Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
The invention relates -to new bicyclic corn-
pounds and pharmaceutical compositions containing the
same, as well as to a process for -the preparation
thereo~.
lhe new bicyclic compounds according to
the inven-tion correspond to the general formula (I),
y L y2
H3C - C r- -~\ SR
(I)
O ~ \ COOQ
wherein
yl and Y represent a removabl.e carbonyl protecting
group a pre~erabLy a ke-tal group or a thio-
analogue thereof,
20 Q a is a Cl_5 alkyl graup, a substituted benzyl
group, hydrogen a-tom or an alkali metal ion,
and
R" is an optionally substituted hydrocarbon
residue, preferably a benzyl, 2~aminoethyl
or 2~acylaminoethyl groupO
The compounds o~ the general ~ormula ~I)
are new and ef~ective thienamycin analogues and, with
the exception o~ -the compounds wherein Q' iS alky~
~,~ A 2669-67-~P~
group, can also be applied as intermediates in the
synthesis of thienamycin.
lhienamycin, an antibiotic w-lth broad
spec-trum of activi-ty, was prepared first on micro-
biological way ~US patent specification MoO 3,950,357)
and later on by chemical synthesis (German O~fenlegungs-
schrift No. 2g751~597)-
lhe invention aims at providing a new route
for the synthesis o~ thienamycin and its analogues,
wherein the azethidinone skeleton and the ~-hydroxy
ethyl side chain~ or a side chain which can be con~
verted easily into ~-hydroxyethyl group, are ~ormed
simultaneously at the early stage of the synthesis,
and the resulting key intermediate is converted then
into the desired end-product.
It has been found that when a dialkyl
(protected amino) malonate is acylated with diketene
and the resulting acylated product is reacted with
iodine and an alkali metal alcoholate, an azet idinone
compound of the general formula (XIII),
~I3C - ~ (Cz)2
¦ (XIII)
O
R
containing an ~-acetyl side chain, is obtained, which
can be utilized as key intermediate in the synthesis.
~''
~ 2~ ~
In the above ~ormula R represents a re-
movable amido protecting groupa preferably a benzyl
group with one or more met~oxy substituents or a
phenyl grou.p bearing optionally one or more met~o~y
substituents, and Z is a Cl 5 alkyl group.
~ he new intermedi~tes o~ ~he g~n~ral ~ormula (XIII~
a~d their preparation ars described in d~tail i~ our pIsv~ou~
Canadian pa~t application NoO 393,595- Th~ preparation o~
thsse new intermediates is also de cribed in the examples of
~h~ pres~nt applicatio~.
I~ has al.so been observed that~ prinr to conver~ing
the intermsdiate o~ the general ~ormula (XIII) in~o ~hianar
~yci~ or an analogue thereof~ it is pre~erable to protect ths
~a~o group of ~he ~C~acet~l sid~ chain with a group,
particularly a ke~al group or a thioanalogue thereo~, which
ca~ be remov~d at a later stage of ths syn~hesisO ~thylene
glycol or a thioanaloguo thereo~ such as mercapto-ethanol~
can be appliad paxti.cularly pra~erably ko ~orm th~ ~thyle~o~
k~ ta 1 or he mi thi oke t3 1 proteeting group~ r~he resul~iDg
15 compound o~ the general formula (XII) 9
~1 y2
H3C - C I 1~ C Z ) 2
O~J N~
wherain ~1 and y2 ~orm toge~her a group îor the ~emporary
protectio~ o~ the carbonyl moiety;, pr~er~bly athylslleketal
group or a thioanalogue ~hereo~9 and R and Z aro as de~i~ed
~bove9 is reacted then with arl a7!~31i metal halide i~ pyridi:lle
or a ralated solvent or i~ aqueous dimet~ ul~o~ide to
obtain a compound ~ the general formula
yl y2 ~ E
f ~ ~ COOZ (XI)
0~ ~
0 ~ R
~ 4 --
wherein R, yl~ y2 and Z are as defined abcve.
~ he resulting compound of the general
formula (XI) is a mixture of cis and trans isomers.
~he isomers can be separated from each o-ther by
chroma-tography or on -the basis of their dif~erent
solubility. ~he separated trans isomer of the general
formula (XIa)
yL y2
~ H ~ COOZ
H3C - C
(XIa)
~ N\
O R
can be converted into the trans carboxylic acid of the
general formula (X)
yL y2 H H COO~I
H3C - C
~ ~'\ (X )
o R
by hydrolysis~ It is more preferable, however, to
subaect the isomeric mixture itself to hydrolysis,
since the reaction is selective, iOe. only the trans
ester converts into the respective carboxylic acid.
~he separated trans carboxylic acid of the
general formu~ (X) is reacted with an activator for
the carboxy group and then with diazomethane, and the
resulting compound of the general formula (IX)
, ~
yL 2 H H
~ ~ ~ . COC~
lI3C - C 2
(IX)
0~
is subjec-ted -to Wolff rearrangemen-t in the presence of
water. ~he resulting azethidinoace-tic acid of the gen-
eral formula (VIII)
yL y2 H EI
\ ~ ~ CEI2cooEI (VIII)
,~ N\
O R
can be converted into the desired end-products of -the
general ~ormula (I) in several ways.
In -the general formulae tx). (IX) and (VIII)
yl~ y2 and R are as defined above.
According to one of the methods for -the
further conversion a compound of the general formula
(VIII) wherein R is phenyl group is nitrated and then
reduced to obtain a compound of the general formula
(VIIIA),
~5
8~
-- 6
yl y2
H3C ~ C ~I .~,CH2COO~I
~ IIIa)
o~Y \ / ~
wherein yl and y2 are as defined above and A stands
for ni.tro group and then for amino group. ~he resulting
compound of the general formula (VIIIa) is esterified
then in a known manner to obtain a compound of the gen-
eral formula (VIIa), wherein yl~ y2 and A are as defined
above and X stands for a selectively removable esteri~y~
ing group, preferably an arylmethyl or diarylmethyl
group.
Y~ Y H H
H3C _ C ~P CH2COOX
o~ ~ ~ ~ (VIIa)
Ihe aminophenyl protecting group of the
resulting compound of the general formula (~IIa) is
removed then by oxidation~ preferably with chromium
trio~ide in the presence of glacial acetlc acid, a~d
-the resulting compound of the general formula (~I),
~92
-- 7
y 1 y2 H
H3C - C CEI2COOX
NlI (VI)
wherein ~ , y2 and X are as defined above, is
separated.
According to another method a compound of
the general formula (VIII) wherein R is a phenyl or
benzyl group bearing one or more methoxy substituents
is esterified in a known way to obtain an ester of -the
general formula (VII),
L y2
\ / ", ~I CH C 00
H3C - C 2
(VII )
N~
wherein R is as defined in this paragraph and yl, ~2
and X are as defined above, and then the R protect-
ing group is removed to obtain a compound of the gen-
eral formula (VI). When R is a dimethoxybenzyl group,
it is split off with a peroxydisulfate compound, whereas
when R is a methoxyphenyl group, it is removed with a
ceric salt in the presence of an acid.
Thereafter the X esterifyii~g group of the
resulting compound of the general formula (VI) is re-
moved preferably by reduction, particularly by cataly-tic
a~
~ 8
hydrogenation, -the resulting compound of the general
formula (V),
1 y2
\ / ~ CH COOH
II3C - C- 2
~ ~EI (V)
wherein Y and y2 are as defined above, is activated
on the carboxy group and then reacted with a salt of
a malonic acid hemies-ter, preferably with the magnesium
or potassium salt o:E an alkyl malonate or a substituted
benzyl malonate. he resulting compound of the general
formula ~IV),
yL y H CH2coclI2cooQ
(IV)
~H
wherein yl and y2 are as defined above and Q is a
Cl 5 alkyl or a substituted benzyl group, is reacted
with a sul:Eonic azide in the presence of a tertiary
amine to obtain a compound of the general formula (III)~
1 2
wherein Y , ~ and Q are as deEined above,
H C - C ~ H CH2cocN2cooQ
3 ~III)
~ N~I
/
"
,,
~ ~ ~r37~
_ 8a -
and this compound is subjected to ring closure in the
presence of a rhodium salt to obtain a compound of the
general formula (II),
yl y2
H3C - c H H ~
tII)
o~ cooQ
wherein yl~ y2 and Q are as defined above. These com-
pounds of the general formula (II) are the new start
ing substances of the thienamycin analogues according
to the invention.
According to a still further method a com-
pound of the general formula (VIII) wherein R is a
phenyl or be~zyl group with one or more me-thoxy
substituents is activated on the carboxy group and
then reacted with a salt of a malonic aci.d hemiester,
preferabl~ with the magnesium or potassium salt of an
alkyl malonate, or a substituted benzyl malonate. The
resulting compound of the general formula tXIV),
1 2
H C - C H E CH2cocH2cooQ
3 ~XIV)
o N~ R'
wherein yl~ y2 and Q are as defined above and R' is
a phenyl or benzyl group with one or more methoxy
'~
- 8b -
substituents, is reacted then with a sulfonic azide
-ln the presence of a tertiary amine to ob-tain a com-
pound of the general formula (XV)~
yl y2
H3C - C 2COC 2C Q
~ ~J \ (XV)
R~
wherein yl~ y2~ R9 a~d ~ are as de~ined aboveO
~ he same compounds o~ the ganaral formula (XV) are
obt~ined whsn a compound of the genaral ~ormula (VIII) wher~-
in ~ is a ph~nyl or be~zgl group with o~e or mors msthox~
substitu~nt~ is activated on the c2rboxy group a~d r~actod
then with a diazoacetat~
~ he R' protec~ing group of the resulti~g compound o~
the general ~ormula ~XV~ i5 then split of ~ as dascribad abov~
an~ the resulting compound of the ganeral ~ormula (III) is
cenver~ed i~o the starting substance o~ the g~eral formul~
: (II)o
~h~ compounds o~ ~he ge~eral ~ormu~ e ¦II) to (~V) are
~w a~d are obtained as rac~mic mi~turesO Some o~ the compounds
of bhe gs~ral ~ormula (~II) are described in our pravious
~u~garian pata~ No. 180,608. The other compounds
o~ the ge~er31 formula (XII), as well as the compounds of the
g~neral formul~e (XI) to (II3 9 (XIV) and (XV) ar~ de~cribed
in deta~ the examples of the present application.
When prsparing a compo~md oY the general f ormula ( I),
a s~arting substance o~ the ge~eral formula ~II) is subjectod
to O~c~lation and then tre3ted with the approprîata mercaptaneO
When a compound of the general formula (I) wherein Q' is
subs~ituted benæyl group i~; obtained, 'Ghe subs~ituted benzyl
group can be split off, and the resulting carboxylic acid
; 30 ~Q' _ H) ca~ be co~lverte,d ~he~ iIltO an alkali carboxylat~
-- 10 .-
On the basis of the above, the inven-tion
relates to a process for the preparation of new bi-
cyclic compounds of -the general formula (I), wherein
yl and y2 represent a removable carbonyl protecting
group, preferably a ketal group or a thio-
analogue thereof,
Q' is a ~1-5 alkyl group~ a sub~titu-ted benzyl
group, hydrogen atom or an alkali metal ion,
and
; 10 R" is an optionally substituted hydrocarbon
residue 3 preferably a benzyl, 2-aminoethyl
or 2~acylaminoeth~1 group,
in the way that
a) a compound of -the general formula (II),
wherein yl and ~2 are as defined above and Q is a C1_5
alkyl group or a substituted benzyl group~ is treated
with an appropriate O~acylating agent, preferably with
a sulfonyl or phosphoryl halide, in the presence of a
tertiary amine and then with a mercaptan) preferably
with benzyl mercaptan, cysteamine or an ~-acylated
derivative thereof, and the resulting product o the
general formula (I), wherein Q' is a ~1-5 alkyl or a
: substituted benzyl group, is separated, or
b) from a compound of the general formula
(I) obtained in step a), wherein R", yl and y2 are as
defined above and Q' stands for a substituted benzyl
ll ~
group, Q' is removed by reduction, and, il~ desired~
the resulting carboxylic acid (~' = H) is conver-ted
into its alkali metal salt.
