JP5338035B2 - Process for producing polycyclic lactams - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a polycyclic lactam compound using easily available reagents. <P>SOLUTION: This method for producing the polycyclic lactam compound comprises reacting a lactone compound represented by formula (2) with an imide compound represented by one of formulas (3a), (3b) and (3c) to prepare a carboxylic acid compound, esterifying the carboxylic acid compound, followed by the reaction with an amine compound. <P>COPYRIGHT: (C)2008,JPO&amp;INPIT

Description

  The present invention relates to a method for producing polycyclic lactams.

  Polycyclic lactams can be produced by reacting 3-oxabicyclo [3.1.0] hexane-2-one, which is a lactone, with potassium phthalimide in an N, N-dimethylformamide solvent, A method of esterification using a supported acid and then lactamization using an amine compound supported on a resin (see Non-Patent Document 1) is known, but this method was supported on a resin. There is a problem in cost because it is necessary to use an expensive reagent.

Synlett, 10, 1641 (2002)

  An object of the present invention is to provide a method for producing polycyclic lactams using an inexpensive reagent.

  As a result of studying an industrially advantageous method for producing polycyclic lactams, the present inventor obtained a carboxylic acid by reacting certain polycyclic lactones with readily available imides, and the carboxylic acids It was found that polycyclic lactams can be produced by esterifying and then reacting with amines.

（式中、Ｒ_３〜Ｒ_６は、それぞれ独立して、水素原子、ハロゲン原子、シアノ基、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアミノ基、−ＯＲ_ａ基、−ＳＲ_ｂ基または−ＣＯＯＲ_ｃ基を表し、Ｒ_ａおよびＲ_ｂは、それぞれ独立して、水素原子、アルキルカルボニル基、アリールカルボニル基、アラルキル基、アルコキシアルキル基、トリアルキルシリル基、アルキル基またはアリール基を表し、Ｒ_ｃは、水素原子、アルキル基またはアラルキル基を表す。Ｒ_３とＲ_４がともに水素原子である場合、Ｒは置換メチレン基もしくは置換基を有していてもよいポリメチレン基を表し、Ｒ_３とＲ_４のうち少なくとも一方が水素原子以外の置換基である場合、Ｒは置換基を有していてもよいメチレン基もしくは置換基を有していてもよいポリメチレン基を表し、かかるポリメチレン基を構成する１つまたは互いに隣接しない２つのメチレン基が酸素原子に置き換わっていてもよく、ポリメチレン基を構成する１つまたは２つのエチレン基がビニレン基に置き換わっていてもよく、ポリメチレン基を構成する互いに隣接しない２つのメチレン基同士が、酸素原子、メチレン基、エチレン基またはビニレン基を介して結合していてもよい。）
で示されるラクトン類と、式（３ａ）、（３ｂ）および（３ｃ）

（各式中、Ａ_１〜Ａ_１０はそれぞれ独立して、水素原子、ハロゲン原子、ニトロ基、アルキル基、アルケニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアシル基または−ＯＲ_ｄ基を表し、Ｒ_ｄは、水素原子、アルキルカルボニル基、アリールカルボニル基、アラルキル基、アルコキシアルキル基、トリアルキルシリル基、アルキル基またはアリール基を表し、Ｍは水素原子またはアルカリ金属原子を表す。Ａ_５〜Ａ_８のうち同一分子上の任意の２つが一緒になって、それらが結合する炭素原子と共に環状構造を形成していてもよく、Ａ_９とＡ_１０が一緒になって、それらが結合する炭素原子と共に環状構造を形成していてもよい。）
のいずれかで示されるイミド類とを反応させて、式（４ａ）、（４ｂ）および（４ｃ）

（各式中、Ｒ、Ｒ_３〜Ｒ_６、Ａ₁〜Ａ_１０およびＭは、上記と同じ意味を表す。）
のいずれかで示されるカルボン酸類を得、該カルボン酸類をエステル化して式（５ａ）、（５ｂ）および（５ｃ）

（各式中、Ｒ、Ｒ_３〜Ｒ_６およびＡ₁〜Ａ_１０は、上記と同じ意味を表し、Ｒ_７はアルキル基、アルケニル基または置換基を有していてもよいアラルキル基を表す。）
のいずれかで示されるエステル類を得、次いで該エステル類をアミン類と反応させる式（１）

（式中、ＲおよびＲ₃〜Ｒ_６は、それぞれ上記と同じ意味を表す。）
で示される多環式ラクタム類の製造方法を提供するものである。 That is, the present invention provides the formula (2)

(In the formula, R _{3 to} R ₆ are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. Represents an aryl group which may have _a group, an amino group which may have a substituent, an —OR _a group, an —SR _b group or a —COOR _c group, wherein R _a and R _b are each independently Te, a hydrogen atom, an alkylcarbonyl group, an arylcarbonyl group, an aralkyl group, an alkoxyalkyl group, a trialkylsilyl group, an alkyl group or an aryl group, R _c is, .R ₃ represents a hydrogen atom, an alkyl group or an aralkyl group And R ₄ are both hydrogen atoms, R represents a substituted methylene group or an optionally substituted polymethylene group, and at least one of R ₃ and R ₄ is other than a hydrogen atom R represents a methylene group which may have a substituent or a polymethylene group which may have a substituent, and one methylene which forms such a polymethylene group or two methylenes which are not adjacent to each other The group may be replaced by an oxygen atom, one or two ethylene groups constituting the polymethylene group may be replaced by a vinylene group, and two methylene groups constituting the polymethylene group are not adjacent to each other, And may be bonded via a methylene group, an ethylene group or a vinylene group.)
A lactone represented by formula (3a), (3b) and (3c)

(In each formula, A _{1 to} A ₁₀ each independently have a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an alkenyl group, an aryl group which may have a substituent, or a substituent. represent also an acyl group or an -OR _d group, R _d represents a hydrogen atom, an alkylcarbonyl group, an arylcarbonyl group, an aralkyl group, an alkoxyalkyl group, a trialkylsilyl group, an alkyl group or an aryl group, M is hydrogen An atom or an alkali metal atom, any two of A _{5 to} A ₈ on the same molecule may be combined to form a cyclic structure with the carbon atom to which they are bonded, and A ₉ and A ₁₀ Together may form a cyclic structure with the carbon atom to which they are attached.)
Is reacted with an imide represented by any one of formulas (4a), (4b) and (4c)

(In each formula, R, R _{3 to} R ₆ , A _{1 to} A ₁₀ and M represent the same meaning as described above.)
And the carboxylic acids are esterified to give the formulas (5a), (5b) and (5c)

(In each formula, R, R _{3 to} R ₆ and A _{1 to} A ₁₀ represent the same meaning as described above, and R ₇ represents an alkyl group, an alkenyl group, or an aralkyl group which may have a substituent. )
Formula (1) in which an ester represented by any of the above is obtained and then the ester is reacted with an amine

(In the formula, R and R _{3 to} R ₆ each have the same meaning as described above.)
The manufacturing method of polycyclic lactam shown by these is provided.

  According to the present invention, polycyclic lactams can be produced without using a special reagent, which is industrially advantageous.

  Hereinafter, the present invention will be described in detail. First, lactones represented by the formula (2) (hereinafter sometimes abbreviated as lactones (2)) and imides represented by any one of the formulas (3a), (3b) and (3c) ( Hereinafter, the reaction with imides (3) may be abbreviated.

In Formula (2), R _{3 to} R ₆ are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group that may have a substituent, or an alkenyl group that may have a substituent. , An aryl group which may have a substituent, an amino group which may have a substituent, an —OR _a group, an —SR _b group or a —COOR _c group, wherein R _a and R _b are Each independently represents a hydrogen atom, an alkylcarbonyl group, an arylcarbonyl group, an aralkyl group, an alkoxyalkyl group, a trialkylsilyl group, an alkyl group or an aryl group, and R _c represents a hydrogen atom, an alkyl group or an aralkyl group. .

  As a halogen atom, a chlorine atom, a bromine atom, a fluorine atom, an iodine atom etc. are mentioned, for example.

