WO2008047909A1

WO2008047909A1 - Novel method for production of 1-methylcarbapenem and novel intermediate

Info

Publication number: WO2008047909A1
Application number: PCT/JP2007/070451
Authority: WO
Inventors: Kinichi Tadano; Masayuki Okue; Yumiko Okada; Keiichi Ajito
Original assignee: Meiji Seika Kaisha, Ltd.
Priority date: 2006-10-20
Filing date: 2007-10-19
Publication date: 2008-04-24
Also published as: JP2010018521A

Abstract

Disclosed is a production method which can synthesize a 1-methylcarbapenem antibacterial agent in a short process. The method comprises the steps of: acylating and oxidizing 1-methylthienamycin or an analogue thereof to convert a sulfide into a sulfoxide in 1-methylthienamycin or the analogue, thereby producing a compound represented by the formula below; and introducing a side chain into the compound to replace the sulfoxide group with the side chain, thereby producing the carbapenem antibacterial agent. The method enables to produce a 1-methylcarbapenem antibacterial agent in a short process while maintaining the configuration at position-1, position-5, position-6 and position-8.

Description

Specification

New production method and new intermediate of 1-methylcarbapenems

Related applications

[0001] This application claims the priority of Japanese Patent Application No. 2006-286734 filed on October 20, 2006, and the specification of this Japanese application is incorporated herein by reference. It is considered a part.

Technical field

The present invention relates to a novel method for synthesizing 1-methylcarbapenem antibacterial agents and novel intermediates. Specifically, a novel synthetic method for producing clinically useful 1-methylcarbapenem antibacterial agents, whether oral or injectable, starting from 1 methylcenamycin or its analogs, and its It relates to novel intermediates used in the process.

Background art

[0003] The powerful rubapenem antibacterial agent has both strong antibacterial activity and high safety, and is classified as a clinically useful injection antibacterial agent. Biapenem (BIPM), an example of injectable rubapenem, is Staphylococcus, Streptococcus, Streptococcus pneumoniae, Enterococcus (except Enterococcus faecium), Moraxella, Escherichia coli, Citrobacter, Klebsiella, Prevents the development of microorganisms of the genus Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Acinetopacter, Peptostreptococcus, Battateroides, Prevotella, and Fusovaterium, and sepsis, secondary infection of chronic respiratory disease, Effective for pneumonia, pulmonary abscess, pyelonephritis, complicated cystitis, peritonitis, etc. In addition, strong rubapenem antibacterial agents have been approved for use in children with fewer side effects than quinolone antibacterial agents that are mainly used orally in Japan. Furthermore, in Japan, clinical development of oral carbapenem, tebipenem pivoxil (both ME1211! / ゝぅ), which is highly effective against Streptococcus pneumoniae and Haemophilus influenzae, including resistant bacteria, is the first trial in the world. Go ahead with the mold!

[0004] However, unlike other β-latatam antibiotics, commercially available strong rubapenem antibacterial agents depend on chemical synthesis and are manufactured by chemical modification. The problem is that the manufacturing cost is high compared to antibiotics. Until now Various research institutes including pharmaceutical companies and universities have studied various effective methods for producing useful lubapenem antibacterial agents themselves or important synthetic intermediates for producing them.

[0005] Here, the structure of the powerful rubapenem antibacterial agent and its physicochemical and biological properties will be briefly confirmed. 1976 The world's first isolated and structurally determined rubapenem antibiotic chemamycin, the first carbapenem antibacterial agent imipenem, and panip The structures of nem (Japan only) are all unsubstituted at position 1 of the force Norabapenem skeleton. On the other hand, 1 of the carbopenem antibacterial agents for injection, meropenem, biapenem, ertapenem (US and Europe only), and dripenem (Japan only) Each position has a 1/3 methyl structure in which the methyl group is substituted on the front side of the page. In the case of having the same 2-position side chain structure, a compound having an unsubstituted structure at the 1-position may have stronger in vitro antibacterial activity, but a compound having a β-methyl structure. Have been reported to have excellent chemical and biological stability (Tetrahedron Lett., 26, 587-590, 1985, Heterocycles, 21, 29-40, 1984, J. Antibiot., 46, 1629-1632, 1993). In addition, there is no report that the derivative of the 1a methyl structure in which the methyl group at the 1-position was substituted from the back side of the paper showed superior properties as an antibacterial agent than the corresponding 1β-methyl. Therefore, the evaluation that a powerful rubapenem antibacterial agent generally having a 1/3 methyl structure is clinically useful is becoming increasingly established today.

[0006] Therefore, one of the important keys to constructing the clinically useful force Lubapenem skeleton by synthetic chemical methods or biochemical methods is to construct a methyl group stereoselectively at the 1-position. That is. When controlling the stereochemistry of the 1-position methyl group and synthesizing 1 β-methylcarbapenem antibacterial agents, several important intermediates are known. For example, acetoxazetidinone (Α), β-methylcarboxylic acid (Β), enol phosphate HC) represented by the following formula is known. The conventional manufacturing method goes through these sequentially, and this method is basically still used (Heterocycles, 21, 29-40, 1984, Tetrahedron, 52, 331-375, 1996).

[Chemical 1]

Cenamycin 1_Methylcenamycin

[Wherein, TBS represents a t-butyldimethylsilyl group, PNB represents a p-nitrobenzyl group, and Ph represents a phenyl group. ]

As described above, the 1 β-methylcarbapenem antibacterial agent that has many steric asymmetries as well as the 1 β methyl group is currently largely dependent on chemical synthesis. In addition, the three-dimensional retention, which is expensive to manufacture compared with other / 3-ratata antibiotics, and the number of steps are extremely high!

[0007] In the production of force rubapenem antibacterial agents, the construction of the 2-position side chain is performed in the latter half of force rubapenem synthesis, specifically, as an example of introducing side chain substitution via sulfoxide. , J.

Forces known to Antibiot., 36, 407-415, 1983 and J. Antibiot., 42, 1520-1522, 1989. All of these examples are based on force rubapenem compounds without 1 methyl group. In addition, in the example described in the former literature, the stereochemistry at the 8-position is opposite to that of clinically useful force rubapenem, and in the latter literature, the example described in 8 A fluorine atom is bonded to the position, and the substituent at the 8-position is not a hydroxyl group.