In the first step of the above process a
compound o~ the general formula (II) is reacted with
an O-acylating agent in -the presence o~ a tertiary
amineO Organic carboxylic acid derivatives or, pre-
ferably, sulfonyl or phosphoryl halides can be applied
as reactants for this purpose Diphenyl phosphoryl
chloride proved to be a particularly preferred reactan-t.
~ he O-acylated intermediate is reacted then
with a mercaptan, preferably benzyl mercaptan, cysteamine
or an ~-acylated derivative thereof, in the presence o~
a tertiary amineO In this reaction a compound of the
general formula (I) wherein Q' is a C1~5 alkyl or a
substituted benzyl group is formed.
lhe substitu-ted benzyl group of a compound
of the general formula O wherein Q' is substituted
benzyl can be split off by reduction, preferably by
catalytic hydrogenation, to obtain the respective
carboxylic acid of the general formula (I) (Q' = ~I).
A carboxylic acid of the general formula (I)-can be
converted into its alkali metal salts, of which the
sodium salt can be prepared particularly easily by
treating the free acid with sodium carbonate OI' sodium
hydrocarbonate~ ~he resulting alkali metal salt can be
separated from the reaction mixture by extraction and/or
,
~z~
- 12 -
evaporation.
~he new compounds of the general formula
(I) are therapeutically active and possess primarily
B-lac-ta~ase inhibiting effec-ts.
The invention also relates -to pharmaceutical
composi-tions which contain as active agen-t a compound
of the general ~ormula (I) in admixture with one or
more con~entional pharmaceu-tical additives (eOg.
carrier9 diluent~ disintegration aid, preserving agent7
buffer, etc.)0 ~hese compositions can be prepared by
methods well known in the art.
~ he invention is elucidated in detail by
the aid of the following non-limiting Examples.
Egample 1
Eth~1 3~form~1amino-eth~lthio)-6-~2-meth~l-
~ 3-dioxolan~2~ 7-oxo-l-azabic~clo~
; C3.2.0]hept-2~ene-2-carbox~late
1~133 g (4.0 mmoles) of ethyl 6-(2 methyl~
-1,3-dioxolan-2-yl)-3~7-dioxo-1-a~abicyclo~3.2.0]-
heptane~2~carboxylate are dissolved in 10 ml of dr~
acetonitrile9 and 0061 ml (4~4 mmoles) of triethyl
amine, ~ollowed by Oo91 ml (4~4 mmoles) of diphenyl
phosphoryl chloride7 are added to the stirred solu-
tion at 0 C within about 10 minutesO Stirring is
continued at 0 C, and then 0061 ml (4a4 mmoles) of
triethyl amine and 0~46 g (4a4 mmoles) of ~-formyl-
,
,,~, ;~
~ A~ ~a'B~b~
- 13
-cysteamine are added to the mixture. After one hour
of stirring at O C the mixture is evaporated in
vacuo and the residue is dissolved in 20 ml of dichloro~
methane. ~he solution is was~e d with 10 ml of 3 %
aqueous sodium hydrocarbonate solution and then twice
with 10 ml of water, each. The organic phase is dried
over magnesium sulfate, filtered, and the filtrate is
evaporated. ~he residue, weighing 2.4 g, is processed
by c~lumn chromatography (adsorbent: Kieselgel 60,
OoO63 `to 0.200 mm, eluting agent: a 7:3 mixture of
benzene and acetone)O 0.51 g (36 %) of the aimed com
pound are obtained; m.p~: 152-153 C ~rom methanol
and ether),
IR (KBr)O 3400, 1790, 1700, 1690 cm 1.
1H NMR (CDC13): ~ = 1.35 tt, 3H), 1-45
(s, 2H), 2.82-3.65 (m, 7H), 3.95-4.5 (m, 7H), 6~1
(s, lH), 8.20 td, lH) ppm.
13C ~R tCDC13): ~ = 14.3, 23.4, 3106, 38.6,
40.1, 52.0, 61 3, 65.2, 65.4, 67.2, 10608, 145.0,
16104, 161.79 174.1 ppm.
Mass spectrum m/~: 370, 284, 242, 1973 87,
43.
~he starting substance used in this Example
can be prepared by the following methods:
Method 1
a) A mixture of 109.8 g to.66 mole) of 2,4-
z
-dimethoxybenzaldehyde, 72 ml (0.66 mole) o~ benzyl-
amine and 660 ml o~ methanol is stirred at room tem-
perature for 20 minutes, whereupon a clear solution
is obtained ~rom the suspension. ~he solution is
cooled with ice water, and 13.2 g (0.33 mole) o~
sodium borohydride are added to it in small portions.
~he progress of the reaction is monitored
by thin layer chromatography tKieselgel G according
to Stahl; developing solvent: a 9:1 mixture of benzene
and acetone), and at the end of the reaction the mix-
ture is evaporated to dryness in vacuo. ~he residue is
extracted with 500 ml7 200 ml and 200 ml portions of
ether. ~he ethereal solutions are combined, dried over
; magnesium sulfate, filtered, and then 112 ml (o.66 mole)
of dlethyl bromomalonate and 93 ml (o.66 mole) of tri-
ethyl amine are added to the filtrate. lhe reactio~
mixture is stirred at room temperature for 2-3 days.
lhe separated triethyl ammonium bromide is filtered
off and washed with ether. ~he mother li~uor is evap~
ora-ted, and the residue is recrystallized from 150 ml
of ethanolO ~he resulting 210 g of crude product is
recrystallized again from 400 ml of ethanol to obtain
197 g t72 %) of diethyl N-benzyl-~T-(2,4-dimethoxy~
benzyl)~amino~malonate; m.p.: 62~63 C (ethanol).
IR (KBr): 1750/1725 cm 1, d.
b) 6107 g (00149 mole) of die-thyl N~benzyl-
-N~(2,4~dimethoxybenzyl)-amino-malonate, prepared as
~ 15 ~
described in point a) of Method I, are hydrogena-~ed
in 500 ml of e-thanol under atmospheric pressure in the
presence of about 20 g of palladium-on~charcoal catalyst.
The catalyst is filtered off and the filtrate is evapor-
atedO 47.1 g (97 %) of diethyl (2,4-dimethoxybenzyl-
amino) malonate are obtainedO The product can be con
verted into its hydrochloride by reacting it with hydro-
chloric aeid. ~he hydroehloride melts at 122~124 C
after reerystallization from ethyl acetateD
Analysis:
calculated for C16H24~1~06 (3
C: 53~11 %, H: 6069 %~ C1: 9.80 %, N: 3087 %1
found: C~ 52.51 %, H: 6~77 %, Cl: 10 30 %, N~ 4O09 %0
IR (~ilm): 3250, 2900, 28507 1730~ 1720 cm 1.
lH ~R (CDC13): ~ = 1.3 (s, 6H), 3.78 (s~ 3H),
3082 (s~ 3H), 4~21 (q3 4H), 6~20 (s, 2H), 6.4~6.5 (m, 2H)
+ 7O3-7~55 (m, lH), 7.7 (broad s~ lH) ppm.
c) A mixture of 39.6 g (0.122 mole) o~
diethyl (2,4-dimethoxyben~ylamino)-malonate, prepared
as aescribed in point b) of Method I, 80 ml of glacial
aeetie acid and 12.3 g (11~2 ml, 0.146 mole) of diketene
is boiled ~or 0O5 hour. The solvent, glaeial aeetic aeid,
is distilled off in vaeuo over water bath, and the oily
residue is triturated with 150 ml of water. ~he result-
ing erystalline substanee is dissolved in 60 ml of ethylaeetate and preeipitabed with petroleum ether. 29.6 g
(60 %) of diethyl N-(2a4-dimethoxybenzyl)-3~hydroxy~
-3-methyl~5-oxo~2,2-pyrrolidine-diearboxylate and/or
v,: :..
- 16 -
its tautomer are obtained; m.p.: 106 107 ~.
Analysis:
calculated for ~20~I27N08 (409.43):
C: 58.67 %, H~ 6.65 %, N: 3.42 %;
found: C: 58079 %, H: 6.33 %g N: 3.34 %~
IR (KBr): 3400, 2950~ 2850, 1730 (1740, sh),
1710 cm 1.
H NMR (C~C13): ~ = 1.1 ~t, 3H), 1.17
(t, 3H), 1.52 (æ, ~ 3H), 2~8 ( ~ Ool H), 2.65 ~broad s,
2H), 3.75 (s; 6H), 3.8 4015 tm, 4H), 607 (broad s, 2H),
6025-6045 (m) + 7~0~7025 tm, 3H) ppm.
d) 20.5 g (50 mmoles) of the product
prepared as described in point c) of Method I are
suspended in 50 ml of dry ether, and a solution of
3-45 g tl50 mmoles) of metallic sodium in 100 ml of
dry e-thanol and a solution of 12.7 g (50 mmoles) of
iodine in 150 ml of dry ether are added simultaneous-
ly, from two dropping funnelsg to the vigorously stirred
suspension under cooling wi-th ice water. r~hereafter 5 g
20 of sodium hydrosulfite, dissolved in 200 ml of a
saturatea aqueous sodium chloride solution, are added
to the stirred mixture. The mi~ture is Eilled into a
separating funnel, and 60 ml of water are added to dis~
solve -the separated inorganic salts. Ihe organic phase
25 is removed, dried over magnesium sulfate, filtered,
and the filtrate is evaporated. r~he oily residue,
weighing 18.5 g, is crystallized from 30 ml of 2-
-propanolO 1099 g (54 ~0) of diethyl 3-acetyl~ 2,4-
',; ~,
~L~
- 17 -
-dimethoxybenzyl)~4-oxo~2,2~azetidine-dicarboxylate
are obtained; m.p.: 84-85 C (2-propanol)~
Analysis:
calculated for ~20H25N08 (407.41):
C: 58~96 %, H: 6~19 %, N: 3044 %;
found: C: 58~99 %, H: 6 04 ~0, M: 3.57 %O
H NMR (CDC13): ~ = 1.12 (t, 3H), 1.21
(t, 3H), 2.31 (s5 3H)g 3076 (s, 6H)3 3~8-3.4 (m, 4H),
4.53 (dg l~I), 4.63 (d, lH), 4~69 (s, lH), 6.3-6.4
(m, 2H) + 7.07 (d 9 lH) ppm~
e) 179 ml (206 g, 1.452 moles) of boron
trifluoride-diethyl etherate are added dropwise to
a vigorously stirred solution of 179 g (0.484 mole)
of diethyl 3-acetyl-1-(294-dimethoxybenzyl)~4-oxo~
~2,2-azetidine-dicarboxylate and 107 ml (120 g7 1.936
moles) of ethylene glycol in 500 ml of dry dioxane
under cooling with ice water. ~he reaction mixture
is allowed to stand at room temperature for one day,
during this period the mixture is occasionally stirred.
