JPH072857A - Production of carbapenem derivative and its intermediate - Google Patents

Abstract

PURPOSE:To obtain a new compound (salt), composed of a 1- phosphorandiylmethyl-3-thiocarbonylalkyl-2-oxoazetidine derivative and useful as an intermediate, etc., for producing carbapenem derivatives having antimicrobial action. CONSTITUTION:A 1-acyl-3-(alkylthio)thiocarbonylalkyl-2-oxoazeditine compound (salt) expressed by formula I [R<1> is (protected)carboxy; R<2> is (protected)hydroxy(lower)alkyl; R<3> is H or lower alkyl; R<4> is organic group] is reacted with a compound expressed by formula II [R<5> to R<7> are lower alkyl, lower alkoxy, (substituted)aryl, etc.] [e.g. diethoxy(methyl)phosphine] to afford the objective 2-oxoazeditine derivative expressed by formula III. Furthermore, the compound expressed by formula III is subjected to cyclizing reaction to provide this carbapenem derivative, expressed by formula IV and having high antimicrobial activity.

Description

Detailed Description of the Invention

[0001]

OBJECT OF THE INVENTION It is an object of the present invention to provide an industrial process for producing a carbapenem derivative or a salt thereof, an important intermediate thereof and a salt thereof, and a process for producing the intermediate.

[0002]

The object carbapenem derivative produced by the production method of the present invention can be represented by the following general formula (I).

[Chemical 14] [Wherein R ¹ represents carboxy or protected carboxy, R ² represents hydroxy (lower) alkyl or protected hydroxy (lower) alkyl, R ³ represents hydrogen or lower alkyl, and R ⁴ represents an organic group] In compound (I) and the intermediates described later, one or more pairs of stereoisomers such as optical isomers due to asymmetric carbon atoms may exist, and such isomers are also included in the scope of the present invention. According to the present invention, the object compound (I) or a salt thereof can be produced by the following processes.

Process 1:

[Chemical 15]

Process 2:

[Chemical 16]

Process 3:

[Chemical 17]

[Chemical 18] [Wherein R ¹ , R ² , R ³ and R ⁴ are each as defined above, R ⁴ _a is an organic group, R ⁵ , R ⁶ and R 4
⁷ is each lower alkyl, lower alkoxy, aryl optionally having one or more suitable substituents, or a formula:

[Chemical 19] (In the formula, R ⁸ and R ⁹ are each lower alkyl, or 1
Represents an aryl optionally having one or more suitable substituents). However, (i)
R ⁴ and R ⁴ _a are not the same, and (ii) R ⁵ , R ⁶ and R ⁷ are not the same at the same time.]

Suitable salts of the object compound (I) are conventional non-toxic salts, which include inorganic base salts such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth metal salts. (Eg calcium salt, magnesium salt etc.), ammonium salt, organic base salt, eg organic amine salt (eg triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N ′).
A salt with a base such as a dibenzylethylenediamine salt, a dibenzylamine salt, etc .; an inorganic acid addition salt (eg, hydrochloride, hydrobromide salt, sulfate, phosphate etc.), an organic acid addition salt (eg, Salts with acids such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate; basic or acidic amino acids (eg arginine, Salts with aspartic acid, glutamic acid, etc.);
Intramolecular quaternary salts and the like are included. In the above and subsequent description of the present specification, suitable examples and specific examples of various definitions included in the scope of the present invention will be described in detail below. The term "lower" means having 1 to 6 carbon atoms unless otherwise specified. Suitable "protected carboxy" includes esterified carboxy and the like.

