JP2970928B2 - Bicyclic γ-lactam derivative - Google Patents

Description

The present invention relates to a novel bicyclic γ-lactam derivative, and more specifically to the following formula (1) In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ²
Represents a hydrogen atom or an anionic charge, and R ³ represents an aminoethyl group, a 4-pyrazolinidyl group or 6,7-dihydro-5.
H-pyrazolo [1,2-a] [1,2,4] triazolium-6
-Substituted thio-7- (1-hydroxyethyl) -8-oxo-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid derivative represented by the formula: An acceptable salt, and the following formula (IIa) useful as a synthetic intermediate thereof: In the formula, R ¹ represents a hydrogen atom or a lower alkyl group;
²¹ represents a carboxyl protecting group, R ⁴ represents a hydrogen atom or a hydroxyl protecting group, R ⁵ represents an acyl group, and represented by (5S, 7S) -3-acyloxy-7-[(1
R) -1-Hydroxyethyl] -8-oxo-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid derivative.

Various searches for antibiotics aimed at antibacterial activity have been studied so far, and a large number of penicillin-based or cephem-based antibiotics having a penicillin skeleton or a cefm skeleton have been provided, and as practical antibiotics, Has been offered for use. Recently, many carbapenem antibiotics have been proposed as compounds following cef antibiotics. The imipenem (INN) represented by is already used as a practical antibacterial agent. These penicillin compounds, cefm compounds and carbapenem compounds have the following formula: Having a β-lactam skeleton represented by
Lactam antibiotics are classified.

On the other hand, in addition to studying the development of the above β-lactam compound,
Further, an antibiotic having a skeleton different from the β-lactam skeleton has been studied. For example, In the formula, X represents —CN or —SO ₃ CH ₃ , and a bicyclopyrazolidione compound represented by the following formula has been proposed, and it has been reported that this compound also has some antibacterial activity (No. 27). ICAAC, September 1987, New Y
ork).

This bicyclopyrazolidione compound has the following formula as a basic skeleton: Can be determined as a derivative of a γ-lactam compound having a structural portion represented by the formula, and it is expected that the γ-lactam compound also has excellent antibacterial activity.

Under such circumstances, the present inventors have previously shown the following formula showing excellent antibacterial activity In the formula, R ¹ represents a hydrogen atom, an alkali metal or a carboxyl protecting group, and R ² represents an unsubstituted or substituted alkyl group or a heterocyclic group. A novel γ-lactam compound represented by See JP-A-1-211589).

The present inventors have further continued synthetic studies on γ-lactam compounds, and as a result, have now found that the 3-substituted thio-7- (1-hydroxyethyl) -8-oxo-1-azabicyclo represented by the above formula (I) is used. [3.3.0] oct-2-ene-
The present invention was completed by newly preparing a 2-carboxylic acid derivative.

 Hereinafter, the present invention will be described in more detail.

As used herein, the term "lower" means that the group or compound to which this term is attached has 1 to 7, preferably 1 to 4, carbon atoms.

"Lower alkyl group" may be linear or branched, for example, methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-
Hexyl, isohexyl and the like are included.

Examples of the “alkali metal” include sodium and potassium. On the other hand, when R ³ in the formula (I) is 6.
When representing a 7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl group, R ² can be an anionic charge paired with the group. As a result, an inner salt can be formed as a whole compound.

Further, the “carboxyl protecting group” can be any carboxyl protecting group known in the field of antibiotic compounds, and specific examples include ester residues. Such ester residues include, for example, methyl, ethyl, n-propyl, isopropyl, n-, iso
Lower alkyl groups such as-, sec- or tert-butyl, n-hexyl, etc .; benzyl, p-nitrobenzyl, o-
Aralkyl groups such as nitrobenzyl and p-methoxybenzyl; lower aliphatic acyloxymethyl groups such as acetoxymethyl, propionyloxymethyl, n-, iso- or tert-butyryloxymethyl and pivaloyloxymethyl; : In particular, aralkyl groups such as benzyl, p-nitrobenzyl, o-nitrobenzyl and p-methoxybenzyl are preferred.

Further, the term "hydroxyl protecting group" means any protecting group generally known as a serine hydroxyl protecting group in peptide chemistry, and examples thereof include aliphatic groups such as acetyl, benzoyl, methanesulfonyl, and p-toluenesulfonyl. Or an aromatic acyl group; an aralkyl group such as benzyl and triphenylmethyl; a substituted or unsubstituted benzyloxycarbonyl group such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, and p-methoxybenzyloxycarbonyl; trimethylsilyl, tert-butyldimethyl Examples thereof include silyl, a tert-butyldiphenylsilyl group, and a silyl group of a phenylisopropyldimethylsilyl group. Among them, silyl groups such as trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and phenylisopropyldimethylsilyl are preferred.

The `` acyl group '' used in the present specification includes not only the remaining atomic groups except OH from the carboxyl group of the organic carboxylic acid, but also broadly includes an acyl group derived from an organic sulfonic acid or an organic phosphoric acid. For example, lower alkanoyl groups such as acetyl, propionyl and butyryl; (halo) lower alkylsulfonyl groups such as methanesulfonyl and trifluoromethanesulfonyl groups; benzenesulfonyl;
a substituted or unsubstituted arylsulfonyl group such as p-nitrobenzenesulfonyl, p-bromobenzenesulfonyl, toluenesulfonyl, and 2,4-6-triisopropylbenzenesulfonyl; a diphenylphosphoryl group;

Representative examples of the compound represented by the formula (I) provided by the present invention are as follows.

(1) 3-aminoethylthio-7- (1-hydroxyethyl) -8-oxo-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid; (2) 3-aminoethylthio- 7- (1-hydroxyethyl) -4-methyl-8-oxo-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid, (3) 7- (1-hydroxyethyl) -8- Oxo-3
-(4-pyrazolinidyl) thio-1-azabicyclo [3.
3.0] Oct-2-ene-2-carboxylic acid, (4) 7- (1-hydroxyethyl) -4-methyl-8
-Oxo-3- (4-pyrazolinidyl) thio-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid, (5) 3-[(6,7-dihydro-5H-pyrazolo [1, 2−
a] [1,2,4] triazolium-6-yl) thio] -7
-(1-Hydroxyethyl) -1-azabicyclo [3.3.
0] oct-2-ene-2-carboxylate, (6) 3-[(6,7-dihydro-5H-pyrazolo [1,2-
a] [1,2,4] triazolium-6-yl) thio] -7
-(1-Hydroxyethyl) -4-methyl-1-azabicyclo [3.3.0] oct-2-en-2-carboxylate.

Further, the compound represented by the formula (I) of the present invention can exist in the form of a pharmacologically acceptable salt, and examples of such a salt include alkali metal salts such as sodium salt and potassium salt; Salts; alkaline earth metal salts such as magnesium salts; ammonium salts; basic amino acid bases such as arginine salts, ornithine salts, lysine salts; amine acids such as diethanolamine salts, triethanolamine salts, ethylamine salts, diethylamine salts, trimethylamine salts Is mentioned. Among them, sodium salts and potassium salts are preferred.

