GB2112772A - Derivatives of azetidin-2-one - Google Patents
Derivatives of azetidin-2-one Download PDFInfo
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- GB2112772A GB2112772A GB08200164A GB8200164A GB2112772A GB 2112772 A GB2112772 A GB 2112772A GB 08200164 A GB08200164 A GB 08200164A GB 8200164 A GB8200164 A GB 8200164A GB 2112772 A GB2112772 A GB 2112772A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
The invention relates to new heterocyclic compounds containing a C-acetyl group, of general formula III <IMAGE> wherein R represents a protecting group suitable for temporary protection of amines and/or amides, or an aryl group, and Z represents an alkyl group. A process for the preparation of the new compounds is described as are novel intermediates for use in the preparation of compounds of formula III. The compounds of formula III have valuable properties; they are useful as intermediates in a new synthetic route to thienamycin. Compounds of formula III wherein R represents an aryl group are pharmaceutically active and possess antihypoxic properties.
Description
SPECIFICATION
Heterocyclic compounds containing a c-acetyl group and process for their preparation
The invention relates to new heterocyclic compounds containing a C-acetyl group, to a process for their preparation and to pharmaceutical compositions containing them.
According to one feature of the present invention there are provided compounds of general formula (Ill)
wherein R represents a protecting group suitable for temporary protection of amines and/or amides or an
aryl group and Z represents an alkyl group.
In the definition of R the said protecting group suitable for temporary protection of amines and/or amides
is preferably an optionally substituted benzyl group and the "aryl group" is preferably an optionally
substituted phenyl group.
In the definition of Z the term "alkyl" is used to refer to a straight chain or branched alkyl group, preferably containing 1 to 4 carbon atoms. More preferably, Z represents a methyl or ethyl group.
The compounds of the general formula (III) in which R is aryl are pharmaceutical active and more
particularly possess anti-hypoxic properties. Pharmaceutical compositions containing such compounds as active ingredient constitute a further feature of the present invention.
The compounds of the general formula (III) are useful as intermediates in a new synthetic route for the
preparation of thienamycin. The new thienamycin synthesis in which the intermediates of general formula (III) are obtained more conveniently and with a higher yield than the intermediates of the previous thienamycin syntheses is illustrated in Figure 1 which accompanies this specification. Most preferred are those compounds of general formula (III) wherein R represents a 2,4-dimethoxybenzyl group.
The key to Figure 1 is as follows: 1. = formation of ketal or thioketal (preferably with ethylene glycol or mercapto-ethanol) 2. = wherein Y' + y2 = ketal orthioketal 3. = aikali metal halide 4. = alkyl-or arylsulfonic acid halide 5. = wherein R1 is an alkyl or aryl group 6. = wherein Q is an alkyl (preferably methyl or ethyl) group 7. = acetone 8. = chloroformic acid P-nitro-benzyl ester 9. = wherein R2 is a P-nitro-benzyloxycarbonyl group 10. = 2,3-dihydropyran or acetic anhydride 11. = wherein R3 is a tetrahydropyranyl or acetic group 12. = elimination of R and R3 Thienamycin is a well known antibiotic with a wide spectrum of activity which has first been prepared microbiologically (US Patent Specification No. 3,950,357) and then synthetically (Published German Patent
Application 2,751,597).
Our intention was to provide a new synthetic route by which the azetidione skeleton and the a-hydroxyethyl side chain (or another side chain which can be easily converted into a a-hydroxyethyl) are formed simultaneously.
It has been found that by acylating a dialkyl (substituted amino)-malonate of the general formula (I).
R - NH - CH(COOZ)2 (I) wherein Rand Z are as hereinbefore defined, with diketene and subjecting the acylated product to cyclization, the corresponding a-acetyl-(N-substituted)-azetidinone derivatives of the general formula (III) are obtained directly. These can easiiy be converted into the desired (a-hydroxyethyl)-azetidione derivatives.
The compounds of the general formula (III) as hereinbefore defined may be prepared by the following process, which process constitutes a further feature of the present inention:
Reacting a compound of general formula (I), as hereinbefore defined, with diketene, and treating the compound of general formula (Ila)
(and optionally also the tautomeric compound of general formula (llb)
wherein Rand Z are as hereinbefore defined) thus obtained with an alkali metal alcoholate and iodine or with a similar reagent, and isolating a compound of general formula (III) from the reaction mixture.