Preferred examples of esterified carboxy ester moieties include lower alkyl esters (eg, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester,
Hexyl ester, etc.), lower alkyl ester having at least one suitable substituent, such as lower alkanoyloxy (lower) alkyl ester [eg, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, etc. , Pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1- (or 2-)
Acetoxyethyl ester, 1- (or 2- or 3
-) Acetoxypropyl ester, 1- (or 2- or 3- or 4-) acetoxybutyl ester, 1-
(Or 2-) propionyloxyethyl ester, 1
-(Or 2-) butyryloxyethyl ester, 1-
(Or 2-) isobutyryloxyethyl ester, 1
-(Or 2-) pivaloyloxyethyl ester, 1
-(Or 2-) hexanoyloxyethyl ester,
Isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1- (or 2-) pentanoyloxyethyl ester, etc.], lower alkanesulfonyl (lower) alkyl ester (For example, 2-mesylethyl ester), mono (or di or tri) halo (lower) alkyl ester (for example, 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
Lower alkoxycarbonyloxy (lower) alkyl ester [eg, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-butoxycarbonyloxymethyl ester, 1- (or 2-) methoxycarbonyloxyethyl ester, 1- (or 2-) ethoxycarbonyloxyethyl ester, 1-
(Or 2-) isopropoxycarbonyloxyethyl ester, etc.], phthalidylidene (lower) alkyl ester, (5-lower alkyl-2-oxo-1,3-dioxol-4-yl) (lower) alkyl ester [eg (5 -Methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-propyl-2-oxo) -1,3-dioxol-4-yl) ethyl ester etc.]; lower alkenyl ester (eg vinyl ester, allyl ester etc.); lower alkynyl ester (eg ethynyl ester, propynyl ester etc.); having halogen or lower alkoxy May be mono or di or triphenyl (lower) Such Kill ester which may have at least one suitable substituent ar (lower) alkyl ester (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester,
Phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.); at least one suitable Optionally substituted aryl ester (eg phenyl ester, 4-
Chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.); and phthalidyl ester.

More preferred examples of the protected carboxy thus defined include C ₂ -C ₄ alkenyloxycarbonyl and phenyl (or nitrophenyl) (C ₁ -C ₄ ) alkoxycarbonyl. Suitable "lower alkyl" and "hydroxy (lower) alkyl" and "protected hydroxy (lower)"
Suitable "lower alkyl moiety" in the expression "alkyl" includes straight chain or branched chain such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, Among them, more preferable examples are C ₁ -C ₄ alkyl. Preferred "protected hydroxy moieties" in the expression "protected hydroxy (lower) alkyl" include those mentioned below in the description of imino protecting groups, mono- or di- or triphenyl (lower) alkyl (for example, Benzyl, benzhydryl, trityl, etc.), tri (lower) alkyl, tri (lower) alkylsilyl (eg, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, diisopropylmethylsilyl, etc.), triarylsilyl (eg, trialkylsilyl). Included are hydroxy protected by conventional hydroxy protecting groups such as tri-substituted silyl such as phenylsilyl), trial (lower) alkylsilyl (eg tribenzylsilyl) and the like. Suitable “organic group” includes the above lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkyl (for example, chloromethyl, dichloromethyl, trichloromethyl,
Bromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, etc.),

Lower alkenyl (eg vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.) , Lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1
Or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), one or more (preferably 1 to 3)
Optionally) an optionally substituted aryl, phenyl (lower) alkyl (eg, benzyl, phenethyl, phenylpropyl, etc.), etc., ar (lower) alkyl, 1 or more (preferably 1 to 3) And a heterocyclic group which may have a suitable substituent. Suitable "lower alkoxy" includes methoxy, ethoxy, propoxy, butoxy, isobutoxy, pentyloxy,
Examples thereof include linear or branched ones such as isopentyloxy and hexyloxy, and more preferable examples thereof include C _{1 to} C ₄ alkoxy. Suitable "aryl" includes phenyl, naphthyl and the like.

Suitable "substituents" in the expression "aryl optionally having one or more suitable substituents" include lower alkyl, halogen (eg chlorine, bromine, iodine, etc.) exemplified above. Fluorine), hydroxy, protected hydroxy as exemplified above, lower alkenyl (eg vinyl, 1-propenyl, allyl, 1-methylallyl, 1
Or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2
Or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), and the lower alkoxy and the like exemplified above. Suitable "heterocyclic group" includes monocyclic or polycyclic saturated or unsaturated heterocyclic group containing at least one hetero atom such as oxygen atom, sulfur atom, nitrogen atom and the like. Preferred heterocyclic groups are 3- to 8-membered, more preferably 5- or 6-membered unsaturated heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, pyridyl. , Pyridyl N-oxide, pyridinio, dihydropyridyl, tetrahydropyridyl [eg 1,2,3,6-tetrahydropyridyl etc.], pyrimidinyl, pyrimidinio, pyrazinyl,
Pyrazinio, pyridazinyl, pyridazinio, triazinyl [eg 1,3,5-triazinyl, 1,2,4-
Triazinyl, 1,2,3-triazinyl], tetrahydrotriazinyl [eg 1,2,5,6-tetrahydro-1,2,4-triazinyl, 1,4,5,6-tetrahydro-1,2,4 -Triazinyl, etc.], triazinio, triazolyl [eg 1H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-
1,2,3-triazolyl, etc.], triazolio, tetrazinyl, tetrazinio, tetrazolyl [eg 1H
-Tetrazolyl, 2H-tetrazolyl and the like], tetrazlio and the like; 3- to 8-membered, more preferably 4- to 6-membered saturated heteromonocyclic group containing 1 to 4 nitrogen atoms, such as azetidinyl, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl Such;