The compound of the present invention represented by the formula (I) is, for example,
It can be produced by the steps shown in the following reaction formula A.

In the above reaction formula, R ⁶ represents a lower alkyl group, R ^a represents an acyl ^{group, R 1, R 2, R} 21, R 3, R 4, and R ⁵ have the same meanings as defined above.

Hereinafter, each step in the above reaction formula A will be further described.

Step (a) comprises cyclizing the 2- (1-hydroxyethyl) -3-formylpropamide derivative of formula (III) and then acylating the 2- (1-hydroxyethyl) -3-formylpropamide derivative of formula (IV).
Producing a pyrrolidinone derivative.

The ring closure reaction of the compound represented by the formula (III) can be carried out by reacting a base in an inert organic solvent, for example, an alcohol such as methanol or ethanol. Examples of the base used in this reaction include alkali metals such as lithium, sodium and potassium; alkaline earth metals such as calcium; alkali metal hydrides such as sodium hydride: alkaline earth metals such as calcium hydride Hydrides; alkali metal hydroxides such as sodium hydride and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; Alkali metal alkoxides such as methoxide, sodium ethoxide, and potassium tert-butoxide; alkali metal salts of alkanoic acids such as sodium acetate; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate; Butylamine, N, N-diisopropyl -N- tri (lower) alkylamine ethylamine; such as pyridine, picoline, lutidine, N, N-
Pyridine compounds such as N, N-di (lower) alkylaminopyridine such as dimethylpyridine; quinolines;
N-lower alkali morpholines such as -methylmorpholine;
For example, a base or an inorganic base such as N, N-di (lower) alkylbenzylamine such as N, N-dimethylbenzylamine can be mentioned, and an alkali metal such as sodium hydroxide and potassium hydroxide is preferable. A hydroxide can be used.

The base may be used in a catalytic amount. For example, when potassium hydroxide is used as the base, the compound 1 of the formula (III)
It can be used in a proportion of about 0. 2 mol to about 2.0 mol per mol.

The reaction temperature is not strictly limited and can vary widely depending on the starting material of the formula (III) used, etc., but is generally about -78 ° C to about room temperature, preferably about -20 ° C. It can be performed at a relatively low temperature of about 10 ° C.

This ring closure reaction can be generally completed in about 10 minutes to about 2 hours. The 2-pyrrolidine derivative obtained by this reaction can be isolated and purified by neutralizing the reaction solution and then treating it by chromatography or the like.

The 2-pyrrolidinone derivative obtained as described above is
In the following formulas R ^a OH type, R ^a is as defined above, in indicated are organic acids such as acetic acid, propionic acid, can be applied, preferably by stirring in acetic acid, of formula (IV) 3- It can be a (1-hydroxyethyl) -5-acyloxy-2-pyrrolidinone derivative.

The temperature of the above reaction is not strictly limited,
Generally, about 0 ° C to 50 ° C, preferably 20 ° C to 30 ° C.
It can be performed at room temperature of about ° C. This reaction can be generally carried out under such conditions for several hours to several days.

The 2-pyrrolidinone derivative of the formula (IV) obtained by this reaction is, for example, extracted by a conventional method. It can be separated and purified by chromatography or the like.

Step (b) comprises reacting the N-acyl-1,3-thiazolidine-2-thione derivative of formula (V) with tin (I
I) reacting with triflate to form an enolate,
Next, the compound of the formula (IV) is reacted with the compound of the formula (VI).
To produce a 2-pyrrolidinone derivative of

N-acyl-1,3-thiazolidine of the above formula (V)
The enolization reaction of a 2-thione derivative with tin (II) triflate is usually carried out in a solvent inert to the reaction, for example, ethers such as diethyl ether and tetrahydrofuran; hydrocarbons such as toluene, xylene and cyclohexane; and dichloromethane. It can be suitably carried out in halogenated hydrocarbons such as chloroform and the like, especially in tetrahydrofuran.

The reaction temperature is not strictly limited and can vary widely depending on the starting materials used, etc., but is generally about -100 ° C. to about room temperature, preferably about −78 ° C.
Relatively low temperatures from about 0 ° C to about 0 ° C are used.

The amount of tin (II) triflate used for the compound of formula (V) is not critical, but usually about 1 to about 2 moles of tin (II) triflate per mole of compound of formula (V), Preferably, it can be used at a ratio of 1 to 1.5 mol.

The above enolization reaction is carried out under the condition of a base, and usable bases include, for example, triethylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.
2] Tertiary amines such as octane, N-methylmorpholine, N-ethylpiperidine, pyridine and the like, among which N-ethylpiperidine is advantageously used. These bases are generally present in an amount of about 1.0 to about 3 per mole of compound of formula (V).
It can be used in a ratio of equivalents, preferably 1.0 to 2.0 equivalents.

The enolization reaction can generally be completed in about 5 minutes to about 4 hours, resulting in an enolate.

Subsequent to this enolization reaction, the compound of the formula (IV) can be reacted with the produced enolate as it is.

The amount of the alkylation reaction between the enolate and the compound of formula (IV) is generally from about -100 ° C to about room temperature, preferably about -7. Formula (V) used in the enolization reaction
About 0.5 to about 5 mol, preferably 0.5 to about 5 mol per mol of the compound
Suitably, it is used in a proportion of 2 mol.

Under such conditions, the reaction can be completed in about 5 minutes to about 5 hours, more usually about 5 minutes to about 2 hours.

Although the above enolization reaction and the above-mentioned alkylation reaction are not essential, they are preferably carried out under an inert atmosphere, for example, a nitrogen gas or argon gas atmosphere.

In addition, the substituent R ⁶ in the compound of the formula (V) used in this step (b) can be preferably an ethyl or isopropyl group.

Finally, the reaction product is treated with water. For example, after completion of the reaction, a weakly acidic to near-neutral phosphate buffer solution or an organic acid aqueous solution, preferably a citric acid aqueous solution is added, and the mixture is stirred to separate insolubles. Can be separated and purified by, for example, extraction, recrystallization, or chromatography.

Step (C) is a step of formula (VI) produced in step (b).
Is reacted with a magnesium malonate compound represented by the formula (R ²¹ OOCCH ₂ CO ₂ ) ₂ Mg in the presence of imidazole to obtain a compound of the formula (VII).

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., and acetonitrile is particularly preferably used.

The magnesium malonate compound and imidazole are generally used in approximately equimolar proportions with respect to the compound of formula (VI), and the reaction is carried out for about 1 hour to about 50 hours, preferably 20 hours.
It can be performed for about an hour.

As the magnesium malonate compound used in this step, for example, para-nitrobenzyl magnesium malonate, benzyl magnesium malonate, methyl magnesium malonate and the like can be mentioned. Among them, para-nitrobenzyl magnesium malonate is used. Is preferred.

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

When the substituent R ⁴ is a protecting group for a hydroxyl group in the compound of the formula (VII) obtained by the above reaction, if necessary, the protecting group for the hydroxyl group may be obtained by performing the following reaction after the above reaction. Can be detached.