Thus, according to one feature of the present invention in the first stage of the synthesis of compounds of general formula (III) a diethyl (substituted amino)-malonate of general formula (I) is acylated with diketene.
If compounds of general formula (III) suitable forthe synthesis ofthienamycin are to be prepared, in the starting materials of general formula (I) R preferably represents a benzyl or substitued benzyl, and more particularly a 4-methoxy-, 3,4-dimethoxy- or 2,4-dimethoxy-benzyl group. The most preferred starting compound of general formula (I) is diethyl (2,4-dimethoxybenzyl-amino)-malonate. The preparation of this new compound is described in Example 1. The compound of the general formula (I) in which R is benzyl is known in the art [P. J. Li: J. Org. Chem. (23) 3414 (1975)1.
In the preparation of compounds of the general formula (III) showing pharmaceutical activity R preferably presents a phenyl or chlorophenyl group. Some of the compounds of general formula (I) in which R stands for an aryl group (including the compounds in which R is phenyl group) are known in the art [Ber.311815 (1895)1. The other starting compounds of general formula (I) may be prepared by methods known from the literature.
The compounds of general formula (I) may be reacted with diketene in the presence of an organic solvent, such as, for example, an inert solvent such as tetrahydrofuran or dioxan, or a saturated aliphatic carboxylic acid which is liquid at room temperature, (e.g. formic acetic or propionic acid).
The reaction is preferably performed at elevated temperature, in certain cases at the boiling temperature of the solvent.
In the first reaction step a compound of general formula (Ila) and in some cases also a compound of the formula (llb) is obtained. In the examples disclosed in the present application under the conditions of 1H-NMR (CDC13) measurement the form correspnding to the general formula (Ila) could be detected. If a compound in which R is 2,4-dimethoxybenzyl is prepared, the tautomeric form corresponding to the general formula (llb) can also be detected in the reaction mixture, in an amount less than 5%. All the compounds of general formulae (Ila) and (llb) are new and constitute a further feature of the invention.
In the second step of the reaction the compounds of the general formula (Ila), and in some cases also compounds of the general formula (llb) are converted into compounds of the general formula (III). In this reaction step as a reagent alkali metal alcoholates and iodine or similar reagents are used. The reaction is preferably performed in the presence of 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 or a rhodanate. The most preferred reagents are iodine and sodium ethylate. The reaction is preferably carried out in the presence of a lower alkanol, preferably ethanol, or a mixture of an alkanol and ether, under cooling.
The new compounds of the general formula (III) obtained in the reaction are isoiated from the reaction mixture by methods known in the art. The isolation may for example be carried out by thin layer chromatography or by extraction and/or evaporation.
The invention is further illustrated by the following, non-limiting Examples.
Example 1
a) 50 g. (0.30 moles) of 2,4-dimethoxybenzaldehyde and 34.4 ml. (33.69., 0.31 moles) of benzyl amine in 300 ml. of dry toluene, in the presence of 1 g. ofp-toluenesulfonic acid are boiled for 8 hours, while the water formed is continuously removed by a water separator. Thereafter the toluene is distilled off. The residual oil is dissolved in 120 ml. of dioxan and 3.2 g. of sodium tetrahydroborate (III) are added with external 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, diluted with 400 ml. 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 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 hydrochoride are obtained, melting at 156 to 157"C after crystallization from ethyl acetate.
Analysis for C16H20C1 NO2 (293.78): calculated: C 65.41 %, H 6.86 %, Cl 12.07 %, N 4.77 %; found: C65.63%, H7.30%, Cl 11.69%, N4.72%.
b) The compound obtained in the step la), is converted into the corresponding base and 175 9. (0.68 moles) of benzyl (2,4-dimethoxybenzyl)-amine obtained are stirred with 89.6 9. (0.38 moles, 64 ml.) of diethyl bromomalonate at room temperature until the reaction mixture solidifies. The solidified mixture is triturated with about one litre of ether and the crystalline precipitate is filtered off. (In this way the excess of the starting amine can be recovered as hydrobromide with a yield of 95 %.) The filtrate is evaporated and the residual oil is triturated with ethanol. 114.5 g. (81 %) of diethyl (N-benzyl-N-(2,4-dimethoxybenzyl)-amino-malonate are obtained, melting at 62 to 63 C after crystallization from ethanol.
Analysis for C23H29NO6 (415.47): calculated: C66.49%, H7.04%, N 3.37 %; found: C66.58%, H7.09%, N3.43%.
