JP2024105489A - Method for producing fused ring derivatives having MGA2 inhibitory activity - Google Patents

Abstract

To provide a condensed ring derivative with MGAT2 inhibitory activity and a method for producing an intermediate thereof.SOLUTION: For example, a production method below is illustrated.SELECTED DRAWING: None

Description

The present invention relates to a compound that inhibits monoacylglycerol acyltransferase 2 (hereinafter also referred to as MGAT2) and a method for producing an intermediate thereof.

（式中、Ｒ^１ａは、置換もしくは非置換のフェニルであり；
Ｒ^１ｂは、置換もしくは非置換のアルキルであり；または、
Ｒ^１ａおよびＲ^１ｂは、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａは、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である）であり、Ｒ^３は置換もしくは非置換のピリジルである）で示される化合物は、ΜＧＡΤ２阻害作用を有するので、例えば、肥満症、メタボリックシンドローム、高脂血症、高中性脂肪血症、高ＶＬＤＬ血症、高脂肪酸血症、糖尿病、動脈硬化症等のΜＧＡΤ２が関与する疾患のための医薬として有用である（特許文献１および２）。また、特許文献１および２の実施例１１、１３、および１４には、ジヒドロピリドン誘導体を用いた縮合環誘導体の製造方法が記載されている。

Formula (VIII):

wherein R ^1a is a substituted or unsubstituted phenyl;
R ^1b is substituted or unsubstituted alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
n is 1 or 2), and ^R3 is substituted or unsubstituted pyridyl) has a MGAT2 inhibitory effect, and is therefore useful as a medicine for diseases involving MGAT2, such as obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyperVLDLemia, hyperfatty acidemia, diabetes, and arteriosclerosis (Patent Documents 1 and 2). In addition, Examples 11, 13, and 14 of Patent Documents 1 and 2 describe methods for producing fused ring derivatives using dihydropyridone derivatives.

However, Patent Documents 1 and 2 do not describe or suggest the safety of the pyridylhydrazine derivative hydrochloride used in the step of reacting a dihydropyridone derivative with a pyridylhydrazine derivative hydrochloride. In addition, they do not describe or suggest the safety of the protected pyridylhydrazine derivative or its salt. Furthermore, they do not describe or suggest that the reaction between a dihydropyridone derivative and a pyridylhydrazine derivative hydrochloride proceeds in high yield when the reaction is carried out in the presence of N,N-diisopropylethylamine, sodium hydroxide, or tripotassium phosphate.

Examples 6, 9, 11, 12, 13, and 14 of Patent Document 1 describe a process for converting the hydroxyl group of a dihydropyridone derivative to a chlorine atom by reacting with phosphoryl chloride, but do not describe or suggest extraction using an aqueous solution of tripotassium citrate.

Examples 11 and 14 of Patent Document 1 describe extraction using a saturated aqueous ammonium chloride solution or an aqueous citric acid solution in the step of reacting with (R)-2-methylpropane-2-sulfinamide in the presence of tetraethoxytitanium, and Example 1 of Patent Document 3 describes extraction using an aqueous ammonium lactate solution. However, extraction using an aqueous ammonium lactate solution and an aqueous citric acid solution is neither described nor suggested.

International Publication No. 2019/013311 International Publication No. 2019/013312 International Publication No. 2019/167981

The object of the present invention is to provide a novel and useful method for producing a fused ring derivative having MGAT2 inhibitory activity represented by formula (VIII) herein and its intermediate represented by formula (I), (III) or (VII).

（式中、Ｒ^１ａは、置換もしくは非置換のフェニルであり；
Ｒ^１ｂは、置換もしくは非置換のアルキルであり；または、
Ｒ^１ａおよびＲ^１ｂは、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａは、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である））で示される化合物を、Ｎ，Ｎ－ジイソプロピルエチルアミン、水酸化ナトリウム、またはリン酸三カリウムの存在下、
式（ＩＩ）：Ｒ^３－ＮＨＮＨ_２
（式中、Ｒ^３は置換もしくは非置換のピリジルである）で示される化合物と反応させることを特徴とする、
式（ＩＩＩ）：

（式中、Ｒ^１ａ、Ｒ^１ｂおよびＲ^３は、上記と同意義である）で示される化合物の製造方法。
（２）式（ＩＶ）：

（式中、Ｒ^３は上記（１）と同意義である）で示される化合物またはその塩から変換した、
式（ＩＩ）：Ｒ^３－ＮＨＮＨ_２
（式中、Ｒ^３は上記（１）と同意義である）で示される化合物と反応させることを特徴とする、（１）記載の製造方法。
（３）反応溶媒として、２－メチルテトラヒドロフランと水との混合溶媒を用いることを特徴とする、（２）記載の製造方法。
（４）リン酸三カリウムの存在下で反応させることを特徴とする、（３）記載の製造方法。
（５）式（Ｖ）：

（式中、Ｒ^１ａおよびＲ^１ｂは、上記（１）と同意義である）で示される化合物を塩化ホスホリルと反応させた後に、クエン酸三カリウム水溶液と有機溶媒を用いて抽出することを特徴とする、
式（Ｉ）：

（式中、Ｒ^１ａおよびＲ^１ｂは、上記（１）と同意義である）で示される化合物の製造方法。
（６）式（ＶＩ）：

（式中、Ｒ^１ａおよびＲ^１ｂは、上記（１）と同意義である）で示される化合物を、テトラエトキシチタンの存在下、（Ｒ）－２－メチルプロパン－２－スルフインアミドと反応させた後に、乳酸アンモニウム水溶液、クエン酸水溶液および有機溶媒を用いて抽出することを特徴とする、
式（ＶＩＩ）：

（式中、Ｒ^１ａおよびＲ^１ｂは、上記（１）と同意義である）で示される化合物の製造方法。
（７）Ｒ^１ａが、
式：

（式中、Ｒ^４は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシである）であり；
Ｒ^１ｂが、置換もしくは非置換のＣ１－Ｃ４アルキルであり；または、
Ｒ^１ａおよびＲ^１ｂが、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａが、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシである）で示される、（１）～（６）のいずれかに記載の製造方法。
（８）Ｒ^１ａが、
式：

（式中、Ｒ^４は、ハロゲン、または置換もしくは非置換のアルキルオキシである）であり；
Ｒ^１ｂが、置換もしくは非置換のＣ１－Ｃ４アルキルであり；または、
Ｒ^１ａおよびＲ^１ｂが、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａが、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシである）で示される、（１）～（６）のいずれかに記載の製造方法。
（９）（１）～（８）のいずれかに記載の少なくとも１つの製造方法を含有する、
式（ＶＩＩＩ）：

（式中、Ｒ^１ａ、Ｒ^１ｂおよびＲ^３は、上記（１）と同意義である）で示される化合物の製造方法。
（１０）（１）～（８）のいずれかに記載の少なくとも１つの製造方法を含有する、
式：

で示される化合物の製造方法。
（１１）式：

で示される化合物、またはその塩。 The present invention relates to the following:
(1) Formula (I):

wherein R ^1a is a substituted or unsubstituted phenyl;
R ^1b is substituted or unsubstituted alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
(n is 1 or 2), in the presence of N,N-diisopropylethylamine, sodium hydroxide, or tripotassium phosphate,
Formula (II): R ³ -NHNH ₂
wherein ^R3 is a substituted or unsubstituted pyridyl,
Formula (III):

(wherein R ^1a , R ^1b and R ³ are as defined above)
(2) Formula (IV):

(wherein ^R3 has the same meaning as in (1) above) or a salt thereof,
Formula (II): R ³ -NHNH ₂
(wherein R ³ has the same meaning as in (1) above),
(3) The production method according to (2), wherein a mixed solvent of 2-methyltetrahydrofuran and water is used as a reaction solvent.
(4) The method according to (3), characterized in that the reaction is carried out in the presence of tripotassium phosphate.
(5) Formula (V):

(wherein R ^1a and R ^1b are as defined in the above (1)) are reacted with phosphoryl chloride, and then extracted with an aqueous tripotassium citrate solution and an organic solvent.
Formula (I):

(wherein R ^1a and R ^1b are as defined in the above (1))
(6) Formula (VI):

(wherein R ^1a and R ^1b are as defined in formula (1) above) is reacted with (R)-2-methylpropane-2-sulfinamide in the presence of tetraethoxytitanium, and then extracted with an aqueous solution of ammonium lactate, an aqueous solution of citric acid, and an organic solvent.
Formula (VII):

(wherein R ^1a and R ^1b are as defined in the above (1))
(7) R ^1a is
formula:

wherein each ^R4 is independently halogen, or substituted or unsubstituted alkyloxy;
R ^1b is a substituted or unsubstituted C1-C4 alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein R ² is each independently a halogen, or a substituted or unsubstituted alkyloxy).
(8) R ^1a is
formula:

where ^R4 is halogen, or substituted or unsubstituted alkyloxy;
R ^1b is a substituted or unsubstituted C1-C4 alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein R ² is each independently a halogen, or a substituted or unsubstituted alkyloxy).
(9) A method comprising at least one of the methods for producing a product according to any one of (1) to (8).
Formula (VIII):

(wherein R ^1a , R ^1b and R ³ are as defined in the above (1))
(10) A method comprising at least one of the methods for producing a product according to any one of (1) to (8).
formula:

A method for producing a compound represented by the formula:
(11) Formula:

or a salt thereof.

（式中、Ｒ^１ａは、置換もしくは非置換のフェニルであり；
Ｒ^１ｂは、置換もしくは非置換のアルキルであり；または、
Ｒ^１ａおよびＲ^１ｂは、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａは、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である））で示される化合物を、Ｎ，Ｎ－ジイソプロピルエチルアミン、水酸化ナトリウム、またはリン酸三カリウムの存在下、
式（ＩＩ）：Ｒ^３－ＮＨＮＨ_２
（式中、Ｒ^３は置換もしくは非置換のピリジルである）で示される化合物と反応させることを特徴とする、
式（ＩＩＩ’）：

（式中、Ｒ^１ａ、Ｒ^１ｂおよびＲ^３は、上記と同意義である）で示される化合物の製造方法。
（２’）式（ＩＶ）：

（式中、Ｒ^３は上記（１’）と同意義である）で示される化合物またはその塩から変換した、
式（ＩＩ）：Ｒ^３－ＮＨＮＨ_２
（式中、Ｒ^３は上記（１’）と同意義である）で示される化合物と反応させることを特徴とする、（１’）記載の製造方法。
（３’）反応溶媒として、２－メチルテトラヒドロフランと水との混合溶媒を用いることを特徴とする、（２’）記載の製造方法。
（４’）リン酸三カリウムの存在下で反応させることを特徴とする、（３’）記載の製造方法。
（５’）式（Ｖ’）：

（式中、Ｒ^１ａおよびＲ^１ｂは、上記（１’）と同意義である）で示される化合物を塩化ホスホリルと反応させた後に、クエン酸三カリウム水溶液と有機溶媒を用いて抽出することを特徴とする、
式（Ｉ’）：

（式中、Ｒ^１ａおよびＲ^１ｂは、上記（１’）と同意義である）で示される化合物の製造方法。
（６’）式（ＶＩ）：

（式中、Ｒ^１ａおよびＲ^１ｂは、上記（１’）と同意義である）で示される化合物を、テトラエトキシチタンの存在下、（Ｒ）－２－メチルプロパン－２－スルフインアミドと反応させた後に、乳酸アンモニウム水溶液、クエン酸水溶液および有機溶媒を用いて抽出することを特徴とする、
式（ＶＩＩ’）：

（式中、Ｒ^１ａ、Ｒ^１ｂ、Ｒ^２およびｎは、上記（１’）と同意義である）で示される化合物の製造方法。
（７’）Ｒ^１ａが、
式：

（式中、Ｒ^４は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシである）であり；
Ｒ^１ｂが、置換もしくは非置換のＣ１－Ｃ４アルキルであり；または、
Ｒ^１ａおよびＲ^１ｂが、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａが、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシである）で示される、（１’）～（６’）のいずれかに記載の製造方法。
（８’）Ｒ^１ａが、
式：

（式中、Ｒ^４は、ハロゲン、または置換もしくは非置換のアルキルオキシである）であり；
Ｒ^１ｂが、置換もしくは非置換のＣ１－Ｃ４アルキルであり；または、
Ｒ^１ａおよびＲ^１ｂが、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａが、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシである）で示される、（１’）～（６’）のいずれかに記載の製造方法。
（９’）（１’）～（８’）のいずれかに記載の少なくとも１つの製造方法を含有する、
式（ＶＩＩＩ’）：

（式中、Ｒ^１ａ、Ｒ^１ｂおよびＲ^３は、上記（１’）と同意義である）で示される化合物の製造方法。
（１０’）（１’）～（８’）のいずれかに記載の少なくとも１つの製造方法を含有する、
式：

で示される化合物の製造方法。 (1') Formula (I'):

wherein R ^1a is a substituted or unsubstituted phenyl;
R ^1b is substituted or unsubstituted alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
(n is 1 or 2), in the presence of N,N-diisopropylethylamine, sodium hydroxide, or tripotassium phosphate,
Formula (II): R ³ -NHNH ₂
wherein ^R3 is a substituted or unsubstituted pyridyl,
Formula (III'):

(wherein R ^1a , R ^1b and R ³ are as defined above)
(2') Formula (IV):

(wherein R ³ has the same meaning as in (1′) above) or a salt thereof,
Formula (II): R ³ -NHNH ₂
(wherein R ³ has the same meaning as in (1′) above),
(3') The production method according to (2'), wherein a mixed solvent of 2-methyltetrahydrofuran and water is used as a reaction solvent.
(4') The production method according to (3'), characterized in that the reaction is carried out in the presence of tripotassium phosphate.
(5') Formula (V'):

(wherein R ^1a and R ^1b are the same as those in the above formula (1')) is reacted with phosphoryl chloride, and then extracted with an aqueous solution of tripotassium citrate and an organic solvent.
Formula (I'):

(wherein R ^1a and R ^1b are as defined above in (1'))
(6') Formula (VI):

(wherein R ^1a and R ^1b are the same as those in the above (1')) is reacted with (R)-2-methylpropane-2-sulfinamide in the presence of tetraethoxytitanium, and then extracted with an aqueous solution of ammonium lactate, an aqueous solution of citric acid, and an organic solvent.
Formula (VII'):

(wherein R ^1a , R ^1b , R ² and n are as defined in the above (1′))
(7') R ^1a is
formula:

wherein each ^R4 is independently halogen, or substituted or unsubstituted alkyloxy;
R ^1b is a substituted or unsubstituted C1-C4 alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein R ² is each independently a halogen, or a substituted or unsubstituted alkyloxy).
(8') R ^1a is
formula:

where ^R4 is halogen, or substituted or unsubstituted alkyloxy;
R ^1b is a substituted or unsubstituted C1-C4 alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein R ² is each independently a halogen, or a substituted or unsubstituted alkyloxy).
(9') A method comprising at least one of the production methods according to any one of (1') to (8').
Formula (VIII′):

(wherein R ^1a , R ^1b and R ³ are as defined above in (1′))
(10') A method comprising at least one of the production methods according to any one of (1') to (8').
formula:

A method for producing a compound represented by the formula:

By using the method of the invention, the fused ring derivatives represented by formula (VIII) and formula (VIII') can be safely and efficiently produced.

