JP2002212183A - Method for producing carbapenem antimicrobial agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a carbapenem antimicrobial agent having a 1-alkylpyrrolidine structure, to obtain a 5-alkyl-2-thia-5- azabicyclo[2.2.1]heptan-3-one which is a useful synthetic intermediate therefor and its salt and to provide a method for producing the same. SOLUTION: This method for producing a carbapenem antimicrobial agent (4) represented by the formula [wherein, R1 denotes a 1-3C alkyl group; and R2 and R3 denote each independently hydrogen atom or the like] or its salt comprises using a compound (1) represented by the formula or its salt as one of starting materials.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a carbapenem antibacterial agent having a 1-alkylpyrrolidine structure having excellent antibacterial activity, and a useful synthetic intermediate thereof.
-Alkyl-2-thia-5-azabicyclo [2.2.
1] Heptan-3-one and a salt thereof, and a method for producing the same.

[0002]

2. Description of the Related Art Hitherto, various carbapenem antibacterial agents having a 1-alkylpyrrolidine structure having excellent antibacterial activity have been known. For example, JP-A-11-71277 discloses that
A carbapenem antibacterial having a 1-alkylpyrrolidine structure and a method for producing the same are described. However, the production method described in the publication discloses that the three partial structures in the carbapenem-based antibacterial agent, which is the production target compound, are bonded stepwise, whereas the 1-alkylpyrrolidine structure according to the present invention is used. The method for producing a carbapenem-based antibacterial agent having the following structure is different in that three partial structures are continuously bonded in one step by so-called one-pot synthesis.

Heterocycles, 41, 147 (1995)
) Describes a carbapenem antibacterial agent (meropenem) having a pyrrolidine structure having no substitution on the nitrogen atom and a method for producing the same. Starting materials for the production method described in the literature and the method for producing the carbapenem antibacterial agent having a 1-alkylpyrrolidine structure according to the present invention are both 2-thia-5-azabicyclo [2.2.1] heptane. They are common in that they are -3-one derivatives. But,
The starting material of the production method described in the literature has a p-nitrobenzyloxycarbonyl group which is a carbonyl protecting group on a nitrogen atom in its structure, and the nucleophilicity of the nitrogen atom is weakened. While a side reaction is prevented from occurring, the starting material of the production method according to the present invention has a structure in which a nitrogen atom has nucleophilicity in its structure and its chemical property is different. For this reason, there was a concern that side reactions and accompanying reduction in yield would occur. Furthermore, the synthesis example described in the literature is of a very small scale (an example in which 315 mg of the product was produced in a 69% yield from the starting material), and thus the carbapenem described in the literature is described. It was not clear whether the method for producing antibacterial agents can be applied to mass synthesis of carbapenem antibacterial agents having a 1-alkylpyrrolidine structure according to the present invention.

Further, 2-thia-5-azabicyclo [2.
2.1] Various methods for producing heptane-3-one derivatives are also known. For example, a compound in which the nitrogen atom of 2-thia-5-azabicyclo [2.2.1] heptan-3-one is protected with an acetyl group and a method for producing the same are described in J. Org. Chem.,
46, 4182 (1981), and Chem. Pharm. Bull., 20,
543 (1972). However, the method described in the literature is such that N, N'-
The use of dicyclohexylcarbodiimide, a condensing agent that is extremely difficult to perform post-treatment, is not suitable for mass synthesis.

[0005]

While carbapenem antibacterial agents have excellent antibacterial activity, their chemical structures are generally complicated. Therefore, with respect to the carbapenem-based antibacterial agent having a 1-alkylpyrrolidine structure according to the present invention, construction of a synthetic route which is more inexpensive, easy, safe and suitable for mass synthesis has been required.

The 5-alkyl-2-thia-5-azabicyclo [2.2.1] heptane-3-one according to the present invention is a carbapenem antibacterial having a 1-alkylpyrrolidine structure for achieving the above object. Although it is a very important intermediate compound in the synthetic route of the above, there has been a demand for a method that can produce the compound inexpensively, easily, safely, and in large quantities.

[0007]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have conducted various studies on the synthesis routes of carbapenem antibacterial agents having a 1-alkylpyrrolidine structure, and found that 5-alkyl-2-thiathiols. It has been found that the synthetic route according to the present invention using -5-azabicyclo [2.2.1] heptan-3-one and a salt thereof as a synthetic intermediate is an excellent synthetic route for solving the above problems. .

Further, the present inventors have proposed that 5-alkyl-2-
Thia-5-azabicyclo [2.2.1] heptane-3-
Various investigations have also been made on the production methods of ON and its salts. The method of intramolecular dehydration condensation of cis-2-carboxyl-4-mercapto-1-alkylpyrrolidine or a salt thereof in the presence of an acid anhydride solves the above problem. The present invention has been found to be an excellent synthetic route to carry out the present invention.

According to the present invention, the formula

[0010]

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Wherein R ¹ represents a C ₁ -C ₃ alkyl group. Or a salt thereof represented by the formula:

[0012]

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Wherein R ² and R ³ are each independently
It represents a hydrogen atom or an organic residue, or R ² and R ³ may form a ring together with the nitrogen atom to which they are attached. And a salt thereof, and a compound represented by the formula:

[0014]

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[In the formula, L represents a leaving group, and the hydroxyl group and the carboxyl group may be each independently protected. By reacting the compound (3) or a salt thereof represented by the formula

[0016]

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[Wherein, R ¹ , R ² and R ³ have the same meanings as described above, and the hydroxyl group and the carboxyl group may be each independently protected. A method for producing the carbapenem antibacterial agent (4) or a salt thereof represented by the formula:

Here, the "alkyl group" for R ¹ is
A linear or branched saturated hydrocarbon group, wherein the C ₁ -C ₃ alkyl group for R ¹ is a methyl, ethyl, propyl or isopropyl group, preferably a C ₁ -C ₂ alkyl group; And more preferably a methyl group.

The “organic residue” in R ² and R ³ is represented by the formula
A carbapenem antibacterial agent in which the nitrogen atom in the group represented by N (R ² ) (R ³ ) has nucleophilicity and has a structure represented by the formula —N (R ² ) (R ³ ) There is no particular limitation as long as (4) or a salt thereof has an excellent antibacterial action.
A hydrogen atom; a substituted or unsubstituted lower alkyl group,
A substituted or unsubstituted cycloalkyl group, a cycloalkylalkyl group, a cycloalkylalkenyl group or a cycloalkylalkynyl group; a substituted or unsubstituted aralkyl group, an aralkenyl group or an aralkynyl group; A substituted or unsubstituted heteroaralkyl group, a heteroaralkenyl group, a heteroaralkynyl group, a heterocyclyl group,
It may be a heterocyclylalkyl group, a heterocyclylalkenyl group or a heterocyclylalkynyl group. "Substituted or unsubstituted lower alkyl group, lower alkenyl group or lower alkynyl group" in R ² and R ^3, 1
Has up to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, 2-propenyl, 2-
Butenyl, ethynyl, 2-butynyl, 2-hydroxyethyl, 2-chloroethyl, 2-methoxyethyl, 3-pentenyl and 4-hexynyl groups. The “substituted or unsubstituted cycloalkyl group, cycloalkylalkyl group, cycloalkylalkenyl group or cycloalkylalkynyl group” in R ² and R ³ has 3 to 6 carbon atoms in the cycloalkyl ring. And having 1 to 6 carbon atoms in the alkyl, alkenyl or alkynyl moiety, for example, cyclopentyl, cyclohexyl,
2-cyclobutylethyl, 6-cyclohexylhexyl, 2- (4-methoxycyclohexyl) ethyl, 5-
(3-bromocyclopentyl) pentyl, 5-cyclopentyl-4-pentenyl and 6-cyclohexyl-3-
A hexynyl group. The “substituted or unsubstituted aralkyl group, aralkenyl group or aralkynyl group” in R ² and R ³ is a phenyl group substituted or unsubstituted with an aryl moiety, and has one or more alkenyl or alkynyl moieties. It has from 3 carbon atoms and includes, for example, benzyl, p-nitrobenzyl, p-chlorobenzyl, 2-phenylethyl, cinnamyl and 3-cyclopentyl-2-propynyl groups. “Substituted or unsubstituted heteroaralkyl group, heteroaralkenyl group, heteroaralkynyl group, heterocyclyl group, heterocyclylalkyl group, heterocyclylalkenyl group or heterocyclylalkynyl group” for R ² and R ³
Is 1 selected from the group consisting of oxygen, nitrogen and sulfur atoms
Having from 1 to 4 heteroatoms and 1 to 6 on the alkyl, alkenyl or alkynyl moiety linked to the heterocyclic moiety.
Carbon atoms, for example, 2-, 3- or 4-
Pyridyl lower alkyl, 2-, 4- or 5-pyrimidyl lower alkyl, 3- (2-pyridyl) -2-propenyl, 4- (3-pyridyl) -2-butynyl, N-methyl-2-, 3- or 4-piperidino, N-propyl-2- or 3-morpholino, N-methyl-2- or 3-thiomorpholino, N-ethyl-2-, 3- or 4-piperidino lower alkyl, N-propyl-2-
Or 3-morpholino lower alkyl, N-methyl-2
-Or 3-thiomorpholino lower alkyl, 6- (N
-Methyl-2-piperidino) -3-hexenyl and 6-
(N-methyl-2-piperidino) -3-hexynyl group.

