JPS5899463A - Preparation of beta-lactam derivative - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an intermediate of antibiotics, economically in an industrial scale, by subjecting a specific beta-lactam derivative to oxymercuration-demercuration reaction, oxidative decarbonation reaction, dearylmethylation reaction, etc. CONSTITUTION:The beta-lactam derivative of formula II (R3 is H, alkyl-substituted silyl, alkyloxycarbonyl, alkyl, etc.) is prepared from the beta-lactam derivative of formulaI(R1 is H, alkyl, mono- or diaryl-alkyl, aryl or protecting group; R2 is mono- or diarylmethyl) by an arbitrary combination of the following three reactions comprising (A) oxymercuration-demercuration reaction, (B) oxidative decarbonation reaction with lead tetraacetate, and (C) removal of mono- or diarylmethyl, which may be combined with various conventional reactions for the removal or introduction of protecting group.

Description

[Detailed description of the invention]

The present invention is directed to the general formula (where λ□ is a hydrogen atom or a lower alkyl group, a mono- or diaryl lower alkyl group, an aryl group, a halogen atom, or a carboxyl group-protecting group such as a lower alkyl group substituted with a lower alkyloxy group). '31
represents a mono- or diarylmethyl group. ) A β-lactam derivative represented by oxy! - Oxymercurmtion - Demerc
ration Reaction) B Oxidative decarboxylation reaction using a tetraacetic acid vessel (Oxidative Decmrboxy1ml!o
nReact! m) A general formula (where k is a hydrogen atom or a lower alkyl-substituted silyl group, an arylmethyloxycarbonyl group, a lower alkyloxycarbonyl group, a carbonyl group, a substituted lower alkyl group) by any combination of C-removal mono- or diarylmethyl reactions This invention relates to the production of a β-lactam derivative represented by a carbonyl group, an arylcarbonyl group, a lower alkyl group, a mono-, di- or triarylmethyl group (Y means a protecting group for a hydroxyl group). Furthermore, if necessary, various commonly used deprotection or protecting group introduction reactions can be incorporated. In the above formula, E, R2, and R8 are described in detail. R is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, or

[Lower alkyl group such as butyl group, benzyl group, P-methoxybenzyl group, 2,4-dimethoxybenzyl group, diphenylmethyl group, di-P-anisinomethyl group, P-nitrobenzyl group, or O-nitrobenzyl group mono- or diaryl lower alkyl groups such as groups, aryl groups such as phenyl groups or p-nitrophenyl groups, 2,2゜2-trichloroethyl groups, 2-a-doethyl groups, benzyloxymethyl groups, or methoxymethyl groups, Halogen atoms such as phenarel group,
It represents a normal carboxyl protecting group such as a benzyloxy group, a methyloxy group, an ethyloxy group, or a lower alkyl group substituted with a benzoyl group. R2 Ha, Hensyl group, P-methoxybenzyl group, t-(
It represents a mono- or diarylmethyl group such as P-methoxyphenyl)-ethyl group, P-nitrobenzyl group, 2,4-dimethoxybenzyl group, diphenylmethyl group, and di-P-aethylmethyl group. Rat means hydrogen atom, lower alkyl-substituted silyl group such as t-butyldimethylsilyl group, benzyloxycarbonyl group -1P-nitrobenzyloxycarbonyl group, O-
Mono- or diarylmethyloxycarbonyl groups such as nitrobenzyloxycarbonyl group, P-methoxybenzyloxycarbonyl group, 2,4-dimethoxybenzyloxycarbonyl group, diphenylmethyloxycarbonyl group, di-P-anisylmethyloxycarbonyl group, etc. , methoxycarbonyl group, lower alkyloxycarbonyl group such as ethoxycarbonyl group, lower alkyloxy substituted with a halogen atom such as 2,2.2-trichloroethyloxycarbonyl group, 2,2.2-tribromoethyloxycarbonyl group, etc. Carbonyl group, lower alkylcarbonyl group such as acetyl group, lower alkylcarbonyl group substituted with a halogen atom or alkyloxy group such as chloroacetyl group, trichloroacetyl group, methoxyacetyl group, benzoyl group, P-nitrobenzoyl group, etc. arylcarbonyl group, p-nitropheloxycarbonyl group, methyl group, ethyl group, n-propyl group, isobutyl group, 1-butyl group, etc. Lower alkyl groups or mono-, di-, or triarylmethyl such as diphenylmethyl, di-P-anisylmethyl, trityl, benzyl, P-nitrobenzyl, 0-nitrobenzyl, or P-methoxybenzyl; Indicates the group. Although methods for producing β-lactam derivatives of the type represented by the general formula (I[) are already known, they have various drawbacks as production methods on an industrial scale. The present inventors have conducted intensive research to develop a more effective production method for the β-lactam derivative represented by the general formula (II), and as a result, we have found that ^) Oxyacculation - Demerculation reaction -) Lead tetraacetate The most common oxidative decarboxylation reaction (
It has been shown that the objective can be achieved by incorporating various commonly used deprotection or protecting group introduction reactions as necessary in the C1 demono-1 or diarylmethyl reaction, and by arbitrarily combining the above A, B, and C reactions. The present invention has been completed. The method of the present invention will be explained in detail below. Reactions A, B, and C used in the method of the present invention and deprotection or protecting group introduction reactions incorporated as necessary are shown below. A: Oxymerculation-demercurage reaction Oxymercurage reaction is performed by subjecting 3-vinyl-azetidin-2-ones to an oxymercurage reaction, followed by about 3 reductions and demercurage reaction. This is a reaction to obtain -(2-hydroxyethyl)azetidin-2-ones. The oxymercurage Ron reaction is a reaction in which a 3-vinylazetidin-2-one derivative is reacted with an oxymercurage reagent in a solvent to