The elimination reaction of the protecting group can be carried out under the conditions of the method for elimination of the protecting group known per se, for example, in a solvent such as methanol, ethanol, tetrahydrofuran, dioxane or the like, an acid such as hydrochloric acid, sulfuric acid or acetic acid. By stirring in the presence of for about 30 minutes to about 18 hours.

The reaction can be carried out at a temperature of about 0 ° C. to about 100 ° C., preferably about room temperature.

The 2-pyrrolidinone derivative of the formula (VII) obtained in the above steps can be separated and purified by, for example, extraction, recrystallization, chromatography and the like.

In the step (d), the compound represented by the formula (VII) obtained in the step (c) is treated with an azide compound in the same inert organic solvent as described in the step (c) in the presence of a base. To form a diazo compound of formula (VII).

Examples of the azide compound to be used include, for example, p-carboxybenzenesulfonyl azide, p-toluenesulfonyl azide, methanesulfonyl azide, dodecylbenzenesulfonyl azide and the like, and bases such as triethylamine, pyridine and diethylamine Bases.

The reaction can be carried out by adding p-toluenesulfonyl azide in acetonitrile, preferably in the presence of triethylamine, and treating at 0 to 100 ° C., preferably at room temperature for 1 to 50 hours. To obtain the diazo compound of the formula (VII).

The step (e) is a step of cyclizing the diazo compound of the formula (VIII) obtained in the step (d) to give a compound represented by the formula (IX). In an inert solvent such as benzene, toluene, tetrahydrofuran, cyclohexane, ethyl acetate, dichloromethane and the like, preferably in ethyl acetate, at 25 to 80 ° C.
1-5 hours at temperature, bis _{(acetylacetonato) Cu (II), CuSO 4} , Cu _{powder, Rh 2 (OCOCH 3) 4} , metal carboxylates such as rhodium octanoate or Rb (OCOCH _{3) 4} The treatment is carried out in the presence of a metal catalyst such as a cathode. On the other hand, as another method, the cyclization step or the compound of the formula (IX) is carried out in a solvent such as benzene, diethyl ether or the like at a temperature of 0 to 250 ° C. for 0.5 to 2 hours using a pyrex filter (wavelength: (Larger than 300 nm).

Next, in the step (f), the compound of the formula (IX) obtained in the step (e) is reacted with a reactive derivative of an acid represented by R ⁵ OH (for example, an acid anhydride, a halide, or the like) to obtain a compound of the formula The compound represented by (II) is obtained.

Examples of the reactive derivative of such an acid include, for example, acetic anhydride, acetyl chloride, propienyl chloride, p-toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4,6-triisopropylbenzenesulfonic anhydride. , methanesulfonic anhydride, trifluoromethanesulfonic anhydride, Jifuenirurin acid chloride, toluenesulfonyl chloride, etc. p- bromobenzenesulfonyl chloride and the like, in particular Jifuenirurin acid chloride (R ⁵ = diphenyl phosphoryl group) are preferred .

The reaction between the compound of the formula (IX) and the reactive derivative of the above acid can be carried out in the same manner as in a general acylation method.
For example, in an inert solvent such as methylene chloride, acetonitrile, and dimethylformamide in the presence of a base such as diisopropylethylamine, triethylamine, and 4-dimethylaminopyridine at a temperature of -20 to 40 ° C for about 30 minutes.
The treatment can be performed by treating the mixture for a period of from about minutes to about 24 hours.

Next, step (g) is performed according to the formula (II) obtained in step (f).
Formula R in ³¹ SH formula to the compound represented in, R ³¹ represents an aminoethyl group or 4-pyrazolidinyl group, which may, in indicated be an amino group contained in these groups are protected by an amino protecting group This is a step of reacting a mercapto reagent to obtain a compound represented by the formula (X).

As the mercapto reagent used in this step, those known per se are used, and 4-mercaptopyrazolidine is used, for example, in JP-A-2-67268 and JP-A-2-67269.
It can also be synthesized according to the method described in Japanese Patent Application Publication No.

The amino protecting group for the amino group in the mercapto reagent may be any protecting group known as a protecting group for an amino group in the field of peptide chemistry,
Preferably a saturated or unsaturated alkoxycarbonyl group such as ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl;
Substituted or unsubstituted benzyloxycarbonyl groups such as p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl and the like can be mentioned.

In this reaction, for example, a compound represented by the formula (II) is converted into an appropriate solvent such as tetrahydrofuran, dichloromethane, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, and hexamethylphosphoramide.
A temperature in the range of about -40 to about 25 ° C. in the presence of an approximately equimolar to about 1.5 molar excess of the mercapto reagent and preferably a base such as sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine. About
The reaction can be performed for 30 minutes to about 24 hours.

By the above reaction, the compound of the formula (X) can be obtained. In the compound, the carboxylic acid at the 2-position is protected by a carboxyl protecting group R ²¹ , and in some cases, the amino group at the 3-position side chain is Protected by an amino protecting group.
These protecting groups can then be removed in step (h) by a deprotecting group reaction known per se, such as solvolysis or hydrogenolysis. Typically, the compound of formula (X) is converted to tetrahydrofuran-water, including, for example, pH 7 morpholinopropanesulfonic acid-sodium hydroxide buffer, pH 7 phosphate buffer, dipotassium phosphate, sodium bicarbonate, and the like. Tetrahydrofuran-ethanol-water, dioxane-water, dioxane-ethanol-
In a mixed solvent such as water, n-butanol-water, etc.
The treatment is carried out at a temperature in the range of about 0 to about 50 ° C. for about 0.25 to about 4 hours using hydrogen at ４4 atm and in the presence of a hydrogenation catalyst such as platinum oxide, palladium-activated carbon, palladium hydroxide-activated carbon. It can be done by doing.

When R ⁴ of the compound of the formula (X) is a protecting group for a hydroxyl group, the compound is protected from the compound of the formula (X) in the same manner as in the method for removing the protecting group for a hydroxyl group described in the step (c). The group can also be eliminated.

Thus, R ² is a hydrogen atom or an alkali metal,
When R ³ is an aminoethyl group or a 4-pyrazolidinyl group, a compound of the formula (I) of the present invention can be obtained.

On the other hand, when R ³ is 6,7-dihydro-5H-pyrazolo [1,2-a]
A compound of formula (I) of the present invention wherein the compound is a [1,2,4] triazolium-6-yl group and R ² is an anionic charge, In the formula, R ¹ has the same meaning as described above. A compound represented by the formula: wherein R ³ produced as described above is 4
A compound of formula (I) of the present invention which is a pyrazolinidyl group,
That is, In the formula, R ¹ and R ² have the same meaning as described above, and can be produced by reacting a compound represented by the following formula with a formimidate derivative.

The above reaction is carried out by adding a compound of formula (I-2) to a reaction medium adjusted to about pH 8.5 with a weakly basic condition (for example, a pH 7.0 phosphate buffer and a 1N sodium hydroxide solution). During)
The reaction can be carried out by reacting with a formimidate derivative such as ethyl formimidate hydrochloride, methyl formimidate hydrochloride or benzyl formimidate hydrochloride.