[0020] "ring formed together with the nitrogen atom bonding R ² and R ^3" in R ² and R ³ has the formula -N (R ²⁾
A carbapenem-based antibacterial agent (4) having a nitrogen atom in the group represented by (R ³ ) having a nucleophilicity and having a structure represented by the formula —N (R ² ) (R ³ ); There is no particular limitation as long as the salt has an excellent antibacterial action.

[0021]

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[Wherein, n represents 0, 1 or 2;
Represents 0, 1 or 2;^aIs a hydrogen atom or C₁-C
_FourRepresents an alkyl group, and B represents phenylene or phenylene
Alkyl (the alkyl moiety is C₁-C_ThreeAlkyl
You. ), Cyclohexylene, cyclohexylenealkyl
(The alkyl moiety is C ₁-C_ThreeAlkyl. ) Or 1
C which may have from 3 to 3 substituents₁-C_FiveAlkylene group
｛The substituent is amino, hydroxyl, cyclohexylalkyl.
(The alkyl moiety is C₁-C_ThreeAlkyl. ), C
₁-C_FourIt is an alkyl, phenyl or benzyl group. ｝
And R^bIs a hydrogen atom or C₁-C_FourRepresents an alkyl group
Then R^cIs of the formula -C (= NH) R^dIn the basic formula represented by
R^dIs a hydrogen atom, C₁-C_FourAlkyl group or formula -NR^eR
^fA group represented by the formula:^eAnd R^fAre independent of each other,
Hydrogen atom or C₁-C_FourShows an alkyl group. ). ｝
Preferably, n is 0 or 1, and p is 0 or
Is 1 and R^aIs a hydrogen atom, a methyl or ethyl group
B is 1,4-phenylene, 1,4-cyclohexyl
Silenemethyl, methylene, methylmethylene (-CH (C
H_Three)-), Ethylene, trimethylene or 2-hydroxy
A cyclic group, R^bIs a hydrogen atom, methyl or
An ethyl group,^cBut formimidyl, acetoi
A midyl or amidino group, more preferably n is
0 or 1, p is 0, R^aIs a hydrogen atom or
Is a methyl group, B is methylene, methylmethylene
(-CH (CH_Three)-), Ethylene, trimethylene or
A 2-hydroxypropylene group, R^bIs a hydrogen atom
Or a methyl group;^cIs an amidino group, and
More preferably, n is 0 or 1 and p is 0
R^aIs a hydrogen atom, and B is methylene, methyl
Methylene (-CH (CH_Three)-) Or an ethylene group
R^bIs a hydrogen atom, and R^cIs an amidino group
You. R^TwoAnd R^ThreeReplaces with the nitrogen atom
It forms a heterocyclic ring which may be
Suitably, R^TwoAnd R^ThreeHas a substitution with a nitrogen atom
It forms a pyrrolidino group which may be substituted.

The "leaving group" in L is described, for example, in
As described in JP-A-11-71277, there is no particular limitation as long as the group is eliminated as a normal nucleophilic residue, for example,
Halogen atoms such as chlorine, bromine and iodine; trihalogenomethyloxy groups such as trichloromethyloxy; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy A halogeno lower alkane sulfonyloxy group; an arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy; or a diarylphosphoryloxy group such as diphenylphosphoryloxy. Is a diarylphosphoryloxy group, more preferably a diphenylphosphoryloxy group (O
-P (= O) (OPh) ₂ ).

The compound (1) has a tertiary amine and can form a salt with an acidic compound. The acidic compound includes, for example, inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; formic acid, acetic acid, trifluoroacetic acid, oxalic acid,
Organic carboxylic acids such as phthalic acid; or organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, preferably inorganic acids, and more preferably Is hydrochloric acid or sulfuric acid.

Since compound (2) is an amine compound, it can form a salt with an acidic compound. Examples of the acidic compound include inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; formic acid, acetic acid, trifluoroacetic acid, oxalic acid, and phthalic acid. Such organic carboxylic acids; or organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and are preferably inorganic acids.

The compound (3) has a carboxyl group and can form a salt with a basic substance. Such salts can be, for example, alkali metal salts such as sodium, potassium, lithium salts; alkaline earth metal salts such as calcium salts, magnesium salts; or inorganic salts such as ammonium salts; Preferably, it is a lithium salt, a sodium salt, a potassium salt or a magnesium salt.

When the carbapenem antibacterial agent (4) can form a salt with an acidic compound, such an acidic compound includes, for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, Inorganic acids such as sulfuric acid, nitric acid, phosphoric acid and carbonic acid; organic carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid and phthalic acid; or methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p -It can be an organic sulfonic acid such as toluenesulfonic acid, preferably an inorganic acid, more preferably hydrochloric acid, sulfuric acid or carbonic acid.

Further, the carbapenem antibacterial agent (4) has a carboxyl group and can form a salt with a basic substance. Such salts include, for example, alkali metal salts such as sodium, potassium, lithium salts;
Alkaline earth metal salts such as calcium and magnesium salts; or ammonium salts, preferably lithium, sodium, potassium or magnesium salts.

When the carboxyl group of the compound (3) is protected, the compound (2) or a salt thereof and the compound (3) are successively acted on the compound (1) or a salt thereof, and then the protected compound is reacted. The compound (4) or a salt thereof can be obtained by removing the group.

Further, the present invention provides a compound represented by the formula

[0031]

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[Wherein R ¹ represents a C ₁ -C ₃ alkyl group. Or a salt thereof represented by the formula:

[0033]

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Wherein R ¹ represents a C ₁ -C ₃ alkyl group. An acid anhydride is allowed to act on the compound (5) or a salt thereof represented by the formula

[0035]

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[Wherein, R ¹ has the same meaning as described above. ]
And a method for producing the compound (1) or a salt thereof.

When the compound (5) forms a salt, such a salt may be a salt of a tertiary amine moiety and an acidic compound, a salt of a carboxyl group and a basic compound, or a metal salt of a carboxyl group. Either may be used.

When the compound (5) forms a salt with an acidic compound, the acidic compound includes, for example, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid. Organic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid and phthalic acid; or organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid And preferably inorganic acids, more preferably hydrochloric acid or sulfuric acid.