  As an alkyl group, C1-C10 linear or branched alkyl groups, such as a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, are mentioned, for example. Examples of the substituent which may be present on these alkyl groups include halogen atoms such as fluorine atom and chlorine atom; hydroxy group; alkylcarbonyloxy group such as acetoxy group; arylcarbonyloxy group such as benzoyloxy group; Alkoxy groups such as methoxy and ethoxy groups; aralkyloxy groups such as benzyloxy groups; aryloxy groups such as phenoxy groups; alkoxyalkoxy groups such as methoxymethoxy groups; trialkylsilyloxy groups such as trimethylsilyloxy groups; amino groups; Alkylcarbonylamino groups such as acetamido groups; arylcarbonylamino groups such as benzamide groups; alkylamino groups such as methylamino groups and ethylamino groups; dialkylamino groups such as dimethylamino groups and diethylamino groups; aralkylamino groups such as benzylamino groups; An arylamino group such as an anilino group; an alkyloxycarbonylamino group such as a tert-butoxycarbonylamino group; an aralkyloxycarbonylamino group such as a benzyloxycarbonylamino group; a carboxy group; a methoxycarbonyl group, an ethoxycarbonyl group, n- Alkoxycarbonyl groups such as propoxycarbonyl and isopropoxycarbonyl groups; Aralkyloxycarbonyl groups such as benzyloxycarbonyl groups; Substituents such as halogen atoms, alkoxy groups, hydroxy groups, nitro groups, cyano groups, alkyl groups, and aryl groups Aryl groups that may be present; and the like. Specific examples of the alkyl group having such a substituent include chloromethyl group, dichloromethyl group, trichloromethyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, hydroxymethyl group, hydroxyethyl group, aminomethyl group, Examples include aminoethyl group, hydroxycarbonylmethyl group, hydroxycarbonylethyl group, benzyl group, phenylethyl group, etc.

  As an alkenyl group, C2-C10 alkenyl groups, such as a vinyl group, an ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, are mentioned, for example. Examples of the substituent which may be present on these alkenyl groups include aryl groups such as phenyl groups; carboxy groups; hydroxy groups; Specific examples of the alkenyl group having such a substituent include a hydroxycarbonylethenyl group.

  As an aryl group, C6-C20 aryl groups, such as a phenyl group and a naphthyl group, are mentioned, for example. Examples of the substituent which may be present on these aryl groups include halogen atoms such as fluorine atom and chlorine atom; alkoxy groups such as methoxy group; methyl group, ethyl group, n-propyl group, isopropyl group, n -An alkyl group such as a butyl group; an aryl group such as a phenyl group or a naphthyl group; a hydroxy group; a nitro group; a cyano group; Examples of the aryl group having such a substituent include 4-fluorophenyl group, 3,4-dichlorophenyl group, 4-methoxyphenyl group, p-tolyl group, 3-biphenyl group, 2-hydroxyphenyl group, and 3-nitrophenyl. Group, 4-cyanophenyl group and the like.

  Examples of the substituent that may be present on the amino group include alkylcarbonyl groups such as acetyl group; arylcarbonyl groups such as benzoyl group; alkyl groups such as methyl group and ethyl group; aralkyl groups such as benzyl group; and alkoxycarbonyl groups such as tert-butoxycarbonyl group; aralkyloxycarbonyl groups such as benzyloxycarbonyl group; and the like. Specific examples of the amino group having such a substituent include acetylamino group, benzoylamino group, methylamino group, dimethylamino group, benzylamino group, tert-butoxycarbonylamino group, and benzyloxycarbonylamino group.

_{R b} in _{R a} and -SR _b group -OR _a group, represents a hydrogen atom, an alkylcarbonyl group, an arylcarbonyl group, an aralkyl group, an alkoxyalkyl group, a trialkylsilyl group, an alkyl group or an aryl group. As an alkylcarbonyl group, C2-C10 alkylcarbonyl groups, such as an acetyl group, are mentioned, for example. Examples of the arylcarbonyl group include arylcarbonyl groups having 7 to 20 carbon atoms such as a benzoyl group. Examples of the aralkyl group include an aralkyl group having 7 to 20 carbon atoms such as a benzyl group. As an alkoxyalkyl group, C2-C10 alkoxyalkyl groups, such as a methoxymethyl group, are mentioned, for example. Examples of the trialkylsilyl group include a trialkylsilyl group having 3 to 10 carbon atoms such as a trimethylsilyl group. Examples of the alkyl group include alkyl groups having 1 to 10 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and a tert-butyl group. As an aryl group, C6-C20 aryl groups, such as a phenyl group, are mentioned, for example.

Specific examples of the —OR _a group include an acetoxy group, a benzoyloxy group, a benzyloxy group, a methoxymethyloxy group, a trimethylsilyloxy group, a methoxy group, and a phenoxy group.

Specific examples of the —SR _b group include an acetylthio group, a benzoylthio group, a benzylthio group, a methoxymethylthio group, a trimethylsilylthio group, a methylthio group, and a phenylthio group.

R _{c in the} —COOR _c group represents a hydrogen atom, an alkyl group or an aralkyl group. As an alkyl group, C1-C10 alkyl groups, such as a methyl group, an ethyl group, n-propyl group, an isopropyl group, are mentioned, for example. Examples of the aralkyl group include an aralkyl group having 7 to 20 carbon atoms such as a benzyl group.

Specific examples of the —COOR _c group include a methoxycarbonyl group, an ethoxycarbonyl group, and a benzyloxycarbonyl group.

R ₃ and R ₄ are preferably both hydrogen atoms.

R ₅ and R ₆ are preferably both hydrogen atoms.

When R ₃ and R ₄ are both hydrogen atoms, R represents a substituted methylene group or an optionally substituted polymethylene group, and at least one of R ₃ and R ₄ is a substituent other than a hydrogen atom. In some cases, R represents a methylene group which may have a substituent or a polymethylene group which may have a substituent, and one methylene group constituting the polymethylene group or two methylene groups which are not adjacent to each other are oxygen atoms. Or one or two ethylene groups constituting the polymethylene group may be replaced by vinylene groups, and two methylene groups that are not adjacent to each other constituting the polymethylene group are oxygen atoms, methylene groups, It may be bonded via an ethylene group or vinylene group.

The carbon number of the polymethylene group represented by R is in the range of 2-4. Examples of the substituent that may be substituted on the methylene group or polymethylene group represented by R include a halogen atom, a cyano group, an alkyl group, an alkenyl group, an aryl group, and an amino group that may have a substituent. , -OR _e group, -SR _f group or -COOR _g group, R _e , R _f and R _g are each independently a hydrogen atom, an alkylcarbonyl group, an arylcarbonyl group, an aralkyl group, an alkoxyalkyl group. Represents a trialkylsilyl group, an alkyl group or an aryl group.

  As a halogen atom, a chlorine atom, a bromine atom, a fluorine atom, an iodine atom etc. are mentioned, for example.

  As an alkyl group, C1-C10 alkyl groups, such as a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, are mentioned, for example.

  Examples of the alkenyl group include alkenyl groups having 2 to 10 carbon atoms such as vinyl group, ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group and 3-butenyl group. .

  As an aryl group, C6-C20 aryl groups, such as a phenyl group and a naphthyl group, are mentioned, for example.

  Examples of the substituent that may be present on the amino group include alkylcarbonyl groups such as acetyl group; arylcarbonyl groups such as benzoyl group; alkyl groups such as methyl group and ethyl group; aralkyl groups such as benzyl group; and alkoxycarbonyl groups such as tert-butoxycarbonyl group; aralkyloxycarbonyl groups such as benzyloxycarbonyl group; and the like. Specific examples of the amino group having such a substituent include acetylamino group, benzoylamino group, methylamino group, dimethylamino group, benzylamino group, tert-butoxycarbonylamino group, and benzyloxycarbonylamino group.

  As an alkylcarbonyl group, C2-C10 alkylcarbonyl groups, such as an acetyl group, are mentioned, for example.

  Examples of the arylcarbonyl group include arylcarbonyl groups having 7 to 20 carbon atoms such as a benzoyl group.

  Examples of the aralkyl group include an aralkyl group having 7 to 20 carbon atoms such as a benzyl group.

  As an alkoxyalkyl group, C2-C10 alkoxyalkyl groups, such as a methoxymethyl group, are mentioned, for example.

  Examples of the trialkylsilyl group include a trialkylsilyl group having 3 to 10 carbon atoms such as a trimethylsilyl group.

Specific examples of the —OR _e group include an acetoxy group, a benzoyloxy group, a benzyloxy group, a methoxymethyloxy group, a trimethylsilyloxy group, a methoxy group, and a phenoxy group.

Specific examples of the —SR _f group include an acetylthio group, a benzoylthio group, a benzylthio group, a methoxymethylthio group, a trimethylsilylthio group, a methylthio group, and a phenylthio group.

Specific examples of the —COOR _g group include a methoxycarbonyl group, an ethoxycarbonyl group, and a benzyloxycarbonyl group.

  Specific examples of R include, for example, a divalent group represented by the following formula.

