JPH0710834B2 - Process for producing 4-substituted azetidinone derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a (1R) -1-substituted carbapenem-3-carboxylic acid derivative and a method for producing the compound, and in particular, it is useful as a carbapenem antibiotic. , A novel (1R) -1-nitrogen atom-substituted carbapenem-3-carboxylic acid derivative having a heteroatom-substituted moiety at the 1-position.

(Conventional technology and its problems) Conventionally, the formula [A] was used for the purpose of various antibacterial activities. Carbapenem antibiotics having a basic skeleton of carba-2-penem-3-carboxylic acid have been proposed. For example, compounds without a substituent (basic skeleton itself)
[Journal of Antibiotics (J.anti
biotics) 35 (6), 653 (1982), JACS 100 (25), 80
06 (1978), etc.] A compound having a substituent at the 2-position [Tetrahedron Letters 21 , 2013
(1978)], a compound having a substituent at the 6-position [JACS 100
(25), 8004 (1978), etc.] Thienamycin-based compounds having substituents at the 2- and 6-positions [JP-A-53-87390,
JP-A-58-32879] and the like] are provided. All of these compounds have some antibacterial activity, but basically have no substituent at the 1-position of the carbapenem bone nucleus.

On the other hand, as a compound having a substituent at the 1-position, a compound having 1 to 2 substituents such as an alkyl group, a cycloalkyl group, an acyl group, an alkoxycarbonyl group and a cyano group at the 1-position (JP-A-55-69586) No., 59-130884, 59-51286, 57-
93981, 59-84887, etc.) have been reported. Of these, for example, a β-configured methyl group at the 1-position (1
R 5, 5 S , 6 S ) -2- (2-N, N-dimethylamino-2-iminoethylthio) -6-[(1R) -1-hydroxyethyl]
-1-Methylcarba-2-penem-3-carboxylic acid is known as an excellent antibiotic with significantly improved resistance to degradation inactivation by renal dehydropeptidase, which is a common weakness of carbapenem antibiotics. Heterocycles, 21 (1), 29 (1984)].

However, although carbapenem antibiotics in which various substituents are substituted at the 1-position through a heteroatom are expected to have excellent antibacterial activity, they are compounds in unexplored fields that have not been actively studied until now. However, its manufacturing method has not been developed in detail.

Recently, a carbapenem antibiotic having a substituent at the 1-position through various heteroatoms has been proposed (JP-A-60-233077), but a very comprehensive compound is generally disclosed in the publication. However, it does not refer to the steric point at the 1-position, which is the object of the present invention. When the production method disclosed therein is examined, the introduction of the 1-position substituent is due to a substitution reaction, and therefore its stereochemistry relates to a production method which can be obtained only as a mixture of α and β. Yes,
Means for selectively obtaining a compound having β configuration, that is, 1R configuration, which is considered to have excellent effects, is not specified.

(Object of the Invention) The present invention is a carbapenem in which the 1-position is substituted via a nitrogen atom having a β-configuration, which has not been previously examined as described above, which is expected to have strong antibacterial action, β-lactamase inhibitory action and the like. An object of the present invention is to provide a method for selectively producing antibiotics and these compounds, that is, compounds having a β-configuration at the 1-position of the carbapenem skeleton.

By the way, the present inventors have the following formula VIII, which is an important starting compound for synthesis of the carbapenem antibiotic targeted by the present invention: (Wherein, X represents a hetero atom, Rb and Rc represent an organically substituted residue), that is, the substituents at the 3- and 4-positions of the azetidinone skeleton each have an S configuration.
Moreover, a method for stereoselectively producing a compound in which the asymmetric carbons of the hydroxyethyl group at the 3-position and the 1-substituted carbonylmethyl group at the 4-position have R configurations has been established and a patent application has been filed. No. 60-269417).

