CN1610663A - 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'-beta-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'-beta 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 R<1> represents hydrogen or a hydroxy-protective group; L represents a leaving group; R<2> represents hydrogen or lower alkyl; R<3> represents alkyl, aralkyl, etc.; and X represents oxygen or sulfur.

Description

The preparation method of azetidinone compound

technical field

The present invention relates to an azetidinone compound as an important synthetic intermediate of carbapenem compounds.

Background technique

An important synthetic intermediate of the azetidinone compound (3S, 4R)-3-[(R)-1-Hydroxyethyl]-4-[(R)-1-methyl-3-diazo-3-substituted oxycarbonyl-2-oxo-propyl] -Azetidin-2-one[A]:

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

The preparation method of is known, for example, the following reaction scheme 1 described in JP-A No. 57-123182:

Represented preparation method; the following reaction scheme 2 of JP-A No. 64-25779 communique record:

The preparation method of expression; The following reaction scheme 3 that the Japanese Patent Application Publication No. 6-321946 records:

The preparation method shown; and the following reaction scheme 4 recorded in the Japanese Patent Application No. 58-103358, the Japanese Patent Application No. 6-199780, and the Japanese Publication No. 61-275284:

Indicates the preparation method, etc.

However, these production methods all have the problems described below, and cannot be said to perform sufficiently.

That is, in the methods of reaction schemes 1 to 3, expensive starting materials are used, and the operation is troublesome due to a large number of steps, and neither the yield nor the price is ideal.

In addition, in the method of Reaction scheme 4, it is prepared through a relatively short process, but since an unstable silyl enol ether must be used, it is difficult to say that it is an industrial method, and it is also difficult to say that it is an economical method.

disclosure of invention

The purpose of the present invention is to solve the problems in the above-mentioned existing methods, provide under mild conditions, short steps, good yield, and selectively obtain the required carbapenicillium having a methyl group at the 1'-β position A method for the synthesis of intermediates of vinyl antibacterial agents.

The present invention relates to compounds represented by general formula [1]:

(In the formula, R ¹ , R ² , R ³ and X are the same as below.)

The preparation method is characterized in that,

Make the compound represented by the following general formula [2]:

(In the formula, R ¹ represents a hydrogen atom or a hydroxyl protecting group, and L represents a leaving group)

With the compound represented by the following general formula [3]:

(In the formula, R ² represents a hydrogen atom or a lower alkyl group with a carbon number of 1 to 4, R ³ represents an alkyl group with a carbon number of 1 to 12, a phenyl group that may have a substituent, and a carbon number that may have a substituent is 7-15 aralkyl groups, or 5-8 membered ring alicyclic groups that may have substituents, X represents an oxygen atom or a sulfur atom)

In the following general formula [4]:

MY _n (R ₄ ) _m (4)

(In the formula, M represents a metal atom, Y represents a halogen atom, ^R4 represents a lower alkyl group with 1 to 4 carbons, a lower alkoxy group with 1 to 4 carbons, a phenoxy group that may have a substituent, an alkane group, etc. Sulfonyldioxy, arylsulfonyldioxy, alkylsulfonyloxy, arylsulfonyloxy, cyclopentadienyl, or pentamethylcyclopentadienyl, n and m are 0 to 4 integer, and n+m is the atomic valence of M)

The reaction occurs in the presence of the indicated metal compound and a base.

That is, the present inventors have conducted diligent research to achieve the above object, and as a result found that only by making the compound represented by the above general formula [2] and the diazo compound represented by the above general formula [3] in the presence of a specific metal compound and a base By carrying out the reaction, the desired azetidinone compound [1] having the 1'-β configuration can be produced selectively and in good yield, thereby completing the present invention.

The present invention provides that it is not necessary to convert the diazo compound into a silyl enol ether, only by making the compound represented by the above general formula [2] and the diazo compound represented by the above general formula [3] in the presence of a specific metal compound and a base By carrying out the reaction, the desired azetidinone compound [1] with 1'-β configuration can be selectively prepared under mild conditions, and the method has short steps and good yield.

The best way to practice the invention

In the compound represented by the aforementioned general formula [2] used in the production method of the present invention, examples of the hydroxyl protecting group represented by ^R include all hydroxyl protecting groups commonly used in the fields of peptide chemistry and β-lactam compounds.

