JP5112070B2 - Intermediate for synthesizing 1β-methylcarbapenem derivative and process for producing the same - Google Patents

Description

Background of the Invention

FIELD OF THE INVENTION The present invention relates to compounds useful for the production of 1β-methylcarbapenem derivatives and methods for their production.

BACKGROUND ART Carbapenem antibiotics are substances that exhibit excellent antibacterial activity against a wide range of pathogenic bacteria. In particular, 1β-methylcarbapenem derivatives are resistant to metabolism by renal dihydropeptidase-1 (DHP-1), which is a hydrolase, and are therefore used clinically as extremely useful antibiotics.

  Several production methods have been reported for 1β-methylcarbapenem derivatives. Among them, the route produced in several steps from 1β-methylcarboxylic acid (A) (hereinafter abbreviated as carboxylic acid (A)) has many research examples that have been reported so far. One. Therefore, it can be said that carboxylic acid (A) is an important intermediate for the production of 1β-methylcarbapenem derivatives.

  Many reports have been made on the production method of the carboxylic acid (A). The typical ones will be described below.

  The first example is a method shown in the following scheme, which is based on the addition of a propionic acid derivative to a 4-acetoxyazetidinone derivative (see, for example, Japanese Patent No. 3220985). And carboxylic acid (A) is obtained from this propionic acid adduct by hydrolysis.

  This method is a useful method with high selectivity and chemical yield as a method for introducing a β-methyl group, but it is disadvantageous in terms of production cost because the raw material 4-acetoxyazetidinone derivative or propionic acid derivative is expensive. is there.

  The second example is a method shown in the following scheme, in which a butenylsilyl group is introduced onto the nitrogen atom of a 4-acetoxyazetidinone derivative, and then the butenyl group is rearranged onto the azetidinone 4-position (for example, Japan). No. 2,902,178 and Tetrahedron Lett. 1991, 32, 2143).

  Even in this method, as in the first example, the 4-acetoxyazetidinone derivative used as a raw material is expensive, and trimethylsilyl trifluoromethanesulfonate used when rearranging the butenyl group is expensive. Increases manufacturing costs.

  A third example is a method shown in the following scheme, in which an imine compound and a diketene are cyclized to a [2 + 2] type to construct an azetidinone ring (for example, Tetrahedron 1988, 44, 2149, and Tetrahedron Lett 1986, 27, 6241).

  Even in this method, after cyclization, expensive K-selectride must be used for stereoselective reduction of the ketone on the azetidinone 3-position substituent, and expensive for deprotection of the protecting group on the azetidinone nitrogen. The need to use a simple CAN is a cost issue.

  A fourth example is a method shown in the following scheme, which includes stereoselective methylation by reduction reaction of a bicyclic compound (for example, J. Org. Chem. 1987, 52, 2563, and Chem. Commun. 1998, 1517).

  This method has a great advantage in that a methyl group can be introduced β-selectively without requiring a special reagent or apparatus, but only a complicated and expensive method for producing a bicyclic compound as a raw material is known. However, improvements are necessary for industrial production.

  As described above, the production of the carboxylic acid (A) is often expensive as a raw material and a reaction reagent, and the production cost of the 1β-methylcarbapenem derivative tends to be high. For this reason, if the cheaper manufacturing method of carboxylic acid (A) can be developed, 1 (beta) -methylcarbapenem derivative can be supplied cheaply and it is industrially useful.

  On the other hand, a method for deriving from a naturally abundant L-threonine to a 4-acetoxyazetidinone derivative (or an analog thereof) (for example, J. Am. Chem. Soc. 1985, 107, 1438, Bull) Korean. Chem. Soc. 1997, 18, 475, Synthesis 2003, 570, W098 / 45260).

Summary of the Invention

  The present inventors have now established a route for synthesizing carboxylic acid (A) using L-threonine which is abundant in nature as a starting material. According to this method, the carboxylic acid (A) can be supplied at a lower cost than in the existing method, which makes it possible to produce a 1β-methylcarbapenem derivative at a lower cost. The present inventors have also found a new intermediate useful in the production of the carboxylic acid (A). The present invention is based on these findings.

  The production method of the carboxylic acid (A) established by the present inventors is as shown in the following scheme I.

In the above, R ¹ and R ² may be the same or different and each represents a hydrogen atom or a lower alkyl group, or R ¹ and R ² are combined to form a carbon atom to which they are bonded. And a 4- to 7-membered ring (wherein the 4- to 7-membered ring may be substituted with a lower alkyl group), R ³ and R ⁴ may be the same or different from each other. Or R ³ and R ⁴ together represent a 4- to 7-membered ring together with the sulfur atom to which they are bonded and the carbon atom to which the sulfur atom is bonded. R ⁵ represents a hydrogen atom or a hydroxyl-protecting group.

  And this invention provides the following aspects among the intermediate compound and process shown by the said scheme I.

（式中、
Ｒ^１およびＲ^２は、それぞれ同一または異なっていてもよく、水素原子または低級アルキル基を表すか、またはＲ^１とＲ^２とが一緒になって、それらが結合している炭素原子とともに４〜７員環（ここで、この４〜７員環は低級アルキル基で置換されてもよい。）を表し、Ｒ^３およびＲ^４は、それぞれ同一または異なっていてもよく、低級アルキル基を表すか、またはＲ^３とＲ^４とが一緒になって、それらが結合している硫黄原子、および当該硫黄原子が結合している炭素原子とともに４〜７員環を表す。）According to one aspect of the present invention, there is provided a compound represented by the following general formula (I), a salt thereof or a solvate thereof.

(Where
R ¹ and R ² may be the same or different and each represents a hydrogen atom or a lower alkyl group, or R ¹ and R ² together form 4 to 4 together with the carbon atom to which they are bonded. Represents a 7-membered ring (wherein this 4- to 7-membered ring may be substituted with a lower alkyl group), and R ³ and R ⁴ may be the same or different and each represents a lower alkyl group Or R ³ and R ⁴ together represent a 4- to 7-membered ring together with the sulfur atom to which they are bonded and the carbon atom to which the sulfur atom is bonded. )

（式中、Ｒ^１およびＲ^２は前記一般式（I）で定義されたものと同義である。）According to another aspect of the present invention, there is provided a compound represented by the following general formula (II), a salt thereof or a solvate thereof.

(In the formula, R ¹ and R ² have the same meanings as defined in the general formula (I).)

（式中、Ｒ^１およびＲ^２は前記一般式（I）で定義されたものと同義であり、Ｒ^５は水素原子または水酸基の保護基を表す。）According to another aspect of the present invention, there is provided a compound represented by the following general formula (III), a salt thereof or a solvate thereof.

(In the formula, R ¹ and R ² have the same meaning as defined in the general formula (I), and R ⁵ represents a hydrogen atom or a hydroxyl-protecting group.)

  According to another aspect of the present invention, there is provided a process for producing a compound represented by the general formula (II), comprising a step of hydrolyzing the compound represented by the general formula (I). Is done.

  According to another aspect of the present invention, the compound represented by the general formula (III) comprises a step of reacting the compound represented by the general formula (II) with an acid or a base, or an acid and a base. A method for producing the compound is provided.

