JP2018070607A - Method for producing oxadiazole derivative substituted with amino group - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an intermediate and a production method of an oxadiazole derivative substituted with an amino group, the derivative having NPY Y5 receptor antagonism.SOLUTION: Provided is an intermediate which is a salt of a compound represented by formula (I) and one basic compound selected from a substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted bezimidazole, substituted benzotriazole, and substituted benzopyrazole. Also provided is a method for producing an oxadiazole derivative substituted with an amino group, comprising reacting the salt with a halogenating agent or a base, if desired, in the presence of a basic compound which forms the salt, the derivative having NPY Y5 receptor antagonism.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing an oxadiazole derivative substituted with an amino group. Specifically, the present invention relates to an oxadiazole derivative substituted with an amino group having an NPY Y5 receptor antagonistic action, and a method for producing an intermediate thereof.

Example 1 of Patent Document 1 describes a method for producing an oxadiazole intermediate 4 using an aryl nitrile derivative and an oxadiazole derivative 6 substituted with an amino group.

  However, the salt of oxadiazolone 3 is neither described nor suggested. In addition, in the coupling reaction between the oxadiazole derivative 4 and the amine 5, Patent Document 1 describes a coupling reaction using chloro as a leaving group, but after converting oxadiazolone to chlorooxadiazole. There is no description or suggestion of a production method in which a leaving group other than chloro, particularly a basic compound used as a salt of oxadiazolone, is introduced as a leaving group and then coupled with an amine.

International Publication No. 2012/147774

The object of the present invention is to provide a useful intermediate of an oxadiazole derivative substituted with an amino group having an NPY Y5 receptor antagonistic activity represented by the formula (V) and a novel and useful compound represented by the formula (V). It is to provide a manufacturing method.
The present inventors have found a novel salt of oxadiazolone and a basic compound, and a new intermediate in which the basic compound is introduced into oxadiazole. In the coupling reaction between an oxadiazole derivative and an amine, the inventors have found a production method in which a new intermediate in which the basic compound is introduced into oxadiazole and an amine are coupled.
In Patent Document 1, Compound 14 described in the present specification is described as Compound I-136. This compound I-136 is produced by producing 5-chloro-3-trifluoromethyloxadiazole and then coupling with the substituted amine compound 5 in the same manner as the compound 6 described in Example 1. Has been. Compound I-136 is a crystal having the peaks shown below.
XRPD peaks (2θ): 11.1, 11.5, 17.4, 19.6, and 22.7.

で示される化合物の、
置換もしくは非置換のイミダゾール、置換トリアゾール、置換ピラゾール、置換ピロール、置換もしくは非置換のベンゾイミダゾール、置換ベンゾトリアゾール、および置換ベンゾピラゾールから選択される１つの塩基性化合物との塩。
（２）塩基性化合物が、
置換もしくは非置換のイミダゾール、置換トリアゾール、置換ピラゾール、置換ピロール、置換もしくは非置換のベンゾイミダゾール、置換ベンゾトリアゾール、および置換ベンゾピラゾール（ただし、置換基は置換もしくは非置換のアルキル）から選択される、上記（１）記載の塩。
（３）塩基性化合物が、
置換もしくは非置換のイミダゾール、置換トリアゾール、置換ピラゾール、置換ピロール、置換もしくは非置換のベンゾイミダゾール、置換ベンゾトリアゾール、および置換ベンゾピラゾール（ただし、置換基は置換もしくは非置換のアルキルであり、環を構成している炭素原子に置換している）から選択される、上記（２）記載の塩。
（４）塩基性化合物が

から選択される、上記（３）記載の塩。
（５）塩基性化合物が

である、上記（４）記載の塩。
（６）結晶である、上記（４）または（５）記載の塩。
（６−１）粉末Ｘ線回折の２θの値が、９．９±０．２°、１１．４±０．２°、１９．８±０．２°、２５．４±０．２°、および２９．８±０．２°から選択される２つ以上である、上記（６）記載の結晶。
（６−２）粉末Ｘ線回折の２θの値が、９．９±０．２°、１１．４±０．２°、１９．８±０．２°、２５．４±０．２°、および２９．８±０．２°である、上記（６）記載の結晶。
（６−３）図１に実質的に一致する粉末Ｘ線回折スペクトルにより特徴付けられる、上記（６）記載の結晶。
（７）式（ＩＩ）:

（式中、Ｒ^３は水素原子、または置換もしくは非置換のアルキル）で示される化合物。
（８）Ｒ^３が水素原子である、上記（７）記載の化合物。
（８−１）粉末Ｘ線回折の２θの値が、１９．９±０．２°、２１．６±０．２°、２５．１±０．２°、２６．０±０．２°、および３０．０±０．２°から選択される２つ以上である、上記（８）記載の結晶。
（８−２）粉末Ｘ線回折の２θの値が、１９．９±０．２°、２１．６±０．２°、２５．１±０．２°、２６．０±０．２°、および３０．０±０．２°である、上記（８）記載の結晶。
（８−３）図３に実質的に一致する粉末Ｘ線回折スペクトルにより特徴付けられる、上記（８）記載の結晶。
（９）式（ＩＩＩ）：

（式中、Ｒ^１は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、または置換もしくは非置換の芳香族複素環式基）で示される化合物を、ハロゲン化剤、塩基、ならびに置換もしくは非置換のイミダゾール、置換トリアゾール、置換ピラゾール、置換ピロール、置換もしくは非置換のベンゾイミダゾール、置換ベンゾトリアゾール、および置換ベンゾピラゾールから選択される１つの塩基性化合物と反応させることを特徴とする、式（ＩＶ）：

（式中、Ｒ^１は上記と同意義、Ｒ^４は置換もしくは非置換のイミダゾリル、置換トリアゾリル、置換ピラゾリル、置換ピロリル、置換もしくは非置換のベンゾイミダゾリル、置換ベンゾトリアゾリル、または置換ベンゾピラゾリル）で示される化合物の製造方法。
（１０）式（ＩＩＩ）：

（式中、Ｒ^１は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、または置換もしくは非置換の芳香族複素環式基）で示される化合物の、置換もしくは非置換のイミダゾール、置換トリアゾール、置換ピラゾール、置換ピロール、置換もしくは非置換のベンゾイミダゾール、置換ベンゾトリアゾール、および置換ベンゾピラゾールから選択される１つの塩基性化合物との塩を、
ハロゲン化剤および塩基と、所望により該塩を形成している塩基性化合物の存在下で、反応させることを特徴とする、式（ＩＶ）：

（式中、Ｒ^１は上記と同意義、Ｒ^４は置換もしくは非置換のイミダゾリル、置換トリアゾリル、置換ピラゾリル、置換ピロリル、置換もしくは非置換のベンゾイミダゾリル、置換ベンゾトリアゾリル、および置換ベンゾピラゾリル）で示される化合物の製造方法。
（１１）上記（９）または（１０）に記載の方法を含む、式（Ｖ）：

（式中、Ｒ^１は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、または置換もしくは非置換の芳香族複素環式基、Ｒ^２は置換もしくは非置換のアルキル）で示される化合物またはその製薬上許容される塩の製造方法。
（１２）式（ＶＩ）：

で示され、
粉末Ｘ線回折の２θの値が、１１．８±０．２°、１７．０±０．２°、１７．２±０．２°、１８．６±０．２°、および１９．４±０．２°から選択される２つ以上である、化合物の結晶。
（１３）粉末Ｘ線回折の２θの値が、１１．８±０．２°、１７．０±０．２°、１７．２±０．２°、１８．６±０．２°、および１９．４±０．２°である、上記（１２）記載の結晶。
（１４−１）式（ＶＩＩ）：

