GB2112392A - Azetidinones - Google Patents
Azetidinones Download PDFInfo
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- GB2112392A GB2112392A GB08236916A GB8236916A GB2112392A GB 2112392 A GB2112392 A GB 2112392A GB 08236916 A GB08236916 A GB 08236916A GB 8236916 A GB8236916 A GB 8236916A GB 2112392 A GB2112392 A GB 2112392A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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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- 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
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
New heterocyclic carboxylic acids of the general formula (I), <IMAGE> wherein Y<1> and Y<2> form together a removable carbonyl protecting group and R is a removable amido protecting group, are prepared in such a way that a compound of the general formula (IV), <IMAGE> wherein Z is a C1-5 alkyl group and R is as defined above, is reacted with a compound capable for the temporary protection of the carbonyl group, the resulting compound of the general formula (III), <IMAGE> wherein R, Z, Y<1> and Y<2> are as defined above, is treated with an alkali metal halide, and the resulting compound of the general formula (II), <IMAGE> wherein Z, R, Y<1> and Y<2> are as defined above, is either hydrolysed selectively or separated into its isomers and the trans isomer is then hydrolysed. The resulting compounds of the general formula (I) are valuable intermediates of the synthesis of thienamycin and thienamycin analogues.
Description
SPECIFICATION
New heterocyclic carboxylic acids and a process for the preparation thereof
The invention relates to new heterocyclic carboxylic acids of the general formula (I),
wherein
Y' and Y2 form together a removable carbonyl protecting group, preferably a ketal group or a thioanalogue thereof, and
R is a removable amido protecting group, preferably a benzyl group bearing one or more C14 alkoxy substituents or a phenyl group bearing optionally one or more C,~4 alkoxy substituents.
These new compounds are valuable intermediates of the synthesis of thienamycin and related compounds. Thienamycin and its analogues can be prepared from the compounds according to the invention e.g. as shown in Scheme (A).
Scheme (A)
Scheme (A) (contd.)
In the formulae shown on Scheme (A) Y1 Y2 and R are as defined above,
X is a selectively removable esterifying group,
Q is a C15 alkyl group or a substituted benzyl group,
Q' is a C15 alkyl group, a substituted benzyl group, hydrogen atom or an alkali metal ion, and
R" is a benzyl, aminoethyl or N-acyl-aminoethyl group.
Thienamycin, an antihiotic of broad spectrum of activity, was prepared first in microbiological way (US patent specification No. 3,950,375) and later on by chemical synthesis (German
Offenlegungsschrift No. 2,751,597).
Our aim was to provide a new route for the synthesis of thienamycin and its analogues, wherein the azethidinone skeleton and the ce-hydroxyethyl side chain, or a side chain which can be converted easily into -hydroxyethyl group, are formed 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 azethidinone compound of the general formula (IV),
containing an a-acetyl side chain, is obtained, which can be utilized as key intermediate in the synthesis.
In the above formula R has the same meaning as given above and Z is a C15 alkyl group.
The intermediates of the general formula (IV) and their preparation are described in detail in our previous Hungarian patent application No. 2262/80. The preparation of these intermediates is also described in the examples of the present application.
It has also been observed that, prior to converting the intermediate of the general formula (IV) into thienamycin or an analogue thereof, it is preferable to protect the keto group of the a-C-acetyl side chain with a group, particularly a ketal group or a thioanalogue thereof, which can be removed at a later stage of the synthesis. Ethylene glycol or a thioanalogue thereof, such as mercapto-ethanol, can
be applied particularly preferably to form the ethyleneketal or hemithioketal protecting group.The
resulting compound of the general formula (III),
wherein R, Z, Y1 and Y2 are as defined above, is reacted then with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide to obtain a compound of the general formula (II),
wherein R, Y1, y2 and Z are as defined above.
The resulting compound of the general formula (II) is a mixture of cis and trans isomers. The isomers can be separated from each other by chromatography or on the basis of their different solubilities. The separated trans isomer of the general formula (ill)
can be converted into the trans carboxylic acid of the general formula (I) by hydrolysis. It is more preferable, however, to subject the isomeric mixture itself to hydrolysis, since the reaction is selective, i.e. only the trans ester converts into the respective carboxylic acid.
The compounds of the general formulae (III), (11) and (Ila) wherein R is a dimethoxybenzyl group,
Y' and Y2 form together an ethyleneketal or hemithioketal group and Z is ethyl are described in our previous Hungarian patent application No. 2263/80, their preparation is, however, described in the examples of the present application as well. The other compounds of the general formulae (III), (11) and (ill) are new. The compounds of the general formulae (I) to (IV) are racemic mixtures.
Based on the above, the invention relates to a process for the preparation of new heterocyclic carboxylic acids of the general formula (I), wherein.
