Note: Descriptions are shown in the official language in which they were submitted.
:~ ~t~S~
The present invention relates to new heterocyclic
compounds containing a C-acetyl group, which are pharma-
ceutically active as well as valuable in-termediates of -the
thienamycin synthesis. The invention also relates to a
process for the preparation of these new heterocyclic
compounds.
More particularly, the compo~mds with which
the invention is concerned have the general formula:
o
H3C-ll (Cz)2
¦ (I)
~ N~
wherein:
R is a protecting ~roup suitable for a temporary
protection of amines and amides or an aryl
group, and
Z is an alkyl group.
In the definition of R, the protecting group
suitable for a temporary protection of amines and amides
is preferably an optionally substituted benzyl group, and
the aryl group is preferably a phenyl group which may also
be optionally substituted~
In the definition of Z, the term "alkyl" is
used to refer to a straight or branched chained alkyl
group, preferably having 1 to 4 carbon atome, and is more
preferably a methyl or ethyl group.
The compounds of the formula (I), in which
R is aryl, preferably an optionally substituted phenyl,
are pharmacrutically active and, more particularly, possess
antihypoxic properties.
~'
--1--
'7
The compounds of the formula (I), in which R
represents a protecting group are valuable intermediates
of a new synthesis route for the preparati.on of thiena-
mycin. The use o~ the intermediates of the formula(I)
enables one to obtain thienamycin more conveni.ently and
with a higher yield than with the intermediates of the
hitherto known thienamycin syntheses. The most preferred
representatives of the compounds of the formula (I) are
those in which R is methoxybenzyl group.
Thienamycin is a well known antibiotic with
a wide spectrum of activity, which has first been prepared
microbiologically (US Patent No. 3,950,357) and then synthe-
tically ~Published German Patent Application DOS No. 2,751,597).
The present invention thus prQvides a new
synthesis route by which the azetidinone skeleton and the
~-hydroxyethyl side chain ~or another side chain, which can
be easily converted into ~-hydroxyethyl) can be formed
simultaneously.
It has been found that by acylating a dialkyl
(substituted amino)-malonate of the general formula:
R - NH - CH(COOZ)2 (II)
wherein R and Z are as defined hereinabove, with diketene
and subjecting the acylated product to cyclization, the
corresponding ~-acetyl-(~-substituted)-azetidinone deri-
vatibes of the general formula (I) are directly obtained,
which can easily be converted into the desired (~-hydro-
xyethyl)-azetidinone derivatives.
The preparation of thienamycin starting with
the compounds of the formula (I) is illustrated as follows:
5~7
Formation
of ketal or 2
thioketal yl y
H3C--C--T~ (CZ)2 ____~ H3C-C r I (Co0~)2
e.q~ with l l
(I) ethylene O ~ ~ R
ethanol
R = protecting group yl + y' = ketal or thioketal
COOZ CH2-H
Alkyl metal halide ~ ~ Na~H~ j ~_ f
~, I -
+H20+DMSOO , N\ O~ N~
Alkyl or aryl- CH2_o_so2_R OEI2 J CH2-~
sulfonic acid
halide ~ N~ ~ N~
R = alkyl or aryl
CH2COOQ ll CH2-COOQ
l.Q-OH,HCl ~ ~ H~ H3C
2.Q-OH,H20 / ~ ~ Ac~tone~
Q = alkyl (e.q. methyl or ethyl)
OR CH2-COOQ OR CH2-COOH
1. NaBH4 ~ 1.0 ~ 3
2. Chloroformic ~ N~ 2- ~ ~ ~
acid p-nitro- o O / R
benzylester
R = p-nitro-benzyloxycarbonyl
.. . . . . . .... , ~ . .... .. . .. . . .. .
iJS ~3 ' ~
OR CH~-CH2-OH OR CH2-CH~-OR
H3C-C ~ H3C-CH-
1. S0~12 l ¦ 2,3-dihydropyrane
2, NaBH4 O// ~ R or ace-tic anhydride/ N
R3 = tetrahydropyranyl
or acetyl
oR2
CH2 -CH2 -
Elimination 3 1 ~
of R and R3 ~ l l DE-OS 2,751,597 ~Thienamycin
o~H
~ he compounds of the general forrnu:la ~I) in
which R and Z have the aforesaid meanings are obtainecll in
accordance with the present invent.ion, by a process com--
prising the steps of:
a) reacting a compound of the ~eneral formula:
R - NH - CH(COOZ)2 (II)
wherein R and Z are as defined above, with diketene to obtain
a compound of the formula:
HO CH3
~ (Cz)2 ~IIIa)
O ~ R
or a mixture thereof with a compound of the formula
H3C-C-CH2 CH(COOZ)2
l l (IIIb)
~ z~C N ~ R
wherein R and Z have the aforesaid meanings;
b) reacting the product of step (a) with an
alkali metal alcoholate and a reactant selected from the
group consisting of iodine, bromine and a mixture of bro-
mine and an alkali metal rhodanide, to obtain a reaction
mi~ture containing the desired compound of the formula (I)
defined above, and
c) isolating -the compound of formu:La (I) from
the reaction mixture obtained in step (b~.
