WO2005033120A1

WO2005033120A1 - Method for producing carbapenem derivative

Info

Publication number: WO2005033120A1
Application number: PCT/JP2004/014877
Authority: WO
Inventors: Takaji Matsumoto; Mitsuhiko Fujiwhara; Hideki Nara; Shinya Yamada
Original assignee: Takasago International Corporation
Priority date: 2003-10-02
Filing date: 2004-10-01
Publication date: 2005-04-14
Also published as: JP2005112728A; JP4463520B2

Abstract

A method for producing a carbapenem compound which comprises treating an azetidinone derivative with a magnesium compound to form a carbapenem derivative, and then reacting the resultant reaction product with an active ester agent for a hydroxyl group. The method is free from problems associated with conventional methods and can be employed for producing a carbapenem compound useful as an intermediate for synthesizing a carbapenem based compound, under mild conditions with a short process in good yield.

Description

Technical Field of the Invention

TECHNICAL FIELD The present invention relates to a novel method for producing a carbane derivative. Background art

Chenamycin found in nature (Non-patent Document 1; see below for literature) Power Since it was reported to have a broad antibacterial spectrum and strong antibacterial activity, various carbamates useful as antibacterial agents have been reported. Nem compounds have been reported. The power of the skeleton

1-position (according to conventional numbering (see formula A below; corresponding to 4-position in numbering in the description of the present invention)) Compounds in which a methylene group is substituted by an alkyl group, particularly 1] 3 monomethylcarbamate Penem derivatives (Non-Patent Document 2) have been reported to be extremely useful as antibacterial agents because of their excellent stability against the renal enzyme, dehydropeptidase Z-I. There has been much interest in developing effective methods of producing penem compounds.

As an intermediate for synthesizing a compound of the general formula (B)

(Wherein, r ¹ is a hydrogen atom or a protecting group for a hydroxyl group; R ¹ is a hydrogen atom or an alkyl group; R ² is a protecting group for a carboxy group; r ² is a leaving group The importance of the compound represented by is widely recognized.

The production method of this compound is described in, for example, the following reaction scheme 1 described in Patent Document 1:

The following reaction scheme 2 described in Patent Document 2 shown below:

And the following reaction scheme 3 described in Patent Document 3:

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 Scheme 1 and Reaction Scheme 2, expensive starting materials are used. And the number of steps makes the operation complicated, which is not desirable not only in terms of yield but also in terms of price.

In addition, the method of Reaction Scheme 3 is manufactured in a relatively short process, but requires the use of large quantities of ignitable reagents such as NaH, or a method such as LDA (lithium diisopropyramide). It is necessary to operate at a very low temperature of ° C, which is not an industrial method.

Patent Document 1 JP-A-57-123 1 18 2

Patent Document 2 JP-A-6-321946

Patent Document 3 JP-A-62-103084

Non-Patent Document 1 J. Am. Chem. Soc., 100, 3 13 (1 978) Non-Patent Document 2 Heterocycles., 21 1, 29 (1 984) In such a situation, A safe and suitable method for large-scale synthesis has been desired. Disclosure of the invention

The present inventors have conducted intensive studies on an industrially advantageous method for producing a carbazine compound represented by the above general formula (B), which is useful as an intermediate for the synthesis of a carbane compound, and consequently found the present invention. completed.

That is, the present invention is as follows. ― „―

1. A azetidinone derivative represented by the following general formula (3) is reacted in the presence of a magnesium compound represented by the following general formula (7), and then treated with an active ester agent for a hydroxyl group. A method for producing a compound of formula (5) represented by the following general formula (5).

Where

R ¹ and R ² may be the same or different and represent a hydrogen atom or a lower alkyl group.

R ³ represents a hydrogen atom or a lower alkyl group.

R ⁴ represents a hydrogen atom or a protecting group for a hydroxyl group.

R ⁵ represents a protecting group for a carbonyl group.

Y represents an active ester group, an arylthio group optionally having a substituent, a heteroarylthio group optionally having a substituent, an aralkylthio group optionally having a substituent, represents the a good Ariruokishi group optionally terrorism § reel O carboxymethyl group into but it may also have a substituent or N (R ^a) group represented by S 0 ₂ R ^b,.

R ^a is an alkyl group, an alkenyl group, an organosilyl group, an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, or an alicyclic group optionally having a substituent; Represents a formula group.

R ^b represents an alkyl group or an aryl group which may have a substituent.

M g R ⁸ R ⁹ (7)

Where-.

R ⁸ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, ( 5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted by a halogen atom, or (6) a substituted alkyl group having 1 to 12 carbon atoms Represents a dialkylamino group.

R ⁹ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. 5- to 8-membered ring An alicyclic group of (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenol group which may be substituted with a halogen atom, (5) a carbon atom of 1 A lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted with a halogen atom, (6) a dialkylamino group substituted with an alkyl group having 1 to 12 carbon atoms, ( 7) halogen atom, (8) methanesulfo-loxy group, (9) benzenesulfonoleoxy group, (10) p-toluenesulfonyloxy group, (11) trifonolomethanesulfonyloxy group, (12) a halogen atom, a Shiano group which may be substituted Asetokishi group or (13) oR ^{1 0} group.

R ^1. Represents a lower alkyl group having 1 to 4 carbon atoms, a phenyl group which may have a substituent or a benzyl group which may have a substituent.

Where

R ^{1 to} R ⁵ are as defined above. -

L represents an active ester group of a hydroxyl group.

2. A carbane derivative represented by the general formula (4).

Where

R ¹ and R ² may be the same or different and each is a hydrogen atom or lower alkyl Represents a group.

R ³ represents a hydrogen atom or a lower alkyl group.

R ⁴ represents a hydrogen atom or a protecting group for a hydroxyl group.

R ⁵ is a protecting group for a carboxyl group.

R ⁸ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkenyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. An 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted by a halogen atom, (5) a 1 carbon atom A lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted with a halogen atom, or (6) a dialkylamino group substituted with an alkyl group having 1 to 12 carbon atoms. Represent.

R ⁹ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a fuel group which may be substituted with a halogen atom, (5) A lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted by a halogen atom, (6) an alkyl group having 1 to 12 carbon atoms 8) methanesulfonyloxy group, (9) benzenesulfonyloxy group, (10) p-toluenesulfonyloxy group, (11) triflorenomethanesulfonylo group A xy group, (12) an acetyl group which may be substituted by a halogen atom or a cyano group, or 13) represents a OR ^{1 0} group.

R ¹ ° represents a lower alkyl group having 1 to 4 carbon atoms, a phenyl group which may have a substituent, or a benzyl group which may have a substituent.

m and n are 0 or 1 and m ≠ n.

3. The azetidinone derivative represented by the following general formula (3) is reacted in the presence of a magnesium compound represented by the following general formula (7), and the azetidinone derivative represented by the following general formula (4) is reacted. A method for producing a nem derivative.

Where:

R ¹ and R ² may be the same or different and represent a hydrogen atom or a lower alkynole group.

R ³ represents a hydrogen atom or a lower alkyl group.

R ⁴ represents a hydrogen atom or a protecting group for a hydroxyl group.

R ⁵ represents a carboxyl-protecting group.

Y represents an active ester group, an arylthio group optionally having a substituent, a heteroarylthio group optionally having a substituent, an aralkylthio group optionally having a substituent, Represents an aryloxy group which may be possessed, a heteroaryloxy group which may be substituted, or a group represented by N (R ^a ) S 0 ₂ R ^b .

R ^a is an alkyl group, an arylalkyl group, an organosilyl group, a substituted or unsubstituted aryl group, an optionally substituted aralkyl group, or an optionally substituted aliphatic group; Represents a cyclic group. .

R ^b represents an alkyl group or an aryl group which may have a substituent.

Where

R ⁸ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, (5) 1 to 4 carbon atoms Represents a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted with a halogen atom, or (6) a dialkylamino group substituted with an alkyl group having 1 to 12 carbon atoms. .

R ⁹ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having ^{2 to} 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, 5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted with a halogen atom, (6) an alkyl group having 1 to 12 carbon atoms. Substituted dialkylamino group, (7) halogen atom, (8) methanesulfonyloxy group, (9) benzenesulfonyloxy group, (10) p-toluenesulfonyloxy group, (11) triflorenomethanesulfonylo A xy group, (12) an acetoxy group which may be substituted by a halogen atom or a cyano group, or (13) OR Represents ¹⁰ groups.