（式中、Ｒ^１およびＲ^２は前記一般式（I）で定義されたものと同義であり、Ｒ^５は前記一般式（III）で定義されたものと同義である。）
一般式（III）：

（式中、Ｒ^１およびＲ^２は前記一般式（I）で定義されたものと同義であり、Ｒ^５は前記一般式（III）で定義されたものと同義である。）
で表される化合物の一炭素増炭反応の工程を含んでなる、方法が提供される。Moreover, according to another aspect of the present invention, there is provided a production method represented by the following general formula (IV):

(In the formula, R ¹ and R ² have the same meaning as defined in the general formula (I), and R ⁵ has the same definition as that defined in the general formula (III).)
General formula (III):

(In the formula, R ¹ and R ² have the same meaning as defined in the general formula (I), and R ⁵ has the same definition as that defined in the general formula (III).)
A method comprising a one-carbon carbonization reaction step of a compound represented by the formula:

またはその塩と、下記一般式（VI）：

（式中、Ｒ^３およびＲ^４は前記一般式（I）で定義されたものと同義である。）
で表される化合物またはその塩と、そして
下記一般式（VII）：

（式中、Ｒ^１およびＲ^２は前記一般式（I）で定義されたもの同義である。）
で表される化合物とを縮合させる工程を含んでなる、方法が提供される。According to another aspect of the present invention, there is provided a process for producing a compound represented by the general formula (I),
(2R, 3R) -epoxybutanoic acid represented by the following formula (V):

Or a salt thereof and the following general formula (VI):

(In the formula, R ³ and R ⁴ have the same meanings as defined in the general formula (I).)
Or a salt thereof, and the following general formula (VII):

(In the formula, R ¹ and R ² have the same meaning as defined in the general formula (I).)
A process comprising the step of condensing the compound represented by:

  By providing the production method of the present invention and the compounds represented by the general formulas (I), (II), and (III), the carboxylic acid (A), which is an important intermediate of the 1β-methylcarbapenem derivative, can be obtained naturally. Can be synthesized at a lower cost than L-threonine, which is easily available.

Detailed description of the invention

Definitions In the present invention, the “lower alkyl group” as a group or a part of the group means a linear, branched or cyclic C _1-8 alkyl group, preferably a linear, branched or cyclic group. C _1-5 alkyl group. Preferable specific examples include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, t-butyl group, i-butyl group and n-pentyl group.

  Examples of the “aryl group” as a group or a part of the group include a phenyl group and a naphthyl group, and a preferable specific example includes a phenyl group.

  Furthermore, the “aralkyl group” as a group or a part of the group represents an arylalkyl group. For example, benzyl group, 4-nitrobenzyl group, 4-methoxybenzyl group and the like can be mentioned.

In the present invention, the “hydroxyl-protecting group” means a silyl-based protecting group (for example, a trialkylsilyl group, preferably a trimethylsilyl group, a triethylsilyl group, or a t-butyldimethylsilyl group), an acyl. Group (for example, alkylcarbonyl group, arylcarbonyl group, preferably formyl group, acetyl group, pivaloyl group, benzoyl group), C _1-6 alkyl group (for example, methyl group, ethyl group, etc.) C _1-6 alkoxyalkyl group (for example, methoxymethyl group, tetrahydropyranyl group, ethoxyethyl group), allyl group, aralkyl group (for example, benzyl group), allyloxycarbonyl _group, the _{C 1-6} alkyloxycarbonyl group (t-butoxycarbonyl group Aralkyloxycarbonyl group (for example, an optionally substituted benzyloxycarbonyl group, preferably benzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group). ), Preferably trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, allyloxycarbonyl group, t-butoxycarbonyl group, 4-nitrobenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group. More preferred are a trimethylsilyl group, a triethylsilyl group, and a t-butyldimethylsilyl group.

In the general formula (I), (II), (III), (IV), the compounds represented by (VII) and (VIII), as defined in ^{R 1} and ^{R 2,} and ^{"R 1} and ^{R 2} together "They are bonded to each other to represent a 4- to 7-membered ring containing a carbon atom" includes a carbon atom to which they are bonded, a cyclobutane ring, a cyclopentane ring, a cyclopentene ring, a cyclohexane ring, a cyclohexene ring. Represents that a cycloheptene ring or a cycloheptane ring may be formed. In addition, they may be substituted with a lower alkyl group. Preferably, a cyclopentane ring, a cyclohexane ring, and a cycloheptane ring are mentioned.

Formula (I), in the compounds represented by (VI), as defined in R ³ and R ^4, by bonding them together and the "R ³ and R ^4, sulfur atom and a sulfur atom is bonded Represents a 4- to 7-membered ring containing carbon atoms that are bonded to each other, and includes a sulfur atom to which they are bonded, and a carbon atom to which the sulfur atom is bonded to a 1,3-dithiolane ring, 1, It represents that 3-dithiane ring, 1,3-dithiepane ring and the like may be formed. Preferably, a 1,3-dithiolane ring and a 1,3-dithiane ring are mentioned.

Compounds represented by formulas (I), (II), and (III) All of the compounds represented by general formulas (I), (II), and (III) according to the present invention form a salt. In particular, a physiologically acceptable acid addition salt is preferable. As the salt, for example, an inorganic acid salt, an organic acid salt, an inorganic base salt, or an organic base salt is used.

  Examples of inorganic acid salts include hydrochloride, phosphate, hydrobromide, sulfate and the like. Examples of organic acid salts include acetate, formate, propionate, fumarate, maleate, succinate, tartrate, citrate, malate, oxalate, benzoate, methanesulfone Acid salt, benzene sulfonate, p-toluene sulfonate, and the like. Examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt. Examples of organic base salts include trimethylamine salts and triethylamine salts.

  Further, the compounds represented by the general formulas (I), (II), and (III) may be hydrates or non-hydrates. In addition, the compound represented by the general formula (III) or a salt thereof has an asymmetric carbon in the molecule, and there are four types of stereoisomers of R coordination or S coordination, Any of those mixtures are included in the present invention.

  Furthermore, the present invention also includes solvates of the compounds represented by the general formulas (I), (II), and (III), their stereoisomers, and their salts. These include water, methanol, ethanol, isopropanol, butanol, acetone, ethyl acetate, chloroform and the like.

  Preferred examples of the compound of the general formula (I) include 3-((2R, 3R) -epoxybutyryl) -5,5-bis (ethylthio) -2,2-dimethyl-1,3-oxazinane, 3- ((2R, 3R) -epoxybutyryl) -2,2-diethyl-5,5-bis (ethylthio) -1,3-oxazinane, 3-((2R, 3R) -epoxybutyryl) -5,5 -Bis (ethylthio) -2,2-dipropyl-1,3-oxazinane, 2,2-dibutyl-3-((2R, 3R) -epoxybutyryl) -5,5-bis (ethylthio) -1,3 -Oxazinan, 3-((2R, 3R) -epoxybutyryl) -5,5-bis (ethylthio) -1,3-oxazinane-2-spirocyclohexane, 3 '-((2R, 3R) -epoxybutyryl )-(Cyclohexanespiro -2 '-(1', 3'-oxazinane) -5'-spiro-2 "-(1", 3 "-dithiolane)) and the like.

  Preferred examples of the compound of the general formula (II) include 3-((2R, 3R) -epoxybutyryl) -2,2-dimethyl-5-oxo-1,3-oxazinane, 3-((2R, 3R ) -Epoxybutyryl) -2,2-diethyl-5-oxo-1,3-oxazinane, 3-((2R, 3R) -epoxybutyryl) -5-oxo-2,2-dipropyl-1,3 -Oxazinane, 2,2-dibutyl-3-((2R, 3R) -epoxybutyryl) -5-oxo-1,3-oxazinane, 3-((2R, 3R) -epoxybutyryl) -5-oxo -1,3-oxazinane-2-spirocyclohexane and the like.