In addition, an excellent feature of the above-mentioned method for producing the compound of the formula (I) of the present invention is that the starting compound of the formula (III) of the reaction formula A and the thiazolidine derivative of the formula (V) are optically active. When the compound is used, it is possible to obtain the target compound stereoselectively. For example, as a starting compound of the formula (III), In the formula, R ⁴ has the same meaning as described above. Using a (2S) -2-[(1R) -1-hydroxyethyl] -3-formylpropamide derivative represented by the following formula:
As a compound of the following formula In the formula, R ¹ and R ⁶ having the same meaning as described above, If the method of the above-mentioned reaction formula A is carried out using a compound in which the 4-position of the thiazolidine ring represented by Formula (Ia) In the formula, R ¹ , R ² and R ³ have the same meaning as described above, and a compound of the present invention having a specific configuration represented by the following formula can be obtained (see Example 3 described later). If this is shown by a reaction formula, it will be as follows.

In the above reaction ^{formula, R 1, R 2, R} 21, R 3, R 31, R 4, R 5, R 6 and R ^a are as defined above.

Specific examples of the compound of the formula (I) of the present invention having the configuration shown in the above formula (Ia) are as follows.

(5S, 7S) -3-aminoethylthio-7-[(1R)-
Hydroxyethyl] -8-oxo-1-azabicyclo [3.3.0] oct-2-en-2-carboxylic acid, (4R, 5S, 7S) -3-aminoethylthio-7-[(1R)
-Hydroxyethyl] -4-methyl-8-oxo-1-
Azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid, (5S, 7S) -7-[(1R) -hydroxyethyl] -8
-Oxo-3- (4-pyrazolidinyl) thio-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid, (4R, 5S, 7S) -7-[(1R) -hydroxyethyl]-
4-methyl-8-oxo-3- (4-pyrazolidinyl)
Thio-1-azabicyclo [3.3.0] oct-2-ene-
2-carboxylic acid, (5S, 7S) -3-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1,2,4] triazolium-6-yl) thio] -7- [ (1R) -hydroxyethyl] -1-azahicyclo [3.3.0] oct-2-ene-2-carboxylate, (4R, 5S, 7S) -3-[(6,7-dihydro-5H-pyrazolo [1 , 2-a] [1,2,4] Triazolium-6-yl) thio] -7-[(1R) -hydroxyethyl] -4-methyl-1-azabicyclo [3.3.0] oct-2-ene- 2-
Carboxylate.

The compound of the formula (I) of the present invention prepared as described above can be converted into a pharmaceutically acceptable salt as described above by a method known per se.

The bicyclic γ-lactam compound of the present invention represented by the formula (I) is a novel compound that has not been published in a conventional literature, and is expected to have high antibacterial activity.

In the reaction formula A, the 2- (1-hydroxyethyl) -3-formylpropamide derivative of the formula (III) used as a starting material can be prepared by a known method (I) according to the method shown in the following reaction formula B. )).

In the above reaction formula, R ⁷ represents a lower alkyl group, and R ⁴ has the same meaning as described above.

 Hereinafter, each step of the above reaction formula B will be described.

Step (i) comprises hydrolyzing γ-butyrolactone of formula (1) to produce ethyl 4-hydroxybutyrate of formula (2).

The reaction can be carried out by adding hydrochloric acid or sulfuric acid to an ethanol solution of the compound of the formula (1) and stirring. The hydrochloric acid or sulfuric acid used may be a catalytic amount, and the reaction can be carried out by stirring at about room temperature for about 1 hour to about 24 hours. The reaction product can be obtained by the usual purification means,
For example, it can be separated and purified by extraction or chromatography.

Step (j) comprises oxidizing the compound of formula (2) obtained in step (i) to produce 3-carboethoxypropanal of formula (3).

The reaction can be carried out using an oxidizing agent, for example, pyridinium chlorochromate, pyridinium dichromate, pyridine sulphate trioxide in an inert organic solvent such as dichloromethane or chloroform, or a so-called DCC-DMSO method known per se. Or Swern oxidation (using DMSO-oxalyl chloride-triethylamine)
Can be done by

When the oxidizing agent is used, the amount of the oxidizing agent used varies depending on the type of the oxidizing agent, but generally, about 1 mol to about 1.5 mol can be used per 1 mol of the compound of the formula (2).

The reaction temperature is not particularly limited, and the reaction can be carried out at room temperature to about 60 ° C., and the compound of formula (3) can be obtained in about 10 minutes to about 5 hours.

Step (k) is a step of protecting the aldehyde group of the compound of the formula (3) obtained in the above step (j).

The protection of the aldehyde group is carried out by a commonly used method. For example, the protection can be carried out by reacting ethylenedithiol in the above-mentioned inert organic solvent in the presence of an acid.
Examples of the acid that can be used include boron trifluoride, p-toluenesulfonic acid, and the like.

The reaction can be carried out at a relatively low temperature of about -20 ° C to room temperature for about 1 hour to about 12 hours.

3- (1,3-) of the formula (4) obtained by the above reaction
Ethyl dithiolan-2-yl) propionate can be separated and purified by usual purification means, for example, extraction or chromatography.

In the step (l), the compound of the formula (4) obtained in the step (k) is reacted with a thiazolidine-2-thione derivative of the formula (5) to form a 4-alkyl-substituted-3- of the formula (6). [3
-(1,3-dithiolan-2-yl) propionyl] -4
This is a step of obtaining an isopropyl-1,3-thiazolidine-2-thione derivative.

In this step, after the compound of formula (4) is hydrolyzed to a carboxylic acid, the resulting 3- (1,3-dithiolan-2-yl) propionic acid is substituted with 4-alkyl-substituted-1,3-thiazolidine-. The reaction is performed by reacting a 2-thione derivative.

In the hydrolysis reaction of the compound of the formula (4), the compound of the formula (4) is added to a base, for example, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in an alcohol solvent such as methanol or ethanol; The reaction can be performed by reacting an alkali metal carbonate such as potassium, or an alkali metal bicarbonate such as sodium hydrogen carbonate or potassium hydrogen carbonate.

The reaction can be carried out at about room temperature for about 30 minutes to about 2 hours. Then, the resulting reaction solution is neutralized in a conventional manner to give 3- (1,3-dithiolan-2-yl).
Il) Propionic acid can be obtained.

3- (1,3-dithiolan-2-) obtained by the above method
Il) Propionic acid has the following formula In the formula, R ⁷ represents a lower alkyl group.

The compound of formula (6) can be obtained by reacting a 4-alkyl 1,3-thiazolidine-2-thione derivative represented by

The reaction is carried out by reacting 3- (1,3-diothylan-2-yl) propionic acid with carboxylic acid activating reagent 3 and thiazolidine-2-thione of the formula (5) in an inert solvent such as chloroform or dichloromethane in the presence of a base. It can be carried out by adding the derivative and stirring.