Where

R ³ represents a hydrogen atom or a lower alkyl group

R ⁴ represents a protecting group for a hydroxyl group.

R ⁵ represents a carboxyl-protecting group.

R ⁸ represents (1) an alkyl group having 1 to 12 carbon atoms, and (2) an alkyl group having 2 to 5 carbon atoms. (3) a 5- to 8-membered alicyclic group which may be substituted by a lower alkyl group having 1 to 4 carbon atoms, (4) a lower alkyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms A lower alkoxy group having 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, (5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, and a halogen atom which are substituted. A benzyl group, or (6) a dianolexy / reamino group substituted by an alkyl group having 1 to 12 carbon atoms.

R represents (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkenyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group optionally having 1 to 4 carbon atoms. To an 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a fuel group which may be substituted with a halogen atom, (5) a carbon atom. A lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted with a halogen atom, (6) a dial substituted with an alkyl group having 1 to 12 carbon atoms Killamino group, (7) halogen atom, (8) methanesulfonyloxy group, (9) benzenesulfonyloxy group, (10) monotoluenesulfoeroxy group, (11) trifluoromethanesulfonyloxy Group, (12) an acetyl group which may be substituted by a halogen atom or a cyano group, or (1 3) represents an OR ¹⁰ group.

m and n are 0 or 1 and m ≠ n.

4. In the azetidinone derivative represented by the general formula (3), a group represented by a Y force N (R ^a ) S 0 ₂ R ^b (R ^a and R ^b are as defined above). 4. The production method according to the above 1 or 3.

5. The magnesium compound represented by the general formula (7) is methylmagnesium chloride, methylmagnesium bromide, methylmagnesium moxide, methylmagnesium methanesulfonate, methylmagnesium tert. — Butoxide, ethynolemagnesium chloride, ethynolemagnesium bromide, ethynolemagnesium mozide, ethynolemagnesium methanesnolehonate, ethynolemagnesium te rt-butoxide,

Mid, propyl magnesium

G-propynolemagnesium tert-butoxide, iso-propynolemagnesium chloride, iso-propizolemagnesium bromide, iso-propynolemagne propynolemagnesium tert-butoxide, n-butynolemagnesium chloride, n- Butylmagnesium bromide, n-butylinoleum magnesium, n-butylinolemagnesium methanesulfonate, n-butylinolemagnesium tert-peptoxide, sec-butylinolemagnesium chloride, sec-butylinoleum Magnesium bromide, sec-butynolemagnesium oxide, sec_butylinolemagnesium methanesulfonate, sec-butylmagnesium tert-butoxide, iso-butylmagnesium chloride, iso-butylmagnesium chloride, iso-butylmagnesium Noremagnesi Mozide, iso-butyl magnesium methanesulphonate, iso-l-butyl / l-magnesium tert-butoxide, tert-l-butyl magnesium chloride, tert-butyl magnesium bromide, tert-l-butyl magnesium methane sulphonate Tert-butylmagnesium tert-butoxide, phenylmagnesium oxide lid, feninolemagnesium promide, feninolemagnesium methoxide, feninolemagnesium methanesulfonate, phenenomagnesium tert —Putoxide, ρ—Torinolemagnesium chloride, ： —Torinolemagnesium bromide, p-Torinolemagnesium moxide, p-Torinolemagnesium methanesorephonate, ρ—Torinolemagnesium Um-tert-butoxide, benzinolemagnesium chloride, benzinolemagnesium bromide, benzine / lemagnesium oxide, benzinolemagnesium methanesulphonate, and benzinolemagnesium tert-butoxide 5. The production method according to 1, 3, or 4, which is one of the above.

The present invention provides a 1i3-methylcanolevanem derivative, which is suitably used for the production of a carpanem antibiotic useful as an antibacterial substance, under mild conditions and in a short process with high yield. It has a remarkable effect in that it provides a method of manufacturing. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The method of the present invention for producing a carbapenem compound is carried out, for example, according to the following reaction.

[Wherein, 1 and ¹² may be the same or different and each is a hydrogen atom or a lower alkyl group; R ³ is a hydrogen atom or a lower alkyl group; R ⁴ is a hydrogen atom R ⁵ is a carboxyl-protecting group; R ⁸ is (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkenyl group having 2 to 5 carbon atoms, (3) a 5- to 8-membered alicyclic group which may be substituted by a lower alkyl group having 1 to 4 carbon atoms; (4) a lower alkyl group having 1 to 4 carbon atoms; a lower alkyl group having 1 to 4 carbon atoms An alkoxy group, a phenyl group which may be substituted by a halogen atom, (5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, and a halogen atom which may be substituted A benzyl group, or (6) a dialkylamino group substituted by an alkyl group having 1 to 12 carbon atoms; R ⁹ is: (1) an alkyl group having 1 to 12 carbon atoms; (3) a 5- to 8-membered alicyclic group which may be substituted by a lower alkyl group having 1 to 4 carbon atoms, (4) a lower alkyl group having 1 to 4 carbon atoms, carbon A lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, (5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, and a halogen atom substituted A benzyl group, (6) a dialkylamino group having an alkyl group having 1 to 12 carbon atoms, (7) a halogen atom, (8) a methanesulfonyloxy group, (9) benzenesulfo- (10) p-toluenesulfo-loxy group, (11) trifluoromethanesulfonyloxy Shi group has (12) a halogen atom, Shiano group substituted with optionally also be Asetokishi group or (13) OR ^{1 0} group (R ^{1 0} is lower alkyl group having 1 to 4 carbon atoms, the substituents X is a halogen atom or an active ester group of a hydroxyl group; Y is an active ester group or a substituted phenyl group which may be substituted or a benzyl group which may be substituted. Aryloxy group which may have a group, heteroarylthio group which may have a substituent, aralkyl group which may have a substituent, aryloxy group which may have a substituent , to which may have a substituent heteroarylalkyl O alkoxy group, or ^{_{N (R a) S 0 2}} R b in the depicted Ru group (R ^a, an alkyl group, an alkenyl group, organosilyl group,脣換An aryl group which may have a substituent, or an aryl group which may have a substituent There Ararukiru group or substituted be also good alicyclic group,; R ^b is an alkyl group or an optionally substituted Ariru group be);. L represents a hydroxyl group M and n are 0 or 1 and m ≠ n. ]

That is, a azetidinone derivative (3) obtained by reacting an azetidinone compound (1) with an acetate derivative (2) is cyclized with a magnesium compound (7) to produce a carbazinem derivative (4). By treating it with an active esterifying agent, the compound of formula (5) is obtained.

In the production method of the present invention, R ¹ and R ² may be the same or different. And a hydrogen atom or a lower alkyl group. Specific examples of the lower alkyl group include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a Examples thereof include an alkyl group having 1 to 4 carbon atoms such as a butyl group and a tert-butyl group.

Preferred R ¹ and R ² include a hydrogen atom and a methyl group.

R ³ is a hydrogen atom or a lower alkyl group. Specific examples of the lower alkyl group include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butynole group, isobutyl group, sec-butyl group And a tert-butynole group, and an alkyl group having 1 to 4 carbon atoms.

Preferred R ³ includes a hydrogen atom and a methyl group.

R ⁴ is a protecting group for a hydrogen atom or a hydroxyl group. As such a protecting group for a hydroxyl group, for example, those used in the fields of peptide chemistry and ratatum compounds can be used.