IR spectrum (KBr): 1750/1725 cm-1, d.
c) 61.7 g. (0.149 moles) of diethyl N-benzyl-N-(2,4-dimethoxybenzyl)-amino-malonate prepared according to Example 1 b) are hydrogenated in the presence of about 20 9. of a palladium-on-charcoal catalyst, in 500 ml. of ethanol, under atmospheric pressure.
47.1 9. (97 %) of diethyl (2,4-dimethocybenzylamino)-malonate are obtained, which if desired can be converted into the corresponding hydrochloride with hydrochloric acid. The HCI salt melts at 122 to 1 240C, after crystallization from ethyl acetate.
Analysis for C16H24CINO6 (361.82): calculated: C 53.11 %, H 6.69 %, Cl 9.80%, N 3.87 %; found: C 52.51 %, H6.77%, Cl 10.30 %, N4.09%.
IR spectrum (film): 3250,2900,2850,1730,1720 cm -1.
1H-NMR spectrum (CDCl3): 1.3 t (6H); 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 (1H); 7,7szs (1H).
d) 39.6 g. (0.122 moles) of diethyl (2,4-dimethoxybenzyl-amino)-malonate prepared according to
Example 1 c) are boiled with 12.3 9. (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 in vacuo, over a water bath, the residual oil is crystallized by trituration with 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-(2,4-dimethoxybenzyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or the tautomer thereof are obtained. Melting point: 106 to 107 C.
Analysis for C20H27NO8 (409.43): calculated: C 58.67 %. H 6.65 %. N 3.42 %.
found: C58.79%. H 6.33 %. N 3.34 %.
IR spectrum (KBr): 3400,2950,2850, (1740 v). 1710 cm-1.
1H-NMRspectrum (CDCl3): 1.1 t (3H); 1,17 t (3H); 1.52s(~3H);
2.08 ( < 0.1 H); 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 9. (50 mmoles) of the product of Example 1d) are suspended in 50 ml. of dry ether and by two dopping funnels, simultaneously 3.45 9. (150 mmoles) of sodium metal in 100 ml. of dry ethanol and 12.7 9.
(50 mmoles) of iodine in 150 ml. of dry ether are rapidly added under vigorous stirring,with external ice cooling. To the mixture 5 9. sodium hydrogensulfite dissolved in 200 ml. saturated aqueous sodium chloride solution are added. The mixture is poured into a separating funnel and the precipitation of inorganic salts is stopped by adding 60 ml. of water. The aqueous phase is separated and shaken with two 100 ml. portions of ether. The organic phase is dried with magnesium sulfate filtered and the filtrate is evaporated. The oily residue (18.5 9.) is recrystallized from 30 ml. of 2-propanol. 10.9 g. (54 %) of diethyl 3-acetyl-1 -(2,4- dimethoxybenzyl)-4-oxo-2,2-azetidine-dicarboxylate are obtained, melting at 84 to 850C after recrystallization from 2-propanol.
Analysis for C20H25N 8 (407.41): calculated: C 58.96 %, H 6.19 %, N 3.44 %; found: C58.99%, H6.04%, N3.57%.
IR spectrum (KBr): 2900, 1780,1740, 1710 cm-1.
H-NMR spectrum (CDCI3): 61.12t (3H); 1,21 t (3H); 2,31 s (3H):
3,6 s (6H); 3,8-4,2 m (4H); 4,53 d
(1 H); 4,63 d (1 H); 4,69s(1 H); 6,3
6,4 m (2H) + 7,07 d (1 H).
Example 2
a) To a mixture of 59.5 g. (41.2 ml., 0.199 moles) of diethyl bromomalonate and 22.5 9. (31.5 ml., 0.225 moles) of triethyl amine 24 g. (24.3 ml., 0.207 moles) of benzyi amine are added dropwise, under continuous external cooling with ice water, with vigorous stirring. A thick mixture is obtained, which is difficult to stir.
The mixture is allowed 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 off and washed with ether.
23 9. (31 %) of diethyl benzylamino-malonate HCI (compound of general formula (I)) are obtained, melting at 146 to 148 Cwith decomposition.
b) 2.52 9. (9.5 mmoles) of diethyl benzylamino-malonate prepared according to Example 2a) 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 off in vacuo. 3.06 9. (92 %) of diethyl N-benzyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate of general formula (ill) and/or the tautomer having the general formula (llb) thereof (N-acetoacetyl-Nbenzylamino malonate) are obtained as an oily product.