That is, for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethyl( 2,3-Dimethyl-2-butyl)silyl, tert-butyldimethylsilyl, dimethylhexylsilyl and other tri(alkyl with 1 to 6 carbons)silyl group, such as dimethyl cumyl silyl and other di(alkyl with 1 to 6 carbons)-aryl-silyl with 6 to 18 carbons, such as tert-butyldiphenylmethyl Di(aryl with 6 to 18 carbons)-alkyl-silyl with 1 to 6 carbons, such as silyl and diphenylmethylsilyl, such as triphenylsilyl, etc. (Aryl)silyl groups with 6 to 18 carbons, such as tris(arylalkyls with 7 to 19 carbons)silyls such as tribenzylsilyl and tri(p-xylyl)silyl Trisubstituted silyl groups such as benzyl, 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenylmethyl, triphenylmethyl, etc. can be An aralkyl group with 7 to 19 carbons whose 1 to 3 hydrogen atoms are replaced by an alkoxy group with 1 to 4 carbons (such as methoxy, ethoxy) or nitro; for example, methoxycarbonyl , ethoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, etc. can be composed of alkoxy groups with 1 to 4 carbons (such as methoxy, ethoxy) or halogen atoms (such as fluorine, chlorine, bromine, iodine, etc.), or three (alkyl with 1 to 4 carbons) silyl groups (such as trimethylsilyl) etc. An alkoxycarbonyl group having 1 to 6 carbon atoms in 1 to 3 hydrogen atoms; for example, benzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, etc., whose carbon number of 1 to 3 hydrogen atoms can be replaced by an alkoxy group with a carbon number of 1 to 4 (such as methoxy, ethoxy, etc.) or a nitro group Aralkyloxycarbonyl with a number of 7 to 10; for example, alkenyloxycarbonyl with a carbon number of 2 to 6 such as vinyloxycarbonyl and allyloxycarbonyl; for example, formyl, acetyl, chloroacetyl , dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, butyryl, benzoyl, 4-toluoyl, 4-methoxybenzoyl, 4-nitrobenzoyl, etc. can be derived from Halogen atom (such as fluorine, chlorine, bromine, iodine, etc.) or acyl group in which 1 to 3 hydrogen atoms are replaced by a nitro group; ring protecting groups such as tetrahydropyranyl, tetrahydrofuranyl, etc.

Preferred among these protecting groups are, for example, aralkyloxycarbonyl groups with 7 to 19 carbons (such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.), alkenyloxycarbonyls with 2 to 6 carbons (such as allyl oxycarbonyl), tri(alkyl having 1 to 6 carbons) silyl and the like, more preferably tert-butyldimethylsilyl and the like.

In addition, the leaving group represented by L includes, for example, acyloxy (for example, alkanoyloxy, aroyloxy, arylalkanoyloxy, alkylsulfonyloxy, arylsulfonyloxy, alkoxy carbonyloxy, aralkoxycarbonyloxy, alkoxyalkanoyloxy, carbamoyloxy, etc.), alkanoylthio, aroylthio, alkylthio, arylthio, alkylsulfinyl , arylsulfinyl group, alkylsulfonyl group, arylsulfonyl group, halogen atom, etc.

Specific examples of when L is an alkanoyloxy group include acetyloxy, propionyloxy, butyryloxy, α-fluoroacetoxy, α-chloroacetoxy, α-bromoacetoxy, α -Iodoacetoxy, α,α-difluoroacetoxy, α,α-dichloroacetoxy, α-cyanoacetoxy, etc. may be substituted by 1 to 3 substituents such as halogen, cyano, etc. branched or cyclic alkanoyloxy groups such as straight-chain alkanoyloxy, isobutyryloxy, cyclohexylcarbonyloxy, and the like.

Specific examples of when L is an aroyloxy group include benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy, nicotinoyloxy, isonicotinoyloxy, furoyloxy A monocyclic or polycyclic aroyloxy group which may have a heteroatom, such as a group (Frufroyruokeshi).

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

Specific examples of when L is an alkylsulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy, propanesulfonyloxy, trifluoromethanesulfonyloxy and the like.

Specific examples of when L is an arylsulfonyl group include benzenesulfonyloxy, p-toluenesulfonyloxy and the like.

Specific examples of when L is an alkoxycarbonyloxy group include methoxycarbonyloxy, ethoxycarbonyloxy and the like.

Specific examples of when L is aralkoxycarbonyloxy include benzyloxycarbonyloxy and the like.

Specific examples of when L is an alkoxyalkanoyloxy group include methoxyacetoxy, ethoxyacetoxy and the like.

Specific examples of when L is a carbamoyloxy group include N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N-phenylcarbamoyloxy and the like.

Specific examples of when L is an alkanoylthio group include acetylthio, propionylthio and the like.

Specific examples of when L is an aroylthio group include benzoylthio, naphthoylthio and the like.

Specific examples of when L is an alkylthio group include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio and the like.

Specific examples of when L is an arylthio group include phenylthio, naphthylthio and the like.

Specific examples of when L is an alkylsulfinyl group include methanesulfinyl, ethanesulfinyl, n-propylsulfinyl, n-butylsulfinyl and the like.

