WO2008020597A1

WO2008020597A1 - Method for producing 1-methylcarbapenem production intermediate

Info

Publication number: WO2008020597A1
Application number: PCT/JP2007/065896
Authority: WO
Inventors: Masayuki Okue; Masaaki Takahashi; Ichiro Ishikawa; Nobuo Ito; Hitoshi Yamaguchi; Shinjiro Sumi; Keiichi Ajito
Original assignee: Meiji Seika Kaisha, Ltd.
Priority date: 2006-08-15
Filing date: 2007-08-15
Publication date: 2008-02-21
Also published as: CN101500992A; KR20090040333A; JPWO2008020597A1

Abstract

Disclosed is a method for producing a commercially suitable 1-methylcarbapenem production intermediate (II), which does not comprise a complicated step, while using low-cost raw material. Specifically disclosed is a method for producing an 1-methylcarbapenem production intermediate (II), wherein a compound represented by the general formula (I) below is reacted with imidazole, then reacted with a malonic acid ester, and finally if necessary, subjected to diazotization.

Description

Specification

1-Methylcarbapenems production intermediate production method

Technical field

The present invention relates to a method for producing a azetidinone derivative useful as an intermediate for producing 1-methylcarbapenems having excellent antibacterial activity.

Background art

[0002] 1-methylcarbapenems, which have excellent antibacterial activity and have high safety / safety, are extremely useful clinically as antibacterial substances for injection. In addition, recently, it has been developed as an oral administration agent, and is one of the substances that are expected to receive more and more attention in the future.

[0003] However, since antibiotics occupying a group of conventional antibacterial agents are derived from natural organic compounds, 1-methylcarbapenems have to depend on chemical synthesis. There is a big problem in terms of cost, and so far, methods for producing the antibacterial substances or intermediates for producing them have been actively studied in Japan and overseas.

[0004] Several key intermediates have been proposed as intermediates for the production of 1-methylcarbapenems. As an example, there is a compound represented by the following general formula (V).

[Chemical 1]

(Wherein R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, R ⁶ represents a protecting group for a hydrogen atom or a carboxyl group, and OR ⁸ represents a leaving group.)

Various methods have been proposed so far for producing the compound represented by the general formula (V). Among them, azetidinone derivatives represented by the general formula (II) are classified as another important intermediate.

[Chemical 2]

(II)

(In the formula, R ¹ represents a protecting group for a hydrogen atom or a hydroxyl group, R ² represents a protecting group for a hydrogen atom or an amino group, R ⁵ represents a hydrogen atom or a nitrogen atom, and R ⁶ represents a hydrogen atom or a carboxyl group. Represents a protecting group for the group.)

For example, the compound represented by the general formula (Π) is described as an intermediate for the production of the general formula (V) in the method disclosed in JP-A-6-321946. That is, it is represented by the following general formula (ΙΠ ′) disclosed in Japanese Patent No. 3220985, Japanese Patent No. 3450193, and Tetrahedron 52, 331-357, 1996, etc., and is commercially available. A compound such as a 4-acetoxyzetidinone derivative and a compound of the following formula (Α) having an auxiliary group are subjected to a stereoselective carbon-carbon bond forming reaction to give a compound of the following general formula (VI): A variety of methods for obtaining compounds have been proposed. Further, after removing the auxiliary group portion (R ⁹ ) of the compound of the following general formula (VI) by a method such as hydrolysis to obtain a compound of the general formula (VII), the carboxyl group is activated, A method of synthesizing a compound of the general formula (II) by increasing the number of carbon units has been shown, and the compound of the general formula (II) is one of the key intermediates for the production of 1-methylcarbapenems. To the compound of general formula (V).

(ll) (V)

(In the formula, R ¹ represents a protecting group for a hydrogen atom or a hydroxyl group, R ² represents a protecting group for a hydrogen atom or an amino group, R ⁵ represents a hydrogen atom or a nitrogen atom, and R ⁶ represents a hydrogen atom or a carboxyl group. Represents a protecting group for the group, OR ⁸ represents a leaving group, and R ⁹ represents an auxiliary group.)

[0008] However, S, et al., 1-methylcarbapenems are expected to be more useful 1

Several problems arise when trying to produce β-methylcarbapenems. For example, when synthesizing a compound of the general formula (VI), high stereoselectivity is required, so that it is indispensable to use an expensive auxiliary group, and a reagent for smoothly forming a carbon-carbon bond is expensive. There is. In addition, once the auxiliary group is removed, the carboxyl group is activated, and it must be subjected to the carbon increase reaction again. As a result, the conventional method leaves room for improvement as an industrially suitable method.

[0009] Specifically, for example, in JP-A-6-256327 and JP-A-7-82248, a titanium reagent used in the present invention in the reaction to obtain the general formula (VI), zirconium Reagents are used, but compounds with expensive auxiliary groups are used to improve stereoselectivity. In addition, the above-mentioned Japanese Patent No. 3220985 suggests that the compound of formula (VII) is led, but the compound of formula (I) is led to the compound of formula (V). There is no suggestion that you can!

[0010] In addition, improved methods that do not include a complicated step of re-addition after the removal of the auxiliary group are disclosed in JP-A-63-284176, JP-A-10-87657, and the like. The It is. That is, starting from the compound of the general formula (VI ′), the auxiliary group required for obtaining the high stereoselectivity in the previous step without passing through the compound of the general formula (VII) is a kind of desorption. A method is disclosed that leads to a compound of general formula (II), considered as a leaving group (see scheme below).

[Chemical 4]

(VI ¹ ) (II)

(Wherein R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, R ² represents a protecting group for a hydrogen atom or an amino group, R ⁵ represents a hydrogen atom or a nitrogen atom, and R ⁶ represents a hydrogen atom. Or a protecting group for a carboxy group, OR ⁸ represents a leaving group, R ⁹ represents an auxiliary group, R ^1Q , R ^U , R ¹² , and R ¹³ are the same or different and are hydrogen or substituted. May represent a group! / Represents a lower alkyl group, and X and Y represent an oxygen atom or a sulfur atom)

[0012] However, this method is specialized for an auxiliary group having a specific cyclic structure in which the auxiliary group regarded as a kind of the leaving group has a complicated substituent, It is expensive due to its poor versatility and complicated manufacturing. As a result, this method also left room for improvement as an industrially suitable method. Further, these prior arts do not suggest that the compound of the formula (I) having an inexpensive auxiliary group as in the present invention is led to the compound of the formula (Π) or the compound of the formula (V)! /, .

[0013] Under the circumstances as described above, development of a more industrially suitable production method of 1-methylcarbapenems production intermediate using inexpensive raw materials without complicated processes is still desired.

Disclosure of the invention

[0014] The present inventors have now completed an industrially suitable production method for the azetidinone derivative represented by the general formula (II), which is one of the useful intermediates for producing 1-methylcarbapenems. .

Therefore, the present invention provides 1-methylcarbapenems or 1 β having excellent antibacterial activity. The purpose of the present invention is to provide an industrially superior method for producing a azetidinone derivative that is useful as an intermediate for the production of methyl carbapenems and using an inexpensive auxiliary group without going through complicated steps. ! /

And according to one aspect of the present invention, there is provided a process for producing a compound represented by the following formula (II), which comprises:

[Chemical 5]

(Where

R ¹ represents a hydrogen atom or a hydroxyl protecting group,

R ² represents a hydrogen atom or a protecting group for an amino group,

R ⁵ represents a hydrogen atom or a nitrogen atom,

R ⁶ represents a hydrogen atom or a protecting group for a carboxyl group. )

(a) Compound represented by the following formula (I):

[Chemical 6]

(Where

R ³ represents an aryl group which may have a substituent, R ⁴ represents an aryl group that may have a substituent, an aralkyl group that may have a substituent, or an alkyl group that may have a substituent. )

Is reacted with imidazole and then with a malonic ester to obtain a compound of formula (Π) wherein R ⁵ is a hydrogen atom,

(b) characterized in that it further comprises diazotization of the compound obtained in step (a) when a compound of formula (Π) wherein R ⁵ is a nitrogen atom is desired It is.

According to another aspect of the present invention, there is provided a process for producing a compound represented by the above general formula (I), which comprises the following formula (III):

[Chemical 7]

(Where

R ¹ and R ² are as defined above,

R ⁷ represents a rualkylcarbonyl-oxy group. )

A compound represented by the following formula (IV) in the presence of a zirconium reagent:

[Chemical 8]

(Wherein R ³ and R ⁴ are as defined above) And reacting with a compound represented by:

[0018] The auxiliary group (one N (R ³ ) SO R ⁴ ) employed in the present invention is required in the conventional method.