Specific examples of the hydroxyl-protecting group include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a dimethylisopropylsilyl group, a dimethylisopropylsilyl group, a dimethyl (2,3-dimethyl-2-butynole) silyl group, and tert-butyl. Di-carbon 1 to 6 alkylsilyl groups such as dimethylsilyl group and dimethylhexylsilyl group, and di-carbon 1 to 6 alkyl alkyl groups such as dimethylcumylsilyl group—C 6 to 18 arylsilyl group, tert-butyldiphene 6 to 18 aryl carbons, such as -silyl group and diphenylmethylsilyl group, 1 to 6 aryl carbon atoms, 1 to 6 alkyl silyl groups, triphenylsilyl group, etc., 6 to 18 aryl carbon groups, tribenzylsilyl group , Tree p-xylylsilyl group, etc. Tree carbon number 7-19 aralkylsilyl group, etc. Tri-substituted silyl groups such as benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenylmethyl, triphenylmethyl, etc. Group (eg, methoxy group, ethoxy group, etc.) or 1 to 3 nitro groups, which may be substituted with 7 to 19 carbon atoms; aralkyl group; for example, methoxycarbyl group, ethoxycarbo L-, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbol, etc. C 1-4 alkoxy groups (for example, methoxy, ethoxy, Etc.), 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.) or 1 to 4 alkylsilyl having a tree carbon number (for example, trimethinolesilinole group, etc.). Alkyloxycarbonyl groups having 1 to 6 carbon atoms which may be mentioned, for example, benzyloxycarbinole group, 2-2 trobenzyloxycarbonyl group, 412-nitrobenzyloxycarbonyl group 1 to 4 alkoxy groups such as a 4-methoxypentinoleoxycanoleboninole group and a 3,4-dimethoxypentinoleoxycarbonyl group (for example, methoxy group, ethoxy group, etc.) Or 1 to 3 carbon atoms, which may be substituted with 1 to 3 nitro groups, 7 to 10 aralkyloxycarbonyl groups; for example, 2 to 6 alkenyl carbon atoms such as a buroxycarboenole group and an aryloxycarbol group Oxycarbonyl group; for example, formyl group, acetyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, propioninole group, butyryl group, benzoyl group, 4-toluoyl group, 4-azeoyl , A halogen group such as 412 trobenzoyl group (for example, fluorine, chlorine, bromine, iodine, etc.) or an acyl group which may be substituted with 1 to 3 nitro groups; for example, a tetrahydrovinylinole group, etc. Is used. Preferable R ⁴ is a C 7 to C 19 aralkyloxycarbol group (for example, a benzyloxycarbonyl group, a 4-to-12-port benzyloxycarbol group, etc.), a carbon number 2 Alkenyloxycarbonyl group (e.g., aryloxycarbonyl group, etc.), tri-C.sub.1-6 alkylsilyl group, etc., more preferably, tert-butyldimethylsilyl group, etc. .

R ⁵ is a protecting group for a carboxyl group, and is generally used as a protecting group for a carboxy group.For example, the number of carbon atoms such as a methyl group, an ethylene group, an isopropyl group, and a t-butyl group Lower alkyl groups having 1 to 4 carbon atoms; lower alkyl groups having 1 to 4 carbon atoms, such as 2-hydroxyethyl group and 2,2,2-trichloroethyl group; methoxymethyl group, ethoxymethyl group, isoprene; (C 1 (Lower α / recoxy) methyl group; acetyloxymethyl, propionyloxymethyl, ptyryloxymethyl, pivaloyloxymethyl, etc. (lower aliphatic acetyl) A substituted or unsubstituted lower alkyl group having 3 to 10 carbon atoms, such as an aryl group, a 2-methylaryl group, a 3-methylaryl group, or a 3-phenylarinole group; a benzyl group, p- or o-diphenyl And substituted or unsubstituted monoarylalkyl groups such as benzyl group and p-hydroxybenzoyl group.

X is a halogen atom or an active ester group of a hydroxyl group; examples of the halogen atom include chlorine, bromine, and iodine; and examples of the active ester group of the hydroxyl group include benzene. Substituted or unsubstituted arylsulfonyloxy groups such as sulfonyloxy group, p-toluenesolephonyloxy group, p-toluene benzenesulfonyloxy group, ρ-promobenzensulfoeroxy group, methanesnoleonylo C1-C4 lower alkylsulfonyloxy such as xy group, ethanesulfonyloxy, etc.Halogeno lower alkenylsulfonyl C1-C4 such as methanesolephoninoleoxy, etc. Xyl groups and the like can be mentioned.

Preferred X includes a halogen atom.

Y represents an active ester group, an arylthio group which may have a substituent, an arylarylthio group which may have a substituent, an aralkylthio group which may have a substituent, An aryloxy group which may have a group, a heteroaryloxy group which may have a substituent, or a group represented by N (R ^a ) S〇 ₂ R ^b (R ^a is Alkyl group, alkyl group, organosilyl group, aryl group optionally having substituent (s), aralkyl group optionally having substituent (s), or alicyclic group optionally having substituent (s) R ^b is an alkyl group or an aryl group which may have a substituent.).

Here, when Y is an active ester group, examples thereof include a heteroaryl group such as an imidazole group and a triazole group; an N-succiimidoxy group; Cyclic imidooxy groups such as a dooxy group and a benzotriazolyloxy group; and heterocyclic alkyl groups such as a 3- (2-thioxo) thiazolidyl group.

In the case of an arylthio group which may have a substituent, examples thereof include a phenyl group, a halognofer group substituted with 1 to 3 halogen atoms such as chlorine, bromine and iodine, p- or o-nitrophene. And p-methoxyphenyl group. In the case of a heteroarylthio group which may have a substituent, for example, 2-, 3- or 4-pyridyl group, 2-pyrimidyl group, 2_ (4,6-dimethyl) pyrimidinole group, etc. No.

When it is an aralkylthio group which may have a substituent, for example, benzyl group, ρ-methoxybenzyl group, 2,4-dimethoxybenzyl group, p- or o-ethoxybenzyl group; And substituted or unsubstituted monoarylalkyl groups such as benzyl group. When it is an aryloxy group which may have a substituent, for example, p- or o-ditropheninoleoxy group, 2,4-di-mouth phenoxy group, 1-3 chlorine, bromine, iodine And a halognophenyloxy group substituted with a halogen atom. When it is a heteroaryloxycarboyl group which may have a substituent, examples thereof include a 2-, 3- or 4-pyridyloxy group.

When Y is a group represented by N (R ^a ) S〇 ₂ R ^b , R ^a is an alkyl group, a alkenyl group, an organosilyl group, an aryl group which may have a substituent, R ^b is an alkyl group which may have a substituent or an alicyclic group which may have a substituent; or an alicyclic group which may have a substituent; Here, specific examples of ^Ra as an alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and a —Alkyl groups having 1 to 12 carbon atoms such as pentyl group, isopentyl group, neopentyl group, hexinole, heptinole, octinole, noel, desinole, pendecinole, dodecinole and the like. Specific examples of the phenol group include alkenyl groups having 2 to 5 carbon atoms, such as butyl, aryl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 2-methylaryl, and the like.

Specific examples of the organosilyl group include, for example, trimethylsilyl group, triethylisopropylsilyl group, dimethyl (2,3-dimethyl-12-butyl) silyl group, tert-butyldimethylsilyl group, dimethylhexylsilyl group and the like. —C1-6 alkylsilyl group; dimethylcumylsilyl group, etc., dicarbon number 1-6 alkyl / carbon C6-18 arylsilyl group; tert-butyldiphenylsilyl group, diphenylmethylsilyl group, etc. 6 to 18 carbon atoms, 1 to 6 carbon atoms, 1 to 6 carbon atoms, 6 to 18 carbon atoms, such as triphenylsilyl group, 6 to 18 carbon atoms, 6 to 18 reel silyl group, tribenzylsilyl group, tree; And trisubstituted silyl groups such as aralkylsilyl groups. In the aryl group which may have a substituent, specific examples of the aryl group include a phenyl group, an a-naphthyl group, a -naphthyl group and a phenanthryl group. Specific examples of the substituent include a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propynole group, an isopropynole group, a butynole group, an isobutynole group, a sec-butynole group, and a tert-butyl group. Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and other lower alkoxy groups having 1 to 4 carbon atoms, fluorine, chlorine, bromine, iodine And a nitro group.

In the aralkyl group which may have a substituent, specific examples of the aralkyl group include a benzyl group, an a-phenylethyl group, a / 3-phenylethyl group, a phenylpropyl group, and a 3-phenylpropyl group. Examples thereof include an aralkyl group having 6 to 13 carbon atoms, such as a phenylpropyl group, a γ-phenylpropyl group, and a naphthylmethyl group. Here, specific examples of the substituent include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. Group, isobutyl group, sec-butyl group, tert-butyl group and other lower alkyl groups having 1 to 4 carbon atoms, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group And lower alkoxy groups having 1 to 4 carbon atoms, such as tert-butoxy group, halogen atoms such as fluorine, chlorine, bromine and iodine, and nitro group.

Specific examples of the alicyclic group in the alicyclic group which may have a substituent include a 5- to 8-membered alicyclic group such as a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclootatyl group. Examples of the substituent include a cyclic group 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. Examples of the lower alkyl group of the formulas 1 to 4 can be given.