[0008] In addition, for the synthesis of Νacetylyl 1 / 3-methyl chenamycin and its para nitrobenzyl ester using enol phosphate HC) as a synthetic intermediate,

-59581 discloses.

[0009] In addition, rubapenems isolated from nature such as chenamicin include CRC

Crit. Rev. BiotechnoL, 4 (1), 111-131, (1986), but there is no disclosure of a compound group having a methyl group at the 1-position of the force rubapenem ring. Summary of the Invention

[0010] The present inventors have recently developed a variety of clinically useful 1-methylcarbapenem antibacterial agents from 1-methylcenamycin or its analogs, including but not limited to injections and oral agents. An efficient method of synthesizing in a short process was established while maintaining this. We have also found new synthetic intermediates useful in the method. The present invention is based on these findings.

Accordingly, an object of the present invention is to provide an efficient method for synthesizing a 1-methylcarbapenem antibacterial agent with a short process and maintaining a three-dimensional structure.

[0012] Another object of the present invention is to provide a novel synthetic intermediate useful in the method according to the present invention.

[0013] The production method according to the present invention is a method for producing a compound of the following general formula (I),

[Wherein, R ² represents a hydrogen atom, a group that can be hydrolyzed in vivo, a protecting group for a carboxyl group, or a carboxylate anion, and R ³ represents an organic group. ]

ω Compounds of the following general formula (Π):

[Chemical 3]

[Wherein R ^la represents a hydrogen atom or a acyl group, R 1 represents a hydrogen atom, a group that can be hydrolyzed in vivo, or a protecting group for a carboxyl group, and a dotted line represents a single bond or a double bond. ]

Is subjected to an oxidation reaction, and when R ^la is a hydrogen atom, it is acylated and the following general formula (III):

[Chemical 4]

(ΙΠ)

[Wherein R ^lb represents a acyl group, R ^2a has the same meaning as defined above, and the dotted line represents a single bond or a double bond. ]

To obtain a compound of

(ii) reacting the compound of general formula (III) with the compound of formula (IV): R ³ SH (wherein R ³ is as defined above) to give a compound of general formula (I ). The novel intermediate compound according to the present invention is a compound represented by the following general formula (V), or a salt or solvate thereof.

[Chemical 5]

[Wherein R ^le represents a acetyl group or a formyl group, R represents a hydrogen atom, hydrolyzed in vivo Represents a protecting group for a carboxyl group, n represents 0 or 1, the dotted line represents a single bond or a double bond, provided that R ^le represents a acetyl group and R ^2a represents a hydrogen atom. Or a compound that represents a paranitrobenzyl group, where n is 0 and the dotted line is a single bond. ]

[0015] According to the method of the present invention, 1 methyl cenamycin or an analog thereof is used as a synthetic intermediate, and it is not necessary to desorb an extra protecting group while maintaining a plurality of asymmetric carbon steric structures. In a short process, 1-methylcarbapenem antibacterial agents can be synthesized without limiting to injections and oral agents.

[0016] In particular, the present invention uses 1β methyl cenamycin or an analog thereof as a starting material, and maintains the 1-, 5-, 6-, and 8-positions in the above-mentioned intermediate state. Advantages of eliminating the need for deprotection of the 8-position hydroxyl-protecting group, and in some cases the carboxyl-protecting group such as ΡΝΒ-group, which are produced by known production methods using the compounds (Α) to (C) as starting materials and intermediates. As a result, it is a very advantageous method in that a 1β-methylcarbapenem antibacterial agent can be produced in a short process.

DETAILED DESCRIPTION OF THE INVENTION

[0017] Method for producing compound of formula (I)

If the method according to the present invention is displayed including its optional steps, it is as shown in the following flow chart 1.

Process diagram 1

[0018] (a) Production object: compound of formula (I)

In the method according to the present invention, the product of manufacture is the compound of the general formula (I) described above.

[0019] The compound represented by the general formula (I) is a 1-methinole (preferably 1β-methyl) canoleva penem antibacterial agent. Further, according to a preferred embodiment of the present invention, the method according to the present invention may be positioned as a method for producing such a prodrug of such a rubapenem antibacterial agent, a synthetic intermediate thereof, and the like.

[0020] Therefore, in the general formula (I), is a forceful rubapenem antibacterial agent currently useful clinically and a forceful rubapenem antibacterial agent that has been found to be clinically useful in the future. Represents a side chain attached through the sulfur atom at the 2-position of the ring. R ³ is a carbapenem antibacterial agent currently clinically useful, a prodrug of a powerful rubapenem antibacterial agent that has been found to be clinically useful in the future, and a synthetic intermediate of the force rubapenem ring. Represents a side chain bonded through the sulfur atom at the 2 position. In the present specification, the “organic group” represented by R ³ should be understood in the above meaning.

[0021] According to a preferred embodiment of the present invention, as currently useful clinically useful rubapenem antibacterial agents, for example, meropenem, biapenem, dripenem, enoletapenem, tevipenem biboxinole , CS-023 ((-)-(4R, 5S, 6S) -3- [[(3S, 5S) -5- [(S) -3- (2-guanidinoacetylamino)) pyrrolidine-1 -Ylcarbonyl] -1-methylpyrrolidine-3-yl] thio] -6-[(R) -l-hydroxyethyl] -4-methyl-7-oxo-azabicyclo [3.2.0] hept-2- -2-carboxylic acid), SMP-601 (or SM-216601), (1R, 5S, 6S) -6 _ ((1R) -1-hydroxyethyl) _2- [[(Z) -2- (4 -Hydroxymethylthiazole-5-yl) ethene-1-yl] thio] -1-methyl-1-strength rubapen-2-em-3-carboxylic acid and the like. Preferably, Biapenem (a), Eltapenem (b), Meropenem (c), Dripenem (d), Tevipenem Biboxinole (e), (1R, 5S, 6S) -6-(( lR) -l-Hydroxyethyl) -2-[[(Z) -2- (4-Hydroxymethylthiazol-5-yl) ethene-1-ynole] thio] -1-methyl-1-force rubapene- 2-em-3-carboxylic acid (f), CS — 023 (g), and the “side chain”, that is, the specific structure of R ³ is as shown in (a) to (g) below.

[Chemical 7]

In this general formula (I), R ² represents a hydrogen atom, a group that can be hydrolyzed in vivo, or a protective group for a carboxyl group, or a carboxylate anion.