The meaning of each term used in this specification will be explained below. Unless otherwise specified, each term has the same meaning whether it is used alone or in combination with other terms.
The term "consisting of" means having only the constituent elements.
The term "comprising" is meant to be open ended and does not exclude unrecited elements.
Hereinafter, the present invention will be described with reference to the embodiments. Throughout this specification, it should be understood that the singular expression includes the plural concept unless otherwise specified. Therefore, it should be understood that the singular article (e.g., in the case of English, "a", "an", "the", etc.) includes the plural concept unless otherwise specified.
In addition, it should be understood that the terms used in this specification are used in the same sense as commonly used in the above field unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, the present specification (including definitions) shall prevail.

"Halogen" includes fluorine, chlorine, bromine, and iodine atoms. Fluorine and chlorine atoms are preferred, with fluorine atoms being particularly preferred.

The term "alkyl" includes straight or branched chain hydrocarbon groups having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 or 2 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, and the like.
Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. More preferred embodiments include methyl and ethyl.
"C1-C4 alkyl" includes straight or branched chain hydrocarbon groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

The term "non-aromatic carbocyclic group" means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group.
The non-aromatic carbocyclic group preferably has 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, indanyl, indenyl, acenaphthyl, and tetrahydronaphthyl.

Examples of the substituent of the "substituted phenyl" in R ^1a include
Halogen; alkyloxy optionally substituted with halogen;
These may be substituted with one or more groups selected from the above.

Examples of the substituent of the "substituted phenyl" in R ^1a include
Halogen; C1-C4 alkyloxy optionally substituted with halogen;
These may be substituted with one or more groups selected from the above.

Examples of the substituent of the "substituted phenyl" in R ^1a include
halogen;
These may be substituted with one or more groups selected from the above.

Examples of the substitution of the "substituted alkyl" in R ^1b include:
halogen;
These may be substituted with one or more groups selected from the above.

The substitution of "substituted alkyloxy" in ^R2 is, for example,
halogen;
These may be substituted with one or more groups selected from the above.

The substitution of the "substituted pyridyl" in ^R3 is, for example,
Halogen; cyano; alkyl optionally substituted with halogen; non-aromatic carbocyclic groups;
It may be substituted with one or more groups selected from these.

The substitution of the "substituted pyridyl" in ^R3 is, for example,
Halogen; cyano; C1-C4 alkyl optionally substituted with halogen; cyclopropyl;
It may be substituted with one or more groups selected from these.

The substitution of "substituted alkyloxy" in ^R4 is, for example,
halogen;
These may be substituted with one or more groups selected from the above.

（式中、Ｒ^１ａは、置換もしくは非置換のフェニルであり；
Ｒ^１ｂは、置換もしくは非置換のアルキルであり；または、
Ｒ^１ａおよびＲ^１ｂは、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａは、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である））が挙げられる。 Preferred embodiments of formula (I) include
Formula (I'):

wherein R ^1a is a substituted or unsubstituted phenyl;
R ^1b is substituted or unsubstituted alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
and n is 1 or 2.

（式中、Ｒ^１ａは、置換もしくは非置換のフェニルであり；
Ｒ^１ｂは、置換もしくは非置換のアルキルであり；または、
Ｒ^１ａおよびＲ^１ｂは、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａは、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である）であり、Ｒ^３は置換もしくは非置換のピリジルである）が挙げられる。 A preferred embodiment of formula (III) is
Formula (III'):

wherein R ^1a is a substituted or unsubstituted phenyl;
R ^1b is substituted or unsubstituted alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
n is 1 or 2, and R ³ is a substituted or unsubstituted pyridyl.

（式中、Ｒ^１ａは、置換もしくは非置換のフェニルであり；
Ｒ^１ｂは、置換もしくは非置換のアルキルであり；または、
Ｒ^１ａおよびＲ^１ｂは、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａは、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である））が挙げられる。 A preferred embodiment of formula (V) is
Formula (V'):

wherein R ^1a is a substituted or unsubstituted phenyl;
R ^1b is substituted or unsubstituted alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
and n is 1 or 2.

（式中、Ｒ^１ａは、置換もしくは非置換のフェニルであり；
Ｒ^１ｂは、置換もしくは非置換のアルキルであり；
Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である）が挙げられる。 A preferred embodiment of formula (VII) is
Formula (VII'):

wherein R ^1a is a substituted or unsubstituted phenyl;
R ^1b is substituted or unsubstituted alkyl;
Each ^R2 is independently halogen, or substituted or unsubstituted alkyloxy;
and n is 1 or 2.

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である）が挙げられる。 A preferred embodiment of formula (VII) is
Formula (VII″):

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
and n is 1 or 2.

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である）が挙げられる。 A preferred embodiment of formula (VII) is
Formula (VII'''):

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
and n is 1 or 2.

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である）が挙げられる。 A preferred embodiment of formula (VII) is
Formula (VII""):

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
and n is 1 or 2.

（式中、Ｒ^１ａは、置換もしくは非置換のフェニルであり；
Ｒ^１ｂは、置換もしくは非置換のアルキルであり；または、
Ｒ^１ａおよびＲ^１ｂは、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａは、式：

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である）であり、Ｒ^３は置換もしくは非置換のピリジルである）が挙げられる。 A preferred embodiment of formula (VIII) is
Formula (VIII′):

wherein R ^1a is a substituted or unsubstituted phenyl;
R ^1b is substituted or unsubstituted alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
n is 1 or 2, and R ³ is a substituted or unsubstituted pyridyl.

Preferred embodiments of R 1a , R 1b , R 2 , R 3 , and R 4 in the compounds represented by formulas (I ⁾ to (VIII), (I'), (III'), ( ^V '), (VII'), (VII ^' ', (VII'^'',(VII'''', and (VIII') are shown below. ^The compounds represented by formulas (I) to (VIII), (I'), (III'), (V'), (VII'), (VII'', (VII''', (VII'''', and (VIII') include all combinations of the specific examples shown below. However, in formulas (I'), (III'), (V'), and (VIII'), the following preferred embodiments have the stereochemistry shown in the formula.

（式中、Ｒ^４は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシである）である。
Ｒ^１ａの別の態様は、
式：

（式中、Ｒ^４は上記と同意義である）である。
Ｒ^１ａの別の態様は、
式：

（式中、Ｒ^４は上記と同意義である）である。 R ^1a is a substituted or unsubstituted phenyl.
Another embodiment of R ^1a is
formula:

wherein each ^R4 is independently halogen, or substituted or unsubstituted alkyloxy.
Another embodiment of R ^1a is
formula:

(wherein R ⁴ has the same meaning as above).
Another embodiment of R ^1a is
formula:

(wherein R ⁴ has the same meaning as above).

Each ^R4 is independently halogen, or substituted or unsubstituted alkyloxy.
Another embodiment for ^R4 is, each independently, halogen, or substituted or unsubstituted C1-C4 alkyloxy.
Another embodiment of R ⁴ is, each independently, halogen, or C1-C4 alkyloxy optionally substituted with halogen.
Another embodiment of ^R4 is that each R4 is independently halogen.
Another embodiment of ^R4 is, each independently, C1-C4 alkyloxy substituted with halogen.

R ^1b is a substituted or unsubstituted alkyl.
Another embodiment of R ^1b is substituted or unsubstituted C1-C4 alkyl, preferably methyl which may be substituted with halogen, and more preferably trifluoromethyl.

（式中、Ｒ^２は、それぞれ独立して、ハロゲン、または置換もしくは非置換のアルキルオキシであり；
ｎは、１または２である））である。
Ｒ^１ａおよびＲ^１ｂの別の態様は、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａが、式：

（式中、Ｒ^２は上記と同意義である）である。
Ｒ^１ａおよびＲ^１ｂの別の態様は、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａが、式：

（式中、Ｒ^２は上記と同意義である）である。
Ｒ^１ａおよびＲ^１ｂの別の態様は、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａが、式：

（式中、Ｒ^２は上記と同意義である）である。 Another embodiment of R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
n is 1 or 2).
Another embodiment of R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein ^R2 has the same meaning as above).
Another embodiment of R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein ^R2 has the same meaning as above).
Another embodiment of R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein ^R2 has the same meaning as above).

（式中、Ｒ^２およびｎは上記と同意義である）である。
Ｒ^１ａおよびＲ^１ｂの別の態様は、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａは、式：

（式中、Ｒ^２は上記と同意義である）である。 Another embodiment of R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein ^R2 and n are as defined above).
Another embodiment of R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein ^R2 has the same meaning as above).

（式中、Ｒ^２およびｎは上記と同意義である）である。
Ｒ^１ａおよびＲ^１ｂの別の態様は、隣接する炭素原子と一緒になって、環Ａを形成し；
環Ａは、式：

（式中、Ｒ^２は上記と同意義である）である。 Another embodiment of R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein ^R2 and n are as defined above).
Another embodiment of R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein ^R2 has the same meaning as above).

Each ^R2 is independently halogen, or substituted or unsubstituted alkyloxy.
Another embodiment for ^R2 is, each independently, halogen, or substituted or unsubstituted C1-C4 alkyloxy.
Another embodiment of ^R2 is, each independently, halogen, or C1-C4 alkyloxy optionally substituted with halogen.
Another embodiment of ^R2 is, independently, halogen.
Another embodiment of ^R2 is, each independently, C1-C4 alkyloxy substituted with halogen.

（式中、Ｒ^５は、それぞれ独立して、ハロゲン、シアノ、ハロゲンで置換されてもよいアルキル、または非芳香族炭素環式基であり；
ｍは、１または２である）である。
Ｒ^３の別の態様は、式：

（式中、Ｒ^５は上記と同意義である）である。 ^R3 is substituted or unsubstituted pyridyl.
Another embodiment of ^R3 is the formula:

(wherein each R ⁵ is independently halogen, cyano, alkyl optionally substituted with halogen, or a non-aromatic carbocyclic group;
and m is 1 or 2.
Another embodiment of ^R3 is the formula:

(wherein R ⁵ has the same meaning as above).

Each ^R5 is independently halogen, cyano, alkyl optionally substituted with halogen, or a non-aromatic carbocyclic group.
Another embodiment of ^R5 is, each independently, halogen, cyano, C1-C4 alkyl optionally substituted with halogen, or cyclopropyl.
Another embodiment of ^R5 is, each independently, halogen, or C1-C4 alkyl optionally substituted with halogen.
Another embodiment of R ⁵ is, independently, methyl.

The compounds of the present invention are not limited to any particular isomer, but include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotamers, etc.), racemates, or mixtures thereof.

The "wedge" and "dashed line" indicate the absolute configuration.

One or more hydrogen, carbon and/or other atoms of the compound according to the present invention may be replaced with isotopes of hydrogen, carbon and/or other atoms. Examples of such isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as ^2H , ^3H , ^11C , ^13C , ^14C , ^15N , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F , ^123I and ^36Cl . The compound according to the present invention also includes compounds replaced with such isotopes. The compound replaced with said isotopes is also useful as a pharmaceutical. The compound according to the present invention includes all radiolabeled compounds replaced with radioisotopes contained in said isotopes. Also encompassed by the present invention is a "radiolabeling method" for producing said "radiolabeled substance", which is useful as a research and/or diagnostic tool in metabolism pharmacokinetic studies, binding assays.

Radiolabeled compounds according to the present invention can be prepared by methods well known in the art. For example, tritium-labeled compounds can be prepared by introducing tritium into a compound by catalytic dehalogenation using tritium. This method involves reacting a precursor of the compound, which is appropriately halogenated, with tritium gas in the presence of a suitable catalyst, such as Pd/C, in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". ¹⁴ C-labeled compounds can be prepared by using a raw material having ¹⁴ C carbon.

In this specification, reacting a compound with another compound includes reacting a salt thereof or a solvate thereof.

Examples of salts of the compounds according to the present invention include salts with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, succinic acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.). These salts can be formed by conventional methods.

