JP2017214369A - Method for producing polymethine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a polymethine compound efficiently with improved yields by effectively inhibiting occurrence of by-products.SOLUTION: A method for producing a compound represented by the following formula (1) has step (II) for reacting a compound represented by the following formula (2) with a compound represented by the following formula (4) while adding a base to a mixture (M2) containing the compound represented by the following formula (2), a compound represented by the following formula (3), and the compound represented by the following formula (4).SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a polymethine compound.

  In general, many polymethine compounds such as merocyanine dyes and pyrazolone dyes have a high molar absorption coefficient and a small half-value width of absorption, and thus are excellent in selective light absorption. Since polymethine compounds have these characteristics, they are used in applications such as sensitizing dyes for photographic printing, materials for optical recording media, and UV absorbers, and are recognized as important compounds. Patent Document 1 discloses a merocyanine dye and a method for producing the same as an ultraviolet absorber used in a color filter. Patent Document 2 discloses a pyrazolone dye and a method for producing the same as an oil-soluble dye.

JP 2014-194508 A JP 2006-16564 A

  However, the polymethine compound (merocyanine dye) disclosed in Patent Document 1 is limited to a compound having an oxazoline ring as a structure serving as an electron donor site. Therefore, the present inventor examined a method for producing a polymethine compound in which the electron donor site is not limited to the oxazoline ring. As a result, in the electron donor site, the 3-position of the nitrogen atom is a methylene structure (for example, 1-pyrroline ring or pyrrolidine ring). In the production of the polymethine compound, it was found that by applying the methods described in Patent Documents 1 and 2, the by-product was produced at a high rate, and the yield of the target compound was lowered.

  An object of the present invention is to provide a method for efficiently producing a polymethine compound in a yield better than that of the prior art by effectively suppressing the production of by-products.

［式中、Ｒ^１及びＲ^２は互いに独立して、水素原子又は置換基を有していてもよい炭素数１〜２０のアルキル基を表し、Ｒ^１及びＲ^２は互いに結合して、それらが結合する炭素原子及び窒素原子と共に環を形成していてもよく、前記炭素数１〜２０のアルキル基を構成する−ＣＨ_２−は、−Ｏ−、−Ｓ−、又は−ＮＨ−と置き換わっていてもよい。Ｒ^３は置換基を有していてもよい炭素数１〜１０のアルキル基を表し、前記炭素数１〜１０のアルキル基を構成する−ＣＨ_２−は、−Ｏ−又は−Ｓ−と置き換わっていてもよい。Ｒ^４は水素原子、置換基を有していてもよい炭素数１〜１０のアルキル基、又は置換基を有していてもよい炭素数６〜１２のアリール基を表す。Ｘ^１及びＸ^２は互いに独立して、電子吸引性基を表し、Ｘ^１とＸ^２は互いに結合してそれらが結合する炭素原子と共に環を形成していてもよい。］
で表される化合物の製造方法であって、
下記式（２）

［式中、Ｒ^５は水素原子、置換基を有していてもよい炭素数１〜６のアルキル基、又は置換基を有していてもよい炭素数６〜１２のアリール基を表す。Ｚ^-はアニオンを表す。Ｒ^１〜Ｒ^４は前記と同じ意味を表す。］
で表される化合物、下記式（３）

［式中、Ｒ^１〜Ｒ^５及びＺ^-は前記と同じ意味を表す。］
で表される化合物、及び下記式（４）

［式中、Ｘ^１及びＸ^２は前記と同じ意味を表す。］
で表される化合物を含む混合物（Ｍ２）に、塩基を添加しながら、前記式（２）で表される化合物と、前記式（４）で表される化合物とを反応させる工程（II）を含む、製造方法。
［２］下記式（５）

［式中、Ｒ^１〜Ｒ^３及びＺ^-は前記と同じ意味を表す。］
で表される化合物に、下記式（６）

［式中、Ｒ^６は水素原子、置換基を有していてもよい炭素数１〜６のアルキル基、又は置換基を有していてもよい炭素数６〜１２のアリール基を表し、Ｒ^４及びＲ^５は前記と同じ意味を表す。］
で表される化合物を添加しながら、前記式（５）で表される化合物と前記式（６）で表される化合物とを反応させることで、前記式（２）で表される化合物と、前記式（３）で表される化合物とを含む混合物（Ｍ１）を得る工程（I）を含む、［１］に記載の方法。
［３］前記式（１）で表される化合物、前記式（２）で表される化合物及び前記式（３）で表される化合物は、それぞれＲ^１及びＲ^２が互いに結合して、それらが結合する炭素原子及び窒素原子とともに環を形成している化合物である、［１］に記載の方法。
［４］前記式（５）で表される化合物は、Ｒ^１及びＲ^２が互いに結合して、それらが結合する炭素原子及び窒素原子と共に環を形成している化合物であり、前記式（６）で表される化合物は、Ｒ^４が水素原子であり、Ｒ^５及びＲ^６がそれぞれ置換基を有していてもよい炭素数６〜１２のアリール基である化合物である、［２］に記載の方法。
［５］前記工程（II）において、前記式（２）で表される化合物１モルに対して、塩基を一時間あたり０．１７〜１０モルの速度で添加する、［１］〜［４］のいずれかに記載の方法。
［６］前記工程（I）において、前記式（５）で表される化合物１モルに対して、前記式（６）で表される化合物を一時間あたり０．０２〜３００モルの速度で添加する、［２］又は［４］に記載の方法。
［７］前記塩基は、酢酸塩、第二級アミン、第三級アミン、及びイミン類からなる群から選択される少なくとも１種である、［１］〜［６］のいずれかに記載の方法。
［８］前記式（４）で表される化合物は、メルドラム酸、バルビツール酸、ジメドン、ベンゾイルアセトニトリル、マロノニトリル、シアノ酢酸エステル、マロン酸エステル、又は、それらの誘導体である、［１］〜［７］のいずれかに記載の方法。
［９］前記工程（II）後に、工程（II）で得られた反応混合物を水中に加える工程を含む、［１］〜［８］のいずれかに記載の方法。
［１０］下記式（５）

［式中、Ｒ^１及びＲ^２は互いに独立して、水素原子又は置換基を有していてもよい炭素数１〜２０のアルキル基を表し、Ｒ^１及びＲ^２は互いに結合して、それらが結合する炭素原子及び窒素原子と共に環を形成していてもよく、前記炭素数１〜２０のアルキル基を構成する−ＣＨ_２−は、−Ｏ−、−Ｓ−、又は−ＮＨ−と置き換わっていてもよい。Ｒ^３は置換基を有していてもよい炭素数１〜１０のアルキル基を表し、前記炭素数１〜１０のアルキル基を構成する−ＣＨ_２−は、−Ｏ−又は−Ｓ−と置き換わっていてもよい。Ｚ^-はアニオンを表す。］
で表される化合物に、下記式（６）

［式中、Ｒ^４は水素原子、置換基を有していてもよい炭素数１〜１０のアルキル基、又は置換基を有していてもよい炭素数６〜１２のアリール基を表す。Ｒ^５及びＲ^６は互いに独立して、水素原子、置換基を有していてもよい炭素数１〜６のアルキル基、又は置換基を有していてもよい炭素数６〜１２のアリール基を表す。］
で表される化合物を添加しながら、前記式（５）で表される化合物と前記式（６）で表される化合物とを反応させることで、下記式（２）

［式中、Ｒ^１〜Ｒ^３及びＺ^-は式（５）中と、Ｒ^４及びＲ^５は式（６）中と同じ意味を表す。］
で表される化合物と、下記式（３）

［式中、Ｒ^１〜Ｒ^３及びＺ^-は式（５）中と、Ｒ^４及びＲ^５は式（６）中と同じ意味を表す。］
で表される化合物とを含む混合物（Ｍ１）を製造する方法。
［１１］前記式（５）で表される化合物は、Ｒ^１及びＲ^２が互いに結合して、それらが結合する炭素原子及び窒素原子と共に環を形成している化合物であり、前記式（６）で表される化合物は、Ｒ^４が水素原子であり、Ｒ^５及びＲ^６がそれぞれ置換基を有していてもよい炭素数６〜１２のアリール基である化合物である、［１０］に記載の方法。
なお、本明細書中、「Ｃ_１−６アルキル基」は、炭素数１〜６のアルキル基を意味し、他の置換基についても同様の意味であり、例えば「Ｃ_６−１０アリール基」は、炭素数６〜１０のアリール基を示す。 As a result of intensive studies in order to solve the above problems, the present inventors have completed the present invention. That is, the following preferred embodiments are included in the present invention.
[1] The following formula (1)

[Wherein, R ¹ and R ² independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 20 carbon atoms, and R ¹ and R ² are bonded to each other, May form a ring together with the carbon atom and nitrogen atom to which — is bonded, —CH ₂ — constituting the alkyl group having 1 to 20 carbon atoms is replaced with —O—, —S—, or —NH—. It may be. R ³ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, and —CH ₂ — constituting the alkyl group having 1 to 10 carbon atoms is replaced with —O— or —S—. It may be. R ⁴ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. X ¹ and X ² each independently represent an electron-withdrawing group, and X ¹ and X ² may be bonded to each other to form a ring together with the carbon atom to which they are bonded. ]
A process for producing a compound represented by
Following formula (2)

[Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aryl group having 6 to 12 carbon atoms which may have a substituent. Z ⁻ represents an anion. R ^{1 to} R ⁴ represent the same meaning as described above. ]
A compound represented by the following formula (3)

[Wherein R ^{1 to} R ⁵ and Z ⁻ represent the same meaning as described above. ]
And a compound represented by the following formula (4)

[Wherein, X ¹ and X ² represent the same meaning as described above. ]
A step (II) of reacting the compound represented by the formula (2) with the compound represented by the formula (4) while adding a base to the mixture (M2) containing the compound represented by A manufacturing method.
[2] The following formula (5)

[Wherein R ^{1 to} R ³ and Z ⁻ represent the same meaning as described above. ]
In the compound represented by the following formula (6)

[Wherein R ⁶ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms; ⁴ and R ⁵ represent the same meaning as described above. ]
While adding the compound represented by the formula (5), the compound represented by the formula (5) and the compound represented by the formula (6) are reacted, The method according to [1], comprising a step (I) of obtaining a mixture (M1) containing the compound represented by the formula (3).
[3] In the compound represented by the formula (1), the compound represented by the formula (2), and the compound represented by the formula (3), R ¹ and R ² are bonded to each other. The method according to [1], wherein is a compound that forms a ring with a carbon atom and a nitrogen atom to which is bonded.
[4] The compound represented by the formula (5) is a compound in which R ¹ and R ² are bonded to each other to form a ring together with the carbon atom and the nitrogen atom to which they are bonded, and the formula (6) ) Is a compound in which R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ are each an aryl group having 6 to 12 carbon atoms which may have a substituent. The method described.
[5] In the step (II), a base is added at a rate of 0.17 to 10 mol per hour with respect to 1 mol of the compound represented by the formula (2). [1] to [4] The method in any one of.
[6] In the step (I), the compound represented by the formula (6) is added at a rate of 0.02 to 300 mol per hour with respect to 1 mol of the compound represented by the formula (5). The method according to [2] or [4].
[7] The method according to any one of [1] to [6], wherein the base is at least one selected from the group consisting of acetates, secondary amines, tertiary amines, and imines. .
[8] The compound represented by the formula (4) is Meldrum's acid, barbituric acid, dimedone, benzoylacetonitrile, malononitrile, cyanoacetic acid ester, malonic acid ester, or a derivative thereof. [7] The method according to any one of [7].
[9] The method according to any one of [1] to [8], comprising a step of adding the reaction mixture obtained in the step (II) into water after the step (II).
[10] The following formula (5)

[Wherein, R ¹ and R ² independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 20 carbon atoms, and R ¹ and R ² are bonded to each other, May form a ring together with the carbon atom and nitrogen atom to which — is bonded, —CH ₂ — constituting the alkyl group having 1 to 20 carbon atoms is replaced with —O—, —S—, or —NH—. It may be. R ³ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, and —CH ₂ — constituting the alkyl group having 1 to 10 carbon atoms is replaced with —O— or —S—. It may be. Z ⁻ represents an anion. ]
In the compound represented by the following formula (6)

[Wherein, R ⁴ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. R ⁵ and R ⁶ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. Represents. ]
The compound represented by the above formula (5) is reacted with the compound represented by the above formula (6) while adding the compound represented by the following formula (2).

[Wherein R ^{1 to} R ³ and Z ⁻ represent the same meaning as in formula (5), and R ⁴ and R ⁵ represent the same meaning as in formula (6). ]
And a compound represented by the following formula (3)

[Wherein R ^{1 to} R ³ and Z ⁻ represent the same meaning as in formula (5), and R ⁴ and R ⁵ represent the same meaning as in formula (6). ]
The method of manufacturing the mixture (M1) containing the compound represented by these.
[11] The compound represented by the formula (5) is a compound in which R ¹ and R ² are bonded to each other and form a ring together with the carbon atom and the nitrogen atom to which they are bonded. In the compound represented by [10], R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ are each an aryl group having 6 to 12 carbon atoms that may have a substituent. The method described.
In the present specification, “C _1-6 alkyl group” means an alkyl group having 1 to 6 carbon atoms, and other substituents have the same meaning. For example, “C _6-10 aryl group” Represents an aryl group having 6 to 10 carbon atoms.

  According to the production method of the present invention, a polymethine compound can be efficiently obtained in a yield better than that of the prior art by effectively suppressing the production of by-products.

  The polymethine compound obtained by the production method of the present invention is a compound represented by the following formula (1) [hereinafter sometimes referred to as a compound (1) or a polymethine compound (1), and other compounds are also represented in the same manner. There is. In a preferred embodiment, it can be produced by steps (I) and (II) as shown below. More specifically, in the step (I), the compound (5) and the compound (6) are reacted while adding the compound represented by the following formula (6) to the compound represented by the following formula (5). Thus, a mixture (M1) containing a compound represented by the following formula (2) and a compound represented by the following formula (3) is obtained, and further, in the step (II), the compound obtained in the step (I) By reacting compound (2) and compound (4) while adding a base to (2), compound (3), and a mixture (M2) containing a compound represented by the following formula (4), Compound (1) can be produced. Hereinafter, embodiments of the present invention will be described in detail. Note that the scope of the present invention is not limited to the embodiment described here, and various modifications can be made without departing from the spirit of the present invention.

［式中、Ｒ^１及びＲ^２は互いに独立して、水素原子又は置換基を有していてもよい炭素数１〜２０のアルキル基を表し、Ｒ^１及びＲ^２は互いに結合して、それらが結合する炭素原子及び窒素原子と共に環を形成していてもよく、前記炭素数１〜２０のアルキル基を構成する−ＣＨ_２−は、−Ｏ−、−Ｓ−、又は−ＮＨ−と置き換わっていてもよい。Ｒ^３は置換基を有していてもよい炭素数１〜１０のアルキル基を表し、前記炭素数１〜１０のアルキル基を構成する−ＣＨ_２−は、−Ｏ−又は−Ｓ−と置き換わっていてもよい。Ｒ^４は水素原子、置換基を有していてもよい炭素数１〜１０のアルキル基、又は置換基を有していてもよい炭素数６〜１２のアリール基を表す。Ｒ^５及びＲ^６は互いに独立して、水素原子、置換基を有していてもよい炭素数１〜６のアルキル基、又は置換基を有していてもよい炭素数６〜１２のアリール基を表し、Ｘ^１及びＸ^２は互いに独立して、電子吸引性基を表し、Ｘ^１とＸ^２は互いに結合してそれらが結合する炭素原子と共に環を形成していてもよく、Ｚ^-はアニオンを表す。］

[Wherein, R ¹ and R ² independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 20 carbon atoms, and R ¹ and R ² are bonded to each other, May form a ring together with the carbon atom and nitrogen atom to which — is bonded, —CH ₂ — constituting the alkyl group having 1 to 20 carbon atoms is replaced with —O—, —S—, or —NH—. It may be. R ³ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, and —CH ₂ — constituting the alkyl group having 1 to 10 carbon atoms is replaced with —O— or —S—. It may be. R ⁴ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. R ⁵ and R ⁶ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. X ¹ and X ² each independently represent an electron-withdrawing group, X ¹ and X ² may be bonded together to form a ring together with the carbon atom to which they are bonded, Z ⁻ is Represents an anion. ]

<Process (I)>
In the step (I), the compound (5) and the compound (6) are reacted with each other while the compound (6) is added to the compound (5), whereby a mixture (M1) containing the compound (2) and the compound (3) is reacted. ).
In the step (I), since the compound (5) has a methylene group [methylene group (—CH ₂ —) adjacent to R ¹ ] at the 3-position of the nitrogen atom, it originates from the methylene group (—CH ₂ —). Side reaction occurs, and compound (3) is produced as a by-product. However, in the step (I) of the present invention, the production of the by-product compound (3) is effectively suppressed by reacting the compound (5) while adding (or dropping) the compound (6). it can. Therefore, by including the step (I) in the production method of the polymethine compound (1), the yield of the compound (2) becomes better than that of the prior art, and further, the target compound, the compound (1), has a good yield. Can be obtained at

In the compound (5), R ¹ and R ² each independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 20 carbon atoms. From the viewpoints of solubility of the target compound (1) in various solvents and light absorption selectivity, the carbon number is preferably 2-15, more preferably 3-12, and more preferably 4 More preferably, it is 10-10. Examples of the alkyl group having 1 to 20 carbon atoms include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-decyl group, n-dodecyl group, n A linear alkyl group such as octadecyl group; a branched alkyl group such as isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, isohexyl group, 2-ethylhexyl group; cyclopentyl group; Examples thereof include cycloalkyl groups such as cyclohexyl group and cyclooctyl noble; bridged cyclic alkyl groups such as norbornyl group and adamantyl group. These alkyl groups are not particularly limited as long as the above preferable carbon number is satisfied.

R ¹ and R ² may be bonded to each other to form a ring together with the carbon atom and nitrogen atom to which they are bonded. That is, in this case, R ¹ and R ² , a carbon atom to which they are bonded, a nitrogen atom, and a carbon atom to which the carbon atom and the nitrogen atom are bonded form a ring. In the case of forming a ring, the total carbon number of R ¹ and R ² is 2 to 11 from the viewpoints of solubility of the target compound (1) in various solvents and light absorption selectivity. Preferably, it is 2-9, more preferably 2-7. That is, the ring is preferably a 5- to 14-membered ring, more preferably a 5- to 12-membered ring, and even more preferably a 5- to 10-membered ring.
In addition, —CH ₂ — constituting the alkyl group having 1 to 20 carbon atoms represented by R ¹ or R ² (when the alkyl group having 1 to 20 carbon atoms has —CH ₂ —), —O—, -S- or -NH- may be substituted.

Specific examples of the ring formed by combining R ¹ and R ² with each other include, for example, rings (a) to (h) represented by the following formulae.

R ¹ and R ² may have a substituent. Examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom; alkyl groups exemplified above as R ¹ and R ² ; C ₆₋ such as phenyl group, naphthyl group and biphenyl group. ₁₂ aryl group; aralkyl group such as C _6-10 aryl-C _1-4 alkyl group such as benzyl group and phenethyl group; hydroxyl group; alkoxy such as C _1-6 alkoxy group such as methoxy group, ethoxy group and ethoxyethyl group A group; a cycloalkoxy group such as a C _4-10 cycloalkoxy group such as a cyclopentyloxy group or a cyclohexyloxy group; an aryloxy group such as a C _6-10 aryloxy group such as a phenoxy group, a naphthyloxy group, or a toluyloxy group; Aralkylo such as C _6-10 aryl-C _1-4 alkyloxy group such as oxy group An alkylthio group such as a C _1-10 alkylthio group such as a methylthio group or an ethylthio group; a cycloalkylthio group such as a C _5-10 cycloalkylthio group such as a cyclohexylthio group; a C _6-10 arylthio group such as a thiophenoxy Arylthio groups such as benzylthio; aralkylthio groups such as C _6-10 aryl-C _1-4 alkylthio groups such as benzylthio; acyl groups such as C _1-6 acyl groups such as acetyl groups; amino groups; such as C _1-4 alkyl sulfonamide group such as methanesulfonamide; dialkyl carbonyl amino group such as a carbonyl amino group - di C _1-4 alkyl, such as diacetyl amino group; - C _1-4 alkyl dialkylamino group such as an amino group Sulfonamide groups; Imido groups such as succinimide and phthalimide Arylsulfonyl group such as a C _6-10 arylsulfonyl group such as benzenesulfonyl; alkylsulfonyl group such as a C _1-4 alkylsulfonyl group such as methanesulfonyl; imino group such as benzylidene amino pyridyl, heterocyclic groups such as morpholino Can be illustrated. Among these, halogen atom; C _1-6 alkyl group such as methyl group, ethyl group, n-propyl group, n-butyl group, isopropyl group, isobutyl group; C _6-12 aryl group such as phenyl group; C _1-4 alkyl groups such as a group and an ethyl group are preferred.

R ¹ and R ² are bonded to each other from the viewpoint of light absorption selectivity of the compound (1) to be produced and light resistance of the compound (1) to form a ring together with the carbon atom and nitrogen atom to which they are bonded. It is preferable.

R ³ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, and in R ³ , —CH ₂ — may be replaced by —O— or —S—. Examples of the alkyl group having 1 to 10 carbon atoms include the alkyl groups having 1 to 10 carbon atoms exemplified above as R ¹ and R ² . The alkyl group of R ³ may have a substituent. Examples of the substituent that may be included include those exemplified above as the substituent that R ¹ and R ² may have. R ³ is preferably a methyl group, ethyl group, n-propyl group, isopropyl, n-butyl group, isobutyl group or the like.

Z ⁻ represents an anion (counter anion), and the anion is usually a halogen atom, an alkylsulfuric acid, or an anion of boron halide. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the alkyl sulfuric acid include an alkyl sulfuric acid having 1 to 6 carbon atoms such as methyl sulfuric acid and ethyl sulfuric acid. Examples of the Meerwein reagent include trimethyloxonium tetrafluoroborate and triethyloxonium tetrafluoroborate. Among these Z, a halogen atom (for example, chlorine, bromine, iodine, etc.) is preferable, and iodine is most preferable. When Z is a halogen atom, particularly iodine, the compound represented by the formula (2) and the compound represented by the formula (3) are insoluble in alcohol-based organic solvents and nitrile-based organic solvents. ) Is preferable because the purification process in (1) becomes easy.

In the compound (6), R ⁴ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. . Examples of the alkyl group having 1 to 10 carbon atoms, for example, an alkyl group having 1 to 10 carbon atoms exemplified above as R ¹ and R ^2. Of those, a methyl group, an ethyl group, n- propyl group A linear or branched C _1-6 alkyl group such as isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like is preferable, and a methyl group is particularly preferable. Moreover, as a C6-C12 aryl group, a phenyl group, a naphthyl group, a biphenyl group etc. are mentioned, for example, A phenyl group and a naphthyl group are preferable and a phenyl group is the most preferable. Among these R ⁴ , a C _1-4 alkyl group such as a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an isopropyl group, or an isobutyl group is preferable, and a hydrogen atom is most preferable. Further, the alkyl group or aryl group of R ⁴ may have a substituent, and examples of the substituent include the substituents exemplified above as the substituents of R ¹ and R ² .

R ⁵ and R ⁶ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. Indicates. Examples of the alkyl group having 1 to 6 carbon atoms include the alkyl groups having 1 to 6 carbon atoms exemplified above as R ¹ and R ² . Examples of the aryl group having 6 to 12 carbon atoms include the aryl groups having 6 to 12 carbon atoms exemplified above as R ⁴ . Of these R ⁵ and R ⁶ , C _1-4 alkyl groups such as a methyl group and an ethyl group, and C _6-12 aryl groups such as a phenyl group are preferable. Moreover, the alkyl group or aryl group of R ⁵ and R ⁶ may have a substituent, and examples of the substituent include the substituents exemplified above as the substituents of R ¹ and R ^2. .

（式中、Ｒ^１〜Ｒ^３及びＺ^-は前記と同じ意味を表す。）
好ましい化合物（８）としては、例えばヨウ化メチル、ヨウ化エチル、ヨウ化ｎ−プロピル、ヨウ化イソプロピル、ヨウ化ｎ−ブチル、及びこれらの化合物のヨウ素原子を塩素原子又は臭素原子で置き換えた化合物、硫酸ジメチル、硫酸ジエチル等のアルキル硫酸エステル、Ｍｅｅｒｗｅｉｎ試薬に代表されるハロゲン化ホウ素化合物等が例示できる。 In addition, a commercial item may be used for a compound (5) and a compound (6), and you may manufacture it by a conventional method. Examples of the method for producing the compound (6) include those exemplified in “New Experimental Chemistry Course 14 Synthesis and Reaction III of Organic Compounds III (1978, Maruzen Publishing Co., Ltd.)”. Compound (6) is obtained by, for example, mixing and heating ethyl orthocarboxylate having R ⁴ , primary amine having R ^5, and primary amine having R ⁶ in the presence of an acid catalyst. The resulting crude product can be obtained by recrystallization from hydrous ethanol. The compound (5) may be obtained, for example, by reacting the compound represented by the following formula (7) with the method represented by the following formula (8) (step A).

(In the formula, R ^{1 to} R ³ and Z ⁻ represent the same meaning as described above.)
Preferred compounds (8) include, for example, methyl iodide, ethyl iodide, n-propyl iodide, isopropyl iodide, n-butyl iodide, and compounds in which the iodine atom of these compounds is replaced with a chlorine atom or a bromine atom. Examples thereof include alkyl sulfates such as dimethyl sulfate and diethyl sulfate, and boron halide compounds represented by Meerwein reagent.

  The ratio of the compound (8) used at a process (A) is 0.5-5 mol with respect to 1 mol of compounds (7), Preferably it is 1-3 mol, More preferably, it is 1.2-2 mol is there. It is preferable for the compound (8) to be in the above ratio because the compound (5) can be obtained in a good yield without unexpected side reaction.

  The reaction in the step (A) may be performed in a solvent (Y1) inert to the reaction. The solvent (Y1) is not particularly limited as long as it does not affect the reaction. For example, alcohols such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol; diethyl ether, diisopropyl ether, tetrahydrofuran, 1 Ethers such as 1,4-dioxane; ketones such as acetone, 2-butanone and methyl isobutyl ketone; N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-ethyl-2 -Aprotic polar solvents such as pyrrolidone and dimethyl sulfoxide; esters such as methyl acetate, ethyl acetate and n-butyl acetate; nitrile solvents such as acetonitrile and benzonitrile; n-pentane, n-hexane, n-heptane, Octane, cyclohexane, methylcyclo Hydrocarbon solvents such as xanthones; aromatic hydrocarbon solvents such as benzene, toluene, xylene, mesitylene; halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, monochlorobenzene, dichlorobenzene, etc. Can be illustrated. Of these solvents, alcohols, ethers, and nitriles are preferable from the viewpoint of solubility of the compound (7) and the compound (5). The amount of the solvent (Y1) to be used is preferably 0.5 to 30 parts by mass, more preferably 1 to 20 parts by mass, and further preferably 3 to 12 parts by mass with respect to 1 part by mass of the compound (7). It is preferable for the amount of solvent (Y1) used to be in the above-mentioned range since compound (7) and compound (5) can be sufficiently dissolved and side reactions can be effectively suppressed.

  The reaction temperature in step (A) may be, for example, 15 to 50 ° C., preferably 20 to 30 ° C., and the reaction time is, for example, 1 minute to 72 hours, preferably 30 minutes to 10 hours, more preferably It may be 2 hours to 6 hours. The reaction can be performed with stirring in air or an inert gas atmosphere [eg, nitrogen, rare gas (such as argon)], and may be performed under normal pressure, increased pressure, or reduced pressure. In a preferred embodiment, it is carried out with stirring under normal pressure and / or inert gas atmosphere.

  In a preferred embodiment of the step (A), the compound (8) is added (or dropped) and reacted with a solution in which the compound (7) is dissolved in the solvent (Y1). At this time, if the compound (8) is liquid in a normal temperature and normal pressure environment, it may be added (or dropped) as it is, or may be diluted with a solvent (Y1) and added (or dropped). Moreover, if a compound (8) is a solid in normal temperature and a normal pressure environment, you may add as a solid and may be dissolved in a solvent (Y1) and may be added (or dripped).

  The produced compound (5) may be separated and purified by a conventional method, for example, separation means such as filtration, concentration, extraction, crystallization, recrystallization, column chromatography, etc., or a separation means combining these. You may use for the following process (I) in an unpurified state.

[Reaction of Compound (5) with Compound (6)]
Step (I) is characterized by reacting both compounds while adding compound (6) to compound (5).
In the step (I), the ratio of the compound (6) to be added (or added dropwise) to the compound (5) is, for example, 0.5 to 5 mol, preferably 1 mol to 1 mol of the compound (5). It is preferable that it is 0.6-3 mol, More preferably, it is 0.7-2 mol, More preferably, it is 0.8-1.5 mol, Especially 0.9-1.1 mol. When the ratio of the compound (6) is in the above range, the amount of the unreacted compound (5) can be suppressed to a small amount, the reaction can proceed at a good conversion rate, and a by-product is produced. Since the amount of (3) can be effectively suppressed, it is preferable.

  In step (I), the rate (molar rate) of compound (6) added (or dropped) to compound (5) is 0.02 to 300 mol per hour per 1 mol of compound (5), Preferably it is 0.05-6 mol, More preferably, it is 0.07-2 mol, More preferably, it is 0.1-1 mol, It is especially preferable that it is 0.15-0.55 mol. Addition (or dropwise addition) at a rate in this range is preferable because generation of the compound (3) can be more effectively suppressed.

  In a preferred embodiment, the mixture (M4) containing the compound (6) and the solvent (Y3) is added to the mixture (M3) containing the compound (5) and the solvent (Y2).

  The mixture (M3) can be obtained by mixing (or mixing and stirring) the compound (5) and the solvent (Y2), and the mixture (M4) includes the compound (6) and the solvent (Y3). It can be obtained by mixing (or mixing and stirring).

  Examples of the solvent (Y2) and the solvent (Y3) include the solvents exemplified above as the solvent (Y1). Among these solvents, alcohols, nitriles, and hydrocarbons (especially aromatic hydrocarbons) are preferable, the solubility of the compound (5) and the compound (6), and the production ratio of the compound (3) by the reaction. From the viewpoint of effectively suppressing the above, alcohols and nitriles are preferable, and alcohols are particularly preferable. These solvents may be used alone or in combination of two or more. In addition, the solvent (Y2) and the solvent (Y3) may be the same or different. Usually, the solvent (Y2) and the solvent (Y3) are the same.

  In the mixture (M3), the amount of the solvent (Y2) used is, for example, 0.5 to 30 parts by mass, preferably 1 to 20 parts by mass, more preferably 2 to 2 parts by mass with respect to 1 part by mass of the compound (5). 10 parts by mass, particularly preferably 2.5 to 5 parts by mass. It is preferable for the amount of solvent (Y2) used to be in the above range because it can react with compound (6) while maintaining the solubility of compound (5).

  In the mixture (M4), the amount of the solvent (Y3) used is, for example, 1 to 30 parts by mass, preferably 2 to 20 parts by mass, more preferably 3 to 15 parts by mass, relative to 1 part by mass of the compound (6). Especially preferably, it is 4-10 mass parts. It is preferable for the amount of solvent (Y3) used to be in the above-mentioned range since the production ratio of compound (3) produced by the reaction can be more effectively suppressed.

  The mixing temperature of the compound (5) and the solvent (Y2) or the compound (6) and the solvent (Y3) is a temperature at which the compound can be dissolved in the solvent, or the compound (5) or the compound (6) is uniformly dispersed. Although it will not specifically limit if it is a state to be, It becomes like this. Preferably it is 40-130 degreeC, More preferably, it is 50-100 degreeC, More preferably, it is 60-90 degreeC. The mixing time is not particularly limited as long as the compound can be dissolved in the solvent or the compound (5) or the compound (6) can be uniformly dispersed. The mixing may be usually performed with stirring, may be performed in air or under an inert gas atmosphere [for example, nitrogen, rare gas (argon, etc.)], or may be performed under normal pressure, increased pressure, or reduced pressure. Good. In a preferred embodiment, it is carried out with stirring under normal pressure and / or an inert gas atmosphere.

  The addition temperature at the time of adding the compound (6) to the compound (5) [in the preferred embodiment, the mixture (M4) to the mixture (M3)] is, for example, 20 to 130 ° C., preferably 40 to 100 ° C., more preferably 60 ~ 90 ° C. The time for addition is, for example, 1 minute to 24 hours, preferably 30 minutes to 12 hours, more preferably 1 hour to 10 hours, still more preferably 1.5 hours to 8 hours, especially 2 hours to 6 hours. It may be. The production | generation of a compound (3) can be suppressed more effectively as it is the addition temperature or addition time of this range. In addition, the addition may be performed while stirring the compound (5), and may be performed in the air or in an inert gas atmosphere [for example, nitrogen, rare gas (argon, etc.)], at normal pressure, under pressure or under reduced pressure. You may do it below. In a preferred embodiment, the compound (6) is added while stirring the compound (5) under normal pressure and / or an inert gas atmosphere.

  After adding the compound (6) to the compound (5), the obtained mixture may be immediately subjected to the purification step described later, but it is preferable to stir and mix the mixture at a predetermined temperature for a predetermined time. As temperature which stirs and mixes, it is the range of 20-130 degreeC, for example, Preferably it is 40-100 degreeC, More preferably, it is 60-90 degreeC. Further, the time for stirring and mixing is, for example, in the range of 1 minute to 24 hours, preferably 30 minutes to 18 hours, more preferably 1 to 12 hours, and particularly preferably 2 to 6 hours. It is preferable for the temperature and time for stirring and mixing to be within the above ranges because the compound (5) and the compound (6) can be reacted without remaining.

  Compound (2) and compound (3) (mixture (M1)) obtained in step (I) can be separated and purified by a conventional method, particularly by crystallization. In a preferred embodiment, the reaction mixture (or reaction solution) obtained in step (I) is cooled to, for example, -20 to 40 ° C, preferably -10 to 20 ° C, more preferably -5 to 10 ° C. Crystal of the mixture (M1) is obtained by crystallization. This method is preferable because crystals of the mixture (M1) can be obtained easily and easily.

[Mixture (M1) obtained in step (I)]
By the step (I), a mixture (M1) containing the compound (2) and the compound (3) can be obtained. In the present invention, as described above, the compound (5) is reacted while adding (or dropping) the compound (6) at a predetermined flow rate (molar flow rate). Compared with the case of making it react or making it react, adding (or dripping) a compound (5) to a compound (6), the production | generation ratio of the compound (3) which is a by-product can be reduced. For this reason, the ratio [compound (2): compound (3)] of the compound (2) and the compound (3) contained in the mixture (M1) is usually obtained in the range of 60:40 to 99: 1. In addition, the ratio of a compound (2) and a compound (3) can be measured by a usual method (for example, high performance liquid chromatography etc.). In the method of step (I), the yield (%) related to the total amount of the compound (2) and the compound (3) is usually in the range of 70 to 99%. In addition, the yield (%) related to the total amount of the compound (2) and the compound (3) is the molar amount of the compound (5) subjected to the step (I) is that of the compound (6) subjected to the step (I). When the amount is equal to or greater than the molar amount, it can be calculated using the following formula: [total molar amount of compound (2) and compound (3) / molar amount of compound (6)] × 100, and used for step (I). When the molar amount of the compound (5) is less than the molar amount of the compound (6), the following formula: [total molar amount of the compound (2) and the compound (3) / molar amount of the compound (5)] It can be calculated using x100.

Specific examples of the mixture (M1) containing the compound (2) and the compound (3) include the mixtures shown in Table 1 below. In addition, the mixture described in each line of Table 1 means the mixture (M1) containing the compound (2) and the compound (3) having R ^{1 to} R ⁵ shown in each line. In Table 1, Me represents a methyl group, Et represents an ethyl group, i-Pr represents an isopropyl group, t-Bu represents a tert-butyl group, H represents a hydrogen atom, Ph represents a phenyl group, and R ¹ and R ² The ring structure indicates a ring formed by R ¹ and R ² with each other.

<Process (II)>
In the step (II), a base is added to the mixture (M2) containing the compound (2) and the compound (3) obtained in the step (I) and the compound represented by the formula (4). In this step, compound (1) is obtained by reacting compound (2) with compound (4). In the method of the step (II), the compound (2) and the compound (4) can be selectively reacted. Therefore, the reaction between the compound (3) which is a by-product of the step (I) and the compound (4) ( The production of by-products generated by side reactions can be effectively suppressed. For this reason, the polymethine compound (1) which is a target compound can be obtained with a favorable yield. Furthermore, according to this production method, a highly pure polymethine compound (1) can be obtained through a simple purification operation.

In the compound (4), X ¹ and X ² each independently represent an electron withdrawing group. Examples of the electron withdrawing group include halogen atoms such as chlorine, bromine and iodine; cyano group; carboxyl group; carbamoyl group; alkylamide group such as C _1-10 alkylamide group such as methylamide group and ethylamide; methoxycarbonyl group , Ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, isopentoxycarbonyl group, hexoxycarbonyl group, 2-methyl-he Linear or branched C _1-20 alkoxy such as toxoxycarbonyl group, 2-ethylbutoxycarbonyl group, 2-ethylhexoxycarbonyl group, heptoxycarbonyl group, octoxycarbonyl group, 2-butyloctoxycarbonyl group -Carbonyl group Preferably a straight chain or branched chain C _1-10 alkoxy - alkoxycarbonyl group such as a carbonyl group; 2-ethoxyethoxy group, 2-methoxyethoxy group, 1-ethoxy methoxycarbonyl group, 2-propoxy ethoxycarbonyl C _1-6 alkoxy such as C _1-6 alkoxy-carbonyl group such as C _1-6 alkoxy-carbonyl group; aryloxy group such as C _6-10 aryloxy group such as phenoxy group; methylcarbonyl group, ethylcarbonyl group etc. An alkylcarbonyl group such as a linear or branched C _1-10 alkyl-carbonyl group; an arylcarbonyl group such as a C _6-10 aryl-carbonyl group such as a phenylcarbonyl group; a straight chain such as a methylsulfonyl group or an ethylsulfonyl group; chain or branched chain _{C 1-10} Alkylsulfonyl groups such as alkylsulfonyl group; C _6-10 aryl such as phenylsulfonyl group - such as an arylsulfonyl group such as a sulfonyl group can be exemplified. Of these, cyano group, alkoxycarbonyl group, poly (alkoxy) carbonyl group, alkylcarbonyl group, carbamoyl group and the like are preferable.

X ¹ and X ² may be bonded to each other to form a ring together with the carbon atom to which they are bonded, and this ring is, for example, a 5- to 10-membered ring, preferably a 5- to 8-membered ring, More preferably, it is a 5-membered ring or a 6-membered ring.

Specific examples of the compound (4) include, for example, Meldrum acid; barbituric acid; 1,3-dialkylbarbituric acid such as 1,3-dimethylbarbituric acid and 1,3-diethylbarbituric acid; -1,3-diaryl barbituric acid such as diphenyl barbituric acid; dimedone; benzoyl acetonitrile; malononitrile; methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate, sec cyanoacetate sec C _1-20 cyanoacetate such as -butyl, tert-butyl cyanoacetate, isopentyl cyanoacetate, hexyl cyanoacetate, 2-methylhexyl cyanoacetate, 2-ethylbutyl cyanoacetate, 2-ethylhexyl cyanoacetate, 2-butyloctyl cyanoacetate Alkyl, preferably cyanoacetic acid C Cyanoacetic acid such as _1-10 alkyl, 2-ethoxyethyl cyanoacetate, 2-methoxyethyl cyanoacetate, 1-ethoxymethyl cyanoacetate, 2-propoxyethyl cyanoacetate, C _1-6 alkoxy C _1-6 alkoxy, etc. ester; dimethyl malonate, such as malonic acid esters or their derivatives, such as malonate C _1-10 alkyl diethyl malonate and the like.

  Examples of the base added to the mixture (M2) include at least one selected from the group consisting of acetates, secondary amines, tertiary amines, and imines.

  Examples of the acetate include alkali metal acetates such as sodium acetate, potassium acetate, and calcium acetate, alkaline earth metal salts, ammonium acetate, and the like. These acetates may be used alone or in combination of two or more.

  Examples of the secondary amine include aliphatic secondary amines such as dimethylamine, diethylamine, di-n-propylamine, and diisopropylamine; alicyclic secondary amines such as pyrrolidine, piperidine, morpholine, and piperazine; N— Aromatic secondary amines such as methylaniline and dibenzylamine can be exemplified. As the tertiary amine, for example, trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, N, N-diisopropylethylamine, N, N, N ′, N′-tetramethylethylenediamine, N, N, N ′ , N′-tetramethylpropanediamine, aliphatic tertiary amines such as 1,4-diazabicyclo [2.2.2] octane; dicyclohexylethylamine, diethylcyclohexylamine, 1-methylpiperidine, 1-ethylpiperidine, 1- Examples thereof include alicyclic tertiary amines such as methylpyrrolidine and 1-ethylpyrrolidine; aromatic tertiary amines such as N, N-dimethylaniline, N, N-diethylaniline and tribenzylamine. These amines may be used alone or in combination of two or more.

  Examples of the imines include 1-propanimine, isopropaneimine, 1-butanimine, N-benzylidenemethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene, 1,5-diazabicyclo [4. .3.0] -5-nonene. These imines may be used alone or in combination of two or more. Moreover, you may use together with the above-mentioned acetate, secondary amine, and tertiary amine.

  Among these bases, at least one selected from acetates, secondary amines, and tertiary amines is preferable, acetates and tertiary amines are more preferable, and tertiary amines are particularly preferable. Of the tertiary amines, aliphatic tertiary amines are particularly preferred. In the step (II), it is preferable from the viewpoint that only the compound (2) and the compound (4) can be selectively reacted.

  The usage-amount of the base added to a mixture (M2) is 0.5-5 mol with respect to 1 mol of compounds (2), Preferably it is 0.8-3 mol, More preferably, it is 1-2 mol Particularly preferred is 1.1 to 1.5 mol. When the amount of the base used is within the above range, the compound (2) and the compound (4) can be selectively reacted while suppressing unintended side reactions, and the compound (1) can be obtained in a good yield. This is preferable because it is possible. Furthermore, it is preferable because a highly pure polymethine compound (1) can be obtained through a simple purification operation.

  In step (II), the rate (molar rate) of the base added (or added dropwise) to the mixture (M2) is, for example, 0.17 to 10 mol per hour relative to 1 mol of the compound (2), Preferably it is 0.2-7.5 mol, More preferably, it is 0.25-6.7 mol, More preferably, it is 0.5-5 mol. When a base is added (or added dropwise) at a rate within these ranges, the compound (2) and the compound (4) are selectively reacted to form a reaction (side reaction) between the compound (3) and the compound (4). Since the production | generation of a by-product can be suppressed effectively, it is preferable.

  In step (II), the addition time of the base added (or added dropwise) to the mixture (M2) is, for example, in the range of 10 minutes to 6 hours, preferably 40 minutes to 5 hours, more preferably 45 minutes to 4 hours. More preferably, it is in the range of 1 to 2 hours. It is preferable for the addition time of the base to be in the above-mentioned range since the above-mentioned preferable base addition flow rate can be obtained.

[Reaction between Compound (2) and Compound (4)]
The step (II) is characterized by reacting the compound (2) and the compound (4) while adding a base to the mixture (M2) containing the compound (2), the compound (3), and the compound (4). And With such a method, the compound (2) and the compound (4) can be selectively reacted while suppressing the reaction between the compound (3) and the compound (4). For this reason, a compound (1) can be obtained with a favorable yield. Furthermore, a high-purity polymethine compound (1) can be obtained through a simple purification operation.

  In step (II), the amount of compound (4) to be used is, for example, 0.5 to 5 mol, preferably 0.8 to 3 mol, more preferably 1 to 1 mol, relative to 1 mol of compound (2). 2 mol, particularly preferably 1.1 to 1.5 mol. It is preferable that the amount of compound (4) used be in the above range because compound (2) and compound (4) can be selectively reacted.

  In a preferred embodiment in step (II), the mixture (M2) contains a carboxylic acid anhydride (hereinafter referred to as an acid anhydride). When an acid anhydride is contained in the mixture (M2), the reaction of the step (II) can be performed under mild conditions.

  Examples of the acid anhydride used in step (II) include acetic anhydride, propionic anhydride, n-butyric anhydride, isobutyric anhydride, succinic anhydride, maleic anhydride, and phthalic anhydride. From the viewpoint of the reactivity between the acid anhydride to be used and the compound (2), an acid anhydride of an aliphatic carboxylic acid is preferable, and acetic anhydride is particularly preferable.

  The usage-amount of the acid anhydride in process (II) is 0.5-5 mol with respect to 1 mol of compounds (2), Preferably it is 0.8-3 mol, More preferably, it is 1-2 mol Particularly preferred is 1.1 to 1.8 mol. It is preferable that the amount of the acid anhydride used be within the above range because the compound (1) can be obtained in high yield without inhibiting the reaction between the target compound (2) and the compound (4).

  In a preferred embodiment of the step (II), a base is used with respect to the mixture (M2) containing the compound (2), the compound (3), the compound (4), and optionally an acid anhydride and a solvent (Y4). Add.

  The mixture (M2) containing the solvent (Y4) is obtained by mixing (or stirring and mixing) the compound (2), the compound (3), the compound (4) and, if necessary, the acid anhydride and the solvent (Y4). Can be obtained.

  As the solvent (Y4), for example, the solvents exemplified above as the solvent (Y1) can be exemplified, and among them, alcohols and nitriles are preferable, and particularly selected from methanol, ethanol, 2-propanol, 1-butanol and acetonitrile. At least one of these is preferred. When the solvent (Y4) is at least one selected from these, the solvent (Y4) is mixed with water at an arbitrary ratio in the purification step described later, and remains without reacting with the compound (1) obtained by the reaction. The compound (3) is preferred because it can be easily separated. As a solvent (Y4), these solvents may be used independently and may be used in combination of 2 or more type.

  In the mixture (M2), the amount of the solvent (Y4) used is, for example, 0.5 to 30 parts by mass, preferably 1 to 20 parts by mass with respect to 1 part by mass of the mixture of the compound (2) and the compound (3). Parts, more preferably 2 to 10 parts by mass, and still more preferably 3 to 5 parts by mass. When the amount of the solvent (Y4) used is within the above range, the compound (2) and the compound (4) can be selectively reacted, and crystals of the compound (1) can be obtained in a high yield in the purification step described later. Therefore, it is preferable.

  The mixing temperature of each component of the mixture (M2) is not particularly limited as long as the compound can be dissolved in the solvent, but is preferably 0 to 65 ° C, more preferably 10 to 50 ° C, and still more preferably 20 to 30 ° C. It is. The mixing time is not particularly limited, but is preferably 1 minute to 2 hours, and more preferably 10 minutes to 1 hour. The mixing may be usually performed with stirring, may be performed in air or under an inert gas atmosphere [for example, nitrogen, rare gas (argon, etc.)], or may be performed under normal pressure, increased pressure, or reduced pressure. Good. In a preferred embodiment, it is carried out with stirring under normal pressure and / or inert gas atmosphere.

  The addition temperature at the time of adding a base to a mixture (M2) is 0-100 degreeC, for example, Preferably it is 5-80 degreeC, More preferably, it is 10-70 degreeC, More preferably, it is 15-60 degreeC. When the addition temperature is within the above range, the compound (2) and the compound (4) are selectively reacted to produce a by-product generated by the reaction (side reaction) between the compound (3) and the compound (4). Can be effectively suppressed, which is preferable.

  The addition of the base may be performed while stirring the mixture (M2), may be performed in the air or in an inert gas atmosphere [eg, nitrogen, rare gas (argon, etc.)] You may carry out under reduced pressure. In a preferred embodiment, the base is added while stirring the mixture (M2) under normal pressure and / or an inert gas atmosphere.

After adding the base to the mixture (M2), the mixture (M2) may be immediately subjected to the purification step described later. However, the mixture (M2) is preferably stirred and mixed at a predetermined temperature for a predetermined time. As temperature to stir and mix, it is the range of 0-100 degreeC normally, Preferably it is 5-80 degreeC, More preferably, it is 10-60 degreeC. The time for stirring and mixing is usually in the range of 1 minute to 24 hours, preferably 30 minutes to 18 hours, and more preferably 1 to 8 hours. When the temperature and time for stirring and mixing are within the above range, the compound (2) can be consumed without remaining, and the reaction (side reaction) between the compound (3) and the compound (4) can be effectively suppressed. Since the compound (1) is obtained in a good yield, it is preferable. Furthermore, it is preferable because a highly pure polymethine compound (1) can be obtained through a simple purification operation.
<Purification method of compound (1)>

  Hereinafter, the purification method of the compound (1) obtained in the step (II) will be described. After the step (II), a step of adding (or adding) the reaction mixture (or reaction solution) obtained in the step (II) to water (hereinafter sometimes referred to as a crystallization step) is performed, and the compound (1) At the same time, the compound (3) remaining unreacted in the step (II) can be dissolved in a solvent and separated.

  The temperature of water in the crystallization step is usually in the range of 0 to 40 ° C, preferably 0 to 10 ° C, more preferably 0 to 5 ° C. In addition, the reaction mixture (or reaction solution) obtained in step (II) is prepared at the same temperature as the above preferred water temperature range before being subjected to the crystallization step, and the crystallization step is carried out. It is preferable to maintain the internal temperature within the above-mentioned preferable temperature range even during the period. When the internal temperature in the crystallization step is within the above range, the compound (1) can be obtained in good properties (for example, powder or granular shape), and the solubility of the compound (3) in the solvent can be increased. Since it can maintain, it is preferable.

  The amount of water used in the crystallization step is usually 0.5 to 30 parts by mass, preferably 1 to 20 parts by mass, more preferably 1 part by mass of the solvent (Y4) used in step (II). Is 2 to 10 parts by mass, more preferably 3 to 7 parts by mass. When the amount of water used is within the above range, the dissolution of the compound (1) in the solvent can be suppressed, and the solubility of the compound (3) in the solvent can be maintained. This is preferable because high-purity crystals of compound (1) can be obtained in good yield.

  In the crystallization step, it is preferable to add (or add dropwise) the reaction mixture (or reaction solution) obtained in step (II) to water while stirring water. The crystallization step may be performed in air or in an inert gas atmosphere [for example, nitrogen, rare gas (such as argon)], or may be performed under normal pressure, increased pressure, or reduced pressure. In a preferred embodiment, the reaction mixture (or reaction solution) obtained in step (II) is added with stirring water under normal pressure and / or an inert gas atmosphere.

（式（９）中、Ｒ^５は式（６）中と同様であり、Ｒ^７は工程(II)で使用した酸無水物に起因するアルキル基を表す。例えば、工程(II)で無水酢酸を使用した場合、Ｒ^７はメチル基を表し、無水プロピオン酸を使用した場合、Ｒ^７はｎ−プロピル基を表す。） The purity of the crystal of the compound (1) obtained in the crystallization step can be further improved by carrying out a step of dispersion cleaning using a solvent (sometimes referred to as a dispersion cleaning step). In particular, when an acid anhydride is used in step (II), it is preferable to carry out dispersion washing because a compound represented by the following formula (9) is by-produced by the reaction.

(In formula (9), R ⁵ is the same as in formula (6), and R ⁷ represents an alkyl group derived from the acid anhydride used in step (II). For example, acetic anhydride is used in step (II). R ⁷ represents a methyl group, and when propionic anhydride is used, R ⁷ represents an n-propyl group.)

  The dispersion cleaning may be performed a plurality of times (for example, 2 to 10 times), may be performed a plurality of times using different solvents, or may be performed a plurality of times by combining a plurality of solvents. The solvent used for the dispersion cleaning can be appropriately selected from, for example, the solvents exemplified above as the solvent (Y1), but water, hydrocarbons (for example, aliphatic hydrocarbons such as hexane, heptane, octane, etc.) A mixed solvent of water and nitriles (for example, acetonitrile) is preferable. In a particularly preferred embodiment, the dispersion cleaning is performed a plurality of times with a mixed solvent of water and acetonitrile, and then the dispersion cleaning is performed a plurality of times with an aliphatic hydrocarbon (preferably hexane, heptane, etc.). In the mixed solvent of water and acetonitrile, the proportion of acetonitrile is preferably 1 to 100 parts by mass, more preferably 5 to 50 parts by mass, and still more preferably 10 to 30 parts by mass with respect to 100 parts by mass of water. As described above, in the present invention, the compound (1) obtained in the step (II) is easily and simply separated and purified by the water addition step and / or the dispersion washing step. And can be obtained in high yield.

[Compound (1) obtained in step (II)]
According to the present invention, the by-product resulting from the reaction (side reaction) between the compound (3) and the compound (4) by selectively reacting the compound (2) and the compound (4) in the step (II). Effectively suppress the occurrence of Moreover, a highly purified compound (1) can be obtained by implementing the subsequent crystallization process and the dispersion | distribution washing process depending on the case. The purity of the obtained compound (1) is usually in the range of 80 to 99.9%.
The purity (%) of compound (1) can be calculated using the following formula: [mass of polymethine compound (1) / total mass of polymethine compound (1) and other components] × 100. The other component indicates a component mixed in the target compound polymethine compound (1), such as a by-product. Further, in the step (II), the production of by-products generated by the reaction between the compound (3) and the compound (4) can be effectively suppressed, so that the target compound (1) has a high yield (for example, 70 ~ 99%). In addition, the yield (%) of the compound (1) is expressed by the following formula: [mol amount of compound (1) / compound (2) when the molar amount of compound (2) is not less than the molar amount of compound (4). 4) molar amount] × 100, and when the molar amount of compound (2) is less than the molar amount of compound (4), the following formula: [molar amount of compound (1) / compound ( 2) molar amount] × 100.

  The polymethine compound (1) obtained by the production method of the present invention is excellent in light absorption selectivity (for example, ultraviolet absorption selectivity) because it contains a small amount of by-products, and preferably contains no by-products. ing. The maximum absorption wavelength of light of the polymethine compound (1) is usually in the range of 300 to 450 nm, preferably 350 to 430 nm, more preferably 380 to 400 nm. The polymethine compound (1) is useful as a sensitizing dye for photographic printing, an optical recording medium material, an ultraviolet absorber, and the like.

Specific examples of the ring formed by R ¹ and R ² of compound (1) include rings (i) to (p) represented by the following formulas.

Specific examples of the compound (1) include the compounds shown in Table 2 and Table 3 below. Incidentally, the compounds described in each line of table 2 and table 3 refers to a compound having ^R 1 ^{to R} 4, ^{X 1} and ^{X 2} shown in each row (1). In Tables 2 and 3, Me is a methyl group, Et is an ethyl group, i-Pr is an isopropyl group, t-Bu is a tert-butyl group, H is a hydrogen atom, Ph is a phenyl group, CN is a cyano group, CO ₂ Me is a methoxycarbonyl group, CO ₂ Et is an ethoxycarbonyl group, CO ₂ Ht (2-Et) is a 2-ethylhexoxycarbonyl group, CO ₂ Et (2-OEt) is a 2-ethoxyethoxycarbonyl group, COPh represents a phenyl group, ring structure of ^{R 1} and ^{R 2} is a ^{ring R 1} and ^{R 2} form together a ring structure ^{X 1} and ^{X 2} are the ^{ring X 1} and ^{X 2} form together Ring (I) is 2,2-dimethyl-1,3-dioxane-4,6-dione, ring (II) is pyrimidine-2,4,6 (1H, 3H, 5H) -trione, ring (III ) Represents 5,5-dimethyl-1,3-cyclohexanedione.

  The production method of the present invention may be any method including at least step (II). When the step (II) is included, the production of by-products can be effectively suppressed as described above, and the polymethine compound can be efficiently obtained with a good yield. Moreover, since the preferable manufacturing method of the present invention described above, that is, the method including the step (I) in addition to the step (II) can suppress the formation of the by-product in both steps, the polymethine can be produced in a better yield. Compound (1) can be obtained. When using a particularly preferred embodiment, that is, a method comprising the step (I) and the water addition step (preferably the water addition step and the dispersion washing step) in addition to the step (II), the highly pure compound (1) is efficiently obtained. It can also be manufactured. In the case of this method, the compound (1) can be obtained with a purity of preferably 90% or more, more preferably 95% or more, especially 99% or more. For this reason, it is possible to efficiently obtain a polymethine compound having excellent absorption selectivity. The production method of the present invention may be a method including the step (A), the step (I) and the step (II).

  In another embodiment of the present invention, the compound represented by the formula (5) and the formula are added to the compound represented by the formula (5) while adding the compound represented by the formula (6). There is also provided a method for producing a mixture (M1) containing the compound represented by the formula (2) and the compound represented by the formula (3) by reacting with the compound represented by (6).

  In this method, by reacting compound (5) while adding (or dropping) compound (6), formation of compound (3) can be effectively suppressed, and the mixture having a high content of compound (2) (M2) can be obtained efficiently. For this reason, for example, when producing the polymethine compound (1) using the compound (2) as a raw material, the mixture (M1) produced by such a method is used as a raw material, thereby improving the efficiency with a good yield. Thus, compound (1) can be obtained.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated further more concretely, this invention is not limited by these examples. Unless otherwise specified, “%” and “part” in the examples indicate mass% and mass part.

Analytical conditions for high performance liquid chromatography (HPLC) are shown below.
<HPLC analysis condition 1>
Measuring apparatus: LC-10AT [manufactured by Shimadzu Corporation]
Column: Kinexex (registered trademark) ODS (5 μm, 4.6 mmφ × 10 cm)
Column temperature: 40 ° C
Mobile phase:
A: 0.1% trifluoroacetic acid aqueous solution B: 0.1% trifluoroacetic acid acetonitrile solution gradient:
0 minutes B = 2%
25 minutes B = 30%
30 minutes B = 30%
30.1 minutes B = 2%
40 minutes STOP (TOTAL analysis time 40 minutes)
Flow rate: 1.0 mL / min Detection: UV absorption (wavelength: 254 nm)

<HPLC analysis condition 2>
Measuring apparatus: LC-10AT [manufactured by Shimadzu Corporation]
Column: Kinexex (registered trademark) ODS (5 μm, 4.6 mmφ × 10 cm)
Column temperature: 40 ° C
Mobile phase:
A: 0.1% trifluoroacetic acid aqueous solution B: 0.1% trifluoroacetic acid acetonitrile solution Gradient: 0 minutes B = 2%
30 minutes B = 100%
35 minutes B = 100%
35.1 minutes B = 2%
45 minutes STOP (TOTAL analysis time 45 minutes)
Flow rate: 1.0 mL / min Detection: UV absorption (wavelength: 254 nm)

(Synthesis Example 1)

  In a 300 mL four-necked flask equipped with a stirrer, a Dimroth condenser, and a thermometer, 20 g of 2-methyl-1-pyrroline (manufactured by Sigma-Aldrich Japan) and 200 g of acetonitrile were stirred in a nitrogen atmosphere. The temperature was kept at an internal temperature of 25 ° C. 51.2 g of methyl iodide (manufactured by Wako Pure Chemical Industries, Ltd.) was dropped from the dropping funnel over 2 hours, and the temperature was further maintained for 2 hours after the completion of the dropping. Next, the solution was concentrated under reduced pressure using a vacuum evaporator to remove acetonitrile, and then the precipitated light brown crystals were put into a vacuum dryer at a temperature of 35 ° C. to obtain 53.6 g of dry crude crystals of compound (A-1). . The apparent yield was 99%.

¹ H-NMR analysis confirmed that the compound (5-1) was produced. The results of ¹ H-NMR analysis are shown below.
¹ H-NMR [CDCl ₃ , δ (ppm)]: 2.36 (quin. 2H), 2.63 (s, 3H), 3.40-3.48 (m, 2H), 3.57 (s 3H), 4.30-4.36 (m, 2H).

Example 1
<Process (I)>

  In a 300 mL four-necked flask equipped with a stirrer, a Dimroth condenser, and a thermometer, under a nitrogen atmosphere, 50 g of crude crystal of compound (5-1) and 1-butanol (manufactured by Wako Pure Chemical Industries, Ltd.) 150 g Was added, and stirring was started. After preparing the mixture (M3-1), the internal temperature was set to 80 ° C. using an oil bath.

  43.2 g and 1 of N, N′-diphenylformamidine (manufactured by Tokyo Chemical Industry Co., Ltd.) under a nitrogen atmosphere in a separately prepared 300 mL-four-necked flask equipped with a stirrer, a Dimroth condenser and a thermometer. -Butanol 216g was prepared, stirring was started, and after preparing a mixture (M4-1), the internal temperature was 80 degreeC using the oil bath. Next, the rate at which N, N′-diphenylformamidine is added dropwise to the mixture (M3-1) and the mixture (M4-1) to 1 mol of the compound (5-1) is 0 per hour. The mixture was added dropwise over 4 hours so as to be 25 mol, and further kept at an internal temperature of 80 ° C. for 4 hours.

  After confirming the consumption of N, N′-diphenylformamidine by HPLC analysis, the mixture was cooled to an internal temperature of 10 ° C., and the deposited wet crystals were collected by filtration. The wet crystals were washed with 2-propanol and then placed in a vacuum dryer at 40 ° C. to obtain 62.8 g of dry crystals of a mixture of the compound (2-1) and the compound (3-1).

As a result of performing HPLC analysis (analysis condition 1) of the dried crystals, the detection peak area ratio between the compound (2-1) and the compound (3-1) was 81:19.
Moreover, it confirmed that the said compound (2-1) and the compound (3-1) produced | generated by < ¹ > H-NMR analysis. The results of ¹ H-NMR analysis are shown below.
¹ H-NMR [DMF-d6, δ (ppm)]: 1.70-1.81 (quin.2H), 2.31 (s, 0.6H), 2.50-2.62 (m, 0 .4H), 2.89 (s, 3H), 3.00-3.08 (m, 5H), 3.54-3.60 (m, 2H), 3.69-3.75 (m, 0) .4H), 5.62 (d, 1H), 6.67-6.80 (m, 1H), 6.94-7.15 (m, 5H), 7.60 (s, 0.2H), 7.96 (s, 0.1H), 8.12 (d, 1H), 10.89 (s, 1H).

<Process (II)>

  In a 100 mL four-necked flask equipped with a stirrer, a Dimroth condenser, and a thermometer, in a nitrogen atmosphere, 10 g of dry crystals of a mixture of the compound (2-1) and the compound (3-1), acetic anhydride (Wako Pure) Yakuhin Kogyo Co., Ltd. (3.0 g), ethyl cyanoacetate (Tokyo Kasei Kogyo Co., Ltd.) 3.3 g, and acetonitrile (Wako Pure Chemical Industries, Ltd.) 30 g were charged and stirring was started. Was brought to 25 ° C. Under an internal temperature of 25 ° C., 3.0 g of triethylamine (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise from a dropping funnel, and triethylamine was added dropwise to 1 mol of compound (2-1). The solution was added dropwise over 2 hours so as to be 0.62 mol, and further kept at an internal temperature of 25 ° C. for 2 hours.

  After confirming the completion of the reaction by HPLC analysis (analysis condition 2 above), the flask was immersed in an ice bath to bring the internal temperature to 2 ° C. Next, 150 g of ice water was placed in a 300 mL beaker and stirred, the reaction solution was dropped into the beaker to crystallize the compound (1-1), and the resulting wet crystals were collected by filtration. The wet crystals were dispersed and washed five times in total using a mixed solvent of water: acetonitrile = 5: 1, and then wet crystals were further washed three times in total using heptane. The wet crystals thus obtained were dried in a vacuum dryer at 75 ° C. to obtain 4.16 g of yellow powdered compound (1-1) (dry crystals). The yield was 74%.

¹ H-NMR analysis confirmed that the compound (1-1) was produced. The results of ¹ H-NMR analysis are shown below.
¹ H-NMR [CDCl ₃ , δ (ppm)]: 1.31 (t, 3H), 2.09 (quin. 2H), 3.01 (m, 5H), 3.64 (t, 2H), 4.23 (q, 2H), 5.52 (d, 1H), 7.92 (d, 1H).

As a result of performing HPLC analysis (the above analysis condition 2) of the obtained dried crystal, it was confirmed that the byproduct (A) having the following structure derived from the above compound (3-1) was not mixed.

(Example 2)

  In a 200 mL four-necked flask equipped with a stirrer, a Dimroth condenser, and a thermometer, the compound (2-1) and the compound (3-1) obtained in step (I) of Example 1 under a nitrogen atmosphere 20 g of dry crystals, 6.0 g of acetic anhydride (Wako Pure Chemical Industries, Ltd.), 11.6 g of 2-ethylhexyl cyanoacetate (Tokyo Chemical Industry Co., Ltd.), and acetonitrile (Wako Pure Chemical Industries, Ltd.) ) 60g) was charged and stirring was started, and the internal temperature was adjusted to 25 ° C. Under an internal temperature of 25 ° C., 7.6 g of N, N′-diisopropylethylamine (hereinafter abbreviated as “DIPEA”, manufactured by Tokyo Chemical Industry Co., Ltd.) was added from the dropping funnel to DIPEA with respect to 1 mol of the compound (2-1). The solution was added dropwise over 2 hours so that the rate of dropwise addition was about 0.62 mol per hour, and further kept at an internal temperature of 25 ° C. for 2 hours.

  After confirming the completion of the reaction by HPLC analysis (analysis condition 2 above), the flask was immersed in an ice bath to bring the internal temperature to 2 ° C. Next, 300 g of ice water was placed in a 500 mL beaker and stirred. The reaction solution was dropped into the beaker to crystallize the compound (1-2), and the resulting wet crystals were collected by filtration. The wet crystals were dispersed and washed five times in total using a mixed solvent of water: acetonitrile = 5: 1, and then wet crystals were further washed three times in total using heptane. The wet crystals thus obtained were dried in a vacuum dryer at 75 ° C. to obtain 12.9 g of yellow powdered compound (1-2) (dry crystals). The yield was 83%.

¹ H-NMR analysis confirmed that the compound (1-2) was produced. The results of ¹ H-NMR analysis are shown below.
1H-NMR [CDCl ₃ , δ (ppm)]: 0.87-0.94 (m, 6H), 1.32-1.67 (m, 8H), 1.59-1.66 (m, 2H) ), 2.09 (quin, 2H), 3.00 (m, 5H), 3.64 (t, 2H), 4.10 (dd, 2H), 5.52 (d, 2H), 7.87 (D, 2H).

As a result of performing HPLC analysis (the above analysis condition 2) of the obtained dried crystal, it was confirmed that the by-product (B) having the following structure derived from the above compound (3-1) was not mixed.

(Example 3)

  In a 200 mL four-necked flask equipped with a stirrer, a Dimroth condenser, and a thermometer, the compound (2-1) and the compound (3-1) obtained in step (I) of Example 1 under a nitrogen atmosphere 20 g of dry crystals, 6.0 g of acetic anhydride (manufactured by Wako Pure Chemical Industries, Ltd.), 9.3 g of 2-ethoxyethyl cyanoacetate (manufactured by Tokyo Chemical Industry Co., Ltd.), and acetonitrile (Wako Pure Chemical Industries, Ltd. ( 120 g) was charged and stirring was started, and the internal temperature was adjusted to 25 ° C. Under an internal temperature of 25 ° C., 7.6 g of DIPEA (manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise from a dropping funnel, and DIPEA was added dropwise to 1 mol of compound (2-1) at a rate of about 0 per hour. The solution was added dropwise over 2 hours so that the amount was 0.62 mol, and further kept at an internal temperature of 25 ° C. for 2 hours.

  After confirming the completion of the reaction by HPLC analysis (analysis condition 2 above), the flask was immersed in an ice bath to bring the internal temperature to 2 ° C. Next, 300 g of ice water was placed in a 500 mL beaker and stirred. The reaction solution was dropped into the beaker to crystallize the compound (1-3), and the resulting wet crystals were collected by filtration. The wet crystals were dispersed and washed five times in total using a mixed solvent of water: acetonitrile = 5: 1, and then wet crystals were further washed three times in total using heptane. The obtained wet crystals were dried in a vacuum dryer at 75 ° C. to obtain 9.05 g of yellow powder compound (1-3) (dry crystals). The yield was 67%.

¹ H-NMR analysis confirmed that the compound (1-3) was produced. The results of ¹ H-NMR analysis are shown below.
¹ H-NMR [CDCl ₃ , δ (ppm)]: 1.21 (t, 3H), 2.10 (quin. 2H), 2.98-3.04 (m, 5H), 3.54-3 .72 (m, 6H), 4.31 (t, 2H), 5.53 (d, 2H), 7.93 (d, 2H).

As a result of performing HPLC analysis (the above analysis condition 2) of the obtained dried crystal, it was confirmed that the by-product (C) having the following structure derived from the compound (3-1) was not mixed.

Example 4
3.66 g of yellow powder compound (1-1) was obtained in the same manner as in Example 1 except that ethanol (manufactured by Nacalai Tesque) was used instead of acetonitrile for the solvent used in the reaction. . The yield was 65%.

As a result of performing HPLC analysis (the above analysis condition 2) of the obtained dried crystal, it was confirmed that the by-product (A) shown above due to the compound (3-1) was not mixed.

(Example 5)
The internal temperature in the four-necked flask when DIPEA was dropped was set to 70 ° C., HPLC analysis was performed at the end of DIPEA dropping, and the completion of the reaction was confirmed. 12.3 g of compound (1-2) was obtained. The yield was 79%.

  As a result of performing HPLC analysis (the above analysis condition 2) of the obtained dried crystal, it was confirmed that the byproduct (B) shown above due to the compound (3-1) was not mixed.

攪拌機、ジムロート冷却管、及び温度計を設置した２００ｍＬ−四ツ口フラスコ内に、窒素雰囲気下、実施例１の工程（I）で得られた化合物（２−１）と化合物（３−１）の混合物の乾燥結晶２０ｇ、無水酢酸（和光純薬工業（株）製）６．３ｇ、シアノ酢酸−２−エチルブチル１０．４ｇ、及びアセトニトリル（和光純薬工業（株）製）６０ｇを仕込んで攪拌を開始し、内温を２５℃にした。２５℃の内温下、滴下漏斗からＤＩＰＥＡ（東京化成工業（株）製）８．０ｇを、化合物（２−１）１モルに対してＤＩＰＥＡを滴下して添加する速度が一時間あたり約０．６３モルとなるように、２時間かけて滴下し、さらに内温２５℃にて２時間保温した。 (Example 6)

In a 200 mL four-necked flask equipped with a stirrer, a Dimroth condenser, and a thermometer, the compound (2-1) and the compound (3-1) obtained in step (I) of Example 1 under a nitrogen atmosphere 20 g of dry crystals of the mixture, 6.3 g of acetic anhydride (manufactured by Wako Pure Chemical Industries, Ltd.), 10.4 g of 2-ethylbutyl cyanoacetate, and 60 g of acetonitrile (manufactured by Wako Pure Chemical Industries, Ltd.) were stirred. The internal temperature was brought to 25 ° C. Under an internal temperature of 25 ° C., 8.0 g of DIPEA (manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise from a dropping funnel and DIPEA was added dropwise to 1 mol of the compound (2-1). The solution was added dropwise over 2 hours so as to be 0.63 mol, and further kept at an internal temperature of 25 ° C. for 2 hours.

  After confirming the completion of the reaction by HPLC analysis (analysis condition 2 above), the flask was immersed in an ice bath to bring the internal temperature to 2 ° C. Next, 300 g of ice water was placed in a 500 mL beaker and stirred. The reaction solution was dropped into the beaker to crystallize the compound (1-4), and the resulting wet crystals were collected by filtration. The wet crystals were dispersed and washed five times in total using a mixed solvent of water: acetonitrile = 5: 1, and then wet crystals were further washed three times in total using heptane. The obtained wet crystals were dried in a vacuum dryer at 75 ° C. to obtain 11.6 g of yellow powder compound (1-4) (dry crystals). The yield was 85%.

¹ H-NMR analysis confirmed that the compound (1-4) was produced. The results of ¹ H-NMR analysis are shown below.
¹ H-NMR [CDCl ₃ , δ (ppm)]: 0.91 (t, 6H), 1.35 to 1.46 (m, 4H), 1.53-1.63 (m, 1H), 2 .09 (quin.2H) 2.98-3.04 (m, 5H), 3.64 (t, 2H), 4.10 (d, 2H), 5.52 (d, 1H), 7.92 (D, 2H).

As a result of performing HPLC analysis (the above analysis condition 2) of the obtained dried crystal, it was confirmed that the by-product (D) having the following structure derived from the compound (3-1) was not mixed.

攪拌機、ジムロート冷却管、及び温度計を設置した２００ｍＬ−四ツ口フラスコ内に、窒素雰囲気下、実施例１の工程（I）で得られた化合物（２−１）と化合物（３−１）の混合物の乾燥結晶２０ｇ、無水酢酸（和光純薬工業（株）製）６．３ｇ、シアノ酢酸−２−ブチルオクチル１５．６ｇ、及びアセトニトリル（和光純薬工業（株）製）６０ｇを仕込んで攪拌を開始し、内温を２５℃にした。２５℃の内温下、滴下漏斗からＮ，Ｎ’−ジイソプロピルエチルアミン（以下、ＤＩＰＥＡと略す。東京化成工業（株）製）８．０ｇを、化合物（２−１）１モルに対してＤＩＰＥＡを滴下して添加する速度が一時間あたり約０．６３モルとなるように、２時間かけて滴下し、さらに内温２５℃にて２時間保温した。 (Example 7)

In a 200 mL four-necked flask equipped with a stirrer, a Dimroth condenser, and a thermometer, the compound (2-1) and the compound (3-1) obtained in step (I) of Example 1 under a nitrogen atmosphere 20 g of dry crystals of the mixture, 6.3 g of acetic anhydride (manufactured by Wako Pure Chemical Industries, Ltd.), 15.6 g of cyanoacetic acid-2-butyloctyl, and 60 g of acetonitrile (manufactured by Wako Pure Chemical Industries, Ltd.) Agitation was started and the internal temperature was adjusted to 25 ° C. Under an internal temperature of 25 ° C., 8.0 g of N, N′-diisopropylethylamine (hereinafter abbreviated as DIPEA, manufactured by Tokyo Chemical Industry Co., Ltd.) was added from the dropping funnel, and DIPEA was added to 1 mol of the compound (2-1). The solution was added dropwise over 2 hours so that the rate of dropwise addition was about 0.63 mol per hour, and further kept at an internal temperature of 25 ° C. for 2 hours.

  After confirming the completion of the reaction by HPLC analysis (analysis condition 2 above), the flask was immersed in an ice bath to bring the internal temperature to 2 ° C. Next, 300 g of ice water was placed in a 500 mL beaker and stirred, and the reaction solution was dropped into the beaker to crystallize the compound (1-5), and the resulting wet crystals were collected by filtration. The wet crystals were dispersed and washed five times in total using a mixed solvent of water: acetonitrile = 5: 1, and then wet crystals were further washed three times in total using heptane. The obtained wet crystals were dried in a vacuum dryer at 75 ° C. to obtain 14.8 g of yellow powder compound (1-5) (dry crystals). The yield was 83%.

¹ H-NMR analysis confirmed that the compound (1-5) was produced. The results of ¹ H-NMR analysis are shown below.
¹ H-NMR [CDCl ₃ , δ (ppm)]: 0.85-0.90 (m, 6H), 1.26 (m, 16H) 1.68 (m, 1H), 2.09 (quin. 2H) 2.94-3.03 (m, 5H), 3.64 (t, 2H), 4.07 (d, 2H), 5.52 (d, 1H), 7.91 (d, 2H) .

As a result of performing HPLC analysis (the above analysis condition 2) of the obtained dried crystal, it was confirmed that the by-product (E) having the following structure derived from the compound (3-1) was not mixed.

(Comparative Example 1)
<Process (I)>
In a 300 mL four-necked flask equipped with a stirrer, a Dimroth condenser, and a thermometer, under a nitrogen atmosphere, 50 g of crude crystals of compound (5-1), N, N′-diphenylformamidine (Tokyo Chemical Industry Co., Ltd.) )) 43.6 g and 1-butanol (manufactured by Wako Pure Chemical Industries, Ltd.) 200 g were charged, stirring was started, the internal temperature was set to 80 ° C. using an oil bath, and the temperature was kept for 4 hours. The consumption of N, N′-diphenylformamidine was confirmed by HPLC analysis, cooled to an internal temperature of 10 ° C., and the deposited wet crystals were collected by filtration. The wet crystals were washed with 2-propanol, and then put into a 40 ° C. vacuum dryer to obtain 60.3 g of dry crystals of a mixture of the compound (2-1) and the compound (3-1).

  As a result of performing the HPLC analysis (the above-mentioned analysis condition 1) of the dried crystal, the detection peak area ratio between the compound (2-1) and the compound (3-1) was 57:43. When this result was compared with the result of Example 1, it was found that the yield of compound (2-1) was reduced by 24%.

<Process (II)>
In a 100 mL four-necked flask equipped with a stirrer, a Dimroth condenser, and a thermometer, in a nitrogen atmosphere, 10 g of dry crystals of a mixture of the compound (2-1) and the compound (3-1), acetic anhydride (Wako Pure) 3.0 g of Yakuhin Kogyo Co., Ltd., 3.0 g of triethylamine (manufactured by Wako Pure Chemical Industries, Ltd.), 3.3 g of ethyl cyanoacetate (manufactured by Tokyo Chemical Industry Co., Ltd.), and acetonitrile (Wako Pure Chemical Industries, Ltd.) 30 g) was charged and stirring was started, and the temperature was kept at 25 ° C. for 3 hours.

  After confirming the completion of the reaction by HPLC analysis (analysis condition 2 above), the flask was immersed in an ice bath to bring the internal temperature to 2 ° C. A 300 mL beaker was charged with 150 g of ice water and stirred. The reaction solution was dropped into the beaker to crystallize the compound (1-1), and the resulting wet crystals were collected by filtration. The wet crystals were dispersed and washed five times in total using a mixed solvent of water: acetonitrile = 5: 1, and then wet crystals were further washed three times in total using heptane. The wet crystals thus obtained were dried in a vacuum dryer at 75 ° C. to obtain 3.99 g of yellow powder compound (1-1) (dry crystals). The yield was 71%.

  As a result of performing HPLC analysis (analysis condition 2) of the obtained dried crystal, 17% (area percentage) of the by-product (A) shown above due to the compound (3-1) is mixed. It was confirmed. Moreover, as a result of measuring the maximum absorption wavelength of each component using a photodiode array (PDA) detector attached to the HPLC apparatus, the compound (1-1) was 383 nm, whereas the by-product (A) was It was 404 nm, and it was confirmed that the by-product (A) was mixed as a coloring component.

(Comparative Example 2)
The rate at which N, N′-diphenylformamidine is added dropwise to the mixture (M4-1) and the mixture (M3-1) to 1 mol of the compound (5-1) is 0.25 per hour. The compound (2-1) and the compound were all added in the same manner as in the step (I) of Example 1 except that the solution was added dropwise over 4 hours so as to be a mole, and further kept at an internal temperature of 80 ° C. for 4 hours. 62.5 g of dry crystals of the mixture of (3-1) was obtained.

  As a result of performing HPLC analysis (the above analysis condition 1) of the dried crystals, the detection peak area ratio of the compound (2-1) to the compound (3-1) was 55:45. When this result was compared with the result of Example 1, it was found that the yield of compound (2-1) was reduced by 26%.

(Reference Example 1)
In Example 1, crystals that had precipitated when the completion of the reaction in step (II) was confirmed were collected by filtration to obtain wet crystals. As a result of performing HPLC analysis (the above analysis condition 2) of the wet crystal, it was confirmed that 6.1% (area percentage) of the compound (3-1) was mixed.

Claims (11)

Following formula (1)

[Wherein, R ¹ and R ² independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 20 carbon atoms, and R ¹ and R ² are bonded to each other, May form a ring together with the carbon atom and nitrogen atom to which — is bonded, —CH ₂ — constituting the alkyl group having 1 to 20 carbon atoms is replaced with —O—, —S—, or —NH—. It may be. R ³ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, and —CH ₂ — constituting the alkyl group having 1 to 10 carbon atoms is replaced with —O— or —S—. It may be. R ⁴ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. X ¹ and X ² each independently represent an electron-withdrawing group, and X ¹ and X ² may be bonded to each other to form a ring together with the carbon atom to which they are bonded. ]
A process for producing a compound represented by
Following formula (2)

[Wherein, R ⁵ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aryl group having 6 to 12 carbon atoms which may have a substituent. Z ⁻ represents an anion. R ^{1 to} R ⁴ represent the same meaning as described above. ]
A compound represented by the following formula (3)

[Wherein R ^{1 to} R ⁵ and Z ⁻ represent the same meaning as described above. ]
And a compound represented by the following formula (4)

[Wherein, X ¹ and X ² represent the same meaning as described above. ]
A step (II) of reacting the compound represented by the formula (2) with the compound represented by the formula (4) while adding a base to the mixture (M2) containing the compound represented by A manufacturing method. Following formula (5)

[Wherein R ^{1 to} R ³ and Z ⁻ represent the same meaning as described above. ]
In the compound represented by the following formula (6)

[Wherein R ⁶ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms; ⁴ and R ⁵ represent the same meaning as described above. ]
While adding the compound represented by the formula (5), the compound represented by the formula (5) and the compound represented by the formula (6) are reacted, The method of Claim 1 including the process (I) of obtaining the mixture (M1) containing the compound represented by the said Formula (3). In the compound represented by the formula (1), the compound represented by the formula (2), and the compound represented by the formula (3), R ¹ and R ² are bonded to each other, and they are bonded. The method of Claim 1 which is a compound which forms the ring with a carbon atom and a nitrogen atom. The compound represented by the formula (5) is a compound in which R ¹ and R ² are bonded to each other and form a ring together with the carbon atom and nitrogen atom to which they are bonded, and represented by the formula (6). The method according to claim 2, wherein R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ are each an aryl group having 6 to 12 carbon atoms that may have a substituent. .   In the said process (II), a base is added at a speed | rate of 0.17-10 mol per hour with respect to 1 mol of compounds represented by the said Formula (2). the method of.   In the step (I), the compound represented by the formula (6) is added at a rate of 0.02 to 300 mol per hour with respect to 1 mol of the compound represented by the formula (5). Item 5. The method according to Item 2 or 4.   The method according to claim 1, wherein the base is at least one selected from the group consisting of acetates, secondary amines, tertiary amines, and imines.   The compound represented by the formula (4) is Meldrum's acid, barbituric acid, dimedone, benzoylacetonitrile, malononitrile, cyanoacetic acid ester, malonic acid ester, or a derivative thereof. The method described in 1.   The method according to any one of claims 1 to 8, comprising a step of adding the reaction mixture obtained in the step (II) into water after the step (II). Following formula (5)

[Wherein, R ¹ and R ² independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 20 carbon atoms, and R ¹ and R ² are bonded to each other, May form a ring together with the carbon atom and nitrogen atom to which — is bonded, —CH ₂ — constituting the alkyl group having 1 to 20 carbon atoms is replaced with —O—, —S—, or —NH—. It may be. R ³ represents an optionally substituted alkyl group having 1 to 10 carbon atoms, and —CH ₂ — constituting the alkyl group having 1 to 10 carbon atoms is replaced with —O— or —S—. It may be. Z ⁻ represents an anion. ]
In the compound represented by the following formula (6)

[Wherein, R ⁴ represents a hydrogen atom, an optionally substituted alkyl group having 1 to 10 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. R ⁵ and R ⁶ are each independently a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aryl group having 6 to 12 carbon atoms. Represents. ]
The compound represented by the above formula (5) is reacted with the compound represented by the above formula (6) while adding the compound represented by the following formula (2).

[Wherein R ^{1 to} R ³ and Z ⁻ represent the same meaning as in formula (5), and R ⁴ and R ⁵ represent the same meaning as in formula (6). ]
And a compound represented by the following formula (3)

[Wherein R ^{1 to} R ³ and Z ⁻ represent the same meaning as in formula (5), and R ⁴ and R ⁵ represent the same meaning as in formula (6). ]
The method of manufacturing the mixture (M1) containing the compound represented by these. The compound represented by the formula (5) is a compound in which R ¹ and R ² are bonded to each other and form a ring together with the carbon atom and nitrogen atom to which they are bonded, and represented by the formula (6). The compound according to claim 10, wherein R ⁴ is a hydrogen atom, and R ⁵ and R ⁶ are each an aryl group having 6 to 12 carbon atoms which may have a substituent. .