2

Unlike the auxiliary groups having a specific cyclic structure and the like, they can be easily produced at low cost, are industrially suitable, and further effectively function as a leaving group. That is, the auxiliary group employed in the present invention (an ^{^{N (R 3) SO R 4}} ) is a general purpose such Anirin acids and sulfonic acid derivatives

2

It can be easily produced from a substance with abundant properties, and the sulfonanilide compound (HN (R ³ ) SO R ⁴ ) itself

The two bodies are versatile, with some being used as industrial raw materials, and can be easily manufactured at low cost. Furthermore, the method according to the present invention is industrially excellent because it does not require a complicated process when the carboxyl group is activated after removing the auxiliary group once!

[0019] In addition, as far as the present inventors know about the method for producing the compound of general formula (I) constituting another aspect of the present invention, 1 / 3-methylcarbapenem is specifically targeted. In the case of producing the compound of the general formula (I), a known method described in Japanese Patent No. 3220985, Japanese Patent No. 3450193, Tetrahedron 52, 331-357, 1996, etc. is supported. When applied to the group (one N (R ³ ) SO R ⁴ ), sufficient stereoselectivity cannot always be obtained.

2

There was a case. However, the above method according to the present invention has the advantageous effect that always high stereoselectivity can be obtained, especially when carried out in the presence of a zirconium reagent.

Yes

DETAILED DESCRIPTION OF THE INVENTION

[0020]

In the present specification, the lower alkyl group as a group or a part of the group represents a chain, branched, or cyclic alkyl group having preferably 1 to 6 carbon atoms. Specific examples thereof include a methyl group, Ethyl group, n-propyl group, i-propyl group, cyclopropyl, n-butyl group, i-butanol group, sec-butyl group, t-butyl group, cyclobutyl group, n-pentyl group, cyclopentyl group, n-hexyl group, cyclohexyl group Groups and the like.

The aryl group is an aromatic cyclic compound, and examples thereof include a phenyl group, a naphthyl group, and a pyridyl group.

The aralkyl group represents an arylalkyl group, and in the group, the alkyl group portion is preferably The lower alkyl group is represented, and the aryl group represents the aryl group. Therefore, specific examples thereof include benzyl group, phenethyl group, 3-phenylpropyl group, naphthylmethyl group, pyridylmethyl group and the like.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0021] Production of compound of formula (II)

Process · ω

In the method according to the present invention, first, a compound of the general formula (I) is reacted with imidazole to give an imidazolide compound, and then reacted with a malonic ester to give a compound of formula (Π) in which R ⁵ is a hydrogen atom. obtain.

In [0022] formula (I) and formula ([pi), R ¹ is a hydrogen atom or a hydroxyl protecting group, R ² is a protecting group of hydrogen atom or Amino group and R ⁶ is hydrogen atom or a protecting group of a carboxyl group, Represents. As the protective groups for the hydroxyl group, amino group, and carboxyl group, respectively, commonly used protective groups described in PROT ECTVE GROUPS in ORGANIC SYNTHESIS THIRD EDITION (WILEY) can be used. Specific examples of the hydroxyl protecting group include silyl protecting groups such as trimethylsilyl group, triethylsilyl group, and t-butyldimethylsilyl group. The amino protecting group includes trimethylsilyl group, triethylsilyl group, and t-butyl group. Examples include silyl protecting groups such as dimethylsilyl group, benzyl protecting groups such as benzyl group, noramethoxybenzyl group, paranitrobenzyl group, benzhydryl group, etc. As protecting groups for carboxyl group, benzyl group, paramethoxybenzyl, etc. , Benzylic protecting groups such as paranitrobenzyl group, benzhydryl group, bivalloyloxymethinole group, 1- (cyclohexinole xycanoleponinole xy) ethinole group, acetoxymethinole group, 1- (isopropyloxy group) Carbonyloxy) ethyl group, 1- (ethoxycal Benzyloxy) ethyl, cyclohexyloxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyloxy) -2-methylpropane-1-yl, isopropyloxycarbonyloxymethyl, phthalidyl And ester groups that can be hydrolyzed in vivo, such as groups.

[0023] In formula (I) and formula (Π),! /, Preferably! /, Is a hydrogen atom or trimethylsilanol. Group, triethylsilyl group, t-butyldimethylsilyl group and the like, more preferably t-butyldimethylsilyl group.

In the formula (I) and the formula (式), preferred R ² is a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a benzyl group, a nonamethoxybenzyl group, or a paranitro group. An benzyl group, a benzhydryl group, and the like, and more preferably a hydrogen atom, a noranitrobenzyl group, and the like.

[0025] In the formula (Π)! /, Preferably! /, R ⁶ includes a benzyl group, a paramethoxybenzyl group, a parabitrobenzyl group, a benzhydryl group, a bivalyloxymethyl group, 1 -(Cyclohexylcarbonyloxy) ethyl group, acetoxymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, cyclohexyloxycarbonyloxymethyl group, ester group that can be hydrolyzed in the body, etc. More preferred examples include a paranitrobenzyl group and a paramethoxybenzyl group.

[0026] R ³ may have a substituent! /, An aryl group, and preferred examples of the aryl group include aromatic cyclic compounds such as a phenyl group, a naphthyl group, and a pyridyl group. Substituents include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, methyl group, trifunoleolomethinole group, trichloromethinole group, ethyl group, n-propyl group and i-propyl group. , N butyl group, i butyl group, sec butyl group, t butyl group, lower alkyl group, methoxy group, ethoxy group and other lower alkyl group, amino group, monoalkyl which may be substituted with halogen atoms Examples include amino groups (for example, monomethylamino group and monoethylamino group), and dialkylamino groups (for example, dimethylamino group, jetylamino group), amino groups such as cyano group and nitro group. There may be one or more substituents, and when there are multiple substituents, they may be the same or different. When there is only one substituent, the substitution position is selected from the 2-position, 3-position or 4-position of the bond position. In the case of disubstitution, the bonding position is selected from the 2,3, 2,4, 2,5, 2,6, 3, 4 or 3,5 position, and beyond In the case where there is a substituent, a position selected from any conceivable position may be substituted. If the substituent is adjacent disubstitution, the ends of both substituents may be integrated. In that case, an aliphatic ring to which propylene, butylene, or the like is bonded, methylenedioxy, ethylenedioxy, or the like is bonded. The thing which formed the cyclic ether compound is mentioned.

[0027] According to a preferred embodiment of the present invention, preferable R ³ includes phenyl group, bromophenyl group, fluorophenyl group, chlorophenyl group, methylphenyl group, dimethylphenyl group, ethenylphenyl group, i-propylphenyl group. , T-butylphenyl group, methyl-methoxyphenyl group, chloro-methylphenyl group, trifluoromethylphenyl group, methoxyphenyl group, cyanophenyl group, nitrophenyl group, methoxycarbonylphenyl group, methylenedioxyphenyl group, ethylenedioxy group A phenyl group etc. are mentioned, The position of the substituent on a phenyl group is as above-mentioned, respectively.

[0028] R ⁴ is an aryl group, aralkyl group, or alkyl group which may have a substituent, and examples of the substituent include the same substituents as those described above for R ³ . An alkyl group is a lower alkyl group that may be substituted with a halogen atom or the like. For example, a methyl group, a trifunoleolomethinole group, a trichloromethinole group, an ethyl group, an n-propyl group, an i-propyl group, Examples include n-butyl group, i-butyl group, sec-butyl group, and t-butyl group. The aryl group which may have a substituent is a force having the same meaning as described above, for example, a phenyl group, a methylphenyl group, a naphthyl group, a pyridyl group and the like. The aralkyl group has the same meaning as described above, and examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group, and a pyridylmethyl group. Preferred R ^4, phenyl group, main Chirufueniru group, a benzyl group, or the like methyl.

R ⁵ is a hydrogen atom or a nitrogen atom.

[0029] The malonic acid ester to be reacted after reacting the compound of formula (I) with imidazole is preferably a malonic acid monoester, and the ester portion of the malonic acid monoester corresponds to. Accordingly, this ester moiety is preferably selected from those listed for R ⁶ , and specific examples of malonic acid monoesters include malonic acid monobenzil ester, malonic acid mono-p-nitrobenzinoreestenole, malonic acid monoester. Examples thereof include pivaloino reoxymethino ester, and preferably, malonic acid mono-p nitrobenzil ester and the like.

[0030] Step (a), that is, the reaction for obtaining a compound in which R ⁵ is a hydrogen atom among the compounds represented by the general formula (Π), is carried out under an inert gas atmosphere such as nitrogen or argon as the first step. , In an organic solvent, imidazole is allowed to act in the presence or absence of a base catalyst.

[0031] As an organic solvent, any solvent that is not involved in the reaction can be used as long as it is an inert solvent. For example, n pentane, n hexane, cyclohexane, n-heptane, or a mixture of isomers thereof. Hydrocarbon solvents such as methylene chloride, chlorine solvents such as 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene, chloroform benzene, toluene and xylene, jetyl ether, diisopropyl ether, dimethoxy Organic solvents such as ether solvents such as ethane, tetrahydrofuran, 1,4 dioxane and cyclopentyl methyl ether, acetate solvents such as ethyl acetate and butyl acetate, or aprotic polar solvents such as acetonitrile , Can be used by appropriately mixing a plurality of types, preferably methylene chloride, ethyl acetate, Tonitoriru and the like.

