~
foun~l: C: 58~L~o %~ H: 5080 %~ N: L~o66 ~o
IR (~3r)0 3400-2700~ 1750 (broad~ cm lo
s
_ 20 ~
1H N~R ~C'DC13). ~ = 105 (S7 3H) 9 3~7 td9 lHq J - 2~5
Hz)~ 3~76 (s~ ~H), 400 (m, 4H) 9 4038 (d, lH~ J = 2~5 Hz)~ 6082
(2~ ~ 7~26 (2H, A~'BB', J = 9 Hz) 7 902 (s, lH) ppmO
f) 1011 g (1056 ml~ 0~011 mole? o~ dry triethyl
ami~ are addad to a solution o.f 3 g (O.Gl mole) o~ a compou~d
prepared a~ dascribed in point e3 abovc ln 20 ml o~ dry tetra-
hydro~uranO ~he solution is coolsd to ~15C 7 and 1.2 g ~1.06
m19 0JO11 mols) of eth.yl chloroformate are added dropwis~ to
t~a s~irred solution~ er 20 min~tes of stirring the separak~
ad ~al~ is f~ltared o~f ~mder nitrogen atmospher~ 9 and a solu
~io~ o~ 408 g (0.025 moie) o~ diazomethane in diethyl. ether
i9 added to ~he ~iltrate at room temperature. A~ter 2 hours
o~ s~irring the excess o~ diazomethane is.decomposed with
acetic acid~ and the solution is evaporated in vacuoe ~he oily
residue slowly crystallizes. 3 g (90 %~ o~ trans-4~(diazo~
acekyl~-3-(2-methyl-1,3 dioxolan-2-yl)~1_(4~metho~yphenyl)~
2-azethidinone are obtai~ed7 m~pO: 95-96C (berlzene and ekher3J
IR. (KBr)- 2209; 1760~ 1640 cm 1.
H NMR (CDC13) ~ = 1.50 (s~ 3H)~ 3~51 (d, 1~{, J
~0 2l6 Hz)5 3075 (~7 3~I), 4.05 (m, ~H)7 4.31 (d~ lH9 J = 2~6 Hæ)~
5.47.(~, lH)~ 6085 ~2H) ~ 7~30 (2H9 AA'BBa~ J = 9 Hz) ppmO
Exam~
~ran~ by~ !y~ol~
~xo-2~a~thid~,7 ~ L~.~a
.
308 g (000126 mole) of krans~4~(dia~oacotyl) 1-
phonyl-3~(2 methyl-1,3-dioxolan-2 yl~-2-azethidinone are dis~
solvad in a mixture o~ 100 ml of totrahydro~uran and 50 ml o~
wat~r7 and the solution is irradiated with a high -pr~ssure
mercury lamp in a pho~oreac~or a~ room temp~rature under nitro~
3 Kon atmo~pher~0 The progre~,~ o~ the reacti.on is monitor3d by
3~
thin layer ~ o.:~ato~raphy (adsorbent: Kies~l~rel G accoxding to
Stanl, developini; solvent: a 7:1 mixture of benzene and ace-
torle)~ At the end of the reaction tetrahydro~uran is evaporat-
ed in vacuo, ~he L~esidue is rendered al~aline ~ith a 20
aqueous socli.um ~ydroxide solution, and the alkaline solutio~
is washed thrice with 15 ml of dichloromethane, aach~ ~he
aqueous phase is acidi.fied to pH = 1-2 with conce~trated
aqueous hydrochloric acid and then ext~ac~sd thrice wi~h 20 ml
o~ d.ichlororl~ethane, each. '~he organic phases are combined~
dried ovex magnesium sul~ate 9 filtered9 and the filtxate is
e~aporateclO The ()i.l~ r~sidu~ i~ triturated with skher to ob-
kai~ 1~8 g (50 ~0) of crystalline ~krans~l-pher~tl-3-(2~methyl-
1~3-dioxolan~-yl)-4~oxo~2-azethidiny ~ -acetic ~cid~ mDp.
128-129C (ethanol,~
Analysis:
calculated fox C15H17N05 (291029):
C: 62000 ~ H: 5.88 %, N: 4082
~ound: C: 61075 '~, H: 5 86 ~0, N: 5.08
IR (KI~.r): 1760~ 17L~ cm 1
lFf NIlE2 (C~Cl~ = loLl8 ( S9 3~f), 2065 (dd~ lH~
Jgem = 15 Hz~ J~ic= 8 Hz) ~ 301~ (dd~ lfI~ Jgem = 15 Hz9
Jvic = 8 Xz), 30~7 (d, lH, J = 205 Hz), ~98 (m9 L~H3, L~oL~ ~m,
lH), 7.3 (m, ~H) a 9~33 (broad s 3 lH) ppm.