When the compound (5) forms a salt with a basic compound, the basic compound is, for example, ammonia;
Or, methylamine, ethylamine, propylamine,
Dimethylamine, diethylamine, diisopropylamine, pyrrolidine, piperidine, morpholine, triethylamine, diisopropylethylamine, pyridine, picoline, lutidine, 4-dimethylaminopyridine, N, N
-Dimethylaniline, 1-methylpyrrolidine, 1-methylpiperidine, 4-methylmorpholine, imidazole,
1-methylimidazole, 1,5-diazabicyclo [4.3.0] -5-nonene (DBN), 1,8-diazabicyclo [5.4.0] -7-undecene (DB
U), organic amines such as ethylenediamine, piperazine, 1,4-diazabicyclo [2.2.2] octane (Dabco), preferably organic amines, more preferably triethylamine, Diisopropylethylamine or N-methylmorpholine.

When the compound (5) forms a metal salt at a carboxyl group, such a metal is, for example, lithium,
It can be an alkali metal such as sodium, potassium, cesium; or an alkaline earth metal such as magnesium, calcium, barium, preferably lithium, sodium, potassium or magnesium.

When the compound (5) forms a salt, such a salt is preferably a salt of a tertiary amine moiety and an acidic compound, and more preferably a hydrochloride of the compound (5). Or a sulfate of compound (5).

The compound (1) according to the present invention contains 2
Stereoisomers having two asymmetric carbons and having the (2S, 4S) configuration or the (2R, 4R) configuration, and the present invention relates to each of them and any mixture thereof in any ratio. Included. In the compound (1), preferably,
(2S, 4S) arrangement.

[0043]

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The compound (5) according to the present invention also has two asymmetric carbons in the molecule and has four stereoisomers, but preferably (2S, 4S) Arrangement or (2
(R, 4R) configuration, more preferably
(2S, 4S) arrangement.

[0045]

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When the compound of the present invention is left in the air or recrystallized, it absorbs water and sometimes adsorbs water or becomes a hydrate. The compounds (1) to (5) and salts thereof according to the present invention each include such a hydrate.

Further, the compound according to the present invention may absorb some other solvent and form a solvate. The compounds (1) to (5) and salts thereof according to the present invention each include such a solvate.

[0048]

BEST MODE FOR CARRYING OUT THE INVENTION The method for producing a carbapenem antibacterial having a 1-alkylpyrrolidine structure according to the present invention comprises:
This is achieved as follows.

[Method A]

[0050]

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In the above formula, R ¹ , R ² and R ³ have the same meaning as described above.

Method A is achieved by reacting compound (1) or a salt thereof with compound (2) or a salt thereof and compound (3) or a salt thereof in an inert solvent in the presence of a base in the same reaction vessel. Preferably, the compound (2) or a salt thereof and the compound (3) or a salt thereof are successively actuated.

If necessary, the functional groups in R ² and R ³ of compound (2) and the hydroxyl group and carboxyl group of compound (3) may be protected.

The protecting group for the hydroxyl group of the compound (3) includes, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl,
3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl,
Such as -methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl and henicosanoyl Carboxylated alkylcarbonyl groups such as alkylcarbonyl group, succinoyl, glutaroyl and adipoyl; halogeno lower alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl and trifluoroacetyl; lower alkoxy lower alkylcarbonyl groups such as methoxyacetyl. , (E) -2-methyl-2
"Aliphatic acyl groups" such as unsaturated alkylcarbonyl groups such as butenoyl; benzoyl, α-naphthoyl, β
Arylcarbonyl groups such as naphthoyl, halogenoarylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl,
A lower alkylated arylcarbonyl group such as 4-toluoyl, a lower alkoxylated arylcarbonyl group such as 4-anisoyl, a carboxylated aryl such as 2-carboxybenzoyl, 3-carboxybenzoyl and 4-carboxybenzoyl; -Nitrated ants such as carbonyl group, 4-nitrobenzoyl and 2-nitrobenzoyl-
"Aromatic acyl groups" such as lower alkoxycarbonyl-substituted arylcarbonyl groups such as carbonyl group, 2- (methoxycarbonyl) benzoyl and arylated arylcarbonyl groups such as 4-phenylbenzoyl; Pyran-2-yl, 3-bromotetrahydropyran-2
"Tetrahydropyranyl or tetrahydrothiopyranyl group" such as -yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2- “Tetrahydrofuranyl or tetrahydrothiofuranyl group” such as yl, tetrahydrothiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl,
“Silyl” such as tri-lower alkylsilyl group such as triisopropylsilyl, tri-lower alkylsilyl group substituted with one or two aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, and phenyldiisopropylsilyl; A lower alkoxymethyl group such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl, and 2-methoxyethoxymethyl Lower alkoxylated lower alkoxymethyl group, 2,2,
"Alkoxymethyl group" such as halogeno lower alkoxymethyl such as 2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; 1-ethoxyethyl, 1-ethoxy
(Substituted ethyl group) such as lower alkoxylated ethyl group such as (isopropoxy) ethyl and halogenated ethyl group such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenyl Lower alkyl group substituted with 1 to 3 aryl groups such as methyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl,
2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, "Aralkyl groups" such as lower alkyl groups such as 4-cyanobenzyl, methyl, and piperonyl, lower alkoxy, halogen, lower alkyl groups substituted with one to three aryl groups each having an aryl ring substituted with a cyano group; A lower alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-
An “alkoxycarbonyl group” such as a lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group such as trimethylsilylethoxycarbonyl; vinyloxycarbonyl, an “alkenyloxycarbonyl group” such as allyloxycarbonyl; benzyloxycarbonyl; 4-methoxybenzyloxycarbonyl,
"Aralkyl" in which the aryl ring may be substituted with one or two lower alkoxy or nitro groups such as 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl Oxycarbonyl group ", preferably an aliphatic acyl group.

The protecting group for the carboxyl group of the compound (3) is, for example, a benzyl group which may have a substituent such as benzyl, p-nitrobenzyl or trimethylbenzyl group; or an allyl group or 2-chloroallyl group Or an allyl group which may have a substituent at the 2-position such as 2-methylallyl, preferably a benzyl group which may have a substituent, more preferably p-nitro. It is a benzyl group.

The base used in this method is, for example, triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, picoline, lutidine, 4-dimethylaminopyridine, 1-methylimidazole, 1,2- Organic bases such as dimethylimidazole; or lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
It can be an inorganic base such as cesium carbonate, sodium bicarbonate, preferably diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate.

The solvent used in the present method is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, nitriles such as acetonitrile; methanol, ethanol, propanol and isopropanol. Alcohols; esters such as methyl acetate and ethyl acetate; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; ethers such as ether, tetrahydrofuran and dioxane; aromatics such as benzene, toluene and xylene Hydrocarbons; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; water; or a combination of any of the aforementioned solvents, preferably nitriles, amides, Sulfoxides, hydrous amide S, or a water-containing sulfoxides, more preferably a amides, sulfoxides or water sulfoxides, even more preferably more, dimethylformamide, dimethylacetamide, dimethyl sulfoxide or hydrous dimethyl sulfoxide.

The reaction temperature depends mainly on the reaction solvent, but is usually from -50 ° C to 100 ° C, preferably from 1 ° C to 100 ° C.
0 ° C. to 50 ° C.

The reaction time varies depending on the reaction solvent and the reaction temperature, but is usually 1 hour to 60 hours, preferably 4 hours to 30 hours.