Y' and Y2 form together a removable carbonyl protecting group, preferably a ketal group or a thioanalogue thereof, and
R is a removable amido protecting group, preferably a benzyl group bearing one or more C14 alkoxy substituents or a phenyl group bearing optionally one or more C14 alkoxy substituents, in which
a compound of the general formula (IV), wherein Z is a C15 alkyl group and R is as defined above, is reacted with a compound capable for the temporary protection of the carbonyl group, preferably with a ketal-forming agent or a thioanalogue thereof, in the presence of a compound which facilitates the reaction, the resulting compound of the general formula (III), wherein Z, R, Y1 and Y2 are as defined above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide, and the resulting compound of the general formula (II), wherein Z, R, Y1 and Y2 are as defined above and which is a mixture of cis and trans isomers, is
a) hydrolysed selectively, or
b) separated into its components, and the trans isomer of the general formula (ill) is hydrolysed; or
a compound of the general formula (III), wherein Z, R, Y1 and Y2 are as defined above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide, and the resulting compound of the general formula (il), wherein Z, R, Y' and Y2 are as defined above and which is a mixture of cis and trans isomers, is
a) hydrolysed selectively, or
b) separated into its components, and the trans isomer of the general formula (Ila) is hydrolysed; or
a compound of the general formula (II), wherein Z, R, Y1 and Y2 are as defined above and which is a mixture of cis and trans isomers, is
a) hydrolysed selectively, or
b) separated into its components, and the trans isomer of the general formula (ill) is hydrolysed,
whereafter the trans compound of the general formula (I) is separated from the reaction mixture.
According to the process of the invention a compound of the general formula (IV) is converted first into a compound of the general formula (III). It is preferred to apply a ketal-forming compound or a thioanalogue thereof as reactant for the temporary protection of the keto group. The reaction is performed preferably in the presence of a compound, such as boron trifluoride-diethyl etherate or an arylsulfonic acid (e.g. p-toluenesulfonic acid or naphthalenesulfonic acid), which facilitates the conversion.
The reaction is performed in an organic solvent, such as benzene, toluene, dioxane, tetrahydrofuran, etc., at a temperature from room temperature to the boiling point of the reaction mixture.
Thereafter a compound of the general formula (III) is reacted with an alkali metal halide, preferably sodium or lithium chloride, in the presence of pyridine, quinoline, a homologue or a mixture thereof, or-preferably-in aqueous dimethyl sulfoxide to obtain a compound of the general formula (II). If desired, this step can also be performed without separating the compound of the general formula (III) from the reaction mixture where it was formed.
The compounds of the general formula (II) are isomeric mixtures. The trans component of the mixture can be utilized for the preparation of thienamycin or thienamycin analogues.
The isomeric mixture of the general formula (II) can be hydrolysed with an alkali, whereupon the trans compound of the general formula (I) is formed selectively. The alkaline hydrolysing agent is used in a molar equivalent amount or in a reasonable excess.
If desired, the isomeric mixture of the general formula (II) is separated first into its components.
The individual isomers of the compounds wherein R is 2,4-dimethoxybenzyl, Z is ethyl and Y' andY2 form a 1,3-dioxolanyl group can be separated from each other e.g. by chromatography, utilizing
Kieselgel 60 (=0.063-0.200 mm) as adsorbent and benzene with gradually increasing acetone content (elution is started with benzene and then the acetone content is increased up to a benzene:acetone ratio of 9:1) as eluting agent. The individual isomers can also be separated from each other on the basis of their different solubilities, since only the cis esters are soluble in ether type solvents, such as diethyl ether.
Thereafter the separated trans isomer of the general formula (ill) is hydrolysed to obtain the trans product of the general formula (I).
The invention is elucidated in detail by the aid of the following non-limiting Examples.
Example 1 trans -(2,4-Dimethoxybenzyl)-3-(2-methyl-1 ,3-dioxolan-2-yI)-4-oxo-2-azethidine-carboxylic acid
A solution of 5.21 g (0.130 mole) of sodium hydroxide in 60 ml of water is added to a suspension of 41.2 g (0.109 mole) of trans-ethyl 1 -(2,4-dimethoxybenzyl)-3-(2-methyl-1 ,3-dioxolan-2-yl)-4-oxo- 2-azethidine-carboxylate in 50 ml of 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. The aqueous phase is acidifed to pH=1 with concentrated aqueous hydrochloric acid, and then shaken quickly with 100 ml and twice with 50 ml of dichloromethane, each.The dichloromethane solutions are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The oily residue is crystallized from a mixture of toluene and petroleum ether to obtain 35 g (92%) of trans -(2,4-dimethoxybenzyl)-3-(2-methyl- 1 ,3-dioxolan-2yl)-4-oxo-2-azethidine-carboxylic acid; m.p.: 117--1180C(toluene).
Analysis:
calculated for C,7H2,NO7 (351.35): C:58.1 1%, H:6.03%, N:3.99%;
found: C:58.17%, H:6.309/o, N:4.24%.
IR (KBr): 3500--2500, 2900, 1760, 1720 cm-'.