Specific examples of when L is an arylsulfinyl group include phenylsulfinyl, p-toluenesulfinyl and the like.

Specific examples of when L is an alkylsulfonyl group include methylsulfonyl, ethylsulfonyl, n-propanesulfonyl, n-butanesulfonyl and the like.

Specific examples of when L is an arylsulfonyl group include benzenesulfonyl, p-toluenesulfonyl and the like.

Specific examples of when L is a halogen atom include fluorine, chlorine, bromine, iodine and the like.

Among these leaving groups, acetoxy group and the like are particularly preferable.

Among the compounds represented by the aforementioned general formula [3] used in the production method of the present invention, specific examples of lower alkyl groups having 1 to 4 carbon atoms represented by ^R include methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

Moreover, a hydrogen atom or a methyl group is mentioned as preferable ^R2 .

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

Specific examples of alkenyl groups having 2 to 5 carbon atoms represented by ^R3 include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 2-butenyl, and 2-butenyl. - Methallyl etc.

Examples of substituents for the optionally substituted phenyl group represented by ^R3 include lower alkyl groups having 1 to 4 carbon atoms, lower alkoxy groups having 1 to 4 carbon atoms, nitro groups, and halogen atoms.

In this case, specific examples of the lower alkyl group having 1 to 4 carbon atoms as the substituent include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- Butyl, etc. In addition, specific examples of lower alkoxy groups having 1 to 4 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butyl Oxygen, tert-butoxy, etc. Specific examples of the halogen atom include fluorine, chlorine, bromine, iodine and the like.

As the substituent of an aralkyl group having 7 to 15 carbons that may have a substituent represented by ^R , examples include lower alkyls with 1 to 4 carbons, lower alkoxyls with 1 to 4 carbons, nitric acid, etc. groups, halogen atoms, etc.

In this case, specific examples of the lower alkyl group having 1 to 4 carbon atoms as the substituent include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- Butyl, etc. In addition, specific examples of lower alkoxy groups having 1 to 4 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butyl Oxygen, tert-butoxy, etc. In addition, specific examples of the halogen atom include fluorine, chlorine, bromine, iodine and the like.

In addition, specific examples of an aralkyl group having 7 to 15 carbon atoms that may have a substituent include benzyl, α-phenylethyl, β-phenylethyl, α-phenylpropyl, β-phenylpropyl , γ-phenylpropyl, naphthylmethyl, etc.

Specific examples of the optionally substituted 5- to 8-membered alicyclic group represented by ^R3 include cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In addition, examples of the substituent include lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.

Among them, as particularly preferable R ³ , lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl; benzyl, p-nitrobenzyl; Aralkyl groups with 7 to 15 carbons that may have substituents (nitro, methoxy, etc.) such as p-methoxybenzyl, p-methoxybenzyl; alkenes with 2 to 5 carbons such as vinyl and allyl Base etc.

In the metal compound represented by the aforementioned general formula [4] used in the production method of the present invention, the metal atom represented by M includes metal atoms generally used in organic synthesis chemistry, carbon-carbon bond formation reaction, etc., more specifically For example, metals of Group 4 of the periodic table of IUPAC such as titanium and zirconium; metals of Group 14 of the periodic table of IUPAC such as silicon and tin; metals of Group 13 of the periodic table of IUPAC such as boron and aluminum; scandium, yttrium, Metals of group 3 of the periodic table such as lanthanides (lanthanum, cerium, praseodymium, neodymium, samarium, gadolinium, dysprosium, erbium, ytterbium); metals of group 8 of the periodic table such as iron and ruthenium; metals of group 12 of the periodic table such as zinc metal etc.

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 lower alkyl groups having 1 to 4 carbon atoms represented by R include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc., and specific examples of lower alkoxy groups having 1 to 4 carbon atoms include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy base, isobutoxy, sec-butoxy, tert-butoxy, etc.

In addition, examples of substituents for the optionally substituted phenoxy group represented by R include lower alkyl groups having 1 to 4 carbon atoms, lower alkoxy groups having 1 to 4 carbon atoms, and halogen atoms ^.

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

Specific examples of the alkylsulfonyldioxy group represented by ^R include methanesulfonyldioxy, ethanesulfonyldioxy, trifluoromethanesulfonyldioxy and the like.

Specific examples of the arylsulfonyldioxy group represented by ^R include benzenesulfonyldioxy, p-toluenesulfonyldioxy, and the like.

Specific examples of the alkylsulfonyloxy group represented by ^R include methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy and the like.

Specific examples of the arylsulfonyloxy group represented by ^R include benzenesulfonyloxy, p-toluenesulfonyloxy, and the like.