When the functional groups in R ² and R ³ of the compound (2) and the hydroxyl group and the carboxyl group of the compound (3) are protected, the protecting groups are removed by a method obvious to those skilled in the art after completion of the reaction. By doing so, compound (4), which is a carbapenem antibacterial agent, can be obtained. For example, when the protecting group of the hydroxyl group of the compound (3) is a silyl group, the compound is treated with a compound that generates a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, and potassium fluoride. Alternatively, the protecting group can be removed by treatment with an organic acid such as acetic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid or an inorganic acid such as hydrochloric acid. When the hydroxyl-protecting group of the compound (3) is an aralkyl group or an aralkyloxycarbonyl group, it is contacted with a reducing agent in a solvent (preferably catalytic reduction at room temperature under a catalyst) or an oxidizing agent is used. To remove the protecting group. When the hydroxyl-protecting group of the compound (3) is an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, the protecting group can be removed by treating with a base in a solvent. Compound (3)
When the protecting group of the hydroxyl group is an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group, protection by treatment with an acid in a solvent. The group can be removed. When the protecting group for the hydroxyl group of the compound (3) is an alkenyloxycarbonyl group, the removal reaction is performed in the same manner as in the case of the above-described case where the protecting group for the hydroxyl group is an aliphatic acyl group, an aromatic acyl group, or an alkoxycarbonyl group. , A protecting group can be removed by treating with a base. When the carboxyl-protecting group of compound (3) is a benzyl group which may have a substituent, hydrogen acts on palladium carbon or a platinum catalyst in water, methanol, ethanol, tetrahydrofuran or a mixed solvent thereof. By doing so, the protecting group can be removed. When the carboxyl-protecting group of the compound (3) is an allyl group which may have a substituent at the 2-position, bis (triphenyl) may be used in water, methanol, ethanol, tetrahydrofuran, acetone or a mixed solvent thereof. Protection by the action of trialkyltin hydrides such as tributyltin hydride or alkali metal salts of organic carboxylic acids such as sodium 2-ethylhexanoate in the presence of a palladium catalyst such as phosphine) palladium chloride or tetrakis (triphenylphosphine) palladium. The group can be removed.

After completion of the reaction, the target compound of the present method can be collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding a solvent in which the product is not dissolved to the reaction mixture to precipitate the product, or by distilling the reaction solvent under reduced pressure, and further purifying by recrystallization, reprecipitation or chromatography. .

The synthetic intermediate compound (1) and the salt thereof in the method for producing a carbapenem-based antibacterial agent having a 1-alkylpyrrolidine structure according to the present invention include the compound (5) or a salt thereof as an acid anhydride as shown below. Can be produced by reacting the same.

[Method B]

[0064]

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In the above formula, R ¹ has the same meaning as described above.

Method B is a method for producing compound (1) and a salt thereof by subjecting compound (5) or a salt thereof to an acid anhydride to carry out an intramolecular cyclization reaction.

This reaction can be carried out in the presence or absence of a solvent.

The solvent used in this method is not particularly limited as long as it does not inhibit the reaction and dissolves the starting compound (5) to some extent. For example, nitriles such as acetonitrile; methyl acetate , Ethyl acetate, acetic acid t-
Esters such as butyl; methanol, ethanol,
Alcohols such as propanol, isopropanol and butanol; ketones such as acetone and methyl ethyl ketone; aliphatic hydrocarbons such as hexane, heptane and petroleum ethers; aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride and dichloroethane; diethyl ether;
Ethers such as diisopropyl ether, tetrahydrofuran and dioxane; amides such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethyl sulfoxide; such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid and trifluoromethanesulfonic acid Organic acids; or any combination of the above solvents in any proportion, preferably organic acids, and more preferably acetic acid.

The acid anhydride used in this method includes, for example, anhydrides of phosphoric acids; acetic anhydride, propionic anhydride,
Anhydrides of organic carboxylic acids such as trifluoroacetic anhydride and phthalic anhydride; and anhydrides of organic sulfonic acids such as methanesulfonic anhydride, trifluoromethanesulfonic anhydride, benzenesulfonic anhydride and p-toluenesulfonic anhydride. It is preferably an anhydride of an organic carboxylic acid, more preferably acetic anhydride.

The amount of the acid anhydride to be used is generally 1.0 to 100.0 molar equivalents, preferably 1.0 to 10.0 molar equivalents, relative to compound (5) or a salt thereof. is there.

The reaction temperature of this method varies depending mainly on the reagent used, but is usually from 0 ° C. to 120 ° C., preferably from 30 ° C. to 80 ° C.

The reaction time of this method mainly depends on the reaction temperature and the solvent, but is usually 0.5 to 20 hours.
Preferably, it is 1.5 hours to 5.0 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, after neutralizing the reaction mixture,
It is obtained by adding an organic solvent that does not mix with water, washing with water, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

The compound (5) and a salt thereof used in the present invention can be produced by the following Method C.

[Method C]

[0076]

Embedded image

In the above formula, R ¹ has the same meaning as described above;
R ⁴ represents a C ₁ -C ₆ alkyl group, R ⁵ and R ⁶ are C ₁
Have a -C ₆ alkyl group or a substituted group represents an C ₆ -C ₁₀ aryl group.

Here, the “alkyl group” for R ⁴ , R ⁵ and R ⁶ is a linear or branched saturated hydrocarbon group, and is a C ₁ -C ⁴ group for R ⁴ , R ⁵ and R ⁶ . ₆ alkyl groups are
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, s-
Pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (s-hexyl), 3,3-dimethyl Butyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-
Dimethylbutyl, 1,3-dimethylbutyl, be a 2,3-dimethylbutyl or 2-ethylbutyl, preferably, C ₁ -C ₄
An alkyl group, more preferably a C ₁ -C ₂ alkyl group, even more preferably more, a methyl group.

Further, R^FiveAnd R⁶"Aryl group" in
Is an aromatic hydrocarbon ring group; ^FiveAnd R⁶C in
₆-C_TenAryl groups include, for example, phenyl, 1-naphthyl
Or 2-naphthyl, preferably phenyl.
When the aryl group has a substituent, the number of substituents is
Preferably one to three, and more preferably one.
Substituents are those such as methyl, ethyl and propyl groups.
Alkyl group; like formyl, acetyl, propionyl
Aliphatic acyl group; acetoxy, propionyloxy group
Aliphatic acyloxy groups such as methoxycarbonyl;
Such as ethoxycarbonyl and propoxycarbonyl groups
Alkoxycarbonyl group; monofluoromethyl, difur
Halogenation such as olomethyl and trifluoromethyl groups
Alkyl group; like methoxy, ethoxy, propoxy group
Alkoxy groups such as fluorine, chlorine, bromine and iodine
Halogen atom; methylsulfonyl, ethylsulfonyl group
An alkylsulfonyl group such as a nitro group;
And preferably an alkyl group, a halogenated alkyl group.
A kill group, a halogen atom, a nitro group or a cyano group,
More preferably, a methyl group, a trifluoromethyl group,
A chlorine, nitro or cyano group.

In the above formula, the compounds (6) to (10) are
A salt may be formed with the acidic compound at the amine site. Examples of the acidic compound include inorganic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; or formic acid, acetic acid, trifluoroacetic acid, oxalic acid, and phthalic acid Organic carboxylic acids such as acids; organic sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid, and are preferably inorganic acids, more preferably
Hydrochloric acid or sulfuric acid.

Step C1 is an esterification reaction of compound (6) and can be carried out with reference to a method obvious to those skilled in the art. For example, the compound (7) can be produced by subjecting the compound (6) to an esterification reaction in a corresponding alcohol in the presence of an acid.

The acids used in this step include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide;
Organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid can be used, and inorganic acids are preferable.

[0083] alcohols used in this step is a compound in which a hydroxyl group has been substituted with C ₁ -C ₆ alkyl group described above,
For example, methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, s-butyl alcohol, t-butyl alcohol, pentanol, s-pentyl alcohol, isopentyl alcohol, 2-methylbutanol, neopentyl alcohol, 1-
Ethylpropanol, hexanol, 4-methylpentanol, 3-methylpentanol, 2-methylpentanol,
1-methylpentanol, 3,3-dimethylbutanol, 2,2-
It can be dimethylbutanol, 1,1-dimethylbutanol, 1,2-dimethylbutanol, 1,3-dimethylbutanol, 2,3-dimethylbutanol or 2-ethylbutanol, preferably methanol.

The reaction temperature in this step mainly depends on the solvent used, but is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

The reaction time in this step mainly depends on the reaction temperature and the solvent, but is usually 1 hour to 40 hours, preferably 1 hour to 7 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it is obtained by distilling off the solvent of the reaction mixture. If necessary, the compound can be further purified by a conventional method, for example, recrystallization, reprecipitation, chromatography, or the like. However, it is also possible to proceed to the next reaction step without purification.