1H NMR (CDCl3): S=1.39 (s, 3H), 3.50 (d, 1 H, J=2.5 Hz), 3.77 (s, 3H), 3.79 (s, 3H), 3.86 (d, 1 H, J=2.5 Hz), 3.96 (m, 4H), 4.21+4.56 (d, 2H, JAB=15 Hz), 6.44 (m, 2H)+7.15 (d, 1 H, J=1 0 Hz), 7.58 (broad s, 1 H) ppm.
The starting substance is prepared as follows:
a) A mixture of 109.8 g (0.66 mole) of 2,4-dimethoxybenzaldehyde, 72 ml (0.66 mole) of benzylamine and 660 ml of methanol is stirred at room temperature for 20 minutes, whereupon a clear solution is obtained from the suspension. The solution is cooled with ice water, and 1 3.2 g (0.33 mole) of sodium borohydride are added to it in small portions.
The progress of the reaction is monitored by thin layer chromatography (Kieselgel G according to
Stahl; developing solvent: a 9:1 mixture of benzene and acetone), and at the end of the reaction the mixture is evaporated to dryness in vacuo. The residue is admixed with 300 ml of water, and the aqueous mixture is extracted with 500 ml, 200 ml and 200 ml portions of ether. The ethereal solutions are combined, dried over magnesium sulfate, filtered, and then 112 ml (0.66 mole) of diethyl bromomalonate and 93 ml (0.66 mole) of triethyl amine are added to the filtrate. The reaction mixture is stirred at room temperature for 2-3 days. The separated triethyl ammonium bromide is filtered off and washed with ether. The mother liquor is evaporated, and the residue is recrystallized from 1 50 ml of ethanol.The resulting 210 g of crude product are recrystallized again from 400 ml of ethanol to obtain 1 97 g (72%) of diethyl N-benzyl-N-(2,4-dimethoxybenzyl)-amino-malonate; m.p.: 62--630C (ethanol).
IR (KBr): 1750/1725 cm-1.
b) 61.7 g (0.149 mole) of diethyl N-benzyl-N-(2,4-di-methoxybenzyl)-amino-malonate, prepared as described in point a) above, are hydrogenated in 500 ml of ethanol under atmospheric pressure in the presence of about 20 g of a palladium-on-charcoal catalyst. The catalyst is filtered off and the filtrate is evaporated. 47.1 g (97%) of diethyl (2,4-dimethoxybenzylamino)-malonate are obtained. The product can be converted into its hydrochloride by reacting it with hydrochloric acid. The hydrochloride melts at 122124aC after recrystallization from ethyl acetate.
Analysis:
calculated for C16H24CIN06 (361.82): C:53.1 1%, H:6.69%, Cl:9.80%, N:3.87%;
found: 0:52.51%, H:6.77%, Cm:10.30%, N:4.09%.
IR (film): 3250, 2900, 2850, 1730, 1720 cm-l.
'H NMR (CDCI3): b=1.3 (s, 6H), 3.78 (s, 3H), 3.82 (s. 3H), 4.21 (q, 4H), 6.20 (s, 2H), 6.4-6.6 (m, 2H)+7.4-7.55 (m, 1 H), 7.7 (broad s, 1 H) ppm.
c) A mixture of 39.6 g (0.122 mole) of diethyl (2,4-dimethoxybenzylamino)-malonate, prepared as described in point b) above, 80 ml of glacial acetic acid and 12.3 g (11.2 ml, 0.146 moie) of diketone is boiled for 0.5 hour. Glacial acetic acid is distilled off in vacuo over a water bath, and the oily residue is triturated with 1 50 ml of water. The resulting crystalline substance is dissolved in 60 ml of ethyl acetate and precipitated with petroleum ether. 29.6 (60%) of diethyl N-(2,4-dimethoxybenzyl)-3 hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate and/or its ta utomer are obtained; m.p.: 106- 1070C.
Analysis:
calculated for C20H27N08 (409.43): C:58.67%, H:6.65%, N:3.42%;
found: C:58.79%, H:6.33%, N:3.34%.
IR (KBr): 3400, 2950, 2850, 1730, (1740 sh), 1710 cm-l.
'H NMR (CDCI3): 6=1.1 (t, 3H), 1.17 (t, 3H), 1.52 (s, 3H), 2.8 ( < 0.1 H), 2.65 (broad s, 2H), 3.75 (s, 6H), 3.8 5 (m, 4H), 6.7 (broad s, 2H), 6.25-6.45 (m)+7.0--7.2 5 (m, 3H) ppm.
d) 20.5 (50 mmoles) of the product prepared as described in point c) above are suspended in 50 ml of dry ether, and a solution of 3.45 g (1 50 mmoles) of metallic sodium in 100 ml of dry ethanol and a solution of 12.7 g (50 mmoles) of iodine in 1 50 ml of dry ether are added simultaneously, from two dropping funnels, to the vigorously stirred suspension under cooling with ice water. Thereafter 5 g of sodium hydrosulfite, dissolved in 200 ml of a saturated aqueous sodium chloride solution, are added to the stirred mixture. The mixture is filled into a separating funnel, and 60 ml of water are added to dissolve the separated inorganic salts. The organic phase is removed, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The oily residue, weighing 18.5 g, is crystallized from 30 ml of 2propanol. 10.9 g (54%) of diethyl 3-acetyl-1 -(2,4-dimethoxybenzyl)-4-oxo-2,2-azethidine- dicarboxylate are obtained; m.p.: 84--850C (2-propanol).