~hereafter 415 g (1.452 moles) o~ Na2C03.10~20 are
added slowly to the stirred mixture under cooling with
ice water9 and the mixture is s-tirred for 15 minutes.
~hereafter 1 litre of ether and 1 litre of water are
added, and the phases are separated from each other
~he aqueous phase is shaken twi¢e with 500 ml of di~
ethyl ether, each~ ~he ethereal phase is dried over
magnesium sulfate, filtered, and the filtrate is evap-
orated. 33.9 g (0.58 mole) of sodium chloride, 17.4 ml
'
- 18 ~
(0.968 mole) of water and 220 ml of dimethyl sulfoxide
are added to the residue, and the mixture is stirred
on an oil bath at 180 CO ~he progress o:E the reac-
tion is monitored by thin layer chromatography (ad-
sorbent: Kieselgel G according to Stahl; developingsolvent: a 6:4 mixture of benzene and ethyl ace-tate)~
A~ the end of the reaction, i.eO after about 15 hours5
the mixture is poured onto 1100 ml of saturated a~ueous
sodium chloride solution, and the resulting mixture is
shaken with 1000 ml a~d then twice with 500 ml of di-
ethyl ether3 each. ~he ethereal solutions are combined,
decolourized with charcoal, dried over magnesium sul-
~ate, and the filtrate is evaporated to a final volume
of cca. 200 ml. ~his concentrated solution is cooled
with ice water to obtain 59 g t35 %) o~ trans~ethyl
1-(2,4-dimethoxybenzyl)-3~ methyl-1,3-dioxolan-2-yl)-
-4-oxo-2-azet~idine-carboxylate; m.p.: 95 C.
f) A mixture of 0~5 g tl.2 mmoles) of diethyl-
3-acetyl-1-(2,4-dimethoxybenzyl)~4-oxo~2,2~azethidine~
~dicarbo~ylate9 prepared as described in point d) of
~ethod I, 3 ml of dry tetrahydrofuran and 0O53 g (3.6
mmoles) of mercapto~e-thanol is boiled for 4 hours, and
then 10 ml of water and 10 ml of chloroform are added
to the reaction mixture. ~he organic phase is separated,
washed wi-th 5 % aqueous sodium hydrocarbonate solu~ion,
dried over magnesium sul~ate, ~iltered, and the product
is separated from the filtrate by preparative thin
layer chromatography (adsorbent: Kieselgel 60 P~254 366,
/: .
- 19 -
developing solvent: a 8:2 mixture of toluene and
acetone) 0~30 g (53 %) o:E diethyl 1-(294-dimethoxy-
benzyl)-3-(2-methyl~1,3-oxathiolarl-2~yl)-4-oxo-2,2-
-azethidine-dicarboxylate are obtainedO
lH NMR (CD~13): ~ = 0.8-1.55 tm, 6H),
1072 ~ 1~7r7 (d, 3H), 2.9-3.~ (m, 2H), 3.75 (S9 6H),
4.0-5.0 (m, 9H),- 6.4 (m, 2H) ~ 7.1 (d, lH) ppm.
g) A solution of 5.21 g (0.130 mole) of
sodium hydroxide in 60 ml of water is added -to a
suspension of 4.102 g (OolO9 mole) of trans-ethyl
1-(2,4~dimethoxybenzyl)~3-(2-methyl-1,3~dioxolan~2-
-yl)-4-oxo-2-azet_~dine-carboxylate, prepared as
described in point e) of NIethod I, in 50 ml o~
ethanol under stirring and cooling with ice water,
and stirring is continued until a clear solution is
obtained (about 20 minutes). 100 ml of water are
added then to the solution, and the mixture is shaken
with 100 ml of ether. ~he aqueous phase is acidified
to pH = 1 with concentrated aqueous hydrochloric acidg
and then shaken quickly with 100 ml and twice with 50
ml of dichloromethane, each. ~he dichloromethane
solutions are combined, dried over magnesium sulfate,
~iltered, and the filtrate is evaporated. ~he oily
residue is crystallized from a mixture of toluene and
petroleum ether to obtain 35 g (92 %) of tra~s-1--(2,4~
-dimethoxybenzyl)-3-(2-methyl-1~3-dioxolan- 2-yl)-4~
-oxo 2~azet~;Ldine-carboxylic acid; m.p.: 117-118 C
(toluene)0
.
- 20
Analysis:
calculated for C17H21N07 (351.35):
C: 58.11 %, H: 6.03 %, N~ 3~99 %;
found: C: 58017 %, H: 6.30 %, M: 4.24 %.
IR (KBr): 3500-2500, 2900, 1760, 1720 cm 1.
H NN~ (CDC13): ~ = 1.39 (s, 3H), 3.50
(d, lH7 J=205 Hz)g 3~77 (s, 3H)~ 3.79 (s, 3H~, 3086
(d, lH, J=2.5 Hz), 3096 (m, 4H), 4~21 ~ 4056 (d, 2H,
JA~ = 15 Hz)~ 6044 (m, 2H) + 7.15 (d, lH, J = 10 Hz),
7058 (broad s, lH) ppmO
h) 7.3 ml ~52~5 mmoles) of triethyl amine
are added to a solution o:E 17.6 g (50 mmoles) of trans~
(2,4~dimethoxy benzyl)~3-(2-methyl~1,3-dioxolan;
-2-yl)-4-oxo~2~azet~idine-carboxylic acid, prepared
as described in point g) of Method I, in 150 ml o~ dry
te-trahydrofuran, and then 5~0 ml (52.5 mmoles) of ethyl
chloro~ormate are added to the mixture under cooling
with ice~ ~he mix-ture is cooled to -15 C, stlrred at
this temperature for 20 minutes, and the separated
triethyl amine salt is fil-tered off at the same tem~
perature under argon atmosphere. A solution of 150
;~ mmoles o~ diazomethane in 230 ml of cold diethyl ether
is added to the fil-trate. ~he mixture is stirred,
allowed to warm ta room temperature, and after 2
hours of stirring it is evapora-ted to dryness. The
brown~ thick residue is dissolved in 20 ml of ben~
zenea and the product is separated by column chro~
matography (adsorbent: 150 g of Kieselgel 60, ~ =
- 21 -
o.o63-00200 mm, elu-~ing agent: a 7:2 mixture of
benzene and acetone)~ 12.0 g (64 %) of trans-4-
-(diazoace-tyl)~ 2,4-dimethoxybenzyl) 3-~2-methyl-
~1,3~dioxolan~2~yl)-2-azet~idinone are obtaine~O
Analysis:
calcula-ted for C18H21N306 ~375O37)
C: 57.59 %, H: 5064 %g
found: C: 57078 %a H: 5-39 %o
IR tK~r). 2900, 2110, 1760 cm 1
i) A mixture of 2.25 g ~6 mmoles) of trans~
-4-~diazoacetyl)~1~(2,4-dimetho~ybenz~ 3-~2~methyl~
~1,3-dioxolan-2~yl)-2-azet~idinone, prepared as
described in point h) of Method I, 100 ml of per-
oxide~free tetrahydrofuran and 50 ml of water is
irradiated for about 4 hours with a high-pressure
mercury lamp (HPK 125) 9 immersed into the reaction
vessel made of pyrex glass, under argon atmosphere~
The solution is evaporated in vacuo to a final volume
of 50 ml, and the concentrate is diluted with water
-to 130 ml. 204 ml of a 10 % aqueous sodium hydroxide
solution are added to the aqueous mixture, and the
alkaline mixture is washed thrice with 20 ml of di~
chloromethane, each. ~`hereafter the aqueous phase is
acidified to pH = 2 with concen-trated aqueous hydro~
chloric acid. The acidic solution is extracted thrice
with 20 ml of dichloromethane, each, the e~tracts are
combined, dried over ma~nesium sulfate, filtered, and,
the filtrate is e~raporated to dryness. The residue is
~, .,
~ r30~
- 22 -
crystallized with ether. 1382 g (83 %) of Ctrans-l~
~(2~4~dimethox~rbenzyl)~3 (2~methy]~1,3~dioxolan-2-
-yl)-4-oxo 2-aze~ idinyl]~acetic acid are obtained,
m.p.: 124 ~ (ether).
Analysis:
calculated for C18H23N07 (365~37):
C: 59.17 %, E: 6034 %, N: 3.83 %~
~ound: C: 59.22 %, H: 6~49 %, N: 4~07 %O
IR (KBr)- 3jO0-2300, 2900, 1730, 1700 cm lo
j) 3O05 g ~15~75 mmoles) of diphenyl diazo~
; methane are added at room temperature to a stirred
solution of 5.48 g (15 mmoles) of Ctrans-1~(2,4-di-
methoxybenzyl)~3-(2~methyl~1,3-dioxolan-2-yl)-4-oxo-
2-azet~dinyl]-ace-tic acid, prepared as described in
point i) of Method Ig in 50 ml o~ dichloromethane~
When the nitrogen evolution ceases, some drops of
acetic acid are added to the mixture to destroy the
excess o~ diphenyl diazomethane. The solution is evap-
orated to dryness, and the residue, weighing 6.77 g,
is dissolved in 84 ml of acetonitrileu 16.20 g ~60
mmoles) of potassium peroxydisulfate ~K2S208),
21~60 g ~120 mmoles) of disodium hydrophosphate
monohydrate ~Na2EP04.E20) and 54 ml of water are
added to the solution~ the mixture is s-tirred vigo~
rously ~or 4 hours, boiled, and -then cooled. r~he cold
reaction mixture is filtered~ and the two pha~es of
the filtrate are separated from each other. rrhe
aqueous phase is extracted thrice with 30 ml of
.. . . . .
- 23 -
ethyl acetate, each~ The orga-nic phases are combinedg
dried over magnesium sulfate, filtered, and the filtrate
is evaporated. ~he residue is dissolved in benzene,
and the solution is processed by column chromatography
(adsorbent: Kieselgel 60, 0 = 0~050~0o200 mm, eluting
agent: a 7:2 mixture of benzene and acetone) to ob~
tain 2.68 g (47 %) of benzhydryl trans-~3-(2-methyl-
~1,3-dioxolan-2~yl)~4-oxo-2-azet~idinyl] ace-tate;
m.p.: 130 C (e-thanol).
IR tKBr): 3250, 2900, 17609 1740 cm 1~
1H NMR (CDC13): ~ = 1.39 ~s, 3H), 2.63
(dd, 2Hg J = 4O4 Hz), 2.89 (dd, 2H, J = 9.1 Hz),
3~97 (m, 5H)5 6.12 (s, lH), 6.9 ts, lH), 7028 (s, lOH)
ppm.
Analysis:
calculated for C22H23N5 (387~41)
C: 69.27 %, H: 6.08 %9 N: 3967 %9
found: C: 69015 %~ H: 6020 %, N: 3.55 %.
k) A mixture of 3.80 g (10 mmoles) of
benzhydryl trans-[3-(2~methyl~1,3-dioxolan-2 yl)~
-4-oxo-2 aze~dinyl~-acetate, 0.4 g of a dry palladium-
~on~charcoal catalyst containing 8 % of palladium and
50 ml of dry ethanol is stirred under hydrogen atmos-
phere. ~he hydrogen uptake stops after 2 hours. ~he
catalyst is filtered off and washed with 10 ml of dry
ethanol. ~he filtrate is evaporated o~er a 30-40 C
water ~ath, the residue is washed thrice with 20 ml
of ether, each, and the liquid is decanted. 2~02 g
-- 24 ~
(94 %) of rtrans~3-(2-methyl-lg3-dioxolan-2~yl)-4-
-oxo~2-azet~idinyl]-acetic acid are obtained; m~p.:
126-129 ~.