Here, the group that can be hydrolyzed in vivo is preferably an ester residue, and specific examples thereof include a lower alkyl group, a lower alkenyl group, a lower alkylcarbonyloxy group, a lower alkyl group, and a lower cyclo group. Alkylcarbonyloxy lower alkyl group, lower cycloalkylmethylcarbonyloxy lower alkyl group, lower alkenylcarbonyloxy Si lower alkyl group, aryloxycarbonyl lower alkyl group, tetrahydrofuranyl carbonyloxymethyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, aryl methyloxy lower alkyl group, aryl methyloxy lower alkoxy Lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxycarbonyloxy lower alkoxy group, lower cycloalkoxy force sulfonyloxy lower alkyl group, lower cycloalkylmethoxycarbonyloxy lower alkyl group, aryloxycarbonyloxy Lower alkyl group, 3 phthalidyl group which may have a substituent on an aromatic ring, 2— (3 phthalidylidene) ethyl group which may have a substituent on an aromatic ring, 2 oxotetrahydrofuran 5yl group The Lower alkylaminocarbonyloxymethyl group, di-lower alkylaminocarbonyloxymethyl group, 2-oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl group, may have substituents V ヽCommonly used ones such as piperidinylcarbonyloxy lower alkyl group, lower alkyl lower cycloalkylaminocarbonyloxy lower alkyl group and the like can be mentioned.

According to a further preferred embodiment, the group that can be hydrolyzed in vivo is preferably a methinole group, an ethyl group, a 1- (cyclohexenooxycanoleponinoreoxy) ethinore group, an acetoxymethyl group, a 1- (Isopropyloxycarbonyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, bivalyloxymethyl group, cyclohexyloxycarbonyl group, 1- (isobutyloxycarbonyloxy) ethyl group 1- (cyclohexyloxycarbonyloxy) -2-methylpropane-1-yl group, isobutyloxycarbonyloxymethyl group, isopropyloxycarbonyloxymethyl group, isobutyryloxymethyl group, (Pentane-1-yl) oxycarbonyloxymethyl group, (butane-1-yl) oxy group norbornyloxymethyl group, 1-Ethylpropane-1-yl) oxycarbonyloxymethyl, isopentyloxycarbonyloxymethyl, (propane-1-yl) oxymethyl, ethoxycarbonyloxymethyl, neopentyloxycarbo Dioxymethoxy group, methoxycarbonyloxymethyl group, cyclopentyloxycarbonyloxymethyl group, t-butoxycarbonyloxymethyl group, phthalidyl group, 1- (methoxycarbonyloxy) ethyl group, 1- (cyclopentyloxycarbonyl) Oxy) ethyl group, (tetrahydropyran-4-yl) oxycarbonyloxymethyl group, 1- (neopentyloxycarbonyl) Oxy) ethyl group, (piperidin-1-yl) carbonyloxymethyl group, allyl group, i- (t-butoxycarbonyloxy) ethyl group, (N, N-di-n-propylamino) carbonyloxymethyl Group, phenyloxycarbonyloxymethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, (cis-2,6-dimethylbiperidine-1 -Yl) carbonyloxymethyl, N, N-di- (butan-1-yl) aminocarbonyloxymethyl, hexane-1-yl, N- (hexane-1- ) -N-methylaminocarbonyloxymethyl group, N, N-diisoptinobutylaminocarbonyloxymethyl group, N, N-diisopropylaminocarbonyloxymethyl group, N-cyclohexyl-N-methylamino Carbonyloxymethyl group, N-pentane-1-ylaminocarbonyloxymethyl group, N- Rohexyl-N-ethylaminocarbonyloxymethyl group, N-isobutyl-N-isopropylaminocarbonyloxymethyl group, Nt-butyl-N-ethylaminocarbonyloxymethyl group, 1-[(cis- 2,6-dimethylbiperidine-1-yl) carbonyloxy] ethyl group, 1- (N, N-diisopropylaminocarbonyloxy) ethyl group, N-ethyl-N-isoamylaminocarbonyloxy A methyl group is mentioned.

[0025] Further, the protective group for carboxyl group is Protective Groups in Organic Synthesis (T.

W. Greene et al., Wiley, New York (1999)) and the like, and those well known to those skilled in the art can be cited as examples. Examples include a lower alkyl group, an optionally substituted benzyl group, a silyl protecting group, an aryl group, a triphenylmethyl group, a diphenylmethyl group, and the like. For example, a methyl group, an ethyl group, a tbutyl group, Aryl group, benzhydryl group, 2-naphthylmethyl group, benzyl group, t-butyldimethylsilyl (abbreviated as TB DMS) group, phenacyl group, p methoxybenzyl group, o ditrobenzyl group, p-methoxyphenyl group, p Nitrobenzyl group, 4-pyridinoremethinole group, triphenylenomethyl group, diphenylmethyl group, etc., preferably methyl group, t-butyl group, benzyl group, 4-methoxybenzyl group, 4-nitro group Examples thereof include a benzyl group, an aryleno group, a triphenylenomethinole group, and a diphenylmethyl group.

[0026] Specific examples of the "acyl group" as a group or a part of the group include forminole group, acetyl group, propionyl group, butyryl group, bivaloyl group, isobutyryl group, valerinole group. , A benzoyl group, a phthaloyl group, an arylcarbonyl group, a heterocyclic carbonyl group, a case where a C-terminus of an oligopeptide is bound, such as a pentyl group. In addition, the above “halogen atom” means fluorine, chlorine, bromine, or iodine.

In the above, the alkyl group or the alkoxy group as a group or a part of the group means a linear or branched, cyclic alkyl group having 16 carbon atoms, preferably 14 carbon groups or an alkoxy group. means. Here, examples of the “alkyl group” as a group or a part of the group include methyl, ethyl, n propyl, isopropyl, n butyl, i-butyl, s butinole, t-butinole, n-pentinole, neopentinole, i-pentinole. T-pentinole, n-hexenole, i-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like S. Examples of an “alkoxy group” as a group or a part of a group include methoxy, ethoxy, n propoxy, i propoxy, n butoxy, s butoxy, t butoxy, n pentyloxy, neopentyloxy, i pentyloxy, t-pentyloxy, n-hexyloxy, i-hexyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

In the above, “aryl group” as a group or part of a group means a phenyl group or a naphthyl group.