The step C2 is an alkylation reaction of the compound (7) and can be carried out with reference to a method obvious to those skilled in the art. For example, a corresponding C ₁ -C ₃ aldehyde or a derivative thereof (eg, formamide) or a combination of an aqueous solution thereof and a reducing agent, or a corresponding C ₁ -C ₃ alkyl in water, methanol, ethanol, tetrahydrofuran, or a mixed solvent thereof Compound (8) can be produced by performing an alkylation reaction of compound (7) with a combination of a halide and a base.

The reducing agent used in this step may be, for example, hydrogen in the presence of formic acid or palladium, preferably hydrogen in the presence of palladium.

The base used in this step is, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate; or triethylamine, diisopropylethylamine, dicyclohexylamine, pyridine, lutidine, 4- ( Dimethylamino) pyridine, 1,5-diazabicyclo [4.3.0] -5-nonene (DBN), 1,8-diazabicyclo [5.4.
0] -7-undecene (DBU) and the like, preferably an alkali metal carbonate, and more preferably sodium carbonate.

The reaction temperature in this step mainly depends on the reagent used, but is usually from -20 ° C to 120 ° C, preferably from 10 ° C to 80 ° C.

The reaction time of this step depends mainly on the reaction temperature and the solvent, but is usually 0.5 to 15 hours, preferably 1 to 5 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it is obtained by distilling off the solvent of the reaction mixture or adding a solvent in which the target compound is not dissolved in the reaction mixture (for example, propanol or isopropyl ether) to precipitate the target compound, followed by filtration. The obtained target compound can be obtained by a conventional method, if necessary.
For example, the compound can be further purified by recrystallization, reprecipitation, chromatography, or the like, but can also proceed to the next reaction step without purification.

Note that any of the C1 step and the C2 step may be performed first. That is, instead of following the above reaction path, the C2 step (alkylation reaction of nitrogen atom) may be performed first, and then the C1 step (esterification reaction) may be performed.

Step C3 is a sulfonylation reaction of a hydroxyl group in compound (8), and can be carried out with reference to a method obvious to those skilled in the art. For example, compound (9) can be produced by performing a sulfonylation reaction of compound (8) using a sulfonylating agent in an inert solvent in the presence of a base.

The solvent used in this step is not particularly limited as long as it does not inhibit the reaction.
Hydrocarbons such as heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; esters such as methyl acetate and ethyl acetate; Nitriles: ketones such as acetone and methyl ethyl ketone; ethers, dioxane,
Ethers such as tetrahydrofuran; sulfoxides such as dimethylsulfoxide; or amides such as dimethylformamide and dimethylacetamide, preferably esters.

The base used in this step is, for example, an inorganic base such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate; or triethylamine, diisopropylethylamine, 4-methylmorpholine, 1-methylimidazole , Pyridine, lutidine,
It can be an organic base such as 4-dimethylaminopyridine, preferably an organic base.

Examples of the sulfonylating agent used in this step include halogens such as methanesulfonyl chloride, chloromethylsulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride. Sulfonyl halides; or sulfonic anhydrides such as methanesulfonic anhydride, p-toluenesulfonic anhydride, and trifluoromethanesulfonic anhydride, and are preferably sulfonyl halides.

The amount of the sulfonylating agent to be used is generally 1 to 10 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (8).

[0099] The reaction temperature in this step mainly depends on the reagent used, but is usually -50 ° C to 100 ° C, preferably -10 ° C to 50 ° C.

The reaction time of this step mainly depends on the reaction temperature and the solvent, but is usually 0.1 to 10 hours, preferably 0.1 to 4 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to a reaction mixture, washing with water and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step C4 is a reaction for substituting the sulfonyloxy group in compound (9) with a thiocarboxylate carboxylate anion, and can be carried out with reference to a method obvious to those skilled in the art. For example, compound (10) can be produced by performing a substitution reaction of compound (9) using a metal salt of thiocarboxylic acid or a combination of thiocarboxylic acid and a base in an inert solvent.

The solvent used in this step is not particularly limited as long as it does not inhibit the reaction.
Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and chloroform; esters such as methyl acetate and ethyl acetate; alcohols such as methanol, ethanol and propanol; Nitriles; ketones such as acetone and methyl ethyl ketone;
Ethers such as ether, dioxane, and tetrahydrofuran; sulfoxides such as dimethylsulfoxide; amides such as dimethylformamide and dimethylacetamide; water; or a combination of any of the above solvents, and preferably , Alcohols, amides, water or a combination thereof.

The metal salt of thiocarboxylic acid used in this step may be, for example, sodium thioacetate, potassium thioacetate, cesium thioacetate, sodium thiobenzoate, potassium thiobenzoate or cesium thiobenzoate,
Preferably, it is potassium thioacetate.

In this step, the reaction can also be carried out using a combination of a thiocarboxylic acid and a base. The thiocarboxylic acid used in this step can be, for example, thioacetic acid or thiobenzoic acid, and is preferably thioacetic acid. Bases used in combination include, for example, sodium hydroxide,
Inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide;
Alkoxides such as potassium t-butoxide; metal hydrides such as sodium hydride and potassium hydride; or triethylamine, diisopropylethylamine, 4-methylmorpholine, 1-methylimidazole, pyridine, 1,5-diazabicyclo [ 4.3.0]
Organic bases such as -5-nonene (DBN) and 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) can be used, and preferably inorganic bases.

The amount of the metal salt of thiocarboxylic acid or thiocarboxylic acid to be used is generally 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (9).

The reaction temperature in this step mainly depends on the reagent used, but is usually 0 ° C. to 150 ° C., preferably 40 ° C. to 100 ° C.

The reaction time of this step depends mainly on the reaction temperature and the solvent, but is usually 1 hour to 20 hours, preferably 1 hour to 10 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent that does not mix with water to the reaction mixture, washing with water, and distilling off the solvent. The obtained target compound can be further purified, if necessary, by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Step C5 is a hydrolysis reaction of compound (10) and is carried out with reference to a method obvious to those skilled in the art. For example, the compound (5) can be produced by performing a hydrolysis reaction of the compound (10) under either acidic or basic conditions.

When the hydrolysis is carried out under acidic conditions,
The acid used in this step can be, for example, an inorganic acid such as hydrochloric acid or sulfuric acid, and is preferably hydrochloric acid or sulfuric acid.

When the hydrolysis is carried out under basic conditions, the base used in this step may be, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide. Is sodium hydroxide or potassium hydroxide.

The reaction temperature in this step mainly depends on the reagent used, but is usually from -20 ° C to 150 ° C, preferably from 0 ° C to 110 ° C.

The reaction time of this step depends mainly on the reaction temperature and the solvent, but is usually 0.1 to 20 hours, preferably 0.1 to 10 hours.

After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it is obtained by distilling off the solvent of the reaction mixture. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

[0117]

【Example】

[0118]

Embodiment 1

[0119]

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In the above formula, PNB represents a p-nitrobenzyl group which is a protecting group for a carboxyl group, and PNZ represents a 4-nitrobenzyloxycarbonyl group which is a protecting group for a guanidino group. Hereinafter, PNB and PNZ have the same meaning.