[0032] According to a preferred embodiment of the present invention, it is possible to smoothly advance the reaction by adding a base catalyst. Base catalysts include pyridine, 4 dimethylaminopyridine, 2 picoline, 3 picoline, 4 picoline, aniline, N methylaniline, N, N dimethylaniline, 2,3-tidine, 2,4,6-collidine, 1, Organic bases such as 4-diazabicyclo [2.2.2] octane, 1,5 diazabicyclo [4 · 3.0] nona 5-ene, 1,8 diazabicyclo [5.4.0] Examples include 4-dimethylaminopyridine.

[0033] The use ratio (weight / volume ratio) of the general formula (I) and the solvent is usually from 1: 5 to 100, and preferably from 1:10 to 50. The use ratio (molar ratio) of the general formula (I) to the base catalyst is usually from 1: 0.0 to 0.5, preferably 1: 0 · 05-0.2. The use ratio (molar ratio) of the general formula (I) and imidazole is usually 1: 1 to 10 and preferably 1 :;! To 5. The reaction temperature is generally −30 to; 100 ° C., preferably 30 to 60 ° C. The reaction usually proceeds in 0.5 to 48 hours, preferably 2 to 24 hours, and 3 to 6 hours is preferable.

[0034] The imidazolide compound obtained by this reaction can be isolated by a general separation and purification method. Since the compound is unstable, it is usually convenient to directly apply to the next step. . The reaction mixture containing the imidazolide compound thus obtained is usually subsequently subjected to the next step, but can be appropriately cooled and stored. The cooling temperature for storage is −80 to 0 ° C., preferably −30 to −10 ° C. Also, The storage period is from several hours to two days, preferably within 24 hours.

[0035] In the step (a), that is, the reaction to obtain a compound in which R ⁵ is a hydrogen atom among the compounds represented by the general formula (Π), imidazole acts on the compound of the formula (I) as the second step. And then add malonic acid ester.

[0036] According to a preferred embodiment of the present invention, the reaction is carried out in the presence of a magnesium compound. Examples of the magnesium compound include magnesium chloride, magnesium bromide, magnesium bromide ether complex, magnesium iodide, magnesium methoxide. , Magnesium ethoxide and the like are used, and preferably magnesium chloride is used.

[0037] According to a preferred embodiment of the present invention, the reaction is carried out in the presence of a base. Examples of the base include trimethylamine, triethylamine, tributylamine, trioctylamine, diisopropyl pyrethylamine, Ν methyl Pyrrolidine, Ν-methylpiperidine, Ν methylmorpholine, pyridine, 4 dimethylaminopyridine, 2 picoline, 3 picoline, 4-picoline, aniline, Ν methylaniline, Ν, Ν-dimethylaniline, 2,3 lutidine, 2, 4 lutidine, 2,5 lutidine, 2,6 lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5 diazabicyclo [ 4.3.0] —Nonah 5 and 1,8 diazabicyclo [5.4.0] —Undecar 7—en, preferably triethylamine.

[0038] In the reaction, there are no particular restrictions on the order in which the reagents are charged. A reaction mixture containing an imidazolide compound obtained separately is added to a mixture obtained by reacting a magnesium compound, a base group, and a malonic ester in an organic solvent. However, it is common to add a magnesium compound, a base and malonic acid monoester to the reaction mixture containing the imidazolide compound obtained above. At this time, the use ratio (molar ratio) of the general formula (I) to the magnesium compound is usually 1: 0 · 5 to 3, preferably 1: 0 · 7 to! The use ratio (molar ratio) of the general formula (I) to the base is usually 1: 1 to 6, preferably 1: 1.5 to 3. The use ratio (molar ratio) of the general formula (I) to the malonic acid monoester is usually 1:;!-3, and preferably 1:;!-2. The temperature at which the magnesium compound, base and malonic acid monoester are added is usually from -80 to 0 ° C, preferably from -30 to -10 ° C. The reaction temperature after adding all necessary reagents is -30 to 100 ° C, preferably 30 to 6 0 ° C. The reaction usually proceeds in 0.5 to 20 hours, preferably 1 to 5 hours.

[0039] The obtained reaction mixture is worked up according to a conventional method, and is isolated by a general separation and purification method to obtain the general formula (II) (wherein R ⁵ is a hydrogen atom). I can do it.

[0040] Step (b)

If a compound of formula (II) in which R ⁵ is a nitrogen atom is desired, the compound obtained in step (a) is further diazotized.

Usually, the general formula (Π) (wherein R ⁵ is a hydrogen atom) obtained in the step (a) is diazotized as it is without isolating the general formula (Π) ( In the formula, R ⁵ is a nitrogen atom). The organic solvent used at this time is an ability to use an inert solvent that does not participate in the aforementioned reaction. Preferably, a hydrocarbon solvent, a chlorinated solvent, an aromatic hydrocarbon, which are convenient for use in the post-treatment of the reaction. System solvents and acetic acid-sterol solvents are used, and η-heptane, methylene chloride, toluene, ethyl acetate, etc. are preferably used.

[0041] An azide compound and a base are used for diazotization. As the azide compound, sulfonyl azides such as methanesulfonyl azide, toluenesulfonyl azide, ρ-carboxybenzenesulfonyl azide and dodecylbenzenesulfonyl azide are used, and preferably dodecylbenzenesulfonyl azide and the like.

Bases include trimethylamine, triethylamine, tributylamine, trioctylamine, diisopropylethylamine, Ν-methylpyrrolidine, Ν-methylpiperidine, Ν-methinole monoreforin, pyridine, 4-dimethylaminopyridine, 2 —Picoline, 3-Picoline, 4-Picoline, Aniline, Ν-Methylaniline, Ν, Ν-Dimethylaniline, 2,3-Lutidine, 2,4-Lutidine, 2,5-Lutidine, 2,6-Lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] —noner-5-ene, 1, 8-Zazabicyclo [5.4.0] -undecar 7-en and the like are used, and preferred is triethylamine.

[0042] The use ratio (molar ratio) of the general formula (I) to the azide compound is usually from 1: 0.7 to 2, preferably;!:;! To 1 · 5. The use ratio (molar ratio) of the general formula (I) to the base is usually 1: 0 ·;! ~ 1, preferably 1: 0.2 ~ 0.5. The reaction normally proceeds at -20-50 ° C, preferably Is 0-50 ° C. The reaction time is usually 0.5 to 48 hours, preferably; !! to 24 hours, 3 to 15 hours is preferred.

[0043] The reaction mixture thus obtained is subjected to work-up according to a general method commonly used by those skilled in the art, and is further isolated by a general separation and purification method to give a general formula (Π) (wherein R ⁵ is a nitrogen atom). In this post-treatment, it is easy to separate and refine the general formula (Π) (where R ⁵ is a nitrogen atom) by washing with a dilute alkaline aqueous solution in addition to the usual water washing. Become. As the dilute alkaline aqueous solution at this time, a sodium hydrogen carbonate aqueous solution, a potassium hydrogen carbonate aqueous solution, a sodium carbonate aqueous solution, a potassium carbonate aqueous solution, a sodium hydroxide aqueous solution, a potassium carbonate aqueous solution, an aqueous ammonia, or the like is used, preferably a sodium hydroxide aqueous solution. It is. In this case, the concentration of the dilute alkaline aqueous solution is usually from 0.;! To 3 mol / L, preferably from 0.5 to Imol / L. Separation and purification is a force that can be used by an ordinary general method, preferably a method of forming a precipitate, and can be performed by appropriately concentrating the post-treatment solution. As another method, an organic solvent such as n-heptane is appropriately added and further aged, and the resulting precipitate is collected by filtration to give a general formula (1) useful as a production intermediate for 1-methylcarbapenems ( II) A azetidinone derivative represented by the formula (wherein R ⁵ is a nitrogen atom) can be obtained.

[0044] When a protective group is present in R ¹ of the obtained general formula (II), it is removed by a commonly used deprotection method described in PROTECTVE GROUPS in ORGANIC SYNTHESIS THIRD EDITION (WILEY). As a protection, it can be a azetidinone derivative represented by the general formula (Π) (wherein R ¹ is a hydrogen atom and R ⁵ is a hydrogen atom or a nitrogen atom).

