WO2003080571A1 - Process for producing azetidinone compounds - Google Patents

Abstract

It is intended to provide a process for selectively obtaining an intermediate in synthesizing a desired carbapenem-type antibacterial agent having a methyl group at the 1’-β-position in a short period and at a high yield under mild conditions while overcoming problems occurring in the existing method. Namely, a process for producing an azetidinone compound having a 1’-β configuration characterized in that a reaction represented by the following formula is carried out in the presence of a specific metal compound and a base: wherein R1 represents hydrogen or a hydroxy-protective group; L represents a leaving group; R2 represents hydrogen or lower alkyl; R3 represents alkyl, aralkyl, etc.; and X represents oxygen or sulfur.

Description

 Description Method for producing azetidinone compounds

 TECHNICAL FIELD The present invention relates to a method for producing an azetidinone compound which is an important synthetic intermediate for a compound of the present invention. Background art

 It is an important synthetic intermediate for azetidinone compounds having a 6-methyl group at the 1'-position of the 4-position side chain used in the production of 13-methylcarbapanem derivatives, which are important as antibacterial substances (3S, 4R) — 3— [(R) — 1-Hydroxy-methyl ”— 4— [(R) 1- 1-Methyl-3 diazo-1 3 monosubstituted oxycarbonyl 21-oxo-1 propyl] 1-azetidine 1 2-one [A]

[A]

[In the formula, R represents an alkyl group, a benzyl group which may have a substituent, or an aryl group which may have a substituent. ].

Examples of the production method include the following reaction scheme 1 described in JP-A-57-123182.

で示される製造法、 特開昭 6 4— 2 5 7 7 9号公報に記載の下記反応スキーム 2

The following reaction scheme 2 described in JP-A-64-257779

で示される製造法、 特開平 6 — 3 2 1 9 4 6号公報に記載の下記反応スキーム 3

The following reaction scheme 3 described in JP-A-6-321 946

で示される製造法、 並びに特開昭 5 8 — 1.0 3· 3 5 8号公報、 特開平 6— 1. 9 9 7 8 0号公報、 特開昭 6 1 - 2 7 5 2 8 4号公報等に記載の下記反応スキーム 4

, And JP-A-58-1.03.358, JP-A-6-1.97980, JP-A-61-275284 Reaction Scheme 4 below

で示される製造法などが知られている。 . しかしながら、 これらの製造方法は、 何れも、 それぞれ以下のような問題点を 有しており、 十分に満足の行くものとは言えなかった。

Are known. . However, each of these manufacturing methods has the following problems, and cannot be said to be sufficiently satisfactory.

 That is, in the methods of Reaction Schemes 1 to 3, expensive starting materials are used, and the number of steps is large, so that the operation becomes complicated, and this is not always desirable not only in terms of yield but also in terms of price.

 In addition, in the method of Reaction Scheme 4, the production is performed in a relatively short process, but since an unstable silyl enol ether has to be used, it is difficult to say that it is an industrial method, and that it is economical. Hard to say. DISCLOSURE OF THE INVENTION,

 An object of the present invention is to solve the problems of the conventional method as described above: a desired intermediate for the synthesis of a potent antibacterial agent having a methyl group at the 1'-3 position can be prepared under a mild condition under a short condition. It is an object of the present invention to provide a method for obtaining a compound with good yield in a process and selectively.

 The present invention has the following general formula [2]

[2]

(Wherein, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, and L represents a leaving group.) And a compound represented by the following general formula [3]

[3]

(Wherein, R ² represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R ³ represents an alkyl group having 1 to 12 carbon atoms, a phenyl group which may have a substituent, Represents an aralkyl group having 1 to 15 carbon atoms which may have a substituent or a 5- to 8-membered alicyclic group which may have a substituent, and X represents an oxygen atom or a sulfur atom Represents.) The compound represented by the following general formula [4]

M Y n (4) m (4)

(In the formula, M represents a metal atom, Y represents a halogen atom, and R ⁴ has a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, and may have a substituent. Good phenoxy, alkylsulfonyldioxy, arylsulfonyldioxy, alkylsulfonyloxy, 7-ylsulfonyloxy grave, cyclopentenyl, or pentamethylcyclopentenyl And n and m are integers from 0 to 4, and n + m is the valence of M.)

Wherein the reaction is carried out in the presence of a metal compound represented by the formula:

[1]

(Wherein, RR ² , R ³ and X are the same as described above.)

And a method for producing the compound represented by the formula:

 That is, the present inventors have conducted intensive studies in order to achieve the above object, and as a result, a compound represented by the above general formula [2] and a diazo compound represented by the above general formula [3] are converted into a specific metal compound. It has been found that a azetidinone compound [1] having a desired 1′- | 3 configuration can be selectively and efficiently produced only by reacting with a base in the presence of a base, and the present invention has been completed. Was.

The present invention does not require the conversion of a diazo compound into a silyl enol ether, and allows the compound represented by the general formula [2] and the diazo compound represented by the general formula [3] to be present in the presence of a specific metal compound and a base. An object of the present invention is to provide a method for selectively producing a azetidinone compound having a desired 1'-1] 3 configuration under mild conditions in a short step with good yield simply by reacting under the following conditions. BEST MODE FOR CARRYING OUT THE INVENTION

In the compound represented by the general formula [2] used in the production method of the present invention, examples of the hydroxyl-protecting group represented by R ¹ include, for example, those commonly used in the field of peptide chemistry and] 3-lactam compounds. All of the hydroxyl protecting groups used are mentioned.