Analysis:
calculated for C2oH25Noa (407.41): C:58.96%, H:6.19%, N:3.44%;
found: C:58.99%, H:6.04%, N:3.57%.
'H NMR (CDCI3): b=1.12 (t, 3H), 1.21 (t, 3H), 2.31 (s, 3H), 3.76 (s, 6H), 3.8-3.4 (m, 4H), 4.53 (d, 1 H), 4.63 (d, 1 H), 4.69 (s, 1 H), 6.3-6.4 (m, 2H)+7.07 (d, 1 H) ppm.
e) 1 79 ml (206 g, 1.452 moles) of boron trifluoridediethyl etherate are added dropwise to a vigorously stirred solution of 1 79 g (0.484 mole) of diethyl 3-acetyl-1 -(2,4-dimethoxybenzyl)-4-oxo2,2-azethidine-dicarboxylate and 107 ml (120 g, 1.936 moles) of ethylene glycol in 500 ml of dry dioxane under cooling with ice water. The reaction mixture is allowed to stand at room temperature for one day, during this period the mixture is occasionally stirred. Thereafter 41 5 g (1.452 moles) of Na2C03. 1 OH20 are added slowly to the stirred mixture under cooling with ice water, and the mixture is stirred for 1 5 minutes. Thereafter 1 litre of ether and 1 litre of water are added, and the phases are separated from each other. The aqeous phase is shaken twice with 500 ml of diethyl ether, each.The etheral phase is dried over magnesium sulfate, filtered, and the filtrate is evaporated. 33.9 g (0.58 mole) of sodium chloride, 1 7.4 ml (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 1800C. 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 acetate). At the end of the reaction, i.e. after about 1 5 hours, the mixture is poured into 1100 ml of saturated aqueous sodium chloride solution, and the resulting mixture is shaken with 1000 ml and then twice with 500 ml of diethyl ether, each.The ethereal solutions are combined, decolourized with charcoal, dried over magnesium sulfate, and the filtrate is evaporated to a final volume of cca. 220 ml. This concentrated solution is cooled with ice water to obtain 59 g (35%) of trans-ethyl 1 -(2,4-dimethoxybenzyl)-3-(2-methyl-1 ,3-dioxolan-2-yl)-4oxo-2-azethidine-carboxylate; m.p.: 950C.
f) A mixture of 0.5 g (1.2 mmoles) of diethyl 3-acetyl-1-(2,4-dimethoxybenzyl)-4-oxo-2,2azethidine-dicarboxylate, prepared as described in point d) above, 3 ml of dry tetrahydrofuran and 0.53 g (3.6 mmoles) of mercapto-ethanol is boiled for 4 hours, and then 10 ml of water and 10 ml of chloroform are added to the reaction mixture. The organic phase is separated, washed with a 5% aqueous sodium hydrocarbonate solution, dried over magnesium sulfate, filtered, and the product is separated from the filtrate by preparative thin layer chromatography (adsorbent: Kieselgel 60 PF254+368, developing solvent: a 8:2 mixture of toluene and acetone). 0.30 g (53%) of diethyl 1-(2,4-dimethoxy benzyl)-3-(2-methyl-1 ,3-oxathiolan-2-yl)-4-oxo-2,2-azethidine-dicarboxylate are obtained.
'H NMR (CDCI3): S=0.8--1.55 (m, 6H), 1.72+1.77 (d, 3H), 2.9-3.4 (m, 2H), 3.75 (s, 6H), 4.05.0 (m, 9H), 6.4 (m, 2H)+7.1 (d, 1 H) ppm.
Example 2 trans -(4-Methoxyphenyl)-3-(2-methyl-l ,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxyl ic acid
11 g (0.0245 mole) of diethyl 3-(2-methyl-1 ,3-dioxolan-2-yl)-1 -(4-methoxyphenyl)-4-oxo-2,2- azethidine-dicarboxylate are dissolved in 20 ml of dimethyl sulfoxide, 1.72 g (0.0295 mole) of sodium chloride and 0.9 ml (0.049 mole) of water are added, and the mixture is stirred at 1750C until a complete reaction is obtained. 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 acetate).
The mixture is cooled, poured into 1 50 ml of a saturated aqueous sodium chloride solution, and extracted thrice with 50 ml of diethyl ether, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The resulting 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 water The mixture is stirred for 0.5 hour, then diluted with 50 ml of water and washed twice with 25 ml of dichloromethane, each. The aqueous phase is acidified to pH=1 with concentrated aqueous hydrochloric acid, and then extracted thrice with 25 ml of dichloromethane, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The oily residue is crystallized with benzene. 4 g (54%) of the aimed compound are obtained. M.p.: 131-132 (benzene).
Analysis:
calculated for C15H17NO6 (307.32): C:58.63%, H:5.57%, N:4.56%;
found: C:58.40%, H:5.80%, N:4.66%.
