JP2013224263A - 4-isopropylphenyl glucitol compound - Google Patents

4-isopropylphenyl glucitol compound Download PDF

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JP2013224263A
JP2013224263A JP2010184462A JP2010184462A JP2013224263A JP 2013224263 A JP2013224263 A JP 2013224263A JP 2010184462 A JP2010184462 A JP 2010184462A JP 2010184462 A JP2010184462 A JP 2010184462A JP 2013224263 A JP2013224263 A JP 2013224263A
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Hiroyuki Kakinuma
浩行 柿沼
Yohei Kobashi
陽平 小橋
Madoka Kawamura
円 川村
Fumiyasu Shiozawa
史康 塩澤
Yuki Iwata
由紀 岩田
Kenichi Kawabe
憲一 川部
Shoichi Kuroda
翔一 黒田
Makoto Hamada
まこと 濱田
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Taisho Pharmaceutical Co Ltd
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Priority to PCT/JP2011/068674 priority patent/WO2012023582A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

PROBLEM TO BE SOLVED: To inhibit abnormal glucose intolerance and postprandial hyperglycemia in diabetic patients by inhibiting the absorption of glucose and the like.SOLUTION: There are provided a 4-isopropylphenyl glucitol compound represented by formula (I) and a pharmaceutically acceptable salt of the compound. In the formula, Rrepresents a hydrogen atom or a substituted 1-4C alkyl group; Rand Rrepresent each a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group; Rand Rrepresent each a hydrogen atom, a methyl group or a hydroxymethyl group; n represents 0 or 1; Rrepresents a hydrogen atom, a substituted piperidyl group or a substituted 1-6C alkyl group; Rrepresents a hydrogen atom or a 1-4C alkyl group; W represents a single bond, a methylene group or a carbonyl group; and Y represents a 1-4C alkylene group or a carbonyl group.

Description

本発明は、小腸でのグルコ−ス及びガラクトースの吸収に関わるナトリウム依存性グルコ−ス共輸送体１（以下、適宜に「ＳＧＬＴ１」と略記する。）に特異的な阻害活性を有する４−イソプロピルフェニル グルシトール化合物に関する。   The present invention is 4-isopropyl having an inhibitory activity specific to sodium-dependent glucose cotransporter 1 (hereinafter abbreviated as “SGLT1” where appropriate) involved in the absorption of glucose and galactose in the small intestine. The present invention relates to a phenyl glucitol compound.

血糖値はメタボリックシンドロームのバイオマーカーの一つとなっており、空腹時血糖が１２６ｍｇ／ｄＬ以上を示すと糖尿病と診断される。また、空腹時血糖が正常であっても、食後２時間血糖値が１４０〜２００ｍｇ／ｄＬの場合には、耐糖能異常（又は食後高血糖）と診断される。近年の疫学的研究によれば、耐糖能異常が心血管障害のリスクを高めると報告されている(非特許文献１及び２参照)。さらに、運動療法や薬物治療を施すことで耐糖能異常から２型糖尿病への移行を抑制し、高血圧の発症も有意に抑制することが報告されている(非特許文献３参照)。   The blood glucose level is one of the biomarkers of metabolic syndrome, and diabetes is diagnosed when the fasting blood glucose level is 126 mg / dL or more. Even if fasting blood glucose is normal, a glucose tolerance abnormality (or postprandial hyperglycemia) is diagnosed when the blood glucose level for 2 hours after meal is 140 to 200 mg / dL. Recent epidemiological studies have reported that impaired glucose tolerance increases the risk of cardiovascular disorders (see Non-Patent Documents 1 and 2). Furthermore, it has been reported that exercise therapy and drug treatment suppress the transition from impaired glucose tolerance to type 2 diabetes and significantly suppress the onset of hypertension (see Non-Patent Document 3).

以上のことから、食後高血糖を抑制することが糖尿病やメタボリックシンドロームの発症抑制に重要であると考えられ、食後高血糖をコントロールする薬剤の需要が高まりつつある。   From the above, suppressing postprandial hyperglycemia is considered to be important for suppressing the onset of diabetes and metabolic syndrome, and the demand for drugs that control postprandial hyperglycemia is increasing.

従来、食後高血糖改善薬としては、糖類の加水分解酵素を阻害し、小腸からの糖の吸収を遅延させるα−グルコシダ−ゼ阻害剤が汎用されてきたが、新しい作用機序を有する食後高血糖改善薬の開発も行われている。   Conventionally, α-glucosidase inhibitors that inhibit saccharide hydrolase and delay sugar absorption from the small intestine have been widely used as postprandial hyperglycemia-improving drugs. Development of drugs to improve blood glucose is also underway.

哺乳動物の小腸上皮には高い頻度でナトリウム依存性グルコ−ス共輸送体１（ＳＧＬＴ１）が発現している。このＳＧＬＴ１は小腸において、ナトリウムに依存し、グルコ−ス又はガラクト−スの能動輸送を司ることが知られている。そこで、ＳＧＬＴ１活性を阻害することによって、食事由来のグルコ−ス吸収を抑制し、食後高血糖の予防又は治療に用いることができる、ピラゾ−ル誘導体が報告されている（特許文献１〜６参照）。一方で、腎臓には高頻度にナトリウム依存性グルコ−ス共輸送体２（ＳＧＬＴ２）が発現しており、糸球体で一旦濾過されたグルコ−スはＳＧＬＴ２を介して再吸収される（非特許文献４参照）。そして、ＳＧＬＴ２活性を阻害することによって、尿への糖***が促進され、血糖低下作用を示すことが報告されている（非特許文献５参照）。ＳＧＬＴ２阻害剤の特徴として、随時血糖を低下させる作用が優れているが、ＳＧＬＴ１阻害剤の様に食後高血糖を是正する作用は低い。また、ＳＧＬＴ１活性に加えて、ＳＧＬＴ２活性も同時に阻害するＣ−フェニル グルシトール誘導体についての報告もある（特許文献７参照）。   Sodium-dependent glucose cotransporter 1 (SGLT1) is frequently expressed in the small intestinal epithelium of mammals. SGLT1 is known to depend on sodium in the small intestine and to control the active transport of glucose or galactose. Thus, pyrazole derivatives that have been reported to inhibit SGLT1 activity to suppress dietary glucose absorption and to be used for the prevention or treatment of postprandial hyperglycemia (see Patent Documents 1 to 6). ). On the other hand, sodium-dependent glucose cotransporter 2 (SGLT2) is frequently expressed in the kidney, and glucose once filtered by the glomerulus is reabsorbed via SGLT2 (non-patent document). Reference 4). And it has been reported that the inhibition of SGLT2 activity promotes the excretion of sugar into urine and exhibits a blood glucose lowering effect (see Non-Patent Document 5). As a feature of SGLT2 inhibitor, it has an excellent effect of lowering blood glucose as needed, but it has a low effect of correcting postprandial hyperglycemia like SGLT1 inhibitor. There is also a report on a C-phenyl glucitol derivative that simultaneously inhibits SGLT2 activity in addition to SGLT1 activity (see Patent Document 7).

一方、食後高血糖改善薬のような持続投与が必要な薬剤にとっては、薬効量と、毒性、副作用の発現量との間の安全域が広いことが重要である。特に、体内残留性薬物の場合は、治療に必要な投与量をコントロールすることが難しく、体内に残留している薬物が加算されて過剰量の薬物の効果が発現されることになり、予期せぬ毒性及び副作用につながる。例えば、分子内に３級アミンの様な親水性基と芳香環の様な疎水性基をもつ、陽イオン性薬物は、リン脂質と疎水結合し、ライソゾーム内に取り込まれ全身の器官に蓄積されることがあることが知られている。代表例として、クロロキンでは網膜障害、パーヘキシリンでは肺や小脳に変化があり神経障害が問題となった（非特許文献６参照）。   On the other hand, for drugs that require continuous administration, such as postprandial hyperglycemic drugs, it is important that there is a wide safety range between the effective amount and the amount of toxicity and side effects. In particular, in the case of a drug remaining in the body, it is difficult to control the dose required for treatment, and the drug remaining in the body is added to express the effect of an excessive amount of drug. Cause toxic and side effects. For example, a cationic drug having a hydrophilic group such as a tertiary amine and a hydrophobic group such as an aromatic ring in the molecule is hydrophobically bound to a phospholipid, and is taken into a lysosome and accumulated in organs throughout the body. It is known that As typical examples, chloroquine caused retinal damage, and perhexiline had changes in the lungs and cerebellum, causing neuropathy (see Non-Patent Document 6).

したがって、薬物は、薬効を示した後に体内から速やかに***されることが望ましく、特に、持続投与が必須の食後高血糖改善薬では、体内残留性の問題のない薬物が望まれる。   Therefore, it is desirable that the drug is rapidly excreted from the body after exhibiting the drug effect. In particular, in the postprandial hyperglycemia improving drug for which continuous administration is essential, a drug having no problem of persistence in the body is desired.

国際公開第ＷＯ２００２／０９８８９３号パンフレットInternational Publication No. WO2002 / 098893 Pamphlet 国際公開第ＷＯ２００４／０１４９３２号パンフレットInternational Publication No. WO2004 / 014932 Pamphlet 国際公開第ＷＯ２００４／０１８４９１号パンフレットInternational Publication No. WO2004 / 018491 Pamphlet 国際公開第ＷＯ２００４／０１９９５８号パンフレットInternational Publication No. WO2004 / 019958 Pamphlet 国際公開第ＷＯ２００５／１２１１６１号パンフレットInternational Publication No. WO2005 / 121161 Pamphlet 国際公開第ＷＯ２００４／０５０１２２号パンフレットInternational Publication No. WO2004 / 050122 Pamphlet 国際公開第ＷＯ２００７／１３６１１６号パンフレットInternational Publication No. WO2007 / 136116 Pamphlet

Pan XR, et al. Diabetes Care, 第20巻, 537頁, 1997年Pan XR, et al. Diabetes Care, 20, 537, 1997 M Tominaga, et al. Diabetes Care, 第22巻, 920頁, 1999年M Tominaga, et al. Diabetes Care, 22, 920, 1999 J.−L. Chiasson, et al. Lancent, 第359巻, 2072頁, 2002年J.-L. Chiasson, et al. Lancent, 359, 2072, 2002 E. M. Wright, Am. J. Physiol. Renal. Physiol., 第280巻, F10頁, 2001年E. M. Wright, Am. J. Physiol. Renal. Physiol., 280, F10, 2001 G. Toggenburger, et al. Biochem. Biophys. Acta., 第688巻, 557頁, 1982年G. Toggenburger, et al. Biochem. Biophys. Acta., 688, 557, 1982 日薬理誌 Folia Pharmacol. Jpn. 第113巻, 19頁, 1999年The Japanese Pharmacology Journal Folia Pharmacol. Jpn. 113, 19, 1999

本発明の目的は、薬効量と毒性、副作用の発現量との間の安全域が広いＳＧＬＴ１阻害作用を示す４−イソプロピルフェニル グルシトール化合物又はその塩、及びそれらを含む医薬を提供することである。   An object of the present invention is to provide a 4-isopropylphenyl glucitol compound or a salt thereof exhibiting an SGLT1 inhibitory action with a wide safety range between a medicinal amount, toxicity, and side effect, and a medicament containing them.

本発明者らは前記課題を解決するために鋭意研究した結果、アグリコンの末端に特異な側鎖を導入して得られる、下記一般式（Ｉ）で示される４−イソプロピルフェニル グルシトール化合物が、優れたＳＧＬＴ１活性阻害作用を有することを見出し、本発明を完成するに至った。   As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a 4-isopropylphenyl glucitol compound represented by the following general formula (I) obtained by introducing a specific side chain at the end of aglycone is excellent. The present invention has been found by having SGLT1 activity inhibitory activity.

以下に、本発明の４−イソプロピルフェニル グルシトール化合物（以下、「本発明化合物」という）の態様を述べる。
（１）下記一般式（Ｉ）で表される４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩： Hereinafter, embodiments of the 4-isopropylphenyl glucitol compound of the present invention (hereinafter referred to as “the compound of the present invention”) will be described.
(1) 4-Isopropylphenyl glucitol compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

Figure 2013224263
式中、
Ｒ1は、水素原子又は“水酸基若しくはハロゲン原子で置換されても良いＣ1-4アルキル基”であり、
Ｒ2及びＲ3は、同一若しくは異なって、水素原子、メチル基、エチル基若しくはヒドロキシメチル基であり、
又は、Ｒ2及びＲ3は、隣接する炭素原子と共にＣ3-6シクロアルキル基を形成し、
Ｒ4及びＲ5は、同一若しくは異なって、水素原子、メチル基若しくはヒドロキシメチル基であり、
又は、Ｒ4及びＲ5は、隣接する炭素原子と共にＣ3-6シクロアルキル基若しくはＣ4-6ヘテロシクリル基を形成し、
ｎは０又は１であり、
Ｒ6は水素原子、“ベンジル基で置換されても良いピペリジル基”若しくは“同一若しくは異なって、水酸基、アミノ基、カルバモイル基、ウレイド基、Ｃ2-7アルコキシカルボニル基、Ｃ1-6アルキルアミノカルボニル基（該Ｃ1-6アルキルアミノカルボニル基は、アミノ基、Ｃ2-7アルコキシカルボニル基、カルバモイル基、ジＣ1-4アルキルアミノ基若しくは水酸基から選ばれる１から３個の基で置換されても良い）、Ｃ2-7アルカノイルアミノ基（該Ｃ2-7アルカノイルアミノ基はアミノ基で置換されても良い）、Ｃ1-6アルキルスルホニルアミノ基、ジＣ1-4アルキルアミノ基、フェニル基（該フェニル基は水酸基で置換されても良い）、ピリジル基若しくはピペリジル基から選ばれる１から３個の基で置換されたＣ1-6アルキル基”であり、
Ｒ7は、水素原子若しくはＣ1-4アルキル基であり、
又は、Ｒ6及びＲ7は、隣接する窒素原子と共に“Ｃ1-6アルキル基（該Ｃ1-6アルキル基はＣ2-7アルコキシカルボニル基若しくは水酸基で置換されても良い）、カルバモイル基若しくはＣ2-7アルカノイル基（該Ｃ2-7アルカノイル基はアミノ基で置換されても良い）から選ばれる１個の基で置換されても良いピペラジニル基”若しくは“水酸基、カルバモイル基、ウレイド基、ジＣ1-4アルキルアミノ基、モルホリノ基、Ｃ2-7アルコキシカルボニル基、Ｃ1-6アルキルスルホニルアミノ基、Ｃ1-6アルキルアミノ基（該Ｃ1-6アルキルアミノ基は、アミノ基、カルバモイル基、ジＣ1-4アルキルアミノ基で置換されても良い）、Ｃ2-7アルカノイルアミノ基（該Ｃ2-7アルカノイルアミノ基はアミノ基で置換されても良い）若しくはＣ1-6アルキルアミノカルボニルアミノ基（該Ｃ1-6アルキルアミノカルボニルアミノ基は１〜３個の水酸基で置換されても良い）から選ばれる１個の基で置換されても良いピペリジノ基“を形成し、
Ｗは単結合、メチレン基（ＣＨ2）又はカルボニル基（Ｃ＝Ｏ）を示し、
ＹはＣ1-4アルキレン基又はカルボニル基（Ｃ＝Ｏ）を示す。
Figure 2013224263
 Where
R 1 is a hydrogen atom or a “C 1-4 alkyl group optionally substituted with a hydroxyl group or a halogen atom”;
R 2 and R 3 are the same or different and are a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group,
Or R 2 and R 3 together with the adjacent carbon atom form a C 3-6 cycloalkyl group,
R 4 and R 5 are the same or different and are a hydrogen atom, a methyl group or a hydroxymethyl group,
Or R 4 and R 5 together with the adjacent carbon atom form a C 3-6 cycloalkyl group or a C 4-6 heterocyclyl group;
n is 0 or 1;
R 6 is a hydrogen atom, “piperidyl group optionally substituted with a benzyl group” or “same or different, hydroxyl group, amino group, carbamoyl group, ureido group, C 2-7 alkoxycarbonyl group, C 1-6 alkylamino group A carbonyl group (the C 1-6 alkylaminocarbonyl group is substituted with 1 to 3 groups selected from an amino group, a C 2-7 alkoxycarbonyl group, a carbamoyl group, a diC 1-4 alkylamino group or a hydroxyl group; C 2-7 alkanoylamino group (the C 2-7 alkanoylamino group may be substituted with an amino group), C 1-6 alkylsulfonylamino group, diC 1-4 alkylamino group, A phenyl group (the phenyl group may be substituted with a hydroxyl group), a pyridyl group or a C 1-6 alkyl group substituted with 1 to 3 groups selected from a piperidyl group;
R 7 is a hydrogen atom or a C 1-4 alkyl group,
Or R 6 and R 7 together with an adjacent nitrogen atom are a “C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with a C 2-7 alkoxycarbonyl group or a hydroxyl group), a carbamoyl group or A piperazinyl group which may be substituted with one group selected from a C 2-7 alkanoyl group (the C 2-7 alkanoyl group may be substituted with an amino group) or a hydroxyl group, a carbamoyl group, a ureido group, Di-C 1-4 alkylamino group, morpholino group, C 2-7 alkoxycarbonyl group, C 1-6 alkylsulfonylamino group, C 1-6 alkylamino group (the C 1-6 alkylamino group is an amino group, A carbamoyl group, which may be substituted with a di-C 1-4 alkylamino group), a C 2-7 alkanoylamino group (the C 2-7 alkanoylamino group may be substituted with an amino group) or C 1-6 Alkylamino Ruboniruamino group (wherein the C 1-6 alkylaminocarbonyl amino group may be substituted with 1 to 3 hydroxyl groups) to form one may piperidino group which may be substituted with a group "chosen from,
W represents a single bond, a methylene group (CH 2 ) or a carbonyl group (C═O),
Y represents a C 1-4 alkylene group or a carbonyl group (C═O).

（２）（１）に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩（ただし、同時にＷとＹがカルボニル基である場合を除く）：
式中、
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7、ｎ、Ｗ及びＹは、（１）で定義した通りである。 (2) The 4-isopropylphenyl glucitol compound or pharmaceutically acceptable salt thereof according to (1) (except when W and Y are carbonyl groups at the same time):
Where
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n, W and Y are as defined in (1).

（３）Ｗは単結合又はメチレン基（ＣＨ2）を示す、（１）又は（２）に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩：
式中、
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7、ｎ及びＹは、（１）で定義した通りである。 (3) W is a single bond or a methylene group (CH 2 ), the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) or (2):
Where
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and Y are as defined in (1).

（４）Ｗがカルボニル基（Ｃ＝Ｏ）を示す、（１）又は（２）に記載の、４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩：
式中、
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7、ｎ及びＹは、（１）で定義した通りである。 (4) The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein W represents a carbonyl group (C═O):
Where
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and Y are as defined in (1).

（５）ＹがＣ1-4アルキレン基を示す、（１）、（２）又は（４）に記載の、４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩：
式中、
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7及びｎは、（１）で定義した通りである。 (5) 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1), (2) or (4), wherein Y represents a C 1-4 alkylene group:
Where
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined in (1).

（６）Ｙがカルボニル基（Ｃ＝Ｏ）を示す、（１）、（２）又は（４）に記載の、４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩：
式中、
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7及びｎは、（１）で定義した通りである。 (6) The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1), (2) or (4), wherein Y represents a carbonyl group (C═O):
Where
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and n are as defined in (1).

（７）Ｒ1が水素原子を、Ｒ2及びＲ3がメチル基を、Ｒ4及びＲ5がメチル基を、ｎが０を、Ｒ6が“水酸基、ジＣ1-4アルキルアミノ基から選ばれる１個の基で置換されたＣ3-5アルキル基”を、Ｒ7が水素原子を、Ｗがカルボニル基（Ｃ＝Ｏ）を、Ｙがカルボニル基（Ｃ＝Ｏ）を示す、（１）、（４）又は（６）に記載の、４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩。 (7) R 1 represents a hydrogen atom, R 2 and R 3 represent a methyl group, R 4 and R 5 represent a methyl group, n represents 0, R 6 represents a “hydroxyl group, a di-C 1-4 alkylamino group “C 3-5 alkyl group substituted with one selected group”, R 7 represents a hydrogen atom, W represents a carbonyl group (C═O), and Y represents a carbonyl group (C═O). 1-, 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (4) or (6).

（８）下記に示す、（１）、（４）、（６）又は（７）に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩： (8) The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1), (4), (6) or (7) shown below:

Figure 2013224263
Figure 2013224263

（９）（１）〜（８）に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含むナトリウム依存性グルコース共輸送体１（ＳＧＬＴ１）活性阻害剤。 (9) A sodium-dependent glucose cotransporter 1 (SGLT1) activity inhibitor comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (8) as an active ingredient.

（１０）（１）〜（８）に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含む食後高血糖改善薬。 (10) A postprandial hyperglycemia remedy comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (8) as an active ingredient.

（１１）（１）〜（８）に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含む糖尿病の予防又は治療薬。 (11) A prophylactic or therapeutic agent for diabetes comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (8) as an active ingredient.

（１２）糖尿病の予防又は治療用の薬剤の製造における、（１）〜（８）に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩の使用。 (12) Use of the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (8) in the manufacture of a drug for preventing or treating diabetes.

本発明により、ＳＧＬＴ１活性を阻害する４−イソプロピルフェニル グルシトール化合物を提供することが可能となった。   According to the present invention, it has become possible to provide a 4-isopropylphenyl glucitol compound that inhibits SGLT1 activity.