IR spectrum (film): 3350,2950, 1750-1670 cm-1.
H-NMR spectrum (CDCl3): 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 Example 2b) is reacted with sodium ethylate and iodine as described Example 1 c). 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-1.
1H-NMR spectrum (CDC13): 1.08 t (3H); 1,22 t (3H); 2,3 s(3H);
3,7-4,3 m (4H); 4,45 d (1 H); 4,8 s
(1 H); 7,28 s (5H).
13C-NMRspctrum (CDCl3): 13,61; 13,75; 30,07; 46,12; 62,47; 62,8; 65,74; 68,67; 127,74; 128,20; 128,37; 128,46; 128,54; 135,53; 162,57; 166,18;166,30;197,42.
Example 3
a) 38 9. (0.152 moles) of diethyl anilino-malonate [R. Blank: Ber. 31. 1815(1898)] 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. The residual oil is crystallized bytrituration with ether.
36.5 (72 %) of diethyl N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate of general formula (Ila) and/or a corresponding compound of general formula (llb) is obtained. Melting point: 98 to 990C ( a mixture of ethyl acetate and petroleum ether)
Analysis for C17H21 NO6 (335.35): calulated: C60.88%, H 6.31 %, N 4.18 %; found: C60.83%, H6.15%, N4.43%.
IR spectrum (KBr): 3350,2950, 1760 + 1750 d, 1700cm1, H-NMR spectrum (CDCl3): 1,02 t (3H); 1,3 t (3H); 1,6 s (3H);
2,8 s (2H); 3,6 sz s (1 H); 4-4,45 m
(4H); 7,2 s (5H).
b) 10.2 g. (0.447 moles) of sodium metal are dissolved in 250 ml. of dry ethanol and 50 g. (0.149 moles) of diethyi N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate prepared according to the Example 3a) are added to the solution, followed by the addition of 37.9 g (0.149 moles) of iodine in 200 ml. of dry ether, under vigorous stirring. When the reaction is complete, 8.5 ml. (89 g., 0.149 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 ethereal phases are combined, dried with magnesium sulfate, filtered and the filtrate is evaporated.The oily residue is recrystallized from 50 ml. of 2-propanol.31 g. (62 /O) of diethyl 3-acetyl-1 -phenyl-4-oxo-2,2-azetidine-dicarboxylate of general formula (III) are obtained, melting at 55 to 560C after crystallization from 2-propanol.
Analysis for C17H19N06: calculated: C 61.25 %, H 5.75 %, N 4.20 %; found: C 61.38 %, H 5.89 %, N 4.24 %.
IR spectrum (KBr): 1770, 1740, 1720 cm-1.
H-NMR spectrum (CDCl3): 1,12 t (6H); 2,3 s (3H); 4,25 q (4H);
4,75 s (1 H); 7,0-7,6 m (5H)
Example 4
The reaction steps described in Examples 1 a) and 1 b) may also be performed together without isolating the product of Example 1a), as follows:
109.79. (0.66 moles) of 2,4-dimethoxy-benzaldehyde and 72 ml. (0.66 moles) of benzylamine in 660 ml. of 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 tetrahydroborate (III) are added in small portions under external cooling with ice water.
The progress of the reaction is monitored by thin layer chromatography (Kieselgel G according to Stahl, a 9:1 mixture of benzene and acetone). When the reaction is complete, the mixture is evaporated to dryness in vacuo, to the residue 300 ml. of water are added and it is shaken with 500 ml. of ether. The aqueous phase is extracted with two 200-ml. portions of ether. The combined ethereal phases are dried with magnesium sulfate, filtered, whereupon 112 ml. (0.66 moles) of diethyl bromomalonate and 93 ml. (0.66 moles) of triethylamine are added to the ethereal solution. The reaction mixture is stirred at room temperature for 2 to 3 days. The precipitated triethylammonium bromide is filtered and washed with ether. The 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 N-benzyl-N-(2,4-dimethoxybenzyl)-amino-malonate are obtained. The physical constants of the product obtained are identical with those of the product of Example 1 b).
Example 5
Diethyl 3-acetyl-1 -(4-methoxyphenyl )-S-oxo-2,2-azetidine dicarboxylate
9.1 g (0.025 moles) of diethyl 1-(4-methoxyphenyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine dicarboxyiate 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 hydrogen sulfite and 2 ml. of glacial acetic acid are added. The 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 in crystalline form. Melting point: 70"C to 710C (ethanol)
Analysis for C18H21 NO7 (363.38): calculated; C 59.50 % H 5.82 % N 3.85 %; found: C 59.04 % H 5.84 %, N 4.08 %.