The compound or its salt according to the present invention may form a solvate (e.g., a hydrate), a cocrystal, and/or a crystal polymorph, and the present invention includes such various solvates, cocrystals, and crystal polymorphs. A "solvate" may be coordinated with any number of solvent molecules (e.g., water molecules) to the compound. When the compound or its salt is left in the air, it may absorb moisture and adsorbed water may adhere to it or a hydrate may be formed. In addition, a crystal polymorph may be formed by recrystallizing the compound or its salt. A "cocrystal" means that the compound or its salt and a counter molecule are present in the same crystal lattice, and may contain any number of counter molecules.

(Method of producing the compound of the present invention)
The compounds according to the present invention can be produced by the general synthesis methods shown below. Extraction, purification, etc. may be carried out by the treatments usually performed in organic chemistry experiments.
The compounds of the present invention can be synthesized with reference to methods known in the art.

The starting compounds may be commercially available compounds, compounds described in the present specification, compounds described in the documents cited in the present specification, or other known compounds.
When it is desired to obtain 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 may be purified as it is, or if it is obtained in the free form, it may be dissolved or suspended in a suitable organic solvent, and an acid or base may be added to form a salt by a conventional method.
The compounds of the present invention and their salts 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.

（式中、Ｒは、非置換アルキルであり、Ｒ^１ａ、Ｒ^１ｂおよびＲ^３は、上記と同意義である。）
（第１工程）
テトラアルコキシチタンの存在下、式（ＶＩ）で示される化合物と（Ｒ）－２－メチルプロパン－２－スルフインアミドを反応させた後、乳酸アンモニウム水溶液、クエン酸水溶液および有機溶媒を用いて抽出することで、式（ＶＩＩ）で示される化合物を得ることができる。
テトラアルコキシチタンとしては、テトラ－ｎ－ブチトキシチタン、テトライソプロポキシチタン、テトラエトキシチタン等が挙げられ、式（ＶＩ）で示される化合物に対して１～１０モル等量用いることができる。
（Ｒ）－２－メチルプロパン－２－スルフインアミドは式（ＶＩ）で示される化合物に対して１～１０モル等量用いることができる。
反応温度は０℃～溶媒の還流温度、好ましくは室温～１００℃である。
反応時間は０．５～４８時間である。
反応溶媒としてテトラヒドロフラン、２－メチルテトラヒドロフラン、１，４－ジオキサン、トルエン、ベンゼン等が挙げられ、単独または混合して用いることができる。
（第２工程）
塩基および塩化チタントリアルコキシドの存在下、式（ＶＩＩ）で示される化合物と酢酸エステルを反応させ、式（ＩＸ）で示される化合物を得ることができる。
塩基としては、リチウムヘキサメチルジシラジド、ナトリウムヘキサメチルジシラジド、リチウムジイソプロピルアミド、ナトリウムｔｅｒｔ－ブトキシド、ナトリウムメトキシド等が挙げられ、式（ＶＩＩ）で示される化合物に対して１～１０モル等量用いることができる。
塩化チタントリアルコキシドとしては、塩化チタントリイソプロポキドが挙げられ、式（ＶＩＩ）で示される化合物に対して１～１０モル等量用いることができる。
酢酸エステルとしては、酢酸ｔｅｒｔ－ブチル、酢酸ｎ－ブチル、酢酸ｎ－プロピル、酢酸イソプロピル、酢酸エチル、酢酸メチルが挙げられ、式（ＶＩＩ）で示される化合物に対して１～１０モル等量用いることができる。
反応温度は－８０℃～５０℃である。
反応時間は０．５～２４時間である。
反応溶媒としてテトラヒドロフラン、２－メチルテトラヒドロフラン、１，４－ジオキサン、トルエン、ベンゼン、ジクロロエタン等が挙げられ、単独または混合して用いることができる。
（第３工程）
酸の存在下、式（ＩＸ）で示される化合物を反応させ、式（Ｘ）で示される化合物を得ることができる。
酸としては、塩酸、塩化水素、臭化水素酸、硫酸、トリフルオロ酢酸、（１０）－カンファースルホン酸等が挙げられ、単独または混合して用いることができ、式（ＩＸ）で示される化合物に対して１～１０モル等量用いることができる。
反応温度は０℃～８０℃である。
反応時間は０．５～４８時間、好ましくは１～２４時間である。
反応溶媒として１，４－ジオキサン、メタノール、ジクロロメタン、酢酸エチル等が挙げられ、単独または混合して用いることができる。
（第４工程）
塩基の存在下または非存在下、式（Ｘ）で示される化合物に、縮合剤の存在下、シアノ酢酸と反応させることにより、式（ＸＩ）で示される化合物を得ることができる。
塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等が挙げられ、式（Ｘ）で示される化合物に対して１～１０モル等量用いることができる。
縮合剤としては、ジシクロへキシルカルボジイミド、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミド－Ｎ－ヒドロキシベンゾトリアゾール、ＥＤＣ、４－（４， ６－ジメトキシ－１，３，５，－トリアジン－２－イル）－４－メチルモルホリニウムクロリド、ＨＡＴＵ、プロピルホスホン酸無水物等が挙げられ、式（Ｘ）で示される化合物に対して１～５モル当量用いることができる。
シアノ酢酸は式（Ｘ）で示される化合物に対して１～３モル等量用いることができる。
反応温度は、－２０℃～６０℃である。
反応時間は、０．１時間～２４時間である。
反応溶媒としては、ＤＭＦ、ＤＭＡ、ＮＭＰ、テトラヒドロフラン、１，４－ジオキサン、ジクロロメタン、アセトニトリル、酢酸エチル等が挙げられ、単独または混合して用いることができる。
（第５工程）
塩基の存在下、式（ＸＩ）で示される化合物を反応させ、式（Ｖ）で示される化合物を得ることができる。
塩基としては、ピペリジン、ピロリジン、トリエチルアミン、ジイソプロピルエチルアミン、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウムｔｅｒｔ－ブトキシド等が挙げられ、式（ＸＩ）で示される化合物に対して１～１０モル等量用いることができる。
反応温度は０℃～１００℃である。
反応時間は０．５～４８時間である。
反応溶媒として１，４－ジオキサン、メタノール、エタノール、テトラヒドロフラン等が挙げられ、単独または混合して用いることができる。
（第６工程）
式（Ｖ）で示される化合物を塩化ホスホリルと反応させた後、クエン酸三カリウム水溶液と有機溶媒を用いて抽出することで、式（Ｉ）で示される化合物を得ることができる。
塩化ホスホリルは、式（Ｖ）で示される化合物に対して０．１～１０モル等量用いることができる。
反応温度は０℃～１００℃である。
反応時間は０．５～４８時間である。
反応溶媒としてＤＭＦ、ＤＭＡ、ＮＭＰ、テトラヒドロフラン、１，４－ジオキサン、ジクロロメタン、ジクロロエタン、アセトニトリル、酢酸イソプロピル等が挙げられ、単独または混合して用いることができる。
抽出に用いる有機溶媒としては、クロロホルム、ジクロロメタン、酢酸エチル、酢酸イソプロピル等が挙げられ、単独または混合して用いることができる。
（第７工程）
塩基の存在下、式（Ｉ）で示される化合物と式（ＩＩ）で示される化合物を反応させ、式（ＩＩＩ）で示される化合物を得ることができる。
塩基としては、トリエチルアミン、Ｎ，Ｎ－ジイソプロピルエチルアミン、炭酸水素ナトリウム、炭酸セシウム、炭酸カリウム、水酸化ナトリウム、リン酸三カリウム等が挙げられ、式（Ｉ）で示される化合物に対して１～１０モル等量用いることができる。
式（ＩＩ）で示される化合物は式（Ｉ）で示される化合物に対して１～３モル等量用いることができる。
反応温度は０℃～１００℃である。
反応時間は０．５～４８時間である。
反応溶媒として１，４－ジオキサン、メタノール、エタノール、テトラヒドロフラン、２－メチルテトラヒドロフラン、水等が挙げられ、単独または混合して用いることができる。
（第８工程）
塩基の存在下または非存在下、式（ＩＩＩ）で示される化合物に、縮合剤の存在下、メタンスルホニル酢酸と反応させることにより、式（ＶＩＩＩ）で示される化合物を得ることができる。
塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、ピリジン等が挙げられ、式（ＩＩＩ）で示される化合物に対して１～１０モル等量用いることができる。
縮合剤としては、ジシクロへキシルカルボジイミド、カルボニルジイミダゾール、ジシクロヘキシルカルボジイミド－Ｎ－ヒドロキシベンゾトリアゾール、ＥＤＣ、４－（４， ６－ジメトキシ－１，３，５，－トリアジン－２－イル）－４－メチルモルホリニウムクロリド、ＨＡＴＵ、プロピルホスホン酸無水物等が挙げられ、式（ＩＩＩ）で示される化合物に対して１～５モル当量用いることができる。
メタンスルホニル酢酸は式（ＩＩＩ）で示される化合物に対して１～３モル等量用いることができる。
反応温度は、－２０℃～６０℃である。
反応時間は、０．１時間～２４時間である。
反応溶媒としては、ＤＭＦ、ＤＭＡ、ＮＭＰ、テトラヒドロフラン、１，４－ジオキサン、ジクロロメタン、アセトニトリル、酢酸エチル等が挙げられ、単独または混合して用いることができる。 The compounds according to the present invention can be produced, for example, by the general synthetic methods shown below.
A method for preparing a compound of formula (VIII).

(In the formula, R is an unsubstituted alkyl group, and R ^1a , R ^1b and R ³ are as defined above.)
(First step)
The compound represented by formula (VI) can be reacted with (R)-2-methylpropane-2-sulfinamide in the presence of tetraalkoxytitanium, and then extracted with an aqueous ammonium lactate solution, an aqueous citric acid solution, and an organic solvent to obtain the compound represented by formula (VII).
The tetraalkoxytitanium includes tetra-n-butyloxytitanium, tetraisopropoxytitanium, tetraethoxytitanium and the like, and can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (VI).
(R)-2-methylpropane-2-sulfinamide can be used in an amount of 1 to 10 molar equivalents based on the compound represented by formula (VI).
The reaction temperature ranges from 0°C to the reflux temperature of the solvent, preferably from room temperature to 100°C.
The reaction time is 0.5 to 48 hours.
Examples of reaction solvents include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, etc., which can be used alone or in combination.
(Second step)
The compound of formula (IX) can be obtained by reacting the compound of formula (VII) with an acetate ester in the presence of a base and titanium chloride trialkoxide.
Examples of the base include lithium hexamethyldisilazide, sodium hexamethyldisilazide, lithium diisopropylamide, sodium tert-butoxide, and sodium methoxide, and can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (VII).
The titanium chloride trialkoxide includes titanium chloride triisopropoxide, which can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (VII).
The acetate ester includes tert-butyl acetate, n-butyl acetate, n-propyl acetate, isopropyl acetate, ethyl acetate and methyl acetate, and can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (VII).
The reaction temperature is -80°C to 50°C.
The reaction time is 0.5 to 24 hours.
Examples of reaction solvents include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, toluene, benzene, dichloroethane, etc., which can be used alone or in combination.
(Third process)
A compound of formula (X) can be obtained by reacting a compound of formula (IX) in the presence of an acid.
The acid includes hydrochloric acid, hydrogen chloride, hydrobromic acid, sulfuric acid, trifluoroacetic acid, (10)-camphorsulfonic acid, etc., which can be used alone or in combination, and can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (IX).
The reaction temperature is from 0°C to 80°C.
The reaction time is from 0.5 to 48 hours, preferably from 1 to 24 hours.
Examples of reaction solvents include 1,4-dioxane, methanol, dichloromethane, ethyl acetate, etc., which can be used alone or in combination.
(Fourth step)
A compound represented by formula (XI) can be obtained by reacting a compound represented by formula (X) with cyanoacetic acid in the presence of a condensing agent in the presence or absence of a base.
The base includes triethylamine, diisopropylethylamine, pyridine, etc., and can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (X).
Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, HATU, propylphosphonic anhydride, and the like. The condensing agent can be used in an amount of 1 to 5 molar equivalents relative to the compound represented by formula (X).
Cyanoacetic acid can be used in an amount of 1 to 3 molar equivalents based on the compound represented by formula (X).
The reaction temperature is -20°C to 60°C.
The reaction time is from 0.1 to 24 hours.
Examples of reaction solvents include DMF, DMA, NMP, tetrahydrofuran, 1,4-dioxane, dichloromethane, acetonitrile, ethyl acetate, etc., and these can be used alone or in combination.
(Fifth step)
The compound of formula (V) can be obtained by reacting the compound of formula (XI) in the presence of a base.
The base includes piperidine, pyrrolidine, triethylamine, diisopropylethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide, etc., and can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (XI).
The reaction temperature is from 0°C to 100°C.
The reaction time is 0.5 to 48 hours.
Examples of reaction solvents include 1,4-dioxane, methanol, ethanol, tetrahydrofuran, etc., which can be used alone or in combination.
(Sixth step)
The compound represented by formula (I) can be obtained by reacting the compound represented by formula (V) with phosphoryl chloride, followed by extraction with an aqueous solution of tripotassium citrate and an organic solvent.
Phosphoryl chloride can be used in an amount of 0.1 to 10 molar equivalents relative to the compound represented by formula (V).
The reaction temperature is from 0°C to 100°C.
The reaction time is 0.5 to 48 hours.
Examples of reaction solvents include DMF, DMA, NMP, tetrahydrofuran, 1,4-dioxane, dichloromethane, dichloroethane, acetonitrile, isopropyl acetate, and the like, which can be used alone or in combination.
Examples of organic solvents used for extraction include chloroform, dichloromethane, ethyl acetate, isopropyl acetate, etc., and these can be used alone or in combination.
(Seventh step)
A compound represented by formula (III) can be obtained by reacting a compound represented by formula (I) with a compound represented by formula (II) in the presence of a base.
The base includes triethylamine, N,N-diisopropylethylamine, sodium hydrogencarbonate, cesium carbonate, potassium carbonate, sodium hydroxide, tripotassium phosphate and the like, and can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (I).
The compound represented by formula (II) can be used in an amount of 1 to 3 molar equivalents based on the compound represented by formula (I).
The reaction temperature is from 0°C to 100°C.
The reaction time is 0.5 to 48 hours.
Examples of reaction solvents include 1,4-dioxane, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, water, etc., and these can be used alone or in combination.
(Step 8)
The compound represented by formula (VIII) can be obtained by reacting the compound represented by formula (III) with methanesulfonylacetic acid in the presence of a condensing agent in the presence or absence of a base.
The base includes triethylamine, diisopropylethylamine, pyridine, etc., and can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (III).
Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, HATU, and propylphosphonic anhydride. The condensing agent can be used in an amount of 1 to 5 molar equivalents relative to the compound represented by formula (III).
Methanesulfonylacetic acid can be used in an amount of 1 to 3 molar equivalents based on the compound represented by formula (III).
The reaction temperature is -20°C to 60°C.
The reaction time is from 0.1 to 24 hours.
Examples of reaction solvents include DMF, DMA, NMP, tetrahydrofuran, 1,4-dioxane, dichloromethane, acetonitrile, ethyl acetate, etc., and these can be used alone or in combination.

（第１工程）
金属触媒および塩基存在下、式（ＸＩＩ）で示される化合物とベンゾフェノンヒドラゾンを反応させることにより、式（ＩＶ）で示される化合物を得ることができる。
金属触媒としては、酢酸パラジウム、ビス（ジベンジリデンアセトン）パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ビス（トリフェニルホスフィン）パラジウム（ＩＩ）二塩化物、ビス（トリ－ｔｅｒｔ－ブチルホスフィン）パラジウム、［２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル］パラジウム等が挙げられ、式（ＸＩＩ）で示される化合物に対して、０．００１～０．５モル当量用いることができる。
塩基としては、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、カリウムｔｅｒｔ－ブトキシド、ナトリウムｔｅｒｔ－ブトキシド、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、リン酸ナトリウム、リン酸水素ナトリウム、リン酸カリウム、リン酸水素カリウム等が挙げられ、式（ＸＩＩ）で示される化合物に対して、１～１０モル当量用いることができる。
ベンゾフェノンヒドラゾンは、式（ＸＩＩ）で示される化合物に対して、１～１０モル当量用いることができる。
反応温度は、０℃～溶媒の還流温度である。
反応時間は、０．１～４８時間である。
反応溶媒としては、テトラヒドロフラン、トルエン、ＤＭＦ、ジオキサン、エタノール、ｔｅｒｔ－アミルアルコール、水等が挙げられ、単独または混合して用いることができる。
（第２工程）
酸の存在下、式（ＩＶ）で示される化合物を反応させ、式（ＩＩ）で示される化合物を得ることができる。
酸としては、塩酸、臭化水素酸、硫酸、トリフルオロ酢酸等が挙げられ、単独または混合して用いることができ、式（ＩＶ）で示される化合物に対して１～１００モル等量用いることができる。
反応温度は０℃～１００℃である。
反応時間は０．５～４８時間である。
反応溶媒としてＤＭＦ、ＤＭＡ、ＮＭＰ、テトラヒドロフラン、１，４－ジオキサン、ジクロロメタン、メタノール、エタノール、アニソール、水等が挙げられ、単独または混合して用いることができる。 A process for preparing a compound of formula (II).

(First step)
The compound of formula (IV) can be obtained by reacting the compound of formula (XII) with benzophenone hydrazone in the presence of a metal catalyst and a base.
Examples of the metal catalyst include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, [2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]palladium, and the like. The metal catalyst can be used in an amount of 0.001 to 0.5 molar equivalents relative to the compound represented by formula (XII).
Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium phosphate, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and the like. The base can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (XII).
The benzophenone hydrazone can be used in an amount of 1 to 10 molar equivalents relative to the compound represented by formula (XII).
The reaction temperature is from 0° C. to the reflux temperature of the solvent.
The reaction time is 0.1 to 48 hours.
Examples of reaction solvents include tetrahydrofuran, toluene, DMF, dioxane, ethanol, tert-amyl alcohol, water, etc., and these can be used alone or in combination.
(Second step)
The compound represented by formula (IV) can be reacted in the presence of an acid to give the compound represented by formula (II).
The acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, etc., which can be used alone or in combination, and can be used in an amount of 1 to 100 molar equivalents relative to the compound represented by formula (IV).
The reaction temperature is from 0°C to 100°C.
The reaction time is 0.5 to 48 hours.
Examples of reaction solvents include DMF, DMA, NMP, tetrahydrofuran, 1,4-dioxane, dichloromethane, methanol, ethanol, anisole, water, etc., and these can be used alone or in combination.

The compound represented by formula (VIII) has a MGAT2 inhibitory effect, and therefore can be used as a medicine for diseases involving MGAT2, such as obesity, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hyper-VLDL blood, hyperfatty acid blood, diabetes, and arteriosclerosis.
The compound represented by formula (VIII) has not only a MGAT2 inhibitory effect but also pharmaceutical utility, and has any or all of the following excellent characteristics:
a) High metabolic stability.
b) It exhibits high solubility.
c) There is little concern about phototoxicity.
d) There is little concern about liver toxicity.
e) There is little concern about nephrotoxicity.
f) There is little concern about toxicity to the cardiovascular system.
g) There is little concern about gastrointestinal disorders.
h) There is little concern about drug interactions.
i) High oral absorbability.
j) The clearance is small.
k) High translocation to target tissues.
l) Strong enzymatic activity.
m) There is little induction of drug metabolizing enzymes.
n) It has strong medicinal properties.
o) The MGAT2 inhibitory effect is highly selective.
p) High chemical stability.

The pharmaceutical composition containing the compound represented by formula (VIII) can be administered orally or parenterally. Parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, ophthalmic, otic, and vaginal administration.

For oral administration, the drug may be administered in any of the commonly used dosage forms, such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.) and liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic perfumes, extracts, decoctions, tinctures, etc.), in accordance with the usual methods. Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets, powders and granules may be dry syrups, and capsules may be soft capsules, microcapsules, or sustained-release capsules.

In the case of parenteral administration, any of the commonly used dosage forms such as injections, drops, topical preparations (e.g., eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, liniments, mouthwashes, enemas, ointments, plasters, jellies, creams, patches, poultices, topical powders, suppositories, etc.) can be suitably administered. Injections may be emulsions such as O/W, W/O, O/W/O, and W/O/W types.

A pharmaceutical composition can be prepared by mixing an effective amount of the compound represented by formula (VIII) with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, disintegrants, lubricants, etc., as necessary. Furthermore, the pharmaceutical composition can be prepared as a pharmaceutical composition for children, elderly people, seriously ill patients, or surgical patients by appropriately changing the effective amount of the compound of the present invention, the dosage form, and/or various pharmaceutical additives. For example, a pharmaceutical composition for children can be administered to newborns (less than 4 weeks after birth), infants (4 weeks to less than 1 year after birth), toddlers (1 year to less than 7 years), children (7 years to less than 15 years), or patients aged 15 to 18 years. For example, a pharmaceutical composition for the elderly can be administered to patients aged 65 years or older.

The dosage of the pharmaceutical composition containing the compound represented by formula (VIII) is desirably set taking into consideration the age and weight of the patient, the type and severity of the disease, the route of administration, etc., but when administered orally, it is usually 0.05 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day. When administered parenterally, it varies greatly depending on the route of administration, but is usually 0.005 to 10 mg/kg/day, preferably 0.01 to 1 mg/kg/day. This can be administered once or in divided doses several times a day.

The dosage of the concomitant drug can be appropriately selected based on the dose used clinically. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the subject, administration route, target disease, symptoms, combination, etc. For example, when the subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

The pharmaceutical composition containing the compound represented by formula (VIII) is also effective for obesity (limited to the case where the patient has both type 2 diabetes and dyslipidemia and has a BMI of 25 kg/ ^m2 or more even with dietary therapy and exercise therapy).

The pharmaceutical composition containing the compound represented by formula (VIII) is also effective for severe obesity in which the effects of previously administered dietary therapy and exercise therapy are insufficient.

The pharmaceutical composition containing the compound represented by formula (VIII) can be used in combination with other anti-obesity drugs (pharmaceutical compositions containing a compound having an anti-obesity effect, drugs that can be used for obesity or weight management in obesity, etc.). For example, by using a pharmaceutical composition containing a compound having an anti-obesity effect in combination with the compound represented by formula (VIII), it can be used for the prevention and/or treatment of obesity, weight management in obesity, etc. In addition, by using a pharmaceutical composition containing a compound represented by formula (VIII) in combination with a pharmaceutical composition containing a compound having an anti-obesity effect, it can be used for the prevention and/or treatment of obesity, weight management in obesity, etc. In addition, the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise, etc.

The present invention will be described in more detail below with reference to examples, reference examples, and test examples, but the present invention is not limited to these.

Furthermore, the abbreviations used in this specification have the following meanings.
DMA: N,N-dimethylacetamide DMF: N,N-dimethylformamide DMSO: dimethylsulfoxide EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate NMP: N-methylpyrrolidone

(Method of identifying compounds)
The NMR analysis obtained in each example was performed at 400 MHz, and was measured using DMSO-d ₆ and CDCl _3. Furthermore, when presenting NMR data, there are cases in which not all measured peaks are listed.

（測定条件２）標品（化合物１２）：ＲＴ＝１２．６ｍｉｎ
カラム：ＸＳｅｌｅｃｔ ＣＳＨ Ｃ１８，１５０×４．６ｍｍ，３．５μｍ
移動相Ａ：０．１％ぎ酸水溶液
移動相Ｂ：アセトニトリル
流速：１．０ｍＬ／ｍｉｎ
注入量：１０μＬ
カラム温度：４０℃
ＵＶ検出波長：２５４ｎｍ
グラジエント：

（測定条件３）標品（化合物１１）：ＲＴ＝１１．０ｍｉｎ
カラム：Ｘｂｒｉｄｇｅ Ｃ１８，１５０×４．６ｍｍ，３．５μｍ
移動相Ａ：０．１％トリフルオロ酢酸水溶液
移動相Ｂ：アセトニトリル
流速：１．０ｍＬ／ｍｉｎ
注入量：１０μＬ
カラム温度：４０℃
ＵＶ検出波長：２５４ｎｍ
グラジエント：

（測定条件４）標品（化合物６）：ＲＴ ＝１３．０
カラム：Ｘｂｒｉｄｇｅ Ｃ１８，１５０×４．６ｍｍ，３．５μｍ
移動相Ａ：０．１％トリフルオロ酢酸水溶液
移動相Ｂ：アセトニトリル
流速：１．０ｍＬ／ｍｉｎ
注入量：１０μＬ
カラム温度：４０℃
ＵＶ検出波長：２１０ｎｍ
グラジエント：

In the specification, "RT" or "retention time" refers to the retention time in liquid chromatography, which was measured under the following conditions. The quantitative value and quantitative yield in the solution were calculated based on the content determined by the absolute quantitative method using the standard specimen to be quantified.
(Measurement conditions 1) Standard sample (compound 12): RT = 21.2
Column: Xbridge C18, 150 x 4.6 mm, 3.5 μm
Mobile phase A: 0.1% trifluoroacetic acid aqueous solution Mobile phase B: Methanol Flow rate: 1.0 mL/min
Injection volume: 10 μL
Column temperature: 40°C
UV detection wavelength: 254 nm
Gradient:

(Measurement conditions 2) Standard sample (compound 12): RT = 12.6 min
Column: XSelect CSH C18, 150 x 4.6 mm, 3.5 μm
Mobile phase A: 0.1% formic acid aqueous solution Mobile phase B: acetonitrile Flow rate: 1.0 mL/min
Injection volume: 10 μL
Column temperature: 40°C
UV detection wavelength: 254 nm
Gradient:

(Measurement conditions 3) Standard sample (compound 11): RT = 11.0 min
Column: Xbridge C18, 150 x 4.6 mm, 3.5 μm
Mobile phase A: 0.1% aqueous trifluoroacetic acid solution Mobile phase B: acetonitrile Flow rate: 1.0 mL/min
Injection volume: 10 μL
Column temperature: 40°C
UV detection wavelength: 254 nm
Gradient:

(Measurement conditions 4) Standard sample (compound 6): RT = 13.0
Column: Xbridge C18, 150 x 4.6 mm, 3.5 μm
Mobile phase A: 0.1% aqueous trifluoroacetic acid solution Mobile phase B: acetonitrile Flow rate: 1.0 mL/min
Injection volume: 10 μL
Column temperature: 40°C
UV detection wavelength: 210 nm
Gradient:

工程１ 化合物３の合成
ｔｅｒｔ－アミルアルコール（３０７ｋｇ）に、ナトリウムｔｅｒｔ－ブトキシド（２８．３ｋｇ、２９４ｍｏｌ）、（±）－２，２’－ビス（ジフェニルホスフィノ）－１，１’－ビナフチル（２．３０ｋｇ、３．６９ｍｏｌ）、化合物１（３４．６ｋｇ、２７１ｍｏｌ）を加え、１０℃に冷却したのち、酢酸パラジウム（０．４３０ｋｇ、１．９２ｍｏｌ）、化合物２（４８．０ｋｇ、２４５ｍｏｌ）を加え、７０℃に昇温し３時間撹拌した。２０℃に冷却後、０℃に冷却したメタノール（４９６ｋｇ）を反応後液が２０℃以下になるよう１時間３０分かけて滴下した。微結晶セルロース（４．８ｋｇ）で濾過し、微結晶セルロースをメタノール（１５０ｋｇ）で洗浄した。濾液を活性炭で濾過し、活性炭をメタノール（９６０Ｌ）で洗浄した。濾液を５８８Ｌまで減圧下濃縮したのち、メタノール洗浄液の半量を加え、５８２Ｌまで減圧下濃縮した。さらに、残りのメタノール洗浄液を加え５０９Ｌまで減圧下濃縮した。２５℃にしたのち、１４％塩酸（６２．０ｋｇ）を２時間かけて滴下した。起晶を確認後、３０分間撹拌し、１４％塩酸（１２９．８ｋｇ）を３時間３０分かけて滴下したのち、１時間撹拌した。２時間３０分かけて０℃に冷却し１時間撹拌した。濾過により湿結晶を分離後、メタノール／ｔｅｒｔ－アミルアルコール／１４％塩酸混合液（１６４ｋｇ）（メタノール（６６ｋｇ）、ｔｅｒｔ－アミルアルコール（６８ｋｇ）、１４％塩酸（３０ｋｇ）を混合させた水溶液）で湿結晶を洗浄した。５％メタノール水／２％塩酸混合液（１９３ｋｇ）（メタノール（９．７ｋｇ）、３５％塩酸（１１．３ｋｇ）、水（１７２ｋｇ）を混合させた水溶液）で湿結晶を洗浄した。得られた湿結晶を６０℃で減圧下２４時間乾燥させることで、化合物３（５７．９４ｋｇ、収率７３％）を得た。
¹H-NMR (400MHz, DMSO-d₆) δ：2.29 (s, 3H), 7.38-7.49 (m, 6H), 7.61-7.70 (m, 5H), 7.95-8.04 (m, 2H), 10.87 (br s, 1H).