This time, the present inventors selected a compound represented by the above formula VIII as a raw material, particularly a compound having a substituted amino group as Xc, and the substituent: XRc is a desired compound with the R configuration retained.
A synthetic method for obtaining a 1-substituted carbapenem-3-carboxylic acid derivative was studied, and as a result, the present invention was completed.

(Means for Achieving the Purpose) Therefore, the present invention has the following formula I: (Wherein R ¹ represents a substituted amino group, R ² represents an unsubstituted or substituted alkyl group or a heterocyclic group, and R ³ represents a hydrogen atom or a carboxyl protecting group) (1R) -1- A substituted carbapenem-3-carboxylic acid derivative is provided.

The present invention also provides a method for producing a (1R) -1-substituted carbapenem-3-carboxylic acid derivative represented by the above formula I, which comprises the following formula II: (Wherein R ¹ represents a substituted amino group and R ³ represents a carboxyl protecting group), and a (1R) -1-substituted-2-oxo-carbapenem-3-carboxylic acid compound represented by the formula: RaX ( In the formula, Ra represents a leaving group, preferably an acyl group, and X represents a halogen atom), and is reacted with an acylating agent represented by the following formula III: (Wherein R ¹ , R ³ and Ra are the same as defined above), and then in the presence of a base, a compound of the formula: R
² SH (wherein R ² represents an unsubstituted or substituted alkyl group or a heterocyclic group) is reacted with a mercapto reagent, and when R ³ is a carboxyl protecting group, the protecting group is further removed. Is the way.

Further, the present invention provides (1R) -1-substituted-2 represented by the formula II.
-Oxo-carbapenem-3-carboxylic acid compound and a process for producing the same are also provided by the following formula IV: (In the formula, R ¹ represents a substituted amino group, R ⁴ represents a hydroxyl-protecting group, and R ⁵ represents a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group). Is reacted with a magnesium malonate compound represented by the formula: (R ³ OOCCH ₂ CO ₂ ) ₂ Mg (wherein R ³ represents a carboxyl protecting group) in the presence of imidazole, and the following formula V: (Wherein R ¹ , R ³ and R ⁴ are the same as defined above), and then the protecting group of R ⁴ is removed to give a compound of the following formula VI: (Wherein R ¹ and R ³ are the same as defined above), and the resulting compound of formula VI is treated with an azide compound in the presence of a base to give the following formula VII: And a cyclization reaction in the presence of a metal catalyst.

The present invention provided as described above can be summarized as follows if it is represented by a chemical reaction formula in order to facilitate understanding.

(Definition of each substituent in the above reaction formula is the same as above) Note: The symbols in parentheses indicate the symbols of the steps.

The feature of the present invention provided in the above reaction scheme is that a compound represented by the formula IV is selected as a starting compound having a desired configuration, and the desired compound of the formula I is retained while retaining the configuration. It is at the point of derivation to the represented (1R) -1-substituted carbapenem-3-carboxylic acid.

And, the manufacturing method while maintaining these three-dimensional configurations is a novel method that has not been studied in the past,
Accordingly, the present invention provides novel compounds of formula I and II.

(Function) In the present specification, the “substituted amino group” means a mono-substituted or di-substituted amino group, and examples of the substituent of the substituted amino group include a lower alkyl group or an amino group-protecting group described later. it can. Examples of the amino protecting group in this case include those commonly used as a protecting group for amino group in peptide chemistry and the like, but preferably include phthaloyl group, benzyloxycarbonyl group, t-butoxycarbonyl group and the like. .

The "lower alkyl group" may be linear or branched and preferably has 1 to 6 carbon atoms, and is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl. , Isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl groups and the like.

Further, the “substituted alkyl group” means an alkyl group in which various substituents are substituted on the above lower alkyl group, and examples of such a substituent include amino, substituted amino, amidino, imino, guanidino, guanidinium, sulfamoyl. , Ureido, amide, mercapto, alkylthio,
Allylthio etc. can be raised.

Further, the substituted alkyl group may be an alkyl group substituted with a “heterocyclic group” described below.