Examples of the base used in this reaction include dimethylaminopyridine, pyridine, quinoline, lutidine, triethylamine, sodium hydride, and the like. It is preferably in the range of about 0.01 mol to about 0.1 mol with respect to 1 mol of certain 3- (1,3-diothylan-2-yl) propionic acid.

Further, as the carboxylic acid activating reagent, hydrochloric acid 1-
Examples thereof include ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, ethyl chlorocarbonate, and thionyl chloride.

The reaction is not particularly limited, but is usually performed at about 0 ° C. to about
40 ° C, preferably at about room temperature for about 1 hour to about 24 hours
Time can be done.

The compound of formula (6) can be isolated by separating and purifying the reaction product by a usual production means, for example, extraction or chromatography.

The thiazolidine of formula (5) used in this reaction
The 2-thione derivative can be prepared by a method known per se, for example, 2-
It can be easily obtained by reacting an amino alcohol with carbon disulfide in the presence of a base (Japanese Patent Laid-open No. Sho 62-62).
No. 42964). The lower alkyl group for the substituent R ⁷ can preferably be ethyl, isopropyl and the like.

In the step (m), the compound of the formula (6) obtained in the above step (l) is alkylated to give 3- [3-hydroxy-2-((1,3-dithiolan-2-yl) of the formula (7). Methyl) butanoyl] -4-alkyl-1,3-thiazolidine 2-thione derivative.

The reaction is basically performed in the same manner as in the reaction of the step (b) described in the reaction formula A. Specifically, a compound of formula (7) can be obtained by reacting a compound of formula (6) with tin (II) triflate in the presence of a base to form an enolate, and then reacting this with acetaldehyde. it can.

The reaction conditions can be arbitrarily selected from the conditions described in the step (b) of the reaction formula A. In this reaction, dichloromethane is particularly preferable as the solvent, and N-ethylpiperidine is used as the base. Is particularly preferably used.

The reaction product finally obtained is mixed with water, for example, a phosphate buffer, stirred to separate insolubles, and then separated and purified by extraction, recrystallization, chromatography, or the like to obtain the compound of the formula (7). Can be isolated.

Step (n) is a step of protecting the hydroxyl group of the compound of formula (7) obtained in the above step (m) to give a compound of formula (8).

The protection of the hydroxyl group of the compound of the formula (7) can be carried out by a method known per se, for example, by reacting t-butyldimethylchlorosilane in a solvent such as dichloromethane or chloroform in the presence of a base. Can do it.

The reaction is preferably carried out in an atmosphere of an inert gas such as a nitrogen gas stream.
C. for about 1 hour to about 24 hours. The resulting compound of the formula (8) can be isolated and purified by conventional purification means, for example, extraction or chromatography.

In the step (o), the compound of the formula (8) obtained in the step (n) is reacted with ammonia to form a hydroxyl-protected 3-hydroxy-2-[(1,3-dithiolane of the formula (9). -2-yl) -methyl] butanamide derivative.

The reaction can be carried out by reacting the compound of formula (8) with an aqueous ammonia solution in an inert solvent such as chloroform or dichloromethane. The aqueous ammonia solution used in the present reaction preferably has a concentration of about 25% to about 30% by weight, and the amount of the aqueous solution is about 1 mol to about 5 mol per 1 mol of the compound of the formula (8) in terms of ammonia. It is preferred that

The reaction can be carried out at about room temperature for about 30 minutes to about 4 hours. The compound of formula (9) can be obtained by subjecting the reaction product to separation and purification such as extraction, chromatography and the like, which are usually performed.

In the step (p), the compound of the formula (9) obtained in the above step (o) is converted to 2- (1-hydroxyethyl) of the formula (III).
This is a step of obtaining a 3-formylpropamide derivative.

The reaction decomposes the thioacetal moiety of the compound of the formula (9) to lead to an aldehyde. Specifically, the reaction can be carried out under the following conditions independently developed by the present inventors.

That is, first, thallium nitrate is added to an alcohol solution of the compound of the formula (9) under an anhydrous condition and reacted to obtain a diethyl acetal compound. In this case, the amount of thallium nitrate used is generally preferably in the range of about 1 mol to about 2 mol per 1 mol of the compound of the formula (9). The reaction temperature is not particularly limited, but may be about 0 ° C. to about 40 ° C., preferably about room temperature, and the reaction can be carried out for about 10 minutes to about 1 hour.

Next, after reacting titanium tetrachloride with the diethyl acetal compound obtained in the above reaction in an inert solvent such as chloroform or dichloromethane, water is added to the reaction solution to obtain the desired compound of formula (III). Can be.

The amount of titanium tetrachloride used can be generally in the range of about 1 mol to about 2 mol per 1 mol of the diethyl acetal compound which is the starting material for the reaction. The reaction temperature can be relatively low, such as from about -100 ° C to about -40 ° C, preferably about -78 ° C. Further, the reaction is not limited to Japanese Patent Application Laid-Open (JP-A) No. 1, but the reaction is preferably carried out in a stream of an inert gas such as nitrogen or argon. The reaction can be carried out for about 5 minutes to about 1 hour, after which the compound of formula (III) can be obtained by adding water to the reaction mixture. The water added to the reaction mixture is usually preferably added as a buffer having a pH around neutrality, for example, a phosphate buffer.

The compound of the formula (III) can be isolated from the reaction product by applying ordinary purification means such as extraction and chromatography.

The compound of the formula (III) obtained by the above method is in a racemic form, but if an optically active substance is used as the thiazolidine-2-thione derivative of the formula (5) used in the step (l), the optically active formula The compound of (III) can also be synthesized.

For example, a thiazolidine-2-thione derivative represented by the following formula: In the formula, R ⁷ has the same meaning as described above.
When the method of the above is carried out, the finally obtained compound (III) has the following formula In the formula, R ⁴ has the same meaning as described above, and is a (2S) -2-[(1R) -1-hydroxyethyl] -3-formylpropamide derivative represented by the following formula (see Reference Examples below).

(4R) -4-alkyl-substituted thiazolidine of the formula (5a)
The 2-thione derivative can be synthesized by the method described in the above-mentioned JP-A-62-42964.

Hereinafter, the present invention will be described in more detail by reference examples and examples, but it goes without saying that the scope of the present invention is not limited by these examples.

In the following description, the following abbreviations are used.

PCC: pyridinium chlorochromate Et: ethyl WSC: 1-ethyl-3- (3-dimethylaminopropyl) -hydrochloride-carbodiimide Ac: acetyl PNB: p-nitrobenzyl Tos: p-toluenesulfonyl Ph: phenyl PNZ: p-nitrobenzyloxycarbonyl Reference example: (2S) -2-[(1R) -1-tert-butyldimethylsilyloxyethyl] Synthesis of -3-formylpropamide (1.) Ethyl 4-hydroxytributyrate (Compound 1) ^* A catalytic amount of sulfuric acid was added to a solution of 10 g of γ-butyrolactone in 150 ml of ethanol, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was neutralized with a 5% sodium hydrogen carbonate solution, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed successively with saturated ammonium chloride solution and brine, and dried over Na ₂ SO ₄ . did. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to obtain 11.3 g of compound (1) as a colorless oil.
(74%) obtained.