A 3- to 8-membered, more preferably 5- or 6-membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiazolyl, isothiazolyl, thiadiazolyl [ For example 1,2,3-
Thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,5-thiadiazolyl], thiadiazolio, thiazolinyl, dihydrothiazinyl and the like; and the like. Suitable substituents in the expression "heterocyclic group optionally having one or more suitable substituents" include lower alkyl optionally having one or more suitable substituents, lower Alkenyl (eg vinyl,
1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-
Pentenyl, 1 or 2 or 3 or 5-hexenyl, etc., lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 Or 2 or 3 or 4 or 5
-Hexynyl, etc.), imino protecting groups, and the like. Suitable substituents in the expression "lower alkyl optionally having one or more suitable substituents" include acid residues and the like. Suitable "acid residue" includes azide, halogen (eg chlorine, bromine, fluorine, iodine).
And the like, as well as organic acid residues such as acyloxy (eg, benzenesulfonyloxy, tosyloxy, methanesulfonyloxy, acetoxy, etc.). Suitable "imino protecting group" is carboxylic acid,
Examples include carbamoyl derived from carbonic acid, sulfonic acid and carbamic acid, aliphatic acyl, aromatic acyl, heterocyclic acyl and aromatic group-substituted or heterocyclic group-substituted aliphatic acyl.

The aliphatic acyl includes acyclic or cyclic saturated or unsaturated alkanoyl such as lower alkanoyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, etc.). , Lower alkylsulfonyl (eg, mesyl, ethylsulfonyl,
Propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl, hexylsulfonyl, etc., alkylsulfonyl, carbamoyl, N-alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl). , Alkoxycarbonyl such as propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, etc., alkenyloxycarbonyl such as lower alkenyloxycarbonyl (eg, vinyloxycarbonyl, allyloxycarbonyl, etc.), lower alkenoyl (eg, acryloyl, methacryloyl, crotonoyl, etc.) Such as alkenoyl, cyclo (lower) alkanecar Sulfonyl (e.g. cyclopropanecarbonyl, cyclopentanecarbonyl, cyclohexane carbonyl) and the like cycloalkanecarbonyl such. As an aromatic group-substituted aliphatic acyl,
Examples include alk (lower) alkoxycarbonyl such as phenyl (lower) alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.) and the like. These acyl groups may be further substituted with one or more appropriate substituents such as nitro, and preferable acyls having such a substituent include nitroar (lower) alkoxycarbonyl (eg nitrobenzyloxycarbonyl etc.). ) And the like.

Preferred embodiments of the object compound (I) are as follows:
Is as follows: R ¹ is carboxy, or protected carboxy [more preferably esterified carboxy, particularly preferably lower alkenyloxycarbonyl], and R ² is hydroxy (lower) alkyl, or protected Hydroxy (lower) alkyl [more preferably tri (lower) alkylsilyloxy (lower) alkyl], R ³ is hydrogen or lower alkyl, R ^3
4 is lower alkyl, or 1 or more (more preferably 1
~ 3) aryl optionally having suitable substituents [more preferably phenyl optionally having lower alkoxy]. Compound used in Process 1 (II
Preferred embodiments of I) are as follows: R ¹ is lower alkyl, R ² is lower alkoxy, and R ³ is lower alkoxy; or R ¹ is aryl (more preferably phenyl), R ² is lower alkoxy, and R
³ is lower alkoxy; or R ¹ is aryl (more preferably phenyl), R ² is aryl (more preferably phenyl), and R ³ is lower alkoxy. The method for producing the object compound (I) of the present invention is described in detail below.