obtain an organic mercury compound. The oxymercurage conversion reagent used in the reaction is not particularly limited as long as it is a mercury reagent that reacts with a compound having a carbon-carbon double bond to form an organic mercury compound, but acetic acid is preferred. Examples include mercuric and mercuric trifluoroacetate. It is also possible to use various mercury salts such as mercuric oxide, mercuric chloride, mercuric bromide, mercuric iodide, mercuric nitrate, and mercuric sulfate. Reaction 1 Solvents used include water, ethers such as tetrahydrofuran and dioxane, alkyl nitriles such as acetonitrile, dialkyl sulfoxides such as dimethyl sulfoxide, fatty acid dialkylamides such as dimethylformamide and dimethylacetamide, methylene chloride chloroform, etc. Preferred are halogenated hydrocarbons and mixtures thereof, including glycol ethers such as ethylene glycol dimethyl ether and diethylene glycol dimethyl ether, alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene,
Aliphatic carboxylic acids such as acetic acid and trifluoroacetic acid, and pyridine solvents such as pyridine and 2,6-lutazine can also be used. Furthermore, it is possible to use an auxiliary agent to accelerate the reaction and suppress side reactions, and preferably metal acetates such as lithium acetate and sodium acetate, acids such as acetic acid, trifluoroacetic acid, and perchloric acid, and trifluorocarbon Examples include boron halides such as boron oxide. It is usually desirable to use the oxymercurage conversion reagent in an amount equal to or more than the equivalent mole of the raw material compound, and the reaction temperature can be suppressed or accelerated by cooling or heating, but it is possible to suppress or accelerate the reaction by cooling or heating. 100'C is preferred. After the reaction is complete, the desired organic mercury compound may be extracted using ordinary organic chemical methods, but it is also possible to perform a demercurage reaction by reacting with a reducing agent without any special treatment. . The demercury carbonate reaction is a reaction in which 3-(1-hydroxyethyl)-acetidin-2-ones are obtained by reacting the above-mentioned organic mercury compound with a reducing agent in a solvent. The reducing agent used in the reaction is not particularly limited as long as it is a normal reducing agent for organic mercury compounds, but preferred examples include sodium borohydride, lithium borohydride, and sodium trimethoxyborohydride. , metal hydride compounds such as lithium aluminum hydride, and alkali metals such as lithium, sodium, and potassium. It is also possible to use various amalgams such as sodium amalgam and aluminum amalgam, and various reducing agents such as sodium stannite, zinc, tin, iron, magnesium, and copper. It is also possible to use the electrolytic reduction method. Solvents used in this reaction include water, ethers such as tetrahydrofuran and dioxane, dialkyl sulfoxides such as dimethyl sulfoxide, fatty acid dialkylamides such as dimethylformamide and dimethylacetamide, alkyl nitriles such as acetonitrile, and chloride. Preferred are halogenated hydrocarbons such as methylene and chloroform, alcohols such as methanol and ethanol, aliphatic carboxylic acids such as acetic acid, and mixtures thereof; glycol ethers such as ethylene glycol dimethyl ether and diethylene glycol dimethyl ether; Various solvents such as alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, and pyridines such as pyridine and 2,6-lutidine can also be used. In order to further promote the reaction and suppress side reactions, a reaction aid may be used, preferably an alkoxyalkali metal such as sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, or sodium ethoxide. Examples include various organic bases such as salt and pyridine. It is desirable to use the reducing agent in an amount equal to or more than the equivalent molar amount to the organic mercury compound. The reaction temperature is not particularly limited, and varies somewhat depending on the raw material compound, reducing agent, auxiliary agent, and type of solvent. However, the preferred reaction temperature is -10'C to 100C. B: Oxidative decarboxylation reaction with lead tetrasate, what is eye=4
This is a reaction in which -carboxyl-azetidin-2-ones are reacted with lead tetramerate to convert the carboxyl group into an acetyloxy group to obtain 4-acetylazetidin-2-ones. Various solvents can be used in the reaction process. Preferred are fatty acid dimethylamides such as dimethylformamide and dimethylacetamide, dialkyl sulfoxides such as dimethyl sulfoxide, aromatic hydrocarbons such as benzene, chlorobenzene and toluene, alkyl nitriles such as acetonitrile, acetic acid, etc. , fatty acids such as chloroform, halogens such as carbon tetrachloride, J hydrogen hydrides, pyridines such as pyridine and 2,6-lutidine, and mixed solvents thereof. Various solvents such as dioxane, diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, etc., and esters such as methyl acetate and ethyl acetate can also be used. As reaction aids, lithium acetate, sodium acetate,
Acetate metal salts such as potassium acetate, cuprous acetate, cupric acetate, etc., or mixtures thereof are preferred, but it is also possible to use various metal salts. Various organic bases such as pyridine and triethylamine can also be used. In the reaction, it is desirable to use lead tetranosate in an amount equivalent to or more than the equivalent mole of the raw material compound, and the amount of the reaction aid is not particularly limited. The reaction temperature is 0°C to 150°C, although it is possible to suppress or accelerate the reaction by cooling or heating.