  Preferable examples of the compound of the general formula (III) include (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dimethyl- (3-oxa-1-aza-bicyclo [4 .2.0] octane-5,8-dione), (6S, 7S) -2,2-diethyl-7-((R) -1-hydroxyethyl)-(3-oxa-1-aza-bicyclo [ 4.2.0] octane-5,8-dione), (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione), (6S, 7S) -2,2-dibutyl-7-((R) -1-hydroxyethyl)-(3-oxa-1-aza- Bicyclo [4.2.0] octane-5,8-dione), (6S, 7S) -7-((R) -1-hydride Xylethyl)-(3-oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione) -2-spirocyclohexane, (6S, 7S) -7-((R) -1-tert -Butyldimethylsilyloxyethyl) -2,2-dimethyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione) and the like.

Production of Compound of Formula (II) from Compound of Formula (I) The compound of general formula (II) can be produced by hydrolyzing the compound represented by general formula (I). For example, the compound of the general formula (II) can be obtained by subjecting the compound of the general formula (I) to conventional conversion conditions (hydrolysis) from a dithioacetal to a carbonyl compound. Examples of conditions for converting dithioacetal to a carbonyl compound include the method described in Protective Group in Organic Synthesis Third Edition (John Wiley and Sons Inc.). Specifically, a method using heavy metal such as mercury salt, silver salt or copper salt with water, an aqueous solution of sodium hypochlorite aqueous solution, dichlorodicyanobenzoquinone (DDQ), bromine, iodine or hydrogen peroxide together with water And a method of using an electrophile such as methyl iodide and methyl trifluoromethanesulfonate together with water. An organic solvent can also be used as a cosolvent. Examples of preferable organic solvents include methanol, ethanol, isopropanol, acetone, dioxane, tetrahydrofuran, diethyl ether, acetonitrile, benzene, toluene, dichloromethane, and chloroform. From the viewpoint of production cost, a method using an oxidizing agent such as aqueous sodium hypochlorite solution, bromine or hydrogen peroxide in a mixed solvent of water and acetonitrile is preferred. Further, acetic acid, chloroacetic acid, trifluoroacetic acid or the like may be added to the reaction system.

  Specific reaction conditions for hydrolysis of the compound of the general formula (I) may be appropriately determined depending on the method employed. For example, when an aqueous sodium hypochlorite solution is used, the hydrolysis is performed at -20 ° C to 30 ° C. Complete in 0-12 hours under temperature.

Production of Compound of Formula (III) from Compound of Formula (II) The compound of general formula (III) can be obtained by reacting the compound of general formula (II) in a solvent not involving an acid.

  As the acid, Lewis acid and Bronsted acid can be used. Lewis acids include zinc chloride, zinc bromide, zinc iodide, titanium tetrachloride, zirconium tetrachloride, aluminum chloride, magnesium chloride, magnesium bromide, boron trifluoride, bismuth chloride, trifluoromethanesulfonium trimethylsilyl, Examples include organic sulfonic acid compounds such as zinc methylbenzene sulfonate, and zinc chloride and zinc bromide are preferable.

  Bronsted acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, tosylic acid, camphorsulfonic acid, acetic acid, formic acid, propionic acid, trifluoroacetic acid, trichloroacetic acid, lactic acid, citric acid, tartaric acid, phenol, and anisole. Organic acids.

  Examples of the solvent not involved in the reaction include diethyl ether, methyl acetate, ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, toluene, dioxane, dimethylformamide, dimethyl sulfoxide, and benzene, preferably Mention may be made of methyl acetate, ethyl acetate, dichloromethane, chloroform or 1,2-dichloroethane. The reaction is performed at a reaction temperature of −20 ° C. to 120 ° C., preferably 0 ° C. to 80 ° C., and a reaction time of 5 minutes to 24 hours, preferably 10 minutes to 6 hours.

  The reaction with the acid can also be carried out in the presence of a base (for example, a secondary amine). Examples of the secondary amine include pyrrolidine, morpholine, piperidine, diethylamine, 2-methoxymethylpyrrolidine or methyl (methoxyethyl) amine, and preferably pyrrolidine. A combination of a Lewis acid and a secondary amine is preferred.

  The compound of the general formula (III) can be obtained by reacting the compound of the general formula (II) with a base in a solvent that does not participate in the reaction.

  As the base, lithium diisopropylamide (LDA), lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, 1,8-diazabicyclo And [5,4,0] -7-undecene (DBU) or 1,5-diazabicyclo [4,3,0] -5-nonene (DBN). Examples of the solvent that does not participate in the reaction include diethyl ether, tetrahydrofuran, toluene, dioxane, dimethylformamide, and benzene. The reaction can be carried out at a reaction temperature of −100 ° C. to 120 ° C., preferably −78 ° C. to 100 ° C.

  Moreover, you may pass through the process of introduce | transducing the protective group of a hydroxyl group between the processes from General formula (II) to General formula (III) as needed. The method for introducing a hydroxyl group can be performed, for example, according to the method described in Protective Group in Organic Synthesis Third Edition (John Wiley and Sons Inc.).

Production of the compound of the formula (IV) from the compound of the formula (III) The compound of the general formula (IV) can be obtained by subjecting the compound of the general formula (III) to a one-carbon carbonization reaction. Examples of the one carbon increase reaction include a method by Wittig reaction using triphenylphosphonium halides such as methyltriphenylphosphonium chloride, methyltriphenylphosphonium bromide and methyltriphenylphosphonium iodide, trimethylsilylmethylmagnesium chloride, trimethylsilylmethylmagnesium bromide, Method by Peterson reaction using trimethylsilylmethylmagnesium iodide, trimethylsilylmethyllithium, etc., Nysted reagent (cyclo-Dibromo-μ-methylene [μ- (tetrahydrofuran)] trizinc), or dibromide methane (or methane diiodide), A method using a complex formed by mixing zinc, titanium tetrachloride, etc., a transition derived from Teve reagent, titanocene dimethyl, zirconocene dimethyl, etc. Examples thereof include a method using a transfer metal carbene complex. The reaction is usually carried out in an organic solvent that does not participate in the reaction. For example, tetrahydrofuran, diethyl ether, dioxane, tert-butyl methyl ether, toluene, dichloromethane, chloroform, acetic acid are used when conducting a Wittig reaction or a reaction using a nested reagent. Ethyl is used. A preferred solvent is tetrahydrofuran.

Specific reaction conditions for the one-carbon increase reaction of the compound of the general formula (III) may be appropriately determined depending on the method employed. For example, when the Wittig reaction is used, When using a Nysted reagent in 12 hours, it is completed in 0 to 24 hours at a temperature of -50 ° C to 50 ° C.

  Preferable examples of the compound of the general formula (IV) thus obtained include (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dimethyl-5-methylene- (3-oxa- 1-aza-bicyclo [4.2.0] octane-8-one), (6S, 7S) -2,2-diethyl-7-((R) -1-hydroxyethyl) -5-methylene- (3 -Oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione), (6S, 7S) -7-((R) -1-hydroxyethyl) -5-methylene-2,2 -Dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one), (6S, 7S) -2,2-dibutyl-7-((R) -1-hydroxyethyl ) -5-methylene- (3-oxa-1-aza-bicyclo [4.2.0] octa -8-one), (6S, 7S) -7-((R) -1-hydroxyethyl) -5-methylene- (3-oxa-1-aza-bicyclo [4.2.0] octane-8- ON) -2-spirocyclohexane, (6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl) -2,2-dimethyl-5-methylene- (3-oxa-1-aza -Bicyclo [4.2.0] octane-8-one) and the like.

  Moreover, you may pass through the process of introduce | transducing the protective group of a hydroxyl group between the processes from general formula (III) to general formula (IV) as needed. The method for introducing a hydroxyl group can be performed, for example, according to the method described above.

Production of Compound of General Formula (I) The compound of general formula (I) is represented by (2R, 3R) -epoxybutanoic acid represented by formula (V) derived from L-threonine by the method described in WO98 / 45260. Alternatively, a salt thereof can be obtained by condensing a compound represented by the general formula (VI) or a salt thereof and a compound represented by the general formula (VII) in a solvent that does not participate in the reaction.