で示される化合物の結晶。
（１４−２）粉末Ｘ線回折の２θの値が、１１．８±０．２°、１６．８±０．２°、１８．８±０．２°、１９．０±０．２°、および２２．５±０．２°から選択される２つ以上である、上記（１４−１）記載の結晶。
（１４−３）粉末Ｘ線回折の２θの値が、１１．８±０．２°、１６．８±０．２°、１８．８±０．２°、１９．０±０．２°、および２２．５±０．２°である、上記（１４−１）記載の結晶。
（１４−４）図２に実質的に一致する粉末Ｘ線回折スペクトルにより特徴付けられる、上記（１４−１）記載の結晶。
（１５−１）式（ＩＸ）：

で示される化合物の結晶。
（１５−２）粉末Ｘ線回折の２θの値が、１０．０±０．２°、１１．２±０．２°、１４．２±０．２°、１７．５±０．２°、および１９．５±０．２°から選択される２つ以上である、上記（１５−１）記載の結晶。
（１５−３）粉末Ｘ線回折の２θの値が、１０．０±０．２°、１１．２±０．２°、１４．２±０．２°、１７．５±０．２°、および１９．５±０．２°である、上記（１５−１）記載の結晶。
（１５−４）図４に実質的に一致する粉末Ｘ線回折スペクトルにより特徴付けられる、上記（１５−１）記載の結晶。
(1) Formula (I):

Of the compound represented by
A salt with one basic compound selected from substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole.
(2) the basic compound is
Selected from substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole, wherein the substituent is substituted or unsubstituted alkyl, The salt according to (1) above.
(3) the basic compound is
Substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole (provided that the substituent is substituted or unsubstituted alkyl and constitutes a ring) The salt according to the above (2), which is selected from the group (substituent substituted on a carbon atom).
(4) Basic compound

The salt according to the above (3), selected from
(5) Basic compound

The salt according to (4), wherein
(6) The salt according to the above (4) or (5), which is a crystal.
(6-1) The 2θ values of powder X-ray diffraction are 9.9 ± 0.2 °, 11.4 ± 0.2 °, 19.8 ± 0.2 °, 25.4 ± 0.2 °. And the crystal according to (6) above, which is two or more selected from 29.8 ± 0.2 °.
(6-2) The values of 2θ of powder X-ray diffraction are 9.9 ± 0.2 °, 11.4 ± 0.2 °, 19.8 ± 0.2 °, 25.4 ± 0.2 °. And the crystal according to the above (6), which is 29.8 ± 0.2 °.
(6-3) The crystal according to (6) above, characterized by a powder X-ray diffraction spectrum substantially corresponding to FIG.
(7) Formula (II):

(Wherein R ³ is a hydrogen atom, or substituted or unsubstituted alkyl).
(8) The compound according to (7) above, wherein R ³ is a hydrogen atom.
(8-1) The values of 2θ of powder X-ray diffraction are 19.9 ± 0.2 °, 21.6 ± 0.2 °, 25.1 ± 0.2 °, 26.0 ± 0.2 °. And the crystal according to (8) above, which is two or more selected from 30.0 ± 0.2 °.
(8-2) 2θ values of powder X-ray diffraction are 19.9 ± 0.2 °, 21.6 ± 0.2 °, 25.1 ± 0.2 °, 26.0 ± 0.2 ° And the crystal according to (8) above, which is 30.0 ± 0.2 °.
(8-3) The crystal according to (8) above, characterized by a powder X-ray diffraction spectrum substantially corresponding to FIG.
(9) Formula (III):

Wherein R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocycle A compound represented by a formula group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic group), a halogenating agent, a base, and a substituted or unsubstituted imidazole, Formula (IV), characterized by reacting with one basic compound selected from triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole:

Wherein R ¹ is as defined above, R ⁴ is substituted or unsubstituted imidazolyl, substituted triazolyl, substituted pyrazolyl, substituted pyrrolyl, substituted or unsubstituted benzoimidazolyl, substituted benzotriazolyl, or substituted benzopyrazolyl. Process for producing the indicated compound.
(10) Formula (III):

Wherein R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocycle Substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole of the compound represented by the formula: group, substituted or unsubstituted non-aromatic heterocyclic group, or substituted or unsubstituted aromatic heterocyclic group) A salt with one basic compound selected from substituted, unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole,
Formula (IV), characterized by reacting with a halogenating agent and a base, optionally in the presence of a basic compound forming the salt,

Wherein R ¹ is as defined above, and R ⁴ is substituted or unsubstituted imidazolyl, substituted triazolyl, substituted pyrazolyl, substituted pyrrolyl, substituted or unsubstituted benzoimidazolyl, substituted benzotriazolyl, and substituted benzopyrazolyl. Process for producing the indicated compound.
(11) Formula (V) including the method according to (9) or (10) above:

Wherein R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocycle Or a pharmaceutically acceptable compound thereof, which is represented by the formula: group, substituted or unsubstituted non-aromatic heterocyclic group, or substituted or unsubstituted aromatic heterocyclic group, R ² is substituted or unsubstituted alkyl) Method for producing salt.
(12) Formula (VI):

Indicated by
The 2θ values of powder X-ray diffraction are 11.8 ± 0.2 °, 17.0 ± 0.2 °, 17.2 ± 0.2 °, 18.6 ± 0.2 °, and 19.4. A crystal of a compound that is two or more selected from ± 0.2 °.
(13) 2θ values of powder X-ray diffraction are 11.8 ± 0.2 °, 17.0 ± 0.2 °, 17.2 ± 0.2 °, 18.6 ± 0.2 °, and The crystal according to (12), which is 19.4 ± 0.2 °.
(14-1) Formula (VII):

A crystal of the compound represented by
(14-2) 2θ values of powder X-ray diffraction are 11.8 ± 0.2 °, 16.8 ± 0.2 °, 18.8 ± 0.2 °, 19.0 ± 0.2 ° And the crystal according to the above (14-1), which is two or more selected from 22.5 ± 0.2 °.
(14-3) 2θ values of powder X-ray diffraction are 11.8 ± 0.2 °, 16.8 ± 0.2 °, 18.8 ± 0.2 °, 19.0 ± 0.2 ° And the crystal according to (14-1), which is 22.5 ± 0.2 °.
(14-4) The crystal according to (14-1) above, characterized by a powder X-ray diffraction spectrum substantially corresponding to FIG.
(15-1) Formula (IX):

A crystal of the compound represented by
(15-2) 2θ value of powder X-ray diffraction is 10.0 ± 0.2 °, 11.2 ± 0.2 °, 14.2 ± 0.2 °, 17.5 ± 0.2 ° And the crystal according to the above (15-1), which is two or more selected from 19.5 ± 0.2 °.
(15-3) 2θ value of powder X-ray diffraction is 10.0 ± 0.2 °, 11.2 ± 0.2 °, 14.2 ± 0.2 °, 17.5 ± 0.2 ° And the crystal according to (15-1), which is 19.5 ± 0.2 °.
(15-4) The crystal according to (15-1) above, which is characterized by a powder X-ray diffraction spectrum substantially corresponding to FIG.

  By using the present invention, an oxadiazole derivative substituted with an amino group having an NPY Y5 receptor antagonistic activity represented by the formula (V) can be efficiently produced.