Preferred Ra is ^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, and a tert-butyl group; a benzyl group, a monophenyl group, and a naphthylethyl group. A aralkyl group having 6 to 13 carbon atoms; an aralkyl group having 2 to 5 carbon atoms such as a bier group or an aryl group, which may have a substituent such as a group.

Specific examples of ^Rb as an alkyl group include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, 11-pentyl group And alkyl groups having 1 to 12 carbon atoms such as isopentyl group, neopentyl group, hexinole, heptyl, octyl, noel, decyl, pendecyl, dodecyl and the like.

In the aryl group which may have a substituent, specific examples of the aryl group include a phenyl group, an α-naphthyl group, a 3-naphthyl group, a phenanthryl group and the like. Here, specific 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, Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy Examples thereof include a lower alkoxy group having 1 to 4 carbon atoms such as an xy group and a tert-butoxy group, a halogen atom such as fluorine, chlorine, bromine and iodine, and a nitro group.

Preferred R ^b is 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 and a tert-butyl group; a substitution such as a phenyl group, a trinole group and a naphthyl group; Examples thereof include an aryl group having 5 to 10 carbon atoms which may have a group.

Suitable Y, active esters, which may have a substituent Ariruchio force Ruponiru group, to which may have a substituent hetero arylthiocarbonyl group, with ^{_{N (R a) S 0 2}} R b And the groups represented.

In the present invention, the active ester group of a hydroxyl group represented by L is an ester group derived by a reaction between a hydroxyl group and an active esterifying agent, and specifically, a substituted or unsubstituted aryl sulfone. Acid ester group (substituted or unsubstituted arylsulfonyloxy group), (for example, benzenesulfonic acid ester group, monotoluenesulfonic acid ester group, ρ-nitrobenzenesulfonic acid ester group, p-bromobenzenesulfonic acid ester group, etc.) , Lower alkane sulfonate group (lower alkane sulfo-loxy group), (for example, methane sulphonate group, ethane sulphonate group, etc.), nodogeno lower alkane sulfonate group (halogen dialkane sulphonyloxy group) Group), (for example, trifluoromethanesulfonic acid ester group, etc.) , Di-lower alkylphosphoric acid ester group (di-lower alkylphosphoryloxy group), (for example, dimethylphosphoric acid ester group, getyl phosphoric acid ester group, etc.), dihalogeno lower alkylphosphoric acid ester group (di (halogeno group) (Lower alkyl) phosphoryloxy group), (for example, di (trichloroethynole) phosphoric acid ester group), di (substituted or unsubstituted aryl) phosphoric acid ester group (di (Substituted or unsubstituted arylene) phosphoryloxy group), (for example, diphenyl; ^ / lephosphonic acid ester group, di-p-chloro phenolic acid ester group, ditrinolejo A sholic acid ester group).

Preferable examples of such an active ester group of an alcohol include a p-tonolenesulfonic acid ester group, a methanesulfonic acid ester group, and a diphenylphosphoric acid ester group. Therefore, an active esterifying agent for a hydroxyl group is an agent which reacts with a carbane derivative (4) to produce an active ester as described above. The active esterification reagents that can be specifically used include benzenesulfonuric oleide, p-tonolene snolephoninolek oleide, anhydrous p-tonoleensenolenoic acid, and nitrosone benzenesnolefonizolek Mouth lid, p-Promobenzenes-nolephoninolechloride, Methanesnolehoninolek mouth, Ethans-norehoninolek mouth, Trifnoreo mouth Methanesulfonylk mouth-lid, Methanesulfonic anhydride, Trifluoromethane anhydride Snorrephonic acid, dimethinolechlorophosphate, getinolechlorophosphate, di (trichloroethynole) chlorophosphate, diphenyl / lechlorophosphate, g-chlorophenylenolechlorophosphate, ditrinolechlorophosphate, etc. Can be.

In the magnesium compound of the general formula (7) of the present invention and the carbamine derivative of the general formula (4), R ⁸ represents (1) an alkyl group having 1 to 12 carbon atoms, (2) An alkenyl group having 1 to 4 carbon atoms, (3) a 5- to 8-membered alicyclic group which may be substituted with a lower alkyl group having 1 to 4 carbon atoms, (4) a lower alkyl group having 1 to 4 carbon atoms, A lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted by a halogen atom, (5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, and a halogen atom An optionally substituted benzyl group, or (6) a dialkylamino group substituted with an alkyl group having 1 to 12 carbon atoms; R ⁹ is (1) an alkyl group having 1 to 12 carbon atoms, (2) alkenyl group having 2 to 5 carbon atoms, (3) lower alkyl group having 1 to 4 carbon atoms which may be substituted with 5 to 8 An alicyclic group of a ring, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, (5) a 1 to 4 carbon atom A lower alkyl group having 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted with a halogen atom, (6) a carbon number A dialkylamino group substituted with an alkyl group of 1 to 12; (7) a halogen atom; (8) a methanesulfoninoleoxy group; (9) a benzenesnorhononoleoxy group; and (10) p-tonolenesulfonyloxy (11) a trifluoromethanesulfonyloxy group, (12) an acetoxy group which may be substituted by a halogen atom or a cyano group, or (13) an OR ¹⁰ group (R ¹⁰ is a group having 1 to 4 carbon atoms. A lower alkyl group, a phenyl group optionally having a substituent, or a benzyl group optionally having a substituent.).

Here, specific examples of R ⁸ include (1) methyl, ethyl, propyl, isopropynole, butynole, isobynole, sec-petitinole, tert-butynole, pentinole, hexyl, heptyl, octinole, noel, decyl, pendecyl, C1 to C12 alkynole groups such as dodecyl; (2) C2 to C4 alkynyl groups such as butyl, aryl, 1-propyl, isopropyl, 1-butyl, 2-butenyl, 2-methylaryl, etc. Alkenyl group, (3) 5- to 8-membered alicyclic group which may have a substituent, such as pentyl, cyclohexyl, cyclohexyl, cyclooctynole, etc. A lower alkyl group having 1 to 4 carbon atoms such as methinole, ethyl, propyl, isopropynole, petitnole, isoptinole, sec-butyl, tert-butyl, etc.), (4) a phenyl group which may have a substituent (here, the substituent means a group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butynole, tert-butynole, etc.) A lower alkyl group having 1 to 4 carbon atoms, such as a lower alkyl group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, a fluorine atom, a chlorine atom, a bromine atom, A halogen atom such as an elemental atom), (5) a benzyl group which may have a substituent (substituents are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl) C 1 -C 4 lower alkyl groups such as tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isotoki A lower alkoxy group having 1 to 4 carbon atoms, such as cis, sec-butoxy, tert-butoxy, etc., and a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.), (6) getylamino, diisopropylamino , Piperidyl, pyrrolidi Examples thereof include a dialkylamino group substituted with an alkyl group having 1 to 12 carbon atoms, such as an alkyl group.

Specific examples of R ⁹ is (1) methyl, Echiru, propyl, isopropyl, Petit Honoré, Isobuchinore, sec Buchinore, tert- Puchinore, pentyl, hexyl, heptyl, Okuchiru, Noel, decyl, Undeshiru, such as dodecyl An alkyl group having 1 to 12 carbon atoms, (2) an alkenyl group having 2 to 4 carbon atoms such as butyl, arinole, 1-produle, isopropyl, 1-butenyl, 2-butenyl, 2-methylaryl, (3) a 5- to 8-membered alicyclic group which may have a substituent such as cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl (where the substituent is methinole, ethyl, propyl, A lower alkyl group having 1 to 4 carbon atoms, such as isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), (4) having a substituent A phenyl group (where the substituent means a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropinole, petitinole, isoptinole, sec-petit / re, tert-butylinole, methoxy, ethoxy) , A lower alkoxy group having 1 to 4 carbon atoms, such as propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.), ( 5) a benzyl group which may have a substituent (where the substituent means a lower alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, etc.) , Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t a lower alkoxy group having 1 to 4 carbon atoms, such as ert_butoxy, and a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.), (6) carbon atoms such as getylamino, diisopropylamino, piperidyl, and pyrrolidyl. number

A dialkylamino group substituted by an alkyl group of 1 to 12; (7) a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; (8) a methanesulfonyloxy group; and (9) a benzenesulfo-oxy group (10) p-toluenesulfonyloxy group, (11) trifluoromethanesulfonyloxy group, (12) halogen atom and cyano group. Optionally substituted acetoxy group (specific examples are α-fluoroacetoxy, α-chloroacetoxy, hy-promoacetoxy, α-odoacetoxy, a, diphenylenoacetoxy, α, _α -dichloroacetate A halogen atom such as xy, cyanoacetoxy, etc., or an acetooxy group which may be substituted by a cyano group.), (13) OR ¹⁰ group (here, specific examples of R ¹⁰ include methyl, ethyl, Lower alkyl groups having 1 to 4 carbon atoms, such as propyl, isopropyl, butyl, isopropyl, sec-butynole, tert-butyl, etc .; a phenyl group which may have a substituent; or a benzyl group which may have a substituent. (Here, the substituents include methyl, ethanol, propynole, isopropynole, petitnole, isopti / le, sec-butynole, tert-butyl, etc. A lower alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec_butoxy, tert-butoxy, a fluorine atom, a chlorine atom, And halogen atoms such as a bromine atom and an iodine atom.) Are exemplified.) And the like.