Further, the “heterocyclic group” means an aromatic or aliphatic heterocyclic group containing at least one of oxygen, nitrogen and sulfur atoms as a hetero atom, and includes, for example, furyl, furfuryl, thienyl, pyridyl, pyrimidyl, pyrrolidinyl, Examples thereof include piperidyl, oxazolidinyl, thiazolidinyl, thiazolyl, oxazolyl, thiadiazolyl, triazolyl, tetrazolyl and the like, which may be bonded via a methylene chain as described above. Further, the ring carbon atom may have the above-mentioned substituents.

Examples of the “carboxyl protecting group” include ester residues, and examples of such ester residues include methyl, ethyl, n-propyl, isopropyl, n-, iso-,
sec-, tert-butyl, lower alkyl ester residues such as n-hexyl ester, benzyl, p-nitrobenzyl, o-nitrobenzyl, araalkyl ester residues such as p-methoxybenzyl, acetoxymethyl, propionyloxymethyl, Lower aliphatic acyloxymethyl residues such as n-, iso-, butyryloxymethyl and pivaloyloxymethyl.

The "aryl group" may be monocyclic or polycyclic, and may further have one or more lower alkyl groups on the ring, for example, phenyl, tolyl, xylyl, α- It includes naphthyl, β-naphthyl, biphenylyl groups and the like.

The "aralkyl group" is an aryl-substituted alkyl group in which the alkyl group is the above lower alkyl group and the aryl group has the above meaning, and specifically, benzyl, phenethyl, α-methylbenzyl, phenylpropyl, naphthylmethyl. A group etc. can be illustrated.

Further, examples of the “hydroxyl group-protecting group” represented by R ⁴ include silyl groups such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, diphenyl-tert-butylsilyl; benzyloxycarbonyl group; p-nitrobenzyloxycarbonyl, o -Substituted benzyloxycarbonyl group such as nitrobenzyloxycarbonyl; and other commonly used hydroxyl-protecting groups.

Therefore, the present invention provides a (1R) -1-substituted carbapenem-3-carboxylic acid derivative of formula I
As the compound represented by II, for example, various compounds in which the above substituents are appropriately substituted are provided.

Hereinafter, the production method of the present invention will be described in detail by explaining each step in the above chemical reaction formula.

Process A: This process was previously proposed by the present inventor (Japanese Patent Application No. 60-26941).
Azetidine-2 of formula IV prepared by
The -one derivative can be converted to the formula: (R ³ OOCH ₂ CO _{2) in} the presence of imidazole.
₂ ) A step of reacting with a magnesium malonate compound represented by ₂ Mg to obtain a compound represented by the formula V.

The reaction is preferably carried out in an inert organic solvent, for example, ether solvents such as ether, tetrahydrofuran, dioxane; hydrocarbon solvents such as toluene, xylene, cyclohexane; halogenated hydrocarbon solvents such as dichloromethane, chloroform; acetonitrile. Etc. can be mentioned, but acetonitrile is particularly preferably used.

The reaction temperature is not strictly limited and can be widely varied depending on the starting materials used and the like, but generally about 0 ° C to about 100 ° C, preferably a relatively low temperature around room temperature is used. It

The magnesium malonate compound is used in an approximately equimolar amount with respect to the compound of the formula IV, and the reaction is carried out for about 50 hours.
It is preferably completed in about 20 hours.

Examples of the magnesium malonate compound used include para-nitrobenzyl magnesium malonate, benzyl magnesium malonate, methyl magnesium malonate, and the like. Among them, para-nitrobenzyl magnesium malonate is preferably used.