（上記各式中、−は１つの結合手を表し、＞および＜はそれぞれ２つの結合手を表す。） _{-CH 2 -, - (CH 2} ) 2 -, - (CH 2) 3 -, - (CH 2) 4 -, (CH 3) 2 C <, (Cl) 2 C <, (F) 2 C <,> CH (CO ₂ C ₂ H ₅ )

(In the above formulas,-represents one bond, and> and <each represent two bonds.)

Examples of the lactones (2) include 3-oxabicyclo [3.2.0] heptan-2-one, 3-oxabicyclo [3.3.0] octane-2-one, and 8-oxabicyclo [4. .3.0] Nonan-7-one, 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one, 6,6-dichloro-3-oxabicyclo [3.1.0] ] Hexan-2-one, 6,6-difluoro-3-oxabicyclo [3.1.0] hexane-2-one, 6-ethoxycarbonyl-3-oxabicyclo [3.1.0] hexane-2- ON, 1-phenyl-3-oxabicyclo [3.1.0] hexane-2-one, 4-oxatricyclo [5.2.1.0 ^2,6 ] dec-3-one, 4-oxatri Cyclo [5.2.2.0 ^2,6 ] undec-3-one , 8-oxabicyclo [4.3.0] nonane-3-en-7-one, 4-oxatricyclo [5.2.1.0 ^2,6 ] dec-8-en-3-one, 4, -Oxatricyclo [5.2.2.0 ^2,6 ] undec-8-en-3-one, 3,3-dimethyl-2,4,7-trioxabicyclo [3.3.0] octane- 6-one, 3-phenyl-2,4,7-trioxabicyclo [3.3.0] octane-6-one, 3,3-dimethyl-2,7-dioxabicyclo [3.3.0] Octane-6-one, 4,10-dioxatricyclo [5.2.1.0 ^2,6 ] dec-3-one, 4,10-dioxatricyclo [5.2.1.0 ^{2, 6} ] Dec-8-en-3-one and the like. These compounds may have two or more stereoisomers, and any stereoisomer may be used in the present invention.

  The lactone (2) may be a commercially available product or may be synthesized according to a known method.

In formulas (3a), (3b) and (3c), A _{1 to} A ₁₀ may each independently have a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an alkenyl group or a substituent. Represents an aryl group, an optionally substituted acyl group or —OR _d group, and R _d represents a hydrogen atom, an alkylcarbonyl group, an arylcarbonyl group, an aralkyl group, an alkoxyalkyl group, a trialkylsilyl group, an alkyl Represents a group or an aryl group, and M represents a hydrogen atom or an alkali metal atom. Any two of A _{5 to} A _{8 on} the same molecule may be combined to form a cyclic structure with the carbon atom to which they are bonded, and A ₉ and A ₁₀ are combined to form A cyclic structure may be formed together with the carbon atoms to be bonded.

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

  As an alkyl group, C1-C10 alkyl groups, such as a methyl group, an ethyl group, n-propyl group, an isopropyl group, n-butyl group, a cyclohexyl group, are mentioned, for example.

  As an alkenyl group, C2-C4 alkenyl groups, such as a vinyl group, an ethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, are mentioned, for example.

  As an aryl group, C6-C20 aryl groups, such as a phenyl group and a naphthyl group, are mentioned, for example. Examples of the substituent which may be present on these aryl groups include halogen atoms such as fluorine atom and chlorine atom; alkoxy groups such as methoxy group; methyl group, ethyl group, n-propyl group, isopropyl group, n -An alkyl group such as a butyl group; an aryl group such as a phenyl group or a naphthyl group; a hydroxy group; a nitro group; a cyano group; Specific examples of the aryl group having such a substituent include 4-fluorophenyl group, 3,4-dichlorophenyl group, 4-methoxyphenyl group, p-tolyl group, 3-biphenyl group, 2-hydroxyphenyl group, 3- A nitrophenyl group, 4-cyanophenyl group, etc. are mentioned.

  As an acyl group, C2-C10 acyl groups, such as an acetyl group, a pivaloyl group, a benzoyl group, are mentioned, for example. Examples of the substituent which may be present on these acyl groups include halogen atoms such as fluorine atom and chlorine atom. Specific examples of the acyl group having such a substituent include a chloroacetyl group.

  As an alkylcarbonyl group, C2-C10 alkylcarbonyl groups, such as an acetyl group, are mentioned, for example. Examples of the arylcarbonyl group include arylcarbonyl groups having 7 to 20 carbon atoms such as a benzoyl group. Examples of the aralkyl group include an aralkyl group having 7 to 20 carbon atoms such as a benzyl group. As an alkoxyalkyl group, C2-C10 alkoxyalkyl groups, such as a methoxymethyl group, are mentioned, for example. Examples of the trialkylsilyl group include a trialkylsilyl group having 3 to 10 carbon atoms such as a trimethylsilyl group.

Specific examples of the —OR _d group include an acetoxy group, a benzoyloxy group, a benzyloxy group, a methoxymethyloxy group, a trimethylsilyloxy group, a methoxy group, and a phenoxy group.

Examples of the cyclic structure that any two of A _{5 to} A _{8 on} the same molecule may form together with the carbon atom to which they are bonded include, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, A cyclohexane ring, a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, etc. are mentioned. Examples of the cyclic structure which A ₉ and A ₁₀ may be formed together with the carbon atom to which they are bonded include a cyclobutene ring, a cyclopentene ring, a cyclohexene ring, and the like.

  Examples of the alkali metal atom represented by M include sodium and potassium.

  Among the imides (3), examples of the imides represented by the formula (3a) (hereinafter sometimes abbreviated as imides (3a)) include phthalimide, 4,5-dichlorophthalimide, and 4-nitrophthalate. Examples of imides represented by the formula (3b) (hereinafter sometimes abbreviated as imides (3b)) include, for example, succinimide, 3-acetyloxy-2,5-pyrrolidinedione. 3,3,4,4-tetramethyl-2,5-pyrrolidinedione, 4-cyclohexene-1,2-dicarboxylic imide, hexahydrophthalimide and the like, and imides represented by the formula (3c) And imides (3c) may be abbreviated as 3,4,5,6-tetrahydrophthalimide, maleic imide, 2,3-dimethylmaleic acid. Bromide, and the like. These imides (3) may be alkali metal salts such as sodium salts and potassium salts.

  The imides (3) may be commercially available, or may be synthesized according to a known method. Of the imides (3), the imides (3a) are preferable, phthalimide, sodium phthalimide, and potassium phthalimide are more preferable, and potassium phthalimide is more preferable.

  The usage-amount of imides (3) is 0.8-5 times mole normally with respect to lactones (2), Preferably it is the range of 1-2 mole times.

  The reaction of the lactone (2) and the imide (3) is usually carried out in the presence of a solvent.

（式中、Ｂ_１およびＢ_２は、それぞれ独立して水素原子または炭素数１〜５のアルキル基を表し、Ｂ_３は水素原子、炭素数１〜１０のアルキル基または炭素数６〜２０のアリール基を表し、Ｂ_２とＢ_３が一緒になって、Ｂ_２が結合する窒素原子およびＢ_３が結合する炭素原子と共に環状構造を形成していてもよい。）
で示されるアミド溶媒（以下、アミド溶媒（６）と略記することもある。）が好ましく用いられる。溶媒は、単独で用いてもよいし、２種以上を同時に用いてもよい。溶媒の使用量は、ラクトン類（２）に対して、通常は０．５〜５０重量倍、好ましくは１〜１０重量倍の範囲である。 Such a solvent is not particularly limited as long as it is inert to the reaction. For example, a nitrile solvent such as acetonitrile or an ether solvent such as tetrahydrofuran can be used.

(In the formula, B ₁ and B ₂ each independently represent a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and B ₃ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or an alkyl group having 6 to 20 carbon atoms. Represents an aryl group, and B ₂ and B ₃ may be combined to form a cyclic structure together with the nitrogen atom to which B ₂ is bonded and the carbon atom to which B ₃ is bonded.
An amide solvent represented by the following (hereinafter sometimes abbreviated as amide solvent (6)) is preferably used. A solvent may be used independently and may use 2 or more types simultaneously. The usage-amount of a solvent is 0.5-50 weight times normally with respect to lactone (2), Preferably it is the range of 1-10 weight times.

In formula (6), examples of the alkyl group having 1 to 5 carbon atoms represented by B ₁ and B ₂ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, and an n-butyl group.

Examples of the alkyl group having 1 to 10 carbon atoms represented by B ₃ include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, and an n-heptyl group. , N-octyl group and the like.