After the completion of the reaction, the target compound may be taken out by ordinary organic chemical techniques, but the next reaction can be carried out without any special treatment. C: Demono- or diarylmethyl reaction n is 1-
(mono- or diarylmethyl)-azetidine-2
-ones with acids or ceric ammonium nitrate (ceric ammonium n1tr)
ate) to obtain azetidin-2-ones. °In the demono- or diarylmethylation reaction with acid, 1-(mono- or diarylmethyl)-azetidine-
Azetidin-2-one can be obtained by reacting 2-ones with an acid directly or in an inert solvent. Further, if necessary, a reaction aid can be added. Preferred acids include trifluoroacetic acid, formic acid, boron trifluoride, aluminum chloride, etc., or mixtures thereof, acetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfone II, p-)luene, etc. Sulfonic acid, titanium tetrachloride, tin tetrachloride, aluminum tribromide, zinc chloride, hydrogen fluoride, and mixtures of these acids can also be used. As the inert solvent, trifluoroacetic acid, formic acid, acetic acid, dichloromethane, 1,2-dichloroethane, chloroform, nitromethane, etc., and mixtures thereof are suitable, but benzene, toluene, xylene, etc. can also be used. In addition, as a reaction aid, anisole, 2.6-
Cymethoxybenzene and the like are preferred, but thioanisole, P-cresol dimethyl ether, O-cresol dimethyl ether, dimethyl sulfide, thiophenol ethyl mercaptan and the like can also be used. It is usually desirable to use the acid in an amount equal to or more than the equivalent mole, and the reaction temperature is preferably 100° C. or lower, although the reaction can be suppressed or accelerated by cooling or heating. When using a reaction auxiliary agent, the reaction auxiliary agent can be used in a trace amount to a large excess amount, but a 1 to 6 times molar amount is appropriate. After the reaction is complete, the desired product can be recovered by conventional organic chemical means. In the demono- or diarylmethyl reaction using ceric ammonium nitrate, 1-(mono- or diarylmethyl)-azetidin-2-ones and ceric ammonium nitrate are reacted in an inert solvent to form azetidine-
2-ones can be obtained. Suitable inert solvents are water, alcohols such as dimethylformamide, acetonitrile, methanol, ethanol, isopropanol, organic acids such as acetic acid, or mixed solvents thereof, but tetrahydrofuran, dioxane, benzene, toluene, etc. Can be used together. If necessary, add disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, borax, sodium carbonate, sodium acetate, etc., and conduct the reaction in an appropriate buffer solution. I can do it. It is usually desirable to use seric ammonium nitrate in an amount of 2 to 3 times the mole, and the reaction temperature can be suppressed or promoted by cooling or heating. Ic is preferred. After the reaction is complete, the desired product can be recovered by conventional organic chemical means. Describing the above-mentioned deprotection or protecting group introduction reaction, for example, the following formula (wherein k has the same meaning as above,
It represents a 1-hydroxylethyl group or a l-hydroxyethyl group protected with a normal hydroxyl group, and ``S'' has the same meaning as the above-mentioned R1 except for the hydrogen atom. ) is the reaction shown by. Various commonly used methods for introducing k′ are possible, but for example, the following (a) * (b> 1 (C
) can achieve the objective. (a+ Compound of general formula (Ilm) and general formula ■HOR
This can be achieved by reacting an active ester derivative of an alcohol derivative represented by ', and sub (in the formula, 1 has the same meaning as above) directly or in an inert solvent in the presence of a deoxidizing agent. The active ester derivative is an ester with no acid or a strong acid among organic acids, and preferable examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, benzenesulfonic acid, P-toluenesulfonic acid, P-toluenesulfonic acid, -esters with bromobenzenesulfonic acid and methylsulfonic acid; As a deoxidizing agent, organic bases such as 4-dimethylaminopyridine, triethylamine, diazabicycloundecene, diazabicyclononenecene, pyridine, picoline, dimethylaniline, sodium ice base, sodium amide, sodium methoxide, sodium ethoxy Examples include various bases such as potassium carbonate, potassium 1-butoxide, sodium chloride, potassium carbonate, and sodium carbonate. Various kinds of solvents can be used as the inert solvent, but preferably halogenated hydrocarbons such as methylene chloride and chloroform, dimethylformamide, dimethylacetamide,
Examples include dimethyl sulfoxide, acetonitrile, water, alcohols such as methyl alcohol and ethyl alcohol, ethers such as tetrahydrofuran, dioxane and diethyl ether, aromatic hydrocarbons such as benzene and toluene, and mixed solvents thereof. As for the reaction temperature, the reaction can be suppressed or promoted by appropriately cooling or heating. It is desirable to use the active ester derivative of the hood in an amount equal to or more than the equivalent mole of the raw material compound (■@), and as a deoxidizer, it is necessary to use at least the equivalent mole of the raw material compound (■). (b) General formula Reacting the compound (II) with a halogenating reagent such as thionyl chloride or oxalyl chloride,
The object can be achieved by introducing an active acid anhydride such as an acid chloride derivative and reacting it with an alcohol derivative represented by the general formula Nipporo in an inert solvent in the presence of a deoxidizing agent. Alternatively, the compound of the general formula (IV) is reacted with a chloroformate such as ethyl dichloroformate or dibutyl chloroformate to form a mixed acid anhydride, and the compound of the general formula (IV)
The objective can also be achieved by reacting with an alcohol derivative represented by Various kinds of solvents can be used as the inert solvent, but suitable examples include halogenated hydrocarbons such as methylene chloride and chloroform, tetrahydrofuran, dimethylformamide, dimethylacetamide, benzene, toluene, and mixed solvents thereof. As the deoxidizing agent, the same one as in the above (!l) is used. It is desirable to use the halogenating reagent and chloroformate in the amount necessary to complete the reaction.
It is used in an amount equal to or more than the equivalent mole. It is desirable to use the alcohol derivative in an amount equal to or more than the mole of the raw material compound.