IR (KBr): 3400-2700, 1750 (broad) cm-1.
'H NMR (CDCl3): ,5=1.5 (s, 3H), 3.7 (d, 1 H, J=2.5 Hz), 3.76 (s, 3H), 4.0 (m, 4H), 4.38 (d, 1 H, J=2.5 Hz). 6.82 (2H)+7.26 (2H, AA'BB', J=9.5 Hz), 9.2 (s, 1 H) ppm.
The starting substance is prepared as follows:
a) A mixture of 24.6 g (0.2 mole) of 4-methoxyaniline and 23.9 g (17 ml, 0.1 mole) of diethyl bromomalonate is stirred at room temperature for 2 days. The resulting 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 diethyl ether. The mother liquor is evaporated and the residue is crystallized from dilute acetic acid. 13.2 g (47%) of diethyl (4-methoxyanilino)-malonate are obtained; m.p.: 64-650C (ethanol).
Analysis:
calculated for C,4H19N05 (281.31): C:59.77%, H:6.81%, N:4.99%;
found: C:59.99%, H:6.97%, N:5.25%.
IR (KBr): 3300, 1775, 1725 cm-l.
'H NMR (CDCl3): S=1.23 (t, 6H, J=7.2 Hz), 3.67 (s, 3H), 4.2 (q, 4H, J=7.2 Hz), 4.62 (s, 1 H), 4.14.5 (broad s, 1 H), 6.55 (2H)+6.73 (2H, AA'BB', J=9 Hz) ppm.
b) A mixture of 11.2 g (0.04 mole) of diethyl (4-methoxyanilino-malonate, prepared as described in point a) above, 1 5 ml of glacial acetic acid and 4 g (3.7 ml, 0.048 mole) of diketene is boiled for 0.5 hour. The solution is evaporated in vacuo, the oily residue is triturated with diethyl ether, and the solid -is filtered off. 10.5 g (72%) of diethyl 1 -(4-methoxyphenyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate and/or its tautomer are obtained; m.p.: 136--1370C (ethyl acetate).
Analysis:
calculated for C18H23NO7 (365.38): C:59.17%, H:6.39%, N:3.83%;
found: C:58.98%, H:6.90%, N:4.04%.
IR (KBr): 3600-3000, 1760, 1740, 1685 cm-l.
1H NMR (CDCI3): X=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) ppm.
c) 9.1 g (0.025 mole) of diethyl 1 -(4-methoxyphenyl)-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine- dicarboxylate, prepared as described in point b) above, 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 (0.025 mole) of iodine in 50 ml of dry diethyl ether are simultaneously dropped into the suspension under vigorous stirring and cooling with ice. Thereafter the mixture is poured into 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 etheral phase is evaporated, and the aqueous phase is extracted thrice with 50 ml of diethyl ether, each. The ethereal phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The oily residue is triturated with 2-propanol to obtain 6.2 g (68%) of crystalline diethyl 3acetyl-1 -(4-methoxyphenyl)-4-oxo-2,2-azethidine-dicarboxylate; m.p.: 70-71 0C (ethanol).
Analysis:
calculated for C,8H2,NO, (363.38): C:59.50%, H:5.82%, N:3.85%;
found: C:59.04%, H:5.84%, N:4.08%.
IR (KBr): 1760, 1735, 1720 cm~'.
'H NMR (CDC13): 6=1.20 (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=7.2 Hz), 4.19 (q, 2H, J=7.2 Hz), 4.7 (s, 1 H), 6.7 (2H)+7.31 (2H, AA'BB', J=9 Hz) ppm.
d) 6 g (0.0165 mole) of diethyl 3-acetyl-1 -(4-methoxyphenyl)-4-oxo-2,2-azethidinedicarboxylate, prepared as described in point c) above, 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 temperature. The solution is rendered alkaline with saturated aqueous sodium hydrocarbonate solution, thereafter 1 00 ml of water are added, and the mixture is extracted thrice with 50 ml of diethyl ether, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The oily residue is triturated with diethyl ether to obtain 6 g (89%) of crystalline diethyl 3-(2-methyl-1,3-dioxolan-2-yl)-2-(4-methoxyphenyl)-4-oxo-2,2- azethidine-dicarboxylate; m.p.: 82--830C (ethanol).
IR (KBr): 1740 cm-l (broad)
1H NMR (CDCl3): S=1.17 (t, 3H, J=7.2 Hz), 1.26 (t, 3H, J=7.2 Hz), 1.5 (s, 3H), 3.7 (s, 3H), 3.9 (m, 4H), 4.2 (m, 5H), 6.67 (2H)+7.34 (2H, AA'BB', J=9 Hz) ppm.
Analysis:
calculated for CzoHz5NO8 (407.43): C:58.96%, H:6.18%, N:3.44%;
found: C:58.70%, H:5.68%, N:3.63%.