  Examples of the aryl group having 6 to 20 carbon atoms include a phenyl group and a tolyl group.

B ₃ is preferably an alkyl group having 1 to 10 carbon atoms or an aryl group having 6 to 20 carbon atoms.

Examples of the cyclic structure that may be formed together with the nitrogen atom to which B ₂ is bonded and the carbon atom to which B ₃ is bonded together with B ₂ and B ₃ include a 2-azetidinone ring, a 2-pyrrolidinone ring, 2 -A piperidinone ring, a 2-pyridone ring, etc. are mentioned.

  Examples of the amide solvent (6) include N, N-dimethylformamide, N-methylacetamide, N, N-dimethylacetamide, N, N-dimethylpropionamide, N, N-dimethylbutyramide, N, N-dimethyl. Examples include acrylamide, 1-methyl-2-pyrrolidinone, 1-methyl-2-piperidone, N-methylcaprolactam, 1-methyl-2-pyridone, and N, N-dimethylacetamide is preferable.

  This reaction is carried out by mixing the imides (3) and the lactones (2) under the reaction temperature conditions described later in the presence of a solvent as necessary. The order of mixing is not particularly limited, and can be carried out, for example, by a method of adding the lactone (2) to the imide (3) in the presence of a solvent within the reaction temperature range, if necessary.

  When M in the imide (3) is a hydrogen atom, the reaction is preferably carried out in the presence of a base.

  Examples of the base include alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal hydroxides such as sodium hydride and potassium hydride. Products; alkali metals such as metallic sodium and metallic potassium; and the like. The usage-amount of a base is 0.5-10 mol times normally with respect to imides (3), Preferably it is the range of 1-5 mol times.

  The order of mixing in the case of using a base is not particularly limited. For example, the base and the imide (3) are mixed in the presence of a solvent as necessary, and the lactones ( 2) a method of adding; a method of adding a mixture of imides (3) and lactones (2) to a base in the presence of a solvent, if necessary, within the reaction temperature range; it can.

  The reaction temperature is usually in the range of 50 to 300 ° C, preferably 80 to 200 ° C. The progress of the reaction can be confirmed by ordinary analytical means such as gas chromatography, high performance liquid chromatography, thin layer chromatography, NMR, IR and the like.

（各式中、Ｒ、Ｒ_３〜Ｒ_６、Ａ₁〜Ａ_１０およびＭは、上記と同じ意味を表す。）
で示されるカルボン酸類（以下、総じてカルボン酸類（４）と略記することもある。）が得られる。すなわちイミド類（３）として、イミド類（３ａ）を用いれば式（４ａ）で示されるカルボン酸類（以下、カルボン酸類（４ａ）と略記することもある。）が、イミド類（３ｂ）を用いれば式（４ｂ）で示されるカルボン酸類（以下、カルボン酸類（４ｂ）と略記することもある。）が、イミド類（３ｃ）を用いれば式（４ｃ）で示されるカルボン酸類（以下、カルボン酸類（４ｃ）と略記することもある。）が、それぞれ得られる。 Compounds obtained by the reaction of lactones (2) and imides (3) are usually represented by the formulas (4a), (4b) and (4c).

(In each formula, R, R _{3 to} R ₆ , A _{1 to} A ₁₀ and M represent the same meaning as described above.)
(Hereinafter, sometimes collectively abbreviated as carboxylic acids (4)). That is, when the imide (3a) is used as the imide (3), the carboxylic acid represented by the formula (4a) (hereinafter sometimes abbreviated as carboxylic acid (4a)) is used as the imide (3b). If the carboxylic acid represented by formula (4b) (hereinafter sometimes abbreviated as carboxylic acid (4b)) is imide (3c), the carboxylic acid represented by formula (4c) (hereinafter referred to as carboxylic acid). (Sometimes abbreviated as (4c)).

  Of the carboxylic acids (4) thus obtained, examples of the carboxylic acids (4a) include 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclobutanecarboxylic acid. 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopentanecarboxylic acid, 2-[(1,3-dihydro-1,3-dioxo-2H -Isoindol-2-yl) methyl] cyclohexanecarboxylic acid, 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid Acid, 2,2-dichloro-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid, 2, -Difluoro-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid, 2-ethoxycarbonyl-3-[(1,3-dihydro- 1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid, 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl]- 1-phenylcyclopropanecarboxylic acid, 3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -bicyclo [2.2.1] heptane-2-carboxylic acid , 3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -bicyclo [2.2.2] octane-2-carboxylic acid, 6-[(1, 3 Dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -cyclohex-3-enecarboxylic acid, 3-[(1,3-dihydro-1,3-dioxo-2H-isoindole-2 -Yl) methyl] -bicyclo [2.2.1] hept-5-ene-2-carboxylic acid, 3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) Methyl] -bicyclo [2.2.2] oct-5-ene-2-carboxylic acid, 5-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl]- 2,2-Dimethyl-1,3-dioxolane-4-carboxylic acid, 5-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -2-phenyl-1 , 3-Dioxolane-4-carboxylic acid 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -5,5-dimethyltetrahydrofuran-3-carboxylic acid, 3-[(1,3-dihydro -1,3-dioxo-2H-isoindol-2-yl) methyl] -7-oxabicyclo [2.2.1] heptane-2-carboxylic acid, 3-[(1,3-dihydro-1,3 -Dioxo-2H-isoindol-2-yl) methyl] -7-oxabicyclo [2.2.1] hept-5-ene-2-carboxylic acid, 2,2-dimethyl-3-[(5,6 -Dichloro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid, 2,2-dimethyl-3-[(1,3-dihydro-5-nitro -1,3-dioxo-2H-iso Ndoru 2-yl) methyl] alkali metal salts as well as their optically active substances such as sodium salts and potassium salts of cyclopropanecarboxylic acid and the like and the above-exemplified compounds, and the like.

  Examples of the carboxylic acids (4b) include 2,2-dimethyl-3-[(2,5-dioxo-1-pyrrolidinyl) methyl] cyclopropanecarboxylic acid, 2,2-dimethyl-3-[(3-acetyloxy -2,5-dioxo-1-pyrrolidinyl) methyl] cyclopropanecarboxylic acid, 2,2-dimethyl-3-[(3,3,4,4-tetramethyl-2,5-dioxo-1-pyrrolidinyl) methyl Cyclopropanecarboxylic acid, 2,2-dimethyl-3-[(3a, 4,7,7a-tetrahydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid, 2, 2-dimethyl-3-[(hexahydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid and the like and the above exemplified compounds Alkali metal salts and their optically active forms, such as potassium salt, potassium salt and the like.

  Examples of the carboxylic acids (4c) include 2,2-dimethyl-3-[(4,5,6,7-tetrahydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid. 2,2-dimethyl-3-[(1,3-dioxo-2H-pyrrol-2-yl) methyl] cyclopropanecarboxylic acid, 2,2-dimethyl-3-[(4,5-dimethyl-1, 3-dioxo-2H-pyrrol-2-yl) methyl] cyclopropanecarboxylic acid and the like, alkali metal salts such as sodium salts and potassium salts of the above exemplified compounds, and optically active substances thereof.

  After completion of the reaction, the obtained reaction mixture may be directly subjected to a reaction with an alcohol described later, or may be subjected to a post-treatment. As such post-treatment operation, for example, an operation of precipitating an alkali metal salt of the carboxylic acid (4) by crystallization treatment and isolating the precipitate by filtration treatment; an operation of removing inorganic salt by filtration treatment; necessary After neutralizing the reaction mixture with an acid in the presence of water and / or an organic solvent that can be separated from water and / or water, and then separating the organic layer from the treated product by liquid separation, etc. It is done. The processed product obtained by the above-mentioned post-treatment may be used as it is in the esterification described later, or may be used after isolating the carboxylic acid (4) by a concentration treatment or the like, or the isolated carboxylic acid ( 4) may be used after further purification treatment such as recrystallization treatment and column chromatography.

  Examples of the organic solvent that can be separated from water include aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane; aromatic hydrocarbon solvents such as toluene and xylene; methyl-tert-butyl ether, 1,2-dimethoxyethane, and the like. Ether solvents; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chlorobutane, monochlorobenzene and dichlorobenzene; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; . These solvents may be used alone or in combination of two or more.

  The amount of the organic solvent separable from water is usually 1 to 100 times by weight, preferably 2 to 20 times by weight with respect to the lactone (2).