The method for producing the compound represented by the general formula [2] is not particularly limited, for example, J.Am.Chem.Soc., volume 112, pages 7820-7822 (1990), Tetrahedron Letters, volume 32, pages 2145-2148 (1991), Tetrahedron Letters, volume 32, pages 5991 to 5994 (1991), etc., or synthesized according to the methods described in these methods.

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

4-Acetoxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-Acetoxy-3-[1-tert-butyldiphenylsilyloxyethyl]-azetidin-2-one,

4-Acetoxy-3-[1-triethylsilyloxyethyl]-azetidin-2-one,

4-Acetoxy-3-[1-trimethylsilyloxyethyl]-azetidin-2-one,

4-Acetoxy-3-[1-dimethyldecyl (Teksil) silyloxyethyl]-azetidin-2-one,

4-Acetoxy-3-[1-hydroxyethylethyl]-azetidin-2-one,

4-α-Chloroacetoxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-isobutyryloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-propionyloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-Benzoyloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-p-Tolylthio-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-Phenylthio-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-p-Toluenesulfinyloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-Benzenesulfinyloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-p-Toluenesulfonyloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-Benzenesulfonyloxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-Chloro-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-Bromo-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-iodo-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one,

4-cyano-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one and the like.

As preferred compounds among these compounds, for example, 4-acetoxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one and 4- α-Chloroacetoxy-3-[1-tert-butyldimethylsilyloxyethyl]-azetidin-2-one and the like.

The preparation method of the diazo compound represented by the general formula [3] is not particularly limited, but for example, the method described in JP-A-58-103385 A, JP-A-61-275284 A, or according to these methods can be used. method for synthesis.

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

2-diazo-3-oxobutanoic acid methyl ester

Methyl 2-diazo-3-oxopentanoate

Methyl 2-diazo-3-oxohexanoate

2-diazo-3-oxobutanoic acid ethyl ester

Ethyl 2-diazo-3-oxopentanoate

Ethyl 2-diazo-3-oxohexanoate

n-Propyl 2-diazo-3-oxobutanoate

n-Propyl 2-diazo-3-oxopentanoate

n-Propyl 2-diazo-3-oxohexanoate

Isopropyl 2-diazo-3-oxobutanoate

Isopropyl 2-diazo-3-oxopentanoate

Isopropyl 2-diazo-3-oxohexanoate

n-Butyl 2-diazo-3-oxobutanoate

n-Butyl 2-diazo-3-oxopentanoate

n-Butyl 2-diazo-3-oxohexanoate

tert-butyl 2-diazo-3-oxobutanoate

tert-Butyl 2-diazo-3-oxopentanoate

tert-butyl 2-diazo-3-oxohexanoate

Benzyl 2-diazo-3-oxobutanoate

Benzyl 2-diazo-3-oxopentanoate

Benzyl 2-diazo-3-oxohexanoate

2-diazo-3-oxobutanoic acid p-nitrobenzyl ester

2-diazo-3-oxopentanoic acid p-nitrobenzyl ester

2-diazo-3-oxohexanoic acid p-nitrobenzyl ester

2-diazo-3-oxobutanoic acid p-methoxybenzyl ester

2-diazo-3-oxopentanoic acid p-methoxybenzyl ester

2-diazo-3-oxohexanoic acid p-methoxybenzyl ester

Vinyl 2-diazo-3-oxobutanoate

Vinyl 2-diazo-3-oxopentanoate

Vinyl 2-diazo-3-oxohexanoate

Allyl 2-diazo-3-oxobutanoate

Allyl 2-diazo-3-oxopentanoate

Allyl 2-diazo-3-oxohexanoate

wait.

Preferred compounds among these compounds include, for example, tert-butyl 2-diazo-3-oxopentanoate, benzyl 2-diazo-3-oxopentanoate, 2-diazo-3- p-nitrobenzyl oxopentanoate, allyl 2-diazo-3-oxopentanoate, and the like.

The metal compound represented by the general formula [4] used in the present invention can be used as it is as a commercial item, and can be purified as necessary.

Specific examples of the metal compound represented by the general formula [4] include, for example, TiCl ₄ , TiCl ₃ (OCH ₃ ), TiCl ₃ (OC ₂ H ₅ ), TiCl ₃ (O-n-propyl), TiCl ₃ (O-isopropyl), TiCl ₃ (O-butyl), TiCl ₃ (O-isobutyl), TiCl ₃ (O-sec-butyl), TiCl ₃ (O-tert-butyl), TiCl ₂ ( O-methyl) ₂ , TiCl ₂ (O-ethyl) ₂ , TiCl ₂ (O-n-propyl) ₂ , TiCl ₂ (O-isopropyl) ₂ , TiCl ₂ (O-butyl) ₂ , TiCl ₂ (O-isobutyl) ₂ , TiCl ₂ (O-sec-butyl) ₂ , TiCl ₂ (O-tert-butyl) ₂ , Ti(Cp) ₂ Cl ₂ , Ti(Cp ^* ) ₂ Cl ₂ , TiBr _4. Titanium compounds such as TiI ₄ ; zinc compounds such as ZnCl ₂ , ZnBr ₂ , ZnI _{2 ,} etc.; ZrCl ₄ , ZrCl ₃ (O-methyl), ZrCl ₃ (O-ethyl), ZrCl ₃ (O-n-propyl base), ZrCl ₃ (O-isopropyl), ZrCl ₃ (O-n-butyl), ZrCl ₃ (O-isobutyl), ZrCl ₃ (O-sec-butyl), ZrCl ₃ (O-tert-butyl base), Zr(Cp) ₂ Cl ₂ , Zr(Cp ^* ) ₂ Cl ₂ , ZrBr ₄ , ZrI ₄ and other zirconium compounds; AlCl ₃ , Al(O-methyl) ₃ , Al(O-ethyl) ₃ , Al(O-n-propyl) ₃ , Al(O-isopropyl) ₃ , AlCl ₂ Me, AlClMe ₂ , AlMe ₃ , AlCl ₂ Et, AlClEt ₂ , AlEt ₃ , AlBr ₃ , AlI ₃ and other aluminum compounds ; tin compounds such as SnCl ₄ , SnBr ₄ , SnI ₄ , Sn(OSO ₂ CF ₃ ) _2, etc.; iron compounds such as FeCl ₃ , FeBr ₃ , FeI _{3 ,} etc.; (C ₂ H ₅ ) ₂ O·BF ₃ , (CH ₃ ) Boron compounds of ₂ BOSO ₂ CF ₃ , (C ₂ H ₅ ) ₂ BOSO ₂ CF ₃ , (Pr) ₂ BOSO ₂ CF ₃ , (Bu) ₂ BOSO ₂ CF _{3 ,} etc.; (CH ₃ ) ₃ SiOSO ₂ CF _3. Silicon compounds such as (CH ₃ ) ₃ SiCl; scandium compounds such as ScF ₃ , ScCl ₃ , ScBr ₃ , ScI ₃ , Sc(O-isopropyl) ₃ , Sc(OSO ₂ CH ₃ ) ₃ ; YF ₃ , YCl ₃ , YBr ₃ , YI ₃ , Y(O-isopropyl) ₃ , Y(OSO ₂ CH ₃ ) ₃ and other yttrium compounds; LaF ₃ , LaCl ₃ , LaBr ₃ , LaI ₃ , La(O-isopropyl) Lanthanum compounds such as propyl) ₃ , La(OSO ₂ CH ₃ ) ₃ ; CeF ₃ , CeCl ₃ , CeBr ₃ , CeI ₃ , Ce(O-isopropyl) ₃ , Ce(OSO ₂ CH ₃ ) ₃ Cerium compounds; PrF ₃ , PrCl ₃ , PrBr ₃ , PrI ₃ , Pr(O-isopropyl) ₃ , Pr(OSO ₂ CH ₃ ) ₃ and other praseodymium compounds; NdF ₃ , NdCl ₃ , NdBr ₃ , NdI ₃ , Neodymium compounds of Nd(O-isopropyl) ₃ , Nd(OSO ₂ CH ₃ ) _{3 ,} etc.; SmF ₃ , SmCl ₃ , SmBr ₃ , SmI ₃ , Sm(O-isopropyl) ₃ , Sm(OSO ₂ CH ₃ ) Samarium compounds such as ₃ ; gadolinium compounds such as GdF ₃ , GdCl ₃ , GdBr ₃ , GdI ₃ , Gd(O-isopropyl) ₃ , Gd(OSO ₂ CH ₃ ) ₃ ; DyF ₃ , DyCl ₃ , DyBr _3. DyI ₃ , Dy(O-isopropyl) ₃ , Dy(OSO ₂ CH ₃ ) ₃ and other dysprosium compounds; ErF ₃ , ErCl ₃ , ErBr ₃ , ErI ₃ , Er(O-isopropyl) ₃ , Erbium compounds such as Er(OSO ₂ CH ₃ ) ₃ ; Ytterbium compounds such as YbF ₃ , YbCl ₃ , YbBr ₃ , YbI ₃ , Yb(O-isopropyl) ₃ , Yb(OSO ₂ CH ₃ ) _{3 ,} etc.

In addition, the above-mentioned Cp represents a cyclopentadienyl group, and Cp ^* represents a pentamethylcyclopentadienyl group.

Among these metal compounds, TiCl ₄ (titanium tetrachloride), ZnCl ₂ (zinc dichloride), ZrCl ₄ (zirconium tetrachloride), AlCl ₃ (aluminum trichloride), SnCl ₄ (tin tetrachloride) are more preferable. , (C ₂ H ₅ ) ₂ O·BF ₃ (boron trifluoride etherate), (CH ₃ ) ₃ SiOSO ₂ CF ₃ (trimethylsilyl triflate), (CH ₃ ) ₃ SiCl (trimethylsilyl chloride) and the like.

These metal compounds may be used alone or in 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, pyridines and the like.

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

Specific examples when the base is a secondary amine include diethylamine, di-n-propylamine, diisopropylamine, methylisopropylamine, ethylisopropylamine, di-n-butylamine, diisobutylamine , Di-sec-butylamine, di-tert-butylamine, N-methylaniline, N-ethylaniline, pyrrolidine, piperidine, morpholine, piperazine, imidazole, dibenzylamine, etc.

Specific examples when the base is a tertiary amine include trimethylamine, triethylamine, tripropylamine, triisopropylamine, diisopropylmethylamine, diisopropylethylamine, tri-n-butylamine, tribenzylamine, N -Methylpiperidine, N-ethylpiperidine, 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,N,N-tetramethylethylenediamine, N, N,N,N-tetramethyl-1,3-propanediamine, dimethylaniline, diethylaniline, etc.

When the base is pyridine, specific examples include pyridine, α-picoline, β-picoline, γ-picoline, 2,6-lutidine, 2-ethylpyridine, 3-ethylpyridine, 4-ethylpyridine, N,N-dimethylaminopyridine, quinoline, isoquinoline, etc.

Among these bases, for example, triethylamine, tri-n-butylamine, diisopropylethylamine, N-methylpiperidine, N-ethylpiperidine, 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. are more preferable because of their versatility, high selectivity and high yield.

These bases may be used alone or in appropriate combination of two or more. The base used in the present invention can be used as it is from a commercial product, and can also be purified if necessary.

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

As the organic solvent used in the reaction, as long as it is an inert solvent that does not affect the reaction, for example, hydrocarbon solvents such as pentane, hexane, and heptane, and alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane , dichloromethane, dichloroethane, chloroform, dibromoethane and other halogenated hydrocarbon solvents, benzene, chlorobenzene, toluene, xylene and other aromatic hydrocarbon solvents, diethyl ether, diisopropyl ether, tetrahydrofuran, dimethyl Oxyethane, 1,3-dioxolane, 1,4-dioxane and other ether solvents, acetonitrile, propionitrile and other nitrile solvents, dimethylformamide, dimethylacetamide and other amides solvent etc.

These solvents may be used alone or in appropriate combination of two or more.

Preferred solvents in these solvents include halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, ether solvents, etc., among which dichloromethane, toluene, xylene, tetrahydrofuran, etc. are more preferred from the aspects of versatility, reaction selectivity and high yield.

The amount of these solvents used is not particularly limited, but is usually within a range of about 1 to 50 times the volume, preferably about 5 to 20 times the volume, of the compound represented by the general formula [2].

The reaction temperature is usually in the range of about -70 to 100°C, preferably about -70 to 0°C, and the reaction can be carried out for about 5 minutes to 5 hours, preferably about 10 minutes to 3 hours, while maintaining the above temperature. Allow the reaction to proceed smoothly.

In the present invention, the amount of the diazo compound represented by the general formula [3] is about 0.5 to 5 times moles, preferably about 0.7 to 4 times the moles, relative to 1 mole of the compound represented by the general formula [2]. .

In the present invention, the metal compound represented by general formula [4] is used in an amount of about 0.5 to 2.5 times moles, preferably about 0.7 to 2 times moles, relative to 1 mole of the compound represented by general formula [2].

In the present invention, the base is used in an amount of about 1 to 8 times moles, preferably about 1.4 to 4 times moles, based on 1 mole of the compound represented by the general formula [2].

In the above reaction, when R ^is an alkyl group such as a methyl group, the α-body and β-body formed according to the kind and various reaction conditions of the diazo compound represented by the general formula [3] and the metal compound represented by the general formula [4] The proportion of -body will vary to some extent, but the content of target β-body is usually not less than about 85%.

The desired azetidinone compound can be obtained from the reaction solution obtained by the above-mentioned reaction by known post-treatment methods such as solvent extraction, transsolution, crystallization, recrystallization, various chromatography and the like.

From the azetidinone compound represented by the general formula [1] obtained by the production method of the present invention, the general formula [B] can be easily obtained by a known production method

(wherein, R ¹ represents an alkyl group, and R ³ is the same as before) represented carbapenems.

Example

The following examples illustrate the present invention in more detail, but the present invention is not limited by these examples.

In addition, the abbreviations in each embodiment are as follows:

TBDMSO: tert-butyldimethylsilyloxy

OAc: acetoxy, PNB: p-nitrobenzyl

Example 1 (3S, 4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(R)-1-methyl-3-diazo - Preparation of 3-p-nitrobenzyloxycarbonyl-2-oxo-propyl]-azetidin-2-one

Under a nitrogen atmosphere, a dichloromethane solution (15 mL) of 2.22 g (8.0 mmol) of 2-diazo-3-oxobutanoic acid-p-nitrobenzyl ester was cooled to -40°C, and 0.39 g of titanium tetrachloride was added. mL (3.55 mmol), stirred at -40°C for 30 minutes, added 1.81 mL (7.57 mmol) of tributylamine, and stirred at -40°C for 30 minutes. Then, (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-azetidine was added dropwise to the reaction solution A dichloromethane solution (5 mL) of 574 mg (2.0 mmol) of 2-ketone was stirred at -40°C for 1 hour. The reaction mixture was poured into 10% aqueous sodium bicarbonate solution to stop the reaction, and the organic layer was sampled and washed with water. As a result of analysis by high performance liquid chromatography, β:α=95:5. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by chromatography to obtain 757 mg (yield 75%) of the β-methyl derivative (the title compound).

The physical property values of this compound corresponded to those described in JP-A-61-275284.

Example 2 (3S, 4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(R)-1-methyl-3-diazo - Preparation of 3-p-nitrobenzyloxycarbonyl-2-oxo-propyl]-azetidin-2-one

Under nitrogen atmosphere, the dichloromethane solution (20mL) of 1.66g (6.0mmol) of 2-diazo-3-oxobutanoic acid-p-nitrobenzyl ester was cooled to -40°C, and titanium tetrachloride 0.66 mL (6.0 mmol), stirred at -40°C for 30 minutes, added 1.65 mL (12.0 mmol) of N-ethylpiperidine, and stirred at -40°C for 30 minutes. Then, (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-azetidine was added dropwise to the reaction solution A dichloromethane solution (5 mL) of 1.72 g (6.0 mmol) of 2-ketone was stirred at -40°C for 1 hour. 10 mL of 1M hydrochloric acid was added to the reaction mixture to stop the reaction, and the organic layer was sampled and washed with water. As a result of analysis by high performance liquid chromatography, β:α=98:2. The obtained organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by chromatography to obtain 2.09 mg (yield 69%) of a β-methyl derivative (the title compound).

Example 3, 4

Except using the various metal compounds shown in the following table 1 to replace the titanium tetrachloride in embodiment 1, carry out reaction and aftertreatment according to the same method as embodiment 1, obtained with following yield and formation ratio respectively with The same azetidinone compound as in Example 1. The results are shown in Table 1.

Table 1 Example metal compound β-methyl isomer: α-methyl isomer Yield (%) 3 _ZrCl4 80:20 25 4 _AlCl3 95:5 26

Example 5

Except using titanium tetrachloride and trimethylsilyl chloride as the metal compound in Example 1, the reaction and post-treatment were carried out in the same manner as in Example 1, and the same nitrogen heterocycle as in Example 1 was obtained. Butanone compound, yield 68%, β-body:α-body (formation ratio)=95:5.

Example 6

Except that the reaction temperature-40°C in Example 1 is set as 5°C, and triethylamine is used instead of tributylamine as a base, the reaction and post-treatment are carried out in the same manner as in Example 1, and the same as in Example 1 is obtained. The yield of the same azetidinone compound was 69%, and the β-body:α-body (formation ratio)=95:5.

Comparative example 1

When the reaction was carried out in the same manner as in Example 1 except that the base in Example 1 was not used, the target product was not obtained at all.

Embodiment 7-9

Except using the various reaction solvents shown in the following table 2 to replace the dichloromethane in the embodiment 1, carry out the reaction and aftertreatment in the same manner as in the embodiment 1, respectively obtain the same as the embodiment with the following yield and formation ratio The same azetidinone compound as Example 1. The results are shown in Table 2.