In the first reaction step (a), a dialkyl (substi-
tuted amino)-malonate of the formula (II) is acylated with
diketene. If a compound of the formule (I) suitable for
the preparation of thienamycin is to be prepared, then
use is made of 21 starting compound oE the fonnula (II) in
which R represents a protecting group suitable for a -tem-
porary protection o amino and amido yroups, preferably
benzyl or substituted benzyl, more preferably 4-methoxy-,
3,4-dimethoxy- or 2,4-dimethoxy-benzyl. The most preferred
starting compound of the formula (II) is diethyl (2,4-dime-
thoxyben~yl-amino)-malonate. The preparation of this new
compound is described hereinafter in Example 1. The
compound of the formula (I) in which R is benzyl is known
in the art [P.J.Li: J.Oxg. Chem. 40(23) 3414 (1975)] .
On the other hand, if a compound of the general
formula (I) showing pharmaceutical activity is to be pre-
pared, a compound of the formula (II) in which R repre-
sents an aryl group, preferably a phenyl or chlorophenyl
group, is used Some of the compounds of the formula ~I)
in which R represents an aryl group, such as phenyl, are
known in the art [Ber. 31 1815 (1895)~ . The other
starting compounds of the formula ~ can be prepared
by literature known processes.
The compound of the formula (II) is generally
5~'~7
reacted with diketene in the presence of an organic solvent.
As an organic solvent, an inert solvent, such as tetra-
hydrofurane and dioxane, or saturated alip~atic carboxylic
acids which are li~uid at room temperature, e.g. formic
acid, acetic acid, propionic acid, etc., can be employed.
The reaction is preferably performed at elevated temperature
and, in certain cases, at the boiling temperature of the
solvent.
In the first reaction s-tep, the compounds of
the general formula (IIIa) and optionally (IIIb) are
obtained. As will be seen from the exarnples hereinbelo~,
under the conditions of lH-`-NMR ~CDC13~ measurement, the
form correspondin~ to the general formula (IIIa) was de~
tected. If a compound in which R is 2,4-dimethoxybenzyl
is prepared, the tautomeric form corresponding to the for-
mula (IIIb) was also detected in the reaction mixture, in
an amount less than 5%. ~11 the compounds of the general
formulae (IIIa) and (IIIb) are new and thus constitute a
further aspect of the present invention.
In the second reaction step (b), the compounds
of the formula (IIIa) and optionally of the formula (IIIb)
are con~erted into the desired compoundsof the general
formula (I). In this reaction step, an alkali metal alco-
holate and iodine or a similar reactant are used. The
reaction is preferably performed in the presence of an
excess amount of the alkali metal alcoholate employed, which
is preferably sodium or potassium ethylate or methylate.
Iodine can be replaced by bromine or a combination of
bromine and an alkali metal rhodanide. The most preferred
reactants are iodine and sodium ethylate. The reaction is
preferably carried out in the presence of a lower alkanol,
-- 6 --
~ t~ 7
preferably ethanol, or a mixture of an alkanol and ether,
under cooling.
The new compounds of the -ormula (I~ -thus
obtained can be isolated from the reaction mi~ture by
methods known in the art. The isolation call be carried out,
for example, by thin layer chromatography or by extrac-
tion and/or evaporation.
The following non-limiting examples illustrate
the invention.
Example 1
a) 50 g~ (0.30 moles) of 2,4-dime~thoxyb~nzal-
dehyde and 34.4 ml. ~33.6 g., 0.31 moles) o benzyl amine
in 300 ml. of dry toluene, in the presence of 1 g. of
p-toluenesulfonic acid are boiled Eor 8 hours, whila -the
water formed is continuously eliminated by a water sepa-
rator. Thereafter, the toluene is distilled off. The
residual oil i9 dissolved in 120 ml. of dioxane and 3.2 g.
of sodium tetrahydroborate (III) are added with an outer
ice cooling, followed by the addition of a further 3.2 g.
portion of the same compound after stirring for two hours.