工程２ 化合物４の合成
アニソール（９３０ｋｇ）に、化合物３（６７．４ｋｇ、２０９ｍｏｌ）、水（５２０．５ｋｇ）を加え、８５℃に昇温後、６２．５％硫酸水溶液（１５９ｋｇ）を２時間かけて滴下し、２時間３０分撹拌した。２５℃に冷却後、抽出により有機層を除いた。アニソール（５１８ｋｇ）で洗浄後、１５℃に冷却し、４８％水酸化ナトリウム溶液を用いてｐＨ３．１に調整して、化合物４の水溶液を得た。 Example 1 Synthesis of Compound 4

Step 1 Synthesis of Compound 3 To tert-amyl alcohol (307 kg), sodium tert-butoxide (28.3 kg, 294 mol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.30 kg, 3.69 mol), and compound 1 (34.6 kg, 271 mol) were added, and the mixture was cooled to 10°C. Then, palladium acetate (0.430 kg, 1.92 mol) and compound 2 (48.0 kg, 245 mol) were added, and the mixture was heated to 70°C and stirred for 3 hours. After cooling to 20°C, methanol (496 kg) cooled to 0°C was added dropwise over 1 hour and 30 minutes so that the reaction liquid was 20°C or less. The mixture was filtered through microcrystalline cellulose (4.8 kg), and the microcrystalline cellulose was washed with methanol (150 kg). The filtrate was filtered through activated carbon, and the activated carbon was washed with methanol (960 L). The filtrate was concentrated under reduced pressure to 588 L, and then half of the methanol washing solution was added, and the mixture was concentrated under reduced pressure to 582 L. The remaining methanol washing solution was added, and the mixture was concentrated under reduced pressure to 509 L. After the mixture was cooled to 25°C, 14% hydrochloric acid (62.0 kg) was added dropwise over 2 hours. After confirming crystallization, the mixture was stirred for 30 minutes, and 14% hydrochloric acid (129.8 kg) was added dropwise over 3 hours and 30 minutes, and then the mixture was stirred for 1 hour. The mixture was cooled to 0°C over 2 hours and 30 minutes, and then stirred for 1 hour. The wet crystals were separated by filtration, and then the wet crystals were washed with a methanol/tert-amyl alcohol/14% hydrochloric acid mixture (164 kg) (aqueous solution obtained by mixing methanol (66 kg), tert-amyl alcohol (68 kg), and 14% hydrochloric acid (30 kg)). The wet crystals were washed with a 5% aqueous methanol/2% hydrochloric acid mixture (193 kg) (aqueous solution obtained by mixing methanol (9.7 kg), 35% hydrochloric acid (11.3 kg), and water (172 kg)). The obtained wet crystals were dried at 60° C. under reduced pressure for 24 hours to obtain compound 3 (57.94 kg, yield 73%).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ: 2.29 (s, 3H), 7.38-7.49 (m, 6H), 7.61-7.70 (m, 5H), 7.95-8.04 (m, 2H), 10.87 (br s, 1H).

Step 2 Synthesis of Compound 4 Compound 3 (67.4 kg, 209 mol) and water (520.5 kg) were added to anisole (930 kg), and the mixture was heated to 85° C., after which 62.5% aqueous sulfuric acid solution (159 kg) was added dropwise over 2 hours and stirred for 2 hours and 30 minutes. After cooling to 25° C., the organic layer was removed by extraction. After washing with anisole (518 kg), the mixture was cooled to 15° C. and adjusted to pH 3.1 using 48% sodium hydroxide solution to obtain an aqueous solution of compound 4.

工程１ 化合物６の合成
２－メチルテトラヒドロフラン（２４８Ｌ）に、化合物５（６１．８ｋｇ、３３６ｍｏｌ）、（Ｒ）－２－メチルプロパン－２－スルフインアミド（６１．４ｋｇ、５０７ｍｏｌ）、テトラエトキシチタン（１６９ｋｇ、７４１ｍｏｌ）を順に加え、６０℃で４０時間撹拌した。反応後液を２５℃に冷却したのち、２－メチルテトラヒドロフラン（５５８Ｌ）を加え、２５℃の乳酸アンモニウム／クエン酸水溶液（９１６ｋｇ）（３５％乳酸アンモニウム水溶液（８０１ｋｇ）にクエン酸一水和物（１１５ｋｇ）を加えた水溶液）に３時間かけて滴下した。１０℃に冷却したのち、抽出により水層を除き、２％クエン酸水溶液（３２２ｋｇ）で洗浄した。５％重曹／５％食塩水（６７４ｋｇ）（重曹（３２．３ｋｇ）、食塩（３２．３ｋｇ）を水（６０９ｋｇ）に溶解させた水溶液）を加え、２５℃に昇温し抽出により水層を除いた。５％重曹／５％食塩水（６６２ｋｇ）で洗浄したのち、３４１Ｌまで減圧下濃縮を行った。テトラヒドロフラン（３７０Ｌ）を加え３４１Ｌまで減圧下濃縮を行う操作を２回行ったのち、テトラヒドロフラン（３７０Ｌ）を加え３１０Ｌまで減圧下濃縮を行う操作を２回行い、化合物６のテトラヒドロフラン溶液を得た。

工程２ 化合物７の合成
１．２ｍｏｌ／Ｌ リチウムヘキサメチルジシラジド－テトラヒドロフラン溶液（５７６ｋｇ、７７３ｍｏｌ）を－５０℃に冷却し、酢酸ｔｅｒｔ－ブチル（８９．８ｋｇ、７７３ｍｏｌ）を３０分かけて滴下したのち３０分間撹拌した。５℃に冷却したクロロトリイソプロポキシチタン－テトラヒドロフラン溶液（５１７ｋｇ）（クロロトリイソプロポキシチタン（２３７ｋｇ、９１０ｍｏｌ）をテトラヒドロフラン（２８０ｋｇ）に溶解させた溶液）を１時間かけて滴下し、３０分間撹拌した。上記の工程１で得られた化合物６のテトラヒドロフラン溶液を１時間かけて滴下し３０分間撹拌した。０℃のクエン酸水溶液（９３９ｋｇ）（クエン酸一水和物（２５６ｋｇ）を水（６８３ｋｇ）に溶かした水溶液）に反応後液を滴下したのち、２５℃に昇温した。抽出により水層を除いたのち、５％重曹水（３３７ｋｇ）で洗浄し、２７９Ｌまで減圧下濃縮を行った。２－メチルテトラヒドロフラン（６８２Ｌ）を加えたのち、２．５％食塩水（６８６ｋｇ）で洗浄し、３１０Ｌまで減圧下濃縮を行った。メタノール（３６６Ｌ）を加え、３１０Ｌまで減圧下濃縮を行う操作を２回行ったのち、メタノール（２５０Ｌ）を加え、活性炭で濾過し、活性炭をメタノール（１３９５Ｌ）で洗浄した。濾液を３１０Ｌまで減圧下濃縮することで化合物７のメタノール溶液を得た。

工程３ 化合物８の合成
上記の工程２で得られた化合物７のメタノール溶液を０℃に冷却し、４ｍｏｌ／Ｌ塩化水素－酢酸エチル溶液（１４５ｋｇ、６２７ｍｏｌ）を１時間３０分かけて滴下し、１時間撹拌した。ｎ－ヘプタン（５５４ｋｇ）、水（８１０ｋｇ）、酢酸エチル（２２２ｋｇ）を加え５℃に昇温し、抽出により有機層を除いた。得られた水層にｎ－ヘプタン（５５０ｋｇ）を加え、抽出により有機層を除いたのち、１ｍｏｌ／Ｌ水酸化ナトリウム溶液を用いてｐＨを９．０に調整し、酢酸エチル（４３６Ｌ）を加え、２５℃に昇温した。抽出により有機層と水層を分離し、水層に酢酸エチル（４３９Ｌ）を加え、抽出により水層を除いた。有機層を混合させたのち、酢酸エチル（３８８ｋｇ）を加え、２．５％食塩水（８５２ｋｇ）で洗浄した。酢酸エチル（３１７Ｌ）を加えたのち、活性炭で濾過し、活性炭を酢酸エチル（１６８５Ｌ）で洗浄した。濾液を７１３Ｌまで減圧下濃縮し、ｎ－ヘプタン（４２２ｋｇ）を１時間かけて滴下し、（－）－１０－カンファースルホン酸－テトラヒドロフラン溶液（９５．０ｋｇ）（（－）－１０－カンファースルホン酸（１２．９ｋｇ、５５．５ｍｏｌ）をテトラヒドロフラン（８２．１ｋｇ）に溶解させた溶液）を２時間３０分かけて滴下し、起晶を確認後１時間撹拌した。（－）－１０－カンファースルホン酸－テトラヒドロフラン溶液（２７９．６ｋｇ）（（－）－１０－カンファースルホン酸（３７．８ｋｇ、１６３ｍｏｌ）をテトラヒドロフラン（２４１．８ｋｇ）に溶解させた溶液）を３時間３０分かけて滴下したのち、ｎ－ヘプタン（１０５６ｋｇ）を５時間かけて滴下し、１時間撹拌した。濾過により湿結晶を分離後、酢酸エチル／ｎ－ヘプタン溶液（４２４ｋｇ）（酢酸エチル（１７１ｋｇ）、ｎ－ヘプタン（２５３ｋｇ）を混合させた溶液）で湿結晶を洗浄した。得られた湿結晶を２５℃で減圧下２４時間乾燥させることで、化合物８（１０９．１２ｋｇ、収率６１％）を得た。
¹H-NMR (400MHz, CDCl₃) δ：0.77 (s, 3H), 0.98 (s, 3H), 1.24-1.35 (m, 1H), 1.29 (s, 9H), 1.44 (ddd, J=14.0, 9.4, 4.6 Hz, 1H), 1.78-2.05 (m, 3H), 2.22-2.37 (m, 2H), 2.54-2.69 (m, 3H), 3.07-3.19 (m, 2H), 3.23-3.32 (m, 1H), 4.28 (ddd, J=11.9, 4.2, 4.2, 1H), 4.37-4.48 (m, 1H), 6.40-6.47 (m, 2H), 8.21-8.47 (br, 2H).

工程４ 化合物９の合成
テトラヒドロフラン（３９０Ｌ）に、化合物８（１０７．９ｋｇ、２０３ｍｏｌ）を加え、１０℃に冷却したのちトリエチルアミン（３１．４ｋｇ）、シアノ酢酸（２５．９ｋｇ、３０４ｍｏｌ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（５８．３ｋｇ、３０５ｍｏｌ）を加え、２５℃に昇温し１時間撹拌した。５％クエン酸水溶液（５２４ｋｇ）、メチル－ｔｅｒｔ－ブチルエーテル（８００ｋｇ）を加え、抽出により水層を除いた。５％重曹水（１０５２ｋｇ）で洗浄したのち、１０％食塩水（１０５０ｋｇ）で洗浄し、３２４Ｌまで減圧下濃縮した。メチル－ｔｅｒｔ－ブチルエーテル（７８９Ｌ）を加え、３１９Ｌまで減圧下濃縮する操作を２回行い、メタノール（７９４Ｌ）を加え、３２３Ｌまで減圧下濃縮したのち、メタノール（７９４Ｌ）を加え、４８６Ｌまで減圧下濃縮し、化合物９のメタノール溶液を得た。

工程５ 化合物１０の合成
上記の工程４で得られた化合物９のメタノール溶液に、メタノール（５５２ｋｇ）、３０％ナトリウムメトキシド－メタノール溶液（７３．４ｋｇ）を加え、５０℃に昇温し３時間撹拌した。２５℃に冷却し、７５１Ｌまで減圧下濃縮し、水（４９８ｋｇ）を加えたのち、３５％塩酸を用いてｐＨ２．０に調整した。起晶を確認後２時間撹拌し、３５％塩酸（５０．８ｋｇ）を加え、１時間撹拌した。濾過により湿結晶を分離後、メタノール水（３６８ｋｇ）（メタノール（５４ｋｇ）、水（３１４ｋｇ）を混合させた水溶液）で湿結晶を洗浄した。得られた湿結晶を８０℃で減圧下２４時間乾燥させることで、化合物１０（５０．４０ｋｇ、収率８５％）を得た。
¹H-NMR (400MHz, DMSO-d₆) δ：2.09-2.19 (m, 2H), 2.74 (d, J=17.8 Hz, 1H), 3.08-3.37 (m, 1H), 4.08-4.26 (m, 2H), 6.62 (dt, J=10.2, 2.0 Hz, 1H), 6.83 (ddd, J=12.0, 9.2, 2.6 Hz, 1H), 8.13 (s, 1H).

工程６ 化合物１１の合成
酢酸イソプロピル（３７０．５ｋｇ）に、化合物１０（４２．８ｋｇ、１４６ｍｏｌ）、Ｎ，Ｎ－ジメチルホルムアミド（８２ｋｇ）を加え、５℃に冷却したのち塩化ホスホリル（２０．８ｋｇ、１３６ｍｏｌ）を加え、９時間撹拌した。０℃に冷却後、クエン酸三カリウム水溶液（４９７ｋｇ）（クエン酸三カリウム（７１ｋｇ）を水（４２６ｋｇ）に溶解させた水溶液）を１時間３０分かけて滴下し、５℃に昇温したのち抽出により水層を除いた。２％食塩水（４３６ｋｇ）で洗浄したのち、２３３Ｌまで減圧下濃縮した。２５℃としたのち、ｎ－ヘプタン（１４．５ｋｇ）を加え、起晶を確認後、１時間３０分撹拌した。ｎ－ヘプタン（３７９ｋｇ）を滴下し、３時間撹拌した。濾過により湿結晶を分離後、酢酸イソプロピル／ｎ－ヘプタン（１５４ｋｇ）（酢酸イソプロピル（３８ｋｇ）、ｎ－ヘプタン（１１６ｋｇ）を混合させた溶液）で湿結晶を洗浄し、ｎ－ヘプタン（１１５ｋｇ）で湿結晶を洗浄した。得られた湿結晶を６０℃で減圧下２４時間乾燥させることで、化合物１１（３７．４６ｋｇ、収率８２％）を得た。
¹H-NMR (400MHz, CDCl₃) δ：2.24 (ddd, J=14.4, 7.4, 3.2 Hz, 1H), 2.36 (ddd, J=14.4, 7.7, 3.3, 1H), 2.89 (d, J=19.0 Hz, 1H), 3.72 (dd, J=19.0, 1.1 Hz, 1H), 4.15-4.27 (m, 2H), 6.39-6.56 (m, 2H), 6.77 (s, 1H).

工程７ 化合物１２の合成
上記の実施例１の工程２で得られた化合物４の水溶液に、化合物１１の２－メチルテトラヒドロフラン溶液（化合物１１（５２．１ｋｇ、１６８ｍｏｌ）を２－メチルテトラヒドロフラン（５７８ｋｇ）に溶解させた溶液）を２時間かけて滴下し、２５℃に昇温した。反応液に、リン酸三カリウム水溶液（リン酸三カリウム（８２．０ｋｇ）を水（１８０ｋｇ）に溶解させた水溶液）を２時間かけて滴下した。１時間撹拌後、５０℃に昇温し６時間撹拌した。２５℃に冷却後、抽出により水層を除いたのち、２－メチルテトラヒドロフラン（２２４ｋｇ）を加え、１ｍｏｌ／Ｌ塩酸／２．５％食塩水（５４２ｋｇ）（食塩（１３．０ｋｇ）、３５％塩酸（５２ｋｇ）、水（４７７ｋｇ）を混合した水溶液）を加え、抽出により水層を除いた。微結晶セルロース（５．２ｋｇ）に濾過し、微結晶セルロースを２－メチルテトラヒドロフラン（１３６ｋｇ）で洗浄した。濾液に２％食塩水（６３１ｋｇ）を加え、抽出により水層を除いた。活性炭で濾過し、活性炭を２－メチルテトラヒドロフラン（６７０ｋｇ）で洗浄した。濾液を４８５Ｌまで濃縮し、起晶後１時間撹拌した。ｎ－ヘプタン（５２７ｋｇ）を５時間かけて滴下し、２時間撹拌した。濾過により湿結晶を分離後、２－メチルテトラヒドロフラン／ｎ－ヘプタン（２－メチルテトラヒドロフラン（７０ｋｇ）、ｎ－ヘプタン（９０ｋｇ）を混合させた溶液）で湿結晶を洗浄し、ｎ－ヘプタン（１４１ｋｇ）で湿結晶を洗浄した。得られた湿結晶を７０℃で減圧下２０時間乾燥させることで、化合物１２（５７．８５ｋｇ、収率８７％）を得た。
¹H-NMR (400MHz, CDCl₃) δ：2.19-2.31 (m, 2H), 2.35 (s, 3H), 2.89 (d, J=16.1Hz, 1H), 3.67 (d, J=16.2 Hz, 1H), 4.16 (t, J=5.4 Hz, 2H), 5.48 (s, 1H), 6.42-6.50 (m, 2H), 7.09-7.26 (m, 2H), 7.62 (dd, J=8.8, 2.0, 1H), 7.77 (d, J=8.5 Hz, 1H), 8.16-8.20 (m, 1H).

工程８ 化合物１３の合成
化合物１２（５７．８ｋｇ、１４５ｍｏｌ）に、テトラヒドロフラン（１５４．２ｋｇ）、酢酸エチル（７８．２ｋｇ）を加え、０℃に冷却したのち、５２％プロピルホスホン酸無水物－酢酸エチル溶液（２５１．３ｋｇ）を１時間３０分かけて滴下し、ピリジン（２７．６ｋｇ）を加えた。メタンスルホニル酢酸のテトラヒドロフラン溶液（メタンスルホニル酢酸（２６．２ｋｇ、１９０ｍｏｌ）をテトラヒドロフラン（１５４．２ｋｇ）に溶解させた溶液）を５時間かけて滴下し、６時間撹拌した。５％重曹水（５６８．９ｋｇ）に酢酸エチル（５２１．４ｋｇ）を加え５℃冷却し、反応後液を１時間かけて滴下し、２０℃に昇温し、抽出により水層を除いた。２５％食塩水（２２８．３ｋｇ）、７％重曹水（４０４．３ｋｇ）を加え、２５℃に昇温し抽出により水層を除いた。メタノール（２２９．１ｋｇ）を加え、活性炭で濾過し、活性炭をメタノール／酢酸エチル溶液（メタノール（４１．４ｋｇ）、酢酸エチル（１０９．５ｋｇ）の混合溶液）で洗浄した。５２６Ｌまで減圧下濃縮し、メタノール（４５．７ｋｇ）、酢酸エチル（１０４．３ｋｇ）を加えた。化合物１３（３５１．２ｇ）を加え、起晶させたのち３時間撹拌しメタノール（４５７．４ｋｇ）を２時間かけて滴下した。７１１Ｌまで減圧下濃縮し、メタノール（４５７．５ｋｇ）を加え、６６５Ｌまで減圧下濃縮した。水（６９３．５ｋｇ）を２時間かけて滴下したのち、２時間撹拌した。濾過により湿結晶を分離後、４％メタノール水（１７２ｋｇ）で２回洗浄した。得られた湿結晶を７０℃で減圧下３０時間乾燥させることで、化合物１３（６８．５７ｋｇ、収率９１％）を得た。
スパイラルジェットミルを用いて、化合物１３を粉砕圧力０．４０ＭＰａ、供給圧力０．５０ＭＰａ、平均処理速度２２～３２ｇ／ｍｉｎで１回目粉砕を行い、１回目粉砕品を粉砕圧力０．４０ＭＰａ、供給圧力０．５０ＭＰａ、平均処理速度２０～４５ｇ／ｍｉｎで２回目粉砕を行うことで化合物１３の粉砕品（５３．１ｋｇ、収率９１％）を得た。
¹H-NMR (400MHz, CDCl₃) δ：2.17-2.27 (m, 1H), 2.31-2.41 (m, 4H), 2.99 (d, J=16.1 Hz, 1H), 3.19 (s, 3H), 3.78 (d, J=16.2 Hz, 1H), 4.13-4.23 (m, 4H), 6.06 (s, 1H), 6.43-6.51 (m, 2H), 7.69 (dd, J=8.7, 2.0 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 8.26-8.30 (m, 1H), 11.20 (s, 1H). Example 2 Synthesis of Compound 13

Step 1 Synthesis of Compound 6 Compound 5 (61.8 kg, 336 mol), (R)-2-methylpropane-2-sulfinamide (61.4 kg, 507 mol), and tetraethoxytitanium (169 kg, 741 mol) were added in this order to 2-methyltetrahydrofuran (248 L), and the mixture was stirred at 60° C. for 40 hours. After the reaction, the liquid was cooled to 25° C., and then 2-methyltetrahydrofuran (558 L) was added, and the mixture was added dropwise to an ammonium lactate/citric acid solution (916 kg) (aqueous solution obtained by adding citric acid monohydrate (115 kg) to a 35% ammonium lactate solution (801 kg)) at 25° C. over 3 hours. After cooling to 10° C., the aqueous layer was removed by extraction, and the mixture was washed with a 2% citric acid solution (322 kg). 5% sodium bicarbonate/5% saline (674 kg) (aqueous solution obtained by dissolving sodium bicarbonate (32.3 kg) and table salt (32.3 kg) in water (609 kg)) was added, the temperature was raised to 25° C., and the aqueous layer was removed by extraction. After washing with 5% sodium bicarbonate/5% saline (662 kg), the mixture was concentrated under reduced pressure to 341 L. Tetrahydrofuran (370 L) was added and the mixture was concentrated under reduced pressure to 341 L twice, after which tetrahydrofuran (370 L) was added and the mixture was concentrated under reduced pressure to 310 L twice to obtain a tetrahydrofuran solution of compound 6.

Step 2 Synthesis of Compound 7 A 1.2 mol/L lithium hexamethyldisilazide-tetrahydrofuran solution (576 kg, 773 mol) was cooled to -50°C, and tert-butyl acetate (89.8 kg, 773 mol) was added dropwise over 30 minutes, followed by stirring for 30 minutes. A chlorotriisopropoxytitanium-tetrahydrofuran solution (517 kg) (a solution obtained by dissolving chlorotriisopropoxytitanium (237 kg, 910 mol) in tetrahydrofuran (280 kg)) cooled to 5°C was added dropwise over 1 hour, followed by stirring for 30 minutes. A tetrahydrofuran solution of Compound 6 obtained in the above step 1 was added dropwise over 1 hour, followed by stirring for 30 minutes. A reaction liquid was added dropwise to a citric acid aqueous solution (939 kg) (aqueous solution obtained by dissolving citric acid monohydrate (256 kg) in water (683 kg)) at 0°C, followed by heating to 25°C. The aqueous layer was removed by extraction, washed with 5% sodium bicarbonate water (337 kg), and concentrated under reduced pressure to 279 L. 2-Methyltetrahydrofuran (682 L) was added, washed with 2.5% saline (686 kg), and concentrated under reduced pressure to 310 L. Methanol (366 L) was added, and the operation of concentrating under reduced pressure to 310 L was repeated twice, after which methanol (250 L) was added, filtered through activated charcoal, and the activated charcoal was washed with methanol (1395 L). The filtrate was concentrated under reduced pressure to 310 L to obtain a methanol solution of compound 7.

Step 3 Synthesis of Compound 8 The methanol solution of compound 7 obtained in step 2 above was cooled to 0°C, and 4 mol/L hydrogen chloride-ethyl acetate solution (145 kg, 627 mol) was added dropwise over 1 hour and 30 minutes, followed by stirring for 1 hour. n-heptane (554 kg), water (810 kg), and ethyl acetate (222 kg) were added, the temperature was raised to 5°C, and the organic layer was removed by extraction. n-heptane (550 kg) was added to the obtained aqueous layer, the organic layer was removed by extraction, the pH was adjusted to 9.0 using 1 mol/L sodium hydroxide solution, ethyl acetate (436 L) was added, and the temperature was raised to 25°C. The organic layer and the aqueous layer were separated by extraction, ethyl acetate (439 L) was added to the aqueous layer, and the aqueous layer was removed by extraction. The organic layers were mixed, and then ethyl acetate (388 kg) was added, followed by washing with 2.5% saline (852 kg). After adding ethyl acetate (317 L), the mixture was filtered through activated carbon and the activated carbon was washed with ethyl acetate (1685 L). The filtrate was concentrated under reduced pressure to 713 L, n-heptane (422 kg) was added dropwise over 1 hour, and a (-)-10-camphorsulfonic acid-tetrahydrofuran solution (95.0 kg) (a solution obtained by dissolving (-)-10-camphorsulfonic acid (12.9 kg, 55.5 mol) in tetrahydrofuran (82.1 kg)) was added dropwise over 2 hours and 30 minutes, and the mixture was stirred for 1 hour after confirming crystallization. A (-)-10-camphorsulfonic acid-tetrahydrofuran solution (279.6 kg) (a solution obtained by dissolving (-)-10-camphorsulfonic acid (37.8 kg, 163 mol) in tetrahydrofuran (241.8 kg)) was added dropwise over 3 hours and 30 minutes, and then n-heptane (1056 kg) was added dropwise over 5 hours and stirred for 1 hour. The wet crystals were separated by filtration, and then washed with an ethyl acetate/n-heptane solution (424 kg) (a solution obtained by mixing ethyl acetate (171 kg) and n-heptane (253 kg)). The obtained wet crystals were dried under reduced pressure at 25° C. for 24 hours to obtain compound 8 (109.12 kg, yield 61%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.77 (s, 3H), 0.98 (s, 3H), 1.24-1.35 (m, 1H), 1.29 (s, 9H), 1.44 (ddd, J=14.0, 9.4, 4.6 Hz, 1H), 1.78-2.05 (m, 3H), 2.22-2.37 (m, 2H), 2.54-2.69 (m, 3H), 3.07-3.19 (m, 2H), 3.23-3.32 (m, 1H), 4.28 (ddd, J=11.9, 4.2, 4.2, 1H), 4.37-4.48 (m, 1H) , 6.40-6.47 (m, 2H), 8.21-8.47 (br, 2H).

Step 4 Synthesis of Compound 9 Compound 8 (107.9 kg, 203 mol) was added to tetrahydrofuran (390 L) and cooled to 10° C., then triethylamine (31.4 kg), cyanoacetic acid (25.9 kg, 304 mol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58.3 kg, 305 mol) were added, and the mixture was heated to 25° C. and stirred for 1 hour. 5% citric acid aqueous solution (524 kg) and methyl-tert-butyl ether (800 kg) were added, and the aqueous layer was removed by extraction. The mixture was washed with 5% sodium bicarbonate water (1052 kg), then with 10% saline (1050 kg), and concentrated under reduced pressure to 324 L. Methyl tert-butyl ether (789 L) was added, and the mixture was concentrated under reduced pressure to 319 L. This operation was repeated twice. Methanol (794 L) was added, and the mixture was concentrated under reduced pressure to 323 L. Methanol (794 L) was then added, and the mixture was concentrated under reduced pressure to 486 L, to obtain a methanol solution of compound 9.

Step 5 Synthesis of Compound 10 Methanol (552 kg) and 30% sodium methoxide-methanol solution (73.4 kg) were added to the methanol solution of compound 9 obtained in step 4 above, and the mixture was heated to 50 ° C. and stirred for 3 hours. The mixture was cooled to 25 ° C., concentrated under reduced pressure to 751 L, and water (498 kg) was added, and the pH was adjusted to 2.0 using 35% hydrochloric acid. After confirming crystallization, the mixture was stirred for 2 hours, and 35% hydrochloric acid (50.8 kg) was added and stirred for 1 hour. After separating the wet crystals by filtration, the wet crystals were washed with methanol water (368 kg) (aqueous solution obtained by mixing methanol (54 kg) and water (314 kg)). The obtained wet crystals were dried under reduced pressure at 80 ° C. for 24 hours to obtain compound 10 (50.40 kg, yield 85%).
¹ H-NMR (400MHz, DMSO-d ₆ ) δ:2.09-2.19 (m, 2H), 2.74 (d, J=17.8 Hz, 1H), 3.08-3.37 (m, 1H), 4.08-4.26 (m, 2H), 6.62 (dt, J=10.2, 2.0 Hz, 1 H), 6.83 (ddd, J=12.0, 9.2, 2.6 Hz, 1H), 8.13 (s, 1H).

Step 6 Synthesis of Compound 11 Compound 10 (42.8 kg, 146 mol) and N,N-dimethylformamide (82 kg) were added to isopropyl acetate (370.5 kg), cooled to 5°C, and then phosphoryl chloride (20.8 kg, 136 mol) was added and stirred for 9 hours. After cooling to 0°C, tripotassium citrate aqueous solution (497 kg) (aqueous solution obtained by dissolving tripotassium citrate (71 kg) in water (426 kg)) was added dropwise over 1 hour and 30 minutes, and the temperature was raised to 5°C, and the aqueous layer was removed by extraction. After washing with 2% saline (436 kg), the mixture was concentrated under reduced pressure to 233 L. After the temperature was raised to 25°C, n-heptane (14.5 kg) was added, and after confirming crystallization, the mixture was stirred for 1 hour and 30 minutes. n-heptane (379 kg) was added dropwise, and the mixture was stirred for 3 hours. After separating the wet crystals by filtration, the wet crystals were washed with isopropyl acetate/n-heptane (154 kg) (a mixed solution of isopropyl acetate (38 kg) and n-heptane (116 kg)), and then washed with n-heptane (115 kg). The obtained wet crystals were dried at 60° C. under reduced pressure for 24 hours to obtain compound 11 (37.46 kg, yield 82%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.24 (ddd, J=14.4, 7.4, 3.2 Hz, 1H), 2.36 (ddd, J=14.4, 7.7, 3.3, 1H), 2.89 (d, J=19.0 Hz, 1H), 3.72 (dd, J=19.0, 1. 1Hz, 1H), 4.15-4.27 (m, 2H), 6.39-6.56 (m, 2H), 6.77 (s, 1H).

Step 7 Synthesis of Compound 12 A 2-methyltetrahydrofuran solution of Compound 11 (a solution obtained by dissolving Compound 11 (52.1 kg, 168 mol) in 2-methyltetrahydrofuran (578 kg)) was added dropwise to the aqueous solution of Compound 4 obtained in Step 2 of Example 1 above over a period of 2 hours, and the temperature was raised to 25° C. An aqueous solution of tripotassium phosphate (aqueous solution obtained by dissolving tripotassium phosphate (82.0 kg) in water (180 kg)) was added dropwise to the reaction solution over a period of 2 hours. After stirring for 1 hour, the temperature was raised to 50° C. and the mixture was stirred for 6 hours. After cooling to 25° C., the aqueous layer was removed by extraction, and then 2-methyltetrahydrofuran (224 kg) was added, and 1 mol/L hydrochloric acid/2.5% saline solution (542 kg) (aqueous solution obtained by mixing table salt (13.0 kg), 35% hydrochloric acid (52 kg), and water (477 kg)) was added, and the aqueous layer was removed by extraction. The mixture was filtered into microcrystalline cellulose (5.2 kg), and the microcrystalline cellulose was washed with 2-methyltetrahydrofuran (136 kg). 2% saline (631 kg) was added to the filtrate, and the aqueous layer was removed by extraction. The mixture was filtered through activated carbon, and the activated carbon was washed with 2-methyltetrahydrofuran (670 kg). The filtrate was concentrated to 485 L, and stirred for 1 hour after crystallization. n-heptane (527 kg) was added dropwise over 5 hours, and stirred for 2 hours. After separating the wet crystals by filtration, the wet crystals were washed with 2-methyltetrahydrofuran/n-heptane (a solution in which 2-methyltetrahydrofuran (70 kg) and n-heptane (90 kg) were mixed), and the wet crystals were washed with n-heptane (141 kg). The obtained wet crystals were dried at 70 ° C. under reduced pressure for 20 hours to obtain compound 12 (57.85 kg, yield 87%).
¹ H-NMR (400MHz, CDCl ₃ ) δ:2.19-2.31 (m, 2H), 2.35 (s, 3H), 2.89 (d, J=16.1Hz, 1H), 3.67 (d, J=16.2 Hz, 1H), 4.16 (t, J=5.4 Hz, 2H), 5.48 (s, 1H), 6.42-6.50 (m, 2H), 7.09-7.26 (m, 2H), 7.62 (dd, J=8.8, 2.0, 1H), 7.77 (d, J=8.5 Hz, 1H), 8.16-8.20 (m, 1H).

Step 8 Synthesis of Compound 13 Compound 12 (57.8 kg, 145 mol) was added with tetrahydrofuran (154.2 kg) and ethyl acetate (78.2 kg) and cooled to 0°C, and then 52% propylphosphonic anhydride-ethyl acetate solution (251.3 kg) was added dropwise over 1 hour and 30 minutes, and pyridine (27.6 kg) was added. A tetrahydrofuran solution of methanesulfonylacetic acid (a solution obtained by dissolving methanesulfonylacetic acid (26.2 kg, 190 mol) in tetrahydrofuran (154.2 kg)) was added dropwise over 5 hours, and the mixture was stirred for 6 hours. Ethyl acetate (521.4 kg) was added to 5% sodium bicarbonate water (568.9 kg) and cooled to 5°C, and the reaction liquid was added dropwise over 1 hour, the temperature was raised to 20°C, and the aqueous layer was removed by extraction. 25% saline (228.3 kg) and 7% sodium bicarbonate water (404.3 kg) were added, and the mixture was heated to 25° C. and extracted to remove the aqueous layer. Methanol (229.1 kg) was added, filtered with activated carbon, and the activated carbon was washed with a methanol/ethyl acetate solution (a mixed solution of methanol (41.4 kg) and ethyl acetate (109.5 kg)). The mixture was concentrated under reduced pressure to 526 L, and methanol (45.7 kg) and ethyl acetate (104.3 kg) were added. Compound 13 (351.2 g) was added, crystallized, stirred for 3 hours, and methanol (457.4 kg) was added dropwise over 2 hours. The mixture was concentrated under reduced pressure to 711 L, methanol (457.5 kg) was added, and the mixture was concentrated under reduced pressure to 665 L. Water (693.5 kg) was added dropwise over 2 hours, and then stirred for 2 hours. The wet crystals were separated by filtration, and then washed twice with 4% methanol water (172 kg). The obtained wet crystals were dried at 70° C. under reduced pressure for 30 hours to obtain compound 13 (68.57 kg, yield 91%).
Using a spiral jet mill, compound 13 was ground a first time at a grinding pressure of 0.40 MPa, a supply pressure of 0.50 MPa, and an average processing speed of 22 to 32 g/min, and the first ground product was ground a second time at a grinding pressure of 0.40 MPa, a supply pressure of 0.50 MPa, and an average processing speed of 20 to 45 g/min, to obtain a ground product of compound 13 (53.1 kg, yield 91%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.17-2.27 (m, 1H), 2.31-2.41 (m, 4H), 2.99 (d, J=16.1 Hz, 1H), 3.19 (s, 3H), 3.78 (d, J=16.2 Hz, 1H), 4.13-4.23 ( m, 4H), 6.06 (s, 1H), 6.43-6.51 (m, 2H), 7.69 (dd, J=8.7, 2.0 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 8.26-8.30 (m, 1H), 11.20 (s, 1H).

The following compounds can be produced according to the general synthesis methods and the methods described in the Examples above.

Example 3: Examination of reaction conditions for synthesis of compound 12 (a) Examination of reaction solvent and base (a-1) Synthesis of compound 4 Compound 3 (2.00 g, 6.2 mmol), anisole (10 mL), and 5% sodium bicarbonate/5% saline (12 mL) were mixed and stirred, and the aqueous layer was separated after standing. An aqueous solution of 64% sulfuric acid (2.84 g) diluted with water (10 mL) was heated to 80° C., and the obtained organic layer and 2-methyltetrahydrofuran (4 mL) were added and stirred at 80° C. for 8 hours and 30 minutes. After cooling to 0° C., 2-methyltetrahydrofuran (6 mL) and water (6 mL) were added. After standing, the organic layer was separated, and the obtained aqueous layer was washed twice with 2-methyltetrahydrofuran (20 mL) to obtain an aqueous solution containing compound 4.
(a-2) Experiments using ethanol and 48% sodium hydroxide solution The compound 4-containing aqueous solution (2.11 g) prepared by the method of (a-1) above, compound 11 (0.20 g, 0.64 mmol) and ethanol (1.5 mL) were mixed and stirred at 50 ° C. 48% sodium hydroxide solution (0.44 mL) was added and stirred for 4 hours, and then cooled to room temperature. Ethanol (0.6 mL) and water (1 mL) were added thereto and stirred at room temperature. After separating the wet crystals by filtration, the wet crystals were washed with 40% ethanol water (6 mL). The obtained wet crystals were dried under reduced pressure at 50 ° C. to obtain compound 12 (0.20 g, content-based yield 46.1%, content 60.6 wt%). The content was calculated using HPLC measurement condition 1.
(a-3) Experiment using tetrahydrofuran and 48% sodium hydroxide solution The compound 4-containing aqueous solution (2.11 g) prepared by the method of (a-1) above, compound 11 (0.20 g, 0.64 mmol) and tetrahydrofuran (1.5 mL) were mixed and heated to 50°C. 48% sodium hydroxide solution (0.39 mL) was added and stirred for 5 minutes, 48% sodium hydroxide aqueous solution (49 mg) was added again and stirred for 2 hours, and cooled to room temperature. 2-Methyltetrahydrofuran (1 mL) was added, and the aqueous layer was left to stand and separated. The mixture was washed successively with 2 mol/L hydrochloric acid (2 mL) and an aqueous solution of saturated saline with water (2 mL) to obtain a compound 12-containing solution. The quantitative yield of compound 12 in the obtained solution was 84%. The quantitative yield was calculated using HPLC measurement condition 1.

(a-4) Experiments using tetrahydrofuran and N,N-diisopropylethylamine The compound 4-containing aqueous solution (12.6 g) prepared by the method of (a-1) above, compound 11 (1.20 g, 3.9 mmol) and 2-methyltetrahydrofuran (9 mL) were stirred at room temperature for 8 hours, and then heated to 50°C. N,N-diisopropylethylamine (4.92 mL) was added to the mixed solution and stirred for 1 hour, and then N,N-diisopropylethylamine (1.84 mL) was added dropwise again over 30 minutes, stirred for 5 hours, and cooled to room temperature. 2-Methyltetrahydrofuran (12 mL) was added, and the solution was left to stand to separate the aqueous layer. The solution was washed with 2 mol/L hydrochloric acid (12 mL) and water (12 mL) in that order, and the resulting organic layer was concentrated to (10.8 g). After adding 2-methyltetrahydrofuran (16.3 g), activated carbon (1.2 g) was added and stirred for 30 minutes, followed by filtration and washing with 2-methyltetrahydrofuran (24 mL) to obtain a solution containing compound 12. The quantitative yield of compound 12 in the obtained solution was 84%. The quantitative yield was calculated using HPLC measurement condition 1.
(a-5) Experiment using tetrahydrofuran and sodium tert-butoxide The compound 4-containing aqueous solution (2.47 g) prepared by the method of (a-1) above, compound 11 (0.20 g, 0.63 mmol) and tetrahydrofuran (1.5 mL) were mixed at room temperature with stirring for 1 hour. Sodium tert-butoxide (539 mg) was added and stirred at room temperature for 1 hour, then the temperature was raised to 50° C., stirred for 3 hours and 40 minutes, and allowed to stand at room temperature for 11 hours and 30 minutes. Sodium tert-butoxide (180 mg) was added and stirred at 50° C. for 1 hour. The quantitative yield of compound 12 in the obtained reaction solution was 21%. The quantitative yield was calculated using HPLC measurement condition 1.
(a-6) Experiments using tetrahydrofuran and pyridine The compound 4-containing aqueous solution (2.35 g) prepared by the method of (a-1) above, compound 11 (0.20 g, 0.64 mmol) and tetrahydrofuran (1.5 mL) were mixed and stirred at 50°C. Pyridine (0.38 mL) was added and stirred for 3 hours and 30 minutes, and then pyridine (0.76 mL) was added again and cooled to room temperature after 1 hour. The quantitative yield of compound 12 in the obtained reaction solution was 2%. The quantitative yield was calculated using HPLC measurement condition 1.
(a-7) Experiments using tetrahydrofuran and triethylamine The compound 4-containing aqueous solution (2.35 g) prepared by the method of (a-1) above, compound 11 (0.20 g, 0.64 mmol) and tetrahydrofuran (1.5 mL) were mixed and stirred at 50° C. Triethylamine (0.66 mL) was added and stirred for 4 hours and 30 minutes, then triethylamine (164 μL) was added again and stirred for 3 hours and cooled to room temperature. The quantitative yield of compound 12 in the obtained reaction solution was 72%. The quantitative yield was calculated using HPLC measurement condition 1.
(b) Experiment using 2-methyltetrahydrofuran and 1 mol/L sodium hydroxide solution Anisole (40 mL), water (22 mL), and compound 3 (2.8 g, 8.6 mmol) were mixed and stirred, and the temperature was raised to 85°C. 64% sulfuric acid (5.9 g) was added dropwise over 1 hour, and the mixture was stirred at 85°C for 4 hours. After cooling to 25°C, the organic layer was separated, and the resulting aqueous layer was washed with anisole (20 mL) to obtain an aqueous solution containing compound 4. Half the amount of the resulting aqueous solution was cooled to 0°C, and a 48% sodium hydroxide solution was added to adjust the pH to 6.5. After heating to 25°C, compound 11 (1.0 g, 3.2 mmol) dissolved in 2-methyltetrahydrofuran (7 mL) was added, and further 2-methyltetrahydrofuran (1 mL) was added. While stirring the mixture at 25°C, 1 mol/L sodium hydroxide solution (3.3 g) was added. The mixture was stirred for 1 hour using 1 mol/L sodium hydroxide solution (3.7 g) while maintaining the pH at 8.5±1.0. The mixture was then heated to 50° C. and stirred for 4 hours. 2-Methyltetrahydrofuran (14 mL) was added, and the mixture was cooled to 25° C. and allowed to stand. The organic layer obtained after separating the aqueous layer was washed with 1 mol/L hydrochloric acid (10 mL) and water (10 mL) in this order to obtain a solution containing compound 12. The quantitative yield of compound 12 in the obtained solution was 97%. The quantitative yield was calculated using HPLC measurement condition 2.
(c) Experiment using 2-methyltetrahydrofuran and tripotassium phosphate Anisole (180 mL), water (90 mL), and compound 3 (12.7 g, 39.3 mmol) were mixed and stirred, and the temperature was raised to 85°C. 64% sulfuric acid (27.1 g) was added dropwise over 2 hours, washed with water (10 mL), and stirred at 85°C for 4 hours. After cooling to 25°C, the organic layer was separated, and the resulting aqueous layer was washed with anisole (100 mL) to obtain an aqueous solution containing compound 4. While maintaining 1/5 of the obtained aqueous solution at 25°C, a 48% sodium hydroxide solution was added to adjust the pH to 3.0±0.5. Compound 11 (2.0 g, 6.4 mmol) dissolved in 2-methyltetrahydrofuran (38 mL) was added, and 2-methyltetrahydrofuran (2 mL) was further added. While stirring the mixture at 25°C, an aqueous solution of tripotassium phosphate (8.9 g) (aqueous solution prepared from tripotassium phosphate (10.9 g) and water (20.0 g)) was added. After stirring at 25°C for 1 hour, the temperature was raised to 50°C and stirring was continued for 4 hours. After cooling to 25°C and allowing to stand, the aqueous layer was separated to obtain a solution containing compound 12. The quantitative yield of compound 12 in the obtained solution was 97%. The quantitative yield was calculated using HPLC measurement condition 2.

Example 4 Measurement of Differential Scanning Calorimetry (DSC) of Compound 4 Hydrochloride and Compound 3 DSC measurement was carried out on Compound 4 hydrochloride and Compound 3. The measurement conditions are shown below.
Equipment: METTLER TOLEDO DSC822e
Measurement temperature range: 25°C-500°C (a), 25°C-300°C (b)
Heating rate: 10° C./min Atmosphere: N2 50 mL/min Generally, measurements by differential scanning calorimetry (DSC) can have an error within a range of ±2° C., so the measured values by differential scanning calorimetry (DSC) also include values within a range of about ±2° C.
(a) The hydrochloride of compound 4 was simply sealed in a glass capillary and measured. The decomposition peak temperature (T onset ) and enthalpy observed by differential scanning calorimetry (DSC) were as follows.
Tonset: 190°C, Enthalpy: 893 J/g
Tonset: 260°C, Enthalpy: 258 J/g
Tonset: 316°C, Enthalpy: 329 J/g
Tonset: 397°C, Enthalpy: 1992 J/g
(b) Compound 3: A sample was weighed into a stainless steel pan, simply sealed, and measured. The decomposition peak temperature (T onset ) and enthalpy observed by differential scanning calorimetry (DSC) were as follows.
Tonset: 249°C, enthalpy: -40 J/g
Tonset: 255°C, Enthalpy: 310 J/g

Example 5 Study of extraction conditions for compound 11 (a) Compound 10 (5.00 g, 17.1 mmol) containing 1.5% enantiomer was added with isopropyl acetate (45 mL) and N,N-dimethylformamide (10 mL), cooled to 5° C., and then phosphorus oxychloride (2.75 g, 17.9 mmol) was added and stirred for 4 hours. After cooling to 0° C., water (50 mL) was added and the aqueous layer was removed by extraction. Subsequently, the mixture was washed with 5% sodium bicarbonate water (50 mL), heated to 35° C., and then the aqueous layer was removed by extraction. Thereafter, the mixture was washed with 5% saline (50 mL) and the aqueous layer was removed by extraction. The obtained organic layer (20 μL) was added to each aqueous layer (20 μL), and after standing at 45° C. for 15 hours, HPLC analysis of each organic layer was performed. Measurement was performed using HPLC measurement condition 3. The results are shown below.

(b) Compound 10 (10.01 g, 34.3 mmol) was mixed with isopropyl acetate (82.7 g) and N,N-dimethylformamide (18.9 g) and cooled to 5°C. Phosphorus oxychloride (6.32 g, 41.2 mmol) was then added dropwise over 30 minutes, isopropyl acetate (4.32 g) was added, and the mixture was stirred for 3 hours. An aqueous solution of tripotassium citrate (133.8 g) (aqueous solution of tripotassium citrate (33.5 g) dissolved in water (100.3 g)) was added dropwise over 2 hours, and the mixture was heated to 25°C, after which the aqueous layer was removed by extraction. The obtained organic layer was left to stand at 25°C and 45°C for 24 hours, and then each organic layer was subjected to HPLC analysis. Measurement was performed using HPLC measurement condition 3. The results are shown below.

Example 6: Study of extraction conditions for compound 6 (a) Stability in aqueous citric acid solution (a-1) Compound 5 (10.00 g), (R)-2-methylpropane-2-sulfinamide (9.91 g), and tetraethoxytitanium (27.41 g) were added to 2-methyltetrahydrofuran (40 mL), and the mixture was heated to 80° C. and stirred for 2 hours. After cooling to 50° C., the mixture was concentrated under reduced pressure to 43.12 g, and then 2-methyltetrahydrofuran (40 mL) was added. After filtration through KC floc, the KC floc was washed with 2-methyltetrahydrofuran (200 mL), cooled to 0° C., and concentrated to 45.00 g to obtain a concentrated liquid.
(a-2) 9.00 g of the concentrated liquid obtained in (a-1) was taken out, 5 mL of 10% citric acid aqueous solution was added, and the mixture was stirred for 30 minutes, after which the aqueous layer was removed by extraction. The organic layer obtained was stirred for 22 hours. When the quantitative value of compound 6 in the organic layer before stirring was taken as 100%, the quantitative value of compound 6 in the organic layer after stirring for 22 hours was 96%. The entire amount of the aqueous layer obtained by extraction was added and stirred for 6 hours. The quantitative value of compound 6 in the organic layer after stirring was 87%. The quantitative value of compound 6 was calculated using HPLC measurement condition 4.
(a-3) 9.00 g of the concentrated liquid obtained in (a-1) was taken out, 5 mL of 5% citric acid aqueous solution was added, and the mixture was stirred for 30 minutes, after which the aqueous layer was removed by extraction. The organic layer obtained was stirred for 22 hours. When the quantitative value of compound 6 in the organic layer before stirring was taken as 100%, the quantitative value of compound 6 in the organic layer after stirring for 22 hours was 98%. The entire amount of the aqueous layer obtained by extraction was added and stirred for 6 hours. The quantitative value of compound 6 in the organic layer after stirring was 92%. The quantitative value of compound 6 was calculated using HPLC measurement condition 4.
(b) Stability in ammonium lactate aqueous solution and ammonium lactate/citric acid aqueous solution (b-1) 35% ammonium lactate aqueous solution (1.26 g) was added to the reaction solution (0.75 g) obtained by the same method as in step 1 of Example 2 above, and the mixture was stirred at 25° C. for 24 hours and then subjected to HPLC measurement. The quantitative yield of compound 6 in the reaction solution was 71%, and the quantitative yield of compound 6 in the organic layer after the addition of 35% ammonium lactate aqueous solution, stirring at 25° C. for 24 hours, and extraction was performed was 60%. The quantitative yield of compound 6 was calculated using HPLC measurement condition 4.
(b-2) To the reaction liquid (0.75 g) obtained by the same method as in step 1 of Example 2 above, a 35% aqueous ammonium lactate solution (1.26 g) containing additional citric acid (aqueous solution obtained by adding citric acid to a 35% aqueous ammonium lactate solution (1.26 g) until the pH reached 4) was added, stirred at 25° C. for 24 hours, and then subjected to HPLC measurement. The quantitative yield of compound 6 in the reaction liquid was 71%, and the quantitative yield of compound 6 in the organic layer after adding a 35% aqueous ammonium lactate solution containing additional citric acid, stirring at 25° C. for 24 hours, and then extraction was performed was 72%.

The method for producing the compound according to the present invention is useful as a method for producing a compound useful as a therapeutic and/or preventive agent for symptoms and/or diseases involving MGAT2. The method of the present invention makes it possible to efficiently produce a compound represented by formula (VIII).

Claims (11)

Formula (I):

wherein R ^1a is a substituted or unsubstituted phenyl;
R ^1b is substituted or unsubstituted alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein each ^R2 is independently a halogen or a substituted or unsubstituted alkyloxy;
(n is 1 or 2), in the presence of N,N-diisopropylethylamine, sodium hydroxide, or tripotassium phosphate,
Formula (II): R ³ -NHNH ₂
wherein ^R3 is a substituted or unsubstituted pyridyl,
Formula (III):

(wherein R ^1a , R ^1b and R ³ are as defined above) Formula (IV):

(wherein ^R3 has the same meaning as in claim 1) or a salt thereof,
Formula (II): R ³ -NHNH ₂
The process according to claim 1, characterized in that the compound represented by the formula: (wherein ^R3 has the same meaning as in claim 1) is reacted with the compound represented by the formula: The method according to claim 2, characterized in that a mixed solvent of 2-methyltetrahydrofuran and water is used as the reaction solvent. The method according to claim 3, characterized in that the reaction is carried out in the presence of tripotassium phosphate. Formula (V):

(wherein R ^1a and R ^1b are as defined in claim 1) is reacted with phosphoryl chloride, and then extracted with an aqueous tripotassium citrate solution and an organic solvent.
Formula (I):

A process for producing a compound represented by the formula: wherein R ^1a and R ^1b are as defined in claim 1. Formula (VI):

(wherein R ^1a and R ^1b are as defined in claim 1) is reacted with (R)-2-methylpropane-2-sulfinamide in the presence of tetraethoxytitanium, and then extracted with an aqueous solution of ammonium lactate, an aqueous solution of citric acid, and an organic solvent.
Formula (VII):

A method for producing a compound represented by the formula: wherein R ^1a and R ^1b are as defined in claim 1. R ^1a is
formula:

wherein each ^R4 is independently halogen, or substituted or unsubstituted alkyloxy;
R ^1b is a substituted or unsubstituted C1-C4 alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein R ² has the same meaning as in claim 1), R ^1a is
formula:

where ^R4 is halogen, or substituted or unsubstituted alkyloxy;
R ^1b is a substituted or unsubstituted C1-C4 alkyl; or
R ^1a and R ^1b together with adjacent carbon atoms form ring A;
Ring A is of the formula:

(wherein R ² has the same meaning as in claim 1), The process comprises at least one method for producing the product according to any one of claims 1 to 8.
Formula (VIII):

A method for producing a compound represented by the formula: wherein R ^1a , R ^1b and R ³ are as defined in claim 1. The process comprises at least one method for producing the product according to any one of claims 1 to 8.
formula:

A method for producing a compound represented by the formula: formula:

or a salt thereof.