[0045] The object of the deprotection, (In the formula, R ¹ is a protecting group of hydroxyl group) isolated and purified general formula ([pi) can also be used, after the reaction, including the general formula ([pi) The treatment solution can be used as it is. Preferably, the organic solvent used is a solvent that does not participate in the reaction, for example, a hydrocarbon solvent such as n-pentane, n-hexane, cyclohexane, n-heptane, or a mixture of isomers thereof. , Chlorinated solvents such as methylene chloride, 1,2-dichloroethane, chloroform, aromatic hydrocarbon solvents such as benzene, black benzene, toluene, xylene, jetyl ether, diisopropyl ether, dimethoxyethane , Tetrahydrofuran, 1,4 dioxane, ether solvents such as cyclopentyl methyl ether, acetate solvents such as ethyl acetate, butyl acetate, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, or methanol , Ethanol, 1-prono, 2-prono, 1-butanol, 2-butanol, organic solvents such as isobutyl alcohol, tert-butyl alcohol, etc. Preferred are, for example, methyl chloride, acetonitrile, tetrahydrofuran, methanol, and more preferred is a mixture of methylene chloride and methanol as appropriate. In this case, the mixing ratio (volume ratio) of methyl chloride and methanol is usually 1: 0 to 0: 1, preferably 1:;! To 4. When the protecting group is a silyl group, the desilylating agents include formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, camphorsulfonic acid and other organic acids, hydrochloric acid, Mineral acids such as hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boron trifluoride, boron trifluoride jetyl ether complex, titanium tetrachloride, zirconium tetrachloride, aluminum chloride, ferric chloride, ferric nitrate Lewis acids such as copper and cerium (III) nitrate, alkali hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide, hydrogen fluoride, ammonium fluoride, triethylamine hydrofluoride complex, fluoride Hydrogen pyridine complex, tetraptyl ammonium fluoride, lithium fluoride, sodium fluoride, potassium fluoride, Tsu cesium fluoride Anmoniumu, boron hydrofluoric acid, only! /, Used and fluorides such as single or multiple kinds mixed and hydrofluoric acid, good Mashiku the like hydrochloric acid.

[0046] In the deprotection, the use ratio (weight / volume ratio) of the general formula (Π) (wherein R ¹ is a hydroxyl-protecting group) and the solvent is usually 1: 2 to 50, preferably 1 : 5-20. The amount of desilylating agent used is in the range of stoichiometric to large excess. The reaction temperature is usually 20-60 ° C, preferably 0-40 ° C. The reaction time is usually 0.5 to 24 hours, preferably 1 to 17 hours.

[0047] The reaction mixture thus obtained is worked up by those skilled in the art according to a general method, and is isolated by a general separation and purification method to give a deprotected general formula (II) (wherein R ¹ is a hydrogen atom and R ⁵ is a hydrogen atom or a nitrogen atom). [0048] Production of compound of formula (I)

The compound of formula (I) used in the production of the compound of formula (II) according to the present invention is known, for example, the above-mentioned Japanese Patent No. 3220985, Japanese Patent No. 3450193, and Tetrahedron 52 331- 357 can be obtained by the method described in 1996. However, according to a preferred embodiment of the present invention, the compound of formula (I) is preferably prepared according to the following scheme, and this method constitutes another embodiment of the present invention.

[Chemical 9

(III) (IV) (I)

(Wherein, R ¹ represents a hydrogen atom or a protecting group of a hydroxyl group, R ² represents a hydrogen atom or a protective group for an amino group, R ³ represents an Ariru group which may have a substituent, R ⁴ Represents an aryl group, aralkyl group or alkyl group which may have a substituent, and R ⁷ represents an alkyl group or a alkoxyloxy group.

In the present invention, an industrially useful auxiliary group (1 N (R ³ ) SO R ⁴ ) which is inexpensive and functions as a leaving group is employed. As described above, in this known method, this auxiliary group

2

In the production of a compound of formula (I), particularly an intermediate for the production of 1 / 3-methylcarbapenem, using the compound, there was a risk that sufficient stereoselectivity could not be obtained. The process for producing the compound of formula (I) according to the present invention solves this problem. This problem is solved by reacting general formula (III) and general formula (IV) in the presence of a zirconium reagent, preferably general formula (III) and general formula (IV) treated with a zirconium reagent. It was solved by obtaining the general formula (I). The treatment with the zirconium reagent of the general formula (IV) preferably means that the general formula (IV) is carried out by reacting a zirconium compound and a base in an organic solvent.

[0050] The compound represented by the general formula (IV) can be carried out by a known method. For example, an aniline compound (R ³ NH) and a sulfonic acid derivative (R ⁴ SO X) are reacted to form a sulfonanilide compound (HN

twenty two

(R ³ ) SO R ⁴ ), and propioylucide lydya propionate anhydride is allowed to act on this Can be obtained by etc.

In the production method according to the present invention, R ¹ and R ² are a hydrogen atom or a protecting group for a hydroxyl group and an amino group, respectively, and the hydroxyl group and the protecting group for an amino group are described in the above-mentioned books and the like. For example, the protecting groups for hydroxyl and amino groups are as defined above, and preferred R ¹ is a hydrogen atom or a trimethylsilyl group, a triethylsilyl group, t-butyldimethyl. Examples thereof include a silyl group, and more preferably a t-butyldimethylsilyl group.

[0052] Preferred R ² is hydrogen atom, trimethylsilyl group, Toryechirushiriru group, t Buchinore dimethylsilyl group, a benzyl group, p-methoxybenzyl group, para nitro downy Njiru group, such as Ben Zuhidoriru group and the like, more preferably, hydrogen Atoms, paranitrobenzyl groups, etc.

[0053] R ³ has the same meaning as described above, and R ³ is an aryl group which may have a substituent. Examples of the aryl group include aromatic cyclic compounds such as a phenyl group, a naphthyl group, and a pyridyl group. Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, a methinore group, a trifunoleolomethinole group, a trichloromethinole group, an ethyl group, an n-propyl group, an i— Propinole group, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, lower alkyl group which may be substituted with halogen atom, etc., methoxy group, lower alkyloxy group such as ethoxy group, amino group Monoalkylamino groups (for example, monomethylamino group, monoethylamino group, etc.), dialkylamino groups (for example, dimethylamino group, jetamino group, etc.). Is) amino group such as, like Shiano and nitro. One or more substituents may be the same or different when there are multiple substituents, and the substitution position is selected from the 2-position, 3-position or 4-position of the bonding position when there is one substituent. In the case of two or two substitutions, substitution positions selected from the 2,3, 2,4, 2,5, 2,6, 3,4, or 3,5 positions of the bond position or more When there is a group, a position selected from any conceivable position may be substituted. If the substituent is adjacent disubstitution, the ends of both substituents may be integrated. In that case, an aliphatic ring to which propylene, butylene, or the like is bonded, methylenedioxy, ethylenedioxy, or the like is bonded. The thing which formed the cyclic ether compound is mentioned. [0054] Preferable! /, As R ³ , phenyl group, bromophenyl group, fluorophenyl group, chlorophenyl group, methylphenyl group, dimethylphenyl group, ethenylphenyl group, i-propylphenyl group, t-butylphenyl group, methyl- Methoxyphenyl group, black mouth-methylphenyl group, trifluoromethylphenyl group, methoxyphenyl group, cyanophenyl group, nitrophenyl group, methoxycarbonylphenyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, etc. And the position of the substituent on the phenyl group is as described above.

[0055] R ⁴ is an aryl group, aralkyl group or alkyl group which may have a substituent, and the substituent has the same meaning as the substituent described above for R ³ . An alkyl group is a lower alkyl group which may be substituted with a halogen atom or the like, for example, methyl group, trifluoromethylol group, trichloromethyl group, ethyl group, n propyl group, i propyl group, n butynole group, i Examples thereof include a butyl group, a sec butyl group, and a t butyl group. The aryl group which may have a substituent includes a force S as defined above, for example, a phenyl group, a methylphenyl group, a naphthyl group, a pyridyl group and the like. The aralkyl group has the same meaning as described above, and examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group, and a pyridylmethyl group. Preferable R ⁴ includes a phenyl group, a methylphenyl group, a benzyl group, or a methyl group.

[0056] R ⁷ represents an alkylcarbonyl group, preferably an acetyloxy group.

[0057] The reaction is preferably carried out in an organic solvent under an inert gas atmosphere such as nitrogen or argon. As the organic solvent, any inert solvent that does not participate in the reaction can be used. For example, hydrocarbon solvents such as n-pentane, n-hexane, cyclohexane, n-heptane, or mixtures of these different substances. Solvents, chlorinated solvents such as methylene chloride, 1,2 dichloroethane, chloroform, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, jetyl ether, diisopropyl ether, dimethoxyethane, A single organic solvent such as an ether solvent such as tetrahydrofuran, 1,4 dioxane, cyclopentyl methyl ether, or the like can be used by appropriately mixing a plurality of types, preferably methylene chloride. [0058] Examples of the dinoleconium compound include dinoleconium tetrafluoride, dinoleconium tetrachloride, zirconium tetrabromide, zirconium tetraiodide, zirconium tetra-i-propoxide, and preferably zirconium tetrachloride.