The reaction mixture is allowed to stand for
3 days. It is then diluted with 400 mlO of water and the
residual oil is shaken with ether, dried over magnesium
sulfate, filtered and the filtrate is evaporated into
half of its original volume. Thereafter, a solution OI
hydrochloric acid in ethanol is added to the ethereal
solution, dropwise, under cooling with ice water.
59 g. ~67%) of benzyl (2,4-dimethoxybenzyl)amine
hydrochloride are obtained, melting at 156 to 157C after
crystallization from ethyl acetate.
~ ~5~
Analysis for Cl6H20ClN0~ (293.78):
calculated: C 65.41%, H 6.86%, Cl 12.07%, N 4.77%;
found: C 65.6~/o~ H 7~30%, Cl 11.69%, N 4.7~/O.
b) The compound obtained in the step ~a) is
converted into the corresponding base and 175 g. (0.~8
moles) of benzyl (2,4-dimethoxybenzyl)-amine obtained are
stirred with 89.6 g. (0.38 m~les, 64 ml~ of diethyl bro-
momalonate at room temperature until the reaction mixture
solidifies. The solidified mixture is triturated with
about one liter oE ether and the crystalline precipitate
is filtered off in this way, the excess of the starting
amine can be regained as hydrobromide with a yield of 95%.
The filtrate is evaporated and the residual oil .i5 -tritu-
rated with ethanol. 11~.5 g. (81%) of die-thyl (N-benæyl-
N-(2,4-dimethoxybenzyl)-amino-malonate are obtained,
melting at 62 to 63C after crystallization from ethanol.
Analysis for C23H29N06 (415-47):
calculated: C 66.49%, H 7.04%, N 3.37%,
found: C 66.58%, H 7.09%, N 3.4~/O.
IR spectrum (~Br) : 1750/1725 cm , d.
c) 61.7 g. (0.149 moles) of diethyl N-benzyl-N-
(2,4-dimethoxybenzyl)-amino-malonate prepared according to
step (b) are hydrogenated in the presence of about 20 g.
of a palladium-on-charcoal catalyst, in 500 ml. of ethanol,
under atmospheric pressure. 47.1 g. (97%) of diethyl
(2,4-dimethoxybenzylamino)-malonate are obtained, which
if desired, can be converted into the corresponding
hydrochloride with hydrochloric acid. The HCl salt melt
at 122 to 124~C, after crystallization from ethyl acetate.
Analysis for C16H24ClN06 ~361.82):
calculated: C 53.11%, H 6,69%, Cl 9~8~o~ N 3.87%;
found: C 52.51%, H 6.77%, Cl 10.30%, N 4,09%.
IR spectrum (film): 3250, 2900, 2850, 1730, 1720 cm
H-NMR spectrum ~CDC13): 1~3 t (6~), 3.78 s (3H); 3~82 s (3H);
4.21 q(4H), 6.20 s (2H); 6.4-6.6 m
(2H) ~ 7.3-7.55 m (lH~, 7,7 sz s 11H).
d) 39.6 g. (0.122 moles) of diethyl (2,4-dime-
thoxybenzyl-amino)-malonate prepared according to step (c)
are boiled with 12.3 g. (11.2 ml. , 0.146 moles) of diketene
in 80 ml. of glacial acetic acid for half an hour. The
glacial acetic acid is distilled off on water bath, in
vacuo, the residual oil is crystallized by tritura-tion
wit~ 150 ml. of water, whereupon the substance is dissolved
in 60 ml. of ethyl acetate and recrystallized by addition
of petroleum ether. 29.6 g (60%) of diethyl N-t2,4-dime-
thoxybenzyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-
dicarboxylate and/or the tautomer thereof are obtained.
Melting point: 106 to 107C.
Analysis for C20H27NO8 (40~.43~
calculated: C 58.67%, H 6.65%, ~ 3.42%,
found: C 58.79%, H 6.33/~, N 3.34%.