Process 1 Compound (IV) or a salt thereof can be prepared by reacting compound (II) or a salt thereof with compound (III). The reaction is usually acetone, dioxane, acetonitrile, hexane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N.
Carried out in a conventional solvent, such as dimethylformamide, dimethylsulfoxide, benzene, toluene, xylene, any other organic solvent which does not adversely influence the reaction. The reaction temperature is not particularly limited, but the reaction is usually performed at room temperature or under heating.

Process 2 Compound (I) or its salt can be prepared by subjecting compound (IV) or its salt to a cyclization reaction. The reaction is
Usually, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene,
It is carried out in a conventional solvent, such as any other organic solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, but usually the reaction is carried out under heating or heating.

Process 3-Compound (V) or a salt thereof can be prepared by subjecting compound (I) or a salt thereof to an oxidation reaction. The main oxidation is
By a conventional method, for example, an inorganic peracid or a salt thereof (for example, periodic acid, persulfuric acid, a sodium salt or potassium salt thereof, etc.), an organic peracid or a salt thereof (for example, perbenzoic acid, m-chloroperbenzoic acid, Performic acid, peracetic acid, chloroperacetic acid, trifluoroperacetic acid, their sodium or potassium salts, etc.), ozone, hydrogen peroxide, peroxoborates (eg sodium peroxoborate), chlorites (eg It is carried out using an oxidizing agent such as sodium chlorite, etc., bromate (eg, sodium bromate, etc.), hypochlorite (eg, sodium hypochlorite, etc.). The reaction is usually
Water, alcohol [eg methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene,
It is carried out in a conventional solvent, such as any other organic solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. The main oxidation may be carried out in the presence of a catalyst. Suitable catalysts have the formula:

[Chemical 20] (In the formula, R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are each hydrogen or an organic group, A is a lower alkylene, M is a metal,
X is each a halogen) and a complex catalyst such as a complex. Suitable halogens include chlorine, bromine,
Fluorine and iodine are mentioned. Suitable "lower alkylene" includes methylene, ethylene, trimethylene,
Examples thereof include linear or branched ones having 1 to 6 carbon atoms such as tetramethylene, pentamethylene and hexamethylene. Suitable organic groups may include those exemplified above. Suitable metals include manganese, chromium and the like.

Process 3-Compound (Ia) or a salt thereof can be prepared by reacting compound (VI) or a salt thereof with compound (V) or a salt thereof. The reaction is usually carried out with water, alcohol [eg methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride,
Ethylene chloride, tetrahydrofuran, ethyl acetate, N,
N-dimethylformamide, dimethylacetamide, dimethylsulfoxide, benzene, toluene, xylene,
It is carried out in a conventional solvent, such as any other organic solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. The reaction is usually performed in the presence of a base. Suitable bases include alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkaline earth metal hydroxides (eg magnesium hydroxide, calcium hydroxide etc.), alkali metal hydrides (eg hydrides). Sodium, potassium hydride etc.), alkaline earth metal hydrides (eg calcium hydride etc.), alkali metal alkoxides (eg sodium methoxide, sodium ethoxide, potassium t-butoxide etc.), alkali metal carbonates (eg sodium carbonate). , Potassium carbonate, etc.), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.), alkali metal bicarbonates (eg sodium bicarbonate, potassium bicarbonate etc.),
Lower alkyl alkali metal (eg butyl lithium,
t-butyllithium etc.), alkali metal di (lower) alkylamides (eg lithium dimethylamide, lithium diethylamide, lithium diisopropylamide etc.), di (lower) alkylamines (eg dimethylamine, diethylamine, diisopropylamine, dibutylamine etc.) , Tri (lower) alkylamines (eg trimethylamine, triethylamine, N, N-diisopropyl-N-ethylamine etc.), pyridine, picoline, lutidine, N, N-di (lower) alkylaminopyridines (eg N, N-dimethylamino). Pyridine etc.), quinoline, N-lower alkylmorpholine (eg N-methylmorpholine etc.), N, N-di (lower) alkylbenzylamine (eg N, N-dimethylbenzylamine etc.) And the like. In order to describe the present invention in more detail, examples will be shown below.

