JPH0931054A - Azetidinone compound and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a compound useful as a synthetic intermediate for carbapenem-based compounds useful as an antimicrobial agent at a low cost by suppressing an increase in the waste water load due to by-products in production. SOLUTION: This azetidinone compound of formula I (R<1> is hydroxyl group which may be protected or an alkyl which may be substituted with a halogen; R<2> is H or a readily eliminable amino-protecting group; R<3> is an alkyl which may be substituted; X is a halogen), e.g. (3S,4S)-3-[(1R)-1-t- butyldimethylsilyloxyethyl]-4-[(1R)-1-chloroformylethyl]azetidin-2-one. The compound of formula I is obtained by reacting an azetidinone compound of formula II with a halogenating agent (e.g. phosgene) in the presence of a deacidifying agent (e.g. diisopropylethylamine) or a catalyst (e.g. dimethylformamide). The compound of formula I is reacted with a compound of formula III (R<4> is a carboxy-protecting group) in the presence of an Mg compound to afford a compound of formula IV which is a synthetic intermediate for carbapenem-based compounds.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an azetidinone compound which is a useful synthetic intermediate for a carbapenem compound.

[0002]

PRIOR ART [IV] useful as an intermediate for the synthesis of carbapenem compounds

Embedded image (In the formula, R ¹ represents a hydroxyl group which may be protected or a lower alkyl group which may be substituted with a halogen atom,
R ² is a hydrogen atom, an easily removable amino protecting group, R ³
Represents an optionally substituted lower alkyl group, and R ⁴ represents a carboxy protecting group. The β-ketoester compound represented by the formula (1) is described in JP-A-64-34957.

Embedded image (Wherein R ¹ , R ² and R ³ have the same meanings as described above), and a method via a 1-imidazolyl compound is shown.

However, in the method via the 1-imidazolyl compound represented by the formula [V], the imidazole compound is converted to the 1-imidazolyl compound and then reacted with the magnesium malonate compound. It is difficult to collect the by-produced imidazole from the wastewater by mixing it with the wastewater due to the above conditions, so that the wastewater treatment load increases, and it is not economically satisfactory as an industrial production method. A compound having a halogen atom instead of the imidazolyl group of the formula [V] is also exemplified as one of the active acyl compounds, but a specific production method or a compound represented by the formula [IV] using the halide No manufacturing method is described.

[0004]

DISCLOSURE OF THE INVENTION The present invention has made extensive studies in order to solve the above problems and provide a method for inexpensively producing an intermediate of a carbapenem compound useful as an antibacterial agent. The present invention has been completed by discovering a method for producing a β-ketoester body which is more important as an intermediate of a carbapenem compound by directly reacting the acid halogen compound with a magnesium malonate compound.

That is, the present invention has the formula [I]

Embedded image (In the formula, R ¹ represents a hydroxyl group which may be protected or a lower alkyl group which may be substituted with a halogen atom,
R ² is a hydrogen atom or an easily removable amino protecting group,
³ represents an optionally substituted lower alkyl group, and X represents a halogen atom. ), An azetidinone compound represented by the formula (1), a method for producing the same and a method for using the same.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, the "lower alkyl group" has 1 to 7 carbon atoms and may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, n-butyl, Isobutyl, sec-butyl, t
and ert-butyl, n-pentyl, isopentyl, n-hexyl and n-heptyl groups. As the hydroxyl-protecting group R ⁵ in R ¹ , a protecting group generally used for protecting a hydroxyl group can be used. As a concrete example,
Tri-substituted silyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, dimethylhexylsilyl, t-butyldiphenylsilyl, dimethylcumylsilyl, and optionally substituted benzyl groups (the nitro group is a substituent). Group, a lower alkoxy group, etc.), a lower alkoxycarbonyl group,
Halogeno lower alkoxycarbonyl group, optionally substituted benzyloxycarbonyl group (substituents include nitro group, lower alkoxy group, etc.), acetyl group, acyl group such as benzoyl group, triphenylmethyl group, tetrahydro group, etc. Examples thereof include pyranyl group and other commonly used protective groups for hydroxyl group.

As the protecting group R ^{2 for} N, a protecting group generally used for protecting N can be used. Specific examples thereof include trisubstituted silyl groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, dimethylhexylsilyl, t-butyldiphenylsilyl, dimethylcumylsilyl, and optionally substituted benzyl groups. (Examples of the substituent include a nitro group and a lower alkoxy group.), A lower alkoxycarbonyl group, a halogeno lower alkoxycarbonyl group, and an optionally substituted benzyloxycarbonyl group (the substituents are a nitro group and a lower alkoxy group. Etc.),
Examples thereof include an acyl group such as an acetyl group and a benzoyl group.