The equivalent mole or more is used. The reaction can be suppressed or accelerated by appropriately cooling or heating the reaction temperature. (C) The object can be achieved by reacting the compound of general formula (Ia) with a diazomethane reagent in an inert solvent. Preferred examples of the diazomethane reagent include diphenyldiazomethane, di-P-anisyldiazomethane, and P-nitrophenyldiazomethane. Various kinds of solvents can be used as the inert solvent, and preferred examples include ether, methanol, ethanol, tetrahydrofuran, ethyl acetate, and mixed solvents thereof. The diazomethane reagent can be used in the same mole or more than the same mole relative to the raw material compound (■), and the reaction can be suppressed or accelerated by appropriately cooling or heating the reaction temperature. Various commonly used desorption methods are possible.Although it differs depending on the type of K', for example, alkaline hydrolysis, acid removal, reductive removal, oxidative removal, or thiol and It can be selected from various methods such as the nuclear substitution method.The alkaline hydrolysis method is a method that achieves the objective by reacting the compound of general formula (mb) with an alkaline reagent directly or in a solvent. Examples include alkali metal hydroxide salts such as lithium, sodium hydroxide, and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate.As the solvent, various solvents can be used, but water is preferably used. , methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, and mixed solvents thereof.The alkaline reagent can be used in an amount equal to or more than the equivalent molar amount to the starting compound (l [b)]. The reaction can be suppressed or accelerated by cooling or heating the reaction temperature.The acid removal method involves reacting the compound of general formula (Illb) with an acid directly or in a solvent. Preferred acids include trifluoroacetic acid, formic acid, boron trifluoride, aluminum chloride, etc., or mixtures thereof.Additionally, hydrochloric acid, sulfuric acid, Various acids such as mineral acids such as hydrogen iodide acid, benzenesulfonic acid, p-)luenesulfonic acid, p-fuymbenzenesulfonic acid, methylsulfonic acid, acetic acid, and phosphoric acid can also be used. As the solvent, various solvents are possible, but preferred examples include methylene chloride, chloroform, benzene, toluene, anisole, 1,3-dimethoxybenzene, dimethylformamide, ether, dioxane, and mixed solvents thereof. There is no particular limitation on the amount of acid. It is possible to suppress or accelerate the reaction by heating the cooled container as appropriate for the reaction temperature. The reductive removal method is a method of achieving the objective by reacting the compound of general formula (Ib) with a reducing agent in a solvent. As the reducing agent, various reducing agents can be used, and preferred examples include zinc, acetic acid or formic acid, water droplet, reduction catalyst, and the like. Examples of reduction catalysts include noble metal catalysts such as platinum, palladium, and rhodium, nickel, and copper chromite, either as they are or with various carriers, and as solvents, alcoholic solvents (e.g., methanol, ethanol,
-Proper tools Examples include isoproper tools. )
, acetic acid, butionic acid, water, ethyl acetate, tetrahydrofuran, dioxane, nonpolar solvents (for example, hexane, benzene, toluene, etc.), or a mixed solvent system thereof. This reaction is usually carried out in the presence of a catalyst weighing from a few inches to several tens of pounds per raw material, at a relatively low temperature, generally around room temperature, and at a low hydrogen pressure, generally at normal pressure. Although the reaction proceeds easily with hydrogen, the reaction can be accelerated by heating or increasing the hydrogen pressure, if necessary. If necessary, an appropriate amount of acid, such as mineral acids such as hydrochloric acid and perchloric acid, and organic acids such as acetic acid, may be used. ) can also be added to the reaction system to promote the reaction. The oxidative removal method is a method of achieving the objective by reacting the compound of general formula (Wb) with an oxidizing agent in a solvent. Various metal compounds can be used as the oxidizing agent, but preferred examples include cerium compounds such as potassium persulfate, ceric ammonium nitrate, ceric acetate, ceric nitrate, and ceric sulfate. It will be done. As the solvent, various solvents are possible, but preferably water,
Examples include alcohols such as acetonitrile, methanol and ethanol, organic acids such as dimethylformamide and acetic acid, and mixed solvents thereof. The oxidizing agent is used in an amount necessary to complete the reaction with respect to the raw material compound, and is preferably in an amount of usually 2 to 3 times the mole. Although the reaction temperature can be suppressed or accelerated by cooling or heating, 0°C to 100°C is preferable. Nuclear substitution reaction with thiols is a method of achieving the objective by reacting the compound of general formula (Ilb) with an alkali metal salt of thiol in an inert solvent. As the alkali metal salt of thiols, various alkali metal salts of thiols are possible, but preferred are thiolate alkali metal salts such as sodium thiophenolate,
Examples include alkali metal sulfides such as sodium sulfide and potassium sulfide. As the inert solvent, the same solvent as that used in the above-mentioned process is used. The alkali metal salt of thiols can be used in an amount equal to or more than the equivalent molar amount based on the raw material compound (Wb), and the reaction temperature can be set to suppress or accelerate the reaction by cooling or heating. In addition, a protecting group introduction reaction represented by the following formula (wherein R,, R, have the same meanings as above, and R4 represents an acetoxy group, a carboxyl group, or a carboxyl group protected with an ordinary protecting group) is also used. k. As the introduction method, various commonly used modes are possible, but for example, the following method is possible. (31e (kl), the objective can be achieved by the method of (1).