Example 1 (3S, 4S) -1- (allyloxyoxalyl) -3
-[(1R) -1- (tertiarybutyldimethylsilyloxy) ethyl] -4-[(1R) -1-{(methylthio)
Thiocarbonyl} ethyl] -2-oxoazetidine (2
To a solution of 30 mg) in n-hexane (5 ml) is added diethoxy (methyl) phosphine (500 mg) and the mixture is stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (ethyl acetate: n-hexane = 1: 3, v / v) to give (3S, 4S) -1- [1 -(Allyloxycarbonyl) -1- {diethoxy (methyl) phosphorandiyl} methyl] -3-[(1R) -1- (tertiarybutyldimethylsilyloxy) ethyl] -4-[(1R)
-1-{(methylthio) thiocarbonyl} ethyl] -2
-Oxoazetidine (289 mg) is obtained as a yellow oil. IR (neat): 1765, 1745, 1405, 1370, 1250, 1185 c
m ^-1

Example 2 In the same manner as in Example 1, the following compound is obtained. (1) (3S, 4S) -1- [1- (allyloxycarbonyl) -1- {diethoxy (phenyl) phosphorandiyl} methyl] -3-[(1R) -1- (tertiary butyldimethylsilyl) Oxy) ethyl] -4-[(1R)-
1-{(methylthio) thiocarbonyl} ethyl] -2-
Oxoazetidine IR (neat): 1750, 1740, 1660, 1625, 1435, 1370,
1250 cm ^-1 (2) (3S, 4S) -1- [1- (allyloxycarbonyl) -1- {dipropoxy (ethyl) phosphorandiyl} methyl] -3-[(1R) -1- (third -Butyldimethylsilyloxy) ethyl] -4-[(1R)-
1-{(methylthio) thiocarbonyl} ethyl] -2-
Oxoazetidine IR (neat): 1750, 1740, 1625, 1450, 1250, 1000 c
m ^-1

Example 3 (3S, 4S) -1- (allyloxyoxalyl) -3
-[(1R) -1- (tertiarybutyldimethylsilyloxy) ethyl] -4-[(1R) -1-{(methylthio)
Thiocarbonyl} ethyl] -2-oxoazetidine (2
30 mg) and diethoxy (methyl) phosphine (1 m
1) in n-hexane (10 ml) at room temperature.
Stir for hours. The solvent was removed under reduced pressure to give (3S, 4
S) -1- [1- (allyloxycarbonyl) -1-
{Diethoxy (methyl) phosphorandiyl} methyl]-
A residue containing 3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -4-[(1R) -1-{(methylthio) thiocarbonyl} ethyl] -2-oxoazetidine is obtained. . This residue is xylene (5m
Dissolve in l). The solution is heated under reflux for 3 hours and concentrated by evaporation. The residue was subjected to silica gel flash chromatography (diethyl ether: n-hexane = 1: 1).
2, v / v) to obtain (4R, 5S, 6S)-
6-[(1R) -1- (tertiarybutyldimethylsilyloxy) ethyl] -4-methyl-3-methylthio-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2 -Allyl carboxylate (180 mg) is obtained. NMR (CDCl ₃ , δ): 0.08 (6H, s), 0.88 (9H, s), 1.23 (3
H, d, J = 6.7Hz), 1.27 (3H, d, J = 5.9Hz), 2.39 (3H, s), 3.1
9 (1H, dd, J = 6.5Hz and 2.5Hz), 3.25-3.40 (1H, m),
4.14 (1H, dd, J = 9.2Hz and 2.5Hz), 4.16-4.29 (1H,
m), 4.63-4.85 (2H, m), 5.20-5.49 (2H, m), 5.86-6.06
The same compound was obtained using diethoxy (phenyl) phosphine instead of (1H, m) diethoxy (methyl) phosphine.