本発明において使用する用語を以下に定義する。   The terms used in the present invention are defined below.

本発明において、「ｎ」はノルマルを、「ｉ」はイソを、「ｓ」及び「ｓｅｃ」はセカンダリーを、「ｔ」及び「ｔｅｒｔ」はターシャリーを、「ｃ」はシクロを、「ｏ」はオルトを、「ｍ」はメタを、「ｐ」はパラを示す。
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を示す。
「Ｃ1-4アルキル基」とは、炭素原子を１−４個有する直鎖状又は分枝状のアルキル基を意味する。例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基が挙げられる。
「Ｃ1-6アルキル基」とは、炭素原子を１−６個有する直鎖状又は分枝状のアルキル基を意味する。例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、イソブチル基、ｔｅｒｔ−ブチル基、ｎ−ペンチル基、ｉ−ペンチル基、ネオペンチル基、ｎ−ヘキシル基、ｉ−ヘキシル基が挙げられる。
「Ｃ3-6シクロアルキル基」とは、炭素原子を３−６個有する環状のアルキル基を意味する。例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基が挙げられる。
「Ｃ4-6ヘテロシクリル基」とは、酸素原子、硫黄原子及び窒素原子からなる群から同一または異なって選ばれる１つ以上の原子と１から５個の炭素原子からなる、４から６員環の単環系飽和複素環基を意味する。例えば、オキセタニル基、テトラヒドロフラニル基、テトラヒドロピラニル基、テトラヒドロチオピラニル基、ピロリジニル基、ピペリジニル基が挙げられる。
「Ｃ2-7アルカノイル基」とは、「炭素原子を１から６個有する直鎖状又は分岐状のアルキル基」を有するカルボニル基を意味する。例えば、アセチル基、プロピオニル基、ｎ−ブチリル基、ｉ−ブチリル基、ｎ−バレリル基、ｉ−バレリル基、ピバロイル基が挙げられる。
「Ｃ1-6アルキルアミノ基」とは、前記の「Ｃ1-6アルキル基」を、置換基として１個有するアミノ基を意味する。例えば、メチルアミノ基、エチルアミノ基、ｎ−プロピルアミノ基、ｉ−プロピルアミノ基、ｎ−ブチルアミノ基が挙げられる。
「ジＣ1-4アルキルアミノ基」とは、前記の「Ｃ1-4アルキル基」を、置換基として同一又は異なって２個有するアミノ基を意味する。例えば、ジメチルアミノ基、ジエチルアミノ基、ジ（ｎ−プロピル）アミノ基、ジ（ｉ−プロピル）アミノ基、エチルメチルアミノ基、メチル（ｎ−プロピル）アミノ基が挙げられる。
「Ｃ2-7アルコキシカルボニル基」とは、「炭素原子を１から６個有する直鎖状又は分岐状のアルコキシ基」とカルボニル基が結合した基を意味する。例えば、メトキシカルボニル基、エトキシカルボニル基が挙げられる。
「Ｃ1-6アルキルアミノカルボニル基」とは、前記の「Ｃ1-6アルキルアミノ基」とカルボニル基が結合した基を意味する。例えば、メチルアミノカルボニル基が挙げられる。
「Ｃ2-7アルカノイルアミノ基」とは、前記の「Ｃ2-7アルカノイル基」とアミノ基が結合した基を意味する。例えば、アセトアミド基が挙げられる。
「Ｃ1-6アルキルスルホニルアミノ基」とは、前記の「Ｃ1-6アルキル基」が結合したスルホニル基がアミノ基に結合した基を意味する。例えば、メタンスルホンアミド基が挙げられる。
「Ｃ1-6アルキルアミノカルボニルアミノ基」とは、前記の「Ｃ1-6アルキルアミノ基」が結合したカルボニル基がアミノ基に結合した基を意味する。例えば、メチルアミノカルボニルアミノ基が挙げられる。
「Ｃ1-4アルキレン基」とは、炭素原子を１から４個有する２価の炭化水素基を意味する。例えば、メチレン基、エチレン基、プロピレン基が挙げられる。 In the present invention, “n” is normal, “i” is iso, “s” and “sec” are secondary, “t” and “tert” are tertiary, “c” is cyclo, “o” "" Indicates ortho, "m" indicates meta, and "p" indicates para.
The “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
“C 1-4 alkyl group” means a linear or branched alkyl group having 1 to 4 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, and tert-butyl group can be mentioned.
The “C 1-6 alkyl group” means a linear or branched alkyl group having 1-6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, i-pentyl group, neopentyl group, n-hexyl group, i-hexyl Groups.
The “C 3-6 cycloalkyl group” means a cyclic alkyl group having 3-6 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
The “C 4-6 heterocyclyl group” is a 4- to 6-membered ring composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom or the same or different and 1 to 5 carbon atoms. Means a monocyclic saturated heterocyclic group. Examples include oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, pyrrolidinyl group, piperidinyl group.
The “C 2-7 alkanoyl group” means a carbonyl group having “a linear or branched alkyl group having 1 to 6 carbon atoms”. Examples include acetyl group, propionyl group, n-butyryl group, i-butyryl group, n-valeryl group, i-valeryl group, and pivaloyl group.
The “C 1-6 alkylamino group” means an amino group having one “C 1-6 alkyl group” as a substituent. Examples thereof include a methylamino group, an ethylamino group, an n-propylamino group, an i-propylamino group, and an n-butylamino group.
The “di-C 1-4 alkylamino group” means an amino group having the above-mentioned “C 1-4 alkyl group” as the same or different two substituents. Examples thereof include a dimethylamino group, a diethylamino group, a di (n-propyl) amino group, a di (i-propyl) amino group, an ethylmethylamino group, and a methyl (n-propyl) amino group.
“C 2-7 alkoxycarbonyl group” means a group in which a “linear or branched alkoxy group having 1 to 6 carbon atoms” and a carbonyl group are bonded. Examples thereof include a methoxycarbonyl group and an ethoxycarbonyl group.
The “C 1-6 alkylaminocarbonyl group” means a group in which the above “C 1-6 alkylamino group” is bonded to a carbonyl group. An example is a methylaminocarbonyl group.
The “C 2-7 alkanoylamino group” means a group in which the above “C 2-7 alkanoyl group” and an amino group are bonded. For example, an acetamide group can be mentioned.
The “C 1-6 alkylsulfonylamino group” means a group in which the sulfonyl group to which the above “C 1-6 alkyl group” is bonded is bonded to an amino group. An example is a methanesulfonamide group.
The “C 1-6 alkylaminocarbonylamino group” means a group in which a carbonyl group to which the above “C 1-6 alkylamino group” is bonded is bonded to an amino group. An example is a methylaminocarbonylamino group.
“C 1-4 alkylene group” means a divalent hydrocarbon group having 1 to 4 carbon atoms. For example, a methylene group, an ethylene group, and a propylene group are mentioned.

「製薬学的に許容される塩」とは、アルカリ金属類、アルカリ土類金属類、アンモニウム、アルキルアンモニウムなどとの塩、鉱酸又は有機酸との塩であり、例えば、ナトリウム塩、カリウム塩、カルシウム塩、アンモニウム塩、アルミニウム塩、トリエチルアンモニウム塩、ぎ酸塩、酢酸塩、プロピオン酸塩、酪酸塩、ヘキサン酸塩、オクタン酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、クエン酸塩、ステアリン酸塩、コハク酸塩、エチルコハク酸塩、ラクトビオン酸塩、グルコン酸塩、グルクロン酸塩、グルコヘプトン酸塩、グルタール酸塩、ピメリン酸塩、スベリン酸塩、アゼライン酸塩、セバシン酸塩、１,９−ノナンジカルボン酸塩、ドデカン二酸塩、トリデカン二酸塩、テトラデカン二酸塩、ペンタデカン二酸塩、ヘキサデカン二酸塩、ヘプタデカン二酸塩、安息香酸塩、２−ヒドロキシ安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、エタンジスルホン酸塩、２−ヒドロキシエタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ−トルエンスルホン酸塩、１,５−ナフタレンジスルホン酸塩、ラウリル硫酸塩、乳酸塩、馬尿酸塩、フマル酸塩、マロン酸塩、トランスケイ皮酸塩、リンゴ酸塩、アスパラギン酸塩、グルタミン酸塩、アジピン酸塩、システインとの塩、Ｎ−アセチルシステインとの塩、塩酸塩、臭化水素酸塩、リン酸塩、硫酸塩、よう化水素酸塩、ニコチン酸塩、シュウ酸塩、ピクリン酸塩、チオシアン酸塩、ウンデカン酸塩、アクリル酸ポリマーとの塩、カルボキシビニルポリマーとの塩を挙げることができる。   “Pharmaceutically acceptable salt” is a salt with an alkali metal, alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, such as a sodium salt or potassium salt. , Calcium salt, ammonium salt, aluminum salt, triethylammonium salt, formate, acetate, propionate, butyrate, hexanoate, octanoate, trifluoroacetate, maleate, tartrate, citric acid Salt, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucuronate, glucoheptonate, glutarate, pimelate, suberate, azelate, sebacate, 1,9-nonanedicarboxylate, dodecanedioate, tridecanedioate, tetradecanedioate, pentadecanedioate, hex Sadecanedioate, heptadecanedioate, benzoate, 2-hydroxybenzoate, methanesulfonate, ethanesulfonate, ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p -Toluenesulfonate, 1,5-naphthalenedisulfonate, lauryl sulfate, lactate, hippurate, fumarate, malonate, transcinnamate, malate, aspartate, glutamate , Adipate, salt with cysteine, salt with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picric acid And salts with thiocyanate, undecanoate, acrylic acid polymer, and carboxyvinyl polymer.

「本発明化合物又はその塩」には、それらの製薬学的に許容される水和物も包含される。本発明化合物又はその塩は、大気にさらされ、あるいは製造過程で、水分を吸収し、吸着水がつく場合や、水和物となる場合がある。本発明における水和物には、そのような水和物も含まれる。   "The compound of the present invention or a salt thereof" also includes pharmaceutically acceptable hydrates thereof. The compound of the present invention or a salt thereof may be exposed to the atmosphere, or may absorb moisture during the production process to form adsorbed water or become a hydrate. The hydrate in the present invention includes such a hydrate.

「食後高血糖改善薬」とは、食後高血糖を抑制することにより、食後高血糖に関連する疾患、例えば、糖尿病やメタボリックシンドロームの発症を抑制する、若しくは、それらの疾患を治療する薬物をいう。ここで、「食後高血糖」とは、食後に血糖値が異常に高くなる状態、具体的には、食後２時間の血糖値が１４０ｍｇ／ｄＬを上回る状態をいう。   “Postprandial hyperglycemia-improving drug” refers to a drug that suppresses postprandial hyperglycemia, thereby suppressing the onset of postprandial hyperglycemia, such as diabetes or metabolic syndrome, or treating these diseases . Here, “postprandial hyperglycemia” refers to a state in which the blood glucose level is abnormally high after the meal, specifically, a state in which the blood glucose level for 2 hours after the meal exceeds 140 mg / dL.

本発明化合物の有用性について以下に説明する（詳細は以下の試験例参照）。   The usefulness of the compound of the present invention will be described below (for details, see the following test examples).

本発明化合物は、強いＳＧＬＴ１阻害活性を有する。したがって、本発明化合物は、優れた血糖低下作用を示す医薬品として実用性に優れた性質を有すると考えられる。   The compound of the present invention has strong SGLT1 inhibitory activity. Therefore, it is considered that the compound of the present invention has a property that is excellent in practicality as a pharmaceutical having an excellent blood glucose lowering action.

本発明化合物を医薬として提供する場合、固形剤、液剤等の種々の態様の製剤形態を適宜に採択することができる。その際、製薬学的に許容される担体を配合することも可能である。そのような担体の例としては、一般的な賦形剤、増量剤、結合剤、崩壊剤、被覆剤、糖衣剤、ｐＨ調整剤、溶解剤又は水性若しくは非水性溶媒などが挙げられる。本発明の化合物とこれらの担体から、錠剤、丸剤、カプセル剤、顆粒剤、粉剤、散剤、液剤、乳剤、懸濁剤等を調製することができる。   When the compound of the present invention is provided as a pharmaceutical, various forms of preparations such as solid preparations and liquid preparations can be appropriately adopted. In that case, it is also possible to mix | blend a pharmaceutically acceptable carrier. Examples of such carriers include common excipients, bulking agents, binders, disintegrants, coating agents, dragees, pH adjusters, solubilizers or aqueous or non-aqueous solvents. Tablets, pills, capsules, granules, powders, powders, liquids, emulsions, suspensions and the like can be prepared from the compound of the present invention and these carriers.

例えば、本発明化合物と固形製剤の製造等に用いられる一般的な賦形剤等を混合した後に打錠し、経口投与用の錠剤として提供することができる。   For example, the compound of the present invention and general excipients used for the production of solid preparations and the like can be mixed and then tableted to provide tablets for oral administration.

また、本発明化合物は、α、β若しくはγ−シクロデキストリン又はメチル化シクロデキストリン等に包接させて、その溶解性を改善することも可能である。   In addition, the compound of the present invention can be included in α, β, γ-cyclodextrin, methylated cyclodextrin or the like to improve its solubility.

本発明化合物の投与量は、疾患、症状、体重、年齢、性別、投与経路等により異なってくるが、成人に対し、１日当たり０．１〜１０００ｍｇ／ｋｇ体重であり、０．１〜２００ｍｇ／ｋｇ体重が好ましく、０．１〜１０ｍｇ／ｋｇ体重がより好ましい。これを１日１回から数回に分けて投与することができる。   The dose of the compound of the present invention varies depending on the disease, symptoms, body weight, age, sex, route of administration, etc., but is 0.1 to 1000 mg / kg body weight per day for an adult, 0.1 to 200 mg / kg. kg body weight is preferable, and 0.1 to 10 mg / kg body weight is more preferable. This can be administered once to several times a day.

本発明化合物は、以下に示す方法によって合成することができるが、下記製造法は一般的製造法例を示すものであり、製造法を限定するものではない。   The compound of the present invention can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.

製造法１
Ｗがカルボニル基でＹが単結合あるいはＣ1-4アルキレン基である本発明化合物（Ｉ）は以下の方法で合成することができる。
ただし、Ｘはアセチル基またはアセチルオキシ基若しくはハロゲン原子で置換されても良いＣ1-4アルキル基を示し、Ｒ2A及びＲ3Aは、同一若しくは異なって、水素原子、メチル基、若しくはエチル基、
又は、Ｒ2A及びＲ3Aは、隣接する炭素原子と共にＣ3-6シクロアルキル基、２,２−ジメチルジオキサニル基を形成する。Ｒ6Aは前記Ｒ6またはアミノ基がｔｅｒｔ−ブチルカーボネート（Ｂｏｃ）で保護されたＲ6を示し、ｍは１から４の整数を示し、その他の記号は前記と同義である。 Manufacturing method 1
The compound (I) of the present invention in which W is a carbonyl group and Y is a single bond or a C 1-4 alkylene group can be synthesized by the following method.
Wherein X represents an acetyl group, an acetyloxy group or a C 1-4 alkyl group which may be substituted with a halogen atom, and R 2A and R 3A are the same or different and represent a hydrogen atom, a methyl group or an ethyl group,
Alternatively, R 2A and R 3A together with the adjacent carbon atom form a C 3-6 cycloalkyl group, a 2,2-dimethyldioxanyl group. R 6A represents a R 6 wherein R 6 or an amino group is protected with tert- butyl carbonate (Boc), m represents an integer of 1 to 4, and other symbols are as defined above.

Figure 2013224263
Figure 2013224263

（１）工程１（アセチル化またはアルキル化）
化合物（１Ａ）の水酸基を、アセチル基で保護する、またはメチル化等のアルキル化を行うことで、中間体（１Ｂ）を製造することができる。化合物（１Ａ）と、無水酢酸、またはアセチルクロリド等を溶媒中、適当な塩基存在下反応させ中間体（１Ｂ）を得ることができる。反応に用いる溶媒としては、クロロホルム、ジクロロメタン、ジオキサン、酢酸エチル、テトラヒドロフラン、Ｎ,Ｎ−ジメチルホルムアミド等である。塩基としてはトリエチルアミン、コリジン、ピリジン等が好挙げられる。触媒として４−ジメチルアミノピリジン等を用いることもできる。また、好ましい反応温度は０℃〜室温である。一方、化合物（１Ａ）と、ヨウ化メチル、ヨウ化エチル等を溶媒中、適当な塩基存在下反応させ中間体（１Ｂ）を得ることができる。反応に用いる溶媒としては、クロロホルム、ジクロロメタン、テトラヒドロフラン、Ｎ,Ｎ−ジメチルホルムアミド、アセトン等である。塩基としては炭酸カリウム、炭酸セシウム等が挙げられる。 (1) Step 1 (acetylation or alkylation)
The intermediate (1B) can be produced by protecting the hydroxyl group of the compound (1A) with an acetyl group or performing alkylation such as methylation. Compound (1A) can be reacted with acetic anhydride, acetyl chloride or the like in a solvent in the presence of a suitable base to obtain intermediate (1B). Examples of the solvent used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. Preferable examples of the base include triethylamine, collidine, pyridine and the like. 4-dimethylaminopyridine or the like can also be used as a catalyst. Moreover, preferable reaction temperature is 0 degreeC-room temperature. On the other hand, the intermediate (1B) can be obtained by reacting the compound (1A) with methyl iodide, ethyl iodide or the like in a solvent in the presence of an appropriate base. Examples of the solvent used for the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetone and the like. Examples of the base include potassium carbonate and cesium carbonate.

（２）工程２（Ｈｅｃｋ反応）
化合物（１Ｂ）とオレフィンカルボン酸（４Ａ）をパラジウム触媒とホスフィンリガンド、及び適当な塩基の存在下、Ｈｅｃｋ反応を行うことにより化合物（１Ｃ）を得ることができる。このとき用いるパラジウム触媒としては、酢酸パラジウム、テトラキス（トリフェニルホスフィン）パラジウム、ジベンジリデンアセトンパラジウム、ビス（トリフェニルホスフィン）パラジウムクロリド、ビス（トリシクロヘキシルホスフィン）パラジウムクロリド、パラジウム活性炭等が挙げられる。ホスフィンリガンドとしてはトリフェニルホスフィンやトリ−ｏ−トリルホスフィン等が挙げられる。また、塩基にはトリエチルアミン、Ｎ−エチル−Ｎ,Ｎ−ジイソプロピルアミン、炭酸カリウム、炭酸カルシウム、炭酸セシウム、カリウム ｔ−ブトキシド等が用いられる。反応に用いられる溶媒としては、アセトニトリル、トルエン、テトラヒドロフラン等が挙げられる。反応温度は０℃〜還流温度である。マイクロウェ−ブを用いることもある。 (2) Step 2 (Heck reaction)
Compound (1C) can be obtained by subjecting compound (1B) and olefin carboxylic acid (4A) to Heck reaction in the presence of a palladium catalyst, a phosphine ligand, and an appropriate base. Examples of the palladium catalyst used at this time include palladium acetate, tetrakis (triphenylphosphine) palladium, dibenzylideneacetone palladium, bis (triphenylphosphine) palladium chloride, bis (tricyclohexylphosphine) palladium chloride, and palladium activated carbon. Examples of the phosphine ligand include triphenylphosphine and tri-o-tolylphosphine. As the base, triethylamine, N-ethyl-N, N-diisopropylamine, potassium carbonate, calcium carbonate, cesium carbonate, potassium t-butoxide and the like are used. Examples of the solvent used for the reaction include acetonitrile, toluene, tetrahydrofuran and the like. The reaction temperature is 0 ° C. to reflux temperature. A microwave may be used.

（３）工程３（アミド基への変換）
化合物（１Ｃ）をアミン（４Ｂ）と縮合し、化合物（１Ｄ）を得ることができる。この反応に使用する溶媒としては、クロロホルム、ジクロロメタン、Ｎ,Ｎ−ジメチルホルムアミド等が挙げられ、縮合剤としては、Ｎ,Ｎ´−ジシクロヘキシルカルボジイミド（ＤＣＣ）、Ｎ−エチル−Ｎ´−３−ジメチルアミノプロピルカルボジイミド塩酸塩（ＥＤＣ−ＨＣｌ）、１、１´−カルボニルジイミダゾ−ル（ＣＤＩ）、ＥＤＣ−ＨＣｌ／１−ヒドロキシベンゾトリアゾ−ル一水和物（ＨＯＢｔ・Ｈ2Ｏ）等が挙げられる。ここでの反応温度は０℃〜６０℃である。 (3) Step 3 (Conversion to amide group)
Compound (1C) can be condensed with amine (4B) to give compound (1D). Examples of the solvent used in this reaction include chloroform, dichloromethane, N, N-dimethylformamide and the like, and examples of the condensing agent include N, N′-dicyclohexylcarbodiimide (DCC), N-ethyl-N′-3-dimethyl. Aminopropylcarbodiimide hydrochloride (EDC-HCl), 1,1′-carbonyldiimidazole (CDI), EDC-HCl / 1-hydroxybenzotriazole monohydrate (HOBt · H 2 O), etc. Can be mentioned. The reaction temperature here is 0 ° C to 60 ° C.