IR spectrum (KBr): 1760, 1735, 1720 cm-1 H-NMR spectrum (CDCl3): 61.20 (t, 3H, J=7.2 Hz),
1.22 (t, 3H, J=7.2 Hz),
2.33 (s,3H),3.7 (s, 3H), 4.17(q,2H,J=7.2Hz),4.19(q,
2H, J=7.2 Hz), 4.7 (s, 1 H), 6.7
(2H) +7.31(2H), (AA'BB', J=9 Hz).
The starting compound ofthis Example is prepared as follows:
a) 24.6 9. (0.2 moles) of 4-methoxyaniline 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 hydrobromide 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 diethyl 4-methoxyanilino-malonate, melting at 64 to 659C (ethanol).
Analysis for C14H19N05 (281.31): calculated: C59.77% H 6.81 % N4.99%; found: C 59.99 % H 6.97 % N 5.25 %.
IR spectrum (KBr): 3300, 1775, 1725 cm-1.
1H-NMRspectrum (CDCl3): 61.23 (t,6H,J=7.2 Hz),
3.67 (s, 3H), 4.2 (q, 4H, J =7.2 Hz), 4.62(s, 1H),
4.1-4.5 (sz. s, 1H),
6.55 (2H) +6.73(2H), (AA'BB',
J=9 Hz).
b) 11.2 g (0.04 moles) of diethyl 4-methoxyanilino-malonate in 15 ml. of glacial acetic acid and 4 9. (3.7 ml., 0.048 moles) are boiled with diketene for half an hour. The 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-S-oxo-2,2-pyrrolidine dicarboxylate and/or its tautomer, melting at 136 to 1370C (ethyl acetate).
Analysis for C18H23N07 (365.38): calculated: C59.17%, H6.39%, N3.83%; found: C 58.98%, H 6.90 %, N 4.04 %.
IR spectrum (KBr): 3600-3000, 1760, 1685 cm-'.
H-NMR spectrum (CDCl3): 1.07 (t, 3H, J=7.2 Hz),
1.28 (t, 3H, J=7.2 Hz),
1.58 (s, 3H), 2.76 (s, 2H), 3.64 (s, 1 H), 3.76 (s,3H),
4.1 (q, 2H, J=7.2 Hz),
4.27 (q, 2H, J=7.2 Hz),
6.7 (2H) +7.0(2H), (AA'BB'
J=9 Hz).
Claims (31)
1. Compounds of general formula (III)
wherein R represents a protecting group suitable for temporary protection of amines and/or amides, or an aryl group; and Z represents an alkyl group.
2. Compounds as claimed in claim 1, in which R represents an optionally substitued benzyl or phenyl group.
3. Compounds as claimed in claim 1 or claim 2 wherein Z represents an alkyl group containing 1 to 4 carbon atoms.
4. Compounds as claimed in claim 3 wherein Z represents a methyl or ethyl group.
5. Compounds as claimed in any one of the preceding claims wherein R represents a phenyl or chlorophenyl group.
6. Compounds as claimed in any one of claims 1 to 4 wherein R represents a 2,4-dimethoxybenzyl group.
7. Diethyl 3-acetyl-1 -(2,4-dimethoxybenzyl)-4-oxo-2,2-azetidine-dica rboxylate.
8. Diethyl 3-acetyl-1 -benzyl-4-oxo-2,2,-azetidinedicarboxylate.
9. Diethyl 3-acetyl-1 -phenyl-4-oxo-2,2-azetidinedicarboxylate.
10. Compounds as claimed in claim 1 as herein specifically described.
11. A process for the preparation of compounds as claimed in claim 1 which comprises treating a compound of formula Ila.
(wherein Rand Z are as defined in claim 1) and/or a tautomeric compound of formula llb
(wherein Rand Z are as defined in claim 1) with an alkali metal alcoholate and iodine or a similar reagent.
12. A process as claimed in claim 11 wherein the compound of formula Ila and/or llb is/are reacted with an alkali metal alcoholate and iodine, bromine or a bromine/alkali metal rhodanide mixture.
13. A process as claimed in claim 11 or claim 12 wherein the compound of formula Ila and/or llb is/are reacted with sodium alkylate and iodine.