~nal
ySl~ .
calcula-ted for C9H13N05 (215.20): ~: 6-51 %;
found: M: 6.34 %.
IR (KBr): 3500-2300, 3350, 29007 17309
1700 cm
1) A mîxture of 2015 g (10 mmoles) of
[trans-3~(2-methyl-1~3-dioxolan-2~yl)-4~oxo-2-
~aæet~idinyl~-acetic acid, prepared as described in
point k) of Metkod I, 1082 g (11 mmoles) of a 98 %
carbonyl diimidazole and 60 ml of dry tetrahydro-
furan is stirred for 30 minutes. 1.58 g (11 mmoles)
o~ magnesium ethyl malonate are added to the solution,
and the reaction mixture is stirred at room temperature
for 2 hoursO ~'he mixture is evaporated in vacuo, 180
ml of dichloromethane and 180 ml of 0.5 n aqueous
hydrochloric acid are added to the residue~ the mix-
ture is stirred for some minutes~ and then the twophases are separated from each other. The aqueous
phase is extracted thrice with 30 ml of dichloro-
metha~e, each~ The organic phases are combined, washed
twice with 20 ml of a 3 % aqueous sodium carbonate
solution, each~ dried over magnesium sulfate, fil~
tered, and the iltrate is evaporated to dryness.
2002 g (71 %) of ethyl trans~4-C3~-~2-me-thyl-1~3-
~dioxolan-2-yl)-4-oxo-2 azet~idinyl~-3-oxo-bu-tanoate
~ 25 -
are obtained, m.p.: 65-68 C (ether)O
IR (KBr): 3220~ 1770, 1735, 1720 cm lo
lH NN~ 28 (t, 3H), 1042 (s, 3H),
2077 (dd) and 3010 (dd, 2H, J = 9.4 Hz and 3.6 Hz)~
3~11 (d, lH, J = 206 Hz), 3.75-4.35 (m, 7H), 6.13
(s, lH) ppm.
m) 0.69 ml (5~0 mmoles) of triethyl amine
and 00986 g (5.0 mmoles) of tosyl azide are added to
a solution of 1.426 g (5.0 mmoles) of ethyl trans-4-
~[3 (2-methyl-1,3~dioxolan~2-yl)-4~oxo-2-azet~idingl]~
3-oxo~butanoate, prepared as described in step 1) of
Method I, in 15 ml of dry acetonitrlle under ice cool
ing. ~he solution is allowed to warm to room tempera~
ture within 3 hours under stirring. The solution is
evaporated to dryness, the residue is dissolved in
benzene, and the solu-tion;is processed by column
chromatography ~adsorbent: 100 g of Kieselgel 60~
0 = 0~063-0.200 mm3 eluting agent: a 7.2 mixture of
benzene and acetone). 1.12 g (72 %) of ethyl 2 diazo-
-4~C~rans~3-(2-methylal,3~dioxolan-2~yl)-4-OxO-2
azetidinyl]-3-oxo~butanoate are obtainedO
IR (film): 3250, 1750l 1710, 1630 cm 1.
lH ~n~R: S = 1.36 (t, 3H), 1.42 ~s, 3H),
2096 and 3.44 (dd, 2H, J = 9~4 Hz and 3.6 Hz)~ 3.75
-4-15 ~m, 5H)~ 4.33 (q, 2H), 6.08 (s~ lH) ppm.
n) Dirhodium tetraacetate ~h2(0Ac)4.2~]
is added in small portions to a boiling solution of
- 1.245 g (400 mmoles) of ethyl 2-diazo-4-~trans~3-
a~ ~!~9
- 26 ~
-(2-methyl~1,3-dioxolan~2-yl)-4-o~o~2-azet~dinyl]-
-3-oxo-butanoate, prepared as described in point m)
of Method I, in 10 ml of benzene until the starting
substance reacts completely (this requires about
0.03 g of the rhodium salt). ~he reaction mixture
is filtered through a Celite pad, and the filtrate
is evaporatedO 1.13 g (100 %) of ethyl 6-(2-methyl-
-1,3-dioxolan-2~yl)~397-dioxo-l~azabicyclo~3.2O0]~
heptane-2-carboxylate are obtained; m.p.: 109 C~
IR (KBr): 1750, 1735 cm 1.
lH NMR~ 30 tt, 3H, J = 7.4 Hz)3
1049 (s, 3H), 2.41 (dd, lH, Jgem = 1905 Hz, Jvic =
- 7.5 Hz), 2.90 (dd, lH, Jgem = 19-5 Hz, Jvic
- 7~0 Hz)~ 3O43 (d, lH, J = 2.4 Hz), 3.97-4.20 (m~
5H), 4024 tq, 2H, J = 7.4 Hz)g 4063 (tg lH, J =
o.6 Hz) ppm.
Method II
a) A mi~ture of 24.6 g (002 mole) of 4-
~methoxyaniline and 23 9 g (17 ml, 0.1 mole) of di~
ethyl bromomalonate is stirred at room temperature
for 2 days~ ~he resu]ting mass is triturated with 100
ml of diethyl ether, the separated 4-methoxy anisidine
hydrobromide is filtered off and washed with a small
amount of die-thyl ether. ~he mother liquor is evapor~
ated and the residue is crystallized from dilute acetic
acid. 13.2 g (47 %) of diethyl ~4~methoxyanilino)-
malonate are obtained~ mOp~: 64-65 C (ethanol)O
~LJIL;J~o
- 27 -
Analysis:
calculated for C1~H1gN05 (281031):
C: 59.77 %, H: 6~81 ~o, N: 4.99 %;
found: C: 59099 %~ H: 6.97 %, N: 5.25 %.
IR (KBr): 3300, 1775, 1725 cm 1~
lH NM~ (CDC13): ~ 23 (t~ 6H~ J = 7-2
Hz), 3.67 (S9 3H), 4.2 ~q, 4H, J = 7.2 Hz), 4062
(s, lH), 4.1~4.5 (broad s, lH), 6.55 (2H) ~ 6.73
(2H, AA'BB' 3 J = 9 Hz) ppm~
b) A mixture of 1102 g ~0004 mole) of di-
ethyl (4-methoxyanilino)-malonate, prepared as
described in point a) of Me-thod II, 15 ml of glacial
acetic acid and 4 g ~3 7 mlg 00048 mole) of diketene
is boiled for 0~5 hourO ~he solution is evaporated in
15 ~acuo, the oily residue is triturated with diethyl
ether, and the solid is filtered off. 10.5 g ~72 %)
of diethyl 1-(4-me-thoxyphenyl)-3-hydroxy~3-methyl-5-
oxo-2,2~pyrrolidine~dioarboxylate and/or its tautomer
~re obtained; m.p.: 136-137 C (ethyl acetate).
Analysis:
calculated for C18H23N07 (365.38):
C: 59017 %g H: 6.39 %, N: 3.83 %,
found: C: 58098 %, H: 6090 %, N: 4.04 %0
IR (K3r): 3600, 30009 1760, 1740, 1685 cm lo
H NMR (CDC13): ~ = 1.07 (t, 3H, J = 7.2 Hz),
1~28 (t, 3Hg J = 702 Hz), 1058 (s~ 3H), 2076 (s, 2H),
3.64 (s, lH)~ 3.76 (sg 3~)~ 4.1 tq, 2H9 J = 702 Hz),
4.27 (q, 2H, J = 7.2 Hz), 607 (2H) ~ 7.0 ~2H3 AAaB~97
~ q~
- 28 _
J = 9 Hz)~ ppm.
c) 9O1 g (0O025 mole) of diethyl 1~(4-
-methoxyphenyl)-3-hydroxy-3-methyl-5-oxo~2,2-
~pyrrolidine-dicarboxylate, prepared as described
in point b) of Method II, are suspended in 50 ml of
dry diethyl ether, and a solution of 1.72 g of
metallic sodium in 30 ml of dry ethanol and a solution
of 6.35 g (00025 mole) of iodine in 50 ml of dry di
ethyl ether are simultaneously dropped into -the sus-
pension under vigorous stirring and cooling with ice~~hereafter the mixture is poured in-to 100 ml of a
saturated aqueous sodium chloride solution~ and 2 g
of sodium hydrosulfite and 2 ml of glacial acetic
acid are added. The ethereal phase is separated, and
the aqueous phase is extrac-ted thrice with 50 ml of
die-thyl ether, each. The ethereal phases are combined7
` dried over magnesium sulfate, filtered, and the
`~ filtrate is evaporated~ The oily residue is triturated
with 2-propanol to obtain 6.2 g t68 %) of crystalline
20 diethyl 3-acetyl-1~(4-methoxyphenyl)~4~oxo-272-
-azet~idine-dicarboxylate; m.p.- 70~71 C (ethanol)O
Analysis:
alculated for C18H21N7 (363.38):
C: 59~50 %, H: 5.82 %, N: 3~85 %;
25 found: C: 59O04 %, H: 5.84 %~ N: 4.08 %0
IR (KBr): 1760, 1735~ 1720 cm lo
H NMR (CDC13): ~ = 1.20 ~t, 3H, J ~ 702
;~ Hz)9 1022 (t, 3H, J = 702 Hz), 2~33 (s, 3H), 3.7 (s, 3H),
- 29 -
4.17 (q, 2H, J = 7~2 Hz), 4.19 (q~ 2H, J = 7.2 Hz),
4~7 (s, l~I)g 6.7 (2H) -~ 7.31 (2H, AA'B~', J = 9 Hz)
ppm.
d) 6 g (0.0165 mole) of diethyl 3-ace-tyl-
~1-(4-methoxyphenyl)-4-oxo-2,2~azet~idine~-dicarboxylate,
prepared as described in point c) of Method IIs are
dissolved in 20 ml of dry dioxane and 4.1 g (3.75 ml,
0.066 mole) of ethylene glycol. 7 1 g (6.3 ml, 0.05
mole) of boron trifluoride-diethyl etherate complex
are added dropwise to the stirred solution under ice
cooling, and the reaction mixture is stirred for
additional 2 hours at room temperatureD ~he solution
is rendered alkaline with saturated aqueous sodium
hydrocarbonate solution, thereaf-ter 100 ml of water
are added, and -the mixture is extrac-ted thrice ~ith
50 ml of diethyl ether, each. ~he organic phases are
combined, dried over magnesium sulfate, filtered, and
the filtrate is evapora-ted. ~he oily residue is tri-
turated with diethyl ether to obtain 6 g (89 %) of
crystalline diethyl 3-(2-methyl-1,3~dioxolan-2-yl)-
-1~(4-methoxyphenyl)-4~oxo-2,2-azet~dine-dicarboxylate9
m~p~: 82-83 C (ethanol)O
Analysis:
calculated for C20H25M08 (47-43)
C: 58~96 %~ H: 6018 %, M: 3O44 %j
found: C: 58070 %, H: 5068 %l M: 3O53 %o
IR (KBr): 1740 cm 1 (broad)
-,
~ 7 p~
~L ~U ~
30 -
lH ~MR ~CDC13) ~ -- 1.17 ~t, 3~, J = 702
Hz), 1.26 (t, 3H~ J = 702 Hz), 105 (s, 3H), 3O7 (s,
3H), 3.9 (m, 4H), 4.2 (m, 5H), 6~67 (2H) + 7O34 (2H,
AA'BB', J = 9 Hz) ppmO
e) 11 g (0.0245 mole) of diethyl 3-(2
-methyl~1,3~dioxolan~2=yl)-1~(4-methoxyphenyl)-4~oxo-
-2,2~azet~,idine~dicarboxylate 9 prepared as described
in point d) of ~ethod II~ are dissolved in 20 ml of
dimethyl sulfoxide, 10~2 g (000295 mole) of sodium
chloride and 009 ml ~0.049 mole) of water are added,
and the mixture is stirred at 175 C until a complete
reaction is obtàined. The progress of the reaction is
monitored by thin layer chromatography (adsorbent:
Kieselgel G according to Stahl; developing solvent:
a 6:4 mixture of benzene and ethyl aceta-te~0
The mixture is cooled, poured into 150 ml
of a saturated aqueous sodium chloride solution, and
extracted thrice with 50 ml of diethyl ether, each.