Step B: This step is a step of eliminating the protecting group for the hydroxyl group represented by R ⁴ in the compound of formula V obtained in step A. For example, removal of a protecting group in which R ⁴ is a triorganosilyl group such as a t-butyldimethylsilyl group can be accomplished by removing V from a solvent such as methanol, ethanol, tetrahydrofuran, dioxane, such as hydrochloric acid, sulfuric acid, acetic acid, etc. Acid hydrolysis in the presence of various acids at a temperature of 0 to 100 ° C. for 0.5 to 18 hours. (The term "triorganosilyl" more preferably includes an organic compound moiety independently selected from an alkyl group having 1 to 6 carbon atoms, a phenyl group and a phenylalkyl group.) The compound represented by the formula VI can be quantitatively obtained.

Step C: The compound of formula VI thus obtained in step B is treated with an azide compound in an inert organic solvent which can be used in the above step A in the presence of a base to obtain the desired diazo compound VII.

The azide compound used may include azides such as p-carboxybenzenesulfonyl azide, toluenesulfonyl azide, methanesulfonyl azide and dodecylbenzenesulfonyl azide, and the base may include triethylamine, pyridine and diethylamine. A base can be illustrated.

The reaction is preferably carried out by adding p-toluenesulfonyl azide in acetonitrile in the presence of triethylamine,
By treating at 0 ° C., preferably at room temperature for 1 to 50 hours, the desired diazo compound of the formula VII can be obtained in high yield.

Step D: This step is a step of cyclizing the diazo compound VII obtained in Step C to give Compound II. For example, VII is an inert solvent such as benzene, toluene, tetrahydrofuran, cyclohexane, ethyl acetate, dichloromethane and the like. , Preferably 1-5 at a temperature of 25-110 ° C in toluene
Time, bis (acetylacetonato) Cu (II); [Cu (ac
ac) ₂ ], CuSO ₄ , copper powder, Rh ₂ (OAc) ₄ , rhodium octanoate or Pd (OAc) ₄ in the presence of a metal acetate catalyst. On the other hand, as another method, the cyclization step involves adding VII to a solvent such as benzene or diethyl ether at a temperature of 0 to 25 ° C for 0.5 to 2
It can be carried out by irradiating through a time Pyrex filter (wavelength greater than 300 nm).

Further, in the obtained compound II, a compound in which R ³ has a carboxyl protecting group can be deprotected at the same time as the subsequent step to obtain a compound in which R ³ is a hydrogen atom.

Steps E and F: represented by the formula II manufactured by the above steps (1
(R) -1-substituted-2-oxo-carbapenem-3-carboxylic acid derivative is acylated with an acylating agent RaX, and then the acyl group Ra is substituted with R ² S to give the desired compound of formula I (1R ) -1-Substituted carbapenem-3-carboxylic acid.

That is, Step E from II to III for introducing the acyl group Ra
Is p-toluenesulfonic anhydride, p-nitrophenylsulfonic anhydride, 2,4,6-triisopropylphenylsulfonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, diphenylchloro It is carried out by acylating a bicyclic compound with an acylating agent RaX such as phosphoric acid, toluenesulfonyl chloride, p-bromophenylsulfonyl chloride and the like.

Here, Ra is introduced by a toluenesulfonyloxy group, a p-nitrophenylsulfonyloxy group, a benzenesulfonyloxy group, a diphenylphosphoryl group and other conventional methods, and is well known in the art. Corresponding leaving groups such as Specifically, the acylation above introducing the leaving group Ra is carried out in a solvent such as methylene chloride, acetonitrile or dimethylformamide in the presence of a base such as diisopropylethylamine, triethylamine, 4-dimethylaminopyridine, etc. -20 to 40 ° C
At a temperature of 0.1 to 5 hours. Leaving group Ra of compound III
Can also be a halogen atom. Halogen leaving group _{II, Ph 3 PCl 2, Ph} 3 PBr 2, (PhO) 3 PBr 2, oxalyl chloride halogenating agent and dichloromethane and the like, acetonitrile, diisopropylethylamine in a solvent such as tetrahydrofuran , Triethylamine or 4-dimethylaminopyridine and the like in the presence of a base.