Specific examples of the magnesium compound represented by the general formula (7) include methylmagnesium chloride, meth / remagnesium bromide, methinoremagnesium methoxide, methinolemagnesium methanesulfonate, and methinolemagnesium ρ— / Reensnore Honate, Methylmagnesium methoxide, Methynoremagnesium ethoxide, Methynoremagnesium tert-butoxide, Methynoremagnesium phenoxide, Etinole magnesium oxide lid, Etinole magnesium bromide, Etch / Lemagnesium roside, ethinolesmagnesium methanesolephonate, ethinolesmagnesium ρ-north / rehonate, ethizolemagnesium methoxide, ethinolesmagnesium ethoxide, ethynolemagnesium tert-butoxide Ethynolemagnesium phenoxide, propylmagnesium chloride, propylmagnesium bromide, propylmagnesium chloride, propylmagnesium methanesulfonate, propylmagnesium p-toluenesulfonate, propylmagnesiummethoxide, propylmagnesiumethoxy Cid, propylmagnesium tert-butoxide, Propinole magnesium phenoxide, iso-propynolemagnesium chloride, iso-propynolemagnesium bromide, iso-propynolemagnesium oxide, iso-propine / lemagnesium methanesulfonate, iso —Propizolemagnesium p—tonoreensenolephonate, iso—propy / lemagnesium methoxide, iso—propylmagnesium ethoxide, iso—propylmagnesium tert-butoxide, iso-propinolemagnesium phenoxide, n—ptinolemagnesium chloride, n —Butinoremagnesium promide, n-butylinomagnesium moxide, n-butylmagnesium methanesulfonate, n-butylinomagnesium p-toluenesulfonate, n_butylethylmagnesium methoxide, n_petite Lemagnesium ethoxy , N-butynolemagnesium tert-butoxide, n-butynolemagnesium phenoxide, iso-butynolemagnesium chloride, iso-butynolemagnesium bromide, iso-butynolemagnesium bromide , Iso-butynolemagnesium methanes / lefonate, iso-butynolemagnesium p-tonorenesnorefonate, iso-butynolemagnesium methoxide, iso-butynolemagnesium ethoxide, iso-butynolemagnesium tert- Butoxide, iso-butylmagnesium phenoxide, sec-butynolemagnesium mouth lid, sec-butynolemagnesium bromide, sec-butynolemagnesium chloride, sec-petitinolemagnesium methanesnorreona .. , Sec-Petinoremac Nesium p-toluenesolephonate, sec-butylmagne Sium methoxide, sec-butinolemagnesium ethoxide, sec-butylmagnesium tert-butoxide, sec-butynolemagnesium phenoxide, iso-butynolemagnesium chloride, iso-butynolemagnesium bromide, iso-butynolemagnesium methane Snorehonate, iso-p-inolemagnesium p-tonolene snorehonate, iso-butinolemagnesium methoxide, iso-butinolemagnesium ethoxide, iso-poutinolemagnesium tert-butoxide, iso-butylinolemagnesium phenoxide Tert-butynolemagnesium chloride, tert-butynolemagnesium chloride, tert-butynolemagnesium chloride, t ert-ptinolemagnesium methanesulfonate, tert-butylmagnesium ρ-tonolenesnolephonate, tert-butynolemagnesium methoxide, tert-butynolemagnesium ethoxide, tert-butyltinolemagnesium tert-butoxide, tert —Ptinolemagnesium phenoxide, pentopenere magnesium chloride, cyclopentinolemagnesium bromide, cyclopentinolemagnesium mosidide, pentopenolemagnesium methanesnolehonate, syrup mouth pentinolemagnesium ρ—tonolenesnorre Hornate, pen mouth magnesium methoxide, pentyl magnesium ethoxide head, pentyl magnesium tert-butoxide, cyclopentinole magnesium phenoxide, cyclohexyl Noremagnesium chloride, cyclohexinolemagnesium bromide, cyclohexiguremagnesium chloride, cyclohexenemagnesium methanesorephonate, cyclohexenemagnesolephonate magnesium Hexinolemagnesium methoxide, cyclohexynolemagnesium ethoxide, cyclohexynolemagnesium tert-butoxide, cyclohexynolemagnesium phenoxide, fenanolene magnesium chloride, feninolemagnesium promide, phe -Nomagnesium oxide, feninolemagnesium methanesulfonate, feninolemagnesium tert-butoxide, ： -tolylmagnesium chloride, p-tolylmagnesiumbutamide, ρ-tolylmagnesium oxide > ρ-tolylmagnesium methanesulfonate, p-tolylmagnesium p-toluenesulfonate, ρ-torinolemagnesium methoxide,: —torinolemagnesium ethoxide, p-torinolemagnesium tert-butoxide, p-torinole An example is magnesium phenoxide.

Specific examples of preferred magnesium compounds represented by the general formula (7) include methyl magnesium chloride, methyl magnesium bromide, methyl magnesium bromide, methinolesmagnesium methanesulfonate, methyl Noremagnesium tert butoxide, ethinole magnesium chloride, ethinole magnesium bromide, ethinoremagnesium moside, ethinole magnesium methanesnolehonate, ethinolema Gnesium tert-butoxide, propylmagnesium chloride, propylmagnesium bromide, propylmagnesium methoxide, propylmagnesium methance / rephonate, propinole magnesium tert-butoxide, iso-propynolemagnesium chloride , Iso-propylmagnesium bromide, iso-propynolemagnesium oxide, iso_propynolemagnesium methanesulfonate, iso-propylmagnesium tert-butoxide, n-butylmagnesium chloride, n-butyltinmagnesium bromide N-butyltin magnesium methanesulfonate, n-butylmagnesium methanesulfonate, n-butylmagnesium tert-butoxide, sec-butylinolemagnesium chloride, sec-butylinolemagnesium bromide, sec-butylinole Magnesium oxide, sec-butynolemagnesium methanesulfonate, sec-butynolemagnesium tert-butoxide, iso-butynolemagnesium chloride, iso-butynolemagnesium chloride, iso-butynolemagnesium chloride , Iso-Ptino-le-magnesium methanolephonate, iso-p-t-in-le-magnesium tert-poxide, tert-p-in-le-magnesium chloride, tert-p-in-le-magnesium bromide, tert-p-in-le-magnesium oxide, tert- Petinolemagnesium methanes olefonate, tert-butyltinmagnesium tert-butoxide, feninolemagnesium chloride, feninolemagnesium bromide, feninolemagnesium methoxide, phenenomagnesium methanes / rehonate, fenin / Remagnesi Pem tert-butoxide, p-tolylmagnesium chloride, p-tolylmagnesium bromide, p-tolynomagnesium oxide, p-tolynomagnesium methanes norefonate, p-tolynomagnesium tert_butoxide Benzinolemagnesium chloride, benzylmagnesium bromide, benzylmagnesium oxide, benzine / lemagnesium methanesulfonate, benzinolemagnesium tert-butoxide and the like.

The method for producing the magnesium compound (7) is not particularly limited, and examples thereof include a method described in DA Shirley; Org. React., Vol. 8, pp. 28-58 (1954). Can be synthesized by a similar method. Also, commercially available products may be used.

These magnesium compounds may be used alone or in combination of two or more.

The method for producing the azetidinone derivative of the general formula (3) is not particularly limited, but it can be produced by the method described in JP-A-9-31055 or a method analogous thereto. For example, it can be produced according to the following reaction formula.

(In the formula, R ^{1 to} R ⁵ , X and Y are as defined above.)