That is, for example, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, getylisopropylsilyl group, dimethyl (2,3-dimethyl-2-butyl) silyl group, tert-butyldimethylsilyl group, dimethyl Trees having 1 to 6 alkylsilyl groups such as xylsilyl groups, for example di-carbons having 1 to 6 alkyl-carbon atoms having 6 to 18 arylsilyl groups such as dimethylcumylsilyl group, for example, tert-butyldiphene 6 to 18 aryl carbons such as erucyl and diphenylmethylsilyl groups—1 to 6 alkylsilyl groups such as triphenylsilyl group and tricarbons such as triphenylsilyl group and 6 to 18 aryl silyl groups such as tri Tri-carbon number such as benzylsilyl group and tri-p-xylylsilyl group? Tri-substituted silyl group such as aralkylsilyl group; for example, benzyl group, 4-methoxybenzyl group, 2-ditrobenzyl group, 412-trobenzyl group, diphenylmethyl group, triphenylmethyl group, etc. An aralkyl group having 7 to 19 carbon atoms, in which 1 to 3 hydrogen atoms may be substituted by an alkoxy group having 1 to 4 carbon atoms (eg, methoxy group, ethoxy group, etc.) or a nitro group; Alkoxy groups having 1 to 4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, etc. For example, a methoxy group, an ethoxy group, etc., a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or a tri-C 1-4 alkylsilyl (eg, , Trimethylsilyl group, etc.), wherein 1 to 3 of the hydrogen atoms thereof may be substituted with 1 to 6 carbon atoms, such as an alkyloxycarbonyl group; for example, a benzyloxycarbonyl group, 2-dibenzobenzene Alkoxy groups having 1 to 4 carbon atoms such as a carbonyl group, a 4-nitrobenzyloxycarbonyl group, a 4-methoxybenzyloxycarbonyl group, and a 3,4-dimethoxybenzyloxycarbonyl group (for example, Methoxy, ethoxy, etc.) or nitro An aralkyloxycarbonyl group having 7 to 10 carbon atoms which may be substituted with 3 to 3 carbon atoms; for example, an alkenyl having 2 to 6 carbon atoms such as a vinyloxycarbonyl group or an aryloxycarbonyl group; Oxycarbonyl group; for example, formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, propionyl group, butyryl group, benzoyl group, 4-toluoyl group, 4-anisyl group, 4- A halogen atom such as a nitrobenzoyl group (eg, fluorine, chlorine, bromine, iodine, etc.) or an acyl group in which one to three hydrogen atoms may be substituted with a nitro group or the like; And other cyclic protecting groups.

 Among these protecting groups, preferred are, for example, aralkyloxycarbonyl groups having 7 to 19 carbon atoms (for example, benzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group, etc.), and carbon atoms having 2 to 19 carbon atoms. An alkenyloxylponyl group (e.g., a 7-lyloxycarbonyl group) and a tri-C1-6alkylsilyl group; and more preferably a tert-butyldimethylsilyl group. Can be

 Examples of the leaving group represented by L include, for example, an acyloxy group (for example, an alkoxyyloxy group, an aryloxy group, an arylalkanoyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group, an alkoxycarbonyl group) An alkoxy group, an aralkoxy carboxy group, an alkoxyalkanoyloxy group, a carbamoyloxy group, etc.), an alkanoylthio group, an aroylthio group, an alkylthio group, an arylthio group, an alkylsulfinyl group, Examples thereof include a arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, and a halogen atom.

When L is an alkanoyloxy group, specific examples include an acetooxy group, a propionyloxy group, a ptyryloxy group, an α-fluoroacetoxy group, an α-chloroacetoxy group, an α-promoacetoxy group, an α- A straight chain which may be substituted with 1 to 3 substituents such as halogen atoms, cyano groups, etc. such as 1-doacetoxy group, α, difluoroacetoxy group, α, dichloroacetoxy group, and cyanoacetoxy group; Alkanoyloxy group, isoptyryloxy group, cyclohexyl carbonyloxy P Examples include branched or cyclic alkanoyloxy groups such as 15 groups.

 When L is an aryloxy group, specific examples include a monocyclic or polycyclic ring such as a benzoyloxy group, a 1-naphthoyloxy group, a 2-naphthyloxy group, a nicotinyloxy group, an isonicotinoyloxy group, and a fluorfluorooxy group. And an aryloxy group which may have a hetero atom.

 Specific examples when L is an arylalkanoyloxy group include a phenylacetoxy group and the like.

 When L is an alkylsulfonyloxy group, specific examples include a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, and a trifluorosulfonyl methanesulfonyloxy group.

 When L is an arylsulfonyloxy group, specific examples include a benzenesulfonyloxy group and a p-toluenesulfonyloxy group.

 When L is an alkoxycarbonyloxy group, specific examples include a methoxycarbonyloxy group and an ethoxycarbonyloxy group.

 When L is an aralkoxycarbonyloxy group, specific examples include a benzyloxycarbonyloxy group and the like.

 When L is an alkoxyalkyl group, specific examples include a methoxyacetoxy group and an ethoxyacetoxy group.

 When L is a carbamoyloxy group, specific examples include an N-methylcarbamoyl group.

 When L is an alkanoylthio group, specific examples include an acetylthio group and a propionylthio group.

 When L is an arylothio group, specific examples include a benzoylthio group and a naphthoylthio group.