Example 3 trans -Phenyl-3-(2-methyl-1 ,3-d ioxol an-2-yl )-4-oxo-2-azethidi ne-carboxyl ic acid
A mixture of 28.5 g (0.075 mole) of diethyl 1 -phenyl-3-(2-methyl-1 ,3-dioxolan-2-yl)-4-oxo-2,2- azethidine-dicarboxylate, 44 ml of dimethyl sulfoxide, 5.6 g (0.1 mole) of sodium chloride and 3.05 ml (0.17 mole) of water is stirred at 1 750C until the reaction proceeds. 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 acetate). The solution is poured into 200 ml of a saturated aqueous sodium chloride solution and extracted thrice with 1 50 ml of diethyl ether, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The resulting 16.4 g of oily residue are dissolved in 100 ml of ethanol, and a solution 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. After 0.5 hour of stirring the mixture is diluted with 1 50 ml of water and extracted thrice with 20 ml of diethyl ether, each. The 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 combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated. The oily residue is crystallized from benzene to obtain 12 g (56%) of the aimed compound; m.p.: 1 650C (benzene).
Analysis:
calculated for C14H,5NOs (277.27): C:60.64%, H:5.45%, N:5.05%;
found: C:60.64%, H:5.72%, N:4.99%.
IR (KBr): 3500-2700, 1770, 1730 cm~'.
1H NMR (CDCI3): =1 8=1.5 3H), 3.69 (d, 1 H, J=3 Hz), 4.0 (m, 4H), 4.42 (d, 1 H, J=3 Hz), 7.3 (m, 5H), 7.55 (s, 1 H) ppm.
The starting substance is prepared as follows:
a) A mixture of 38 g (0.1 52 mole) of diethyl anilinomalonate [R. Blank: Ber. 31, 1615 (1898)], 38 ml of glacial acetic acid and 15.3 g (13.9 ml, 0.182 mole) of diketene is boiled for 0.5 hour. Glacial acetic acid is evaporated in vacuo over a water bath, and the oily residue is crystallized by triturating it with ether. 36.5 g (72%) of diethyl (N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidine-dicarboxylate) and/or its tautomer are obtained; m.p.: 98--990C (ethyl acetate and petroleum ether).
Analysis:
calculated for C,7H2,NO6 (335.35): C:60.88%, H:6.31 %, N:4.18%;
found: C:60.83%, H:6.15%, N:4.43%.
IR (KBr): 3350, 2950, 1760, 1750 (d), 1700cm1.
1H NMR (CDCl3): d=1.02 (t, 3H), 1.3 (t, 3H), 1.6 (s, 3H), 2.8 (s, 3H), 3.6 (broad s, 1 H), 4.45 (m, 4H), 7.2 (s, 5H) ppm.
b) 50 g (0.149 mole) of diethyl (N-phenyl-3-hydroxy-3-methyl-5-oxo-2,2-pyrrolidinedicarboxylate), prepared as described in point a) above, are added to a solution of 10.2 g (0.447 mole) of metallic sodium in 250 mi of dry ethanol, thereafter a solution of 37.9 g (0.149 mole) of iodine in 200 ml of dry ether is added under vigorous stirring. When the reaction is over, 8.5 ml (8.9 g, 0.149 mole) of glacial acetic acid, 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. The ethereal phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated.The oily residue is crystallized from 50 ml of 2-propanol to obtain 31 g (62%) of diethyl (3-acetyl-1 -phenyl-4-oxo-2,2azethidine-dicarboxylate); m.p.: 55-56 C (2-propanol).
Analysis:
calculated for C17H1gNO: C:61.25%, H:5.75%, N:4.20%;
found: C:61.38%, H :5.89%, N:4.24%.
IR (KBr): 1770, 1740, 1720 cm-'.
H NMR (CDCl3): S=1.12 (t, 6H), 2.3 (s, 3H), 4.25 (q, 4H), 4.75 (s, 1 H), 7.0-7.6 (m, 5H) ppm.
c) 28.5 g (0.085 mole) of diethyl 3-acetyl-1 -phenyl-4-oxo-2,2-azethidine-dicarboxylate, prepared as described in step b) above, are dissolved in a mixture of 90 ml of dry dioxane and 21 g (18.8 ml, 0.34 mole) of dry ethylene glycol, and 36.5 g (31.5 ml, 0.255 mole) of boron trifluoride-diethyl etherate complex are added dropwise to the solution under vigorous stirring and cooling with ice water. The solution is stirred for additional 2 hours at room temperature and then neutralized with saturated aqueous sodium carbonate solution. The neutral solution is diluted with 1 00 ml of water and then extracted thrice with 50 ml of diethyl ether, each. The organic phases are combined, dried over magnesium sulfate, filtered, and the filtrate is evaporated in vacuo. The oily residue is crystallized by triturating it with ether. 28.5 g (90%) of diethyl 1 -phenyl-3-(2-methyl-1,3-dioxolan-2-yl)-4-oxo-2,2- azethidine-dicarboxylate are obtained; m.p.: 59-61 C(benzene).