(1R, 5S, 6S) -6-[(1R)-
1-hydroxyethyl] -1-methyl-2-[(2S,
4S) -2-[(3S) -3- [2- [3- (4-nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1 -Carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (A
Method) (2S, 4S) -5-Methyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one (250 mg)
And a suspension of (S) -3- [2- [3- (4-nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidine disulfate (979 mg) in methanol / methylene chloride (1: 2) (7. 5 mL) was added with diisopropylethylamine (1.49 mL), and the mixture was stirred at 50 ° C for 7 hours. After evaporating the solvent of the reaction solution under reduced pressure, dimethylformamide (7 mL) and (1R, 5R, 6S) were added under ice cooling.
-6-[(1R) -1-hydroxyethyl] -2-
[(Diphenylphosphino) oxy] -1-methyl-carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (934 mg) and diisopropylethylamine (0.6 mL) were sequentially added, and the mixture was left overnight at the same temperature. The reaction solution was poured into 1% aqueous sodium bicarbonate (70 mL), and the precipitated solid was collected by filtration to give the title compound (1.4 g, purity 7%).
9%, yield: 83%). Infrared absorption spectrum (KBr) νmax cm ^-1 : 3384, 311
3, 3080, 2970, 2875, 2789, 1770, 1643, 1609, 1522,
1450, 1379, 1346, 1322, 1287, 1209, 1181, 1136, 1
109. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 1.08-
2.22 (m, 6H), 1.75-2.26 (m, 6H), 2.44-2.76 (m, 2H),
2.89-3.00 (m, 1H), 3.03-3.15 (m, 1H), 3.18-3.65
(m, 6H), 3.68-3.90 (m, 3H), 3.93-4.06 (m, 1H), 4.1
3-4.35 (m, 2H), 5.05-5.15 (m, 2H), 5.30 (d, J = 14.1
Hz, 1H), 5.45 (d, J = 14.1Hz, 1H), 7.58 (dd, J = 8.8 a
nd 2.7Hz, 2H), 7.74 (d, J = 8.7Hz, 2H), 8.18-8.33
(m, 4H).

[0122]

Embodiment 2

[0123]

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(1R, 5S, 6S) -6-[(1R)-
1-hydroxyethyl] -1-methyl-2-[(2S,
4S) -2-[(3S) -3- [2- [3- (4-nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidin-1-ylcarbonyl] -1-methylpyrrolidin-4-ylthio] -1 -Carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester (A
Method) (2S, 4S) -5-Methyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one hydrochloride (8
9.8 g) and (S) -3- [2- [3- (4-nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidine disulfate (265.0 g, purity 95.0 g).
8%) in dimethyl sulfoxide (2.65 L), and sodium hydrogen carbonate (209.2 g) was added thereto.
Stirred at C for 3 hours. The reaction solution was added at room temperature (1R, 5R,
6S) -6-[(1R) -1-hydroxyethyl] -2
-[(Diphenylphosphino) oxy] -1-methyl-
Carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (269.2 g) and sodium hydrogen carbonate (42.0 g) were sequentially added and left overnight. The reaction solution was poured into water (7.95 L), stirred at 20 to 35 ° C. for 1 hour, and the precipitated solid was collected by filtration to give the title compound (400.
3 g, purity 85.6%, yield: 85%). Spectral data was consistent with the compound of Example 1.

[0125]

Embodiment 3

[0126]

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(2S, 4S) -5-methyl-2-thia-
5-Azabicyclo [2.2.1] heptan-3-one (Method B) (2S, 4S) -4-acetylthio-1-methyl-2-
2 mol / L aqueous hydrochloric acid (2 mL) was added to pyrrolidine carboxylic acid methyl ester (200 mg), and the mixture was heated and stirred at 70 ° C. for 12 hours to form an acetyl group which is a mercapto-protecting group and a methyl group which is a carboxylic acid-protecting group. Removed. After water of the reaction solution was distilled off under reduced pressure, acetic anhydride (1 mL) was added to the obtained residue, and the mixture was heated and stirred at 60 ° C. for 1 hour. Ethyl acetate (20 mL) and saturated aqueous sodium hydrogen carbonate (20 mL) were added to the reaction solution, and the mixture was extracted. After separating the aqueous layer, the solvent of the organic layer was distilled off under reduced pressure to give the title compound (73.4).
mg, yield: 52%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 2.10
(s, 2H), 2.47 (s, 3H), 2.55 (d, J = 10.0Hz, 1H), 3.59
(s, 1H), 3.74 (dd, J = 10.0 and 2.9Hz, 1H), 3.86-3.
89 (m, 1H). MS spectrum m / z: 144 (M + l) ^<+> .

[0128]

Embodiment 4

[0129]

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(2S, 4S) -5-methyl-2-thia-
5-Azabicyclo [2.2.1] heptan-3-one (Method B) (2S, 4S) -4-acetylthio-1-methyl-2-
2 mol / L hydrochloric acid aqueous solution (2 mL) was added to pyrrolidine carboxylic acid methyl ester (204 mg), and the mixture was heated and stirred at 80 ° C. for 7 hours to form a mercapto-protecting group acetyl group and a carboxylic acid-protecting group methyl group. Removed.
After water of the reaction solution was distilled off under reduced pressure, acetic acid (1 mL) and acetic anhydride (0.6 mL) were added to the obtained residue,
For 1 hour. Ethyl acetate (20m
L) and saturated aqueous sodium bicarbonate (20 mL) were added and extracted. After separating the aqueous layer, the solvent of the organic layer was distilled off under reduced pressure to obtain the title compound (77.8 mg, yield: 54%). Spectral data was consistent with the compound of Example 3.

[0131]

Embodiment 5

[0132]

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(2S, 4S) -5-methyl-2-thia-
5-Azabicyclo [2.2.1] heptan-3-one.
Hydrochloride (Method B) Acetic acid of (2S, 4S) -4-mercapto-1-methyl-2-pyrrolidinecarboxylic acid hydrochloride (6 g) (24 m
Acetic anhydride (8.6 mL) was added dropwise to the mixture of L) at 15 ° C or lower, and the mixture was heated and stirred at 55 to 60 ° C for 2 hours. After the acetic acid in the reaction solution was distilled off under reduced pressure, ethyl acetate (72 mL) and water (36 mL) were added, and the aqueous layer was adjusted to pH = 8 to 9 with an aqueous sodium hydroxide solution and extracted. After separating the organic layer, the aqueous layer was further extracted with ethyl acetate (36 mL). The ethyl acetate layer was combined, and the solvent was distilled off under reduced pressure. 4 mol / L HC was added to a solution of the obtained residue in ethyl acetate (35 mL).
A 1 / ethyl acetate (7.6 mL) solution was added dropwise at 25 ° C. or lower, and the mixture was stirred at the same temperature for 1 hour. The precipitated solid is collected by filtration,
The title compound (4.4 g, yield: 80%) was obtained. 191-192 ° C. Nuclear magnetic resonance spectrum _{(400MHz, CDCl 3) δ ppm} : 2.54
(d, J = 12.5Hz, 1H), 2.90 (d, J = 12.5Hz, 1H), 2.95 (s,
3H), 3.14 (d, J = 11.2Hz, 1H), 4.32 (s, 1H), 4.35
(s, 1H), 4.40 (d, J = 11.2Hz, 1H). Elemental analysis Calculated: C, 40.11%; H, 5.61%; N, 7.80%; S, 17.85%; Cl, 19.73% Found: C, 39.93%; H, 5.52%; N, 7.75%; S, 17.93 %; Cl, 19.76%.