 When L is an alkylthio group, specific examples include a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, a tert-butylthio group, and the like.

When L is an arylthio group, specific examples include a phenylthio group and a naphthylthio group. 1615 groups and the like.

 When L is an alkylsulfinyl group, specific examples include a methanesulfinyl group, a benzenesulfinyl group, an n-propanesulfenyl group, and an n-butanesulfinyl group.

 When L is an arylsulfinyl group, specific examples include a benzenesulfinyl group and a p-toluenesulfinyl group.

 When L is an alkylsulfonyl group, specific examples include a methanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group, and an n-butanesulfonyl group.

 When L is an arylsulfonyl group, specific examples include a benzenesulfonyl group and a p-toluenesulfonyl group.

 When L is a halogen atom, specific examples include fluorine, chlorine, bromine, iodine and the like. -Among these leaving groups, particularly preferred are an acetoxyl group and the like.

In the compound represented by the general formula [3] used in the production method of the present invention, specific examples of the lower alkyl group having 1 to 4 carbon atoms represented by R ² include a methyl group and an ethyl group. Group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like.

Preferred R ² is a hydrogen atom or a methyl group.

In the general formula [3], specific examples of the alkyl group having 1 to 12 carbon atoms represented by R ³ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, Examples include an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, a decyl group, a decyl group and a dodecyl group.

Specific examples of the alkenyl group having 2 to 5 carbon atoms represented by R ³ include, for example, a bier group, an aryl group, a 1-propenyl group, an isopropyl group, a 1-butenyl group, a 2-butenyl group, 2-methylaryl group and the like.

Examples of the substituent of the phenyl group which may have a substituent represented by R ³ include, for example, 5 Lower alkyl groups having 1 to 4 carbon atoms, lower alkoxy groups having 1 to 4 carbon atoms, nitro groups, and haptogen atoms.

 Specific examples of the lower alkyl group having 1 to 4 carbon atoms as a substituent include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, te It—butyl group and the like. Specific examples of the lower alkoxy group having 1 to 4 carbon atoms include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- Butoxy group and the like. Further, specific examples of the halogen atom include, for example, fluorine, chlorine, bromine, and iodine.

Even if it has a substituent represented by R ³ , examples of the substituent of the aralkyl group having 7 to 15 carbon atoms include a lower alkyl group having 1 to 4 carbon atoms and a lower alkyl group having 1 to 4 carbon atoms. And a nitro group, a nitro group and a halogen atom.

 Specific examples of the lower alkyl group having 1 to 4 carbon atoms as a substituent include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like. Specific examples of lower alkoxy groups having 1 to 4 carbon atoms include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec butoxy, tert-butoxy. And the like. Further, specific examples of the halogen atom include, for example, fluorine, chlorine, bromine, and iodine.

 Specific examples of the aralkyl group having a carbon number of 7 to 15 even if it has a substituent include a benzyl group, a para-phenyl group, a 3-phenyl group, a ο-phenyl group, and a β-phenyl group. Enylpropyl group, α-phenylpropyl group, naphthylmethyl group and the like,

Specific examples of the 5- to 8-membered alicyclic group which may have a substituent represented by R ³ include a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like. Examples of the substituent include a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group. Can be

Of these, particularly preferred R ³ is lower alkyl having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl. 01615 kill group; aralkyl having 7 to 15 carbon atoms which may have a substituent such as a benzyl group, a p-nitrobenzyl group, or a p-methoxybenzyl group (nitro group, methoxy group, etc.) A alkenyl group having 2 to 5 carbon atoms, such as a vinyl group and an aryl group.

 In the metal compound represented by the general formula [4] used in the production method of the present invention, the metal atom represented by M is, for example, commonly used in organic synthetic chemistry, carbon-carbon bond formation reaction, and the like. And more specifically, for example, metals of Group 4 of the periodic table by IUPAC such as titanium and zirconium; metals of Group 14 of the periodic table by IUPAC such as gayne and tin; Metals of Group 1 and 3 of the Periodic Table by IUPAC, such as boron and aluminum; scandium, yttrium, lanthanides (lanthanum, cerium, praseodymium, neodymium, samaridium, gadolinium, dysprosium, erbium, ytterbium, etc.) Group 3 metals; Periodic table metals such as iron and ruthenium; Groups 8 metals; The first Group II metal such as Table and the like.

 In the general formula [4], examples of the halogen atom represented by Y include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the general formula [4], specific examples of the lower alkyl group having 1 to 4 carbon atoms represented by R ⁴ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an isobutyl group. , Sec-butyl group, tert-butyl group and the like. Specific examples of the lower alkoxy group having 1 to 4 carbon atoms include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, Examples thereof include n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group and the like.

Examples of the substituent of the phenoxy group which may have a substituent represented by R ⁴ include a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, and a halogen atom. And the like.

Here, specific examples of the lower alkyl group having 1 to 4 carbon atoms as a substituent include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isopropyl group, sec-butyl group, tert-butyl group and the like. Specific examples of the lower alkoxy group having 1 to 4 carbon atoms include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, and the like. Further, examples of the halogen atom include fluorine, chlorine, bromine, and iodine. And the like.

Specific examples of the alkylsulfonyldioxy group represented by R ⁴ include, for example, a methanesulfonyldioxy group, an ethanesulfonyldioxy group, and a trifluoromethanesulfonyldioxy group.

Specific examples of the arylsulfonyldioxy group represented by R ⁴ include, for example, a benzenesulfonyldioxy group and a p-toluenesulfonyldioxy group.