  Examples of the acid used in the post-treatment operation include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; organic acids such as acetic acid, citric acid, and methanesulfonic acid. When M in the imides (3) used in the reaction is an alkali metal atom, the amount of the acid used is usually 0.5 to 3 mol times, preferably 1 to 2 mol times with respect to the alkali metal atom. It is a range. Moreover, when using a base for reaction, it is 0.5-3 mol times normally with respect to this base, Preferably it is the range of 1-2 mol times.

  The temperature during the post-treatment is not particularly limited as long as it is a temperature at which the phthaloyl group in the imides described above does not undergo hydrolysis. When water coexists, it is usually in the range of 0 to 100 ° C, preferably 10 to 80 ° C.

  Next, esterification of the carboxylic acids (4) obtained by the above reaction will be described.

This esterification may be performed by a general method for esterifying a carboxylic acid or a salt thereof. The reaction reagent used for esterification is usually represented by the formula (7)
R ₇ -OH ₍₇₎
(In the formula, R ₇ represents an alkyl group, an alkenyl group, or an aralkyl group which may have a substituent.)
(Hereinafter abbreviated as alcohols (7)), and the formula (8)
R ₇ -X (8)
(In the formula, R ₇ represents the same meaning as described above, and X represents a chlorine atom, a bromine atom or an iodine atom.)
And the like (hereinafter abbreviated as halide (8)) and the like.

As the alkyl group represented by R ₇ , for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or the like, An alkyl group is mentioned, As an alkenyl group, C2-C10 alkenyl groups, such as an allyl group and 3-butenyl group, are mentioned, for example.

  Examples of the aralkyl group include an aralkyl group having 7 to 20 carbon atoms such as a benzyl group. Examples of the substituent which may be present on these aralkyl groups include halogen atoms such as fluorine atom and chlorine atom; alkoxy groups such as methoxy group; methyl group, ethyl group, n-propyl group, isopropyl group, n- An alkyl group such as a butyl group; a nitro group; a cyano group; and the like. Specific examples of the aralkyl group having such a substituent include 4-fluorobenzyl group, 3,4-dichlorobenzyl group, 4-methoxybenzyl group, 4-methylbenzyl group, 4-nitrobenzyl group, 4-cyanobenzyl group. Etc.

  Examples of alcohols (7) include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol, allyl alcohol, and benzyl alcohol. And p-methoxybenzyl alcohol.

  Examples of the halide (8) include bromoethane, 1-bromopropane, 2-bromopropane, 1-bromobutane, 2-bromobutane, 1-bromo-2-methylpropane, 2-bromo-2-methylpropane, and allyl bromide. , Benzyl bromide, p-methoxybenzyl bromide, and compounds in which the bromine atom in the above exemplary compounds is substituted with a chlorine atom or an iodine atom, respectively.

  The amount of the alcohol (7) or halide (8) used may be 1 mole or more with respect to the carboxylic acid (4), and it can also be used in excess as a solvent. Usually, it is 1-100 mol times, Preferably it is the range of 2-50 mol times.

  This esterification may be carried out in the presence of a solvent. Examples of such solvents include aliphatic hydrocarbon solvents such as hexane, heptane and cyclohexane; aromatic hydrocarbon solvents such as toluene and xylene; tetrahydrofuran, methyl-tert-butyl ether, 1,4-dioxane, 1,2-dimethoxyethane. Ether solvents such as: halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, chlorobutane, monochlorobenzene, dichlorobenzene; and the like. The amide solvent (6) can also be used. These may be used alone or in combination of two or more. The usage-amount of a solvent is 0.01-100 weight times normally with respect to carboxylic acids (4), Preferably it is the range of 0.1-20 weight times.

  When the carboxylic acid (4) and the alcohol (7) are reacted, specific esterification methods include, for example, a method using an acid catalyst; a method using a chlorinating agent; a method using a dehydrating condensing agent; A method using alkyl carbonate; and the like.

  Examples of the acid catalyst include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid; organic acids such as p-toluenesulfonic acid and camphor-10-sulfonic acid; and acidic ion exchange such as amberlite and amberlist. Resin; and the like. The amount of the acid catalyst such as an inorganic acid or organic acid used is usually 0.01 to 1 mole times the amount of the carboxylic acid (4), and the amount of the acid catalyst such as an ion exchange resin used for the carboxylic acid (4). On the other hand, it is usually in the range of 0.01-1 weight times.

  Examples of the chlorinating agent include thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride and the like. The usage-amount of a chlorinating agent is 0.8-10 mol times normally with respect to carboxylic acids (4), Preferably it is the range of 1-5 mol times.

  Examples of the dehydrating condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopyrrolyl) -carbodiimide and the like. The usage-amount of a dehydration condensing agent is 0.8-10 mol times normally with respect to carboxylic acids (4), Preferably it is the range of 1-5 mol times.

  Examples of the alkyl chlorocarbonate include ethyl chlorocarbonate and isopropyl chlorocarbonate. The amount of alkyl chlorocarbonate used is usually in the range of 0.8 to 10 mol times, preferably 1 to 5 mol times relative to the carboxylic acids (4).

  When the halide (8) is used, esterification proceeds normally when the carboxylic acid (4) and the halide (8) are mixed, but M in the formulas (4a), (4b) and (4c) is hydrogen. When it is an atom, esterification is preferably performed in the presence of an organic solvent and a base.

  Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate Alkali metal alkoxides such as sodium methoxide and sodium ethoxide; alkali metal hydroxides such as sodium hydride and potassium hydride; triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7 And organic bases such as ene and pyridine. The usage-amount of a base is 0-10 mol times normally with respect to carboxylic acids (4), Preferably it is the range of 1-5 mol times.

  Among the esterification methods, a method using an alcohol (7) is preferable, and a method in which a carboxylic acid (4) and an alcohol (7) are reacted using a chlorinating agent is more preferable. As a specific embodiment, for example, a mode in which a chlorinating agent is added to a mixture containing carboxylic acids (4) and alcohols (7); a chlorinating agent is added to carboxylic acids (4), and alcohol is added thereto. A mode in which the class (7) is added;

  The reaction temperature for esterification varies depending on the method used, but is usually in the range of -20 to 100 ° C, preferably 0 ° C or higher, and below the boiling point of the alcohol (7) or solvent.

（各式中、Ｒ、Ｒ_３〜Ｒ_７およびＡ₁〜Ａ_１０は、上記と同じ意味を表す。）
のいずれかで示されるエステル類（以下、総じてエステル類（５）と略記することもある。）が得られる。すなわち、カルボン酸類（４）として、カルボン酸類（４ａ）を用いれば式（５ａ）で示されるエステル類（以下エステル類（５ａ）と略記することもある。）が、カルボン酸類（４ｂ）を用いれば式（５ｂ）で示されるエステル類（以下エステル類（５ｂ）と略記することもある。）が、カルボン酸類（４ｃ）を用いれば式（５ｃ）で示されるエステル類（以下エステル類（５ｃ）と略記することもある。）が、それぞれ得られる。 Such esterification usually results in formulas (5a), (5b) and (5c)

(In each formula, R, R _{3 to} R ₇ and A _{1 to} A ₁₀ represent the same meaning as described above.)
(Hereinafter sometimes abbreviated as “esters (5)”). That is, if the carboxylic acid (4a) is used as the carboxylic acid (4), the ester represented by the formula (5a) (hereinafter sometimes abbreviated as ester (5a)) is used as the carboxylic acid (4b). For example, an ester represented by the formula (5b) (hereinafter sometimes abbreviated as an ester (5b)) may be converted into an ester represented by the formula (5c) (hereinafter referred to as an ester (5c)) by using a carboxylic acid (4c). ) May be abbreviated as ")", respectively.

  The reaction mixture after the esterification reaction can be used for the reaction with the next amine as it is, or can be used after, for example, post-treatment such as washing treatment, concentration treatment, crystallization treatment, and filtration treatment. .

  Specific operations of such post-treatment include, for example, crystallization of the esters (5) by concentrating the reaction mixture or mixing a solvent that does not substantially dissolve the esters (5) with the reaction mixture. And an operation of isolating the esters (5) by filtering the resulting mixture. When crystals of esters (5) are precipitated in the reaction mixture, the reaction mixture may be filtered as it is. Moreover, the operation which mixes the reaction mixture after esterification with the organic solvent which can be liquid-separated as needed, and wash-processes using water, basic aqueous solution, etc. is also mentioned. Before performing the washing treatment, the reaction mixture may be concentrated in advance. Moreover, you may perform this washing | cleaning operation repeatedly. The mixture after the washing treatment may be subjected to the reaction with the next amine as it is, or may be used after being isolated by the above-mentioned method, for example. The isolated esters (5) may be further purified by ordinary treatment such as column chromatography and recrystallization.

  Examples of organic solvents that can be separated from water include aliphatic hydrocarbon solvents such as hexane, heptane and cyclohexane; aromatic solvents such as toluene, xylene, monochlorobenzene and dichlorobenzene; methyl-tert-butyl ether, 1,2 -Ether solvents such as dimethoxyethane; Halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chlorobutane; Ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; Ester solvents such as methyl acetate, ethyl acetate and butyl acetate; The amount of the organic solvent that can be separated from water is usually in the range of 1 to 100 times by weight, preferably 2 to 20 times by weight with respect to the carboxylic acids (4).

  Examples of the base used as the basic aqueous solution include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metals such as sodium hydrogen carbonate and potassium hydrogen carbonate Bicarbonates; alkali metal phosphates such as trisodium phosphate, disodium hydrogen phosphate, tripotassium phosphate, and dipotassium hydrogen phosphate; organic bases such as pyridine and triethylamine; ammonia; The amount of base used is not particularly limited. When esterification is performed by a method of reacting the carboxylic acid (4) and the alcohol (7) using a chlorinating agent, the amount of the base used for the washing treatment is based on the chlorinating agent used for the esterification. The range is usually 0.5 to 20 mole times, preferably 1 to 10 mole times.

  The washing treatment described above is preferably performed in a pH range where the ester bond and amide bond of the esters (5) are not subject to hydrolysis. Such a pH range is usually in the range of pH 1-10.

  Among the esters (5) thus obtained, examples of the esters (5a) include 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclobutanecarboxylic acid. Methyl, methyl 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopentanecarboxylate, 2-[(1,3-dihydro-1,3-dioxo -2H-isoindol-2-yl) methyl] methyl cyclohexanecarboxylate, 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] Methyl cyclopropanecarboxylate, 2,2-dichloro-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopro Methyl 2-carboxylate, 2,2-difluoro-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate, 2-ethoxycarbonyl-3- [(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate methyl, 2-[(1,3-dihydro-1,3-dioxo-2H-iso Indol-2-yl) methyl] -1-phenylcyclopropanecarboxylate, 3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -bicyclo [2. 2.1] methyl heptane-2-carboxylate, 3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -bicyclo [2 2.2] methyl octane-2-carboxylate, methyl 6-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -cyclohex-3-enecarboxylate, 3 -[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -bicyclo [2.2.1] methyl hept-5-ene-2-carboxylate, 3- [ (1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -bicyclo [2.2.2] oct-5-ene-2-carboxylate, 5-[(1 , 3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -2,2-dimethyl-1,3-dioxolane-4-carboxylate, 5-[(1,3-dihydro -1,3-dioxo-2H-isoy Ndol-2-yl) methyl] -2-phenyl-1,3-dioxolane-4-carboxylate, 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) Methyl] -5,5-dimethyltetrahydrofuran-3-carboxylate, 3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -7-oxabicyclo [2 2.1] methyl heptane-2-carboxylate, 3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -7-oxabicyclo [2.2. 1] methyl hepta-5-ene-2-carboxylate, 2,2-dimethyl-3-[(5,6-dichloro-1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl ) Methyl] cyclo Methyl lopancarboxylate, methyl 2,2-dimethyl-3-[(1,3-dihydro-5-nitro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate, and the above examples The methyl ester portion of the compound is ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, allyl ester, 3-butenyl ester, benzyl ester and p-methoxy. Examples include compounds in which benzyl esters are substituted, and optically active forms of these compounds.

  Examples of the esters (5b) include methyl 2,2-dimethyl-3-[(2,5-dioxo-1-pyrrolidinyl) methyl] cyclopropanecarboxylate, 2,2-dimethyl-3-[(3-acetyl Oxy-2,5-dioxo-1-pyrrolidinyl) methyl] cyclopropanecarboxylate, 2,2-dimethyl-3-[(3,3,4,4-tetramethyl-2,5-dioxo-1-pyrrolidinyl) ) Methyl] cyclopropanecarboxylic acid methyl, 2,2-dimethyl-3-[(3a, 4,7,7a-tetrahydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid Methyl, 2,2-dimethyl-3-[(hexahydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid methyl Etc. and the methyl ester part of the above exemplified compounds are ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, allyl ester, 3-butenyl ester, benzyl ester And compounds in which p-methoxybenzyl ester is substituted, and optically active forms of these compounds.

  Examples of the esters (5c) include 2,2-dimethyl-3-[(4,5,6,7-tetrahydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid. Methyl, 2,2-dimethyl-3-[(1,3-dioxo-2H-pyrrol-2-yl) methyl] cyclopropanecarboxylate, 2,2-dimethyl-3-[(4,5-dimethyl- 1,3-dioxo-2H-pyrrol-2-yl) methyl] cyclopropanecarboxylate and the like and the above-mentioned exemplified compounds are ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, sec- Butyl ester, tert-butyl ester, allyl ester, 3-butenyl ester, benzyl ester and p-methoxy Compound was replaced by benzyl esters and optically active forms thereof and the like compounds.

  Next, reaction of ester (5) and amines is demonstrated.

As amines, for example, the formula (8)
R ₈ —NH ₂ (8)
(In the formula, R ₈ represents an amino group which may have a substituent, or an alkyl group which may be substituted with an amino group.)
And amines represented by

Examples of the amino group which may have a substituent represented by R ₈ in Formula (8) include an amino group, a methylamino group, an ethylamino group, and a phenylamino group. Among the alkyl groups that may be substituted with an amino group, examples of the unsubstituted alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, C1-C5 alkyl groups, such as a tert- butyl group, are mentioned. Examples of the alkyl group substituted with an amino group on the alkyl group include a 2-aminoethyl group and an N, N-dimethyl-3-aminopropyl group.

  Examples of the amines include hydrazines such as hydrazine, methyl hydrazine, ethyl hydrazine, and phenyl hydrazine and hydrates thereof; methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec- And alkylamines such as butylamine, tert-butylamine, 1,2-ethylenediamine, N, N-dimethyl-1,3-propanediamine; and the like.

  The usage-amount of the said amine is 1-10 mol times normally with respect to ester (5), Preferably it is the range of 1-5 mol times.

  The reaction between the esters (5) and the amines is usually performed in the presence of a solvent. As the solvent, water, an organic solvent, or a mixed solvent of water and an organic solvent is used. Examples of the organic solvent include alcohol solvents such as methanol, ethanol, 2-propanol and ethylene glycol; amide solvents such as N, N′-dimethylformamide, N, N′-dimethylacetamide and N-methylpyrrolidinone; tetrahydrofuran, methyl -Ether solvents such as tert-butyl ether, 1,4-dioxane, 1,2-dimethoxyethane; amine solvents such as triethylamine, tri-n-butylamine and pyridine; nitrile solvents such as acetonitrile and propionitrile; dichloromethane, dichloroethane and chlorobutane Halogenated hydrocarbon solvent; aliphatic hydrocarbon solvent such as hexane, heptane, cyclohexane; aromatic solvent such as toluene, xylene, monochlorobenzene, dichlorobenzene; methyl acetate, ethyl acetate, butyl acetate Ester solvents such as Le; and the like. Two or more of these organic solvents may be used simultaneously. Among the above solvents, an organic solvent miscible with water or a mixed solvent of the organic solvent and water is preferably used. Examples of the water-miscible solvent include the alcohol solvent, the amide solvent, the ether solvent, the amine solvent, the nitrile solvent, and the like. The usage-amount of a solvent is 1-100 weight times normally with respect to ester (5), Preferably it is the range of 2-20 weight times.

  The mixing order of the esters (5) and the amines is not particularly limited. For example, the ester (5) and the amines are mixed in the presence of a solvent as necessary, and adjusted to a predetermined temperature. Or the method of adding the said amines or the solution containing this to the mixture which consists of ester (5) and a solvent, etc. are mentioned. The reaction temperature is usually in the range of 0 ° C. or higher and below the boiling point of the reaction system, preferably in the range of 10 to 100 ° C. The progress of the reaction can be confirmed by ordinary analytical means such as gas chromatography, high performance liquid chromatography, thin layer chromatography, NMR, IR and the like.

（式中、ＲおよびＲ₃〜Ｒ_６は、それぞれ上記と同じ意味を表す。）
で示される多環式ラクタム類（以下、ラクタム類（１）と略記する。）が得られる。 This reaction results in the formula (1)

(In the formula, R and R _{3 to} R ₆ each have the same meaning as described above.)
Is obtained (hereinafter abbreviated as lactams (1)).