  Examples of the solvent not involved in the reaction include diethyl ether, ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, toluene, dioxane, dimethylformamide, dimethyl sulfoxide, and benzene.

  The condensation reaction can be performed at a reaction temperature of −78 ° C. to 100 ° C., preferably −20 ° C. to 30 ° C., and a reaction time of 5 minutes to 24 hours, preferably 10 minutes to 2 hours.

  The condensation reaction may be performed by adding a base as necessary. Bases added include organic bases such as pyridine, collidine, triethylamine or diisopropylamine or sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate. And inorganic bases such as

  According to a preferred embodiment of the present invention, the compound of the general formula (VI) and the compound of the general formula (VII) are used by mixing them in advance. Mixing of the compound of general formula (VI) and the compound of general formula (VII) is carried out while removing water in a solvent not involved in the reaction between the compound of general formula (VI) and the compound of general formula (VII). Or while removing water with a dehydrating agent.

  Examples of the solvent that does not participate in the reaction in this mixing include diethyl ether, ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, toluene, dioxane, dimethylformamide, dimethyl sulfoxide, and benzene.

  The water is removed at a temperature of −20 ° C. to 200 ° C., preferably 0 ° C. to 120 ° C., a reaction time of 10 minutes to 24 hours, preferably 1 hour to 6 hours, and if necessary, using a Dean Stark apparatus. It can be carried out. Examples of the dehydrating agent include sodium sulfate, magnesium sulfate, calcium chloride, molecular sieve and silica gel.

  According to a preferred embodiment of the present invention, (2R, 3R) -epoxybutanoic acid (V) or a salt thereof can be used as a reaction derivative. Examples of methods for deriving (2R, 3R) -epoxybutanoic acid (V) to reaction derivatives include acid halide methods using oxalyl chloride, thionyl chloride, phosphorus oxychloride, methanesulfonyl chloride, pivaloyl chloride, chloroformate Examples thereof include a mixed acid anhydride method using an ester or the like, or a dehydration method using N, N′-dicyclohexylcarbodiimide (DCC), benzotriazoleoxytrisdimethylaminophosphonium tetrafluorophosphate (BOP), or the like.

Production of carboxylic acid (A) As described above, a compound of general formula (IV) is obtained from L-threonine via a compound of general formula (I), general formula (II), or general formula (III). I can do it. Furthermore, the carboxylic acid (A) can be produced through the steps shown in the above-mentioned scheme I and described below.

  First, the conversion from the compound of general formula (IV) to the compound of general formula (VIII) can be performed by the method described in J. Org. Chem. 1987, 52, 2563.

  Subsequently, the conversion of the compound of the general formula (VIII) to the carboxylic acid (A) can be performed by the method described in J. Org. Chem. 1987, 52, 2563 or the method of Scheme II shown below.

In the formula, R ¹ and R ² have the same meanings as defined in Scheme I.

  The compound of the general formula (IX) can be obtained by heating and stirring the compound of the general formula (VIII) at 50 to 200 ° C, preferably 80 to 150 ° C in a water-containing solvent. Solvents include methanol, ethanol, normal propanol, isopropanol, dioxane, butyl acetate, dimethylformamide, dimethyl sulfoxide, dimethylimidazolidinone, dimethylacetamide, tert-butyl methyl ether, cyclohexyl methyl ether, diphenyl ether, hexamethylphosphoramide, ethylene glycol Examples thereof include dimethyl ether, and these can be used singly or in combination. The proportion of water contained in the hydrous solvent is 2 to 95%, preferably 2 to 50%.

  The carboxylic acid (A) can be obtained by subjecting the compound of the general formula (IX) to oxidation conditions in a solvent that does not participate in the reaction. As the solvent not involved in the reaction, it is necessary to select a solvent in consideration of the kind of the oxidizing agent, and examples thereof include water, acetone, diethyl ether, tert-butanol, dichloromethane, chloroform and the like. The oxidation conditions are chromic acid, dichromic acid, pyridinium chromate, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), potassium permanganate, osmium tetroxide, ruthenium tetroxide, hydrogen peroxide, Using oxygen, periodic acid, sodium periodate, sodium hypochlorite, sodium hypobromite, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), etc., acidic, neutral, Or the method of reacting under alkali, electrolytic oxidation, etc. are mentioned. The oxidation reaction in this step includes not only a method of directly oxidizing the hydroxy group of the general formula (IX) to a carboxylic acid but also a method via an aldehyde.

  The compound of general formula (X) can be obtained by subjecting the compound of general formula (VIII) to normal oxidation conditions in a solvent not involved in the reaction. As the solvent not involved in the reaction, it is necessary to select a solvent in consideration of the kind of the oxidizing agent, and examples thereof include water, acetone, diethyl ether, tert-butanol, dichloromethane, chloroform and the like. Normal oxidation conditions are chromic acid, dichromic acid, pyridinium chromate, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), potassium permanganate, osmium tetroxide, ruthenium tetroxide, hydrogen peroxide water , Oxygen, periodic acid, sodium periodate, sodium hypochlorite, sodium hypobromite, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), etc. And a method of reacting under alkaline or alkaline conditions, electrolytic oxidation and the like.

  Carboxylic acid (A) can be obtained by subjecting a compound of general formula (X) to a hydrolysis reaction. Hydrolysis is achieved by using lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, ammonia or the like as a base, and adding hydrogen peroxide water as necessary.

  Specific production examples of the compounds included in the general formulas (I) to (IV) will be described below as examples of the present specification, but the present invention is not limited thereto. In addition, with reference to the above description and examples, the reaction reagent, reaction conditions and the like are appropriately selected, and the compounds and carboxylic acids (A) included in the general formula (IV) can be modified or modified as necessary. Obviously, it can be carried out by those skilled in the art.

Example 1 :
(6S, 7S) -7-((R) -1-hydroxyethyl) -5-methylene-2,2-dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-8- on)

(A): To a solution of 3-amino-2,2-bis (ethylthio) -propan-1-ol hydrochloride (15.5 g) and 4-heptanone (18.7 ml) in toluene (400 ml) was added sodium bicarbonate (8 .45 g) was added, and the mixture was refluxed for 2 hours and 40 minutes under an argon atmosphere while removing water with a Dean-Stark apparatus. After standing at room temperature for 1 hour, (2R, 3R) -epoxybutanoic acid chloride ((2R, 3R) -epoxybutanoic acid sodium salt (18.3 g), oxalyl chloride (11.7 ml), pyridine (11.8 ml) The mixture was added to a tetrahydrofuran (350 ml) solution of triethylamine (20.6 ml) and stirred at 0 ° C. for 30 minutes. Water was added to the reaction mixture to stop the reaction, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 4: 1 to 2: 1) to give 3-((2R, 3R) -epoxybutyryl) -5,5-bis (ethylthio). ) -2,2-dipropyl-1,3-oxazinane (19.4 g, 75%) was obtained.

¹ H-NMR (CDCl ₃ ): δ 0.89 (3H, s), 0.91 (3H, s), 1.15 to 1.35 (2H, m), 1.26 (3H, t), 1.28 (3H, t), 1.3 (3H, d), 1.4-1.5 (2H, m), 2.0-2.3 (4H, m), 2.65 (2H, q), 2.67 (2H, q), 3.30 (1H, dq), 3.61 (1H, d), 3.74 (1H, d), 3.85 (1H, d), 3. 89 (1H, d), 3.93 (1H, d).
API-MS (m / z): 376 (M ⁺⁺ 1).