The reaction of the azetidinone compound (1) with the esterinole acetate derivative (2) can be carried out in an atmosphere of an inert gas such as argon or nitrogen, in an organic solvent, in the presence of a base. .

The solvent may be any inert solvent that does not participate in the reaction, for example, hydrocarbon solvents such as pentane, hexane and heptane; chlorine solvents such as methylene chloride and chloroform; benzene; Organic solvents such as aromatic solvents such as benzene, toluene, xylene, etc., organic solvents such as getyl ether, diisopropinoether, tetrahydrofuran, dimethoxyethane, 1,3-dioxolan, and dioxane, or a mixed solvent thereof. Can be suitably used.

Examples of the base include organic bases such as 1,8-diazabicyclo [5.4.0] _7-indene (DBU), alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diisopropylamide , Lithium hexamethi Examples thereof include metal salts of amines such as rudisilazide, and various bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and potassium t-butoxide.

The reaction is carried out at a temperature of from 150 to 80 ° C, preferably from 120 to 60 ° C, for a reaction time of 60 to 180 minutes. The molar ratio of the reaction is such that the acetate derivative represented by the general formula (2) is about 1 to 2 mol, preferably about 1.2 to 1 mol per mol of the azetidinone compound represented by the general formula (1). The base is equimolar to the ester acetate derivative in about 5 moles. After completion of the reaction, the target substance can be isolated by performing ordinary post-treatment.

The method for producing the azetidinone derivative represented by the general formula (1) as a raw material is not particularly limited, but it can be produced by the method described in JP-A-2000-44538 or a method analogous thereto.

Hereinafter, the production method of the present invention will be specifically described.

In order to carry out the production method of the present invention, for example, the azetidinone derivative of the general formula (3) is reacted with the magnesium compound of the general formula (7) in an organic solvent under an atmosphere of an inert gas such as argon or nitrogen. After cyclization to produce a carbanemine derivative (4), which is a magnesium salt, the compound is then treated with an active esterifying agent for a hydroxyl group, whereby a carbanemene compound represented by the general formula (5) can be produced. . ―. In the cyclization reaction of the azetidinone derivative (3) with the magnesium compound (7), the azetidinone derivative (3) was dissolved in the organic solvent in a solution in which the magnesium compound was dissolved or suspended in the organic solvent. A method in which a solution is dropped and reacted is preferably employed.

The ratio of the azetidinone derivative (3) and the magnesium compound (7) used is preferably about 1 to 8 mol of the magnesium compound (7) per 1 mol of the azetidinone derivative (3). More preferably, it is 5 mol.

Specific examples of the magnesium compound (7) include the compounds described above, and one or more of these compounds may be used. As the organic solvent, an organic solvent that does not adversely affect the cyclization reaction of the azetidinone derivative (3) with the magnesium compound (7) is used. For example, hydrocarbon solvents such as pentane, hexane, heptane, methylene chloride, Chlorinated solvents such as chloroform, aromatic solvents such as benzene, benzene, toluene, xylene, etc.

Examples thereof include ether solvents such as 5-butyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, 1,3-dioxolan, and dioxane, and one or more of them can be used. Among them, tetrahydrofuran and / or toluene are preferably used because they have good operability and are economically inexpensive. Usually, the amount of the organic solvent used is preferably about 0.5 to 20 times by volume, and more preferably about 1 to L0 times by volume, relative to 1 part by mass of the azetidinone compound (3). Les, more preferred to be.

In performing a cyclization reaction by dropping a solution in which the azetidinone derivative (3) was dissolved in an organic solvent to a solution in which the magnesium compound was dissolved or suspended in the organic solvent, the azetidinone derivative (3) was dissolved in the organic solvent. The dropping time of the solution is usually preferably about;! To 5180 minutes, more preferably about 5 to 60 minutes.

The temperature of the cyclization reaction is preferably about 150 to 150 ° C, more preferably about 120 to 80 ° C, and the azetidinone derivative (3)

The carpanem derivative (4) can be produced smoothly by reacting for about 0.5 to 15 hours, preferably about 1 to 5 hours after the completion of the dropwise addition of the solution in which-is dissolved in the organic solvent. .

The potassium salt derivative (4), which is a magnesium salt obtained by the above-mentioned cyclization reaction, is a novel compound which has not been known before, and is stably present in the mixed solution of the above-mentioned cyclization reaction for several hours. However, during long-term storage, it is converted from a phenolic form to a ketone form under the influence of water. Therefore, after the carbane derivative (4) obtained by the cyclization reaction is cooled, if necessary, it is subjected to the next active esterification of a hydroxyl group without post-treatment such as purification. (Step A;). Alternatively, the forceba obtained by the cyclization reaction The penem derivative (4) may be immediately post-treated at a low temperature (under ice cooling) and used in the next treatment step with an activated ester of a hydroxyl group (step).

In step A, the magnesium salt obtained by the above-described cyclization reaction is treated with an active ester agent having a hydroxyl group, followed by treating the magnesium salt (4) with the active compound represented by the general formula (5). Penem compound (5).

In the active esterification reaction of the hydroxyl group, the amount of the active esterifying agent is required to be sufficient for the reaction to proceed sufficiently, and it can be carried out using 1 to 2.5 equivalents to the compound represented by the general formula (3). it can. The reaction can be suppressed or promoted by appropriately cooling or heating. Usually, the reaction is carried out at a temperature in the range of 50 ° C to 50 ° C, preferably in the range of 120 ° C to 20 ° C. After completion of the reaction, the product can be removed by ordinary organic chemical means. The force obtained by reacting the compound represented by the general formula (3) in an inert solvent in the presence of the magnesium compound (7), the lubadenem derivative (4) is converted to the starting compound (3) under production conditions. It retains the steric structure based on the asymmetric carbon (C 5 position), and retains the steric structure of the alkyl group of R ³ of the starting compound even after derivation to the compound. That is, the present reaction yields the compound of formula (5) without formation of an epimer. In the step B, the magnesium salt obtained by the above-mentioned cyclization reaction, i.e., the magnesium salt (4), is immediately post-treated at a low temperature (under ice-cooling), and then in an organic solvent and a base. By treating the compound with an active esterifying agent for a hydroxyl group, the compound can be derived into a canolevanedene compound represented by the general formula (5). For the post-treatment of the magnesium salt obtained by the cyclization reaction, a well-known post-treatment method is used. However, in consideration of the stability of the product, the post-treatment is carried out at a relatively low temperature (about 1%). (5 to 20 ° C) in a short time (within 1 hour). It is desirable that the product be used in the next step without purification.

In the next step, the base is treated with an active esterifying agent for the hydroxyl group, and the product obtained by the above post-treatment is treated under an inert gas atmosphere such as argon-nitrogen. A method in which an active esterifying agent for a hydroxyl group and a base are added dropwise to a solution dissolved or suspended in an organic solvent and reacted therewith is preferably employed.

Bases used in this reaction include tertiary amines and pyridines. When the base is a tertiary amine, specifically, trimethylamine, triethylamine, tripropylamine, triisopropylamine, diisopropylmethylamine, disopropylethylamine, tri-n-butylamine, triethylamine Benzylamine, N-methinoleviperidine, N-ethylpiperidine, N-methylmorpholine, N-ethylmorpholin, 1,5-diazabicyclo [4.3.0] —5_nonene, 1,8_ Diazabicyclo [5.4.0] —7-indene, 1,4-diazabicyclo [2.2.2] otatan, N, N, N, N-tetramethylethylenediamine, N, N, N, N-tetramethyl 1,3-propanediamine, dimethylaniline, getylaniline and the like can be mentioned.

When the base is a pyridine, specifically, pyridine, α-picoline,] 3-picolin, y-picoline, 2,6-lutidine, 2-ethynolepyridine, 3-ethynolepyridine, 4-ethylethylpyridine, N, N-dimethylaminopyridine, quinoline, isoquinoline and the like can be mentioned.

Preferable are triethylamine, tri-n-butylamine, diisopropylethylamine, N-methylpiperidine, N-ethylbutylperidine, N-methylmorpholine, N-ethylmorpholine, 1,5-diazabicyclo [4. 3. 0] — 5-Nonene, 1,8-diazabicyclo [5. 4. 0] -7-undecene, 1, 4-diazabicyclo [2.2.2] octane, N, N-dimethylaminopyridine, etc. It is more preferable because of its versatility and high reaction selectivity and yield.

These may be used alone or as a mixture of two or more.

As the base used in the present invention, a commercially available product can be used as it is, or it can be purified and used.