he organic phases are combined, dried over magnesium
sulfate~ filtered, and the filtrate is evaporated. The
resulti~g oily residue, weighing 6 g, is dissolved in
25 ml of 96 % ethanol, and a solution of 0.72 g
(0.018 mole) of sodium hydroxide in 10 ml of water is
added to the alcoholic mixture under cooling with ice
25 water. The mixture is stirred for Oa5 hour, then
diluted with 50 ml of water and washed twice with 25
ml of dichloromethane~ each~ ~he aqueous phase is
acidified to pH = 1 with concentrated aqueous hydro~
- 31 -
chLoric acid, and then extracted thrice ~ith 25 ml of
dichloromethane, each. The organic phases are combined,
dried over magnesium sulfate, filtered, and the filtrate
is evaporatedO ~he oily residue is crys-tallized wi-th
benzene~ 4 g (54 %) of trans-3~(2~methyl-1,3-dioxolan-
-2-yl)-1-(4-methoxyphenyl)-4~oxo-2-azet idine-carboxylic
acid are obtained.
Analysis:
15 17 6 (3 7.3 ):
C: 58036 %, H: 5.57 %, ~: 4~56 %;
found: C: 58,40 %, H: 5.80 %g ~: 4~66 %.
IR (KBr): 3400-2700~ 1750 (broad) cm 1~
lH NMR (CDC13): ~ = 1.5 ts, 3H), 3~7 td,
lH, J = 2.5 Hz), 3076 (sa 3H), 4~0 (m, 4H), 4.38 (d,
lH, J = 2.5 Hz), 6.82 (2H) -~ 7~26 ~2H, A~'B~, J =
= 9O5 Hz), 9~2 (s, lH) ppm.
f) 1~11 g (1~56 ml9 OQO11 mole) of dry
trieth~l amine are added to a solution of 3 g (0,01
mole) o~ a compound prepared as described in point e)
f ~ethod II in 20 ml of dry tetrahydrofuran~ ~he
solution is cooled to -15 C, and 102 g C1~06 mlg
0~011 mole) of ethyl chloroformate are added drop-
wise -to the stirred solution. After 20 minutes of
stirring the separated salt is filtered off under
nitrogen atmosphere, and a solution of 4.8 g (00025
mole) of diazomethane in dieth~l ether is added -to
the filtrate at room temperature~i After 2 hours of
stirring the excess of diazomethane is decomposed
2~
~ 32 -
with acetic acid, and the solution is evaporated in
vacuo. ~he oily residue slowly crystallizes 3 g (90 %)
of trans-4-(diazoace-tyl)~3-(2-methyl-1~3-dioxolan-2-
-yl)~ methoxyphenyl)-2-azet~}d-lnone are o~tained;
5 m.p.: 95-96 C (benzere and ether)~
IR (KBr): 2200, 1760 ~ 16~0 cm lo
lH NMR (CDC13): ~ = 1050 (s~ 3H)9 3.5
(d, lH, J = 2n6 ~Iz), 3.75 (s, 3H), 4.05 (m, 4EI),
~.31 (d, lH~ J = 2~6 Hz), 5.~7 (s, lH), 6.85 (2H) +
+ 7O30 (2H, AA~BB'~ J = 9 Hz) ppm.
g) 3.3 g (OoOl mole) of trans~~(diazo-
acetyl)-3-(2~methyl~1,3~dioxolan-2-yl)-1-(4 methoxy-
phenyl)~2-azet~idinoneg prepared as described in point
f) of Method II, are dissolved in a mixture of 50 ml
15 of water and 100 ml of tetrahydrofuran. The mixture is
; irradiated with a hi~h pressure mercury lamp in a
photoreactor under nitrogen atmosphere (the reaction
is performed at room temperature), and the progress
o~ the reaction is monitored by thin layer chromato~
20 graphy (adsorbent: ~ieselgel G according to Stahl
developing solvent: a 7:1 mixture of benzene and
acetone)0 When the reaction is over, tetrahydrofuran
is distilled off under vacuo, the residue is rendered
alkaline with 20 % aqueous sodium hydroxide solution,
25 and the solution is washed twice with 15 ml of dichloro-
me-thane, each. The aqueous phase is acidi~ied to pH 1~2
with concentratad aqueous hydrochloric acid and then
- 33 -
extracted thrice with 20 ml of dichloromethane, each.
~he organic phases are combined 9 dried over magnesium
sulfate, filtered, and the filtrate is evaporated.
1~6 g (50 %) of ~-trans~3-(2-methyl-1,3-dioxolan~2-
-yl)-]-(4-methoxyphenyl)-4-oxo-2-azet idinyl]-acetic
acid are obtained.
Analysis:
calculated for C16HlgM06 (321033):
C: 59.80 %~ H: 5~96 %, M: 4.36 %;
found: C: 59.60 %, H: 5~76 %, N 4.08 %O
IR (film): 35003 2500, 1760--1700 cm 1.
h) 1.0 g (3~12 mmoles~ of the compound
prepared as described in point g) of Me-thod II is
dissolved in 10 ml of dichloromethane, and a solution
of 0.53 g (3.12 mmoles) of diphenyl diazomethane in
10 ml of dichloromethane is added dropwise to the
stirred solution at room temperature. When the gas
evolution ceases, the solution is evaporated in vacuo.
1045 g (98 %) of benzhydryl trans;-[3-(2-methyl~lS3-
~dioxolan 2~yl)~1-(4 methoxyphenyl) 4-oxo-2~azet~,idinyl]-
acetate are obtained.
Analysis:
calculated for C29H29M06 (487O55)
C: 71.44 %, H: 5.99 %, N: 2~87 %;
25found: C: 71~13 %, H: 6021 %, N: 2093 %D
lH MMR (C~C13): ~ - 1035 (s, 3H)g 2.7-
-3.1 (m9 2H), 3.38 (d, lHg J = 2.5 Hz), 3072 (s, 3H)g
3.8~401 (m9 4H), 4.1~4.5 (~, lH), 6085 (s, lH), 6D7~7.4
- 34 -
(m~ 14H) ppmO
i) 0.28 g (0.65 mmole) o~ benzhydryl
trans~3-(2-me-thyl~1,3-dioxolan-2-yl)~l-(4-methoxy~
phenyl)-4~oxo-2-aze-t idinyl]-aceta-te, prepared as
described in point h) o~ Method II, is dissolved in
2 ml of acetone, and a solution of 0~9 g (1.6 mmole)
of ceric ammonium nitrate [~e(N~I4)2(~03)6~ in 2 ml of
a 5 % aqueous sul~uric acid is added dropwise to the
stirred mixture at room temperature. Ihe reaction mix-
ture is stirred ~or addi-tional 2 minutes and then
neutralized cautiously with a 5 % aqueous sodium hydro~
carbonate solution. ~hereafter the mixture is extracted
thrice with 4 ml o~ ethyl acetate, each. Ihe organic
phases are combined, dried over magnesium sulfate~
filtered, and the filtrate is e~apora-ted in vacuo.
Ihe oily residue is purified by preparati~e -thin
layer chromatography (adsorbent: Kieselgel 60, ~ =
= 0.050-00200 mm, eluting agent: a 7:2 mixture o~ ben-
zene and acetone) to obtain 0006 g (30 %) o~ benz~
hydryl trans~C3~(2~methyl-1~3~dioxolan~2-yl)~4-oxo~
-2 azet~dinyl]-acetate. Ihis compound is identical
with the product prepared as described in point j)
of Method Io
~he resulting product can be con~erted into
the desired starting substance as described in points
k) to n) of Method Io
. . . --
- 35
Me-thod III
a) A mixture of 38 g (0~152 mole) of diethyl
anilinomalonate CR. Blank: Ber. 31, 1815 (1898)~,
38 ml o:E glacial acetic acid and 15.3 g ~1309 ml,
0.182 mole) of diketene is boiled for 0~5 hour. Glacial
acetic acid is evapora-ted in vacuo over a water bath,
and the oily residue is crystallized by triturating it
with ether. 36.5 g (72 ~0) of diethyl (N~phenyl-3-hydr-
oxy-3-methylw5-oxo-2~2-pyrrolidine-dicarboxylate)
and/or its tautomer are obtained, m~p.: 98-99 C
(ethyl acetate and petroleum ether)
Analysis:
calculated for C17H21~06 (335 3
C: 60088 %, H: 6.31 %~ N: 4.18 %;
found: C: 60083 %, H: 6.15 %, N: 4~43 %.
IR (KBr): 3350, 2950, 1760, 1750 td),
1700 cm ~O
;~ lH MMR (CDC13) ~ = 1.02 (t, 3H), 1.3
(t, 3H), 106 (s, 3H), 2.8 (s, 3H), 3.6 (bro~d s~ lH),
4_4.45 (m, 4H), 702 ~s, 5H) ppm.
b) 50 g (0~149 mole) of diethyl (M-phe~yl-
-3~hydroxy-3-methyl-5 oxo 2,2-pyrrolidine-dicarboxylate),
prepared as described in point a) of Method IIIg are
added to a solution of 10.2 g (0.447 mole) of metallic
sodium in 250 ml of dry e-thanol7 thereafter a solution
of 37.9 g (00149 mole) of iodine in 200 ml of dry e-ther
is added under vigorous stirring. When the reaction is
over, 8.5 ml (809 g, 00149 mole) of glacial acetic acid,
~ 36 -
200 ml of water and 100 ml of ether are added to the
mixture, the organic phase is separated, and -the
aqueous phase is extracted with 100 ml of ether.
~he ethereal phases are combined, dried over mag-
nesium sulfate, filtered, and the fil-trate is evapor-
ated. ~he oily residue is crystallized from 50 ml of
2~propanol to obtain 31 g (62 %) o~ diethyl (3-acetyl-
; -l~phenyl-4-oxo-2,2~azet~idine~dicarboxylate~ m.p.:
55-56 C ~2-propanol)O
Analysis:
calculated for ~17H19N6
C: 61 25 %, H: 5.75 %, N: 4.20 %;
foundo C: 61038 %, H: 5.89 %, N: 4.24 %0
IR (KBr): 1770) 1740, 1720 cm 1.
lH NMR (CDC13): ~ = 1.12 (t, 6H), 2.3
(s, 3H), 4.25 (~, 4H), 4.75 (s, lH), 7.o-706 (m, 5H)
ppm.
c) 28~5 g (0 085 mole) of diethyl 3-acetyl-
phenyl-4 oxo~2,2-azet~,idine~dicarboxylate, prepared
as described in step d) o~ Method III, are dissolved
in a mi~ture of 90 ml o~ dry dioxane and 21 g (18.8
ml, 0O3~ mole) of dry ethylene glycol, and 36.5 g
(3105 ml, 00255 mole) of boron trifluoride - diethyl
etherate complex are added dropwise to the solution
under vigorous stirring and cooling with ice water.