  (B): 3-((2R, 3R) -epoxybutyryl) -5,5-bis (ethylthio) -2,2-dipropyl-1,3-oxazinane (864 mg) obtained in (a) above 5% Aqueous sodium hypochlorite solution (9.3 ml) was added to 75% aqueous acetonitrile solution (53 ml) at 10-13 ° C. and stirred for 10 minutes. The organic matter was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 2: 1) to give 3-((2R, 3R) -epoxybutyryl) -5-oxo-2,2-dipropyl-1. , 3-oxazinane (621 mg, 91%) was obtained.

¹ H-NMR (CDCl ₃ ): δ 0.926 (3H, t), 0.931 (3H, t), 1.25-1.40 (2H, m), 1.28 (3H, d), 1.45-1.60 (2H, m), 3.34 (1H, dq), 3.51 (1H, d), 4.15 (1H, d), 4.17 (1H, d), 4 .20 (1H, d), 4.33 (1H, d).
FAB-MS (m / z): 270 (M ⁺⁺ 1).

  (C): 3-((2R, 3R) -epoxybutyryl) -5-oxo-2,2-dipropyl-1,3-oxazinane (265.4 mg) obtained in (b) under an argon atmosphere Anhydrous sodium sulfate (1.42 g), zinc chloride (241 mg) and pyrrolidine (0.165 ml) were added to a chloroform (6 ml) solution, and the mixture was stirred at 60 ° C. for 70 minutes. The reaction mixture was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 1: 2) to give (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dipropyl- (3 -Oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione) (210.5 mg, 79%).

¹ H-NMR (CDCl ₃ ): δ 0.96 (3H, t), 0.97 (3H, t), 1.27-1.90 (6H, m), 1.31 (3H, d), 2.25-2.40 (2H, m), 3.15 (1H, dd), 4.09 (1H, d), 4.11 (1H, d), 4.20 (1H, d), 4 .27 (1H, d).
FAB-MS (m / z): 270 (M ⁺⁺ 1).

  (D): Methyltriphenylphosphonium bromide (1,37 g) was suspended in tetrahydrofuran (20 ml), and 1.6 mol / l n-butyllithium hexane solution (1.9 ml) was added at 0 ° C. under an argon atmosphere. It was. After 30 minutes, (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dipropyl- (3-oxa-1-aza-bicyclo [4. 2.0] octane-5,8-dione) (257.0 mg) was added, and the mixture was further stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture to stop the reaction, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 1: 1) to give the title compound (6S, 7S) -7-((R) -1-hydroxyethyl) -5-methylene- 2,2-dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one) (194.8 mg, 76%) was obtained.

¹ H-NMR (CDCl ₃ ): δ 0.94 (3H, t), 0.95 (3H, t), 1.33 (3H, d), 1.35 to 1.45 (4H, m), 1.65-1.70 (2H, m), 1.85-1.95 (1H, m), 2.10-2.20 (2H, m), 3.04 (1H, dd), 4. 16-4.30 (4H, m), 4.93 (1H, s), 5.05 (1H, s).
EI-MS (m / z): 270 (M ^<+> ).

Example 2 :
(6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dimethyl-5-methylene- (3-oxa-1-aza-bicyclo [4.2.0] octane-8- on)
The following compound was obtained by applying acetone instead of 4-heptanone in Example 1 (a) and following Example 1.

(A): 3-((2R, 3R) -epoxybutyryl) -5,5-bis (ethylthio) -2,2-dimethyl-1,3-oxazinane
¹ H-NMR (CDCl ₃ ): δ 1.22-1.36 (9H, m), 1.62 (3H, s), 1.72 (3H, s), 2.66 (2H, q), 2.68 (2H, q), 3.31 (1H, dq), 3.65 (1H, d), 3.68 (1H, d), 3.81 (1H, d), 3.92 (2H , S).

(B): 3-((2R, 3R) -epoxybutyryl) -2,2-dimethyl-5-oxo-1,3-oxazinane
¹ H-NMR (CDCl ₃ ): δ 1.26 (3H, d), 1.73 (3H, s), 1.76 (3H, s), 3.32 (1H, dq), 3.50 ( 1H, d), 4.13 (1H, d), 4.16 (1H, d), 4.22 (1H, d), 4.33 (1H, d).
FAB-MS (m / z): 214 (M ⁺⁺ 1).

(C): (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dimethyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-5 8-dione)
¹ H-NMR (CDCl ₃ ): δ 1.32 (3H, d), 1.54 (3H, s), 1.73 (3H, s), 2.38 (1H, brs), 3.17 ( 1H, dd), 4.11 (1H, d), 4.14 (1H, d), 4.22 (1H, d), 4.27 (1H, m).
FAB-MS (m / z): 214 (M ⁺⁺ 1).

(D) Title compound: (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dimethyl-5-methylene- (3-oxa-1-aza-bicyclo [4.2. 0] Octane-8-on)
¹ H-NMR (CDCl ₃ ): δ 1.32 (3H, d), 1.45 (3H, s), 1.71 (3H, s), 3.08 (1H, dd), 3.13 ( 1H, brs), 4.14-4.24 (2H, m), 4.21 (1H, d), 4.29 (1H, d), 4.99 (1H, s), 5.08 (1H , S).
FAB-MS (m / z): 212 (M ⁺⁺ 1).

Example 3 :
(6S, 7S) -2,2-diethyl-7-((R) -1-hydroxyethyl) -5-methylene- (3-oxa-1-aza-bicyclo [4.2.0] octane-5 8-dione)

  The following compound was obtained by using 3-pentanone instead of 4-heptanone in Example 1 (a) and following Example 1.

(A): 3-((2R, 3R) -epoxybutyryl) -2,2-diethyl-5,5-bis (ethylthio) -1,3-oxazinane
¹ H-NMR (CDCl ₃ ): δ 0.884 (6H, t), 1.27 (3H, t), 1.28 (3H, t), 1.34 (3H, d), 2.02- 2.40 (4H, m), 2.66 (2H, q), 2.67 (2H, q), 3.32 (1H, dq), 3.63 (1H, d), 3.78 (1H , D), 3.88 (1H, d), 3.94 (1H, d), 3.95 (1H, d).
ESI-MS (m / z): 348 (M ⁺⁺ 1).

(B): 3-((2R, 3R) -epoxybutyryl) -2,2-diethyl-5-oxo-1,3-oxazinane
¹ H-NMR (CDCl ₃ ): δ 0.94 (3H, t), 0.95 (3H, t), 1.29 (3H, t), 2.08-2.20 (2H, m), 2.26-2.40 (2H, m), 3.34 (1H, dq), 3.52 (1H, d), 4.17 (1H, d), 4.20 (1H, d), 4 .22 (1H, d), 4.35 (1H, d).
ESI-MS (m / z): 242 (M ⁺⁺ 1).

(C): (6S, 7S) -2,2-diethyl-7-((R) -1-hydroxyethyl)-(3-oxa-1-aza-bicyclo [4.2.0] octane-5 8-dione)
¹ H-NMR (CDCl ₃ ): δ 0.93 (3h, t), 1.02 (3H, t), 1.31 (3H, t), 1.70-1.85 (2H, m), 1.85-2.00 (1H, m), 2.30-2.40 (1H, m), 2.60 (1H, brs), 3.16 (1H, dd), 4.10 (1H, d), 4.12 (1H, d), 4.20 (1H, d), 4.27 (1H, m).
ESI-MS (m / z): 242 (M ⁺⁺ 1).

(D) Title compound: (6S, 7S) -2,2-diethyl-7-((R) -1-hydroxyethyl) -5-methylene- (3-oxa-1-aza-bicyclo [4.2. 0] octane-5,8-dione)
¹ H-NMR (CDCl ₃ ): δ 0.923 (3H, t), 0.939 (3H, s), 1.33 (3H, d), 1.65 to 1.80 (2H, m), 1.9-2.05 (1H, m), 2.10-2.25 (1H, m), 2.7581H, brs), 3.05 (1H, dd), 4.17-4.27 ( 3H, m), 4.25 (1H, d), 4.95 (1H, s), 5.06 (1H, s).
FAB-MS (m / z): 242 (M ⁺⁺ 1).