The proportion of the base used is preferably about 1 to 8 mol, more preferably about 1 to 2 mol, per 1 mol of the azetidinone derivative (3). As the organic solvent, an organic solvent that does not adversely affect the reaction is used. Examples thereof include hydrocarbon solvents such as pentane, hexane, and heptane; chlorine solvents such as methylene chloride and chloroform; benzene; , Toluene, xylene and the like; and ether solvents such as getyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, 1,3-dioxolan, dioxane, etc., and one or more of them. Can be used. Among them, tetrahydrofuran and Z or toluene are preferably used because they have good operability and are economically inexpensive. Usually, the amount of the organic solvent used is preferably about 0.5 to 20 times by volume, and more preferably about 1 to 10 times by volume with respect to 1 part by mass of the azetidinone compound (3). Is more preferred.

The amount of the active esterifying agent in the active ester reaction of the hydroxyl group is required to be sufficient for the reaction to proceed sufficiently, and it can be carried out using 1 to 5 equivalents of the compound represented by the general formula (3).

In carrying out the reaction by dropping the active esterifying agent and the base into a solution in which the cyclization reaction product is dissolved or suspended in an organic solvent, the dropping time of the active esterifying agent and the base is as follows. Usually, it is preferably about 1 to 180 minutes, more preferably about 5 to 60 minutes. The temperature of the cyclization reaction is preferably about -50 to 50 ° C, more preferably about 120 to 30 ° C. By reacting for about 0.5 to 15 hours, preferably for about 1 to 5 hours after the completion of the dropwise addition, the carbane derivative (5) can be produced smoothly.

After completion of the reaction, the desired product can be isolated by performing ordinary post-treatments.

Further, the compound of the present invention (5) obtained by the present invention is represented by the following scheme:

(Wherein, R ^{1 to} R ⁵ have the same meanings as described above; R represents an organic group.)

According to the production method described in (1), it is possible to lead to various kinds of force / levanemine compounds (6). Example

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto and may be changed without departing from the scope of the present invention.

In addition, the apparatus used for the measurement of the physical properties in each example is as follows.

Nuclear magnetic resonance scan Bae-vector (¾- NMR): AM-400 (manufactured by ⁴ 00MHz, Purukka one company), Gemini-2000 (200MHz, manufactured by Varian Inc.)

Abbreviations in the examples are as follows. _ TBSO: t e r t-butyldimethylsilyloxy group

T s: ρ-Tonorenensorehoninole group

[Synthesis Example 1] 3-{(2R) -1-2-((3S, 4R) -13-[(1R) -1-tert-tert-peptinoresimeti / resilinoleoxyethinole] 1-1- (tert-butizoleoxycarbonylmethyl) ) 1 2-Oxosezetidine 1-4 1] Propioniru N-(R)-Hueneruechiru! ) Manufacture of toluenesulfonamide

Under a stream of nitrogen, 3-{(2R) -2-[(3S, 4R) —3 -— [(1R) -1-tert-butyldimethylsilyloxyxetyl] -1-2-oxoazetidine-14- ] Propionyl N— (R) — phenyleluate: — toluenesnorefone amide (Compound 1) (559 mg, 1.0 mmo 1) in tetrahydrofuran (2 mL) was cooled to 0 ° C, 1. Omo 1ZL salt butyl magnesium tetrahydrofuran solution (1. lmol) was added dropwise. After stirring for 30 minutes, a tetrahydrofuran (1 mL) solution of t-peptinoleestenolate acetic acid (215 mg, 1. lmmo 1) was added dropwise. The ice bath was removed, and the mixture was stirred at room temperature for 2 hours and further at 50 ° C for 2 hours. The reaction was stopped with 5% hydrochloric acid, extracted with toluene, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. Purification was performed using a silica gel column chromatography (eluent: hexane Z-ethyl acetate = 3/1) to obtain 350 mg of the title compound (Compound 2). Yield 52%.

I Example 1] (4R, 5R, 6S) _- 6 — [(1R) —— 1—tert-butyldimethylsilyloxoxethyl] 1-3-diphenylphosphoryloxy-14-methyl-17 —Oxo-1 1-azabicyclo [3. 2. 0] Preparation of hepto-2-ene-2-carboxylic acid-tert-butyl ester

Under a nitrogen stream, 1. a solution of OmolZL in tert-butylmagnesium chloride in tetrahydrofuran (3. OmL) was cooled on ice, and the 3 -— ((2R) 1-2 — [(3S, 4R) obtained in Synthesis Example 1 was obtained. ) — 3— [(1R) _ 1— tert-butyldimethylsilyl oxetchinole] 1-11 (tert-butynoleoxycarbo-noremetinole) 1-2-oxosazetidine 14 _yl] propionyl N— (R ) One funeru le roux! ) A solution of toluene sulphonamide (compound 2) (673 mg, 1.0 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was stirred as it was for 3 hours. After confirming that the raw materials had disappeared, the mixture was poured into toluene and water while stirring. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate, and concentrated. The crude product was dissolved in acetonitrile (5 mL) and cooled on ice. After addition of diphenylphosphoryl chloride (537 mg, 2.Ommo 1), diisopropylethylamine (0.35 mL, 2.Ommo 1) was added dropwise. The reaction mixture was stirred as it was for 2 hours. The mixture was poured into aqueous toluene monohydrochloride with stirring. The organic layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate, and concentrated. The crude product was purified by silica gel gel chromatography (eluent: hexane: ethyl acetate = 3: 1) to obtain 327 mg of the title compound (Compound 3). Yield 52%.

Comparative Example 1 As Comparative Example 1, the same treatment as in Example 1 was performed, except that calcium hydride was used instead of tert-butylmagnesium chloride in Example 1. _ As a result, the reaction only recovered the raw material without any progress.

As is clear from Example 1 and Comparative Example 1, in Example 1 using a magnesium compound, the desired product could be obtained in a favorable yield, but calcium hydride, which is a hydride of an alkaline earth metal, was obtained. In Comparative Example 1, which used the same method, the target product could not be obtained only by collecting the raw materials.

[Example 2] (4R, 5R, 6S) — 6 — [(1R) — 11-tert-butyldimethylsilyloxyxethyl] 13-oxo-1 4-methyl-7-oxo-1 1-aza Bicyclo [3. 2. 0] Hept-2-ene-2-carboxylic acid tert-butyl ester Preparation of magnesium chloride salt

Under a nitrogen stream, 1. Omo 1ZL solution of tert-peptide ^ / magnesium chloride in heavy tetrahydrofuran (0.3 mL) was cooled on ice, and the 3 -— ((2R)-2-[(3 S, 4 R) — 3— [(1 R) — 1— tert-butyldimethylsilyloxyschityl] — 1- (tert-butynoleoxycanoleboninolemethyl) — 2 _ oxoazetidine-1-inole] propioninole N— (R A solution of 6-mg (0.1 mmo1) of heavy ethanol (0.5 ml) in tetrahydrofuran (0.5 mL) was added dropwise. The reaction mixture was stirred as it was for 3 hours. After confirming the disappearance of the raw materials, the reaction mixture was directly subjected to NMR measurement. ^ -NMR δ [THF d ₈ ]: 1.00 (3H, d, J = 7.2 Hz), 1.13 (3H, d, 6 Hz), 2.87 (1H, dm, J = 5.4 Hz, 1-H).

After the reaction solution was left at room temperature for 3 hours, the ¹ H-NMR spectrum showed that the methyl form remained as it was. .

Claims

The scope of the claims

1. A azetidinone derivative represented by the following general formula (3) is reacted in the presence of a magnesium compound represented by the following general formula (7), and then treated with a hydroxyl group active ester agent. A method for producing a compound represented by the following general formula (5).

Where

! ^^ ^ May be the same or different and represents a hydrogen atom or a lower alkyl group.

R ³ represents a hydrogen atom or a lower alkyl group.

R ⁴ represents a hydrogen atom or a protecting group for a hydroxyl group.

R ⁵ represents a carboxyl-protecting group.

Y is an active ester group, an arylthio group optionally having a substituent, a heteroarylthio group optionally having a substituent, an aralkylthio group optionally having a substituent, a substituent Represents an aryloxy group which may have a substituent, a heteroaryloxy group which may have a substituent, or a group represented by N (R ^a ) S〇 ₂ R ^b .

^Ra may be an alkyl group, an alkenyl group, an organosilyl group, an aryl group which may have a substituent, an aralkyl group which may have a substituent, or a substituent! / Represents an alicyclic group.