3 is powder X-ray diffraction data of Compound 8. The vertical axis represents intensity, and the horizontal axis represents 2θ. 3 is powder X-ray diffraction data of Compound 11. The vertical axis represents intensity, and the horizontal axis represents 2θ. 3 is powder X-ray diffraction data of Compound 9. The vertical axis represents intensity, and the horizontal axis represents 2θ. 3 is a powder X-ray diffraction data of Compound 13. The vertical axis represents intensity, and the horizontal axis represents 2θ. 3 is a powder X-ray diffraction data of Compound 14. The vertical axis represents intensity, and the horizontal axis represents 2θ.

The meaning of each term used in this specification will be described below. Unless otherwise specified, each term is used in the same meaning when used alone or in combination with other terms.
The term “consisting of” means having only the configuration requirements.
The term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.
“Halogen” includes fluorine, chlorine, bromine and iodine. Fluorine and chlorine are preferred, and fluorine is particularly preferred.

“Alkyl” means linear or branched alkyl having 1 to 6 carbon atoms. Including alkyl having 1 to 4 carbon atoms and alkyl having 1 to 3 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like can be mentioned.
As alkyl in R ¹ , methyl, ethyl and the like are preferable, and methyl is particularly preferable.
As alkyl in R ² , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like are preferable, and tert-butyl is particularly preferable.
As alkyl in R ³ , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like are preferable, and methyl and ethyl are particularly preferable.

“Alkenyl” means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at any position. Including alkenyl having 2 to 8 carbon atoms, alkenyl having 3 to 6 carbon atoms and the like. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.
“Alkynyl” means a linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. C2-C6 alkynyl, C2-C4 alkynyl, etc. are included. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.

“Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic saturated hydrocarbon groups. Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, a cycloalkyl having 3 to 6 carbon atoms and a cycloalkyl having 5 or 6 carbon atoms are preferable.
Examples of the ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring, Cyclopentene ring) and the like, and non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
For example, the following groups are also exemplified by cycloalkyl and are included in cycloalkyl. These groups may be substituted at any substitutable position.

「非芳香族炭素環式基」とは、上記「シクロアルキル」および上記「シクロアルケニル」を包含する。 “Cycloalkenyl” refers to a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups. Means. Examples of the cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like. In particular, cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
Examples of the ring condensed with the C3-C8 cyclic unsaturated aliphatic hydrocarbon group include carbocycles (aromatic carbocycles (for example, benzene rings, naphthalene rings)), non-aromatic carbocycles (for example, cycloalkane rings). (Example: cyclohexane ring, cyclopentane ring, etc.), cycloalkene ring (example: cyclohexene ring, cyclopentene ring, etc.)), heterocycle (aromatic heterocycle (pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring, etc.) And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.) The bond is derived from a C3-C8 cyclic unsaturated aliphatic hydrocarbon group. .
For example, the following groups are also exemplified as cycloalkenyl and are included in cycloalkenyl. These groups may be substituted at any substitutable position.

The “non-aromatic carbocyclic group” includes the above “cycloalkyl” and the above “cycloalkenyl”.

The “aromatic carbocyclic group” is a monocyclic or polycyclic aromatic carbocyclic group, and these monocyclic or polycyclic aromatic carbocyclic groups are each further substituted by 1 or 3 to 8 membered rings. It means a group condensed with two. Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
Rings condensed with monocyclic or polycyclic aromatic carbocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to be from a monocyclic or polycyclic aromatic carbocyclic group.
For example, the following groups are also exemplified as the aromatic carbocyclic group, and are included in the aromatic carbocyclic group. These groups may be substituted at any substitutable position.

“Aromatic heterocyclic group” means a monocyclic or polycyclic aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these monocyclic rings Alternatively, it means a group in which one or two 3- to 8-membered rings are condensed to a polycyclic aromatic heterocyclic group.
As the “monocyclic aromatic heterocyclic group”, a 5- or 6-membered aromatic heterocyclic group is particularly preferable. For example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, Examples include tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
As the “polycyclic aromatic heterocyclic group”, an aromatic heterocyclic group in which a 5-membered or 6-membered ring is condensed is particularly preferable. For example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, Phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzo A bicyclic aromatic heterocyclic group such as thienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazopyridyl; carbazolyl, Kurijiniru, xanthenyl, phenothiazinyl, phenoxathiinyl, cycloalkenyl, phenoxazinyl, and aromatic heterocyclic group of tricyclic dibenzofuryl and the like. In the case of a polycyclic aromatic heterocyclic group, any ring may have a bond.
Rings condensed with monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to be from a monocyclic or polycyclic aromatic heterocyclic group.
For example, the following groups are also exemplified as the aromatic heterocyclic group, and are included in the aromatic heterocyclic group. These groups may be substituted at any substitutable position.

“Non-aromatic heterocyclic group” means a non-aromatic heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N in the ring, and these non-aromatic heterocyclic groups In addition, it means a group in which one or two 3- to 8-membered rings are condensed. It contains a monocyclic non-aromatic heterocyclic group or a polycyclic non-aromatic heterocyclic group.
Specific examples of the `` monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.
Specific examples of the “polycyclic non-aromatic heterocyclic group” include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like. In the case of a polycyclic non-aromatic heterocyclic group, any ring may have a bond.
For example, the following groups are also included in the non-aromatic heterocyclic group.

  Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted is substituted or unsubstituted non-aromatic heterocyclic group, or substituted or unsubstituted heterocyclyl is It may be substituted with 1 or 2 oxo, thioxo or substituted or unsubstituted imino.

“Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted non-aromatic carbocyclic group”, “substituted aromatic carbocyclic group”, “substituted non-aromatic heterocyclic group”, or “substituted” Substituents for `` aromatic heterocyclic group '' include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, amino, carboxy, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, hetero Aryl, heterocyclyl, substituted carbamoyl, substituted sulfamoyl, substituted amidino, group represented by formula: —O—R ¹⁰ , group represented by formula: —O—C (═O) —R ¹⁰ , formula: —C ( ═O) —R ¹⁰ group, formula: —C (═O) —O—R ¹⁰ group, formula: —S—R ¹⁰ group or formula: —SO ₂ A group represented by -R ¹⁰ (wherein R ¹⁰ is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, carbamoyl, sulfamoyl or amidino). With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.
As the substituent of “substituted alkyl”, halogen is preferable, and fluorine is particularly preferable.
The substituent of the “basic compound” is preferably an electron donating group, and examples thereof include substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy and the like. Alkyl or alkyloxy is preferred, especially alkyl (especially methyl or ethyl).

  In the present specification, reacting a compound with a compound includes reacting a salt thereof or a solvate thereof.

  Examples of the pharmaceutically acceptable salt of the compound according to the present invention include a compound according to the present invention, an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium, barium, etc.), Magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids Or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid) Acid, lactic acid, tartaric acid, oxalic acid, maleic acid, Le acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, and salts with ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

  The compound according to the present invention or a pharmaceutically acceptable salt thereof may form solvates (for example, hydrates and the like) and / or crystal polymorphs, and the present invention includes such various solvates. And crystalline polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound according to the present invention. When the compound according to the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound according to the present invention or a pharmaceutically acceptable salt thereof is recrystallized to form a crystal polymorph.

(Method for producing the compound of the present invention)
A general method for producing the compound of the present invention is illustrated below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.