14. A process as claimed in any one of claims 11 to 13 wherein the compound of formula Ila and/or the compound of formula llb are obtained by reacting a compound of formula I
R - NH - CH(COOZ)2 (I) (wherein R and Z are as defined in claim 1) with diketene.
15. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of the Examples.
16. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 11 to 15.
17. Compounds of general formula Ill as claimed in claim 1 wherein R represents an aryl group, for use in the treatment of hypoxia.
18. Pharmaceutical compositions comprising, as active ingredient, a compound as claimed in claim 1 wherein R represents an aryl group.
19. The use of compounds as claimed in claim 1 in the synthesis of thienamycin.
20. The use of compounds as claimed in claim 1 wherein R represents a protecting group in the synthesis of thienamycin.
21. A process for the preparation of thienamycin substantially as herein described with reference to
Figure 1 of the accompanying drawings.
22. A process as claimed in claim 21 wherein the group R in the starting compound formula Ill represents a group suitable for the temporary protection of an amine and/or amide group.
Thienamycin whenever prepared by a process as claimed in claim 21 or claim 22.
24. Compounds of general formula (Ila)
and/or their tautomers of general formula (llb)
wherein Rand Z are as defined in claim 1.
25. Compounds as claimed in claim 24 in which R represents an optionally substitued benzyl or phenyl group and/or Z represents a methyl or ethyl group.
26. Diethyl N-(2,4-dimethoxybenzyl)-3-hydroxy-3-methyl-S-oxo-2,2-pyrrolidine-dicarboxylate and/or the tautomer thereof.
27. Diethyl N-benzyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or the tautomer thereof.
28. Diethyl N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or the tautomer thereof.
29. A process for the preparation of compounds as claimed in any one of claims 24 to 28 substantially as herein described.
30. The use of compounds of formula Ila and/or llb in the preparation of compounds as claimed in claim 1.
31. Each and every novel method, process and compound herein disclosed.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08200164A GB2112772A (en) | 1982-01-05 | 1982-01-05 | Derivatives of azetidin-2-one |
| FR8200065A FR2519339B1 (en) | 1982-01-05 | 1982-01-05 | HETEROCYCLIC COMPOUNDS CONTAINING A C-ACETYL GROUP AND PROCESS FOR THEIR PREPARATION |
| DE19823200129 DE3200129A1 (en) | 1982-01-05 | 1982-01-05 | A NEW HETEROCYCLIC COMPOUNDS CONTAINING A C-ACETYL GROUP AND METHOD FOR THE PRODUCTION THEREOF |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08200164A GB2112772A (en) | 1982-01-05 | 1982-01-05 | Derivatives of azetidin-2-one |
| FR8200065A FR2519339B1 (en) | 1982-01-05 | 1982-01-05 | HETEROCYCLIC COMPOUNDS CONTAINING A C-ACETYL GROUP AND PROCESS FOR THEIR PREPARATION |
| DE19823200129 DE3200129A1 (en) | 1982-01-05 | 1982-01-05 | A NEW HETEROCYCLIC COMPOUNDS CONTAINING A C-ACETYL GROUP AND METHOD FOR THE PRODUCTION THEREOF |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2112772A true GB2112772A (en) | 1983-07-27 |
Family
ID=27189839
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08200164A Withdrawn GB2112772A (en) | 1982-01-05 | 1982-01-05 | Derivatives of azetidin-2-one |
Country Status (3)
| Country | Link |
|---|---|
| DE (1) | DE3200129A1 (en) |
| FR (1) | FR2519339B1 (en) |
| GB (1) | GB2112772A (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3943123A (en) * | 1971-04-30 | 1976-03-09 | Koninklijke Nederlandsche Gist-En Spiritusfabriek N.V. | Novel beta-lactams and novel process |
| JPS55111463A (en) * | 1979-02-21 | 1980-08-28 | Sankyo Co Ltd | Beta-lactam compound and its preparation |
-
1982
- 1982-01-05 FR FR8200065A patent/FR2519339B1/en not_active Expired
- 1982-01-05 DE DE19823200129 patent/DE3200129A1/en not_active Withdrawn
- 1982-01-05 GB GB08200164A patent/GB2112772A/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| DE3200129A1 (en) | 1983-07-14 |
| FR2519339A1 (en) | 1983-07-08 |
| FR2519339B1 (en) | 1986-08-14 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |