JP2004292427A - Sustained release preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sustained release preparation controlling the release of a medicinally active ingredient, further delaying its staying property or transport in digestive tract, and releasing the active ingredient over a long time.

SOLUTION: This capsule agent contains tablets, granules or fine particles controlled with the release of the active ingredient by forming a release-controlling film on core particles containing the active ingredient, and a gel-forming polymer.

COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to sustained release formulations, especially capsules, containing tablets, granules or granules with controlled release of an active ingredient and a gel-forming polymer that retards gastrointestinal migration.

Orally administered preparations are the most frequently used dosage form among pharmaceuticals, and in recent years, from the viewpoint of improving QOL, many orally administered preparations with sustained efficacy have been developed with administration once or twice a day. Attempts have been made to synthesize a compound that exhibits kinetics such that its efficacy can be sustained by administering once or twice a day from the synthesis stage of the compound itself, but it is possible to modify the kinetics by designing a long-lasting formulation through formulation ingenuity. It is not uncommon to do so. The dosage forms of oral sustained formulations include controlled release by compound diffusion control by release control membranes and matrices, controlled release by erosion of the matrix (base), controlled release by pH-dependent compounds, and after a certain lag time. Various controlled release systems have been developed and applied, such as timed release controlled release of compounds. Combining the control of the gastrointestinal transit rate with the above-described controlled release system is thought to make it possible to further extend the duration.
In addition, acid-labile compounds such as benzimidazole (also referred to as benzimidazole) compounds (hereinafter referred to as benzimidazole compounds in this specification) having proton pump inhibitor (hereinafter sometimes referred to as PPI) action An enteric coating is required for formulations containing drugs with specific properties as active ingredients. That is, since a composition containing a benzimidazole compound with a PPI action needs to disintegrate quickly in the small intestine, it is formulated as granules or fine granules that have a larger surface area than tablets and are easily disintegrated or dissolved quickly. In the case of tablets, it is desirable to use small tablets (see, for example, Patent Document 1).
After being orally administered, tablets, granules, and granules themselves move through the digestive tract through the stomach, duodenum, jejunum, ileum, and large intestine while releasing the active ingredient, during which the active ingredient is absorbed at each absorption site. be done. Controlled-release formulations are intended to control absorption by some form of delayed release of the active ingredient. It is thought that it will be possible to further extend the persistence by combining a release control system with a function that controls the speed of gastrointestinal migration, such as adherence and floating properties.
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SUMMARY OF THE INVENTION An object of the present invention is to provide a sustained-release preparation that releases an active ingredient over a long period of time while the release of the active ingredient is controlled and that the active ingredient stays or moves slowly in the gastrointestinal tract.

〔式中、環Ｃ’は置換基を有していてもよいベンゼン環または置換基を有していてもよい芳香族単環式複素環を、Ｒ^０は水素原子、置換基を有していてもよいアラルキル基、アシル基またはアシルオキシ基を、Ｒ^１、Ｒ^２およびＲ^３は、それぞれ同一または異なって、水素原子、置換基を有していもよいアルキル基、置換基を有していてもよいアルコキシ基または置換基を有していてもよいアミノ基を、およびＹは窒素原子またはＣＨを示す〕で表されるイミダゾール系化合物もしくはその塩またはその光学活性体である上記（１６）記載のカプセル剤、
（１８）イミダゾール系化合物が、ランソプラゾールである上記（１７）記載のカプセル剤、
（１９）ＰＰＩが、ランソプラゾールの光学活性Ｒ体である上記（１７）記載のカプセル剤、
（２０）ゲル形成性ポリマーが、ポリエチレンオキサイド（ＰＥＯ、分子量400000−10000000）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、カルボキシメチルセルロース（ＣＭＣ−Ｎａ）、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシエチルセルロース、カルボキシビニルポリマーからなる群から選ばれる１種以上の物質である上記（１）、（７）または（８）記載のカプセル剤、
（２１）ゲル形成性ポリマーが、ポリエチレンオキサイド（分子量400000−10000000）である上記（１）、（７）または（８）記載のカプセル剤、
（２２）ゲル形成性ポリマーが粉末状、細粒状または顆粒状で配合された上記（１）または（８）記載のカプセル剤、
（２３）ｐＨ依存的に溶解するポリマーが、メタクリル酸メチル・メタクリル酸共重合体である上記（３）記載のカプセル剤、
（２４）活性成分の放出が制御された錠剤、顆粒または細粒であって、式（Ｉ’）：

〔式中、環Ｃ’は置換基を有していてもよいベンゼン環または置換基を有していてもよい芳香族単環式複素環を、Ｒ^０は水素原子、置換基を有していてもよいアラルキル基、アシル基またはアシルオキシ基を、Ｒ^１、Ｒ^２およびＲ^３は、それぞれ同一または異なって、水素原子、置換基を有していもよいアルキル基、置換基を有していてもよいアルコキシ基または置換基を有していてもよいアミノ基を、およびＹは窒素原子またはＣＨを示す〕で表されるイミダゾール系化合物もしくはその塩またはその光学活性体を活性成分として含有する核粒と、
ヒドロキシプロピルメチルセルロースフタレート、セルロースアセテートフタレート、カルボキシメチルエチルセルロース、メタクリル酸メチル・メタクリル酸共重合体、メタクリル酸・アクリル酸エチル共重合体、メタクリル酸・アクリル酸メチル・メタクリル酸メチル共重合体、ヒドロキシプロピルセルロースアセテートサクシネート、ポリビニルアセテートフタレートおよびシェラックからなる群から選ばれる１種または放出条件が異なる２種以上の混合物で、ｐＨ６．０以上ｐＨ７．５以下の範囲で溶解する高分子物質を含有するｐＨ依存溶解性放出制御被膜とを有する錠剤、顆粒または細粒、
（２５）ｐＨ依存溶解性放出制御被膜が核粒上に形成された中間層を介して形成されていることを特徴とする上記（２４）記載の錠剤、顆粒または細粒、
（２６）上記（２４）記載の錠剤、顆粒または細粒を含有するカプセル、
（２７）上記（２４）記載の錠剤、顆粒または細粒と式（Ｉ’）の化合物を含有する腸溶コーティングされた錠剤、顆粒または細粒とを含有するカプセル、
（２８）活性成分が、ランソプラゾールである上記（２４）記載の錠剤、顆粒または細粒、
（２９）活性成分が、ランソプラゾールの光学活性Ｒ体である上記（２４）記載の錠剤、顆粒または細粒、
（３０）活性成分が、ランソプラゾールの光学活性Ｓ体である上記（２４）記載の錠剤、顆粒または細粒、
（３１）活性成分が、ランソプラゾールの誘導体である上記（２４）記載の錠剤、顆粒または細粒、
（３２）活性成分が、ランソプラゾールの光学活性Ｒ体の誘導体である上記（２４）記載の錠剤、顆粒または細粒、
（３３）活性成分を含有する核粒上に腸溶性被膜と、該腸溶性被膜上に崩壊剤を含有する崩壊剤層と、該崩壊剤層上に放出制御被膜とを有することを特徴とする上記（２４）、（２５）または（２８）〜（３２）のいずれか１に記載の錠剤、顆粒または細粒、
（３４）ゲル形成性ポリマーにより被覆されていることを特徴とする上記（２８）〜（３３）のいずれか１に記載の錠剤、顆粒または細粒、
（３５）上記（２８）〜（３２）のいずれか１に記載の錠剤、顆粒または細粒とゲル形成性ポリマーとを含有する持続性カプセル、
（３６）活性成分の放出が２種類以上の放出制御被膜によって制御される錠剤、顆粒または細粒であって、最外層放出制御被膜が内層の放出制御被膜よりも高いｐＨで溶解することを特徴とする上記（２４）記載の錠剤、顆粒または細粒、
（３７）内層の放出制御被膜が、ｐＨ６.０−７.０の範囲で溶解し、最外層の放出制御被膜が、ｐＨ７.０以上で溶解することを特徴とする上記（３６）記載の錠剤、顆粒または細粒、
（３８）内層の放出制御被膜が、ｐＨ６.５−７.０の範囲で溶解し、最外層の放出制御被膜が、ｐＨ７.０以上で溶解することを特徴とする上記（３６）記載の錠剤、顆粒または細粒、
（３９）最外層放出制御被膜厚が、100μm以下であることを特徴とする上記（３６）記載の錠剤、顆粒または細粒、
（４０）放出が制御された顆粒または細粒が、約100‐1500μｍの粒径を有する上記（３６）記載の顆粒または細粒、
（４１）（ｉ）活性成分の放出が制御された錠剤、顆粒または細粒であって、式（Ｉ’）：

〔式中、環Ｃ’は置換基を有していてもよいベンゼン環または置換基を有していてもよい芳香族単環式複素環を、Ｒ^０は水素原子、置換基を有していてもよいアラルキル基、アシル基またはアシルオキシ基を、Ｒ^１、Ｒ^２およびＲ^３は、それぞれ同一または異なって、水素原子、置換基を有していもよいアルキル基、置換基を有していてもよいアルコキシ基または置換基を有していてもよいアミノ基を、およびＹは窒素原子またはＣＨを示す〕で表されるイミダゾール系化合物もしくはその塩またはその光学活性体を活性成分として含有する核粒と、
ヒドロキシプロピルメチルセルロースフタレート、セルロースアセテートフタレート、カルボキシメチルエチルセルロース、メタクリル酸メチル・メタクリル酸共重合体、メタクリル酸・アクリル酸エチル共重合体、メタクリル酸・アクリル酸メチル・メタクリル酸メチル共重合体、ヒドロキシプロピルセルロースアセテートサクシネート、ポリビニルアセテートフタレートおよびシェラックからなる群から選ばれる１種または放出条件が異なる２種以上の混合物で、ｐＨ６．０以上ｐＨ７．５以下の範囲で溶解する高分子物質を含有するｐＨ依存溶解性放出制御被膜とを有する錠剤、顆粒または細粒と、
（ｉｉ）活性成分を含有する核粒と、ｐＨ５．０以上ｐＨ６．０未満の範囲で溶解して、活性成分を放出する腸溶性被膜とを有する錠剤、顆粒または細粒とを含有するカプセル剤、
（４２）ｐＨ依存溶解性放出制御被膜が活性成分を含有する核粒上に形成された中間層を介して形成されていることを特徴とする上記（４１）記載のカプセル剤、
（４３）活性成分が、ランソプラゾールである上記（４１）記載のカプセル剤、
（４４）活性成分が、ランソプラゾールの光学活性Ｒ体である上記（４１）記載のカプセル剤、
（４５）活性成分が、ランソプラゾールの光学活性Ｓ体である上記（４１）記載のカプセル剤、
（４６）活性成分を含有する核粒が、塩基性無機塩の安定化剤を含有する上記（４１）記載のカプセル剤、
（４７）活性成分の放出が制御された錠剤、顆粒または細粒におけるｐＨ依存溶解性放出制御被膜が、ｐＨ６．５以上ｐＨ７．０以下の範囲で溶解する被膜である上記（４１）記載のカプセル剤、
（４８）ｐＨ依存溶解性放出制御被膜が、放出制御条件の異なる２種以上のメタクリル酸メチル・メタクリル酸共重合体を含有することを特徴とする上記（４７）記載のカプセル剤、および
（４９）さらにゲル形成性ポリマーを含有する上記（４１）記載のカプセル剤を提供する。 That is, the present invention
(1) tablets, granules or capsules containing controlled-release active ingredients and gel-forming polymers;
(2) The capsule according to (1) above, wherein the release of the active ingredient is controlled by a release-controlling coating formed on the core granules containing the active ingredient.
(3) the capsule according to (2) above, wherein the controlled-release coating contains a polymer that dissolves in a pH-dependent manner;
(4) the capsule according to (2) above, wherein the release-controlling coating is a diffusion-controlling membrane;
(5) Capsules according to (1) above, wherein the release of the active ingredient is controlled by dispersing the active ingredient in a controlled release matrix that constitutes the tablet, granule or granule;
(6) Tablets, granules or fine granules with controlled release of the active ingredient are formed on the disintegrant layer containing the disintegrant formed on the core granules containing the active ingredient and on the disintegrant layer A capsule according to (3) or (4) above, which is a tablet, granule or granule having a release-controlling coating, wherein release of the active ingredient is initiated after a certain lag time;
(7) Capsules according to any one of (3) to (6) above, wherein the tablets, granules or granules with controlled release of the active ingredient are coated with a gel-forming polymer. ,
(8) The capsule according to claim 7, which further contains a gel-forming polymer.
(9) The capsule according to any one of (1) to (7) above, which contains two types of tablets, granules, or fine granules with different release conditions for the active ingredient.
(10) tablets, granules or granules with an enteric coating that releases the active ingredient at a pH of about 5.5 and tablets, granules or granules with a controlled release coating that releases the active ingredient at a pH of about 6.0 or higher; The capsule according to (9) above containing fine granules,
(11) The capsule according to (1), (7) or (8) above, wherein the gel-forming polymer has a viscosity of about 3000 mPa·s or more in a 5% aqueous solution at 25°C.
(12) Capsules according to (1), (7) or (8) above, wherein the gel-forming polymer has a molecular weight of 400,000 to 1,000,000.
(13) The controlled release coating is hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, methyl methacrylate/methacrylic acid copolymer, methacrylic acid/ethyl acrylate copolymer, ethyl acrylate/methyl methacrylate/methacrylic selected from the group consisting of trimethylammonium ethyl oxychloride copolymer, methyl methacrylate/ethyl acrylate copolymer, methacrylic acid/methyl acrylate/methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate and polyvinyl acetate phthalate The capsule according to any one of (2) to (4) or (6) above, which is a coating containing one or more
(14) The capsule according to (13) above, wherein the controlled-release coating consists of two or more coatings;
(15) The capsule of (1) above, wherein the controlled-release granules or granules are granules or granules with a particle size of about 100-1500 μm.
(16) The capsule according to (1) above, wherein the active ingredient is a proton pump inhibitor (PPI);
(17) PPI is of formula (I′):

[Wherein, ring C′ is a benzene ring optionally having substituent(s) or an aromatic monocyclic heterocyclic ring optionally having substituent(s); R ⁰ is a hydrogen atom; an aralkyl group ^, an acyl group or ^{an acyloxy} group which may be an alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH], a salt thereof, or an optically active substance thereof described in (16) above. capsules of
(18) the capsule according to (17) above, wherein the imidazole compound is lansoprazole;
(19) The capsule according to (17) above, wherein the PPI is an optically active R form of lansoprazole.
(20) The gel-forming polymer consists of polyethylene oxide (PEO, molecular weight 400000-10000000), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC-Na), hydroxypropylcellulose (HPC), hydroxyethylcellulose and carboxyvinyl polymer. The capsule according to (1), (7) or (8) above, which is one or more substances selected from the group;
(21) The capsule according to (1), (7) or (8) above, wherein the gel-forming polymer is polyethylene oxide (molecular weight: 400000-10000000);
(22) Capsules according to (1) or (8) above, in which the gel-forming polymer is blended in the form of powder, fine granules, or granules;
(23) The capsule according to (3) above, wherein the pH-dependently soluble polymer is methyl methacrylate/methacrylic acid copolymer.
(24) A tablet, granule or granule with controlled release of an active ingredient, comprising formula (I'):

[Wherein, ring C′ is a benzene ring optionally having substituent(s) or an aromatic monocyclic heterocyclic ring optionally having substituent(s); R ⁰ is a hydrogen atom; an aralkyl group ^, an acyl group or ^{an acyloxy} group which may be an alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH], or a nucleus containing an imidazole compound represented by the following as an active ingredient: Grains and
Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, methyl methacrylate/methacrylic acid copolymer, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl acrylate/methyl methacrylate copolymer, hydroxypropyl cellulose One selected from the group consisting of acetate succinate, polyvinyl acetate phthalate and shellac, or a mixture of two or more selected from the group consisting of different release conditions, pH-dependent containing a polymeric substance that dissolves in the range of pH 6.0 to pH 7.5 tablets, granules or granules having a dissolvable controlled release coating,
(25) The tablets, granules or fine granules according to (24) above, wherein the pH-dependent soluble controlled release coating is formed via an intermediate layer formed on the core granule;
(26) Capsules containing tablets, granules or fine granules according to (24) above,
(27) Capsules containing the tablets, granules or granules according to (24) above and enteric-coated tablets, granules or granules containing the compound of formula (I'),
(28) The tablets, granules or granules according to (24) above, wherein the active ingredient is lansoprazole,
(29) The tablets, granules or granules according to (24) above, wherein the active ingredient is an optically active R-form of lansoprazole;
(30) The tablets, granules or granules according to (24) above, wherein the active ingredient is an optically active S-isomer of lansoprazole;
(31) The tablets, granules or granules according to (24) above, wherein the active ingredient is a lansoprazole derivative,
(32) The tablets, granules or granules according to (24) above, wherein the active ingredient is an optically active R derivative of lansoprazole;
(33) Characterized by having an enteric coating on core granules containing an active ingredient, a disintegrant layer containing a disintegrant on the enteric coating, and a controlled release coating on the disintegrant layer. The tablets, granules or granules according to any one of (24), (25) or (28) to (32) above,
(34) The tablets, granules or granules according to any one of (28) to (33) above, which are coated with a gel-forming polymer;
(35) A long-acting capsule containing the tablet, granules or granules according to any one of (28) to (32) above and a gel-forming polymer,
(36) Tablets, granules or granules in which the release of an active ingredient is controlled by two or more types of controlled release coatings, wherein the outermost controlled release coating dissolves at a higher pH than the inner controlled release coating. The tablets, granules or granules according to (24) above,
(37) The tablet according to (36) above, wherein the controlled release coating of the inner layer dissolves in the range of pH 6.0 to 7.0, and the controlled release coating of the outermost layer dissolves at pH 7.0 or higher. , granules or granules,
(38) The tablet according to (36) above, wherein the inner controlled-release coating dissolves in the pH range of 6.5 to 7.0, and the outermost controlled-release coating dissolves at pH 7.0 or higher. , granules or granules,
(39) The tablets, granules or granules according to (36) above, characterized in that the thickness of the outermost controlled release coating is 100 μm or less;
(40) The granules or granules according to (36) above, wherein the controlled-release granules or granules have a particle size of about 100-1500 μm;
(41)(i) A controlled-release tablet, granule or granule of an active ingredient of formula (I'):

[Wherein, ring C′ is a benzene ring optionally having substituent(s) or an aromatic monocyclic heterocyclic ring optionally having substituent(s); R ⁰ is a hydrogen atom; an aralkyl group ^, an acyl group or ^{an acyloxy} group which may be an alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH], or a nucleus containing an imidazole compound represented by the following as an active ingredient: Grains and
Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, methyl methacrylate/methacrylic acid copolymer, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl acrylate/methyl methacrylate copolymer, hydroxypropyl cellulose One selected from the group consisting of acetate succinate, polyvinyl acetate phthalate and shellac, or a mixture of two or more selected from the group consisting of different release conditions, pH-dependent containing a polymeric substance that dissolves in the range of pH 6.0 to pH 7.5 tablets, granules or granules having a dissolvable controlled release coating;
(ii) Capsules containing tablets, granules or fine granules having a core granule containing an active ingredient and an enteric coating that dissolves in the range of pH 5.0 or more and less than pH 6.0 to release the active ingredient. ,
(42) The capsule according to (41) above, wherein the pH-dependent soluble controlled release coating is formed via an intermediate layer formed on the core grain containing the active ingredient.
(43) The capsule according to (41) above, wherein the active ingredient is lansoprazole.
(44) The capsule according to (41) above, wherein the active ingredient is an optically active R-form of lansoprazole.
(45) The capsule according to (41) above, wherein the active ingredient is an optically active S-isomer of lansoprazole.
(46) The capsule according to (41) above, wherein the core granule containing the active ingredient contains a basic inorganic salt stabilizer.
(47) The capsule according to (41) above, wherein the pH-dependent dissolvable release control coating in the tablets, granules or fine granules with controlled release of the active ingredient is a coating that dissolves in the range of pH 6.5 or more and pH 7.0 or less. agent,
(48) The capsule according to (47) above, wherein the pH-dependent soluble controlled release coating contains two or more methyl methacrylate/methacrylic acid copolymers with different release control conditions, and (49) ) to provide a capsule according to (41) above, which further contains a gel-forming polymer.

The sustained-release formulation of the present invention enables the sustained therapeutically effective concentration by controlling the release of the active ingredient over a long period of time. It is possible to reduce the side effects caused by the increase in concentration.

The present invention relates to tablets, granules or granules with controlled release of an active ingredient, or to pharmaceutical compositions containing these tablets, granules or granules and a gel-forming polymer that retards gastrointestinal transit. The pharmaceutical composition of the present invention is a capsule filled into a capsule, even in the form of these tablets, granules or granules themselves, or a mixture of tablets, granules or granules and a gel-forming polymer. capsules are particularly preferred. It was found that these combinations markedly prolonged the persistence of blood concentration after oral administration.
The control of the release of the active ingredient in the "tablets, granules or granules with controlled release of the active ingredient" of the present invention is achieved by coating the active ingredient in the tablet or the tablet, granules or granules with a film that controls the release of the active ingredient. This is done by coating or by dispersing the active ingredient in a controlled release matrix. The "tablets, granules or fine granules with controlled release of active ingredient" of the present invention include tablets, granules or fine granules coated with an ordinary enteric coating that dissolves at about pH 5.5, and Tablets containing these granules or fine granules are also included.
On the other hand, when the term "release-controlled coating" is used in this specification, the coating or the membrane itself that dissolves depending on the pH that dissolves in a higher pH range than the usual enteric coating that dissolves at about pH 5.5. Membrane that has the function of delaying or sustaining the release of the active ingredient, such as a diffusion-controlled membrane that releases the active ingredient through pores that do not dissolve in the membrane. As such, it does not contain the usual enteric coating membranes and/or layers that release the active ingredient. In addition, pH here means the pH adjusted with the McIlvaine solution or the Clark-Lubs solution. The pH of the membrane that dissolves in a pH-dependent manner hereinafter means this pH.
In addition, the coating in the "controlled release coating" of the present invention includes not only a film-like coating layer, but also a coating layer having a greater thickness, and furthermore, if it is only a coating layer that completely covers the inner core grain or layer, Although there are parts that are not partially covered, it also includes a coating layer that covers most of the inner core grains or layers (at least 80% or more of the surface of the inner core grains or layers, preferably the entire coating).
The absorption of the active ingredient from the pharmaceutical composition of the present invention from the gastrointestinal tract can be achieved by (1) controlled release of the active ingredient by controlled release tablets, granules or fine granules and (2) tablets, granules or fine granules by gel-forming polymers. It is regulated by two systems or a combination thereof that utilizes the prolongation of gastrointestinal retention of . Among the pharmaceutical compositions of the present invention, a composition containing a gel-forming polymer, when orally administered, forms an adhesive gel due to rapid absorption of water by the gel-forming polymer in the digestive tract. The tablets, granules or granules are retained on or in the gel and slowly move through the gastrointestinal tract. In the meantime, the release of the active ingredient is controlled, and the active ingredient is released from the tablets, granules or granules in a continuous or pulsatile manner in a controlled manner, resulting in sustained absorption and development of efficacy.
The above system, which enables sustained therapeutically effective concentrations by controlling release over a long period of time, not only reduces the number of administrations, but also reduces the efficacy of treatment at low doses and the side effects caused by the rise in blood concentrations. and other advantages.

The gel-forming polymer may be any polymer that rapidly forms a highly viscous gel upon contact with water and extends retention in the gastrointestinal tract. As such a gel-forming polymer, a polymer having a viscosity of about 3000 mPa·s or more in a 5% aqueous solution at 25° C. is preferable. In addition, the gel-forming polymer is generally preferably a polymer having a molecular weight of about 400,000 to 1,000,000. Such gel-forming polymers are suitable for formulation in the form of powder, granules or fine particles. Such gel-forming polymers include polyethylene oxide (PEO, such as Polyox WSR 303 (molecular weight 7,000,000), Polyox WSR Coagulant (molecular weight 5,000,000), Polyox WSR 301 (molecular weight 4,000,000), Polyox WSR N-60K (molecular weight 2,000,000), Polyox WSR 205 (molecular weight 600000; manufactured by Dow Chemical), hydroxypropyl methylcellulose (HPMC, Metlose 90SH10000, Metlose 90SH50000, Metlose 90SH30000, manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethylcellulose (CMC-Na, Sanlose F-1000MC), hydroxy Propyl cellulose (HPC, e.g., HPC-H, manufactured by Nippon Soda Co., Ltd.), hydroxyethyl cellulose (HEC), carboxyvinyl polymer (Hibis Wako (R) 103, 104, 105, manufactured by Wako Pure Chemical Industries, Ltd.; Carbopol 943 , Goodrich), chitosan, sodium alginate, pectin and the like. These powders may be used singly or as a mixture of at least two or more powders in an appropriate ratio. Among them, PEO, HPMC, HPC, CMC-Na, carboxyvinyl polymer and the like are preferably used as the gel-forming polymer.

As a preferred embodiment of tablets, granules or fine granules with controlled release of an active ingredient, tablets, granules or fine granules comprising core granules containing at least one active ingredient coated with a release-controlling film, or granules or fine granules thereof. Tablets containing granules are mentioned. Nonpareil-101 (particle size 850-710, 710-500, 500-355), Nonpareil-103 (particle size 850-710, 710-500) can be used to prepare such dry-coated tablets, granules or granules. , 500-355), Nonpareil-105 (particle size 710-500, 500-355, 300-180), manufactured by Freund), Celphia (CP-507 (particle size 500-710), CP-305 (particle size 300 -500), manufactured by Asahi Kasei Co., Ltd.), tablets, granules or fine granules coated with an active ingredient, tablets prepared using these granules or fine granules, or active ingredients Particles obtained by granulation using excipients commonly used for formulation can be used as core particles. For example, it can be produced by the method described in JP-A-63-301816. For example, when obtaining core granules by coating the core of an inert carrier with an active ingredient, for example, a centrifugal tumbling granulator (CF-mini, CF-360, manufactured by Freund) or a tumbling granulator Active ingredient-containing core granules can be prepared by wet granulation using (Powrex MP-10) or the like. Alternatively, a solution containing a binder and the like may be added onto the core of the inert carrier by spraying or the like while the active ingredient is dispersed for coating. Although the production apparatus is not limited, for example, in the latter coating, it is preferable to use a centrifugal tumbling granulator or the like for production. Coating by the two devices described above may be combined to coat the active ingredient in two stages. When an inert carrier core is not used, excipients such as lactose, sucrose, mannitol, corn starch, microcrystalline cellulose, and the active ingredient are combined with hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, macrogol, Pluronic F68, arabic. Using a binder such as rubber, gelatin, starch, etc., if necessary, carboxymethylcellulose sodium, carboxymethylcellulose calcium, cross-carboxymethylcellulose sodium (Ac-Di-Sol, manufactured by FMC International), polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, etc. It can be obtained by adding a disintegrant and producing with a stirring granulator, a wet extrusion granulator, a fluidized bed granulator, or the like.
The obtained granules or fine granules can be sieved to obtain particles of a desired size. Core granules may be prepared by dry granulation using a roller compactor or the like. Particles having a size of 50 μm to 5 mm, preferably 100 μm to 3 mm, more preferably 100 μm to 2 mm are used.

The active ingredient-containing core particles thus obtained may be further coated to provide an intermediate coating layer, and such particles may be used as core particles. For example, when the active ingredient is an acid-labile drug such as PPI, providing an intermediate coating layer to block direct contact between the active-ingredient-containing core particles and the release-controlling membrane can improve the stability of the drug. It is preferable in terms of improving the Such an intermediate coating layer may be formed of multiple layers.
Examples of coating materials for the intermediate coating layer include polymers such as low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (eg, TC-5), polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, and hydroxyethylmethylcellulose. As a base, sucrose [refined sucrose (pulverized (powdered sugar) or non-pulverized)], starch sugar such as cornstarch, lactose, honey, and sugars such as sugar alcohols (D-mannitol, erythritol, etc.) are appropriately added. and the like. In addition to this, excipients (e.g., masking agents (titanium oxide, etc.), antistatic agents (titanium oxide, talc, etc.)) that are added as necessary for the formulation described below are added to the intermediate coating layer as appropriate. may
The coating amount of the intermediate coating layer is generally about 0.02 to about 1.5 parts by weight, preferably about 0.05 to about 1 part by weight, per 1 part by weight of the granules containing the active ingredient. Coating can be done by conventional methods. For example, it is preferable to dilute these components of the intermediate layer coating layer with purified water or the like, and apply the liquid as a liquid for coating. At that time, it is preferable to carry out while spraying a binder such as hydroxypropyl cellulose.

The controlled-release tablets, granules, or fine granules contained in the pharmaceutical composition of the present invention are coated with a coating substance that dissolves/dissolves in a pH-dependent manner and controls the release on such core granules. or a tablet containing these controlled-release granules or granules. Here, "pH-dependent" means that the active ingredient is released by dissolving/eluting in an environment of a certain pH or higher. With normal enteric coating, the drug is eluted at about pH 5.5 and the drug starts to be released. A substance that is eluted at a pH of 5 or more and less than 7.2 is preferred, and that further suppresses drug release in the stomach.
Coating substances for controlling the release of such pharmaceutically active ingredients in a pH-dependent manner include hydroxypropylmethylcellulose phthalate (HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd.), cellulose acetate phthalate, and carboxymethylethylcellulose. (CMEC, manufactured by Freund Corporation), methyl methacrylate/methacrylic acid copolymer (Eudragit L100 (methacrylic acid copolymer L) or Eudragit S100 (methacrylic acid copolymer S), manufactured by Rohm), methacrylic acid/ethyl acrylate copolymer Polymer (Eudragit L100-55 (dry methacrylic acid copolymer LD) or Eudragit L30D-55 (methacrylic acid copolymer LD), manufactured by Rohm), methacrylic acid/methyl acrylate/methyl methacrylate copolymer (Eudragit FS30D, manufactured by Rohm ), hydroxypropyl cellulose acetate succinate (HPMCAS, manufactured by Shin-Etsu Chemical Co., Ltd.), polyvinyl acetate phthalate, and shellac. Tablets, granules or fine granules having two or more types of controlled release coatings with different release conditions for the active ingredient may be used, and the above-described coating materials may be coated with the polymer alone or at least two or more types of polymers in combination. Alternatively, at least two or more polymers may be sequentially coated to form multiple layers. It is desirable to use the coating materials alone or in combination as necessary so as to dissolve at pH>6.0 or higher, more preferably pH>6.5, and even more preferably pH6.75 or higher. Further, it is more desirable to use a combination of a polymer that dissolves at pH 6.0 or higher and a polymer that dissolves at pH 7.0 or higher. More preferably, they are used in combination at a ratio of 5-1:5.
Furthermore, plasticizers such as polyethylene glycol, dibutyl sebacate, diethyl phthalate, triacetin, and triethyl citrate, stabilizers, and the like may be used for coating, if necessary. The amount of coating material is preferably 5%-200%, preferably 20%-100%, more preferably 30%-60%, based on the core grain. The dissolution rate of the active ingredient from the controlled release tablets, granules or fine granules thus obtained is 10% or less in 5 hours in a pH 6.0 liquid, and the dissolution rate in a pH 6.8 liquid is is 5% or less in 1 hour and 60% or more in 8 hours.
Polyethylene oxide (PEO, such as Polyox WSR 303 (molecular weight 7,000,000), Polyox WSR Coagulant (molecular weight 5,000,000), Polyox WSR 301 (molecular weight 4,000,000), Polyox WSR 301 (molecular weight 4,000,000), Polyox WSR N-60K (molecular weight 2,000,000), Polyox WSR 205 (molecular weight 600,000; manufactured by Dow Chemical), hydroxypropyl methylcellulose (HPMC, Metlose 90SH10000, Metlose 90CMSH50000, Metlose 90SH30000, manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) -Na, Sanlose F-1000MC), hydroxypropyl cellulose (HPC, such as HPC-H, manufactured by Nippon Soda Co., Ltd.), hydroxyethyl cellulose (HEC), carboxyvinyl polymer (Hibis Wako (R) 103, 104, 105, sum Kojunyaku Co., Ltd.; Carbopol 943, Goodrich Co., Ltd.), chitosan, sodium alginate, pectin, and other substances that become viscous when in contact with water. Granules (hereinafter sometimes simply referred to as controlled-release granules) may also be used.

The controlled-release granules may be in the form of coating the core granules containing the active ingredient with a diffusion-controlling membrane that functions to control the release of the active ingredient by diffusion. As such a diffusion control film, ethyl acrylate/methyl methacrylate/trimethylammonium ethyl methacrylate chloride copolymer (Eudragit RS (aminoalkyl methacrylate copolymer RS) or Eudragit RL (aminoalkyl methacrylate copolymer RL), manufactured by Rohm Co., Ltd.) may be used. (manufactured by Rohm), methyl methacrylate/ethyl acrylate copolymer (Eudragit NE30D, manufactured by Rohm), and ethyl cellulose. In addition, these membranes may be mixed at an appropriate ratio, and used by mixing with a hydrophilic pore-forming substance such as HPMC, HPC, carboxyvinyl polymer, polyethylene glycol 6000, lactose, mannitol, organic acid, etc. at a given ratio. can also

Furthermore, in order to obtain tablets, granules or fine granules in which the active ingredient is controlled to be released after a certain lag time, a swellable substance such as a disintegrant is pre-coated prior to coating with the diffusion-controlling membrane. A disintegrant layer is provided between the active ingredient-containing core granules and the controlled release coating. For example, croscarmellose sodium (Ac-Di-Sol, manufactured by FMC International), carmellose calcium (ECG505, manufactured by Gotoku Yakuhin), crospovidone (ISP Inc), low-substituted hydroxypropyl A swelling substance such as cellulose (L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) is first coated, and further ethyl acrylate/methyl methacrylate/trimethylammonium ethyl methacrylate chloride copolymer (Eudragit RS or Eudragit RL, Rohm Co., Ltd.), methyl methacrylate/ethyl acrylate copolymer (Eudragit NE30D, manufactured by Rohm), ethyl cellulose, etc. alone or in combination, and also HPMC, HPC, carboxyvinyl polymer, polyethylene glycol 6000, lactose, mannitol, It is preferable to secondary-coat a diffusion control film mixed with a hydrophilic pore-forming substance such as an organic acid at a certain ratio. Examples of such secondary coating materials include hydroxypropylmethylcellulose phthalate (HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd.), cellulose acetate phthalate, carboxymethylethylcellulose (CMEC, manufactured by Freund Sangyo Co., Ltd.), methacrylic Methyl acid/methacrylic acid copolymer (Eudragit L100 (methacrylic acid copolymer L) or Eudragit S100 (methacrylic acid copolymer S), manufactured by Rohm), methacrylic acid/ethyl acrylate copolymer (Eudragit L100-55 (dry methacrylic acid copolymer LD) or Eudragit L30D-55 (methacrylic acid copolymer LD), manufactured by Rohm), methacrylic acid/methyl acrylate/methyl methacrylate copolymer (Eudragit FS30D, manufactured by Rohm), hydroxypropyl cellulose acetate succinate (HPMCAS Shin-Etsu Chemical (manufactured by Kabushiki Kaisha), polyvinyl acetate phthalate, shellac, and other enteric polymers that release active ingredients in a pH-dependent manner. The amount of coating material is preferably 1%-200%, preferably 20%-100%, more preferably 30%-60%, based on the core grain.

Furthermore, plasticizers such as polyethylene glycol, dibutyl sebacate, diethyl phthalate, triacetin, and triethyl citrate, stabilizers, and the like may be used for coating, if necessary. Polyethylene oxide (PEO, such as Polyox WSR 303 (molecular weight 7,000,000), Polyox WSR Coagulant (molecular weight 5,000,000), Polyox WSR 301 (molecular weight 4,000,000), Polyox WSR 301 (molecular weight 4,000,000), Polyox WSR N-60K (molecular weight 2,000,000), Polyox WSR 205 (molecular weight 600,000; manufactured by Dow Chemical), hydroxypropyl methylcellulose (HPMC, Metlose 90SH10000, Metlose 90CMSH50000, Metlose 90SH30000, manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.) -Na, Sanlose F-1000MC), hydroxypropyl cellulose (HPC, such as HPC-H, manufactured by Nippon Soda Co., Ltd.), hydroxyethyl cellulose (HEC), carboxyvinyl polymer (Hibis Wako (R) 103, 104, 105, sum Carbopol 943 manufactured by Kojunyaku Co., Ltd.; manufactured by Goodrich), chitosan, sodium alginate, pectin, and other substances that become viscous when in contact with water. Granules may be used.

In tablets, granules, and granules having two or more types of release-controlling membranes with different release conditions for the active ingredient, a layer containing the active ingredient may be provided between the release-controlling membranes. As an embodiment of a multi-layer structure containing an active ingredient between such controlled release coatings, the active ingredient is coated on tablets, granules or granules in which the release of the active ingredient is controlled by the controlled release coating of the present invention, and then the active ingredient of the present invention is coated. tablets, granules or granules further coated with a controlled release coating of

Another form of controlled release tablet, granule or granule of at least one active ingredient may be a tablet, granule or granule in which the active ingredient is dispersed in a controlled release matrix. Such controlled-release tablets, granules or granules are produced by uniformly dispersing the active ingredient in a hydrophobic carrier such as waxes such as hydrogenated castor oil, hydrogenated rapeseed oil, stearic acid and stearyl alcohol, and polyglycerin fatty acid esters. can be manufactured by A matrix is a composition in which an active ingredient is uniformly dispersed in a carrier, and if necessary, excipients such as lactose, mannitol, cornstarch, and microcrystalline cellulose, which are commonly used in pharmaceutical preparation, are added to the active ingredient. may be dispersed together. In addition, polyoxyethylene oxide, crosslinked acrylic acid polymer (Hibis Wako (R) 103, 104, 105, Carbopol), HPMC, which forms a viscous gel when in contact with water, is added to this matrix along with active ingredients and excipients. , HPC, chitosan, etc. may be dispersed.
Preparation methods include spray drying, spray chilling, melt granulation, and the like.
Polyethylene oxide polyethylene oxide (PEO, such as Polyox WSR303 (molecular weight 7,000,000), Polyox WSR Coagulant (molecular weight 5,000,000), Polyox WSR 301 (molecular weight 4,000,000) is added to the active ingredient controlled-release tablets, granules or granules thus obtained). , Polyox WSR N-60K (molecular weight 2000000), Polyox WSR 205 (molecular weight 600000); manufactured by Dow Chemical), hydroxypropyl methylcellulose (HPMC, Metlose 90SH10000, Metlose 90SH50000, Metlose 90SH30000), Carboxy methyl cellulose manufactured by Shin-Etsu Chemical Co., Ltd. (CMC-Na, Sanlose F-1000MC), hydroxypropyl cellulose (HPC, such as HPC-H, manufactured by Nippon Soda Co., Ltd.), hydroxyethyl cellulose (HEC), carboxyvinyl polymer (Hivis Wako (R) 103, 104, 105 , manufactured by Wako Pure Chemical Industries, Ltd.; Carbopol 943, manufactured by Goodrich), chitosan, sodium alginate, pectin, and other substances that become viscous when in contact with water. Alternatively, fine particles may be used. In addition to using such a substance that becomes viscous upon contact with water for coating, it may be coexisted in the same formulation such as a capsule.
The controlled-release tablets, granules, or granules of the present invention may be in the form of a combination of various release-controlling membranes, release-controlling matrices, and the like as described above.
The size of the tablets, granules or granules with controlled release of the active ingredient is from 50 μm to 5 mm, preferably from 100 μm to 3 mm, more preferably from 100 μm to 2 mm. Most preferred are granules or granules of about 100-1500 μm.

Excipients for further formulation (e.g., glucose, fructose, lactose, sucrose, D-mannitol, erythritol, maltitol, trehalose, sorbitol, corn starch, potato starch, wheat starch, rice starch, microcrystalline cellulose, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, etc.), binders (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, polyvinyl alcohol, sodium carboxymethylcellulose, partially pregelatinized starch, pregelatinized starch, sodium alginate, pullulan, gum arabic powder, gelatin, etc.), disintegrants (e.g., low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, hydroxypropyl starch, etc.), Flavoring agents (e.g., citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, dipotassium glycyrrhizinate, sodium glutamate, 5′-sodium inosinate, 5′-sodium guanylate, etc.), surfactants agents (e.g., polysorbate (polysorbate 80, etc.), polyoxyethylene-polyoxypropylene copolymer, sodium lauryl sulfate, etc.), fragrances (e.g., lemon oil, orange oil, menthol, peppermint oil, etc.), lubricants (e.g., , magnesium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, etc.), coloring agent (e.g., titanium oxide, food yellow No. 5, food blue No. 2, iron sesquioxide, yellow iron sesquioxide etc.), antioxidants (e.g., sodium ascorbate, L-cysteine, sodium sulfite, etc.), masking agents (e.g., titanium oxide, etc.), antistatic agents (e.g., talc, titanium oxide, etc.). be able to.
The particle size of the raw materials used for these is not particularly limited, but particles of about 500 μm or less are preferable from the viewpoint of manufacturability and administration.

The tablets, granules or granules thus obtained may be mixed with a gel-forming polymer retentive in the gastrointestinal tract and administered as such, or may be filled into capsules to form capsules. . The amount of the gastrointestinal retentive gel-forming polymer relative to the controlled release tablets, granules or granules is 0.1%-100%, preferably 2%-50%, more preferably 10%-40%, still more preferably 10%. -35% is preferred.
The pharmaceutical composition of the present invention thus obtained exhibits a therapeutic effect for at least 6 hours, preferably 8 hours, more preferably 12 hours, and even more preferably 16 hours. composition.

The active ingredient is not particularly limited, and can be applied regardless of the therapeutic area. Anti-inflammatory drugs such as indomethacin and acetaminophen, analgesics such as morphine, cardiovascular agents such as diazepam and diltiazem, antihistamines such as chlorpheniramine maleate, antitumor drugs such as fluorouracil and aclarubicin, midazolam, etc. hypnotics, anticongestants such as ephedrine, diuretics such as hydrochlorothiazide and furosemide, bronchodilators such as theophylline, antitussives such as codeine, antiarrhythmic drugs such as quinidine and dizoxine, tolbutamide, pyroglitazone, troglitazone, etc. vitamins such as ascorbic acid, anticonvulsants such as phenytoin, local anesthetics such as lidocaine, adrenocortical hormones such as hydrocortisone, drugs that act on the central nervous system such as Eisai, antihyperlipidemia such as pravastatin Antibiotics such as amoxicillin and cephalexin, gastrointestinal prokinetics such as mosapride and cisapride, H2 _blockers such as famotidine, ranitidine, cimetidine and lansoprazole for the treatment of gastritis, gastroesophageal reflux disease, gastric and duodenal ulcers and optically active forms thereof (R form and S form, preferably R form (hereinafter sometimes referred to as compound A)), omeprazole and an optically active form thereof (S form: esomeprazole), rabeprazole and an optically active form thereof, Examples include benzimidazole-based proton pump inhibitors (PPIs) typified by pantoprazole and optically active substances thereof, and imidazopyridine-based PPIs typified by tenatoprazole.

式中、環Ｃ’は置換基を有していてもよいベンゼン環または置換基を有していてもよい芳香族単環式複素環を、Ｒ^０は水素原子、置換基を有していてもよいアラルキル基、アシル基またはアシルオキシ基を、Ｒ^１、Ｒ^２およびＲ^３は、それぞれ同一または異なって、水素原子、置換基を有していもよいアルキル基、置換基を有していてもよいアルコキシ基または置換基を有していてもよいアミノ基を、およびＹは窒素原子またはＣＨを示す。
上記式（Ｉ’）で表される化合物のうち、特に、環Ｃ’が置換基を有していてもよいベンゼン環である化合物については下記式（Ｉ）で表す。

すなわち、式（Ｉ）中、環Ａは置換基を有していてもよいベンゼン環を示し、Ｒ^０、Ｒ^１、Ｒ^２、Ｒ^３およびＹは上記式（Ｉ’）におけると同意義である。
前記式（Ｉ）において、好ましい化合物は、環Ａが、ハロゲン原子、ハロゲン化されていてもよいＣ_1-4アルキル基、ハロゲン化されていてもよいＣ_1-4アルコキシ基および５または６員複素環基から選ばれた置換基を有していてもよいベンゼン環であり、Ｒ^０は水素原子、置換されていてもよいアラルキル基、アシル基またはアシルオキシ基であり、Ｒ^１がＣ_１−６アルキル基、Ｃ_１−６アルコキシ基、Ｃ_１−６アルコキシ−Ｃ_１−６アルコキシ基またはジ−Ｃ_１−６アルキルアミノ基であり、Ｒ^２が水素原子、Ｃ_１−６アルコキシ−Ｃ_１‐６アルコキシ基またはハロゲン化されていてもよいＣ_１−６アルコキシ基であり、Ｒ^３が水素原子またはＣ_１−６アルキル基であり、Ｙが窒素原子である化合物である。
特に好ましくは、式（Ｉａ）：

〔式中、Ｒ^１はＣ_１−３アルキル基またはＣ_１−３アルコキシ基、Ｒ^２はハロゲン化されているかまたはＣ_１−３アルコキシ基で置換されていてもよいＣ_１−３アルコキシ基、Ｒ^３は水素原子またはＣ_１−３アルキル基、Ｒ^４は、水素原子、ハロゲン化されていてもよいＣ_１−３アルコキシ基またはピロリル基（例えば、１‐,２−または３−ピロリル基）を示す〕で表される化合物である。
式（Ｉａ）において、Ｒ^１がＣ_１−３アルキル基、Ｒ^２がハロゲン化されていてもよいＣ_１−３アルコキシ基、Ｒ^３が水素原子、Ｒ^４が水素原子またはハロゲン化されていてもよいＣ_１−３アルコキシ基である化合物が特に好ましい。 According to the present invention, in particular, acid-labile imidazole compounds represented by the following general formula (I′) such as lansoprazole and its optically active substance, especially acid-labile benz represented by (I) An imidazole compound, or a relatively acid-stable imidazole compound derivative (pro-drug type PPI) represented by general formulas (II) and (III) below, or a salt thereof, or an optically active PPI thereof, etc. Formulations and the like used as active ingredients exhibit excellent persistence of efficacy. As a result, compliance with administration is improved, and the therapeutic effect is enhanced.

In the formula, ring C' is an optionally substituted benzene ring or an optionally substituted aromatic monocyclic heterocycle; R ⁰ is a hydrogen atom; R ¹ , R ² and R ³ may be the same or different, and may be a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted aralkyl group, acyl group or acyloxy group. A good alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH.
Among the compounds represented by the above formula (I'), compounds in which the ring C' is an optionally substituted benzene ring are represented by the following formula (I).

That is, in formula (I), ring A represents an optionally substituted benzene ring, and R ⁰ , R ¹ , R ² , R ³ and Y have the same meanings as in formula (I′) above. be.
In the above formula (I), preferable compounds are those in which Ring A is a halogen atom, an optionally halogenated C _1-4 alkyl group, an optionally halogenated C _1-4 alkoxy group and a 5- or 6-membered a benzene ring optionally having a substituent selected from heterocyclic groups, R ⁰ is a hydrogen atom, an optionally substituted aralkyl group, an acyl group or an acyloxy group, and R ¹ is C _{1- 6} alkyl group, _C1-6 alkoxy group, _C1-6 alkoxy- _C1-6 alkoxy group or di- _C1-6 alkylamino group, wherein ^R2 is a hydrogen atom and _C1-6 alkoxy _- C1 _-6 alkoxy group or an optionally halogenated _C1-6 alkoxy group ^, R3 is a hydrogen atom or a _C1-6 alkyl group, and Y is a nitrogen atom.
Particular preference is given to compounds of the formula (Ia):

[In the formula, R ¹ is a C _1-3 alkyl group or a C _1-3 alkoxy group, R ² is a C _{1-3 alkoxy group optionally substituted with a halogenated or C 1-3 alkoxy} group, R3 is a hydrogen atom or a _C1-3 alkyl group ^{, R4} is a hydrogen atom, an optionally halogenated C1-3 alkoxy group or a pyrrolyl group (e.g., 1-, 2- or ₃ -pyrrolyl group) is a compound represented by
In formula (Ia), R ¹ is a C _1-3 alkyl group, R ² is an optionally halogenated C _1-3 alkoxy group, R ³ is a hydrogen atom, R ⁴ is a hydrogen atom or halogenated Especially preferred are compounds which are C _1-3 alkoxy groups having a

In the compound represented by the above formula (I) [hereinafter referred to as compound (I)], the "substituent" of the "optionally substituted benzene ring" represented by ring A includes, for example, halogen atom, cyano group, nitro group, optionally substituted alkyl group, hydroxy group, optionally substituted alkoxy group, aryl group, aryloxy group, carboxy group, acyl group, acyloxy groups, 5- to 10-membered heterocyclic groups, etc., and about 1 to 3 of these substituents may be substituted on the benzene ring. When the number of substituents is 2 or more, each substituent may be the same or different. Among these substituents, a halogen atom, an optionally substituted alkyl group, an optionally substituted alkoxy group, and the like are preferable.
Halogen atoms include fluorine, chlorine, and bromine atoms. Among them, fluorine is preferred.
The "alkyl group" of the "optionally substituted alkyl group" includes, for example, a _C1-7 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, pentyl, hexyl, heptyl groups, etc.). The "substituent" of the "optionally substituted alkyl group" includes, for example, a halogen atom, a hydroxy group, _{a C1-6} alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), C1 Examples include _-6 alkoxy-carbonyl groups (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl groups, etc.), carbamoyl groups, and the like, and the number of these substituents may be about 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
The "alkoxy group" of the "optionally substituted alkoxy group" includes, for example, a _C1-6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, etc.), etc. mentioned. Examples of the "substituent" of the "optionally substituted alkoxy group" include those similar to the "substituent" of the above "optionally substituted alkyl group". The number of substitutions of is also the same.
Examples of the "aryl group" include _C6-14 aryl groups (eg, phenyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-anthryl groups, etc.) and the like.
The "aryloxy group" includes, for example, a _C6-14 aryloxy group (eg, phenyloxy, 1-naphthyloxy, 2-naphthyloxy group, etc.).
Examples of "acyl group" include formyl, alkylcarbonyl, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, alkylsulfinyl, alkylsulfonyl groups and the like.
The "alkylcarbonyl group" includes a _C1-6 alkyl-carbonyl group (eg, acetyl, propionyl group, etc.) and the like.
The "alkoxycarbonyl group" includes, for example, a _C1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group, etc.) and the like.
Examples of the "alkylcarbamoyl group" include N-C _1-6 alkyl-carbamoyl groups (e.g., methylcarbamoyl, ethylcarbamoyl groups, etc.), N,N-diC _1-6 alkyl-carbamoyl groups (e.g., N,N- dimethylcarbamoyl, N,N-diethylcarbamoyl group, etc.).
The "alkylsulfinyl group" includes, for example, a _C1-7 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl group, etc.).
The "alkylsulfonyl group" includes, for example, a _C1-7 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl group, etc.).
The "acyloxy group" includes, for example, an alkylcarbonyloxy group, an alkoxycarbonyloxy group, a carbamoyloxy group, an alkylcarbamoyloxy group, an alkylsulfinyloxy group, an alkylsulfonyloxy group and the like.
"Alkylcarbonyloxy group" includes _C1-6 alkyl-carbonyloxy group (eg, acetyloxy, propionyloxy group, etc.) and the like.
The "alkoxycarbonyloxy group" includes, for example, a _C1-6 alkoxy-carbonyloxy group (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy group, etc.) and the like.
The "alkylcarbamoyloxy group" includes _C1-6 alkyl-carbamoyloxy groups (eg, methylcarbamoyloxy, ethylcarbamoyloxy groups, etc.) and the like.
The "alkylsulfinyloxy group" includes, for example, a _C1-7 alkylsulfinyloxy group (eg, methylsulfinyloxy, ethylsulfinyloxy, propylsulfinyloxy, isopropylsulfinyloxy group, etc.).
The "alkylsulfonyloxy group" includes, for example, a _C1-7 alkylsulfonyloxy group (eg, methylsulfonyloxy, ethylsulfonyloxy, propylsulfonyloxy, isopropylsulfonyloxy group, etc.).
As the "5- to 10-membered heterocyclic group", for example, a 5- to 10-membered (e.g., (preferably 5- or 6-membered) heterocyclic groups, and specific examples include 2- or 3-thienyl group, 2-, 3- or 4-pyridyl group, 2- or 3-furyl group, 1-, 2 - or 3-pyrrolyl group, 2-, 3-, 4-, 5- or 8-quinolyl group, 1-, 3-, 4- or 5-isoquinolyl group, 1-, 2- or 3-indolyl group, etc. mentioned. Among these, 5- or 6-membered heterocyclic groups such as 1-, 2- or 3-pyrrolyl groups are preferred.
Ring A preferably has a substituent selected from a halogen atom, an optionally halogenated _C1-4 alkyl group, an optionally halogenated _C1-4 alkoxy group and a 5- or 6-membered heterocyclic group. It is a benzene ring which may have one or two.

In the above formula (I′), the “aromatic monocyclic heterocycle” of the “aromatic monocyclic heterocycle optionally having substituent(s)” represented by ring C′ includes, for example, furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, 5- to 6-membered aromatic monocyclic heterocycles such as triazine and the like. As the "aromatic monocyclic heterocyclic ring" represented by these C' rings, in particular, the "benzene ring optionally having substituents" and "having substituents" represented by ring A described above. "good pyridine ring" is preferred. The "pyridine ring optionally having substituents" represented by C' ring is substituted with the same substituents as the "benzene ring optionally having substituents" represented by ring A above. You may have 1 to 4 at each position.
There is no particular limitation on the position at which the "aromatic monocyclic heterocyclic ring" of the "optionally substituted aromatic monocyclic heterocyclic ring" is condensed with the imidazole moiety.

In the above formula (I′) or (I), the “aralkyl group” of the “optionally substituted aralkyl group” represented by R ⁰ includes, for example, a C _7-16 aralkyl group (e.g., benzyl , _C6-10 aryl _C1-6 alkyl groups such as phenethyl, etc.). Examples of the "substituent" of the "optionally substituted aralkyl group" include the same substituents as the "substituent" of the above "optionally substituted alkyl group". The number of groups is about 1 to 4. When the number of substituents is 2 or more, each substituent may be the same or different.
Examples of the “acyl group” represented by R ⁰ include the “acyl group” described as the substituent of ring A above.
Examples of the "acyloxy group" represented by R ⁰ include the "acyloxy group" described as the substituent of ring A above.
A preferred R ⁰ is a hydrogen atom.
In formula (I′) or (I) above, the “optionally substituted alkyl group” represented by R ¹ , R ² or R ³ includes the “substituted an alkyl group optionally having a group".
As the “optionally substituted alkoxy group” for R ¹ , R ² or R ³ , the “optionally substituted alkoxy group” described as the substituent for the above ring A can be used. mentioned.
Examples of the "optionally substituted amino group" for R ¹ , R ² or R ³ include an amino group and a mono-C _1-6 alkylamino group (e.g., methylamino, ethylamino, etc.) , mono- _C6-14 arylamino group (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di- _C1-6 alkylamino group (e.g., dimethylamino, diethylamino, etc.), di _- C6 _-14 arylamino group (eg, diphenylamino, etc.) and the like.
Preferred R ¹ is a C _1-6 alkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxy-C _1-6 alkoxy group and a di-C _1-6 alkylamino group. More preferred ^R2 is a _C1-3 alkyl group or a _C1-3 alkoxy group.
Preferred ^R2 is a hydrogen atom, a _C1-6 alkoxy- _C1-6 alkoxy group or an optionally halogenated _C1-6 alkoxy group. More preferred R3 is a ^C1-3 alkoxy group which is optionally halogenated or substituted with a _{C1-3 alkoxy} group.
Preferred ^R3 is a hydrogen atom or a _C1-6 alkyl group. More preferred R3 is a hydrogen atom or a _C1-3 alkyl group ⁽ particularly a hydrogen atom).
Preferred Y is a nitrogen atom.

Specific examples of compound (I) include the following compounds.
2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-imidazole (lansoprazole), 2-[[(3,5-dimethyl-4 -methoxy-2-pyridinyl)methyl]sulfinyl]-5-methoxy-1H-benzimidazole, 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H- benzimidazole sodium salt, 5-difluoromethoxy-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole;
Of these compounds, lansoprazole, ie 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole, is particularly preferred.
The present invention is preferably applied to PPIs of imidazopyridine compounds in addition to the above PPIs of benzimidazole compounds. PPIs of such imidazopyridine compounds include, for example, tenatoprazole.
The compound (I) and the compound (I') including the imidazopyridine compound may be a racemate or an optically active form such as an R-form or an S-form. For example, optically active forms of lansoprazole, namely (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole and Optically active forms such as (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole are particularly useful in the present invention. preferred. Lansoprazole, lansoprazole R form, lansoprazole S form and the like are usually preferably crystals, but in addition to being stabilized by formulation itself as described later, a basic inorganic salt is blended and an intermediate coating layer is formed. Since it is more stabilized by providing it, not only a crystal but also an amorphous one can be used.

Compound (I′) and salts of compound (I) are preferably pharmaceutically acceptable salts, such as salts with inorganic bases, salts with organic bases, and salts with basic amino acids.
Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts.
Suitable examples of salts with organic bases include alkylamines (trimethylamine, triethylamine, etc.), heterocyclic amines (pyridine, picoline, etc.), alkanolamines (ethanolamine, diethanolamine, triethanolamine, etc.), dicyclohexylamine. , N,N'-dibenzylethylenediamine and the like.
Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
Among these salts, alkali metal salts or alkaline earth metal salts are preferred. Sodium salts are particularly preferred.

Compound (I') or (I) can be produced by a method known per se. It is produced by the methods described in JP-A-52-62275, JP-A-54-141783, or similar methods. The optically active compound (I) can be obtained by an optical resolution method (fractional recrystallization method, chiral column method, diastereomer method, method using microorganisms or enzymes, etc.), asymmetric oxidation, and the like. The R-form of lansoprazole can also be produced, for example, according to the production methods described in WO 00-78745, WO 01/83473, and the like.

The benzimidazole compounds having antiulcer activity used in the present invention include lansoprazole, omeprazole, rabeprazole, pantoprazole, leminoprazole, tenatoprazole (TU-199), optically active compounds thereof, and pharmaceutically acceptable compounds thereof. and more preferably lansoprazole or its optically active form, especially the R form. Lansoprazole or its optically active form, particularly the R form, is preferably in a crystalline form, but may be in an amorphous form. It is also advantageously applied to prodrugs of these PPIs.

上記式（ＩＩ）で表される化合物〔以下、化合物（ＩＩ）と称する〕において、Ｂ環は「置換基を有していてもよいピリジン環」を示す。
Ｂ環で示される「置換基を有していてもよいピリジン環」のピリジン環はその置換可能な位置に１ないし４個の置換基を有していてもよい。置換基としては、例えばハロゲン原子（例えば、フッ素、塩素、臭素、ヨウ素等）、置換基を有していてもよい炭化水素基（例えば、メチル基、エチル基、ｎ−プロピル基等の炭素数１ないし６のアルキル基等）、置換基を有していてもよいアミノ基（例えば、アミノ；メチルアミノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ基等の炭素数１ないし６のアルキル基でモノ−置換ないしジ−置換されたアミノ基等）、アミド基（例えば、ホルムアミド、アセトアミド等のＣ_1-3アシルアミノ基等）、置換基を有していてもよい低級アルコキシ基（例えば、メトキシ、エトキシ、２，２，２−トリフルオロエトキシ、３−メトキシプロポキシ基等の炭素数１ないし６のアルコキシ基等）、低級アルキレンジオキシ基（例えば、メチレンジオキシ、エチレンジオキシ等のＣ_1-3アルキレンジオキシ基等）等が挙げられる。 Preferred examples of these prodrugs include the compounds represented by the following general formulas (II) and (III) in addition to the prodrugs contained in compound (I) or (I').

In the compound represented by the above formula (II) [hereinafter referred to as compound (II)], ring B represents an "optionally substituted pyridine ring".
The pyridine ring of the "pyridine ring optionally having substituents" for ring B optionally has 1 to 4 substituents at its substitutable positions. Examples of substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), hydrocarbon groups which may have substituents (e.g., methyl group, ethyl group, n-propyl group, etc.). 1 to 6 alkyl groups, etc.), optionally substituted amino groups (e.g., amino; mono-substituted with C 1 to 6 alkyl groups such as methylamino, dimethylamino, ethylamino, diethylamino groups, etc.) to di-substituted amino groups, etc.), amide groups (e.g., C _1-3 acylamino groups such as formamide, acetamide, etc.), optionally substituted lower alkoxy groups (e.g., methoxy, ethoxy, 2 , 2,2-trifluoroethoxy, alkoxy groups having 1 to 6 carbon atoms such as 3-methoxypropoxy groups, etc.), lower alkylenedioxy groups (e.g., C _1-3 alkylenedioxy groups such as methylenedioxy, ethylenedioxy, etc.). oxy group, etc.).

Examples of substituents that the substituents of the "pyridine ring optionally having substituents" represented by ring B may have include halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) and lower alkyl groups. (e.g., alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl groups, etc.), lower alkenyl groups (e.g., alkenyl groups having 2 to 6 carbon atoms, such as vinyl and allyl groups, etc.), lower alkynyl groups (e.g., C2-C6 alkynyl groups such as , ethynyl and propargyl groups, etc.), cycloalkyl groups (e.g., C3-C8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, etc.), lower alkoxy groups (e.g., alkoxy groups having 1 to 6 carbon atoms such as methoxy and ethoxy groups, etc.), nitro groups, cyano groups, hydroxy groups, thiol groups, carboxyl groups, lower alkanoyl groups (e.g., formyl; acetyl, propionyl, butyryl groups, etc.) C1-C6 alkyl-carbonyl group, etc.), lower alkanoyloxy group (e.g., formyloxy; C1-C6 alkyl-carbonyloxy group such as acetyloxy, propionyloxy group, etc.), lower alkoxycarbonyl group (e.g., C1-C6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl groups), aralkyloxycarbonyl groups (e.g., C7-C11 aralkyloxy-carbonyl groups such as benzyloxycarbonyl groups) groups, etc.), aryl groups (e.g., aryl groups having 6 to 14 carbon atoms such as phenyl and naphthyl groups), aryloxy groups (e.g., aryloxy groups having 6 to 14 carbon atoms such as phenyloxy and naphthyloxy groups, etc.) ), arylcarbonyl groups (e.g., aryl-carbonyl groups having 6 to 14 carbon atoms such as benzoyl and naphthoyl groups), arylcarbonyloxy groups (e.g., aryl groups having 6 to 14 carbon atoms such as benzoyloxy and naphthoyloxy groups). -carbonyloxy group, etc.), optionally substituted carbamoyl group (e.g., carbamoyl; carbamoyl mono-substituted or di-substituted with an alkyl group having 1 to 6 carbon atoms such as methylcarbamoyl, dimethylcarbamoyl group, etc.) group, etc.), an optionally substituted amino group (e.g., amino; mono-substituted or di-substituted with an alkyl group having 1 to 6 carbon atoms such as methylamino, dimethylamino, ethylamino, diethylamino group, etc.). substituted amino groups, etc.), and the number and substitution positions of the substituents are not particularly limited.
Although there are no particular limitations on the number and substitution positions of the substituents of the "pyridine ring optionally having substituents" for ring B, 1 to 3 of the above substituents are 3, 4, and 3 of the pyridine ring. Substitution at any of the 5-positions is preferred.
As the "optionally substituted pyridine ring" for ring B, 3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl is preferable.

In the present invention, the C ring represents an "optionally substituted benzene ring" or an "optionally substituted aromatic monocyclic heterocyclic ring" condensed with the imidazole moiety, especially the former is preferred.
The benzene ring of the "optionally substituted benzene ring" represented by ring C may have 1 to 4 substituents at the substitutable position, and the substituents include, for example , halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), optionally substituted hydrocarbon groups (e.g., alkyls having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, etc.) groups, etc.), optionally substituted amino groups (e.g., amino; mono-substituted or di-substituted with C 1-6 alkyl groups such as methylamino, dimethylamino, ethylamino, and diethylamino groups) amino groups, etc.), amide groups (e.g., C _1-3 acylamino groups such as formamide, acetamide, etc.), optionally substituted lower alkoxy groups (e.g., methoxy, ethoxy, difluoromethoxy groups such as carbon alkoxy groups of numbers 1 to 6, etc.), lower alkylenedioxy groups (eg, C _1-3 alkylenedioxy groups such as methylenedioxy, ethylenedioxy, etc.), and the like.

Substituents that may be possessed by the substituents of the "optionally substituted benzene ring" represented by ring C include, for example, halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), lower alkyl groups (e.g., alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl groups, etc.), lower alkenyl groups (e.g., alkenyl groups having 2 to 6 carbon atoms, such as vinyl and allyl groups, etc.), lower alkynyl groups (e.g., C2-C6 alkynyl groups such as , ethynyl and propargyl groups, etc.), cycloalkyl groups (e.g., C3-C8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, etc.), lower alkoxy groups (e.g., alkoxy groups having 1 to 6 carbon atoms such as methoxy and ethoxy groups, etc.), nitro groups, cyano groups, hydroxy groups, thiol groups, carboxyl groups, lower alkanoyl groups (e.g., formyl; acetyl, propionyl, butyryl groups, etc.) C1-C6 alkyl-carbonyl group, etc.), lower alkanoyloxy group (e.g., formyloxy; C1-C6 alkyl-carbonyloxy group such as acetyloxy, propionyloxy group, etc.), lower alkoxycarbonyl group (e.g., C1-C6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl groups), aralkyloxycarbonyl groups (e.g., C7-C17 aralkyloxy-carbonyl groups such as benzyloxycarbonyl groups) groups, etc.), aryl groups (e.g., aryl groups having 6 to 14 carbon atoms such as phenyl and naphthyl groups), aryloxy groups (e.g., aryloxy groups having 6 to 14 carbon atoms such as phenyloxy and naphthyloxy groups, etc.) ), arylcarbonyl groups (e.g., aryl-carbonyl groups having 6 to 14 carbon atoms such as benzoyl and naphthoyl groups), arylcarbonyloxy groups (e.g., aryl groups having 6 to 14 carbon atoms such as benzoyloxy and naphthoyloxy groups). -carbonyloxy group, etc.), optionally substituted carbamoyl group (e.g., carbamoyl; carbamoyl mono-substituted or di-substituted with an alkyl group having 1 to 6 carbon atoms such as methylcarbamoyl, dimethylcarbamoyl group, etc.) group, etc.), an optionally substituted amino group (e.g., amino; mono-substituted or di-substituted with an alkyl group having 1 to 6 carbon atoms such as methylamino, dimethylamino, ethylamino, diethylamino group, etc.). substituted amino groups, etc.), and the number and substitution positions of the substituents are not particularly limited.
As the "optionally substituted benzene ring" for ring C, a benzene ring is preferred.

Examples of the "aromatic monocyclic heterocyclic ring" of the "optionally substituted aromatic monocyclic heterocyclic ring" for ring C include furan, thiophene, pyrrole, oxazole, isoxazole, and thiazole. , isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1, 5- to 6-membered aromatics such as 2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine A monocyclic heterocycle etc. are mentioned. As the "aromatic monocyclic heterocyclic ring" represented by these C rings, a pyridine ring is particularly preferred. It may have 1 to 4 substituents at the substitutable position similar to the "benzene ring optionally having substituents" for ring C.
There is no particular limitation on the position at which the "aromatic monocyclic heterocyclic ring" of the "optionally substituted aromatic monocyclic heterocyclic ring" is condensed with the imidazole moiety.
In the present invention, X ₁ and X ₂ each represent an oxygen atom or a sulfur atom. It is preferred if X ₁ and X ₂ both represent an oxygen atom.

（式中、Ｗ₁、Ｗ₂はそれぞれ「二価の鎖状炭化水素基」または結合手を示し、Ｚは「置換基を有していてもよい二価の炭化水素環基」、「置換基を有していてもよい二価の複素環基」、酸素原子、ＳＯ_n（式中、ｎは０、1または２を示す）または＞Ｎ−Ｅ（式中、Ｅは水素原子、置換基を有していてもよい炭化水素基、置換基を有していてもよい複素環基、低級アルカノイル基、低級アルコキシカルボニル基、アラルキルオキシカルボニル基、チオカルバモイル基、低級アルキルスルフィニル基、低級アルキルスルホニル基、スルファモイル基、モノ−低級アルキルスルファモイル基、ジ−低級アルキルスルファモイル基、アリールスルファモイル基、アリールスルフィニル基、アリールスルホニル基、アリールカルボニル基、置換基を有していてもよいカルバモイル基を示す）を示し、Ｚが酸素原子、ＳＯ_nまたは＞Ｎ−Ｅである場合、Ｗ₁、Ｗ₂はそれぞれ「二価の鎖状炭化水素基」を示す）で表わされる二価の基を示す。なかでも、Ｗとしては「置換基を有していてもよい二価の鎖状炭化水素基」が好ましい。
Ｗで示される「置換基を有していてもよい二価の鎖状炭化水素基」の「二価の鎖状炭化水素基」および、Ｗ₁、Ｗ₂で示される「二価の鎖状炭化水素基」としては、例えば、Ｃ_1-6アルキレン基（例えば、メチレン、エチレン、トリメチレン等）、Ｃ_2-6アルケニレン基（例えば、エテニレン等）、Ｃ_2-6アルキニレン基（例えば、エチニレン等）等が挙げられる。Ｗの二価の鎖状炭化水素基は、Ｃ環で示される「置換基を有していてもよいベンゼン環」と同様の置換基をその置換可能な位置に１ないし６個有していてもよい。
Ｗで示される「置換基を有していてもよい二価の鎖状炭化水素基」の「二価の鎖状炭化水素基」および、Ｗ₁、Ｗ₂で示される「二価の鎖状炭化水素基」としては、メチレン基、エチレン基が好ましい。Ｗとしては、エチレン基が特に好ましい。Ｚが酸素原子、ＳＯ_nまたは＞Ｎ−Ｅ（ｎ及びＥは前義の通り）のとき、Ｗ₁で示される「二価の鎖状炭化水素基」としては、炭素数２以上の炭化水素基が好ましい。 In the present invention, W is an "optionally substituted divalent chain hydrocarbon group" or the formula:

(Wherein, W ₁ and W ₂ each represent a “divalent chain hydrocarbon group” or a bond, Z represents an “optionally substituted divalent hydrocarbon ring group”, a “substituted a divalent heterocyclic group optionally having a group", an oxygen atom, SOn (wherein _n represents 0, 1 or 2) or >N-E (wherein E is a hydrogen atom, substituted optionally substituted hydrocarbon group, optionally substituted heterocyclic group, lower alkanoyl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, thiocarbamoyl group, lower alkylsulfinyl group, lower alkyl sulfonyl group, sulfamoyl group, mono-lower alkylsulfamoyl group, di-lower alkylsulfamoyl group, arylsulfamoyl group, arylsulfinyl group, arylsulfonyl group, arylcarbonyl group, even if it has a substituent a good carbamoyl group), and when Z is an oxygen atom, SO _n or >N-E, W ₁ and W ₂ each represent a “divalent chain hydrocarbon group”). represents the group of Among them, W is preferably an "optionally substituted divalent chain hydrocarbon group".
The "divalent chain hydrocarbon group" of the "optionally substituted divalent chain hydrocarbon group" represented by W, and the "divalent chain hydrocarbon group" represented by W ₁ and W ₂ Examples of "hydrocarbon groups" include C _1-6 alkylene groups (e.g., methylene, ethylene, trimethylene, etc.), C _2-6 alkenylene groups (e.g., ethenylene, etc.), C _2-6 alkynylene groups (e.g., ethynylene, etc. ) and the like. The divalent chain hydrocarbon group of W has 1 to 6 substituents at substitutable positions similar to the "benzene ring optionally having a substituent" for ring C. good too.
The "divalent chain hydrocarbon group" of the "optionally substituted divalent chain hydrocarbon group" represented by W, and the "divalent chain hydrocarbon group" represented by W ₁ and W ₂ The "hydrocarbon group" is preferably a methylene group or an ethylene group. W is particularly preferably an ethylene group. When Z is an oxygen atom, SOn or >N-E ( _n and E are as defined above), the "divalent chain hydrocarbon group" represented by W1 includes _a hydrocarbon having 2 or more carbon atoms groups are preferred.

Examples of the "hydrocarbon ring" of the "optionally substituted divalent hydrocarbon ring group" represented by Z include alicyclic hydrocarbon rings and aromatic hydrocarbon rings, Those having 3 to 16 carbon atoms are preferable, and may have 1 to 4 substituents at the substitutable position similar to the "benzene ring optionally having substituents" for ring C. . As hydrocarbon rings, for example, cycloalkanes, cycloalkenes, arenes, and the like are used.
As the "cycloalkane" of the "optionally substituted divalent hydrocarbon ring group" for Z, for example, lower cycloalkanes are preferable, such as cyclopropane, cyclobutane, cyclopentane, cyclohexane , cycloheptane, cyclooctane, bicyclo[2.2.1]heptane and C _3-10 cycloalkanes such as adamantane are commonly used.
The "cycloalkene" of the "optionally substituted divalent hydrocarbon ring group" for Z is preferably lower cycloalkene, such as cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclo C _4-9 cycloalkenes such as octene are commonly used.
The "arene" of the "optionally substituted divalent hydrocarbon ring group" represented by Z is preferably _C6-14arene such as benzene, naphthalene, phenanthrene, etc. For example, phenylene, etc. General purpose.

The "heterocyclic ring" of the "optionally substituted divalent heterocyclic group" represented by Z includes, as atoms (ring atoms) constituting the ring system, an oxygen atom, a sulfur atom, a nitrogen atom, and the like. at least one (preferably 1 to 4, more preferably 1 to 2) 5- to 12-membered "heteroaromatic ring" containing 1 to 3 (preferably 1 to 2) heteroatoms selected from Alternatively, a "saturated or unsaturated non-aromatic heterocyclic ring" or the like may be mentioned, and a substituent similar to the "benzene ring optionally having substituents" represented by the C ring may be substituted at the substitutable position from 1 to You may have four.
The "aromatic heterocyclic ring" of the "optionally substituted divalent heterocyclic group" for Z includes an aromatic monocyclic heterocyclic ring, an aromatic condensed heterocyclic ring, and the like.
Examples of the "aromatic monocyclic heterocycle" include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4 -oxadiazole, 1,3,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1 ,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, and other 5- to 6-membered aromatic monocyclic heterocycles.
Examples of the "aromatic condensed heterocyclic ring" include benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisoxazole, and benzothiazole. , 1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine, purine, pteridine, carbazole, carboline, acridine, phenoxazine, phenothiazine, phenazine, phenoxathiin, thianthrene , phenanthridine, phenanthroline, indolizine, pyrrolo[1,2-b]pyridazine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrimidine, 1,2,4-triazolo[4,3-a]pyridine, 1,2,4-triazolo[4,3-b] 8- to 12-membered aromatic condensed heterocycles such as pyridazine.

The "saturated or unsaturated non-aromatic heterocyclic ring" of the "optionally substituted divalent heterocyclic group" for Z includes, for example, oxirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocycles (aliphatic heterocycles). These may be oxo-substituted, for example 2-oxoazetidine, 2-oxopyrrolidine, 2-oxopiperidine, 2-oxoazepane, 2-oxoazocane, 2-oxotetrahydrofuran, 2-oxotetrahydropyran, 2-oxotetrahydro Thiophene, 2-oxothiane, 2-oxopiperazine, 2-oxoxepane, 2-oxoxazepane, 2-oxothiepane, 2-oxothiazepane, 2-oxooxocane, 2-oxothiocane, 2-oxooxazocane, 2-oxothiazocane etc.
"Hydrocarbon ring group" of "optionally substituted divalent hydrocarbon ring group" or "heterocyclic ring group" of "optionally substituted divalent heterocyclic group" for Z The two bonds from the "cyclic group" may be at any possible position.

The "hydrocarbon group optionally having substituent(s)" and "heterocyclic group optionally having substituent(s)" for E are as defined below.
Examples of the "lower alkanoyl group" for E include formyl; _C1-6 alkyl-carbonyl groups such as acetyl, propionyl, butyryl, isobutyryl, and the like.
Examples of the "lower alkoxycarbonyl group" for E include _C1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and the like.
As the "aralkyloxycarbonyl" represented by E, for example, a _C7-11 aralkyloxy-carbonyl group such as benzyloxycarbonyl and the like are used.
Examples of the "lower alkylsulfinyl group" for E include C _1-6 alkylsulfinyl groups such as methylsulfinyl and ethylsulfinyl.
Examples of the "lower alkylsulfonyl group" for E include C _1-6 alkylsulfonyl groups such as methylsulfonyl and ethylsulfonyl.
Examples of the "mono-lower alkylsulfamoyl group" for E include mono- _C1-6 alkylsulfamoyl groups such as methylsulfamoyl and ethylsulfamoyl.
Examples of the "di-lower alkylsulfamoyl group" for E include di- _C1-6 alkylsulfamoyl groups such as dimethylsulfamoyl and diethylsulfamoyl.
As the "arylsulfamoyl group" for E, for example, _C6-10 arylsulfamoyl groups such as phenylsulfamoyl and naphthylsulfamoyl are used.
As the "arylsulfinyl group" for E, for example, _C6-10 arylsulfinyl groups such as phenylsulfinyl, naphthylsulfinyl and the like are used.
As the "arylsulfonyl group" for E, for example, a _C6-10 arylsulfonyl group such as phenylsulfonyl, naphthylsulfonyl and the like is used.
As the "arylcarbonyl group" for E, for example, a _C6-10 aryl-carbonyl group such as benzoyl, naphthoyl, etc. is used.
Examples of the "optionally substituted carbamoyl group" represented by E include the formula -CONR ₂ R ₃ (wherein R ₂ and R ₃ are each a hydrogen atom and optionally have a substituent represents a hydrocarbon group or an optionally substituted heterocyclic group, and in the formula -CONR ₂ R ₃ , R ₂ and R ₃ may form a ring together with the adjacent nitrogen atoms. and the like are used.

In the present invention, R represents an "optionally substituted hydrocarbon group" or a "optionally substituted heterocyclic group", and R can be bonded to W, Among them, an optionally substituted C _1-6 hydrocarbon group, particularly a lower (C _1-6 )alkyl group, is preferred. The “hydrocarbon group optionally having substituent(s)” and “heterocyclic group optionally having substituent(s)” for R are as defined below. Further, the case where R is combined with W will be described in detail later.

In the present invention, D ₁ and D ₂ each represent a bond, an oxygen atom, a sulfur atom or >NR ₁ , where R ₁ is a hydrogen atom or an optionally substituted hydrocarbon group. show. However, in the present invention, the case where both D ₁ and D ₂ are bonds is excluded. Among them, D ₁ and D ₂ are each preferably a bond or an oxygen atom, and particularly preferably D ₁ is an oxygen atom and D ₂ is an oxygen atom or a bond. The “hydrocarbon group optionally having substituent(s)” for R ₁ is as defined below.

In the present invention, G represents an "optionally substituted hydrocarbon group" or a "optionally substituted heterocyclic group", especially C A _1-6 hydrocarbon group, or an optionally substituted saturated heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms as ring-constituting atoms is preferred. In particular, G is an optionally substituted C _1-6 hydrocarbon group, or an optionally substituted hetero group selected from an oxygen atom, a nitrogen atom and a sulfur atom as a ring-constituting atom. Saturated oxygenated heterocyclic groups which may contain from 1 to 3 additional atoms are preferred. The “hydrocarbon group optionally having substituent(s)” or “heterocyclic group optionally having substituent(s)” for G is as defined below.

The "hydrocarbon group" of the "optionally substituted hydrocarbon group" represented by E, R, R ₁ and G includes, for example, a saturated or unsaturated aliphatic hydrocarbon group, a saturated or unsaturated alicyclic hydrocarbon groups, saturated or unsaturated alicyclic-aliphatic hydrocarbon groups, aromatic hydrocarbon groups, aromatic-saturated or unsaturated alicyclic hydrocarbon groups, etc. Those having 1 to 16 carbon atoms are preferred, and those having 1 to 6 carbon atoms are more preferred. Specifically, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkylalkyl group, a cycloalkenylalkyl group, an aryl group, an arylalkyl group, and the like are used.
"Alkyl group" is preferably, for example, a lower alkyl group ( _C1-6 alkyl group) and the like, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethyl C _1-6 alkyl groups such as propyl and hexyl are commonly used. R is preferably a lower alkyl group (C _1-6 alkyl group), particularly preferably a methyl group.
The "alkenyl group" is preferably, for example, a lower alkenyl group, such as a _C2-7 alkenyl group such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl and 2,2-dimethyl-pent-4-enyl. etc. are commonly used.
The "alkynyl group" is preferably, for example, a lower alkynyl group, and commonly used _C2-6 alkynyl groups such as ethynyl, propargyl and 1-propynyl.
The "cycloalkyl group" is preferably, for example, a lower cycloalkyl group and the like, for example, C _{3- 10} Cycloalkyl groups and the like are commonly used.
The "cycloalkenyl group" is preferably, for example, a lower cycloalkenyl group, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-5-ene-2- C _3-10 cycloalkenyl groups such as yl are generally used.
The "cycloalkylalkyl group" is preferably, for example, a lower cycloalkylalkyl group, such as C _4-9 cycloalkylalkyl groups such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl and cyclohexylethyl. base etc. are widely used.
"Cycloalkenylalkyl group" is preferably, for example, a lower cycloalkenylalkyl group, such as cyclopentenylmethyl, cyclohexenylmethyl, cyclohexenylethyl, cyclohexenylpropyl, cycloheptenylmethyl, cycloheptenylethyl and bicyclo[2.2 .1] _C4-9 cycloalkenylalkyl such as hept-5-en-2-ylmethyl and the like are commonly used.
The "aryl group" is preferably, for example, a _C6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl and 2-anthryl, and a phenyl group is commonly used.
An "arylalkyl group" has an "aryl group" as defined above as the aryl moiety and an "alkyl group" as defined above as the alkyl moiety. Among them, for example, a _C6-14 aryl- _C1-6 alkyl group is preferable, and for example, benzyl, phenethyl and the like are commonly used.

Examples of substituents that the "hydrocarbon group" of the "hydrocarbon group optionally having substituent(s)" represented by E, R, R ₁ and G may have include halogen atoms (e.g. , fluorine, chlorine, bromine, iodine, etc.), nitro group, cyano group, hydroxy group, thiol group, sulfo group, sulfino group, phosphono group, optionally halogenated lower alkyl group (e.g., methyl, ethyl, propyl C _1-6 alkyl such as , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl and hexyl, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl, 6, mono-, di- or tri-halogeno-C _1-6 alkyl groups such as 6,6-trifluorohexyl), oxo groups, amidino groups, imino groups, alkylenedioxy groups (e.g. methylenedioxy, ethylenedioxy C _1-3 alkylenedioxy groups such as oxy, etc.), lower alkoxy groups (e.g., C _1-6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, etc.), halogen optionally substituted lower alkoxy groups (e.g., chloromethyloxy, dichloromethyloxy, trichloromethyloxy, fluoromethyloxy, difluoromethyloxy, trifluoromethyloxy, 2-bromoethyloxy, 2,2,2-tri fluoroethyloxy, pentafluoroethyloxy, 3,3,3-trifluoropropyloxy, 4,4,4-trifluorobutyloxy, 5,5,5-trifluoropentyloxy, 6,6,6-trifluoro mono-, di- or tri-halogeno _{- C1-6} alkoxy groups such as hexyloxy), lower alkylthio groups (e.g. C1 groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, pentylthio and hexylthio) _-6 alkylthio group, etc.), carboxyl group, lower alkanoyl group (e.g., formyl; C _1-6 alkyl-carbonyl group such as acetyl, propionyl, butyryl, isobutyryl, etc.), lower alkanoyloxy group (e.g., formyl oxy; _C1-6 alkyl _- carbonyloxy groups such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.), lower alkoxycarbonyl groups (e.g., C1 groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl) _-6 alkoxy-carbonyl group, etc.), aralkyloxycarbonyl group (e.g., _C7-11 aralkyloxy-carbonyl group such as benzyloxycarbonyl, etc.), thiocarbamoyl group, lower alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl, etc.) C _1-6 alkylsulfinyl groups, etc.), lower alkylsulfonyl groups (e.g., C _1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, etc.), sulfamoyl groups, mono-lower alkylsulfamoyl groups (e.g., methyl mono-C _1-6 alkylsulfamoyl groups such as sulfamoyl and ethylsulfamoyl), di-lower alkylsulfamoyl groups (e.g. di-C ₁ groups such as dimethylsulfamoyl and diethylsulfamoyl) _-6 alkylsulfamoyl group, etc.), arylsulfamoyl group (e.g., _C6-10 arylsulfamoyl group such as phenylsulfamoyl, naphthylsulfamoyl, etc.), aryl group (e.g., phenyl, naphthyl, etc.) C _6-10 aryl group, etc.), aryloxy group (e.g., C _6-10 aryloxy group such as phenyloxy, naphthyloxy, etc.), arylthio group (e.g., C _6-10 arylthio group such as phenylthio, naphthylthio, etc.) ), arylsulfinyl groups (e.g., C _6-10 arylsulfinyl groups such as phenylsulfinyl and naphthylsulfinyl), arylsulfonyl groups (e.g., C _6-10 arylsulfonyl groups such as phenylsulfonyl and naphthylsulfonyl), arylcarbonyl groups (e.g., _C6-10 aryl-carbonyl groups such as benzoyl, naphthoyl, etc.), arylcarbonyloxy groups (e.g., _C6-10 aryl-carbonyloxy groups such as benzoyloxy, naphthoyloxy, etc.), halogenated optionally substituted lower alkylcarbonylamino group (e.g., optionally halogenated C _1-6 alkyl-carbonylamino group such as acetylamino, trifluoroacetylamino, etc.), optionally substituted carbamoyl Groups (e.g., of the formula _-CONR2 R ₃ (wherein R ₂ and R ₃ each represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; _In the formula _{-CONR2R3 , R2} and R3 may form a ring together with the adjacent nitrogen atoms. ), an optionally substituted amino group (e.g., formula -NR ₂ R ₃ (wherein R ₂ and R ₃ have the same meanings as above), and formula -NR ₂ In R ₃ , R ₂ and R ₃ may form a ring together with the adjacent nitrogen atoms.), an optionally substituted ureido group (e.g., —NHCONR ₂ R ₃ (In the formula, R ₂ and R ₃ have the same meanings as above. In the formula —NHCONR ₂ R ₃ , R ₂ and R ₃ may form a ring together with the adjacent nitrogen atoms.) group), an optionally substituted carboxamide group (e.g., a group represented by the formula —NR ₂ COR ₃ (wherein R ₂ and R ₃ have the same meanings as above)), optionally having a sulfonamide group (e.g., a group represented by the formula —NR ₂ SO ₂ R ₃ (wherein R ₂ and R ₃ have the same meanings as above)), A good heterocyclic group (having the same meanings as those represented by R ₂ and R ₃ ) and the like are used.
The "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R ₂ and R ₃ includes, for example, a lower alkyl group (e.g., a C 1 to 6 group such as a methyl, ethyl, propyl group, etc.) alkyl groups, etc.), lower alkenyl groups (e.g., alkenyl groups having 2 to 6 carbon atoms such as vinyl and allyl groups, etc.), lower alkynyl groups (e.g., alkynyl groups having 2 to 6 carbon atoms, such as ethynyl and propargyl groups, etc. ), cycloalkyl groups (e.g., cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, etc.), cycloalkenyl groups (e.g., cyclobutenyl, cyclopentenyl, cyclohexenyl groups, etc. having 3 carbon atoms) to 8 cycloalkenyl groups, etc.), cycloalkylalkyl groups (e.g., C3-8 cycloalkyl-C1-C6 alkyl groups such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl groups, etc.) ), cycloalkenylalkyl groups (e.g., cyclobutenylmethyl, cyclopentenylmethyl, cyclohexenylmethyl groups, etc., cycloalkenyl groups having 3 to 8 carbon atoms-alkyl groups having 1 to 6 carbon atoms, etc.), aryl groups (e.g., phenyl , aryl groups having 6 to 14 carbon atoms such as naphthyl group, etc.), arylalkyl groups (e.g., aryl groups having 6 to 14 carbon atoms such as benzyl and naphthylmethyl groups, alkyl groups having 1 to 6 carbon atoms, etc.), and the like. be done.
The “heterocyclic group” of the “optionally substituted heterocyclic group” represented by R ₂ and R ₃ includes pyridyl, pyrrolidinyl, piperazinyl, piperidinyl, 2-oxoazepinyl, furyl, decahydroisoquinolyl , quinolinyl, indolyl, isoquinolyl, thienyl, imidazolyl, morpholinyl, etc. 5- to 12-membered monocyclic containing 1 to 4 heteroatoms selected from 1 to 2 kinds of nitrogen atoms, sulfur atoms and oxygen atoms Alternatively, a condensed heterocyclic group and the like can be mentioned. Examples of substituents of the “optionally substituted hydrocarbon group” and “optionally substituted heterocyclic group” for R ₂ and R ₃ include halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), lower alkyl groups (e.g., alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl groups, etc.), lower alkenyl groups (e.g., vinyl, allyl groups, etc. having 2 carbon atoms) to 6 alkenyl groups, etc.), lower alkynyl groups (e.g., ethynyl, propargyl groups, etc., such as C2 to C6 alkynyl groups, etc.), cycloalkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl groups, etc., having carbon atoms such as 3 to 8 cycloalkyl groups, etc.), lower alkoxy groups (e.g., C 1 to 6 alkoxy groups such as methoxy and ethoxy groups, etc.), nitro groups, cyano groups, hydroxy groups, thiol groups, carboxyl groups, lower alkanoyl groups (e.g., formyl; C1-6 alkyl-carbonyl groups such as acetyl, propionyl, butyryl groups, etc.), lower alkanoyloxy groups (e.g., formyloxy; C1-6 groups such as acetyloxy, propionyloxy groups, etc.) alkyl-carbonyloxy group, etc.), lower alkoxycarbonyl group (e.g., alkoxy-carbonyl group having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl group, etc.), aralkyloxycarbonyl group (e.g., benzyloxycarbonyl aralkyloxy-carbonyl groups having 7 to 17 carbon atoms such as groups), aryl groups (e.g. aryl groups having 6 to 14 carbon atoms such as phenyl and naphthyl groups), aryloxy groups (e.g. phenyloxy, naphthyloxy aryloxy groups having 6 to 14 carbon atoms such as groups), arylcarbonyl groups (e.g., aryl-carbonyl groups having 6 to 14 carbon atoms such as benzoyl, naphthoyl groups, etc.), arylcarbonyloxy groups (e.g., benzoyloxy, an aryl-carbonyloxy group having 6 to 14 carbon atoms such as a naphthoyloxy group), a carbamoyl group optionally having a substituent (e.g., carbamoyl; a carbamoyl group mono- or di-substituted with an alkyl group, etc.), an amino group optionally having a substituent (e.g., amino; carbon such as methylamino, dimethylamino, ethylamino, diethylamino group an amino group mono-substituted or di-substituted with an alkyl group of numbers 1 to 6, etc.). There are no particular restrictions on the number and positions of substituents.
Examples of the ring formed by R ₂ and R ₃ together with adjacent nitrogen atoms include pyrrolidine, piperidine, homopiperidine, morpholine, piperazine, tetrahydroquinoline and tetrahydroisoquinoline.
The “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” represented by E, R, R ₁ and G above means that each of the above substituents is at a substitutable position of the hydrocarbon group. It may have 1 to 5, preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different.

The "heterocyclic group" of the "optionally substituted heterocyclic group" represented by E, R, and G includes, as atoms (ring atoms) constituting the ring system, an oxygen atom, a sulfur atom and 5- to 12-membered aromatic containing at least one (preferably 1 to 4, more preferably 1 to 3) heteroatoms (preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from nitrogen atoms, etc. heterocyclic groups, saturated or unsaturated non-aromatic heterocyclic groups, and the like. As described above, the "heterocyclic group" of the "heterocyclic group optionally having substituent(s)" represented by G includes, as a ring atom, a hetero atom selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like. A saturated oxygen-containing heterocyclic group containing 1 to 4, more preferably 1 to 3, is preferred, and a 5- to 12-membered saturated oxygen-containing heterocyclic group is particularly preferred.

The "aromatic heterocyclic group" includes an aromatic monocyclic heterocyclic group, an aromatic condensed heterocyclic group, and the like.
Examples of the "aromatic monocyclic heterocyclic group" include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1 ,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl , pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and other 5- to 6-membered aromatic monocyclic heterocyclic groups.
The "aromatic condensed heterocyclic group" includes, for example, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxa zolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, napthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ -carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl , imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4 8- to 12-membered aromatic condensed heterocyclic groups such as 1,2,4-triazolo[4,3-b]pyridazinyl (preferably the above-mentioned 5- to 6-membered aromatic monocyclic a heterocyclic ring in which the formula heterocyclic group is condensed with a benzene ring, or a heterocyclic ring in which two identical or different heterocyclic rings of the above-mentioned 5- to 6-membered aromatic monocyclic heterocyclic groups are condensed), and the like.

The "saturated or unsaturated non-aromatic heterocyclic group" includes, for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidinyl, tetrahydropyranyl, thianyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, 3- to 8-membered (preferably 5- to 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic groups (aliphatic group heterocyclic group) and the like. These may be optionally oxo-substituted, for example 2-oxoazetidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxoazepanyl, 2-oxoazocanyl, 2-oxotetrahydrofuryl, 2- oxotetrahydropyranyl, 2-oxothiolanyl, 2-oxothianyl, 2-oxopiperazinyl, 2-oxoxepanyl, 2-oxoxazepanyl, 2-oxothiepanyl, 2-oxothiazepanyl, 2-oxo oxocanyl, 2-oxothiocanyl, 2-oxooxazocanyl, 2-oxothiazocanyl and the like. Preferred are 5-membered non-aromatic heterocyclic groups such as 2-oxopyrrolidinyl.

Examples of substituents that the "heterocyclic group" of the "heterocyclic group _optionally having substituents" represented by E, R, and G above may have include: , the same as the “substituent” of the “hydrocarbon group optionally having substituent(s)” represented by G, and the like.
The "heterocyclic group" of the "heterocyclic group optionally having substituents" for E, R, and G each has 1 to 5 of the above substituents at substitutable positions of the heterocyclic group. , preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different.

The case where R is bonded to W in the compound of the present invention will be described. When R and W are bonded, the positions at which R and W are bonded are not particularly limited as long as they are bondable positions in R and W, respectively.
The bondable positions in R include the bondable positions in the “hydrocarbon group” and “substituent” of the “hydrocarbon group optionally having a substituent” defined for R above, and The positions at which the defined “heterocyclic group optionally having substituents” in the “heterocyclic group” and “substituent” can be attached.
As the bondable position in W, the bondable position in the "divalent chain hydrocarbon group" of the "divalent chain hydrocarbon group optionally having a substituent" defined for W above , the bondable position in the “divalent chain hydrocarbon group” defined by W ₁ and W ₂ above, and the “hydrocarbon ring optionally having a substituent” defined by the above Z ring Examples include the bondable position in the "hydrocarbon ring" and the bondable position in the "heterocyclic ring" of the "heterocyclic ring optionally having substituents" defined for the above Z ring.
R and W may be bonded at a mutually bondable position and together with adjacent nitrogen atoms may form a ring. Examples of the ring include saturated nitrogen-containing rings (e.g., azetidine, pyrrolidine, piperidine, homopiperidine, etc.), unsaturated nitrogen-containing rings (e.g., tetrahydropyridine, etc.), aromatic nitrogen-containing rings (e.g., pyrrole, etc.), Heterocyclic rings containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur in addition to the nitrogen atoms to which R and W are adjacent (e.g., piperazine, morpholine, etc.), condensed rings (e.g., indole, indoline) , isoindole, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, etc.). Among them, a 4- to 7-membered ring is preferred.
The ring formed by bonding R and W together at a mutually bondable position and forming together with the adjacent nitrogen atoms may have 1 to 4 substituents at the substitutable positions. When the number of substituents is 2 or more, each substituent may be the same or different. The substituents include the substituents of "optionally substituted hydrocarbon group" and "heterocyclic group optionally having substituents" defined by R, and " divalent chain hydrocarbon group optionally having a substituent". Specifically, halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-ethylpropyl, hexyl, etc. Substituents such as C _1-6 alkyl groups are included.

等が形成されるがこれらに限定されない。これらは、上記で定義するように置換基を有していてもよく、また、異性体を含み得ることは当業者に理解されるべきである。
本発明において、Ｘは、例えば、ハロゲン原子、ベンゾトリアゾリル基、（２，５−ジオキシピロリジン−1−イル）オキシ基等の脱離基を示し、中でもフッ素、塩素、臭素、ヨウ素等のハロゲン原子が好ましく、塩素が特に好ましい。 By combining R and W, for example,

etc. are formed, but are not limited to these. It should be understood by those skilled in the art that these may have substituents as defined above and may include isomers.
In the present invention, X represents, for example, a halogen atom, a benzotriazolyl group, a leaving group such as (2,5-dioxypyrrolidin-1-yl)oxy group, among which fluorine, chlorine, bromine, iodine, etc. is preferred, and chlorine is particularly preferred.

In the present invention, M represents a hydrogen atom, a metal cation or a quaternary ammonium ion.
The "metal cation" in the present invention includes alkali metal ions (eg, Na ⁺ , K ⁺ , Li ⁺ , Cs ⁺ , etc.), with Na ⁺ being preferred.
The "quaternary ammonium ion" in the present invention includes, for example, tetramethylammonium ion, tetraethylammonium ion, tetrapropylammonium ion, tetrabutylammonium ion, etc. Among them, tetrabutylammonium ion is preferred.

In compound (II), the acidic group in the molecule and an inorganic or organic base can form a pharmacologically acceptable base salt. can form pharmacologically acceptable acid addition salts.
Examples of inorganic base salts of compound (II) include salts with alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, etc.), ammonia and the like, and organic salts of compound (II). Examples of base salts include salts with dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, collidine and the like.

Acid addition salts of compound (II) include, for example, inorganic acid salts (e.g., hydrochlorides, sulfates, hydrobromides, phosphates, etc.), organic acid salts (e.g., acetates, trifluoroacetates, , succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.).
Compound (II) of the present invention includes hydrates. The "hydrate" includes 0.5-hydrate to 5.0-hydrate. Among these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, and 2.0 hydrate are preferred.

〔式中の記号は前記と同意義を示す〕で表わされる（Ｒ）体が好ましい。
化合物（ＩＩ）に含まれる好ましい化合物としては、具体的には例えば次のような化合物が挙げられる。 Compound (II) of the present invention includes racemates and optically active compounds. As the optically active compound, one enantiomer preferably has an enantiomeric excess (ee) of 90% or more, and more preferably has an enantiomeric excess of 99% or more. As an optically active substance, the general formula

The (R) form represented by [the symbols in the formula have the same meanings as defined above] is preferred.
Specific examples of preferred compounds included in compound (II) include the following compounds.

i.e.
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl acetate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl trimethyl acetate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl cyclohexanecarboxylate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl benzoate,
2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino ] ethyl benzoate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 4-methoxybenzoate, 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl 3-chlorobenzoate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 3,4-difluorobenzoate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 4-trifluoromethoxybenzoate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 4-fluorobenzoate, 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl] sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino]ethyl 3,4,5-trimethoxybenzoate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 2-pyridinecarboxylate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl methoxyacetate,
Ethyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate,
Isopropyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate,
Isopropyl 2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl] amino]ethyl carbonate,
benzyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl tetrahydropyran-4-yl carbonate,
2-Methoxyethyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethyl carbonate,
2-[ethyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl acetate,
2-[isopropyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl acetate,
Ethyl 2-[isopropyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate,
2-[cyclohexyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl acetate,
2-[cyclohexyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl ethyl carbonate,
2-[[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl] carbonyl](phenyl)amino]ethyl acetate,
2-[[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl ) amino]ethyl acetate,
tert-butyl [2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]-3-pyridyl]methyl carbonate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]benzyl acetate,
2-[[2-(acetyloxy)ethyl][[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]- 1H-benzimidazol-1-yl]carbonyl]amino]ethyl acetate,
[(2S)-1-[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole- 1-yl]carbonyl]-2-pyrrolidinyl]methyl acetate,
Ethyl [methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl] carbonyl]amino]acetate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl benzoate,
3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]propyl benzoate,
2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino ] ethyl tetrahydropyran-4-yl carbonate,
Ethyl 2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl] amino]ethyl carbonate,
Ethyl 2-[methyl[[(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate,
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl] carbonyl](methyl)amino]ethyl carbonate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl ](methyl)amino]ethyl acetate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl ](phenyl)amino]ethyl acetate,
4-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]butyl acetate,
Ethyl 4-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]butyl carbonate,
Ethyl 3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]propyl carbonate,
3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]propyl acetate,
3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]propane-1,2-diyl diacetate,
Diethyl 3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]propane-1,2-diyl biscarbonate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl ](methyl)amino]ethyl 3-chlorobenzoate,
2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino ] ethyl acetate,
2-ethoxyethyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethyl carbonate,
3-methoxypropyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethyl carbonate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl N,N-dimethylglycinate,
S-[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole- 1-yl]carbonyl]amino]ethyl]thioacetate,
Ethyl 2-[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethoxy]ethyl carbonate,
Ethyl 2-[methyl[[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H -benzimidazol-1-yl]carbonyl]amino]ethoxy]carbonyl]amino]ethyl carbonate,
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino] ethyl carbonate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate,
ethyl 2-[[[(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]( methyl)amino]ethyl carbonate,
Ethyl 2-[[[2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate,
2-[[[2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate ,
2-[[[5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl ethyl carbonate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 1-methylpiperidine-4-carboxylate,
2-[[4-(aminocarbonyl)phenyl][[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]- 1H-benzimidazol-1-yl]carbonyl]amino]ethyl acetate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 1-methyl-4-piperidinyl carbonate,
2-[[4-(aminocarbonyl)phenyl][[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethyl acetate,
(−)-ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridine- 3-yl]carbonyl](methyl)amino]ethyl carbonate and (+)-ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl ]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl](methyl)amino]ethyl carbonate and salts thereof.

Among others, the following compounds and salts thereof are preferred.
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl acetate,
Ethyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate,
2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl tetrahydropyran-4-yl carbonate,
2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino ] ethyl tetrahydropyran-4-yl carbonate,
Ethyl 2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl] amino]ethyl carbonate,
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl] carbonyl](methyl)amino]ethyl carbonate,
2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl ](methyl)amino]ethyl acetate,
2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino ] ethyl acetate,
Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino] ethyl carbonate,
ethyl 2-[[[(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]( methyl)amino]ethyl carbonate,
Ethyl 2-[[[2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate, and 2-[[[5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino ] ethyl ethyl carbonate.

Compound (II) can be produced by method A or B below.
(Method A)
Compound (II) or a salt thereof can be obtained by condensing compound (IV) or a salt thereof and compound (V) or a salt thereof in the presence or absence of a base. Salts of compound (IV) and salts of compound (V) include salts similar to the salts of compound (II) above. For example, inorganic acid salts (e.g., hydrochloride, sulfate, hydrobromide, phosphate, etc.), organic acid salts (e.g., acetate, trifluoroacetate, succinate, maleate, fumaric acid) salt, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.).

(式中の各記号は前記と同意義を示す。）
方法Ａにおける反応は一般に溶媒中で行われ、方法Ａの反応を阻害しない溶媒が適宜に選択される。このような溶媒としては、例えば、エーテル類（例えば、ジオキサン、テトラヒドロフラン、ジエチルエーテル、tert−ブチルメチルエーテル、ジイソプロピルエーテル、エチレングリコールジメチルエーテル等）、エステル類（例えば、ギ酸エチル、酢酸エチル、酢酸ブチル等）、ハロゲン化炭化水素類（例えば、ジクロロメタン、クロロホルム、四塩化炭素、トリクレン、１,２−ジクロロエタン等）、炭化水素類（例えば、ｎ−ヘキサン、ベンゼン、トルエン等）、アミド類（例えば、ホルムアミド、Ｎ,Ｎ−ジメチルホルムアミド、Ｎ,Ｎ−ジメチルアセトアミド等）、ケトン類（例えば、アセトン、メチルエチルケトン、メチルイソブチルケトン等）、ニトリル類（例えば、アセトニトリル、プロピオニトリル等）等の他、ジメチルスルホキシド、スルホラン、ヘキサメチルホスホルアミド、水等が挙げられ、これらは単独または混合溶媒として用いられる。これらの溶媒の使用量は、反応混合物を撹拌できる量であれば特に限定はなく、化合物（ＩＶ）またはその塩１モルに対して、通常２〜１００倍重量、好ましくは５〜５０倍重量である。

(Each symbol in the formula has the same meaning as above.)
The reaction in Method A is generally carried out in a solvent, and a solvent that does not interfere with the reaction in Method A is appropriately selected. Examples of such solvents include ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.), esters (e.g., ethyl formate, ethyl acetate, butyl acetate, etc.). ), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane, etc.), hydrocarbons (e.g., n-hexane, benzene, toluene, etc.), amides (e.g., formamide , N,N-dimethylformamide, N,N-dimethylacetamide, etc.), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), nitriles (e.g., acetonitrile, propionitrile, etc.), etc., as well as dimethyl sulfoxide , sulfolane, hexamethylphosphoramide, water, etc., and these may be used alone or as a mixed solvent. The amount of these solvents to be used is not particularly limited as long as the reaction mixture can be stirred, and is usually 2 to 100 times by weight, preferably 5 to 50 times by weight, relative to 1 mol of compound (IV) or a salt thereof. be.

The amount of compound (V) or a salt thereof to be used is generally 1 mol-10 mol, preferably 1 mol-3 mol, per 1 mol of compound (IV) or a salt thereof.
The reaction of Method A is generally carried out at a temperature range of 0°C to 100°C, preferably 20°C to 80°C.
The reaction time of method A varies depending on the type of compound (IV), (V) or salts thereof, solvent, reaction temperature, etc., but is usually 1 minute to 96 hours, preferably 1 minute to 72 hours, more preferably 15 minutes. ~24 hours.
Examples of bases for Method A include inorganic bases (e.g., sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, etc.), tertiary amines (e.g., triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 4-dimethylaminopyridine, etc.), alkylene oxides (e.g., propylene oxide, epichlorohydrin, etc.), etc. mentioned. The amount of the base to be used is generally 0.01 mol-10 mol, preferably 1 mol-3 mol, per 1 mol of compound (V) or a salt thereof.

（式中、各記号は前記と同義である）で表わされる化合物またはその塩にホスゲン、クロロギ酸トリクロロメチル、炭酸ビス（トリクロロメチル）、チオホスゲン等を作用させることにより得ることができる。あるいは、化合物（ＶＩＩ）またはその塩とクロロギ酸エチルを作用させることにより得られるエチルカルバメート体を、シンセティック コミュニケーションズ（ＳＧｎｔｈｅｔｉｃ Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ） 第１７巻、１８８７頁（１９８７年）に記載の方法またはこれに準じた方法に従い、オキシ塩化リンで処理することによっても得ることができる。化合物（ＶＩＩ）の塩としては、例えば、無機酸塩（例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸塩等）、有機酸塩（例えば、酢酸塩、トリフルオロ酢酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、プロピオン酸塩、クエン酸塩、酒石酸塩、乳酸塩、蓚酸塩、メタンスルホン酸塩、ｐ−トルエンスルホン酸塩等）等の酸付加塩等が挙げられる。 Compound (IV) or a salt thereof can be produced by the methods described in JP-A-61-50978, US Pat. No. 4,628,098 or similar methods.
Compound (V) or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, when X is a chlorine atom, formula (VII):

(wherein each symbol has the same meaning as above) or a salt thereof with phosgene, trichloromethyl chloroformate, bis(trichloromethyl)carbonate, thiophosgene or the like. Alternatively, the ethyl carbamate obtained by reacting compound (VII) or a salt thereof with ethyl chloroformate is treated with the method described in SGnthetic Communications, Vol. 17, p. 1887 (1987) or according to this method. It can also be obtained by treatment with phosphorus oxychloride according to the method. Salts of compound (VII) include, for example, inorganic acid salts (e.g., hydrochlorides, sulfates, hydrobromides, phosphates, etc.), organic acid salts (e.g., acetates, trifluoroacetates, succinates). acid addition salts such as acid salts, maleates, fumarates, propionates, citrates, tartrates, lactates, oxalates, methanesulfonates, p-toluenesulfonates, etc.) .

Examples of deacidifiers used herein include inorganic bases (e.g., sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, etc.), tertiary amines (e.g., triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, pyridine, lutidine, γ-collidine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, 4-dimethylaminopyridine, etc.).

（式中、Ｒ₄は水素原子あるいは窒素原子の保護基、他の記号は前記と同義である）で表わされる化合物またはその塩と、式（ＩＸ）：

（式中、各記号は前記と同義である）で表わされるカルボン酸もしくはチオン酸またはそれらの反応性誘導体（例えば、無水物、ハロゲン化物等）、あるいはそれらの塩とを縮合させた後、必要に応じて脱保護することにより得ることができる。化合物（ＶＩＩＩ）の塩としては、例えば、無機酸塩（例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸塩等）、有機酸塩（例えば、酢酸塩、トリフルオロ酢酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、プロピオン酸塩、クエン酸塩、酒石酸塩、乳酸塩、蓚酸塩、メタンスルホン酸塩、ｐ−トルエンスルホン酸塩等）等の酸付加塩等が挙げられる。
あるいは、Ｄ₁が結合手の場合は、適切な溶媒（例えば、酢酸エチル、テトラヒドロフラン、ジクロロメタン、Ｎ,Ｎ−ジメチルホルムアミド等）中、式（Ｘ）：

（式中、各記号は前記と同義である）で表わされるカルボン酸またはチオン酸もしくはそれらの反応性誘導体（例えば、無水物、ハロゲン化物等）、あるいはそれらの塩と、Ｇ−Ｄ₂−Ｈで表わされる化合物とを縮合させた後、必要に応じて脱保護することにより得ることができる。化合物（Ｘ）の塩としては、例えば、無機酸塩（例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸塩等）、有機酸塩（例えば、酢酸塩、トリフルオロ酢酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、プロピオン酸塩、クエン酸塩、酒石酸塩、乳酸塩、蓚酸塩、メタンスルホン酸塩、ｐ−トルエンスルホン酸塩等）等の酸付加塩、例えば、アルカリ金属（例えば、ナトリウム、カリウム等）、アルカリ土類金属（例えば、カルシウム等）、アンモニア等との塩等、及び例えば、ジメチルアミン、トリエチルアミン、ピペラジン、ピロリジン、ピペリジン、２−フェニルエチルアミン、ベンジルアミン、エタノールアミン、ジエタノールアミン、ピリジン、コリジン等との有機塩基塩等が挙げられる。 Compound (VII) or a salt thereof can be produced by a method known per se or a method analogous thereto. For example, when D ₁ is other than a bond, formula (VIII):

(wherein R ₄ is a protecting group for a hydrogen atom or a nitrogen atom, other symbols are as defined above) or a salt thereof, and formula (IX):

(where each symbol is as defined above) or a reactive derivative thereof (e.g., anhydride, halide, etc.) or a salt thereof, and then the necessary can be obtained by deprotection according to Salts of compound (VIII) include, for example, inorganic acid salts (e.g., hydrochlorides, sulfates, hydrobromides, phosphates, etc.), organic acid salts (e.g., acetates, trifluoroacetates, succinates). acid addition salts such as acid salts, maleates, fumarates, propionates, citrates, tartrates, lactates, oxalates, methanesulfonates, p-toluenesulfonates, etc.) .
Alternatively, when D ₁ is a bond, formula (X):

(wherein each symbol is as defined above) or a reactive derivative thereof (e.g., anhydride, halide, etc.) or a salt thereof, and G-D2 _- H It can be obtained by condensing with a compound represented by and optionally deprotecting. Salts of compound (X) include, for example, inorganic acid salts (e.g., hydrochlorides, sulfates, hydrobromides, phosphates, etc.), organic acid salts (e.g., acetates, trifluoroacetates, succinates, acid, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.); salts with metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, etc.), ammonia, etc.; Examples include organic base salts with ethanolamine, diethanolamine, pyridine, collidine and the like.

In formula (VIII) and formula (X), protective groups represented by _R4 include, for example, formyl group, _C1-6 alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl, etc.), benzyl group, tert-butyl Oxycarbonyl group, benzyloxycarbonyl group, allyloxycarbonyl group, _C7-10 aralkyl-carbonyl group (for example, benzylcarbonyl etc.), trityl group and the like are used. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, etc.), nitro groups, and the like.
As a method for removing these protecting groups, a method known per se or a method based thereon is used, and for example, a method using an acid, a base, reduction, ultraviolet light, palladium acetate, or the like is used.

（式中、各記号は前記と同義である）
方法Ｂにおける反応は、例えば、硝酸、過酸化水素、過酸類、過エステル、オゾン、四酸化二窒素、ヨードソベンゼン、Ｎ−ハロスクシンイミド、１−クロロベンゾトリアゾール、次亜塩素酸tert−ブチル、ジアザビシクロ[２．２．２]オクタン臭素錯体、メタ過ヨウ素酸ナトリウム、二酸化セレン、二酸化マンガン、クロム酸、硝酸セリウムアンモニウム、臭素、塩素、スルフリルクロライド、モノパーオキシフタル酸マグネシウム塩等の酸化剤を用いて行うことができる。酸化剤の使用量は、化合物（ＶＩ）またはその塩１モルに対して、通常０．５モル〜２モル、好ましくは０．８モル〜１．２モルである。上記過酸化水素や過酸類の酸化剤を用い、さらにバナジウムアセテート、酸化バナジウムアセチルアセトナート、チタンテトライソプロポキシド等の触媒存在下に酸化を行うこともできる。 (Method B)
Compound (II) or a salt thereof can be obtained by subjecting compound (VI) or a salt thereof to an oxidation reaction.

(In the formula, each symbol has the same meaning as above)
Reactions in Method B include, for example, nitric acid, hydrogen peroxide, peracids, peresters, ozone, dinitrogen tetroxide, iodosobenzene, N-halosuccinimide, 1-chlorobenzotriazole, tert-butyl hypochlorite, Oxidizing agents such as diazabicyclo[2.2.2]octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, ceric ammonium nitrate, bromine, chlorine, sulfuryl chloride, magnesium monoperoxyphthalate, etc. can be performed using The amount of the oxidizing agent to be used is generally 0.5 mol-2 mol, preferably 0.8 mol-1.2 mol, per 1 mol of compound (VI) or a salt thereof. Oxidation can also be carried out in the presence of a catalyst such as vanadium acetate, vanadium oxide acetylacetonate, titanium tetraisopropoxide, or the like, using an oxidizing agent such as hydrogen peroxide or peracids.

The reaction of method B is usually carried out in a solvent inert to the above oxidation reaction. Examples of the "inert solvent" include water, alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile , propionitrile, etc.), amides (e.g., formamide, N,N-dimethylformamide, etc.), ethers (e.g., diethyl ether, tert-butyl methyl ether, diisopropyl ether, dioxane, tetrahydrofuran, etc.), sulfoxides (e.g., , dimethylsulfoxide, etc.), and polar solvents (eg, sulfolane, hexamethylphosphoramide, etc.), which may be used singly or as a mixture of two or more thereof. The "inert solvent" is generally used in an amount of 1 to 100 times the weight of compound (VI) or a salt thereof.
The reaction temperature is generally -80°C to 80°C, preferably 0°C to 30°C.
The reaction time is generally 1 minute to 6 hours, preferably 15 minutes to 1 hour.

（式中、各記号は前記と同義である）で表される化合物を用い、方法Ａと同様の反応によって得ることができる。
化合物（ＸＩ）は、以下の文献に記載の方法またはそれに準じた方法に従って合成することができる：特開昭６１−５０９７８号、特開昭５４−１４１７８３号、特開昭６１−２２０７９号、特開平１−６２７０号、特開昭６３−１４６８８２号。 Compound (VI), which is the starting material for Method B, is, for example, the following formula (XI) instead of compound (IV):

(wherein each symbol has the same meaning as defined above), it can be obtained by the same reaction as in Method A.
Compound (XI) can be synthesized according to the methods described in the following documents or methods analogous thereto: JP-A-61-50978, JP-A-54-141783, JP-A-61-22079, JP-A-1-6270, JP-A-63-146882.

Salts of compound (VI) include the same salts as the salts of compound (II) above, such as inorganic acid salts (e.g., hydrochlorides, sulfates, hydrobromides, phosphates, etc.), Organic acid salts (e.g. acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p- acid addition salts such as toluenesulfonate, etc.).

Compound (II) or a salt thereof obtained in Method A or B above is subjected to a reaction by known separation means (e.g., concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, redissolution, chromatography, etc.). It can be isolated and purified from mixtures. In addition, since compound (II) or a salt thereof obtained by method A or B above includes all isomers thereof, compound (II) or a salt thereof is subjected to optical resolution, or compound (VI) or a salt thereof is An optically pure compound (II) or a salt thereof can be obtained by asymmetric oxidation of .
As a method for optical resolution, a method known per se can be used, for example, a fractional recrystallization method, a chiral column method, a diastereomer method, and the like are used. Asymmetric oxidation may be performed by a method known per se, such as the method described in WO96/02535.
As the "fractional recrystallization method", a racemate and an optically active compound [e.g., (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1 -phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.], separated by fractional recrystallization or the like, optionally subjected to a neutralization step, and free and a method for obtaining an optical isomer of

The "chiral column method" includes a method of subjecting a racemate or a salt thereof to a column for separating optical isomers (chiral column). For example, in the case of liquid chromatography, the racemate is added to a chiral column such as ENANTIO-OVM (manufactured by Toso Corporation) or Daicel's CHIRAL series, water, a buffer (e.g., phosphate buffer, etc.), an organic solvent (e.g., , hexane, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, triethylamine, etc.) or a mixed solvent thereof to separate optical isomers. For example, gas chromatography includes a separation method using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).

In the "diastereoisomer method", a mixture of diastereomers is obtained by reacting a racemate with an optically active reagent, and then one diastereomer is separated by conventional separation means (e.g., fractional recrystallization, chromatography, etc.). After obtaining the mer, it is subjected to a chemical reaction (e.g., acid hydrolysis, basic hydrolysis, hydrogenolysis, etc.) to cleave off the optically active reagent site, thereby obtaining the desired optical isomer. mentioned. Examples of the "optically active reagent" include optically active organic acids such as MTPA [α-methoxy-α-(trifluoromethyl)phenylacetic acid] and (-)-menthoxyacetic acid; -(Chloromethoxy)-1,3,3-trimethylbicyclo[2.2.1]heptane and other optically active alkoxymethyl halides.

で表わされるベンズイミダゾール化合物またはその塩も上記プロドラッグの具体例として挙げられる。
上記式（ＩＩＩ）において、Ｄは酸素原子又は結合手を、Ｑは置換基を有していてもよい炭化水素基を示す。 Further, the following general formula (III):

A benzimidazole compound represented by or a salt thereof is also included as a specific example of the prodrug.
In the above formula (III), D represents an oxygen atom or bond, and Q represents a hydrocarbon group which may have a substituent.

The “hydrocarbon group” of the “hydrocarbon group optionally having substituent(s)” represented by Q includes an aliphatic or aromatic hydrocarbon group, and the aliphatic hydrocarbon group as used herein is It means a saturated or unsaturated, linear, branched or cyclic hydrocarbon group. The hydrocarbon group is preferably a hydrocarbon group having 1 to 14 carbon atoms, such as a _C1-6 alkyl group, a _C2-6 alkenyl group, a _C2-6 alkynyl group, and a _C3-8 cycloalkyl group. , C _6-14 aryl groups, preferably C _1-6 alkyl groups, C _3-8 cycloalkyl groups and C _6-14 aryl groups, especially C _1-6 alkyl groups and C _3-8 cycloalkyl groups is more preferred.

The above-mentioned "alkyl group" is a linear or branched alkyl group, preferably an alkyl group having 1 to 6 carbon atoms ("C _1-6 alkyl group"), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2- Dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl and the like can be mentioned, and an alkyl group having 1 to 4 carbon atoms is more preferable. Among Q, methyl, ethyl, isopropyl and tert-butyl are preferred, and tert-butyl is particularly preferred.

The above-mentioned " _C2-6 alkenyl group" is a linear or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec- butenyl, tert-butenyl, n-pentenyl, isopentenyl, neopentenyl, 1-methylpropenyl, n-hexenyl, isohexenyl, 1,1-dimethylbutenyl, 2,2-dimethylbutenyl, 3,3-dimethylbutenyl Examples include thenyl, 3,3-dimethylpropenyl, 2-ethylbutenyl, etc. Alkenyl groups having 2 to 4 carbon atoms are preferred, and among these, vinyl, n-propenyl and isopropenyl are preferred.

The above-mentioned "C _2-6 alkynyl group" is a linear or branched alkynyl group having 2 to 6 carbon atoms, such as ethynyl, n-propynyl (1-propynyl), isopropynyl (2-propynyl ), n-butynyl, isobutynyl, sec-butynyl, tert-butynyl, n-pentynyl, isopentynyl, neopentynyl, 1-methylpropynyl, n-hexynyl, isohexynyl, 1,1-dimethylbutynyl, 2,2-dimethylbutynyl , 3,3-dimethylbutynyl, 3,3-dimethylpropynyl, 2-ethylbutynyl, etc., preferably an alkynyl group having 2 to 3 carbon atoms, with ethynyl, 1-propynyl and 2-propynyl being particularly preferred.

The above-mentioned " _C3-8 cycloalkyl group" is a linear or branched cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, and cycloalkyl groups having 5 to 7 carbon atoms are preferred, among which cyclopentyl, cyclohexyl and cycloheptyl are preferred, and cyclohexyl is particularly preferred.

The above-mentioned "aryl group" is a monocyclic or condensed polycyclic aromatic hydrocarbon group, preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms (" _C6-14 aryl group"). , for example, phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, preferably an aromatic hydrocarbon group having 6 to 10 carbon atoms, and particularly preferably phenyl for Q.

The above "hydrocarbon group" may be substituted, and examples of substituents include, for example, a C _6-14 aryl group, a hydroxyl group, a halogen, a C _1-6 alkoxy group optionally substituted with halogen, C _7-12 aralkyloxy group, C _1-5 alkoxy-carbonyl group, C _1-6 alkyl group optionally substituted with halogen, amino group optionally substituted with C _1-6 alkyl group, and the like. be done.

Examples of substituents in the "alkyl group optionally having substituent(s)" include aryl group, hydroxyl group, halogen, alkoxy group optionally substituted with 1 to 5 halogens, C _7-12 aralkyloxy groups, C _1-5 alkoxy-carbonyl groups, and the like. The number of substituents is 1-5, preferably 1-3.

Examples of substituents in the "optionally substituted aryl group" include halogen, an alkyl group optionally substituted with 1 to 5 halogens, an aryl group, a hydroxyl group, and 1 to 5 halogens. an alkoxy group optionally substituted with, a _C7-12 aralkyloxy group, a _C1-5 alkoxy-carbonyl group, and the like. The number of substituents is 1-5, preferably 1-3.

The above "C _1-6 alkyl group", "C _2-6 alkenyl group" and "C _2-6 alkynyl group" may be substituted, and examples of substituents include (i) C _6-14 aryl group, (ii) hydroxyl group, (iii) halogen, (iv) C _1-6 alkoxy group optionally substituted with halogen, (v) C _7-12 aralkyloxy group, (vi) C _1-5 alkoxy -carbonyl group, (vii) an acylamino group, (viii) an amino group optionally substituted with a _C1-6 alkyl group, and the like, among which (i) to (vii) are preferred. The number of substituents is 1-5, preferably 1-3.

The above "C _3-8 cycloalkyl group" and "C _6-14 aryl group" may be substituted, and examples of substituents include (i) a C _6-14 aryl group, (ii) a hydroxyl group, (iii) halogen, (iv) C _1-6 alkoxy group optionally substituted with halogen, (v) C _7-12 aralkyloxy group, (vi) C _1-5 alkoxy-carbonyl group, (vii) halogen and (viii) an amino group _optionally substituted with a _C1-6 alkyl group, among which (i) to (vii) are preferred. The number of substituents is 1-5, preferably 1-3.

In formula (III), Q is (i) a C _6-14 aryl group, (ii) a hydroxyl group, (iii) a halogen, (iv) a C _1-6 alkoxy group optionally substituted with halogen, (v) C a C _1-6 alkyl group optionally having a substituent selected from the group consisting of a _7-12 aralkyloxy group, (vi) a C _1-5 alkoxy-carbonyl group and (vii) an acylamino group, C _{2- 6} alkenyl group or C _2-6 alkynyl group, or
(i) C _6-14 aryl group, (ii) hydroxyl group, (iii) halogen, (iv) C _1-6 alkoxy group optionally substituted with halogen, (v) C _7-12 aralkyloxy group, ( _C3-8 cycloalkyl optionally having a substituent selected from the group consisting of vi) a _C1-5 alkoxy-carbonyl group and (vii) a _C1-6 alkyl group optionally substituted with halogen or a C _6-14 aryl group,

(1) (i) C _6-14 aryl group, (ii) hydroxyl group, (iii) halogen, (iv) C _1-6 alkoxy group optionally substituted with 1 to 5 halogens, (v) C a C _1-6 alkyl group optionally having 1 to 5 substituents selected from the group consisting of a _7-12 aralkyloxy group and (vi) a C _1-5 alkoxy-carbonyl group, or (2) ( i) halogen, (ii) a _C1-6 alkyl group optionally substituted with 1 to 5 halogens, (iii) a _C6-14 aryl group, (iv) a hydroxyl group, (v) 1 to 5 1 to 5 substituents selected from the group consisting of a C _1-6 alkoxy group optionally substituted with halogen, (vi) a C _7-12 aralkyloxy group and (vii) a C _1-5 alkoxy-carbonyl group It is more preferably a C _6-14 aryl group optionally having

(i) C _6-14 aryl group, (ii) hydroxyl group, (iii) halogen, (iv) C _1-6 alkoxy group optionally substituted with halogen, (v) C _7-12 aralkyloxy group, ( vi) a C _1-6 alkyl group optionally having a substituent selected from the group consisting of a C _1-5 alkoxy-carbonyl group and (vii) an acylamino group, or
(i) C _6-14 aryl group, (ii) hydroxyl group, (iii) halogen, (iv) C _1-6 alkoxy group optionally substituted with halogen, (v) C _7-12 aralkyloxy group, ( _C3-8 cycloalkyl optionally having a substituent selected from the group consisting of vi) a _C1-5 alkoxy-carbonyl group and (vii) a _C1-6 alkyl group optionally substituted with halogen or a C _6-14 aryl group,

Among them, Q is preferably a C _1-6 alkyl group optionally substituted with a C _6-14 aryl group or a C _6-14 aryl group, Q is a phenyl group, or methyl or tert-butyl is particularly preferred.

Compound (III) can form a pharmacologically acceptable base salt with an acidic group in the molecule and an inorganic or organic base, etc., and can form a base salt with a basic group in the molecule and an inorganic acid or an organic acid. can form pharmacologically acceptable acid addition salts.

As one preferred embodiment of the compound (III) of the present invention, D is a bond and Q is an optionally substituted alkyl group or an optionally substituted aryl group Certain compounds are mentioned.

Examples of inorganic base salts of compound (III) include salts with alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, etc.), ammonia and the like, and organic salts of compound (III). Examples of base salts include salts with dimethylamine, triethylamine, piperazine, pyrrolidine, piperidine, 2-phenylethylamine, benzylamine, ethanolamine, diethanolamine, pyridine, collidine and the like.

Acid addition salts of compound (III) include, for example, inorganic acid salts (e.g., hydrochlorides, sulfates, hydrobromides, phosphates, etc.), organic acid salts (e.g., acetates, trifluoroacetates, , succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.).

Compound (III) of the present invention includes hydrates. The "hydrate" includes 0.5-hydrate to 5.0-hydrate. Among these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate and 2.0 hydrate are preferred.

〔式中の記号は前記と同意義を示す〕で表わされる（Ｒ）体が好ましい。 Compound (III) of the present invention includes racemates and optically active compounds. The optically active compound preferably has an enantiomeric excess (ee) of 90% or more for one enantiomer, more preferably 99% or more enantiomeric excess. As an optically active substance, the general formula

The (R) form represented by [the symbols in the formula have the same meanings as defined above] is preferred.

Compound (III) can be produced by a method known per se, for example, by the method described in JP-A-2002-187890, WO 02/30920, or a method analogous thereto. The optically active compound (III) can be obtained by an optical resolution method (fractional recrystallization method, chiral column method, diastereomer method, method using microorganisms or enzymes, etc.), asymmetric oxidation, and the like. As PPIs of other benzimidazole-based compound derivatives, compounds described in WO03/27098 are also applicable to the present invention.

The amount of the active ingredients represented by the general formulas (I'), (I), (II) and (III) used in the present invention varies depending on the type of active ingredient and dosage. About 1% to about 60% by weight, preferably about 1% to about 50% by weight, more preferably about 8% to about 40% by weight, based on the total weight of the tablets or granules of the invention. When the active ingredient is a benzimidazole PPI, particularly lansoprazole, it is about 8% to about 40% by weight.

imidazole-based PPIs represented by formula (I') or (I) such as lansoprazole or its optically active forms (such as R forms), especially benzimidazole-based PPIs and imidazole-based derivatives represented by formulas (II) and (III) In the case of PPI-containing capsules, two or more types of tablets, granules, or granules with different release modes (e.g., relatively fast-release granules and slower two types of granules that release the active ingredient as a mixture) may be combined and filled. In addition, two or more layers of such two types of release controlling membranes may be laminated in each granule or fine granule. In addition to the tablets, granules or fine granules having a controlled-release coating of the present invention and the gastrointestinal-retentive gel-forming polymer, the core grains containing the active ingredient as described above are optionally coated with an intermediate coating, and then usually granules (preferably capsules ), or a preparation containing only tablets, granules or fine granules having the controlled release coating of the present invention and capsules containing a gel-forming polymer that retains in the gastrointestinal tract, and granules coated with ordinary enteric coating By co-administration, the blood concentration rises at an early stage and the drug effect begins to be exhibited, and thereafter the drug effect of the controlled-release granules manifests, making it possible to produce a preparation with a sustained drug effect. It should be noted that the capsule of the present invention may not necessarily contain a gel-forming polymer if the tablets (in this case, small tablets are preferred), granules or fine granules to be filled have sufficient release controllability. Controlled-release tablets, granules, fine granules, or the like alone, or controlled-release tablets, granules, fine granules, or the like, and enteric-coated fast-release granules, etc. may be combined into capsules. In the case of such a combination formulation or combination administration, preferably the blood concentration rises from an early stage and begins to exert its efficacy, reaching the initial maximum blood concentration, and then releasing the active ingredient from more controlled-release granules. It is possible to prepare a formulation that exhibits two peaks to reach the maximum blood concentration at the second time. The sustained-release preparation such as the sustained-release capsule of the present invention and the usual capsule that releases the active ingredient relatively quickly may be administered at the same time or after some time. A high blood concentration of the active ingredient can be maintained for a long time even by such combined administration.

Ordinary enteric-coated granules can be produced, for example, according to the method described in JP-A-63-301826. Furthermore, it is preferable to prepare a stabilized preparation according to the method described in JP-A-62-277322.
Further, sufficiently stabilized granules containing lansoprazole or its optically active substance at a higher concentration can be produced as follows. That is, using a known granulation method such as a tumbling granulation method (e.g., centrifugal tumbling granulation method), a fluidized bed granulation method, an agitation granulation method (e.g., a tumbling fluidized bed granulation method), , an intermediate coating layer formed on the active ingredient layer, and an enteric coating layer formed on the intermediate coating layer, wherein the active ingredient layer is about 10% by weight to about 40% by weight based on the total weight of the granule % of lansoprazole, etc. and a basic inorganic salt as a stabilizer, and granules having an average particle size of about 600 μm to about 2500 μm are produced.
Specifically, the main agent layer is coated with a powdery dusting agent containing imidazole-based PPI, a basic metal salt, an excipient, a disintegrant, etc. while spraying a binding liquid such as hydroxypropylcellulose onto core granules. obtained by the method of Examples of the core granules include Nonpareil, which is obtained by coating sucrose (75 parts by weight) with corn starch (25 parts by weight) by a method known per se, and spherical core granules using crystalline cellulose. Alternatively, the core granules themselves may be the above-described active ingredients. The average particle size of the core granules is generally 14-80 mesh.
The core includes spherical granules of sucrose and starch, spherical granules of crystalline cellulose, spherical granules of crystalline cellulose and lactose, and the like.
The ratio of the coating layer to the core can be selected within a range in which the dissolution of the active ingredient and the particle size of the granules can be controlled. from about 0.1 parts by weight to about 5 parts by weight.
Next, an intermediate coating layer is formed on the obtained main agent layer by a conventional method. For example, the intermediate coating layer component is diluted with purified water or the like and sprayed as a liquid for coating. At that time, it is preferable to carry out while spraying a binder such as hydroxypropyl cellulose. Examples of intermediate coating layer components include polymer bases such as low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (e.g., TC-5, etc.), polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, and hydroxyethylmethylcellulose. , sucrose [refined sucrose (pulverized (powdered sugar) or non-pulverized)], starch sugar such as cornstarch, lactose, honey and sugar alcohol (D-mannitol, erythritol, etc.) etc. In addition to this, excipients (eg, masking agents (titanium oxide, etc.), antistatic agents (titanium oxide, talc, etc.)) that are added as necessary for formulation may be added to the intermediate coating layer as appropriate. good.
The coating amount of the intermediate coating layer is generally about 0.02 to about 1.5 parts by weight, preferably about 0.05 to about 1 part by weight, per 1 part by weight of the granules containing the benzimidazole PPI. Department.
Furthermore, sufficiently stabilized granules containing a high concentration of lansoprazole or the like can be produced by forming an enteric coating layer on the intermediate coating layer by a conventional method. Examples of enteric coating layer components include cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, ethyl acrylate/methyl methacrylate/trimethylammonium ethyl methacrylate chloride copolymer ( Eudragit RS or RL, manufactured by Rohm), methyl methacrylate/ethyl acrylate copolymer (Eudragit NE30D, manufactured by Rohm), water-based enteric polymer bases such as carboxymethylethylcellulose and shellac, water-based materials such as carboxymethylethylcellulose and shellac Sustained-release bases such as enteric polymer bases, water-soluble polymers, triethyl citrate, polyethylene glycol (polyethylene glycol 6000 (trade name: Macrogol 6000, etc.)), acetylated monoglycerides, triacetin, castor oil, etc. A plasticizer is used. These may be used singly or in combination of two or more.
The coating amount of the enteric coating layer is about 10% to about 70% by weight, preferably about 10% to about 50% by weight, more preferably about 15% by weight, based on the total amount of the granules before the enteric coating. % to about 30% by weight.

In the case of tablets, for example, benzimidazole compounds, excipients, binders, disintegrants, lubricants, etc. are mixed and tablets are directly compressed, or granulated powder produced in the same manner as the above granules. should be tableted. As an alternative method, the granulated powder obtained by granulation may be used to form a two-layer tablet by a commercially available laminated tablet machine.

Among the preparations of the present invention, PPIs of imidazole compounds represented by general formula (I′) such as lansoprazole and optically active substances thereof as active ingredients, especially benzimidazole PPI compounds represented by general formula (I) and prodrug-type imidazole compound derivative PPI (especially the compounds represented by the above general formulas (II) and (III) and optically active substances thereof) have excellent antiulcer action, gastric acid It has secretion-suppressing action, mucosal-protecting action, anti-Helicobacter pylori action, etc., and has low toxicity, so it is useful as a medicine. In particular, since the imidazole compound represented by the above general formula (II) is stable to acid, it is not necessary to prepare an enteric-coated formulation when orally administered, which reduces the cost of enteric-coated formulation and also reduces the size of the formulation. This makes it easier for sick people with weak swallowing power, especially the elderly and small people, to take it. Moreover, since it is absorbed more rapidly than an enteric-coated preparation, the gastric acid secretion inhibitory action is rapidly exhibited, and since it is gradually converted into the original compound in vivo, it has a long-lasting effect and is useful as an anti-ulcer agent and the like. The PPI compound such as compound (I') or a salt thereof of the present invention has low toxicity, and can be used as such or in accordance with a method known per se to prepare pharmaceutical compositions such as tablets (sugar-coated tablets, (including film-coated tablets), powders, granules, capsules (including soft capsules), orally disintegrating tablets, liquids, injections, suppositories, sustained-release preparations, patches, etc., orally or parenterally It can be safely administered to various targets (eg, topically, rectally, intravenously, etc.).

The tablets, granules and granules of the present invention can be used in mammals (e.g. humans, monkeys, sheep, horses, dogs, cats, rabbits, rats, mice, etc.) for peptic ulcers (e.g. gastric ulcers, duodenal ulcers, anastomotic ulcers). ulcers, etc.), Zollinger-Ellison syndrome, gastritis, reflux esophagitis, gastroesophageal reflux disease (Symptomatic GERD), NUD (Non Ulcer Dyspepsia), gastric cancer ( including gastric cancer associated with promotion of interleukin-1β production due to interleukin-1 gene polymorphism), treatment and prevention of gastric MALT lymphoma, eradication of Helicobacter pylori, peptic ulcer, acute stress ulcer and hemorrhagic gastritis Suppression of upper gastrointestinal bleeding, upper gastrointestinal bleeding due to invasive stress (stress caused by major surgery requiring intensive care after surgery, cerebrovascular disease requiring intensive care, head injury, multiple organ failure, extensive burns) It can be administered orally for the purpose of suppressing , treatment and prevention of ulcers caused by nonsteroidal anti-inflammatory drugs, and treatment and prevention of gastric hyperacidity and ulcers caused by postoperative stress. For Helicobacter pylori eradication, the granules or capsules of the present invention may be used in combination with other active ingredients (eg, 1 to 3 active ingredients).

"Other active ingredients" include, for example, anti-Helicobacter pylori active substances, antibacterial agents such as imidazole compounds, quinolone compounds, and bismuth salts. In particular, pharmaceuticals obtained by combining the granules or capsules of the present invention with an antibacterial agent are preferred. Among these, combined use with anti-bacterial agents such as anti-Helicobacter pylori active substances and imidazole compounds is preferred. Examples of "anti-Helicobacter pylori active substance" include penicillin antibiotics (e.g., amoxicillin, benzylpenicillin, piperacillin, mecillinum, etc.), cephem antibiotics (e.g., cefixime, cefaclor, etc.), macrolide antibiotics (e.g., Examples include erythromycin antibiotics such as erythromycin and clarithromycin), tetracycline antibiotics (eg, tetracycline, minocycline, streptomycin, etc.), aminoglycoside antibiotics (eg, gentamicin, amikacin, etc.), imipenem, and the like. Among them, penicillin antibiotics, macrolide antibiotics and the like are preferable.

"Imidazole compounds" include, for example, metronidazole, miconazole and the like. "Bismuth salt" includes, for example, bismuth acetate, bismuth citrate and the like. Antibacterial agents of "quinolone compounds" are also preferred, and include, for example, ofloxacin, ciproxacin, and the like. In particular, for the eradication of Helicobacter pylori, the granules or capsules of the present invention are used in combination with a penicillin antibiotic (e.g., amoxicillin, etc.) and/or an erythromycin antibiotic (e.g., clarithromycin, etc.). It is preferable to use
For example, in the case of lansoprazole, capsules containing 15 mg of crystalline lansoprazole were often filled into No. 3 capsules, and capsules containing 30 mg of crystalline lansoprazole were often filled into No. 1 capsules. By blending inorganic salt stabilizers and adjusting the particle size of granules, granules containing an unexpectedly high concentration of active ingredients can be obtained without compromising the stability of the active ingredient or formulation. Capsules containing 15 mg can be downsized to No. 4 or No. 5 capsules, and capsules containing 30 mg can be downsized to No. 3 or No. 5 capsules.
Furthermore, for capsules containing 60 mg, No. 1 to No. 3 capsules can be used.
Also, in the case of the optically active form of lansoprazole, capsules Nos. 3 to 5, Nos. 2 to 4, and Nos. 1 to 3 can be used for capsules containing 30 mg, 40 mg, and 60 mg, respectively. .
For example, a capsule containing 60 mg of lansoprazole or lansoprazole R form is suitable for the treatment of acid hypersecretion, especially Zollinger-Ellison syndrome, because the miniaturized capsule containing a high concentration of the active ingredient is easy to swallow. is.

The daily dose varies depending on the severity of symptoms, age, sex, body weight, timing and interval of administration, type of active ingredient, etc., and is not particularly limited. On the other hand, when administered orally, it is about 0.5 to 1500 mg/day, preferably about 5 to 150 mg/day as an active ingredient. These benzimidazole-based or imidazole-based compound-containing preparations may be administered once or divided into 2 to 3 times a day.

In order to improve the stability of the solid preparation of the present invention during storage, transportation, etc., the form of packaging may also be stabilized. For example, the benzimidazole system of the present invention can be obtained by using packaging forms such as packaging that suppresses moisture or oxygen permeation, gas replacement packaging (that is, packaging that replaces with a gas other than oxygen), vacuum packaging, and oxygen scavenger packaging. Alternatively, it is possible to improve the stability of a capsule formulation containing an imidazole compound. By using such a packaging form, the amount of oxygen with which the solid preparation comes into direct contact is reduced, thereby improving the stability. In the case of enclosing an oxygen scavenger, the solid pharmaceutical preparation may be packaged with a material permeable to oxygen, and then newly packaged together with the packaged product.

Hereinafter, the present invention will be described in more detail based on Reference Examples, Synthesis Examples, Examples and Test Examples, but the present invention is not limited thereto.
Corn starch, hydroxypropyl cellulose (HPC-L), polyethylene glycol 6000, and titanium oxide used in the following formulation examples were those conforming to the Japanese Pharmacopoeia 14th Edition.
In the following reference examples and synthesis examples, room temperature means about 15 to 30°C.
¹ H-NMR was measured using Varian Gemini-200 or Mercury-300, using CDCl ₃ , DMSO-d ₆ , CD ₃ OD as solvents, chemical shift δ (ppm) from internal standard tetramethylsilane showed that.
Other symbols in this specification have the following meanings.
s: singlet d: doublet t: triplet q: quartet m: multiplet
br: Broad
bs: broad singlet
bm: broad multiplet J: coupling constant

Reference example 1

２−（メチルアミノ）エタノール（３０．０４ｇ）と酢酸エチル（９０ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（８７．３０ｇ）と酢酸エチル（１０ｍＬ）の混合物を滴下した。室温で２時間攪拌後、減圧濃縮した。残留物を酢酸エチル（１５０ｍＬ）に溶解し、水（１００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、標題化合物（６６．１９ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．４７（９Ｈ，ｓ），２．９２（３Ｈ，ｓ），３．４０（２Ｈ，ｔ，Ｊ＝５．１Ｈｚ），３．７２−３．８０（２Ｈ，ｍ）． tert-butyl 2-hydroxyethyl(methyl)carbamate

A mixture of di-tert-butyl dicarbonate (87.30 g) and ethyl acetate (10 mL) was added dropwise to a mixture of 2-(methylamino)ethanol (30.04 g) and ethyl acetate (90 mL) under ice cooling. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), washed with water (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (66.19 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.47 (9H, s), 2.92 (3H, s), 3.40 (2H, t, J = 5.1 Hz), 3.72-3.80 ( 2H, m).

Reference example 2

２−（メチルアミノ）エタノール（１．５０ｇ）と酢酸エチル（２０ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（４．３７ｇ）を添加した。氷冷下、１．５時間攪拌後、無水酢酸(２．０８ｍＬ)、ピリジン（１．７８ｍＬ）、４−ジメチルアミノピリジン（０．１２ｇ）を添加した。室温で２時間攪拌後、反応液に酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）、５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物に４Ｎ塩化水素−酢酸エチル溶液（２０ｍＬ）を加え、室温で２時間攪拌した。ジエチルエーテル（１０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（２．９３ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．０７（３Ｈ，ｓ），２．５３（３Ｈ，ｓ），３．１２−３．１７（２Ｈ，ｍ），４．２４−４．３０（２Ｈ，ｍ），９．２９（２Ｈ，ｂｒ）． 2-(methylamino)ethyl acetate hydrochloride

Di-tert-butyl dicarbonate (4.37 g) was added to a mixture of 2-(methylamino)ethanol (1.50 g) and ethyl acetate (20 mL) under ice cooling. After stirring for 1.5 hours under ice-cooling, acetic anhydride (2.08 mL), pyridine (1.78 mL) and 4-dimethylaminopyridine (0.12 g) were added. After stirring at room temperature for 2 hours, ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL). After drying over anhydrous magnesium sulfate, the extract was concentrated under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution (20 mL) was added to the residue, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (10 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (2.93 g) was obtained as a white solid.
1H ^- NMR (DMSO _- d6): 2.07 (3H, s), 2.53 (3H, s), 3.12-3.17 (2H, m), 4.24-4.30 ( 2H, m), 9.29 (2H, br).

Reference example 3

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（１５ｍＬ）の混合物にトリエチルアミン（１．６７ｍＬ）を添加した後、トリメチルアセチルクロリド(１．３５ｍＬ)と酢酸エチル（５ｍＬ）の混合物を滴下した。室温で２時間攪拌後、ピリジン（１．６２ｍＬ）を添加し、室温で終夜攪拌した。反応液に酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）、５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で２時間攪拌後、ジエチルエーテル（１０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（１．６５ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．１８（９Ｈ，ｓ），２．５６（３Ｈ，ｓ），３．１７（２Ｈ，ｔ，Ｊ＝１０．５Ｈｚ），４．２２−４．２８（２Ｈ，ｍ），９．１９（２Ｈ，ｂｒ）． 2-(Methylamino)ethyl trimethylacetate hydrochloride

After adding triethylamine (1.67 mL) to a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (15 mL), trimethylacetyl chloride (1. 35 mL) and ethyl acetate (5 mL) was added dropwise. After stirring for 2 hours at room temperature, pyridine (1.62 mL) was added and stirred overnight at room temperature. Ethyl acetate (50 mL) was added to the reaction solution, washed with water (50 mL), 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, diethyl ether (10 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (1.65 g) was obtained as a white solid.
1H ^- NMR (DMSO _- d6): 1.18 (9H, s), 2.56 (3H, s), 3.17 (2H, t, J = 10.5 Hz), 4.22-4. 28 (2H, m), 9.19 (2H, br).

Reference example 4

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（２０ｍＬ）の混合物にピリジン（０．９７ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加した後、シクロヘキサンカルボニルクロリド(１．６０ｍＬ)を滴下した。室温で２時間攪拌後、ピリジン（０．６５ｍＬ）、シクロヘキサンカルボニルクロリド（０．５８ｍＬ）を追加し、室温で終夜攪拌した。反応液に酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）、５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で２時間攪拌後、ジエチルエーテル（１０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（１．８８ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．１０−１．４５（５Ｈ，ｍ），１．５４−１．７３（３Ｈ，ｍ），１．８３−１．９３（２Ｈ，ｍ），２．２９−２．４２（１Ｈ，ｍ），２．５４（３Ｈ，ｓ），３．１２−３．１８（２Ｈ，ｍ），４．２３−４．２９（２Ｈ，ｍ），９．２３（２Ｈ，ｂｒ）． 2-(methylamino)ethyl cyclohexanecarboxylate hydrochloride

Pyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount) were added to a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL). After the addition, cyclohexanecarbonyl chloride (1.60 mL) was added dropwise. After stirring at room temperature for 2 hours, pyridine (0.65 mL) and cyclohexanecarbonyl chloride (0.58 mL) were added, and the mixture was stirred at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction solution, washed with water (50 mL), 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, diethyl ether (10 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (1.88 g) was obtained as a white solid.
1H ^- NMR (DMSO-d6): _1.10-1.45 (5H, m), 1.54-1.73 (3H, m), 1.83-1.93 (2H, m), 2.29-2.42 (1 H, m), 2.54 (3 H, s), 3.12-3.18 (2 H, m), 4.23-4.29 (2 H, m), 9. 23 (2H, br).

Reference example 5

２−（メチルアミノ）エタノール（３０．０４ｇ）と酢酸エチル（９０ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（８７．３０ｇ）と酢酸エチル（１０ｍＬ）の混合物を滴下した。室温で１時間攪拌後、塩化ベンゾイル(６１．８ｇ)、ピリジン（３８．８ｍＬ）を氷冷下添加した。室温で１時間攪拌後、固体を濾去した。固体を酢酸エチル（１００ｍＬ）で洗浄し、濾液と洗浄液を合わせ、水（１００ｍＬ）、飽和食塩水（１００ｍＬ）で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物を酢酸エチル（１００ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（２００ｍＬ）を加え、室温で３０分間攪拌した。ジエチルエーテル（１００ｍＬ）を添加後、固体を濾取した。酢酸エチル（１００ｍＬ）で２回洗浄した後、減圧下６０℃で乾燥し、標題化合物（５７．４ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．６２（３Ｈ，ｓ），３．３２（２Ｈ，ｍ），４．５３（２Ｈ，ｔ，Ｊ＝９．９Ｈｚ），７．５１−７．５７（２Ｈ，ｍ），７．６８（１Ｈ，ｍ），８．１１（２Ｈ，ｄ，Ｊ＝７．８Ｈｚ），９．２６（２Ｈ，ｂｓ）． 2-(methylamino)ethyl benzoate hydrochloride

A mixture of di-tert-butyl dicarbonate (87.30 g) and ethyl acetate (10 mL) was added dropwise to a mixture of 2-(methylamino)ethanol (30.04 g) and ethyl acetate (90 mL) under ice cooling. After stirring at room temperature for 1 hour, benzoyl chloride (61.8 g) and pyridine (38.8 mL) were added under ice cooling. After stirring for 1 hour at room temperature, the solid was filtered off. The solid was washed with ethyl acetate (100 mL), the filtrate and washings were combined, and washed with water (100 mL) and saturated brine (100 mL). After drying over anhydrous magnesium sulfate, the extract was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), 4N hydrogen chloride-ethyl acetate solution (200 mL) was added, and the mixture was stirred at room temperature for 30 minutes. After adding diethyl ether (100 mL), the solid was collected by filtration. After washing twice with ethyl acetate (100 mL), it was dried at 60° C. under reduced pressure to give the title compound (57.4 g) as a white solid.
1H ^- NMR (DMSO _- d6): 2.62 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J = 9.9 Hz), 7.51-7. 57 (2H, m), 7.68 (1 H, m), 8.11 (2H, d, J=7.8 Hz), 9.26 (2H, bs).

Reference example 6

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（１０ｍＬ）の混合物に４−メトキシベンゾイルクロリド(１．８８ｇ)、ピリジン（０．９７ｍＬ）を添加した。室温で１４時間攪拌後、４−メトキシベンゾイルクロリド(０．７０ｇ)、ピリジン（０．９７ｍＬ）を追加し、室温で１時間攪拌した。反応液に酢酸エチル（８０ｍＬ）を加え、水（２０ｍＬ）、飽和炭酸水素ナトリウム水溶液（２０ｍＬ）、水（２０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を酢酸エチル（１０ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で１時間攪拌後、ジエチルエーテル（２０ｍＬ）を添加して、析出した固体を濾取した。酢酸エチル（１５ｍＬ）で２回洗浄した後、減圧下６０℃で乾燥し、標題化合物（１．９９ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．６２（３Ｈ，ｓ），３．３２（２Ｈ，ｍ），４．４８（２Ｈ，ｔ，Ｊ＝５．０Ｈｚ），７．０７（２Ｈ，ｄ，Ｊ＝８．７Ｈｚ），８．０６（２Ｈ，ｄ，Ｊ＝８．７Ｈｚ），９．０４（２Ｈ，ｂｓ）． 2-(methylamino)ethyl 4-methoxybenzoate hydrochloride

A mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) was added with 4-methoxybenzoyl chloride (1.88 g) and pyridine (0.97 mL). was added. After stirring at room temperature for 14 hours, 4-methoxybenzoyl chloride (0.70 g) and pyridine (0.97 mL) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (80 mL) was added to the reaction solution, washed with water (20 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), and 4N hydrogen chloride-ethyl acetate solution (10 mL) was added. After stirring at room temperature for 1 hour, diethyl ether (20 mL) was added and the precipitated solid was collected by filtration. After washing twice with ethyl acetate (15 mL), it was dried at 60°C under reduced pressure to give the title compound (1.99 g) as a white solid.
1H ^- NMR (DMSO _- d6): 2.62 (3H, s), 3.32 (2H, m), 4.48 (2H, t, J = 5.0 Hz), 7.07 (2H, d, J = 8.7 Hz), 8.06 (2H, d, J = 8.7 Hz), 9.04 (2H, bs).

Reference example 7

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（１０ｍＬ）の混合物に３−クロロベンゾイルクロリド(１．９２ｇ)、ピリジン（０．９７ｍＬ）を添加した。室温で１時間攪拌後、６０℃で６時間攪拌した。反応液に酢酸エチル（８０ｍＬ）を加え、水（２０ｍＬ）、飽和炭酸水素ナトリウム水溶液（２０ｍＬ）、水（２０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で２２時間攪拌後、ジエチルエーテル（１５ｍＬ）を添加して、析出した固体を濾取した。酢酸エチル（１５ｍＬ）で２回洗浄した後、減圧下６０℃で乾燥し、標題化合物（２．０１ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．６３（３Ｈ，ｓ），３．３２（２Ｈ，ｍ），４．５３（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．６０（１Ｈ，ｔ，Ｊ＝８．０Ｈｚ），７．７８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．０５（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．１５（１Ｈ，ｓ），９．０７（２Ｈ，ｂｓ）． 2-(methylamino)ethyl 3-chlorobenzoate hydrochloride

A mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) was added with 3-chlorobenzoyl chloride (1.92 g) and pyridine (0.97 mL). was added. After stirring at room temperature for 1 hour, the mixture was stirred at 60° C. for 6 hours. Ethyl acetate (80 mL) was added to the reaction solution, washed with water (20 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 22 hours, diethyl ether (15 mL) was added and the precipitated solid was collected by filtration. After washing twice with ethyl acetate (15 mL), it was dried at 60° C. under reduced pressure to give the title compound (2.01 g) as a white solid.
1H ^- NMR (DMSO _- d6): 2.63 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J = 4.9 Hz), 7.60 (1H, t, J = 8.0 Hz), 7.78 (1H, d, J = 8.0 Hz), 8.05 (1H, d, J = 8.0 Hz), 8.15 (1H, s), 9. 07 (2H, bs).

Reference example 8

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（１０ｍＬ）の混合物に３，４−ジフルオロベンゾイルクロリド(１．７７ｇ)、ピリジン（０．９７ｍＬ）を添加した。室温で３日間攪拌後、反応液に酢酸エチル（８０ｍＬ）を加え、水（２０ｍＬ）、飽和炭酸水素ナトリウム水溶液（２０ｍＬ）、水（２０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で４時間攪拌後、減圧濃縮した。残留物を酢酸エチル（１５ｍＬ）で洗浄後、減圧下６０℃で乾燥し、標題化合物（２．０５ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．６２（３Ｈ，ｓ），３．３２（２Ｈ，ｍ），４．５３（２Ｈ，ｔ，Ｊ＝５．０Ｈｚ），７．６４（１Ｈ，ｍ），８．００（１Ｈ，ｍ），８．２５（１Ｈ，ｍ），９．２５（２Ｈ，ｂｓ）． 2-(methylamino)ethyl 3,4-difluorobenzoate hydrochloride

A mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) was added with 3,4-difluorobenzoyl chloride (1.77 g) and pyridine (0.7 g). 97 mL) was added. After stirring at room temperature for 3 days, ethyl acetate (80 mL) was added to the reaction mixture, washed with water (20 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate (15 mL) and dried at 60°C under reduced pressure to give the title compound (2.05 g) as a white solid.
1H ^- NMR (DMSO _- d6): 2.62 (3H, s), 3.32 (2H, m), 4.53 (2H, t, J = 5.0 Hz), 7.64 (1H, m), 8.00 (1 H, m), 8.25 (1 H, m), 9.25 (2 H, bs).

Reference example 9

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．３０ｇ）と酢酸エチル（１０ｍＬ）の混合物に４−トリフルオロメトキシベンゾイルクロリド(１．８３ｇ)、ピリジン（０．７２ｍＬ）を添加した。６０℃で２５時間攪拌した。反応液に酢酸エチル（６０ｍＬ）を加え、水（３０ｍＬ）、飽和炭酸水素ナトリウム水溶液（２０ｍＬ）、水（２０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で１４．５時間攪拌後、減圧濃縮した。残留物を酢酸エチル（１５ｍＬ）で２回洗浄した後、減圧下６０℃で乾燥し、標題化合物（１．８３ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．６３（３Ｈ，ｓ），３．３１（２Ｈ，ｍ），４．５４（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．５５（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），８．２４（２Ｈ，ｄ，Ｊ＝８．５Ｈｚ），９．０２（２Ｈ，ｂｓ）． 2-(methylamino)ethyl 4-trifluoromethoxybenzoate hydrochloride

A mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.30 g) obtained in Reference Example 1 and ethyl acetate (10 mL) was added with 4-trifluoromethoxybenzoyl chloride (1.83 g) and pyridine (0. 72 mL) was added. Stirred at 60° C. for 25 hours. Ethyl acetate (60 mL) was added to the reaction solution, washed with water (30 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 14.5 hours, the mixture was concentrated under reduced pressure. The residue was washed twice with ethyl acetate (15 mL) and dried at 60°C under reduced pressure to give the title compound (1.83 g) as a white solid.
1H ^- NMR (DMSO _- d6): 2.63 (3H, s), 3.31 (2H, m), 4.54 (2H, t, J = 4.9 Hz), 7.55 (2H, d, J = 8.5 Hz), 8.24 (2H, d, J = 8.5 Hz), 9.02 (2H, bs).

Reference example 10

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（１０ｍＬ）の混合物に４−フルオロベンゾイルクロリド(１．７４ｇ)、ピリジン（０．９７ｍＬ）を添加した。室温で６．５時間攪拌した。反応液に酢酸エチル（８０ｍＬ）を加え、水（３０ｍＬ）、飽和炭酸水素ナトリウム水溶液（３０ｍＬ）、水（３０ｍＬ）、飽和食塩水（３０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で１時間攪拌後、析出した固体を濾取した。酢酸エチル（１５ｍＬ）で２回洗浄した後、減圧下６０℃で乾燥し、標題化合物（１．８９ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．６２（３Ｈ，ｓ），３．３２（２Ｈ，ｍ），４．５２（２Ｈ，ｔ，Ｊ＝４．９Ｈｚ），７．３４−７．４４（２Ｈ，ｍ），８．１６−８．２４（２Ｈ，ｍ），９．１８（２Ｈ，ｂｓ）． 2-(methylamino)ethyl 4-fluorobenzoate hydrochloride

A mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) was added with 4-fluorobenzoyl chloride (1.74 g) and pyridine (0.97 mL). was added. Stir at room temperature for 6.5 hours. Ethyl acetate (80 mL) was added to the reaction solution, washed with water (30 mL), saturated aqueous sodium hydrogencarbonate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 1 hour, the precipitated solid was collected by filtration. After washing twice with ethyl acetate (15 mL), it was dried at 60°C under reduced pressure to give the title compound (1.89 g) as a white solid.
1H ^- NMR (DMSO _- d6): 2.62 (3H, s), 3.32 (2H, m), 4.52 (2H, t, J = 4.9 Hz), 7.34-7. 44 (2H, m), 8.16-8.24 (2H, m), 9.18 (2H, bs).

Reference example 11

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（１０ｍＬ）の混合物に３，４，５−トリメトキシベンゾイルクロリド(２．５４ｇ)、ピリジン（０．９７ｍＬ）を添加した。６０℃で１４時間攪拌後、３，４，５−トリメトキシベンゾイルクロリド(１．３０ｇ)、ピリジン（０．９７ｍＬ）、酢酸エチル（１０ｍＬ）を追加し、６０℃で２４時間攪拌した。反応液を濾過し、濾液に酢酸エチル（５０ｍＬ）、水（３０ｍＬ）を添加した。分液後、酢酸エチル層を１Ｎ塩酸（３０ｍＬ）、水（３０ｍＬ）、硫酸銅（ＩＩ）水溶液（３０ｍＬ）、水（３０ｍＬ）、飽和食塩水（３０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１で溶出）で精製した。精製物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で４時間攪拌後、減圧濃縮した。トルエン（１０ｍＬ）を加え、減圧濃縮した。残留物を酢酸エチルに懸濁させ、固体を濾取した。酢酸エチル（１５ｍＬ）で洗浄した後、減圧下乾燥し、標題化合物（１．７９ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．６１（３Ｈ，ｓ），３．２８−３．３５（２Ｈ，ｍ），３．７４（３Ｈ，ｓ），３．８７（６Ｈ，ｓ），４．４８−４．５４（２Ｈ，ｍ），７．４０（２Ｈ，ｓ），９．４３（２Ｈ，ｂｒ）． 2-(methylamino)ethyl 3,4,5-trimethoxybenzoate hydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL) was added 3,4,5-trimethoxybenzoyl chloride (2.54 g) and pyridine. (0.97 mL) was added. After stirring at 60°C for 14 hours, 3,4,5-trimethoxybenzoyl chloride (1.30 g), pyridine (0.97 mL) and ethyl acetate (10 mL) were added, and the mixture was stirred at 60°C for 24 hours. The reaction solution was filtered, and ethyl acetate (50 mL) and water (30 mL) were added to the filtrate. After liquid separation, the ethyl acetate layer was washed with 1N hydrochloric acid (30 mL), water (30 mL), copper (II) sulfate aqueous solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. . After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:1). A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the purified product. After stirring at room temperature for 4 hours, the mixture was concentrated under reduced pressure. Toluene (10 mL) was added and concentrated under reduced pressure. The residue was suspended in ethyl acetate and the solid was collected by filtration. After washing with ethyl acetate (15 mL), it was dried under reduced pressure to give the title compound (1.79 g) as a white solid.
1H ^- NMR (DMSO _- d6): 2.61 (3H, s), 3.28-3.35 (2H, m), 3.74 (3H, s), 3.87 (6H, s) , 4.48-4.54 (2H, m), 7.40 (2H, s), 9.43 (2H, br).

Reference example 12

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）、２−ピリジンカルボニルクロリド塩酸塩（２．６７ｇ）、ピリジン（１．２１ｍＬ）及び４−ジメチルアミノピリジン（０．１２２ｇ）のテトラヒドロフラン溶液（１００ｍＬ）に、氷冷下、トリエチルアミン（２．０９ｍＬ）を滴下し、室温で６時間攪拌した。反応液に水（２００ｍＬ）を加え酢酸エチル（１５０ｍＬ）で抽出した。有機層を５％硫酸銅（ＩＩ）水溶液（１００ｍＬ）、水（１００ｍＬ）及び飽和食塩水（１００ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥後、減圧留去した。残留物を酢酸エチル（５０ｍＬ）、エタノール（１００ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（１５ｍＬ）を加え、室温で１時間攪拌した。析出した固体を濾取し、酢酸エチル（１００ｍＬ）で２回洗浄した後、減圧下６０℃で乾燥し、標題化合物（１．０８ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．６２（３Ｈ，ｔ，Ｊ＝５．４Ｈｚ），３．３５（２Ｈ，ｍ），４．６３（２Ｈ，ｔ，Ｊ＝５．０Ｈｚ），５．２６（１Ｈ，ｂｓ），７．７７−７．８４（１Ｈ，ｍ），８．１４−８．１８（１Ｈ，ｍ），８．３６−８．４０（１Ｈ，ｍ），８．７０−８．９０（１Ｈ，ｍ），９．４８（２Ｈ，ｂｒ）． 2-(Methylamino)ethyl 2-pyridinecarboxylate dihydrochloride

tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1, 2-pyridinecarbonyl chloride hydrochloride (2.67 g), pyridine (1.21 mL) and 4-dimethylaminopyridine (0.122 g) in tetrahydrofuran (100 mL) was added dropwise with triethylamine (2.09 mL) under ice cooling, and the mixture was stirred at room temperature for 6 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed successively with 5% copper (II) sulfate aqueous solution (100 mL), water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and ethanol (100 mL), 4N hydrogen chloride-ethyl acetate solution (15 mL) was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed twice with ethyl acetate (100 mL), and dried at 60°C under reduced pressure to give the title compound (1.08 g) as a white solid.
1H ^- NMR (DMSO _- d6): 2.62 (3H, t, J = 5.4 Hz), 3.35 (2H, m), 4.63 (2H, t, J = 5.0 Hz), 5.26 (1 H, bs), 7.77-7.84 (1 H, m), 8.14-8.18 (1 H, m), 8.36-8.40 (1 H, m), 8. 70-8.90 (1H, m), 9.48 (2H, br).

Reference example 13

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（１０ｍＬ）の混合物にメトキシアセチルクロリド(１．２０ｇ)、ピリジン（０．９７ｍＬ）を添加した。室温で３時間攪拌後、反応液に酢酸エチル（７０ｍＬ）を加え、水（２０ｍＬ）、飽和炭酸水素ナトリウム水溶液（２０ｍＬ）、水（２０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を酢酸エチル（５ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で１時間攪拌後、減圧濃縮した。残留物に水（６０ｍＬ）とジエチルエーテル（３０ｍＬ）を加え、攪拌した後、水層を分取した。水層を炭酸水素ナトリウムで塩基性にした後、酢酸エチル（４０ｍＬ）で２回抽出した。酢酸エチル層を無水硫酸マグネシウムで乾燥後、減圧濃縮し、標題化合物（１．００ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．４０（１Ｈ，ｂｓ），３．０６（３Ｈ，ｓ），３．４４（３Ｈ，ｓ），３．５７（２Ｈ，ｔ，Ｊ＝５．１Ｈｚ），３．７５−３．８２（２Ｈ，ｍ），４．１３（２Ｈ，ｓ）． 2-(methylamino)ethyl methoxyacetate

Methoxyacetyl chloride (1.20 g) and pyridine (0.97 mL) were added to a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (10 mL). did. After stirring at room temperature for 3 hours, ethyl acetate (70 mL) was added to the reaction mixture, washed with water (20 mL), saturated aqueous sodium hydrogencarbonate solution (20 mL) and water (20 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (5 mL), and 4N hydrogen chloride-ethyl acetate solution (10 mL) was added. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. Water (60 mL) and diethyl ether (30 mL) were added to the residue, and after stirring, the aqueous layer was separated. The aqueous layer was basified with sodium bicarbonate and then extracted twice with ethyl acetate (40 mL). The ethyl acetate layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (1.00 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 2.40 (1H, bs), 3.06 (3H, s), 3.44 (3H, s), 3.57 (2H, t, J = 5.1 Hz) , 3.75-3.82 (2H, m), 4.13 (2H, s).

Reference example 14

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（２０ｍＬ）の混合物にピリジン（０．９７ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加した後、クロロ炭酸エチル(１．２５ｍＬ)を滴下した。室温で終夜攪拌した後、酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）、５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で２時間攪拌後、ジエチルエーテル（１０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（１．６６ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２３（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），２．５４（３Ｈ，ｓ），３．１６−３．２２（２Ｈ，ｍ），４．１５（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），４．３２−４．３７（２Ｈ，ｍ），９．２５（２Ｈ，ｂｒ）． Ethyl 2-(methylamino)ethyl carbonate hydrochloride

Pyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount) were added to a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL). After the addition, ethyl chlorocarbonate (1.25 mL) was added dropwise. After stirring overnight at room temperature, ethyl acetate (50 mL) was added, washed with water (50 mL), 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, diethyl ether (10 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (1.66 g) was obtained as a white solid.
@ ¹ H-NMR (DMSO _- d6): 1.23 (3H, t, J=7.1 Hz), 2.54 (3H, s), 3.16-3.22 (2H, m), 4. 15 (2H, q, J=7.1 Hz), 4.32-4.37 (2H, m), 9.25 (2H, br).

Reference example 15

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（３．５０ｇ）と酢酸エチル（２０ｍＬ）の混合物に氷冷下、クロロ炭酸イソプロピル(１．３５ｇ)、ピリジン（１．９４ｍＬ）を添加した。氷冷下、３．５時間攪拌後、クロロ炭酸イソプロピル（１．８４ｇ）を追加し、室温で２．５時間攪拌した。反応液に酢酸エチル（１２０ｍＬ）を加え、水（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で２時間攪拌後、析出した固体を濾取した。酢酸エチル（１５ｍＬ）で洗浄した後、減圧下６０℃で乾燥し、標題化合物（１．３８ｇ）を白色固体として得た。¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２５（６Ｈ，ｄ，Ｊ＝６．２Ｈｚ），２．５６（３Ｈ，ｓ），３．２０（２Ｈ，ｔ，Ｊ＝５．１Ｈｚ），４．３２（２Ｈ，ｔ，Ｊ＝５．１Ｈｚ），４．８０（１Ｈ，ｍ），８．９５（２Ｈ，ｂｓ）． Isopropyl 2-(methylamino)ethyl carbonate hydrochloride

To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (3.50 g) obtained in Reference Example 1 and ethyl acetate (20 mL) was added isopropyl chlorocarbonate (1.35 g) and pyridine (1.35 g) under ice cooling. 94 mL) was added. After stirring for 3.5 hours under ice-cooling, isopropyl chlorocarbonate (1.84 g) was added, and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate (120 mL) was added to the reaction solution, washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, the precipitated solid was collected by filtration. After washing with ethyl acetate (15 mL), it was dried at 60° C. under reduced pressure to give the title compound (1.38 g) as a white solid. 1H ^- NMR (DMSO _- d6): 1.25 (6H, d, J = 6.2 Hz), 2.56 (3H, s), 3.20 (2H, t, J = 5.1 Hz), 4.32 (2H, t, J=5.1Hz), 4.80 (1H, m), 8.95 (2H, bs).

Reference example 16

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（２０ｍＬ）の混合物にピリジン（０．９７ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加した後、クロロ炭酸ベンジル(１．５７ｍＬ)を滴下した。室温で２時間攪拌後、ピリジン（０．６５ｍＬ）、クロロ炭酸ベンジル（１．２８ｍＬ）を追加した。室温で５日間攪拌後、氷冷下、ピリジン（０．８１ｍＬ）を追加し、さらにクロロ炭酸ベンジル（１．４３ｍＬ）の酢酸エチル溶液（５ｍＬ）をゆっくり滴下した。室温で２時間攪拌後、酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）、５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加した。室温で２時間攪拌後、ジエチルエーテル（１０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（１．９９ｇ）を白色固体として得た。¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．５５（３Ｈ，ｓ），３．２１（２Ｈ，ｔ，Ｊ＝５．１Ｈｚ），４．３７（２Ｈ，ｔ，Ｊ＝５．１Ｈｚ），５．１８（２Ｈ，ｓ），７．３０−７．５０（５Ｈ，ｍ），９．０７（２Ｈ，ｂｒ）． Benzyl 2-(methylamino)ethyl carbonate hydrochloride

Pyridine (0.97 mL) and 4-dimethylaminopyridine (catalytic amount) were added to a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL). After the addition, benzyl chlorocarbonate (1.57 mL) was added dropwise. After stirring at room temperature for 2 hours, pyridine (0.65 mL) and benzyl chlorocarbonate (1.28 mL) were added. After stirring at room temperature for 5 days, pyridine (0.81 mL) was added under ice-cooling, and an ethyl acetate solution (5 mL) of benzyl chlorocarbonate (1.43 mL) was slowly added dropwise. After stirring at room temperature for 2 hours, ethyl acetate (50 mL) was added, washed with water (50 mL), 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue. After stirring at room temperature for 2 hours, diethyl ether (10 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (1.99 g) was obtained as a white solid. 1H ^- NMR (DMSO _- d6): 2.55 (3H, s), 3.21 (2H, t, J = 5.1 Hz), 4.37 (2H, t, J = 5.1 Hz), 5.18 (2H, s), 7.30-7.50 (5H, m), 9.07 (2H, br).

Reference example 17

炭酸ビス（トリクロロメチル）（２．９７ｇ）のテトラヒドロフラン溶液（４０ｍＬ）に氷冷下、ピリジン（２．４３ｍＬ）のテトラヒドロフラン溶液（１０ｍＬ）を滴下した。氷冷下、１０分間攪拌後、テトラヒドロピラン−４−オール（１．９１ｇ）のテトラヒドロフラン溶液（２０ｍＬ）をゆっくり滴下した。室温で２時間攪拌後、減圧濃縮し、残留物に酢酸エチル（５０ｍＬ）と水（５０ｍＬ）を加えた。酢酸エチル層を分取し、０．２Ｎ塩酸（２０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮して、クロロ炭酸テトラヒドロピラン−４−イル（１．５３ｇ）を得た。参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．４０ｇ）とテトラヒドロフラン（２０ｍＬ）の混合物にピリジン（０．７８ｍＬ）を添加した後、上記で得られたクロロ炭酸テトラヒドロピラン−４−イル（１．５３ｇ）のテトラヒドロフラン溶液（１０ｍＬ）を滴下し、室温で終夜攪拌した。反応液を減圧濃縮後、水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝４：１、続いて３：２で溶出）で精製した。得られた無色油状物（２．０３ｇ）をジエチルエーテル（２ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（５ｍＬ）を添加した。室温で３０分間攪拌後、ジエチルエーテル（１０ｍＬ）を添加して、終夜攪拌した。析出した固体を濾取し、減圧下乾燥して、標題化合物（１．２０ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．５０−１．６５（２Ｈ，ｍ），１．８７−１．９８（２Ｈ，ｍ），２．５４（３Ｈ，ｓ），３．２０（２Ｈ，ｍ），３．４０−３．５０（２Ｈ，ｍ），３．７４−３．８３（２Ｈ，ｍ），４．３６（２Ｈ，ｔ，Ｊ＝５．１Ｈｚ），４．７２−４．８３（１Ｈ，ｍ），９．３２（２Ｈ，ｂｒ）． 2-(methylamino)ethyl tetrahydropyran-4-yl carbonate hydrochloride

A tetrahydrofuran solution (10 mL) of pyridine (2.43 mL) was added dropwise to a tetrahydrofuran solution (40 mL) of bis(trichloromethyl) carbonate (2.97 g) under ice-cooling. After stirring for 10 minutes under ice-cooling, a tetrahydrofuran solution (20 mL) of tetrahydropyran-4-ol (1.91 g) was slowly added dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure, and ethyl acetate (50 mL) and water (50 mL) were added to the residue. The ethyl acetate layer was separated, washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave tetrahydropyran-4-yl chlorocarbonate (1.53 g). After adding pyridine (0.78 mL) to a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.40 g) obtained in Reference Example 1 and tetrahydrofuran (20 mL), the chlorocarbonic acid obtained above A tetrahydrofuran solution (10 mL) of tetrahydropyran-4-yl (1.53 g) was added dropwise, and the mixture was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The extract was washed with 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=4:1, then eluted with 3:2). The obtained colorless oil (2.03 g) was dissolved in diethyl ether (2 mL), and 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring for 30 minutes at room temperature, diethyl ether (10 mL) was added and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.20 g) as a white solid.
1H ^- NMR (DMSO-d6): _1.50-1.65 (2H, m), 1.87-1.98 (2H, m), 2.54 (3H, s), 3.20 ( 2H, m), 3.40-3.50 (2H, m), 3.74-3.83 (2H, m), 4.36 (2H, t, J = 5.1 Hz), 4.72- 4.83 (1H, m), 9.32 (2H, br).

Reference example 18

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）と酢酸エチル（２０ｍＬ）の混合物にピリジン（１．６２ｍＬ）を添加した後、クロロ炭酸２−メトキシエチル（２．７７ｇ）の酢酸エチル溶液（５ｍＬ）をゆっくり滴下し、室温で終夜攪拌した。反応液を減圧濃縮後、水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をジエチルエーテル（２ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（５ｍＬ）を添加した。室温で３０分間攪拌後、ジエチルエーテル（１０ｍＬ）を添加して、終夜攪拌した。析出した固体を濾取し、減圧下乾燥して、標題化合物（１．５６ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．５４（３Ｈ，ｓ），３．１９（２Ｈ，ｍ），３．２６（３Ｈ，ｓ），３．５２−３．５７（２Ｈ，ｍ），４．２０−４．２５（２Ｈ，ｍ），４．３３−４．３９（２Ｈ，ｍ），９．２６（２Ｈ，ｂｒ）． 2-Methoxyethyl 2-(methylamino)ethyl carbonate hydrochloride

After adding pyridine (1.62 mL) to a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1 and ethyl acetate (20 mL), 2-methoxyethyl chlorocarbonate (2.77 g) in ethyl acetate (5 mL) was slowly added dropwise and stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The extract was washed with 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in diethyl ether (2 mL), and 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring for 30 minutes at room temperature, diethyl ether (10 mL) was added and stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.56 g) as a white solid.
1H ^- NMR (DMSO _- d6): 2.54 (3H, s), 3.19 (2H, m), 3.26 (3H, s), 3.52-3.57 (2H, m) , 4.20-4.25 (2H, m), 4.33-4.39 (2H, m), 9.26 (2H, br).

Reference example 19

２−（エチルアミノ）エタノール（８．９１ｇ）と酢酸エチル（１００ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（２１．８ｇ）を添加した。室温で３日間攪拌後、飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、標題化合物（１９．０ｇ）を無色油状物として得た。¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．１１（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），１．４７（９Ｈ，ｓ），３．２７（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），３．３７（２Ｈ，ｔ，Ｊ＝５．２Ｈｚ），３．７３（２Ｈ，ｑ，Ｊ＝５．２Ｈｚ）． tert-butyl ethyl(2-hydroxyethyl)carbamate

Di-tert-butyl dicarbonate (21.8 g) was added to a mixture of 2-(ethylamino)ethanol (8.91 g) and ethyl acetate (100 mL) under ice cooling. After stirring at room temperature for 3 days, the mixture was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (19.0 g) as a colorless oil. @ ¹ H-NMR ( _CDCl3 ): 1.11 (3H, t, J=7.0 Hz), 1.47 (9 H, s), 3.27 (2H, q, J=7.0 Hz), 3. 37 (2H, t, J=5.2 Hz), 3.73 (2H, q, J=5.2 Hz).

Reference example 20

参考例１９で得られたエチル（２−ヒドロキシエチル）カルバミン酸ｔｅｒｔ−ブチル（１．８９ｇ）と酢酸エチル（２０ｍＬ）の混合物に無水酢酸(１．０４ｍＬ)、ピリジン（０．８９ｍＬ）、４−ジメチルアミノピリジン（０．０６１ｇ）を添加した。室温で３時間攪拌後、酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）、５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を加え、室温で１時間攪拌した。酢酸エチル（１０ｍＬ）、ジエチルエーテル（２０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（１．５４ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２２（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），２．０７（３Ｈ，ｓ），２．９５（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ），３．１５（２Ｈ，ｔ，Ｊ＝５．３Ｈｚ），４．２４−４．３０（２Ｈ，ｍ），９．１７（２Ｈ，ｂｒ）． 2-(ethylamino)ethyl acetate hydrochloride

Acetic anhydride (1.04 mL), pyridine (0.89 mL), 4- Dimethylaminopyridine (0.061 g) was added. After stirring at room temperature for 3 hours, ethyl acetate (50 mL) was added, and the mixture was washed with water (50 mL), 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL). After drying over anhydrous magnesium sulfate, the extract was concentrated under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (10 mL) and diethyl ether (20 mL) were added, and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (1.54 g) was obtained as a white solid.
1H ^- NMR (DMSO _- d6): 1.22 (3H, t, J = 7.3 Hz), 2.07 (3H, s), 2.95 (2H, q, J = 7.3 Hz), 3.15 (2H, t, J=5.3 Hz), 4.24-4.30 (2H, m), 9.17 (2H, br).

Reference example 21

２−（イソプロピルアミノ）エタノール（１０．０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に、二炭酸ジ−ｔｅｒｔ−ブチル（２２．２ｇ）を加え、室温で１時間撹拌した。反応液を減圧濃縮した後、残留物に水（１００ｍＬ）を加え、酢酸エチル（２００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮することで、標題化合物（２１．２１ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．１２（６Ｈ，ｄ，Ｊ＝６．６Ｈｚ），３．３０（２Ｈ，ｔ，Ｊ＝５．０Ｈｚ），３．７１（２Ｈ，ｔ，Ｊ＝５．０Ｈｚ），３．８０−４．３０（１Ｈ，ｍ）． tert-butyl 2-hydroxyethyl(isopropyl)carbamate

Di-tert-butyl dicarbonate (22.2 g) was added to a tetrahydrofuran solution (30 mL) of 2-(isopropylamino)ethanol (10.0 g), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (200 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (21.21 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.12 (6H, d, J = 6.6 Hz), 3.30 (2H, t, J = 5.0 Hz), 3.71 (2H, t, J = 5 .0 Hz), 3.80-4.30 (1 H, m).

Reference example 22

参考例２１で得られた２−ヒドロキシエチル（イソプロピル）カルバミン酸ｔｅｒｔ−ブチル（５．０ｇ）のテトラヒドロフラン溶液（１５ｍＬ）にピリジン（６．０ｍＬ）と無水酢酸（２．７９ｍＬ）を加え室温で１８時間撹拌した。反応液を減圧濃縮した後、残留物に水（５０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた無色油状物を４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）に溶解し、室温で１時間撹拌した。析出した固体を濾取し、減圧下乾燥することで、標題化合物（３．１４ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２５（６Ｈ，ｄ，Ｊ＝６．６Ｈｚ），２．０８（３Ｈ，ｓ），３．１０−３．４０（３Ｈ，ｍ），４．２９（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），９．１１（２Ｈ，ｂｒ）． 2-(isopropylamino)ethyl acetate hydrochloride

Pyridine (6.0 mL) and acetic anhydride (2.79 mL) were added to a tetrahydrofuran solution (15 mL) of tert-butyl 2-hydroxyethyl(isopropyl)carbamate (5.0 g) obtained in Reference Example 21, and the mixture was stirred at room temperature for 18 hours. Stirred for an hour. After the reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting colorless oil was dissolved in 4N hydrogen chloride-ethyl acetate solution (10 mL) and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (3.14 g) as a colorless solid.
@ ¹ H-NMR (DMSO-d6): 1.25 (6H, d, J= _6.6 Hz), 2.08 (3H, s), 3.10-3.40 (3H, m), 4. 29 (2H, t, J=6.0 Hz), 9.11 (2H, br).

Reference example 23

参考例２１で得られた２−ヒドロキシエチル（イソプロピル）カルバミン酸ｔｅｒｔ−ブチル（５．０ｇ）のテトラヒドロフラン溶液（１５ｍＬ）にピリジン（６．０ｍＬ）とクロロ炭酸エチル（２．８１ｍＬ）を加え室温で１８時間撹拌した。反応液を減圧濃縮した後、残留物に水（５０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた無色油状物を４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）に溶解し、室温で１時間撹拌した。析出した固体を濾取し、減圧下乾燥することで、標題化合物（３．３４ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２０−１．３０（９Ｈ，ｍ），３．１０−３．４０（３Ｈ，ｍ），４．１７（２Ｈ，ｑ，Ｊ＝７．４Ｈｚ），４．３７（２Ｈ，ｔ，Ｊ＝５．６Ｈｚ），９．１３（２Ｈ，ｂｒ）． Ethyl 2-(isopropylamino)ethyl carbonate hydrochloride

Pyridine (6.0 mL) and ethyl chlorocarbonate (2.81 mL) were added to a tetrahydrofuran solution (15 mL) of tert-butyl 2-hydroxyethyl(isopropyl)carbamate (5.0 g) obtained in Reference Example 21, and the mixture was stirred at room temperature. Stirred for 18 hours. After the reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting colorless oil was dissolved in 4N hydrogen chloride-ethyl acetate solution (10 mL) and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (3.34 g) as a colorless solid.
1H ^- NMR (DMSO _- d6): 1.20-1.30 (9H, m), 3.10-3.40 (3H, m), 4.17 (2H, q, J = 7.4 Hz ), 4.37 (2H, t, J=5.6 Hz), 9.13 (2H, br).

Reference example 24

２−（シクロヘキシルアミノ）エタノール（１４．３ｇ）のエタノール溶液（２００ｍＬ）に、二炭酸ジ−ｔｅｒｔ−ブチル（２１．８ｇ）を滴下した。室温で２日間攪拌後、減圧濃縮した。残留物を酢酸エチル（２００ｍＬ）に溶解し、水（１００ｍＬ）及び飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、標題化合物（２４．２ｇ）を無色油状物として得た。¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２６−１．３９（４Ｈ，ｍ），１．４７（９Ｈ，ｓ），１．６１−１．８１（６Ｈ，ｍ），３．３０−３．４０（２Ｈ，ｍ），３．６９（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），３．６６−３．９０（２Ｈ，ｂｒ）． tert-butyl cyclohexyl(2-hydroxyethyl)carbamate

Di-tert-butyl dicarbonate (21.8 g) was added dropwise to an ethanol solution (200 mL) of 2-(cyclohexylamino)ethanol (14.3 g). After stirring at room temperature for 2 days, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (24.2 g) as a colorless oil. < ¹ >H-NMR ( _CDCl3 ): 1.26-1.39 (4H, m), 1.47 (9H, s), 1.61-1.81 (6H, m), 3.30-3. 40 (2H, m), 3.69 (2H, t, J=5.4 Hz), 3.66-3.90 (2H, br).

Reference example 25

参考例２４で得られたシクロヘキシル（２−ヒドロキシエチル）カルバミン酸ｔｅｒｔ−ブチル（２．４３ｇ）のテトラヒドロフラン溶液（５０ｍＬ）に氷冷下、ピリジン（１．０５ｍＬ）、無水酢酸（１．２３ｍＬ）及び４−ジメチルアミノピリジン（０．１２２ｇ）を加え、室温で１２時間攪拌した。反応液に酢酸エチル（１００ｍＬ）を加え、飽和炭酸水素ナトリウム水溶液（１００ｍＬ）、５％硫酸銅（ＩＩ）水溶液（１００ｍＬ）及び飽和食塩水（１００ｍＬ）で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を酢酸エチル（１５ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（１５ｍＬ）を添加した。室温で３時間攪拌後、ジイソプロピルエーテル（２０ｍＬ）を加え、析出した固体を濾取することにより、標題化合物（１．７８ｇ）を白色固体として得た。¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．０５−２．０３（１０Ｈ，ｍ），２．０７（３Ｈ，ｓ），２．９０−３．１０（１Ｈ，ｍ），３．１７（２Ｈ，ｔ，Ｊ＝５．２Ｈｚ），４．２９（２Ｈ，ｔ，Ｊ＝５．２Ｈｚ），９．１９（２Ｈ，ｂｒ）． 2-(Cyclohexylamino)ethyl acetate hydrochloride

To a tetrahydrofuran solution (50 mL) of tert-butyl cyclohexyl(2-hydroxyethyl)carbamate (2.43 g) obtained in Reference Example 24 was added pyridine (1.05 mL), acetic anhydride (1.23 mL) and 4-dimethylaminopyridine (0.122 g) was added and stirred at room temperature for 12 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with saturated aqueous sodium hydrogencarbonate solution (100 mL), 5% aqueous copper(II) sulfate solution (100 mL) and saturated brine (100 mL) in that order, and dried over anhydrous sodium sulfate. Concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), and 4N hydrogen chloride-ethyl acetate solution (15 mL) was added. After stirring at room temperature for 3 hours, diisopropyl ether (20 mL) was added, and the precipitated solid was collected by filtration to give the title compound (1.78 g) as a white solid. 1H ^- NMR (DMSO-d6): _1.05-2.03 (10H, m), 2.07 (3H, s), 2.90-3.10 (1H, m), 3.17 ( 2H, t, J = 5.2 Hz), 4.29 (2H, t, J = 5.2 Hz), 9.19 (2H, br).

Reference example 26

参考例２４で得られたシクロヘキシル（２−ヒドロキシエチル）カルバミン酸ｔｅｒｔ−ブチル（２．４３ｇ）のテトラヒドロフラン溶液（５０ｍＬ）に氷冷下、ピリジン（１．４５ｍＬ）、クロロ炭酸エチル（１．７１ｍＬ）及び４−ジメチルアミノピリジン（０．１２２ｇ）を加え、室温で１５時間攪拌した。反応液に酢酸エチル（１００ｍＬ）を加え、飽和炭酸水素ナトリウム水溶液（１００ｍＬ）、５％硫酸銅（ＩＩ）水溶液（１００ｍＬ）、水（１００ｍＬ）及び飽和食塩水（１００ｍＬ）で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を酢酸エチル（１５ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（１５ｍＬ）を添加した。室温で３時間攪拌後、ジイソプロピルエーテル（２０ｍＬ）を加え、析出した固体を濾取することにより、標題化合物（２．１２ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．０１−２．０８（１０Ｈ，ｍ），１．２３（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），２．９０−３．１０（１Ｈ，ｍ），３．２１（２Ｈ，ｔ，Ｊ＝５．２Ｈｚ），４．１６（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），４．３９（２Ｈ，ｔ，Ｊ＝５．２Ｈｚ），９．２７（２Ｈ，ｂｒ）． 2-(Cyclohexylamino)ethyl ethyl carbonate hydrochloride

To a tetrahydrofuran solution (50 mL) of tert-butyl cyclohexyl(2-hydroxyethyl)carbamate (2.43 g) obtained in Reference Example 24 was added pyridine (1.45 mL) and ethyl chlorocarbonate (1.71 mL) under ice-cooling. and 4-dimethylaminopyridine (0.122 g) were added and stirred at room temperature for 15 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution (100 mL), 5% aqueous copper (II) sulfate solution (100 mL), water (100 mL) and saturated brine (100 mL), followed by anhydrous sulfuric acid. Dried over sodium and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), and 4N hydrogen chloride-ethyl acetate solution (15 mL) was added. After stirring at room temperature for 3 hours, diisopropyl ether (20 mL) was added, and the precipitated solid was collected by filtration to give the title compound (2.12 g) as a white solid.
1H ^- NMR (DMSO-d6): _1.01-2.08 (10H, m), 1.23 (3H, t, J = 7.0 Hz), 2.90-3.10 (1H, m ), 3.21 (2H, t, J = 5.2 Hz), 4.16 (2H, q, J = 7.0 Hz), 4.39 (2H, t, J = 5.2 Hz), 9.27 (2H, br).

Reference example 27

２−アニリノエタノール（１３７ｇ）のテトラヒドロフラン溶液（７００ｍＬ）に氷冷下でピリジン（９７．１ｍＬ）、無水酢酸（１１３．２ｍＬ）及び４−ジメチルアミノピリジン（１２．２２ｇ）を加え、室温で２０時間攪拌した。反応液に酢酸エチル（１Ｌ）を加え、水（１Ｌ）、飽和炭酸水素ナトリウム水溶液（１Ｌ）、５％硫酸銅（ＩＩ）水溶液（１Ｌ）及び飽和食塩水（１Ｌ）で順次洗浄後、無水硫酸ナトリウムで乾燥し、減圧留去した。得られた残留物の酢酸エチル（７００ｍＬ）溶液に氷冷下、４Ｎ塩化水素−酢酸エチル溶液（２５０ｍＬ）を加え、析出した固体を濾取することにより、標題化合物（１５６ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤ₃ＯＤ）：２．１１（３Ｈ，ｓ），３．７１−３．７６（２Ｈ，ｍ），４．３２−４．３７（２Ｈ，ｍ），７．４９−７．６４（５Ｈ，ｍ）． 2-anilinoethyl acetate hydrochloride

Pyridine (97.1 mL), acetic anhydride (113.2 mL) and 4-dimethylaminopyridine (12.22 g) were added to a tetrahydrofuran solution (700 mL) of 2-anilinoethanol (137 g) under ice-cooling. Stirred for hours. Ethyl acetate (1 L) was added to the reaction solution, washed with water (1 L), saturated aqueous sodium hydrogencarbonate solution (1 L), 5% copper(II) sulfate aqueous solution (1 L) and saturated brine (1 L), followed by anhydrous sulfuric acid. Dry over sodium and evaporate under reduced pressure. To a solution of the obtained residue in ethyl acetate (700 mL) was added 4N hydrogen chloride-ethyl acetate solution (250 mL) under ice-cooling, and the precipitated solid was collected by filtration to give the title compound (156 g) as a white solid. rice field.
1H ^- NMR ( _CD3OD ): 2.11 (3H, s), 3.71-3.76 (2H, m), 4.32-4.37 (2H, m), 7.49-7 .64(5H, m).

Reference example 28

［２−（メチルアミノ）−３−ピリジル］メタノール（２ｇ：ＷＯ ０１／３２６５２に記載の方法で合成）のテトラヒドロフラン溶液（５０ｍＬ）に二炭酸ジ−ｔｅｒｔ−ブチル（３．４８ｇ）及び４−ジメチルアミノピリジン（０．１８ｇ）を加え、１時間還流した。反応液に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出し、得られた有機層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮して得た残留物をフラッシュシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：５で溶出）で精製することにより、標題化合物（１．５１ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．４９（９Ｈ，ｓ），３．０２（３Ｈ，ｄ，Ｊ＝４．８Ｈｚ），４．９９（２Ｈ，ｓ），５．００（１Ｈ，ｂｓ），６．５５（１Ｈ，ｄｄ，Ｊ＝７．０，５．０Ｈｚ），７．３７（１Ｈ，ｄｄ，Ｊ＝７．０，１．８Ｈｚ），８．１６（１Ｈ，ｄｄ，Ｊ＝５．０，１．８Ｈｚ）． tert-butyl [2-(methylamino)-3-pyridyl]methyl carbonate

Di-tert-butyl dicarbonate (3.48 g) and 4-dimethyl dicarbonate (3.48 g) were added to a tetrahydrofuran solution (50 mL) of [2-(methylamino)-3-pyridyl]methanol (2 g; synthesized as described in WO 01/32652). Aminopyridine (0.18 g) was added and refluxed for 1 hour. Water (30 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (50 mL), and the resulting organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by flash silica gel column chromatography (eluted with ethyl acetate:hexane=1:5) to give the title compound (1.51 g) as a white solid.
1H ^- NMR ( _CDCl3 ): 1.49 (9H, s), 3.02 (3H, d, J=4.8Hz), 4.99 (2H, s), 5.00 (1H, bs) , 6.55 (1H, dd, J=7.0, 5.0 Hz), 7.37 (1H, dd, J=7.0, 1.8 Hz), 8.16 (1H, dd, J=5 .0, 1.8 Hz).

Reference example 29

［２−（メチルアミノ）フェニル］メタノール（１．３７ｇ：ＷＯ ０１／３２６５２に記載の方法で合成）のテトラヒドロフラン溶液（５０ｍＬ）にピリジン（１．０５ｍＬ）、無水酢酸（１．２３ｍＬ）及び４−ジメチルアミノピリジン（０．１８ｇ）を加え、室温で８時間攪拌した。反応液に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。有機層を５％硫酸銅（ＩＩ）水溶液（５０ｍＬ）、飽和炭酸水素ナトリウム水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で順次洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。得られた残留物をフラッシュシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：５、続いて１：３で溶出）で精製することにより、標題化合物（０．３８ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．０８（３Ｈ，ｓ），２．８７（３Ｈ，ｓ），４．４０（１Ｈ，ｂｒ），５．０８（２Ｈ，ｓ），６．６４−６．７４（２Ｈ，ｍ），７．１７−７．３２（２Ｈ，ｍ）． 2-(methylamino)benzyl acetate

To a tetrahydrofuran solution (50 mL) of [2-(methylamino)phenyl]methanol (1.37 g; synthesized by the method described in WO 01/32652) was added pyridine (1.05 mL), acetic anhydride (1.23 mL) and 4- Dimethylaminopyridine (0.18 g) was added and stirred at room temperature for 8 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with 5% aqueous copper (II) sulfate solution (50 mL), saturated aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL) in that order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by flash silica gel column chromatography (eluted with ethyl acetate:hexane=1:5, then 1:3) to give the title compound (0.38 g) as a white solid.
< ¹ >H-NMR ( _CDCl3 ): 2.08 (3H, s), 2.87 (3H, s), 4.40 (1H, br), 5.08 (2H, s), 6.64-6 .74 (2H, m), 7.17-7.32 (2H, m).

Reference example 30

２，２'−イミノジエタノール（２．１０ｇ）と酢酸エチル（２０ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（４．３７ｇ）を添加した。氷冷下、１．５時間攪拌後、無水酢酸(２．０８ｍＬ)、ピリジン（１．７８ｍＬ）、４−ジメチルアミノピリジン（０．１２ｇ）を添加した。室温で２時間攪拌後、反応液に酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）、５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物に４Ｎ塩化水素−酢酸エチル溶液（２０ｍＬ）を加え、室温で２時間攪拌した。ジエチルエーテル（１０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（６．１８ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．０７（６Ｈ，ｓ），３．２３（４Ｈ，ｔ，Ｊ＝５．３Ｈｚ），４．２７−４．３３（４Ｈ，ｍ），９．４０（２Ｈ，ｂｒ）． 2-[(2-acetyloxyethyl)amino]ethyl acetate hydrochloride

Di-tert-butyl dicarbonate (4.37 g) was added to a mixture of 2,2′-iminodiethanol (2.10 g) and ethyl acetate (20 mL) under ice-cooling. After stirring for 1.5 hours under ice-cooling, acetic anhydride (2.08 mL), pyridine (1.78 mL) and 4-dimethylaminopyridine (0.12 g) were added. After stirring at room temperature for 2 hours, ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL). After drying over anhydrous magnesium sulfate, the extract was concentrated under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution (20 mL) was added to the residue, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (10 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (6.18 g) was obtained as a white solid.
1H ^- NMR (DMSO _- d6): 2.07 (6H, s), 3.23 (4H, t, J = 5.3 Hz), 4.27-4.33 (4H, m), 9. 40 (2H, br).

Reference example 31

（Ｓ）−２−ピロリジニルメタノール（１．０１ｇ）と酢酸エチル（１０ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（２．１８ｇ）を添加した。氷冷下、１時間攪拌後、無水酢酸(１．０４ｍＬ)、ピリジン（０．８９ｍＬ）、４−ジメチルアミノピリジン（０．０６１ｇ）を添加した。室温で１時間攪拌後、反応液に酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）、５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を加え、室温で１時間攪拌した。ジエチルエーテル（１０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（１．６８ｇ）を微褐色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．５６−２．１０（４Ｈ，ｍ），２．０６（３Ｈ，ｓ），３．０５−３．２４（２Ｈ，ｍ），３．６３−３．６８（１Ｈ，ｍ），４．１５（１Ｈ，ｄｄ，Ｊ＝１１．８，８．１Ｈｚ），４．２６（１Ｈ，ｄｄ，Ｊ＝１１．８，４．１Ｈｚ），９．２１（１Ｈ，ｂｒ），９．８７（１Ｈ，ｂｒ）． (S)-2-pyrrolidinylmethyl acetate hydrochloride

Di-tert-butyl dicarbonate (2.18 g) was added to a mixture of (S)-2-pyrrolidinylmethanol (1.01 g) and ethyl acetate (10 mL) under ice cooling. After stirring for 1 hour under ice-cooling, acetic anhydride (1.04 mL), pyridine (0.89 mL) and 4-dimethylaminopyridine (0.061 g) were added. After stirring at room temperature for 1 hour, ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL). After drying over anhydrous magnesium sulfate, the extract was concentrated under reduced pressure. A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hour. Diethyl ether (10 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (1.68 g) was obtained as a pale brown solid.
1H ^- NMR (DMSO-d6): _1.56-2.10 (4H, m), 2.06 (3H, s), 3.05-3.24 (2H, m), 3.63- 3.68 (1H, m), 4.15 (1H, dd, J = 11.8, 8.1 Hz), 4.26 (1H, dd, J = 11.8, 4.1 Hz), 9.21 (1H, br), 9.87 (1H, br).

Reference example 32

３−アミノ−１−プロパノ−ル（０．７５ｇ）と酢酸エチル（２．２５ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（２．１８ｇ）の酢酸エチル溶液（０．２５ｍＬ）を添加した。室温で２１．５時間攪拌後、塩化ベンゾイル(１．３０ｍＬ)、ピリジン（０．９８ｍＬ）、４−ジメチルアミノピリジン（０．０１２ｇ）を添加した。室温で５時間攪拌後、反応液に酢酸エチル（３２．５ｍＬ）を加え、水（１２．５ｍＬ）、飽和食塩水（１２．５ｍＬ）で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物をＮ，Ｎ−ジメチルホルムアミド（２０ｍＬ）に溶解し、ヨウ化メチル（５ｍＬ）を添加した。氷冷下、６０％水素化ナトリウム（０．４ｇ）を添加した。室温で３時間攪拌後、反応液を氷冷した塩化アンモニウム水溶液（６０ｍＬ）に注いだ。ジエチルエーテル（８０ｍＬ）で抽出し、飽和食塩水（３０ｍＬ）で洗浄した。無水硫酸マグネシウムで乾燥後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２：１、続いて酢酸エチル、続いてアセトン：酢酸エチル＝１：９）で精製し、３−［（ｔｅｒｔ−ブトキシカルボニル）（メチル）アミノ］プロピル ベンゾエート（２．５２ｇ）を無色油状物として得た。４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を加え、室温で１時間攪拌した。減圧濃縮後、残留物を酢酸エチル（１０ｍＬ）を添加して析出した固体を濾取した。ジエチルエーテル（１０ｍＬ）で洗浄後、減圧下乾燥し、標題化合物（１．７３ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．０２−２．１６（２Ｈ，ｍ），２．５６（３Ｈ，ｓ），３．０５（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ），４．３５（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），７．５１（２Ｈ，ｍ），７．６５−７．７３（１Ｈ，ｍ），８．０１（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），８．９５（２Ｈ，ｂｒ）． 3-(methylamino)propyl benzoate hydrochloride

To a mixture of 3-amino-1-propanol (0.75 g) and ethyl acetate (2.25 mL) was added ethyl acetate solution (0.25 mL) of di-tert-butyl dicarbonate (2.18 g) under ice cooling. was added. After stirring at room temperature for 21.5 hours, benzoyl chloride (1.30 mL), pyridine (0.98 mL) and 4-dimethylaminopyridine (0.012 g) were added. After stirring at room temperature for 5 hours, ethyl acetate (32.5 mL) was added to the reaction solution and washed with water (12.5 mL) and saturated brine (12.5 mL). After drying over anhydrous magnesium sulfate, the extract was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (20 mL) and methyl iodide (5 mL) was added. 60% sodium hydride (0.4 g) was added under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was poured into an ice-cooled ammonium chloride aqueous solution (60 mL). Extracted with diethyl ether (80 mL) and washed with saturated brine (30 mL). After drying over anhydrous magnesium sulfate, the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1, then ethyl acetate, then acetone:ethyl acetate=1:9) to give 3-[(tert-butoxycarbonyl)(methyl)amino ] to give propyl benzoate (2.52 g) as a colorless oil. A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, ethyl acetate (10 mL) was added to the residue and the precipitated solid was collected by filtration. After washing with diethyl ether (10 mL), it was dried under reduced pressure to give the title compound (1.73 g) as a colorless solid.
@ ¹ H-NMR (DMSO-d6): _2.02-2.16 (2H, m), 2.56 (3H, s), 3.05 (2H, t, J=7.3 Hz), 4. 35 (2H, t, J = 6.1 Hz), 7.51 (2H, m), 7.65-7.73 (1 H, m), 8.01 (2H, d, J = 7.2 Hz), 8.95 (2H, br).

Reference example 33

２−（メチルアミノ）エタノール（１００ｇ）の酢酸エチル溶液（１０００ｍＬ）にピリジン（２２２ｍＬ）を加え、氷冷下、クロロ炭酸エチル（２４０ｍＬ）を２時間かけて滴下した。滴下終了後、反応液を室温で１８時間攪拌した。水（３００ｍＬ）を加え、酢酸エチル層を分離した後、１Ｎ塩酸（２００ｍＬ）と飽和食塩水（２００ｍＬ）で洗浄した。無水硫酸ナトリウムで乾燥した後、減圧濃縮した。残留物を減圧蒸留することにより、標題化合物（１８０ｇ）を沸点９５−１００℃（圧力：０．１−０．２ｍｍＨｇ）の無色留分として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２０−１．４０（６Ｈ，ｍ），２．９７（３Ｈ，ｓ），３．５０−３．６０（２Ｈ，ｍ），４．０５−４．３５（６Ｈ，ｍ）． 2-[(ethoxycarbonyl)(methyl)amino]ethyl ethyl carbonate

Pyridine (222 mL) was added to an ethyl acetate solution (1000 mL) of 2-(methylamino)ethanol (100 g), and ethyl chlorocarbonate (240 mL) was added dropwise over 2 hours under ice-cooling. After the dropwise addition was completed, the reaction solution was stirred at room temperature for 18 hours. Water (300 mL) was added, and the ethyl acetate layer was separated and washed with 1N hydrochloric acid (200 mL) and saturated brine (200 mL). After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain the title compound (180 g) as a colorless fraction with a boiling point of 95-100°C (pressure: 0.1-0.2 mmHg).
@ ¹ H-NMR ( _CDCl3 ): 1.20-1.40 (6H, m), 2.97 (3H, s), 3.50-3.60 (2H, m), 4.05-4. 35 (6H, m).

Reference example 34

参考例３３で得た２−［（エトキシカルボニル）（メチル）アミノ］エチル エチル カーボネート（１５０ｇ）のアセトニトリル溶液（１５００ｍＬ）にオキシ塩化リン（２００ｍＬ）を加え、４日間還流した。反応液を減圧濃縮した後、残留物を水（５００ｍＬ）−氷（７００ｇ）−酢酸エチル（３００ｍＬ）の混合物に少しずつ攪拌しながら加えた。１分間攪拌した後、飽和食塩水（５００ｍＬ）を加え、酢酸エチル（５００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３００ｍＬ）、飽和炭酸水素ナトリウム水溶液（３００ｍＬ）、飽和食塩水（３００ｍＬ）で順次洗浄し、無水硫酸ナトリウムで乾燥した後、減圧濃縮した。残留物を減圧蒸留することにより、標題化合物（７７ｇ）を沸点１００−１０５℃（圧力：０．１−０．２ｍｍＨｇ）の無色留分として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３３（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．１２（３Ｈ×０．４，ｓ），３．２２（３Ｈ×０．６，ｓ），３．６８（２Ｈ×０．６，ｔ，Ｊ＝４．８Ｈｚ），３．７８（２Ｈ×０．４，ｔ，Ｊ＝４．８Ｈｚ），４．２３（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．３０−４．４０（２Ｈ，ｍ）． 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate

Phosphorus oxychloride (200 mL) was added to an acetonitrile solution (1500 mL) of 2-[(ethoxycarbonyl)(methyl)amino]ethyl ethyl carbonate (150 g) obtained in Reference Example 33, and the mixture was refluxed for 4 days. After the reaction solution was concentrated under reduced pressure, the residue was added little by little to a mixture of water (500 mL)-ice (700 g)-ethyl acetate (300 mL) with stirring. After stirring for 1 minute, saturated brine (500 mL) was added, and the mixture was extracted with ethyl acetate (500 mL). The ethyl acetate layer was washed successively with saturated brine (300 mL), saturated aqueous sodium hydrogencarbonate solution (300 mL) and saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain the title compound (77 g) as a colorless fraction having a boiling point of 100-105°C (pressure: 0.1-0.2 mmHg).
1H ^- NMR ( _CDCl3 ): 1.33 (3H, t, J = 7.2 Hz), 3.12 (3H x 0.4, s), 3.22 (3H x 0.6, s), 3.68 (2H×0.6, t, J=4.8 Hz), 3.78 (2H×0.4, t, J=4.8 Hz), 4.23 (2H, q, J=7. 2 Hz), 4.30-4.40 (2H, m).

Reference example 35

４−アミノブタノール（３．５７ｇ）と酢酸エチル（９ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（８．７３ｇ）と酢酸エチル（１ｍＬ）の混合物を滴下した。室温で２４時間攪拌後、減圧濃縮した。残留物を酢酸エチル（２００ｍＬ）に溶解し、水（５０ｍＬ）、１Ｎ塩酸（４０ｍＬ）、水（３０ｍＬ）、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、標題化合物（７．５４ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．４４（９Ｈ，ｓ），１．４７−１．６１（４Ｈ，ｍ），３．０７−３．２２（２Ｈ，ｍ），３．６１−３．７６（２Ｈ，ｍ），４．６２（１Ｈ，ｂｓ）． tert-butyl 4-hydroxybutylcarbamate

A mixture of di-tert-butyl dicarbonate (8.73 g) and ethyl acetate (1 mL) was added dropwise to a mixture of 4-aminobutanol (3.57 g) and ethyl acetate (9 mL) under ice-cooling. After stirring at room temperature for 24 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with water (50 mL), 1N hydrochloric acid (40 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (7.54 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.44 (9H, s), 1.47-1.61 (4H, m), 3.07-3.22 (2H, m), 3.61-3. 76 (2H, m), 4.62 (1H, bs).

Reference example 36

参考例３５で得られた４−ヒドロキシブチルカルバミン酸ｔｅｒｔ−ブチル（３．８３ｇ）と酢酸エチル（２０ｍＬ）の混合物にピリジン（１．８０ｍＬ）、無水酢酸(２．２７ｇ)を添加した後、室温で１９時間攪拌した。反応液に酢酸エチル（１００ｍＬ）を加え、水（５０ｍＬ）、硫酸銅水溶液（３０ｍＬ）、水（３０ｍＬ）、飽和食塩水（３０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、標題化合物（４．５５ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．４４（９Ｈ，ｓ），１．５１−１．６９（４Ｈ，ｍ），２．０５（３Ｈ，ｓ），３．１５（２Ｈ，ｍ），４．０７（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），４．５５（１Ｈ，ｂｓ）． 4-[(tert-butoxycarbonyl)amino]butyl acetate

After adding pyridine (1.80 mL) and acetic anhydride (2.27 g) to a mixture of tert-butyl 4-hydroxybutylcarbamate (3.83 g) obtained in Reference Example 35 and ethyl acetate (20 mL), and stirred for 19 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with water (50 mL), aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.55 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.44 (9H, s), 1.51-1.69 (4H, m), 2.05 (3H, s), 3.15 (2H, m), 4 .07 (2H, t, J=6.5Hz), 4.55 (1H, bs).

Reference example 37

参考例３６で得られた４−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］ブチル アセテート（４．５０ｇ）とヨウ化メチル（４．８５ｍＬ）のＮ，Ｎ−ジメチルホルムアミド溶液（２０ｍＬ）に氷冷下、水素化ナトリウム（６０％油性，０．９４ｇ）を添加した。室温で４時間攪拌後、反応液を氷−塩化アンモニウム水溶液に注入した後、ジエチルエーテル（１２０ｍＬ）で抽出し、ジエチルエーテル層を飽和食塩水（３０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：９で溶出）で精製した。精製物に４Ｎ塩化水素−酢酸エチル溶液（２０ｍＬ）を加え、室温で２時間攪拌した。ジエチルエーテル（４０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（２．２８ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．５８−１．７０（４Ｈ，ｍ），２．０１（３Ｈ，ｓ），２．５０（３Ｈ，ｓ），２．８２−２．９０（２Ｈ，ｍ），４．００（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），８．９０（２Ｈ，ｂｒ）． 4-(methylamino)butyl acetate hydrochloride

To an N,N-dimethylformamide solution (20 mL) of 4-[(tert-butoxycarbonyl)amino]butyl acetate (4.50 g) obtained in Reference Example 36 and methyl iodide (4.85 mL) under ice cooling, Sodium hydride (60% oily, 0.94g) was added. After stirring at room temperature for 4 hours, the reaction mixture was poured into ice-ammonium chloride aqueous solution, extracted with diethyl ether (120 mL), and the diethyl ether layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:9). A 4N hydrogen chloride-ethyl acetate solution (20 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (40 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (2.28 g) was obtained as a white solid.
1H ^- NMR (DMSO-d6): _1.58-1.70 (4H, m), 2.01 (3H, s), 2.50 (3H, s), 2.82-2.90 ( 2H, m), 4.00 (2H, t, J = 6.0 Hz), 8.90 (2H, br).

Reference example 38

参考例３５で得られた４−ヒドロキシブチルカルバミン酸ｔｅｒｔ−ブチル（３．７１ｇ）と酢酸エチル（２０ｍＬ）の混合物に氷冷下、ピリジン（１．７１ｍＬ）、クロロ炭酸エチル(２．５５ｇ)を添加した後、室温で２４時間攪拌した。反応液に酢酸エチル（１００ｍＬ）を加え、水（５０ｍＬ）、硫酸銅水溶液（３０ｍＬ）、水（３０ｍＬ）、飽和食塩水（３０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、標題化合物（４．９２ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３１（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．４４（９Ｈ，ｓ），１．４６−１．８０（４Ｈ，ｍ），３．１５（２Ｈ，ｍ），４．１１−４．２５（４Ｈ，ｍ），４．５４（１Ｈ，ｂｓ）． 4-[(tert-butoxycarbonyl)amino]butyl ethyl carbonate

To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.71 g) obtained in Reference Example 35 and ethyl acetate (20 mL) was added pyridine (1.71 mL) and ethyl chlorocarbonate (2.55 g) under ice cooling. After the addition, it was stirred at room temperature for 24 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with water (50 mL), aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.92 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.31 (3H, t, J = 7.1 Hz), 1.44 (9H, s), 1.46-1.80 (4H, m), 3.15 ( 2H, m), 4.11-4.25 (4H, m), 4.54 (1H, bs).

Reference example 39

参考例３８で得られた４−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］ブチル エチル カーボネート（４．９０ｇ）とヨウ化メチル（４．６７ｍＬ）のＮ，Ｎ−ジメチルホルムアミド溶液（２０ｍＬ）に氷冷下、水素化ナトリウム（６０％油性，０．９０ｇ）を添加した。室温で６時間攪拌後、反応液を氷−塩化アンモニウム水溶液に注入した後、ジエチルエーテル（１２０ｍＬ）で抽出し、ジエチルエーテル層を飽和食塩水（３０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：９で溶出）で精製した。精製物に４Ｎ塩化水素−酢酸エチル溶液（２０ｍＬ）を加え、室温で２時間攪拌した。ジエチルエーテル（４０ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（２．８６ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２１（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．５１−１．７３（４Ｈ，ｍ），２．５０（３Ｈ，ｓ），２．８２−２．９４（２Ｈ，ｍ），４．０５−４．１５（４Ｈ，ｍ），８．８８（２Ｈ，ｂｒ）． Ethyl 4-(methylamino)butyl carbonate hydrochloride

4-[(tert-butoxycarbonyl)amino]butyl ethyl carbonate (4.90 g) obtained in Reference Example 38 and methyl iodide (4.67 mL) were added to an N,N-dimethylformamide solution (20 mL) under ice cooling. , sodium hydride (60% oily, 0.90 g) was added. After stirring at room temperature for 6 hours, the reaction mixture was poured into ice-ammonium chloride aqueous solution, extracted with diethyl ether (120 mL), and the diethyl ether layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:9). A 4N hydrogen chloride-ethyl acetate solution (20 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (40 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (2.86 g) was obtained as a white solid.
1H ^- NMR (DMSO _- d6): 1.21 (3H, t, J = 7.1 Hz), 1.51-1.73 (4H, m), 2.50 (3H, s), 2. 82-2.94 (2H, m), 4.05-4.15 (4H, m), 8.88 (2H, br).

Reference example 40

３−アミノプロパノール（７．５１ｇ）と酢酸エチル（３０ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（２１．８ｇ）と酢酸エチル（３ｍＬ）の混合物を滴下した。室温で２２時間攪拌後、減圧濃縮した。残留物を酢酸エチル（２００ｍＬ）に溶解し、水（８０ｍＬ）、１Ｎ塩酸（６０ｍＬ）、水（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、標題化合物（１６．０１ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．４５（９Ｈ，ｓ），１．６２−１．７０（２Ｈ，ｍ），３．２４（２Ｈ，ｑ，Ｊ＝６．６Ｈｚ），３．６６（２Ｈ，ｑ，Ｊ＝５．１Ｈｚ），４．７３（１Ｈ，ｂｓ）． tert-butyl 3-hydroxypropylcarbamate

A mixture of di-tert-butyl dicarbonate (21.8 g) and ethyl acetate (3 mL) was added dropwise to a mixture of 3-aminopropanol (7.51 g) and ethyl acetate (30 mL) under ice-cooling. After stirring at room temperature for 22 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with water (80 mL), 1N hydrochloric acid (60 mL), water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (16.01 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.45 (9H, s), 1.62-1.70 (2H, m), 3.24 (2H, q, J = 6.6 Hz), 3.66 ( 2H, q, J=5.1 Hz), 4.73 (1 H, bs).

Reference example 41

参考例４０で得られた３−ヒドロキシプロピルカルバミン酸ｔｅｒｔ−ブチル（８．００ｇ）と酢酸エチル（５０ｍＬ）の混合物にピリジン（４．０６ｍＬ）、無水酢酸(５．１３ｇ)を添加した後、室温で２１時間攪拌した。反応液に酢酸エチル（２００ｍＬ）を加え、水（１００ｍＬ）、硫酸銅水溶液（４０ｍＬ）、水（６０ｍＬ）、飽和食塩水（６０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、標題化合物（８．３４ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．４４（９Ｈ，ｓ），１．７７−１．８６（２Ｈ，ｍ），２．０６（３Ｈ，ｓ），３．２０（２Ｈ，ｑ，Ｊ＝６．３Ｈｚ），４．１２（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），４．６７（１Ｈ，ｂｓ）． 3-[(tert-butoxycarbonyl)amino]propyl acetate

After adding pyridine (4.06 mL) and acetic anhydride (5.13 g) to a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL), and stirred for 21 hours. Ethyl acetate (200 mL) was added to the reaction solution, washed with water (100 mL), aqueous copper sulfate solution (40 mL), water (60 mL) and saturated brine (60 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (8.34 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.44 (9H, s), 1.77-1.86 (2H, m), 2.06 (3H, s), 3.20 (2H, q, J = 6.3 Hz), 4.12 (2H, t, J=6.3 Hz), 4.67 (1H, bs).

Reference example 42

参考例４１で得られた３−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］プロピル アセテート（１７．２８ｇ）とヨウ化メチル（１９．８ｍＬ）のＮ，Ｎ−ジメチルホルムアミド溶液（８０ｍＬ）に氷冷下、水素化ナトリウム（６０％油性，３．８２ｇ）を添加した。室温で１５時間攪拌後、反応液を氷−塩化アンモニウム水溶液に注入した後、ジエチルエーテル（３００ｍＬ）で抽出し、ジエチルエーテル層を飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：８で溶出）で精製した。精製物に４Ｎ塩化水素−酢酸エチル溶液（４０ｍＬ）を加え、室温で２時間攪拌した。ジエチルエーテル（１００ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（２．９３ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．８５−１．９７（２Ｈ，ｍ），２．０２（３Ｈ，ｓ），２．５０（３Ｈ，ｓ），２．８７−２．９６（２Ｈ，ｍ），４．０６（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），８．８７（２Ｈ，ｂｒ）． 3-(methylamino)propyl acetate hydrochloride

3-[(tert-butoxycarbonyl)amino]propyl acetate (17.28 g) obtained in Reference Example 41 and methyl iodide (19.8 mL) were added to an N,N-dimethylformamide solution (80 mL) under ice cooling. Sodium hydride (60% oily, 3.82g) was added. After stirring at room temperature for 15 hours, the reaction mixture was poured into ice-ammonium chloride aqueous solution, extracted with diethyl ether (300 mL), and the diethyl ether layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:8). A 4N hydrogen chloride-ethyl acetate solution (40 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (100 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (2.93 g) was obtained as a white solid.
1H ^- NMR (DMSO-d6): _1.85-1.97 (2H, m), 2.02 (3H, s), 2.50 (3H, s), 2.87-2.96 ( 2H, m), 4.06 (2H, t, J=6.3 Hz), 8.87 (2H, br).

Reference example 43

参考例４０で得られた３−ヒドロキシプロピルカルバミン酸ｔｅｒｔ−ブチル（８．００ｇ）と酢酸エチル（５０ｍＬ）の混合物に氷冷下、ピリジン（４．０６ｍＬ）、クロロ炭酸エチル(５．９５ｇ)を添加した後、室温で２４時間攪拌した。反応液に酢酸エチル（１００ｍＬ）を加え、水（５０ｍＬ）、硫酸銅水溶液（３０ｍＬ）、水（３０ｍＬ）、飽和食塩水（３０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、標題化合物（９．３１ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３１（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．４４（９Ｈ，ｓ），１．８２−１．９０（２Ｈ，ｍ），３．２２（２Ｈ，ｔ，Ｊ=６．３Ｈｚ），４．１５−４．２３（４Ｈ，ｍ），４．６８（１Ｈ，ｂｓ）． 3-[(tert-butoxycarbonyl)amino]propyl ethyl carbonate

To a mixture of tert-butyl 3-hydroxypropylcarbamate (8.00 g) obtained in Reference Example 40 and ethyl acetate (50 mL) was added pyridine (4.06 mL) and ethyl chlorocarbonate (5.95 g) under ice cooling. After the addition, it was stirred at room temperature for 24 hours. Ethyl acetate (100 mL) was added to the reaction solution, washed with water (50 mL), aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (9.31 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.31 (3H, t, J = 7.1 Hz), 1.44 (9H, s), 1.82-1.90 (2H, m), 3.22 ( 2H, t, J=6.3 Hz), 4.15-4.23 (4H, m), 4.68 (1H, bs).

Reference example 44

参考例４３で得られた３−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］プロピル エチル カーボネート（９．３１ｇ）とヨウ化メチル（９．００ｍＬ）のＮ，Ｎ−ジメチルホルムアミド溶液（４０ｍＬ）に氷冷下、水素化ナトリウム（６０％油性，１．８２ｇ）を添加した。室温で１２時間攪拌後、反応液を氷−塩化アンモニウム水溶液に注入した後、ジエチルエーテル（２００ｍＬ）で抽出し、ジエチルエーテル層を飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：８で溶出）で精製した。精製物に４Ｎ塩化水素−酢酸エチル溶液（４０ｍＬ）を加え、室温で２時間攪拌した。ジエチルエーテル（２００ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（４．９８ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２１（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．９１−２．００（２Ｈ，ｍ），２．５０（３Ｈ，ｓ），２．８８−２．９８（２Ｈ，ｍ），４．０８−４．１６（４Ｈ，ｍ），８．９０（２Ｈ，ｂｒ）． Ethyl 3-(methylamino)propyl carbonate hydrochloride

3-[(tert-butoxycarbonyl)amino]propyl ethyl carbonate (9.31 g) obtained in Reference Example 43 and methyl iodide (9.00 mL) were added to an N,N-dimethylformamide solution (40 mL) under ice cooling. , sodium hydride (60% oily, 1.82 g) was added. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-ammonium chloride aqueous solution, extracted with diethyl ether (200 mL), and the diethyl ether layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:8). A 4N hydrogen chloride-ethyl acetate solution (40 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (200 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (4.98 g) was obtained as a white solid.
@ ¹ H-NMR (DMSO _- d6): 1.21 (3H, t, J=7.1 Hz), 1.91-2.00 (2H, m), 2.50 (3H, s), 2.00 (2H, m), 2.50 (3H, s). 88-2.98 (2H, m), 4.08-4.16 (4H, m), 8.90 (2H, br).

Reference example 45

３−（メチルアミノ）−１，２−プロパンジオール（２４．５ｇ）と酢酸エチル（５０ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（５１．４ｇ）と酢酸エチル（１０ｍＬ）の混合物を滴下した。室温で１５時間攪拌後、減圧濃縮した。残留物を酢酸エチル（１５０ｍＬ）に溶解し、水（８０ｍＬ）、１Ｎ塩酸（６０ｍＬ）、水（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、標題化合物（２６．９ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．４７（９Ｈ，ｓ），２．９２（３Ｈ，ｓ），３．２０−３．３６（２Ｈ，ｍ），３．４１（２Ｈ，ｂｓ），３．５０−３．６２（２Ｈ，ｍ），３．７３−３．８８（１Ｈ，ｍ）． tert-butyl (2,3-dihydroxypropyl)methylcarbamate

Di-tert-butyl dicarbonate (51.4 g) and ethyl acetate (10 mL) were added to a mixture of 3-(methylamino)-1,2-propanediol (24.5 g) and ethyl acetate (50 mL) under ice cooling. The mixture was added dropwise. After stirring at room temperature for 15 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), washed with water (80 mL), 1N hydrochloric acid (60 mL), water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave the title compound (26.9 g) as a colorless oil.
< ¹ >H-NMR ( _CDCl3 ): 1.47 (9H, s), 2.92 (3H, s), 3.20-3.36 (2H, m), 3.41 (2H, bs), 3 .50-3.62 (2H, m), 3.73-3.88 (1 H, m).

Reference example 46

参考例４５で得られた（２，３−ジヒドロキシプロピル）メチルカルバミン酸ｔｅｒｔ−ブチル（１０．２６ｇ）と酢酸エチル（５０ｍＬ）の混合物にピリジン（１０．１１ｍＬ）、無水酢酸(１２．７６ｇ)を添加した後、室温で２４時間攪拌した。反応液に酢酸エチル（３００ｍＬ）を加え、水（１５０ｍＬ）、硫酸銅水溶液（１００ｍＬ）、水（１００ｍＬ）、飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：８で溶出）で精製した。精製物に４Ｎ塩化水素−酢酸エチル溶液（４０ｍＬ）を加え、室温で３時間攪拌した。ジエチルエーテル（１００ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（２．７６ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．０３（３Ｈ，ｓ），２．０７（３Ｈ，ｓ），２．５５（３Ｈ，ｓ），３．１８−３．２２（２Ｈ，ｍ），４．０９−４．２８（２Ｈ，ｍ），５．２０−５．２７（１Ｈ，ｍ），９．０１（２Ｈ，ｂｒ）． 3-(Methylamino)propane-1,2-diyl diacetate hydrochloride

Pyridine (10.11 mL) and acetic anhydride (12.76 g) were added to a mixture of tert-butyl (2,3-dihydroxypropyl)methylcarbamate (10.26 g) obtained in Reference Example 45 and ethyl acetate (50 mL). After that, the mixture was stirred at room temperature for 24 hours. Ethyl acetate (300 mL) was added to the reaction solution, washed with water (150 mL), aqueous copper sulfate solution (100 mL), water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:8). A 4N hydrogen chloride-ethyl acetate solution (40 mL) was added to the purified product, and the mixture was stirred at room temperature for 3 hours. Diethyl ether (100 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (2.76 g) was obtained as a white solid.
1H ^- NMR (DMSO _- d6): 2.03 (3H, s), 2.07 (3H, s), 2.55 (3H, s), 3.18-3.22 (2H, m) , 4.09-4.28 (2H, m), 5.20-5.27 (1 H, m), 9.01 (2H, br).

Reference example 47

参考例４５で得られた（２，３−ジヒドロキシプロピル）メチルカルバミン酸ｔｅｒｔ−ブチル（１５．５３ｇ）と酢酸エチル（１００ｍＬ）の混合物に氷冷下、ピリジン（１８．３５ｍＬ）、クロロ炭酸エチル(２４．６２ｇ)を添加した後、室温で９６時間攪拌した。反応液に酢酸エチル（３００ｍＬ）を加え、水（１５０ｍＬ）、硫酸銅水溶液（１００ｍＬ）、水（１００ｍＬ）、飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：６で溶出）で精製した。精製物に４Ｎ塩化水素−酢酸エチル溶液（８０ｍＬ）を加え、室温で３時間攪拌した。ジエチルエーテル（２００ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（５．９３ｇ）を白色固体として得た。¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２０−１．２８（６Ｈ，ｍ），２．５７（３Ｈ，ｓ），３．１２−３．２８（２Ｈ，ｍ），４．１０−４．４３（６Ｈ，ｍ），５．１３−５．２２（１Ｈ，ｍ），９．１４（２Ｈ，ｂｒ）． Diethyl 3-(methylamino)propane-1,2-diyl biscarbonate hydrochloride

To a mixture of tert-butyl (2,3-dihydroxypropyl)methylcarbamate (15.53 g) obtained in Reference Example 45 and ethyl acetate (100 mL) was added pyridine (18.35 mL), ethyl .62 g) was added followed by stirring at room temperature for 96 hours. Ethyl acetate (300 mL) was added to the reaction solution, washed with water (150 mL), aqueous copper sulfate solution (100 mL), water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:6). A 4N hydrogen chloride-ethyl acetate solution (80 mL) was added to the purified product, and the mixture was stirred at room temperature for 3 hours. Diethyl ether (200 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (5.93 g) was obtained as a white solid. 1H ^- NMR (DMSO-d6): _1.20-1.28 (6H, m), 2.57 (3H, s), 3.12-3.28 (2H, m), 4.10- 4.43 (6H, m), 5.13-5.22 (1 H, m), 9.14 (2H, br).

Reference example 48

炭酸ビス（トリクロロメチル）（２．９７ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、２−エトキシエタノール（１．８０ｇ）のテトラヒドロフラン溶液（１０ｍＬ）を滴下した。続いてピリジン（２．４３ｍＬ）のテトラヒドロフラン溶液（１０ｍＬ）を滴下した後、室温で２時間攪拌した。反応液を減圧濃縮した後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を０．２Ｎ塩酸（２０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮することにより、クロロ炭酸２−エトキシエチル（１．２９ｇ）を得た。参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．２３ｇ）のテトラヒドロフラン溶液（１５ｍＬ）にピリジン（０．６８ｍＬ）を添加した後、上記で得られたクロロ炭酸２−エトキシエチルのテトラヒドロフラン溶液（５ｍＬ）を滴下し、室温で３日間攪拌した。反応液を減圧濃縮後、水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：５、続いて２：３で溶出）で精製した。精製物（１．６０ｇ）をジエチルエーテル（３ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（３ｍＬ）を添加した。室温で終夜攪拌した後、析出した固体を濾取し、減圧下乾燥して、標題化合物（０．９４ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．１０（３Ｈ，ｔ，Ｊ＝７．０Ｈｚ），２．５７（３Ｈ，ｓ），３．１８−３．２５（２Ｈ，ｍ），３．４４（２Ｈ，ｑ，Ｊ＝７．０Ｈｚ），３．５６−３．６０（２Ｈ，ｍ），４．１９−４．２４（２Ｈ，ｍ），４．３０−４．３７（２Ｈ，ｍ），８．７９（２Ｈ，ｂｒ）． 2-ethoxyethyl 2-(methylamino)ethyl carbonate hydrochloride

A tetrahydrofuran solution (10 mL) of 2-ethoxyethanol (1.80 g) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (2.97 g) under ice cooling. Subsequently, a tetrahydrofuran solution (10 mL) of pyridine (2.43 mL) was added dropwise, followed by stirring at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-ethoxyethyl chlorocarbonate (1.29 g). . After adding pyridine (0.68 mL) to a tetrahydrofuran solution (15 mL) of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.23 g) obtained in Reference Example 1, the chlorocarbonate 2 obtained above was - Ethoxyethyl in tetrahydrofuran (5 mL) was added dropwise and stirred at room temperature for 3 days. After the reaction mixture was concentrated under reduced pressure, water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5, then eluted with 2:3). The purified product (1.60 g) was dissolved in diethyl ether (3 mL), and 4N hydrogen chloride-ethyl acetate solution (3 mL) was added. After stirring overnight at room temperature, the precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (0.94 g) as a white solid.
1H ^- NMR (DMSO _- d6): 1.10 (3H, t, J = 7.0 Hz), 2.57 (3H, s), 3.18-3.25 (2H, m), 3. 44 (2H, q, J = 7.0 Hz), 3.56-3.60 (2H, m), 4.19-4.24 (2H, m), 4.30-4.37 (2H, m ), 8.79 (2H, br).

Reference example 49

水素化リチウムアルミニウム（２．８５ｇ）とジエチルエーテル（１００ｍＬ）の混合物に氷冷下、メチル ３−メトキシプロパノエート（１１．８ｇ）のテトラヒドロフラン溶液（５０ｍＬ）をゆっくり滴下した。室温で１時間攪拌後、再び氷冷し、水（３ｍＬ）、１０％水酸化ナトリウム水溶液（３ｍＬ）を滴下した。室温に戻し、水（９ｍＬ）を滴下した後、しばらく攪拌した。析出物を濾別し、濾液を減圧濃縮することにより、３−メトキシプロパノール（７．６４ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．８３（２Ｈ，ｑｕｉｎｔｅｔ，Ｊ＝５．８Ｈｚ），２．４３（１Ｈ，ｔ，Ｊ＝５．３Ｈｚ），３．３６（３Ｈ，ｓ），３．５７（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），３．７７（２Ｈ，ｑ，Ｊ＝５．５Ｈｚ）．
炭酸ビス（トリクロロメチル）（４．４５ｇ）のテトラヒドロフラン溶液（５０ｍＬ）に氷冷下、Ｎ−エチルジイソプロピルアミン（５．７５ｍＬ）を滴下した。しばらく攪拌した後、上記で得られた３−メトキシプロパノール（２．７０ｇ）のテトラヒドロフラン溶液（１５ｍＬ）を滴下した。氷冷下で３０分間、室温で１日間攪拌した。反応液を減圧濃縮した後、残留物に希塩酸（５０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を０．２Ｎ塩酸（３０ｍＬ）、飽和食塩水（３０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮することにより、クロロ炭酸３−メトキシプロピル（４．３９ｇ）を得た。参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）のテトラヒドロフラン溶液（２０ｍＬ）にピリジン（０．９７ｍＬ）を添加した後、上記で得られたクロロ炭酸３−メトキシプロピル（１．８３ｇ）のテトラヒドロフラン溶液（５ｍＬ）を滴下し、室温で２時間攪拌した。ピリジン（０．６５ｍＬ）、クロロ炭酸３−メトキシプロピル（１．２２ｇ）のテトラヒドロフラン溶液（５ｍＬ）を追加して更に１時間攪拌した後、反応液を減圧濃縮した。残留物に水（５０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を５％クエン酸水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：９、続いて３：７で溶出）で精製した。精製物（３．４０ｇ）をジエチルエーテル（５ｍＬ）に溶解し、４Ｎ塩化水素−酢酸エチル溶液（５ｍＬ）を添加した。室温で終夜攪拌した後、反応液を減圧濃縮した。ジエチルエーテルを加えて結晶化することにより、標題化合物（２．０６ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．７８−１．９０（２Ｈ，ｍ），２．５４（３Ｈ，ｓ），３．１５−３．２５（２Ｈ，ｍ），３．２３（３Ｈ，ｓ），３．３３−３．４２（２Ｈ，ｍ），４．１６（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），４．３６（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），９．２７（２Ｈ，ｂｒ）． 3-Methoxypropyl 2-(methylamino)ethyl carbonate hydrochloride

A tetrahydrofuran solution (50 mL) of methyl 3-methoxypropanoate (11.8 g) was slowly added dropwise to a mixture of lithium aluminum hydride (2.85 g) and diethyl ether (100 mL) under ice cooling. After stirring at room temperature for 1 hour, the mixture was ice-cooled again, and water (3 mL) and 10% aqueous sodium hydroxide solution (3 mL) were added dropwise. After returning to room temperature and adding dropwise water (9 mL), the mixture was stirred for a while. The precipitate was filtered off and the filtrate was concentrated under reduced pressure to give 3-methoxypropanol (7.64 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.83 (2H, quintet, J=5.8Hz), 2.43 (1H, t, J=5.3Hz), 3.36 (3H, s), 3. 57 (2H, t, J=6.0 Hz), 3.77 (2H, q, J=5.5 Hz).
To a tetrahydrofuran solution (50 mL) of bis(trichloromethyl) carbonate (4.45 g) was added dropwise N-ethyldiisopropylamine (5.75 mL) under ice cooling. After stirring for a while, a tetrahydrofuran solution (15 mL) of 3-methoxypropanol (2.70 g) obtained above was added dropwise. The mixture was stirred under ice cooling for 30 minutes and at room temperature for 1 day. After the reaction mixture was concentrated under reduced pressure, dilute hydrochloric acid (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (30 mL) and saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-methoxypropyl chlorocarbonate (4.39 g). . After adding pyridine (0.97 mL) to a tetrahydrofuran solution (20 mL) of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1, the chlorocarbonic acid 3 obtained above was added. A tetrahydrofuran solution (5 mL) of -methoxypropyl (1.83 g) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Pyridine (0.65 mL) and a tetrahydrofuran solution (5 mL) of 3-methoxypropyl chlorocarbonate (1.22 g) were added, and the mixture was further stirred for 1 hour, and then concentrated under reduced pressure. Water (50 mL) was added to the residue and extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with 5% aqueous citric acid solution (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9, then eluted with 3:7). The purified product (3.40 g) was dissolved in diethyl ether (5 mL), and 4N hydrogen chloride-ethyl acetate solution (5 mL) was added. After stirring overnight at room temperature, the reaction solution was concentrated under reduced pressure. Crystallization by adding diethyl ether gave the title compound (2.06 g) as a colorless solid.
1H ^- NMR (DMSO-d6): _1.78-1.90 (2H, m), 2.54 (3H, s), 3.15-3.25 (2H, m), 3.23 ( 3H, s), 3.33-3.42 (2H, m), 4.16 (2H, t, J = 6.0 Hz), 4.36 (2H, t, J = 6.0 Hz), 9. 27 (2H, br).

Reference example 50

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（３．５０ｇ）、Ｎ，Ｎ−ジメチルグリシン塩酸塩（５．２９ｇ）、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（７．６７ｇ）、トリエチルアミン（５．５８ｍＬ）、４−ジメチルアミノピリジン（１．２２ｇ）及びＮ，Ｎ−ジメチルホルムアミド（５０ｍＬ）の混合物を室温で終夜攪拌した。反応液を減圧濃縮した後、残留物に飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（メタノール：酢酸エチル＝５：９５、続いて２０：８０で溶出）で精製した。精製物（２．４６ｇ）に１Ｎ塩酸（２４ｍＬ）を添加して、室温で終夜攪拌した。反応液を減圧濃縮することにより、標題化合物（２．１４ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．５２（３Ｈ，ｓ），２．８５（６Ｈ，ｓ），３．２０（２Ｈ，ｍ），４．３０（２Ｈ，ｓ），４．４３−４．４９（２Ｈ，ｍ），９．６０（２Ｈ，ｂｒ），１０．８１（１Ｈ，ｂｒ）． 2-(Methylamino)ethyl N,N-dimethylglycinate dihydrochloride

tert-butyl 2-hydroxyethyl(methyl)carbamate (3.50 g) obtained in Reference Example 1, N,N-dimethylglycine hydrochloride (5.29 g), 1-ethyl-3-[3-(dimethyl A mixture of amino)propyl]carbodiimide hydrochloride (7.67 g), triethylamine (5.58 mL), 4-dimethylaminopyridine (1.22 g) and N,N-dimethylformamide (50 mL) was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with methanol:ethyl acetate=5:95, then 20:80). 1N Hydrochloric acid (24 mL) was added to the purified product (2.46 g), and the mixture was stirred overnight at room temperature. The title compound (2.14 g) was obtained as a colorless solid by concentrating the reaction solution under reduced pressure.
1H ^- NMR (DMSO _- d6): 2.52 (3H, s), 2.85 (6H, s), 3.20 (2H, m), 4.30 (2H, s), 4.43 - 4.49 (2H, m), 9.60 (2H, br), 10.81 (1H, br).

Reference example 51

参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（３．５０ｇ）、チオ酢酸（１．７２ｍＬ）、トリフェニルホスフィン（７．８７ｇ）のテトラヒドロフラン溶液（５０ｍＬ）に氷冷下、アゾジカルボン酸ジイソプロピル（５．９１ｍＬ）のテトラヒドロフラン溶液（１０ｍＬ）をゆっくり滴下した。氷冷下で１時間、室温で２時間攪拌した。再度反応液を氷冷し、トリフェニルホスフィン（７．８７ｇ）、アゾジカルボン酸ジイソプロピル（５．９１ｍＬ）のテトラヒドロフラン溶液（１０ｍＬ）を追加して、氷冷下で３０分間攪拌した。チオ酢酸（１．１４ｍＬ）を追加して、氷冷下で３０分間、室温で終夜攪拌した。反応液を減圧濃縮した後、残留物にヘキサン、ジイソプロピルエーテルを加え、析出物を濾別し、濾液を減圧濃縮した。この操作を再度繰り返した後、飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝５：９５、続いて１５：８５で溶出）で精製した。精製物（４．４７ｇ）に４Ｎ塩化水素−酢酸エチル溶液（１０ｍＬ）を添加して、室温で終夜攪拌した。反応液を減圧濃縮し、残留物に酢酸エチル、ジエチルエーテルを加えて結晶化することにより、標題化合物（１．７９ｇ）を淡黄色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：２．３８（３Ｈ，ｓ），２．５２（３Ｈ，ｓ），２．９６−３．０８（２Ｈ，ｍ），３．１２−３．２０（２Ｈ，ｍ），９．３５（２Ｈ，ｂｒ）． S-[2-(methylamino)ethyl]thioacetate hydrochloride

A tetrahydrofuran solution (50 mL) of tert-butyl 2-hydroxyethyl(methyl)carbamate (3.50 g) obtained in Reference Example 1, thioacetic acid (1.72 mL) and triphenylphosphine (7.87 g) was cooled with ice. A tetrahydrofuran solution (10 mL) of diisopropyl azodicarboxylate (5.91 mL) was slowly added dropwise. The mixture was stirred under ice cooling for 1 hour and at room temperature for 2 hours. The reaction mixture was ice-cooled again, triphenylphosphine (7.87 g) and diisopropyl azodicarboxylate (5.91 mL) in tetrahydrofuran (10 mL) were added, and the mixture was stirred under ice-cooling for 30 minutes. Thioacetic acid (1.14 mL) was added, and the mixture was stirred under ice-cooling for 30 minutes and at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, hexane and diisopropyl ether were added to the residue, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. After repeating this operation again, a saturated aqueous sodium hydrogencarbonate solution (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95, then eluted with 15:85). A 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the purified product (4.47 g), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and diethyl ether were added to the residue for crystallization to give the title compound (1.79 g) as a pale yellow solid.
1H ^- NMR (DMSO _- d6): 2.38 (3H, s), 2.52 (3H, s), 2.96-3.08 (2H, m), 3.12-3.20 ( 2H, m), 9.35 (2H, br).

Reference example 52

２−（２−アミノエトキシ）エタノール（９９．５２ｇ）と酢酸エチル（２００ｍＬ）の混合物に氷冷下、二炭酸ジ−ｔｅｒｔ−ブチル（２０８．５７ｇ）と酢酸エチル（５０ｍＬ）の混合物を滴下した。室温で６０時間攪拌後、減圧濃縮した。残留物を酢酸エチル（５００ｍＬ）に溶解し、水（２００ｍＬ）、１Ｎ塩酸（２００ｍＬ）、水（３００ｍＬ）、飽和食塩水（３００ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、［２−（２−ヒドロキシエトキシ）エチル］カルバミン酸ｔｅｒｔ−ブチル（１６９．２ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．４５（９Ｈ，ｓ），３．３３（２Ｈ，ｑ，Ｊ＝５．１Ｈｚ），３．５４−３．５９（４Ｈ，ｍ），３．７４（２Ｈ，ｑ，Ｊ＝５．１Ｈｚ），４．８８（２Ｈ，ｂｓ）．
上記で得られた［２−（２−ヒドロキシエトキシ）エチル］カルバミン酸ｔｅｒｔ−ブチル（５３．９３ｇ）と酢酸エチル（３５０ｍＬ）の混合物に氷冷下、ピリジン（５３．７８ｍＬ）、クロロ炭酸エチル(７０．５７ｇ)を添加した後、室温で９６時間攪拌した。反応液に酢酸エチル（５００ｍＬ）を加え、水（５００ｍＬ）、硫酸銅水溶液（２００ｍＬ）、水（３００ｍＬ）、飽和食塩水（３００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、２−［２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］エトキシ］エチル エチル カーボネート（９３．１９ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３２（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．４４（９Ｈ，ｓ），３．３２（２Ｈ，ｔ、Ｊ＝５．１Ｈｚ），３．５４（２Ｈ，ｔ、Ｊ＝５．１Ｈｚ），３．６７−３．７４（２Ｈ，ｍ），４．２１（２Ｈ，ｑ、Ｊ＝７．２Ｈｚ），４．２６−４．３１（２Ｈ，ｍ），４．９１（１Ｈ，ｂｓ）．
上記で得られた２−［２−［（ｔｅｒｔ−ブトキシカルボニル）アミノ］エトキシ］エチル エチル カーボネート（９３．１５ｇ）とヨウ化メチル（８３．６ｍＬ）のＮ，Ｎ−ジメチルホルムアミド溶液（３５０ｍＬ）に氷冷下、水素化ナトリウム（６０％油性，１６．１２ｇ）を添加した。室温で２４時間攪拌後、反応液を氷−塩化アンモニウム水溶液に注入した後、ジエチルエーテル（８００ｍＬ）で抽出し、ジエチルエーテル層を飽和食塩水（３００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：８で溶出）で精製した。精製物に４Ｎ塩化水素−酢酸エチル溶液（３００ｍＬ）を加え、室温で２時間攪拌した。ジエチルエーテル（３００ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（３３．２１ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２１（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．５１（３Ｈ，ｓ），３．０２−３．０９（２Ｈ，ｍ），３．６５−３．７２（４Ｈ，ｍ），４．１２（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．２２（２Ｈ，ｔ，Ｊ＝４．５Ｈｚ），９．０６（２Ｈ，ｂｒ）． Ethyl 2-[2-(methylamino)ethoxy]ethyl carbonate hydrochloride

A mixture of di-tert-butyl dicarbonate (208.57 g) and ethyl acetate (50 mL) was added dropwise to a mixture of 2-(2-aminoethoxy)ethanol (99.52 g) and ethyl acetate (200 mL) under ice cooling. . After stirring at room temperature for 60 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with water (200 mL), 1N hydrochloric acid (200 mL), water (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave tert-butyl [2-(2-hydroxyethoxy)ethyl]carbamate (169.2 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.45 (9H, s), 3.33 (2H, q, J = 5.1 Hz), 3.54-3.59 (4H, m), 3.74 ( 2H, q, J=5.1 Hz), 4.88 (2H, bs).
To a mixture of tert-butyl [2-(2-hydroxyethoxy)ethyl]carbamate (53.93 g) obtained above and ethyl acetate (350 mL) was added pyridine (53.78 mL) and ethyl chlorocarbonate ( 70.57 g) was added, followed by stirring at room temperature for 96 hours. Ethyl acetate (500 mL) was added to the reaction solution, washed with water (500 mL), aqueous copper sulfate solution (200 mL), water (300 mL) and saturated brine (300 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 2-[2-[(tert-butoxycarbonyl)amino]ethoxy]ethyl ethyl carbonate (93.19 g) as a colorless oil.
< ¹ >H-NMR ( _CDCl3 ): 1.32 (3H, t, J = 7.2 Hz), 1.44 (9H, s), 3.32 (2H, t, J = 5.1 Hz), 3. 54 (2H, t, J = 5.1 Hz), 3.67-3.74 (2H, m), 4.21 (2H, q, J = 7.2 Hz), 4.26-4.31 (2H , m), 4.91 (1H, bs).
To an N,N-dimethylformamide solution (350 mL) of 2-[2-[(tert-butoxycarbonyl)amino]ethoxy]ethyl ethyl carbonate (93.15 g) obtained above and methyl iodide (83.6 mL), Sodium hydride (60% oily, 16.12 g) was added under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was poured into ice-aqueous ammonium chloride solution, extracted with diethyl ether (800 mL), and the diethyl ether layer was washed with saturated brine (300 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:8). A 4N hydrogen chloride-ethyl acetate solution (300 mL) was added to the purified product, and the mixture was stirred at room temperature for 2 hours. Diethyl ether (300 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (33.21 g) was obtained as a white solid.
1H ^- NMR (DMSO _- d6): 1.21 (3H, t, J = 7.2Hz), 2.51 (3H, s), 3.02-3.09 (2H, m), 3. 65 - 3.72 (4H, m), 4.12 (2H, q, J = 7.2 Hz), 4.22 (2H, t, J = 4.5 Hz), 9.06 (2H, br).

Reference example 53

炭酸ビス（トリクロロメチル）（１１．８７ｇ）のテトラヒドロフラン溶液（１００ｍＬ）に氷冷下、ピリジン（９．７１ｍＬ）のテトラヒドロフラン溶液（２０ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１７．５２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）を滴下後、室温で１５時間攪拌した。減圧濃縮後、残留物に水（５００ｍＬ）および無水硫酸ナトリウムを加え、ろ過した後、ろ液を減圧濃縮した。得られた残留物に、氷冷下、２−（メチルアミノ）エタノール（５．００ｇ）の酢酸エチル溶液（５０ｍＬ）とトリエチルアミン（１０．０ｍＬ）を加え、室温で１５時間攪拌した。反応液に酢酸エチル（３００ｍＬ）を加え、水（１５０ｍＬ）、飽和食塩水（２００ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残留物と酢酸エチル（１００ｍＬ）の混合物に氷冷下、ピリジン（２．９１ｍＬ）、クロロ炭酸エチル(３．４４ｇ)を添加した後、室温で４８時間攪拌した。反応液に酢酸エチル（２００ｍＬ）を加え、水（１００ｍＬ）、硫酸銅水溶液（５０ｍＬ）、水（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：３で溶出）で精製した。精製物に４Ｎ塩化水素−酢酸エチル溶液（３０ｍＬ）を加え、室温で３時間攪拌した。ジエチルエーテル（１００ｍＬ）を添加して、析出した固体を濾取した。減圧下乾燥し、標題化合物（２．９０ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．２１（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．５７（３Ｈ，ｂｓ），２．８６（１．５Ｈ，ｓ），２．９３（１．５Ｈ，ｓ），３．１６（２Ｈ，ｂｓ），３．３４（１Ｈ，ｂｓ），３．４８（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），３．５８（１Ｈ，ｔ，Ｊ＝５．１Ｈｚ），４．１２（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．１６−４．２４（４Ｈ，ｍ），８．９４（１Ｈ，ｂｒ）． Ethyl 2-[methyl[[2-(methylamino)ethoxy]carbonyl]amino]ethyl carbonate hydrochloride

A tetrahydrofuran solution (20 mL) of pyridine (9.71 mL) was added dropwise to a tetrahydrofuran solution (100 mL) of bis(trichloromethyl) carbonate (11.87 g) under ice cooling. After stirring for 30 minutes under ice-cooling, a tetrahydrofuran solution (20 mL) of tert-butyl 2-hydroxyethyl(methyl)carbamate (17.52 g) obtained in Reference Example 1 was added dropwise, followed by stirring at room temperature for 15 hours. After concentration under reduced pressure, water (500 mL) and anhydrous sodium sulfate were added to the residue, filtered, and the filtrate was concentrated under reduced pressure. An ethyl acetate solution (50 mL) of 2-(methylamino)ethanol (5.00 g) and triethylamine (10.0 mL) were added to the resulting residue under ice-cooling, and the mixture was stirred at room temperature for 15 hours. Ethyl acetate (300 mL) was added to the reaction solution, washed with water (150 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, pyridine (2.91 mL) and ethyl chlorocarbonate (3.44 g) were added to a mixture of the residue and ethyl acetate (100 mL) under ice-cooling, and the mixture was stirred at room temperature for 48 hours. Ethyl acetate (200 mL) was added to the reaction solution, washed with water (100 mL), aqueous copper sulfate solution (50 mL), water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:3). A 4N hydrogen chloride-ethyl acetate solution (30 mL) was added to the purified product, and the mixture was stirred at room temperature for 3 hours. Diethyl ether (100 mL) was added and the precipitated solid was collected by filtration. After drying under reduced pressure, the title compound (2.90 g) was obtained as a white solid.
1H ^- NMR (DMSO _- d6): 1.21 (3H, t, J = 7.2Hz), 2.57 (3H, bs), 2.86 (1.5H, s), 2.93 ( 1.5H, s), 3.16 (2H, bs), 3.34 (1H, bs), 3.48 (1H, t, J = 5.1 Hz), 3.58 (1H, t, J = 5.1 Hz), 4.12 (2H, q, J=7.2 Hz), 4.16-4.24 (4H, m), 8.94 (1H, br).

Reference example 54

エチル ピペリジン−４−カルボキシレート（４．７２ｇ）、ヨウ化メチル（２．２４ｍＬ）、炭酸カリウム（８．２９ｇ）及びアセトニトリル（５０ｍＬ）の混合物を室温で２時間攪拌した。反応液を減圧濃縮した後、水（１５０ｍＬ）を加え、酢酸エチル（１５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧濃縮した。残留物（２．６４ｇ）に１Ｎ水酸化ナトリウム水溶液（２０ｍＬ）を加え、室温で終夜攪拌した。反応液に１Ｎ塩酸（２０ｍＬ）を加えて中和した後、減圧濃縮した。残留物にエタノールを加え、析出物を濾別し、濾液を減圧濃縮した。この操作を再度繰り返した後、残留物にエタノール、酢酸エチルを加えて結晶化することにより、１−メチルピペリジン−４−カルボン酸（１．７９ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤ₃ＯＤ）：１．８０−１．９８（２Ｈ，ｍ）,２．００−２．１４（２Ｈ，ｍ），２．２８−２．４２（１Ｈ，ｍ），２．７８（３Ｈ，ｓ），２．８８−３．０４（２Ｈ．ｍ），３．３２−３．４４（２Ｈ．ｍ）．
上記で得られた１−メチルピペリジン−４−カルボン酸（１．７２ｇ）、参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（１．７５ｇ）、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（２．３０ｇ）、４−ジメチルアミノピリジン（０．２４ｇ）及びアセトニトリル（５０ｍＬ）の混合物を室温で１６時間攪拌した。反応液を減圧濃縮した後、残留物に飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝５０：５０、続いて８０：２０で溶出）で精製した。精製物（２．７３ｇ）に１Ｎ塩酸（２５ｍＬ）を添加して、室温で終夜攪拌した。反応液を減圧濃縮した後、イソプロパノールを加え、再度減圧濃縮した。析出した固体を濾取することにより、標題化合物（１．７２ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．７０−２．２０（４Ｈ，ｍ），２．４０−３．５０（１３Ｈ，ｍ），４．３１（２Ｈ，ｍ），９．２５（２Ｈ，ｂｒ），１０．７７（１Ｈ，ｂｒ）． 2-(methylamino)ethyl 1-methylpiperidine-4-carboxylate dihydrochloride

A mixture of ethyl piperidine-4-carboxylate (4.72 g), methyl iodide (2.24 mL), potassium carbonate (8.29 g) and acetonitrile (50 mL) was stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, water (150 mL) was added and the mixture was extracted with ethyl acetate (150 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1N aqueous sodium hydroxide solution (20 mL) was added to the residue (2.64 g), and the mixture was stirred overnight at room temperature. The reaction solution was neutralized by adding 1N hydrochloric acid (20 mL), and then concentrated under reduced pressure. Ethanol was added to the residue, the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. After repeating this operation again, ethanol and ethyl acetate were added to the residue for crystallization to give 1-methylpiperidine-4-carboxylic acid (1.79 g) as a colorless solid.
< ¹ >H-NMR ( _CD3OD ): 1.80-1.98 (2H, m), 2.00-2.14 (2H, m), 2.28-2.42 (1H, m), 2 .78 (3 H.s), 2.88-3.04 (2 H.m), 3.32-3.44 (2 H.m).
1-methylpiperidine-4-carboxylic acid (1.72 g) obtained above, tert-butyl 2-hydroxyethyl(methyl)carbamate (1.75 g) obtained in Reference Example 1, 1-ethyl-3 A mixture of -[3-(dimethylamino)propyl]carbodiimide hydrochloride (2.30 g), 4-dimethylaminopyridine (0.24 g) and acetonitrile (50 mL) was stirred at room temperature for 16 hours. After the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=50:50, then eluted with 80:20). 1N Hydrochloric acid (25 mL) was added to the purified product (2.73 g), and the mixture was stirred overnight at room temperature. After concentrating the reaction solution under reduced pressure, isopropanol was added thereto and concentrated again under reduced pressure. The precipitated solid was collected by filtration to give the title compound (1.72 g) as a colorless solid.
1H ^- NMR (DMSO-d6): _1.70-2.20 (4H, m), 2.40-3.50 (13H, m), 4.31 (2H, m), 9.25 ( 2H, br), 10.77 (1H, br).

Reference example 55

４−フルオロベンゾニトリル（６．０６ｇ）、２−アミノエタノール（３．７１ｇ）、炭酸カリウム（８．２９ｇ）及びジメチルスルホキシド（５０ｍＬ）の混合物を１００℃で終夜攪拌した。反応液に水（２００ｍＬ）を加え、酢酸エチル（２００ｍＬ×４）で抽出した。酢酸エチル層を飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３０：７０、続いて５０：５０、続いて８０：２０、続いて酢酸エチルで溶出）で精製することにより、４−［（２−ヒドロキシエチル）アミノ］ベンゾニトリル（５．８９ｇ）を黄色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．０４（１Ｈ，ｔ，Ｊ＝４．８Ｈｚ），３．３３（２Ｈ，ｍ），３．８６（２Ｈ，ｑ，Ｊ＝４．８Ｈｚ），４．６６（１Ｈ，ｂｒ），６．５８（２Ｈ，ｄ，Ｊ＝８．７Ｈｚ），７．３９（２Ｈ，ｄ，Ｊ＝８．７Ｈｚ）．
上記で得た４−［（２−ヒドロキシエチル）アミノ］ベンゾニトリル（０．８１ｇ）、水酸化カリウム（１．１２ｇ）及びｔｅｒｔ−ブタノール（２０ｍＬ）の混合物を１００℃で１時間攪拌した。反応液に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（８０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した後、減圧濃縮した。残留物（０．８３ｇ）、ピリジン（０．４９ｍＬ）及び４−ジメチルアミノピリジン（０．０６１ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に、無水酢酸（０．５７ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。室温で１時間攪拌した後、水（８０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（８０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３０：７０、続いて６０：４０で溶出）で精製することにより、標題化合物（０．６８ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．０８（３Ｈ，ｓ），３．４４（２Ｈ，ｑ，Ｊ＝５．６Ｈｚ），４．２９（２Ｈ，ｔ，Ｊ＝５．４Ｈｚ），４．４８（１Ｈ，ｂｒ），６．５９（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．４３（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ）． 2-[[4-(aminocarbonyl)phenyl]amino]ethyl acetate

A mixture of 4-fluorobenzonitrile (6.06 g), 2-aminoethanol (3.71 g), potassium carbonate (8.29 g) and dimethylsulfoxide (50 mL) was stirred at 100°C overnight. Water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL×4). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70, then 50:50, then 80:20, then eluted with ethyl acetate) to give 4-[(2-hydroxyethyl ) Amino]benzonitrile (5.89 g) was obtained as a yellow solid.
@ ¹ H-NMR ( _CDCl3 ): 2.04 (1 H, t, J=4.8 Hz), 3.33 (2 H, m), 3.86 (2 H, q, J=4.8 Hz), 4. 66 (1H,br), 6.58 (2H,d,J=8.7Hz), 7.39 (2H,d,J=8.7Hz).
A mixture of 4-[(2-hydroxyethyl)amino]benzonitrile (0.81 g) obtained above, potassium hydroxide (1.12 g) and tert-butanol (20 mL) was stirred at 100° C. for 1 hour. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (80 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To a tetrahydrofuran solution (10 mL) of the residue (0.83 g), pyridine (0.49 mL) and 4-dimethylaminopyridine (0.061 g) was added dropwise a tetrahydrofuran solution (1 mL) of acetic anhydride (0.57 mL). After stirring at room temperature for 1 hour, water (80 mL) was added and extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (80 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70, then eluted with 60:40) to give the title compound (0.68 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.08 (3H, s), 3.44 (2H, q, J = 5.6 Hz), 4.29 (2H, t, J = 5.4 Hz), 4. 48 (1H,br), 6.59 (2H,d,J=8.9Hz), 7.43 (2H,d,J=8.9Hz).

Reference example 56

Ｎ，Ｎ'−カルボニルジイミダゾール（３．３６ｇ）のテトラヒドロフラン溶液（４０ｍＬ）に、参考例１で得られた２−ヒドロキシエチル（メチル）カルバミン酸ｔｅｒｔ−ブチル（３．３０ｇ）のテトラヒドロフラン溶液（１０ｍＬ）を氷冷下、ゆっくり滴下した。氷冷下で４０分間、室温で２時間攪拌した後、Ｎ，Ｎ'−カルボニルジイミダゾール（０．３１ｇ）を加え、更に３日間攪拌した。反応液を減圧濃縮した後、残留物に酢酸エチル（１５０ｍＬ）を加え、飽和食塩水（１００ｍＬ×２）、水（５０ｍＬ×３）、飽和食塩水（５０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮することにより、２−［（ｔｅｒｔ−ブトキシカルボニル）（メチル）アミノ］エチル １Ｈ−イミダゾール−１−カルボキシレ−ト（５．２４ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３９（９Ｈ×０．５，ｓ），１．４２（９Ｈ×０．５，ｓ），２．９４（３Ｈ，ｍ），３．６３（２Ｈ，ｍ），４．５１（２Ｈ，ｔ，Ｊ＝５．３Ｈｚ），７．０６（１Ｈ，ｍ），７．４２（１Ｈ，ｍ），８．１３（１Ｈ，ｓ）．
上記で得た２−［（ｔｅｒｔ−ブトキシカルボニル）（メチル）アミノ］エチル １Ｈ−イミダゾール−１−カルボキシレ−ト（１．３５ｇ）、１−メチル−４−ピペリジノール（１．３８ｇ）及びアセトニトリル（２０ｍＬ）の混合物を室温で終夜攪拌した。１−メチル−４−ピペリジノール（０．９２ｇ）を加えて更に終夜攪拌した。反応液を減圧濃縮した後、残留物に飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物（１．６０ｇ）に１Ｎ塩酸（１２ｍＬ）を添加して、室温で終夜攪拌した。反応液を減圧濃縮した後、水、イソプロパノール、酢酸エチルを加えて、析出した固体を濾取することにより、標題化合物（１．０９ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ₆）：１．８５−２．２０（４Ｈ，ｍ），２．５５（３Ｈ，ｓ），２．７０（３Ｈ×０．５，ｓ），２．７３（３Ｈ×０．５，ｓ），２．９０−３．５０（６Ｈ，ｍ），４．３８（２Ｈ，ｍ），４．６５−５．００（１Ｈ，ｍ），９．２１（２Ｈ，ｂｒ），１１．１０（１Ｈ，ｂｒ）． 2-(Methylamino)ethyl 1-methyl-4-piperidinyl carbonate dihydrochloride

A tetrahydrofuran solution (10 mL) of tert-butyl 2-hydroxyethyl(methyl)carbamate (3.30 g) obtained in Reference Example 1 was added to a tetrahydrofuran solution (40 mL) of N,N'-carbonyldiimidazole (3.36 g). ) was slowly added dropwise under ice cooling. After stirring for 40 minutes under ice-cooling and for 2 hours at room temperature, N,N'-carbonyldiimidazole (0.31 g) was added and the mixture was further stirred for 3 days. After the reaction mixture was concentrated under reduced pressure, ethyl acetate (150 mL) was added to the residue, washed with saturated brine (100 mL x 2), water (50 mL x 3) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Drying and concentration under reduced pressure gave 2-[(tert-butoxycarbonyl)(methyl)amino]ethyl 1H-imidazole-1-carboxylate (5.24 g) as a colorless oil.
< ¹ >H-NMR ( _CDCl3 ): 1.39 (9H x 0.5, s), 1.42 (9H x 0.5, s), 2.94 (3H, m), 3.63 (2H, m), 4.51 (2H, t, J=5.3 Hz), 7.06 (1 H, m), 7.42 (1 H, m), 8.13 (1 H, s).
2-[(tert-butoxycarbonyl)(methyl)amino]ethyl 1H-imidazole-1-carboxylate (1.35 g) obtained above, 1-methyl-4-piperidinol (1.38 g) and acetonitrile ( 20 mL) of the mixture was stirred overnight at room temperature. 1-Methyl-4-piperidinol (0.92 g) was added and the mixture was further stirred overnight. After the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1N Hydrochloric acid (12 mL) was added to the residue (1.60 g) and stirred overnight at room temperature. After the reaction solution was concentrated under reduced pressure, water, isopropanol and ethyl acetate were added, and the precipitated solid was collected by filtration to give the title compound (1.09 g) as a colorless solid.
1H ^- NMR (DMSO-d6): _1.85-2.20 (4H, m), 2.55 (3H, s), 2.70 (3H x 0.5, s), 2.73 ( 3H × 0.5, s), 2.90-3.50 (6H, m), 4.38 (2H, m), 4.65-5.00 (1H, m), 9.21 (2H, br), 11.10(1H, br).

Synthesis example 1

炭酸ビス（トリクロロメチル）（０．５０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２で得られた２−（メチルアミノ）エチル アセテート塩酸塩（０．７７ｇ）を添加した。トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で１時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチルで溶出）で精製し、さらにシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２：１、続いて酢酸エチル、続いてアセトン：酢酸エチル＝１：４、続いて１：１で溶出）で精製することにより、標題化合物（１．１３ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．１０（３Ｈ，ｓ），２．２４（３Ｈ，ｓ），３．０９（３Ｈ，ｂｓ），３．６０−４．００（２Ｈ，ｂｒ），４．２５−４．５０（４Ｈ，ｍ），４．８９（１Ｈ，ｄ，Ｊ＝１３．３Ｈｚ），５．０５（１Ｈ，ｄ，Ｊ＝１３．３Ｈｚ），６．６５（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），７．３５−７．５１（３Ｈ，ｍ），７．８０−７．９０（１Ｈ，ｍ），８．３５（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.40 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.50 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl acetate hydrochloride (0.77 g) obtained in Reference Example 2 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (catalytic amount) were added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with ethyl acetate), and further purified by silica gel column chromatography (ethyl acetate:hexane=2:1, then eluted with ethyl acetate). followed by elution with ethyl acetate, then acetone:ethyl acetate=1:4, then 1:1) to give the title compound (1.13 g) as a yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 2.10 (3H, s), 2.24 (3H, s), 3.09 (3H, bs), 3.60-4.00 (2H, br), 4 .25-4.50 (4H, m), 4.89 (1H, d, J = 13.3 Hz), 5.05 (1H, d, J = 13.3 Hz), 6.65 (1H, d, J=5.5 Hz), 7.35-7.51 (3H, m), 7.80-7.90 (1 H, m), 8.35 (1 H, d, J=5.5 Hz).

Synthesis example 2

炭酸ビス（トリクロロメチル）（０．５０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例３で得られた２−（メチルアミノ）エチル トリメチルアセテート塩酸塩（０．９８ｇ）を添加した。トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をフラッシュシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：３、続いて３：２で溶出）で精製した。アセトン−ジイソプロピルエーテルより結晶化し、アセトン−ジイソプロピルエーテルから再結晶することにより、標題化合物（１．０１ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２３（９Ｈ，ｓ），２．２３（３Ｈ，ｓ），３．０８（３Ｈ，ｂｓ），３．４０−４．３０（２Ｈ，ｂｒ），４．３０−４．５０（４Ｈ，ｍ），４．８０−５．２０（２Ｈ，ｂｒ），６．６４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５−７．５０（３Ｈ，ｍ），７．７８−７．８８（１Ｈ，ｍ），８．３５（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]Carbonyl]amino]ethyl trimethylacetate

A tetrahydrofuran solution (1 mL) of pyridine (0.40 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.50 g) under ice-cooling. After stirring for 1 hour under ice-cooling, 2-(methylamino)ethyl trimethylacetate hydrochloride (0.98 g) obtained in Reference Example 3 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL), the mixture was stirred overnight at room temperature. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 84 mL), 4-dimethylaminopyridine (0.037 g) was added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:3, then 3:2). Crystallization from acetone-diisopropyl ether and recrystallization from acetone-diisopropyl ether gave the title compound (1.01 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.23 (9H, s), 2.23 (3H, s), 3.08 (3H, bs), 3.40-4.30 (2H, br), 4 .30-4.50 (4H, m), 4.80-5.20 (2H, br), 6.64 (1H, d, J = 5.7 Hz), 7.35-7.50 (3H, m), 7.78-7.88 (1H, m), 8.35 (1H, d, J=5.7 Hz).

Synthesis example 3

炭酸ビス（トリクロロメチル）（０．５０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例４で得られた２−（メチルアミノ）エチル シクロヘキサンカルボキシレート塩酸塩（１．１１ｇ）を添加した。トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で１時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をフラッシュシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：３、続いて３：２で溶出）で精製した。アセトン−ジイソプロピルエーテルより結晶化し、アセトン−ジイソプロピルエーテルから再結晶することにより、標題化合物（１．１１ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．１０−１．５５（５Ｈ，ｍ），１．５５−１．８２（３Ｈ，ｍ），１．８４−１．９８（２Ｈ，ｍ），２．２３（３Ｈ，ｓ），２．２７−２．４０（１Ｈ，ｍ），３．０８（３Ｈ，ｂｓ），３．４０−４．３０（２Ｈ，ｂｒ），４．３０−４．５０（４Ｈ，ｍ），４．８０−５．１５（２Ｈ，ｂｒ），６．６４（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．３５−７．４８（３Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl cyclohexanecarboxylate

A tetrahydrofuran solution (1 mL) of pyridine (0.40 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.50 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl cyclohexanecarboxylate hydrochloride (1.11 g) obtained in Reference Example 4 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 84 mL), 4-dimethylaminopyridine (0.037 g) was added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:3, then 3:2). Crystallization from acetone-diisopropyl ether and recrystallization from acetone-diisopropyl ether gave the title compound (1.11 g) as a colorless solid.
@ ¹ H-NMR ( _CDCl3 ): 1.10-1.55 (5H, m), 1.55-1.82 (3H, m), 1.84-1.98 (2H, m), 2. 23 (3H, s), 2.27-2.40 (1H, m), 3.08 (3H, bs), 3.40-4.30 (2H, br), 4.30-4.50 ( 4H, m), 4.80-5.15 (2H, br), 6.64 (1H, d, J = 5.4 Hz), 7.35-7.48 (3H, m), 7.84 ( 1H, d, J = 6.9 Hz), 8.34 (1 H, d, J = 5.4 Hz).

Synthesis example 4

炭酸ビス（トリクロロメチル）（０．５０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例５で得られた２−（メチルアミノ）エチル ベンゾエート塩酸塩（１．０８ｇ）を添加した。トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をフラッシュシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：３、続いて３：２で溶出）で精製した。アセトン−ジエチルエーテルより結晶化し、アセトン−ジエチルエーテルから再結晶することにより、標題化合物（１．０９ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２２（３Ｈ，ｓ），３．１２（３Ｈ，ｂｓ），３．５０−４．３０（２Ｈ，ｂｒ），４．３７（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．６８（２Ｈ，ｍ），４．８０−５．２０（２Ｈ，ｂｒ），６．６３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２６−７．４８（５Ｈ，ｍ），７．５３−７．６１（１Ｈ，ｍ），７．８２（１Ｈ，ｄ，Ｊ＝８．１Ｈｚ），８．０４（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl benzoate

A tetrahydrofuran solution (1 mL) of pyridine (0.40 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.50 g) under ice-cooling. After stirring for 1 hour under ice-cooling, 2-(methylamino)ethyl benzoate hydrochloride (1.08 g) obtained in Reference Example 5 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL), the mixture was stirred overnight at room temperature. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 84 mL), 4-dimethylaminopyridine (0.037 g) was added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:3, then 3:2). Crystallization from acetone-diethyl ether and recrystallization from acetone-diethyl ether gave the title compound (1.09 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.22 (3H, s), 3.12 (3H, bs), 3.50-4.30 (2H, br), 4.37 (2H, q, J = 7.8 Hz), 4.68 (2H, m), 4.80-5.20 (2H, br), 6.63 (1H, d, J = 5.7 Hz), 7.26-7.48 ( 5H, m), 7.53-7.61 (1H, m), 7.82 (1H, d, J = 8.1 Hz), 8.04 (2H, d, J = 7.2 Hz), 8. 33 (1H,d,J=5.7Hz).

Synthesis example 5

炭酸ビス（トリクロロメチル）（０．９９ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．８１ｍＬ）のテトラヒドロフラン溶液（２ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例５で得られた２−（メチルアミノ）エチル ベンゾエート塩酸塩（２．１６ｇ）を添加した。トリエチルアミン（１．３９ｍＬ）のテトラヒドロフラン溶液（２ｍＬ）を添加後、室温で１時間攪拌した。減圧濃縮後、残留物に酢酸エチル（１００ｍＬ）と水（１００ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（４０ｍＬ）に溶解した。２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（２．９０ｇ）、トリエチルアミン（２．２０ｍＬ）、４−ジメチルアミノピリジン（０．０９６ｇ）を添加し、６０℃で２時間攪拌した。減圧濃縮後、残留物に酢酸エチル（１５０ｍＬ）と水（８０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチルで溶出）で精製した。アセトンから再結晶することにより、標題化合物（２．６２ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２２（３Ｈ，ｓ），３．１３（３Ｈ，ｂｓ），３．６８−３．９８（２Ｈ，ｂｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．６９（２Ｈ，ｍ），４．８０−５．１０（２Ｈ，ｂｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２７−７．４８（５Ｈ，ｍ），７．５９（１Ｈ，ｍ），７．８３（１Ｈ，ｍ），８．０６（２Ｈ，ｄ，Ｊ＝６．０Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino ] ethyl benzoate

A tetrahydrofuran solution (2 mL) of pyridine (0.81 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.99 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl benzoate hydrochloride (2.16 g) obtained in Reference Example 5 was added. After adding a tetrahydrofuran solution (2 mL) of triethylamine (1.39 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, ethyl acetate (100 mL) and water (100 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (40 mL). 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (2.90 g), triethylamine (2.20 mL), 4 -Dimethylaminopyridine (0.096 g) was added and stirred at 60°C for 2 hours. After concentration under reduced pressure, ethyl acetate (150 mL) and water (80 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with ethyl acetate). Recrystallization from acetone gave the title compound (2.62 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.22 (3H, s), 3.13 (3H, bs), 3.68-3.98 (2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.69 (2H, m), 4.80-5.10 (2H, bm), 6.64 (1H, d, J = 5.7 Hz), 7.27-7.48 ( 5H, m), 7.59 (1H, m), 7.83 (1H, m), 8.06 (2H, d, J = 6.0 Hz), 8.35 (1H, d, J = 5.0 Hz). 7 Hz).

Synthesis example 6

炭酸ビス（トリクロロメチル）（０．５８４ｇ）のテトラヒドロフラン溶液（１８ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、４０分間攪拌後、参考例６で得られた２−（メチルアミノ）エチル ４−メトキシベンゾエート塩酸塩（１．４８ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を添加後、室温で８０分間攪拌した。減圧濃縮後、残留物に酢酸エチル（８０ｍＬ）と水（５０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２５ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．５５ｇ）、トリエチルアミン（１．１７ｍＬ）、４−ジメチルアミノピリジン（０．０５１ｇ）を添加し、６０℃で３時間攪拌した。減圧濃縮後、残留物に酢酸エチル（１５０ｍＬ）と水（５０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチルで溶出）で精製した。酢酸エチル−ヘキサンから再結晶することにより、標題化合物（１．０８ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２２（３Ｈ，ｓ），３．１１（３Ｈ，ｂｓ），３．６８−３．９０（２Ｈ，ｂｍ），３．８５（３Ｈ，ｓ），４．３７（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．５８−４．７２（２Ｈ，ｍ），４．８２−５．１４（２Ｈ，ｂｍ），６．６３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），６．９１（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．２７−７．４０（３Ｈ，ｍ），７．８２（１Ｈ，ｍ），７．９９（２Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 4-methoxybenzoate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (18 mL) of bis(trichloromethyl) carbonate (0.584 g) under ice-cooling. After stirring for 40 minutes under ice-cooling, 2-(methylamino)ethyl 4-methoxybenzoate hydrochloride (1.48 g) obtained in Reference Example 6 was added. After adding a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 80 minutes. After concentration under reduced pressure, ethyl acetate (80 mL) and water (50 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (25 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.55 g), triethylamine (1. 17 mL) and 4-dimethylaminopyridine (0.051 g) were added and stirred at 60° C. for 3 hours. After concentration under reduced pressure, ethyl acetate (150 mL) and water (50 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with ethyl acetate). Recrystallization from ethyl acetate-hexane gave the title compound (1.08 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.22 (3H, s), 3.11 (3H, bs), 3.68-3.90 (2H, bm), 3.85 (3H, s), 4 .37 (2H, q, J = 7.9 Hz), 4.58-4.72 (2 H, m), 4.82-5.14 (2 H, bm), 6.63 (1 H, d, J = 5.7 Hz), 6.91 (2H, d, J = 9.0 Hz), 7.27-7.40 (3H, m), 7.82 (1H, m), 7.99 (2H, d, J=9.0 Hz), 8.33 (1H, d, J=5.7 Hz).

Synthesis example 7

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例７で得られた２−（メチルアミノ）エチル ３−クロロベンゾエート塩酸塩（１．５０ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を添加後、室温で２時間攪拌した。減圧濃縮後、残留物に酢酸エチル（８０ｍＬ）と水（４０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（２５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．４４ｇ）、トリエチルアミン（１．０９ｍＬ）、４−ジメチルアミノピリジン（０．０４８ｇ）を添加し、６０℃で３時間攪拌した。減圧濃縮後、残留物に酢酸エチル（８０ｍＬ）と水（４０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製し、標題化合物（０．８４ｇ）を無色シロップとして得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２１（３Ｈ，ｓ），３．１２（３Ｈ，ｂｓ），３．７８−４．０８（２Ｈ，ｂｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．６４−５．０８（４Ｈ，ｂｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．２Ｈｚ），７．３４−７．４２（４Ｈ，ｍ），７．５６（１Ｈ，ｍ），７．８２（１Ｈ，ｍ），７．９４（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），８．０２（１Ｈ，ｓ），８．３４（１Ｈ，ｄ，Ｊ＝５．２Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 3-chlorobenzoate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl 3-chlorobenzoate hydrochloride (1.50 g) obtained in Reference Example 7 was added. After adding a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (40 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (25 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.44 g), triethylamine (1. 09 mL) and 4-dimethylaminopyridine (0.048 g) were added and stirred at 60° C. for 3 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (40 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (0.84 g) as a colorless syrup.
1H ^- NMR ( _CDCl3 ): 2.21 (3H, s), 3.12 (3H, bs), 3.78-4.08 (2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.64-5.08 (4H, bm), 6.64 (1H, d, J = 5.2 Hz), 7.34-7.42 (4H, m), 7.56 ( 1 H, m), 7.82 (1 H, m), 7.94 (1 H, d, J=7.6 Hz), 8.02 (1 H, s), 8.34 (1 H, d, J=5. 2 Hz).

Synthesis example 8

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例８で得られた２−（メチルアミノ）エチル ３，４−ジフルオロベンゾエート塩酸塩（１．５１ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を添加後、室温で３時間攪拌した。減圧濃縮後、残留物に酢酸エチル（８０ｍＬ）と水（５０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２５ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．７１ｇ）、トリエチルアミン（１．２９ｍＬ）、４−ジメチルアミノピリジン（０．０５６ｇ）を添加し、６０℃で１７時間攪拌した。減圧濃縮後、残留物に酢酸エチル（１００ｍＬ）と水（５０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、水層を酢酸エチル（２０ｍＬ）で抽出した。酢酸エチル層を合わせ、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて２：１で溶出）で精製し、さらに塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１で溶出）で精製した。アセトン−ジイソプロピルエーテルより結晶化し、酢酸エチル−ヘキサンから再結晶することにより、標題化合物（１．３７ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２１（３Ｈ，ｓ），３．１１（３Ｈ，ｂｓ），３．８２−４．０８（２Ｈ，ｂｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．６０−５．１４（４Ｈ，ｂｍ），６．６３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２０（１Ｈ，ｍ），７．３３−７．４１（３Ｈ，ｍ），７．７８−７．９２（３Ｈ，ｍ），８．３３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 3,4-difluorobenzoate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl 3,4-difluorobenzoate hydrochloride (1.51 g) obtained in Reference Example 8 was added. After adding a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (50 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (25 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.71 g), triethylamine (1. 29 mL) and 4-dimethylaminopyridine (0.056 g) were added and stirred at 60° C. for 17 hours. After concentration under reduced pressure, ethyl acetate (100 mL) and water (50 mL) were added to the residue and stirred. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The ethyl acetate layers were combined, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with 2:1), and further purified by basic silica gel column chromatography (ethyl acetate:hexane=1:1). elution). Crystallization from acetone-diisopropyl ether and recrystallization from ethyl acetate-hexane gave the title compound (1.37 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.21 (3H, s), 3.11 (3H, bs), 3.82-4.08 (2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.60-5.14 (4H, bm), 6.63 (1H, d, J = 5.7 Hz), 7.20 (1H, m), 7.33-7.41 ( 3H, m), 7.78-7.92 (3H, m), 8.33 (1 H, d, J = 5.7 Hz).

Synthesis example 9

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例９で得られた２−（メチルアミノ）エチル ４−トリフルオロメトキシベンゾエート塩酸塩（１．７９ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を添加後、室温で１．５時間攪拌した。減圧濃縮後、残留物に酢酸エチル（８０ｍＬ）と水（５０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２５ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．５７ｇ）、トリエチルアミン（１．１８ｍＬ）、４−ジメチルアミノピリジン（０．０５２ｇ）を添加し、６０℃で４．５時間攪拌した。減圧濃縮後、残留物に酢酸エチル（１００ｍＬ）と水（５０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、水層を酢酸エチル（３０ｍＬ）で抽出した。酢酸エチル層を合わせ、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１で溶出）で精製し、さらに塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１で溶出）で精製することにより、標題化合物（１．４４ｇ）を無色シロップとして得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２２（３Ｈ，ｓ），３．１１（３Ｈ，ｂｓ），３．８５−４．０５（２Ｈ，ｂｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．６０−５．１２（４Ｈ，ｂｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２４（２Ｈ，ｄ，Ｊ＝８．７Ｈｚ），７．２５−７．４０（３Ｈ，ｍ），７．８２（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ），８．０９（２Ｈ，ｄ，Ｊ＝８．７Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 4-trifluoromethoxybenzoate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl 4-trifluoromethoxybenzoate hydrochloride (1.79 g) obtained in Reference Example 9 was added. After adding a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 1.5 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (50 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (25 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.57 g), triethylamine (1. 18 mL) and 4-dimethylaminopyridine (0.052 g) were added and stirred at 60° C. for 4.5 hours. After concentration under reduced pressure, ethyl acetate (100 mL) and water (50 mL) were added to the residue and stirred. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The ethyl acetate layers were combined, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with ethyl acetate:hexane=1:1), and further purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:1). gave the title compound (1.44 g) as a colorless syrup.
1H ^- NMR ( _CDCl3 ): 2.22 (3H, s), 3.11 (3H, bs), 3.85-4.05 (2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.60-5.12 (4H, bm), 6.64 (1H, d, J = 5.7 Hz), 7.24 (2H, d, J = 8.7 Hz), 7. 25-7.40 (3H, m), 7.82 (1H, d, J = 7.2 Hz), 8.09 (2H, d, J = 8.7 Hz), 8.33 (1H, d, J = 5.7 Hz).

Synthesis example 10

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例１０で得られた２−（メチルアミノ）エチル ４−フルオロベンゾエート塩酸塩（１．４０ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を添加後、室温で２時間攪拌した。減圧濃縮後、残留物に酢酸エチル（８０ｍＬ）と水（４０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．３２ｇ）、トリエチルアミン（１．００ｍＬ）、４−ジメチルアミノピリジン（０．０４９ｇ）を添加し、６０℃で１４．５時間攪拌した。減圧濃縮後、残留物に酢酸エチル（１５０ｍＬ）と水（５０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を酢酸エチル：ヘキサン＝１：１から結晶化し、濾取した。続いてアセトンから再結晶することにより、標題化合物（１．３９ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２２（３Ｈ，ｓ），３．１２（３Ｈ，ｂｓ），３．７８−４．２０（２Ｈ，ｂｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．５８−５．０８（４Ｈ，ｂｍ），６．６５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．１１（２Ｈ，ｔ，Ｊ＝８．４Ｈｚ），７．２８−７．４４（３Ｈ，ｍ），７．８１−７．８６（１Ｈ，ｍ），８．０３−８．１１（２Ｈ，ｍ），８．３５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 4-fluorobenzoate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl 4-fluorobenzoate hydrochloride (1.40 g) obtained in Reference Example 10 was added. After adding a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (40 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.32 g), triethylamine (1. 00 mL) and 4-dimethylaminopyridine (0.049 g) were added and stirred at 60° C. for 14.5 hours. After concentration under reduced pressure, ethyl acetate (150 mL) and water (50 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was crystallized from ethyl acetate:hexane=1:1 and collected by filtration. Subsequent recrystallization from acetone gave the title compound (1.39 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.22 (3H, s), 3.12 (3H, bs), 3.78-4.20 (2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.58-5.08 (4H, bm), 6.65 (1H, d, J = 5.6 Hz), 7.11 (2H, t, J = 8.4 Hz), 7. 28-7.44 (3H, m), 7.81-7.86 (1H, m), 8.03-8.11 (2H, m), 8.35 (1H, d, J = 5.6Hz ).

Synthesis Example 11

炭酸ビス（トリクロロメチル）（０．６０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１０分間攪拌後、参考例１１で得られた２−（メチルアミノ）エチル ３，４，５−トリメトキシベンゾエート塩酸塩（１．２２ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で１時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を希塩酸（２０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で３時間、室温で２日間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をフラッシュシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：３、続いて３：２で溶出）で精製することにより、標題化合物（１．５６ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２１（３Ｈ，ｓ），３．１２（３Ｈ，ｂｓ），３．５０−４．３０（２Ｈ，ｂｒ），３．８３（６Ｈ，ｓ），３．９０（３Ｈ，ｓ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．６７（２Ｈ，ｍ），４．８０−５．１５（２Ｈ，ｂｒ），６．６４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２５−７．４０（５Ｈ，ｍ），７．７８−７．８６（１Ｈ，ｍ），８．３３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 3,4,5-trimethoxybenzoate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.60 g) under ice-cooling. After stirring for 10 minutes under ice-cooling, 2-(methylamino)ethyl 3,4,5-trimethoxybenzoate hydrochloride (1.22 g) obtained in Reference Example 11 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with diluted hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added and stirred at 60° C. for 3 hours and at room temperature for 2 days. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:3, then 3:2) to give the title compound (1.56 g) as a yellow amorphous solid. .
1H ^- NMR ( _CDCl3 ): 2.21 (3H, s), 3.12 (3H, bs), 3.50-4.30 (2H, br), 3.83 (6H, s), 3 .90 (3H, s), 4.38 (2H, q, J = 7.8 Hz), 4.67 (2H, m), 4.80-5.15 (2H, br), 6.64 (1H , d, J = 5.7 Hz), 7.25-7.40 (5 H, m), 7.78-7.86 (1 H, m), 8.33 (1 H, d, J = 5.7 Hz) .

Synthesis Example 12

炭酸ビス（トリクロロメチル）（０．４２２ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．３４５ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例１２で得られた２−（メチルアミノ）エチル ２−ピリジンカルボキシレート二塩酸塩（１．０８ｇ）を添加し、トリエチルアミン（１．１９ｍＬ）を滴下後、室温で２時間攪拌した。析出した固体を濾別し、濾液を減圧濃縮した。残留物をテトラヒドロフラン（１０ｍＬ）に溶解し、（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．３１ｇ）、トリエチルアミン（０．９９ｍＬ）及び４−ジメチルアミノピリジン（０．０４３ｇ）を添加し、６０℃で２４時間攪拌した。反応液に酢酸エチル（１００ｍＬ）を加え、水（１００ｍＬ）及び飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝４：１で溶出）で精製した。アセトン−ジエチルエーテルから結晶化することにより、標題化合物（０．９ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２２（３Ｈ，ｓ），３．１６（３Ｈ，ｓ），３．８０−４．２０（２Ｈ，ｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．６０−５．１０（４Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），７．２９−７．４０（２Ｈ，ｍ），７．４７−７．５２（２Ｈ，ｍ），７．８１−７．８９（２Ｈ，ｍ），８．１４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），８．７５−８．７９（１Ｈ，ｍ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 2-pyridinecarboxylate

Pyridine (0.345 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.422 g) under ice cooling. After stirring for 30 minutes under ice cooling, 2-(methylamino)ethyl 2-pyridinecarboxylate dihydrochloride (1.08 g) obtained in Reference Example 12 was added, triethylamine (1.19 mL) was added dropwise, Stir at room temperature for 2 hours. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and treated with (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benz. Imidazole (1.31 g), triethylamine (0.99 mL) and 4-dimethylaminopyridine (0.043 g) were added and stirred at 60°C for 24 hours. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=4:1). Crystallization from acetone-diethyl ether gave the title compound (0.9 g) as a white solid.
1H ^- NMR ( _CDCl3 ): 2.22 (3H, s), 3.16 (3H, s), 3.80-4.20 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.60-5.10 (4H, m), 6.64 (1H, d, J = 5.8 Hz), 7.29-7.40 (2H, m), 7.47- 7.52 (2H, m), 7.81-7.89 (2H, m), 8.14 (1H, d, J = 7.8 Hz), 8.34 (1H, d, J = 5.8 Hz ), 8.75-8.79 (1H, m).

Synthesis Example 13

炭酸ビス（トリクロロメチル）（０．６５２ｇ）のテトラヒドロフラン溶液（１５ｍＬ）に氷冷下、ピリジン（０．５５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例１３で得られた２−（メチルアミノ）エチル メトキシアセテート（０．９９ｇ）を添加した。室温で３時間攪拌した。減圧濃縮後、残留物に酢酸エチル（８０ｍＬ）と水（５０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１５ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１３ｇ）、トリエチルアミン（０．８６ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で４日間攪拌した。減圧濃縮後、残留物に酢酸エチル（８０ｍＬ）と水（３０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、酢酸エチル層を飽和炭酸水素ナトリウム水溶液（３０ｍＬ）、水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル、続いてアセトン：酢酸エチル＝１：３で溶出）で精製し、さらに塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて３：１で溶出）で精製することにより、標題化合物（０．５８８ｇ）を無色シロップとして得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．３２（３Ｈ，ｓ），２．６８（３Ｈ，ｓ），３．４８（３Ｈ，ｓ），３．６９−４．０２（４Ｈ，ｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．６７（２Ｈ，ｔ，Ｊ＝６．６Ｈｚ），４．９９（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），５．１２（１Ｈ，ｄ，Ｊ＝１３．９Ｈｚ），６．６３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２９−７．４６（２Ｈ，ｍ），７．６２（１Ｈ，ｍ），７．８１（１Ｈ，ｍ），８．２５（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]Carbonyl]amino]ethyl methoxyacetate

A tetrahydrofuran solution (1 mL) of pyridine (0.55 mL) was added dropwise to a tetrahydrofuran solution (15 mL) of bis(trichloromethyl) carbonate (0.652 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl methoxyacetate (0.99 g) obtained in Reference Example 13 was added. Stir at room temperature for 3 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (50 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (15 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.13 g), triethylamine (0. 86 mL), 4-dimethylaminopyridine (0.037 g) was added and stirred at 60° C. for 4 days. After concentration under reduced pressure, ethyl acetate (80 mL) and water (30 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated aqueous sodium hydrogencarbonate solution (30 mL) and water (30 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate, then eluted with acetone:ethyl acetate=1:3), and further purified by basic silica gel column chromatography (ethyl acetate:hexane=1:1, then elution with 3:1) to give the title compound (0.588 g) as a colorless syrup.
1H ^- NMR ( _CDCl3 ): 2.32 (3H, s), 2.68 (3H, s), 3.48 (3H, s), 3.69-4.02 (4H, m), 4 .38 (2H, q, J = 7.8 Hz), 4.67 (2H, t, J = 6.6 Hz), 4.99 (1 H, d, J = 13.9 Hz), 5.12 (1 H, d, J = 13.9 Hz), 6.63 (1 H, d, J = 5.7 Hz), 7.29-7.46 (2 H, m), 7.62 (1 H, m), 7.81 ( 1H, m), 8.25 (1H, d, J=5.7 Hz).

Synthesis Example 14

炭酸ビス（トリクロロメチル）（１．３１ｇ）のテトラヒドロフラン溶液（４０ｍＬ）に氷冷下、ピリジン（１．０７ｍＬ）のテトラヒドロフラン溶液（２ｍＬ）を滴下した。氷冷下、１０分間攪拌後、参考例１４で得られたエチル ２−（メチルアミノ）エチル カーボネート塩酸塩（２．０２ｇ）を添加した。トリエチルアミン（１．８４ｍＬ）のテトラヒドロフラン溶液（２ｍＬ）を滴下後、室温で１時間攪拌した。減圧濃縮後、残留物に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を０．２Ｎ塩酸（５０ｍＬ）、飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（５０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（３．６９ｇ）、トリエチルアミン（２．０９ｍＬ）、４−ジメチルアミノピリジン（０．１２ｇ）を添加し、６０℃で６時間、室温で８時間攪拌した。減圧濃縮後、残留物に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７、続いて酢酸エチルで溶出）で精製した。ジエチルエーテルより結晶化し、ジエチルエーテルから再結晶することにより、標題化合物（３．８４ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３２（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．２３（３Ｈ，ｓ），３．１０（３Ｈ，ｂｓ），３．５０−４．２０（２Ｈ，ｂｒ），４．２２（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．３９（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．４５（２Ｈ，ｍ），４．８０−５．１５（２Ｈ，ｂｒ），６．６５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３６−７．５０（３Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． Ethyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate

A tetrahydrofuran solution (2 mL) of pyridine (1.07 mL) was added dropwise to a tetrahydrofuran solution (40 mL) of bis(trichloromethyl) carbonate (1.31 g) under ice-cooling. After stirring for 10 minutes under ice-cooling, ethyl 2-(methylamino)ethyl carbonate hydrochloride (2.02 g) obtained in Reference Example 14 was added. After dropping a tetrahydrofuran solution (2 mL) of triethylamine (1.84 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (50 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (50 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (3.69 g), triethylamine (2. 09 mL) and 4-dimethylaminopyridine (0.12 g) were added, and the mixture was stirred at 60° C. for 6 hours and at room temperature for 8 hours. After concentration under reduced pressure, water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=3:7, then eluted with ethyl acetate). Crystallization from diethyl ether and recrystallization from diethyl ether gave the title compound (3.84 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.32 (3H, t, J = 7.2 Hz), 2.23 (3H, s), 3.10 (3H, bs), 3.50-4.20 ( 2H, br), 4.22 (2H, q, J = 7.2 Hz), 4.39 (2H, q, J = 7.9 Hz), 4.45 (2H, m), 4.80-5. 15 (2H, br), 6.65 (1H, d, J = 5.6 Hz), 7.36-7.50 (3H, m), 7.84 (1H, d, J = 7.8 Hz), 8.35 (1H,d,J=5.6Hz).

Synthesis example 15

炭酸ビス（トリクロロメチル）（０．５０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例１５で得られたイソプロピル ２−（メチルアミノ）エチル カーボネート塩酸塩（０．９９ｇ）を添加した。トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で１時間攪拌した。炭酸ビス（トリクロロメチル）（０．５０ｇ）、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）、トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を順次追加し、室温で１時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で１２時間、室温で３日間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をフラッシュシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：３、続いて３：２で溶出）で精製し、さらに塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７、続いて酢酸エチルで溶出）で精製した。ジエチルエーテルより結晶化し、アセトン−ジイソプロピルエーテルから再結晶することにより、標題化合物（０．５８ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３１（６Ｈ，ｄ，Ｊ＝６．３Ｈｚ），２．２３（３Ｈ，ｓ），３．０８（３Ｈ，ｂｓ），３．４０−４．３０（２Ｈ，ｂｒ），４．３７（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．３２−４．５３（２Ｈ，ｍ），４．８０−５．２０（３Ｈ，ｍ），６．６３（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５−７．５０（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． Isopropyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.40 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.50 g) under ice-cooling. After stirring for 1 hour under ice-cooling, isopropyl 2-(methylamino)ethyl carbonate hydrochloride (0.99 g) obtained in Reference Example 15 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL), the mixture was stirred at room temperature for 1 hour. Bis(trichloromethyl) carbonate (0.50 g), a tetrahydrofuran solution (1 mL) of pyridine (0.40 mL), and a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added and stirred at 60° C. for 12 hours and at room temperature for 3 days. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:3, then 3:2), and further purified by basic silica gel column chromatography (ethyl acetate:hexane=3:7, followed by elution with ethyl acetate). Crystallization from diethyl ether and recrystallization from acetone-diisopropyl ether gave the title compound (0.58 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.31 (6H, d, J = 6.3 Hz), 2.23 (3H, s), 3.08 (3H, bs), 3.40-4.30 ( 2H, br), 4.37 (2H, q, J = 7.9 Hz), 4.32-4.53 (2H, m), 4.80-5.20 (3H, m), 6.63 ( 1H, d, J = 5.7 Hz), 7.35-7.50 (3H, m), 7.83 (1H, d, J = 7.2 Hz), 8.34 (1H, d, J = 5 .7 Hz).

Synthesis Example 16

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例１５で得られたイソプロピル ２−（メチルアミノ）エチル カーボネート塩酸塩（１．１８ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を添加後、室温で２時間攪拌した。減圧濃縮後、残留物に酢酸エチル（８０ｍＬ）と水（３０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２５ｍＬ）に溶解した。２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．７３ｇ）、トリエチルアミン（１．３１ｍＬ）、４−ジメチルアミノピリジン（０．０５７ｇ）を添加し、６０℃で５時間攪拌した。減圧濃縮後、残留物に酢酸エチル（１００ｍＬ）と水（５０ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１で溶出）で精製し、さらにシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて２：１で溶出）で精製した。ジイソプロピルエーテル−ヘキサンより結晶化し、ジイソプロピルエーテルから再結晶することにより、標題化合物（１．２０ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３１（６Ｈ，ｄ，Ｊ＝６．６Ｈｚ），２．２３（３Ｈ，ｓ），３．０８（３Ｈ，ｂｓ），３．５０−３．９０（２Ｈ，ｂｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．３６−４．５８（２Ｈ，ｂｍ），４．７９−５．１５（３Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５−７．４８（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． Isopropyl 2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl] Amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, isopropyl 2-(methylamino)ethyl carbonate hydrochloride (1.18 g) obtained in Reference Example 15 was added. After adding a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, ethyl acetate (80 mL) and water (30 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (25 mL). 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.73 g), triethylamine (1.31 mL), 4 -Dimethylaminopyridine (0.057 g) was added and stirred at 60°C for 5 hours. After concentration under reduced pressure, ethyl acetate (100 mL) and water (50 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:1), and further purified by silica gel column chromatography (ethyl acetate:hexane=1:1, then 2:1). elution). Crystallization from diisopropyl ether-hexane and recrystallization from diisopropyl ether gave the title compound (1.20 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.31 (6H, d, J = 6.6Hz), 2.23 (3H, s), 3.08 (3H, bs), 3.50-3.90 ( 2H, bm), 4.38 (2H, q, J = 7.8 Hz), 4.36-4.58 (2H, bm), 4.79-5.15 (3H, m), 6.64 ( 1H, d, J = 5.7 Hz), 7.35-7.48 (3H, m), 7.83 (1H, d, J = 7.5 Hz), 8.34 (1H, d, J = 5 .7 Hz).

Synthesis Example 17

炭酸ビス（トリクロロメチル）（０．５０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例１６で得られたベンジル ２−（メチルアミノ）エチル カーボネート塩酸塩（１．０８ｇ）を添加した。トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をフラッシュシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：３、続いて３：２で溶出）で精製した。アセトン−ジエチルエーテルより結晶化し、アセトン−ジエチルエーテルから再結晶することにより、標題化合物（１．１７ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２２（３Ｈ，ｓ），３．０５（３Ｈ，ｂｓ），３．５０−４．２０（２Ｈ，ｂｒ），４．３７（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．４６（２Ｈ，ｍ），４．８０−５．１０（２Ｈ，ｂｒ），５．１７（２Ｈ，ｓ），６．６２（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．２６−７．４８（８Ｈ，ｍ），７．７７−７．８８（１Ｈ，ｍ），８．３３（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． benzyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.40 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.50 g) under ice-cooling. After stirring for 1 hour under ice-cooling, benzyl 2-(methylamino)ethyl carbonate hydrochloride (1.08 g) obtained in Reference Example 16 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL), the mixture was stirred overnight at room temperature. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 84 mL), 4-dimethylaminopyridine (0.037 g) was added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:3, then 3:2). Crystallization from acetone-diethyl ether and recrystallization from acetone-diethyl ether gave the title compound (1.17 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.22 (3H, s), 3.05 (3H, bs), 3.50-4.20 (2H, br), 4.37 (2H, q, J = 7.8 Hz), 4.46 (2H, m), 4.80-5.10 (2H, br), 5.17 (2H, s), 6.62 (1H, d, J = 5.6 Hz) , 7.26-7.48 (8H, m), 7.77-7.88 (1 H, m), 8.33 (1 H, d, J=5.6 Hz).

Synthesis Example 18

炭酸ビス（トリクロロメチル）（０．４８ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．３９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、２０分間攪拌後、参考例１７で得られた２−（メチルアミノ）エチル テトラヒドロピラン−４−イル カーボネート塩酸塩（０．９６ｇ）を添加した。トリエチルアミン（０．６７ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を０．２Ｎ塩酸（２０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．２６ｇ）、トリエチルアミン（０．７１ｍＬ）、４−ジメチルアミノピリジン（０．０４２ｇ）を添加し、６０℃で６時間、室温で８時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７、続いて酢酸エチルで溶出）で精製した。ジエチルエーテルより結晶化し、アセトン−ジイソプロピルエーテルから再結晶することにより、標題化合物（１．４５ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．６４−１．８１（２Ｈ，ｍ），１．９２−２．０３（２Ｈ，ｍ），２．２３（３Ｈ，ｓ），３．０９（３Ｈ，ｂｓ），３．４０−４．３０（２Ｈ，ｂｒ），３．４５−３．５７（２Ｈ，ｍ），３．８７−３．９７（２Ｈ，ｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．４５（２Ｈ，ｍ），４．７７−５．１５（３Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５−７．５０（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]Carbonyl]amino]ethyl tetrahydropyran-4-yl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.39 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.48 g) under ice-cooling. After stirring for 20 minutes under ice-cooling, 2-(methylamino)ethyl tetrahydropyran-4-yl carbonate hydrochloride (0.96 g) obtained in Reference Example 17 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.67 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.26 g), triethylamine (0. 71 mL) and 4-dimethylaminopyridine (0.042 g) were added and stirred at 60° C. for 6 hours and at room temperature for 8 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=3:7, then eluted with ethyl acetate). Crystallization from diethyl ether and recrystallization from acetone-diisopropyl ether gave the title compound (1.45 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.64-1.81 (2H, m), 1.92-2.03 (2H, m), 2.23 (3H, s), 3.09 (3H, bs), 3.40-4.30 (2H, br), 3.45-3.57 (2H, m), 3.87-3.97 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.45 (2H, m), 4.77-5.15 (3H, m), 6.64 (1H, d, J = 5.7 Hz), 7.35-7. 50 (3H,m), 7.83 (1H,d,J=6.9Hz), 8.35 (1H,d,J=5.7Hz).

Synthesis Example 19

炭酸ビス（トリクロロメチル）（０．５９ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１０分間攪拌後、参考例１８で得られた２−メトキシエチル ２−（メチルアミノ）エチル カーボネート塩酸塩（１．０７ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で１時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を０．２Ｎ塩酸（２０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．８５ｇ）、トリエチルアミン（１．０５ｍＬ）、４−ジメチルアミノピリジン（０．０６１ｇ）を添加し、６０℃で６時間、室温で８時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７、続いて酢酸エチルで溶出）で精製した。酢酸エチル−ジエチルエーテルより結晶化し、酢酸エチル−ジイソプロピルエーテルから再結晶することにより、標題化合物（１．３９ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２３（３Ｈ，ｓ），３．０９（３Ｈ，ｂｓ），３．３７（３Ｈ，ｓ），３．５０−４．２０（２Ｈ，ｂｒ），３．５９−３．６５（２Ｈ，ｍ），４．２８−４．３３（２Ｈ，ｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．４６（２Ｈ，ｍ），４．８０−５．１５（２Ｈ，ｂｒ），６．６４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５−７．４７（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-Methoxyethyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.59 g) under ice-cooling. After stirring for 10 minutes under ice-cooling, 2-methoxyethyl 2-(methylamino)ethyl carbonate hydrochloride (1.07 g) obtained in Reference Example 18 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.85 g), triethylamine (1. 05 mL) and 4-dimethylaminopyridine (0.061 g) were added and stirred at 60° C. for 6 hours and at room temperature for 8 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=3:7, then eluted with ethyl acetate). Crystallization from ethyl acetate-diethyl ether and recrystallization from ethyl acetate-diisopropyl ether gave the title compound (1.39 g) as a colorless solid.
< ¹ >H-NMR ( _CDCl3 ): 2.23 (3H, s), 3.09 (3H, bs), 3.37 (3H, s), 3.50-4.20 (2H, br), 3 .59-3.65 (2H, m), 4.28-4.33 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.46 (2H, m), 4 .80-5.15 (2H, br), 6.64 (1H, d, J = 5.7 Hz), 7.35-7.47 (3H, m), 7.83 (1H, d, J = 7.8 Hz), 8.34 (1H, d, J=5.7 Hz).

Synthesis example 20

炭酸ビス（トリクロロメチル）（０．５９ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１０分間攪拌後、参考例２０で得られた２−（エチルアミノ）エチル アセテート塩酸塩（０．６７ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で１時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７、続いて酢酸エチルで溶出）で精製することにより、標題化合物（１．５８ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２５（３Ｈ，ｍ），２．０８（３Ｈ，ｓ），２．２３（３Ｈ，ｓ），３．３０−４．１０（４Ｈ，ｂｒ），４．２３−４．４５（２Ｈ，ｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．７５−５．２０（２Ｈ，ｂｒ），６．６４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５−７．４６（３Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３６（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[ethyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]Carbonyl]amino]ethyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.59 g) under ice-cooling. After stirring for 10 minutes under ice-cooling, 2-(ethylamino)ethyl acetate hydrochloride (0.67 g) obtained in Reference Example 20 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 84 mL), 4-dimethylaminopyridine (0.037 g) was added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=3:7, then eluted with ethyl acetate) to give the title compound (1.58 g) as a yellow amorphous solid. rice field.
1H ^- NMR ( _CDCl3 ): 1.25 (3H, m), 2.08 (3H, s), 2.23 (3H, s), 3.30-4.10 (4H, br), 4 .23-4.45 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.75-5.20 (2H, br), 6.64 (1H, d, J = 5.7 Hz), 7.35-7.46 (3H, m), 7.84 (1 H, d, J = 6.9 Hz), 8.36 (1 H, d, J = 5.7 Hz).

Synthesis example 21

炭酸ビス（トリクロロメチル）（０．５４３ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．４４５ｍＬ）のテトラヒドロフラン溶液（５ｍＬ）を滴下し、０℃で３０分間撹拌した。反応液に参考例２２で得られた２−（イソプロピルアミノ）エチル アセテート塩酸塩（１．０ｇ）を添加した。トリエチルアミン（０．８０５ｍＬ）のテトラヒドロフラン溶液（５ｍＬ）を添加後、室温で３０分間撹拌した。反応液を減圧濃縮した後、残留物に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた油状物をテトラヒドロフラン（５ｍＬ）に溶解し、（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．７３ｇ）、トリエチルアミン（１．５３ｍＬ）、４−ジメチルアミノピリジン（０．１３４ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に加え、４０℃で１２時間撹拌した。反応液を減圧濃縮した後、残留物に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２：１、続いて酢酸エチルで溶出）で精製し、標題化合物（１．５０ｇ）を淡黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２０−１．４０（６Ｈ，ｍ），２．０５（３Ｈ×０．４，ｓ），２．１１（３Ｈ×０．６，ｓ），２．１８（３Ｈ×０．６，ｓ），２．２７（３Ｈ×０．４，ｓ），３．４０−３．６０（１Ｈ，ｍ），３．７０−４．６０（６Ｈ，ｍ），４．７０−５．２５（２Ｈ，ｍ），６．６５（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），７．３０−７．５０（３Ｈ，ｍ），７．７５−７．９０（１Ｈ，ｍ），８．３７（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ）． 2-[isopropyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl acetate

A tetrahydrofuran solution (5 mL) of pyridine (0.445 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.543 g) under ice cooling, and the mixture was stirred at 0°C for 30 minutes. 2-(Isopropylamino)ethyl acetate hydrochloride (1.0 g) obtained in Reference Example 22 was added to the reaction solution. After adding a tetrahydrofuran solution (5 mL) of triethylamine (0.805 mL), the mixture was stirred at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was dissolved in tetrahydrofuran (5 mL) and (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]- 1H-benzimidazole (1.73 g), triethylamine (1.53 mL) and 4-dimethylaminopyridine (0.134 g) were added to a tetrahydrofuran solution (20 mL) and stirred at 40°C for 12 hours. After the reaction mixture was concentrated under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1, then eluted with ethyl acetate) to give the title compound (1.50 g) as a pale yellow amorphous solid.
< ¹ >H-NMR ( _CDCl3 ): 1.20-1.40 (6H, m), 2.05 (3H x 0.4, s), 2.11 (3H x 0.6, s), 2. 18 (3H x 0.6, s), 2.27 (3H x 0.4, s), 3.40-3.60 (1H, m), 3.70-4.60 (6H, m), 4.70-5.25 (2H, m), 6.65 (1H, d, J=5.8Hz), 7.30-7.50 (3H, m), 7.75-7.90 (1H , m), 8.37 (1H, d, J=5.8 Hz).

Synthesis example 22

炭酸ビス（トリクロロメチル）（０．４６７ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．３８１ｍＬ）のテトラヒドロフラン溶液（５ｍＬ）を滴下し、０℃で３０分間撹拌した。反応液に参考例２３で得られたエチル ２−（イソプロピルアミノ）エチル カーボネート塩酸塩（１．０ｇ）を添加した。トリエチルアミン（０．６９ｍＬ）のテトラヒドロフラン溶液（５ｍＬ）を添加後、０℃で１５分間、室温で３０分間撹拌した。反応液を減圧濃縮した後、残留物に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた油状物をテトラヒドロフラン（５ｍＬ）に溶解し、（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．４８ｇ）、トリエチルアミン（１．３２ｍＬ）、４−ジメチルアミノピリジン（０．１１５ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に加え、４０℃で１２時間撹拌した。反応液を減圧濃縮した後、残留物に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２：１、続いて酢酸エチルで溶出）で精製し、標題化合物（１．２０ｇ）を淡黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２０−１．４０（９Ｈ，ｍ），２．１７（３Ｈ×０．６，ｓ），２．２７（３Ｈ×０．４，ｓ），３．４０−３．７０（１Ｈ，ｍ），３．７５−４．６５（８Ｈ，ｍ），４．７０−５．３０（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），７．３５−７．５５（３Ｈ，ｍ），７．７５−７．９０（１Ｈ，ｍ），８．３８（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ）． Ethyl 2-[isopropyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate

A tetrahydrofuran solution (5 mL) of pyridine (0.381 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.467 g) under ice cooling, and the mixture was stirred at 0°C for 30 minutes. Ethyl 2-(isopropylamino)ethyl carbonate hydrochloride (1.0 g) obtained in Reference Example 23 was added to the reaction solution. After adding a tetrahydrofuran solution (5 mL) of triethylamine (0.69 mL), the mixture was stirred at 0° C. for 15 minutes and at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was dissolved in tetrahydrofuran (5 mL) and (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]- 1H-benzimidazole (1.48 g), triethylamine (1.32 mL) and 4-dimethylaminopyridine (0.115 g) were added to a tetrahydrofuran solution (20 mL) and stirred at 40°C for 12 hours. After the reaction mixture was concentrated under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1, then eluted with ethyl acetate) to give the title compound (1.20 g) as a pale yellow amorphous solid.
< ¹ >H-NMR ( _CDCl3 ): 1.20-1.40 (9H, m), 2.17 (3H x 0.6, s), 2.27 (3H x 0.4, s), 3. 40-3.70 (1H, m), 3.75-4.65 (8H, m), 4.70-5.30 (2H, m), 6.64 (1H, d, J = 5.8Hz ), 7.35-7.55 (3H, m), 7.75-7.90 (1 H, m), 8.38 (1 H, d, J=5.8 Hz).

Synthesis Example 23

炭酸ビス（トリクロロメチル）（０．５９３ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．４８５ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２５で得られた２−（シクロヘキシルアミノ）エチル アセテート塩酸塩（１．３３ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）を滴下後、室温で２時間攪拌した。反応液に酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）及び飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をテトラヒドロフラン（２０ｍＬ）に溶解し、（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．６１ｇ）、トリエチルアミン（１．２１ｍＬ）及び４−ジメチルアミノピリジン（０．０５３ｇ）を添加し、６０℃で２４時間攪拌した。反応液に酢酸エチル（５０ｍＬ）を加え、水（２０ｍＬ）及び飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をフラッシュシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４、続いて酢酸エチルで溶出）で精製することにより、標題化合物（２．１２ｇ）を薄黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．００−２．４２（１６Ｈ，ｍ），３．３０−３．７０（２Ｈ，ｍ），３．８０−４．００（１Ｈ，ｍ），４．２７−４．４２（２Ｈ，ｍ），４．４０（２Ｈ，ｑ，Ｊ＝８．２Ｈｚ），４．７８（１Ｈ×０．５，ｄ，Ｊ＝１３．２Ｈｚ），４．９７（２Ｈ×０．５，ｓ），５．２０（１Ｈ×０．５，ｄ，Ｊ＝１３．２Ｈｚ），６．６７（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），７．３６−７．４６（３Ｈ，ｍ），７．８１−７．９１（１Ｈ，ｍ），８．３９（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ）． 2-[cyclohexyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl acetate

Pyridine (0.485 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.593 g) under ice cooling. After stirring for 30 minutes under ice-cooling, 2-(cyclohexylamino)ethyl acetate hydrochloride (1.33 g) obtained in Reference Example 25 was added. After adding triethylamine (0.84 mL) dropwise, the mixture was stirred at room temperature for 2 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL) and treated with (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benz. Imidazole (1.61 g), triethylamine (1.21 mL) and 4-dimethylaminopyridine (0.053 g) were added and stirred at 60°C for 24 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (20 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate:hexane=1:4, then eluted with ethyl acetate) to give the title compound (2.12 g) as a pale yellow amorphous solid.
@ ¹ H-NMR ( _CDCl3 ): 1.00-2.42 (16 H, m), 3.30-3.70 (2 H, m), 3.80-4.00 (1 H, m), 4. 27-4.42 (2H, m), 4.40 (2H, q, J = 8.2 Hz), 4.78 (1H x 0.5, d, J = 13.2 Hz), 4.97 (2H × 0.5, s), 5.20 (1H × 0.5, d, J = 13.2 Hz), 6.67 (1H, d, J = 5.8 Hz), 7.36-7.46 ( 3H, m), 7.81-7.91 (1H, m), 8.39 (1H, d, J = 5.8 Hz).

Synthesis example 24

炭酸ビス（トリクロロメチル）（０．２３８ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．２０ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２６で得られた２−（シクロヘキシルアミノ）エチル エチル カーボネート塩酸塩（０．６０５ｇ）を添加した。トリエチルアミン（０．３３５ｍＬ）を滴下後、室温で２時間攪拌した。反応液に酢酸エチル（５０ｍＬ）を加え、水（５０ｍＬ）及び飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。残留物をテトラヒドロフラン（１０ｍＬ）に溶解し、（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．６０ｇ）、トリエチルアミン（０．４５ｍＬ）及び４−ジメチルアミノピリジン（０．０２ｇ）を添加し、６０℃で２４時間攪拌した。反応液に酢酸エチル（５０ｍＬ）を加え、水（２０ｍＬ）及び飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をフラッシュシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４、続いて酢酸エチルで溶出）で精製することにより、標題化合物（０．９２ｇ）を薄黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．０２−２．２７（１６Ｈ，ｍ），３．４０−４．６０（９Ｈ，ｍ），４．７８（１Ｈ×０．５，ｄ，Ｊ＝１３．２Ｈｚ），４．９７（２Ｈ×０．５，ｓ），５．４４（１Ｈ×０．５，ｄ，Ｊ＝１３．２Ｈｚ），６．６９（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３２−７．５４（３Ｈ，ｍ），７．８０−７．９１（１Ｈ，ｍ），８．３８（１Ｈ，ｄ，Ｊ＝ ５．６Ｈｚ）． 2-[cyclohexyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl ethyl carbonate

Pyridine (0.20 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.238 g) under ice cooling. After stirring for 30 minutes under ice-cooling, 2-(cyclohexylamino)ethyl ethyl carbonate hydrochloride (0.605 g) obtained in Reference Example 26 was added. After adding triethylamine (0.335 mL) dropwise, the mixture was stirred at room temperature for 2 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL) and treated with (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benz. Imidazole (0.60 g), triethylamine (0.45 mL) and 4-dimethylaminopyridine (0.02 g) were added and stirred at 60°C for 24 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with water (20 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate:hexane=1:4, then eluted with ethyl acetate) to give the title compound (0.92 g) as a pale yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.02-2.27 (16H, m), 3.40-4.60 (9H, m), 4.78 (1H x 0.5, d, J = 13 .2 Hz), 4.97 (2H x 0.5, s), 5.44 (1H x 0.5, d, J = 13.2 Hz), 6.69 (1H, d, J = 5.6 Hz) , 7.32-7.54 (3H, m), 7.80-7.91 (1 H, m), 8.38 (1 H, d, J = 5.6 Hz).

Synthesis example 25

炭酸ビス（トリクロロメチル）（１３．４ｇ）のテトラヒドロフラン溶液（３５０ｍＬ）に氷冷下、ピリジン（１０．３８ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２７で得られた２−アニリノエチル アセテート塩酸塩（２５．９ｇ）を添加した。トリエチルアミン（１８．４ｍＬ）を滴下後、室温で２時間攪拌した。減圧濃縮後、残留物に酢酸エチル（５００ｍＬ）と水（５００ｍＬ）を加え、攪拌した。酢酸エチル層を分取し、飽和食塩水（５００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮することにより、２−［（クロロカルボニル）（フェニル）アミノ］エチル アセテートを得た。これをテトラヒドロフラン（３００ｍＬ）に溶解し、（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（４１．２ｇ）、トリエチルアミン（１５．６ｍＬ）及び４−ジメチルアミノピリジン（１．３６３ｇ）を添加し、６０℃で３時間攪拌した。反応液に酢酸エチル（８００ｍＬ）を加え、水（８００ｍＬ）で２回、さらに飽和食塩水（８００ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７、続いて１：１で溶出）で精製した。ジエチルエーテルから結晶化することにより、標題化合物（５４．１ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．００（３Ｈ，ｓ），２．２５（３Ｈ，ｓ），４．１５−４．４８（６Ｈ，ｍ），４．８３（１Ｈ，ｄ，Ｊ＝１３．６Ｈｚ），５．０５（１Ｈ，ｄ，Ｊ＝１３．６Ｈｚ），６．６７（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．０３−７．４５（８Ｈ，ｍ），７．６４−７．６９（１Ｈ，ｍ），８．４０（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ）． 2-[[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl] carbonyl](phenyl)amino]ethyl acetate

Pyridine (10.38 mL) was added dropwise to a tetrahydrofuran solution (350 mL) of bis(trichloromethyl) carbonate (13.4 g) under ice cooling. After stirring for 30 minutes under ice-cooling, 2-anilinoethyl acetate hydrochloride (25.9 g) obtained in Reference Example 27 was added. After dropping triethylamine (18.4 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, ethyl acetate (500 mL) and water (500 mL) were added to the residue and stirred. The ethyl acetate layer was separated, washed with saturated brine (500 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-[(chlorocarbonyl)(phenyl)amino]ethyl acetate. This was dissolved in tetrahydrofuran (300 mL) to give (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole. (41.2 g), triethylamine (15.6 mL) and 4-dimethylaminopyridine (1.363 g) were added and stirred at 60° C. for 3 hours. Ethyl acetate (800 mL) was added to the reaction mixture, and the mixture was washed with water (800 mL) twice and saturated brine (800 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=3:7, then eluted with 1:1). Crystallization from diethyl ether gave the title compound (54.1 g) as a white solid.
1H ^- NMR ( _CDCl3 ): 2.00 (3H, s), 2.25 (3H, s), 4.15-4.48 (6H, m), 4.83 (1H, d, J = 13.6 Hz), 5.05 (1 H, d, J = 13.6 Hz), 6.67 (1 H, d, J = 5.4 Hz), 7.03-7.45 (8 H, m), 7. 64-7.69 (1 H, m), 8.40 (1 H, d, J=5.4 Hz).

Synthesis example 26

合成例２５と同様にして調製した２−［（クロロカルボニル）（フェニル）アミノ］エチル アセテート（０．５８ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に、２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．７３９ｇ）、トリエチルアミン（０．５５８ｍＬ）及び４−ジメチルアミノピリジン（０．０２４ｇ）を添加し、６０℃で１５時間攪拌した。反応液に酢酸エチル（３０ｍＬ）を加え、水（５０ｍＬ）及び飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をフラッシュシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：４、続いて３：２で溶出）で精製した。ジエチルエーテルから結晶化することにより、標題化合物（０．７７９ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．９９（３Ｈ，ｓ），２．２５（３Ｈ，ｓ），４．２０−４．４８（６Ｈ，ｍ），４．８３（１Ｈ，ｄ，Ｊ＝１３．６Ｈｚ），５．０５（１Ｈ，ｄ，Ｊ＝１３．６Ｈｚ），６．６７（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ），７．０３−７．４５（８Ｈ，ｍ），７．６４−７．６９（１Ｈ，ｍ），８．４０（１Ｈ，ｄ，Ｊ＝５．８Ｈｚ）． 2-[[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl ) amino] ethyl acetate

2-[[[3-methyl-4-(2, 2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (0.739 g), triethylamine (0.558 mL) and 4-dimethylaminopyridine (0.024 g) were added and 60 C. for 15 hours. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:4, then 3:2). Crystallization from diethyl ether gave the title compound (0.779 g) as a white solid.
1H ^- NMR ( _CDCl3 ): 1.99 (3H, s), 2.25 (3H, s), 4.20-4.48 (6H, m), 4.83 (1H, d, J = 13.6 Hz), 5.05 (1 H, d, J = 13.6 Hz), 6.67 (1 H, d, J = 5.8 Hz), 7.03-7.45 (8 H, m), 7. 64-7.69 (1 H, m), 8.40 (1 H, d, J=5.8 Hz).

Synthesis Example 27

炭酸ビス（トリクロロメチル）（０．３０ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．２４ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２８で得られたｔｅｒｔ−ブチル ［２−（メチルアミノ）−３−ピリジル］メチル カーボネート（０．７１ｇ）を添加し、室温で２時間攪拌した。析出した固体を濾別し、濾液を減圧濃縮した。残留物をテトラヒドロフラン（２０ｍＬ）に溶解し、（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．９２ｇ）、トリエチルアミン（０．７０ｍＬ）及び４−ジメチルアミノピリジン（０．０３１ｇ）を添加し、６０℃で１時間攪拌した。反応液に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で２回抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をフラッシュシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：２で溶出）で精製し、さらに塩基性シリカゲルカラムクロマトグラフィー（酢酸エチルで溶出）で精製することにより、標題化合物（０．３８ｇ）を薄黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．４６（９Ｈ，ｓ），２．２５（３Ｈ，ｓ），３．５４（３Ｈ，ｓ），４．３７（２Ｈ，ｑ，Ｊ＝８．０Ｈｚ），４．９５（２Ｈ，ｓ），５．１５（１Ｈ，ｄ，Ｊ＝１４．０Ｈｚ），５．２７（１Ｈ，ｄ，Ｊ＝１４．０Ｈｚ），６．６３（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．２６−７．４５（３Ｈ，ｍ），７．６９−７．８７（３Ｈ，ｍ），８．３３（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），８．４４−８．４６（１Ｈ，ｍ）． tert-butyl [2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]-3-pyridyl]methyl carbonate

Pyridine (0.24 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.30 g) under ice cooling. After stirring for 30 minutes under ice-cooling, tert-butyl [2-(methylamino)-3-pyridyl]methyl carbonate (0.71 g) obtained in Reference Example 28 was added, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL) and treated with (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benz. Imidazole (0.92 g), triethylamine (0.70 mL) and 4-dimethylaminopyridine (0.031 g) were added and stirred at 60°C for 1 hour. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:2) and further purified by basic silica gel column chromatography (eluted with ethyl acetate) to give the title compound (0.38 g). Obtained as a pale yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.46 (9H, s), 2.25 (3H, s), 3.54 (3H, s), 4.37 (2H, q, J = 8.0 Hz) , 4.95 (2H, s), 5.15 (1H, d, J = 14.0 Hz), 5.27 (1H, d, J = 14.0 Hz), 6.63 (1H, d, J = 5.4 Hz), 7.26-7.45 (3H, m), 7.69-7.87 (3H, m), 8.33 (1H, d, J = 5.4 Hz), 8.44- 8.46 (1 H, m).

Synthesis Example 28

炭酸ビス（トリクロロメチル）（１．４６ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（１．１６ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２９で得られた２−（メチルアミノ）ベンジル アセテート（２．５７ｇ）を添加し、室温で３時間攪拌した。析出した固体を濾別し、濾液を減圧濃縮した。残留物をテトラヒドロフラン（４０ｍＬ）に溶解し、（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（４．４１ｇ）、トリエチルアミン（３．３３ｍＬ）及び４−ジメチルアミノピリジン（０．１５ｇ）を添加し、６０℃で１８時間攪拌した。反応液に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をフラッシュシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝１：４、続いて１：２で溶出）で精製した。酢酸エチル−ジエチルエーテル−ヘキサンから結晶化することにより、標題化合物（２．７６ｇ）を白色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．１０（３Ｈ，ｓ），２．００−２．３０（３Ｈ，ｂｒ），３．２０−３．５０（３Ｈ，ｂｒ），４．３８（２Ｈ，ｑ，Ｊ＝７．６Ｈｚ），４．７０−５．２０（２Ｈ，ｍ），５．２０−５．５０（２Ｈ，ｍ），６．６５（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．１０−７．８２（８Ｈ，ｍ），８．３８（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]benzyl acetate

Pyridine (1.16 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (1.46 g) under ice cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)benzyl acetate (2.57 g) obtained in Reference Example 29 was added, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (40 mL) and treated with (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benz. Imidazole (4.41 g), triethylamine (3.33 mL) and 4-dimethylaminopyridine (0.15 g) were added and stirred at 60°C for 18 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluted with acetone:hexane=1:4, then 1:2). Crystallization from ethyl acetate-diethyl ether-hexane gave the title compound (2.76 g) as a white solid.
1H ^- NMR ( _CDCl3 ): 2.10 (3H, s), 2.00-2.30 (3H, br), 3.20-3.50 (3H, br), 4.38 (2H, q, J = 7.6 Hz), 4.70-5.20 (2H, m), 5.20-5.50 (2H, m), 6.65 (1H, d, J = 5.4 Hz), 7.10-7.82 (8H, m), 8.38 (1H, d, J = 5.4 Hz).

Synthesis Example 29

炭酸ビス（トリクロロメチル）（０．５０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１０分間攪拌後、参考例３０で得られた２−［（２−アセチルオキシエチル）アミノ］エチル アセテート塩酸塩（１．１３ｇ）を添加した。トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２時間攪拌した。析出した固体を濾別し、濾液を減圧濃縮した。残留物に酢酸エチル（２０ｍＬ）を加え、析出した固体を濾別し、濾液を減圧濃縮した。残留物をテトラヒドロフラン（３０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．４８ｇ）、トリエチルアミン（１．１２ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチルで溶出）で精製し、さらに塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチルで溶出）で精製した。酢酸エチル（２０ｍＬ）に溶解し、活性炭を加えて終夜攪拌した。活性炭を濾別し、濾液を減圧濃縮することにより、標題化合物（１．６０ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．０６（３Ｈ，ｓ），２．０８（３Ｈ，ｓ），２．２４（３Ｈ，ｓ），３．４０−４．４５（８Ｈ，ｍ），４．３９（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．８８（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），５．０５（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），６．６６（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３８−７．５０（３Ｈ，ｍ），７．８７（１Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３６（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． 2-[[2-(acetyloxy)ethyl][[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]- 1H-benzimidazol-1-yl]carbonyl]amino]ethyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.40 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.50 g) under ice-cooling. After stirring for 10 minutes under ice-cooling, 2-[(2-acetyloxyethyl)amino]ethyl acetate hydrochloride (1.13 g) obtained in Reference Example 30 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL), the mixture was stirred at room temperature for 2 hours. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (20 mL) was added to the residue, the precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.48 g), triethylamine (1. 12 mL) and 4-dimethylaminopyridine (catalytic amount) were added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, followed by elution with ethyl acetate), and further purified by basic silica gel column chromatography (ethyl acetate:hexane=1:1, followed by and eluted with ethyl acetate). The mixture was dissolved in ethyl acetate (20 mL), activated carbon was added, and the mixture was stirred overnight. The activated carbon was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.60 g) as a yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 2.06 (3H, s), 2.08 (3H, s), 2.24 (3H, s), 3.40-4.45 (8H, m), 4 .39 (2H, q, J = 7.9 Hz), 4.88 (1 H, d, J = 13.2 Hz), 5.05 (1 H, d, J = 13.2 Hz), 6.66 (1 H, d, J = 5.6 Hz), 7.38-7.50 (3 H, m), 7.87 (1 H, d, J = 6.9 Hz), 8.36 (1 H, d, J = 5.6 Hz ).

Synthesis example 30

炭酸ビス（トリクロロメチル）（０．５０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例３１で得られた（Ｓ）−２−ピロリジニルメチル アセテート塩酸塩（０．９０ｇ）を添加した。トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で１日間、室温で２日間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチルで溶出）で精製し、さらにシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：１、続いて酢酸エチル、続いてアセトン：酢酸エチル＝１：４、続いて２：３で溶出）で精製することにより、標題化合物（０．８０ｇ）を淡黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．８０−２．３０（４Ｈ，ｍ），２．０９（３Ｈ，ｓ），２．３０（３Ｈ，ｓ），３．３９（１Ｈ，ｍ），３．５０−３．６２（１Ｈ，ｍ），４．２０−４．４５（４Ｈ，ｍ），４．５８（１Ｈ，ｍ），４．８９（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），４．９６（１Ｈ，ｄ，Ｊ＝１３．５Ｈｚ），６．６５（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．３６−７．４８（３Ｈ，ｍ），７．８９（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ），８．３８（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）． [(2S)-1-[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole- 1-yl]carbonyl]-2-pyrrolidinyl]methyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.40 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.50 g) under ice-cooling. After stirring for 1 hour under ice-cooling, (S)-2-pyrrolidinylmethyl acetate hydrochloride (0.90 g) obtained in Reference Example 31 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, extracted with ethyl acetate (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 84 mL) and 4-dimethylaminopyridine (0.037 g) were added and stirred at 60° C. for 1 day and at room temperature for 2 days. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with ethyl acetate), and further purified by silica gel column chromatography (ethyl acetate:hexane=3:1, then eluted with ethyl acetate). followed by elution with ethyl acetate, followed by acetone:ethyl acetate = 1:4, then 2:3) to give the title compound (0.80 g) as a pale yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.80-2.30 (4H, m), 2.09 (3H, s), 2.30 (3H, s), 3.39 (1H, m), 3 .50-3.62 (1 H, m), 4.20-4.45 (4 H, m), 4.58 (1 H, m), 4.89 (1 H, d, J = 13.5 Hz), 4 .96 (1H, d, J=13.5 Hz), 6.65 (1 H, d, J=5.9 Hz), 7.36-7.48 (3 H, m), 7.89 (1 H, d, J=8.7 Hz), 8.38 (1H, d, J=5.9 Hz).

Synthesis example 31

炭酸ビス（トリクロロメチル）（０．５０ｇ）のテトラヒドロフラン溶液（３０ｍＬ）に氷冷下、ピリジン（０．４０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、サルコシンエチルエステル塩酸塩（０．７７ｇ）を添加した。トリエチルアミン（０．７０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で１時間攪拌した。析出した固体を濾別し、濾液を減圧濃縮した。残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（３３ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾールナトリウム塩（１．３７ｇ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチルで溶出）で精製することにより、標題化合物（０．４０ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３３（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），２．２４（３Ｈ，ｓ），３．１０（３Ｈ，ｂｓ），３．７０−４．３０（２Ｈ，ｂｒ），４．２８（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．８２−５．１０（２Ｈ，ｂｒ），６．６３（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ），７．３４−７．５２（２Ｈ，ｍ），７．７０−７．９０（２Ｈ，ｍ），８．３２（１Ｈ，ｄ，Ｊ＝５．５Ｈｚ）． Ethyl [methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl] carbonyl]amino]acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.40 mL) was added dropwise to a tetrahydrofuran solution (30 mL) of bis(trichloromethyl) carbonate (0.50 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, sarcosine ethyl ester hydrochloride (0.77 g) was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.70 mL), the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered off, and the filtrate was concentrated under reduced pressure. Water (50 mL) was added to the residue and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (33 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt (1.37 g), 4- Dimethylaminopyridine (catalytic amount) was added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with ethyl acetate) to give the title compound (0.40 g) as a yellow amorphous solid. rice field.
1H ^- NMR ( _CDCl3 ): 1.33 (3H, t, J = 7.1 Hz), 2.24 (3H, s), 3.10 (3H, bs), 3.70-4.30 ( 2H, br), 4.28 (2H, q, J = 7.1 Hz), 4.38 (2H, q, J = 7.8 Hz), 4.82-5.10 (2H, br), 6. 63 (1H, d, J = 5.5Hz), 7.34-7.52 (2H, m), 7.70-7.90 (2H, m), 8.32 (1H, d, J = 5 .5Hz).

Synthesis Example 32

炭酸ビス（トリクロロメチル）（０．３４４ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．２８１ｍＬ）のテトラヒドロフラン溶液（５ｍＬ）を滴下し、０℃で３０分間撹拌した。反応液に参考例５で得られた２−（メチルアミノ）エチル ベンゾエート塩酸塩（０．７５０ｇ）を添加した。トリエチルアミン（０．４８５ｍＬ）のテトラヒドロフラン溶液（５ｍＬ）を添加後、０℃で１時間、室温で３０分間撹拌した。反応液を減圧濃縮した後、残留物に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた油状物をテトラヒドロフラン（５ｍＬ）に溶解し、５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンゾイミダゾール（１．０ｇ）、トリエチルアミン（０．８０８ｍＬ）、４−ジメチルアミノピリジン（０．０７１ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に加え、４０℃で１８時間撹拌した。反応液を減圧濃縮した後、残留物に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチルで溶出）で精製し、標題化合物と２−［［［６−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンゾイミダゾール−１−イル］カルボニル］（メチル）アミノ］エチル ベンゾエートの１：１混合物（１．５０ｇ）を淡黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．０５−２．３５（６Ｈ，ｍ），３．００−３．３０（３Ｈ，ｂｒ），３．６０−４．４０（８Ｈ，ｍ），４．６０−５．１０（４Ｈ，ｍ），６．８０−７．００（２Ｈ，ｍ），７．２０−７．７０（４Ｈ，ｍ），７．９５−８．２５（３Ｈ，ｍ）． 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl Benzoate

A tetrahydrofuran solution (5 mL) of pyridine (0.281 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.344 g) under ice cooling, and the mixture was stirred at 0°C for 30 minutes. 2-(Methylamino)ethyl benzoate hydrochloride (0.750 g) obtained in Reference Example 5 was added to the reaction solution. After adding a tetrahydrofuran solution (5 mL) of triethylamine (0.485 mL), the mixture was stirred at 0° C. for 1 hour and at room temperature for 30 minutes. After the reaction mixture was concentrated under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oil was dissolved in tetrahydrofuran (5 mL) and treated with 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (1.0 g). ), triethylamine (0.808 mL) and 4-dimethylaminopyridine (0.071 g) in tetrahydrofuran solution (10 mL), and stirred at 40° C. for 18 hours. After the reaction mixture was concentrated under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with ethyl acetate) to give the title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3). ,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl benzoate (1.50 g) as a pale yellow amorphous solid. rice field.
@ ¹ H-NMR ( _CDCl3 ): 2.05-2.35 (6H, m), 3.00-3.30 (3H, br), 3.60-4.40 (8H, m), 4. 60-5.10 (4H, m), 6.80-7.00 (2H, m), 7.20-7.70 (4H, m), 7.95-8.25 (3H, m).

Synthesis Example 33

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４８５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例３２で得られた３−（メチルアミノ）プロピル ベンゾエート塩酸塩（１．３８ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２時間攪拌した。減圧濃縮後、残留物に水（４０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（２５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．６３ｇ）、トリエチルアミン（１．２３ｍＬ）、４−ジメチルアミノピリジン（０．０５４ｇ）を添加し、６０℃で４時間攪拌した。減圧濃縮後、残留物に水（４０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（１．２６ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２１（３Ｈ，ｓ），２．２０−２．３０（２Ｈ，ｂｍ），３．０６（３Ｈ，ｂｓ），３．６０−３．７５（２Ｈ，ｂｍ），４．３６（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．３０−４．５０（２Ｈ，ｂｍ），４．８０−５．１５（２Ｈ，ｂｍ），６．６２（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２６−７．４４（５Ｈ，ｍ），７．５４（１Ｈ，ｍ），７．８１（１Ｈ，ｍ），７．９３−８．０３（２Ｈ，ｂｍ），８．３５（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]propyl benzoate

A tetrahydrofuran solution (1 mL) of pyridine (0.485 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 1 hour under ice-cooling, 3-(methylamino)propyl benzoate hydrochloride (1.38 g) obtained in Reference Example 32 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (25 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.63 g), triethylamine (1. 23 mL) and 4-dimethylaminopyridine (0.054 g) were added and stirred at 60° C. for 4 hours. After concentration under reduced pressure, water (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (1.26 g) as a yellow amorphous solid. Obtained.
< ¹ >H-NMR ( _CDCl3 ): 2.21 (3H, s), 2.20-2.30 (2H, bm), 3.06 (3H, bs), 3.60-3.75 (2H, bm), 4.36 (2H, q, J = 7.8 Hz), 4.30-4.50 (2H, bm), 4.80-5.15 (2H, bm), 6.62 (1H, d, J = 5.7 Hz), 7.26-7.44 (5H, m), 7.54 (1 H, m), 7.81 (1 H, m), 7.93-8.03 (2H, bm), 8.35 (1H,d,J=5.7Hz).

Synthesis Example 34

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４８５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、２０分間攪拌後、参考例１７で得られた２−（メチルアミノ）エチル テトラヒドロピラン−４−イル カーボネート塩酸塩（１．４３ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（２０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．６３ｇ）、トリエチルアミン（１．２３ｍＬ）、４−ジメチルアミノピリジン（０．０２７ｇ）を添加し、６０℃で１７．５時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（１２０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製した。続いてシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて２：１で溶出）で精製した。ジエチルエーテルより結晶化することにより、標題化合物（１．２３ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．６４−１．８１（２Ｈ，ｍ），１．９２−２．０３（２Ｈ，ｍ），２．２３（３Ｈ，ｓ），３．１０（３Ｈ，ｂｓ），３．４０−４．３０（２Ｈ，ｂｒ），３．４６−３．５９（２Ｈ，ｍ），３．８７−３．９９（２Ｈ，ｍ），４．３９（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．４５（２Ｈ，ｍ），４．７７−５．１５（３Ｈ，ｍ），６．６５（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．３５−７．５０（３Ｈ，ｍ），７．８５（１Ｈ，ｍ），８．３６（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ）． 2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino ] Ethyl tetrahydropyran-4-yl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.485 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 20 minutes under ice-cooling, 2-(methylamino)ethyl tetrahydropyran-4-yl carbonate hydrochloride (1.43 g) obtained in Reference Example 17 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.63 g), triethylamine (1.23 mL), 4 -Dimethylaminopyridine (0.027 g) was added and stirred at 60°C for 17.5 hours. After concentration under reduced pressure, water (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (120 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1). Subsequently, it was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with 2:1). Crystallization from diethyl ether gave the title compound (1.23 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.64-1.81 (2H, m), 1.92-2.03 (2H, m), 2.23 (3H, s), 3.10 (3H, bs), 3.40-4.30 (2H, br), 3.46-3.59 (2H, m), 3.87-3.99 (2H, m), 4.39 (2H, q, J = 7.9 Hz), 4.45 (2H, m), 4.77-5.15 (3H, m), 6.65 (1H, d, J = 5.4 Hz), 7.35-7. 50 (3H, m), 7.85 (1 H, m), 8.36 (1 H, d, J=5.4 Hz).

Synthesis example 35

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４８５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例１４で得られたエチル ２−（メチルアミノ）エチル カーボネート塩酸塩（１．１０ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．６３ｇ）、トリエチルアミン（１．２３ｍＬ）、４−ジメチルアミノピリジン（０．０５４ｇ）を添加し、６０℃で１４時間攪拌した。減圧濃縮後、残留物に水（４０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製した。続いてシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて２：１で溶出）で精製することにより、標題化合物（１．２７ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３２（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），２．２３（３Ｈ，ｓ），３．０９（３Ｈ，ｂｓ），３．５０−４．７６（４Ｈ，ｂｒ），４．２１（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），４．３８（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．８４−５．１４（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３６−７．４６（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝７．２Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． Ethyl 2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl] Amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.485 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, ethyl 2-(methylamino)ethyl carbonate hydrochloride (1.10 g) obtained in Reference Example 14 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.63 g), triethylamine (1.23 mL), 4 -Dimethylaminopyridine (0.054 g) was added and stirred at 60°C for 14 hours. After concentration under reduced pressure, water (40 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1). Subsequent purification by silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with 2:1) gave the title compound (1.27 g) as a yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.32 (3H, t, J = 7.1 Hz), 2.23 (3H, s), 3.09 (3H, bs), 3.50-4.76 ( 4H, br), 4.21 (2H, q, J=7.1 Hz), 4.38 (2H, q, J=7.9 Hz), 4.84-5.14 (2H, m), 6. 64 (1 H, d, J = 5.6 Hz), 7.36-7.46 (3 H, m), 7.83 (1 H, d, J = 7.2 Hz), 8.34 (1 H, d, J = 5.6 Hz).

Synthesis Example 36

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４８５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例１４で得られたエチル ２−（メチルアミノ）エチル カーボネート塩酸塩（１．１０ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｓ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１５ｇ）、トリエチルアミン（０．８７ｍＬ）、４−ジメチルアミノピリジン（０．０３５ｇ）を添加し、６０℃で１２時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製した。ジエチルエーテルより結晶化することにより、標題化合物（０．４０ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３２（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．２３（３Ｈ，ｓ），３．１０（３Ｈ，ｂｓ），３．５０−４．５６（４Ｈ，ｂｒ），４．２２（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．３８（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．８４−５．１４（２Ｈ，ｍ），６．６５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３４−７．５０（３Ｈ，ｍ），７．８５（１Ｈ，ｍ），８．３６（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． Ethyl 2-[methyl[[(S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.485 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 1 hour under ice-cooling, ethyl 2-(methylamino)ethyl carbonate hydrochloride (1.10 g) obtained in Reference Example 14 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (S)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.15 g), triethylamine (0. 87 mL) and 4-dimethylaminopyridine (0.035 g) were added and stirred at 60° C. for 12 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1). Crystallization from diethyl ether gave the title compound (0.40 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.32 (3H, t, J = 7.2 Hz), 2.23 (3H, s), 3.10 (3H, bs), 3.50-4.56 ( 4H, br), 4.22 (2H, q, J=7.2 Hz), 4.38 (2H, q, J=7.9 Hz), 4.84-5.14 (2H, m), 6. 65 (1 H, d, J=5.6 Hz), 7.34-7.50 (3 H, m), 7.85 (1 H, m), 8.36 (1 H, d, J=5.6 Hz).

Synthesis Example 37

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４８５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例１４で得られたエチル ２−（メチルアミノ）エチル カーボネート塩酸塩（１．１０ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２．５時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。特開昭６３−１４６８８２に記載の方法で合成した５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−イミダゾ［４，５−ｂ］ピリジン（１．４４ｇ）、トリエチルアミン（１．１６ｍＬ）、４−ジメチルアミノピリジン（０．０４９ｇ）を添加し、６０℃で６時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製した。ジエチルエーテルより結晶化することにより、標題化合物（０．７２１ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２５−１．３４（３Ｈ，ｍ），２．２３（６Ｈ，ｓ），３．１５，３．３２（合計３Ｈ，ｓ），３．７２（３Ｈ，ｓ），３．９０−４．５３（９Ｈ，ｍ），４．８６（１Ｈ，ｄ，Ｊ＝１３．４Ｈｚ），４．９５（１Ｈ，ｄ，Ｊ＝１３．４Ｈｚ），６．７９（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ），７．９５（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ），８．２２（１Ｈ，ｓ）． Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl] Carbonyl](methyl)amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.485 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, ethyl 2-(methylamino)ethyl carbonate hydrochloride (1.10 g) obtained in Reference Example 14 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2.5 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b synthesized by the method described in JP-A-63-146882 ] Pyridine (1.44 g), triethylamine (1.16 mL) and 4-dimethylaminopyridine (0.049 g) were added and stirred at 60° C. for 6 hours. After concentration under reduced pressure, water (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1). Crystallization from diethyl ether gave the title compound (0.721 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.25-1.34 (3H, m), 2.23 (6H, s), 3.15, 3.32 (total 3H, s), 3.72 (3H , s), 3.90-4.53 (9H, m), 4.86 (1H, d, J = 13.4 Hz), 4.95 (1H, d, J = 13.4 Hz), 6.79 (1H, d, J=8.7 Hz), 7.95 (1 H, d, J=8.7 Hz), 8.22 (1 H, s).

Synthesis Example 38

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４８５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２で得られた２−（メチルアミノ）エチル アセテート塩酸塩（０．９２２ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１０ｍＬ）に溶解した。特開昭６３−１４６８８２に記載の方法で合成した５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−イミダゾ［４，５−ｂ］ピリジン（０．８５ｇ）、トリエチルアミン（０．７０ｍＬ）、４−ジメチルアミノピリジン（０．０２５ｇ）を添加し、６０℃で５時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（９０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製した。ジエチルエーテルより結晶化することにより、標題化合物（０．１７３ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．０４，２．０９（合計３Ｈ，ｓ），２．２４（６Ｈ，ｓ），３．１３，３．３０（合計３Ｈ，ｓ），３．４５−３．９７（２Ｈ，ｍ），３．７２（３Ｈ，ｓ），３．９７（３Ｈ，ｓ），４．１５−４．５０（２Ｈ，ｍ），４．８５（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），４．９６（１Ｈ，ｄ，Ｊ＝１３．１Ｈｚ），６．８０（１Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝８．９Ｈｚ），８．２２（１Ｈ，ｓ）． 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl ](methyl)amino]ethyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.485 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl acetate hydrochloride (0.922 g) obtained in Reference Example 2 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (10 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b synthesized by the method described in JP-A-63-146882 ] Pyridine (0.85 g), triethylamine (0.70 mL) and 4-dimethylaminopyridine (0.025 g) were added and stirred at 60° C. for 5 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (90 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1). Crystallization from diethyl ether gave the title compound (0.173 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.04, 2.09 (total 3H, s), 2.24 (6H, s), 3.13, 3.30 (total 3H, s), 3.45- 3.97 (2H, m), 3.72 (3H, s), 3.97 (3H, s), 4.15-4.50 (2H, m), 4.85 (1H, d, J = 13.1 Hz), 4.96 (1H, d, J = 13.1 Hz), 6.80 (1H, d, J = 8.9 Hz), 7.96 (1H, d, J = 8.9 Hz), 8.22 (1H, s).

Synthesis Example 39

炭酸ビス（トリクロロメチル）（０．２９１ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．２４３ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２７で得られた２−アニリノエチル アセテート塩酸塩（０．６４７ｇ）を添加した。トリエチルアミン（０．４１９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（２０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１０ｍＬ）に溶解した。特開昭６３−１４６８８２に記載の方法で合成した５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−イミダゾ［４，５−ｂ］ピリジン（０．８６７ｇ）、トリエチルアミン（０．６９７ｍＬ）、４−ジメチルアミノピリジン（０．０２０ｇ）を添加し、６０℃で１０時間攪拌した。減圧濃縮後、残留物に水（２０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１で溶出）で精製した。ジエチルエーテルより結晶化することにより、標題化合物（０．３１１ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．９６（３Ｈ，ｓ），２．２３（３Ｈ，ｓ），２．２５（３Ｈ，ｓ），３．７２（３Ｈ，ｓ），４．０１（３Ｈ，ｓ），４．１２−４．５２（４Ｈ，ｍ），４．７８−５．２２（２Ｈ，ｍ），６．６２（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ），７．０２−７．１８（３Ｈ，ｍ），７．３２−７．４８（２Ｈ，ｍ），７．７３（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ），８．２６（１Ｈ，ｓ）． 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl ](phenyl)amino]ethyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.243 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.291 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Example 27 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.419 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (20 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (10 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b synthesized by the method described in JP-A-63-146882 ] Pyridine (0.867 g), triethylamine (0.697 mL) and 4-dimethylaminopyridine (0.020 g) were added and stirred at 60° C. for 10 hours. After concentration under reduced pressure, water (20 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:1). Crystallization from diethyl ether gave the title compound (0.311 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.96 (3H, s), 2.23 (3H, s), 2.25 (3H, s), 3.72 (3H, s), 4.01 (3H , s), 4.12-4.52 (4H, m), 4.78-5.22 (2H, m), 6.62 (1H, d, J = 8.7 Hz), 7.02-7 .18 (3H, m), 7.32-7.48 (2H, m), 7.73 (1 H, d, J=8.7 Hz), 8.26 (1 H, s).

Synthesis example 40

炭酸ビス（トリクロロメチル）（０．５９ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例３７で得られた４−（メチルアミノ）ブチル アセテート塩酸塩（１．０８ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．０２ｇ）、トリエチルアミン（０．７７ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（０．９３ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．６５−１．８５（４Ｈ，ｍ），２．０３（３Ｈ，ｓ），２．２３（３Ｈ，ｓ），３．０２（３Ｈ，ｂｓ），３．４５−３．６３（２Ｈ，ｍ），４．０３−４．１３（２Ｈ，ｍ），４．３７（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．８５−５．１３（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３６−７．４６（３Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． 4-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]Carbonyl]amino]butyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.59 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 4-(methylamino)butyl acetate hydrochloride (1.08 g) obtained in Reference Example 37 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.02 g), triethylamine (0. 77 mL) and 4-dimethylaminopyridine (catalytic amount) were added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (0.93 g) as a yellow amorphous solid. Obtained.
1H ^- NMR ( _CDCl3 ): 1.65-1.85 (4H, m), 2.03 (3H, s), 2.23 (3H, s), 3.02 (3H, bs), 3 .45-3.63 (2H, m), 4.03-4.13 (2H, m), 4.37 (2H, q, J = 7.8 Hz), 4.85-5.13 (2H, m), 6.64 (1H, d, J = 5.6 Hz), 7.36-7.46 (3H, m), 7.84 (1H, d, J = 8.4 Hz), 8.35 ( 1H, d, J=5.6 Hz).

Synthesis Example 41

炭酸ビス（トリクロロメチル）（０．５９ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例３９で得られたエチル ４−（メチルアミノ）ブチル カーボネート塩酸塩（１．２７ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．２６ｇ）、トリエチルアミン（０．９５ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（１．０８ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３１（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），１．７３−１．９１（４Ｈ，ｍ），２．２３（３Ｈ，ｓ），３．０１（３Ｈ，ｂｓ），３．５０−３．６２（２Ｈ，ｍ），４．１５−４．２２（４Ｈ，ｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．８７−５．１３（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ），７．３５−７．４６（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．４Ｈｚ）． Ethyl 4-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]butyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.59 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, ethyl 4-(methylamino)butyl carbonate hydrochloride (1.27 g) obtained in Reference Example 39 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.26 g), triethylamine (0. 95 mL) and 4-dimethylaminopyridine (catalytic amount) were added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (1.08 g) as a yellow amorphous solid. Obtained.
1H ^- NMR ( _CDCl3 ): 1.31 (3H, t, J = 7.2 Hz), 1.73-1.91 (4H, m), 2.23 (3H, s), 3.01 ( 3H, bs), 3.50-3.62 (2H, m), 4.15-4.22 (4H, m), 4.38 (2H, q, J = 7.8 Hz), 4.87- 5.13 (2H, m), 6.64 (1H, d, J = 5.4Hz), 7.35-7.46 (3H, m), 7.83 (1H, d, J = 7.8Hz) ), 8.35 (1H, d, J=5.4 Hz).

Synthesis Example 42

炭酸ビス（トリクロロメチル）（０．５９ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例４４で得られたエチル ３−（メチルアミノ）プロピル カーボネート塩酸塩（１．１８ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１０ｇ）、トリエチルアミン（０．８３ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（０．８８ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２９（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．１０−２．２０（２Ｈ，ｍ），２．２２（３Ｈ，ｓ），３．０２（３Ｈ，ｂｓ），３．５５−３．７７（２Ｈ，ｍ），４．１４−４．３０（４Ｈ，ｍ），４．３７（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．８３−５．１３（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３５−７．４６（３Ｈ，ｍ），７．８２（１Ｈ，ｄ，Ｊ＝８．１Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． Ethyl 3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]propyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.59 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, ethyl 3-(methylamino)propyl carbonate hydrochloride (1.18 g) obtained in Reference Example 44 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.10 g), triethylamine (0. 83 mL), 4-dimethylaminopyridine (catalytic amount) was added, and the mixture was stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (0.88 g) as a yellow amorphous solid. Obtained.
¹ H-NMR (CDCl ₃ ): 1.29 (3H, t, J = 7.2 Hz), 2.10-2.20 (2H, m), 2.22 (3H, s), 3.02 ( 3H, bs), 3.55-3.77 (2H, m), 4.14-4.30 (4H, m), 4.37 (2H, q, J = 7.8 Hz), 4.83- 5.13 (2H, m), 6.64 (1H, d, J = 5.6 Hz), 7.35-7.46 (3H, m), 7.82 (1H, d, J = 8.1 Hz ), 8.35 (1H, d, J=5.6 Hz).

Synthesis Example 43

炭酸ビス（トリクロロメチル）（１．１９ｇ）のテトラヒドロフラン溶液（４０ｍＬ）に氷冷下、ピリジン（０．９５ｍＬ）のテトラヒドロフラン溶液（２ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例４２で得られた３−（メチルアミノ）プロピル アセテート塩酸塩（１．９０ｇ）を添加した。トリエチルアミン（１．６８ｍＬ）のテトラヒドロフラン溶液（２ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（４０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．９９ｇ）、トリエチルアミン（１．５０ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（１．２２ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．９７（３Ｈ，ｓ），２．０５−２．１５（２Ｈ，ｍ），２．２２（３Ｈ，ｓ），３．０３（３Ｈ，ｂｓ），３．４２−３．７２（２Ｈ，ｍ），４．１０−４．２２（２Ｈ，ｍ），４．３７（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．８５−５．１３（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．２４−７．４４（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． 3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]Carbonyl]amino]propyl acetate

A tetrahydrofuran solution (2 mL) of pyridine (0.95 mL) was added dropwise to a tetrahydrofuran solution (40 mL) of bis(trichloromethyl) carbonate (1.19 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 3-(methylamino)propyl acetate hydrochloride (1.90 g) obtained in Reference Example 42 was added. After dropping a tetrahydrofuran solution (2 mL) of triethylamine (1.68 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (40 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.99 g), triethylamine (1. 50 mL), 4-dimethylaminopyridine (catalytic amount) was added, and the mixture was stirred at 60° C. overnight. After concentration under reduced pressure, water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (1.22 g) as a yellow amorphous solid. Obtained.
1H ^- NMR ( _CDCl3 ): 1.97 (3H, s), 2.05-2.15 (2H, m), 2.22 (3H, s), 3.03 (3H, bs), 3 .42-3.72 (2H, m), 4.10-4.22 (2H, m), 4.37 (2H, q, J = 7.8 Hz), 4.85-5.13 (2H, m), 6.64 (1H, d, J = 5.6 Hz), 7.24-7.44 (3H, m), 7.83 (1H, d, J = 7.5 Hz), 8.35 ( 1H, d, J=5.6 Hz).

Synthesis Example 44

炭酸ビス（トリクロロメチル）（０．５９ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例４６で得られた３−（メチルアミノ）プロパン−１，２−ジイル ジアセテート塩酸塩（１．３５ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．２７ｇ）、トリエチルアミン（０．９６ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（０．６４ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．０５（３Ｈ，ｓ），２．１３（３Ｈ，ｓ），２．２３（３Ｈ，ｓ），３．０７（３Ｈ，ｂｓ），３．４２−３．９５（２Ｈ，ｍ），４．０６−４．４３（２Ｈ，ｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．８５−５．０５（２Ｈ，ｍ），５．４２−５．５０（１Ｈ，ｍ），６．６３−６．６６（１Ｈ，ｍ），７．３８−７．５１（３Ｈ，ｍ），７．７８−７．８５（１Ｈ，ｍ），８．３３−８．３６（１Ｈ，ｍ）． 3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]propane-1,2-diyl diacetate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.59 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 3-(methylamino)propane-1,2-diyl diacetate hydrochloride (1.35 g) obtained in Reference Example 46 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.27 g), triethylamine (0. 96 mL) and 4-dimethylaminopyridine (catalytic amount) were added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (0.64 g) as a yellow amorphous solid. Obtained.
< ¹ >H-NMR ( _CDCl3 ): 2.05 (3H, s), 2.13 (3H, s), 2.23 (3H, s), 3.07 (3H, bs), 3.42-3 .95 (2H, m), 4.06-4.43 (2H, m), 4.38 (2H, q, J = 7.8 Hz), 4.85-5.05 (2H, m), 5 .42-5.50 (1 H, m), 6.63-6.66 (1 H, m), 7.38-7.51 (3 H, m), 7.78-7.85 (1 H, m) , 8.33-8.36 (1H, m).

Synthesis example 45

炭酸ビス（トリクロロメチル）（０．５９ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例４７で得られたジエチル ３−（メチルアミノ）プロパン−１，２−ジイル ビスカーボネート塩酸塩（１．７１ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．５３ｇ）、トリエチルアミン（１．１６ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（１．４２ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２８−１．３４（６Ｈ，ｍ），２．２２（３Ｈ，ｓ），３．０７（３Ｈ，ｂｓ），３．４２−４．６０（１０Ｈ，ｍ），４．８５−５．０８（２Ｈ，ｍ），５．３０−５．４２（１Ｈ，ｍ），６．６２−６．６４（１Ｈ，ｍ），７．３７−７．４２（３Ｈ，ｍ），７．８０−７．８３（１Ｈ，ｍ），８．３２−８．３５（１Ｈ，ｍ）． Diethyl 3-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]propane-1,2-diyl biscarbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.59 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, diethyl 3-(methylamino)propane-1,2-diyl biscarbonate hydrochloride (1.71 g) obtained in Reference Example 47 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.53 g), triethylamine (1. 16 mL) and 4-dimethylaminopyridine (catalytic amount) were added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (1.42 g) as a yellow amorphous solid. Obtained.
1H ^- NMR ( _CDCl3 ): 1.28-1.34 (6H, m), 2.22 (3H, s), 3.07 (3H, bs), 3.42-4.60 (10H, m), 4.85-5.08 (2H, m), 5.30-5.42 (1H, m), 6.62-6.64 (1H, m), 7.37-7.42 ( 3H, m), 7.80-7.83 (1H, m), 8.32-8.35 (1H, m).

Synthesis Example 46

炭酸ビス（トリクロロメチル）（０．１９４ｇ）のテトラヒドロフラン溶液（７ｍＬ）に氷冷下、ピリジン（０．１６２ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例７で得られた２−（メチルアミノ）エチル ３−クロロベンゾエート塩酸塩（０．５０ｇ）を添加した。トリエチルアミン（０．２７９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２．５時間攪拌した。減圧濃縮後、残留物に水（１５ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１０ｍＬ）に溶解した。特開昭６３−１４６８８２に記載の方法で合成した５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−イミダゾ［４，５−ｂ］ピリジン（０．４４５ｇ）、トリエチルアミン（０．３５７ｍＬ）、４−ジメチルアミノピリジン（０．０１２ｇ）を添加し、６０℃で１４時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（７０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（２０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（０．３６０ｇ）を無色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２１（３Ｈ，ｓ），２．２３（３Ｈ，ｓ），３．３２，３．３８（合計３Ｈ，ｓ），３．７２（３Ｈ，ｓ），３．８１（３Ｈ，ｓ），３．９２−４．０９（２Ｈ，ｍ），４．５０−４．７３（２Ｈ，ｍ），４．８７（１Ｈ，ｄ，Ｊ＝１３．４Ｈｚ），４．９４（１Ｈ，ｄ，Ｊ＝１３．４Ｈｚ），６．７７（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ）、７．３６（１Ｈ，ｍ），７．５２（１Ｈ，ｍ），７．８０−８．０３（３Ｈ，ｍ），８．２０（１Ｈ，ｓ）． 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridin-3-yl]carbonyl ](methyl)amino]ethyl 3-chlorobenzoate

A tetrahydrofuran solution (1 mL) of pyridine (0.162 mL) was added dropwise to a tetrahydrofuran solution (7 mL) of bis(trichloromethyl) carbonate (0.194 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-(methylamino)ethyl 3-chlorobenzoate hydrochloride (0.50 g) obtained in Reference Example 7 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.279 mL), the mixture was stirred at room temperature for 2.5 hours. After concentration under reduced pressure, water (15 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (10 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b synthesized by the method described in JP-A-63-146882 ] Pyridine (0.445 g), triethylamine (0.357 mL) and 4-dimethylaminopyridine (0.012 g) were added and stirred at 60° C. for 14 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (70 mL). The ethyl acetate layer was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (0.360 g) as a colorless amorphous solid. Obtained.
1H ^- NMR ( _CDCl3 ): 2.21 (3H, s), 2.23 (3H, s), 3.32, 3.38 (total 3H, s), 3.72 (3H, s), 3.81 (3H, s), 3.92-4.09 (2H, m), 4.50-4.73 (2H, m), 4.87 (1H, d, J = 13.4 Hz), 4.94 (1H, d, J = 13.4Hz), 6.77 (1H, d, J = 8.8Hz), 7.36 (1H, m), 7.52 (1H, m), 7.7. 80-8.03 (3H, m), 8.20 (1 H, s).

Synthesis Example 47

炭酸ビス（トリクロロメチル）（０．５８２ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４８５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例２で得られた２−（メチルアミノ）エチル アセテート塩酸塩（０．９２２ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２．５時間攪拌した。減圧濃縮後、残留物に水（４０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（２５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１５ｍＬ）に溶解した。２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１０ｇ）、トリエチルアミン（０．８４ｍＬ）、４−ジメチルアミノピリジン（０．０３６ｇ）を添加し、６０℃で４．５時間攪拌した。減圧濃縮後、残留物に水（４０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて２：１で溶出）で精製することにより、標題化合物（１．１８ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．１０（３Ｈ，ｓ），２．２４（３Ｈ，ｓ），３．０９（３Ｈ，ｂｓ），３．６０−４．００（２Ｈ，ｂｒ），４．２５−４．５０（２Ｈ，ｍ），４．３８（２Ｈ、ｑ，Ｊ＝７．８Ｈｚ），４．８４−５．１８（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３６−７．４８（３Ｈ，ｍ），７．８５（１Ｈ，ｄ,Ｊ＝７．８Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． 2-[methyl[[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl]amino ] ethyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.485 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.582 g) under ice-cooling. After stirring for 1 hour under ice-cooling, 2-(methylamino)ethyl acetate hydrochloride (0.922 g) obtained in Reference Example 2 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 2.5 hours. After concentration under reduced pressure, water (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (25 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (15 mL). 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.10 g), triethylamine (0.84 mL), 4 -Dimethylaminopyridine (0.036 g) was added and stirred at 60°C for 4.5 hours. After concentration under reduced pressure, water (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with 2:1) to give the title compound (1.18 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.10 (3H, s), 2.24 (3H, s), 3.09 (3H, bs), 3.60-4.00 (2H, br), 4 .25-4.50(2H,m), 4.38(2H,q,J=7.8Hz), 4.84-5.18(2H,m), 6.64(1H,d,J= 5.6 Hz), 7.36-7.48 (3 H, m), 7.85 (1 H, d, J = 7.8 Hz), 8.35 (1 H, d, J = 5.6 Hz).

Synthesis Example 48

（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１３０ｇ）、トリエチルアミン（６３．８ｍＬ）、４−ジメチルアミノピリジン（０．８６ｇ）、参考例３４で得た２−［（クロロカルボニル）（メチル）アミノ］エチル エチル カーボネート（８４．８ｇ）のテトラヒドロフラン（８１３ｍＬ）溶液を４５−５０℃で１８時間攪拌した。反応液を減圧濃縮した後、残留物に水（３００ｍＬ）を加え、酢酸エチル（７００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３００ｍＬ）で３回洗浄した後、無水硫酸マグネシウム（１３０ｇ）と活性炭（１３ｇ）を加えた。室温で３０分間攪拌した後、濾過した。濾液を減圧濃縮した後、残留物をトリエチルアミン（０．４９ｍＬ）を含むジエチルエーテル（６００ｍＬ）に溶かし、減圧濃縮した。この操作をさらに２回繰り返した。得られた油状物をトリエチルアミン（２．４５ｍＬ）を含むエタノール（２００ｍＬ）に溶かし、氷冷下、水（１２０ｍＬ）を滴下した。析出した結晶を濾取し、氷冷したエタノール−水（体積比１：１，１５０ｍＬ）で３回洗浄し、乾燥することにより、標題化合物（１７２．２ｇ）を無色固体として得た。¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）は合成例１４で得られた化合物と同一のチャートを示した。 Ethyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole-1- yl]carbonyl]amino]ethyl carbonate

(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (130 g), triethylamine (63.8 mL) , 4-dimethylaminopyridine (0.86 g) and 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (84.8 g) obtained in Reference Example 34 in tetrahydrofuran (813 mL) at 45-50°C. Stirred for 18 hours. After the reaction mixture was concentrated under reduced pressure, water (300 mL) was added to the residue and the mixture was extracted with ethyl acetate (700 mL). After the ethyl acetate layer was washed with saturated saline (300 mL) three times, anhydrous magnesium sulfate (130 g) and activated carbon (13 g) were added. After stirring for 30 minutes at room temperature, it was filtered. After the filtrate was concentrated under reduced pressure, the residue was dissolved in diethyl ether (600 mL) containing triethylamine (0.49 mL) and concentrated under reduced pressure. This operation was repeated two more times. The resulting oil was dissolved in ethanol (200 mL) containing triethylamine (2.45 mL), and water (120 mL) was added dropwise under ice cooling. The precipitated crystals were collected by filtration, washed three times with ice-cooled ethanol-water (volume ratio 1:1, 150 mL), and dried to give the title compound (172.2 g) as a colorless solid. ¹ H-NMR (CDCl ₃ ) showed the same chart as the compound obtained in Synthesis Example 14.

Synthesis Example 49

炭酸ビス（トリクロロメチル）（０．４３ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．３５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１０分間攪拌後、参考例４８で得られた２−エトキシエチル ２−（メチルアミノ）エチル カーボネート塩酸塩（０．８２ｇ）を添加した。トリエチルアミン（０．６０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３日間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を０．２Ｎ塩酸（２０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．６３ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で６時間、室温で１１時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７、続いて酢酸エチル：ヘキサン＝７：３で溶出）で精製することにより、標題化合物（１．３９ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．１９（３Ｈ，ｔ，Ｊ＝６．９Ｈｚ），２．２３（３Ｈ，ｓ），３．０９（３Ｈ，ｂｓ），３．４０−４．２０（２Ｈ，ｂｒ），３．５３（２Ｈ，ｑ，Ｊ＝６．９Ｈｚ），３．６３−３．６９（２Ｈ，ｍ），４．２７−４．３４（２Ｈ，ｍ），４．３９（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．４７（２Ｈ，ｍ），４．８０−５．２０（２Ｈ，ｍ），６．６５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３０−７．５２（３Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． 2-ethoxyethyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.35 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.43 g) under ice-cooling. After stirring for 10 minutes under ice-cooling, 2-ethoxyethyl 2-(methylamino)ethyl carbonate hydrochloride (0.82 g) obtained in Reference Example 48 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.60 mL), the mixture was stirred at room temperature for 3 days. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 63 mL) and 4-dimethylaminopyridine (0.037 g) were added and stirred at 60° C. for 6 hours and at room temperature for 11 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate:hexane=7:3) to give the title compound (1.39 g). Obtained as a yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.19 (3H, t, J = 6.9 Hz), 2.23 (3H, s), 3.09 (3H, bs), 3.40-4.20 ( 2H, br), 3.53 (2H, q, J = 6.9 Hz), 3.63-3.69 (2H, m), 4.27-4.34 (2H, m), 4.39 ( 2H, q, J = 7.8 Hz), 4.47 (2H, m), 4.80-5.20 (2H, m), 6.65 (1 H, d, J = 5.6 Hz), 7. 30-7.52 (3H, m), 7.84 (1H, d, J = 7.5 Hz), 8.35 (1 H, d, J = 5.6 Hz).

Synthesis example 50

炭酸ビス（トリクロロメチル）（０．５３ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、５分間攪拌後、参考例４９で得られた３−メトキシプロピル ２−（メチルアミノ）エチル カーボネート塩酸塩（０．８２ｇ）を添加した。トリエチルアミン（０．７５ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で１時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を０．２Ｎ塩酸（２０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．６３ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で６時間、室温で６時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７、続いて酢酸エチル：ヘキサン＝７：３で溶出）で精製した。ジエチルエーテルから結晶化することにより、標題化合物（０．７０ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．９４（２Ｈ，ｑｕｉｎｔｅｔ，Ｊ＝６．２Ｈｚ），２．２３（３Ｈ，ｓ），３．０９（３Ｈ，ｂｓ），３．３１（３Ｈ，ｓ），３．４０−４．２０（２Ｈ，ｂｒ），３．４４（２Ｈ，ｔ，Ｊ＝６．２Ｈｚ），４．２５（２Ｈ，ｔ，Ｊ＝６．５Ｈｚ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．４４（２Ｈ，ｍ），４．８０−５．２０（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３５−７．４８（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． 3-methoxypropyl 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.44 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.53 g) under ice-cooling. After stirring for 5 minutes under ice-cooling, 3-methoxypropyl 2-(methylamino)ethyl carbonate hydrochloride (0.82 g) obtained in Reference Example 49 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.75 mL), the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 63 mL) and 4-dimethylaminopyridine (0.037 g) were added and stirred at 60° C. for 6 hours and at room temperature for 6 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then ethyl acetate:hexane=7:3). Crystallization from diethyl ether gave the title compound (0.70 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 1.94 (2H, quintet, J = 6.2Hz), 2.23 (3H, s), 3.09 (3H, bs), 3.31 (3H, s) , 3.40-4.20 (2H, br), 3.44 (2H, t, J = 6.2 Hz), 4.25 (2H, t, J = 6.5 Hz), 4.38 (2H, q, J = 7.8 Hz), 4.44 (2H, m), 4.80-5.20 (2H, m), 6.64 (1H, d, J = 5.6 Hz), 7.35- 7.48 (3H, m), 7.83 (1H, d, J = 7.8 Hz), 8.34 (1 H, d, J = 5.6 Hz).

Synthesis example 51

参考例５０で得られた２−（メチルアミノ）エチル Ｎ，Ｎ−ジメチルグリシネート二塩酸塩（１．０６ｇ）をテトラヒドロフラン（４０ｍＬ）に加えてしばらく攪拌した後、炭酸ビス（トリクロロメチル）（０．７７ｇ）を加えた。氷冷した後、トリエチルアミン（２．１７ｍＬ）のテトラヒドロフラン溶液（５ｍＬ）を滴下し、室温で３時間攪拌した。析出した固体を濾別した後、酢酸エチル（８０ｍＬ）を加え、氷冷した炭酸水素ナトリウム水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ×２）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．６３ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で６時間、室温で３日間攪拌した。４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃でさらに６時間攪拌した。減圧濃縮後、残留物に炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチル、続いてメタノール：酢酸エチル＝１：１９で溶出）で精製した。ジエチルエーテルから結晶化することにより、標題化合物（０．４１ｇ）を無色固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２３（３Ｈ，ｓ），２．３５（６Ｈ，ｓ），３．０８（３Ｈ，ｂｓ），３．２１（２Ｈ，ｓ），３．５０−４．２０（２Ｈ，ｂｒ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．４４（２Ｈ，ｍ），４．８０−５．１８（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３６−７．４８（３Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]Carbonyl]amino]ethyl N,N-dimethylglycinate

2-(Methylamino)ethyl N,N-dimethylglycinate dihydrochloride (1.06 g) obtained in Reference Example 50 was added to tetrahydrofuran (40 mL) and stirred for a while, then bis(trichloromethyl) carbonate (0 .77 g) was added. After cooling with ice, a tetrahydrofuran solution (5 mL) of triethylamine (2.17 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. After filtering off the precipitated solid, ethyl acetate (80 mL) was added, washed with ice-cooled aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL×2), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 63 mL) and 4-dimethylaminopyridine (0.037 g) were added and stirred at 60° C. for 6 hours and at room temperature for 3 days. 4-Dimethylaminopyridine (0.037 g) was added and stirred at 60°C for an additional 6 hours. After concentration under reduced pressure, an aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:1, then ethyl acetate, then methanol:ethyl acetate=1:19). Crystallization from diethyl ether gave the title compound (0.41 g) as a colorless solid.
1H ^- NMR ( _CDCl3 ): 2.23 (3H, s), 2.35 (6H, s), 3.08 (3H, bs), 3.21 (2H, s), 3.50-4 .20 (2H, br), 4.38 (2H, q, J = 7.8 Hz), 4.44 (2H, m), 4.80-5.18 (2H, m), 6.64 (1H , d, J = 5.6 Hz), 7.36-7.48 (3H, m), 7.84 (1H, d, J = 6.9 Hz), 8.35 (1H, d, J = 5.9 Hz). 6 Hz).

Synthesis example 52

参考例５１で得られたＳ−[２−（メチルアミノ）エチル] チオアセテート塩酸塩（０．７５ｇ）をテトラヒドロフラン（３０ｍＬ）に加えてしばらく攪拌した後、炭酸ビス（トリクロロメチル）（０．６６ｇ）を加えた。氷冷した後、トリエチルアミン（１．８５ｍＬ）のテトラヒドロフラン溶液（１０ｍＬ）を滴下し、氷冷下で３０分間、室温で３０分間攪拌した。析出した固体を濾別し、濾液に酢酸エチル（５０ｍＬ）を加え、氷冷した０．２Ｎ塩酸（２０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．９６ｇ）、トリエチルアミン（０．５４ｍＬ）、４−ジメチルアミノピリジン（０．０３２ｇ）を添加し、６０℃で６時間、室温で８時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物をシリカゲルカラムクロマトグラフィー（アセトン：ヘキサン＝３：７、続いてアセトン：ヘキサン＝７：３で溶出）で精製することにより、標題化合物（１．１９ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：２．２３（３Ｈ，ｓ），２．３４（３Ｈ，ｓ），３．１０（３Ｈ，ｂｓ），３．２２（２Ｈ，ｔ，Ｊ＝６．６Ｈｚ），３．６７（２Ｈ，ｍ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．８０−５．２０（２Ｈ，ｍ），６．６４（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５−７．５０（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． S-[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole- 1-yl]carbonyl]amino]ethyl]thioacetate

S-[2-(methylamino)ethyl]thioacetate hydrochloride (0.75 g) obtained in Reference Example 51 was added to tetrahydrofuran (30 mL) and stirred for a while, then bis(trichloromethyl) carbonate (0.66 g) was added. ) was added. After ice-cooling, a tetrahydrofuran solution (10 mL) of triethylamine (1.85 mL) was added dropwise, and the mixture was stirred for 30 minutes under ice-cooling and for 30 minutes at room temperature. The precipitated solid was filtered off, ethyl acetate (50 mL) was added to the filtrate, washed with ice-cooled 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (0.96 g), triethylamine (0.96 g). 54 mL) and 4-dimethylaminopyridine (0.032 g) were added and stirred at 60° C. for 6 hours and at room temperature for 8 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluted with acetone:hexane=3:7, then acetone:hexane=7:3) to give the title compound (1.19 g) as a yellow amorphous solid. obtained as
1H ^- NMR ( _CDCl3 ): 2.23 (3H, s), 2.34 (3H, s), 3.10 (3H, bs), 3.22 (2H, t, J = 6.6 Hz) , 3.67(2H,m), 4.38(2H,q,J=7.8Hz), 4.80-5.20(2H,m), 6.64(1H,d,J=5. 7 Hz), 7.35-7.50 (3 H, m), 7.83 (1 H, d, J = 6.9 Hz), 8.35 (1 H, d, J = 5.7 Hz).

Synthesis example 53

炭酸ビス（トリクロロメチル）（１．１９ｇ）のテトラヒドロフラン溶液（４０ｍＬ）に氷冷下、ピリジン（０．９５ｍＬ）のテトラヒドロフラン溶液（２ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例５２で得られたエチル ２−［２−（メチルアミノ）エトキシ］エチル カーボネート塩酸塩（２．７３ｇ）を添加した。トリエチルアミン（１．６８ｍＬ）のテトラヒドロフラン溶液（２ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（４０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（２．８０ｇ）、トリエチルアミン（２．１１ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（１００ｍＬ）を加え、酢酸エチル（１００ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１００ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（２．１９ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２８（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），２．２４（３Ｈ，ｓ），３．１０（３Ｈ，ｂｓ），３．３８−３．８０（６Ｈ，ｍ），４．１８（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．２７−４．３４（２Ｈ，ｍ），４．３８（２Ｈ，ｑ，Ｊ＝８．４Ｈｚ），４．８３−５．３０（２Ｈ，ｍ），６．６５（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．３５−７．５０（３Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３６（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． Ethyl 2-[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethoxy]ethyl carbonate

A tetrahydrofuran solution (2 mL) of pyridine (0.95 mL) was added dropwise to a tetrahydrofuran solution (40 mL) of bis(trichloromethyl) carbonate (1.19 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, ethyl 2-[2-(methylamino)ethoxy]ethyl carbonate hydrochloride (2.73 g) obtained in Reference Example 52 was added. After dropping a tetrahydrofuran solution (2 mL) of triethylamine (1.68 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (40 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (2.80 g), triethylamine (2. 11 mL), 4-dimethylaminopyridine (catalytic amount) was added, and the mixture was stirred at 60° C. overnight. After concentration under reduced pressure, water (100 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL). The ethyl acetate layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (2.19 g) as a yellow amorphous solid. Obtained.
1H ^- NMR ( _CDCl3 ): 1.28 (3H, t, J = 7.2 Hz), 2.24 (3H, s), 3.10 (3H, bs), 3.38-3.80 ( 6H, m), 4.18 (2H, q, J=7.2 Hz), 4.27-4.34 (2H, m), 4.38 (2H, q, J=8.4 Hz), 4. 83-5.30 (2H, m), 6.65 (1H, d, J = 5.7 Hz), 7.35-7.50 (3H, m), 7.84 (1H, d, J = 7 .8 Hz), 8.36 (1H, d, J=5.7 Hz).

Synthesis Example 54

炭酸ビス（トリクロロメチル）（０．５９ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、ピリジン（０．４９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例５３で得られたエチル ２−［メチル［［２−（メチルアミノ）エトキシ］カルボニル］アミノ］エチル カーボネート塩酸塩（１．７１ｇ）を添加した。トリエチルアミン（０．８４ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．５９ｇ）、トリエチルアミン（１．２０ｍＬ）、４−ジメチルアミノピリジン（触媒量）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物（１．６２ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２４−１．３１（３Ｈ，ｍ），２．２４（３Ｈ，ｂｓ），２．９７−２．９９（３Ｈ，ｍ），３．１０（３Ｈ，ｂｓ），３．５５−３．５８（２Ｈ，ｍ），４．０９−４．５０（１０Ｈ，ｍ），４．８８−５．０８（２Ｈ，ｍ），６．６５（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ），７．３６−７．４８（３Ｈ，ｍ），７．８５（１Ｈ，ｄ，Ｊ＝６．９Ｈｚ），８．３６（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． Ethyl 2-[methyl[[2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H -benzimidazol-1-yl]carbonyl]amino]ethoxy]carbonyl]amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.49 mL) was added dropwise to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.59 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, ethyl 2-[methyl[[2-(methylamino)ethoxy]carbonyl]amino]ethyl carbonate hydrochloride (1.71 g) obtained in Reference Example 53 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.84 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.59 g), triethylamine (1. 20 mL) and 4-dimethylaminopyridine (catalytic amount) were added and stirred at 60° C. overnight. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound (1.62 g) as a yellow amorphous solid. Obtained.
1H ^- NMR ( _CDCl3 ): 1.24-1.31 (3H, m), 2.24 (3H, bs), 2.97-2.99 (3H, m), 3.10 (3H, bs), 3.55-3.58 (2H, m), 4.09-4.50 (10H, m), 4.88-5.08 (2H, m), 6.65 (1H, t, J=5.7 Hz), 7.36-7.48 (3H, m), 7.85 (1 H, d, J=6.9 Hz), 8.36 (1 H, d, J=5.7 Hz).

Synthesis example 55

炭酸ビス（トリクロロメチル）（０．２９１ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．２４３ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例１４で得られたエチル ２−（メチルアミノ）エチル カーボネート塩酸塩（０．５５１ｇ）を添加した。トリエチルアミン（０．４１８ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２時間攪拌した。減圧濃縮後、残留物に水（１５ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１０ｍＬ）に溶解した。５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．８１７ｇ）、トリエチルアミン（０．６６１ｍＬ）、４−ジメチルアミノピリジン（０．０１２ｇ）を添加し、６０℃で１２時間攪拌した。減圧濃縮後、残留物に水（２０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物とエチル ２−［［［６−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンズイミダゾール−１−イル］カルボニル］（メチル）アミノ］エチル カーボネートの３：２の混合物（０．９２ｇ）を淡黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２７−１．３４（３Ｈ，ｍ），２．１０−２．３０（３Ｈ，ｍ），２．２３（３Ｈ，ｓ），２．９９−３．２３（３Ｈ，ｍ），３．４０−３．８５（２Ｈ，ｍ），３．６９（６／５Ｈ,ｓ），３．７１（９／５Ｈ，ｓ），３．８６（６／５Ｈ，ｓ），３．８８（９／５Ｈ，ｓ），４．１４−４．２５（２Ｈ，ｍ），４．３８−４．６０（２Ｈ，ｍ），４．８２−５．０６（２Ｈ，ｍ），６．９２−７．０８（７／５Ｈ,ｍ）,７．３３（３／５Ｈ,ｄ,Ｊ＝９．０Ｈｚ）,７．６６（１Ｈ，ｍ），８．２１（１Ｈ，ｓ）． Ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino] ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.243 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.291 g) under ice-cooling. After stirring for 1 hour under ice-cooling, ethyl 2-(methylamino)ethyl carbonate hydrochloride (0.551 g) obtained in Reference Example 14 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.418 mL), the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, water (15 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (10 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.817 g), triethylamine (0.661 mL), 4-dimethylaminopyridine (0.012 g) was added and stirred at 60° C. for 12 hours. After concentration under reduced pressure, water (20 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound and ethyl 2-[[[6-methoxy- A 3:2 mixture of 2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate (0 .92 g) as a pale yellow amorphous solid.
@ ¹ H-NMR ( _CDCl3 ): 1.27-1.34 (3H, m), 2.10-2.30 (3H, m), 2.23 (3H, s), 2.99-3. 23 (3H, m), 3.40-3.85 (2H, m), 3.69 (6/5H, s), 3.71 (9/5H, s), 3.86 (6/5H, s), 3.88 (9/5H, s), 4.14-4.25 (2H, m), 4.38-4.60 (2H, m), 4.82-5.06 (2H, m), 6.92-7.08 (7/5H, m), 7.33 (3/5H, d, J = 9.0 Hz), 7.66 (1H, m), 8.21 (1H, s).

Synthesis example 56

炭酸ビス（トリクロロメチル）（０．２９１ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．２４３ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２７で得られた２−アニリノエチル アセテート塩酸塩（０．６４７ｇ）を添加した。トリエチルアミン（０．４１９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（２０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１０ｍＬ）に溶解した。５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．８２９ｇ）、トリエチルアミン（０．６６９ｍＬ）、４−ジメチルアミノピリジン（０．０１２ｇ）を添加し、６０℃で１４時間攪拌した。減圧濃縮後、残留物に水（４０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２で溶出）で精製することにより、標題化合物と２−［［［６−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンズイミダゾール−１−イル］カルボニル］（フェニル）アミノ］エチル アセテートの１：１の混合物（１．１０ｇ）を無色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．９９（３Ｈ，ｓ），２．１９（１．５Ｈ．ｓ），２．２１（１．５Ｈ，ｓ），２．２５（３Ｈ，ｓ），３．７０（１．５Ｈ，ｓ），３．７１（３Ｈ，ｓ），３．７８（１．５Ｈ，ｓ），３．８４（１．５Ｈ，ｓ），４．１５−４．５６（４Ｈ，ｍ），４．７４−４．８０（１Ｈ，ｍ），４．９１−４．９８（１Ｈ，ｍ），６．８３−６．９１（１．５Ｈ，ｍ），７．０４−７．１９（３．５Ｈ，ｍ），７．２５−７．５３（２．５Ｈ，ｍ），７．５１（０．５Ｈ，ｄ，Ｊ＝８．７Ｈｚ），８．２５（１Ｈ，ｓ）． 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.243 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.291 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Example 27 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.419 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (20 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (10 mL). 5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.829 g), triethylamine (0.669 mL), 4-dimethylaminopyridine (0.012 g) was added and stirred at 60° C. for 14 hours. After concentration under reduced pressure, water (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2) to give the title compound and 2-[[[6-methoxy-2-[[(4- A 1:1 mixture of methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate (1.10 g) was obtained as a colorless amorphous substance. Obtained as a solid.
< ¹ >H-NMR ( _CDCl3 ): 1.99 (3H, s), 2.19 (1.5H.s), 2.21 (1.5H, s), 2.25 (3H, s), 3 .70 (1.5H, s), 3.71 (3H, s), 3.78 (1.5H, s), 3.84 (1.5H, s), 4.15-4.56 (4H , m), 4.74-4.80 (1 H, m), 4.91-4.98 (1 H, m), 6.83-6.91 (1.5 H, m), 7.04-7 .19 (3.5 H, m), 7.25-7.53 (2.5 H, m), 7.51 (0.5 H, d, J = 8.7 Hz), 8.25 (1 H, s) .

Synthesis Example 57

特表平１０−５０４２９０の合成例１に記載の方法で合成した（Ｓ）−５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．３４ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に参考例３４で得られた２−［（クロロカルボニル）（メチル）アミノ］エチル エチル カーボネート（０．９ｍＬ）、トリエチルアミン（１．０８ｍＬ）、４−ジメチルアミノピリジン（０．０１０ｇ）を添加し、６０℃で６時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）で精製することにより、標題化合物とエチル ２−［［［（Ｓ）−６−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンズイミダゾール−１−イル］カルボニル］（メチル）アミノ］エチル カーボネートの３：２の混合物（０．９２ｇ）を淡黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２５−１．３４（３Ｈ，ｍ），２．１０−２．３０（３Ｈ，ｍ），２．２３（３Ｈ，ｓ），２．９９−３．２３（３Ｈ，ｍ），３．４０−３．８５（２Ｈ，ｍ），３．６９（６／５Ｈ,ｓ），３．７１（９／５Ｈ，ｓ），３．８６（６／５Ｈ，ｓ），３．８８（９／５Ｈ，ｓ），４．１４−４．２５（２Ｈ，ｍ），４．３８−４．６０（２Ｈ，ｍ），４．７９−５．０５（２Ｈ，ｍ），６．９２−７．０８（７／５Ｈ,ｍ）,７．３３（３／５Ｈ,ｄ,Ｊ＝９．３Ｈｚ）,７．６５（１Ｈ，ｍ），８．２１（１Ｈ，ｓ）． ethyl 2-[[[(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl] ( Methyl)amino]ethyl carbonate

(S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H synthesized by the method described in Synthesis Example 1 of JP-A-10-504290 - 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.9 mL) obtained in Reference Example 34, triethylamine (1.08 mL), in a tetrahydrofuran solution (10 mL) of benzimidazole (1.34 g), 4-Dimethylaminopyridine (0.010 g) was added and stirred at 60°C for 6 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1) to give the title compound and ethyl 2-[[[(S)-. 6-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate 3:2 (0.92 g) was obtained as a pale yellow amorphous solid.
@ ¹ H-NMR ( _CDCl3 ): 1.25-1.34 (3H, m), 2.10-2.30 (3H, m), 2.23 (3H, s), 2.99-3. 23 (3H, m), 3.40-3.85 (2H, m), 3.69 (6/5H, s), 3.71 (9/5H, s), 3.86 (6/5H, s), 3.88 (9/5H, s), 4.14-4.25 (2H, m), 4.38-4.60 (2H, m), 4.79-5.05 (2H, m), 6.92-7.08 (7/5H, m), 7.33 (3/5H, d, J = 9.3 Hz), 7.65 (1H, m), 8.21 (1H, s).

Synthesis Example 58

炭酸ビス（トリクロロメチル）（０．２９１ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．２４３ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例１４で得られたエチル ２−（メチルアミノ）エチル カーボネート塩酸塩（０．５５１ｇ）を添加した。トリエチルアミン（０．４１８ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で２．５時間攪拌した。減圧濃縮後、残留物に水（１５ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１０ｍＬ）に溶解した。２−［［［４−（３−メトキシプロポキシ）−３−メチル−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．７２３ｇ）、トリエチルアミン（０．５２８ｍＬ）、４−ジメチルアミノピリジン（０．０１２ｇ）を添加し、６０℃で１７時間攪拌した。減圧濃縮後、残留物に水（４０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２で溶出）、続いてシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１続いて酢酸エチルで溶出）で精製することにより、標題化合物（０．４４ｇ）を無色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３１（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），２．０５（２Ｈ，ｍ），２．１８（３Ｈ，ｓ），３．０８（３Ｈ，ｂｓ），３．３４（３Ｈ，ｓ），３．５４（２Ｈ，ｔ，Ｊ＝６．１Ｈｚ），３．６１−４．０１（２Ｈ，ｍ），４．０８（２Ｈ，ｔ，Ｊ＝６．３Ｈｚ），４．２１（２Ｈ，ｔ，Ｊ＝７．１Ｈｚ），４．３８−４．５４（２Ｈ，ｍ），４．８１−５．１２（２Ｈ，ｍ），６．６８（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３４−７．４８（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．２７（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． Ethyl 2-[[[2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.243 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.291 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, ethyl 2-(methylamino)ethyl carbonate hydrochloride (0.551 g) obtained in Reference Example 14 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.418 mL), the mixture was stirred at room temperature for 2.5 hours. After concentration under reduced pressure, water (15 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (10 mL). 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (0.723 g), triethylamine (0.528 mL), 4-dimethylaminopyridine ( 0.012 g) was added and stirred at 60° C. for 17 hours. After concentration under reduced pressure, water (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2), followed by silica gel column chromatography (ethyl acetate:hexane=1:1, then eluted with ethyl acetate). By doing so, the title compound (0.44 g) was obtained as a colorless amorphous solid.
@ ¹ H-NMR ( _CDCl3 ): 1.31 (3H, t, J=7.1 Hz), 2.05 (2H, m), 2.18 (3H, s), 3.08 (3H, bs) , 3.34 (3H, s), 3.54 (2H, t, J = 6.1 Hz), 3.61-4.01 (2H, m), 4.08 (2H, t, J = 6.1 Hz). 3 Hz), 4.21 (2H, t, J = 7.1 Hz), 4.38-4.54 (2H, m), 4.81-5.12 (2H, m), 6.68 (1H, d, J = 5.6 Hz), 7.34-7.48 (3 H, m), 7.83 (1 H, d, J = 7.8 Hz), 8.27 (1 H, d, J = 5.6 Hz ).

Synthesis Example 59

炭酸ビス（トリクロロメチル）（０．２９１ｇ）のテトラヒドロフラン溶液（１０ｍＬ）に氷冷下、ピリジン（０．２４３ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、３０分間攪拌後、参考例２７で得られた２−アニリノエチル アセテート塩酸塩（０．６４７ｇ）を添加した。トリエチルアミン（０．４１９ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（２０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１０ｍＬ）に溶解した。２−［［［４−（３−メトキシプロポキシ）−３−メチル−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．８７７ｇ）、トリエチルアミン（０．６４１ｍＬ）、４−ジメチルアミノピリジン（０．０１２ｇ）を添加し、６０℃で１６時間攪拌した。減圧濃縮後、残留物に水（４０ｍＬ）を加え、酢酸エチル（８０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１５ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２で溶出）、続いてシリカゲルカラムクロマトグラフィー（酢酸エチルで溶出）で精製することにより、標題化合物（０．９３ｇ）を無色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．９９（３Ｈ，ｓ），２．０７（３Ｈ．ｓ），２．１９（３Ｈ，ｓ），３．３５（３Ｈ，ｓ），３．５４（２Ｈ，ｔ，Ｊ＝６．２Ｈｚ），４．０９（２Ｈ，ｔ，Ｊ＝６．２Ｈｚ），４．１４−４．４０（４Ｈ，ｍ），４．８０（１Ｈ，ｄ，Ｊ＝１３．７Ｈｚ），５．００（１Ｈ，ｄ，Ｊ＝１３．７Ｈｚ），６．７１（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．０３−７．３４（７Ｈ，ｍ），７．３８（１Ｈ，ｍ），７．６５（１Ｈ，ｍ），８．３２（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[[[2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate

A tetrahydrofuran solution (1 mL) of pyridine (0.243 mL) was added dropwise to a tetrahydrofuran solution (10 mL) of bis(trichloromethyl) carbonate (0.291 g) under ice-cooling. After stirring for 30 minutes under ice-cooling, 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Example 27 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.419 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (20 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (10 mL). 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (0.877 g), triethylamine (0.641 mL), 4-dimethylaminopyridine ( 0.012 g) was added and stirred at 60° C. for 16 hours. After concentration under reduced pressure, water (40 mL) was added to the residue and the mixture was extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (15 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2), followed by silica gel column chromatography (eluted with ethyl acetate) to give the title compound (0.93 g). ) was obtained as a colorless amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.99 (3H, s), 2.07 (3H.s), 2.19 (3H, s), 3.35 (3H, s), 3.54 (2H , t, J=6.2 Hz), 4.09 (2H, t, J=6.2 Hz), 4.14-4.40 (4H, m), 4.80 (1H, d, J=13. 7 Hz), 5.00 (1H, d, J = 13.7 Hz), 6.71 (1H, d, J = 5.7 Hz), 7.03-7.34 (7H, m), 7.38 ( 1 H, m), 7.65 (1 H, m), 8.32 (1 H, d, J=5.7 Hz).

Synthesis example 60

炭酸ビス（トリクロロメチル）（０．１７４ｇ）のテトラヒドロフラン溶液（８ｍＬ）に氷冷下、ピリジン（０．１４６ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下した。氷冷下、１時間攪拌後、参考例１４で得られたエチル ２−（メチルアミノ）エチル カーボネート塩酸塩（０．３３０ｇ）を添加した。トリエチルアミン（０．２５０ｍＬ）のテトラヒドロフラン溶液（１ｍＬ）を滴下後、室温で３時間攪拌した。減圧濃縮後、残留物に水（１０ｍＬ）を加え、酢酸エチル（３０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（８ｍＬ）に溶解した。５−（ジフルオロメトキシ）−２−［［（３，４−ジメトキシ−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．４３２ｇ）、トリエチルアミン（０．２７９ｍＬ）、４−ジメチルアミノピリジン（０．００８ｇ）を添加し、６０℃で１７．５時間攪拌した。減圧濃縮後、残留物に水（２０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（１０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：２、続いて１：１で溶出）、続いてシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２：１、続いて酢酸エチルで溶出）で精製することにより、標題化合物と２−［［［６−（ジフルオロメトキシ）−２−［［（３，４−ジメトキシ−２−ピリジル）メチル］スルフィニル］−１Ｈ−ベンズイミダゾール−１−イル］カルボニル］メチルアミノ］エチル エチル カーボネートの１：１の混合物（０．０９ｇ）を淡黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３１（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ），３．０６（３Ｈ，ｓ），３．４２−３．９８（２Ｈ，ｍ），３．８７（３Ｈ，ｓ），３．９０（３Ｈ，ｓ），４．２１（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ），４．３６−４．５４（２Ｈ，ｍ），４．９０（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），４．９８（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），６．５４（０．５Ｈ，ｔ，Ｊ＝７３．５Ｈｚ），６．６１（０．５Ｈ，ｔ，Ｊ＝７３．５Ｈｚ），６．７８（１Ｈ，ｄ，Ｊ＝５．３Ｈｚ），７．１５−７．２５（１．５Ｈ，ｍ），７．４４（０．５Ｈ，ｄ，Ｊ＝９．０Ｈｚ），７．５９（０．５Ｈ，ｓ），７．８０（０．５Ｈ，ｄ，Ｊ＝９．０Ｈｚ），８．１７（１Ｈ，ｄ，Ｊ＝５．３Ｈｚ）． 2-[[[5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl ethyl carbonate

A tetrahydrofuran solution (1 mL) of pyridine (0.146 mL) was added dropwise to a tetrahydrofuran solution (8 mL) of bis(trichloromethyl) carbonate (0.174 g) under ice-cooling. After stirring for 1 hour under ice-cooling, ethyl 2-(methylamino)ethyl carbonate hydrochloride (0.330 g) obtained in Reference Example 14 was added. After dropping a tetrahydrofuran solution (1 mL) of triethylamine (0.250 mL), the mixture was stirred at room temperature for 3 hours. After concentration under reduced pressure, water (10 mL) was added to the residue and the mixture was extracted with ethyl acetate (30 mL). The ethyl acetate layer was washed with saturated brine (10 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (8 mL). 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.432 g), triethylamine (0.279 mL), 4-dimethylaminopyridine ( 0.008 g) was added and stirred at 60° C. for 17.5 hours. After concentration under reduced pressure, water (20 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (10 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to basic silica gel column chromatography (ethyl acetate:hexane=1:2, then eluted with 1:1), followed by silica gel column chromatography (ethyl acetate:hexane=2:1, followed by elution with ethyl acetate) to give the title compound and 2-[[[6-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole. A 1:1 mixture of -1-yl]carbonyl]methylamino]ethyl ethyl carbonate (0.09 g) was obtained as a pale yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.31 (3H, t, J = 7.2 Hz), 3.06 (3H, s), 3.42-3.98 (2H, m), 3.87 ( 3H, s), 3.90 (3H, s), 4.21 (2H, q, J = 7.2 Hz), 4.36-4.54 (2H, m), 4.90 (1H, d, J = 13.2 Hz), 4.98 (1H, d, J = 13.2 Hz), 6.54 (0.5H, t, J = 73.5 Hz), 6.61 (0.5H, t, J = 73.5 Hz), 6.78 (1 H, d, J = 5.3 Hz), 7.15-7.25 (1.5 H, m), 7.44 (0.5 H, d, J = 9.3 Hz). 0 Hz), 7.59 (0.5 H, s), 7.80 (0.5 H, d, J = 9.0 Hz), 8.17 (1 H, d, J = 5.3 Hz).

Synthesis Example 61

参考例５４で得られた２−（メチルアミノ）エチル １−メチルピペリジン−４−カルボキシレート二塩酸塩（０．９８ｇ）をテトラヒドロフラン（５０ｍＬ）に加えてしばらく攪拌した後、炭酸ビス（トリクロロメチル）（０．５３ｇ）を加えた。氷冷した後、トリエチルアミン（２．０１ｍＬ）のテトラヒドロフラン溶液（５０ｍＬ）を滴下し、室温で３時間攪拌した。酢酸エチル（１００ｍＬ）を加え、炭酸水素ナトリウム水溶液（１００ｍＬ）、飽和食塩水（８０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．７４ｇ）、トリエチルアミン（０．５６ｍＬ）、４−ジメチルアミノピリジン（０．０４９ｇ）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝７：３、続いて酢酸エチル、続いてメタノール：酢酸エチル＝１：１９で溶出）で精製することにより、標題化合物（０．７８ｇ）を黄緑色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．６５−２．０５（６Ｈ，ｍ），２．２３（３Ｈ，ｓ），２．２５（３Ｈ，ｓ），２．２４−２．３８（１Ｈ，ｍ），２．７５−２．８５（２Ｈ，ｍ），３．０７（３Ｈ，ｂｓ），３．４０−４．１０（２Ｈ，ｂｒ），４．３８（２Ｈ，ｑ，Ｊ＝７．８Ｈｚ），４．４０（２Ｈ，ｍ），４．８０−５．１０（２Ｈ，ｂｒ），６．６４（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ），７．３６−７．４７（３Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝７．８Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．６Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]carbonyl]amino]ethyl 1-methylpiperidine-4-carboxylate

2-(Methylamino)ethyl 1-methylpiperidine-4-carboxylate dihydrochloride (0.98 g) obtained in Reference Example 54 was added to tetrahydrofuran (50 mL) and stirred for a while, followed by bis(trichloromethyl)carbonate. (0.53 g) was added. After cooling with ice, a tetrahydrofuran solution (50 mL) of triethylamine (2.01 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (100 mL) was added, and the mixture was washed with aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (80 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (0.74 g), triethylamine (0.74 g). 56 mL), 4-dimethylaminopyridine (0.049 g) was added and stirred at 60° C. overnight. After concentration under reduced pressure, an aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=7:3, then ethyl acetate, then methanol:ethyl acetate=1:19) to give the title compound ( 0.78 g) was obtained as a yellow-green amorphous solid.
< ¹ >H-NMR ( _CDCl3 ): 1.65-2.05 (6H, m), 2.23 (3H, s), 2.25 (3H, s), 2.24-2.38 (1H, m), 2.75-2.85 (2H, m), 3.07 (3H, bs), 3.40-4.10 (2H, br), 4.38 (2H, q, J=7. 8Hz), 4.40 (2H, m), 4.80-5.10 (2H, br), 6.64 (1H, d, J = 5.6Hz), 7.36-7.47 (3H, m), 7.84 (1 H, d, J = 7.8 Hz), 8.35 (1 H, d, J = 5.6 Hz).

Synthesis Example 62

炭酸ビス（トリクロロメチル）（０．４５ｇ）のテトラヒドロフラン溶液（２０ｍＬ）に氷冷下、参考例５５で得られた２−[［４−（アミノカルボニル）フェニル］アミノ]エチル アセテート（０．６７ｇ）とトリエチルアミン（０．６３ｍＬ）のテトラヒドロフラン溶液（１０ｍＬ）を滴下し、室温で１時間攪拌した。減圧濃縮後、残留物に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を０．２Ｎ塩酸（２０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（３０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．６３ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で３０分間、室温で終夜攪拌した。減圧濃縮後、残留物に炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝４：６、続いて６：４、続いて８：２で溶出）で精製することにより、標題化合物（１．２６ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．９９（３Ｈ，ｓ），２．２６（３Ｈ，ｓ），４．１５−４．５５（４Ｈ，ｍ），４．４１（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．８０−５．２０（２Ｈ，ｂｒ），６．６９（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ），７．２６−７．３８（３Ｈ，ｍ），７．４８（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．５４（２Ｈ，ｄ，Ｊ＝８．９Ｈｚ），７．６６−７．７３（１Ｈ，ｍ），８．３９（１Ｈ，ｄ，Ｊ＝５．７Ｈｚ）． 2-[[4-(aminocarbonyl)phenyl][[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]- 1H-benzimidazol-1-yl]carbonyl]amino]ethyl acetate

2-[[4-(aminocarbonyl)phenyl]amino]ethyl acetate (0.67 g) obtained in Reference Example 55 was added to a tetrahydrofuran solution (20 mL) of bis(trichloromethyl) carbonate (0.45 g) under ice cooling. and triethylamine (0.63 mL) in tetrahydrofuran (10 mL) were added dropwise, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with 0.2N hydrochloric acid (20 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (30 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 63 mL), 4-dimethylaminopyridine (0.037 g) was added and stirred at 60° C. for 30 minutes and at room temperature overnight. After concentration under reduced pressure, an aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=4:6, then 6:4, then 8:2) to give the title compound (1.26 g). was obtained as a yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.99 (3H, s), 2.26 (3H, s), 4.15-4.55 (4H, m), 4.41 (2H, q, J = 7.9 Hz), 4.80-5.20 (2H, br), 6.69 (1H, d, J = 5.7 Hz), 7.26-7.38 (3H, m), 7.48 ( 2H, d, J = 8.9 Hz), 7.54 (2H, d, J = 8.9 Hz), 7.66 - 7.73 (1 H, m), 8.39 (1 H, d, J = 5 .7 Hz).

Synthesis example 63

参考例５６で得られた２−（メチルアミノ）エチル １−メチル−４−ピペリジニル カーボネート二塩酸塩（１．０１ｇ）をテトラヒドロフラン（３０ｍＬ）に加えてしばらく攪拌した後、氷冷した。炭酸ビス（トリクロロメチル）（０．６９ｇ）を添加後、トリエチルアミン（１．９５ｍＬ）のテトラヒドロフラン溶液（１０ｍＬ）を滴下した。氷冷下１時間、室温で１時間攪拌した後、析出した固体を濾別した。減圧濃縮後、酢酸エチル（５０ｍＬ）を加え、氷冷した炭酸水素ナトリウム水溶液（５０ｍＬ）、飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（２０ｍＬ）に溶解した。（Ｒ）−２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（１．１１ｇ）、トリエチルアミン（０．６３ｍＬ）、４−ジメチルアミノピリジン（０．０３７ｇ）を添加し、６０℃で終夜攪拌した。減圧濃縮後、残留物に炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：１、続いて酢酸エチル、続いてメタノール：酢酸エチル＝１：１９で溶出）で精製することにより、標題化合物（０．７０ｇ）を黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．７０−１．８６（２Ｈ，ｍ），１．９０−２．０４（２Ｈ，ｍ），２．２３（３Ｈ，ｓ），２．２８（３Ｈ，ｓ），２．１０−２．３５（２Ｈ，ｍ），２．６０−２．７２（２Ｈ，ｍ），３．０８（３Ｈ，ｂｓ），３．４０−４．２０（２Ｈ，ｂｒ），４．３９（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．４４（２Ｈ，ｍ），４．６０−４．７４（１Ｈ，ｍ），４．８０−５．１５（２Ｈ，ｂｒ），６．６５（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．３５−７．５２（３Ｈ，ｍ），７．８４（１Ｈ，ｄ，Ｊ＝７．５Ｈｚ），８．３５（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）． 2-[methyl[[(R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazol-1-yl ]Carbonyl]amino]ethyl 1-methyl-4-piperidinyl carbonate

2-(Methylamino)ethyl 1-methyl-4-piperidinyl carbonate dihydrochloride (1.01 g) obtained in Reference Example 56 was added to tetrahydrofuran (30 mL), stirred for a while, and cooled with ice. After adding bis(trichloromethyl) carbonate (0.69 g), a tetrahydrofuran solution (10 mL) of triethylamine (1.95 mL) was added dropwise. After stirring for 1 hour under ice-cooling and for 1 hour at room temperature, the precipitated solid was separated by filtration. After concentration under reduced pressure, ethyl acetate (50 mL) was added, washed with ice-cooled aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (20 mL). (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (1.11 g), triethylamine (0. 63 mL), 4-dimethylaminopyridine (0.037 g) was added and stirred at 60° C. overnight. After concentration under reduced pressure, an aqueous sodium hydrogencarbonate solution (50 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (50 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:1, then ethyl acetate, then methanol:ethyl acetate=1:19) to give the title compound ( 0.70 g) as a yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.70-1.86 (2H, m), 1.90-2.04 (2H, m), 2.23 (3H, s), 2.28 (3H, s), 2.10-2.35 (2H, m), 2.60-2.72 (2H, m), 3.08 (3H, bs), 3.40-4.20 (2H, br) , 4.39 (2H, q, J=7.9 Hz), 4.44 (2H, m), 4.60-4.74 (1 H, m), 4.80-5.15 (2H, br) , 6.65 (1H, d, J = 5.9 Hz), 7.35-7.52 (3H, m), 7.84 (1H, d, J = 7.5 Hz), 8.35 (1H, d, J=5.9 Hz).

Synthesis example 64

炭酸ビス（トリクロロメチル）（０．１２ｇ）のテトラヒドロフラン溶液（５ｍＬ）に氷冷下、参考例５５で得られた２−[［４−（アミノカルボニル）フェニル］アミノ]エチル アセテート（０．２２ｇ）とトリエチルアミン（０．１７ｍＬ）のテトラヒドロフラン溶液（５ｍＬ）を滴下し、室温で３０分間攪拌した。水（２０ｍＬ）を加え、酢酸エチル（３０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（２０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残留物をテトラヒドロフラン（１０ｍＬ）に溶解した。２−［［［３−メチル−４−（２，２，２−トリフルオロエトキシ）−２−ピリジル］メチル］スルフィニル］−１Ｈ−ベンズイミダゾール（０．３７ｇ）、トリエチルアミン（０．２８ｍＬ）、４−ジメチルアミノピリジン（０．０１２ｇ）を添加し、６０℃で１時間攪拌した。減圧濃縮後、残留物に炭酸水素ナトリウム水溶液（２０ｍＬ）を加え、酢酸エチル（３０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（２０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：７、続いて５：５、続いて８：２で溶出）で精製することにより、標題化合物（０．３４ｇ）を淡黄色アモルファス状固体として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．９９（３Ｈ，ｓ），２．２６（３Ｈ，ｓ），４．１５−４．５５（４Ｈ，ｍ），４．４１（２Ｈ，ｑ，Ｊ＝７．９Ｈｚ），４．８０−５．２０（２Ｈ，ｂｒ），６．６９（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ），７．２６−７．４０（３Ｈ，ｍ），７．４７（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．５４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．６５−７．７４（１Ｈ，ｍ），８．３８（１Ｈ，ｄ，Ｊ＝５．９Ｈｚ）． 2-[[4-(aminocarbonyl)phenyl][[2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole -1-yl]carbonyl]amino]ethyl acetate

2-[[4-(aminocarbonyl)phenyl]amino]ethyl acetate (0.22 g) obtained in Reference Example 55 was added to a tetrahydrofuran solution (5 mL) of bis(trichloromethyl) carbonate (0.12 g) under ice cooling. and triethylamine (0.17 mL) in tetrahydrofuran (5 mL) were added dropwise, and the mixture was stirred at room temperature for 30 minutes. Water (20 mL) was added and extracted with ethyl acetate (30 mL). The ethyl acetate layer was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and dissolve the residue in tetrahydrofuran (10 mL). 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (0.37 g), triethylamine (0.28 mL), 4 -Dimethylaminopyridine (0.012 g) was added and stirred at 60°C for 1 hour. After concentration under reduced pressure, an aqueous sodium hydrogencarbonate solution (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mL). The ethyl acetate layer was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=3:7, then 5:5, then 8:2) to give the title compound (0.34 g). was obtained as a pale yellow amorphous solid.
1H ^- NMR ( _CDCl3 ): 1.99 (3H, s), 2.26 (3H, s), 4.15-4.55 (4H, m), 4.41 (2H, q, J = 7.9 Hz), 4.80-5.20 (2H, br), 6.69 (1H, d, J = 5.9 Hz), 7.26-7.40 (3H, m), 7.47 ( 2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz), 7.65-7.74 (1 H, m), 8.38 (1 H, d, J = 5 .9 Hz).

Synthesis example 65

特開昭６３−１４６８８２に記載の方法で合成した５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−イミダゾ［４，５−ｂ］ピリジンを分取ＨＰＬＣで光学分割して得た（−）エナンチオマー体（０．１０ｇ）のテトラヒドロフラン溶液（５ｍＬ）に、参考例３４で得た２−［（クロロカルボニル）（メチル）アミノ］エチル エチル カーボネート（０．０８１ｇ）、トリエチルアミン（０．０８０ｍＬ）、４−ジメチルアミノピリジン（０．００７ｇ）を添加し、５０℃で１８時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２：１で溶出）で精製することにより、標題化合物（０．０５３ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．３０（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），２．２４（６Ｈ，ｓ），３．１５，３．３２（合計３Ｈ，ｓ），３．７３（３Ｈ，ｓ），３．９０−４．５５（９Ｈ，ｍ），４．８５（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），４．９７（１Ｈ，ｄ，Ｊ＝１３．２Ｈｚ），６．８０（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．２３（１Ｈ，ｓ）． (−)-ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridine- 3-yl]carbonyl](methyl)amino]ethyl carbonate

5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b synthesized by the method described in JP-A-63-146882 ] 2-[(Chlorocarbonyl)(methyl)amino]ethyl Ethyl carbonate (0.081 g), triethylamine (0.080 mL) and 4-dimethylaminopyridine (0.007 g) were added and stirred at 50°C for 18 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=2:1) to give the title compound (0.053 g) as a colorless oil.
1H ^- NMR ( _CDCl3 ): 1.30 (3H, t, J = 7.1Hz), 2.24 (6H, s), 3.15, 3.32 (total 3H, s), 3.73 (3H, s), 3.90-4.55 (9H, m), 4.85 (1H, d, J = 13.2 Hz), 4.97 (1H, d, J = 13.2 Hz), 6 .80 (1H,d,J=8.8Hz), 7.96 (1H,d,J=8.8Hz), 8.23 (1H,s).

Synthesis Example 66

特開昭６３−１４６８８２に記載の方法で合成した５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−イミダゾ［４，５−ｂ］ピリジンを分取ＨＰＬＣで光学分割して得た（＋）エナンチオマー体（０．１０ｇ）のテトラヒドロフラン溶液（５ｍＬ）に、参考例３４で得た２−［（クロロカルボニル）（メチル）アミノ］エチル エチル カーボネート（０．０８１ｇ）、トリエチルアミン（０．０８０ｍＬ）、４−ジメチルアミノピリジン（０．００７ｇ）を添加し、５０℃で１８時間攪拌した。減圧濃縮後、残留物に水（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ）で抽出した。酢酸エチル層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮後、残留物を塩基性シリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝２：１で溶出）で精製することにより、標題化合物と（＋）−エチル ２−［［［５−メトキシ−２−［［（４−メトキシ−３，５−ジメチル−２−ピリジル）メチル］スルフィニル］−１Ｈ−イミダゾ［４，５−ｂ］ピリジン−１−イル］カルボニル］（メチル）アミノ］エチル カーボネートの２：１の混合物（０．１１５ｇ）を無色油状物として得た。
¹Ｈ−ＮＭＲ（ＣＤＣｌ₃）：１．２０−１．３８（３Ｈ，ｍ），２．２４（６Ｈ，ｓ），３．０８，３．１５，３．３３（合計３Ｈ，ｓ），３．７３（３Ｈ，ｓ），３．８８−４．５５（９Ｈ，ｍ），４．７８−５．０５（２Ｈ，ｍ），６．８０，６．８６（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．７６，７．９６（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），８．２１，８．２２（合計１Ｈ，ｓ）． (+)-ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-3H-imidazo[4,5-b]pyridine- 3-yl]carbonyl](methyl)amino]ethyl carbonate

5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b synthesized by the method described in JP-A-63-146882 ] To a tetrahydrofuran solution (5 mL) of the (+) enantiomer (0.10 g) obtained by optical resolution of pyridine by preparative HPLC, 2-[(chlorocarbonyl)(methyl)amino]ethyl Ethyl carbonate (0.081 g), triethylamine (0.080 mL) and 4-dimethylaminopyridine (0.007 g) were added and stirred at 50°C for 18 hours. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=2:1) to give the title compound and (+)-ethyl 2-[[[5-methoxy-2- [[(4-Methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridin-1-yl]carbonyl](methyl)amino]ethyl carbonate 2: A mixture of 1 (0.115 g) was obtained as a colorless oil.
< ¹ >H-NMR ( _CDCl3 ): 1.20-1.38 (3H, m), 2.24 (6H, s), 3.08, 3.15, 3.33 (total 3H, s), 3 .73 (3H, s), 3.88-4.55 (9H, m), 4.78-5.05 (2H, m), 6.80, 6.86 (1H, d, J=8. 8 Hz), 7.76, 7.96 (1 H, d, J = 8.8 Hz), 8.21, 8.22 (total 1 H, s).

Of the following composition, 247.7 g of lansoprazole R form (hereinafter referred to as "compound A"), 184.6 g of magnesium carbonate, 492.2 g of refined sucrose, 299.9 g of corn starch and 329.6 g of low-substituted hydroxypropyl cellulose Mix well to make a dusting powder. 880 g of sucrose/starch spherical granules (trade name: Nonpareil-101, manufactured by Freund Sangyo Co., Ltd.) was put into a centrifugal tumbling granulator (CF-360, manufactured by Freund Sangyo Co., Ltd.), and a hydroxypropyl cellulose solution (2 w/w) was added. %) to obtain spherical granules. The spherical granules were vacuum dried at 40° C. for 16 hours and sieved with a round sieve to obtain granules of 710 μm to 1400 μm.

Composition in granules 300.0 mg White sugar/starch spherical granules 110.0 mg
Compound A 30.0 mg
Magnesium carbonate 22.4mg
Refined white sugar 59.8mg
Corn starch 36.4mg
Low-substituted hydroxypropyl cellulose 40.0 mg
Hydroxypropyl cellulose 1.4 mg
Total 300.0mg

25 g of macrogol 6000 and 10 g of polysorbate 80 were dissolved in 1206 g of purified water, and 78 g of talc, 25 g of titanium oxide and 866.7 g of methacrylic acid copolymer LD (260 g as solid content) were dispersed in the resulting solution to produce an enteric coating solution. did. The above enteric coating solution was applied to the granules obtained in Example 1 in a tumbling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 45°C and a rotor rotation speed of 200 rpm. Coating was carried out under conditions of injection rate: 3.8 g/min, spray air pressure: 1.0 kg/cm ² , drying as it was, and sieving with a round sieve to obtain enteric granules of 710 µm to 1400 µm having the following composition. The resulting spherical granules were vacuum dried at 40° C. for 16 hours.

300.0 mg of granules of Composition Example 1 in 369.2 mg of enteric coated granules
Methacrylic acid copolymer LD 148.7 mg (44.6 mg as solids)
Talc 13.8mg
Macrogol 6000 4.4mg
Titanium oxide 4.4mg
Polysorbate 80 2.0 mg
Total 369.2mg

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymer L and 4.8 g of triethyl citrate were dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc was dispersed in the resulting solution to prepare a coating solution. manufactured. 100 g of the enteric-coated granules obtained in Example 2 were coated with the above coating solution in a rolling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30°C and a rotor rotation speed of 150 rpm. Injection rate: 3.3 g/min, Spray air pressure: 1.0 kg/cm ² By coating, pH-dependent dissolution (release of active ingredient in an environment above a certain pH) is released. Controlled release granules coated with a control membrane and having the following composition were obtained. The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 710 μm to 1400 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

Composition in 605.5 mg of controlled-release granules Enteric-coated granules obtained in Example 2 369.2 mg
Methacrylic acid copolymer S 110.8 mg
Methacrylic acid copolymer L 36.9 mg
Talc 73.8mg
Triethyl citrate 14.8 mg
Total 605.5mg

24 g of methacrylic acid copolymer S, 24 g of methacrylic acid copolymer L and 4.8 g of triethyl citrate were dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc was dispersed in the resulting solution to prepare a coating solution. manufactured. 100 g of the enteric-coated granules obtained in Example 2 were coated with the above coating solution in a rolling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30°C and a rotor rotation speed of 150 rpm. Injection rate: 3.3 g/min, Spray air pressure: 1.0 kg/cm ² By coating, pH-dependent dissolution (release of active ingredient in an environment above a certain pH) is released. Controlled release granules coated with a control membrane and having the following composition were obtained. The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 710 μm to 1400 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

Composition in 605.5 mg of controlled-release granules Enteric-coated granules obtained in Example 2 369.2 mg
Methacrylic acid copolymer S 73.85 mg
Methacrylic acid copolymer L 73.85 mg
Talc 73.8mg
Triethyl citrate 14.8 mg
Total 605.5mg

104 mg of the enteric-coated granules obtained in Example 2 and 500 mg of the controlled-release granules obtained in Example 3 were mixed, and 205 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical Co.) was added to form a No. 0 gelatin capsule. Two capsules were obtained.

104 mg of the enteric-coated granules obtained in Example 2 and 500 mg of the controlled-release granules obtained in Example 4 were mixed, and 205 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical Co.) was added to form a No. 0 gelatin capsule. Two capsules were obtained.

300 g of compound A, 105 g of magnesium carbonate, 195 g of refined sucrose and 75 g of low-substituted hydroxypropylcellulose were thoroughly mixed to prepare a dusting agent for the active ingredient layer. 75 g of refined sucrose, 48.8 g of titanium oxide and 18.8 g of low-substituted hydroxypropyl cellulose were thoroughly mixed to prepare an intermediate layer dusting agent. 375 g of sucrose/starch spherical granules (trade name: Nonpareil-101, manufactured by Freund Sangyo Co., Ltd.) was put into a centrifugal tumbling granulator (CF-360, manufactured by Freund Sangyo Co., Ltd.), and a hydroxypropyl cellulose solution (2 w/ %) was sprayed while coating the above main agent layer dusting agent to obtain spherical granules. Subsequently, while spraying a hydroxypropyl cellulose solution (2 w/w %), the intermediate layer dusting agent was coated to obtain spherical granules. The resulting spherical granules were vacuum dried at 40° C. for 16 hours and sieved through a round sieve to obtain granules of 710 μm to 1400 μm.

Composition in granules 120.0mg Sucrose/starch spherical granules 37.5mg
Hydroxypropyl cellulose 0.75 mg
Main agent dusting agent Compound A 30.0 mg
Magnesium carbonate 10.5mg
Refined white sugar 19.5mg
Low-substituted hydroxypropyl cellulose 7.5 mg
Intermediate layer dusting agent Refined sucrose 7.5 mg
Low substituted hydroxypropyl cellulose 1.875mg
Titanium oxide 4.875mg
Total 120.0mg

25 g of macrogol 6000 and 10 g of polysorbate 80 were dissolved in 1206 g of purified water, and 78 g of talc, 25 g of titanium oxide and 866.7 g of methacrylic acid copolymer LD (260 g as solid content) were dispersed in the resulting solution to produce an enteric coating solution. did. The above enteric coating solution was applied to the granules obtained in Example 7 in a tumbling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 45°C and a rotor rotation speed of 200 rpm. Coating was carried out under conditions of injection rate: 3.8 g/min, spray air pressure: 1.0 kg/cm ² , drying as it was, and sieving with a round sieve to obtain enteric granules of 710 µm to 1400 µm having the following composition. The resulting spherical granules were vacuum dried at 40° C. for 16 hours.

120.00 mg of granules of Composition Example 7 in 149.86 mg of enteric coated granules
Methacrylic acid copolymer LD 65 mg (19.5 mg as solid content)
Talc 5.85mg
Macrogol 6000 1.88mg
Titanium oxide 1.88mg
Polysorbate 80 0.75 mg
Total 149.86mg

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymer L and 4.8 g of triethyl citrate are dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc is dispersed in the resulting solution to prepare a coating solution. did. 100 g of the enteric-coated granules obtained in Example 8 were coated with the above coating solution in a rolling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30°C and a rotor rotation speed of 150 rpm. Injection rate: 3.3 g/min, Spray air pressure: 1.0 kg/cm ² By coating, pH-dependent dissolution (release of active ingredient in an environment above a certain pH) is released. Controlled release granules coated with a control membrane and having the following composition were obtained. The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 710 μm to 1400 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

149.86 mg of enteric coated granules of Composition Example 8 in 245.86 mg of controlled release granules
Methacrylic acid copolymer S 45.00 mg
Methacrylic acid copolymer L 15.00 mg
Talc 30.00 mg
Triethyl citrate 6.00 mg
Total 245.86mg

24 g of methacrylic acid copolymer S, 24 g of methacrylic acid copolymer L and 4.8 g of triethyl citrate were dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc was dispersed in the resulting solution to prepare a coating solution. manufactured. 100 g of the enteric-coated granules obtained in Example 8 were coated with the above coating solution in a rolling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30°C and a rotor rotation speed of 150 rpm. Injection rate: 3.3 g/min, Spray air pressure: 1.0 kg/cm ² By coating, pH-dependent dissolution (release of active ingredient in an environment above a certain pH) is released. Controlled release granules coated with a control membrane and having the following composition were obtained. The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 710 μm to 1400 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

149.86 mg of enteric coated granules of Composition Example 8 in 245.86 mg of controlled release granules
Methacrylic acid copolymer S 30.0 mg
Methacrylic acid copolymer L 30.0 mg
Talc 30.0 mg
Triethyl citrate 6.0 mg
Total 245.86mg

35.5 mg of the enteric-coated granules obtained in Example 8 and 175 mg of the controlled-release granules obtained in Example 9 were mixed, and 70.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical) was added, One No. 1 capsule (compound A: equivalent to 30 mg) was filled to obtain a capsule.

35.5 mg of the enteric-coated granules obtained in Example 8 and 175 mg of the controlled-release granules obtained in Example 10 were mixed, and 70.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical) was added, One No. 1 capsule (compound A: equivalent to 30 mg) was filled to obtain a capsule.

Test example 1

The capsules obtained in Example 5 were orally administered to beagle dogs under fasting conditions together with 30 mL of water. The plasma drug concentrations of Compound A at 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours after administration were 186 ng/mL, 132 ng/mL, 107 ng/mL, 303 ng/mL and 355 ng, respectively. /mL, 216 ng/mL, and 113 ng/mL.

Test example 2

The capsules obtained in Example 6 were orally administered to fasting beagle dogs together with 30 mL of water. The plasma drug concentrations of Compound A at 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours after administration were 192 ng/mL, 137 ng/mL, 473 ng/mL, 478 ng/mL and 364 ng, respectively. /mL, 257 ng/mL and 28 ng/mL.

Test example 3

The capsules obtained in Example 11 were orally administered to fasting beagle dogs together with 30 mL of water. The plasma drug concentrations of Compound A at 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours after administration were 308 ng/mL, 245 ng/mL, 323 ng/mL, 81 ng/mL and 39 ng, respectively. /mL, 26 ng/mL, and 0 ng/mL.

Test example 4

The capsules obtained in Example 12 were orally administered to fasting beagle dogs together with 30 mL of water. The plasma drug concentrations of compound A at 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours after administration were 160 ng/mL, 319 ng/mL, 631 ng/mL, 371 ng/mL and 230 ng, respectively. /mL, 144 ng/mL, 25 ng/mL.

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymer L and 4.8 g of triethyl citrate are dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc is dispersed in the resulting solution to prepare a coating solution. did. 100 g of the enteric-coated granules obtained in Example 8 were coated with the above coating solution in a rolling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30°C and a rotor rotation speed of 150 rpm. Injection rate: 3.3 g/min, Spray air pressure: 1.0 kg/cm ² By coating, pH-dependent dissolution (release of active ingredient in an environment above a certain pH) is released. Controlled release granules coated with a control membrane and having the following composition were obtained. The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 710 μm to 1400 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

149.86 mg of enteric coated granules of Composition Example 8 in 221.86 mg of controlled release granules
Methacrylic acid copolymer S 33.75 mg
Methacrylic acid copolymer L 11.25 mg
Talc 22.5 mg
Triethyl citrate 4.5 mg
Total 221.86mg

24 g of methacrylic acid copolymer S, 24 g of methacrylic acid copolymer L and 4.8 g of triethyl citrate are dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc is dispersed in the resulting solution to prepare a coating solution. did. 100 g of the enteric-coated granules obtained in Example 8 were coated with the above coating solution in a rolling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30°C and a rotor rotation speed of 150 rpm. Injection rate: 3.3 g/min, Spray air pressure: 1.0 kg/cm ² By coating, pH-dependent dissolution (release of active ingredient in an environment above a certain pH) is released. Controlled release granules coated with a control membrane and having the following composition were obtained. The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 710 μm to 1400 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

149.86 mg of enteric coated granules of Composition Example 8 in 221.86 mg of controlled release granules
Methacrylic acid copolymer S 22.5 mg
Methacrylic acid copolymer L 22.5 mg
Talc 22.5 mg
Triethyl citrate 4.5 mg
Total 221.86mg

35.5 mg of the enteric-coated granules obtained in Example 8 and 168 mg of the controlled-release granules obtained in Example 13 were mixed, and 68.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical) was added, One No. 1 capsule (compound A: equivalent to 30 mg) was filled to obtain a capsule.

35.5 mg of the enteric coated granules obtained in Example 8 and 168 mg of the controlled-release granules obtained in Example 14 were mixed, and 68.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical) was added, One No. 1 capsule (compound A: equivalent to 30 mg) was filled to obtain a capsule.

35.5 mg of the enteric-coated granules obtained in Example 8 and 168 mg of the controlled-release granules obtained in Example 13 were mixed and filled into one No. 3 capsule (compound A: equivalent to 30 mg) to obtain a capsule.

35.5 mg of the enteric-coated granules obtained in Example 8 and 168 mg of the controlled-release granules obtained in Example 13 were mixed and filled into one No. 3 capsule (compound A: equivalent to 30 mg) to obtain a capsule.

Test example 5

The capsules obtained in Example 14 were orally administered to fasting beagle dogs together with 30 mL of water. The plasma drug concentrations of Compound A at 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours after administration were 403 ng/mL, 687 ng/mL, 803 ng/mL, 463 ng/mL and 329 ng, respectively. /mL, 217 ng/mL, 65 ng/mL.

100 g of the granules obtained in Example 1 were placed in a centrifugal tumbling granulator (CF-mini, manufactured by Freund Corporation) and disintegrated while spraying a hydroxypropylcellulose solution (8 w/w%) dissolved in isopropyl alcohol. The granules were coated with 32 w/w% of Ac-Di-Sol as an agent to obtain spherical granules. The spherical granules were vacuum-dried at 40° C. for 16 hours and passed through a round sieve to obtain granules of 1400 μm or less.

A coating solution was prepared by dissolving 24 g of aminoalkyl methacrylate copolymer RS in a mixture of 120 g of acetone and 288 g of isopropyl alcohol, and dispersing 48 g of talc in the resulting solution. To 100 g of the granules obtained in Example 19, the above coating solution was injected in a tumbling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30 ° C. and a rotor rotation speed of 150 rpm. Controlled-release granules having the following composition were obtained by coating at a rate of 3.1 g/min and a spray air pressure of 1.0 kg/cm ² . The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 710 μm to 1700 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

Composition in 130.0 mg controlled release granules Granules obtained in Example 19 100 mg
Aminoalkyl methacrylate copolymer RS 10.0 mg
Talc 20.0 mg
Total 130.0mg

104 mg of the enteric-coated granules obtained in Example 2 and 420 mg of the controlled-release granules obtained in Example 20 were mixed, and 175 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical Co.) was added to form a No. 0 gelatin capsule. Two capsules (compound A: equivalent to 30 mg) were filled to obtain capsules.

104 mg of the enteric-coated granules obtained in Example 2 and 420 mg of the controlled-release granules obtained in Example 20 were mixed and filled into two No. 0 gelatin capsules (compound A: equivalent to 30 mg) to obtain capsules.

Test example 6

The capsules obtained in Example 21 were orally administered to fasting beagle dogs together with 30 mL of water. The plasma drug concentrations of Compound A at 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours after administration were 657 ng/mL, 406 ng/mL, 223 ng/mL, 504 ng/mL and 399 ng, respectively. /mL, 228 ng/mL, 50 ng/mL.

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymer L and 4.8 g of triethyl citrate are dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc is dispersed in the resulting solution to prepare a coating solution. did. To 100 g of the granules obtained in Example 19, the above coating solution was injected in a tumbling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30 ° C. and a rotor rotation speed of 150 rpm. Controlled-release granules having the following composition were obtained by coating under conditions of a rate of 3.3 g/min and a spray air pressure of 1.0 kg/cm ² . The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 710 μm to 1700 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

Composition in 164.0 mg controlled release granules Granules obtained in Example 19 100 mg
Methacrylic acid copolymer S 30.0 mg
Methacrylic acid copolymer L 10.0 mg
Talc 20.0 mg
Triethyl citrate 4.0 mg
Total 164.0mg

104 mg of the enteric-coated granules obtained in Example 2 and 614 mg of the controlled-release granules obtained in Example 23 were mixed, and 239 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical Co.) was added to form a No. 0 gelatin capsule. Two capsules (compound A: equivalent to 30 mg) were obtained.

104 mg of the enteric-coated granules obtained in Example 2 and 614 mg of the controlled-release granules obtained in Example 23 were mixed and filled into two No. 0 gelatin capsules to obtain capsules (compound A: equivalent to 30 mg).

Test example 7

The capsules obtained in Example 24 were orally administered to fasting beagle dogs together with 30 mL of water. The plasma drug concentrations of Compound A at 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours after administration were 106 ng/mL, 135 ng/mL, 639 ng/mL, 129 ng/mL and 49 ng, respectively. /mL, 16 ng/mL, and 0 ng/mL.

Comparative example 1

One No. 0 gelatin capsule filled with 414 mg of the enteric-coated granules obtained in Example 2 was orally administered to fasting beagle dogs together with 30 mL of water. The plasma drug concentrations of compound A at 1 hour, 2 hours, 4 hours, 6 hours, 7 hours, 8 hours and 10 hours after administration were 2068 ng/mL, 689 ng/mL, 70 ng/mL, 0 ng/mL and 0 ng, respectively. /mL, 0 ng/mL, and 0 ng/mL.

150 g of Compound A, 50 g of magnesium carbonate, 25 g of low-substituted hydroxypropyl cellulose and 25 g of hydroxypropyl cellulose were suspended in 1420 g of purified water to prepare a spray solution. 200 g of crystalline cellulose (granules) was put into a rolling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation), supplied air temperature was 62°C, rotor rotation speed was 300 rpm, liquid injection speed was 10 g/min. , spray air pressure: 1.0 kg/cm ² to obtain spherical granules having the following composition. The resulting spherical granules were vacuum dried at 40° C. for 16 hours and passed through a round sieve to obtain granules of 500 μm to 1400 μm.

Composition Microcrystalline cellulose (granules) 22.5 mg in granules 41.24 mg
Compound A 11.25 mg
Magnesium carbonate 3.75mg
Low substituted hydroxypropyl cellulose 1.87mg
Hydroxypropyl cellulose 1.87 mg
Total 41.24mg

90 g of Compound A, 31.5 g of magnesium carbonate, 58.5 g of refined sucrose, and 22.5 g of low-substituted hydroxypropylcellulose were thoroughly mixed to prepare a dusting agent for the active ingredient layer. 110 g of the granules obtained in Example 26 were put into a centrifugal tumbling granulator (CF-mini, manufactured by Freund Corporation), and the main agent layer dusting agent was sprayed with a hydroxypropylcellulose solution (2 w/w%). was coated to obtain spherical granules having the following composition. The resulting spherical granules were vacuum dried at 40° C. for 16 hours and sieved through a round sieve to obtain granules of 710 μm to 1400 μm.

41.25 mg of granules of composition example 26 in 118.03 mg of granules
Compound A 33.75 mg
Magnesium carbonate 11.81mg
Refined sucrose 21.94 mg
Low-substituted hydroxypropyl cellulose 8.44 mg
Hydroxypropyl cellulose 0.84 mg
Total 118.03mg

The granules obtained in Example 27 were coated with the intermediate layer coating liquid using a tumbling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) and dried as is to obtain granules having the following composition. . An intermediate layer coating solution was prepared by dissolving 20.09 g of hydroxypropyl methylcellulose 2910 in 361.55 g of purified water and dispersing 8.03 g of titanium oxide and 12.05 g of talc in the resulting solution. The coating operation conditions were as follows: supply air temperature: 62°C, rotor speed: 200 rpm, injection rate: 3.0 g/min, spray air pressure: 1.0 kg/cm ² . The resulting spherical granules were vacuum dried at 40° C. for 16 hours and sieved through a round sieve to obtain granules of 710 μm to 1400 μm.

118.03 mg of granules of Composition Example 27 in 133.03 mg of interlayer coated granules
Hydroxypropyl methylcellulose 2910 7.5 mg
Talc 4.5mg
Titanium oxide 3.0 mg
Total 133.03mg

25 g of macrogol 6000 and 10 g of polysorbate 80 were dissolved in 1206 g of purified water, and 78 g of talc, 25 g of titanium oxide and 866.7 g of methacrylic acid copolymer LD (260 g as solid content) were dispersed in the resulting solution to produce an enteric coating solution. did. The granules obtained in Example 28 were coated with the above enteric coating liquid in a tumbling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 45°C and a rotor rotation speed of 200 rpm. Coating was carried out under the conditions of injection rate: 3.8 g/min, spray air pressure: 1.0 kg/cm ² , drying as it was, and sieving with a round sieve to obtain enteric granules of 710 µm to 1400 µm having the following composition. The resulting spherical granules were vacuum dried at 40° C. for 16 hours.

133.03 mg of granules of composition example 28 in 165.18 mg of enteric coated granules
70 mg of methacrylic acid copolymer LD (21 mg as solids)
Talc 6.30 mg
Macrogol 6000 2.02mg
Titanium oxide 2.02mg
Polysorbate 80 0.81 mg
Total 165.18mg

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymer L and 4.8 g of triethyl citrate were dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc was dispersed in the resulting solution to prepare a coating solution. manufactured. To 100 g of the granules obtained in Example 28, the above coating solution was injected in a rolling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Sangyo Co., Ltd.) at an air supply temperature of 30 ° C. and a rotor rotation speed of 100 rpm. A controlled release membrane that achieves pH-dependent dissolution (releases the active ingredient in an environment above a certain pH) by coating under the conditions of a rate of 3.0 g/min and a spray air pressure of 1.0 kg/cm ² . to obtain controlled-release granules having the following composition coated with The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 1180 μm to 1700 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

133.03 mg of granules of composition example 28 in 196.88 mg of controlled release granules
Methacrylic acid copolymer S 29.93 mg
Methacrylic acid copolymer L 9.98 mg
Talc 19.95mg
Triethyl citrate 3.99 mg
Total 196.88mg

24 g of methacrylic acid copolymer S, 24 g of methacrylic acid copolymer L, and 4.8 g of triethyl citrate were dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc was dispersed in the resulting solution to prepare a coating solution. manufactured. 100 g of the granules obtained in Example 28 were coated with the above coating solution in a tumbling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30°C and a rotor rotation speed of 100 rpm. A controlled release membrane that achieves pH-dependent dissolution (releases the active ingredient in an environment above a certain pH) by coating under the conditions of a rate of 3.0 g/min and a spray air pressure of 1.0 kg/cm ² . to obtain controlled-release granules having the following composition coated with The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 1180 μm to 1700 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

133.03 mg of granules of composition example 28 in 196.88 mg of controlled release granules
Methacrylic acid copolymer S 19.95 mg
Methacrylic acid copolymer L 19.95 mg
Talc 19.95mg
Triethyl citrate 3.99 mg
Total 196.88mg

28 mg of the enteric coated granules obtained in Example 29 and 98.7 mg of the controlled release granules obtained in Example 30 were mixed, and further 42.3 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical) was added, One No. 1 capsule (compound A: equivalent to 30 mg) was filled to obtain a capsule.

28 mg of the enteric coated granules obtained in Example 29 and 98.7 mg of the controlled release granules obtained in Example 31 were mixed, and further 42.3 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, Dow Chemical) was added, One No. 1 capsule (compound A: equivalent to 30 mg) was filled to obtain a capsule.

56 mg of the enteric coated granules obtained in Example 29 and 197.4 mg of the controlled release granules obtained in Example 30 were mixed and filled into one No. 2 capsule (compound A: equivalent to 60 mg) to obtain a capsule.

84 mg of the enteric-coated granules obtained in Example 29 and 296.1 mg of the controlled-release granules obtained in Example 30 were mixed and filled into one No. 1 capsule (compound A: equivalent to 90 mg) to obtain a capsule.

42 mg of the enteric-coated granules obtained in Example 29 and 148.05 mg of the controlled-release granules obtained in Example 30 were mixed and filled into one No. 3 capsule (compound A: equivalent to 45 mg) to obtain a capsule.

A coating solution was prepared by dissolving 48 g of methacrylic acid copolymer S and 4.8 g of triethyl citrate in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and dispersing 24 g of talc in the resulting solution. The above coating solution was injected into 100 g of the granules obtained in Example 30 in a rolling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30 ° C. and a rotor rotation speed of 100 rpm. A controlled release membrane that achieves pH-dependent dissolution (releases the active ingredient in an environment above a certain pH) by coating under the conditions of a rate of 3.0 g/min and a spray air pressure of 1.0 kg/cm ² . to obtain controlled-release granules having the following composition coated with The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 1180 μm to 1700 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

196.88 mg of granules of composition example 30 in 207.52 mg of controlled release granules
Methacrylic acid copolymer S 6.65 mg
Talc 3.32 mg
Triethyl citrate 0.67 mg
Total 207.52mg

A coating solution was prepared by dissolving 48 g of methacrylic acid copolymer S and 4.8 g of triethyl citrate in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and dispersing 24 g of talc in the resulting solution. To 100 g of the granules obtained in Example 31, the above coating solution was injected in a tumbling stirring fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30 ° C. and a rotor rotation speed of 100 rpm. A controlled release membrane that achieves pH-dependent dissolution (releases the active ingredient in an environment above a certain pH) by coating under the conditions of a rate of 3.0 g/min and a spray air pressure of 1.0 kg/cm ² . to obtain controlled-release granules having the following composition coated with The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 1180 μm to 1700 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

196.88 mg of granules of composition example 31 in 207.52 mg of controlled release granules
Methacrylic acid copolymer S 6.65 mg
Talc 3.32mg
Triethyl citrate 0.67 mg
Total 207.52mg

28 mg of the enteric-coated granules obtained in Example 29 and 103.8 mg of the controlled-release granules obtained in Example 37 were mixed, and 43.9 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical) was added, One No. 1 capsule (compound A: equivalent to 30 mg) was filled to obtain a capsule.

28 mg of the enteric-coated granules obtained in Example 29 and 103.8 mg of the controlled-release granules obtained in Example 38 were mixed, and 43.9 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical) was added, One No. 1 capsule (compound A: equivalent to 30 mg) was filled to obtain a capsule.

56 mg of the enteric-coated granules obtained in Example 29 and 207.5 mg of the controlled-release granules obtained in Example 37 were mixed and filled into one No. 2 capsule (compound A: equivalent to 60 mg) to obtain a capsule.

84 mg of the enteric-coated granules obtained in Example 29 and 311.3 mg of the controlled-release granules obtained in Example 37 were mixed and filled into one No. 1 capsule (compound A: equivalent to 90 mg) to obtain a capsule.

42 mg of the enteric coated granules obtained in Example 29 and 155.6 mg of the controlled release granules obtained in Example 37 were mixed and filled into one No. 3 capsule (compound A: equivalent to 45 mg) to obtain a capsule.

300 g of compound A, 105 g of magnesium carbonate, 195 g of refined sucrose and 75 g of low-substituted hydroxypropylcellulose were thoroughly mixed to prepare a dusting agent for the active ingredient layer. 75 g of refined sucrose, 48.8 g of titanium oxide and 18.8 g of low-substituted hydroxypropyl cellulose were thoroughly mixed to prepare an intermediate layer dusting agent. 375 g of sucrose/starch spherical granules (trade name: Nonpareil-101, manufactured by Freund Sangyo Co., Ltd.) was put into a centrifugal tumbling granulator (CF-360, manufactured by Freund Sangyo Co., Ltd.), and a hydroxypropyl cellulose solution (2 w/ W %) was sprayed while coating the above main agent layer dusting agent to obtain spherical granules. The resulting spherical granules were vacuum dried at 40° C. for 16 hours and sieved through a round sieve to obtain granules of 710 μm to 1400 μm.

Composition in granules 158.07mg Sucrose/starch spherical granules 56.25mg
Hydroxypropyl cellulose 0.57 mg
Main agent dusting agent Compound A 45.00 mg
Magnesium carbonate 15.75mg
Refined sucrose 29.25 mg
Low-substituted hydroxypropyl cellulose 11.25 mg
Total 158.07mg

The granules obtained in Example 44 were coated with the intermediate layer coating liquid using a tumbling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) and dried as is to obtain granules having the following composition. . An intermediate layer coating solution was prepared by dissolving 20.09 g of hydroxypropyl methylcellulose 2910 in 361.55 g of purified water and dispersing 8.03 g of titanium oxide and 12.05 g of talc in the resulting solution. The coating operation conditions were as follows: supply air temperature: 62°C, rotor speed: 200 rpm, injection rate: 3.0 g/min, spray air pressure: 1.0 kg/cm ² . The resulting spherical granules were vacuum dried at 40° C. for 16 hours and sieved through a round sieve to obtain granules of 710 μm to 1400 μm.

158.07 mg of granules of composition example 44 in 188.07 mg of interlayer coated granules
Hydroxypropyl methylcellulose 2910 15.00 mg
Talc 9.00 mg
Titanium oxide 6.00mg
Total 188.07mg

36 g of methacrylic acid copolymer S, 12 g of methacrylic acid copolymer L and 4.8 g of triethyl citrate were dissolved in a mixture of 69.12 g of purified water and 622.08 g of absolute ethanol, and 24 g of talc was dispersed in the resulting solution to prepare a coating solution. manufactured. 100 g of the granules obtained in Example 45 were coated with the above coating solution in a tumbling agitation fluidized bed coating machine (SPIR-A-FLOW, manufactured by Freund Corporation) at an air supply temperature of 30°C and a rotor rotation speed of 100 rpm. A controlled release membrane that achieves pH-dependent dissolution (releases the active ingredient in an environment above a certain pH) by coating under the conditions of a rate of 3.0 g/min and a spray air pressure of 1.0 kg/cm ² . to obtain controlled-release granules having the following composition coated with: The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 1180 μm to 1700 μm. Then, it was vacuum-dried at 40° C. for 16 hours.

188.07 mg of granules of composition example 45 in 278.35 mg of controlled release granules
Methacrylic acid copolymer S 42.32 mg
Methacrylic acid copolymer L 14.11 mg
Talc 28.21 mg
Triethyl citrate 5.64 mg
Total 278.35mg

35.5 mg of the enteric-coated granules obtained in Example 8 and 139.2 mg of the controlled-release granules obtained in Example 46 were mixed, and 58.2 mg of polyethylene oxide (trade name: Polyox WSR Coagulant, manufactured by Dow Chemical) was added. Then, one No. 1 capsule (compound A: equivalent to 30 mg) was filled to obtain a capsule.

71 mg of the enteric-coated granules obtained in Example 8 and 278.35 mg of the controlled-release granules obtained in Example 46 were mixed and filled into one No. 1 capsule (compound A: equivalent to 60 mg) to obtain capsules.

106.5 mg of the enteric coated granules obtained in Example 8 and 417.5 mg of the controlled release granules obtained in Example 46 were mixed and filled into two No. 2 capsules (compound A: equivalent to 90 mg) to obtain capsules. .

53.3 mg of the enteric-coated granules obtained in Example 8 and 208.8 mg of the controlled-release granules obtained in Example 46 were mixed and filled into one No. 2 capsule (compound A: equivalent to 45 mg) to obtain a capsule. .

824.4 g of compound A, 303.2 g of magnesium carbonate, 1062 g of refined sucrose and 228.2 g of low-substituted hydroxypropyl cellulose were thoroughly mixed to prepare a main agent layer dusting agent. 722.4 g of sucrose/starch spherical granules (trade name: Nonpareil-101, manufactured by Freund Sangyo Co., Ltd.) was put into a centrifugal tumbling granulator (CF-360, manufactured by Freund Sangyo Co., Ltd.), and a hydroxypropylcellulose solution ( 2 w/w%) was coated while spraying the main agent layer dusting agent to obtain spherical granules. The resulting spherical granules were vacuum dried at 40° C. for 16 hours and sieved through a round sieve to obtain granules of 710 μm to 1400 μm.

Composition in granules 86.67mg White sugar/starch spherical granules 20.64mg
Hydroxypropyl cellulose 0.24 mg
Main agent dusting agent Compound A 22.50 mg
Magnesium carbonate 8.25mg
Refined white sugar 28.83mg
Low-substituted hydroxypropyl cellulose 6.21 mg
Total 86.67mg

The granules obtained in Example 51 were coated with the intermediate layer coating liquid using a tumbling fluidized bed coating machine (MP-10, manufactured by Powrex Co., Ltd.) and dried as they were to obtain granules having the following composition. An intermediate layer coating solution was prepared by dissolving 270.0 g of hydroxypropyl methylcellulose 2910 in 4874 g of purified water and dispersing 163.5 g of titanium oxide and 108 g of talc in the resulting solution. The coating operation conditions were air supply temperature: 67°C, air supply amount: 1.5 m ³ /min, injection rate: 12.0 g/min, spray air pressure: 0.28 MPa, spray air amount: 90 Nl/hr. . The resulting spherical granules were vacuum dried at 40° C. for 16 hours and sieved through a round sieve to obtain granules of 710 μm to 1400 μm.

86.67 mg of granules of composition example 51 in 97.50 mg of interlayer coated granules
Hydroxypropyl methylcellulose 2910 5.40 mg
Talc 2.16 mg
Titanium oxide 3.27mg
Total 97.50mg

57.60 g of macrogol 6000 and 26.40 g of polysorbate 80 were dissolved in 2724 g of purified water, and 174 g of talc, 57.6 g of titanium oxide and 1932 g of methacrylic acid copolymer LD (579.6 g as solid content) were dispersed in the resulting solution. An enteric coating solution was prepared. The above enteric coating liquid was applied to the granules obtained in Example 52 in a tumbling agitation fluidized bed coating machine (MP-10, manufactured by Powrex Co., Ltd.) at an air supply temperature of 65°C and an air supply amount of 1.5 m ³ . /min, injection rate: 15.0 g/min, spray air pressure: 0.30 MPa, spray air amount: 90 Nl/hr. It was dried as it was and sieved with a round sieve to obtain enteric granules of 710 μm to 1400 μm having the following composition. The resulting spherical granules were vacuum-dried at 40° C. for 16 hours, and 0.96 g of talc and 0.96 g of aerosil were mixed with 1,918 g of granules to obtain enteric-coated granules.

97.5 mg of granules of composition example 52 in 120.0 mg of enteric coated granules
Methacrylic acid copolymer LD 48.3 mg (14.49 mg as solids)
Talc 4.35mg
Macrogol 6000 1.44mg
Titanium oxide 1.44 mg
Polysorbate 80 0.66 mg
Talc 0.06 mg
Aerosil 0.06mg
Total 120.0mg

1131 g of Compound A, 302.4 g of magnesium carbonate, 750.1 g of refined sucrose and 226.8 g of low-substituted hydroxypropyl cellulose were thoroughly mixed to prepare a main agent layer dusting agent. A centrifugal tumbling granulator (CF-360, Freund Corporation) was charged with 720.0 g of sucrose/starch spherical granules (trade name: Nonpareil-101, Freund Corporation), and a hydroxypropyl cellulose solution ( 2 w/w%) was coated while spraying the main agent layer dusting agent to obtain spherical granules. The resulting spherical granules were vacuum dried at 40° C. for 16 hours and sieved through a round sieve to obtain granules of 710 μm to 1400 μm.

Composition in granules 189.0 mg White sugar/starch spherical granules 45.0 mg
Hydroxypropyl cellulose 0.54 mg
Main agent dusting agent compound A 67.5 mg
Magnesium carbonate 18.0mg
Refined sucrose 44.46 mg
13.5 mg of low-substituted hydroxypropyl cellulose
Total 189.0mg

The granules obtained in Example 54 were coated with the intermediate layer coating liquid using a tumbling fluidized bed coating machine (MP-10, manufactured by Powrex Co., Ltd.) and dried as they were to obtain granules having the following composition. An intermediate layer coating solution was prepared by dissolving 236.4 g of hydroxypropyl methylcellulose 2910 in 4255 g of purified water and dispersing 141.6 g of titanium oxide and 94.8 g of talc in the resulting solution. Coating operation conditions: air supply temperature: 65°C, air supply amount: 1.5 m ³ /min, injection rate: 12.0 g/min, spray air pressure: 0.26 MPa, spray air amount: 90 Nl/hr
I went with The resulting spherical granules were vacuum dried at 40° C. for 16 hours and sieved through a round sieve to obtain granules of 710 μm to 1400 μm.

189.0 mg of granules of composition example 54 in 212.64 mg of interlayer coated granules
Hydroxypropyl methylcellulose 2910 11.82 mg
Talc 4.74 mg
Titanium oxide 7.08mg
Total 212.64mg

Dissolve 382.8 g of methacrylic acid copolymer S, 127.7 g of methacrylic acid copolymer L and 50.88 g of triethyl citrate in a mixture of 734.8 g of purified water and 6614 g of absolute ethanol, and disperse 255.1 g of talc in the resulting solution. A coating solution was prepared. The above coating solution was applied to the granules obtained in Example 55 in a rolling agitation fluidized bed coating machine (MP-10, manufactured by ^Powrex Co., Ltd.) at an air supply temperature of 65°C and an air supply amount of 1.5 m3/min. Injection rate: 15.0 g/min, spray air pressure: 0.30 MPa, spray air volume: 90 Nl/hr. Controlled-release granules coated with a release-controlling membrane that dissolves in the following composition were obtained. The obtained spherical granules were sieved with a round sieve to obtain controlled release granules of 1180 to 1700 µm. The resulting spherical granules were vacuum-dried at 40° C. for 16 hours, and 0.525 g of talc and 0.525 g of aerosil were mixed with 1101 g of the granules to obtain controlled-release granules.

212.64 mg of granules of composition example 55 in 315.0 mg of controlled release granules
Methacrylic acid copolymer S 47.85 mg
Methacrylic acid copolymer L 15.96 mg
Talc 31.89mg
Triethyl citrate 6.36 mg
Talc 0.15 mg
Aerosil 0.15mg
Total 315.0mg

120 mg of the enteric coated granules obtained in Example 53 and 315 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 1 capsule (compound A: equivalent to 90 mg) to obtain a capsule.

80 mg of the enteric-coated granules obtained in Example 53 and 210 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 2 capsule (compound A: equivalent to 60 mg) to obtain a capsule.

40 mg of the enteric-coated granules obtained in Example 53 and 105 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 3 capsule (compound A: equivalent to 30 mg) to obtain a capsule.

240 mg of the enteric-coated granules obtained in Example 53 and 210 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 1 capsule (compound A: equivalent to 90 mg) to obtain a capsule.

160 mg of the enteric coated granules obtained in Example 53 and 280 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 1 capsule (compound A: equivalent to 90 mg) to obtain a capsule.

192 mg of the enteric-coated granules obtained in Example 53 and 252 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 1 capsule (compound A: equivalent to 90 mg) to obtain capsules.

160 mg of the enteric coated granules obtained in Example 53 and 210 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 1 capsule (compound A: equivalent to 75 mg) to obtain a capsule.

100 mg of the enteric-coated granules obtained in Example 53 and 262.5 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 1 capsule (compound A: equivalent to 75 mg) to obtain a capsule.

133.3 mg of the enteric coated granules obtained in Example 53 and 233.3 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 1 capsule (compound A: equivalent to 75 mg) to obtain a capsule. .

200 mg of the enteric-coated granules obtained in Example 53 and 175 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 1 capsule (compound A: equivalent to 75 mg) to obtain a capsule.

106.7 mg of the enteric coated granules obtained in Example 53 and 186.7 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 2 capsule (compound A: equivalent to 60 mg) to obtain a capsule. .

128 mg of the enteric coated granules obtained in Example 53 and 168 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 2 capsule (compound A: equivalent to 60 mg) to obtain a capsule.

160 mg of the enteric-coated granules obtained in Example 53 and 140 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 2 capsule (compound A: equivalent to 60 mg) to obtain a capsule.

60 mg of the enteric-coated granules obtained in Example 53 and 157.5 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 2 capsule (equivalent to 45 mg of compound A) to obtain a capsule.

120 mg of the enteric coated granules obtained in Example 53 and 105 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 2 capsule (compound A: equivalent to 45 mg) to obtain a capsule.

80 mg of the enteric coated granules obtained in Example 53 and 140 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 2 capsule (compound A: equivalent to 45 mg) to obtain a capsule.

96 mg of the enteric-coated granules obtained in Example 53 and 126 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 2 capsule (compound A: equivalent to 45 mg) to obtain a capsule.

53.3 mg of the enteric coated granules obtained in Example 53 and 93.3 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 3 capsule (Compound A: equivalent to 30 mg) to obtain a capsule. .

64 mg of the enteric coated granules obtained in Example 53 and 84 mg of the controlled release granules obtained in Example 56 were mixed and filled into one No. 3 capsule (compound A: equivalent to 30 mg) to obtain a capsule.

80 mg of the enteric-coated granules obtained in Example 53 and 70 mg of the controlled-release granules obtained in Example 56 were mixed and filled into one No. 3 capsule (compound A: equivalent to 30 mg) to obtain a capsule.

Since the release-controlling film of the present invention can be applied to solid formulations, preparations are made by applying the release-controlling film or by combining a composition with a release-controlling film and a gel-forming polymer. As a result, it can be applied to sustained release of drug active ingredients in orally administered preparations and stabilization of unstable drugs.

Claims (49)

Tablets, granules or capsules containing controlled-release active ingredients and gel-forming polymers. 2. A capsule according to claim 1, wherein the release of the active ingredient is controlled by a release-controlling coating formed on the core granules containing the active ingredient. 3. The capsule formulation according to claim 2, wherein the controlled release coating contains a polymer that dissolves in a pH-dependent manner. 3. The capsule formulation according to claim 2, wherein the release controlling coating is a diffusion controlling membrane. 2. Capsules according to claim 1, wherein the release of the active ingredient is controlled by dispersing the active ingredient in a controlled release matrix that constitutes tablets, granules or granules. A tablet, granule or fine granule with controlled release of an active ingredient comprises a disintegrant layer containing a disintegrant formed on a core granule containing an active ingredient and a controlled release coating formed on the disintegrant layer 5. A capsule according to claim 3 or 4, wherein the release of the active ingredient is initiated after a certain lag time. 7. Capsules according to any one of claims 3 to 6, characterized in that the tablets, granules or granules with controlled release of active ingredient are coated with a gel-forming polymer. 8. Capsules according to claim 7, further comprising a gel-forming polymer. 8. Capsules according to any one of claims 1 to 7, characterized in that they contain two types of tablets, granules or granules with different active ingredient release conditions. Tablets, granules or granules with an enteric coating that releases the active ingredient at a pH of about 5.5 and tablets, granules or granules with a controlled release coating that releases the active ingredient at a pH of about 6.0 or higher. The capsule according to claim 9, containing 9. Capsules according to claim 1, 7 or 8, wherein the gel-forming polymer has a viscosity of about 3000 mPa·s or more in a 5% aqueous solution at 25°C. 9. Capsules according to claim 1, 7 or 8, wherein the gel-forming polymer has a molecular weight of 400000-10000000. Controlled release coating: hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, methyl methacrylate/methacrylic acid copolymer, methacrylic acid/ethyl acrylate copolymer, ethyl acrylate/methyl methacrylate/trimethyl methacrylate chloride One or more selected from the group consisting of ammonium ethyl copolymer, methyl methacrylate/ethyl acrylate copolymer, methacrylic acid/methyl acrylate/methyl methacrylate copolymer, hydroxypropyl cellulose acetate succinate and polyvinyl acetate phthalate The capsule according to any one of claims 2 to 4 or 6, which is a coating containing 14. Capsules according to claim 13, characterized in that the controlled release coating consists of two or more coatings. A capsule according to claim 1, wherein the controlled-release granules or granules are granules or granules having a particle size of about 100-1500 µm. A capsule according to claim 1, wherein the active ingredient is a proton pump inhibitor (PPI). PPI of formula (I′):

[ ^Wherein , ring C′ is a benzene ring optionally having substituent(s) or an aromatic monocyclic heterocyclic ring optionally having substituent(s); an aralkyl group ^, an acyl group or ^{an acyloxy} group which may be an alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH], a salt thereof, or an optically active substance thereof according to claim 16. capsule. 18. Capsules according to claim 17, wherein the imidazole compound is lansoprazole. 18. Capsules according to claim 17, wherein the PPI is the optically active R form of lansoprazole. The gel-forming polymer is selected from the group consisting of polyethylene oxide (PEO, molecular weight 400000-10000000), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC-Na), hydroxypropylcellulose (HPC), hydroxyethylcellulose and carboxyvinyl polymer. 9. Capsules according to claim 1, 7 or 8, which are one or more substances containing 9. Capsules according to claim 1, 7 or 8, wherein the gel-forming polymer is polyethylene oxide (molecular weight 400000-10000000). 9. Capsules according to claim 1 or 8, wherein the gel-forming polymer is blended in the form of powder, fine granules or granules. 4. The capsule according to claim 3, wherein the pH-dependently soluble polymer is methyl methacrylate/methacrylic acid copolymer. A tablet, granule or granule with controlled release of an active ingredient, comprising formula (I'):

[Wherein, ring C′ is a benzene ring optionally having substituent(s) or an aromatic monocyclic heterocyclic ring optionally having substituent(s); R ⁰ is a hydrogen atom; an aralkyl group ^, an acyl group or ^{an acyloxy} group which may be an alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH], or a nucleus containing an imidazole compound represented by the following as an active ingredient: Grains and
Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, methyl methacrylate/methacrylic acid copolymer, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl acrylate/methyl methacrylate copolymer, hydroxypropyl cellulose One selected from the group consisting of acetate succinate, polyvinyl acetate phthalate and shellac, or a mixture of two or more selected from the group consisting of different release conditions, pH-dependent containing a polymeric substance that dissolves in the range of pH 6.0 to pH 7.5 tablets, granules or granules with a dissolvable controlled release coating. 25. The tablets, granules or granules according to claim 24, wherein the pH-dependent soluble controlled release coating is formed through an intermediate layer formed on the core granule. 25. A capsule containing the tablets, granules or granules according to claim 24. 25. A capsule containing tablets, granules or granules according to claim 24 and enteric coated tablets, granules or granules containing a compound of formula (I'). 25. Tablets, granules or granules according to claim 24, wherein the active ingredient is lansoprazole. 25. The tablets, granules or granules according to claim 24, wherein the active ingredient is the optically active R form of lansoprazole. 25. The tablets, granules or granules according to claim 24, wherein the active ingredient is the optically active S-isomer of lansoprazole. 25. Tablets, granules or granules according to claim 24, wherein the active ingredient is a derivative of lansoprazole. 25. The tablets, granules or granules according to claim 24, wherein the active ingredient is an optically active R derivative of lansoprazole. (24) characterized by having an enteric coating on the core granule containing the active ingredient, a disintegrant layer containing a disintegrant on the enteric coating, and a controlled release coating on the disintegrant layer; , 25 or 28-32. 34. Tablets, granules or granules according to any one of claims 28 to 33, characterized in that they are coated with a gel-forming polymer. 33. A sustained release capsule containing the tablets, granules or granules according to any one of claims 28-32 and a gel-forming polymer. Tablets, granules or granules in which the release of an active ingredient is controlled by two or more types of controlled release coatings, characterized in that the outermost controlled release coating dissolves at a higher pH than the inner controlled release coating. Item 25. Tablets, granules or granules according to item 24. 37. The tablet, granule or powder according to claim 36, wherein the inner layer of the controlled release coating dissolves in the pH range of 6.0 to 7.0, and the outermost layer of the controlled release coating dissolves at pH 7.0 or higher. grain. 37. The tablet, granule or powder according to claim 36, wherein the inner layer of the controlled release coating dissolves in the range of pH 6.5-7.0, and the outermost layer of the controlled release coating dissolves at pH 7.0 or higher. grain. 37. The tablets, granules or granules according to claim 36, wherein the thickness of the outermost controlled release coating is 100 μm or less. 37. Granules or granules according to claim 36, wherein the controlled release granules or granules have a particle size of about 100-1500 [mu]m. (i) a controlled-release tablet, granule or granule of an active ingredient of formula (I'):

[ ^Wherein , ring C′ is a benzene ring optionally having substituent(s) or an aromatic monocyclic heterocyclic ring optionally having substituent(s); an aralkyl group ^, an acyl group or ^{an acyloxy} group which may be an alkoxy group or an optionally substituted amino group, and Y represents a nitrogen atom or CH], or a nucleus containing an imidazole compound represented by the following as an active ingredient: Grains and
Hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, carboxymethylethylcellulose, methyl methacrylate/methacrylic acid copolymer, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/methyl acrylate/methyl methacrylate copolymer, hydroxypropyl cellulose One selected from the group consisting of acetate succinate, polyvinyl acetate phthalate and shellac, or a mixture of two or more selected from the group consisting of different release conditions, pH-dependent containing a polymeric substance that dissolves in the range of pH 6.0 to pH 7.5 tablets, granules or granules having a dissolvable controlled release coating;
(ii) Capsules containing tablets, granules or fine granules having a core granule containing an active ingredient and an enteric coating that dissolves in the range of pH 5.0 or more and less than pH 6.0 to release the active ingredient. . 42. Capsules according to claim 41, wherein the pH-dependent soluble controlled release coating is formed via an intermediate layer formed on core grains containing the active ingredient. 42. Capsules according to claim 41, wherein the active ingredient is lansoprazole. 42. Capsules according to claim 41, wherein the active ingredient is the optically active R form of lansoprazole. 42. Capsules according to claim 41, wherein the active ingredient is the optically active S-isomer of lansoprazole. 42. The capsule formulation according to claim 41, wherein the core granule containing the active ingredient contains a basic inorganic salt stabilizer. 42. The capsule according to claim 41, wherein the pH-dependent soluble release control coating in the tablet, granule or granule with controlled release of the active ingredient is a coating that dissolves in the range of pH 6.5 or more and pH 7.0 or less. 48. The capsule according to claim 47, wherein the pH-dependent soluble controlled release coating contains two or more methyl methacrylate/methacrylic acid copolymers with different release control conditions. 42. The capsule of Claim 41, further comprising a gel-forming polymer.