Analysis:
calculated for C1gH23NO7: C:60.47%, H:6.14%, N:3.71%;
found: C:60.74%, H:6.21%, N:3.79%.
iR (KBr): 1770, 1740 cm1.
'H NMR (CDCí3): b=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, 5H) ppm.
Claims (17)
1. A process for the preparation of a new heterocyclic carboxylic acid of the general formula (I),
wherein
Y' and Y2 form together a removable carbonyl protecting group, preferably a ketal group or a thioanalogue thereof, and
R is a removable amido protecting group, preferably a benzyl group bearing one or more C14 alkoxy substituents or a phenyl group bearing optionally one or more C14 alkoxy substituents, characterized in that
a compound of the general formula (lV),
wherein Z is a 0i-5 alkyl group and R is as defined above, is reacted with a compound capable for the temporary protection of the carbonyl group, preferably with a ketal-forming agent or a thioanalogue thereof, in the presence of a compound which facilitates the reaction, the resulting compound of the general formula (III),
wherein Z, R, Y' and Y2 are as defined above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide, and the resulting compound of the general formula (Il),
wherein Z, R, Y' and Y2 are as defined above and which is a mixture of cis and trans isomers, is
a) hydrolysed selectively, or
b) separated into its components, and the trans isomer of the general formula (ill)
is hydrolysed; or
a compound of the general formula (Ill), wherein Z, R, Y1 and Y are as defined above, is reacted with an alkali metal halide in pyridine or a related solvent or in aqueous dimethyl sulfoxide, and the resulting compound of the general formula (II), wherein Z, R, Y' and Y2 are as defined above and which is a mixture of cis and trans isomers, is
a) hydrolysed selectively, or
b) separated into its components, and the trans isomer of the general formula (ill) is hydrolysed; or
a compound of the general formula (II), wherein Z, R, Y1 and Y2 are as defined above and which is a mixture of cis and trans isomers, is
a) hydrolysed selectively, or
b) separated into its components, and the trans isomer of the general formula (ill) is hydrolysed,
whereafter the trans compound of the general formula (I) is separated from the reaction mixture.
2. A process as claimed in claim 1, characterized in that hydrolysis is performed in the presence of a molar equivalent of an alkali, calculated for the compound of the general formula (Il) or jlla), or the alkali is applied in a reasonable excess.
3. A process as claimed in claim 1, characterized in that the trans isomer of the general formula (ill) is separated from the cis isomer by dissolving it in an ether type solvent.
4. A process as claimed in claim 1 for the preparation of trans-l -(2,4-dimethoxybenzy1)-3-(2- methyl-i ,3-dioxolan-2-yI)-4-oxo-2-azethidine-carboxylic acid, characterized in that ethyl 1-(2,4 dimethoxybenzyl)-3-(2-methyl- I ,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylate or the trans isomer thereof is hydrolysed.
5. A process as claimed in claim 1 for the preparation of trans -(4-methoxyphenyl)-3-(2-methyl 1 ,3-dioxola n-2-yl)-4-oxo-2-azethidine-carboxylic acid, characterized in that ethyl 1-(4 methoxyphenyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylate is hydrolysed.
6. A process as claimed in claim 1 for the preparation of trans-1 -phenyl-3-(2-methyl-1,3- dioxola n-2-yl)-4-oxo-2-azethidine-carboxylic acid, characterized in that ethyl 1 -phenyl-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidine -ca rboxylate is hydrolysed.
7. A compound of the general formula (I),
wherein
Y1 and Y2 form together a removable carbonyl protecting group, preferably a ketal group or a thioanalogue thereof, and
R is a removable amido protecting group, preferably a benzyl group bearing one or more C14 alkoxy substituents or a phenyl group bearing optionally one or more C14 alkoxy substituents.
8. trans -(2,4-Di methoxybenzyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid.
9. trans-1 -(4-Methoxyphenyl)-3-(2-methyl- 1 ,3-dioxolan-2-yI)-4-oxo-2-azethidine-carboxylic acid.
10. trans-i-P henyl-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylic acid.
11. Ethyl 1 -(4-methoxyphenyl)-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylate, a compound of the general formula (II).
12. Ethyl 1 -phenyl-3-(2-methyl- 1 ,3-dioxolan-2-yl)-4-oxo-2-azethidine-carboxylate, a compound of the general formula (II).
13. Diethyl 1 -(4-methoxyphenyl)-3-(2-methyl-1 ,3-dioxolan-2-yl)-4-oxo-2,2-azethidine- dicarboxylate, a compound of the general formula (III).
14. Diethyl 1 -phenyl-3-(2-methyl- 1 ,3-dioxolan-2-yl )-4-oxo-2-azethidi ne-dica rboxylate, a compound of the general formula (III).
1 5. A process substantially as hereinbefore described in any one of Examples 1 to 3.
16. A compound of the general formula (I), wherein Y1, Y2 and R are as defined in claim 1, whenever prepared by the process of any one of claims 1 to 6.