[0030] According to a preferred embodiment of the present invention, in the general formula (I), a compound in which the methyl group at the 1-position represents the β-position and the arrangement power at the 8-position is preferred. This configuration is obtained in principle by the following production method, and the configuration of the compound of the general formula (II) and the compound of the general formula (VI) as starting materials is preserved. This preservation of configuration is one of the advantages of the method according to the invention.

[0031] (b) Starting material 晳: compound of general formula (II)

In the method according to the present invention, the compound represented by the general formula (II) is a starting material, and this compound must be prepared.

[0032] The compound of the formula (II) is preferably prepared as follows from the compound represented by the general formula (VI) as described in the above-mentioned process chart 1.

[0033] The compound represented by the general formula (VI) is 1 methyl (preferably 1 β-methyl) chenamycin (a compound in which the dotted line is a single bond), or 1 methyl (preferably 1 β-methyl) -dehydro chenamicin (dotted line). Are double bond compounds), both of which can be prepared by known methods It is. For example, 1 β-methinoretenamycin can be prepared by the method described in Tetrahedron Lett., 26, 587-590, 1985 (Non-patent Document 1). In addition, the culture method described in the specification of Japanese Patent Application No. 2006-84348 can also be prepared without using enol phosphatate.

Next, the free amino group in the general formula (VI) is acylated to obtain a compound in which R ^2a is a hydrogen atom among the compounds represented by the formula (II). Here, the introduced acyl group includes a formyl group, an alkylcarbonyl group (preferably a C 1-6 alkylcarbonyl group), an aryl group (wherein the aryl group preferably represents phenyl or naphthyl). Examples include amino acids such as pantothel groups and those linked to the C-terminus of oligopeptides. Specific examples thereof include formyl group, acetyl group, propionyl group, butyrinol group, bivaloyl group, isobutyryl group, valeryl group, benzoyl group. And a phthaloyl group, preferably a formyl group, a acetyl group, a propionyl group, a benzoyl group, and a pantotenyl group.

[0035] The method of acylation may be appropriately determined according to the acyl group to be introduced. For example, in the case of formylation, as the formylation reagent, formic acid anhydride or formic acid and dicyclohexylcarbodiimide And a condensing agent. The reaction is generally carried out in the presence of a solvent, and an organic solvent is preferred as the reaction solvent.For example, use of 1,4 dioxane, tetrahydrofuran, methylene chloride, chloroform, or carbon tetrachloride is preferred. Tetrahydrofuran is preferred. In the case of acetylation, acetic anhydride and acetylated halogen such as acetylyl chloride can be used as the acetylating reagent, and acetic anhydride is preferred. A base may be used to promote the reaction. The base may be an organic base such as triethylamine, an inorganic base such as sodium bicarbonate, or a mixture thereof. . A method using sodium bicarbonate as the base or not using a base is preferred. In the reaction, an organic solvent as a reaction solvent may be used alone or mixed with water. As the organic solvent, 1,4 dioxane, tetrahydrofuran, methanol, ethanol, pyridine can be used, and preferably tetrahydrofuran. A mixed solvent of water and water, or a single solvent of methanol. It is also possible to acetylate in anhydrous tetrahydrofuran with acetic anhydride using sodium hydrogen carbonate as a base. is there. In this case, the carboxyl group is isolated as a sodium salt.

[0036] Further, as an acylation means, for example, an acetylyltransferase, which is an acetylyltransferase, may be used to acylate the amino group such as acetylation. Therefore, the present invention also includes a method for carrying out the acylation of the amino group by a method not based on chemical synthesis, such as microbial conversion or enzymatic conversion.

[0037] Next, in formula (II), the compound R ^2a is a hydrogen atom, optionally, be converted to a compound R ^2a is represented by a group other than a hydrogen atom. When a protective group for a carboxyl group is introduced as R ^2a , the above-mentioned conventional protective group can be introduced by a conventional method. According to a preferred embodiment of the present invention, preferred examples of the carboxyl group as R ^2a include a paranitrobenzyl group, a paramethoxybenzyl group, a benzyl group, and an aryl group.

[0038] When R ^2a is a group that can be hydrolyzed in vivo, the introduction thereof includes a compound of formula (II) in which R ^2a is a hydrogen atom and a halide compound of a group that can be hydrolyzed in vivo. This can be done by reacting. Specifically, for the compound of the formula (II) which is an R ² hydrogen atom, a halide compound of a group that can be hydrolyzed in vivo in the presence of a catalytic amount or an excess amount of a base, if necessary, alone or It can be obtained by reacting in a mixed inert solvent at −70 ° C. to 50 ° C. (preferably at −30 ° C. to 30 ° C.) for 10 minutes to 24 hours.

[0039] Here, specific examples of the halide compound having a group that can be hydrolyzed in vivo include methylol iodide, acetyl iodide, 1- (cyclohexyloxycarbonyloxy) ethyl iodide, bromomethyl acetate 1- (Isopropyloxycarbonyloxy) ethyl iodide, 1- (ethoxycarbonyloxy) ethyl iodide, odomethyl bivalate, cyclohexyl xydecanolepinoreoxymethinoreidoide, 1- (isobutinoreoxycanoide) Reponinoreoxy) ethreotide, 1- (cyclohexyloxycarbonyloxy) -2-methylpropane-1-yl iodide, isobutyloxycarbonyloxymethyl iodide, isopropyloxycarbonyloxymethyl Rhizobide, Isobutyryloxymethyl Ryodide, (Pentane-1-Inole) Cycarbonyloxymethyl iodide, (Butane-1-yl) oxycarbonyloxymethyl iodide, (1-Ethylpropane-1-yl) oxycarboxylmethyl iodide, Isopentyloxy Carbonyloxymethyl iodide, (propane-1-yl) o Xymethyl iodide, ethoxycarbonyloxymethyl iodide, neopentyloxy shicanoreponinole ximethinoredoide, methoxycanoleponinole ximethinoredoide, cyclopentyloxycarbonyloxymethyl iodide, t_ Butoxycarbonyloxy methyl iodide, 3-bromophthalide, 1- (methoxycarbonyloxy) ethyl iodide, 1- (cyclopentinole-xicanoreponino-reoxy) etino-reotide, (tetrahydropyran-4-inole) Oxycarbonyloxymethyl iodide, 1- (neopentyloxycarbonyloxy) ethyl iodide, (piperidine-1-yl) carbonyloxymethyl iodide, aralkyl iodide, l- (t_butoxycarbonyloxy ) Ethylchoide, N, N-di (propane-1) -Yl) aminocarbonyloxymethyl iodide, phenyloxycarbonyloxymethyl iodide, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl bromide, (Z)- 2- (3_phthalidylidene) ethyl bromide, (cis-2,6-dimethylbiperidine-1-yl) carbonyloxymethyl chloride, chloromethyl N, N-di-n butylcarbamate, 1 iodine Hexane, chloromethyl Nn-hexyl-N-methylcarbamate, chloromethyl N, N-diisobutylcarbamate, chloromethyl N, N-diisopropylcarbamate, chloromethyl N-cyclohexole-N-methylcarbamate Methyl, N-pentane-1-ylcarbamate chloromethyl, N-cyclohexyl-N-ethylcarbamate chloromethyl, N-isobutyl-N-isopropylene chloromethyl rubamate, Nt-butyl -N-ethylcarbamate chloromethyl, Ν, Ν-diisopropyl-powered rubamate-1-chloroethyl, 1-[((^-2,6-dimethylpiperidine-1_yl) carbonyloxy] ethyl Chloride, Ν-ethyl-Ν-isoamylcarbamate chloromethyl and the like.