Example 4 (3S, 4S) -1- (allyloxyoxalyl) -3
-[(1R) -1- (tertiarybutyldimethylsilyloxy) ethyl] -4-[(1R) -1-{(methylthio)
Thiocarbonyl} ethyl] -2-oxoazetidine (1
15 mg) and dipropoxy (ethyl) phosphine (45
A mixture of 1 mg) in n-hexane (3 ml) was stirred at room temperature for 4 hours to give (3S, 4S) -1- [1- (allyloxycarbonyl) -1- {dipropoxy (ethyl) phosphorandiyl} methyl. ] -3-[(1R) -1- (tert-Butyldimethylsilyloxy) ethyl] -4-
A solution containing [(1R) -1-{(methylthio) thiocarbonyl} ethyl] -2-oxoazetidine is obtained.
This solution is diluted with xylene (5 ml) and heated under reflux for 3 hours equipped with a Dean Stark apparatus. The solvent was removed under reduced pressure and the residue was subjected to silica gel flash chromatography (diethyl ether: n-hexane = 1: 1).
2, v / v) to obtain (4R, 5S, 6S)-
6-[(1R) -1- (tertiarybutyldimethylsilyloxy) ethyl] -4-methyl-3-methylthio-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2 -Allyl carboxylate (93 mg) is obtained. NMR (CDCl ₃ , δ): 0.08 (6H, s), 0.88 (9H, s), 1.23 (3
H, d, J = 6.7Hz), 1.27 (3H, d, J = 5.9Hz), 2.39 (3H, s), 3.1
9 (1H, dd, J = 6.5Hz and 2.5Hz), 3.25-3.40 (1H, m),
4.14 (1H, dd, J = 9.2Hz and 2.5Hz), 4.16-4.29 (1H,
m), 4.63-4.85 (2H, m), 5.20-5.49 (2H, m), 5.86-6.06
(1H, m)

Example 5 (3S, 4S) -1- (allyloxyoxalyl) -3
-[(1R) -1- (tert-Butyldimethylsilyloxy) ethyl] -4-[(1R) -1-{(4-isopropoxyphenylthio) thiocarbonyl} ethyl] -2-
Oxoazetidine (145 mg) in n-hexane (6 m
l) In the solution, diethoxy (methyl) phosphine (500
mg) and the mixture is stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give crude (3S, 4S) -1- [1-
(Allyloxycarbonyl) -1- {diethoxy (methyl) phosphorandiyl} methyl] -3-[(1R) -1
-(Tert-Butyldimethylsilyloxy) ethyl] -4
-[(1R) -1-{(4-isopropoxyphenylthio) thiocarbonyl} ethyl] -2-oxoazetidine (256 mg) is obtained as a yellow oil. IR (neat): 1740, 1625, 1490, 1365, 1250, 1025 c
m ^-1 This product is dissolved in xylene (5 ml) and the solution is heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography (diethyl ether: n-hexane = 1: 2, v / v) to give (4R, 5S, 6S) -6-[(1R). -1- (tert-Butyldimethylsilyloxy) ethyl] -3- (4
-Allyl (isopropoxyphenylthio) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (115 mg) is obtained. IR (neat): 1780, 1710 cm ^-1 NMR (CDCl ₃ ,, δ): 0.05 (6H, s), 0.81 (9H, s), 0.89 (3
H, d, J = 7Hz), 1.11 (3H, d, J = 6Hz), 1.30 (6H, d, J = 6Hz),
2.76-2.93 (1H, m), 3.07 (1H, dd, J = 6Hz and 3Hz),
4.03 (1H, dd, J = 9Hz and 3Hz), 4.08-4.19 (1H, m),
4.45-4.58 (1H, m), 4.62-4.83 (2H, m), 5.17-5.47 (2H,
m), 5.84-6.03 (1H, m), 6.82 and 7.40 (2H, d, respectively
J = 7Hz) FAB Ms: (M + 1) 532.2

Example 6 In the same manner as in Example 1, the following compound is obtained. (3S, 4
S) -1- [1- (allyloxycarbonyl) -1-
{Diphenyl (ethoxy) phosphorandiyl} methyl]
-3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -4-[(1R) -1-{(methylthio) thiocarbonyl} ethyl] -2-oxoazetidine IR (nujol): 1742 , 1635 cm ^-1 FAB Ms: 674.5 (M + 1)