NMR (δ, CDCl ₃ ) 1.26 (3H, t) 1.8-2.1 (2H, m) 2.4
5 (2H, t) 3.7 (2H, q) 4.14 (2H, q) (2.) 3-Carboethoxypropanal (Compound 2) ^* To a solution of 1.2 g of the compound (1) in 30 ml of methylene chloride were added 2.9 g of pyridinium chlorochromate and 81 mg of sodium acetate, and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction, 100 ml of diethyl ether was added to the reaction solution, followed by florisil filtration. The liquid was distilled off under reduced pressure to obtain 1.1 g of the crude compound (2) as a colorless oil.
Obtained.

NMR (δ, CDCl ₃ ) 1.25 (3H, t) 2.5-2.9 (4H, m) 4.1
3 (2H, q) 9.78 (1H, s) (3.) Ethyl 3- (1,3-dithiolan-2-yl) propionate (Compound 3) ^* To a solution of 4.7 g of compound (2) in 90 ml of chloroform was added 3.65 ml of ethanedithiol, and the mixture was stirred at room temperature for 1 hour, and then BF ₃ .Et ₂
1.63 ml of O2 was added and the mixture was stirred overnight under ice cooling. After completion of the reaction, the mixture was neutralized with 1N sodium hydroxide solution, methylene chloride was added, and the mixture was washed with water and saturated saline in that order, and dried over Na ₂ SO ₄ .
The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to give 5.89 g of compound (3) as a colorless oil.
(79%).

NMR (δ, CDCl ₃ ) 1.26 (3H, t) 2.0-2.6 (4H, m) 3.2
0 (4H, s) 4.10 (2H, q) 4.52 (1H, t) (4.) 3- (1,3-dithiolan-2-yl) propionic acid (compound 4) ^* To a solution of 5.89 g of compound (3) in 80 ml of ethanol was added a 37 ml solution of 1 N sodium hydroxide, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was neutralized with 1N hydrochloric acid, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was acidified with 1N hydrochloric acid. ₂ SO ₄
And dried. The solvent was distilled off under reduced pressure to obtain 4.38 g (86%) of compound (4) as white crystals.

(5.) (4R) -3- (3- (1,3-dithiolan-2-yl) propionyl) -4-isopropyl-1,3-thiazolidine-2-thione (compound 5) To a solution of 4.38 g of compound (4) in 100 ml of methylene chloride (4R)
3.96 g of -isopropylthiazolidine-2-thione, 4.72 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) and 0.15 g of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature overnight. After the completion of the reaction, the reaction solution was sequentially washed with water and a saturated saline solution, and dried over Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to give compound (5) as a yellow oil in 7.
14 g (90%) were obtained.

IR 1685 cm ^-1 NMR (δ, CDCl ₃ ) 0.97 (3H, d) 1.06 (3H, d) 2.1-2.
5 (3H, m) 3.0-3.7 (8H, m) 4.62 (1H, t) 5.15 (1
H, t) (6.) (4R) -3-[(2R, 3R) -3-hydroxy-2
-((1,3-dithiolan-2-yl) methyl) butanoyl] -4-isopropyl-1,3-thiazolidine-2-thione (compound 6) To a solution of 2.945 g of tin triflate (Sn (OTf) ₂ ) in 10 ml of methylene chloride was added 1.07 l of N-ethylpiperidine and a solution of 1.134 g of compound (5) in 4 ml of methylene chloride, and the mixture was stirred at 0 ° C. in a nitrogen stream for 4 hours. An excess amount of a solution of acetaldehyde in 2 ml of methylene chloride was added, and the mixture was stirred for 1 hour under the same conditions. After the reaction was completed, 0.1N phosphate buffer was added, and the mixture was passed through celite.The solution was washed successively with water and a saturated saline solution.
And dried over ₂ SO _4. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to obtain 1.259 g (98%) of compound (6) as a yellow oil.

IR 3400 1670cm ^-1 NMR (δ, CDCl ₃ ) 1.00 (3H, d) 1.06 (3H, d) 1.24 (3
H, d) 1.6 (1H, brs) 1.9-2.6 (3H, m) 3.0-3.7
(6H, m) 4.2-5.2 (4H, m) (7.) (4R) -3-[(2R, 3R) -3-tert-butyldimethylsilyloxy-2-((1,3-dithiolane-2 -Yl) methyl) butanoyl] -4-isopropylthiazolidine-2-thione (compound 7) To a solution of 4.29 g of t-butyldimethylchlorosilane in 23 ml of methylene chloride was added 1.94 g of imidazole, and the mixture was cooled to 0 ° C in a nitrogen stream.
After stirring for 1 hour, a solution of 4.724 g of compound (6) in 14 ml of methylene chloride was added, and the mixture was stirred overnight under the same conditions. After the reaction,
The reaction solution was washed sequentially with water and saturated saline, and dried over Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to give compound (7) as a yellow oil (5.74).
g (93%).

IR 1690cm ^-1 NMR (δ, CDCl ₃ ) 0.02 (3H, s) 0.09 (3H, s) 0.88 (9
H, s) 0.98 (3H, d) 1.07 (3H, d) 1.9−2.6 (3H, d
m) 2.9-3.6 (6H, m) 4.2-5.2 (4H, m) (8.) (2R, 3R) -3-tert-butyldimethylsilyloxy-2-((1,3-dithiolan-2-yl) ) Methyl) butanamide (compound 8) To a methylene chloride solution of 5.84 g of the compound (7) was added 7.6 ml of 28% aqueous ammonia, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was neutralized with 10% citric acid, washed with saturated saline, and dried over Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to give compound (8).
Was obtained as white crystals (3.43 g, 84%).

IR 3300, 1660 cm ^-1 NMR (δ, CDCl ₃ ) 0.09 (3H, s) 0.11 (3H, s) 0.90 (9
H, s) 1.12 (3H, d) 1.5-2.5 (3H, m) 3.20 (4H,
s) 3.8-3.9 (1H, m) 4.5-4.6 (1H, m) (9.) (2S) -2-((1R) -1-tert-butyldimethylsilyloxyethyl) -4,4-diethoxy Butanamide (Compound 9) To a solution of 3.45 g of thallium nitrate in 20 ml of ethanol was added 5 g of MgSO ₄ and a solution of 1.3 g of compound (8) in 70 ml of ethanol.
Stirred for 20 minutes. After the completion of the reaction, the reaction solution was saturated with aqueous sodium bicarbonate 120m.
The solution was extracted with ethyl acetate, washed with saturated saline, and dried over Na ₂ SO ₄ . The solvent is distilled off under reduced pressure,
The obtained residue was purified by silica gel chromatography to obtain 0.84 g (65%) of compound (9) as a colorless oil.