Examples of the substituent of the alkyl group of R ³ include a lower alkoxy group and a halogen atom.

Examples of the carboxy protecting group for R ⁴ include a lower alkyl group, an alkenyl group, an alkynyl group and a benzyl group, which may have a substituent. Examples of the substituent include a lower alkoxyl group, a halogen atom and a nitro group.

The present invention will be described in more detail, but for the sake of easy understanding, a step of reacting the reaction with a halogenating agent to synthesize an acid halide (hereinafter referred to as "previous step") and the resulting acid halide and malonic acid half The present invention will be described by dividing it into a step of reacting with an ester (hereinafter referred to as a post-step).

The previous step is a step of reacting the compound of the formula [I] with a halogenating agent in the presence of a deoxidizing agent or a catalyst to synthesize an acid halide.

The solvent used in this step is not particularly limited as long as it is inert to the reaction reagents and the like. For example, chlorine-based solvents such as methylene chloride and chloroform, aromatic solvents such as chlorobenzene and toluene. Ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, ether solvents such as ether and tetrahydrofuran, nitrile solvents such as acetonitrile and propionitrile, and the like. And a mixed solvent thereof.

Examples of the halogenating agent include phosgene, thionyl chloride, oxalyl chloride, phosphorus pentachloride, triphenylphosphine / carbon tetrachloride and the like, but phosgene is preferably used. The halogenating agent is used in an amount of 0.7 to 3 times, preferably 0.9 to 2 times the mol of the compound of the formula [II].

When a deoxidizing agent is used in this step, examples of the deoxidizing agent include diisopropylethylamine,
Trialkylamines such as diisopropylmethylamine and triethylamine, dialkylanilines such as N, N-dimethylaniline, 1-ethylpiperidine, 4-methylmorpholine, 1-ethylpyrrolidine, 1,4-diazabicyclo [2,2,2] ] Heterocyclic amines such as octane and 1,8-diazabicyclo [5,4,0] -7-undecene or tertiary amines such as diamines such as N, N, N ', N'-tetramethylethylenediamine , Α, β
Or γ-picoline, 1,2-, 2,4-, 2,5-,
2,6-, 3,4-, 3,5-lutidine, 2,4,6-
Examples thereof include alkylpyridines such as collidine, dialkylpyridines such as dimethylaminopyridine, and pyridines such as condensed heterocyclized pyridines such as quinoline. The amount of deoxidizer used is 0.5 with respect to the compound of the formula [II].
It is suitable to be 5 to 5 times mol, preferably 0.8 to 3 times mol. In addition, dimethylformamide (D
When MF) or the like is reacted as a catalyst, the amount used is 0.001 to 1.0 times mol, preferably 0.05 to 0.5 times mol, of the compound of the formula [II].

The reaction temperature is -50 ° C to the boiling point of the solvent, preferably -20 to 40 ° C.

The reaction time varies depending on the reaction temperature, the reaction conditions such as the kind and amount of the solvent, and the reaction scale, but is usually in the range of about 5 minutes to 5 hours.

Although not essential in carrying out this reaction, the solvent used is preferably anhydrous.

After completion of the reaction, the acid halide obtained in this step is usually used as it is in the reaction solution without being isolated in the next step, but the deoxidizing agent is removed by filtration, the solvent is distilled off, or the reaction solution is removed. The crystals obtained after concentration can be used as they are, or if necessary, purified by recrystallization, washing with a solvent or the like before use.

The second step is a step of reacting the acid halide obtained in the first step with a malonic acid half ester, a magnesium compound and, if necessary, magnesium malonate prepared by using a base.

The solvent used in this step is not particularly limited as long as it is inert to the reaction reagents and the like. For example, chlorine-based solvents such as methylene chloride and chloroform, aromatic solvents such as chlorobenzene and toluene. , Ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, ether solvents such as ether and tetrahydrofuran, nitrile solvents such as acetonitrile and propionitrile, DMF and the like. Alternatively, a mixed solvent thereof or the like can be used.

The amount of the compound [III] used is 0.8 to 5 times mol of the compound [I].

Examples of magnesium compounds include anhydrous magnesium halides such as magnesium chloride and magnesium bromide, magnesium alkoxides such as magnesium methoxide and magnesium ethoxide, and Grignard reagents such as isopropyl magnesium bromide and t-butyl magnesium chloride. The amount used is 0.5 to 4 times mol of the compound [I].