k′□ has the same meaning as above. The purpose can be achieved by using the derivative represented by ) in a manner similar to the method described above. (j) The objective can be achieved by reacting the compound of general formula (Vl) with an acid chloride in an inert solvent in the presence of a deoxidizing agent. Various acid chlorides can be used as the acid chloride, and preferred examples include chloroacetyl chloride, J bromoacetyl chloride, trichloroacetyl chloride, and benzoyl chloride. As the inert solvent and deoxidizing agent, the same solvents and deoxidizing agents as mentioned above (&) are used. The reaction can be carried out once in the same manner as fa) above. (kl) The objective can be achieved by reacting a compound of general formula (VI) with an active ester salt conductor of an alcohol derivative represented by general formula ff in an inert solvent in the presence of a deoxidizing agent. Regarding the inert solvent and deoxidizing agent, the same solvent and deoxidizing agent as those mentioned above (tortoise) can be used, and one reaction can be carried out in the same manner. (11) The objective can be achieved by reacting the compound of general formula (v3) with a halogenated organosilicon reagent in an inert solvent in the presence of a deoxidizing agent. As the inert solvent, the above-mentioned (III The same solvents as in (1) above are used as the deoxidizing agent. Preferably, tetrahydrofuran, acetonitrile, dimethylformamide, and methylene chloride are used. , 2,6-lutidine, 4-dimethylaminopyridine, triethylamine, etc. Various silicon reagents can be used as the halogenated organosilicon reagent, but L-butyldimethyl chloride, methyl-di-t -butylsilino chloride. The reaction can be carried out in the same manner as in the above-mentioned +1>. By appropriately combining each of the above-mentioned reactions, a β-lactam derivative represented by the general formula ) A β-lactam conductor represented by the following can be produced. Although not necessarily limited to the method shown below, an example of the production method is as follows. (Reaction route-I) ( n) (In the formula, K, R, and R have the same meanings as described above.) Perform each reaction of the above reaction route (as shown by Il), A#B#C, and follow the above-mentioned procedure as appropriate. Compound (If) can be obtained by carrying out the deprotection and protecting group introduction reaction. Alternatively, the objective can also be achieved by the following production method. (Reaction route - ■) (Ill (Reaction route - ■ ) (In the formula, λ1eRJ1tR3 has the same meaning as described above.) The above reaction route (II), (As shown in Ill (A
. Compound (n) could be obtained by sequentially carrying out the reactions B and C, and by carrying out deprotection and protecting group introduction reactions as appropriate. Further, this method can be effectively used in the production of an optically active raw material compound (more specifically, an optically active 3-(1-hydroxyethyl)-4-acetoxy-azetidin-2-one rust conductor (III). As described above, the method of the present invention provides an excellent synthetic intermediate for the production of various β-lactam derivatives such as carbapenem derivatives and venem conductors, which are useful as pharmaceuticals with excellent antibacterial activity. This method provides a new and useful method for producing β-lactam conductors represented by the general formula (I The introduced carbon is an asymmetric carbon, and has a threo form and an erythro form.
Although it has two stereoisomers, it has the characteristic that the threo isomer can be obtained with very high selectivity. [Example 1] 2 (wherein, DAM=-CH(-Sakakie): ae PNB
--ωδ Garden 2) (G4) Step n-butyl ester salt derivative 1 (0,5F) is lN
NλOH aqueous solution (1,2sj)-tetrahydrofuran (15tR1)-dissolved in methanol (15m), 2
Stirred at room temperature for an hour. 2N-hydrochloric acid (0.7 sj) was added, and the mixture was concentrated to about 14 ml, then water was added and extracted with ether. After re-extracting with alkaline water, the aqueous layer was re-extracted. The aqueous layer was acidified with hydrochloric acid, extracted with ether, washed with water, dried with sodium sulfate, and the solvent was distilled off.
-(di-P-anisylmethyl)-3-ethynyl-4-carboxyl-azetidin-2-one 2 was obtained. ■Rci-ic et al. (n-1): 1753, 161
2, 1297. ax 1245, 1170, 1109. 1027, 828 NMRδ (CDC13): 3.80 (6H, s)
, 5.1-5.9 (3H, m), 5.83 (IH, I)
, 8.64 (IH, 1) (1-b) Step ethynyl-conductor 2 (1, OF) was dissolved in tetrahydrofuran (8, 8+nj), water (2, 0sj>) and mercuric acetate (0,9F ) and heated under reflux for 8 hours.
Add N-NaOH water (7,2d) at 0 °C, and add sodium borohydride (0,11) to IN-N NaOH water (1-
) was added dropwise, and after stirring at the same temperature for 5 to 6 minutes,
The mixture was neutralized with 6N + HC4, ether was added, and the mixture was filtered through Celite. Ether extraction, saturated saline washing, mirabilite drying,
1-(G-P-
anisylmethyl)3-(1-hydroxyethyl)-4-
Carboxyl-azetidin-2-one 3 (0,85)
I got it. IRnu"' (cm-1): 3250, 175
0, 1723. 1x 1515, 1305, 1250. 1177, 1030, 835 NMRJ (CDC4,): 1.22 (3H, dJ
-6H, 3.18 (IH, m), 3.72 (6H, l