~he solution is stirred for additional 2 hours at
room temperature and then neutralized with saturated
~.~
q`~f ~
- 37 -
aqueous sodium carbona-te solutionO ~he neutral solution
is diluted with 100 ml of wa-ter and then extracted
thrice with 50 ml O:e diethyl ether, each~ ~he organic
phases are combined, dried over magnesium sulfate,
filtered, and the filtrate is evaporated in ~acuoO
~he oily residue is crystallized by triturating it
with ether. 28.5 g (90 %) of diethyl l~phenyl-2-(2-
~methyl~1,3-dioxolan-2-yl)-4-oxo-2,2-azet~idine~di-
carboxylate are obtained~ m.p.O 59-61 C (petrol).
Analysis:
calculated for C1gH23M07:
C. 60047 %, H: 6.14 %, N: 3.71 %3
found: C: 60.74 %~ H: 6.21 %, N: 3.79 %O
IR (K~r): ]770, 1740 cm lo
lH NMR (CDC13): ~ = 1.18 (t, 3H, J = 7.2 Hz)~
1.24 (t, 3H, J = 7.2 Hz), 1.51 (s, 3H)~ 3.92 (m, 4H),
4.3 (m, 5H), 7.2 (m, 5~I) ppm.
d) A mixture of 28.5 g ~0,075 mole) o~
diethyl l-phenyl-3-(2~methyl~1,3~dioxolan-2 yl)~4-
; 20 -oxo~2,2-azet~idine-dicarboxylate, prepared as
described in point c) of Method III, 44 ml of di~
methyl sulfoxide, 5.6 g (0.1 mole) of sodium ch]oride
and 3.05 ml (0~17 mole) of water is stirred at 175 C
until the reaction proceeds. ~he progress of the re~
action is monitored by thin layer chromatography
(adsorbent: Kieselgel G according to S-tahl, developing
solvent: a 6:4 mixture of benzene and ethyl acetate)O
~he solution is poured into 200 ml of a saturated
~38 ~
aqueous sodium chloride solution and extracted thrice
with 150 ml of diethyl ether~ each. ~he organic phases
are combined, dried over magnesium sulfate, ~ tered,
and the ~iltrate is evaporated. The resulti~lg 16.4 g
of oily residue are dissolved in 100 ml of ethanol,
and a solu-tion of 2.15 g (0.054 mole) of sodium
hydroxide in 30 ml of water is added to it under stirring
over an ice water bath. A~ter 0.5 hour of stirring the
mixture is diluted with 150 ml of water and extracted
-thrice with 20 ml of diethyl ether, each. '~he aqueous
phase is acidified to pH = 1 with concentrated aqueous
hydrochloric acid and extracted then thrice with 50 ml
of dichloromethane, each. The organic phases are com-
bined, dried over magnesium sulfate, filtered, and
the filtra~e is evaporated. The oily residue is
crystallized from benzene to obtain 12 g (56 %) of
trans-l-phenyl-3-(2-methyl~1,3-diox~olcm~2-yl)-4-oxo~
-2-azet_idine-carbox~ylic acid; mOp.: 165 C (benzene)O
Analysis:
calculated for C14~15~5 (277.27):
C 60o64 ~0, H: 5.45 %, N: 5.05 %;
found: C: 60064 %~ H: 5.72 %, N: 4099 %~
IR (KBr): 3500-2700, 1770, 1730 cm 1
lH NM~ (CDC13)~ 5 (s, 3H), 3r69
(d, lH~ J = 3 Hz)g 4.0 (m, 4H), 4.42 (d~ lH, J = 3 Hz),
7O3 (m, 5H), 7O55 (s~ lH) ppm.
e) 13.~ g (0O05 mole) of trans~l-phenyl-3-
, -(2-methyl-1,3-dioxolan~2~-yl)-4-oxo-2-azet~dine-
'IJ6~
- 39 ~
carboxylic acid, prepared as described in point d)
of Method III, are dissolved in 100 ml of dry tetra-
hydrofurana and 5.55 g (7.7 ml, 00055 mole) of ethyl
chloro~ormate are added to -the solution a-t -15 ~O
~fter 20 minutes of stirring -the separated sal-t is
filtered off under nitrogen atmosphere~ and an etheral
solution of 22.6 g (0.15 mole) of diazomethane is added
to the filtrate under stirring. ~hen the gas evolution
ceases, the excess o~ diazomethane is decomposed with
glacial acetic acid, and the solution is evaporated.
; ~he oily residue is triturated with ether to obtain
11.5 g (77 %) of crystalline trans~4-(diazoacetyl)-
-1-phenyl 3~(2~methyl-1,3-dioxolan 2-yl~azet_}dinone;
m.p.: 96~97 C ~benzene and ether)~
IR (KBr): 2150, 1760, 1635 cm lo
lx NMR (CD~13): ~ = 1.50 (s, 3H), 3.5
(d, lH~ J = 2.6 Hz), 3.50 (m, 4H), 4.34 (d, lH7 J =
= 2.6 Hz)g 5.45 (sa lH), 7025 (m7 5H) ppm.
~) 3.8 g (000126 mole) o~ trans~-(diazo-
acetyl)-1-phenyl-3-(2~methyl~1,3-dioxolan-2-yl)~2-
-azet~idinone, prepared as described in point e) of
~ethod III, are dissolved in a mixture o~ 100 ml o~
tetrahydrofuran and 50 ml of water, and the solution
is irradiated with a high pressure mercury lamp in a
photoreac-tor at room temperature under ni-troge~
atmosphere~ The progress of the reaction is monitored
by thin layer chromatography (adsorbent: Kieselgel ~
accordin~ to ~tahl, developing sol~nt: a 7:1 mi~ture
~ ~ ~l~q~
40 -
o~ benzene and acetone)~ At the end of the reaction
tetrahydrofuran is evaporated in vacuo 9 the residue
is rendered alkaline wi-th a 20 % aqueous sodium
hydroxide solu-tion, and -the alkaline solution is
washed thrice with 15 ml of dichloromethane, each.
~he aqueous phase is acidified to pH = 1~2 ~ith con-
centrated aqueous hydrochloric acid and then e~tract-
ed thrice wi-th 20 ml o~ dichloromethane, each. ~he
organic phases are combined, dried over magnesium
sulfate, filtered, and the filtrate is evaporatedO
~he oily residue is tritura-ted with ether to obtain
1.8 g (50 %) of crystalline ~trans-1-phenyl~3-(2
~methyl~1,3-dioxolan-2-yl)~4-o~o~2~azet~idinylJ-
-acetic acid; m~p.: 128-129 C (ethanol)O
AnalysisO
calculated for C15H17~5 (291029)
C: 6200o %, H: 5.88 %, ~: 4082 %,
found: C: 61075 %, H: 5.86 %, ~: 5008 %,
IR (KBr): 17609 1740 cm 1.
lH NMR (CDC13): 3 = 1~48 (s, 3H), 2.65 ~dd,
9 Jgem 15 Hz~ Jvic = 8 Hz) ~ 3.12 (dd, lH, J
~ Jvic = 8 Hz), 3O47 (d, lH, J = 2 5 Hz) 3 98
(m3 4H), 4.4 (m, lH), 7O3 (m, 5H), 9O33 (broad s, lH)
ppm.
g) 0,81 ml of concen-trated nitric acid
(S = 1.5) is added dropwise, under constant stirring
and cooling wi-th ice, to 3 ml of acetic anhydride so
that the temperature of -the mixture does not rise
- 41 -
above ~5 ~. ~he resulting -nitrating rnixture is
added dropwise, at ~5 C, to a stirred solution of
2~9 g (0 01 mole) of Ctrans-l-phenyl~3-(2-meth~l-
-1 7 3-dioxolan-2-yl)-4-oxo-2-azet idinyl]-acetic
acid, prepared as described in point f) of Method
III, in 20 ml of dry dichloromethane~ After one
hour of stirring the solution is poured onto ice
water, and the phases are separated from each other~
I'he aqueous phase is extracted twice with 25 ml of
dichloromethane, each. ~he organic phases are com~
bined, dried over magnesium sulfate, filtered~ and
the filtrate is evaporated in vacuo. The oily residue
is triturated with ether to obtain 1.95 g (58 %) of
crystalline ~trans-3~(2-methyl-1,3-dioxolan-2-yl)-1-
-(2-nitrophenyl)~4-oxo-2-azet~,idinyl~-acetic acid;
mOp.: 175-176 C (ethanol).
AVL 1 '' S -
~ a ys.. .
calculated for C15H16N207 (336D33):
C~ 53~57 %, H: 4O79 %, N: 8~33 ~0;
20 - found: C: 53.31 %, H: 4.68 ~Og N~ 8~21 %.
IR (KBr): 3600-2900~ 1740, 1540, 1340 cm 1.
h) 00336 g (1 mmole) of Ctrans~3-(2~me-thyl~
-1,3~dioxolan-2-yl) 1~(2~nitrophenyl)-4-oxo-2~azet~idinyl~
-acetic acid, prepared as described in point g) of Method
III, is dissolved in 15 ml of methanol, and the solution
is hydrogenated under atmospheric pr~ssure in the pre~_
ence of 0O05 g of a palladium-on~charcoal catalystc
~he catalyst is filtered off, and the filtrate is evap-
.., ~,,v~, ,,~.
2~2
- ~2 -
orated. The oily residue is dissolved in 10 ml of
dichloromethane, 0.17 g (1 mmole) of diphenyl diazo-
methane is added, and the mixture is stirred for 24
hours~ ~hereafter the mixture is evaporated to obtain
0O4 g (90 %) of benzhydryl trans~ (2-am-inophenyl)~
-3~(2-methyl-1,3~dioxolan-2-yl)~4-oxo-2~azet idinyl]-
-acetate.
IR (KBr): 17~09 1720 cm lo
Mass spectrum: m/z = 472 ~M~)~
i) 0.45 g (1 mmole) of benzhydryl trans-
- Ll- ( 2-aminophenyl)-3-(2-methyl~193-dioxolan-2-yl)-
-4-oxo~2-azet~idinyl]-acetate is dissolved in 2 ml
~ of glacial acetic aci~7 and a solution of 0.2 g
;~ (2 mmoles) of chromium trio~ide in 2 ml of glacial
acetic acid and 0.2 ml of water is added dropwise to
the above solution at room temperature. The mix-ture
is stirred at room temperature for 3 hours, there-
after poured into 10 ml of ethyl acetate and washed
with an 5 % aqueous sodium hydrocarbonate solution
; 20 until neutral. The organic phase is dried over mag-
nesium svlfate, filtered, and the filtrate is evap-
orated in vacuo. The residue is purified by prepara-
tive thin layer chromatography (adsorbent: Kieselgel
60 P~25~+366, developing solvent: a 7:3 mixture of
benzene and acetone)~ 0.09 g (30 %) of benzhydryl
trans-L3~(2~methyl-1 J 3~dioxolan~2-yl)-4-oxo~2~azet~idinyl]~
-acetate is obtained. The physical constants of this
- 43 -
compound are identical. with those of the product
prepared according to point j) of Meth.od I.