Specific examples of the alkylsulfonyloxy group represented by R ⁴ include, for example, a methanesulfonyloxy group, an ethanesulfonyloxy group, and a trifluoromethanesulfonyloxy group.

Specific examples of the arylsulfonyloxy group represented by R ⁴ include, for example, a benzenesulfonyloxy group and a p-toluenesulfonyloxy group.

 The method for producing the compound represented by the general formula [2] is not particularly limited thereto. For example, J. Am. Chem. So, Vol. II2, pp. 7820-7822 (1990), Tetr. ahedron Letters, Vol. 32, pp. 25-2148 (1991), Tetrahedron Letters, Vol. 32, pp. 5991-5994 (1991), etc., or a method analogous thereto. it can.

 Specific examples of the compound represented by the general formula [2] include, for example,

 4-Acetoxy 3 — [1-tert e-butyldimethylsilyloxyxetyl] 1-azetidine 1-2 —one,

 4-acetoxy 3 — [1—tert-butyldiphenylsilyloxyxetyl] —azetidine-1 2—one,

 4—Acetoxy-1 3— [1—Triethylsilyloxyxetil] 1—azetidine—2-one,

 4-acetoxy 3— [1—trimethylsilyloxexetil] 1-azetidine 1-2—one,

4 1-Acetoxy 1 3 — [1-Dimethyltexylsilyloxyxetil] 1-azetidine 1 2 — One, 4-Acetoxy 1 3 — [1-Hydroxyscheruethyl] 1-azetidine 1 2 —

 4 α-chloroacetoxy 3 — [1-tert-butyl-dimethylsilyloxy-shethyl] —azetidin-1-one,

 4-isobutyryloxy 3 — [1-tert e-butyldimethylsilyloxyxethyl] azetidine— 2 —one,

 4-propionyloxy 31- [1-tert e-butyldimethylsilyloxyethyl] azetidine-1'-one,

 4-benzoyloxy 3 -— [1-tert-butyldimethylsilyloxyxethyl] azetidine-1 2—one,

 4-P-tolylthio-3-3- [1-tert-butyldimethylsilyloxexetil] azetidine-1-2-,

 4—Fenrylthio 3— [1-t ert 1-butyldimethylsilyloxexetil] 1-azetidine-1 2—one,

 4 1-p-toluenesulfinyloxy-3 — [1-tert e-butyldimethylsilyloxetyl] 1-azetidin-12-one,

 4 1 benzenesulfinyloxy 1 3 — [1 t ert 1 butyl dimethylsilyl oxexetyl] 1 azetidine 1 2 -one,

 4 1-P-toluenesulfonyloxy 3 — [1-t er 1-butyldimethylsilyloxyxethyl] 1-azetidine— 2-one,

 4 1 benzenesulfonyloxy 3 — [1 t ert 1 butyldimethylsilylloxityl] 1 azetidine 1 2 -one,

 4-Chloro-3— [1-tert e-Butyldimethylsilyloxoxetyl] azetidine-1 2—one,

 4—Promote 3 — [1—t e rt—Butyldimethylsilyloxechil] azetidine—1 on,

 4-3-[1 -tert-butyl-dimethylsilyloxyxethyl] -azetidine-1-on,

4-cyano 3 — [1-tert-butyldimethylsilyloxyxetil] ase Thidine 1-on

And the like.

 Among these compounds, more preferred are, for example, 4-acetoxy-3- [1-1-tert-butyldimethylsilyloxyxethyl] -1-azetidine-12-one and 4-chloroacetoxy-13- [1-tert- —Butyldimethylsilyloxyshethyl] 1-azetidin-2-one and the like.

 The method for producing the diazo compound represented by the general formula [3] is not particularly limited, and examples thereof include, for example, JP-A-58-103358, JP-A-61 The compound can be synthesized by the method described in Japanese Patent Application Laid-Open No. 2752528 or a method analogous thereto.

 Specific examples of the diazo compound represented by the general formula [3] include, for example,

 Methyl 2-diazo 3 3-year-old xobutanoate

 Methyl 2 — diazo 3 — oxopentanoate

 Methyl 2 — diazo 3 — oxohexanoate

 Ethel 2—Diazo 3—Kiss

 Ethyl 2 — diazo 3 — oxopentanoate

 Ethyl 2-diazo 3-oxohexanoe

 n — propyl 2 — diazo 3 — oxobutanoate

 n — propyl 2 — diazo 3 — oxopentanoate

 n—Propyl 2 —Diazo 1 3 —Oxohexanoate

 Isopropyl 2-diazo 3-oxobutenoate

 Isopropyl 2 — diazo 3 — oxopentanoate

 Isopropyl 2 — diazo 3 — oxohexanoate

 n-Butyl 2-diazo-3-oxoptanoate

 n—Butyl 2-diazo 3 _oxopen

 n —Butyl 2 —Diazo 3 —Oxohexanoate

 t e r t-butyl 2-diazo-3-oxobutanoate

 t e r t-butyl 2 — diazo 3 — oxopentanoate

tert —butyl 2 —diazo 3 —oxohexanoate Benzyl 2-diazo-3 3-year-old

 Benzyl 2-diazo 3-sodium pentapent

 Benzyl 2-diazo 3-oxohexanoate

 p-Nitrobenzil 2-diazo-3-oxobutanoate

 p-Nitrobenzil 2-diazo-3-oxopentanoate

 p-Nitrobenzyl 2-diazo 3-oxohexanoate

 p-Methoxybenzyl 2-diazo-3-oxobutanoate

 P-Methoxybenzyl 2-diazo-3-oxopentanoate

 p_Methoxybenzyl 2-diazo-3-oxohexanoe 1,

 Vinyl 2-diazo 3-oxobutanoate

 Bier 2-Diazo 3-oxopentanoate

 Pier 2—Diazo 3—Oxohexanoate

 Aryl 2 Giazo 3 1—Kisobutano 1

 Aryl 2-diazo 3-oxopentanoate

 Aryl 2-diazo 3-oxohexanoate

And the like.