Table 2 Example solvent β-isomer: α-isomer Yield (%) 7 toluene 95:5 45 8 Acetonitrile 95:5 48 9 THF 92:8 45

Examples 10-13

In addition to using the p-nitrobenzyl group of 2-diazo-3-oxobutanoic acid-p-nitrobenzyl ester (R=p-nitrobenzyl compound in the above chemical formula) in Example 1, the following table 3 The compounds substituted with the various substituents shown were reacted and post-treated in the same manner as in Example 1 except for the diazo compound. Among the obtained various azetidinone compounds, β- methyl body. The results are shown in Table 3.

table 3 Example R β-methyl isomer: α-methyl isomer Yield (%) 10 Benzyl 96:4 38 11 methyl 96:4 36 12 tert-butyl 86:14 40 13 Allyl 94:6 34

Reference Example 1 (1R, 5R, 6S)-p-nitrobenzyl-2-diphenylphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem - Preparation of 3-carboxylates

Under nitrogen flow, (3S, 4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(R)-1-methyl-3- Diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl]-azetidin-2-one 149.7g (314mmol) was dissolved in 750mL of methanol, and 44.5mL of 2M aqueous hydrochloric acid was added , stirred at room temperature for 22.5 hours. After adding 1.1 L of ethyl acetate and stirring, the organic layer was sampled 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. 107.6 g of the obtained desilylated product was dissolved in 1.1 L of ethyl acetate, 0.65 g of rhodium octanoate (Rh ₂ (Oct) ₄ ) was added, and the mixture was stirred at 50° C. for 2.5 hours. The solvent was distilled off, and the obtained residue was dissolved in 550 mL of acetonitrile, cooled to -10°C, 77.8 g of diphenyl chlorophosphate and 39.2 g of diisopropylethylamine were sequentially added thereto, followed by stirring at -10°C 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 to crystallize. The crystals were filtered and dried to obtain 137.9 g of the title compound.

The physical property values of this compound are consistent with the physical property values of this compound described in Heterocycles, Vol. 21, pp. 29-40 (1984) and JP-A-6-321946.

Industrial Applicability

The invention provides a method for selectively preparing azetidinone compounds under mild conditions with fewer steps and good yields, wherein the azetidinone compounds are used for the industrial preparation of 1β-methylcarbocyanine It is an important synthetic intermediate of mycocene derivatives, and 1β-methyl carbapenem derivatives are suitable for preparing carbapenem antibiotics used as antibacterial substances. The present invention achieves remarkable effects in this respect.

Claims (14)

1. A method for producing a compound represented by the following formula [1], In the formula, R ¹ , R ² , R ³ and X are the same as in the following formula, It is characterized in that, The compound represented by the following formula [2] is reacted with the compound represented by the following formula [3] in the presence of the compound represented by the following general formula [4] and a base, In the formula, ^R represents a hydrogen atom or a hydroxyl protecting group, and L represents a leaving group, In the formula, ^R2 represents a hydrogen atom or a lower alkyl group with a carbon number of 1 to 4, and ^R3 represents an alkyl group with a carbon number of 1 to 12, an alkenyl group with a carbon number of 2 to 5, or a benzene group that may have a substituent A group, an aralkyl group with a carbon number of 7 to 15 that may have a substituent, or an alicyclic group with a 5 to 8-membered ring that may have a substituent, X represents an oxygen atom or a sulfur atom, MY _n (R ⁴ ) _m (4) In the formula, M represents a metal atom, Y represents a halogen atom, ^R4 represents a lower alkyl group with 1 to 4 carbons, a lower alkoxy group with 1 to 4 carbons, a phenoxy group that may have a substituent, an alkyl group Sulfonyldioxy, arylsulfonyldioxy, alkylsulfonyloxy, arylsulfonyloxy, cyclopentadienyl, or pentamethylcyclopentadienyl, n and m are 0-4 integer, and n+m is the atomic valence of M. 2. The preparation method according to claim 1, wherein the metal atom represented by M in the general formula [4] is a metal atom of Group 4 of the periodic table. 3. The production method according to claim 2, wherein the metal atom of Group 4 of the periodic table is titanium or zirconium. 4. The preparation method according to claim 1, wherein, in the general formula [4], the metal atom represented by M is a metal atom of Group 14 of the periodic table. 5. The preparation method according to claim 4, wherein the metal atom of group 14 of the periodic table is silicon or tin. 6. The preparation method according to claim 1, wherein, in the general formula [4], the metal atom represented by M is a metal atom of 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 preparation method according to claim 1, wherein, in the general formula [4], the metal atom represented by M is a metal atom of Group 3 of the periodic table. 9. The preparation method according to claim 8, wherein the metal atom of group 3 of the periodic table is scandium, yttrium or lanthanide. 10. The preparation method according to claim 1, wherein, in the general formula [4], the metal atom represented by M is a metal atom of Group 8 of the periodic table. 11. The production method according to claim 10, wherein the metal atom in Group 8 of the periodic table is iron or ruthenium. 12. The production method according to claim 1, wherein, in the general formula [4], the metal atom represented by M is a metal atom of Group 12 of the periodic table. 13. The preparation method according to claim 12, wherein the metal atom of group 12 of the periodic table is zinc. 14. The preparation 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 pyridines.