[0059] Examples of the base include dimethylamine, trimethylamine, jetylamine, triethylamine, dibutylamine, tributylamine, trioctylamine, diisopropylethylamine, bistrimethinoresinoleamine, pyrrolidine, N-methylpyrrolidine, Piperidine, N-methylbiperidine, morpholine, N-methylmorpholine, tetramethylethylenediamine, pyridine, 4-dimethylaminopyridine, 2-picoline, 3-picoline, 4-picoline, aniline, N-methylaniline, N, N-dimethyla Nilin, 2,3 lutidine, 2,4 lutidine, 2,5 lutidine, 2,6-norethidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2 · 2-2] Octane, 1,5 diazabicyclo [4.3.0] Noner 5, 1,8 diazabicyclo [5.4.0] —Undeka 1 E emissions and the like are used, preferably Toriechiruamin, Toribuchiruamin, like diisopropyl E chill § Min.

[0060] The order in which the reagents are added is not particularly limited, but is preferably added in the order of the zirconium compound, the base and then the general formula (III) to the solution of the organic solvent of the general formula (IV). The use ratio (weight / volume ratio) of the general formula (III) and the solvent is usually from 1:10 to 100; preferably from 1:10 to 30. The use ratio (molar ratio) of the general formula (III) to the general formula (IV) is usually!:;! ~ 3, preferably 1: 1: 2 ~ 2. The use ratio (molar ratio) of the zirconium compound is usually 1 ::! To 3, preferably 1: 1.2-2. The use ratio (molar ratio) of the base catalyst is usually 1: 1 to 3, preferably 1: 1.2-2. In addition, it is recommended that an aprotic polar solvent such as acetonitrile, Ν, Ν dimethylformamide, dimethyl sulfoxide, etc. be added as appropriate, thereby improving the reaction yield and / or stereoselectivity. According to another embodiment, the yield can be further improved by adding a trace amount of a protic solvent such as water and methanol. The reaction temperature is usually from 30 to 50 ° C, preferably from 15 to 30 ° C. The reaction time is usually 0.5 to 24 hours, preferably 1 to 5 hours.

[0061] The obtained reaction mixture is subjected to post-treatment according to a conventional method, and is isolated by a general separation and purification method, for example, purification by silica gel column chromatography or a method of forming a precipitate. ) Can be obtained. Example

[0062] The ability to explain the present invention in more detail with reference to specific examples below The present invention is not limited to these specific examples. The following abbreviations may be used:

Ts: p-toluenesulfonyl group

TEA: Trietylamine

DMAP: 4-Dimethylaminopyridine

Ac: Acetyl group

TBS: t butyldimethylsilyl group

DIPEA: Diisopropylethylamine

[0063] ¹ H nuclear magnetic resonance spectroscopy relating to the description of physical properties in each of the terms exemplified below

U NMR)! /, Using a JNM-AL400 nuclear magnetic resonance apparatus manufactured by JEOL Ltd., and the chemical shift value is the value when tetramethylsilane (TMS) is δ 0.00 ppm. The spin coupling constant is expressed as J value in Hz, and the spin coupling splitting mode is s = —double line, d = double line, t = triple line, dd = double double line, td = triple two Represents a double line and m = multiple line, and those with br. Represent broad peaks, and the number of hydrogen atoms is represented as 1H or 2H. Some compounds have been observed as a mixture of two rotational isomers that may be due to steric hindrance. In this case, only the chemical shift value, the spin bond splitting mode, and the number of hydrogen atoms are shown.

[0064] Production Example 1

N-propionyl N— (2-trifluoromethylphenol) p Toluenesulfonamide (Compound 3)

[Chemical 10]

[0065] 2 Aminobenzzotrifluoride 32.23 g (0.20 mol) in pyridine (85 mL) was cooled in an ice bath, p-toluenesulfuryl chloride 38.52 g (0.20 mol) was added, and the same temperature was maintained for 1 hour. Reacted. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl hexane acetate, and N- (2-trifluoromethylphenol) p-toluenesulfonamide (Compound 2) 55.79 g (yield 96.5%) was obtained as a yellowish white powder. I got it.

^: H NMR (400 MHZ, CDCl): δ ppm 2.37 (s, 3H), 6.84 (br. S, 1H), 7. 16—7.23 (m, 3

Three

H), 7.47-7.53 (m, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.3 Hz, 1H).

[0066] Compound 2 In a solution of 61.49 g (0.20 mol) in methylene chloride (350 mL), 31.25 mL (0.24 mol) of propionic anhydride, 40.77 mL (0.29 mol) of TEA and 1.19 g (0.0097 mol) of DMAP Were sequentially added and allowed to react at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was vigorously stirred, allowed to stand, and separated. The organic layer was concentrated under reduced pressure, and then hexane was added to the concentrate to give the title compound (Compound 3) 67.4 1 g (yield 93.1% ) Was obtained as a white powder.

^: H NMR (400 MHZ, CDCl): δ ppm 0.97 (t, J = 7.3 Hz, 3H), 1.91 2.06 (m, 2H),

Three

2.46 (s, 3H), 7.35-7.38 (m, 3H), 7.65-7.70 (m, 2H), 7.86 (dd, J = 7.6, 1.7 Hz, 1H),

8.02 (d, J = 8.3 Hz, 2H).

[0067] Other N propionyl N-phenyl p-toluenesulfonamide derivatives can be produced in the same manner as in Production Example 1.

[0068] Example 1

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] 2 oxozetidine 4 inole} propioninore N (2 trifluoromethylphenol) p Production of toluenesulfonamide (compound 4)

[Chemical 1 1]

[0069] N-propionyl N— (2-trifluoromethylphenol) p-toluenesulfonamide (Compound 3) 22.29 g (60.0 mmol) in methylene chloride (345 mU solution in an ice bath) After cooling at room temperature, 2098 g (90.0 mmol) of zirconium chloride was added and stirred at the same temperature for 30 minutes, and then 16.5 mL (94.7 mmol) of DIPEA was added and stirred at the same temperature for 30 minutes, and then (3R, 4R) — 4 [(R) 1 (tert-butyldimethylsilyloxy) ethyl] 2 azetidinone 17.25 g (60.0 mmol) was added, and the reaction was allowed to proceed for 1 hour while removing the ice bath and raising the temperature to room temperature. The ratio (HPLC) was 58.4%, and the diastereomer formation ratio (HPLC) was /3/α=93.5/6.5 Water was added to the reaction mixture, and the mixture was vigorously stirred, allowed to stand, and separated. After washing sequentially with 10% saline, the organic layer was concentrated under reduced pressure, and the resulting concentrated solution was concentrated and replaced with toluene. When hexane was added later, 19.28 g (yield 53.7%) of the title compound (Compound 4) was obtained as a white powder.

^: H NMR (400 MHZ, CDCl): δ ppm -0.01, -0.01, 0.01, 0.05 (s, 6H), 0.77-1.04 (

Three

m, 15H), 2.33-2.46 (m, 4H), 2.62, 2.70 (dd, 1H), 3.74, 3.86 (dd, 1H), 4.08 (m, 1H), 5.49, 5.86 (br. s, 1H), 7.24— 7.43 (m, 3H), 7.63— 7.72 (m, 2H), 7.85 (m, 1H), 7.95 (m, 2H), the data were observed as rotamers at a ratio of about 1: 1. Yes.

[0070] Example 2

In a nitrogen gas atmosphere, N propionyl N— (2-trifluoromethylphenol) p toluenesulfonamide (compound 3) 26.75 g (72.0 mmol) of methylene chloride (345 mU solution was cooled in an ice bath). Zirconium chloride (21.67 g, 93.0 mmol) was added and stirred at the same temperature for 30 minutes, then DIPEA 16.2 mL (93.0 mmol) was added, and the mixture was stirred at the same temperature for 30 minutes. Add 17.3 mL of DMF, stir at the same temperature for 30 minutes, and then add (3R, 4R) —4 acetyloxy-3-([(R) —l- (tert butyldimethylsilyloxy) ethyl) -2 azetidinone 17.25 g (60.0 After adding (mmol), the ice bath was removed and the reaction was allowed to proceed to room temperature for 30 minutes. The reaction yield (HPLC) at this time was 63.0%, and the diastereomer formation ratio (HPLC) was / 3 / α = 9 7.4 / 2.6. Water was added to the reaction mixture, and the mixture was vigorously stirred, allowed to stand, and separated. The organic layer was washed successively with water and 10% brine, and the organic layer was concentrated under reduced pressure. The resulting concentrated solution was concentrated and replaced with toluene to form a precipitate, whereby 19.71 g (yield 54.9%) of the title compound (Compound 4) was obtained as a white powder.

The ¹ H NMR of the obtained compound was the same as that of Example 1.