 Among these azo compounds, more preferred are, for example,

t e r t-butyl 2-diazo-3-oxopene

Benzyl 2-diazo-3-oxopenite,

p-Nitrobenzil 2-Diazo 3-Oxopene

Aryl 2-diazo 1-3-oxopen can be mentioned.

 As the metal compound represented by the general formula [4] used in the present invention, a commercially available product may be used as it is, or it may be purified and used as needed.

Specific examples of the metal compound represented by the general formula [4], for _{example, T i C 1 4, T} i C 1 (OCH 3), T i C 1 (OC 3 H 5), T i C "(O - n - P r), T i C 1 (O- i - P r), T i C 1 (OB u), T i C 1 3 (O - i - B u),

T i C "(O- sec - B u), T i C 1 3 ( 〇- tert -B u), T i C " (OM e) 2, T i C "(OE t) 2, T i C "(O - n- P r) 2, T i C 1 2 (O - i one _{P r) 2, T i C} 1 (OB u) 2, T i C" (O - i - B u) 2, T i C 12 (O-sec-B u) ₂ , T i C 1 2 (O-tert-B u) ₂ , T i (CP) z C 1 T i '(C p *) C 1 T i B r ₄ , T i I _{4 and} other titanium compounds; Z n C l ₂ , Z n B r 2 Zn I _{2 and} other zinc compounds; Z r C l ₄ , Z r C l ₃ (OM e), Z r C 1 (OEt), ZrC1 (O-n-Pr), ZrC1a (O—i-Pr), ZrC1 (O-n-Bu), ZrC "( O - i - B u), Z r C 1 3 (O - sec one B u), Z r C 1 a (O- tert- B u), Z r (C p) 2 C, Z r (C p *) z C 1 Z r B r Z rl zirconium compounds such as _{4; a 1 C 1 3,} a 1 ( 〇_M _{e) 3, a 1 (OE} t) 3, a 1 (O- n- P r) ₃ , A 1 (O— i-PR)

_{3, A l C "M e} , A 1 C 1 M e 2, A l M e 3, A 1 CE t, A 1 C 1 E, A l E t 3, A 1 B r A 1 I 3 , etc. aluminum _{compounds; S n C l 4, S} n B r

_{4, S n IS n (OSOCF} 3) tin compounds such as _{2; F e C l 3,} F e B r 3, iron compounds such as _{F e I 3; (C 2} H 5) 2O - BF (CH 3) ₂ BOS 0 ₂ CF ₃ , (C 2 H ₅ ) ₂ BOSO 2 CF (Pr) ₂ BOS 0 ₂ CF ₃ , (Bu) ₂ BOS 0 ₂ CF _3, etc .; boron compounds; (CH ₃ ) Si OSOCF (Silicon compounds such as CH ₃ S i Cl; S c F ₃ , S c C 1 S c Br ₃ , S cl ₃ , S c (O i -P r) ₃ , S c

(OSO 2 CH 3) scandium compounds such as _{3; YF 3, YC 1 3} , YB r 3, YI 3, Y (O - i - P r) 3, Y (OS 0 2 CH 3) ₃ such as acme thorium _{compounds; L a F 3, L a} C ", L a B r L a", L a (O i - P r) 3, L a ( lanthanum compounds such _{OSOCH 3; C e F 3,} C e C 1 _{C e B r 3, C el} 3, C e (O - i one _{P r) 3, C e (} OSO 2C H3) Seriumu compounds such _{3; P r F 3, P} r C l 3, P r B r _{P rl 3, P r (O-} i one _{P r) 3, P r (} OSO 2 CH 3) Plastic Seojimu compounds such _{3; N d F 3, Nd} C l 3, N d B ra N d I 3, N d (O- i - P r ) 3, N d (OSO 2 CH 3) neodymium compounds such as _{3; SmF 3, SmC l 3} , S m B r 3, Sm l 3, S m (O i - P _{r) 3, S m (OSO} 2 CH 3) samarium compounds such as _{3; G d F 3, G} d C 1, G d B r 3 G dl 3, G d (O i - P r) 3, G d (OS 0 ₂ CH ₃₎ gadolinium compounds such as _{3; D y F 3, D} y C 1 3, D y B r 3, D yl 3, D y (O- i one _{P r) 3, D y (} OS 0 ₂ Dysprosium compounds such as CH ₃ ) ₃ ; E r F ₃ , E r C 1 E r B r ₃ , E rl ₃ , E r (O-i-P r) ₃ , E r

(OSO 2 CH ₃₎ erbium compounds such as _{3; Y b F 3, Y} b C l 3, Yb B r 3, Y Ytterbium compounds such as PC Lanto 15 b I ₃ , Y b (〇i-i-Pr) ₃ , Y b (OSO ₂ CH ₃ ) _{3 and the} like.

 In the above, C p represents a cyclopentagenenyl group, and C p * represents a pentamethylcyclopentenyl group.