), 4.10 (IH, dJ-2Hz), C75 (IJ') P@pHm (1-C) Step 1-(di-P-anisylmethyl)-3-2(1-hydroxyethyl)-4-carboxyl- Azetidin-2-one 3 (4,OF) was dissolved in dimethylformamide 20-, potassium acetate (1,OF) was added, and the mixture was heated to 40°C with stirring. The mixture was added in portions, the solvent was distilled off, and the mixture was subjected to silica gel chromatography to obtain 1-(di-P-anisylmethyl)-3-(1-hydroxyethyl)-4-acetoxy-azetidin-2-one 4 (3,01). Ta. IR"c'3 (3-1): 1752, 1357
, 1302. m■ 1242, 1174, 102B. 53 NMRδ(”'C41t3): 1.26(3H,
dJ=6.5Hz), 1.90 (38, I), 3.07
-(IH, broad dJ-f, , 5Hz),
3.78 (6H, l), 4.07 (IH, m), 5, B
3 (IH, broad s), 5.88 (IH, bro
ad 1) (1-d) process! -(di-P-aethylmethyl)-3-(1-hydroxyethyl)-4-acetoxy-azetidin-2-one 4
(1', OF) was dissolved in methylene chloride (5-) and cooled on ice. Add 4-dimethylaminopyridine (0,61F),
P-Nitropenzylchloroforme) (0,77F)
A solution of methylene chloride (5-) was added dropwise, and after stirring for 1 hour,
Toluene (25-) was added. After removing the precipitate,
The solution was washed with 2N hydrochloric acid and saturated saline, dried with mirabilite,
By evaporating the solvent and performing silica gel column chromatography, 1-(di-P-aethylmethyl)-3-(1-p-nitrobenzyloxycarponyloxyethyl)-4-acetokyle-azetidin-2-one 5(1, 2F) was obtained. IRrn,, (ca-1): 1770, 174
0, 161G. 1583, #11t, 1020 850, 818, 735 NMR δ (0%): 1.42 (3H, dJ-6H, 1.85 (3H-), 3.28 (IH, dJ 5Hz
), 3.73 (6H, s), 5.22 (2H, I), 5
．． 87 (IH, I), 66-11 (IH-) P-P- (1-e) Step Compound 5 (0,75F) was added dropwise to 1000 ml of a solution of water-acetonitrile (5-) at room temperature. Stirred for 30 minutes. Sodium sulfite (0.05F) Japanese salt solution washing, mirabilite drying,
After evaporation of the solvent and silica gel column chromatography, 1-(di-P-anisylmethyl)-3-(1-P-nitrobenzyloxycarbonylokylethyl)-4-acetoxy-azetidin-2-one 6 (0,42F) was obtained. Ta. IRneat 1 m□ (cm): 3300, 1774, 174
5. -1602, 1344, 1258. 1029, 843 NMRδ<””dB)” j −45(3He
'J-8-0''), 2.09 (38, I), 3.37
(IH, ddJ low 1.21.OH, 5-25 (2H*
= 25Hz), 5.87 (IHedJ-1, 28X
), 6.96 (IH, brl), ? −53(,2H,d
J=9Hz), 8.22(2H, dJ=9Hsp, p,
In addition, step (1-b) using the optically active substance (3S,4R)-1-(di-P-anisylmethyl)-3-ethynyl-4-carbothousylazetidin-2-one, (1-C
), (1-d), and (1-e) are carried out in sequence to obtain (3S,4K)-1-(di-P-anisylmethyl)-33-(each)-1-hydroxyethyl). −
4-carboxyl-azetidin-2one (specific optical rotation [σ]: ” = + 22.0° (C-0,14, Q(
CJ8)), (38,4R)-1-(di-P-anisylmethyl)-3-((R)-1-hydroxyethyl)
-4-acetoxy-azetidin-2-one (specific optical rotation [
a] 22℃=+26.0@(c xO, 04, ωq3
)), (38,4R)-1-′□ □・. (di-P-anisylmethyl)-3-(ll)-1-P-
nitrobenzyloxycarbonyl-ethyl)-4-
Acetoxyazethi 22℃ Zin-2-one (Specific optical rotation [α] o -14 o, s'
(C=0.38μ](CJ,)) to (33゜4R)-3-((R)-1-p-nitrobenzyloxyethyl)-4-acetoxy-azetidine-2- On (specific optical rotation [α]: ”=+ae, e°
(c = 0.09, >c4.)) was obtained. The starting material compound (38,4R)-1-(di-P-anisylmethyl)-3-ethynyl-4-carboxyl-azetidin-2-one was obtained by the method shown below. (d, 1-3-ethynyl-4-carboxynobi-azetidin-2-one (10,24p) in methylene chloride (45
s+7) Add dimethylformamide (1 drop) to the solution,
Oxalyl chloride (4,25P) in methylene chloride (5
-) The solution was added dropwise for 20 minutes at room temperature. After stirring at the same temperature for 1.5 hours, the solvent was distilled off. The residue was dissolved in methylene chloride (30s+
j) Dissolved, l-←)-menthol C4,59
f), The mixture was immersed in a solution of 4-dimethylaminopyridine (3,58F) in methylene chloride (30-) under water cooling, and stirred for 2 hours. The reaction solution was washed with 2N hydrochloric acid and saturated aqueous sodium bicarbonate, and then with water, dried over sodium sulfate, and the solvent was distilled off. Methanol was added to the resulting residue, heated and dissolved, and then cooled to give crystals of J-H-menthol ester with a ratio of the two isomers of Compound 7 of about 1:1 (mp, 96-97°C). ) was obtained. (3814R)-1-(di-P-anisylmethyl)-3-ethenyl-4 was obtained by heating and dissolving the above crystals (for/) in methanol (400 d), cooling to -5°C, and filtering the precipitated crystals. -1-H-menthylcarboxyl-azetidin-2-one was obtained. A pure product (mP, 11
4-115℃, specific optical rotation Cd): "= 120.2' (
0.26.0-1 (Js)) was obtained. In addition, the above-mentioned l-←)-menthol ester with an isomer ratio of about 181 can be obtained by high-performance liquid chromatography (
Column: Lickrosorb SI-60, solvent 1.5%
-isopropanol-n-hexane). (38,4R)-1-(di-P-anisylmethyl)-3
-ethynyl-4-menthylcarboxyl-azetidine-
The ester group of 2-one was hydrolyzed in the same manner as described in Reference Example 2 to give (35,4R)-1-(di-P-anisylmethyl)-3-ethynyl-4-carboxyl-azetidine-2- Oni/8 (specific optical rotation Cd) Ha℃
-+as, 3@(cs-0,12,ωq,)) was obtained. Compound 61 was obtained from compound (4) obtained in the same manner as above through the following route. (1-d)' Step Alcohol-conductor 4 (599"?) was dissolved in dimethylformamide (3,0d), tert-butyldimethylchlorosilane (318M9) and i[dazole (143")
8F) was added and stirred at room temperature for 3 hours. After adding water, extracting with ethyl acetate, washing with water, drying with Glauber's salt, and distilling off the solvent, the product was purified with silica gel chromatography.