[0134]

Embodiment 6

[0135]

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(2S, 4S) -5-methyl-2-thia-
5-Azabicyclo [2.2.1] heptan-3-one.
Hydrochloride (Steps C3-C5 and Method B) (2S, 4R) -4-Hydroxy-1-methylpyrrolidinecarboxylic acid methyl ester hydrochloride (5 g, purity 9)
Triethylamine (8.2 mL) was added to a suspension of 2%) in ethyl acetate (50 mL), and the mixture was refluxed for 3 hours. Under ice cooling, a solution of methanesulfonyl chloride (2 mL) in ethyl acetate (10 mL) was added dropwise. Warm for 1 hour. A saturated saline solution (25 mL) was added to the reaction solution, followed by extraction. After separating the organic layer, the aqueous layer was further extracted with ethyl acetate (50 mL). The ethyl acetate layer was combined, and the solvent was distilled off under reduced pressure. Dimethylformamide (50 mL) and potassium thioacetate (4.0 g) were sequentially added to the residue, and the mixture was heated and stirred at 70 to 75 ° C for 2 hours. After the reaction solution was cooled to room temperature, toluene (50 mL) and saturated saline (25 mL) were added for extraction. After separating the organic layer, the aqueous layer was further extracted with toluene (50 mL), the toluene layer was matched, and the solvent was distilled off under reduced pressure. Water (15 mL) and concentrated hydrochloric acid (4.2 mL) were sequentially added to the residue, and the mixture was heated and stirred at 80 to 85 ° C. for 6 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and water was distilled off under reduced pressure. Furthermore, acetic acid (15 m
L) and acetic anhydride (6.65 mL) were sequentially added.
The mixture was heated and stirred at 60 ° C. for 2 hours. After the acetic acid in the reaction solution was distilled off under reduced pressure, ethyl acetate (50 mL) and saturated saline (25 mL) were added to the residue, and the pH of the aqueous layer was adjusted to 8 to 9 with an aqueous sodium hydroxide solution, followed by extraction. . After separating the organic layer, the aqueous layer was further extracted with ethyl acetate (50 mL). The ethyl acetate layer was combined, and the solvent was distilled off under reduced pressure. 4 mol / L HC was added to a solution of the obtained residue in ethyl acetate (25 mL).
A 1 / ethyl acetate (4.7 mL) solution was added dropwise at 25 ° C. or lower, and the mixture was stirred at the same temperature for 1 hour. The precipitated solid is collected by filtration,
Title compound (3.1 g, purity 94%, total yield: 69)
%). Spectral data was consistent with the compound of Example 5.

[0137]

[Reference Example 1]

[0138]

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(2S, 4R) -4-Hydroxy-1-methyl-2-pyrrolidinecarboxylic acid methyl ester hydrochloride (Steps C1 and C2) Methanol (1 g) blown with hydrogen chloride gas (127 g)
L) The solution was added with (2S, 4R) -trans-4-hydroxyproline (100 g) and then stirred under reflux for 2 hours.
After the completion of the reaction, the pH of the reaction solution was adjusted to 3 to 4 using a 28% sodium methoxide / methanol solution, and the solvent was distilled off under reduced pressure. Methanol (200
mL), 37% aqueous formamide solution (93 g) and 7.
5% Pd / C (1.1 g) was added, and under hydrogen pressure conditions,
Stirred at room temperature for 5 hours. After removing Pd / C by filtration,
Propanol (200 mL) and isopropyl ether (1 L) were added to the residue obtained by evaporating the solvent of the filtrate under reduced pressure, and the mixture was stirred at 20 to 25 ° C. for 2 hours. The precipitated crystals were collected by filtration to give the title compound (156 g, purity 92%, yield: 9).
6%). Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 2.26-
2.34 (m, 1H), 2.44-2.51 (m, 1H), 3.11 (s, 3H), 3.21
(d, J = 12.4Hz, 1H), 3.87 (s, 3H), 3.87-3.92 (m, 1
H), 4.53-4.64 (m, 2H).

[0140]

[Reference Example 2]

[0141]

Embedded image

(2S, 4R) -4-Hydroxy-1-methyl-2-pyrrolidinecarboxylic acid (Step C2) (2S, 4R) -trans-4-hydroxyproline (5 g), 37% aqueous formamide solution (4. 6g) and 7.5% Pd / C (53% water wet: 3.2 g) in water (1
5 mL) suspension was stirred at room temperature under hydrogen pressure for 10 hours. After removing Pd / C by filtration, water of the filtrate was distilled off under reduced pressure. The obtained solid residue is ethanol (25
The suspension was stirred and filtered, and filtered to give the title compound (5.1
g, yield: 92%). Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 2.12-
2.21 (m, 1H), 2.40-2.47 (m, 1H), 3.01 (s, 3H), 3.09
(d, J = 12.4Hz, 1H), 3.85 (dd, J = 12.4 and 4.6Hz, 1
H), 4.06 (dd, J = 10.8 and 7.6Hz, 1H), 4.48-4.52 (m,
1H).

[0143]

[Reference Example 3]

[0144]

Embedded image

(2S, 4R) -4-Hydroxy-1-methyl-2-pyrrolidinecarboxylic acid methyl ester hydrochloride (Steps C1 and C2) (2S, 4R) -4-Hydroxy-1-methyl-2- Methanol (15 mL) of pyrrolidine carboxylic acid (3 g)
Concentrated hydrochloric acid (3 mL) was added to the suspension, and the mixture was refluxed for 4 hours. The solvent of the reaction solution was distilled off under reduced pressure to give the title compound (4.0.
g, yield: 100%). The spectrum data corresponded to the compound of Reference Example 1.

[0146]

[Reference Example 4]

[0147]

Embedded image

(2S, 4R) -4-methylsulfonyloxy-1-methyl-2-pyrrolidinecarboxylic acid methyl ester (Step C3) (2S, 4R) -4-hydroxy- obtained in Reference Example 1 or 3 1-methyl-2-pyrrolidinecarboxylic acid methyl ester hydrochloride (1 g) in tetrahydrofuran (10 g)
Triethylamine (1.53 mL) was added to the suspension, and the mixture was stirred at 40 ° C. for 3 hours. Then, mesyl chloride was added under ice cooling, and the mixture was further stirred for 2 hours. Ethyl acetate (2
0 mL) and 5% aqueous sodium bicarbonate (10 mL) were added for extraction. After separating the aqueous layer, the solvent of the organic layer was distilled off under reduced pressure to obtain the title compound (1.0 g, yield: 83%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 2.41
(d, J = 7.8Hz, 1H), 2.43 (dd, J = 7.8 and 1.7Hz, 1H),
2.47 (s, 3H), 2.74 (dd, J = 11.2 and 3.9 Hz, 1H), 3.
04 (s, 3H), 3.42 (dd, J = 7.8 and 7.8Hz, 1H), 3.59
(dd, J = 11.2 and 6.1 Hz, 1H), 3.76 (s, 3H), 5.20-5.
5.26 (m, 1H).

[0149]

[Reference Example 5]

[0150]

Embedded image

(2S, 4S) -4-acetylthio-1-
Methyl-2-pyrrolidinecarboxylic acid methyl ester (Step C4) (2S, 4R) -4-methylsulfonyloxy-1-methyl-2-pyrrolidinecarboxylic acid obtained in Reference Example 4
Methyl ester (609 mg) in ethanol / water (9:
1) Potassium thioacetate (677m) was added to the mixture (6mL).
After the addition of g), the mixture was heated and stirred at 80 ° C. for 3 hours and left at room temperature overnight. Ethyl acetate (20 mL) and 10%
Brine (10 mL) was added and extracted. After separating the organic layer and washing with water (10 mL), the solvent was distilled off under reduced pressure.
The title compound (543 mg, yield: 97%) was obtained. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 1.96-
2.03 (m, 1H), 2.30 (s, 3H), 2.43 (s, 3H), 2.65-2.74
(m, 1H), 2.82-2.87 (m, 1H), 3.05-3.10 (m, 2H), 3.
76 (s, 3H), 3.93-4.00 (m, 1H).

[0152]

[Reference Example 6]

[0153]

Embedded image

(2S, 4S) -4-Mercapto-1-methyl-2-pyrrolidinecarboxylic acid hydrochloride (Step C5) (2S, 4S) -4-acetylthio-1-methyl-2-
Pyrrolidinecarboxylic acid methyl ester (10.7 g),
A mixture of concentrated hydrochloric acid (14.9 g) and water (16 mL) was added to 7
The mixture was heated and stirred at 5-85 ° C for 5 hours. After completion of the reaction, water of the reaction solution was distilled off under reduced pressure, acetic acid (10 mL) and ethyl acetate (20 mL) were added to the residue, and the mixture was stirred at 0 to 5 ° C for 1 hour. The precipitated crystals were collected by filtration, and the title compound (9.2 g,
(Yield: 95%). Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm: 2.11-
2.20 (m, 1H), 2.97-3.05 (m, 1H), 3.02 (s, 3H), 3.56
-3.68 (m, 2H), 3.80-3.88 (m, 1H), 4.35-4.41 (m, 1
H).