The conversion of III to I is then carried out, for example, by reacting III in a solvent such as tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, etc. in the presence of approximately equivalent to excess mercapto reagent R ² SH. In the presence of a base such as sodium hydrogen carbonate, potassium carbonate, triethylamine, diisopropylethylamine, etc.
It is carried out by treating at 25 ° C for 30 minutes to 24 hours.

Thus, compounds of formula I in which R ³ is substituted with a carboxyl protecting group can be obtained.

Removal of this carboxyl protecting group to give the free carboxylic acid is carried out by conventional methods such as solvolysis or hydrogenation. That is, the conditions for the deprotecting group are as follows. Typically, a compound in which R ³ is a carboxyl protecting group in I is a morpholinopropanesulfonic acid-sodium hydroxide buffer solution having a pH of 7, a pH 7 phosphate buffer solution, dipotassium phosphate, or a tetrahydrofuran-water solution containing sodium bicarbonate. , Tetrahydrofuran-ethanol-water, dioxane-water, dioxane-ethanol-water, n-butanol-water, etc. under a hydrogen pressure of 1 to 4 atm, platinum oxide, palladium-activated carbon, palladium hydroxide-
In the presence of a catalyst such as activated carbon, etc. at a temperature of 0 to 50 ° C.
It is processed for 25 to 4 hours to produce the desired I. In the case of groups such as the R ³ o-nitrobenzyl group, for example photolysis can also be used for the deprotecting group.

As described above, according to the present invention, the 1st position of the carbapenem skeleton has already been
It can be said to be a particularly excellent production method in consideration of the fact that the substituted amino group having the R configuration can be selectively produced, and the conventional method can be produced only with a cerami body.

The (1R)-represented by formula I of the invention thus prepared
The 1-substituted carbapenem-3-carboxylic acid derivative is stable against attack by a renal enzyme known as dehydropeptidase and has an excellent antibacterial action.

(Examples) The present invention will be further described below with reference to examples, but the invention is not limited thereto.

The symbols Z and PNB in the examples represent the following groups.

Z: benzyloxycarbonyl group PNB: para-nitrobenzyl group Example 1: 12.75 g (30.5 mM) of tin triflate was dissolved in 50 ml of anhydrous tetrahydrofuran, and N-ethylpiperidine 4. was added to this solution.
41 ml (32.2 mM) and 25 ml of a solution of 8.34 g (23.7 mM) of compound (2) in anhydrous tetrahydrofuran were added, and the mixture was stirred at room temperature for 1 hour to generate an enolate. Then, 25 ml of an anhydrous tetrahydrofuran solution of 4.86 g (16.9 mM) of the compound (1) was added to the above reaction solution, and the mixture was stirred at room temperature for 0.5 hours,
20 ml of 0.1 M phosphate buffer and 20 ml of ether were added, and the mixture was stirred at the same temperature for 5 minutes. The precipitate was removed by filtration through Celite, and the filtrate was washed with 1N-HCl, H ₂ O and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: chloroform: acetone = 95: 5) to give 5.88 g (6) of a yellow oil (3).
0.0%) was obtained.

Example 2: (3S, 4S) -3-[(1R) -1-t-butyldimethylsiloxyethyl] -4-[(1R) -1- (N-methyl-N-benzyloxycarbonyl) amino-3 -Paranitrobenzyloxycarbonyl-2-oxopropyl] -2-azetidin-2-one (4) Compound (3) 518.3g (0.89mM) and imidazole 122.
Dissolve 5 mg (1.8 mM) in 10 ml of acetonitrile, and stir at room temperature under an argon gas atmosphere for 45 minutes. Then para-nitrobenzyl magnesium malonate 477.2 mg (0.87 mM)
10 ml of an acetonitrile suspension of is added, and the mixture is stirred at 60 ° C. for 3.5 hours. Acetonitrile was distilled off and ethyl acetate was added to the residue.
ml was added, and the mixture was washed with 1N-HCl, H ₂ O, 5% NaHCO ₃ , and saturated saline and then dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent ethyl acetate), and 177.5 mg (31.
8%).