Example 7 (3S, 4S) -1- (allyloxyoxalyl) -3
-[(1R) -1- (tertiarybutyldimethylsilyloxy) ethyl] -4-[(1R) -1-{(methylthio)
Thiocarbonyl} ethyl] -2-oxoazetidine (1
To a solution of 06 mg) in n-hexane (1.1 ml) is added diphenyl (ethoxy) phosphine (0.28 ml) and triethyl phosphite (0.21 ml). The mixture is stirred at 50 ° C. for 9 hours. The solvent was removed under reduced pressure,
(3S, 4S) -1- [1- (allyloxycarbonyl) -1- {diphenyl (ethoxy) phosphorandiyl} methyl] -3-[(1R) -1- (tertiary butyldimethylsilyloxy) ethyl ] -4-[(1R) -1-
{(Methylthio) thiocarbonyl} ethyl] -2-oxoazetidine and (3S, 4S) -1- [1- (allyloxycarbonyl) -1- (triethoxyphosphorandiyl) methyl] -3-[(1R)- 1- (tertiary butyldimethylsilyloxy) ethyl] -4-[(1R) -1-
Mixture with {(methylthio) thiocarbonyl} ethyl] -2-oxoazetidine (4.24 according to HPLC:
1) is obtained. This mixture is dissolved in xylene (2.1 ml) and the solution is heated under reflux for 8.5 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (10% ethyl acetate-n-hexane) to give (4R, 5S, 6S) -6-[(1R) -1-
(Tertiary butyldimethylsilyloxy) ethyl] -4-
Methyl-3-methylthio-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (51 mg) is obtained.

Example 8 (3S, 4S) -1- [1- (allyloxycarbonyl) -1- {diphenyl (ethoxy) phosphorandiyl} methyl] -3-[(1R) -1- (tertiary Butyldimethylsilyloxy) ethyl] -4-[(1R) -1-
{(Methylthio) thiocarbonyl} ethyl] -2-oxoazetidine (270 mg) was added to xylene (5.4 ml).
And heated under reflux for 9.5 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (10% ethyl acetate-n-hexane) to give (4R, 5S, 6S) -6-[(1R) -1.
-(Tert-Butyldimethylsilyloxy) ethyl] -4
-Allyl 3-methyl-3-methylthio-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate (156 mg) is obtained.

Example 9 A solution of sodium hypochlorite (1.9 ml), 0.05 M disodium hydrogen phosphate (0.75 ml) and 4.2 M potassium carbonate (1.5 ml) was cooled with ice. ,
(4R, 5S, 6S) -3-Methylthio-6-[(1
R) -1- (tert-Butyldimethylsilyloxy) ethyl] -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate allyl (309 mg) Add a solution of manganese complex ^* (10 mg) in dichloromethane (5 ml). The biphasic mixture is stirred at 0 ° C. After 2 hours, the mixture is poured into sodium thiosulfate solution, extracted with dichloromethane and the extract washed with brine. Montmorillonite K10 was added to this solution.
(3.0 g) is added, the mixture is stirred and filtered. The solution was concentrated under reduced pressure to (4R, 5S, 6S) -3-
((R) -Methylsulfinyl) -6-[(1R) -1
-(Tert-Butyldimethylsilyloxy) ethyl] -4
-Methyl-7-oxo-1-azabicyclo [3.2.
0] allyl hept-2-ene-2-carboxylate (hereinafter R
-Called isomer) and (4R, 5S, 6S) -3-
((S) -Methylsulfinyl) -6-[(1R) -1
-(Tert-Butyldimethylsilyloxy) ethyl] -4
-Methyl-7-oxo-1-azabicyclo [3.2.
0] allyl hept-2-ene-2-carboxylate (hereinafter S
-Mixture with the isomer) is obtained (8.4: 1). R
-Isomer is a less polar compound and S-isomer is a polar compound. The mixing ratio of R-isomer and S-isomer was determined by HPLC and NMR analysis. R-isomer NMR (CDCl ₃ , δ): 0.08 (6H, s), 0.88 (9H, s), 1.25 (3
H, d, J = 6.1Hz), 1.38 (3H, d, J = 7.2Hz), 2.86 (3H, s), 3.3
5 (1H, m), 3.65 (1H, m), 4.23-4.31 (2H, m), 4.75 (2H,
d, J = 5.4Hz), 5.27-5.52 (2H, m), 5.85-6.01 (1H, m) ^* Manganese complex

[Chemical 21]