As the raw material compounds, commercially available compounds, those described in the present specification, those described in the literature cited in the present specification, and other known compounds can be used.
When obtaining a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, it may be suspended and an acid or base is added to form a salt by an ordinary method.
In addition, the compounds of the present invention and pharmaceutically acceptable salts thereof may exist in the form of adducts (hydrates or solvates) with water or various solvents, and these adducts are also included in the present invention. Is included.

  “Wedge shape” and “dashed line” indicate the absolute configuration.

（式中、Ｒ^１は置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換の非芳香族炭素環式基、置換もしくは非置換の芳香族炭素環式基、置換もしくは非置換の非芳香族複素環式基、または置換もしくは非置換の芳香族複素環式基、Ｘは置換もしくは非置換のイミダゾール、置換トリアゾール、置換ピラゾール、置換ピロール、置換もしくは非置換のベンゾイミダゾール、置換ベンゾトリアゾール、または置換ベンゾピラゾールである。）
式（ＩＩＩ）で示される化合物を、Ｘで示される塩基性化合物と反応させることにより、式（ＩＩＩ）で示される化合物とＸで示される塩基性化合物との塩（式（ＩＩＩ−１）で示される塩）を得る工程である。
溶媒としては、上記工程を効率よく進行させるものであれば特に制限されない。メタノール、エタノール、４−メチル−２−ペンタノン等が挙げられ、単独もしくは混合、または無溶媒下で反応させることができる。
Ｘで示される塩基性化合物としては、式（ＩＩＩ）で示される化合物と塩を形成し、かつ昇華性、揮発性、潮解性が低い塩を形成するものが好ましい。
また、Ｘで示される塩基性化合物としては、第２工程で、式（ＩＶ）で示される化合物を生成するものが好ましい。さらに、第３工程で、脱離基として働く塩基性化合物が好ましい。
具体的には、置換もしくは非置換のイミダゾール、置換トリアゾール、置換ピラゾール、置換ピロール、置換もしくは非置換のベンゾイミダゾール、置換ベンゾトリアゾール、または置換ベンゾピラゾールが挙げられる。
イミダゾール、トリアゾール、ピラゾール、ピロール、ベンゾイミダゾール、ベンゾトリアゾールまたはベンゾピラゾールの環上の置換基としては、置換もしくは非置換のアルキル（各置換基はメチル、エチル、イソプロピルなどから選択される）、置換もしくは非置換のアルキルオキシ（各置換基は、メトキシ、エトキシなどから選択される）が好ましく、特に、置換もしくは非置換のアルキル（特に、非置換アルキル）が好ましい。
なお、当該置換基は、イミダゾール、トリアゾール、ピラゾール、ピロール、ベンゾイミダゾール、ベンゾトリアゾールまたはベンゾピラゾールの環を構成している炭素原子に置換している場合が好ましい。
さらに具体的には、

が好ましく、特に、

が好ましい。
塩基性化合物は、化合物（ＩＩＩ）に対して１モル当量〜５モル当量、好ましくは１モル当量〜２モル当量用いて反応させればよい。
反応温度は、特に制限されないが通常、約０〜１００℃、好ましくは、室温で行うことができる。
反応時間は、特に制限されないが通常、０．１時間〜２４時間、好ましくは、０．１〜６時間である。
The production method of the present invention can be carried out as follows, for example.
First step

Wherein R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocycle Formula group, substituted or unsubstituted non-aromatic heterocyclic group, or substituted or unsubstituted aromatic heterocyclic group, X represents substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole, substituted or non-substituted Substituted benzimidazole, substituted benzotriazole, or substituted benzopyrazole.)
By reacting the compound represented by the formula (III) with the basic compound represented by X, a salt of the compound represented by the formula (III) and the basic compound represented by X (in the formula (III-1) A salt to be obtained).
The solvent is not particularly limited as long as it allows the above process to proceed efficiently. Methanol, ethanol, 4-methyl-2-pentanone and the like can be mentioned, and the reaction can be performed alone or in combination or without solvent.
The basic compound represented by X is preferably a compound that forms a salt with the compound represented by the formula (III) and forms a salt with low sublimation, volatility, and deliquescence.
Moreover, as a basic compound shown by X, what produces | generates the compound shown by Formula (IV) at a 2nd process is preferable. Furthermore, a basic compound that acts as a leaving group in the third step is preferable.
Specific examples include substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole.
Substituents on the ring of imidazole, triazole, pyrazole, pyrrole, benzimidazole, benzotriazole or benzopyrazole include substituted or unsubstituted alkyl (each substituent is selected from methyl, ethyl, isopropyl, etc.), substituted or Unsubstituted alkyloxy (each substituent is selected from methoxy, ethoxy and the like) is preferred, and substituted or unsubstituted alkyl (particularly unsubstituted alkyl) is particularly preferred.
The substituent is preferably substituted with a carbon atom constituting a ring of imidazole, triazole, pyrazole, pyrrole, benzimidazole, benzotriazole or benzopyrazole.
More specifically,

Are preferred, especially

Is preferred.
The basic compound may be reacted in an amount of 1 to 5 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (III).
The reaction temperature is not particularly limited, but is usually about 0 to 100 ° C., preferably room temperature.
The reaction time is not particularly limited, but is usually 0.1 hour to 24 hours, preferably 0.1 to 6 hours.

（式中、Ｒ^１およびＸは上記と同意義、Ｒ^４は置換もしくは非置換のイミダゾリル、置換トリアゾリル、置換ピラゾリル、置換ピロリル、置換もしくは非置換のベンゾイミダゾリル、置換ベンゾトリアゾリル、および置換ベンゾピラゾリルである。）
式（ＩＩＩ−１）で示される塩を、ハロゲン化剤および塩基と所望により該塩を形成している塩基性化合物の存在下で反応させることにより、式（ＩＶ）で示される化合物を得る工程である。
溶媒としては、上記工程を効率よく進行させるものであれば特に制限されない。酢酸イソプロピル、アセトニトリル、酢酸エチル、シクロヘキサン、酢酸プロピル、トルエン、１，４−ジオキサン、DMA、DMF、トルエン、ヘプタン、シクロペンチルメチルエーテル等が挙げられ、単独または混合して用いることができる。好ましくは、酢酸イソプロピルとアセトニトリルの混合溶媒が挙げられる。
ハロゲン化剤としては、オキシ塩化リン、塩化チオニル、五塩化リン等が挙げられる。好ましくは、オキシ塩化リンが挙げられる。ハロゲン化剤は、化合物（ＩＩＩ−１）に対して１モル当量〜５モル当量、好ましくは１モル当量〜３モル当量用いて反応させればよい。
塩基としては、Ｎ，Ｎ―ジイソプロピルエチルアミン、トリエチルアミン等が挙げられる。好ましくは、Ｎ，Ｎ―ジイソプロピルエチルアミンが挙げられる。塩基は、化合物（ＩＩＩ−１）に対して１モル当量〜５モル当量、好ましくは１モル当量〜３モル当量用いて反応させればよい。
反応温度は、特に制限されないが通常、約０〜１００℃、好ましくは、室温〜８０℃で行うことができる。
反応時間は、特に制限されないが通常、０．５時間〜２４時間、好ましくは、１〜５時間である。
なお、本工程は、所望により該塩を形成している塩基性化合物の存在下で行うことができる。塩基性化合物は、第１工程と同じものを用いることができる。塩基性化合物は、化合物（ＩＩＩ−１）に対して０．１モル当量〜５モル当量、好ましくは１モル当量〜３モル当量用いて反応させればよい。
式（ＩＶ）で示される化合物のうち、式（ＩＩ）:

（式中、Ｒ^３は水素原子、または置換もしくは非置換のアルキル）で示される化合物が好ましい。特に、Ｒ^３が水素原子である化合物が好ましい。
Second step (A)

Wherein R ¹ and X are as defined above, R ⁴ is substituted or unsubstituted imidazolyl, substituted triazolyl, substituted pyrazolyl, substituted pyrrolyl, substituted or unsubstituted benzoimidazolyl, substituted benzotriazolyl, and substituted benzopyrazolyl .)
A step of obtaining a compound represented by the formula (IV) by reacting a salt represented by the formula (III-1) with a halogenating agent and a base, optionally in the presence of a basic compound forming the salt. It is.
The solvent is not particularly limited as long as it allows the above process to proceed efficiently. Examples include isopropyl acetate, acetonitrile, ethyl acetate, cyclohexane, propyl acetate, toluene, 1,4-dioxane, DMA, DMF, toluene, heptane, cyclopentyl methyl ether, and the like. These can be used alone or in combination. Preferably, a mixed solvent of isopropyl acetate and acetonitrile is used.
Examples of the halogenating agent include phosphorus oxychloride, thionyl chloride, phosphorus pentachloride and the like. Preferably, phosphorus oxychloride is used. The halogenating agent may be reacted in an amount of 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to compound (III-1).
Examples of the base include N, N-diisopropylethylamine, triethylamine and the like. Preferably, N, N-diisopropylethylamine is used. The base may be reacted with respect to compound (III-1) by using 1 molar equivalent to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents.
While the reaction temperature is not particularly limited, it can be generally performed at about 0 to 100 ° C, preferably room temperature to 80 ° C.
The reaction time is not particularly limited, but is usually 0.5 hour to 24 hours, preferably 1 to 5 hours.
In addition, this process can be performed in presence of the basic compound which forms this salt if desired. The same basic compound as in the first step can be used. The basic compound may be reacted with respect to compound (III-1) in an amount of 0.1 molar equivalent to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents.
Of the compounds represented by formula (IV), formula (II):

A compound represented by the formula (wherein R ³ is a hydrogen atom, or substituted or unsubstituted alkyl) is preferable. In particular, a compound in which R ³ is a hydrogen atom is preferable.

（Ｒ^１、ＸおよびＲ^４は上記と同意義。）
本工程は、第２工程（Ａ）の代わりに用いることができる。
式（ＩＩＩ）で示される化合物を、ハロゲン化剤、塩基および塩基性化合物と反応させることにより、式（ＩＶ）で示される化合物を得る工程である。
溶媒は、第２工程（Ａ）で用いられる溶媒と同じものを用いることができる。
ハロゲン化剤は、第２工程（Ａ）で用いられるハロゲン化剤と同じものを用いることができ、第２工程（Ａ）と同様のモル当量用いて反応させればよい。
塩基は、第２工程（Ａ）で用いられる塩基と同じものを用いることができ、第２工程（Ａ）と同様のモル当量、または第２工程（Ａ）よりも１当量多いモル当量用いて反応させればよい。
塩基性化合物は、第１工程と同じものを用いることができる。
反応温度は、特に制限されないが通常、約０〜１００℃、好ましくは、室温〜８０℃で行うことができる。
反応時間は、特に制限されないが通常、０．５時間〜２４時間、好ましくは、１〜５時間である。
なお、本工程は、所望により該塩を形成している塩基性化合物の存在下で行うことができる。塩基性化合物は、化合物（ＩＩＩ）に対して０．１モル当量〜５モル当量、好ましくは１モル当量〜３モル当量用いて反応させればよい。 Second step (B)

(R ¹ , X and R ⁴ are as defined above.)
This step can be used in place of the second step (A).
In this step, a compound represented by the formula (IV) is obtained by reacting the compound represented by the formula (III) with a halogenating agent, a base and a basic compound.
As the solvent, the same solvent as that used in the second step (A) can be used.
As the halogenating agent, the same halogenating agent as used in the second step (A) can be used, and the reaction may be performed using the same molar equivalent as in the second step (A).
The same base as that used in the second step (A) can be used as the base, and the same molar equivalent as in the second step (A), or a molar equivalent higher by one equivalent than in the second step (A) is used. What is necessary is just to make it react.
The same basic compound as in the first step can be used.
While the reaction temperature is not particularly limited, it can be generally performed at about 0 to 100 ° C, preferably room temperature to 80 ° C.
The reaction time is not particularly limited, but is usually 0.5 hour to 24 hours, preferably 1 to 5 hours.
In addition, this process can be performed in presence of the basic compound which forms this salt if desired. The basic compound may be reacted with respect to compound (III) using 0.1 molar equivalent to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents.

（式中の記号は上記と同意義である。）
式（ＩＶ）で示される化合物を化合物１０と反応させることにより、式（Ｘ）で示される化合物を得る工程である。
溶媒としては、上記工程を効率よく進行させるものであれば特に制限されない。ＤＭＦ、アセトニトリル、Ｎ−メチルピロリドン、N, N-ジメチルアセトアミド等が挙げられ、単独または混合して用いることができる。好ましくは、ＤＭＦ、アセトニトリルが挙げられる。
化合物１０は化合物（ＩV）に対して、１モル当量〜５モル当量、好ましくは１モル当量〜３モル当量用いて反応させればよい。
反応温度は、特に制限されないが通常、約０〜１００℃、好ましくは、約０℃〜室温で行うことができる。
反応時間は、特に制限されないが通常、０．５時間〜４８時間、好ましくは、０．５〜１２時間である。 Third step

(The symbols in the formula are as defined above.)
In this step, the compound represented by the formula (IV) is reacted with the compound 10 to obtain the compound represented by the formula (X).
The solvent is not particularly limited as long as it allows the above process to proceed efficiently. Examples thereof include DMF, acetonitrile, N-methylpyrrolidone, N, N-dimethylacetamide, and the like can be used alone or in combination. Preferably, DMF and acetonitrile are used.
Compound 10 may be reacted with respect to compound (IV) using 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents.
While the reaction temperature is not particularly limited, it can be generally performed at about 0 to 100 ° C, preferably about 0 ° C to room temperature.
The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 12 hours.

（式中、Ｒ^２は置換もしくは非置換のアルキル、その他の記号は上記と同意義である。）
式（Ｘ）で示される化合物を、縮合剤およびトリフェニルホスフィン存在下、化合物１２と反応させることにより、式（Ｖ）で示される化合物を得る工程である。
溶媒としては、上記工程を効率よく進行させるものであれば特に制限されない。ＴＨＦ等が挙げられ、単独または混合して用いることができる。好ましくは、ＴＨＦが挙げられる。
トリフェニルホスフィンは、式（Ｘ）で示される化合物に対して、１モル当量〜５モル当量、好ましくは１モル当量〜３モル当量用いて反応させればよい。
縮合剤としては、アゾジカルボン酸ジイソプロピル、アゾジカルボン酸ジエチル等が挙げられ、式（Ｘ）で示される化合物に対して、１モル当量〜５モル当量、好ましくは１モル当量〜３モル当量用いて反応させればよい。
化合物１２は式（Ｘ）で示される化合物に対して、１モル当量〜５モル当量、好ましくは１モル当量〜３モル当量用いて反応させればよい。
反応温度は、特に制限されないが通常、約０〜１００℃、好ましくは、約０℃〜室温で行うことができる。
反応時間は、特に制限されないが通常、０．５時間〜４８時間、好ましくは、０．５〜１２時間である。 Fourth step

(Wherein R ² is substituted or unsubstituted alkyl, and other symbols are as defined above.)
In this step, the compound represented by the formula (X) is reacted with the compound 12 in the presence of a condensing agent and triphenylphosphine to obtain a compound represented by the formula (V).
The solvent is not particularly limited as long as it allows the above process to proceed efficiently. THF etc. are mentioned, It can use individually or in mixture. Preferably, THF is used.
Triphenylphosphine may be reacted with respect to the compound represented by the formula (X) by using 1 molar equivalent to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents.
Examples of the condensing agent include diisopropyl azodicarboxylate, diethyl azodicarboxylate, and the like, and 1 mole equivalent to 5 mole equivalent, preferably 1 mole equivalent to 3 mole equivalent is used with respect to the compound represented by the formula (X). What is necessary is just to make it react.
The compound 12 may be reacted with respect to the compound represented by the formula (X) by using 1 molar equivalent to 5 molar equivalents, preferably 1 molar equivalent to 3 molar equivalents.
While the reaction temperature is not particularly limited, it can be generally performed at about 0 to 100 ° C, preferably about 0 ° C to room temperature.
The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 12 hours.

（式中の記号は上記と同意義である。）
式（Ｖ）で示される化合物を、加水分解することにより、式（ＶＩ）で示される化合物を得る工程である。
溶媒としては、上記工程を効率よく進行させるものであれば特に制限されない。メタノール、エタノール、ＴＨＦ等が挙げられ、単独または混合して用いることができる。好ましくは、メタノールが挙げられる。
塩基としては、ナトリウムメチラート、水酸化リチウム、水酸化カリウム、水酸化ナトリウム等が挙げられ、化合物（V）に対して、１モル当量〜５モル当量、好ましくは１モル当量〜３モル当量用いて反応させればよい。
反応温度は、特に制限されないが通常、約０〜５０℃、好ましくは、約０℃〜室温で行うことができる。
反応時間は、特に制限されないが通常、０．５時間〜４８時間、好ましくは、０．５〜１２時間である。 5th process

(The symbols in the formula are as defined above.)
In this step, the compound represented by the formula (V) is obtained by hydrolyzing the compound represented by the formula (V).
The solvent is not particularly limited as long as it allows the above process to proceed efficiently. Examples thereof include methanol, ethanol, THF, and the like, which can be used alone or in combination. Preferably, methanol is used.
Examples of the base include sodium methylate, lithium hydroxide, potassium hydroxide, sodium hydroxide and the like, and 1 mole equivalent to 5 mole equivalent, preferably 1 mole equivalent to 3 mole equivalent is used relative to compound (V). And react.
While the reaction temperature is not particularly limited, it can be generally performed at about 0 to 50 ° C., preferably about 0 ° C. to room temperature.
The reaction time is not particularly limited, but is usually 0.5 to 48 hours, preferably 0.5 to 12 hours.

  The present invention will be described in more detail with reference to the following examples and intermediate synthesis examples, but the present invention is not limited thereto.

The NMR analysis obtained in the examples was performed at 400 MHz and measured using DMSO-d ₆ and CDCl ₃ .

Measurement of powder X-ray diffraction pattern According to the powder X-ray diffraction measurement method described in the general test method of the Japanese Pharmacopoeia, the powder X-ray diffraction measurement of the crystals obtained in each Example was performed. The measurement conditions are shown below.

(apparatus)
Rigaku MiniFlex600
(Method of operation)
Detector: High-speed one-dimensional detector (D / teX Ultra2) and variable knife edge measurement method: Reflection method Light source type: Cu tube Use wavelength: CuKα ray tube current: 10 mA or 15 mA
Tube voltage: 30Kv or 40Kv
Sample plate: Aluminum or glass X-ray incident angle (θ): 4-40 °, sampling width: 0.02 °

Measurement of TG / DTA TG / DTA of the crystals obtained in each example was measured. A sample was weighed on an aluminum pan and measured in an open system. The measurement conditions are shown below.
Equipment: TG / DTA7200 manufactured by Hitachi High-Tech Science Co., Ltd.
Measurement temperature range: 30 ° C-250 ° C
Temperature increase rate: 10 ° C / min

Moisture absorption / desorption isotherm measurement (DVS)
The moisture adsorption / desorption isotherm of the crystal obtained in each example was measured. A sample was weighed and measured in a sample pan. The measurement conditions are shown below.
Apparatus: Hidden Isochem Ltd. IGAsorp
Measurement points: from 0% RH to 95% RH every 5%. Then from 95% RH to 0% RH every 5%: 25 ° C

Measurement of Differential Scanning Calorimetry (DSC) The DSC of the crystals obtained in each example was measured. A sample was weighed on a stainless steel pan, and sealed and measured. The measurement conditions are shown below.
Device: METTLER TOLEDO DSC823e
Measurement temperature range: 25 ° C or 30 ° C-300 ° C
Temperature increase rate: 10 ° C./min Atmosphere: N2 40 mL / min

DMA: N, N-dimethylacetamide DMF: N, N-dimethylformamide THF: Tetrahydrofuran

化合物３（１３０．６２ｇ）、ピリジン（５０５．８２ｇ）、トリフルオロ酢酸無水物（２０９．７８ｇ）を１０℃で反応させ、化合物４のガスを得た。
別途、化合物１（４０．００ｇ、５７５．６ｍｍｏｌ）、およびメタノール（７９．２２ｇ）を−１０℃に冷却し、２８％ナトリウムメチラート／メタノール溶液（１１１．１６ｇ）、およびメタノールを加えて撹拌し、系中で化合物２を調製した。得られた反応液に、化合物４のガスを−１０℃で導入し、撹拌し、系中で化合物５を調製した。２５℃に昇温後、炭酸ジメチル（１５５．６８ｇ）、２８％ナトリウムメチラート／メタノール溶液（１６６．６２ｇ）を加えて、６０℃で反応させ、系中で化合物６を調製した。
得られた反応液に水（４００．０５ｇ）、およびメタンスルホン酸（１１０．６６ｇ）を加え、系中で化合物７を調製した。４−メチル−２−ペンタノン（４８１．２５ｇ）で抽出し、水層と有機層を分離した。得られた有機層を水（４００．２１ｇ）で洗浄した。得られた２つの水層を順に４−メチル−２−ペンタノン（３２０．１１ｇ）で抽出した。２つの有機層を合わせて、４−メチル−２−ペンタノン（３２．０５ｇ）、イミダゾール（４３．１２ｇ）、およびメタノール（６３．３２ｇ）を加えた。得られた溶液を液量３４３．７２ｇまで濃縮した。２５℃でトルエン（９７０．８１ｇ）を加え、得られた固体を濾取し粗生成物（化合物８）を得た。
粗生成物にメタノール（９４９．８２ｇ）、およびメタンスルホン酸（８８．２５ｇ）を加え、液量３９５．８０ｇまで濃縮し、水（１２０．５１ｇ）を加えた。４−メチル−２−ペンタノン（４８１．８２ｇ）で抽出し、有機層を水（２００．１２ｇ）で洗浄した。
２つの水層を順に４−メチル−２−ペンタノン（３２０．５１ｇ）で逆抽出した。２つの有機層を合わせ、化合物７を含む有機層を得た。得られた有機層に４−メチル−２−ペンタノン（３２．１１ｇ）、イミダゾール（３３．１６ｇ）、およびメタノール（６３．３６ｇ）を加えた。得られた溶液を液量３４０．７５ｇまで濃縮した。２５℃でトルエン（９７０．２２ｇ）を加えた。得られた固体を濾取し、化合物８（１０５．０３ｇ、収率８２％）を白色結晶として得た。
融点：９６℃
^１Ｈ ＮＭＲ（ｄ６−ＣＤ_３ＯＤ）；δ（ｐｐｍ）７．５７（２Ｈ，ｓ）、８．８９（１Ｈ，ｓ）
化合物８の粉末Ｘ線回折結果を図１に示す。
粉末Ｘ線回折の主なピーク（2θ）：９．９、１１．４、１９．８、２５．４、２９．８
粉末Ｘ線回折のピーク（2θ）を以下に示す。

Method for producing compound 8 (imidazole salt of compound 7)

Compound 3 (130.62 g), pyridine (505.82 g), and trifluoroacetic anhydride (209.78 g) were reacted at 10 ° C. to obtain Compound 4 gas.
Separately, compound 1 (40.00 g, 575.6 mmol) and methanol (79.22 g) were cooled to −10 ° C., 28% sodium methylate / methanol solution (111.16 g) and methanol were added and stirred. Compound 2 was prepared in the system. The compound 4 gas was introduced into the obtained reaction solution at −10 ° C. and stirred to prepare the compound 5 in the system. After raising the temperature to 25 ° C., dimethyl carbonate (155.68 g) and a 28% sodium methylate / methanol solution (166.62 g) were added and reacted at 60 ° C. to prepare Compound 6 in the system.
Water (400.05 g) and methanesulfonic acid (110.66 g) were added to the resulting reaction solution to prepare compound 7 in the system. Extraction with 4-methyl-2-pentanone (481.25 g) separated the aqueous and organic layers. The obtained organic layer was washed with water (400.21 g). The two aqueous layers obtained were extracted sequentially with 4-methyl-2-pentanone (320.11 g). The two organic layers were combined and 4-methyl-2-pentanone (32.05 g), imidazole (43.12 g), and methanol (63.32 g) were added. The resulting solution was concentrated to a liquid volume of 343.72 g. Toluene (970.81 g) was added at 25 ° C., and the resulting solid was collected by filtration to obtain a crude product (Compound 8).
Methanol (949.82 g) and methanesulfonic acid (88.25 g) were added to the crude product, concentrated to a liquid volume of 395.80 g, and water (120.51 g) was added. Extraction with 4-methyl-2-pentanone (481.82 g) and the organic layer was washed with water (200.12 g).
The two aqueous layers were back extracted sequentially with 4-methyl-2-pentanone (320.51 g). The two organic layers were combined to obtain an organic layer containing compound 7. 4-Methyl-2-pentanone (32.11 g), imidazole (33.16 g), and methanol (63.36 g) were added to the obtained organic layer. The resulting solution was concentrated to a liquid volume of 340.75 g. Toluene (970.22 g) was added at 25 ° C. The obtained solid was collected by filtration to obtain Compound 8 (105.03 g, yield 82%) as white crystals.
Melting point: 96 ° C
¹ H NMR (d6-CD ₃ OD); δ (ppm) 7.57 (2H, s), 8.89 (1H, s)
The powder X-ray diffraction result of Compound 8 is shown in FIG.
Main peak (2θ) of powder X-ray diffraction: 9.9, 11.4, 19.8, 25.4, 29.8
The peak (2θ) of powder X-ray diffraction is shown below.

  Method for producing compound 14

第一工程 化合物１１の製造方法
化合物８（１２．０ｇ、５４．０ｍｍｏｌ）、イミダゾール（０．３７２ｇ、５．５ｍｍｏｌ）、酢酸イソプロピル（３１．３ｇ）、Ｎ，Ｎ―ジイソプロピルエチルアミン（１４．７ｇ、１１３．７ｍｍｏｌ）、およびアセトニトリル（２．３６ｇ）を２５℃で加え、６０℃に加熱した。オキシ塩化リン（１０．８ｇ、７０．２ｍｍｏｌ）を５９分かけて滴下し、アセトニトリル（２．３６ｇ）を加えて系中で化合物９を得た。反応液を１６５分間撹拌し、２５℃に冷却した。反応液を１６％リン酸水素二カリウム水溶液（２４１．８ｇ）に５℃で２８分かけて滴下し、酢酸イソプロピル（２０．９ｇ）を加え、抽出した。抽出液にさらに１６％リン酸水素二カリウム水溶液（６０．４ｇ）、および酢酸イソプロピル（１０．４ｇ）を加え、洗浄した。得られた抽出液を、化合物１０（７．０ｇ、５４．２ｍｍｏｌ）のＮ，Ｎ−ジメチルアセトアミド（１７．０ｇ）溶液に７２分かけて滴下し、アセトニトリル（９．４５ｇ）を加えた。反応液を７０分間撹拌し、２５℃に冷却した。反応液を３９．６ｍＬまで減圧濃縮し、アセトニトリル（９６．０ｍＬ）を加えた。反応液を３３．６ｍＬまで減圧濃縮し、水道水（２２．５ｍＬ）を加えた。得られたスラリーを３０分間撹拌し、水道水（８４．１ｍＬ）を９５分かけて滴下し、５℃に冷却した。得られた固体を濾取し、化合物１１（１２．５ｇ、４７．１ｍｍｏｌ）を得た。
融点：１６１℃
^１Ｈ ＮＭＲ（ＣＤＣｌ_３）；δ（ｐｐｍ）１．０９−１．１９（２Ｈ，ｍ）、１．２６−１．３９（３Ｈ、ｍ），１．４６−１．５７（１Ｈ，ｍ），１．９０−１．９４（２Ｈ，ｍ），２．１８−２．２２（２Ｈ，ｍ），３．４７−３．５２（２Ｈ，ｍ），３．５７−３．６７（１Ｈ，ｍ），５．５１（１Ｈ，ｂｒｄ，Ｊ＝６．８Ｈｚ）．
化合物１１の粉末Ｘ線回折結果を図２に示す。
粉末Ｘ線回折の主なピーク（２θ）：１１．８，１６．８，１８．８，１９．０，２２．５
粉末Ｘ線回折のピーク（２θ）を以下に示す。

First Step Method for Producing Compound 11 Compound 8 (12.0 g, 54.0 mmol), imidazole (0.372 g, 5.5 mmol), isopropyl acetate (31.3 g), N, N-diisopropylethylamine (14.7 g, 113.7 mmol) and acetonitrile (2.36 g) were added at 25 ° C. and heated to 60 ° C. Phosphorous oxychloride (10.8 g, 70.2 mmol) was added dropwise over 59 minutes, and acetonitrile (2.36 g) was added to obtain compound 9 in the system. The reaction was stirred for 165 minutes and cooled to 25 ° C. The reaction solution was added dropwise to a 16% aqueous solution of dipotassium hydrogen phosphate (241.8 g) at 5 ° C. over 28 minutes, and isopropyl acetate (20.9 g) was added for extraction. A 16% aqueous solution of dipotassium hydrogen phosphate (60.4 g) and isopropyl acetate (10.4 g) were further added to the extract and washed. The obtained extract was added dropwise to a solution of compound 10 (7.0 g, 54.2 mmol) in N, N-dimethylacetamide (17.0 g) over 72 minutes, and acetonitrile (9.45 g) was added. The reaction was stirred for 70 minutes and cooled to 25 ° C. The reaction solution was concentrated under reduced pressure to 39.6 mL, and acetonitrile (96.0 mL) was added. The reaction solution was concentrated under reduced pressure to 33.6 mL, and tap water (22.5 mL) was added. The obtained slurry was stirred for 30 minutes, tap water (84.1 mL) was added dropwise over 95 minutes, and the mixture was cooled to 5 ° C. The obtained solid was collected by filtration to obtain Compound 11 (12.5 g, 47.1 mmol).
Melting point: 161 ° C
¹ H NMR (CDCl ₃ ); δ (ppm) 1.09-1.19 (2H, m), 1.26-1.39 (3 H, m), 1.46-1.57 (1 H, m) 1.90-1.94 (2H, m), 2.18-2.22 (2H, m), 3.47-3.52 (2H, m), 3.57-3.67 (1H, m), 5.51 (1H, brd, J = 6.8 Hz).
The powder X-ray diffraction result of Compound 11 is shown in FIG.
Main peaks (2θ) of powder X-ray diffraction: 11.8, 16.8, 18.8, 19.0, 22.5
The peak (2θ) of powder X-ray diffraction is shown below.