[0040] In addition, as the organic base, which may be an organic base or an inorganic base, diisopropylethylamine, 1,8 diazabicyclo [5.4.0] -7 Examples of inorganic bases include sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and cesium carbonate.

[0041] Preferable! / As the inert solvent, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, Ν, Ν-jetylformamide, Ν, Ν-jetylacetamide, Ν- Methylpyrrolidinone, Ν, Ν-dimethylimidazolidinone, dimethyl sulfoxide, sulfolane, acetonitrile, acetone, Examples thereof include ethyl acetate, tetrahydrofuran, 1,4 dioxane, jetyl ether, anisole, dichloromethane, 1,2-dichlorodiethane, chlorophonolem, tonoleene, benzene, hexamethylphosphoric triamide, methanol, ethanol and the like.

[0042] In one embodiment of the present invention, when a bivalyloxymethyl group is introduced as a group that can be hydrolyzed in vivo, the reaction reagent is bivalyloxymethyl chloride or pivalyloxymethyl iodide. It is preferable to use a halogenated bivalyloxymethyl, such as bivalyloxymethyl chloride. The base used for promoting the reaction may be an organic base such as triethylamine or an inorganic base such as sodium hydrogen carbonate, or a mixture thereof. Preferably, sodium hydrogen carbonate is used. The organic solvents that can be used alone or in combination with other organic solvents include 1,4 dioxane, tetrahydrofuran, N, N-dimethylformamide, dimethylolacetamide, and pyridine. Preferred is N, N-dimethylformamide.

[0043] It should be noted that the order of the acylation of the 2-amino group of the side chain of the compound of the general formula (VI) and the introduction of a group other than a hydrogen atom into the carboxyl group is as long as it does not interfere with the mutual reaction. , Especially not limited.

[0044] (c) Step (i)

The compound represented by the general formula (II) prepared as described above is regioselectively oxidized to obtain a compound represented by the formula (III). In this process, R ^la and R ^2a are not changed in principle.

[0045] This step is a step of converting a sulfide to a sulfoxide. If this oxidation reaction proceeds, the oxidizing reagent, reaction conditions, etc. may be appropriately selected and set! /.

[0046] According to a preferred embodiment of the present invention, an example of the reaction is an oxidation reaction with a peroxide. As the oxidizing agent, hydrogen peroxide and organic peroxide can be used, and as the organic peroxide, peracetic acid, perpropionic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperoxy acid are used. Magnesium phthalate hexahydrate can be used. Preferably, the use of 3-chloroperbenzoic acid is mentioned.

[0047] When the oxidation reaction is carried out using an organic peroxide, the reaction solvent is not particularly limited, but black form or methylene chloride is preferred. [0048] It is also possible to use oxidizing reagents other than peroxides. Examples of such oxidizing reagents include manganese dioxide, chromic acid, lead tetraacetate, ruthenium tetroxide, periodate (for example, Sodium metaperiodate), permanganate (eg, potassium permanganate), OXONE (registered trademark) (manufactured by DuPont), N-halocarboxylic acid amide, hypohalite ester, eodecyl compound, oxygen , Nitric acid, dinitrogen tetroxide, dimethyl sulfoxide, ethyl azodicarboxylate, chloro (II) acid, anodic oxidation and the like.

[0049] When a sulfide is oxidized to be converted into a sulfoxide, the state of formation of the stereoisomer of the sulfoxide varies depending on the structure of the molecule. Usually, the stereochemistry of sulfoxide is almost 1: 1, but it can be used as a mixture in the next step or isolated! From the viewpoint of efficiency, it is preferable to use the mixture as it is! /, In many cases! /. It is also possible to synthesize sulfoxide stereoselectively by appropriately setting the oxidation reaction conditions, and to carry out the oxidation reaction using a single stereochemistry, and this embodiment is also included in the present invention.

[0050] In this step, that is, the reaction of oxidizing a sulfide to convert it to a sulfoxide, as long as the compound to be subjected to the step (described later) is a compound in which R ^la is an acyl group, the above R ^la is a hydrogen atom. It may be performed before or after the acylation of a compound represented by the general formula (II).

[0051] (d) Step (ii)

In this step, formula (IV): RH (where R ³ represents an “organic group”) is introduced at the 2-position of the compound represented by general formula (III), and represented by formula (I) To obtain a compound. In this reaction, the sulfoxide group of the compound of general formula (I II) acts as a leaving group, and the 2-position side chain (one SR ³ group) containing the above-mentioned “organic group” is located at the 2-position of the force rubapenem skeleton be introduced.

[0052] Although the reaction conditions may be appropriately determined according to the structure of the “organic group”! /, For example, the reaction is preferably carried out in the presence of a base in order to promote the reaction. As the base, any of an organic base such as triethylamine and an inorganic base such as sodium hydrogen carbonate can be used, and they may be used in combination. A preferred base is diisopropylethylamine. The organic solvents that can be used alone or in combination with other organic solvents include 1,4-dioxane, tetrahydrofuran, N, N-dimethyl. Examples include ruhonolemamide, dimethinoreacetamide, and acetonitrile. Acetonitrile is preferred. In addition, this reaction proceeds well under conditions from which moisture has been removed. The reaction temperature is generally 20 ° C to 50 ° C, preferably 0 ° C to 30 ° C, and the reaction time is generally 10 minutes to 10 hours, preferably 1 hour to 3 hours. .