IR spectrum (KBr): 3400, 2950, 2850, 1730 (1740 v~, 1710 cm
H-NMR spectrum (CDC13): 1.1 t (3H), 1.17 t (3H); 1.52 s~ 3H),
2.08 (~0 lH); 2.65 sz s (2H); 3.75 s
(6H), 3.8-4.15 m (4H); 6.7 sz s (2H),
6.25-6.45 m + 7.0-7.25 m (3H).
e) 20.5 g. (50 mmoles) of the product of step
(d) are suspended in 50 ml. of dry ether and by two dopping
funnels, simultaneously 3.45 g. (150 mmoles) of sodium
_g_
~:~75~4~
metal in 100 ml. of dry ethanol and 12 7 g. (50 mmoles) of
iodine in 150 ml. of dry ether are rapidly added under
vigorous stirring, with outer ice cooling. To the mixture,
5g. sodium hydrogensulfite dissolved in 200 ml. sa-turated
aqueous sodium chloride solution are added. l~he mixture is
poured into a separating funnel and the precipi-tation of
inorganic salts is stopped by adding 60 ml. of water. qhe
aqueous phase is separated and shaken with two 100-ml.
portions of ether. The organic phase is dehydrated with
magnesium sulfate, filtered and the filtrate is evaporated.
me oily residue (18.5 g.) is recrystallized from 30 ml.
of 2-propanol. 10.9 g. (5~ %) of diethyl 3-acetyl-1-
(2,4-dimethoxybenzyl)-4-oxo-2,2-azetidine-dicarboxylate are
obtained, melting at 84 to 85C aEter recrystallization
from 2-propanol
Analysis for C20H25~O8 (
calculated: C 58.96 %, H 6.19 %, N 3.44%,
found: C 58.99 %, H 6.04 %, N 3.57%.
IR spectrum (KBr): 2900, 1780, 1740, 1710 cm
lH-NMR spectrum (CDC13): ~1.12 t (3H), 1.21 t (3H); 2.31 s (3H):
3.76 s (6H), 3.8-4.2 ~ (4H); 4,53 d
(lH), 4.63 d (lH), 4.69 s (lH), 6.3-
6.4 m (2H) + 7.07 d (lHl.
Example 2
a~ To a mixture of 59.2 g. (41.2 ml., 0.199 moles)
of diethyl bromomalonate and 22.5 g, (31.5 ml~, 0.225 moles~
of triethyl amine, 24 g. (24.3 ml., 0.207 moles) of benzyl
amine are added dropwise, under intensive outer cooling with
ice water, with vigorous stirring~ A thick mixture is
obtained, which is difficult to stir. The mixture is allowed
-- 10 --
Lt;~S~
to stand for 1.5 hours, triturated with 100 ml. of ether, the
precipitated crystals are filtered off and to the filtrate
hydrochloric acid in ethanol is added dropwise. The
crystalline precipitate is filtered of and washed with
ether. 23 g. (31 %) of diethyl benzylamino-mcllonate hydro-
chloride are obtained, melting at 146 to 148C, with
decompositionO
b) 2.52 g. (9~5 mmoles) of diethyl benzylamino-
malonate prepared according to step (a~ in 10 ml. of glacial
acetic acid are stirred with 0.8 g. (0.73 ml., 9.5 mmoles) of
diketene. The glacial acetic acid is distilled oEf in vacuo~
3.06 g. (92 %) of diethyl N-benzyl-3-hydroxy-3-methyl-5-oxo~
2,2-pyrrolidine-dicarboxylate and/or the tautomer thereof
~N-acetoacetyl-N-henzylamirlo malonate) are obtained as an
oily product.
IR spectrum (film): 3350, 2950, 1750-1670 cm
H-NMR spectrum (CDC13): 1.12 t (6H); 1.51 (3H); 2.68 s ~2H),
3.65-4.25 m (5H) 4.8 s (2H~; 7.2 s
(5H).
c) The product of step (b) is reacted wi h sodium
ethylate and iodine as described Example (lc). By preparative
thin layer chromatography, diethyl 3-acetyl-1-benzyl-4-oxo-2,2-
azetidine-dicarboxylate is isolated as an oily product.
(Kieselgel-60, PF254+366, 7093 mixture of benzene and acetone.)
IR spectrum (film): 2900, 1770-1700 cm
H-~MR spectrum (CDC13) 1.08 t ~3H) 1.22 t (3H); 2.3 s (3H);
3 7-4 3 m (4H); 4.45 d (lH), 4.8 s
(lH); 7.28 s (5H).
13C-NMR spectrum (CDC13): 13061; 13.75 30.07; 46.12 62 47;
62.68, 65.74; 68.67, 127,74: 128.20;
1~8. 37; 1~8.46, 128.54, 135.53;
162.57, 166.18, 166.30, 197.42.