When anhydrous magnesium halides such as magnesium chloride and magnesium bromide are used, trialkylamines such as diisopropylethylamine, diisopropylmethylamine, triethylamine, 1-ethylpiperidine, 4-methylmorpholine, etc. are used as deoxidizing agents. Heterocyclic amines such as 1-ethylpyrrolidine, 1,4-diazabicyclo [2,2,2] octane and 1,8-diazabicyclo [5,4,0] -7-undecene, or N, N, N ', Tertiary amines such as diamines such as N'-tetramethylethylenediamine, α, β or γ-picoline, 1,2-, 2,4-, 2,5-, 2,
Alkylpyridines such as 6-, 3,4-, 3,5-lutidine and 2,4,6-collidine, dialkylaminopyridines such as dimethylaminopyridine, and pyridines such as condensed heterocyclized pyridines such as quinoline. And the like. The amount of the deoxidizer used is 1.0 with respect to the compound of the formula [I].
~ 5 times the molar amount.

The reaction is usually carried out by preparing magnesium malonate from a malonic acid half ester and a magnesium compound in advance and adding the acid halide synthesized in the previous step to this solution. In the preparation of magnesium malonate, the reaction temperature at that time varies depending on the magnesium compound used, but it is carried out in the range of -50 ° C to 60 ° C. Further, when magnesium alkoxide is used, it is preferable to distill off alcohols produced as by-products.

The reaction temperature between the acid halide and magnesium malonate is -20 ° C to the boiling point of the solvent, preferably -20 to 20 ° C.
50 ° C. Reaction time is reaction conditions (molar ratio, temperature, etc.)
Although it varies depending on the situation, it is usually about 0.5 to 20 hours.
After completion of the reaction, the desired product can be obtained by performing usual post-treatment.

[0026]

Next, the present invention will be described in more detail by way of examples. Example 1 Preparation of (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-chloroformylethyl] azetidin-2-one

Embedded image (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-carboxyethyl] azetidin-2-one 6.03 g, DM
2.2 g of phosgene was blown into a mixture of 0.2 g of F and 100 ml of tetrahydrofuran at 3 to 5 ° C over 15 minutes.
The mixture was aged at the same temperature for 50 minutes and analyzed by high performance liquid chromatography to find that it contained 6.27 g of the desired product. In addition, the analysis is a separately synthesized benzylamide compound.

[Chemical 12] ((3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-carboxyethyl] azetidin-2-one and N, N′-carbonyldi After reacting with imidazole, it was reacted with benzylamine to synthesize.mp.163-164
(.Degree. C.) as a standard, the produced acid chloride was reacted with an excess of benzylamine, and the benzylamide product produced as the reaction proceeded 100% was quantified and defined as the amount of acid chloride produced. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was washed with dry hexene to obtain white crystals. The compound obtained from the NMR spectrum of this product was (3S, 4S) -3-[(1
R) -1-t-butyldimethylsilyloxyethyl]-
It was confirmed to be 4-[(1R) -1-chloroformylethyl] azetidin-2-one. 1H NMR (CDCl ₃ ) δ ppm (TMS standard) = 0.07 (3H, s),
0.09 (3H, s), 0.88 (9H, s), 1.22 (3H, d), 1.40 (3H, d), 3.
00 (1H, dd), 3.12 (1H, m), 4.02 (1H, dd), 4.21 (1H, m), 6.4
5 (1H, br) 13C NMR (CDCl ₃ ) δ ppm (TMS standard) =-5.00, -4.
32, 12.70, 17.89, 22.45, 25.70, 51.26, 54.39, 62.1
7, 65.08, 168.13, 175.76 Example 2 (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-chloroformylethyl] azetidine-2 -On manufacturing

Embedded image (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-carboxyethyl] azetidin-2-one 6.03 g, N,
N-dimethylaniline 2.67 g, acetonitrile 10
Phosgene, 2.2 g, was bubbled through 0 ml of the mixture at 0-5 ° C. over 15 minutes. The reaction was carried out at the same temperature for 2 hours, and the reaction mixture was analyzed in the same manner as in Example 1 to find that it contained 5.9 g of the desired product.

Example 3 (3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-methyl-3-p-nitrobenzyloxycarbonyl- 2-oxopropyl] azetidin-2-one

Embedded image Synthesized in the same manner as in Example 1 (3S, 4S) -3-[(1
R) -1-t-butyldimethylsilyloxyethyl]-
A solution of 9.21 g of 4-[(1R) -1-chloroformylethyl] azetidin-2-one in 75 ml of THF was separately added 7.14 g of magnesium chloride, 15.48 g of triethylamine, 15.48 g of p-nitrobenzyl malonate.
The mixture was added to a 240 ml solution of a magnesium malonate compound prepared from 07 g in acetonitrile and reacted at 22 to 30 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled and analyzed by high performance liquid chromatography to find that the title compound 1
It contained 0.8 g. The reaction solution was poured into ice water, extracted with ethyl acetate, and washed with diluted hydrochloric acid, aqueous sodium carbonate solution and water. After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and it was confirmed by NMR to be the title compound.