NMR (CDCl ₃ ) δppm: 0.05 (6H, s), 0.86 (9H, s), 1.26
(3H, d, J = 6.5Hz), 2.83-3.06 (1H, m), 2.95 (3H, s),
3.55 (2H, s), 4.03-4.50 (3H, m), 5.16 (2H, s), 5.23
(2H, s), 5.89 (1H, br s), 7.35 (5H, s), 7.50 (2H, d, J
= 8.9Hz), 8.25 (2H, d, J = 8.9Hz). Example 3: (3S, 4S) -3-[(1R) -1-Hydroxyethyl] -4-[(1R) -1- (N-methyl-N-benzyloxycarbonyl) amino-3-paranitrobenzyl Oxycarbonyl-2-oxopropyl] -azetidin-2-one (5) 591.9 mg (0.944 mM) of the compound (4) obtained in Example 2 was dissolved in a mixed solution of 5.6 ml of methanol and 2.8 ml of water to obtain 0.24 ml of concentrated HCl.
And stir at room temperature for 1 hour. Then, methanol was distilled off under reduced pressure, 10 ml of water was added to the obtained residue, and the mixture was extracted with 30 ml of ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, the residue was purified by column chromatography (eluent-ethyl acetate), and 359.8 mg (74.3%) of a slightly yellow oily compound (5) was obtained. Obtained.

NMR (CDCl ₃ ) δppm; 1.30 (3H, d, J = 7Hz), 2.90-3.07 (1
H, m), 3.00 (3H, s), 3.45-3.65 (2H, m), 4.00-4.30 (2
H, m), 4.37-4.53 (1H, m), 5.20 (2H, s), 5.26 (2H, s),
6.20 (1H, s), 7.40 (5H, s), 7.53 (2H, d, J = 8.5Hz), 8.
26 (2H, d, J = 8.5Hz) Example 4: (3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1- (N-methyl-N- Benzyloxycarbonyl) amino-3-diazo-3-paranitrobenzyloxycarbonyl-2-oxopropyl] -azetidine-2-
On (6) 403.7 mg (0.787 mM) of the compound (5) obtained in Example 3 and 186 mg (0.943 mM) of paratoluenesulfonyl azide were dissolved in 3 ml of acetonitrile, and triethylamine was added thereto at room temperature.
Add 0.12 ml (0.867 mM) and stir for 45 minutes. Then, the acetonitrile was distilled off under reduced pressure, 30 ml of ethyl acetate was added, the mixture was washed with saturated brine and dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by column chromatography (eluent chloroform-ethyl acetate 1/1) and purified. 249.0 mg (58.7%) of compound (6) was obtained as a yellow viscous oil.

NMR (CDCl ₃ ) δppm: 1.10 (3H, J = 6Hz), 2.90-3.10 (4H,
m), 4.03-4.25 (2H, m), 5.05-5.23 (3H, m), 5.30 (2H,
s), 5.90, 6.13 (1H, bs), 7.35 (5H, s), 7.50 (2H, d, J =
8.7 Hz), 8.23 (2H, d, J = 8.7) Example 5: (1R, 5S, 6S) -2-oxo-6-[(1R) -1-hydroxyethyl] -1- (N-methyl- N-benzyloxycarbonyl) aminocarbapenamu-3-carboxylic acid paranitrobenzyl ester (7) 19.9 mg (3.69 × 10 ^-2 mM) of the compound (6) obtained in Example 4,
Toluene 0.5m in catalytic amount of rhodium (II) octanoate
l was added and stirred at 80 ° C for 30 minutes, and then toluene was distilled off under reduced pressure.
Purify the residue using a preparative thin-layer chromatography plate,
7.5 mg (40%) of compound (7) was obtained.