Example 10 A mixture of the R-isomer and the S-isomer obtained in Example 9 (2
67 mg) is dissolved in a solution of 2-propanethiol in dimethylacetamide (3.5 g) (0.357 mmol / g) and cooled to -20 ° C. To this solution, -20 ℃
At, triethylamine (0.17 ml) is added and the mixture is stirred at 0 ° C. for 3 hours. Toluene and water are added to this mixture, the organic phase is separated, washed with water and brine and dried. The solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane =
1: 9, v / v) and purified (4R, 5S, 6
S) -3-Isopropylthio-6-[(1R) -1-
(Tertiary butyldimethylsilyloxy) ethyl] -4-
Methyl-7-oxo-1-azabicyclo [3.2.0]
Allyl hept-2-ene-2-carboxylate (153m
g) is obtained. IR (nujor): 1770, 1700 cm ^-1 NMR (CDCl ₃ , δ): 0.08 (6H, s), 0.89 (9H, s), 1.22-1.
38 (12H, m), 3.20 (1H, dd, J = 6.1Hz and 2.6Hz), 3.24
-3.42 (2H, m), 4.12-4.29 (2H, m), 4.63-4.85 (2H, m),
5.23 (1H, dd, J = 10.5Hz and 1.0Hz), 5.44 (1H, dd, J =
17.2Hz and 1.2Hz), 5.86-6.06 (1H, m)

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // A61K 31/40 ADZ 9454-4C

Claims (3)

[Claims] 1. A general formula: [Wherein R ¹ is carboxy or protected carboxy, R ² is hydroxy (lower) alkyl or protected hydroxy (lower) alkyl, R ³ is hydrogen or lower alkyl, R ⁴ is an organic group, R ⁵ , R ^{5 6} and R ⁷ are each lower alkyl, lower alkoxy, aryl optionally having one or more suitable substituents, or a compound of the formula: (In the formula, R ⁸ and R ⁹ are each lower alkyl, or 1
Represents an aryl optionally having one or more suitable substituents). However, R ⁵ ,
R ⁶ and R ⁷ shall not be the same at the same time]
A compound represented by or a salt thereof. 2. A general formula: [Wherein R ¹ is carboxy or protected carboxy, R ² is hydroxy (lower) alkyl or protected hydroxy (lower) alkyl, R ³ is hydrogen or lower alkyl, R ⁴ is an organic group, R ⁵ , R ^{5 6} and R ⁷ are each lower alkyl, lower alkoxy, aryl optionally having one or more suitable substituents, or a compound of the formula: (In the formula, R ⁸ and R ⁹ are each lower alkyl, or 1
Represents an aryl optionally having one or more suitable substituents). However, R ⁵ ,
R ⁶ and R ⁷ shall not be the same at the same time]
A method for producing a compound represented by: or a salt thereof, comprising the general formula: [Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above] or a salt thereof is represented by the general formula: The above method characterized by reacting with a compound of the formula: wherein R ⁵ , R ⁶ and R ⁷ are each as defined above. 3. A general formula: [Wherein R ¹ represents carboxy or protected carboxy, R ² represents hydroxy (lower) alkyl or protected hydroxy (lower) alkyl, R ³ represents hydrogen or lower alkyl, and R ⁴ represents an organic group]. A method for producing the represented carbapenem derivative or a salt thereof, comprising:
(1) General formula: [Wherein R ¹ , R ² , R ³ and R ⁴ are each as defined above and R ⁵ , R ⁶ and R ⁷ are each a lower alkyl, a lower alkoxy and one or more suitable substituents. Aryl which may have or a formula: (In the formula, R ⁸ and R ⁹ are each lower alkyl, or 1
Represents an aryl optionally having one or more suitable substituents). However, R ⁵ ,
R ⁶ and R ⁷ shall not be the same at the same time]
By subjecting the compound represented by or a salt thereof to a cyclization reaction,
General formula: A compound represented by the formula: wherein R ¹ , R ² , R ³ and R ⁴ are each as defined above, or a salt thereof, or (2) the general formula: [Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above] or a salt thereof is represented by the general formula: [In the formula, R ⁴ _a represents an organic group. Provided that R ⁴ and R ⁴ _a are not the same], and the compound represented by the general formula: The method as described above, wherein a compound represented by the formula: wherein R ¹ , R ² , R ³ and R ⁴ _a are as defined above or a salt thereof is obtained.