As more preferable among these metallic compounds, T i C 1 ₄ (four titanium emissions chloride), Z n CI ₂ (zinc dichloride), Z r C 1 ₄ (zirconium tetrachloride), A 1 C 1 ( aluminum trichloride), S n C 1 ₄ (tin _{tetrachloride), (C 2 H 5)} 2 0 'BF 3 ( boron trifluoride _{etherate), (CH 3) SOS 0} 2 CF ( Torimechirushi Rirutori Fuller g) , (CH ₃ ) ₃ SiC 1 (trimethylsilyl chloride) and the like.

 These metal compounds may be used alone or in an appropriate combination of two or more.

 Examples of the base used in the production method of the present invention include primary amines, secondary amines, tertiary amines, and pyridines.

 Specific examples when the base is a primary amine include, for example, ethylamine, propylamine, butyramine, aniline, benzylamine and the like.

 Specific examples of the case where the base is a secondary amine include, for example, getylamine, di-n-propylamine, diisopropylamine, methylisopropylamine, ethylisopropylamine, di-n-butylamine, diisobutylamine, di-sec— Butylamine, ditert-butylamine, N-methylaniline, N-ethylaniline, pyrrolidine, piperidine, morpholin, piperazine, imidazole, dibenzylamine, and the like.

When the base is a tertiary amine, specific examples include trimethylamine, triethylamine, tripropylamine, triisopropylamine, diisopropylmethylamine, diisopropylethylamine, tri-n-butylamine, tribenzylamine, and N-methyl. Piperidine, N-Ethylbiperidine, N-Methylmorpholin, N-Ethylmorpholin, 1,5-Diazapiciclo [4.3.0] — 5-Nonene, 1,8-Diazabicyclo [5.4.0] -17 Pendene, 1,4 diazabicyclo [2.2.2] octane, N, N, N, N-tetramethylethylenediamine, N, N, N, N-tetramethyl 1,3-propanediamine, dimethylanilin, getylanilin and the like.

 When the base is a pyridine, specific examples include pyridine, α-picolin, i3-picoline, apicolin, 2,6-lutidine, 2-ethylpyridin, 3-ethylpyridine, 4-ethylpyridin, N, N— Examples include dimethylamino pyridine, quinoline, and isoquinoline.

 Among these bases, for example, triethylamine, tri-n-butylethylamine, diisopropylethylamine, N-methylpiperidine, N-ethylpiperidine, N-methylmorpholin, N-ethylmorpholin, 1,5-diazabicyclo [4.3.0] — 5—Nonene, 1,8-diazabicyclo [5.4.0] — 7-Dindecene, 1,4 diazabicyclo [2.2.2] octane, N, N-dimethylamino pyridine, etc. Is more preferred because of its versatility and high reaction selectivity and yield.

 These bases may be used alone or in combination of two or more. As the base used in the present invention, a commercially available product may be used as it is, or may be purified and used as needed.

 In order to carry out the production method of the present invention, it is desirable to carry out the method in an organic solvent under an atmosphere of an inert gas such as argon or nitrogen. Under such conditions, first, the diazo compound represented by the general formula [3] is reacted with the metal compound represented by the general formula [4] and a base, and then the compound represented by the general formula [2] is reacted with the compound. By reacting, the azetidinone compound represented by the general formula [1] can be produced.

As the organic solvent used in the reaction, any solvent may be used as long as it is an inert solvent that does not participate in the reaction. Examples thereof include hydrocarbon solvents such as pentane, hexane, and heptane; cyclohexane; and methylcyclohexane. Alicyclic hydrocarbon solvents, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, dibromoethane, etc., aromatic hydrocarbon solvents such as benzene, cyclobenzene, toluene, xylene, etc., dimethyl ether, Ether solvents such as diisopropyl ether, tetrahydrofuran, dimethoxetane, 1,3-dioxolan and 1,4-dioxane; nitrile solvents such as acetonitrile and propionitrile; Examples include amide solvents such as methylformamide and dimethylacetamide.

 These solvents may be used alone or as a mixed solvent of two or more. Among these solvents, more preferred are halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, ether solvents, etc. Among them, dichloromethane, toluene, xylene, tetrahydrofuran, etc. It is more preferable because of its high selectivity and high reaction selectivity and yield.

 The amount of these solvents to be used is not particularly limited, but is usually about 1 to 50 times, preferably about 5 to 20 times the volume of the compound represented by the general formula [2]. . The reaction temperature is usually about −70 to 100 ° C., preferably about 170 to 0 ° C., and is maintained for about 5 minutes to 5 hours, preferably about 5 minutes to 5 hours. The reaction can be carried out smoothly by reacting for about 10 minutes to 3 hours. In the present invention, the amount of the diazo compound represented by the general formula [3〗] relative to the compound represented by the general formula [2] is preferably about 0.5 to 5 moles per 1 mol of the former. Is used in a range of about 0.7 to 4 times mol.

 In the present invention, the amount of the metal compound represented by the general formula [4] to the compound represented by the general formula [2] is about 0.5 to 2.5 times as much as 1 mol of the former. Degree, preferably in the range of about 0.7 to 2 times mol.

 In the present invention, the amount of the base used relative to the compound represented by the general formula [2] is about 1 to 8 moles, preferably about 1.4 to 4 moles per mole of the former. A range is adopted.