IR (CHCl ₃ ) cm ⁻¹ : 1770,1695, NMR (CDCl ₃ ) δppm, 1.35 (3H, d, J = 7Hz), 3.00 (3H,
s), 3.25-3.40 (1H, m), 3.92-4.07 (1H, m), 4.20-4.40
(1H, m), 4.82 (1H, s), 5.08-5.40 (5H, m), 7.53 (5H,
s), 7.57 (2H, d, J = 7.5Hz), 8.25 (2H, d, J = 7.5Hz). Example 6: (1R, 5S, 6S) -2- (2-Pyrimidylthio) -6-
[(1R) -1-Hydroxyethyl] -1- (N-methyl-N-benzyloxycarbonyl) aminocarbapenem-3-carboxylic acid para-nitrobenziester (8) 20.0 mg (3.91 × 10 ⁻² mM) of the compound (7) obtained in Example 5 was dissolved in 0.2 ml of acetonitrile and stirred at 0 ° C., and 0.009 ml (4.43 × 10 ⁻² mM) of diphenylphosphoric acid chloride was dissolved therein. ,
Diisopropylethylamine 0.008 ml (3.87 × 10 ^-2 mM)
Are sequentially added and stirred for 2 hours. Thereafter, 4.6 mg of 2-mercaptopyrimidine suspended in 0.2 ml of N, N-dimethylformamide.
(4.06 × 10 ^-2 mM), diisopropylethylamine 0.07 ml
Add (4.24 × 10 ^-2 mM) at 0 ° C for 30 minutes and then at room temperature for 20 minutes.
Stir for hours, extract with ethyl acetate, wash with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off, and the product was purified using a preparative thin layer chromatography plate to obtain compound (8) 4 mg (21%)
Got

IR (CHCl ₃ ) cm ⁻¹ : 1750,1720 NMR (CDCl ₃ ) δppm: 1,30 (3H, d, J = 7Hz), 2.90 (3H,
s), 2.87-3.13 (1H, m), 3.65-4.33 (3H, m), 4.87-5.30
(5H, m), 7.23-7.57 (8H, m), 8.15 (2H, d, J = 9Hz), 8.7
7 (2H, d, J = 9Hz). Example 7: (5S, 6S)-(1R) -1- (N-methyl-N-benzyloxycarbonyl) amino-2- (2-pyrimidylthio)
-6-[(1R) -1-hydroxyethyl] -carbapenem-
3-carboxylic acid (9) After shaking the compound (8) obtained in Example 6 and 5% palladium-carbon in a tetrahydrofuran-water mixture for 9 hours under hydrogen at 3 atm, tetrahydrofuran was distilled off under reduced pressure and washed with ether, and the aqueous layer was frozen. Drying gave compound (9) as a pale yellowish white powder.

Example 8: (1R, 5S, 6S) -2-Oxo-6-[(1R) -hydroxyethyl] -1- (N-methyl-N-benzyloxycarbonyl) aminocarbapenam-3-carboxylic acid ( Ten) The same operation as in Example 7 was performed using the compound (7) obtained in Example 5.

Example 9: (3S, 4S) -3-[(1R) -1-t-Butyldimethylsiloxyethyl] -4-[(1R) -1-benzyloxycarbonylamino- (4S-ethyl-1,3- Thiazolidine-2-thione-3-ylcarbonylmethyl) -azetidin-2-one (11) According to the method described in Example 1, tin triflate, compound (1) and the corresponding 1,3-thiazolidine-2-thione compound were used to carry out the same reaction to obtain the target compound (11).
Got

Example 10: (3S, 4S) -3-[(1R) -1-t-Butyldimethylsiloxyethyl] -4-[(1R) -1-benzyloxycarbonylamino-3-paranitrobenzyloxycarbonyl-2 -Oxopropyl] -2-azetidin-2-one (12) The compound (11) obtained in Example 9 was reacted according to the method described in Example 2 at 50 ° C. for 3 hours to obtain the target compound (12) in a yield of 31.8%.