[0071] Example 3

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] 2 oxozetidine 4 inole} propioninore] N (2 bromopheninole) p tonoleene Production of sulfonamides

N Propionolinol N (2 bromopheninole) 1 p Tonorecens norehonamide 27.53 g (7 2.02 mmol) was used in the same manner as in Example 2 to obtain the title compound 23.38 g (yield 63. 9%) was obtained as a white powder. The reaction yield (HPLC) in this reaction was 72.5%, and the diastereomer production ratio (HPLC) was 0 Za = 95.4 / 4.6.

^: H NMR (400 MHz, CDC1): δ ppm -0.01, -0.01, 0.01, 0.02 (s, 6H), 0.81, 0.83 (s, 9H), 0.83, 0.96, 1.05, 1.12 (d, 6H), 2.25 , 2.44 (m, 1H), 2.44 (s, 3H), 2.68, 2.80 (dd, 1H), 3.77, 3.93 (dd, 1H), 4.09 (m, 1H), 5.65, 5.85 (br. S, 1H) , 7.31-7.47 (m, 5 H), 7.72 (m, 1H), 7.96 (d, 2H), the data are observed as rotamers at a ratio of about 1: 1.9.

[0072] Example 4

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] — 2 oxazetidine 4 Inole} propioninore]-N-Pheninole p Toluenesulfo Namide production

N Propionyl N Phenolux p Toluenesulfonamide 3.03 g (10.0 mmol) was used in the same manner as in Example 1 to obtain 2.66 g (yield 50.1%) of the title compound as white powder. I got it as a powder. The reaction yield (HPLC) in this reaction was 60.5%, and the diastereomer production ratio (HPLC) was 0 Z a = 85.6 / 14.4.

^: H NMR (400 MHZ, CDCl): δ ppm -0.01 (s, 3H), 0.01 (s, 3H), 0.81 (s, 9H), 0.9

Three

4 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 7.1 Hz, 3H), 2.44—2.47 (m, 4H), 2.61 (dd, J = 4.0, 2.2 Hz, 1H) , 3.77 (dd, J = 4.5, 2.2 Hz, 1H), 4.05 (td, J = 6.3, 4.5 Hz, 1H), 5.77, (br. S, 1H), 7.21-7.24 (m, 2H), 7.32 ( d, J = 8.1 Hz, 2H), 7.46—7.50 (m, 3H), 7.86 (d, J = 8.1 Hz, 2H).

[0073] Example 5

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert-butyldimethylsilyloxy) ethyl] — 2 oxazetidine 4 Inole} propioninole] N (2 ethylpheninole) p Ruensulfonamide production

N Propionileu N— (2 ethylphenol) 1 p Toluenesulfonamide 3.32 g (10.0 mmol) was used in the same manner as in Example 1 to obtain the title compound 2.81 g (yield 52.8%) Was obtained as a white powder. The reaction yield (HPLC) was 57.0% and the diastereomer formation ratio (H PLC) was = 89. 1 / 10.9.

^: Η NMR (400 MHZ, CDCl): δ ppm -0.04, -0.00, 0.01, 0.03 (s, 6H), 0.79, 0.82 (

Three

s, 9H), 0.76, 0.90, 0.97, 1.02 (d, 6H), 1.30, 1.32 (t, 3H), 2.26, 2.42 (m, 1H), 2.44, 2.45 (s, 3H), 2.61 (m, 1H ), 2.62, 2.84 (m, 2H), 3.68, 3.88 (dd, 1H), 4.02, 4.12 (m, 1 H), 5.59, 5.82 (br. S, 1H), 6.97, 7.06 (d, 1H ), 7.23-7.35 (m, 3H), 7.39 (m, 2H), 7.9 1 (d, 2H), and the data are observed as rotamers at a ratio of about 1.5: 1.

It is measured.

[0074] Example 6

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] 2 oxozetidine 4 inole} propioninole] N (3 methinorefinole) p Production of sulfonamides

N Propionyl N— (3 methylphenol) 1 p Toluenesulfonamide 5.67 g (18.0 mmol) was used in the same manner as in Example 2 to obtain the title compound 5.26 g (yield 64.2%) Was obtained as a white powder. The reaction yield (HPLC) was 73.0%, and the diastereomer formation ratio (H PLC) was β / α = 94.4 / 5.6.

^: Η NMR (400 MHZ, CDCl): δ ppm -0.01 (s, 3H), 0.01 (s, 3H), 0.82 (s, 9H), 0.9

Three

3 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 2.39 (s, 3H), 2.44-2.47 (m, 4H), 2.61 (dd, J = 4.6, 2.4 Hz , 1H), 3.77 (dd, J = 4.6, 2.2 Hz, 1H), 4.05 (td, J = 6.3, 2.2 Hz, 1H), 5.77 (br. S, 1H), 6.99 (d, J = 7.6 Hz, 1H, 7.07 (s, 1H), 7.28—7.36 (m, 4H), 7.87 (d, J = 8.5 Hz, 2H).

[0075] Example 7

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] 2 oxazetidine 4 inole} propioninole N (2 ethoxyphenolinole) p Amide production

N Propionyl N— (2 ethoxyphenol) 1 p Toluenesulfonamide 3.48 g (1 0.0 mmol) was used in the same manner as in Example 1 to obtain the title compound 2.89 g (yield 48.8%). Obtained as a white powder. The reaction yield was 01.5%, and the diastereomer production ratio (H PLC) was [i / a = 80.0 / 20.0.

^: H NMR (400 MHZ, CDCl): δ ppm -0.01, -0.00, 0.00, 0.02 (s, 6H), 0.79, 0.82 (

Three

s, 9H), 0.84, 0.94, 0.97, 1.02 (d, 6H), 1.18, 1.19 (t, 3H), 2.29, 2.46 (m, 1H), 2.42 (s, 3H), 2.66 (m , 1H), 3.78— 4.10 (m, 4H), 5.72, 5.80 (br. S, 1H), 6.95—7.07 (m, 2H), 7.27-7.45 (m, 4H), 7.91 (d, 2H) The data are observed as rotamers at a ratio of about 1: 1.6.

[0076] Example 8

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert-butyldimethylsilyloxy) ethyl] 2 oxazetidine 4 Inole} propioninole N (4-methoxyphenolinole) p toluenesulfone Amide production

N Propionyl mono N— (4 methoxyphenol) 1 p Toluenesulfonamide 16.01 g (4 8.0 mmol) was used in the same manner as in Example 2 to obtain the title compound 1 1.56 g (yield 51.5%). Obtained as a white powder. The reaction yield (HPLC) was 69.6%, and the diastereomer formation ratio (HPLC) was [i / a = 93.5 / 6.5.

^: H NMR (400 MHZ, CDCl): δ ppm -0.01 (s, 3H), 0.01 (s, 3H), 0.81 (s, 9H), 0.9 6 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 2.44 (s, 3H), 2.49 (m, 1H), 2.61 (m, 1H), 3.76 (dd, J = 4.6, 2.2 Hz, 1H), 3.84 (s, 3H), 4.05 (m, 1H), 5.78 (br. S, 1H), 6.95 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.85 (d, J = 8.3 Hz).

[0077] Example 9

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert-butyldimethylsilyloxy) ethyl] 2 oxazetidine 4 Inole} propioninore] N (2,6-Getinorefeninore p) Production of toluenesulfonamide

N-propionyl N— (2,6 jetylphenol) p Toluenesulfonamide 3 · 60 g (10.0 mmol) was used in the same manner as in Example 1 to obtain the title compound 2.66 g (yield 45.4 g). %) Was obtained as a white powder. The reaction yield (HPLC) was 56.4%, and the diastereomer formation ratio (HPLC) was = 87 · 1 / 12.9.

^: Η NMR (400 MHZ, CDCl): δ ppm 0.01 (s, 3H), 0.01 (s, 3H), 0.81 (d, J = 7.8 Hz,

Three

3H), .84 (s, 9H), 0.92 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 7.3 Hz, 6H), 2.29 (m, 1H), 2.45 (s, 3H), 2.46 -2.69 (m, 5H), 3.79 (dd, J = 2.9, 2.7 Hz, 1H), 4.08 (m, 1H), 5.78 (br. S, 1H), 7.23-7.26 (m, 2H), 7.32—7.40 (m, 3H), 8.00 (d, J = 8.3 Hz, 2H).

[0078] Example 10

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] 2 oxazetidine 4 inole} propioninore] N (2,6-diisopropino lefeni Nole) -p-Toluenesulfonamide

N-propionyl N (2,6 diisopropylphenol) p Toluenesulfonamide 3.48 g (10.0 mmol) was used in the same manner as in Example 1 to obtain the title compound 4.18 g (yield 50.0 %) Was obtained as a white powder. The reaction yield (HPLC) was 60.6%, and the diastereomer production ratio (HPLC) was 0 Za = 91.6 / 8.4.

^: H NMR (400 MHz, CDCl): δ ppm 0.00 (s, 6H), 0.81 (s, 9H), 0.94-0.98 (m, 3

Three

H), 1.12-1.34 (m, 15H), 2.45 (s, 3H), 2.75 (br. M, 1H), 3.01-3.05 (m, 3H), 3.82 (br. M, 1H), 4. 10 (m, 1H), 5.85 (br. S, 1H), 7.25—7.45 (m, 5H), 7.97 (br. D, J = 7.6 H z, 2H).

[0079] Example 1 1 N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] — 2 oxoazetidine 4 inole} propioninole N (3,5 dimethylphenolinole)- p Production of toluenesulfonamide

N-propionyl N— (3,5 dimethylphenol) p Toluenesulfonamide 15 · 92 g (48.0 mmol) was used in the same manner as in Example 2 to obtain the title compound 14.40 g (yield 64.4%) Was obtained as a white powder. The reaction yield (HPLC) was 70.6%, and the diastereomer production ratio (HPLC) was 0 Za = 94.6 / 5.4.

^: H NMR (400 MHZ, CDCl): δ ppm 0.01 (s, 3H), 0.01 (s, 3H), 0.82 (s, 9H), 0.93

Three

(d, J = 6.3 Hz, 1H), 0.99 (d, J = 6.8 Hz, 3H), 2.34 (s, 6H), 2.44 (s, 3H), 2.47 (td, J = 6.8, 2.2 Hz, 1H, 2.60 (m, 1H), 3.77 (dd, J = 4.6, 2.4 Hz, 1H), 4.06 (td, J = 6.3, 4.6 Hz, 1H), 5.77 (s, 1H), 6.84 (s, 2H) 7.11 (s, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H).

[0080] Example 12

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] 2 oxazetidine 4 inole} propioninore N Preparation of phenylenomethanesnorephonamide

Reaction was carried out in the same manner as in Example 2 using 5.45 g (24.0 mmol) of N propionyl, N phenylmethanesulfonamide, and 3.74 g (yield 41.1%) of the title compound was obtained as a white powder.

. The reaction yield (HPLC) was 52.1%, and the diastereomer formation ratio (HPLC) was /3/α=92.3/7.7.

^: Η NMR (400 MHZ, CDCl): δ ppm 0.03 (s, 3H), 0.04 (s, 3H), 0.84 (s, 9H), 1.09

Three

(d, J = 6.3 Hz, 3H), 1.12 (d, J = 7.1 Hz, 3H), 2.54 (td, J = 7.1, 4.4 Hz, 1H), 2.75 (dd, J = 4.4 , 2.2 Hz, 1H), 3.42 (s, 3H), 3.87 (dd, 4.6, 2.2 Hz, 1H), 4.12 (td, J = 6.3, 4.6 Hz, 1H), 5.94 (br. S, 1H) 7.25-7.28 (m, 2H), 7.47-7.50 (m, 3H).

[0081] Example 13

N [(2R) 2-{(3S, 4R) 3— [(1R) — 1 (tert-butyldimethylsilyloxy) ethyl] 2 oxazetidine 4 Inole} propioninole N (2 Ethylphenyl) methanes Norehon

Amide production

N-propionyl, N— (2-ethylphenyl) methanesulfonamide 1.35 g (5.29 mmol) was used in the same manner as in Example 2 to obtain 0.45 g (yield 21.2%) of the title compound as a white powder. Got as. The reaction yield (HPLC) was 60.3%, and the diastereomer formation ratio (HPLC) was /3/α=94.8/5.2.

^: Η NMR (400 MHZ, CDCl): δ ppm 0.03, 0.03, 0.04, 0.04 (s, 6H), 0.84, 0.85 (s,

Three

9H), 1.02, 1.03, 1.06, 1.08 (d, 6H), 1.29, 1.30 (t, 3H), 2.28, 2.50 (m, 1H), 2.56—2.82 (m, 3H), 3.46, 3.47 (s , 3H), 3.84, 3.93 (dd, 1H), 4.14 (m, 1H), 5.86,

5.94 (br. S, 1H), 7.10, 7.17 (d, 1H), 7.24-7.29 (m, 1H), 7.41 -7.46 (m, 2H), the data are about 1: 1 in rotamers. Observed.

[0082] Reaction was carried out in the same manner as in Example 1 or Example 2 using the donor described in the following table as the compound of the formula (IV). The reaction yield (HPLC) and diastereomer formation ratio (HPLC) of these reactions are shown in Table 1.

[0083] [Table 1]

Comparative Example 1 (when using TiCl with the same donor as in Example 4)

Four

In a nitrogen gas atmosphere, a solution of 303 mg (1.00 mmol) of N-propionyl, N-phenol p-toluenesulfonamide 303 mg (1.00 mmol) in methylene chloride was cooled to 5 ° C, and titanium tetrachloride 164 μL (1.50 mmol), DIPEA 274 μL (1.58 mmol) and (3R, 4R) — 4 Acetoxy 1 — [(R) —l— (tert-butyldimethylsilyloxy) ethyl] -2 azetidinone 287 mg (1.00 mmol) was sequentially added at 10-minute intervals and reacted at the same temperature. The diastereomer formation ratio (HPLC) after 2 hours in this reaction was /3/α=48.9/51.1.

[0086] Example 13

(4R) — 4 {(3R, 4R) — 3— [(1R) — 1 (tert-Butyldimethylsilyloxy) ethinole 2--oxoazitidine-4-yl} -3-oxopentanoic acid 4-12 Nyl ester (Compound 5)

[0087] [Chemical 12]

[0088] In a nitrogen gas atmosphere, N [(2R) — 2— {(3S, 4R) — 3— [(1R) — 1 (tert-butyldimethyldimethyloxy) ethinole 2 oxazotidine 4 inole} propioninore N mono (2 trifluoromethylphenyl) p toluenesulfonamide (compound 4) 600 mg (1.00 mmol) of acetonitrile (9 mU solution with imidazole 200 mg (3.00 mmol) and DMAP 1 2.5 mg (0.102 mmol) ) And allowed to react for 16 hours at 60 ° C. The reaction mixture was cooled in an ice bath, magnesium chloride 95.5 mg (1.00 mmol), TEA 280 μL (2.01 mmol) and malonic acid mono-p ditrobenzyl ester. 407 mg (1.70 mmol) was added in turn, and the mixture was allowed to react for 2 hours by raising the temperature to 50 ° C. The reaction mixture was concentrated under reduced pressure, the concentrated solution was diluted with toluene, 1M hydrochloric acid, 5% aqueous sodium bicarbonate, and 10% sodium chloride. After washing sequentially with water, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (solution). Solvent: purified with hexane / acetic acid Echiru = 1/1) to give target title compound (Compound 5) 453 mg of (94.6% yield) as a white solid.

The title compound (Compound 5) is a known substance, and the retention time and ¹ H wake R spectrum of the existing product and the HPLC coincided.

[0089] Example 14

(4R) — 4 {(3R, 4R) — 3— [(1R) — 1 (tert-butyldimethylsilyloxy) ethynole 2— Year-old xoazitidine 4-inole} 2 diazo 3-year-old xoxopentanoic acid = 4-12 trobenzinole ester (compound 6)

[0090] [Chemical 13]

[0091] In a nitrogen gas atmosphere, N [(2R) — 2— {(3S, 4R) — 3— [(1R) — 1 (tert-butyldimethyldimethyloxy) ethinole 2 oxazotidine 4 inole} propioninore N- (2 trifluoromethylphenyl) p-toluenesulfonamide (compound 4) 3.0 g (5.00 mmol) of acetonitrile (1.0 m imidazole (15.0 mmol) and DMAP 60 mg (0.491 mmol) added to 9 mU solution) The mixture was allowed to react for 19 hours at 60 ° C. The reaction mixture was cooled in an ice bath and 0.48 g (5.01 mmol) of magnesium chloride, 1.4 mL (10.0 mmol) of TEA and 2.04 g of malonic acid mono-p-nitrobenzyl ester ( 8.53 mmol) was added in order, and the mixture was heated to 50 ° C. and reacted for 2 hours, the reaction mixture was concentrated under reduced pressure, and the concentrated solution was diluted with methylene chloride (48 mL), and 1M hydrochloric acid, water, 5% aqueous sodium bicarbonate and The solution was washed successively with 10% brine, and the resulting solution containing Compound 5 was added to dodecinolebenzenesulfonyl azimuth. After 2.29 g (6.51 mmol) and TEA 210 μL (1.51 mmol) were added and reacted at room temperature for 17 hours, the reaction mixture was cooled with ice, 1M aqueous sodium hydroxide solution, water, 0.5M hydrochloric acid and 10%. The organic layer was concentrated under reduced pressure, and the resulting concentrate was added with n-heptane to cause precipitation, filtered, washed and dried to give the title compound (Compound 6) 1.23 g ( Yield 48.3%) was obtained as a white powder.