[0053] Novel, intermediate: compound of general formula (V)

According to the present invention, a novel synthetic intermediate useful for the synthesis of a compound of general formula (I) is provided. The novel synthetic intermediate is a compound represented by the above general formula (V). In formula (V), R ^le represents a Ashiru group, R ^2a represents a hydrogen atom, in vivo in hydrolyzable group or a protecting group of carboxyl group,, n represents 0 or 1, the dotted line represents a single A compound that represents a bond or a double bond, except that R ^le represents a acetyl group, R ^2a represents a hydrogen atom or a paranitrobenzyl group, n is 0, and a dotted line represents a single bond is excluded.

[0054] According to a preferred embodiment of the present invention, as a preferred group of compounds of the formula (V), R ^lc represents a acetyl group or a formyl group, R ^2a represents a hydrogen atom, a group that can be hydrolyzed in vivo, Or a protecting group for a carboxyl group, n represents 0 or 1, and a group of compounds in which a dotted line represents a single bond or a double bond is exemplified.

[0055] The compound of the general formula (V) may be a salt thereof, and is preferably a pharmaceutically acceptable salt. Specific examples thereof include inorganic salts such as lithium, sodium, potassium, calcium and magnesium, or salts with organic bases such as ammonium salt, triethylamine and diisopropylethylamine, or hydrochloric acid, sulfuric acid and phosphoric acid. , Salts with mineral acids such as nitric acid, or salts with organic acids such as acetic acid, carbonic acid, citrate, malic acid, oxalic acid, methanesulfonic acid, sodium salt, potassium salt, or hydrochloride Is preferred.

[0056] The compound of the general formula (V) may be a solvate. Examples of the solvent include water, methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, chlorophenol and the like. Examples of preferred solvates include hydrates.

[0057] According to a preferred embodiment of the present invention, in the general formula (V), a compound in which the methyl group at the 1-position represents the β-position and the arrangement power at the 8-position is preferred.

Example

[0058] The ability to explain the present invention in more detail with reference to the following examples. It is not limited.

[0059] Example 1

Preparation of a compound of formula (II) where _R ifl is acetylyl, is a hydrogen atom, and the dotted line is a single bond (N-acetylyl 1; 3 -methylcenamycin):

217 mg (0.758 mmol) of 1 β-methylcenamycin was dissolved in 10 ml of methanol, and 0.11 ml of acetic anhydride was added at 0 ° C. The reaction was performed at room temperature for 1 hour, and the reaction solution was concentrated under reduced pressure to dryness. The obtained residue was purified by MCI (registered trademark) GEL CHP20P (manufactured by Mitsubishi Chemical) (20 g, H 0 → 9% aq. THF). This was then lyophilized to give 117 mg (47%) of the title compound as a colorless syrup.

[0060] The title compound is disclosed in Japanese Patent Publication No. 7-59581 (Patent Document 1), and can also be obtained from enol phosphate as described in the document.

[0061] Example 2

Preparation of a compound of formula (II) in which is is acetyl 某, is bivalyloxymethyl 、, and the dotted line is a single bond (N-acetylyl 1; 3-methylmethylenamycin bivalerooxymethyl ester):

122 mg (0.372 mmol) of the compound obtained in Example 1 (N-acetylyl 1 / 3-methylcenamycin) was dissolved in 5.0 ml of N, N-dimethylformamide, and 0.20 ml (1.38 ml) of bivalloylshimetinole chloride at room temperature. mmol) and 300 mg (3.57 mmol) of sodium hydrogen carbonate) and stirred at room temperature for 25 hours. The reaction was stopped by adding 50 ml of saturated brine, and extracted three times with 50 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (20 g, chloroform: 2: 1) → acetone) to give 103 mg (6 3%) of the title compound as a colorless syrup. Obtained.

[0062] Specific rotation: [α] ²⁴ + 121 ° (c 3.3, CHC1)

D 3

Mass spectrometry: HR FAB MS: found: 443.1854, calcd: 443.1852 as C H O N S

20 31 7 2

^: H NMR (270 MHz, CDC1): δ 1.22 (s, 9H), 1.23 (d, 3H, J = 6.2 Hz), 1.32 (d, 3H

Three

, J = 6.2 Hz), 1.99 (s, 3H), 2.84 (m, 1H), 3.10 (m, 1H), 3.23-3.34 (m, 3H), 3.51-3.6 2 (m, 2H), 4.19-4.26 (m, 2H), 5.83 (d, 1H, J = 5.5 Hz), 5.95 (d, 1H, J = 5.5 Hz), 6. 49 (br, 1H)

¹³ C NMR (68 MHz, CDC1): δ 16.8, 21.6, 23.0, 26.8 x 3C, 30.8, 38.7, 39.9, 43.0,

Three

56.0, 59.9, 65.7, 79.6, 124.3, 152.4, 159.5, 171.0, 172.9, 177.2

Preparation of a compound of formula (III) in which _R lh is acetylyl 某, is bivalyloxymethyl 某 and the dotted line is a single bond (N-acetylyl 1; 3 methylcenamycin bivalyloxymethyl esterenole S oxide) :

66.2 mg (0.150 mmol) of the compound obtained in Example 2 (N-acetylyl 1/3 methyl chenamycin bivalloy ruoxymethyl ester) was dissolved in 2.0 ml of methylene chloride, and 3 ° C. 43.8 mg (0. 165 mmol) of acid was added and reacted at 18 ° C for 20 minutes. The reaction solution was diluted with 5.0 ml of methylene chloride, and the organic layer was washed successively with 5.0 ml of saturated aqueous sodium hydrogensulfite solution and once with saturated aqueous sodium hydrogencarbonate solution. The organic layer was then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (2 g, black form: acetone (1: 5) → same (1:10)) to give 35.0 mg of the title compound as a colorless syrup ( 51%). Incidentally, the stereochemistry of the sulfoxide of the compound was almost 1: 1.