In the above reaction, when R ² is an alkyl group such as a methyl group, the generated α depends on the kind of the diazo compound represented by the general formula [3] and the metal compound represented by the general formula [4] and various reaction conditions. Although the ratio of —body and / 3-body is slightly different, the target content of 3-body is usually about 85% or more.

 From the reaction solution obtained by the above reaction, a desired azetidinone compound can be obtained by a post-treatment method known per se, that is, for example, by solvent extraction, phase transfer, crystallization, recrystallization, various chromatographies, or the like. .

An azetidinone compound represented by the general formula [1] obtained by the production method of the present invention From known production methods, the general formula [B]

[B]

(Wherein, R ′ represents an acyl group, and R ³ is the same as described above.). Implementation-

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

 In addition, the symbol in each Example is as follows.

TBDMS O: t e r t-butyldimethylsilyloxy group

0 A c: acetoxy group, PNB: p-nitrobenzyl group Example 1 (3S, 4I0-3-[(R) -1-tert-butyl-dimethylsilyloxyxethyl] -4-[(R) -triol Preparation of Methyl 3-Diazo-3-p-nitro-2-benzyloxycarbonyl-2-oxo-propyl] -azetidin-2-one

Under a nitrogen atmosphere, a solution of 2.22 g (8.0 mmo 1) of methylene diazide (15 mL) in p-nitrobenzyl 2-diazo 3-butadioxide at 140 ° C. Then, add 0.39 mL (3.55 mmo1) of titanium tetrachloride, stir at 140 ° C for 30 minutes, add 1.81 mL (7.57 mmol) of triptylamine, The mixture was further stirred at 140 ° C. for 30 minutes. Next, (3R, 4R) -4-ase was added to the reaction mixture. Toxic-3-[(R) -1-tert-butyldimethylsilyloxetyl] -azetidine-2-one 577.4 mg (2.0 mmo 1) of methylene chloride solution (5 mL) was added dropwise. Then, the mixture was further stirred at −40 ° C. for 1 hour. The reaction mixture was poured into a 10% aqueous sodium hydrogen carbonate solution to stop the reaction, and the organic layer was separated and washed with water. As a result of analysis by high performance liquid chromatography, it was found that 3: α = 95: 5. After the obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography to obtain 757 mg of] 3-methyl derivative (title compound) (yield) 75%). Physical properties of this compound were consistent with those described in JP-A-61-275284. Example 2 (3S, 4R) -3-[(R) -1-tert-butyldimethylsilyloxhexyl] -4-[(R) -trimethyl-3-diazo-3-P-two-mouth Preparation of benzyloxycarbonyl-2-oxo-propyl] -azetidin-2-one

 In a nitrogen atmosphere, a solution of 1.66 g (6.0 mmol) of p-nitrobenzoyl 2-diazo-3-oxobutanoate in methylene chloride (20 mL) was cooled to-40 ° C. Then, 0.66 mL (6.0 mmo1) of titanium tetrachloride was added, and the mixture was stirred at 40 ° C for 30 minutes, and 1.65 mL (12.Ommol) of n-edubiperidine was added. In addition, the mixture was further stirred at 140 ° C. for 30 minutes. Then, 1.72 g of (3R, 4R) -4-acetoxy-3-[(R) -l-tert-butyldimethylsilyl oxexetyl] -azetidine-2-g 6. Ommol) in methylene chloride (5 mL) was added dropwise, and the mixture was further stirred at 140 ° C. for 1 hour. The reaction was stopped by adding 10 mL of 1M hydrochloric acid to the reaction mixture, and the organic layer was separated and washed with water. As a result of analysis by high performance liquid chromatography, it was found that the ratio of (3): hi = 98: 2. After the obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography to obtain 2.09 g of a] -methyl derivative (the title compound). Rate 69%). Examples 3 and 4

In Example 1, various metal compounds shown in Table 1 below were used in place of titanium tetrachloride, and the reaction and post-treatment were performed in the same manner as in Example 1 except for the above. The same azetidinone compounds were obtained in the following yields and production ratios, respectively. The results are summarized in Table 1. table 1

Example 5

 In Example 1, titanium tetrachloride and trimethylsilyl chloride were used as the metal compounds, and the reaction and post-treatment were carried out in the same manner as in Example 1 except for the above. 3—body: body (production ratio) = 95: 5. Example 6

 In Example 1, the reaction temperature was raised from 40 ° C to 5 ° C, triethylamine was used as the base instead of tributylamine, and the reaction and post-treatment were carried out in the same manner as in Example 1, except that The same azetidinone compound as in Example 1 was obtained in a yield of 69%,] 3-body: unitary (production ratio) = 95: 5. Comparative Example 1

 When the reaction was carried out in the same manner as in Example 1 except that no base was used in Example 1 and no other reaction was carried out, no desired product was obtained. Examples 7 to 9

In Example 1, various reaction solvents shown in Table 2 below were used in place of methylene chloride. Other than that, the reaction and post-treatment were performed in the same manner as in Example 1, and the same as in Example 1 / 01615 The azetidinone compounds were obtained in the following yields and production ratios, respectively. The results are summarized in Table 2. '' Table 2

実施例 1 0〜 1 3

Examples 10 to 13

In + Example 1, as § zo compounds, the p- two Torobe Njiru 2- Jiazo one 3 over O Kiso butanoate (In the above formula, the compound of R = p- nitro downy Njiru group) _P -. Two A compound in which the trobenzyl group was replaced with various substituents shown in Table 3 below was used, and the reaction and post-treatment were carried out in the same manner as in Example 1 to obtain the i8-methyl compound of various azetidinone compounds. Obtained selectively. The results are summarized in Table 3. '' Table 3 Example R β-Methyl form: 0; -Methyl form Yield (%)