[0155]

[Reference Example 7]

[0156]

Embedded image

(S) -3- [2- [3- (4-Nitrobenzyloxycarbonyl) guanidino] acetylamino] pyrrolidine disulfate (S) was added to a solution of concentrated sulfuric acid (234 g) in methanol (2.45 L). -1- (t-butyloxycarbonyl) -3-
[2- [3- (4-nitrobenzyloxycarbonyl)]
Guanidino] acetylamino] pyrrolidine 1/2 sulfate (350 g, purity 86%) was added, and the mixture was stirred at 40 to 45 ° C for 2.5 hours. The reaction solution was cooled to 20 to 30 ° C., stirred at the same temperature for 0.5 hour, added with diisopropyl ether (3.5 L), and further stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration to give the title compound (328 g, purity 9).
(5.8%, yield: 95.4%). Nuclear magnetic resonance spectrum (400 MHz, D ₂ O) δ ppm: 1.85-
1.96 (m, 1H), 2.10-2.25 (m, 1H), 3.13-3.44 (m, 4H),
4.01 (s, 2H), 4.31-4.39 (m, 1H), 5.25 (s, 2H), 7.
48 (d, J = 8.6Hz, 2H), 8.10 (d, J = 8.6Hz, 2H).

[0158]

The method for producing a carbapenem-based antibacterial agent having a 1-alkylpyrrolidine structure according to the present invention is inexpensive,
It is easy, safe and suitable for mass synthesis, and 5-alkyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one is very important in the production method. Useful as an intermediate compound.

Further, the method for producing 5-alkyl-2-thia-5-azabicyclo [2.2.1] heptan-3-one according to the present invention is also described in 5-Alkyl-2-thia-5-azabicyclo [2. 2.2.1] Heptan-3-one can be produced inexpensively, easily, safely, and in large quantities.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C050 KA18 KB05 KB13 KB16 KC04 4C071 AA03 BB01 CC01 CC21 EE13 FF03 GG01 HH08 KK01 LL01 4C086 AA01 AA04 CC08 MA01 MA04 NA20 ZB35

Claims (19)

[Claims] (1) Formula (1) [Wherein, R ¹ represents a C ₁ -C ₃ alkyl group. Or a salt thereof represented by the formula: [Wherein, R ² and R ³ each independently represent a hydrogen atom or an organic residue, or R ² and R ³ may form a ring together with the nitrogen atom to which they are attached. Good. And a salt thereof, and a compound represented by the formula: [In the formula, L represents a leaving group, and the hydroxyl group and the carboxyl group may be each independently protected. By reacting the compound (3) or a salt thereof represented by the formula: [Wherein, R ¹ , R ² and R ³ have the same meanings as described above, and the hydroxyl group and the carboxyl group may be each independently protected. ] The method of manufacturing the carbapenem antibacterial agent (4) or its salt represented by these. 2. The compound (1) or a salt thereof is reacted with the compound (2) or a salt thereof and the compound (3) or a salt thereof in an inert solvent in the presence of a base in the same reaction vessel. The carbapenem antibacterial agent according to claim 1, (4).
Or a method for producing a salt thereof. 3. Compound (2) or a salt thereof and compound (3)
The method for producing a carbapenem antibacterial agent (4) or a salt thereof according to claim 1 or 2, wherein the salt is allowed to act sequentially. 4. The method according to claim 1, wherein R ¹ is a methyl group.
The method for producing the carbapenem antibacterial agent (4) or a salt thereof according to any one of the above. 5. The carbapenem antibacterial agent (4) according to any one of claims 1 to 4, wherein R ² and R ³ form a ring together with the nitrogen atom to which they are bonded. A method for producing a salt. 6. R^TwoAnd R^ThreeIs the nitrogen atom to which they are attached
Along with the formula[In the formula, n represents 0, 1, or 2, and p represents 0, 1, or
2 and R^aIs a hydrogen atom or C₁-C_FourAn alkyl group
B is phenylene, phenylene alkyl (the
Kill part is C₁-C_ThreeAlkyl. ), Cyclohexyl
, Cyclohexylenealkyl (where the alkyl moiety is C
₁-C_ThreeAlkyl. ) Or having 1 to 3 substituents
C₁-C_FiveAn alkylene group;
, Hydroxyl, cyclohexylalkyl (the alkyl moiety
Is C₁-C_ThreeAlkyl. ), C₁-C_FourAlkyl,
Phenyl or benzyl. ｝ And R^bIs hydrogen
Atom or C₁-C_FourRepresents an alkyl group;^cIs the formula -C
(= NH) R^dIn the formula, R represents^dIs a hydrogen atom,
C₁-C_FourAlkyl group or formula -NR^eR^fGroup represented by the formula (formula
Medium, R^eAnd R^fAre, independently of one another, a hydrogen atom or C₁−
C_FourShows an alkyl group. ). Indicates｝. ]
5. The ring according to claim 1, wherein the ring forms
Carbapenem antibacterial agent (4) or a salt thereof
Method. 7. In R ² and R ³ , n is 0 or 1, p is 0 or 1, ^Ra is a hydrogen atom, a methyl or ethyl group, and B is 1,4. -Phenylene, 1,
4- cyclohexylene methyl, methylene, methylmethylene _{(-CH (CH 3) -)} , ethylene, trimethylene or 2-hydroxypropylene group, R ^b is a hydrogen atom, a methyl or ethyl group, R ^c is, The method for producing a carbapenem antibacterial agent (4) or a salt thereof according to claim 6, which is a formimidyl, acetimidoyl or amidino group. 8. In R ² and R ³ , n is 0 or 1, p is 0, ^Ra is a hydrogen atom or a methyl group, and B is methylene, methylmethylene (—CH (CH
₃₎ -), ethylene, trimethylene or 2-hydroxypropylene group, R ^b is hydrogen atom or a methyl group, R ^c is an amidino group, carbapenem antibacterial agent according to claim 6 (4 ) Or a method for producing the salt thereof. 9. In R ² and R ³ , n is 0 or 1, p is 0, ^Ra is a hydrogen atom, and B is
The carbapenem antibacterial agent (4) according to claim 6, wherein methylene, methylmethylene (—CH (CH ₃ ) —) or an ethylene group, R ^b is a hydrogen atom, and R ^c is an amidino group. Or a method for producing a salt thereof. 10. The method for producing a carbapenem antibacterial agent (4) or a salt thereof according to any one of claims 1 to 9, wherein L is a diarylphosphoryloxy group. 11. The method for producing a carbapenem antibacterial agent (4) or a salt thereof according to any one of claims 1 to 9, wherein L is a diphenylphosphoryloxy group. 12. The method for producing a carbapenem antibacterial agent (4) or a salt thereof according to any one of claims 1 to 11, wherein the compound (1) has a (2S, 4S) configuration. 13. A compound of the formula [Wherein, R ¹ represents a C ₁ -C ₃ alkyl group. Or a salt thereof. 14. The compound (1) or a salt thereof according to claim 13, wherein R ¹ is a methyl group. 15. The compound (1) or a salt thereof according to claim 13, wherein the compound (1) has a (2S, 4S) configuration. 16. A compound of the formula [Wherein, R ¹ represents a C ₁ -C ₃ alkyl group. An acid anhydride is allowed to act on the compound (5) or a salt thereof represented by the formula: [Wherein, R ¹ has the same meaning as described above. Or a salt thereof. 17. The method for producing a compound (1) or a salt thereof according to claim 16, wherein R ¹ is a methyl group. 18. The method for producing a compound (1) or a salt thereof according to claim 16 or 17, wherein the compound (5) has a (2S, 4S) configuration or a (2R, 4R) configuration. 19. The method for producing a compound (1) or a salt thereof according to claim 16, wherein the compound (5) has a (2S, 4S) configuration.