17. A pharmaceutical preparation containing a compound of the general formula (I), wherein Y',
Y2 and R are as defined in claim 1 , together with a pharmaceutically acceptable carrier.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU814011A HU184494B (en) | 1981-12-30 | 1981-12-30 | Process for producing new azetidinone-caraoxylic acids |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2112392A true GB2112392A (en) | 1983-07-20 |
| GB2112392B GB2112392B (en) | 1985-08-14 |
Family
ID=10966500
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08236916A Expired GB2112392B (en) | 1981-12-30 | 1982-12-30 | Azetidinones |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS58118565A (en) |
| AT (1) | AT378769B (en) |
| AU (1) | AU556905B2 (en) |
| BE (1) | BE895493A (en) |
| CA (1) | CA1189864A (en) |
| CH (1) | CH655927A5 (en) |
| DE (1) | DE3248671A1 (en) |
| ES (1) | ES8504119A1 (en) |
| FI (1) | FI824515L (en) |
| FR (1) | FR2518997B1 (en) |
| GB (1) | GB2112392B (en) |
| GR (1) | GR78430B (en) |
| HU (1) | HU184494B (en) |
| IT (1) | IT1210967B (en) |
| LU (1) | LU84566A1 (en) |
| NL (1) | NL8205069A (en) |
| PL (1) | PL137738B1 (en) |
| SE (1) | SE453082B (en) |
| ZA (1) | ZA829592B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55111463A (en) * | 1979-02-21 | 1980-08-28 | Sankyo Co Ltd | Beta-lactam compound and its preparation |
| ATE15039T1 (en) * | 1979-04-27 | 1985-09-15 | Merck & Co Inc | PROCESS FOR THE PREPARATION OF 3-(1-HYDROXYAETHYL)-AZETIDINONES. |
| JPS56142259A (en) * | 1980-03-11 | 1981-11-06 | Sankyo Co Ltd | Beta-lactam compound and its preparation |
-
1981
- 1981-12-30 HU HU814011A patent/HU184494B/en not_active IP Right Cessation
-
1982
- 1982-12-10 AT AT0450682A patent/AT378769B/en not_active IP Right Cessation
- 1982-12-24 JP JP57235005A patent/JPS58118565A/en active Pending
- 1982-12-28 BE BE1/10680A patent/BE895493A/en not_active IP Right Cessation
- 1982-12-29 LU LU84566A patent/LU84566A1/en unknown
- 1982-12-29 FR FR8221977A patent/FR2518997B1/en not_active Expired
- 1982-12-29 CH CH7603/82A patent/CH655927A5/en not_active IP Right Cessation
- 1982-12-29 SE SE8207474A patent/SE453082B/en not_active IP Right Cessation
- 1982-12-30 DE DE19823248671 patent/DE3248671A1/en not_active Withdrawn
- 1982-12-30 CA CA000418738A patent/CA1189864A/en not_active Expired
- 1982-12-30 FI FI824515A patent/FI824515L/en not_active Application Discontinuation
- 1982-12-30 ZA ZA829592A patent/ZA829592B/en unknown
- 1982-12-30 NL NL8205069A patent/NL8205069A/en not_active Application Discontinuation
- 1982-12-30 PL PL1982239884A patent/PL137738B1/en unknown
- 1982-12-30 AU AU91967/82A patent/AU556905B2/en not_active Ceased
- 1982-12-30 ES ES518719A patent/ES8504119A1/en not_active Expired
- 1982-12-30 IT IT8225059A patent/IT1210967B/en active
- 1982-12-30 GB GB08236916A patent/GB2112392B/en not_active Expired
- 1982-12-30 GR GR70185A patent/GR78430B/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE895493A (en) | 1983-06-28 |
| ZA829592B (en) | 1983-10-26 |
| PL239884A1 (en) | 1984-01-02 |
| LU84566A1 (en) | 1984-10-22 |
| GB2112392B (en) | 1985-08-14 |
| PL137738B1 (en) | 1986-07-31 |
| CH655927A5 (en) | 1986-05-30 |
| DE3248671A1 (en) | 1983-07-07 |
| FR2518997A1 (en) | 1983-07-01 |
| ATA450682A (en) | 1985-02-15 |
| AU9196782A (en) | 1983-07-07 |
| HU184494B (en) | 1984-08-28 |
| NL8205069A (en) | 1983-07-18 |
| SE8207474D0 (en) | 1982-12-29 |
| CA1189864A (en) | 1985-07-02 |
| AT378769B (en) | 1985-09-25 |
| ES518719A0 (en) | 1985-04-16 |
| AU556905B2 (en) | 1986-11-27 |
| IT1210967B (en) | 1989-09-29 |
| GR78430B (en) | 1984-09-27 |
| ES8504119A1 (en) | 1985-04-16 |
| IT8225059A0 (en) | 1982-12-30 |
| FI824515A0 (en) | 1982-12-30 |
| JPS58118565A (en) | 1983-07-14 |
| FR2518997B1 (en) | 1985-09-06 |
| SE8207474L (en) | 1983-07-01 |
| SE453082B (en) | 1988-01-11 |
| FI824515L (en) | 1983-07-01 |
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