IR 3500, 1680 cm ^-1 NMR (δ, CDCl ₃ ) 0.13 (3H, s) 0.14 (3H, s) 0.94 (9
H, s) 1.1-1.3 (9H, m) 1.5-2.6 (3H, m) 3.4-3.
7 (4H, m) 3.9-4.1 (1H, m) 4.6-4.7 (1H, m) (10.) (2S) -2-((1R) -1-tert-butyldimethylsilyloxyethyl) -3- Formylpropamide (Compound 10) 0.46 ml of titanium tetrachloride was added to a solution of 0.84 g of compound (9) in 38 ml of methylene chloride, and the mixture was stirred at -78 ° C for 20 minutes in a nitrogen stream. After the reaction is completed, the reaction solution is phosphate buffered solution (pH 7.4) 320 ml
Poured into the mixture, extracted with methylene chloride, washed with saturated saline, and dried over Na ₂ SO ₄ . The solvent was distilled off under reduced pressure to obtain 0.64 g (98%) of a crude compound (10) as a colorless oil.

IR 3450, 3350, 1725, 1670 cm ^-1 NMR (δ, CDCl ₃ ) 0.13 (3H, s) 0.15 (3H, s) 0.93 (9
H, s) 1.18 (3H, d) 2.3-3.4 (3H, m) 3.9-4.1 (1
H, m) 9.64 (1H, s) Example 1: (3S) -3-((1R) -1-tert-butyldimethylsilyloxyethyl) -5-ethoxy-2-pyrrolidinone (Compound 11) To a solution of 0.64 g of the compound (10) in 36 ml of ethanol was added a 14.8 ml solution of 1% potassium hydroxide-ethanol, and the mixture was stirred at 0 ° C. for 30 minutes.
The mixture was stirred for 10 minutes under the same conditions. After completion of the reaction, the mixture was neutralized with 1% potassium hydroxide-ethanol solution, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to obtain 0.48 g of compound (11) as a pale yellow oil ( 68%).

IR 3200, 1710 cm ^-1 NMR (δ, CDCl ₃ ) 0.05 (3H, s) 0.07 (3H, s) 0.83 (9
H, s) 1.15 (3H, s) 1.2 (3H, t) 1.9−3.6 (5H, m)
4.2-4.9 (2H, m) Example 2: (3S) -3-((1R) -1-tert-butyldimethylsilyloxyethyl) -5-acetoxy-2-pyrrolidinone (Compound 12) A solution of 435 mg of compound (11) in 20 ml of acetic acid was applied under a slight reduced pressure to 27-30.
Stirred at C for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure, and 422 g (92%) of crude compound (12) as a pale yellow oily substance.
Obtained.

IR 3250, 1720 cm ^-1 NMR (δ, CDCl ₃ ) 0.05 (3H, s) 0.07 (3H, s) 0.83 (9
H, s) 1.20 (3H, s) 2.1 (3H, s) 2.4−3.2 (4H, m)
4.3-4.5 (2H, m) Example 3: (3S, 5S) -3-((1R) -1-tert-butyldimethylsilyloxyethyl) -5-[(4S)-(1,3-
Thiazolidine-2-thion-3-yl) carbonylmethyl] pyrrolidin-2-one (compound 14) In a nitrogen stream, 585 mg of tin triflate was suspended in 3 ml of tetrahydrofuran, cooled to −40 to −50 ° C., 0.23 ml of N-ethylpiperidine and a solution of 220 g of compound (13) in 2 ml of tetrahydrofuran were added, and the mixture was added at the same temperature for 3.5 hours. Stirred. Thereafter, a solution of (12) 422 mg in tetrahydrofuran was added, and the mixture was stirred at 0 ° C. for 2 hours. A 10% aqueous citric acid solution and chloroform were added to the reaction solution, the mixture was filtered through celite, and the solution was washed with saturated saline and dried over Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 309 mg (64%) of compound (14) as a yellow oil.

IR 1690cm ^-1 NMR (δ, CDCl ₃ ) 0.05 (3H, s) 0.07 (3H, s) 0.83 (9
H, s) 0.9−1.2 (9H, m) 1.6−4.4 (10H, m) 5.0−
5.2 (1H, m) 6.0 (1H, s) Example 4: (3S, 5S) -3-((1R) -1-tert-butyldimethylsilyloxyethyl) -5- (3-p-nitrobenzyloxy Carbonyl-2-oxopropyl) pyrrolidin-2-one (Compound 15) To a solution of 300 mg of compound (14) in 7 ml of acetonitrile was added 115 mg of imidazole in a nitrogen stream, and after stirring at room temperature for 5.5 hours, 507 mg of MgCO ₂ (CH ₂ CO ₂ PNB) ₂ was added.
Stirred at 60 ° C. for 16 hours. After completion of the reaction, ethyl acetate was added to the reaction solution, and the mixture was washed with 1 N hydrochloric acid, 5% aqueous sodium bicarbonate and saturated brine in that order, and dried over Na ₂ SO ₄ . The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to obtain 226 mg (70%) of (15) as white crystals.

IR 1740, 1690 cm ^-1 NMR (δ, CDCl ₃ ) 0.04 (3H, s) 0.06 (3H, s) 0.85 (9
H, s) 1.15 (3H, d) 2.2−2.9 (5H, m) 3.55 (2H,
s) 3.9-4.1 (1H, m) 4.3-4.4 (1H, m) 7.5-8.2 (4
H, m) Example 5: (3S, 5S) -3-((1R) -1hydroxyethyl) -5- (3-p-nitrobenzyloxycarbonyl-2-oxopropyl) pyrrolidin-2-one (compound
16) To a solution of 327 mg of compound (15) in 2.6 mg of methanol was added a solution of 0.7 ml of concentrated hydrochloric acid-methanol, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the reaction solution was neutralized with 5% sodium bicarbonate solution, the solvent was distilled off under reduced pressure of the residue was added ethyl acetate, water, successively washed with saturated brine and dried over Na ₂ SO _4. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 202 mg (81%) of compound (16) as white crystals.

IR 3400, 1730, 1710, 1680 cm ^-1 NMR (δ, CDCl ₃ ) 1.20 (3H, d) 1.7-3.0 (6H, m) 3.5
7 (2H, S) 3.9-4.4 (2H, m) 5.28 (2H, s) 7.5-8.
3 (4H, m) Example 6: (3S, 5S) -3-((1R) -1hydroxyethyl) -5- (3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxopropyl) pyrrolidine -2-
ON (compound 17) To a solution of 191 mg of compound (16) in 2.5 acetonitrile was added p
-134 mg of toluenesulfonyl azide and 95 µ of triethylamine were added, followed by stirring at room temperature for 20 minutes. After the reaction,
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to give compound (17) as a pale yellow substance (170 mg, 83%)
Obtained.