The resu.lting compound can be converted
into the desired end substance as described in points
k) to n) of Method Io
Method IV
a) o.364 g (2.2 mmoles) of a 98 % carbonyl
diimidazole is added to a solu-tion of 0~730 g (2 mmoles)
of ~trans-l (2,4-dimethoxybenzyl)~3 (2~methyl-1,3-
-dioxolan-2-yl)-4-oxo~2-azet~ idinyl~acetic acid in
10 ml of dry tetrahydrofuran9 and the mixture is stirred
for 20 minutes. 0.315 g (2~2 mmoles) of monoethyl
malonate magnesium salt is added to the solution,
and the mixture is stirred :Eor 2 hoursO The reaction
mixture is evaporated, the residue is sha~en with a
mixture of 40 ml of d.lchloromethane and 40 ml of a
005 n aqueous hydrochloric acid, and then the phases
are separated from each other. The aqueous phase is
extracted with 20 ml of dichloromethane. The organic
phases are combined, washed twice with 10 ml of a 3%
aqueous sodium carbonate solution7 each, dried o~er
magnesium sulfate7 filtered, and the fil-trate is evap-
orated. 0~41 g (47 %) of ethyl trans~4~ (2,4~dimethoxy-
benzyl) 3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo~2-
azet~,idinyl]-3~oxo~butanoate are obtained.
IR (film): 1750, 1740~ 1720 cm 1
lH ~MR (CDC13)~ 26 (t, 3H), 1.39 (s,
3H), 202-3.3 (m, 5H), 3065-4.45 (m, 14H), 6.25~606 and
7.05-7.25 (m, 3H) ppm.
b) o~69 ml (5O0 rnmoles) of triethyl amine
and 0.986 g (500 mmoles) of tosyl azide are added to
a solution of 2077 g (5.0 mmoles) of ethyl trans~4-
l-(2,4-dimethoxybenzyl)-3-(2-methyl--1,3 dioxolan-2-
-yl)-4-oxo-2-azet~idinyl~-3-oxo-butanoate, prepared as
described in point a) of Method IV, in 15 ml of dr~
acetonitrile under ice coolingO '~he solution is
stirred for 3 hours under allowing it to warm to room
temperature. '~hereafter the solution is evaporatea to
dryness, and the residue is processed by column chromato-
graphy (adsorbent- Kieselgel 60, ~ = 0~063-0.200 mm,
eluting agent: a 7:3 mixture of benzene and acetone).
1041 g (61 %) of ethyl 2~diazo~4-trans-~1-(2,4~di~
methoxybenzyl)-3-(2-methyl-1~3~dioxolan-2-yl)-4~oxo~
-2-azet~idinyl~3-oxo-butanoate are obtained.
IR (~ilm)O 2160, 1750, 1720, 1640 cm l.
c) 5O4 g (20 mmoles) of potassium persulfate
(K2S208)~ 7.2 g (40 mmoles) of disodium hydrophosphate
monohydrate (Na2~IP04,~20) and 18 ml of water are added
to a solution of 2.340 g (5~0 mmoles) of a compound
prepared as described ln point b) of Method IV in 30
ml of acetonitrile, and the mixture is boiled for 10
hours~ '~he reaction mixture is cooled, filtered, and
the two phases of the filtrate are separated from each
other. '~he aqueous phase is extracted thrice with
~ 4~a ~
10 ml of ethyl acetate, each. ~he organic phases are
combined, dried over magnesium sulfate, filtered~ and
the filtrate is evaporated. ~he residue is processed
by column chromatograph~ (adsorbent: Kieselgel 60,
~ = 0.063-00200 mm, eluting agent: a 7-3 mixture of
ben~ene and ace-to~e) to obtain oO56 g (36 %) of ethyl
2~diazo~4-~trans-3-(2~me-thyl~193-dioxolan-2~yl)~-4-oxo~
~2~azet~idinyl]-3-oxo~butanoate. ~he physical constants
o~ this compound are identical with those o:~ the
product prepared according to point m) of Method I.
~he compound can be converted into the desired star-t-
ing substance as described in point n) o~ Method I.
Method V
One drop o~ dimethyl formamide and 0.37 ml
(5.0 mmoles) o~ thionyl chloride are added to a stirred
solution o~ 1.830 g (5.0 mmoles) of ~trans-1-(2,4-
- -dimethoxybenzyl)~3-(2-methyl~1,3-dioxolan 2-yl)~4~
-oxo~2-azet~idinyl]~;acetic acid in 10 ml o~ dichloro-
methane under ice cooling, and the reaction mixture is
stirred under cooling for 2 hours~ la7 ml of e-thyl
diazoacetate are added then to the mixture~ and
stirring is continued at room temperature for 24
hours~ ~he dark solution is evaporated3 and the
residue is processed by column chromatograph~ (ad
sorbent: ~ieselgel 60J ~ = 0.063~00200 mm, eluting
agent: a 7:2 mixture of benzene and acetone).
0.17 g (7.3 %) of ethyl 2-diazo-4-trans~ (2,4-
- 44b -
-dimethoxybenzyl)-3-(2-meth~l~ 1,3-dioxolan-2-yl)-4-
oxo-~2~azet idinyl] 3-oxo-butanoate is ob-tained; the
IR spectrum of -this compound is identical with that
of the product obtained according to point b) of
5 Method IV.
~ his compound can be converted into the
desired starting subs-tance as described in point c)
of Method IV.
Method VI
a) 0O4 g (1024 mmoles) of Ctrans-3~(2-
-methyl-1,3~dioxolan-2- yl)-1-(4-methoxyphenyl)-~-
-oxo- 2~azet~idinyl]-acetic acid, prepared as described
in point g) of Method II, is dissolved in 15 ml of dry
15 tetrahydrofuran, and 0022 g (1.36 mmoles) of carbonyl
diimidazole is addedO ~he resulting mix ture is stirred
at room temperature for about one hour. When the gas
euolution ceases, 00196 g ~1.36 mmoles) of monoethyl
malonate magnesium salt is added, and stirring of the
20 mixture is continued for one hour. ~he solution is
evaporated, the residue is dissolved in 50 ml of diJ-
chloromethane, and the solution is washed with 25 ml
of a 2 n ~3aus hydrochloric acid. ~he aqueous mix-
ture is extracted with 25 ml of dichloromethane~ ~he
25 organic phases are comb-lned, washed twice 1Jvith 20 ml
of a 5 % aqueous sodium carbonate solution, each~ dried
over magnesium sulfate, filtered~ and the filtrate is
e~aporated. 0~3 g (62 %) of ethyl trans~4- ~3~ (2;~methyl-
, ~ .. .
~L~w
- 44c -
-1,3-dioxolan-2-yl)-1-(4-methoxyphenyl)-4~oxo-2-
~azet~ idinyl]-3~oxobutanoate is obtainedO
Analysis:
calculated for C20H25~7 (391-42)
~: 61.37 %, ~: 6.44 ~cg N: 3.5~ %;
found: C: 61.20 ~0~ H: 6.59 %~ N: 3072 %0
IR (~ilm) 1750 cm 1.
b) 0028 g (1.44 mmoles) of tosyl azide and
0~2 ml (1.44 mmoles) of trie-thyl amine are added -to a
s-tirred solution of 0.5 g (1.44 mmoles) of the compound
prepared according to point a) of Method ~I in 6 ml
of dry acetonitrile under cooling with ice or water.
~he reaction mixture is stirred at room temperature
for 2 hours, and the progress of the reaction is moni-
; 15 tored by thin layer chromatography (adsorbent: Kiesel-
gel G according to Stahl, developing solvent: a 7:3
mixture of benzene and acetone). At the end of the
reaction the mixture is evaporated, the residue is
; dissolved in 40 ml of dichloromethane, and the sol-
ution is washed acid-free with 10 ml of a 40 % a~ueous
potassium hydroxide solution and then with 10 ml of
water. ~he organic phase is dried over magnesium sul~
fate, filtered, and the filtrate is evapora-ted. ~he
residue is purified by preparative thin layer chro-
matography (adsorbent: Kieselgel 60 P~254~366, eluting
agent: a 7:3 mixture of benzene and acetone). 0025 g
(36 %) of ethyl 2--diazo-4-~trans-3~(2-methyl-193-
dioxolan-2-yl)-1~(4~methoxyphenyl)-4-oxo-2~azet~,idinyl]-
~ i ,
- 44d -
w3-oxo-butanoate is obtained~ m.p~: 131-132 C (ether)O
IR (KBr): 2200, 1740, 1710 9 16~0 cm 1.
Anal~sis
calculated for C20H23M307 (417O41):
C: 57O55 %, H: 5t55 %9 N: 10907 %,
foundO C: 57.56 %9 H: 5.80 %, N: 10~08 %O
c) 0045 g (0.106 mmole) of the compound
prepared as described in point b) of Method VI is
dissolved in 4~5 ml of acetone, and a solution of
1.5 g (2.7 mmoles) of ceric ammonium nitrate in 4.5
ml of a 5% aqueous sulfuric acid is added dropwise to
the stirred mixture. ~he reaction mixture is stirred
for additional 5 minutes, thereafter the yello~ soL-
ution is neutralized with a 5 % aqueous sodium hydro~
carbonate solution, and extracted then thrice ~ith 10
ml of ethyl acetate, each. ~he organic phases are
combined, dried over magnesium sulfate, filtered,
and the filtrate is evaporated. ~he residue is
purified as described in the previous point. OolO g
(27 %) of ethyl 2-diazo~4-[trans-3-(2-me-thyl~1,3-di-
oxolan-2-yl)~4-oxo-2-azet~idinyl~-3-oxo butanoate is
obtained; the IR spectrum of this compound is identical
with that of the substance obtained according -to point
b) of Method I~.
~he resulting compound can be conver-ted into
the desired starting subs-tance as described in point n)
of Method I.
'~ .t
"
_ 44e -
Example 2
Eth~l 3-benz~lthio~6-(2 meth~] 1~3-dioxolan-
-2~ 7-oxo-1 azabic~clo[3.2.0]hept-2-ene-
-2-carbo~la-te
0~91 ml (4.4 mmoles) of diphenyl phosphoryl
chloride (Ph203PCl) is added at O C, within 10 minutes,
to a stirred solution of 1.133 g (4.0 mmoles) of ethyl
6-(2-methyl~1,3-dioxolan-2-yl)~3,7~dioxo~1-azabicyc]o-
C3.2 0]heptane-2-carbox~late and Os61 ml (4.4 mmoles)
Of triethyl amine in 10 ml of dry acetonitrile. ~here~
after 0061 ml (4~4 mmoles) of triethyl amine and then
0.52 ml (4.~ mmoles) of benzyl mercaptan are added to
the mixture, and the resulting mixture is stirred at
O C for one hour. ~he mixture is evaporated in vacuo,
the residue is dissolved in 50 ml of dichloromethaneg
; and the solution is washed twice with 5 ml of a 3 %
aqueous sodium hydrocarbonate solution, each~ and then
thrice with 5 ml o~ waterg each. ~he organic phase is
dried over magnesium sulfate, filtered, and the filtrate
is evaporated~ ~he oily residue, weighing 1.0 g, is
processed by column chromatography (adsorbent: Kiesel~
gel 607 0 = 00063~00200 mm, eluting agent. a 7:1 mix-
ture of benzene and acetone). 0090 g ~58 %) of the
aimed compound (a fraction which crystallizes from
ether) is obtained~ m.p.: 109 C.