~he starting substance can be prepared as follows,
a) h rnixture of 38 g (0~.152 mole) of diethyl ~nilino
malonate ~. Blank: BerO ,~19 1815 (1898~77 38 ml of glacial
acetic acid and 15~3 g~ (13.9 mlg 0"182 mole) of diketene is
boiled ~or 0.5 hourO ~lacial acetic acid i~; evaporated in vacuo
over a t;Jal~er bath, and the oil~y residue is crystallized by
~0 tritllr~3ting it; with ethex 0 3605 ~, (72 '70) of diethyl (N~phenyl-
8~i5
~ 22 ~
3~hydroxy~3~me thyl-~oxo-2,2~pyrroliclir3e-dicarb~a~ylate) and~or
:i.ts tautomer are obtained3 mOpo 98~99 (~ (ethyl acetate and
pe troleum etihcr~ ~.
Ana lysis:
ca lc u la te d I or ~17H21N6 (335 ~P 35):
C. 60088 %, H: 6031 %" N- 4~18 %D
.Eound~ ~: 60083 (~, H: 6015 %1 N- 4~43
IR (K13r): 33~0~ 29501 17609 1750 (d~ 9 1700 cm ~
lH NA~ (aDc~= 1.02 ( k9 3H) 3 1.3 (t; 3 3E) 3 106
(s5, 3H) 92,.8 ~,s~ 3II) q 3.~6 (broad s, lH) ~ 4-4045 (m? 4H) 9 702
( s~ 5H) ppm.
b) 50 g (00149 mole) o:f diethy;l. ~N-phe~yl-3~hydrox~
3-m~thyl-5~oxo-2 j2~pyrrolidine-dicarbo.~{yla te) ~ prepared as
des~rib0d in point a~ above 3 are added to a solutio~ of ï0e,2 g
(00447 mole) of metallic sodium in 250 ml oE dry e~ha~ol3
ther0aïter a solution of 37ç9 g ~00149 mole) of iodine in 200 ml
of dry ether is added under vigorous s~i:rri~g~0 When the reac~
tiorl is over~ 805 ml (8.9 g7 0~,149 molo),~o~ glacial acetic
acid, 200 ml of: water and 100 ml o:E e ther are added to the
mixture, tha organic phase is separated~ and ~he aqueou~ pha~e
is extracted with 100 ml o~ e~her~ ~he c~ crc~ phases are com~
bined, dried over magnesium sulfate, ~iltorsd9 and tho filtrate
is evaporatedO '~he oily residue is crys~alliz~d from 50 ml o~
2-propa~ol to obtai~ 31 g (62 ~0) of diethyl (3-acetyl~l-phe~yl=
4-oxo-232~azethidi~e-dicarbox-ylate~ mOp~ 55-56~C (2-propanol~;
Anal~sis:
calculated for C17HlgN06: C~ 61025 %~ H, 5075 %~ N 4020 %~
fou~d: C, 61O38 %; H~ 5089 ~07 N: 432~ %o
IR (K~r): 17707 17L~0~ 1720 cm~
~-H I~rlJ~ (CDCl~): ~= 1.12 (t, 6H~ 9 203 (s, 3H)~ 4j25
~ ~3 -
(q? 4~ L~o75 ~s, lH), 70V--7~6 Im~ 5H) ppmO
c) 28~5 g (0~085 mole~ of diethyl ~-acetyl_l-phenyl~
4-oxo-292~azetihidine-dicarboxylate 9 prepared as described i~
poi~t d) above, are dissolved in a mixture o.~ 90 ml of ~ry
dioxa~e and 21 g (18.8 ml9 0~34 mole) of dry othyl~ne glycol3
a~d 369~ g (3105 ml, 00255 mole) of boro~ tri~luoride ~ di~
o~hyl et~erate complex are added d~opwise to the solutio~
undeI vigorous stirring and cooli~g with ice water~ The solu_
~ion is stirr~d for additional 2 hours at room tamperature
and then neutralized with saturated aqueous ~odium carbona~e
solutio~. qlh~ neutral solution i~ dilutod wîth 100 ml o~ wat2r
a~d then extract~d thrice with 50 ml o~ diethyl ether, 3achO
~he organic phas~s a.re combined, dried over magnasium sul~ato 9
~ erad~ and ~lla filtrate is evaporated in vacuo~ q~hs oily
residue is crystallized by triturating it with ether~ 2805 g
~90 %) of diethyl 1-phenyl~3~(2-mo~hyl-1,3-dio~olan-2~yl)-4-
oxo~2~2~azethidi~e~dicarbo~yla$e are o~tained~ m~pO: 59-61~C
(petrol)0
Analy~
caleulat~d :for Cl9H23N070 C: 60n47 %~ ~I 6014 %~ N: 3017 %~
.f~ou-nd: ~ C: 60~74 %, H: 642~1 %~ N. ~079
:IR (E~r). 1770" 1740 cm~l. -
H ~ (CDC13): ~= 1.18 (ti~ 3EI~ J = 7.2 Ez) 7 1024
(tg 3H,.i = 7.2 Hz) 9 1051 ~s~ 3H), 3~92 (m,, 4H)~ 4~,3 ~m, 5H)~
~5 702 (m,5H) ppm.