NMR (CDCl ₃ ) δppm: 0.07 (6H, s), 0.86 (6H, s), 1.18
(3H, d, J = 6Hz), 2.90-3.03 (1H, m), 3.63 (2H, s), 4.0
0-4.30 (1H, m), 5.13-5.30 (4H, m), 5.86 (1H, d, J = 9H
z), 6.30 (1H, bs), 7.35 (5H, s), 7.50 (2H, d, J = 8.6H
z), 8.23 (2H, d, J = 8.6Hz). Example 11: (3S, 4S) -3-[(1R) -1-Hydroxyethyl] -4-[(1R) -1-benzyloxycarbonylamino-3-paranitrobenzyloxycarbonyl-2-oxopropyl] -Azetidin-2-one (13) The compound (12) obtained in Example 10 was subjected to the same reaction as described in Example 3 to obtain the target compound (13) in a yield of 96.6%.

NMR (CDCl ₃ ) δppm: 1.23 (3H, d, J = 6.2Hz), 2.95-3.15
(1H, m), 3.73 (2H, s), 4.06-4.26,4.50-4.73 (2H, m),
5.13 (2H, s), 5.22-5.36 (3H, m), 5.90,6.23 (1H, d, J =
9Hz), 6.46, 6.53 (1H, s), 7.33 (5H, s), 7.50 (2H, d, J
= 9Hz), 8.22 (2H, d, J = 9Hz). Example 12: (3S, 4S) -3-[(1R) -1-Hydroxyethyl] -4-[(1R) -1-benzyloxycarbonylamino-3-diazo-3-paranitrobenzyloxycarbonyl-
2-Oxopropyl] -azetidin-2-one (14) The compound (13) obtained in Example 11 was reacted in the same manner as in Example 4 to obtain the target compound (14) in a yield of 95.0%.

IR (CHCl ₃ ) cm ^-1 : 2160,1760,1720,1650. NMR (CDCl ₃ ) δppm: 1.29 (3H, d, J = 5.8Hz), 2.85 (1H, b
r), 3.13 (1H, dd, J = 4.5Hz), 4.03-4.30 (2H, m), 5.08
(2H, s), 5.36 (2H, s), 5.62 (1H, dd, J = 9.0,2.8Hz),
6.10 (1H, d, J = 9.0Hz), 6.13 (1H, bs), 7.33 (5H, s),
7.53 (2H, d, J = 9.0Hz), 8.26 (2H, d, J = 9.0Hz). Example 13: (1R, 5S, 6S) -2-Oxo-6-[(1R) -1-hydroxyethyl] -1-benzyloxycarbonylaminocarbapenamu-3-carboxylic acid paranitrobenzyl ester (15) The compound (14) obtained in Example 12 was reacted in the same manner as in Example 5 to obtain the compound (15) in a yield of 50%.

IR (CHCl ₃ ) cm ^-1 : 1750, 1705. NMR (CDCl ₃ ) δppm: 1.13 (3H, d, J = 6.0Hz), 3.15 (1H, d
d, J = 8.0,2.5Hz), 4.10 (3H, m), 4.90 (1H, s), 5.20 (5
H, m), 7.32 (5H, s), 7.63 (2H, d, J = 9Hz), 8.30 (2H, d,
J = 9Hz).

Claims (1)

[Claims] 1. The following formula IV: (In the formula, R ¹ represents a lower alkyl group or an amino group mono- or di-substituted with an amino-protecting group, R ⁴ represents a hydroxyl-protecting group, and R ⁵ represents a hydrogen atom, a lower alkyl group or an aryl group. Or an aralkyl group) in the presence of imidazole is represented by the formula: (R ³ OOCCH ₂ CO ₂ ) ₂ Mg (wherein R ³ represents a carboxyl protecting group) The following formula V characterized by reacting with a magnesium malonate compound: (Wherein R ¹ , R ³ and R ⁴ are the same as defined above).