[0092] The title compound (Compound 6) was a known substance, and the retention time and ¹ HN MR spectrum of the existing product were in agreement with those of HPLC.

[0093] Example 15

(4R) — 4 {(3R, 4R) — 3— [(1R) — 1 (tert-Butyldimethylsilyloxy) ethinole 2—year-old xoazitidine 4 inole 2 diazo 3 year-old xopentanoic acid = 4 Production of (Compound 6)

N [(2R) 2— {(3S, 4R) — 3— [(1R) — 1 (tert-butyldimethylsilyloxy) ethyl ] 1 oxazotidine 4 Inole} propioninole N (2 bromopheninole) p Toluenesulfonamide 3.05 g (5.00 mmol) was used in the same manner as in Example 14 to obtain the title compound (Compound 6) 1.67 g ( Yield 65.9%) was obtained as a white powder. The mother liquor when the precipitate was filtered contained 0.39 g of the title compound (Compound 6), and the total yield was 81.4%.

[0094] Example 16

N [(2R) 2— {(3S, 4R) — 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] — 2 oxazetidine 4 Inole} propioninole N Phenyl p Toluene sulfonamide 5.32 g ( 10.0 mmol) was used in the same manner as in Example 14 to obtain 3.70 g (yield 73.4%) of the title compound (Compound 6) as a white powder.

[0095] Example 17

N [(2R) 2— {(3S, 4R) — 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] — 2 oxazetidine 4 Inole} propioninole N (3 methylphenolinole) p The title compound (Compound 6) (1.77 g, yield 70.0%) was obtained as a white powder in the same manner as in Example 14 using 2.73 g (5.01 mmol) of ruenesulfonamide.

[0096] Example 18

N [(2R) 2— {(3S, 4R) — 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] 1 2 oxazetidine 1 4 1-inole} propioninole] 1 N (4-methoxyphenol No.) By a method similar to Example 14, using 2.80 g (5.00 mmol) of 1 p toluenesulfonamide. 1.75 g (yield 69.5%) of the title compound (Compound 6) was obtained as a white powder. The mother liquor when the precipitate was filtered contained 0.24 g of the title compound (Compound 6), and the total yield was 79.1%.

[0097] Example 19

(4R) — 4 {(3R, 4R) — 3— [(1R) — 1 (tert-Butyldimethylsilyloxy) ethinole] 2— oxoazitidine 4 inole} 2 diazo 3 oxopentanoic acid 4 nitrobenzenole ester (compound 6 )Manufacturing of

N [(2R) 2— {(3S, 4R) — 3— [(1R) — 1 (tert butyldimethylsilyloxy) ethyl] 1 2 oxazetidine 4 Inole} propioninole] N Phenolemethanesnorephonamide 2.28 The title compound (Compound 6) 1.74 g (yield 68.8%) was obtained as a white powder in the same manner as in Example 14 using g (5.01 mmol). The mother liquor obtained by filtering the precipitate contained 0.14 g of the title compound (Compound 6), and the total yield was 74.5%.

[0098] Example 20

(4R) — 4 {(3R, 4R) — 3— [(1R) — 1-Hydroxyethinole] 2 Doxoazitidine 4-Ainole} 2 Diazo 3 Oxopentanoic acid 4-12 Trobendilyl ester (Compound 8) Construction

[Chemical 14]

6 8

[0099] In a nitrogen gas atmosphere, N [(2R) — 2— {(3S, 4R) — 3— [(1R) — 1 (tert-butyldimethylsilyloxy) ethinole] 2 oxazotidine 4 inole} propionate Nore] N phenyl p-toluenesulfonamide (compound 7) 5.32 g (10.0 mmol) of acetonitrile (Into an 80 mU solution, 2.05 g (30.1 mmol) of imidazole and 0.12 g (1.00 mmol) of DMAP were added and allowed to react for 6 hours at 60 ° C. The reaction mixture was cooled to 15 ° C. and 0.95 g of magnesium chloride. (10.0 mmol), TEA 2.8 mL (20.1 mmol) and malonic acid mono-p nitrobenzyl ester 4.07 g (17.0 mmol) were added sequentially, and the mixture was heated to 50 ° C and reacted for 3 hours. The concentrated solution was diluted with methylene chloride (96 mL) and washed successively with 1M hydrochloric acid, water, 5% aqueous sodium bicarbonate and 10% brine, and the resulting solution containing compound 5 was 4.58 g of dodecylbenzenesulfonyl azide. (13.0 mmol) and 420 μL of TEA (3.01 mmol) were added and reacted at room temperature for 19 hours, and then the reaction mixture was ice-cooled, 1M aqueous sodium hydroxide solution, water, 0.5M hydrochloric acid and 10% brine The organic layer was concentrated under reduced pressure, and methanol (32 mL), water (5.3 mL) and water were added to the concentrated solution containing Compound 6. Concentrated hydrochloric acid (2.7 mL) was added, and the mixture was allowed to react for 4 hours at room temperature.The reaction mixture was made weakly alkaline by adding 6.5% aqueous sodium bicarbonate with stirring, and extracted with methylene chloride. The organic layer was concentrated under reduced pressure, followed by displacement concentration with ethyl acetate, and the resulting concentrate was added with n-heptane to cause precipitation, filtered, washed and dried to give the title compound ( Compound 8) (3.12 g, yield 82.1%) was obtained as a white powder.

The title compound (Compound 8) is a known substance, and the retention time and ¹ H-wake R spectrum of the existing product and the HPLC coincided.

Production example 1

(41¾, 51¾, 65) — 3— [(Diphenoxyphosphoryl) oxy] -6— [(11¾ 1-hydroxyethyl) —4 Methylolone 7 oxo 1-diazabicyclo [3.2.0] hept-2-ene 2 Production of strong norebonic acid 4-12 trobenzyl ester (compound 10)

[Chemical 15]

10 (4R) — 4 {(3R, 4R) — 3— [(1R) — 1-hydroxyethinole] 2 oxoazitidine 4 inole 2 diazo 3 oxopentanoic acid 4 Nyl ester (Compound 8) To a solution of 5.00 g (12.8 mmol) in methylene chloride (50 mU), 29.9 mg (0.038 mmol) of rhodium caprylate was added and refluxed for 4 hours. Cool to C and add dropwise a mixture of diphenylchlorophosphate 3.2 mL (15.4 mmol), DIPEA 3.0 mL (16.9 mmol) and DMAP 31.3 mg (0.256 mmol) in methylene chloride (10 mL) at the same temperature. The reaction mixture was washed with 0.3% hydrochloric acid, 5% aqueous sodium hydrogen carbonate and 10% brine, and the organic layer was concentrated under reduced pressure to add η-heptane to the resulting concentrated solution to form a precipitate. Filtration, washing and drying gave 6.91 g (yield 98.1%) of the title compound (Compound 10) as a fine yellowish white powder.

The title compound (Compound 10) was a known substance, and the retention time and ¹ HN MR spectrum of the existing product were in agreement with those of HPLC.

Claims

A method for producing a compound represented by the following formula (II):

[Chemical 1]

(ID

(Where

R ¹ represents a hydrogen atom or a hydroxyl protecting group,

R ² represents a hydrogen atom or a protecting group for an amino group,

R ⁵ represents a hydrogen atom or a nitrogen atom,

R ⁶ represents a hydrogen atom or a protecting group for a carboxyl group. )

(a) Compound represented by the following formula (I):

[Chemical 2]

(I)

(Where

R ³ represents an aryl group which may have a substituent,

R ⁴ represents an aryl group that may have a substituent, an aralkyl group that may have a substituent, or an alkyl group that may have a substituent. )

And a imidazole, by subsequent reaction with malonic acid ester, wherein R ⁵ is a hydrogen atom ([pi )

(b) A method comprising further diazotizing the compound obtained in step ω when a compound of formula (π) wherein R ⁵ is a nitrogen atom is desired.

[2] The step (a) is performed in the presence of 1S magnesium compound and / or base.

The method according to 1.

[3] The method according to claim 1, wherein the malonic acid ester is a malonic acid monoester.

[4] The method according to claim 1, further comprising washing the reaction product obtained in step (b) with a dilute aqueous alkali solution.

[5] The compound represented by the formula (I) is represented by the following formula (III):

[Chemical 3]

(Where

R ¹ and R ² are as defined above,

R ⁷ represents a rualkylcarbonyl-oxy group. )

[Chemical 4

R ³

H ₃ C S0 ₂ R ⁴

O

(IV) (Wherein R ³ and R ⁴ are as defined above)

2. The method according to claim 1, which is obtained by reacting with a compound represented by the formula:

6. The production method according to claim 5, wherein the general formula (IV) is reacted with a compound represented by the formula (III) after allowing a zirconium compound and a base to act.