Example 4 :
(6S, 7S) -7-((R) -1-hydroxyethyl) -5-methylene- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one) -2-spiro Cyclohexane

  The following compound was obtained by applying cyclohexanone instead of 4-heptanone in Example 1 (a) and following Example 1.

(A): 3-((2R, 3R) -epoxybutyryl) -5,5-bis (ethylthio) -1,3-oxazinane-2-spirocyclohexane
¹ H-NMR (CDCl ₃ ): δ 1.26 (3H, t), 1.28 (3H, t), 1.30 (3H, d), 1.40-1.65 (7H, m), 1.80-1.95 (2H, m), 2.35-2.50 (1H, m), 2.65 (2H, q), 2.67 (2H, q), 3.30 (1H, d), 3.64 (1H, d), 3.69 (1H, d), 3.80 (1H, d), 3.89 (1H, d), 3.91 (1H, d).
ESI-MS (m / z): 360 (M ⁺⁺ 1).

(B): 3-((2R, 3R) -epoxybutyryl) -5-oxo-1,3-oxazinane-2-spirocyclohexane
¹ H-NMR (CDCl ₃ ): δ 1.24-1.29 (2H, m), 1.25 (3H, d), 1.40-1.90 (6H, m), 2.50-2 .80 (2H, m), 3.31 (1H, dq), 3.48 (1H, d), 4.12 (1H, d), 4.13 (1H, d), 4.19 (1H, d), 4.31 (1H, d).
EI-MS (m / z): 253 (M ^<+> ).

(C): (6S, 7S) -7-((R) -1-hydroxyethyl)-(3-oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione) -2 -Spirocyclohexane
¹ H-NMR (CDCl ₃ ): δ 1.30-1.50 (1H, m), 1.32 (3H, d), 1.50-2.10 (8H, m), 2.30-2 .40 (1H, m), 3.17 (1H, dd), 4.11 (1H, d), 4.17 (1H, d), 4.20 (1H, d), 4.27 (1H, m).
FAB-MS (m / z): 254 (M ⁺⁺ 1).

(D): Title compound: (6S, 7S) -7-((R) -1-hydroxyethyl) -5-methylene- (3-oxa-1-aza-bicyclo [4.2.0] octane-8 -On) -2-spirocyclohexane
¹ H-NMR (CDCl ₃ ): δ 1.33 (3H, d), 1.35-1.90 (9H, m), 2.25-2.35 (1H, m), 2.65 (1H , Brs), 3.09 (1H, dd), 4.14 (1H, d), 4.18-4.28 (2H, m), 4.36 (1H, d), 4.97 (1H, s), 5.09 (1H, s).
FAB-MS (m / z): 252 (M ⁺⁺ 1).

Example 5 :
(6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl) -2,2-dimethyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-5 , 8-dione)

  (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dimethyl- (3-oxa-1-aza-bicyclo [4.2.0] octane- at room temperature under argon atmosphere Triethylamine (1.3 ml) and tert-butyldimethylsilyl chloride (715 mg) were added to a solution of 5,8-dione) (428 mg) in dimethylformamide (13 ml). After stirring at room temperature for 15 hours, water was added to the reaction mixture, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 4: 1) to give (6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl) -2. , 2-Dimethyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione) (456 mg, 75%).

¹ H-NMR (CDCl ₃ ): δ 0.072 (3H, s), 0.093 (3H, s) 0.89 (9H, s), 0.91 (3H, t), 0.96 (3H , T), 1.22 (3H, d), 1.3-1.65 (4H, m), 1.65-1.8 (2H, m), 1.8-1.9 (1H, m ), 2.25-2.4 (1H, m), 2.98-3.05 (1H, m), 4.07 (1H, d), 4.18 (1H, d), 4.06- 4.26 (2H, m).

Example 6 :
(6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl) -2,2-dimethyl-5-methylene- (3-oxa-1-aza-bicyclo [4.2.0 ] Octane-8-on)

  Potassium tert-butoxide (27 mg) was added to a suspension of methyltriphenylphosphonium bromide (100 mg) in diethyl ether (2 ml) at room temperature under an argon atmosphere. After stirring at room temperature for 30 minutes, (6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl) -2,2-dimethyl- (3-oxa-1-aza-bicyclo [4. 2.0] Octane-5,8-dione) (34 mg) in diethyl ether (1 ml) was added and stirred at room temperature for 10 minutes. Water was added to the reaction mixture to stop the reaction, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 9: 1) to give (6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl) -2. , 2-Dimethyl-5-methylene- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one) (19 mg, 55%) was obtained.

¹ H-NMR (CDCl ₃ ): δ 0.077 (3H, s), 0.094 (3H, s), 0.89 (9H, s), 0.92 (3H, t), 0.94 ( 3H, t), 1.25 (3H, d), 1.3-1.5 (4H, m), 1.6-1.75 (2H, m), 1.8-1.9 (1H, m), 2.1-2.2 (1H, m), 2.97 (1H, dd), 4.15-4.3 (4H, m), 4.91 (1H, s), 5.02 (1H, s).
API-MS (m / z): 382 (M ⁺⁺ 1).

Example 7 :
(6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl) -2,2-dipropyl-5-methylene- (3-oxa-1-aza-bicyclo [4.2.0 ] Octane-8-on)

  (A): (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dimethyl- (3-oxa-1-aza-bicyclo [4.2.0] of Example 5 (6S, 7S) -7-((R) -1-hydroxyethyl) -2,2-dipropyl- (3-) obtained in (c) of Example 1 instead of octane-5,8-dione) (6S, 7S) -7-((R) -1-tert-butyl) using oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione) according to Example 5. Dimethylsilyloxyethyl) -2,2-dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione) was obtained.

¹ H-NMR (CDCl 3): δ 0.071 (3H, s), 0.093 (3H, s), 0.89 (9H, s), 0.90-1.00 (6H, m), 1 .22 (3H, d), 1.40-1.90 (7H, m), 2.30-2.45 (1H, m), 3.09 (1H, d), 4.07 (1H, d) ), 4.10-4.25 (1H, m), 4.18 (1H, d), 4.30-4.40 (1H, m).

  (B): Zinc (62 mg) was suspended in tetrahydrofuran (2 ml) under an argon atmosphere, diiodomethane (0.04 ml) was added, and the mixture was stirred at 25 ° C. for 30 minutes. 1M Titanium tetrachloride in dichloromethane (0.1 ml) was added, and the mixture was stirred at 25 ° C. for 30 minutes, and then (6S, 7S) -7-((R) -1-tert-butyl obtained in (a) was obtained. Add a solution of dimethylsilyloxyethyl) -2,2-dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione) (30 mg) in tetrahydrofuran (1 ml) at 25 ° C. For 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to stop the reaction, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 9: 1) to give the title compound (6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl). -2,2-dipropyl-5-methylene- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one) (9.8 mg, 33%) was obtained.

¹ H-NMR (CDCl 3): δ 0.077 (3H, s), 0.094 (3H, s), 0.89 (9H, s), 0.90-1.00 (6H, m), 1 .25 (3H, d), 1.30-1.50 (4H, m), 1.55-1.75 (2H, m), 1.80-1.85 (1H, m), 2.10 -2.25 (1H, m), 2.97 (1H, dd), 4.15-4.30 (4H, m), 4.91 (1H, s), 5.02 (1H, s).
ESP-MS (m / z): 382 (M ⁺⁺ 1).