  After completion of the reaction, the lactam (1) can be isolated by subjecting the resulting reaction mixture to post-treatment such as concentration treatment, washing treatment, and filtration treatment.

  The washing treatment is usually carried out in the presence of water and a solvent that can be separated. Examples of the solvent that can be separated from water include aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane; aromatic solvents such as toluene, xylene, monochlorobenzene, and dichlorobenzene; methyl-tert-butyl ether, 1,2- Ether solvents such as dimethoethane; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chlorobutane; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; ester solvents such as methyl acetate, ethyl acetate and butyl acetate; The amount of these solvents used is usually in the range of 1 to 100 times by weight, preferably 2 to 20 times by weight, relative to the esters (5).

  An acid is preferably used for the purpose of removing amines remaining in the reaction mixture. Examples of the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, citric acid, methanesulfonic acid, and p-toluenesulfonic acid. The amount of these acids used is usually in the range of 0.5 to 20 mol times, preferably 1 to 5 mol times relative to the remaining amines. Examples of a method for removing amines using such an acid include a method of washing a reaction mixture using an aqueous solution of an acid, mixing a reaction mixture and an acid to precipitate a salt of an amine, and filtering this. The method of removing by a process etc. are mentioned.

  For the purpose of removing reaction by-products, for example, when a by-product is precipitated in the reaction mixture obtained after completion of the reaction, the reaction mixture is filtered as it is or after being concentrated as necessary. What is necessary is just to process. Alternatively, a by-product may be precipitated from the reaction mixture using a solvent, and the mixture may be filtered. Such a solvent may be any solvent that can dissolve the lactams (1) and precipitate a by-product, such as aliphatic hydrocarbon solvents such as hexane, heptane, and cyclohexane; toluene, xylene, Aromatic solvents such as monochlorobenzene and dichlorobenzene; ether solvents such as methyl-tert-butyl ether and 1,2-dimethoxyethane; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chlorobutane; ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone; And ester solvents such as methyl acetate, ethyl acetate, and butyl acetate. The amount of these solvents used is usually in the range of 1 to 100 times by weight, preferably 2 to 20 times by weight, relative to the esters (5).

  The isolated lactams (1) may be further purified by ordinary methods such as column chromatography and recrystallization.

Examples of the lactams (1) include 3-azabicyclo [3.2.0] heptan-2-one, 3-azabicyclo [3.3.0] octan-2-one, and 8-azabicyclo [4.3. 0] nonan-7-one, 6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-one, 6,6-dichloro-3-azabicyclo [3.1.0] hexane-2- ON, 6,6-difluoro-3-azabicyclo [3.1.0] hexane-2-one, 6-ethoxycarbonyl-3-azabicyclo [3.1.0] hexane-2-one, 1-phenyl-3 -Azabicyclo [3.1.0] hexane-2-one, 4-azatricyclo [5.2.1.0 ^2,6 ] dec-3-one, 4-azatricyclo [5.2.2.0 ^2,6 ] Undec-3-one, 8-azabicyclo [ 4.3.0] nonan-3-en-7-one, 4-azatricyclo [5.2.1.0 ^2,6 ] dec-8-en-3-one, 4-azatricyclo [5.2.2 .0 ^2,6] undec-8-en-3-one, 3,3-dimethyl-2,4-dioxa-7-azabicyclo [3.3.0] octan-6-one, 3-phenyl-2, 4-dioxa-7-azabicyclo [3.3.0] octane-6-one, 3,3-dimethyl-2-oxa-7-azabicyclo [3.3.0] octane-6-one, 4-aza- 10-oxatricyclo [5.2.1.0 ^2,6 ] dec-3-one, 4-aza-10-oxatricyclo [5.2.1.0 ^2,6 ] dec-8-ene- Examples include 3-one and optically active substances of these compounds.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these examples.

Example 1
Synthesis example of (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid

29.70 g (235 mmol) of (1R, 5S) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one, 66.8 g of N, N-dimethylacetamide and 48.0 g of potassium phthalimide (259 mmol) was mixed, heated to 155 ° C., stirred for 9 hours, and (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H -Isoindole-2-yl) methyl] cyclopropanecarboxylic acid potassium salt was obtained. This solution was added dropwise at 15 ° C. to a mixed solution of 67 g of water and 104 g of toluene. Next, 26.5 g of 35% hydrochloric acid was added dropwise, and the temperature was raised to 60 ° C., followed by liquid separation. As an organic layer, 213 g of a solution was obtained.
In this solution, (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid 61 .96 g (227 mmol) was contained.
The yield based on (1R, 5S) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one was 96.3%.
Quantification of 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid was determined by high performance liquid chromatography. The column of the high performance liquid chromatograph was SUMPAX ODS D-210FF, 4.6 mmφ × 150 mm, 3 μm (manufactured by Sumika Chemical Analysis Co., Ltd.).

(1R, 3S) -2,2-Dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid has a melting point of 159-160. ° C.
^Also, mark the measurement result of 1 H-NMR (CDCl ₃₎ below.
δ = 7.69-7.89 m (4H), 4.17 dd (1H), 4.00 dd (1H), 1.54-1.66 m (2H), 1.41 s (3H), 1.18 s (3H) )

Example 2
Synthesis example of (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid

218 g (1.73 mol) of (1R, 5S) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one, 1090 g of N, N-dimethylacetamide and 352 g (1.90 mol) of potassium phthalimide ) And the temperature was raised to 155 ° C., followed by stirring for 17 hours. (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindole A reaction solution containing 2--2-yl) methyl] cyclopropanecarboxylic acid potassium salt was obtained. Next, the solvent was removed by concentration under reduced pressure, and 763 g of toluene was added. Furthermore, 693 g of 10% hydrochloric acid was added dropwise and mixed, followed by liquid separation. After the solvent was distilled off from the obtained organic layer by concentration under reduced pressure, 1275 g of methanol was added and (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H -Isoindole-2-yl) methyl] 2070 g of a solution containing 427 g (1.56 mol) of cyclopropanecarboxylic acid was obtained.
The yield based on (1R, 5S) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one was 90.5%.

Comparative Example 1
Synthesis example of (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid

(1R, 5S) -6,6-Dimethyl-3-oxabicyclo [3.1.0] hexane-2-one 0.50 g (4.0 mmol), potassium phthalimide 0.81 g and N-methyl-2-pyrrolidinone 5.0 g was mixed, heated to 160 ° C., stirred for 24 hours, and (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H -Isoindole-2-yl) methyl] cyclopropanecarboxylic acid potassium salt was obtained. After cooling the reaction solution, 3.2 g of 5% hydrochloric acid was added, and extracted twice with 10 g of methyl-tert-butyl ether to obtain (1R, 3S) -2,2-dimethyl-3-[(1,3 A solution containing 0.84 g (3.1 mmol) of -dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid was obtained.
The yield based on (1R, 5S) -6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one was 77.5%.

Comparative Example 2
Synthesis example of 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid

6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one 12.0 g (95 mmol), N, N-dimethylformamide 120 g and potassium phthalimide 17.6 g (95 mmol) were mixed and stirred. Reaction containing 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid potassium salt after heating to 155 ° C. A liquid was obtained. After the reaction solution was cooled to 25 ° C., 10.9 g of 35% hydrochloric acid was added dropwise, and 634 g of water was further added dropwise. After cooling this to 0 ° C., the resulting crystals were filtered. The crystals were washed with water and dried under reduced pressure to give 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid 23 .3 g was obtained.
The yield based on 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2-one was 84.5%.

The measurement result of ¹ H-NMR (DMSO) of 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid is shown below. To
δ = 7.60 to 8.15 m (4H), 4.04 m (1H), 3.78 dd (1H), 1.48 to 1.56 m (2H), 1.26 s (3H), 1.09 s (3H) )

Example 5
Synthesis example of methyl (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate

(1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] obtained in the same manner as in Example 1 Toluene was distilled off by concentrating 52.7 kg of a toluene solution containing 13.1 kg (46.8 mol) of cyclopropanecarboxylic acid under reduced pressure. 26.1 kg of methanol was added thereto, and the temperature was adjusted to 50 ° C., and then 6.8 kg of thionyl chloride was added dropwise and stirred for 19 hours. After adding 13.1 kg of toluene to the reaction solution, the reaction solution was added dropwise to a solution in which 4.9 kg of sodium bicarbonate was dissolved in 55.5 kg of water. Further, 52.3 kg of toluene was added, and the pH was adjusted to around 7 using 12.7 kg of 28% aqueous sodium hydroxide solution. The mixture was separated, and the resulting organic layer was concentrated under reduced pressure to distill off toluene. Then, 105 kg of methanol was added, and (1R, 3S) -2,2-dimethyl-3-[(1 , 3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] 125 kg of a solution containing 13.7 kg (47.6 mol) of methyl cyclopropanecarboxylate was obtained.
The yield based on (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid was 99.99. 2%.