（４）工程４（酸化）
化合物（１Ｄ）の１級アルコールを酸化することで、化合物（１Ｅ）を得ることができる。この反応に使用する溶媒としては、クロロホルム、ジクロロメタン、ジメチルスルホキシド等が好ましく、酸化剤としては、Ｄｅｓｓ−Ｍａｒｔｉｎ ｐｅｒｉｏｄｉｎａｎｅ、ＩＢＸ等が好ましい。ここでの反応温度は０℃〜室温である。 (4) Step 4 (oxidation)
The compound (1E) can be obtained by oxidizing the primary alcohol of the compound (1D). As the solvent used in this reaction, chloroform, dichloromethane, dimethyl sulfoxide and the like are preferable, and as the oxidizing agent, Dess-Martin periodinane, IBX and the like are preferable. The reaction temperature here is 0 ° C. to room temperature.

（５）工程５（還元的アミノ化）
化合物（１Ｅ）とアミン（Ｒ6AＲ7ＮＨ（４Ｃ））を用いた還元的アミノ化反応によって、化合物（１Ｆ）を得ることができる。この反応に使用する溶媒としては、Ｎ,Ｎ−ジメチルホルムアミド、クロロホルム、ジクロロメタン、メタノール等が挙げられる。また、基質によっては酢酸を加えると収率が向上することがある。還元剤としては、ＮａＢＨ（ＯＡｃ）3、ＮａＢＨ3ＣＮ、ボラン−２−ピコリン錯体等が挙げられる。ここでの反応温度は０℃〜室温である。
（６）工程６（脱保護）
化合物（１Ｆ）中のＢｏｃ基を酸性条件下で除去し、アセチル（Ａｃ）基を塩基性条件下除去することで化合物（Ｉ）を得ることができる。Ｂｏｃ基には、ジクロロメタン、クロロホルム、ジオキサン等の溶媒中、または無溶媒で塩酸またはトリフルオロ酢酸を作用させる。アセチル基には、ナトリウムメトキシド、ナトリウムエトキシド、水酸化ナトリウム、水酸化リチウム、炭酸カリウム、炭酸セシウム、トリエチルアミン等の塩基を用いることができる。溶媒としては、メタノール、エタノール、含水メタノール等が挙げられる。ここでの反応温度は０℃〜６０℃である。Ｒ2A及びＲ3Aが隣接する炭素原子と共に２,２−ジメチルジオキサニル基を形成している場合、そのアセタール基を酸性条件下で除去し、ヒドロキシメチル基へ変換することができる。この反応に使用する溶媒としては、テトラヒドロフラン、ジオキサン、酢酸エチル等が挙げられ、酸としては塩酸、トリフルオロ酢酸、ｐ−トルエンスルホン酸等を用いることができる。 (5) Step 5 (Reductive amination)
Compound (1F) can be obtained by reductive amination reaction using compound (1E) and an amine (R 6A R 7 NH (4C)). Examples of the solvent used in this reaction include N, N-dimethylformamide, chloroform, dichloromethane, methanol and the like. Depending on the substrate, addition of acetic acid may improve the yield. Examples of the reducing agent include NaBH (OAc) 3 , NaBH 3 CN, and borane-2-picoline complex. The reaction temperature here is 0 ° C. to room temperature.
(6) Step 6 (deprotection)
Compound (I) can be obtained by removing the Boc group in compound (1F) under acidic conditions and removing the acetyl (Ac) group under basic conditions. Hydrochloric acid or trifluoroacetic acid is allowed to act on the Boc group in a solvent such as dichloromethane, chloroform, dioxane or the like or without a solvent. For the acetyl group, a base such as sodium methoxide, sodium ethoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine or the like can be used. Examples of the solvent include methanol, ethanol, hydrous methanol and the like. The reaction temperature here is 0 ° C to 60 ° C. When R 2A and R 3A form a 2,2-dimethyldioxanyl group with adjacent carbon atoms, the acetal group can be removed under acidic conditions and converted to a hydroxymethyl group. Examples of the solvent used in this reaction include tetrahydrofuran, dioxane, ethyl acetate, and examples of the acid include hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like.

製造法２
また、Ｗが単結合、またはメチレン基でＹがカルボニル基である本発明化合物（Ｉａ）は以下の方法で合成することができる。 Manufacturing method 2
In addition, the compound (Ia) of the present invention in which W is a single bond or methylene group and Y is a carbonyl group can be synthesized by the following method.

Figure 2013224263
Figure 2013224263

（７）工程７（Ｈｅｃｋ反応）
化合物（１Ｂ）とアクリリックアシッドやブテノイックアシッド（４Ｄ）から製造法１の工程２に記載したＨｅｃｋ反応を行うことにより、化合物（２Ｃ）を得ることができる。 (7) Step 7 (Heck reaction)
Compound (2C) can be obtained by performing Heck reaction described in Step 2 of Production Method 1 from Compound (1B) and acrylic acid or butenoic acid (4D).

（８）工程８（還元）
化合物（２Ｃ）のカルボキシ基を還元することで、化合物（２Ｄ）を得ることができる。この反応に使用する溶媒としては、テトラヒドロフラン、ジエチルエーテル等が挙げられる。還元剤としては、ボラン−テトラヒドロフラン錯体が挙げられる。反応温度は０℃〜６０℃であり、室温が好ましい。 (8) Step 8 (reduction)
Compound (2D) can be obtained by reducing the carboxy group of compound (2C). Examples of the solvent used in this reaction include tetrahydrofuran and diethyl ether. An example of the reducing agent is borane-tetrahydrofuran complex. The reaction temperature is 0 ° C to 60 ° C, preferably room temperature.

（９）工程９（臭素化またはメシル化）
化合物（２Ｄ）の１級アルコールを臭素化またはメシル化することで、化合物（２Ｅ）を得ることができる。この反応に使用する溶媒としては、クロロホルム、ジクロロメタン、テトラヒドロフラン等が好ましい。ブロモ化の試薬としては、トリフェニルホスフィン（ＰＰｈ3）−ＤＥＡＤ−臭化リチウム、ＰＰｈ3−四臭化炭素、Ｎ−ブロモスクシンイミド（ＮＢＳ）等が挙げられる。また、メシル化の試薬としてはトリエチルアミン存在下にメタンスルホニルクロリドを用いる。反応温度は０℃〜室温である。また、メタンスルホニル誘導体は不安定であるため、製造後工程１０、アミン（４E）との置換反応に速やかに供することが好ましい。
(9) Step 9 (bromination or mesylation)
The compound (2E) can be obtained by brominating or mesylating the primary alcohol of the compound (2D). As the solvent used in this reaction, chloroform, dichloromethane, tetrahydrofuran and the like are preferable. Examples of the bromination reagent include triphenylphosphine (PPh 3 ) -DEAD-lithium bromide, PPh 3 -carbon tetrabromide, N-bromosuccinimide (NBS), and the like. As a reagent for mesylation, methanesulfonyl chloride is used in the presence of triethylamine. The reaction temperature is 0 ° C. to room temperature. Moreover, since a methanesulfonyl derivative is unstable, it is preferable to use for a substitution reaction with the post-production process 10 and an amine (4E) promptly.

（１０）工程１０（アミノ化）
化合物（２Ｅ）にアミン（４Ｅ）を作用させ、化合物（２Ｆ）を得ることができる。この反応に使用する溶媒としては、テトラヒドロフラン、Ｎ,Ｎ−ジメチルホルムアミド、ジメチルスルホキシド等が挙げられ、反応温度は室温〜１５０℃である。 (10) Step 10 (amination)
Compound (2F) can be obtained by reacting compound (2E) with amine (4E). Examples of the solvent used in this reaction include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and the reaction temperature is from room temperature to 150 ° C.

（１１）工程１１（脱保護）
上記で得られた化合物（２Ｆ）を製造法１の工程６に記載した脱保護反応によって化合物（Ｉａ）へ導くことができる。 (11) Step 11 (deprotection)
Compound (2F) obtained above can be led to compound (Ia) by the deprotection reaction described in Step 6 of Production Method 1.

製造法３
ＷとＹが共にカルボニル基である本発明化合物（Ｉｂ）は以下に示す方法で合成することができる。 Production method 3
The compound (Ib) of the present invention in which W and Y are both carbonyl groups can be synthesized by the method shown below.

Figure 2013224263
Figure 2013224263

（１２）工程１２（Ｈｅｃｋ反応）
化合物（１Ｂ）と化合物（４Ｆ）を用いて製造法１の工程２に記載したＨｅｃｋ反応を行うことにより、化合物（３Ａ）を得ることができる。 (12) Step 12 (Heck reaction)
Compound (3A) can be obtained by performing the Heck reaction described in Step 2 of Production Method 1 using Compound (1B) and Compound (4F).

（１３）工程１３（アミド基への変換）
化合物（３Ａ）とアミン（４Ｃ）を用いて製造法１の工程３に記載した脱水縮合反応を行うことにより、化合物（３Ｂ）を得ることができる。 (13) Step 13 (Conversion to amide group)
Compound (3B) can be obtained by performing the dehydration condensation reaction described in Step 3 of Production Method 1 using Compound (3A) and amine (4C).

（１４）工程１４（脱保護）
上記で得られた化合物（３Ｂ）を製造法１の工程６に記載した脱保護反応によって化合物（Ｉｂ）へ導くことができる。 (14) Step 14 (deprotection)
Compound (3B) obtained above can be led to compound (Ib) by the deprotection reaction described in Step 6 of Production Method 1.

中間体（１Ａ）の製造法
中間体（１Ａ）は以下に示す方法で合成することができる。
ただし、記号は前記と同義である。 Production method of intermediate (1A) Intermediate (1A) can be synthesized by the method shown below.
However, the symbols are as defined above.

Figure 2013224263
Figure 2013224263

（１５）工程１５（カップリング）
化合物（５Ａ）にｎ−ブチルリチウム、ｓｅｃ−ブチルリチウム、ｔｅｒｔ−ブチルリチウム等の有機金属試薬を用いてアリ−ルリチウム試薬を調製することができる。これに、グルコノラクトン（５Ｂ）を加えることで化合物（５Ｃ）を得ることができる。このとき反応に用いられる溶媒としては、テトラヒドロフラン、ジエチルエ−テル、トルエン等が挙げられる。反応温度は−８０℃〜室温であり、好ましくは−７８℃〜−２５℃である。 (15) Step 15 (coupling)
An aryl lithium reagent can be prepared using an organometallic reagent such as n-butyllithium, sec-butyllithium, tert-butyllithium and the like for compound (5A). Compound (5C) can be obtained by adding gluconolactone (5B) to this. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is −80 ° C. to room temperature, preferably −78 ° C. to −25 ° C.

（１６）工程１６（シリル化）
上記工程１５に引き続いて、化合物（５Ｃ）の１位水酸基をトリメチルシリル基等のシリル基で保護することができる。工程１５の反応液に、トリメチルシリルクロリドを反応させ化合物（５Ｄ）を得ることができる。反応に用いる溶媒および反応温度は、工程１５と同じである。 (16) Step 16 (silylation)
Subsequent to the step 15, the 1-position hydroxyl group of the compound (5C) can be protected with a silyl group such as a trimethylsilyl group. The reaction liquid in Step 15 can be reacted with trimethylsilyl chloride to obtain compound (5D). The solvent and reaction temperature used for the reaction are the same as in Step 15.

（１７）工程１７（カップリング）
上記工程１６に引き続いて、生成した化合物（５Ｄ）にｎ−ブチルリチウム、ｓｅｃ−ブチルリチウム、ｔｅｒｔ−ブチルリチウム等の有機金属試薬を用いてアリ−ルリチウム試薬を調製することができる。これに、アルデヒド（５Ｅ）を加えることで化合物（５Ｆ）を得ることができる。このとき反応に用いられる溶媒および好ましい反応温度は、工程１５と同じである。 (17) Step 17 (coupling)
Subsequent to the step 16, an aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for the compound (5D) produced. Compound (5F) can be obtained by adding aldehyde (5E) to this. At this time, the solvent used for the reaction and the preferred reaction temperature are the same as in Step 15.

（１８）工程１８（酸加水分解及びメチルエーテル化）
化合物（５Ｆ）中のＭＯＭ基とシリル基を同時に酸性条件下メタノール中で除去すると共に、糖の１位をメチルエーテル化し、化合物（５Ｇ）を得ることができる。このとき用いる酸としては、塩酸、硫酸、メタンスルホン酸、ｐ−トルエンスルホン酸一水和物、ピリジニウム ｐ−トルエンスルホン酸等を用いることができる。反応温度は用いる酸によって異なるが、０℃〜１００℃、好ましくは２５℃〜８０℃である。 (18) Step 18 (acid hydrolysis and methyl etherification)
The MOM group and silyl group in the compound (5F) can be simultaneously removed in methanol under acidic conditions, and the 1-position of the sugar can be methyletherified to obtain the compound (5G). Examples of the acid used at this time include hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid monohydrate, pyridinium p-toluenesulfonic acid, and the like. The reaction temperature varies depending on the acid used, but is 0 ° C to 100 ° C, preferably 25 ° C to 80 ° C.

（１９）工程１９（アセチル化）
化合物（５Ｇ）中の水酸基をアセチル基で保護することにより、化合物（５Ｈ）を得ることができる。化合物（５Ｇ）と、無水酢酸、またはアセチルクロリド等を溶媒中、適当な塩基存在下反応させ化合物（５Ｈ）を得ることができる。反応に用いる溶媒としては、クロロホルム、ジクロロメタン、ジオキサン、酢酸エチル、テトラヒドロフラン、Ｎ,Ｎ−ジメチルホルムアミド等である。塩基としてはトリエチルアミン、コリジン、ピリジン等が挙げられる。反応の触媒として４−ジメチルアミノピリジンを用いることもできる。また、反応温度は０℃〜室温である。 (19) Step 19 (acetylation)
A compound (5H) can be obtained by protecting the hydroxyl group in the compound (5G) with an acetyl group. Compound (5H) can be obtained by reacting compound (5G) with acetic anhydride, acetyl chloride or the like in a solvent in the presence of a suitable base. Examples of the solvent used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. Examples of the base include triethylamine, collidine, pyridine and the like. 4-Dimethylaminopyridine can also be used as a catalyst for the reaction. The reaction temperature is 0 ° C. to room temperature.

（２０）工程２０（還元）
化合物（５Ｈ）とＥｔ3ＳｉＨ、ｉ−Ｐｒ3ＳｉＨ、ｔ−ＢｕＭｅ2ＳｉＨ又はＰｈ2ＳｉＨＣｌを、酸の存在下で反応させ、化合物（１Ａ）を得ることができる。この反応に使用する酸としては、ＢＦ3・ＯＥｔ2、ＣＦ3ＣＯＯＨ、ＩｎＣｌ3、ＴｉＣｌ4、ＴＭＳＯＴｆ、ｐ−トルエンスルホン酸一水和物、メタンスルホン酸等が挙げられ、溶媒としては、クロロホルム、ジクロロメタン、トルエン、テトラヒドロフラン、アセトニトリル又はそれらの混合溶媒が挙げられ、好ましい溶媒はアセトニトリル／クロロホルム、アセトニトリル／ジクロロメタン、アセトニトリル／テトラヒドロフラン、アセトニトリル／テトラヒドロフラン／トルエン等のアセトニトリルと他の溶媒との混合溶媒である。 (20) Step 20 (reduction)
Compound (1A) can be obtained by reacting compound (5H) with Et 3 SiH, i-Pr 3 SiH, t-BuMe 2 SiH or Ph 2 SiHCl in the presence of an acid. Examples of the acid used in this reaction include BF 3 · OEt 2 , CF 3 COOH, InCl 3 , TiCl 4 , TMSOTf, p-toluenesulfonic acid monohydrate, methanesulfonic acid, and the like. , Dichloromethane, toluene, tetrahydrofuran, acetonitrile or a mixed solvent thereof, and a preferable solvent is a mixed solvent of acetonitrile and other solvents such as acetonitrile / chloroform, acetonitrile / dichloromethane, acetonitrile / tetrahydrofuran and acetonitrile / tetrahydrofuran / toluene. .

以下に、参考例、実施例及び試験例を挙げ、本発明をより詳細に説明するが、本発明はこれらの記載によって限定的に解釈されるものではない。
参考例１ 中間体（１Ａ）の製造 Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples. However, the present invention is not limited to these descriptions.
Reference Example 1 Production of Intermediate (1A)

Figure 2013224263
Figure 2013224263

（１）参考例１−１ 化合物（５Ａ） (1) Reference Example 1-1 Compound (5A)

Figure 2013224263
３−イソプロピルフェノール（１６０ｇ,１．１８ｍｏｌ）の酢酸（１．６Ｌ）溶液に、氷冷で内温が１９℃を超えないように臭素（４６９ｇ,２．９４ｍｏｌ）の酢酸（３２０ｍＬ）溶液を３２分かけて滴下し、室温で１時間撹拌した。トルエン（１．６Ｌ）を加えた後に氷冷し、内温２０℃を超えないように１０％亜硫酸ナトリウム水溶液（１．０Ｌ）を滴下して有機層を分離した。その有機層を１０％亜硫酸ナトリウム水溶液（１．０Ｌ）、１０％食塩水（１．０Ｌ）で２回洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、淡黄色油状の２,４−ジブロモ−５−イソプロピルフェノール（３４２ｇ,９９％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J=6.8 Hz, 6 H) 3.25 (sept, J=6.8 Hz, 1 H) 5.40 (s, 1 H) 6.96 (s, 1 H) 7.61 (s, 1 H).
Figure 2013224263
 To a solution of 3-isopropylphenol (160 g, 1.18 mol) in acetic acid (1.6 L), a solution of bromine (469 g, 2.94 mol) in acetic acid (320 mL) was added with ice-cooling so that the internal temperature did not exceed 19 ° C. The solution was added dropwise over a minute and stirred at room temperature for 1 hour. Toluene (1.6 L) was added and then ice-cooled, and a 10% aqueous sodium sulfite solution (1.0 L) was added dropwise so that the internal temperature did not exceed 20 ° C., and the organic layer was separated. The organic layer was washed twice with 10% aqueous sodium sulfite (1.0 L) and 10% brine (1.0 L), and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 2,4-dibromo-5-isopropylphenol (342 g, 99%) as a pale yellow oil.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J = 6.8 Hz, 6 H) 3.25 (sept, J = 6.8 Hz, 1 H) 5.40 (s, 1 H) 6.96 (s, 1 H ) 7.61 (s, 1 H).

２,４−ジブロモ−５−イソプロピルフェノール（５１２ｇ,１．７４ｍｏｌ）のクロロホルム（１．７４Ｌ）溶液に、Ｎ、Ｎ−ジイソプロピルエチルアミン（３６４ｍＬ,２．０９ｍｏｌ）を加えて氷冷した。クロロメチルメチルエーテル（１５９ｍＬ,２．０９ｍｏｌ）を１時間かけて滴下し、室温で１時間撹拌した。反応液を氷冷し、１Ｍ水酸化ナトリウム水溶液（１．５Ｌ）を滴下して有機層を分離した。その有機層を１Ｍ水酸化ナトリウム水溶液（１．５Ｌ）、水（１．５Ｌ）で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。得られた残渣を減圧蒸留（０．９３〜１．５ｈＰａ,１２２℃〜１３７℃）にて精製し、淡黄色油状化合物（５Ａ）（５４８ｇ,９６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J=6.8 Hz, 6 H) 3.28 (sept, J=6.8 Hz, 1 H) 3.52 (s, 3 H) 5.23 (s, 2 H) 7.06 (s, 1 H) 7.69 (s, 1 H).
MS ESI/APCI Dual posi : 339[M+H]+, 341[M+2+H]+. N, N-diisopropylethylamine (364 mL, 2.09 mol) was added to a chloroform (1.74 L) solution of 2,4-dibromo-5-isopropylphenol (512 g, 1.74 mol), and the mixture was ice-cooled. Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled, and 1M aqueous sodium hydroxide solution (1.5 L) was added dropwise to separate the organic layer. The organic layer was washed with 1M aqueous sodium hydroxide solution (1.5 L) and water (1.5 L), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by distillation under reduced pressure (0.93 to 1.5 hPa, 122 ° C. to 137 ° C.) to obtain a pale yellow oily compound (5A) (548 g, 96%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J = 6.8 Hz, 6 H) 3.28 (sept, J = 6.8 Hz, 1 H) 3.52 (s, 3 H) 5.23 (s, 2 H ) 7.06 (s, 1 H) 7.69 (s, 1 H).
MS ESI / APCI Dual posi: 339 [M + H] + , 341 [M + 2 + H] + .

（２）参考例１−２ 中間体（１Ａ）
化合物（５Ａ）（２００ｇ,０．５９２ｍｏｌ）のテトラヒドロフラン（２．８４Ｌ）溶液に、アルゴン雰囲気下−８０〜−７６℃にて２．６９Ｍ ｎ−ブチルリチウムへキサン溶液（２３１ｍＬ,０．６２１ｍｏｌ）を２０分かけて滴下し、同温にて３５分間撹拌した。次いで２,３,４,６−テトラ−Ｏ−トリメチルシリル−Ｄ−グルコノ−１,５−ラクトン（２９０ｇ,０．６２１ｍｏｌ）のテトラヒドロフラン（８００ｍＬ）溶液を５５分かけて滴下し、同温にて５０分間撹拌した。さらにトリメチルクロロシラン（７５．７ｍＬ,０．６２１ｍｏｌ）を１５分かけて滴下し、同温にて２時間撹拌した。次いで２．６９Ｍ ｎ−ブチルリチウムへキサン溶液（３１９ｍＬ,０．８５８ｍｏｌ）を２９分かけて滴下し、同温にて４０分間撹拌した。最後に４−ブロモ−２−メチルベンズアルデヒド（１３０ｇ,０．６５１ｍｏｌ）のテトラヒドロフラン（８００ｍＬ）溶液を５４分かけて滴下し、同温にて３０分間撹拌した。反応液に水（２.８５Ｌ）を加えて室温まで温めた。トルエン（２．０Ｌ）を加えて有機層を分離し、溶媒を減圧下留去した。 (2) Reference Example 1-2 Intermediate (1A)
To a tetrahydrofuran (2.84 L) solution of the compound (5A) (200 g, 0.592 mol), a 2.69 M n-butyllithium hexane solution (231 mL, 0.621 mol) was added at −80 to −76 ° C. in an argon atmosphere. The solution was added dropwise over 20 minutes and stirred at the same temperature for 35 minutes. Next, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (290 g, 0.621 mol) in tetrahydrofuran (800 mL) was added dropwise over 55 minutes, and 50 ° C. at the same temperature. Stir for minutes. Further, trimethylchlorosilane (75.7 mL, 0.621 mol) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 2 hours. Subsequently, 2.69M n-butyllithium hexane solution (319 mL, 0.858 mol) was added dropwise over 29 minutes, and the mixture was stirred at the same temperature for 40 minutes. Finally, a tetrahydrofuran (800 mL) solution of 4-bromo-2-methylbenzaldehyde (130 g, 0.651 mol) was added dropwise over 54 minutes, and the mixture was stirred at the same temperature for 30 minutes. Water (2.85 L) was added to the reaction solution and warmed to room temperature. Toluene (2.0 L) was added to separate the organic layer, and the solvent was distilled off under reduced pressure.