Example 4 (3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-methyl-3-p-nitrobenzyloxycarbonyl- 2-oxopropyl] azetidin-2-one

Embedded image Synthesized and isolated as in Example 1 (3S, 4S) -3-
[(1R) -1-t-Butyldimethylsilyloxyethyl] -4-[(1R) -1-chloroformylethyl] azetidin-2-one (8.11 g) was dissolved in THF (70 ml), and magnesium chloride (7.14 g) was added. Triethylamine 15.48 g, p-nitrobenzyl malonate 15.
The mixture was added to a 240 ml solution of a magnesium malonate compound prepared from 07 g in acetonitrile and reacted at 22 to 31 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled and analyzed by high performance liquid chromatography to find that it contained 9.4 g of the title compound.

Example 5 (3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-methyl-3-p-nitrobenzyloxycarbonyl- 2-oxopropyl] azetidin-2-one

Embedded image Synthesized in the same manner as in Example 2 (3S, 4S) -3-[(1
R) -1-t-butyldimethylsilyloxyethyl]-
50 ml of acetonitrile containing 3.10 g of 4-[(1R) -1-chloroformylethyl] azetidin-2-one
The above solution was added to 160 ml of a solution of magnesium malonate compound prepared from 4.76 g of magnesium chloride, 10.32 g of triethylamine and 10.05 g of p-nitrobenzyl malonate in acetonitrile, and reacted at 20 ° C. for 4 hours. After completion of the reaction, the reaction solution was cooled and analyzed by high performance liquid chromatography to find that it contained 3.9 g of the title compound.

Example 6 (3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-methyl-3-p-nitrobenzyloxycarbonyl- 2-oxopropyl] azetidin-2-one

Embedded image Synthesized in the same manner as in Example 1 (3S, 4S) -3-[(1
R) -1-t-butyldimethylsilyloxyethyl]-
40 m of tetrahydrofuran containing 6.1 g of 4-[(1R) -1-chloroformylethyl] azetidin-2-one
l solution was added to 160 ml of acetonitrile solution of magnesium malonate compound prepared from 4.76 g of magnesium chloride, 12.46 g of 4-dimethylaminopyridine and 10.05 g of p-nitrobenzyl malonate at 25-28 ° C. Reacted for 1.5 hours. After the reaction,
When the reaction solution was analyzed by high performance liquid chromatography, it contained 7.6 g of the title compound.

Example 7 (3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-methyl-3-p-nitrobenzyloxycarbonyl- 2-oxopropyl] azetidin-2-one

Embedded image (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-chloro synthesized in the same manner as in Example 2 except that the solvent was ethyl acetate. Formylethyl] azetidin-2-one 10.1 g
A solution of 100 ml of ethyl acetate containing 1 ml of magnesium chloride, 15.9 g of magnesium chloride, 25.8 g of triethylamine, p-
Nitrobenzyl malonate was added to a 160 ml solution of a magnesium malonate compound prepared from 25.1 g of ethyl acetate and reacted at 25 to 30 ° C. for 4 hours. After completion of the reaction, the reaction solution was cooled and analyzed by high performance liquid chromatography to find that it contained 12.6 g of the title compound.

[0033]

In the production according to the present invention, N, N'-carbonyldiimidazole, which is expensive and easily decomposed by moisture absorption or the like, or an imidazolide compound obtained by reacting with a carboxylic acid activator and then reacting with imidazole is used. By directly synthesizing an acid halide and directly reacting the same, an intermediate of a carbapenem compound useful as an antibacterial agent can be manufactured at a lower cost, while suppressing an increase in wastewater load due to byproducts.

Claims (5)

[Claims] 1. A compound of the formula [I] (In the formula, R ¹ represents a hydroxyl group which may be protected or a lower alkyl group which may be substituted with a halogen atom,
R ² is a hydrogen atom or an easily removable amino protecting group,
³ represents an optionally substituted lower alkyl group, and X represents a halogen atom. ) Azetidinone compound represented by. 2. A compound of formula [I] is The compound according to claim 1, wherein R ⁵ represents a hydroxyl-protecting group. 3. The formula [II]: (Wherein R ¹ , R ² and R ³ have the same meanings as described above), and an azetidinone compound represented by the formula [I] embedded image is reacted with a halogenating agent. (In the formula, R ¹ , R ² , R ³ and X have the same meanings as described above.) A method for producing the compound represented by the formula. 4. The halogenating agent is phosgene.
Manufacturing method. 5. The formula [I]: (Wherein R ¹ , R ² , R ³ and X have the same meanings as described above), and an azetidinone compound represented by the formula [III] (Wherein R ⁴ represents a carboxy protecting group) is reacted with a compound represented by the formula [IV] (Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above).