IR 3350, 2150, 1710, 1690 cm ^-1 NMR (δ, CDCl ₃ ) 1.20 (3H, d) 1.7-3.3 (6H, m) 4.0
−4.2 (2H, m) 5.37 (2H, s) 6.59 (1H, s) 7.5−8.
3 (4H, m) Example 7: (3S, 5S) -1-aza-2,7-dioxo-3-
((1) -hydroxyethyl) -8-p-nitrobenzyloxycarbonyl-bicyclo [3.3.0] octane (compound 18) To a solution of compound (17) (160 mg) in ethyl acetate (1.8) was added rhodium (II) acetate (1.4 mg) and the mixture was stirred at 80 ° C. in a nitrogen stream at 150 ° C. for 15 minutes.
Stirred for minutes. The solvent was distilled off under reduced pressure, and the residue was purified on a silica gel column to give compound (18) as a pale yellow oil.
4 mg (90%) were obtained.

IR 3400, 1770, 1690 cm ^-1 NMR (δ, CDCl ₃ ) 1.32 (3H, d) 2.0-2.9 (6H, m) 4.2
−4.5 (2H, m) 4.86 (1H, s) 5.30 (2H, m) 7.5−8.
3 (4H, m) Example 8: (3S, 5S) -1-aza-2-oxo-3-((1
R) -1-Hydroxyethyl) -7-diphenylphosphoryloxy-8-p-nitrobenzyloxycarbonyl-bicyclo [3.3.0] oct-7-ene (compound 19) To a solution of 144 mg of compound (18) in 1.8 ml of acetonitrile were added 0.1 ml of diphenylphosphoric acid chloride and 0.09 ml of diisopropylethylamine under ice cooling, and the mixture was stirred for 2 hours in a nitrogen stream. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 176 mg (75%) of compound (19) as a yellow oil.

IR 3450, 1730, 1690 cm ^-1 NMR (δ, CDCl ₃ ) 1.3 (3H, d) 1.9-3.2 (6H, m) 4.1
−4.3 (1H, m) 4.5−4.3 (1H, m) 4.5−4.7 (1H, m)
5.33 (2H, m) 7.0-8.2 (14H, m) Example 9: (5S, 7S) -p-nitrobenzyl-3- (2-
p-nitrobenzyloxycarbonylaminoethyl) thio-7-((1R) -1-hydroxyethyl) -8-oxo-1-azabicyclo [3.3.0] oct-2-ene-2
-Carboxylic acid (compound 20) In a solution of 165 mg of compound (19) in 1.5 acetonitrile,
(20) 85 mg and diisopropylethylamine 0.06 were added under ice-cooling, and the mixture was stirred in a nitrogen stream for 2 hours. After the reaction,
The reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to obtain 137 mg of compound (21) as a yellow substance.
(82%).

IR 3400, 1690cm ^-1 NMR (δ, CDCl ₃ ) 1.3 (3H, d) 1.9-2.2 (2H, m) 2.4
−3.2 (7H, m) 3.4 (2H, d) 4.1−4.3 (1H, m) 4.4
−4.7 (1H, m) 5.2 (2H, s) 5.38 (2H, m) 7.6−8.3
(8H, m) Example 10: (5S, 7S) -3- (2-aminoethyl) thio-
7-((1R) -hydroxyethyl) -8-oxo-1-
Azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid (Compound 22) 130 mg of compound (21) in tetrahydrofuran-water (1: 1)
30 mg of 10% palladium carbon was added to the 2 ml mixture, and the mixture was stirred overnight at room temperature in a hydrogen stream (4 atm). After completion of the reaction, the reaction solution was passed through celite, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography and then lyophilized to give 14 mg (23%) of compound (22) as a white powder. Obtained.

NMR (δ, CDCl ₃ ) 1.25 (3H, d) 1.7−3.4 (7H, m) 3.6−
4.7 (4H, m) Example 11: (5S, 7S) -p-nitrobenzyl-3- [N,
N'-di (p-nitrobenzyloxycarbonyl) pyrazolidin-4-ylthio] -7-((1R) -1-hydroxyethyl) -8-oxo-1-azabicyclo [3.3.
0] Oct-2-ene-2-carboxylic acid (compound 24) To a solution of 200 mg of compound (19) in 2 ml of acetonitrile (23)
187 mg and diisopropylethylamine 0.07 ml were added under ice cooling, and the mixture was stirred in a nitrogen stream for 1.5 hours. After completion of the reaction, the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography to obtain 270 mg of compound (24) as a yellow substance.
(Quantitative) obtained.

IR 3450, 1720, 1700 cm ^-1 NMR (δ, CDCl ₃ ) 1.31 (3H, d) 1.9-2.2 (2H, m) 2.4
−3.0 (4H, m) 3.2−3.8 (2H, m) 3.9−4.7 (3H, m)
5.1-5.6 (7H, m) 7.4-8.3 (12H, m) Example 12: (5S, 7S) -3-[(6,7-dihydro-5H-pyrazolo [1,2-a] [1.2.4 ] Triazol-4-ium-6-yl) thio] -7-((1R) -1-hydroxyethyl) -8-oxo-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid ( Compound 26) To a mixture of 150 mg of compound (21) and 4 ml of tetrahydrofuran-0.1N phosphate buffer (1: 1) was added 10% palladium-carbon 30%.
The mixture was stirred in a hydrogen stream (4 atm) at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered through celite, and the aqueous layer was washed with ethyl acetate. Subsequently, 100 mg of (25) was added to the reaction solution under ice cooling, followed by stirring for 5 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography, and then freeze-dried to obtain 31 mg (48 mg) of compound (26) as a white powder.
%)Obtained.

NMR (δ, CDCl ₃ ) 1.24 (3H, d) 1.9-2.2 (1H, m) 2.4
−3.0 (4H, m) 4.1−4.2 (1H, m) 4.4−5.2 (6H, m)
9.0 (2H, s)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ identification code FI A61K 31/415 605 A61K 31/415 605 (58) Fields investigated (Int.Cl. ⁶ , DB name) C07D 487/04 A61K 31 / 40,31 / 415 CA (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. The following formula (1) In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ²
Represents a hydrogen atom or an anionic charge, and R ³ represents an aminoethyl group, a 4-pyrazolidinyl group or 6,7-dihydro-5
H-pyrazolo [1,2-a] [1,2,4] triazolium-6
-Substituted thio-7- (1-hydroxyethyl) -8-oxo-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid derivative represented by the formula: Acceptable salts. 2. The formula (Ia) Wherein R ¹ , R ² and R ³ have the meaning of claim 1 and are represented by the following formula: (5S, 7S) -3-substituted thio-7-[(1R) 1
The compound according to claim 1, which is -hydroxyethyl] -8-oxo-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid derivative and a pharmacologically acceptable salt thereof. 3. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom. 4. The compound according to claim 1, wherein R ¹ is a methyl group. 5. A compound represented by the following formula (IIa): In the formula, R ¹ represents a hydrogen atom or a lower alkyl group;
²¹ represents a carboxyl protecting group, R ⁴ represents a hydrogen atom or a hydroxyl protecting group, R ⁵ represents an acyl group, and represented by (5S, 7S) -3-acyloxy-7-[(1
R) -Hydroxyethyl] -8-oxo-1-azabicyclo [3.3.0] oct-2-ene-2-carboxylic acid derivative.