得られた残渣（５４６ｇ）をメタノール（３．０Ｌ）に溶解し、メタンスルホン酸（３．８４ｍＬ,０．０５９２ｍｏｌ）を加えて１．５時間加熱還流を行った。反応液を室温まで冷却後、トリエチルアミン（２５ｍＬ,０．１７９ｍｏｌ）で中和し、反応混合物を濃縮した。濃縮物をトルエン（１．０Ｌ）に溶解し、水（０．５Ｌ、１．０Ｌ）で洗浄した。その有機層に１Ｍ水酸化ナトリウム水溶液（０．６Ｌ）とトルエン（１．０Ｌ）を加えて分液操作を行い、水層を分離した。その水層をトルエン（１．０Ｌ,０．５Ｌ）で洗浄した。水層に１０％塩酸（０．７Ｌ）を加えトルエン（１．０Ｌ）て抽出し、有機層を分離した。その有機層を１０％食塩水(１．０Ｌ)、水（０．５Ｌ）で洗浄し、溶媒を減圧下留去した。
得られた残渣（３１４ｇ）をピリジン（１．０Ｌ）に溶解し、無水酢酸（０．８Ｌ,８．５１ｍｏｌ）を加え、室温で１８時間撹拌した。反応液を氷冷して氷（１．５Ｌ）とトルエン（１．０Ｌ）を加え３時間撹拌した。水層を分離しトルエン(１．０Ｌ)で抽出、混合した有機層を２Ｍ塩酸（１．５Ｌ）で２回、５％炭酸水素ナトリウム水溶液（１．０Ｌ）、１０％食塩水（１．０Ｌ）で洗浄し、溶媒を減圧下留去した。 The obtained residue (546 g) was dissolved in methanol (3.0 L), methanesulfonic acid (3.84 mL, 0.0592 mol) was added, and the mixture was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, neutralized with triethylamine (25 mL, 0.179 mol), and the reaction mixture was concentrated. The concentrate was dissolved in toluene (1.0 L) and washed with water (0.5 L, 1.0 L). A 1 M aqueous sodium hydroxide solution (0.6 L) and toluene (1.0 L) were added to the organic layer to perform a liquid separation operation, and the aqueous layer was separated. The aqueous layer was washed with toluene (1.0 L, 0.5 L). To the aqueous layer, 10% hydrochloric acid (0.7 L) was added and extracted with toluene (1.0 L), and the organic layer was separated. The organic layer was washed with 10% brine (1.0 L) and water (0.5 L), and the solvent was evaporated under reduced pressure.
The obtained residue (314 g) was dissolved in pyridine (1.0 L), acetic anhydride (0.8 L, 8.51 mol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was ice-cooled, ice (1.5 L) and toluene (1.0 L) were added, and the mixture was stirred for 3 hr. The aqueous layer was separated, extracted with toluene (1.0 L), and the combined organic layer was washed twice with 2 M hydrochloric acid (1.5 L), 5% aqueous sodium hydrogen carbonate solution (1.0 L), 10% brine (1.0 L). ) And the solvent was distilled off under reduced pressure.

得られた残渣（３５０ｇ）をアセトニトリル（３．４Ｌ）に溶解し、水（９．１ｍＬ,０．５０６ｍｏｌ）、Ｅｔ3ＳｉＨ（３２８ｍＬ,２．０５ｍｏｌ）を加え、氷冷下ＴＭＳＯＴｆ（４０３ｍＬ,２．２３ｍｏｌ）を８５分かけて滴下した。同温で２時間撹拌後、３％炭酸水素ナトリウム水溶液（１．９２Ｌ）を４０分かけて滴下し、反応溶液をトルエン（１．０Ｌ）で希釈し１５分撹拌した後、有機層を分離した。水層をトルエン（１．５Ｌ）で抽出して、有機層を飽和炭酸水素ナトリウム水溶液（１．５Ｌ）で洗浄し、溶媒を減圧下留去して無色液状の中間体（１Ａ）（３９２ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.09 - 1.19 (m, 6 H) 1.69 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.25 (s, 3 H) 2.80 - 2.97 (m, 1 H) 3.66 - 3.96 (m, 3 H) 4.08 - 4.35 (m, 2 H) 4.42 - 4.57 (m, 1 H) 5.19 - 5.37 (m, 3 H) 6.52 (s, 1 H) 6.57 (d, J=8.1 Hz, 1 H) 6.87 (s, 1 H) 7.12 - 7.20 (m, 1 H) 7.30 - 7.33 (m, 1 H)．
参考例２ 中間体（１Ｂ−１）の製造 The obtained residue (350 g) was dissolved in acetonitrile (3.4 L), water (9.1 mL, 0.506 mol), Et 3 SiH (328 mL, 2.05 mol) were added, and TMSOTf (403 mL, 2) was added under ice cooling. .23 mol) was added dropwise over 85 minutes. After stirring at the same temperature for 2 hours, 3% aqueous sodium hydrogen carbonate solution (1.92 L) was added dropwise over 40 minutes, the reaction solution was diluted with toluene (1.0 L) and stirred for 15 minutes, and then the organic layer was separated. . The aqueous layer was extracted with toluene (1.5 L), the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (1.5 L), and the solvent was distilled off under reduced pressure to obtain a colorless liquid intermediate (1A) (392 g). Got.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.09-1.19 (m, 6 H) 1.69 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.25 (s, 3 H) 2.80-2.97 (m, 1 H) 3.66-3.96 (m, 3 H) 4.08-4.35 (m, 2 H) 4.42-4.57 (m, 1 H) 5.19-5.37 (m, 3 H ) 6.52 (s, 1 H) 6.57 (d, J = 8.1 Hz, 1 H) 6.87 (s, 1 H) 7.12-7.20 (m, 1 H) 7.30-7.33 (m, 1 H).
Reference Example 2 Production of intermediate (1B-1)

Figure 2013224263
中間体（１Ａ）（６００ｇ,０．５９２ｍｏｌ）のピリジン(７７０ｍＬ)溶液に無水酢酸（３８５ｍＬ）を氷冷下１０分かけて滴下した。反応溶液を室温まで上げ、同温で１８時間撹拌し再び氷冷した後、氷（１．０Ｌ）で反応を停止した。反応溶液をトルエン（１．０Ｌ）で希釈した後、１．５時間撹拌した。有機層を分離し、２Ｍ塩酸（１．２５Ｌ）で２回、５％炭酸水素ナトリウム水溶液（１．０Ｌ）、１０％食塩水（１．０Ｌ）、水（０．５Ｌ）で洗浄し、減圧下濃縮した。残渣にイソプロピルアルコール（１．５Ｌ）を加え、８０℃に加熱して溶解した。室温で１．５時間撹拌した後、沈殿物を濾別乾燥した。得られた白色粉末をイソプロピルアルコール（８００ｍＬ）に８０℃に過熱下溶解し、１．５時間室温で撹拌、沈殿物を濾別、乾燥して（１Ｂ−１）（１８６ｇ,４５％）を白色粉末として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H)1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.36 (s, 3 H) 2.86 - 3.01 (m, 1 H) 3.72 - 3.80 (m, 1 H) 3.87 (s, 2 H) 4.01 - 4.09 (m, 1 H) 4.23 - 4.32 (m, 1 H) 4.46 - 4.53 (m, 1 H) 5.11 - 5.20 (m, 1 H) 5.22 - 5.29 (m, 2 H) 6.56 - 6.61 (m, 1 H) 6.98 - 7.01 (m, 2 H) 7.18 - 7.23 (m, 1 H) 7.32 - 7.35 (m, 1 H).
参考例３ 中間体（１Ｂ−２）の製造
Figure 2013224263
 Acetic anhydride (385 mL) was added dropwise to a solution of intermediate (1A) (600 g, 0.592 mol) in pyridine (770 mL) over 10 minutes under ice cooling. The reaction solution was raised to room temperature, stirred at the same temperature for 18 hours, and ice-cooled again, and then the reaction was stopped with ice (1.0 L). The reaction solution was diluted with toluene (1.0 L) and then stirred for 1.5 hours. The organic layer was separated, washed twice with 2M hydrochloric acid (1.25L), washed with 5% aqueous sodium hydrogen carbonate solution (1.0L), 10% brine (1.0L), water (0.5L) and reduced pressure. The bottom was concentrated. Isopropyl alcohol (1.5 L) was added to the residue and dissolved by heating to 80 ° C. After stirring at room temperature for 1.5 hours, the precipitate was filtered off and dried. The obtained white powder was dissolved in isopropyl alcohol (800 mL) at 80 ° C. under heating, stirred at room temperature for 1.5 hours, the precipitate was filtered off and dried to give (1B-1) (186 g, 45%) as white Obtained as a powder.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H ) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.36 (s, 3 H) 2.86-3.01 (m, 1 H) 3.72-3.80 (m, 1 H) 3.87 (s , 2 H) 4.01-4.09 (m, 1 H) 4.23-4.32 (m, 1 H) 4.46-4.53 (m, 1 H) 5.11-5.20 (m, 1 H) 5.22-5.29 (m, 2 H) 6.56 -6.61 (m, 1 H) 6.98-7.01 (m, 2 H) 7.18-7.23 (m, 1 H) 7.32-7.35 (m, 1 H).
Reference Example 3 Production of intermediate (1B-2)

Figure 2013224263
中間体（１Ａ）（３９２ｇ,０．５０６ｍｏｌ）と炭酸カリウム（７３．４ｇ,０．５３１ｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド（０．９５Ｌ）懸濁液にヨウ化メチル（３３ｍＬ,０．５３０ｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド（５０ｍＬ）溶液を滴下した。反応溶液を１時間撹拌した後、炭酸カリウム（７０．０ｇ,０．５０６ｍｏｌ）、ヨウ化メチル（３１．５ｍＬ,０．５０６ｍｏｌ）を加え１時間撹拌した。再び炭酸カリウム（７０．０ｇ,０．５０６ｍｏｌ）、ヨウ化メチル（３１．５ｍＬ,０．５０６ｍｏｌ）を加え１時間撹拌した。ヨウ化メチル（１５．８ｍＬ,０．２５４ｍｏｌ）を加え、室温で一晩撹拌した。５０℃で２時間撹拌した後、トルエン（１．２５Ｌ）で希釈、水（１．０Ｌ）を加えた。２層を分離し、有機層を水（１．０Ｌ）で２回、１０％食塩水（１．０Ｌ）で洗浄し、減圧下濃縮した。残渣にイソプロピルアルコール（３５０ｍＬ）を加え４０℃に加熱して溶解し、室温で撹拌した。得られた沈殿物を濾別、乾燥し（１Ｂ−２）（１５５ｇ,４６％）を白色粉末として得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J=6.8 Hz, 3 H) 1.13 (d, J=6.8 Hz, 3 H) 1.55 (s, 3 H) 1.75 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.29 (s, 3 H) 2.83 - 2.96 (m, 1 H) 3.86 (s, 3 H) 4.08 - 4.17 (m, 1 H) 4.18 - 4.28 (m, 1 H) 4.78 - 4.89 (m, 1 H) 5.13 - 5.23 (m, 1 H) 5.27 - 5.35 (m, 2 H) 6.51 - 6.57 (m, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.12 - 7.20 (m, 1 H) 7.30 (s, 1 H).
参考例４ 中間体（１Ｂ−３）の製造
Figure 2013224263
 To a suspension of intermediate (1A) (392 g, 0.506 mol) and potassium carbonate (73.4 g, 0.531 mol) in N, N-dimethylformamide (0.95 L), methyl iodide (33 mL, 0.530 mol) Of N, N-dimethylformamide (50 mL) was added dropwise. After the reaction solution was stirred for 1 hour, potassium carbonate (70.0 g, 0.506 mol) and methyl iodide (31.5 mL, 0.506 mol) were added and stirred for 1 hour. Potassium carbonate (70.0 g, 0.506 mol) and methyl iodide (31.5 mL, 0.506 mol) were added again and stirred for 1 hour. Methyl iodide (15.8 mL, 0.254 mol) was added, and the mixture was stirred overnight at room temperature. The mixture was stirred at 50 ° C. for 2 hours, diluted with toluene (1.25 L), and water (1.0 L) was added. The two layers were separated, and the organic layer was washed twice with water (1.0 L), 10% brine (1.0 L), and concentrated under reduced pressure. Isopropyl alcohol (350 mL) was added to the residue and dissolved by heating to 40 ° C., followed by stirring at room temperature. The resulting precipitate was filtered off and dried to give (1B-2) (155 g, 46%) as a white powder.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 6.8 Hz, 3 H) 1.13 (d, J = 6.8 Hz, 3 H) 1.55 (s, 3 H) 1.75 (s, 3 H ) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.29 (s, 3 H) 2.83-2.96 (m, 1 H) 3.86 (s, 3 H) 4.08-4.17 (m , 1 H) 4.18-4.28 (m, 1 H) 4.78-4.89 (m, 1 H) 5.13-5.23 (m, 1 H) 5.27-5.35 (m, 2 H) 6.51-6.57 (m, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.12-7.20 (m, 1 H) 7.30 (s, 1 H).
Reference Example 4 Production of intermediate (1B-3)

Figure 2013224263
Figure 2013224263

工程１
中間体（１Ｂ−１）(１００ｇ,０．１４５ｍｏｌ)のトリエチルアミン−水−メタノール混合懸濁液（１：１：５,１．１２Ｌ）を室温で３日間撹拌した。反応液を濃縮後、２Ｍ塩酸に溶かして酸性とし、クロロホルムで２回抽出を行った。有機層を合わせて飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、淡褐色アモルファスとして中間体（１Ｂ−１ａ）(８０．４ｇ）を得た。 Process 1
A suspension of intermediate (1B-1) (100 g, 0.145 mol) in triethylamine-water-methanol (1: 1: 5, 1.12 L) was stirred at room temperature for 3 days. The reaction solution was concentrated, dissolved in 2M hydrochloric acid, acidified, and extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain an intermediate (1B-1a) (80.4 g) as a light brown amorphous.

工程２
中間体（１Ｂ−１ａ）（１．００ｇ,２．０８ｍｍｏｌ）と炭酸カリウム（８６２ｍｇ,６．２４ｍｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド（６．０ｍＬ）懸濁液にヨウ化エチル（５００μＬ,６．２４ｍｍｏｌ）を加え、５０℃で８時間撹拌した。反応溶液に水を加え、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、濾過、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール：クロロホルム＝０：１００→１０：９０）で精製し、無色液体として中間体（１Ｂ−３ａ）（９５０ｍｇ,９０％）を得た。 Process 2
To a suspension of intermediate (1B-1a) (1.00 g, 2.08 mmol) and potassium carbonate (862 mg, 6.24 mmol) in N, N-dimethylformamide (6.0 mL), ethyl iodide (500 μL, 6. 24 mmol) was added and the mixture was stirred at 50 ° C. for 8 hours. Water was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 0: 100 → 10: 90) to obtain intermediate (1B-3a) (950 mg, 90%) as a colorless liquid.

工程３
中間体（１Ｂ−３ａ）(８６７ｍｇ,１．７０ｍｍｏｌ)、無水酢酸（４．３ｍＬ）のピリジン（５．２ｍＬ）溶液を室温で３日間撹拌した。氷水へ反応液を加え、トルエン抽出した。有機層を２Ｍ塩酸、飽和食塩水で順次洗浄後、硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８５：１５→６５：３５）で精製し、無色アモルファスとして中間体（１Ｂ−３）（１．００ｇ,８７％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 - 1.15 (m, 6 H) 1.46 (t, J=6.9 Hz, 3 H) 1.75 (s, 3 H) 2.00 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.83 - 2.94 (m, 1 H) 3.72 - 3.90 (m, 3 H) 4.02 - 4.15 (m, 3 H) 4.19 - 4.28 (m, 1 H) 4.76 - 4.89 (m, 1 H) 5.15 - 5.22 (m, 1 H) 5.27 - 5.38 (m, 2 H) 6.54 (d, J=8.2 Hz, 1 H) 6.79 (s, 1 H) 6.94 (s, 1 H) 7.16 (dd, J=8.2, 1.7 Hz, 1 H) 7.31 (d, J=1.7 Hz, 1 H).
MS ESI/APCI Dual posi : 699[M+Na]+.
参考例５ 中間体（１Ｂ−４）の製造 Process 3
A solution of intermediate (1B-3a) (867 mg, 1.70 mmol) and acetic anhydride (4.3 mL) in pyridine (5.2 mL) was stirred at room temperature for 3 days. The reaction solution was added to ice water and extracted with toluene. The organic layer was washed successively with 2M hydrochloric acid and saturated brine, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15 → 65: 35) to give an intermediate (1B-3) as a colorless amorphous product (1.00 g, 87%) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.15 (m, 6 H) 1.46 (t, J = 6.9 Hz, 3 H) 1.75 (s, 3 H) 2.00 (s, 3 H) 2.04 ( s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.83-2.94 (m, 1 H) 3.72-3.90 (m, 3 H) 4.02-4.15 (m, 3 H) 4.19-4.28 ( m, 1 H) 4.76-4.89 (m, 1 H) 5.15-5.22 (m, 1 H) 5.27-5.38 (m, 2 H) 6.54 (d, J = 8.2 Hz, 1 H) 6.79 (s, 1 H ) 6.94 (s, 1 H) 7.16 (dd, J = 8.2, 1.7 Hz, 1 H) 7.31 (d, J = 1.7 Hz, 1 H).
MS ESI / APCI Dual posi: 699 [M + Na] + .
Reference Example 5 Production of intermediate (1B-4)

Figure 2013224263
中間体（１Ａ）(４００ｍｇ,０．６２ｍｍｏｌ)、炭酸セシウム（６０２ｍｇ,１．８５ｍｍｏｌ）の脱水Ｎ,Ｎ−ジメチルホルムアミド(４ｍＬ)懸濁液に、氷冷でブロモフルオロメタン（２００μＬ）を加え、マイクロウェーブ照射下１００℃で１０分間撹拌した。反応液に酢酸エチルを加え、水、飽和食塩水で順次洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して、残渣をＮＨ型シリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝８０：２０→６６：３４）で精製し、淡褐色アモルファスとして中間体（１Ｂ−４）（２００ｍｇ,４８％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.09 - 1.17 (m, 6 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.28 (s, 3 H) 2.86 - 2.98 (m, 1 H) 3.75 - 3.94 (m, 3 H) 4.06 - 4.15 (m, 1 H) 4.17 - 4.27 (m, 1 H) 4.73 - 4.84 (m, 1 H) 5.11 - 5.37 (m, 3 H) 5.61 - 5.66 (m, 1 H) 5.79 - 5.85 (m, 1 H) 6.55 (d, J=8.2 Hz, 1 H) 7.01 (s, 1 H) 7.05 (s, 1 H) 7.19 (dd, J=8.2, 2.0 Hz, 1 H) 7.33 (d, J=2.0 Hz, 1 H).
MS ESI/APCI Dual nega : 715[M+Cl]-.
参考例６ 中間体（１Ｂ−５）の製造
Figure 2013224263
 To a suspension of intermediate (1A) (400 mg, 0.62 mmol), cesium carbonate (602 mg, 1.85 mmol) in dehydrated N, N-dimethylformamide (4 mL) was added bromofluoromethane (200 μL) with ice cooling, The mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. Ethyl acetate was added to the reaction mixture, washed successively with water and saturated brine, and dried over sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by NH-type silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 66: 34) to give an intermediate (1B -4) (200 mg, 48%) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.09-1.17 (m, 6 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.28 (s, 3 H) 2.86-2.98 (m, 1 H) 3.75-3.94 (m, 3 H) 4.06-4.15 (m, 1 H) 4.17-4.27 (m, 1 H) 4.73-4.84 (m, 1 H) 5.11-5.37 (m, 3 H) 5.61-5.66 (m, 1 H) 5.79-5.85 (m, 1 H) 6.55 (d, J = 8.2 Hz, 1 H) 7.01 (s, 1 H) 7.05 ( s, 1 H) 7.19 (dd, J = 8.2, 2.0 Hz, 1 H) 7.33 (d, J = 2.0 Hz, 1 H).
MS ESI / APCI Dual nega: 715 [M + Cl] - .
Reference Example 6 Production of intermediate (1B-5)