-10 benzyl group 9 6: 4 3 8

 1 1 'Methyl group 9 6: 4 3 6'

1 2 t e rt -butyl group 8 6: 1 4 '40

1 3 aryl group 9 4: 6 3 4 Reference Example 1 (1R, 5R, 6S) -p_Nitobenzyl-2-diphenylphosphoryloxy-6-[(R) -l-hydroxyethyl] -trimethyl-carbabenem-3-carboxyle Manufacturing

窒素気流下において、 (3S, 4R)-3-[(R)-l-tert-~

Under a nitrogen stream, (3S, 4R) -3-[(R) -l-tert- ~

Tyl] -4- [00-trimethyl-3 diazo-3-p-nitrobenzoyloxycarbonyl-2-oxo-propyl] -azetidin-2-one 1 49.7 g (3 1 4 mmol) in methanol (750 mL), 24.5 mL of 2M hydrochloric acid was added, and the mixture was stirred at room temperature for 22.5 hours. After adding 1.1 L of ethyl acetate and stirring, the organic layer was separated and washed with water. After the obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain 107.6 g of a desilylated product. The obtained desilylation body 1 0 7. 6 g was dissolved in acetic acid Echiru 1. 1 L, rhodium O Kuta Noe Ichito _{(R h 2 (O ct)} 4) was added to 0. 6 5 g, ·. The reaction was carried out at 50 ° C for 2.5 hours. The solvent was distilled off, and the obtained residue was dissolved in acetonitrile (550 mL), cooled to -10, and then diphenyl chloride phosphate.77.8 g, diisopropylethylamine 39.2 g The mixture was stirred at 110 for 3 hours. The solvent was distilled off, and the obtained residue was dissolved in 2.2 L of ethyl acetate. After the obtained organic layer was washed with water, the solvent was distilled off, and heptane was added for crystallization. The crystals were collected by filtration and dried to obtain 137.9 g of the title compound.

The physical properties of this compound were consistent with those of the compound described in Heterocycles, Vol. 21, pp. 29-40 (1984) and JP-A-6-321946. 3/01615 Industrial applicability

 The present invention relates to an azetidinone compound which is an important synthetic intermediate for industrially producing a 1 / 3-methylcarbapanem derivative which is suitably used for producing a potent antibacterial substance useful as an antibacterial substance. It has a remarkable effect in that it provides a method for selective production under mild conditions in a short process with high yield.

Claims

Scope of claim General formula below [2] [2]

(Wherein, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, and L represents a leaving group.) And a compound represented by the following general formula [3] [3]

(In the formula, R ² represents a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and R ³ has an alkyl group having 1 to 12 carbon atoms, an alkenyl go having 2 to 5 carbon atoms, and a substituent. Represents an optionally substituted phenyl group, an optionally substituted aralkyl group having 7 to 15 carbon atoms, or an optionally substituted 58-membered alicyclic group, Represents' an oxygen atom or a sulfur atom.) A compound represented by the general formula [4] M Yn (R ⁴ ) m [4] (Wherein, M represents a metal atom; Y represents a halogen atom; R ⁴ has a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, and a substituent. Phenoxy group, alkylsulfonyldioxy group, arylsulfonyldioxy group, alkylsulfonyloxy group, arylsulfonyloxy group, cyclopentadienyl group, or pentamethylcyclopentyl Represents a genenyl group, n and m are integers of 0 to 4, and n + m 'is the valence of M.) Wherein the reaction is carried out in the presence of a metal compound represented by the general formula [1] and a base, [1]

(Wherein, RR ² , R ³ and X are the same as described above.) A method for producing a compound represented by the formula: . 2. The production method according to claim 1, wherein in formula [4], the metal atom represented by M is a metal atom belonging to Group 4 of the periodic table. ',. 3. The method according to claim 2, wherein the metal atom belonging to Group 4 of the periodic table is titanium or zirconium. 4. The production method according to claim 1, wherein in the 'general formula' [4], the metal atom represented by M is a metal atom belonging to Group 14 of the periodic table. 5. The production method according to claim 4, wherein the metal atom of Group 14 of the periodic table is gay or tin. · 6. The production method according to claim 1, wherein in the general formula [4], the metal atom represented by M is a metal atom belonging to Group 13 of the periodic table. 7. The production method according to claim 6, wherein the metal atom of Group 13 of the periodic table is boron or aluminum. ' 8. —The production method according to claim 1, wherein in formula [4], the metal atom represented by M is a metal atom belonging to Group 3 of the periodic table. 9. The production method according to claim 8, wherein the metal atom of Group 3 of the periodic table is scandium, yttrium, or lanthanide. 10. The method according to claim 1, wherein in the general formula [4], the metal atom represented by M is a metal atom belonging to Group 8 of the periodic table. 1 1. The production method according to claim 10, wherein the metal atom of Group 8 of the periodic table is iron or ruthenium. 1 2. —The production method according to claim 1, wherein in the general formula [4], the metal atom represented by M is a metal atom belonging to Group 1 or 2 of the periodic table. 1 3. The production method according to claim 12, wherein the metal atom of Group 1 and 2 of the periodic table is zinc. 14. The production method according to any one of claims 1 to 13, wherein the base is a primary amine, a secondary amine, a tertiary amine, and / or a pyridine.