d) A mixtiure of 28~5 g (0.075 mole) of diethyl 1-phe~yl~
( 2-me thyl-l a ~-diox olan-2-yl) ~oxo-2 ~ 2-a ~ e tihidi~e-dicarb~
ox~ylate~ p:repared as described in point c) abova) 44 ml of
dimetihyl sulfoxid~t 5~6 g (Ool mol~) of sodium chloride and
~i405 ml ~0017 mole) o~ watier is stirred at 175C u~til the
~ 2~ -
reaction proceeds~ The progress Q~ the r~action is moni~or~a
by ~hin layer chromatography (adsorbent: Kieselg~l G according
~o Stahl; d.eveloping solvent- a 6:4 mixtura o~ benzene and
~thyl ace~ate)O Th~ solution is poured into 200 ml of a sa-
turated aqueous sodium chloride solution and e~tracted thricewi~h 150 ml of diethyl ether9 eachO The organic phases are
~ombined, dried over ma~nesium sulfate, ~iltered~ and the
~iltrate is evaporated. ~he resulting 16~4 g of oily rasidue
are dissolved in 100 ml of ethanol, and a solu~ion o~ 2~15 g
(0O054 mole) of sodium hydroxide in 30 ml o~ water is added
~o it under stirring over an ice bathO A~ter 0.5 hour o~
stirrin~ the mixture is diluted with 150 ml of water and
e~tracted thrice with 20 ml o~ dieth~l ether9 each. The
aqueous phase is acidi~ied to pH = 1 with concentrated aqueous
hydrochloric acid and extracted then thrice with 50 ml of di-
chloromethane, each. The orga~ic phas~s are combined, dried
.over magnesium sul~ate9 filt~red~ and the ~ilt.ra~e i5 ~vapora~-
ed. '~he oily residue is crystalli7.ed ~rcm behze~e to obtain
12 g (56 %) o~ trans-l~phenyl-3~(2-m~thyl-1~3~dioxolan~2-yl~
L~oxo 2~aæethidine carbo~ylic acid; mOp~ 165C (be~zene~O
Analysis:
calculated ~or ClL~H15N05 (277027)
Cu 60.64 %, H: ~945 %~ ~: 55 %?
~ound: C: 60~64 %, H' 5972 %9 N: 4.99 ~o
J-H ~R (CDC13): ~ = 1.5 (s, 3H); 3~69 (d, lH9 J = 3
Hæ), ~-~0O (m, 4H)~ 4942 (d~ lH~ J = 3 Hz); 703 (m, 5H)~ 7O55
( s, lH) ppm.,
e) 13u8 g (0005 mols~ o:E trans-l-phen~lw3-(2~mathyl~
1,3-dioxolan-2~yl~-4~oxo~2-aze~hidi~o carboxylic acid~ pre~
pared as de3cribed in point d3 above, are di~solv~3d in 100 m:L
~8~ 5
-- 25 _
o~ dry tQ~rahydrofura~9 and 5.55 g 57~7 mla 09055 mole~ of
ethyl chloro~ormate aro added to ~h~ solutio~ at ~15Co A~er
20 minut~s o~ stirring the separated salt is fil~ered o~f
. under nitrogen atmospher~ and an othe~al solution o~ 2206 g
~0015 mols) of diazomothane is added ~o th~ filtrat~ u~der
stirri~g. When the gas svolution ceases,th~ e~co~ o~ dlazo~
methane is decompo~ad with glacial acot~c acid9 and. the solutio~
is avaporatod~ ~he oil-~ rssidue is triturat~d with ether to ob~
tain 11~5 g (77 %) of cry~tallin~ trans-4~(diazoacotyl)-1
phe~yl-3~(2-methyl-1,3-dioxolan-2~yl)-azethidinon~; m.pO:
96-97C (bsnzene and ether)~
- IR (KBr): 2150 3 1760 9 .1635 cm 1.
lH NMR (CDCl~ = 1.50 (S? 3~ 3.5 (da i~9 J = ~06
Hz)~ 3050 (m~ 4H)~ 4~34 (d~ lE9 J = 206 Hz)~ 5045 td7 lH)
7~25 ~m, 5H) ppmO