Figure 2013224263
中間体（１Ａ）(１５．３ｇ,２３．５ｍｍｏｌ)のアセトニトリル−水混合溶液（１：１,２３５ｍＬ）に内温−８．９℃で水酸化カリウム（１９．８ｇ,３５．２ｍｍｏｌ）を少しずつ加え、７分間撹拌した。次いで、内温−１．３℃でジエチル（ブロモジフルオロメチル）ホスホネート（９．４０ｇ,３５．２ｍｍｏｌ）を滴下し、７分間撹拌した。内温０．４℃で酢酸を加えて酸性とし、トルエン(３００ｍＬ)を加えて２層を分離後、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧濃縮し、残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→２５：７５）で精製し、無色アモルファスとして中間体（１Ｂ−５）（１０．４ｇ,６３％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.5 Hz, 3 H) 1.14 (d, J=6.5 Hz, 3 H) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.95 (spt, J=6.5 Hz, 1 H) 3.75 - 3.94 (m, 3 H) 4.07 - 4.24 (m, 2 H) 4.64 - 4.74 (m, 1 H) 5.11 - 5.21 (m, 1 H) 5.26 - 5.37 (m, 2 H) 6.23 - 6.77 (m, 2 H) 6.99 (s, 1 H) 7.06 (s, 1 H) 7.16 - 7.23 (m, 1 H) 7.32 - 7.37 (m, 1 H).
MS ESI/APCI Dual posi : 721[M+Na]+.
MS ESI/APCI Dual nega : 733[M+Cl]-.
参考例７ 中間体（１Ｂ−６）の製造
Figure 2013224263
 Potassium hydroxide (19.8 g, 35.2 mmol) was slightly added to an acetonitrile-water mixed solution (1: 1, 235 mL) of intermediate (1A) (15.3 g, 23.5 mmol) at an internal temperature of -8.9 ° C. Added in portions and stirred for 7 minutes. Next, diethyl (bromodifluoromethyl) phosphonate (9.40 g, 35.2 mmol) was added dropwise at an internal temperature of −1.3 ° C., and the mixture was stirred for 7 minutes. Acetic acid was added to make it acidic at an internal temperature of 0.4 ° C., toluene (300 mL) was added to separate the two layers, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 95: 5 → 25: 75) to give intermediate (1B-5) (10.4 g, 63 as a colorless amorphous product). %).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.5 Hz, 3 H) 1.14 (d, J = 6.5 Hz, 3 H) 1.77 (s, 3 H) 2.00 (s, 3 H ) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.95 (spt, J = 6.5 Hz, 1 H) 3.75-3.94 (m, 3 H) 4.07-4.24 (m, 2 H) 4.64-4.74 (m, 1 H) 5.11-5.21 (m, 1 H) 5.26-5.37 (m, 2 H) 6.23-6.77 (m, 2 H) 6.99 (s, 1 H) 7.06 (s, 1 H) 7.16-7.23 (m, 1 H) 7.32-7.37 (m, 1 H).
MS ESI / APCI Dual posi: 721 [M + Na] + .
MS ESI / APCI Dual nega: 733 [M + Cl] - .
Reference Example 7 Production of intermediate (1B-6)

Figure 2013224263
Figure 2013224263

工程１
中間体（１Ｂ−１ａ）(１．００ｇ,２．０８ｍｍｏｌ)、炭酸カリウム（８６１ｍｇ,６．２３ｍｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド(５ｍＬ)懸濁液に、２−ヨードエタノール（４８５μＬ,６．２３ｍｍｏｌ）を加え、８０℃で２時間、１２０℃で３．５時間、さらに１５０℃で３時間撹拌した。反応液に水を加え、酢酸エチルで２回抽出を行った。有機層を合わせて、これを１０％食塩水、水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧濃縮し、残渣をシリカゲルクロマトグラフィー（酢酸エチルのみ→酢酸エチル：エタノール：水＝１５：２：１）で精製し、無色アモルファスとして中間体（１Ｂ−６ａ）（３７０ｍｇ,３４％）を得た。 Process 1
To a suspension of intermediate (1B-1a) (1.00 g, 2.08 mmol), potassium carbonate (861 mg, 6.23 mmol) in N, N-dimethylformamide (5 mL), 2-iodoethanol (485 μL, 6. 23 mmol), and the mixture was stirred at 80 ° C. for 2 hours, 120 ° C. for 3.5 hours, and further at 150 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with 10% brine and water, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate only → ethyl acetate: ethanol: water = 15: 2: 1) to give intermediate (1B-6a) (370 mg as a colorless amorphous). 34%).

工程２
中間体（１Ｂ−６ａ）(３６０ｍｇ,０．６８５ｍｍｏｌ)のピリジン（１．０８ｍＬ）溶液に無水酢酸（９００μＬ）を加え、室温で一晩撹拌した。反応液を氷冷後、水を加え、酢酸エチルで抽出を行った。有機層を２Ｍ塩酸で２回、飽和食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、無色アモルファスとして中間体（１Ｂ−６）（４８０ｍｇ,９５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 - 1.15 (m, 6 H) 1.74 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.17 (s, 3 H) 2.28 (s, 3 H) 2.88 - 2.94 (m, 1 H) 3.72 - 3.92 (m, 3 H) 4.04 - 4.33 (m, 4 H) 4.36 - 4.49 (m, 1 H) 4.52 - 4.64 (m, 1 H) 4.75 (br. s., 1 H) 5.19 (t, J=9.2 Hz, 1 H) 5.30 (t, J=9.2 Hz, 1 H) 5.41 (br. s., 1 H) 6.53 (d, J=8.2 Hz, 1 H) 6.79 (s, 1 H) 6.93 (s, 1 H) 7.18 (d, J=8.2 Hz, 1 H) 7.32 (s, 1 H).
MS ESI/APCI Dual posi : 757[M+Na]+.
MS ESI/APCI Dual nega : 769[M+Cl]-.
参考例８ 中間体（１Ｃ−１）の製造 Process 2
Acetic anhydride (900 μL) was added to a solution of intermediate (1B-6a) (360 mg, 0.685 mmol) in pyridine (1.08 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was ice-cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 2M hydrochloric acid twice and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain Intermediate (1B-6) (480 mg, 95%) as a colorless amorphous substance.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.15 (m, 6 H) 1.74 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.17 (s, 3 H) 2.28 (s, 3 H) 2.88-2.94 (m, 1 H) 3.72-3.92 (m, 3 H) 4.04-4.33 (m, 4 H) 4.36-4.49 (m, 1 H) 4.52-4.64 (m, 1 H) 4.75 (br. S., 1 H) 5.19 (t, J = 9.2 Hz, 1 H) 5.30 (t, J = 9.2 Hz, 1 H) 5.41 (br. S., 1 H) 6.53 (d, J = 8.2 Hz, 1 H) 6.79 (s, 1 H) 6.93 (s, 1 H) 7.18 (d, J = 8.2 Hz, 1 H) 7.32 (s, 1 H).
MS ESI / APCI Dual posi: 757 [M + Na] + .
MS ESI / APCI Dual nega: 769 [M + Cl] - .
Reference Example 8 Production of intermediate (1C-1)

Figure 2013224263
アルゴン雰囲気下、中間体（１Ｂ−１）（２１６ｇ,０．３１２ｍｏｌ）、２,２−ジメチル−３−ブテノイックアシッド（５３．４ｇ,０．４６７ｍｏｌ）、酢酸パラジウム（ＩＩ）（３．５０ｇ,１５．６ｍｍｏｌ）、トリ−ｏ−トリルホスフィン（９．４８ｇ,３１．２ｍｍｏｌ）、トリエチルアミン（８６．９ｍＬ,０．６２３ｍｏｌ）のアセトニトリル（６２３ｍＬ）懸濁液を、３時間加熱還流した。反応液を室温まで冷却した後にクロロホルム（３００ｍＬ）とメタノール（１００ｍＬ）を加えて希釈し、セライトろ過した。ろ液を減圧下濃縮し、得られた残渣を酢酸エチル（１．３２Ｌ）に溶解させた。１Ｍ塩酸（０．９６Ｌ）、１０％食塩水（１．２Ｌ）で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、ろ液にさらに酢酸エチル（１．２Ｌ）を追加して、イソプロピルアミン（２８．２ｍＬ,０．３２７ｍｏｌ）を加え、室温から０℃にかけて１時間撹拌した。析出した沈殿をろ過して中間体（１Ｃ−１）のイソプロピルアミン塩を得た。この塩を酢酸エチル（１．２Ｌ）、１Ｍ塩酸（５００ｍＬ）に溶解させて３０分間撹拌し、有機層を分離した。その有機層を１０％食塩水（５００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して無色アモルファスとして中間体（１Ｃ−１）（２０７ｇ,８８％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.43 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.37 (s, 3 H) 2.98 (spt, J=6.8 Hz, 1 H) 3.70 - 3.80 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J=12.4, 2.2 Hz, 1 H) 4.28 (dd, J=12.4, 4.4 Hz, 1 H) 4.43 - 4.50 (m, 1 H) 5.11 - 5.20 (m, 1 H) 5.22 - 5.33 (m, 2 H) 6.33 - 6.49 (m, 2 H) 6.68 (d, J=7.9 Hz, 1 H) 6.96 (s, 1 H) 6.99 (s, 1 H) 7.06 - 7.14 (m, 1 H) 7.23 (d, J=1.4 Hz, 1 H).
MS ESI/APCI Dual posi : 747[M+Na]+.
参考例９ 中間体（１Ｃ−２）の製造
Figure 2013224263
 Under an argon atmosphere, intermediate (1B-1) (216 g, 0.312 mol), 2,2-dimethyl-3-butenoic acid (53.4 g, 0.467 mol), palladium acetate (II) (3.50 g) , 15.6 mmol), a suspension of tri-o-tolylphosphine (9.48 g, 31.2 mmol), triethylamine (86.9 mL, 0.623 mol) in acetonitrile (623 mL) was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with chloroform (300 mL) and methanol (100 mL), and filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (1.32 L). It was washed with 1M hydrochloric acid (0.96 L), 10% brine (1.2 L), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, ethyl acetate (1.2 L) was further added to the filtrate, isopropylamine (28.2 mL, 0.327 mol) was added, and the mixture was stirred from room temperature to 0 ° C. for 1 hour. The deposited precipitate was filtered to obtain an isopropylamine salt of intermediate (1C-1). This salt was dissolved in ethyl acetate (1.2 L) and 1 M hydrochloric acid (500 mL) and stirred for 30 minutes, and the organic layer was separated. The organic layer was washed with 10% brine (500 mL) and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to obtain an intermediate (1C-1) (207 g, 88%) as a colorless amorphous substance.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.43 (s, 6 H) 1.76 (s, 3 H ) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.37 (s, 3 H) 2.98 (spt, J = 6.8 Hz, 1 H) 3.70- 3.80 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J = 12.4, 2.2 Hz, 1 H) 4.28 (dd, J = 12.4, 4.4 Hz, 1 H) 4.43-4.50 (m, 1 H ) 5.11-5.20 (m, 1 H) 5.22-5.33 (m, 2 H) 6.33-6.49 (m, 2 H) 6.68 (d, J = 7.9 Hz, 1 H) 6.96 (s, 1 H) 6.99 (s , 1 H) 7.06-7.14 (m, 1 H) 7.23 (d, J = 1.4 Hz, 1 H).
MS ESI / APCI Dual posi: 747 [M + Na] + .
Reference Example 9 Production of intermediate (1C-2)

Figure 2013224263
中間体（１Ｂ−１）（５０．０ｇ,７２．０ｍｍｏｌ）とビニル酢酸（１．６０ｇ,１７３ｍｍｏｌ）を出発原料として、参考例８に記載されている方法に準拠して、中間体（１Ｃ−２）（４４．０ｇ,８６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.73 - 1.78 (m, 3 H) 1.98 - 2.00 (m, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.91 - 3.04 (m, 1 H) 3.28 (d, J=7.1 Hz, 2 H) 3.71 - 3.80 (m, 1 H) 3.91 (s, 2 H) 4.01 - 4.09 (m, 1 H) 4.27 (dd, J=12.4, 4.5 Hz, 1 H) 4.46 (d, J=9.6 Hz, 1 H) 5.09 - 5.32 (m, 3 H) 6.17 - 6.32 (m, 1 H) 6.47 (d, J=16.2 Hz, 1 H) 6.68 (d, J=7.8 Hz, 1 H) 6.95 (s, 1 H) 6.99 (s, 1 H) 7.09 (dd, J=7.8, 1.8Hz, 1 H) 7.19 - 7.23 (m, 1 H).
参考例１０ 中間体（１Ｃ−３）の製造
Figure 2013224263
 In accordance with the method described in Reference Example 8, using intermediate (1B-1) (50.0 g, 72.0 mmol) and vinyl acetic acid (1.60 g, 173 mmol) as starting materials, intermediate (1C- 2) (44.0 g, 86%) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.73-1.78 (m, 3 H) 1.98-2.00 ( m, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.91-3.04 (m, 1 H) 3.28 (d, J = 7.1 Hz , 2 H) 3.71-3.80 (m, 1 H) 3.91 (s, 2 H) 4.01-4.09 (m, 1 H) 4.27 (dd, J = 12.4, 4.5 Hz, 1 H) 4.46 (d, J = 9.6 Hz, 1 H) 5.09-5.32 (m, 3 H) 6.17-6.32 (m, 1 H) 6.47 (d, J = 16.2 Hz, 1 H) 6.68 (d, J = 7.8 Hz, 1 H) 6.95 (s , 1 H) 6.99 (s, 1 H) 7.09 (dd, J = 7.8, 1.8Hz, 1 H) 7.19-7.23 (m, 1 H).
Reference Example 10 Production of intermediate (1C-3)

Figure 2013224263
中間体（１Ｂ−２）（１０．０ｇ,０．０１５１ｍｏｌ）を出発原料として、参考例８に記載されている方法に準拠して、中間体（１Ｃ−３）（１０．４ｇ,９９％）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J=6.9 Hz, 3 H) 1.13 (d, J=6.9 Hz, 3 H) 1.43 (s, 6 H) 1.75 (s, 3 H) 1.99 (s, 3 H) 2.01 - 2.06 (m, 6 H) 2.29 (s, 3 H) 2.90 - 2.98 (m, 1 H) 3.77 - 3.81 (m, 1 H) 3.81 - 3.91 (m, 5 H) 4.08 - 4.13 (m, 1 H) 4.21 (dd, J=12.2, 4.4 Hz, 1 H) 4.79 (br. d, J=8.3 Hz, 1 H) 5.17 (t, J=9.6 Hz, 1 H) 5.27 - 5.36 (m, 2 H) 6.35 (d, J=16.0 Hz, 1 H) 6.43 (d, J=16.0 Hz, 1 H) 6.64 (d, J=8.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.06 (d, J=8.3 Hz, 1 H) 7.21 (s, 1 H).
MS ESI/APCI Dual posi : 719[M+Na]+.
参考例１１ 中間体（１Ｃ−４）の製造
Figure 2013224263
 Intermediate (1C-3) (10.4 g, 99%) according to the method described in Reference Example 8 using Intermediate (1B-2) (10.0 g, 0.0151 mol) as a starting material Got.
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 6.9 Hz, 3 H) 1.13 (d, J = 6.9 Hz, 3 H) 1.43 (s, 6 H) 1.75 (s, 3 H ) 1.99 (s, 3 H) 2.01-2.06 (m, 6 H) 2.29 (s, 3 H) 2.90-2.98 (m, 1 H) 3.77-3.81 (m, 1 H) 3.81-3.91 (m, 5 H ) 4.08-4.13 (m, 1 H) 4.21 (dd, J = 12.2, 4.4 Hz, 1 H) 4.79 (br.d, J = 8.3 Hz, 1 H) 5.17 (t, J = 9.6 Hz, 1 H) 5.27-5.36 (m, 2 H) 6.35 (d, J = 16.0 Hz, 1 H) 6.43 (d, J = 16.0 Hz, 1 H) 6.64 (d, J = 8.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.06 (d, J = 8.3 Hz, 1 H) 7.21 (s, 1 H).
MS ESI / APCI Dual posi: 719 [M + Na] + .
Reference Example 11 Production of intermediate (1C-4)

Figure 2013224263
中間体（１Ｂ−２）（６．００ｇ,９．０４ｍｍｏｌ）とビニル酢酸（２．３０ｍＬ,２７．１ｍｍｏｌ）を出発原料として、参考例８に記載されている方法に準拠して、中間体（１Ｃ−４）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 - 1.16 (m, 6 H) 1.75 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.28 (s, 3 H) 2.85 - 3.00 (m, 1 H) 3.15 - 3.21 (m, 2 H) 3.76 - 3.87 (m, 1 H) 3.86 (s, 3 H) 4.06 - 4.15 (m, 1 H) 4.18 - 4.28 (m, 1 H) 4.71 - 4.82 (m, 1 H) 5.12 - 5.43 (m, 3 H) 6.35 - 6.42 (m, 1 H) 6.58 (d, J=8.1 Hz, 1 H) 6.79 - 6.96 (m, 3 H) 7.05 (dd, J=8.1, 1.7 Hz, 1 H) 7.18 - 7.23 (m, 1 H).
MS ESI/APCI Dual posi : 691[M+Na]+.
参考例１２ 中間体（１Ｅ−１）の製造
Figure 2013224263
 Intermediate (1B-2) (6.00 g, 9.04 mmol) and vinyl acetic acid (2.30 mL, 27.1 mmol) were used as starting materials according to the method described in Reference Example 8, and the intermediate ( 1C-4) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.16 (m, 6 H) 1.75 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.28 (s, 3 H) 2.85-3.00 (m, 1 H) 3.15-3.21 (m, 2 H) 3.76-3.87 (m, 1 H) 3.86 (s, 3 H) 4.06-4.15 (m, 1 H) 4.18-4.28 (m, 1 H) 4.71-4.82 (m, 1 H) 5.12-5.43 (m, 3 H) 6.35-6.42 (m, 1 H) 6.58 (d, J = 8.1 Hz, 1 H) 6.79- 6.96 (m, 3 H) 7.05 (dd, J = 8.1, 1.7 Hz, 1 H) 7.18-7.23 (m, 1 H).
MS ESI / APCI Dual posi: 691 [M + Na] + .
Reference Example 12 Production of intermediate (1E-1)

Figure 2013224263
Figure 2013224263

工程１
中間体（１Ｃ−１）（１．００ｇ,１．３８ｍｍｏｌ）、２−アミノ−２−メチルプロパン−１−オール（１８４ｍｇ,２．０７ｍｍｏｌ）、ＥＤＣ−ＨＣｌ（３４２ｍｇ,１．７９ｍｍｏｌ）、ＨＯＢｔ・Ｈ2Ｏ（２４２ｍｇ,１．７９ｍｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド溶液（３０ｍＬ）を室温で一晩撹拌した。減圧下溶媒を留去した後、水を加え、酢酸エチルで抽出後、有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、粗精製の中間体（１Ｄ−１）（１．０２ｇ）を得た。 Process 1
Intermediate (1C-1) (1.00 g, 1.38 mmol), 2-amino-2-methylpropan-1-ol (184 mg, 2.07 mmol), EDC-HCl (342 mg, 1.79 mmol), HOBt. A solution of H 2 O (242 mg, 1.79 mmol) in N, N-dimethylformamide (30 mL) was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain crude intermediate (1D-1) (1.02 g).

工程２
中間体（１Ｄ−１）（６６０ｍｇ,０．８３０ｍｍｏｌ）、Ｄｅｓｓ−Ｍａｒｔｉｎ ｐｅｒｉｏｄｉｎａｎｅ（４２２ｍｇ,１．２５ｍｍｏｌ）のクロロホルム懸濁液（２０ｍＬ）を室温で３時間撹拌した。溶媒を減圧下留去した後、残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝４：１→１：４）で精製し、黄色アモルファスとして中間体（１Ｅ−１）（６０２ｍｇ,２工程８５％）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.09 - 1.18 (m, 6 H) 1.33 (s, 6 H) 1.39 (s, 6 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.98 (spt, J=6.9 Hz, 1 H) 3.73 - 3.80 (m, 1 H) 3.89 - 3.98 (m, 2 H) 4.06 (dd, J=12.4, 2.3 Hz, 1 H) 4.26 (dd, J=12.4, 4.6 Hz, 1 H) 4.46 - 4.53 (m, 1 H) 5.11 - 5.18 (m, 1 H) 5.23 - 5.30 (m, 2 H) 6.13 (br. s, 1 H) 6.33 (d, J=16.5 Hz, 1 H) 6.53 (d, J=16.5 Hz, 1 H) 6.71 (d, J=7.8 Hz, 1 H) 6.99 - 7.01 (m, 2 H) 7.13 (d, J=7.8 Hz, 1 H) 7.26 (s, 1 H) 9.34 (s, 1 H)．
参考例１３ 中間体（１Ｅ−２）の製造 Process 2
A chloroform suspension (20 mL) of intermediate (1D-1) (660 mg, 0.830 mmol) and Dess-Martin periodinane (422 mg, 1.25 mmol) was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 4) to give intermediate (1E-1) (602 mg, 85% over 2 steps) as a yellow amorphous. )
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.09-1.18 (m, 6 H) 1.33 (s, 6 H) 1.39 (s, 6 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.98 (spt, J = 6.9 Hz, 1 H) 3.73-3.80 (m, 1 H) 3.89 -3.98 (m, 2 H) 4.06 (dd, J = 12.4, 2.3 Hz, 1 H) 4.26 (dd, J = 12.4, 4.6 Hz, 1 H) 4.46-4.53 (m, 1 H) 5.11-5.18 (m , 1 H) 5.23-5.30 (m, 2 H) 6.13 (br.s, 1 H) 6.33 (d, J = 16.5 Hz, 1 H) 6.53 (d, J = 16.5 Hz, 1 H) 6.71 (d, J = 7.8 Hz, 1 H) 6.99-7.01 (m, 2 H) 7.13 (d, J = 7.8 Hz, 1 H) 7.26 (s, 1 H) 9.34 (s, 1 H).
Reference Example 13 Production of intermediate (1E-2)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−１）（１．０ｇ,１．４ｍｍｏｌ）と３−アミノプロパノール（０．１４ｍＬ,１．８ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、中間体（１Ｅ−２）（０．７７ｇ,２工程７２％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.36 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.70 (t, J=6.1 Hz, 2 H) 2.92 - 3.04 (m, 1 H) 3.42 - 3.57 (m, 2 H) 3.71 - 3.80 (m, 1 H) 3.93 (s, 2 H) 4.05 (dd, J=12.5, 2.0 Hz, 1 H) 4.26 (dd, J=12.5, 4.6 Hz, 1 H) 4.45 - 4.51 (m, 1 H) 5.10 - 5.30 (m, 3 H) 6.27 (d, J=16.0 Hz, 1 H) 6.47 (d, J=16.0 Hz, 1 H) 6.70 (d, J=7.9 Hz, 1 H) 6.98 (s, 1 H) 7.00 (s, 1 H) 7.08 - 7.14 (m, 1 H) 7.24 (s, 1 H) 9.77 (s, 1 H).
参考例１４ 中間体（１Ｅ−３）の製造 Step 1 and Step 2
The method described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-1) (1.0 g, 1.4 mmol) and 3-aminopropanol (0.14 mL, 1.8 mmol) as starting materials. In this way, intermediate (1E-2) (0.77 g, 72% for 2 steps) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.36 (s, 6 H) 1.77 (s, 3 H ) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.70 (t, J = 6.1 Hz, 2 H) 2.92- 3.04 (m, 1 H) 3.42-3.57 (m, 2 H) 3.71-3.80 (m, 1 H) 3.93 (s, 2 H) 4.05 (dd, J = 12.5, 2.0 Hz, 1 H) 4.26 (dd, J = 12.5, 4.6 Hz, 1 H) 4.45-4.51 (m, 1 H) 5.10-5.30 (m, 3 H) 6.27 (d, J = 16.0 Hz, 1 H) 6.47 (d, J = 16.0 Hz, 1 H) 6.70 (d, J = 7.9 Hz, 1 H) 6.98 (s, 1 H) 7.00 (s, 1 H) 7.08-7.14 (m, 1 H) 7.24 (s, 1 H) 9.77 (s, 1 H ).
Reference Example 14 Production of intermediate (1E-3)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−１）（１．０ｇ,１．４ｍｍｏｌ）と３−アミノ−３−メチルブタノール（０．１９ｇ,１．８ｍｍｏｌ,Ｊｏｕｒｎａｌ ｏｆ Ｌａｂｅｌｌｅｄ Ｃｏｍｐｏｕｎｄｓ ＆ Ｒａｄｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ (２００１), ４４(４), ２６５-２７５．）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、中間体（１Ｅ−３）（０．７７ｇ,２工程５５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.34 (s, 6 H) 1.36 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.90 - 3.04 (m, 1 H) 2.93 (d, J=2.2 Hz, 2 H) 3.71 - 3.80 (m, 1 H) 3.93 (s, 2 H) 4.05 (dd, J=12.4, 1.9 Hz, 1 H) 4.27 (dd, J=12.4, 4.5 Hz, 1 H) 4.45 - 4.53 (m, 1 H) 5.11 - 5.32 (m, 3 H) 5.74 (br. s, 1 H) 6.28 (d, J=15.9 Hz, 1 H) 6.49 (d, J=15.9 Hz, 1 H) 6.69 (d, J=8.1 Hz, 1 H) 6.98 - 7.03 (m, 2 H) 7.09 - 7.15 (m, 1 H) 7.24 - 7.27 (m, 1 H) 9.73 (t, J=2.2 Hz, 1 H).
MS ESI/APCI Dual posi : 808[M+H]+.
参考例１５ 中間体（１Ｅ−４）の製造 Step 1 and Step 2
Intermediate (1C-1) (1.0 g, 1.4 mmol) and 3-amino-3-methylbutanol (0.19 g, 1.8 mmol, Journal of Labeled Compounds & Radiopharmaceuticals (2001), 44 (4), 265 -275.) As a starting material, intermediate (1E-3) (0.77 g, 2 steps 55%) was obtained according to the method described in steps 1 and 2 of Reference Example 12.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.34 (s, 6 H) 1.36 (s, 6 H ) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.90-3.04 (m, 1 H) 2.93 (d, J = 2.2 Hz, 2 H) 3.71-3.80 (m, 1 H) 3.93 (s, 2 H) 4.05 (dd, J = 12.4, 1.9 Hz, 1 H) 4.27 (dd, J = 12.4, 4.5 Hz, 1 H) 4.45-4.53 (m, 1 H) 5.11-5.32 (m, 3 H) 5.74 (br.s, 1 H) 6.28 (d, J = 15.9 Hz, 1 H) 6.49 (d , J = 15.9 Hz, 1 H) 6.69 (d, J = 8.1 Hz, 1 H) 6.98-7.03 (m, 2 H) 7.09-7.15 (m, 1 H) 7.24-7.27 (m, 1 H) 9.73 ( t, J = 2.2 Hz, 1 H).
MS ESI / APCI Dual posi: 808 [M + H] + .
Reference Example 15 Production of intermediate (1E-4)

Figure 2013224263
Figure 2013224263

工程１
４−アミノ−４−メチル−１−ペンタノール（１．０６ｇ,９．０５ｍｍｏｌ）のクロロホルム溶液（１８ｍＬ）にトリエチルアミン（５．００ｍＬ,３６．２ｍｍｏｌ）およびｔｅｒｔ−ブチルジメチルシリルクロリド（１．３７ｇ,９．０５ｍｍｏｌ）を加え、室温で３．５時間撹拌した。反応液を水および飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、残渣をＮＨシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９：１→２：８）で精製し、茶色油状物として中間体（４Ｂ−４ａ）（５９９ｍｇ,２９％）を得た。 Process 1
To a chloroform solution (18 mL) of 4-amino-4-methyl-1-pentanol (1.06 g, 9.05 mmol) was added triethylamine (5.00 mL, 36.2 mmol) and tert-butyldimethylsilyl chloride (1.37 g, (9.05 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (chloroform: methanol = 9: 1 → 2: 8) to obtain an intermediate (4B-4a) as a brown oil (599 mg, 29%) was obtained.

工程２
中間体（１Ｃ−１）（７００ｍｇ,０．９６６ｍｍｏｌ）と中間体（４Ｂ−４ａ）（２９１ｍｇ,１．２６ｍｍｏｌ）を出発原料として、参考例１２の工程１に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｄ−４ａ）（３２５ｍｇ,３６％）を得た。 Process 2
In accordance with the method described in Step 1 of Reference Example 12, using Intermediate (1C-1) (700 mg, 0.966 mmol) and Intermediate (4B-4a) (291 mg, 1.26 mmol) as starting materials Intermediate (1D-4a) (325 mg, 36%) was obtained as a colorless amorphous product.

工程３
中間体（１Ｄ−４ａ）（３１７ｍｇ,０．３３８ｍｍｏｌ）を酢酸：テトラヒドロフラン：水＝３：１：１の混合液（１ｍＬ）に溶解し、室温で２．５時間撹拌した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→１：９）で精製し、無色アモルファスとして中間体（１Ｄ−４）（２４４ｍｇ,８８％）を得た。 Process 3
Intermediate (1D-4a) (317 mg, 0.338 mmol) was dissolved in a mixture (1 mL) of acetic acid: tetrahydrofuran: water = 3: 1: 1 and stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 9) to obtain intermediate (1D-4) (244 mg, 88%) as a colorless amorphous substance. It was.

工程４
中間体（１Ｄ−４）（２４０ｍｇ,０．２９１ｍｍｏｌ）を出発原料として、参考例１２の工程２に記載されている方法に準拠して、黄色アモルファスとして中間体（１Ｅ−４）（１９５ｍｇ,８２％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 - 1.17 (m, 6 H) 1.27 (s, 6 H) 1.35 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.02 (s, 3 H) 2.05 (s, 3 H) 2.10 (m, 2 H) 2.31 (s, 3 H) 2.33 - 2.41 (m, 5 H) 2.91 - 3.03 (m, 1 H) 3.72 - 3.80 (m, 1 H) 3.93 (s, 2 H) 4.05 (dd, J=12.4, 2.3 Hz, 1 H) 4.27 (dd, J=12.9, 4.4 Hz, 1 H) 4.46 - 4.52 (m, 1 H) 5.10 - 5.19 (m, 1 H) 5.24 - 5.30 (m, 2 H) 5.48 (br. s, 1 H) 6.28 (d, J=14.9 Hz, 1 H) 6.48 (d, J=14.9 Hz, 1 H) 6.69 (d, J=7.8 Hz, 1 H) 6.99 - 7.02 (m, 2 H) 7.11 (d, J=7.8 Hz, 1 H) 7.24 (s, 1 H) 9.72 (t, J=1.8 Hz, 1 H).
MS ESI/APCI Dual posi : 822[M+H]+.
参考例１６ 中間体（１Ｅ−５）の製造
Process 4
Intermediate (1D-4) (240 mg, 0.291 mmol) as a starting material, Intermediate (1E-4) (195 mg, 82) as a yellow amorphous substance according to the method described in Step 2 of Reference Example 12 %).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.17 (m, 6 H) 1.27 (s, 6 H) 1.35 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.02 (s, 3 H) 2.05 (s, 3 H) 2.10 (m, 2 H) 2.31 (s, 3 H) 2.33-2.41 (m, 5 H) 2.91-3.03 (m, 1 H) 3.72-3.80 ( m, 1 H) 3.93 (s, 2 H) 4.05 (dd, J = 12.4, 2.3 Hz, 1 H) 4.27 (dd, J = 12.9, 4.4 Hz, 1 H) 4.46-4.52 (m, 1 H) 5.10 -5.19 (m, 1 H) 5.24-5.30 (m, 2 H) 5.48 (br.s, 1 H) 6.28 (d, J = 14.9 Hz, 1 H) 6.48 (d, J = 14.9 Hz, 1 H) 6.69 (d, J = 7.8 Hz, 1 H) 6.99-7.02 (m, 2 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.24 (s, 1 H) 9.72 (t, J = 1.8 Hz, 1 H).
MS ESI / APCI Dual posi: 822 [M + H] + .
Reference Example 16 Production of intermediate (1E-5)

Figure 2013224263
Figure 2013224263

工程１
１−アミノシクロプロパンカルボン酸エチルエステル（５００ｍｇ,３．８７ｍｍｏｌ）の酢酸エチル（３１ｍＬ）溶液に炭酸水素カリウム（１．５５ｇ,１５．５ｍｍｏｌ）の水溶液（２０ｍＬ）を氷温下、滴下した。次いでクロロギ酸ベンジル（０．８２９ｍｌ,５．８０ｍｍｏｌ）を氷冷下滴下した。反応溶液を室温で一晩撹拌し、１Ｍ塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、濾過した後、減圧下濃縮した。残渣をシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝０：１００→３０：７０）にて精製し、中間体（４Ｂ−５ａ）（７００ｍｇ,６９％）を得た。 Process 1
An aqueous solution (20 mL) of potassium hydrogen carbonate (1.55 g, 15.5 mmol) was added dropwise to an ethyl acetate (31 mL) solution of 1-aminocyclopropanecarboxylic acid ethyl ester (500 mg, 3.87 mmol) at ice temperature. Subsequently, benzyl chloroformate (0.829 ml, 5.80 mmol) was added dropwise under ice cooling. The reaction solution was stirred at room temperature overnight, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 0: 100 → 30: 70) to obtain intermediate (4B-5a) (700 mg, 69%).

工程２
中間体（４Ｂ−５ａ）（７００ｍｇ,２．６７ｍｍｏｌ）のジエチルエーテル（１５ｍＬ）溶液に水素化ホウ素リチウム（１２６ｍｇ,５,７９ｍｍｏｌ）のジエチルエーテル（１０ｍＬ）懸濁液を加え、室温で一晩撹拌した。メタノール、１Ｍ塩酸を加え室温で１時間撹拌し、水層を酢酸で抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、濾過、減圧下濃縮した。残渣をシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝０：１００→５０：５０）にて精製し、中間体（４Ｂ−５ｂ）（４６５ｍｇ,７９％）を得た。 Process 2
To a solution of intermediate (4B-5a) (700 mg, 2.67 mmol) in diethyl ether (15 mL) was added a suspension of lithium borohydride (126 mg, 5,79 mmol) in diethyl ether (10 mL) and stirred at room temperature overnight. did. Methanol and 1M hydrochloric acid were added and stirred at room temperature for 1 hour, and the aqueous layer was extracted with acetic acid. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 0: 100 → 50: 50) to obtain intermediate (4B-5b) (465 mg, 79%).

工程３
中間体（４Ｂ−５ｂ）（４６５ｍｇ,２．２０ｍｍｏｌ）と５％パラジウムカーボン（２５ｍｇ）のメタノール（５．０ｍＬ）懸濁液を水素雰囲気下、室温で３時間撹拌した。反応液をセライト濾過し、濾液を減圧下濃縮して中間体（４Ｂ−５ｃ）（１７１ｍｇ,８９％）を得た。 Process 3
A suspension of intermediate (4B-5b) (465 mg, 2.20 mmol) and 5% palladium carbon (25 mg) in methanol (5.0 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain Intermediate (4B-5c) (171 mg, 89%).

工程４、工程５
中間体（１Ｃ−１）（５００ｍｇ,０．６９ｍｍｏｌ）と中間体（４Ｂ−５ｃ）（７２ｍｇ,０．８３ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、中間体（１Ｅ−５）（３０５ｍｇ,２工程９８％）を無色アモルファスとして得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 - 1.16 (m, 6 H) 1.42 (s, 6 H) 1.46 - 1.55 (m, 4 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.91 - 3.06 (m, 1 H) 3.72 - 3.80 (m, 1 H) 3.91 - 3.95 (m, 2 H) 4.01 - 4.08 (m, 1 H) 4.20 - 4.28 (m, 1 H) 4.46 - 4.52 (m, 1 H) 5.09 - 5.18 (m, 1 H) 5.22 - 5.29 (m, 2 H) 6.26 - 6.30 (m, 1 H) 6.35 (d, J=16.2 Hz, 1 H) 6.55 (d, J=16.2 Hz, 1 H) 6.68 - 6.74 (m, 1 H) 7.00 (s, 2 H) 7.10 - 7.16 (m, 1 H) 7.26(s, 1H) 9.06 (s, 1 H).
MS ESI/APCI Dual posi : 792[M+H]+, 814[M+Na]+.
MS ESI/APCI Dual nega : 826[M+Cl]-.
参考例１７ 中間体（１Ｅ−６）の製造 Step 4 and Step 5
Using the intermediate (1C-1) (500 mg, 0.69 mmol) and the intermediate (4B-5c) (72 mg, 0.83 mmol) as starting materials, the methods described in steps 1 and 2 of Reference Example 12 were used. Based on the above, Intermediate (1E-5) (305 mg, 98% for 2 steps) was obtained as colorless amorphous.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10-1.16 (m, 6 H) 1.42 (s, 6 H) 1.46-1.55 (m, 4 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.91-3.06 (m, 1 H) 3.72-3.80 (m, 1 H) 3.91- 3.95 (m, 2 H) 4.01-4.08 (m, 1 H) 4.20-4.28 (m, 1 H) 4.46-4.52 (m, 1 H) 5.09-5.18 (m, 1 H) 5.22-5.29 (m, 2 H) 6.26-6.30 (m, 1 H) 6.35 (d, J = 16.2 Hz, 1 H) 6.55 (d, J = 16.2 Hz, 1 H) 6.68-6.74 (m, 1 H) 7.00 (s, 2 H ) 7.10-7.16 (m, 1 H) 7.26 (s, 1H) 9.06 (s, 1 H).
MS ESI / APCI Dual posi: 792 [M + H] + , 814 [M + Na] + .
MS ESI / APCI Dual nega: 826 [M + Cl] - .
Reference Example 17 Production of intermediate (1E-6)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−１）（１．００ｇ,１．３８ｍｍｏｌ）と（１−アミノシクロブチル）メタノール（２１０ｍｇ,２．０７ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、淡黄色アモルファスとして中間体（１Ｅ−６）（３５５ｍｇ,２工程３２％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 - 1.19 (m, 6 H) 1.40 (s, 6 H) 1.78 (s, 3 H) 1.91 - 2.08 (m, 11 H) 2.22 - 2.40 (m, 8 H) 2.42 - 2.56 (m, 2 H) 2.91 - 3.05 (m, 1 H) 3.70 - 3.81 (m, 1 H) 3.94 (s, 2 H) 4.05 (dd, J=12.4, 1.9 Hz, 1 H) 4.26 (dd, J=12.4, 4.5 Hz, 1 H) 4.44 - 4.55 (m, 1 H) 5.10 - 5.20 (m, 1 H) 5.21 - 5.33 (m, 2 H) 6.28 - 6.41 (m, 2 H) 6.49 - 6.61 (m, 1 H) 6.71 (d, J=7.9 Hz, 1 H) 7.00 (s, 2 H) 7.14 (d, J=7.9 Hz, 1 H) 7.27 (s, 1 H) 9.55 (s, 1 H).
MS ESI/APCI Dual posi : 806[M+H]+, 828[M+Na]+.
MS ESI/APCI Dual nega : 840[M+Cl]-.
参考例１８ 中間体（１Ｅ−７）の製造 Step 1 and Step 2
Described in Step 1 and Step 2 of Reference Example 12 using intermediate (1C-1) (1.00 g, 1.38 mmol) and (1-aminocyclobutyl) methanol (210 mg, 2.07 mmol) as starting materials The intermediate (1E-6) (355 mg, 2 steps 32%) was obtained as a pale yellow amorphous based on the above method.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10-1.19 (m, 6 H) 1.40 (s, 6 H) 1.78 (s, 3 H) 1.91-2.08 (m, 11 H) 2.22-2.40 (m , 8 H) 2.42-2.56 (m, 2 H) 2.91-3.05 (m, 1 H) 3.70-3.81 (m, 1 H) 3.94 (s, 2 H) 4.05 (dd, J = 12.4, 1.9 Hz, 1 H) 4.26 (dd, J = 12.4, 4.5 Hz, 1 H) 4.44-4.55 (m, 1 H) 5.10-5.20 (m, 1 H) 5.21-5.33 (m, 2 H) 6.28-6.41 (m, 2 H) 6.49-6.61 (m, 1 H) 6.71 (d, J = 7.9 Hz, 1 H) 7.00 (s, 2 H) 7.14 (d, J = 7.9 Hz, 1 H) 7.27 (s, 1 H) 9.55 (s, 1 H).
MS ESI / APCI Dual posi: 806 [M + H] + , 828 [M + Na] + .
MS ESI / APCI Dual nega: 840 [M + Cl] - .
Reference Example 18 Production of intermediate (1E-7)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−１）（１．００ｇ,１．３８ｍｍｏｌ）と１−アミノ−１−シクロペンタンメタノール（２０７ｍｇ,１．７９ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−７）（８５０ｍｇ,２工程７１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 - 1.18 (m, 6 H) 1.39 (s, 6 H) 1.64 - 2.18 (m, 8 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.32 (s, 3 H) 2.37 (s, 3 H) 2.89 - 3.04 (m, 1 H) 3.71 - 3.81 (m, 1 H) 3.93 (s, 2 H) 4.01 - 4.10 (m, 1 H) 4.25 - 4.30 (m, 1 H) 4.45 - 4.53 (m, 1 H) 5.10 - 5.20 (m, 1 H) 5.23 - 5.30 (m, 2 H) 6.18 (s, 1 H) 6.26 - 6.39 (m, 1 H) 6.47 - 6.60 (m, 1 H) 6.70 (d, J=7.6 Hz, 1 H) 6.96 - 7.05 (m, 2 H) 7.10 - 7.16 (m, 1 H) 7.23 - 7.26 (m, 1 H) 9.43 (s, 1 H).
MS ESI/APCI Dual posi : 820[M+H]+, 842[M+Na]+.
MS ESI/APCI Dual nega : 854[M+Cl]-.
参考例１９ 中間体（１Ｅ−８）の製造 Step 1 and Step 2
It is described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-1) (1.00 g, 1.38 mmol) and 1-amino-1-cyclopentanemethanol (207 mg, 1.79 mmol) as starting materials. The intermediate (1E-7) (850 mg, 2 steps 71%) was obtained as a colorless amorphous product.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10-1.18 (m, 6 H) 1.39 (s, 6 H) 1.64-2.18 (m, 8 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.32 (s, 3 H) 2.37 (s, 3 H) 2.89-3.04 (m, 1 H) 3.71-3.81 (m, 1 H) 3.93 ( s, 2 H) 4.01-4.10 (m, 1 H) 4.25-4.30 (m, 1 H) 4.45-4.53 (m, 1 H) 5.10-5.20 (m, 1 H) 5.23-5.30 (m, 2 H) 6.18 (s, 1 H) 6.26-6.39 (m, 1 H) 6.47-6.60 (m, 1 H) 6.70 (d, J = 7.6 Hz, 1 H) 6.96-7.05 (m, 2 H) 7.10-7.16 ( m, 1 H) 7.23-7.26 (m, 1 H) 9.43 (s, 1 H).
MS ESI / APCI Dual posi: 820 [M + H] + , 842 [M + Na] + .
MS ESI / APCI Dual nega: 854 [M + Cl] - .
Reference Example 19 Production of intermediate (1E-8)

Figure 2013224263
Figure 2013224263

工程１
メチレンシクロペンタン（１．００ｇ,１２．２ｍｍｏｌ）のジエチルエーテル（１２ｍＬ）溶液にクロロスルホニルイソシアネート（１．７３ｇ,１２．２ｍｍｏｌ）を氷冷下加えた。反応溶液を室温で３０分間撹拌し、チオ硫酸ナトリウム水溶液、１０％水酸化カリウム水溶液をｐＨが１０になるように氷冷下加え、同温で２時間撹拌し、水層をジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、濾過、減圧下濃縮して無色アモルファスとして中間体（４Ｂ−８ａ）（６８４ｍｇ,４５％）を得た。 Process 1
Chlorosulfonyl isocyanate (1.73 g, 12.2 mmol) was added to a solution of methylenecyclopentane (1.00 g, 12.2 mmol) in diethyl ether (12 mL) under ice cooling. The reaction solution was stirred at room temperature for 30 minutes, an aqueous sodium thiosulfate solution and a 10% aqueous potassium hydroxide solution were added under ice-cooling so that the pH was 10, and stirred at the same temperature for 2 hours. . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate (4B-8a) (684 mg, 45%) as a colorless amorphous substance.

工程２
中間体（４Ｂ−８ａ）（６８０ｍｇ,５．４３ｍｍｏｌ）と濃硫酸（０．５ｍＬ）のメタノール（１５ｍＬ）溶液を７５℃で４０分、室温で一晩撹拌した。反応溶液を減圧下濃縮し、残渣を酢酸エチルで希釈した。この溶液を１Ｍ塩酸で抽出し、炭酸カリウムで中和した。この水溶液を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、濾過、減圧下濃縮し、無色液体として中間体（４Ｂ−８ｂ）（５８６ｍｇ,６９%）を得た。 Process 2
A solution of intermediate (4B-8a) (680 mg, 5.43 mmol) and concentrated sulfuric acid (0.5 mL) in methanol (15 mL) was stirred at 75 ° C. for 40 minutes and at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. This solution was extracted with 1M hydrochloric acid and neutralized with potassium carbonate. This aqueous solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain Intermediate (4B-8b) (586 mg, 69%) as a colorless liquid. .

工程３
中間体（４Ｂ−８ｂ）（５８０ｍｇ,３．６９ｍｍｏｌ）と炭酸ナトリウム（５８０ｍｇ,５．４７ｍｍｏｌ）の水（１２ｍＬ）溶液にクロロギ酸ベンジル（０．５８ｍＬ,４．０６ｍｍｏｌ）の１,４−ジオキサン（３．０ｍＬ）溶液を氷冷下加えた。反応溶液を室温で２時間撹拌した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウムで乾燥、濾過、減圧下濃縮して、無色液体として中間体（４Ｂ−８ｃ）（１．０ｇ,９３％）を得た。 Process 3
A solution of intermediate (4B-8b) (580 mg, 3.69 mmol) and sodium carbonate (580 mg, 5.47 mmol) in water (12 mL) in 1,4-dioxane (0.58 mL, 4.06 mmol) of benzyl chloroformate (0.58 mL, 4.06 mmol) 3.0 mL) solution was added under ice cooling. The reaction solution was stirred at room temperature for 2 hours and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain Intermediate (4B-8c) (1.0 g, 93%) as a colorless liquid.

工程４
中間体（４Ｂ−８ｃ）（１．０ｇ,３．４３ｍｍｏｌ）を出発原料として、参考例１６の工程２に記載されている方法に準拠して、中間体（４Ｂ−８ｄ）（４４０ｍｇ,４９％）を得た。 Process 4
Intermediate (4B-8c) (1.0 g, 3.43 mmol) as a starting material, intermediate (4B-8d) (440 mg, 49%) according to the method described in Step 2 of Reference Example 16 )

工程５
中間体（４Ｂ−８ｄ）（４４０ｍｇ,１．６７ｍｍｏｌ）を出発原料として、参考例１６の工程３に記載されている方法に準拠して、中間体（４Ｂ−８ｅ）（２１０ｍｇ,９７％）を得た。 Process 5
According to the method described in Step 3 of Reference Example 16, using Intermediate (4B-8d) (440 mg, 1.67 mmol) as a starting material, Intermediate (4B-8e) (210 mg, 97%) Obtained.

工程６,工程７
中間体（１Ｃ−１）（５００ｍｇ,０．６９０ｍｍｏｌ）と中間体（４Ｂ−８ｅ）（１０７ｍｇ,０．８３０ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−８）（８９ｍｇ,２工程１６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8, Hz, 3 H) 1.33 (s, 6 H) 1.60 - 1.75 (m, 6 H) 1.77 (s, 3 H) 1.97 - 2.05 (m, 11 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.91 - 3.05 (m, 3 H) 3.72 - 3.81 (m, 1 H) 3.93 (s, 2 H) 4.01 - 4.08 (m, 1 H) 4.20 - 4.26 (m, 1 H) 4.44 - 4.53 (m, 1 H) 5.16 - 5.20 (m, 1 H) 5.23 - 5.32 (m, 2 H) 5.76 (s, 1 H) 6.26 (d, J=16.2 Hz, 1 H) 6.48 (d, J=16.2 Hz, 1 H) 6.69 (d, J=7.9 Hz, 1 H) 6.92 - 7.04 (m, 2 H) 7.08 - 7.15 (m, 1 H) 7.24 (s, 1 H) 9.70 - 9.76 (m, 1 H).
MS ESI/APCI Dual posi : 834[M+H]+, 856[M+Na]+.
参考例２０ 中間体（１Ｅ−９）の製造 Step 6, Step 7
Using the intermediate (1C-1) (500 mg, 0.690 mmol) and the intermediate (4B-8e) (107 mg, 0.830 mmol) as starting materials, the method described in steps 1 and 2 of Reference Example 12 was used. Based on the above, Intermediate (1E-8) (89 mg, 16% for 2 steps) was obtained as colorless amorphous.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8, Hz, 3 H) 1.33 (s, 6 H) 1.60-1.75 (m , 6 H) 1.77 (s, 3 H) 1.97-2.05 (m, 11 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.91-3.05 (m, 3 H) 3.72-3.81 (m, 1 H) 3.93 (s, 2 H) 4.01-4.08 (m, 1 H) 4.20-4.26 (m, 1 H) 4.44-4.53 (m, 1 H) 5.16-5.20 (m, 1 H) 5.23-5.32 (m , 2 H) 5.76 (s, 1 H) 6.26 (d, J = 16.2 Hz, 1 H) 6.48 (d, J = 16.2 Hz, 1 H) 6.69 (d, J = 7.9 Hz, 1 H) 6.92-7.04 (m, 2 H) 7.08-7.15 (m, 1 H) 7.24 (s, 1 H) 9.70-9.76 (m, 1 H).
MS ESI / APCI Dual posi: 834 [M + H] + , 856 [M + Na] + .
Reference Example 20 Production of intermediate (1E-9)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−１）（１．００ｇ,１．３８ｍｍｏｌ）と（１−アミノシクロヘキシル）メタノール（２６７ｍｇ,２．０７ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、中間体（１Ｅ−９）を得た。
MS ESI/APCI Dual posi : 834[M+H]+, 856[M+Na]+.
MS ESI/APCI Dual nega : 868[M+Cl]-.
参考例２１ 中間体（１Ｅ−１０）の製造 Step 1 and Step 2
It is described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-1) (1.00 g, 1.38 mmol) and (1-aminocyclohexyl) methanol (267 mg, 2.07 mmol) as starting materials. In accordance with the method, intermediate (1E-9) was obtained.
MS ESI / APCI Dual posi: 834 [M + H] + , 856 [M + Na] + .
MS ESI / APCI Dual nega: 868 [M + Cl] - .
Reference Example 21 Production of intermediate (1E-10)

Figure 2013224263
Figure 2013224263

工程１
３−（ベンジルアミノ）オキセタン−３−カルボニトリル（２．１３ｇ,１１．３ｍｍｏｌ,Ｊｏｕｒｎａｌ ｏｆ Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ（２０１０）, １３２（２５）, ８５５０‐８５５１）のエタノール溶液（２０ｍＬ）に２０％水酸化ナトリウム水溶液を０℃にて加えた後、２時間加熱還流した。この混合液を０℃に冷却し、酢酸を加えてｐＨ７に調整した。生成した白色固体を濾取し、冷水で洗浄した後減圧下乾燥した。得られた白色固体のメタノール溶液（５ｍＬ）を０℃に冷却し、これに１Ｍ トリメチルシリルジアゾメタン・ジエチルエーテル溶液を、溶液が黄色く呈色するまで加えた。続いて酢酸を溶液が無色になるまで加えた。減圧下溶媒を留去し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→３：７）で精製し、無色油状物として中間体（４Ｂ−１０ａ）（４８４ｍｇ,１９％）を得た。 Process 1
20% hydroxylation to an ethanol solution (20 mL) of 3- (benzylamino) oxetane-3-carbonitrile (2.13 g, 11.3 mmol, Journal of American Chemical Society (2010), 132 (25), 8550-8551) An aqueous sodium solution was added at 0 ° C., and the mixture was heated to reflux for 2 hours. The mixture was cooled to 0 ° C. and adjusted to pH 7 by adding acetic acid. The produced white solid was collected by filtration, washed with cold water, and dried under reduced pressure. The obtained white solid methanol solution (5 mL) was cooled to 0 ° C., and 1 M trimethylsilyldiazomethane / diethyl ether solution was added thereto until the solution turned yellow. Subsequently acetic acid was added until the solution became colorless. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 3: 7) to give intermediate (4B-10a) (484 mg, 19%) as a colorless oil. Got.

工程２
アルゴン雰囲気下、０℃に冷却した水素化リチウムアルミニウム（９９ｍｇ,２．６１ｍｍｏｌ）のジエチルエーテル懸濁液（４ｍＬ）に中間体（４Ｂ−１０ａ）（４８１ｍｇ,２．１７ｍｍｏｌ）のジエチルエーテル溶液（３．２ｍＬ）を３０分かけて滴下した。この混合液を室温下３時間撹拌した後、０℃に冷却し、水（０．１３ｍＬ）、１５％水酸化ナトリウム水溶液（０．１３ｍＬ）、水（０．３９ｍＬ）をゆっくり加えた。混合液を室温で２０分撹拌した後、沈殿物をセライト濾過により除去し、ジエチルエーテル（５０ｍＬ）で沈殿物を洗浄した。濾液および洗浄液を混合し、減圧下溶媒を留去して得られる残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝９：１→０：１０）で精製し、白色固体として中間体（４Ｂ−１０ｂ）（３２８ｍｇ,７８％）を得た。 Process 2
In a diethyl ether suspension (4 mL) of lithium aluminum hydride (99 mg, 2.61 mmol) cooled to 0 ° C. under an argon atmosphere, a solution of intermediate (4B-10a) (481 mg, 2.17 mmol) in diethyl ether (3 .2 mL) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 3 hours, then cooled to 0 ° C., and water (0.13 mL), 15% aqueous sodium hydroxide (0.13 mL), and water (0.39 mL) were slowly added. After the mixture was stirred at room temperature for 20 minutes, the precipitate was removed by celite filtration, and the precipitate was washed with diethyl ether (50 mL). The filtrate and washings were mixed, the solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 0: 10) to give an intermediate (4B- 10b) (328 mg, 78%) was obtained.

工程３
中間体（４Ｂ−１０ｂ）（３２６ｍｇ,１．６９ｍｍｏｌ）および２０％水酸化パラジウムカーボン（６５ｍｇ）のエタノール懸濁液（５ｍＬ）を水素雰囲気下３時間撹拌した。反応液をセライト濾過後、濾液を減圧濃縮し、淡黄色油状物として中間体（４Ｂ−１０ｃ）（１７４ｍｇ,１００％）を得た。 Process 3
An ethanol suspension (5 mL) of intermediate (4B-10b) (326 mg, 1.69 mmol) and 20% palladium hydroxide on carbon (65 mg) was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give intermediate (4B-10c) (174 mg, 100%) as a pale yellow oil.

工程４、工程５
中間体（１Ｃ−１）（８１５ｍｇ,１．１２ｍｍｏｌ）と中間体（４Ｂ−１０ｃ）（１７４ｍｇ,１．６９ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−１０）（４８３ｍｇ,２工程６９％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 - 1.10 (m, 6 H) 1.43 (s, 6 H) 1.79 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.36 (s, 3 H) 2.93 - 3.06 (m, 1 H) 3.71 - 3.80 (m, 1 H) 3.93 (s, 2 H) 4.04 (dd, J=12.3, 2.2 Hz, 1 H) 4.23 (dd, J=12.4, 4.6 Hz, 1 H) 4.48-4.52 (m, 1 H) 4.76 (d, J=6.7 Hz, 2 H) 4.87 (d, J=6.7 Hz, 2 H) 5.08 - 5.18 (m, 1 H) 5.18 - 5.33 (m, 2 H) 6.36 (d, J=16.0 Hz, 1 H) 6.59 (d, J=16.0 Hz, 1 H) 6.60 (br. s, 1 H) 6.73 (d, J=7.9 Hz, 1 H) 6.98 (s, 1 H) 7.00 (s, 1 H) 7.15 (d, J=7.9 Hz, 1 H) 7.27 (s, 1 H) 9.74 (s, 1 H).
MS ESI/APCI Dual posi : 808[M+H]+.
参考例２２ 中間体（１Ｅ−１１）の製造 Step 4 and Step 5
Using the intermediate (1C-1) (815 mg, 1.12 mmol) and the intermediate (4B-10c) (174 mg, 1.69 mmol) as starting materials, the methods described in steps 1 and 2 of Reference Example 12 were used. Based on the above, Intermediate (1E-10) (483 mg, 69% for 2 steps) was obtained as colorless amorphous.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.10 (m, 6 H) 1.43 (s, 6 H) 1.79 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.36 (s, 3 H) 2.93-3.06 (m, 1 H) 3.71-3.80 (m, 1 H) 3.93 (s, 2 H) 4.04 (dd, J = 12.3, 2.2 Hz, 1 H) 4.23 (dd, J = 12.4, 4.6 Hz, 1 H) 4.48-4.52 (m, 1 H) 4.76 (d, J = 6.7 Hz, 2 H) 4.87 (d, J = 6.7 Hz, 2 H) 5.08-5.18 (m, 1 H) 5.18-5.33 (m, 2 H) 6.36 (d, J = 16.0 Hz, 1 H) 6.59 (d, J = 16.0 Hz, 1 H) 6.60 (br. s, 1 H) 6.73 (d, J = 7.9 Hz, 1 H) 6.98 (s, 1 H) 7.00 (s, 1 H) 7.15 (d, J = 7.9 Hz, 1 H) 7.27 (s, 1 H) 9.74 (s, 1 H).
MS ESI / APCI Dual posi: 808 [M + H] + .
Reference Example 22 Production of intermediate (1E-11)

Figure 2013224263
Figure 2013224263

工程１
トリス（ヒドロキシメチル）アミノメタン（５．０ｇ,４１ｍｍｏｌ）、炭酸水素ナトリウム（５．２ｇ,６２ｍｍｏｌ）の酢酸エチル−水混合懸濁液（１：２,６０ｍＬ）に室温でクロロギ酸ベンジル（５．０ｍＬ,３５ｍＬ）を加え,同温で一晩撹拌した。反応液をろ過後、ろ液を酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧濃縮した。残渣をイソプロピルエーテルで洗浄後、減圧乾燥した。
得られた残渣（８．１ｇ）をＮ,Ｎ−ジメチルホルムアミドに溶解し、２,２−ジメトキシプロパン（４．３ｍＬ,３５ｍｍｏｌ）、ｐ−トルエンスルホン酸一水和物（６．３ｇ,３３ｍｍｏｌ）を加え、室温で一晩撹拌した。これに酢酸エチルを加えた後、水で洗浄し、水層を酢酸エチルで抽出し有機層を合わせた。これを１０％食塩水で２回洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧濃縮し、残渣をシリカゲルクロマトグラフィー（クロロホルム：メタノール＝１００：０→９５：５）にて精製し、中間体（４Ｂ−１１ａ）（３．７ｇ,３９％）を得た。 Process 1
Tris (hydroxymethyl) aminomethane (5.0 g, 41 mmol), sodium hydrogen carbonate (5.2 g, 62 mmol) in ethyl acetate-water mixed suspension (1: 2, 60 mL) at room temperature with benzyl chloroformate (5. (0 mL, 35 mL) was added, and the mixture was stirred overnight at the same temperature. After filtering the reaction solution, the filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was washed with isopropyl ether and then dried under reduced pressure.
The obtained residue (8.1 g) was dissolved in N, N-dimethylformamide, 2,2-dimethoxypropane (4.3 mL, 35 mmol), p-toluenesulfonic acid monohydrate (6.3 g, 33 mmol). And stirred at room temperature overnight. Ethyl acetate was added thereto, washed with water, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined. This was washed twice with 10% brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol = 100: 0 → 95: 5) to obtain intermediate (4B-11a) (3.7 g, 39%). Obtained.

工程２
中間体（４Ｂ−１１ａ）（３．６ｇ,１２ｍｍｏｌ）、１０％水酸化パラジウムカーボン（０．７２ｇ）のメタノール懸濁液（３６ｍＬ）を水素雰囲気下、室温で一晩撹拌した。反応液をセライトろ過後、溶媒を減圧下留去し、中間体（４Ｂ−１１ｂ）（１．５ｇ,７８％）を得た。 Process 2
A methanol suspension (36 mL) of intermediate (4B-11a) (3.6 g, 12 mmol), 10% palladium hydroxide carbon (0.72 g) was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give intermediate (4B-11b) (1.5 g, 78%).

