CA1175847A - Acetyl-azetidinones dicarboxylates - Google Patents

Abstract

ABSTRACT

New heterocyclic compounds containing a C-acetyl group and having the general formula:

(I) wherein R is a protecting group suitable for a temporary protection of amines and amides or an aryl group, and Z is an alkyl group, are prepared by reacting a compound of the general formula:
R - NH - CH(COOZ)2 (II) wherein R and Z are as defined above, with diketene to obtain a compound of the formula:

(IIIa) or a mixture thereof with a compound of the formula:

(IIIb) wherein R and Z have the aforesaid meanings, which is reacted with an alkali metal alcoholate and a reactant selected from the group consisting of iodine, bromine and a mixture of bromine and an alkali metal rhodanide, to obtain a reaction mixture containing the desired compound of the formula (I) which is then isolated therefrom.

The compounds of the formula (I) in which R is an aryl group possess antihypoxic properties, while those in which R is a protecting group are valuable intermediates for the synthesis of thienamycin.

Description

:~ ~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.

~' '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 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) 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 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:

~ (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, ~ 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 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 __ . ._ _ _ _ _ _ ... .. . _ .. . . .. .. _ _ . _. ... _. . _.. , . ,.. . __ . _ . ~ .. _ ... . _.. ... ~ . ~ .... .
. ..... ~ .. ... . .. .. .

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 . . , ., .. _ . . ~ , _ _ . _ _ . .. .. . . . _ . . . . . .

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 . ..

~ ~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), '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).

Claims (28)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of compounds having the general formula.

(I) wherein:
R is a protecting group suitable for a temporary protection of amines and amides or an aryl group, and Z is an alkyl group, which comprises the steps of:
a) reacting a compound of the general formula:
R - NH - CH(COOZ)2 (II) wherein R and Z are as defined above, with diketene to obtain a compound of the formula:

(IIIa) or a mixture thereof with a compound of the formula:

(IIIb) 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 m:ixture of bromine and an alkali metal rhodanide, to obtain a reaction mixture containing the desired compound of the formula (I) defined above; and c) isolating the compound of fonnula (I) from the reaction mixture obtained in step (b).

2. A process according to claim 1, wherein the starting compound of the formula (II) is reacted with diketene in the presence of an inert organic solvent, at a temperature of up to the boiling temperature of the solvent.

3. A process according to claim 1, wherein the reaction product oE step (a) is reacted with iodine and sodium ethylate.

4. A process according to claims 1 or 3, wherein step (b) is carried out in the presence of a lower alkanol or a mixture of an alkanol and ether, under cooling.

5. A process according to claim 1, wherein use is made of a starting compound of the formula (II) in which R is an optionally substituted benzyl group and Z has the aforesaid meaning.

6. A process according to claim 5, wherein use is made of a starting compound of the formula (II) in which R is a 4-methoxy, 3,4-dimethoxy or 2,4-dimethoxy-benzyl group and Z has the aforesaid meaning.

7. A process according to claim 6, wherein use is made of a starting compound of the formula (II) in which R is a 2,4-dimethoxybenzyl group and Z has the aforesaid meaning.

8. A process according to claim 1, wherein use is made of a starting compound of the formula (II) in which R is an optionally substltuted phenyl group and Z has the aforesaid meaning.

9. A process according to claim l, wherein use is made of a starting compound of the formula (II) in which Z is a straight or branched chained alkyl group having 1 to 4 carbon atoms and R has the aforesaid meaning.

10. A process according to claim 9, wherein use is made of a starting compound of the formula (II) in which Z is a methyl or ethyl group and R has the aforesaid meaning.

11. A process according to claim l, wherein use is made of a starting compouhd of the formula (II) in which R is an optionally substituted benzyl or phenyl group and Z is a methyl or ethyl group.

12. A process according to claim l, for the preparation of diethyl 3-acetyl-l-(2,4-dimethoxybenzyl)-4-oxo-2,2-azetidine dicarboxylate, wherein use is made of diethyl (2,4-dimethoxybenzyl-amino)-malonate as starting compound of the formula (II).

13. A process according to claim l, for the preparation of diethyl 3-acetyl-l-benzyl-4-oxo-2,2-azetidine dicarboxylate, wherein use is made of diethyl benzylamino-malonate as starting compound of the formula (II).

14. A process according to claim 1, for the preparation of diethyl 3-acetyl-1-phenyl-4-oxo-2,2-azetidine dicarboxylate, wherein use is made of diethyl anilino-malonate as starting compound of the formula (II).

15. A process according to claim 1, for the preparation of diethyl 3-acetyl-1-(4-methoxyphenyl)-4-oxo-2,2-azetidine dicarboxylate, wherein use is made of diethyl 4-methoxy anilino-malonate as starting compound of the formula (II).

16. The compounds having the general formula:

(I) wherein:
R is a protecting group suitable for a temporary protection of amines and amides or an aryl group, and Z is an alkyl group, whenever prepared by a process according to claim 1 or its obvious chemical equivalents.

17. The compounds of the general formula (I) as defined in claim 16, whenever prepared by a process according to claims 2 or 3, or their obvious chemical equivalents.

18. The compounds of the general formula (I) as defined in claim 16, wherein R is an optionally substituted benzyl group and Z has the aforesaid meaning, whenever prepared by a process according to claim 5 or its obvious chemical equivalents.

19. The compounds of the general formula (I) as defined in claim 16, wherein R is a 4-methoxy, 3,4-dimethoxy or 2,4-dimethoxy-kenzyl group and Z has the aforesaid meaning, whenever prepared by a process according to claim 6 or its obvious chemical equivalents

20. The compounds of the general formula (I) as defined in claim 16, wherein R is a 2,4-dimethoxybenzyl group and Z has the aforesaid meaning, whenever prepared by a process according to claim 7 or its obvious chemical equivalents.

21. The compounds of the general formula (I) as defined in claim 16, wherein R is an optionally substituted phenyl group and Z has the aforesaid meaning, whenever prepared by a process according to claim 8 or its obvious chemical equivalents.

22. The compounds of the general formula (I) as defined in claim 16, wherein Z is a straight or branched chained alkyl group having l to 4 carbon atoms and R has the aforesaid meaning, whenever prepared by a process according to claim 9 or its obvious chemical equivalents.

23. The compounds of the general formula (I) as defined in claim 16, wherein z is a methyl or ethyl group and R has the aforesaid meaning, whenever prepared by a process according to claim 10 or its obvious chemical equivalents.

24 The compounds of the general formula (I) as defined in claim 16, wherein R is an optionally substituted benzyl or phenyl group and Z is a methyl or ethyl group;
whenever prepared by a process according to claim 11 or its obvious chemical equivalents.

25. Diethyl 3-acetyl-1-(2,4-dimethoxybenzyl)-4-oxo-2,2-azetiaine dicarboxylate, whenever prepared by a process according to claim 12 or its obvious chemical equivalents.

26. Diethyl 3-acetyl-1-benzyl-4-oxo-2,2-azetidine dicarboxylate, whenever prepared by a process according to claim 13 or its obvious chemical equivalents.

27. Diethyl 3-acetyl-1-phenyl-4-oxo-2,2-azetidine dicarboxylate, whenever prepared by a process according to claim 14 or its obvious chemical equivalents.

28. Diethyl 3-acetyl-1-(4-methoxyphenyl)-4-oxo-2,2-azetidine dicarboxylate, whenever prepared by a process according to claim 15 or its obvious chemical equivalents.