Specific ^{rotation: [α] 24 - 19 °} (c 1.8, CHC1)

D 3

Mass spectrometry: HR FAB MS: found: 459. 1801, calcd: 459. 1801 as C H O N S

20 31 8 2

^: H NMR (270 MHz, CDC1): δ 1.23 (s, 9H x 0.5), 1.23 (s, 9H x 0.5), 1.24 (d, 3H

Three

x 0.5, J = 7.3 Hz), 1.32 (d, 3H x 0.5, J = 6.2 Hz), 1.37 (d, 3H x 0.5, J = 7.3 Hz), 1.41 (d, 3H x 0.5, J = 7.7 Hz), 2.01 (s, 3H x 0.5), 2.03 (s, 3H x 0.5), 3. 14-3.47 (m, 3 H), 3.66-3.90 (m, 3H), 4.23-4.48 (m, 2H) , 5.81 (d, 1H x 0.5, J = 5.5 Hz), 5.85 (d, 1 H x 0.5, J = 5.5 Hz), 5.90 (d, 1H x 0.5, J = 5.5 Hz), 5.94 (d, 1H x 0.5, J = 5.5 Hz), 6.66 (br s, 1H x 0.5), 6.75 (br s, 1H x 0.5)

1 ³ C NMR (68 MHz, CDC1): δ 16.5 x 0.5C, 17.4 x 0.5C, 21.48 x 0.5C, 21.5 x 0.5

Three

C, 23.0, 26.8 x 3C, 34.5 x 0.5C, 35. 1 x 0.5C, 38.8 x 0.5C, 39.3 x 0.5C, 40.2, 54.3 x 0.5C, 55.2 x 0.5C, 56.5 x 0.5C, 56.9 x 0.5 C, 59.6 x 0.5C, 61.0 x 0.5C, 65.0 x 0.

5C, 65.1 x 0.5C, 79.8 x 0.5C, 80.1 x 0.5C, 129.6 x 0.5C, 129.9 x 0.5C, 154.4 x 0.5 C, 155.2 x 0.5C, 158.2 x 0.5C, 158.3 x 0.5C, 170.8 x 0.5C, 171.3 x 0.5C, 173.6 x 0.5C, 177.2 x 0.5C

Example 4

[Chemical 8]

(e)

Preparation of a compound of formula (I) (Tevipenem pivoxil):

35.0 mg (0.0765 mmol) of the compound obtained in Example 3 (N-acetylethyl 1 / 3-methylchenamicin bivalloy ruoxymethyl ester S-oxide) was dissolved in 5.0 ml anhydrous acetonitrile at 0 ° C. In an argon atmosphere, the following formula (h):

[Chemical 9]

20.5 mg of the compound represented by the formula and diisopropylethylamine 21 H 1 were sequentially added, stirred at 0 ° C. for 30 minutes, and further reacted at room temperature for 2 hours. To the reaction solution, 25 ml of saturated brine was added, and the aqueous layer was extracted three times with 25 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (10 g, chloroform-form: acetone (1:15) → acetone) to give 23.5 mg (62%) of the title compound as a colorless solid. It was.

[0064] The obtained compound was completely identified as tevipenem pivoxil produced by a known method in various physicochemical properties including ^{: 1} H NMR spectrum!

[0065] Example 5

Preparation of a compound of formula (II) wherein N is acetylyl 某, R ² is bivalyloxymethyl 某 and the dotted line is a single bond (N-acetylyl 1; 3-methylmethylenamycin bivalyloxymethyl ester) : 1β-Methylchenamycin 163 mg (0.569 mmol) was dissolved in methanol 10 ml, and acetic anhydride 80 1 (0.85 mmol) was added at 0 ° C. The reaction was allowed to proceed at room temperature for 1.5 hours, and the reaction solution was concentrated under reduced pressure to dryness. The obtained residue was dissolved in 10 ml of dimethylformamide, 0.20 ml (1.38 mmol) of bivaleroyloxymethyl chloride and 333 mg (3.96 mmol) of sodium hydrogencarbonate were sequentially added at room temperature, and the mixture was stirred at room temperature for 25 hours. The reaction was stopped by adding 50 ml of saturated brine, and extracted four times with 50 ml of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (80 g, black-form: acetone (2: 1) → acetone) to give the title compound as a colorless syrup 143 mg (57%) Got.

[0066] Production Example 1

Preparation of a compound of formula (Π) wherein is is acetyl 某, is sodium, and the dotted line is a single bond (N-acetyl-1; 3-methylchenamicin sodium salt):

1 β-methylcenamycin 22.0 mg (0.0768 mmol) was dissolved in 1.0 ml of 20% aqueous tetrahydrofuran, and acetic anhydride 11 1 (0.12 mmol) and sodium bicarbonate 64.5 mg (0.768 mmol) were added at 0 ° C. The reaction was performed at room temperature for 30 minutes, and the reaction solution was directly lyophilized. The obtained residue was purified by CHP-20P resin (2 g, H 0) to obtain 7.7 mg (29%) of the title compound as a colorless solid.

[0067] Mass spectrometry: FAB MS: m / z 351 (M + Na) ⁺ as CHONS + Na ⁺

14 20 5 2

^: H NMR (400 MHz, DO): δ 1.19 (d, 3H, J = 7.4 Hz), 1.27 (d, 3H, J = 6.4 Hz), 2. 00 (s, 3H), 2.83 (dt, 1H) , 3.07 (dt, 1H), 3.35—3.50 (m, 4H), 4.19 (dd, 1H), 4.25 (dt, 1H)

¹³ C NMR (100 MHz, CDC1): δ 18.8, 22.9, 24.7, 32.8, 42.4, 44.7, 58.7, 61.2, 68.

Three

1, 134.0, 144.7, 170.9, 177.2, 179.3

[0068] Example 6

Preparation of a compound of formula (II) wherein N is acetylyl 某, is paranitrobenzil (PNB) 某, and the dotted line is a single bond (N-acetylyl 1; 3-methylmethylenamycin paranitrobenzil ester):

1 β -Methylchenamycin 14.2 mg (0.0496 mmol) dissolved in methanol (1 mL) Hydroacetic acid (7 n 0.074 mmol) was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude N-acetyl-1-beta-methylcenamycin. Dissolve this in dimethylphenolamide (1 mL) without purification, add cesium carbonate (21.6 mg, 0.066 mmol) and paranitrobenzyl bromide (30.6 mg, 0.142 mmol) in this order, and react at room temperature for 2 hours. The disappearance of N-acetylcarboxylic acid was confirmed. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 mL X 3). The combined organic layers were dehydrated and concentrated under reduced pressure to give 10.3 mg (45%) of the title PNB ester.

[0069] The resulting compounds ^are: the H NMR, are prepared by known methods /, it was identified as identical to the Ru compound.