Second Step Production Method of Compound 9 Compound 7 (3.09 g, 20.1 mmol), isopropyl acetate (14.7 mL), imidazole (1.67 g, 24.5 mmol), N, N-diisopropylethylamine (5.12 g, 39.6 mmol) and N-methylmorpholine (0.06 g, 0.6 mmol) were mixed at 25 ° C. and phosphorus oxychloride (4.49 g, 29.3 mmol) was added. The reaction was heated to 40 ° C. and stirred for 5 hours. The reaction solution was cooled to 25 ° C., and dropped into a 25% aqueous solution of dipotassium hydrogen phosphate (46.4 mL) at 0 ° C. over 20 minutes for extraction. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give compound 9 (3.13 g, 15.3 mmol).
Melting point: 55 ° C
¹ H NMR (d6-DMSO); δ (ppm) 7.28 (1H, dd, J = 0.8, 1.5 Hz), 7.97 (1H, dd, J = 1.5, 1.5 Hz) , 8.63 (1H, dd, J = 0.8, 1.5 Hz).
The powder X-ray diffraction result of Compound 9 is shown in FIG.
Main peak (2θ) of powder X-ray diffraction: 19.9, 21.6, 25.1, 26.0, 30.0
The peak (2θ) of powder X-ray diffraction is shown below.

Third Step Method for Producing Compound 13 Compound 11 (5.00 g, 18.85 mmol), Compound 12 (4.14 g), triphenylphosphine (5.43 g), tetrahydrofuran (48.52 g), diisopropyl azodicarboxylate (4 .38 g) was added and stirred at 20 ° C. Water (0.35 g) was added to the obtained reaction solution, and the solution was concentrated to 29.85 g. Methanol (19.80 g) was added and the solution was further concentrated to 29.78 g. Methanol (35.64 g) and water (45.50 g) were added and stirred, and the precipitated solid was collected by filtration to give compound 13 (7.84 g, yield 91%) as white crystals.
Melting point: 159 ° C
¹ H NMR (d ₆ -CDCl ₃ ); δ (ppm) 1.09-1.32 (m, 4H), 1.34 (t, J = 7.2 Hz, 3H), 1.47 (s, 9H ) 1.78-1.91 (m, 3H), 2.15-2.20 (m, 2H), 3.56 (d, J = 6.6 Hz, 2H), 3.58-3.66 (M, 1H), 4.27 (q, J = 7.2 Hz, 2H), 5.61 (brs, 1H)
The powder X-ray diffraction result of Compound 13 is shown in FIG.
Main peak (2θ) of powder X-ray diffraction: 10.0, 11.2, 14.2, 17.5, 19.5
The peak (2θ) of powder X-ray diffraction is shown below.

Fourth Step Production Method of Compound 14 Compound 13 (0.29 g, 0.63 mmol), methanol (1.3 g), and 28% sodium methylate / methanol solution (0.15 g) were stirred at 45 ° C. for 2 hours. The resulting reaction solution was concentrated to dryness and water (5.0 g) was added. The obtained solid was collected by filtration to obtain a crystal of compound 14 (0.17 g, 0.44 mmol).
¹ H NMR (d ₆ -DMSO); δ (ppm) 0.93-1.06 (2H, m), 1.14-1.41 (12H, m), 1.74-1.86 (2H, m), 1.93-2.03 (2H, m), 2.84-2.90 (2H, m), 6.84 (1H, t, J = 5.8 Hz), 9.07 (1H, brs). 1H overlapped with the solvent peak.
The powder X-ray diffraction result of Compound 14 is shown in FIG.
Main peak (2θ) of powder X-ray diffraction: 11.8, 17.0, 17.2, 18.6, 19.4
The peak (2θ) of powder X-ray diffraction is shown below.

  The compound and the production method according to the present invention are useful as an intermediate for producing an oxadiazole derivative substituted with an amino group having an NPY Y5 receptor antagonistic action. According to the present invention, the compound represented by the formula (V) can be produced efficiently.

Claims (11)

Formula (I):

Of the compound represented by
A salt with one basic compound selected from substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole.
Basic compounds
Selected from substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole, wherein the substituent is substituted or unsubstituted alkyl, The salt according to claim 1.
Basic compounds
Substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole (provided that the substituent is substituted or unsubstituted alkyl and constitutes a ring) 3. The salt of claim 2, wherein the salt is substituted on a carbon atom.
Basic compounds

4. A salt according to claim 3, selected from:
Basic compounds

The salt according to claim 4, wherein
The salt according to claim 4 or 5, which is a crystal.
Formula (II):

(Wherein R ³ is a hydrogen atom, or substituted or unsubstituted alkyl).
The compound according to claim 7, wherein R ³ is a hydrogen atom.
Formula (III):

Wherein R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocycle A compound represented by a formula group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic group), a halogenating agent, a base, and a substituted or unsubstituted imidazole, Formula (IV), characterized by reacting with one basic compound selected from triazole, substituted pyrazole, substituted pyrrole, substituted or unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole:

Wherein R ¹ is as defined above, and R ⁴ is substituted or unsubstituted imidazolyl, substituted triazolyl, substituted pyrazolyl, substituted pyrrolyl, substituted or unsubstituted benzoimidazolyl, substituted benzotriazolyl, and substituted benzopyrazolyl. Process for producing the indicated compound.
Formula (III):

Wherein R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocycle Substituted or unsubstituted imidazole, substituted triazole, substituted pyrazole, substituted pyrrole of the compound represented by the formula: group, substituted or unsubstituted non-aromatic heterocyclic group, or substituted or unsubstituted aromatic heterocyclic group) A salt with one basic compound selected from substituted, unsubstituted benzimidazole, substituted benzotriazole, and substituted benzopyrazole,
Formula (IV), characterized by reacting with a halogenating agent and a base, optionally in the presence of a basic compound forming the salt,

Wherein R ¹ is as defined above, and R ⁴ is substituted or unsubstituted imidazolyl, substituted triazolyl, substituted pyrazolyl, substituted pyrrolyl, substituted or unsubstituted benzoimidazolyl, substituted benzotriazolyl, and substituted benzopyrazolyl. Process for producing the indicated compound.
Formula (V) comprising the method of claim 9 or 10:

Wherein R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocycle Or a pharmaceutically acceptable compound thereof, which is represented by the formula: group, substituted or unsubstituted non-aromatic heterocyclic group, or substituted or unsubstituted aromatic heterocyclic group, R ² is substituted or unsubstituted alkyl) Method for producing salt.

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