Example 3
a) 38 g. (0.152 moles) of die~lyl anilino-malonate
/R. Blank: Ber. 31, 181S (1898)_ 7 are boiled in 38 ml. of
glacial acetic acid with 15.3 g. (13.9 ml., 0.182 moles) of
diketene for half an hour. The glacial acetic acid is
distilled off in vacuo, on water bath. q~e residual oil is
crystallized by trituration with ether. 36,5 g. (72 %)
of diethyl N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-
dicarboxylate and/or the tautomer thereof are obtained.
Melting point: 98 to 99C ~a mixture of ethyl ac~?tate and
petroleum e ther).
~nalysis for C17H21~O6 ~ 335,35)
calculated: C 60.88 %, H 6 31 %, N 4.18%
found: C 60.83 %, H 6.15 %r N 4.43 /.,.
IR spectrum (KBr): 3350, 2950, 1760 + 1750 d, 1700 cm 1,
H-~MR spectrum (CDC13): 1.02 t t3H), 1.3 t (3H), 1 6 s (3H),
2~8 s (2H), 3.6 sz s (lH), 4-4.45 m
(4H); 7.2 s (5H).
b) 10.2 g. (0.447 moles) of sodium metal are
dissclved in 250 ml, of dry ethanol and 50 g. (0.149 moles)
of diethyl N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-
dicarboxylate prepared according to step (a) are added to the
solution, followed by the addition of 37.9 g. (0.149 moles)
of iodine in 200 mlO of dry ether, under vigorous stirring.
When the reaction is complete, 8.5 ml. (89 g~, 0.143 moles)
of glacial acetic acid, 200 ml. of water and 100 ml. of
ether are added to the reaction mixture, the organic phase is
separated and the aqueous phase is shaken with 100 ml. of
-- 12 --
__ . ._ _ _ _ _ _ ... .. . _ .. . . .. .. _ _ . _. ... _. . _.. , . ,.. . __ . _ . ~ .. _ ... . _.. ... ~ . ~ .... .
. ..... ~ .. ... . .. .. .
ether. The e-thereal phases are combined, dried wi-th magnesium
sulfate, filtered and the fil-tra-te is evapora-ted~ The oily
residue is recrystallized from 50 ml. of 2-propanol, 31 g.
(62 %) of diethyl 3-acetyl-1-phenyl-4-oxo-2,2-azetidine-
dicarboxylate are obtained, melting at 55 to 56C aEter
crystallization from 2-propanol.
Analysis for C17HlgN06:
calculated: C 61 25 %, H 5.75 %, N 4.20 %
found: C 61.38 %, H 5~89 %, ~ 4.24 %.
IR spectrum (KBr): 1770, 1740, 1720 cIn
H-NMR spectrum (CDC13): 1.12 t (6H), 2,3 s (3~I); 4,25 q (4~I),
4.75 s (1~1), 7.0-7~6 m (5H).
Example 4
The reaction steps descrik~d in Examples (la)
and (lb) can be performed also in a combined version, without
isolating the product of Example (la), as follows:
iO9.7 g. (0.66 moles) of 2,4-dimethoxy-benzaldehyde
and 72 ml. (0.66 moles) of benzyl amine in 660 ml. oE methanol
are stirred at room temperature for 20 minutes. The initial
suspension slowly turns to a clear solution. To this
solution 13.2 g. ~0.33 moles) of sodium tetrahydroburate
(III) are added in small portions, under outer cooling with
ice water.
The progress of the reaction is monitored by thin
layer chromatography (Kieselgel G according to Stahl, a 9:1
mixture o~ benzene and acetone). When the reaction is
complete, the mixture is evaporated to dryness in vacuo,
300 ml. of water are added to the residue and it is shaken
with 500 ml. of ether. The aqueous phase is extracted with
two 2Q0-ml, portions of ether. The combined ethereal phases
- 13 -
. . , ., .. _ . . ~ , _ _ . _ _ . .. .. . . . _ . . . . . .
7~ 7
are dried with magnesium sulfate, filtered, whereupon 112 ml.
(0.66 moles) of diethyl bromomalonate and 93 ml. (0.66 moles)
of triethyl amine are added to the ethereal solution. q~e
reaction mixture is s-tirred a-t room temperature for 2 to 3
days. ~he precipitated triethyla~moni~ bromide is filtered
and washed with ether. ~e mother liquor is crystallized
from 150 ml. of ethanol. 210 g.of a crude product are
obtained, which is recrystallized from 400 ml. of ethanol.
197 g, (72 %) of diethyl ~-benzyl-~-(2,4-
dimethoxybenzyl)-amino-malonate are obtained. The
physicaL constants oE the product obtained are identical
with those o the product of Example ~lb).