-(1-dimethyl-butylsilyloxyethyl)-
4-acetoxy-azetidin-2-one 5 (514
mg) was obtained. IRne” (cIm-1): 1755, 160
8, 1505. ax 1460, 1370, 1300. 1242, 1175, 1030. 830, 778 NMR δ(”'J3): 0.82 (9H, s),
1.22 (3H, dJ = 6.5H depth), 1.83 (3H
, g), 3.10 (IH, ddJ=3.8!1.5Hz
), 3.78 (6H, l), 5.87 (IH.su, 8.15 (IH, dJ-1,58X) P, P, m
(1-4)' Step compound 5 m (514''P) 3-(1-dimethyl-1-butylsilyloxyethyl)-4-acetoxy-azetidine-2 was treated in the same manner as in the (1-e') step. -on 6m (196jlf) was obtained. IRneslc(n-”): 1775, 1745
, 1370. 3x \ 1230, 1135, 1027. 832, 772 NMRJ (CIQ!,): 0.07 (8H-), 0
．． 87 (9H, l), 1.28 (3H, dJ-6,58
, 2.10 (3H, l), 3.18 (IH, ddJ=
1.5 & 3.5H, 5.83 (IH, dJ2l, 5H
z) p, p, m [Example 2] a) (2-Information) Step Carboxylic acid derivative 2 (1,5F) was dissolved in dimethylformamide (7,5d), and potassium acetate (0,8F) was added. , While stirring at room temperature, lead tetranosate (2,17j') was added in several portions at -, and the mixture was stirred at room temperature for 1 hour. Add water, extract with ethyl acetate, wash with water, dry with sodium sulfate, remove solvent, chromatograph on silica gel, 1-(P-7 Nisylmethyl)-3-
Ethynyl-4-acetoxy-azetidin-2-one 9
(1,17F) was obtained. IRcHc′5(cs-”): 1760, 160
8, 1298 *1x 1240, 1174, 1024. 974.923 NMRδ(”'j?3): 1-90(3H,s)
, 3.79 (8H, s), 5.74 (IH, br, s)
, 5.91 (IH-)b) (2-b) Step Ethynyl rust conductor 9 (3,80F) was dissolved in tetrahydrofuran (10sd), and water (4-) and mercuric acetate (3,2F) were dissolved. After stirring at room temperature for 1 hour, lN-
N! IOH water (9 ml) was added at 0°C, and sodium borohydride (o, 4f) was added to INN Kame OH water (2-
) was added dropwise, and after stirring at the same temperature for 5 to 6 minutes,
Neutralize with dilute hydrochloric acid, add ether, and remove through Celite. Ether extraction single layer washing with water, washing with water, drying with Glauber's salt, solvent distillation, silica gel chromatography! -(di-P-anisylmethyl)-3-(1-hydroxyethyl)-4-acetoxy-azetidin-2-one 4 (2°99f) was obtained. IRQ'N'4 (n-1): 1752, 160
8, 135? . 3x 1302, 1242, 1174. 1028, 953 NMRaccDcl,): 1.25(3H,d,
J-7), 1.90 (3H, l), 3.07 (1B, b
r, d, J-6, 5), 3°7B (6H, 8), 5.8
3(iHII), 5.88(IH#br-) Step (2-c) The same reaction as in Step (1-C) of Example 1 was carried out to produce the same compound 1-(di-P-anisylmethyl ) -3-(
1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-azetidin-2-one 5 was obtained. The same reaction as in step (1-d) of dX2-d) [Example 1] was carried out, and the same compound, 3-(1-P-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-azetidine-
2-on 6 was obtained. [Example 3] Li(3-turtle) step 1-(di-P-anisylmethyl)-3-ethynyl-4-
Carboxyl-azetidin-2-one 2 (10F)
was dissolved in dimethylformamide (50d), washed sequentially with an aqueous solution of triethylamine (3,30F), P-methoxybenzylchloride (bicarbonate), IJum, dried, and the solvent was distilled off. P-anisylmethyl)-3-ethynyl-4-
P-methoxybenzylcarboxyl-azetidine-2-
Got 10 on. 1R2::' (cs-1): 1745, 161
0, 1505, '1455.1300.11
70. 1027.822.75O NMRδ (CDC46): 3.72 (3Hμ), 3.7
5 (6H, Su, 4.83 (2H, Su, 5.1-6.0)
3H, m), C78 (IH-) PmPam b) (3-b) Step! -(di-P-anylmethyl)-3-ethynyl-4-
P-methoxybenzylcarboxyl-azetidine-2-
Dissolve On 10 (IOF) in tetrahydrofuran (40m) and water (20ak), and add mercuric acetate (6,6F).
was added, and after stirring at room temperature for 5 hours, N-sodium hydroxide (40d) and sodium borohydride A (0,78
After adding the N-sodium hydroxide solution (2-) of F) and stirring, 2N-hydrochloric acid (25 wJ) was added. The precipitate was removed, extracted with ether, washed with water, washed with an aqueous sodium bicarbonate solution, dried with sodium sulfate, and distilled off the solvent.
-HydroxyxTil)-4-P-methoxybenzylcarboxyl-azetidin-2-one 11 was obtained. 1R"C'B (n-1): 3400, 1?42
, 1510. 1x 1303, 1242, 11?5. 1032, 824 NMRa (c■4): 1. t7(3HedJ-6
Hz), 4.88 (2H, s), 5J2 (lH1')
PmPs-C) (3-C) Step 112 1-(di-P-anisylmethyl)-3-(1-hydroxyethyl)-4-P-methoxybenzylcarboxyl-
Azetidin-2-one 11 (4,5P) was added to a solution of 4-N,N-dimethylaminopyridine (1
, 31P) and diluted with methylene chloride (20m) of P-nitrobenzylchloroforme) (2,31F) under water cooling.