IR (XBr): ].780, 1700 cm 1.
- 4~f -
lH NMR (CDC13): ~ = 1.33 (t, 3H, J = 705
Hz)~ 2.87 3.3 (m, 2H), 3.35 (d, lH, J = 3 Hz), 3.95-
-4.45 (m, 7H), 7.33 (s~ 5H) ppm.
13C MMR (CDC13): 14.30, 23.35, 36.85, 40.28,
51~94, 61.15, 65.18, 65033, 67.15, 106085~ L24.4, 127~2
128~69, 128.88, 136.42, 145.933 1610329 173.~1 ppmO
Mass spectrum: m/z = 389, 303, 261, 91, 87, 43.
Example 3
~-Nitrobenz~l 3-(~orm~l~min~eth~lthio~-6-
-(2-meth~1~1,3-dioxolan-2~ 7-oxo-l~aza~
bic~clo[3.2QO]he~-t-2~ene-2-carbox~late
0.61 ml (4~4 mmoles) of triethyl amine and
the~, within about 10 minutes~ Oo91 ml (4.4 mmoles) of
` ~ 15 diphenyl phosphoryl chloride are added at O C to a
stirred solution o~ 1.561 g (4.0 mmoles) of p~nitro-
benzyl 6-(2-methyl-1,3 dioxolan 2-yl)-3,7~dioxo~1-
-azabicyclo~3.2.0]heptane-2-carbo~ylate in 10 ml of
dry acetonitrile~ Stirring ls continued, a~d further
0061 ml (4.4 rnmoles) of triethyl amine and Oo46 g
(4.4 mmoles) of M-formyl-cysteamine are added to the
mixture at O CO After one hour o~ stirring the mix-
ture is evaporated i~ ~acuo, the residue is dissolved
in 20 ml of dichlorornethane, and the solution is washed
with 10 ml o~ a 3 % aqueous sodium hydrocarbonate
solution and then twice with 10 ml of water, each.
~he organic phase is dried o~er magnesium sulfa-te,
filtered,~ and the filtrate is evaporated. ~he residue
~z~
- 4~g ~
is processed by column chromatography (adsorbent:
Kieselgel 60, ~ = 0Oo63-0~200 mm, eluting agent: a
7:3 mixture of benzene and acetone) -to obtain 1.05 g
(64 %) of the title compound; mOp.: 183 C (ether).
IR (KBr)- 3330, 1750, 1680 ~shoulder),
1670 cm 1.
lH ~MR (CDC13 ~ DMSO~d6)~ 43 (s~ 3H),
2.85-3.45 (m, 6H)9 3.58 (d, lH, J = 3 Hz), 4O0-4O3
(m, 5H), 5.24~5.51 (d, 2H, JA~ = 13.8 EIz)~ 7068 -~ 8020
(d, 4H, JA~3 = 11 Hz), 8~16 (s, lH) ppm.
p-Nitrobenzyl 6-(2~methyl~1,3~dioxolan-2-
~yl)-3,7-dioxoazabicyclo~3.2.0]heptane-2-carboxylate,
the starting substance o~ the process described in
Example 3, can be prepared from
A) Ctrans~3-(2=methyl~1,3-dioxolan~2-yl)-
-4-oxo~2-azet~,idinyl]~acetic acid, a substance prepared
as described in points a) to k) of Method I, points
a) to i) o~ Method II plus point k) of Method I, or
points a) to c) o~ Method III plus point k) of Method
I; or
trans 1-(2,4~dimetho~benzyl)-3~(2~methyl-
-1,3-dioxoIan-2-yl)~4~oxo-2-azet_idinyl]-acetic acid,
a substance prepared as described in point i) of MethOd
I, or
C) Ctrans-3~(2-methyl 1,3~dioxolan-2~yl)-1-
-(4-methoxyphenyl)~4~oxo 2-azet idinyl]-acetic acid, a
substance prepared as described in point g) o~ Method
IIo
- 44h -
Method A) is performed as followso
a) A mixture of o.645 g (3.0 mmoles) of
Ltrans-3-(2-me-thyl-1,3-dioxolan-2-yl)~4-oxo-2-azet idinyl]-
-acetic acid, 0O535 g (3~3 mmoles) of carbon~l di-
imidazole and 15 ml of dry tetrahydrofuran is stirredat room temperature for 30 minutes, thereafter 00825 g
(3.3 mmoles) of p-nitrobenzyl malonate magnesium salt
is added to the mixture, and stirring is continued at
room temperature for 2 hours. ~he mixture is allowed
to stand overnight and then evaporated in vacuoO ~he
residue is shaken with a mixture of 50 ml of dichloro-
methane and 50 ml of a 0O5 n aqueous hydrochloric acid,
and the organic phase is separated~ ~he aqueous phase
is extracted with 25 ml of dichloromethane. ~he
organic solutions are combined, washed twice with
10 ml of a 3% aqueous sodium carbonate solution,
each~ dried over magnesium sulfate~ filtered, and the
filtrate is evaporated. 0.730 g (62~1 %) of p-nitro~
benzyl trans-4-~3-(2-methyl-1,3-dioxolan~2 yl)-4-oxo~
~2-azet ~dinyl~-3-oxo-butanoate is obtained.
IR (film): 3250, 1760, 1740, 1720 cm 1.
b) 10962 g (5O0 mmoles) of the compound
prepared as described in point a) above are dissolved
in 15 ml of dry acetonitrile, and 0.69 ml (5.0 mmoles)
of triethyl amine and oog85 g (5~0 mmoles) of tosyl
azide are added to the solution under ice cooling.
~fter 5 minutes of the addition a crystalline substance
Y ~; separatss. ~he mixture is stirred for 20 minutes,
4~i -
thereafter the separated substance LS fil-tered off 3
washed with ether and dried~ 1~326 g (63.4 %) of p-
-nitrobenzyl 2-diazo~4~trans-3-(2-methyl-1,3~dioxolan-
2-yl)-4-oxo-2~azetidinyl~~3-oxo-butanoate are obtained~
m~pO 163~164 C.
IR (KBr): 3320, 2160, 1750, 1710, 1630 cm lo
lH NMR: ~ = 1041 ~s~ 3EI), 2.98 (dd) and
3.44 (dd, 2H,
, -
45 ~-
J - 10 Hz and 4 Hz) " 3.18 (dy lH; J = 2.4 Hz) ~ 3083-4~15
(m9 5H)9 ,~36 (~p 2E), ~oO l~s,, J:H), 7,,5* ~d) and 8026 (d~ 4H,,
~B, J = 9 Hz ) ppm.
c) ~ suspensio~ of 10673 g (400 mmol~3s) of the com-
pound pr~p~r3d as describetl in point b) abov~ in 45 ml of
dr;s~ ben~ene is stirrad and h~at~d to boiling~ and ODO50 g
of dirhodium tatraacetate ~h2(0hc)~.2~H~ is added in
~veral portio~s,. A~ter 10 hours of boilin~; the star~ing sub
~t~nce reacts comple~el~sr. The mix~ure is cooled~ bh~ separa~-
1() ed subst9~ce is dissolved irl dichlorometha~0 ~ ~nd the 301u~
tio~ i9 ~iltered through a Celite p~d~ ~he ~iltrate ls
~aporated in ~acuo, ~he r~sidue i~ ~dmIxed with ethar, a~d
the susp~nsion i5 f ilteredl 1032 g ( 840 6 %) o~ p-rlitrobellzyl
6-~2-m~t~yl~1,3-dioxsla~-2-yl)~3,7-dioxo-1-a~abicyclo ~ .2 9~-
h~p~ne-2-car~oxylats are obtained; m~p~ 167Co
IR (EBr~: 1760, 1735. cm 10
o~= 1.,48 ~s~ 3H~ 2~47 (dd" lH~, Jg~3m = 19 Hzs,
J ic = 8 Hz)~ 2.92 (dd9 ~ g Jgel~ = 19 H~s9 JVi.C 8 ~ 3
(d~ lH~ J = 204 Hz), 400-402 ~m~ 5H~ 4075 (~ lH)9 5.30
(d~ 2H~ JA~ = 14 Hz), 7~,53 and 8,,23 (d9 4H, JAB = 9 Hz) ppm~
~ethod B) i~ 2~alogou5 l;o laathod IV or ~T ~see ~xample
1) ~ whorYas Dlothod C) is a~logou3 to Method VI (sa0 Examplc
1)~ In both iustance~ p-rlitrobenzyl 2-di~zo~ trar~ (2-
methyl~l,3-diozolan~2~ oxo~2-azethidin;sr~7-3-oxo-butarLoat~
i~ obtai~ed~ the phy~ical.co~tant~ o~ which ar~ identical
to the~ of the compound prepared according ~o poi~t b) o~
~ethod A) o The resultin~ compound can be conv~rted into the
de~ired ~tarting ~ub~ta~ce ~IB degcribed iD poin~ c~ of
Me thod ~) 0
*Trade M~rk. Silicic acid product of Johns-Manville
International Corp., New York, sold as a filtering aid.
p ''3 ' I~llrl. ~D
- 46
Examp:le 4
Sodi um ~ orm:yla mino-e th;Yl~hi o) ~; ( 2~me th~yl~l, 3-di-
oxolarl 2~ 7-oxo 1-azabic~clo/3~.2"07hept- 2~ 2-carbo~;~late
~ suspension of 0.25 g o~ a 10~ palladium-on-charcoal
catalys~ in 70 ml of a 2~,1 mi~tur6 of dioxans arld wat~r is
stirrad in h;ydrogell atmosphera at room temperatur~ ïor 20
mi~ut0s~ and the~ a warm so.lution of 00477 g ~loO mmole) o~
p-ni~robe~zyl 3~(~ormylami~o-eth;srlthio~-6-(2-methyl-193 di-
oxolan-2-yl)-7-cxo-1 zabicyclo~2c~7hept-2-ene~ 2-carboxyla~e~
1() prepar~d as de~cribad- in Example 3~ in 30 ml of peroxide-frae
dio~:ane i8 added~ The reaction mixtura is stirrad irl hydrogen
atmo~phere for additional 3 hours, and the~ a solu~ion o~
0~084 g ~loO mmole) o~ ~oclium hydrocarbonate in the minimum
amount o~ wa~er is added. ~ha reac~ion mixture is ~iltered
through ~ Celite*pad~ Dioxa~e is evaporated ~rom ~he ~ r~te
i~ vacuo~ and the aqueous residua i5 e~racted bhrice with
lQ ml o~ dichloromethane9 eaoh~ ~heroa~ter the a~u~ous phasa
is ev~por~t~d i~ ~acuo ~ room temperat~reO The rasidua
cry~talliz~s upon cooling. The cry~talline substance is ad-
29 mi~ed wikh 6 ml of et~anol7 and ~ha cry~tal~ are ~iltered
o~ 0~25 g (73 %) o~ the aimad ¢ompound i~ ob~ained; m,p~:
201C (under decompositio~0
IR (KBr): 3420, 177Q (shoulder)~ 1760~ 1690, 1610
cm 1
~H ~ ~D20): d = la~42 (s~ 3H)~ 207-3.6 (m9 6H)g
3.65 (d, lH" J = 3 Hz) g 3~.95-4,,3 ~m~ 5H); 8.03 (s, lH) ppm.
*Trade Mark