Example 5
Diethyl 3-acetyl-1 (~ methoxyphenyl) ~-oxo-
2,2-azetidine dicarboxylate.
9.1 g (0.025 moles) of diethyL 1-(4-methoxy-
phenyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine
dicarboxylate are suspended in 50 ml. of dry diethyl ether.
To the suspension a solution of 1~72 g. of sodium metal in
30 ml of dry ethanol and a solution of 6.35 g (0.025 moles)
of iodine in 50 ml. of dry diethyl ether are added dropwise,
under vigorous stirring and outer cooling with ice. The
mixture is poured into 100 ml of a saturated aqueous sodium
chloride solution,whereupon 2 g. of sodium hydrogensulfite
and 2 ml. of glacial acetic acid are added. me ethereal
phase is separated and the aqueous phase is shaken with three
50 ml. portions of diethyl ether. The combined ethereal
phases are dried with magnesium sulfate, filtered and the
filtrate is evaporated. The oily residue is triturated
with 2-propanol to give 6.2 g. (68%) of the title compound
- 14 -
. ..
~ ~t~5~7
in crystalline form. Melting point: 70C -to 71C (ethanol).
Analysis for C18H21NO7 (363-38):
calculated: C 59.50 % H S,82 % N 3.85 %,
found: C 59.04 % H 5.84 % N 4.03 %.
IR spectrum (~r): 1760, 1735, 1720 cm
H-~MR spectrum (CDC13): ~ 1.20 (t, 3H, J=7.2 Hz),
1.22 (t, 3H, ~=7.2 Hz),
2.33 (s, 3H), 3.7 (s, 3H)
4.17 (q, 2H, ~=7.2 Hz), 4119 (q,
2H, ~=7~2 Hz), 4.7 (s, lH), 6.7
(2H)~7.31(2H), (AA'BB', ~=9 Hz).
The starting compound o~ -this Example is prepare~d
as follows:
a) 24.6 g. (0.2 moles) of 4-methoxyanillne
and 23.9 g. (17 ml, 0.1 moles) of diethyl bromomalonate
are stirred at room temperature for 2 days. The substance
obtained is triturated with 100 ml. of diethyl ether, the
precipitated 4-methoxyanizidine hydrogen bromiae is filtered
off and washed with a small amount of diethyl ether. The mother
liquor is evaporated and the residue is crystallized by adding
a dilute aqueous acetic acid solution.
Yield: 13.2 g. (47 %) of die~hyl 4-methoxyanilino malonate,
melting at 64 to 65C (ethanol).
Analysis for C14HlgN05 (281,31):
calculated: C 59.77 % H 6.81 % H 4.99 %;
found: C 59.g9 % H 6.97 % ~ 5.25 %.
IR spectrum (KBr): 3300, 1775, 1725 cm
H-NMR spectrum ~CDC13~: ~ 1.23 (t, 6H, ~=7,2 H7),
3.67 (s, 3H), 4.2 (q, 4H,
~=7,2 Hz), 4.62 (s, lH),
- 15 -
'7
4.1-4.5 (sz. s, lH),
6.55 (2H)~6.73(2H), (AA'BB',
~=9Hz).
b) 11.2 g.(0.04 moles) of diethyl 4 methoxy-
anilino ~alonate in 15 ml. of glacial acetic acid
and 4 g. ~3.7 ml., 0.048 moles) are boiled with diketene
for half an hour. ~he solution is evaporated in vacuo,
the oily residue is triturated with diethyl ether and
filtered.
Yield: 10.5 g. ~72 %) of diethyl 1-(4-methoxyphenyl)-
3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxylate
and/or its tautomer, melting at 136 to 137C ~ethyl
acetate).
Analy9iS for C18H23~O7 t365-38):
calculated: C 59.17 %, H 6.39 %, N 3.83 %;
found: C 58.98 %, H 6.90 %, N 4.04 %.
IR spectrum ~KBr): 3600-3000, 1760, 1685 cm
H-MMR spectrum ~CDC13): 1~07 tt, 3H, ~=7.2 Hz),
1.28 (t, 3H, ~=7.2 Hz),
1.58 (s, 3H), 2.76 (s, 2H),
3.64 (s, lH), 3.76 (s, 3H),
4.1 (q, 2H, ~=7.2 Hz),
4.27 (q, 2H, ~=7.2 Hz),
6.7 (2H)+7.0(2H), (AA'BB'
~=9 Hz).
- 16 -