R ^b represents an alkyl group or a substituted or unsubstituted aryl group.

MgR ⁸ R ⁹ (7) Where

R ⁸ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, 5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted by a halogen atom, or (6) a substituted alkyl group having 1 to 12 carbon atoms Represents a dialkylamino group.

R ⁹ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, (5) A lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted by a halogen atom, (6) a dialkylamino substituted by an alkyl group having 1 to 12 carbon atoms Group, (7) halogen atom, (8) methanesulfonyloxy group, (9) benzenesulfonyloxy group, (10) monotoluenesulfonyloxy group, (11) triflorenomethans / levoninoleoxy group, (1¾ A halogen atom, an acetoxy group which may be substituted by cyano, or (13) represents an OR ^{1 0} group.

R ¹⁰ represents a lower alkyl group having 1 to 4 carbon atoms, a phenyl group which may have a substituent, or a benzyl group which may have a substituent.

Where

1 to ¹⁵ are as defined above.

L represents an active ester group of a hydroxyl group.

2. A carbane derivative represented by the general formula (4).

Where

R ³ represents a hydrogen atom or a lower alkyl group.

R ⁴ represents a hydrogen atom or a protecting group for a hydroxyl group.

R ⁵ is a protecting group for a carboxyl group.

R ⁸ is (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkenyl group having 2 to 5 carbon atoms, and (3) an alkyl group having 1 to 4 carbon atoms which may be substituted with 5 to An 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted by a halogen atom, ( ⁵ ) a carbon atom A lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted with a halogen atom, or (6) a dialkylamino substituted with an alkyl group having 1 to 12 carbon atoms Represents a group.

R ⁹ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, (5) 1 to 4 carbon atoms A lower alkyl group having 1 to 4 carbon atoms, a benzyl group which may be substituted with a halogen atom, (6) a dialkylamino group substituted with an alkyl group having 1 to 12 carbon atoms, (7) Halogen atom, (8) methanesulfonyloxy group, (9) benzenesulfonyloxy group, (10) p-toluenesulfonyloxy group, (11) triflorenomethanesulfonyloxy group, (12) halogen atom, cyano group is which may be substituted Asetokishi group or (13) oR ^{1 0} group.

R ^{1 G} is a lower alkyl group having 1 to 4 carbon atoms, a phenyl group which may have a substituent, or a benzyl group which may have a substituent.

m and n are 0 or 1 and m ≠ n.

3. An azetidinone derivative represented by the following general formula (3) is reacted in the presence of a magnesium compound represented by the following general formula (7): A method for producing a nem derivative.

Where

R ³ represents a hydrogen atom or a lower alkyl group.

R ⁴ represents a hydrogen atom or a protecting group for a hydroxyl group.

R ⁵ represents a carboxyl-protecting group.

Y represents an active ester group, an arylthio group optionally having a substituent, a heteroarylthio group optionally having a substituent, an aralkylthio group optionally having a substituent, Aryloxy group which may have a substituent Terrorism § reel O carboxymethyl group to have a or N group represented by ^{_{(R a) S 0 2 R}} b,.

^Ra is an alkyl group, an alkenyl group, an organosilyl group, a substituted or unsubstituted aryl group, an optionally substituted aralkyl group, or an optionally substituted aliphatic group. Represents a cyclic group.

R ^b represents an alkyl group or an aryl group which may have a substituent.

M g R ⁸ R ⁹ (7)

R ⁸ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenol group which may be substituted with a halogen atom, 5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted by a halogen atom, or (6) an alkyl group having 1 to 12 carbon atoms Represents a substituted dianolequinoleamino group.

R ⁹ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkoxy group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to ⁴ carbon atoms. ^{A 5- to} ^8- membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, 5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted with a halogen atom, (6) an alkyl group having 1 to 12 carbon atoms. Substituted dialkynoleamino group, (7) halogen atom, (8) methanesulfonyloxy group, (9) benzenesulfonyloxy group, (10) ρ-toluenesulfonyloxy group, (11) trifluoromethanesulfonyloxy group A (12) halogen atom, an acetyloxy group which may be substituted by a cyano group, or (13 ) OR ¹⁰ represents a group.

R ¹⁰ is a lower alkyl group having 1 to 4 carbon atoms, phenyl which may have a substituent Represents a group or a benzyl group which may have a substituent.

Where

R ³ represents a hydrogen atom or a lower alkyl group

R ⁴ represents a protecting group for a hydroxyl group.

R ⁵ represents a carboxyl-protecting group.

R ⁸ may be substituted by (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, (5) a lower alkyl group of 1 to 4 carbon atoms, lower alkoxy group having 1 to 4 carbon atoms, substituted with c port Gen atoms - optionally base may be Njiru group or ⁽⁶⁾ an alkyl group of 1 to 1 ² carbon atoms, Represents a substituted dialkylamino group.

R ⁹ may be substituted with (1) an alkyl group having 1 to 12 carbon atoms, (2) an alkyl group having 2 to 5 carbon atoms, and (3) a lower alkyl group having 1 to 4 carbon atoms. A 5- to 8-membered alicyclic group, (4) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a phenyl group which may be substituted with a halogen atom, 5) a lower alkyl group having 1 to 4 carbon atoms, a lower alkoxy group having 1 to 4 carbon atoms, a benzyl group which may be substituted by a halogen atom, (6) an alkyl group having 1 to 12 carbon atoms Dialkylamino group, (7) halogen atom, (8) methanesulfonyloxy group, (9) benzenesulfonyloxy group, (10) p-toluenesulfonyloxy group, (11) trifur O b methanesulfonyl O alkoxy group, (12) a halogen atom, may be Shiano group substituted Asetokishi group or (13) OR ¹⁰ group,.

R ¹⁰ represents a lower alkyl group having 1 to ⁴ carbon atoms, a phenyl group which may have a substituent or a benzyl group which may have a substituent.

m and n are 0 or 1 and m ≠ n.

4. In the azetidinone derivative represented by the general formula (3), Y is a group represented by N (R ^a ) S 0 ₂ R ^b (R ^a and R ^b are as defined above). The production method according to claim 1 or 3.

5. When the magnesium compound represented by the general formula (7) is methylmagnesium chloride, methylmagnesium bromide, methylmagnesium hydroxide, methylmagnesium methanesulfonate, methyl / remagnesium tert-butoxide, Ethylene / magnesium chloride, ethinolemagnesium bromide, ethylmagnesium mozide, ethinolemagnesium methanesulfonate, ethinolemagnesium tert-butoxide, propynolemagnesium mouthride, propinole magnesium bromide, Propyl magnesium oxide, propyl magnesium methanesulfonate, propyl magnesium tert-butoxide, iso-propyl magnesium chloride, iso-propynolemagnesium promide, iso-propynolemagnesium , Is'ο-propynolemagnesium methanesulfonate, iso-propynolemagnesium tert-butoxide, n-butynolemagnesium chloride, n-butynolemagnesium bromide, n-butynolemagnesium bromide Azide, n-butyl magnesium methanesulfonate, n-butyl magnesium tert-butoxide, sec-butyl magnesium chloride, sec-butyl magnesium bromide, sec-butyl magnesium Magnesium oxide, sec-butynolemagnesium metal salt, sec-butynolemagnesium tert-butoxide, iso-butynolemagnesium chloride, iso-butynolemagnesium bromide, iso- Petinoremagnesium, iso-butinoremagnesium methanes / lefonate, isobutinoremagnesium tert-butoxide, tert-butinoremagnesium mouth lid, tert-butinoremagnesium bromide, tert-butinoremagnesium bromide, tert-butinoremagnesium —Butynolemagnesium methanesulfonate, tert-butynolemagnesium tert-butoxide, feninolemagnesium chloride, feninolemagnesium bromide, feninolemagnesium bromide, feninolemagnesium Nesium methanesulfonate, feninolemagnesium tert-butoxide, monolinolemagnesium chloride, p-trinolemagnesium bromide, ρ-trinolemagnesium chloride, ρ-trinolemagnesium methanesulfonate, p —Tori no Magnesium selected from the group consisting of tert-butoxide, benzinolemagnesium chloride, benzinolemagnesium carbamide, benzinolemagnesium moxide, benzinolemagnesium methanesulfonate, and benzinolemagnesium tert-butoxide The manufacturing method according to claim 1, 3 or 4, which is one of the methods.