The solution was added dropwise and stirred for 2 hours. The reaction solution was diluted with ethyl acetate, washed with 2N-hydrochloric acid, dried with sodium sulfate, and the solvent was distilled off. 1-(G-P-
Anisylmethyl)-3-(1-P-nitrobenzyloxycarbonyloxyethyl)-4-P-methoxybenzylcarboxyl-azetidin-2-one 12 was obtained. ~IR”8 (cs-1): 1760, 1515
e 1347 *m wealth X 1250, 11?6, 1030, 847NMRJ
(CIQ!,) : 1.38(3H, dJ-78ri, 3.32(IH, ddJ-=347Hri, 3.70(
3H-), a, ya (aHesu, 3.77 (3H, 1)
, 4.10 (IH. dJ-3Hz), 4.87 (2H, I), 5.18 (2
H, l), 5.78 (IH, l), p, p, m d) (3-d) Step 213 1-(di-P-anisylmethyl)-3-(1-P-nitropenzyloxycarponyloxymethyl ethyl)-4-P-
Methoxybenzylcarboxyl-azetidin-2-one 12 (0,64F) anisole (0,43F),
Add trifluoroacetic acid (1, 2d) and heat at 40°C for 20
Stir for a while. After concentration, dilute with ethyl acetate, wash with water,
After drying with Glauber's salt and evaporating the solvent, 3-(1-P-nitrobenzyloxvcarbonyloxylethyl)-4-carboxyl-azetidin-2-one 13 was obtained by silica gel column chromatography. lR'LB'(n-"): 3380, 1?60
, 1520. 1K 1350, 1270, 1016, 85ONMRI
((CD,), So): 1,33 (38, dJ=7
Hz), 3.40 (IH, ddJ=2&6Hg), 3.
95 (IH, dJ-2Hz), 5.28 (2H-),
7.57 (2HtdJ-9H Tomi), 5-t7 (2Ht
dJ-9H) P, P, mri (3-e) Step 3-(1-P-nitrobenzyloxycarbo-luokylethyl)-4-carboxyl-azetidin-2-one
13 (3,40f) of dimethylformamide (20s
') Potassium acetate (1, OF) was added to the solution, heated to 40°C, and lead tetrasate (5,30 jl) was added in several 1ζ portions, followed by stirring for 1 hour. Add ethylene glycol, stir for several minutes, dilute with ethyl acetate, and evaporate 1. 3-((1-P-nitosybenzyloxycarponyloxyethyl)-4-acetoxy-azetidin-2-one 6 (2,46F)) was obtained from 1, -2 and 7□3. **cHc' 8 (n-1): 1752, 13
57s 1302mm turtle! 1242, 1174, 1028, 958NMIL
a (CDCJ, ): 1.26 (3H, dJ-8
, 5H, 1.90 (3H, s), 3 * 07 (l
H* b rot d d J-6, 5 Hz), 3.7
8 (6H, l), 4.07 (1B, m), 5, B3 (
IH, broshd s), 5.69 (IH, broa
d s) p, p, m [Example 4] ~ 3ζ 112 ~
~ Tortoise) (4-reaction process [Example!] The same reaction as in step (i) was carried out, and the same compound, 1-(di-P-anisylmethyl)-3-(1-hydroxyethyl)-4- Carboxyl-azetidin-2-one 3 was obtained. b) (4-b) Step 1-(di-P-anisylmethyl)-3-(1-hydroxyethyl)-4-carboxyl-azetidin-2-one 3 (10 , 59) dimethylformamide (50d)
Triethylamine (3,30F) and P-nitrobenzyl chloride (5,12F) were added to the solution for 70'
The mixture was stirred for 20 hours. The reaction solution was diluted with ethyl acetate, washed with water, washed with 2N hydrochloric acid and aqueous sodium bicarbonate, washed with water, dried with sodium sulfate,
After evaporating the solvent. By silica gel column chromatography, 1-(di-P-anisylmethyl)-3-(1-hydroxyethyl)-4-p
-Methoxybenzylcarboxyl-azetidin-2-one 11 was obtained. The IR and NMR spectra were the same as those of compound (2) in [Example 3]. C) Perform the same reaction as in step (3-C') of step (4-C) [Example 3],
The same compound, 1-(di-P-anisylmethyl)-3-
(1-P-W) lobenzyloxyethyl, carbonyloxyethyl)-4-P-methoxybenzylcarboxyl-azetidin-2-one 12 was obtained. d) Step (4-d) The same reaction as in step (3-d) of [Example 3] was carried out to produce the same compound, 3-(1-P-nitropenzyloxycarbonyloxyethyl)-4-carboxyl- Azetidin-2-one 13 was obtained. e) Step (4-d) The same reaction as in step (3-d) of [Example 3] was carried out to produce the same compound, 3-(1-P-nitrobenzyloxylecarbonylokylethyl)-4- Acetoxy-azetidine-
2-on 6 was obtained. Procedural amendment (voluntary) July 2, 1980 and Japan Patent Office Commissioner Kazuo Wakasugi 1 Indication of the case 1977 Patent essay / No. 94037 2 Name of the invention Process for producing β-lactam derivatives 3 Acting person making the amendment 4 Address: 5-chome, Kitahama, Higashi-ku, Osaka ■The following location in the "Detailed Description of the Invention" column 6 of the description of the address and the description of the amendments will be corrected as follows. that's all

Claims (1)

[Claims] General formula (wherein k is a hydrogen atom or a lower alkyl group mono,
Alternatively, diaryl represents a carboxyl protecting group such as a lower alkyl group, an aryl group, a halogen atom, or a lower alkyl group substituted with a lower alkyloxy group, and R8 represents a mono- or diarylmethyl group. ) A β-lactam derivative represented by
urltiOn Reaction)B
on Reactlon) C by any combination of demono- or diarylmethyl reactions (wherein k is a hydrogen atom or a lower alkyl-substituted silyl group, an arylmethyloxycarbonyl group, a lower alkyloxycarbonyl group, a substituted lower alkyloxycarbonyl group) , aryloxycarbonyl group, lower alkylcarbonyl group, substituted lower alkylcarbonyl group, arylcarbonyl group, lower alkyl group, mono-, di- or triarylmethyl group, etc.) Derivative manufacturing method