Example 8 :
3 '-((2R, 3R) -epoxybutyryl)-(cyclohexanespiro-2'-(1 ', 3'-oxazinane) -5'-spiro-2 "-(1", 3 "-dithiolane))
Instead of 4-heptanone in Example 1 (a) cyclohexane, 2-aminomethyl-2-hydroxymethyl-1 instead of 3-amino-2,2-bis (ethylthio) -propan-1-ol hydrochloride , 3-Dithiolane hydrochloride was used to obtain the title compound.

¹ H-NMR (CDCl 3): δ 1.1-1.7 (6H, m), 1.29 (3H, d), 1.81 (2H, t), 2.40 (1H, dt), 2 .68 (1H, dt), 3.1-3.4 (5H, m), 3.73 (1H, d), 3.77 (1H, d), 3.84 (1H, d), 4. 06 (1H, d), 4.09 (1 H, d).

Example 9 :
(6S, 7S) -7-((R) -1-hydroxyethyl) -5-methylene- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one) -2-spiro Cyclohexane

  Titanium tetrachloride (0.26 ml), (6S, 7S) -7-((R) -1-hydroxyethyl)-in a 20% tetrahydrofuran suspension (5.41 g) of a Nysted reagent at 0 ° C. under an argon atmosphere (3-Oxa-1-aza-bicyclo [4.2.0] octane-5,8-dione) -2-spirocyclohexane (200.8 mg) was added and stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a mixture of saturated sodium bicarbonate and ethyl acetate to stop the reaction, and the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 1: 1) to give the title compound (6S, 7S) -7-((R) -1-hydroxyethyl) -5-methylene- (3-Oxa-1-aza-bicyclo [4.2.0] octane-8-one) -2-spirocyclohexane (124.2 mg, 62%) was obtained.

1H-NMR (CDCl3): δ 1.33 (3H, d), 1.35-1.90 (9H, m), 2.25-2.35 (1H, m), 2.65 (1H, brs) ), 3.09 (1H, dd), 4.14 (1H, d), 4.18-4.28 (2H, m), 4.36 (1H, d), 4.97 (1H, s) , 5.09 (1H, s).
FAB-MS (m / z): 252 (M ⁺⁺ 1).

Production Example 1 :
3-Amino-2,2-bis (ethylthio) -propan-1-ol hydrochloride

  (A): Potassium carbonate (31.9 g) was added to a solution of dimethoxyacetaldehyde (120 g) in nitromethane (186 ml) under an argon atmosphere. After stirring at 50 ° C. for 3.5 hours, water was added to stop the reaction. The organic matter was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was concentrated to give crude 1,1-dimethoxy-3-nitro-2-propanol (156.7 g, 82%). The crude 1,1-dimethoxy-3-nitro-2-propanol was used in the next reaction without further purification.

¹ H-NMR (CDCl ₃ ): δ 2.56 (1H, d), 3.490 (3H, s9, 3.494 (3H, s), 4.36-4.40 (2H, m), 4 .44-4.52 (1H, m), 4.53-4.63 (1H, m).

  (B): Raney nickel (5 g) was added to a solution of the crude 1,1-dimethoxy-3-nitro-2-propanol (3.32 g) obtained in (a) above in isopropanol (100 ml). After replacing the reaction system with hydrogen, the mixture was vigorously stirred at room temperature for 36 hours. After removing Raney nickel by Celite filtration, the solvent was concentrated to obtain crude 1-amino-3,3-dimethoxy-2-propanol (2.30 g, 85%). The crude 1-amino-3,3-dimethoxy-2-propanol was used in the next reaction without further purification.

¹ H-NMR (CDCl ₃ ): δ 2.77 (1H, dd), 2.91 (1H, dd), 3.44 (3H, s), 3.46 (3H, s), 3.55- 3.62 (1H, m), 4.25 (1H, d).

  (C): Concentrated hydrochloric acid (30 ml) was added to the crude 1-amino-3,3-dimethoxy-2-propanol (2.40 g) obtained in (b) above and stirred at 75 ° C. for 1 hour. Once the hydrochloric acid was distilled off, concentrated hydrochloric acid (10 ml) and ethanethiol (3.94 ml) were added again. After stirring at room temperature for 3 hours, the reaction system was neutralized by adding potassium carbonate. The organic matter was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and volatile substances were distilled off to give crude 3-amino-2,2-bis (ethylthio) -propan-1-ol (2.95 g, 72%). Got. An equivalent amount of hydrochloric acid was added to the resulting crude 3-amino-2,2-bis (ethylthio) -propan-1-ol, and then recrystallized from ethyl acetate to give the title compound 3-amino-2,2-bis ( Ethylthio) -propan-1-ol hydrochloride was obtained.

¹ H-NMR (D ₂ O): δ 0.78 (6H, t), 2.26 (4H, q), 2.92 (2H, s), 3.41 (2H, s).

Production Example 2
(3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl) -4-((R) -1-carboxyethyl) -2-azetidinone

  (A): (6S, 7S) -7-((R) -1-hydroxyethyl) -5-methylene-2,2-dipropyl- (3-oxa-1) obtained in (d) of Example 1 -Raney nickel (300 mg) was added to a solution of aza-bicyclo [4.2.0] octane-8-one) (289 mg) in methanol (12 ml). The reaction system was replaced with hydrogen and then stirred vigorously at room temperature for 5 hours. After removing Raney nickel by Celite filtration, the solvent was distilled off. The residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 1: 2) (5R, 6S, 7S) -7-((R) -1-hydroxyethyl) -5-methyl-2,2- Dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one) and (5S, 6S, 7S) -7-((R) -1-hydroxyethyl) -5-methyl A mixture (306 mg) of -2,2-dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one) was obtained. The resulting mixture was used in the next reaction without further purification.

  (B): (5R, 6S, 7S) -7-((R) -1-hydroxyethyl) -5-methyl-2,2-dipropyl- (3- Oxa-1-aza-bicyclo [4.2.0] octane-8-one) and (5S, 6S, 7S) -7-((R) -1-hydroxyethyl) -5-methyl-2,2- A mixture of dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one) (306 mg) was dissolved in dimethylformamide (2.5 ml), triethylamine (0.31 ml), tert -Butyldimethylsilyl chloride (216 mg) was added. After stirring at room temperature for 20 hours, the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After solvent concentration, the residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 9: 1), and (5R, 6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl). ) -5-methyl-2,2-dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octan-8-one) (358 mg, 83%, 2 steps).

¹ H-NMR (CDCl ₃ ): δ 0.067 (3H, s), 0.080 (3H, s), 0.89 (9H, s), 0.92 (3H, t), 0.93 ( 3H, t), 1.08 (3H, d), 1.18 (3H, d), 1.25-1.40 (2H, m), 1.40-1.60 (2H, m), 1 .60-1.75 (2H, m), 1.80-2.10 (3H, m,), 2.98 (1H, dd), 3.54 (1H, dd), 3.78 (1H, dd), 3.91 (1H, dd), 4.14 (1H. dq).
EI-MS (m / z): 383 (M ^<+> ).

(C): (5R, 6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl) -5-methyl-2,2- obtained in (b) under an argon atmosphere To dipropyl- (3-oxa-1-aza-bicyclo [4.2.0] octane-8-one) (1.00 g) was added dioxane (20 ml), dimethyl sulfoxide (20 ml) and water (3 ml). Reflux for hours. The organic matter was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After solvent concentration, the residue was purified by silica gel column chromatography (eluted from ethyl acetate), and (3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl) -4-((R) -1-Hydroxypropan-2-yl) -2-azetidinone (611 mg, 82%) was obtained.