A compound of formula (V) in which _R is acetyl 某, is para nitrobenzil 、, _n is 1 and the dotted line is a single bond (N acetyl -1; 3-methylchenamycin para nitro benzyl ester S oxide) Manufacturing of:

The PNB ester (37.1 mg, 0.0800 mmol) obtained in Example 6 was dissolved in methylene chloride (1 mL), and m-cloperbenzoic acid (22.3 mg, 0.0840 mmol) was added at 18 ° C. .

After stirring at 18 ° C for 20 minutes, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride (2 mLX 3). The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (acetone-chloroform, 1: 2), and the title S-oxide (mixed approximately 1: 1) as a colorless syrup. ) Was obtained 25.9 mg (68%).

[0071] TLC R 0.12 (CHC1: acetone, 1: 1); [a] D ²⁶ +1.32 (c 1.30, CHC1); IR 3350, 2970, 17 f

^{^{90-1650 cm- 1;: H NMR (}} 270 MHz) δ 1.34 (d, 3H, J = 5.9 Hz), 1.42 (d, 3H, J = 7.7 Hz), 1.998 (s, 3HX1 / 2), 2.003 ( s, 3HX 1/2), 3.07—3.52 (m, 3H), 3.63—3.95 (m, 3H), 4.21-4.53 (m, 2H), 5.24 (d, 1HX1 / 2, J = 8.4 Hz), 5.29 (d, 1HX1 / 2, J = 8.4 Hz), 5.44 (d, 1H X 1/2, J = 9.9 Hz), 5.49 (d, 1H X 1/2, J = 9.9 Hz), 6.49 (br, 1H X 1/2), 6.61 (br, 1HX1 / 2), 7.64 (m, 2H), 8.23 (d, 2H, J = 8.8 Hz); ¹³ C NMR (68 MHz) δ 1 6.5X 1/2, 17.4 X 1/2, 21.6X 1/2, 21.7X 1/2, 23.1, 29.2, 34.8X 1/2, 35.3X 1/2, 39 • 2X1 / 2, 40.1X1 / 2, 54.0X1 / 2, 55.1 X1 / 2, 56.7X1 / 2, 57.1X1 / 2, 59.6X1 / 2, 60. 8X1 / 2, 65.0X1 / 2, 65.2X1 / 2, 66.3, 123.9, 128.2, 129.8, 141.5X1 / 2, 141.6X1 / 2 , 147.8, 154.3 X 1/2, 155.2 X 1/2, 159.4 X 1/2, 159.5 X 1/2, 170.6 X 1/2, 170.7 X 1/2, 171.4 173.6; HRMS calcd for CHONS (M + H ) ⁺ m / z 480.1441, found.480.144

21 25 8 3

Three

Example 8

N-paranitropenzinoreoxycanoreponino remeopenem No Lanitrobenzenore Estenore:

PNB ester (20.3 mg, 0.0438 mmol) was dissolved in methylene chloride (1 mL), and m-cloperbenzoic acid (12.8 mg, 0.0482 mmol) was added at 18 ° C. After stirring at 18 ° C. for 20 minutes, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride (2 mL × 3). The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure to obtain 21.0 mg of compound S-oxide as a colorless syrup. This compound was used in the next step without purification. The following reactions were performed in an argon atmosphere. Unpurified S oxide (21.0 mg) was dissolved in acetonitrile (1 mL), and ice-cooled, N-ethyldiisopropylamine (11 μ, 0.0632 mmol) and thiol corresponding to the meropenem side chain (formula (IV )-(c) PNZ (paranitrobenzyloxycarbonyl), 22.3 mg, 0.0632 mmol) of acetonitrile solution was added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with saturated brine and extracted with ethyl acetate (3 X 3 mL). The organic layers are combined, dried with sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (acetone-ethyl acetate, 1: 8 to 1: 4), and the title meropemem is fully protected as a colorless syrup. 9.3 mg (30% for 2 steps) was obtained.

The thiol and meropemem full protectors corresponding to the meropenem side chain are described in the literature Suna gawa, M .; Matsumura, Η; Inoue, Τ; Fukusawa, M .; ato, MJ Antibiot. 1990, 519- 532 is reported as a known compound. In addition, the deprotection to mepenem from the meropenem complete protector can be derived from the literature already disclosed.

The reaction steps of Examples 7 and 8 are as follows.

[Chemical 10]

PNB ester (ll) -PNB S-oxide (111) Merope book body (l)-(c) PNB-PNZ body

Claims

The scope of the claims

A method for producing a compound of the following general formula (I):

[Chemical 1

ω Compounds of the following general formula (Π):

[Chemical 2]

(Π)

[Wherein R ^la represents a hydrogen atom or an acyl group, R represents a hydrogen atom, a group that can be hydrolyzed in vivo, or a protecting group for a carboxyl group, and a dotted line represents a single bond or a double bond. ]

[Chemical 3]

(ΙΠ)

[In the formula, R ^lb represents a acyl group, is the same as defined above, and the dotted line represents a single bond or a double bond. ]

To obtain a compound of

(ii) reacting the compound of general formula (III) with the compound of formula (IV): RH (wherein R ³ has the same meaning as defined above) to give the general formula (I) To get

Comprising a method.

[2] The method according to claim 1, wherein the compound of the general formula (II) is obtained by acylating 1-methylcenamycin.

[3] The method according to claim 1 or 2, wherein R ^la or R ^lb represents a acetyl group or a formyl group.

4. The method according to any one of claims 1 to 3, wherein [4] represents any of the following (a) to (g).

[Chemical 4]

The method according to any one of claims 1 to 4, wherein in the general formulas (1), (II) and (III), the methyl group at the 1-position represents the / 3-position and the 8-position configuration is R. .

A compound represented by the following general formula (V) or a salt or solvate thereof.

[Chemical 5]

[Wherein R ^le represents a acetyl group or a formyl group, R represents a hydrogen atom, a group that can be hydrolyzed in vivo, or a protecting group for a carboxyl group, n represents 0 or 1, and the dotted line represents a single Represents a bond or a double bond, except that R ^le represents a acetyl group, R ^2a represents a hydrogen atom or a paranitrobenzyl group, n is 0, and a dotted line is a single bond. ]

[7] The compound according to claim 6, or a salt or solvate thereof, wherein the methyl group at the 1-position represents the β-position and has a configurational power at the 8-position.