  Determination of methyl (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate is a high performance liquid Obtained by chromatography. The column of the high performance liquid chromatograph was SUMPAX ODS D-210FF, 4.6 mmφ × 150 mm, 3 μm (manufactured by Sumika Chemical Analysis Co., Ltd.).

The melting point of methyl (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate is 85-85. It was 86 ° C.
^Also, mark the measurement result of 1 H-NMR (CDCl ₃₎ below.
δ = 7.68-7.88 m (4H), 4.17 dd (1 H), 3.97 dd (1 H), 3.71 s (3 H), 1.62 d (1 H), 1.44 to 1.59 m (1 H ), 1.37 s (3H), 1.15 s (3H)

Example 6
Synthesis example of methyl 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate

Mixing 30.3 g (110 mmol) of 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid with 130 g of methanol After adjusting the temperature to 50 ° C., 47.0 g of thionyl chloride was added dropwise and stirred for 5 hours. The reaction solution was concentrated under reduced pressure to distill off the solvent, 130 g of methanol was added, and the solution was concentrated under reduced pressure to distill off the solvent. The resulting solid was dried under reduced pressure to give methyl 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate 31. 5 g was obtained.
99% yield based on (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid.

The results of ¹ H-NMR (DMSO) measurement of methyl 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate Described below.
δ = 7.82-7.90 m (4H), 4.02 dd (1 H), 3.77 dd (1 H), 3.62 s (3 H), 1.65 d (1 H), 1.60 to 1.51 m (1 H ), 1.25 s (3H), 1.10 s (3H)

Example 7
Synthesis example of (1R-cis) -6,6-dimethyl-3-azabicyclo [3.1.0] hexan-2-one

(1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylic acid obtained in Example 5 125 kg of a methanol solution containing 13.6 kg (47.4 mol) of methyl and 5.4 kg (64 mol) of a 60% aqueous solution of hydrazine monohydrate were mixed, heated to 65 ° C., and stirred for 25 hours. The reaction solution was cooled to 25 ° C., 1.6 kg of 78% sulfuric acid was added, and the solvent was distilled off by concentration under reduced pressure. Furthermore, 54.5 kg of toluene was added, and the solvent was distilled off again by concentration under reduced pressure. After 47.7 kg of toluene was added thereto, the precipitated crystals were separated by filtration. The solvent was removed from the filtrate by concentration under reduced pressure, and 36 kg of a solution containing 5.94 kg (47 mol) of (1R-cis) -6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-one was obtained. Obtained.
Yield based on methyl (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate is 100% Met.
Quantification of (1R-cis) -6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-one was determined by high performance liquid chromatography. The column used was SUMPAX ODS D-210FF, 4.6 mmφ × 150 mm, 3 μm (manufactured by Sumika Chemical Analysis Service).

Example 8
Synthesis example of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-one

Methyl 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate obtained in Example 6 (97 mmol) ) And 222 g of methanol were added, 5.9 g (118 mmol) of hydrazine monohydrate was added thereto, and the temperature was adjusted to 78 ° C., followed by stirring for 21 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. To the obtained solid, 98 g of methyl-tert-butyl ether was added and stirred, and then the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to evaporate the solvent, and the resulting solid was dried under reduced pressure to obtain 11.1 g of 6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2-one.
The yield based on methyl 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] cyclopropanecarboxylate was 99%.

  Polycyclic lactams obtained by the production method of the present invention are useful compounds as chemical raw materials and intermediates for medicines and agricultural chemicals (see, for example, International Patent Publication WO 2004/113295).

Claims (11)

Formula (2)

(In the formula, R _{3 to} R ₆ are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. Represents an aryl group which may have _a group, an amino group which may have a substituent, an —OR _a group, an —SR _b group or a —COOR _c group, wherein R _a and R _b are each independently R ₃ represents a hydrogen atom, an alkylcarbonyl group, an arylcarbonyl group, an aralkyl group, an alkoxyalkyl group, a trialkylsilyl group, an alkyl group or an aryl group, and R _c represents a hydrogen atom, an alkyl group or an aralkyl group. And R ₄ are both hydrogen atoms, R represents a substituted methylene group or an optionally substituted polymethylene group, and at least one of R ₃ and R ₄ is a substituent other than a hydrogen atom. R represents a methylene group which may have a substituent or a polymethylene group which may have a substituent, and one or two methylene groups which are not adjacent to each other constitute an oxygen atom. One or two ethylene groups constituting the polymethylene group may be substituted with vinylene groups, and two methylene groups constituting the polymethylene group that are not adjacent to each other are oxygen atoms, methylene groups, ethylene. Or may be bonded via a vinylene group.)
A lactone represented by formula (3a), (3b) and (3c)

(In each formula, A _{1 to} A ₁₀ each independently have a hydrogen atom, a halogen atom, a nitro group, an alkyl group, an alkenyl group, an aryl group which may have a substituent, or a substituent. represent also an acyl group or an -OR _d group, R _d represents a hydrogen atom, an alkylcarbonyl group, an arylcarbonyl group, an aralkyl group, an alkoxyalkyl group, a trialkylsilyl group, an alkyl group or an aryl group, M is hydrogen An atom or an alkali metal atom, any two of A _{5 to} A ₈ on the same molecule may be combined to form a cyclic structure with the carbon atom to which they are bonded, and A ₉ and A ₁₀ Together may form a cyclic structure with the carbon atom to which they are attached.)
Is reacted with an imide represented by any of the following formulas in the presence of N, N-dimethylacetamide to give a compound of formula (4a), (4b) and (4c):

(In each formula, R, R _{3 to} R ₆ , A _{1 to} A ₁₀ and M have the same meaning as described above.)
And the carboxylic acids are esterified to give the formulas (5a), (5b) and (5c)

(In each formula, R, R _{3 to} R ₆ and A _{1 to} A ₁₀ represent the same meaning as described above, and R ₇ represents an alkyl group, an alkenyl group, or an aralkyl group which may have a substituent. )
Formula (1) in which an ester represented by any of the above is obtained and then the ester is reacted with an amine

(In the formula, R and R _{3 to} R ₆ each have the same meaning as described above.)
The manufacturing method of polycyclic lactam shown by these. Formula (3a), (3b) and imides represented by any one of (3c) The production method according to claim 1 is a potassium phthalimide. Esterification of carboxylic acids represented by any of formulas (4a), (4b) and (4c)
R ₇ —OH (7)
(Wherein R ₇ represents the same meaning as described above.)
The process according to claim 1 or 2 in an esterified carried out using an alcohol represented. Amines have the formula (8)
R ₈ —NH ₂ (8)
(In the formula, R ₈ represents an amino group which may have a substituent or an alkyl group which may be substituted with an amino group.)
The process according to any one of claims 1 to 3 in which amines represented. R is group selected from the following group, The manufacturing method in any one of Claims 1-4 .
_{- (CH 2) 2 -,} - (CH 2) 3 -, - (CH 2) 4 -, (CH 3) 2 C <,
(Cl) ₂ C <, (F) ₂ C <,> CH (CO ₂ C ₂ H ₅ ),

(In the above formulas,-represents one single bond, and> and <each represent two single bonds.) R is, (CH _{3) 2} C <method according to any one of claims 1 to 5, which is a group (isopropylidene group). 2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -cyclopropanecarboxylic acid or 2,2-dimethyl-3-[(1 , 3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -cyclopropanecarboxylic acid potassium salt . (1R, 3S) -2,2-dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -cyclopropanecarboxylic acid or (1R, 3S) -2,2-Dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -cyclopropanecarboxylic acid potassium salt . Formula (5a)

(Wherein R _{3 to} R ₆ and A _{1 to} A ₄ each represents a hydrogen atom, R represents ( CH ₃ ) ₂ C < , R ₇ represents an alkyl group having 1 to 10 carbon atoms, carbon This represents an alkenyl group having 2 to 10 carbon atoms or an aralkyl group having 7 to 20 carbon atoms which may have a substituent.
Esters represented by 2,2-Dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -methyl cyclopropanecarboxylate. (1R, 3S) -2,2-Dimethyl-3-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl) methyl] -cyclopropanecarboxylate methyl.