¹ H-NMR (CDCl ₃ ): δ 0.13 (3H, s), 0.14 (3H, s), 0.91 (3H, d), 0.92 (9H, s), 1.36 ( 3H, d), 1.80-1.93 (1H, m), 3.18 (1H, dd), 3.27 (1H, dd), 3.47 (H, dd), 3.58 (1H , Dd), 4.14 (1H, dq), 6.03 (1H, brs).
TSP-MS (m / z): 288 (M ⁺⁺ 1).

  (D): (3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl) -4-((R) -1-hydroxy obtained in (c) under an argon atmosphere To a solution of propan-2-yl) -2-azetidinone (501 mg) in dimethylformamide (20 ml) was added pyridinium dichromate (PDC) (3.28 g). After stirring at room temperature for 20 hours, the organic matter was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, washed with diethyl ether, and acidified with hydrochloric acid. The liberated organic matter was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous magnesium sulfate. The title compound (3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl) -4-((R) -1-carboxyethyl) -2-azetidinone ( 408 mg, 77%). The spectral data of the obtained 3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl) -4-((R) -1-carboxyethyl) -2-azetidinone were obtained from J. Org. It showed good homology with the data described in Chem. 1987, 52, 2563.

¹ H-NMR (CDCl ₃ ): δ 0.069 (3H, s), 0.076 (3H, s), 0.87 (9H, s), 1.20 (3H, d), 1.26 ( 3H, d), 2.75 (1H, dq), 3.03 (1H, dd), 3.93 (1H, dd), 4.20 (1H, dq), 6.21 (1H, brs).
FAB-MS (m / z): 302 (M ⁺⁺ 1).

Production Example 3
(3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl) -4-((R) -1-carboxyethyl) -2-azetidinone

  (A): (5R, 6S, 7S) -7-((R) -1-tert-butyldimethylsilyloxyethyl) -5-methyl-2,2-dipropyl obtained in (b) of Reference Example 2 -(3-Oxa-1-aza-bicyclo [4.2.0] octane-8-one) (508 mg) was dissolved in acetone (15 ml) and at 0 ° C. Jones reagent (1 ml, Organic Syntheses Collect Volume 5, 310 Concentrated sulfuric acid (0.5 ml) was added and stirred for 10 minutes. The reaction mixture was poured into a mixture of dichloromethane and water, and then the organic layer was separated. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration of the solvent, the residue was purified by silica gel column chromatography (eluted from hexane: ethyl acetate = 3: 2), and (3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl)- 1-Butyryl-4-((R) -1-carboxyethyl) -2-azetidinone (261 mg, 47%) was obtained.

¹ H-NMR (CDCl ₃ ): δ 0.04 (3H, s), 0.07 (3H, s), 0.83 (9H, s), 1.21 (3H, d), 1.23 ( 3H, d), 1.67-1.82 (2H, m), 2.58-2.87 (2H, m), 1.98-3.23 (1H, m), 3.30-3. 40 (1H, m), 4.25-4.38 (2H, m).
ESI-MS (m / z): 372 (M ⁺⁺ 1).

(B): (3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl) -1-butyryl-4-((R) -1-carboxyethyl) obtained in (a) above ) -2-Azetidinone (39 mg) in tetrahydrofuran (1 ml) was added 0.4N aqueous sodium hydroxide solution (1 ml) at 0 ° C. After stirring at 0 ° C. for 15 minutes and at room temperature for 1 hour, diethyl ether was added. The aqueous layer was separated and acidified with hydrochloric acid. The liberated organic matter was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous magnesium sulfate. The title compound (3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl) -4-((R) -1-carboxyethyl) -2-azetidinone was obtained by distilling off the solvent. (24 mg, 75%) was obtained. The spectral data of the obtained (3S, 4S) -3-((R) -1-tert-butyldimethylsilyloxyethyl) -4-((R) -1-carboxyethyl) -2-azetidinone were obtained from J. Org. It showed good homology with the data described in Chem. 1987, 52, 2563.

¹ H-NMR (CDCl ₃ ): δ 0.069 (3H, s), 0.076 (3H, s), 0.87 (9H, s), 1.20 (3H, d), 1.26 ( 3H, d), 2.75 (1H, dq), 3.03 (1H, dd), 3.93 (1H, dd), 4.20 (1H, dq), 6.21 (1H, brs).
FAB-MS (m / z): 302 (M ⁺⁺ 1).

Claims (16)

A compound represented by the following general formula (I) or a salt thereof or a solvate thereof:

(Where
R ¹ and R ² may be the same or different and each represents a hydrogen atom or a linear, branched or cyclic C _1-8 alkyl group, or R ¹ and R ² are taken together; Represents a 4- to 7-membered ring together with the carbon atoms to which they are attached (wherein the 4- to 7-membered ring may be substituted with a linear, branched or cyclic C _1-8 alkyl group);
R ³ and R ⁴ may be the same or different and each represents a linear, branched or cyclic C _1-8 alkyl group, or R ³ and R ⁴ are combined to form a bond Represents a 4- to 7-membered ring together with the sulfur atom and the carbon atom to which the sulfur atom is bonded. ). A compound represented by the following general formula (II) or a salt or solvate thereof:

(In the formula, R ¹ and R ² have the same meaning as defined in the general formula (I) described in claim 1). A compound represented by the following general formula (III) or a salt or solvate thereof:

(In the formula, R ¹ and R ² have the same meanings as defined in the general formula (I) described in claim 1, and R ⁵ represents a hydrogen atom or a hydroxyl-protecting group).   The manufacturing method of the compound represented by general formula (II) of Claim 2 including the process of hydrolyzing the compound represented by general formula (I) of Claim 1.   The method according to claim 4, wherein the hydrolysis is performed in the presence of an oxidizing agent. 6. The method of claim 5 , wherein the oxidant is sodium hypochlorite, bromine, or hydrogen peroxide. The manufacturing method of the compound of the following formula (A) which comprises the manufacturing method of Claim 4.

  The compound represented by the general formula (II) according to claim 2 is represented by the general formula (III) according to claim 3, comprising a step of reacting the compound represented by the general formula (II) according to claim 2 with an acid or a base, or an acid and a base. Compound production method.   9. A method according to claim 8, wherein the acid is a Lewis acid or a Bronsted acid.   The method according to claim 8, wherein the acid is a Lewis acid, and the reaction is further performed in the presence of a secondary amine.   A process for the preparation of a compound of formula (A) according to claim 7, comprising the process according to claim 8. A production method represented by the following general formula (IV),

Wherein R ¹ and R ² have the same meaning as defined in general formula (I) described in claim 1, and R ⁵ is defined in general formula (III) described in claim 3. Is synonymous with.)
General formula (III):

Wherein R ¹ and R ² have the same meaning as defined in general formula (I) described in claim 1, and R ⁵ is defined in general formula (III) described in claim 3. Is synonymous with.)
A method comprising a step of one-carbon carbonization reaction of a compound represented by:   A process for producing a compound of formula (A) according to claim 7, comprising the process according to claim 12. A process for producing a compound represented by the general formula (I) according to claim 1,
(2R, 3R) -epoxybutanoic acid represented by the following formula (V):

Or a salt thereof and the following general formula (VI):

(In the formula, R ³ and R ⁴ have the same meanings as defined in the general formula (I) described in claim 1.)
Or a salt thereof, and the following general formula (VII):

(In the formula, R ¹ and R ² have the same meaning as defined in formula (I) described in claim 1)
A method comprising a step of condensing a compound represented by:   The method according to claim 14, wherein the compound of the general formula (VI) and the compound of the general formula (VII) are condensed with the compound of the formula (V) as a mixture in which the compound is preliminarily mixed.   A process for producing a compound of formula (A) according to claim 7, comprising the process according to claim 14.