工程３、工程４
中間体（１Ｃ−１）（７．０ｇ,９．７ｍｍｏｌ）と中間体（４Ｂ−１１ｂ）（１．５ｇ,９．３ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、中間体（１Ｅ−１１）（２．０ｇ,２工程２５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.42 - 1.46 (m, 12 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.90 - 3.02 (m, 1 H) 3.72 - 3.80 (m, 1 H) 3.89 - 3.97 (m, 4 H) 4.02 - 4.09 (m, 3 H) 4.27 (dd, J=12.4, 4.7 Hz, 1 H) 4.45 - 4.52 (m, 1 H) 5.10 - 5.31 (m, 3 H) 6.37 (d, J=16.0 Hz, 1 H) 6.58 (d, J=16.0 Hz, 1 H) 6.66 - 6.73 (m, 2 H) 6.96 - 7.03 (m, 2 H) 7.09 - 7.17 (m, 1 H) 7.24 - 7.29 (m, 1 H) 9.54 (s, 1 H).
参考例２３ 中間体（１Ｅ−１２）の製造 Step 3 and Step 4
The intermediate (1C-1) (7.0 g, 9.7 mmol) and intermediate (4B-11b) (1.5 g, 9.3 mmol) are used as starting materials, and are described in Step 1 and Step 2 of Reference Example 12. The intermediate (1E-11) (2.0 g, 2 steps 25%) was obtained according to the above method.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.42-1.46 (m, 12 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.90-3.02 (m, 1 H) 3.72-3.80 (m, 1 H) 3.89-3.97 (m, 4 H) 4.02-4.09 (m, 3 H) 4.27 (dd, J = 12.4, 4.7 Hz, 1 H) 4.45-4.52 (m, 1 H) 5.10-5.31 (m, 3 H) 6.37 (d, J = 16.0 Hz, 1 H) 6.58 (d, J = 16.0 Hz, 1 H) 6.66-6.73 (m, 2 H) 6.96-7.03 (m, 2 H) 7.09- 7.17 (m, 1 H) 7.24-7.29 (m, 1 H) 9.54 (s, 1 H).
Reference Example 23 Production of intermediate (1E-12)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−２）（１．００ｇ,１．４４ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、黄色アモルファスとして中間体（１Ｅ−１２）（８１５ｍｇ,２工程７３％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 - 1.17 (m, 6 H) 1.39 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.90 - 3.04 (m, 1 H) 3.11 - 3.21 (m, 2 H) 3.70 - 3.81 (m, 1 H) 3.92 (s, 2 H) 4.00 - 4.10 (m, 1 H) 4.21 - 4.31 (m, 1 H) 4.41 - 4.55 (m, 1 H) 5.09 - 5.33 (m, 3 H) 6.03 - 6.13 (m, 1 H) 6.20 - 6.32 (m, 1 H) 6.46 - 6.56 (m, 1 H) 6.66 - 6.71 (m, 1 H) 6.95 - 7.03 (m, 2 H) 7.07 - 7.14 (m, 1 H) 7.21 - 7.25 (m, 1 H) 9.38 (s, 1 H).
MS ESI/APCI Dual posi : 766[M+H]+, 788[M+Na]+.
MS ESI/APCI Dual nega : 800[M+Cl]-.
参考例２４ 中間体（１Ｅ−１３）の製造 Step 1 and Step 2
Intermediate (1C-12) (1.00 g, 1.44 mmol) as a starting material, intermediate (1E-12) as a yellow amorphous substance according to the method described in Step 1 and Step 2 of Reference Example 12 ) (815 mg, 73% over 2 steps).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.17 (m, 6 H) 1.39 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.90-3.04 (m, 1 H) 3.11-3.21 (m, 2 H) 3.70-3.81 (m, 1 H) 3.92 ( s, 2 H) 4.00-4.10 (m, 1 H) 4.21-4.31 (m, 1 H) 4.41-4.55 (m, 1 H) 5.09-5.33 (m, 3 H) 6.03-6.13 (m, 1 H) 6.20-6.32 (m, 1 H) 6.46-6.56 (m, 1 H) 6.66-6.71 (m, 1 H) 6.95-7.03 (m, 2 H) 7.07-7.14 (m, 1 H) 7.21-7.25 (m , 1 H) 9.38 (s, 1 H).
MS ESI / APCI Dual posi: 766 [M + H] + , 788 [M + Na] + .
MS ESI / APCI Dual nega: 800 [M + Cl] - .
Reference Example 24 Production of intermediate (1E-13)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−２）（３．００ｇ,４．３１ｍｍｏｌ）と３−アミノ−３−メチルブタノール（５６７ｍｇ,５．６０ｍｍｏｌ,参考例１４）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、淡黄色アモルファスとして中間体（１Ｅ−１３）（２．５８ｇ,２工程７４％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.41 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.02 (s, 3 H) 2.05 (s, 3 H) 2.29 (s, 3 H) 2.37 (s, 3 H) 2.91 - 3.02 (m, 3 H) 3.08 (d, J=6.2 Hz, 2 H) 3.72 - 3.80 (m, 1 H) 3.89 - 3.95 (m, 2 H) 4.05 (dd, J=12.5, 1.9 Hz, 1 H) 4.45 - 4.53 (m, 1 H) 4.27 (dd, J=12.5, 4.6 Hz, 1 H) 5.09 - 5.19 (m, 1 H) 5.21 - 5.31 (m, 2 H) 5.61 (br. s, 1 H) 6.22 (dt, J=16.0, 6.2 Hz, 1 H) 6.47 (d, J=16.0 Hz, 1 H) 6.67 (d, J=8.1 Hz, 1 H) 6.99 (s, 1 H) 7.00 (s, 1 H) 7.10 (d, J=8.1 Hz, 1 H) 7.23 (s, 1 H) 9.75 (t, J=2.2 Hz, 1 H).
MS ESI/APCI Dual posi : 780[M+H]+, 802[M+Na]+.
MS ESI/APCI Dual nega : 814[M+Cl]-.
参考例２５ 中間体（１Ｅ−１４）の製造 Step 1 and Step 2
Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-2) (3.00 g, 4.31 mmol) and 3-amino-3-methylbutanol (567 mg, 5.60 mmol, Reference Example 14) as starting materials The intermediate (1E-13) (2.58 g, 2 steps 74%) was obtained as a pale yellow amorphous substance in accordance with the method described in 1).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.41 (s, 6 H) 1.76 (s, 3 H ) 1.99 (s, 3 H) 2.02 (s, 3 H) 2.05 (s, 3 H) 2.29 (s, 3 H) 2.37 (s, 3 H) 2.91-3.02 (m, 3 H) 3.08 (d, J = 6.2 Hz, 2 H) 3.72-3.80 (m, 1 H) 3.89-3.95 (m, 2 H) 4.05 (dd, J = 12.5, 1.9 Hz, 1 H) 4.45-4.53 (m, 1 H) 4.27 ( dd, J = 12.5, 4.6 Hz, 1 H) 5.09-5.19 (m, 1 H) 5.21-5.31 (m, 2 H) 5.61 (br. s, 1 H) 6.22 (dt, J = 16.0, 6.2 Hz, 1 H) 6.47 (d, J = 16.0 Hz, 1 H) 6.67 (d, J = 8.1 Hz, 1 H) 6.99 (s, 1 H) 7.00 (s, 1 H) 7.10 (d, J = 8.1 Hz, 1 H) 7.23 (s, 1 H) 9.75 (t, J = 2.2 Hz, 1 H).
MS ESI / APCI Dual posi: 780 [M + H] + , 802 [M + Na] + .
MS ESI / APCI Dual nega: 814 [M + Cl] - .
Reference Example 25 Production of intermediate (1E-14)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−２）（３．００ｇ,４．３１ｍｍｏｌ）と１−アミノ−１−シクロペンタンメタノール（６４５ｍｇ,５．６０ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、淡黄色アモルファスとして中間体（１Ｅ−１４）（２．７４ｇ,２工程８１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15 - 1.18 (m, 6 H) 1.68 - 1.89 (m, 9 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.08 - 2.17 (m, 2 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.91 - 3.03 (m, 1 H) 3.18 (d, J=7.1 Hz, 2 H) 3.72 - 3.81 (m, 1 H) 3.89 - 3.95 (m, 2 H) 4.05 (dd, J=12.4, 1.9 Hz, 1 H) 4.27 (dd, J=12.4, 4.6 Hz, 1 H) 4.44 - 4.54 (m, 1 H) 5.10 - 5.19 (m, 1 H) 5.21 - 5.32 (m, 2 H) 6.09 (br. s, 1 H) 6.26 (dt, J=15.9, 7.1 Hz, 1 H) 6.51 (d, J=15.9 Hz, 1 H) 6.68 (d, J=8.1 Hz, 1 H) 6.98 (s, 1 H) 7.00 (s, 1 H) 7.10 (d, J=8.1 Hz, 1 H) 7.23 (s, 1 H) 9.47 (s, 1 H).
MS ESI/APCI Dual posi : 792[M+H]+, 815[M+Na]+.
MS ESI/APCI Dual nega : 826[M-H]-.
参考例２６ 中間体（１Ｅ−１５）の製造 Step 1 and Step 2
It is described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-2) (3.00 g, 4.31 mmol) and 1-amino-1-cyclopentanemethanol (645 mg, 5.60 mmol) as starting materials. The intermediate (1E-14) (2.74 g, 81% for 2 steps) was obtained as a pale yellow amorphous product.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.18 (m, 6 H) 1.68-1.89 (m, 9 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.08-2.17 (m, 2 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.91-3.03 (m, 1 H) 3.18 (d, J = 7.1 Hz, 2 H) 3.72-3.81 ( m, 1 H) 3.89-3.95 (m, 2 H) 4.05 (dd, J = 12.4, 1.9 Hz, 1 H) 4.27 (dd, J = 12.4, 4.6 Hz, 1 H) 4.44-4.54 (m, 1 H ) 5.10-5.19 (m, 1 H) 5.21-5.32 (m, 2 H) 6.09 (br. S, 1 H) 6.26 (dt, J = 15.9, 7.1 Hz, 1 H) 6.51 (d, J = 15.9 Hz) , 1 H) 6.68 (d, J = 8.1 Hz, 1 H) 6.98 (s, 1 H) 7.00 (s, 1 H) 7.10 (d, J = 8.1 Hz, 1 H) 7.23 (s, 1 H) 9.47 (s, 1 H).
MS ESI / APCI Dual posi: 792 [M + H] + , 815 [M + Na] + .
MS ESI / APCI Dual nega: 826 [MH] - .
Reference Example 26 Production of intermediate (1E-15)

Figure 2013224263
Figure 2013224263

工程１、工程２、工程３
中間体（１Ｂ−１）（１．００ｇ,１．４５ｍｍｏｌ）と２,２−ジエチルブト−３−エノイック アシッド（４９３ｍｇ,３．４７ｍｍｏｌ,Ｊｏｕｒｎａｌ ｏｆ Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ（２００５）,４２,３２７）を出発原料として、参考例８、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−１５）（７０９ｍｇ,３工程６０％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.84 - 0.93 (m, 6 H) 1.11 - 1.18 (m, 6 H) 1.34 (s, 6 H) 1.75 - 1.86 (m, 4 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.33 (s, 3 H) 2.36 (s, 3 H) 2.91 - 3.04 (m, 1 H) 3.72 - 3.81 (m, 1 H) 3.94 (s, 2 H) 4.01 - 4.09 (m, 1 H) 4.21 - 4.31 (m, 1 H) 4.44 - 4.55 (m, 1 H) 5.10 - 5.19 (m, 1 H) 5.22 - 5.32 (m, 2 H) 6.11 (s, 1 H) 6.23 - 6.32 (m, 1 H) 6.46 - 6.55 (m, 1 H) 6.67 - 6.73 (m, 1 H) 7.01 (s, 1 H) 7.02 (s, 1 H) 7.10 - 7.16 (m, 1 H) 7.25 - 7.27 (m, 1 H) 9.36 (s, 1 H).
MS ESI/APCI Dual posi : 823[M+H]+, 845[M+Na]+.
MS ESI/APCI Dual nega : 857[M+Cl]-.
参考例２７ 中間体（１Ｅ−１６）の製造 Step 1, Step 2, Step 3
Starting from intermediate (1B-1) (1.00 g, 1.45 mmol) and 2,2-diethylbut-3-enoic acid (493 mg, 3.47 mmol, Journal of Heterocyclic Chemistry (2005), 42, 327) Based on the methods described in Steps 1 and 2 of Reference Example 8 and Reference Example 12, Intermediate (1E-15) (709 mg, 3 steps 60%) was obtained as a colorless amorphous substance.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.84-0.93 (m, 6 H) 1.11-1.18 (m, 6 H) 1.34 (s, 6 H) 1.75-1.86 (m, 4 H) 1.78 (s , 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.33 (s, 3 H) 2.36 (s, 3 H) 2.91-3.04 (m, 1 H) 3.72- 3.81 (m, 1 H) 3.94 (s, 2 H) 4.01-4.09 (m, 1 H) 4.21-4.31 (m, 1 H) 4.44-4.55 (m, 1 H) 5.10-5.19 (m, 1 H) 5.22-5.32 (m, 2 H) 6.11 (s, 1 H) 6.23-6.32 (m, 1 H) 6.46-6.55 (m, 1 H) 6.67-6.73 (m, 1 H) 7.01 (s, 1 H) 7.02 (s, 1 H) 7.10-7.16 (m, 1 H) 7.25-7.27 (m, 1 H) 9.36 (s, 1 H).
MS ESI / APCI Dual posi: 823 [M + H] + , 845 [M + Na] + .
MS ESI / APCI Dual nega: 857 [M + Cl] - .
Reference Example 27 Production of intermediate (1E-16)

Figure 2013224263
Figure 2013224263

工程１、工程２、工程３
中間体（１Ｂ−１）（１４６ｍｇ,０．２１ｍｍｏｌ）と１−ビニルシクロブタンカルボン酸（４０ｍｇ,０．３２ｍｍｏｌ,Ｊｏｕｒｎａｌ ｏｆ Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ（２００５）,４２,３２７）を出発原料として、参考例８、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−１６）（７０９ｍｇ,３工程６０％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 - 1.18 (m, 6 H) 1.34 (s, 6 H) 1.78 (s, 3 H) 1.88 - 2.67 (m, 6 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.32 (s, 3 H) 2.37 (s, 3 H) 2.92 - 3.04 (m, 1 H) 3.71 - 3.81 (m, 1 H) 3.94 (s, 2 H) 4.01 - 4.10 (m, 1 H) 4.22 - 4.32 (m, 1 H) 4.45 - 4.54 (m, 1 H) 5.10 - 5.20 (m, 1 H) 5.22 - 5.32 (m, 2 H) 5.88 - 5.94 (m, 1 H) 6.33 - 6.42 (m, 1 H) 6.53 - 6.62 (m, 1 H) 6.70 (d, J=7.8 Hz, 1 H) 7.00 (s, 1 H) 7.01 (s, 1 H) 7.11 - 7.17 (m, 1 H) 7.25 - 7.30 (m, 1 H) 9.37 (s, 1 H).
MS ESI/APCI Dual posi : 806[M+H]+.
MS ESI/APCI Dual nega : 840[M+Cl]-.
参考例２８ 中間体（１Ｅ−１７）の製造 Step 1, Step 2, Step 3
Intermediate Example (1B-1) (146 mg, 0.21 mmol) and 1-vinylcyclobutanecarboxylic acid (40 mg, 0.32 mmol, Journal of Heterocyclic Chemistry (2005), 42,327) were used as starting materials. Based on the method described in Step 1 and Step 2 of Example 12, intermediate (1E-16) (709 mg, 3 steps 60%) was obtained as a colorless amorphous substance.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.18 (m, 6 H) 1.34 (s, 6 H) 1.78 (s, 3 H) 1.88-2.67 (m, 6 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.32 (s, 3 H) 2.37 (s, 3 H) 2.92-3.04 (m, 1 H) 3.71-3.81 (m, 1 H) 3.94 ( s, 2 H) 4.01-4.10 (m, 1 H) 4.22-4.32 (m, 1 H) 4.45-4.54 (m, 1 H) 5.10-5.20 (m, 1 H) 5.22-5.32 (m, 2 H) 5.88-5.94 (m, 1 H) 6.33-6.42 (m, 1 H) 6.53-6.62 (m, 1 H) 6.70 (d, J = 7.8 Hz, 1 H) 7.00 (s, 1 H) 7.01 (s, 1 H) 7.11-7.17 (m, 1 H) 7.25-7.30 (m, 1 H) 9.37 (s, 1 H).
MS ESI / APCI Dual posi: 806 [M + H] + .
MS ESI / APCI Dual nega: 840 [M + Cl] - .
Reference Example 28 Production of intermediate (1E-17)

Figure 2013224263
Figure 2013224263

工程１、工程２、工程３
中間体（１Ｂ−１）（６８３ｍｇ,０．９９０ｍｍｏｌ）と２,２−ジメチル−５−ビニル−１,３−ジオキサン−５−カルボン酸（２７６ｍｇ,１．４８ｍｍｏｌ,Ｊｏｕｒｎａｌ ｏｆ Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍｉｓｔｒｙ（２００５）,４２,３２７）を出発原料として、参考例８、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−１７）（７０９ｍｇ,３工程６６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08 - 1.16 (m, 6 H) 1.41 (s, 6 H) 1.48 (s, 3 H) 1.53 (s, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.27 (s, 3 H) 2.36 (s, 3 H) 2.87 - 3.03 (m, 1 H) 3.69 - 3.81 (m, 1 H) 3.91 (s, 2 H) 4.01 - 4.32 (m, 6 H) 4.42 - 4.51 (m, 1 H) 5.10 - 5.19 (m, 1 H) 5.22 - 5.31 (m, 2 H) 6.22 - 6.29 (m, 1 H) 6.38 - 6.46 (m, 1 H) 6.67 (d, J=7.8 Hz, 1 H) 6.95 (s, 1 H) 6.99 (s, 1 H) 7.04 - 7.10 (m, 1 H) 7.23 (s, 1 H) 7.46 (s, 1 H) 9.43 (s, 1 H).
MS ESI/APCI Dual posi : 866[M+H]+, 888[M+Na]+.
MS ESI/APCI Dual nega : 864[M-H]-, 900[M+Cl]-.
参考例２９ 中間体（１Ｅ−１８）の製造 Step 1, Step 2, Step 3
Intermediate (1B-1) (683 mg, 0.990 mmol) and 2,2-dimethyl-5-vinyl-1,3-dioxane-5-carboxylic acid (276 mg, 1.48 mmol, Journal of Heterocyclic Chemistry (2005), 42,327) as a starting material, intermediate (1E-17) (709 mg, 3 steps 66% as a colorless amorphous) according to the methods described in steps 1 and 2 of Reference Example 8 and Reference Example 12. )
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08-1.16 (m, 6 H) 1.41 (s, 6 H) 1.48 (s, 3 H) 1.53 (s, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.27 (s, 3 H) 2.36 (s, 3 H) 2.87-3.03 (m, 1 H) 3.69-3.81 (m, 1 H) 3.91 (s, 2 H) 4.01-4.32 (m, 6 H) 4.42-4.51 (m, 1 H) 5.10-5.19 (m, 1 H) 5.22-5.31 (m, 2 H) 6.22-6.29 ( m, 1 H) 6.38-6.46 (m, 1 H) 6.67 (d, J = 7.8 Hz, 1 H) 6.95 (s, 1 H) 6.99 (s, 1 H) 7.04-7.10 (m, 1 H) 7.23 (s, 1 H) 7.46 (s, 1 H) 9.43 (s, 1 H).
MS ESI / APCI Dual posi: 866 [M + H] + , 888 [M + Na] + .
MS ESI / APCI Dual nega: 864 [MH] - , 900 [M + Cl] - .
Reference Example 29 Production of intermediate (1E-18)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−３）（９．００ｇ,０．０１２９ｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、黄色アモルファスとして中間体（１Ｅ−１８）（７．６０ｇ,２工程７７％）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.09 - 1.18 (m, 6 H) 1.32 (s, 6 H) 1.38 (s, 6 H) 1.77 (s, 3 H) 1.98 (s, 3 H) 2.00 - 2.07 (m, 6 H) 2.33 (s, 3 H) 2.95 (spt, J=6.8 Hz, 1 H) 3.77 - 3.94 (m, 6 H) 4.08 - 4.15 (m, 1 H) 4.22 (dd, J=11.9, 4.6 Hz, 1 H) 4.82 (br. s., 1 H) 5.14 - 5.20 (m, 1 H) 5.27 - 5.35 (m, 2 H) 6.11 (br. s, 1 H) 6.31 (d, J=16.5 Hz, 1 H) 6.52 (d, J=16.5 Hz, 1 H) 6.67 (d, J=7.8 Hz, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.10 (d, J=7.8 Hz, 1 H) 7.24 (s, 1 H) 9.33 (s, 1 H)．
MS ESI/APCI Dual posi : 766[M+H]+, 788[M+Na]+.
MS ESI/APCI Dual nega : 800[M+Cl]-.
参考例３０ 中間体（１Ｅ−１９）の製造 Step 1 and Step 2
Intermediate (1C-18) (9.00 g, 0.0129 mol) was used as a starting material, and the intermediate (1E-18) was converted into a yellow amorphous substance according to the method described in Step 1 and Step 2 of Reference Example 12. ) (7.60 g, 77% over 2 steps).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.09-1.18 (m, 6 H) 1.32 (s, 6 H) 1.38 (s, 6 H) 1.77 (s, 3 H) 1.98 (s, 3 H) 2.00-2.07 (m, 6 H) 2.33 (s, 3 H) 2.95 (spt, J = 6.8 Hz, 1 H) 3.77-3.94 (m, 6 H) 4.08-4.15 (m, 1 H) 4.22 (dd, J = 11.9, 4.6 Hz, 1 H) 4.82 (br. S., 1 H) 5.14-5.20 (m, 1 H) 5.27-5.35 (m, 2 H) 6.11 (br. S, 1 H) 6.31 (d , J = 16.5 Hz, 1 H) 6.52 (d, J = 16.5 Hz, 1 H) 6.67 (d, J = 7.8 Hz, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.10 (d , J = 7.8 Hz, 1 H) 7.24 (s, 1 H) 9.33 (s, 1 H).
MS ESI / APCI Dual posi: 766 [M + H] + , 788 [M + Na] + .
MS ESI / APCI Dual nega: 800 [M + Cl] - .
Reference Example 30 Production of intermediate (1E-19)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−４）（６．０５ｇ,９．０４ｍｍｏｌ）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、黄色アモルファスとして中間体（１Ｅ−１９）（３．４４ｇ,２工程５２％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.38 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.31 (s, 3 H) 2.88 - 2.99 (m, 1 H) 3.16 (dd, J=7.2, 1.2 Hz, 2 H) 3.76 - 3.84 (m, 1 H) 3.86 - 3.88 (m, 5 H) 4.07 - 4.14 (m, 1 H) 4.18 - 4.26 (m, 1 H) 4.78 - 4.84 (m, 1 H) 5.13 - 5.22 (m, 1 H) 5.29 - 5.34 (m, 2 H) 6.07 (br. s, 1 H) 6.23 (dt, J=15.7, 7.2 Hz, 1 H) 6.50 (d, J=15.7 Hz, 1 H) 6.64 (d, J=7.8 Hz, 1 H) 6.81 (s, 1 H) 6.98 (s, 1 H) 7.08 (d, J=7.8 Hz, 1 H) 7.22 (s, 1 H) 9.37 (s, 1 H).
MS ESI/APCI Dual posi : 738[M+H]+, 760[M+Na]+.
MS ESI/APCI Dual nega : 736[M-H]-, 772[M+Cl]-.
参考例３１ 中間体（１Ｅ−２０）の製造 Step 1 and Step 2
Intermediate (1C-19) (6.05 g, 9.04 mmol) was used as a starting material according to the method described in Step 1 and Step 2 of Reference Example 12, and the intermediate (1E-19 ) (3.44 g, 2 steps 52%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.38 (s, 6 H) 1.76 (s, 3 H ) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.31 (s, 3 H) 2.88-2.99 (m, 1 H) 3.16 (dd, J = 7.2, 1.2 Hz, 2 H) 3.76-3.84 (m, 1 H) 3.86-3.88 (m, 5 H) 4.07-4.14 (m, 1 H) 4.18-4.26 (m, 1 H) 4.78-4.84 (m, 1 H) 5.13-5.22 (m, 1 H) 5.29-5.34 (m, 2 H) 6.07 (br.s, 1 H) 6.23 (dt, J = 15.7, 7.2 Hz, 1 H) 6.50 (d, J = 15.7 Hz, 1 H) 6.64 (d, J = 7.8 Hz, 1 H) 6.81 (s, 1 H) 6.98 (s, 1 H) 7.08 (d, J = 7.8 Hz, 1 H) 7.22 (s, 1 H) 9.37 (s, 1 H).
MS ESI / APCI Dual posi: 738 [M + H] + , 760 [M + Na] + .
MS ESI / APCI Dual nega: 736 [MH] - , 772 [M + Cl] - .
Reference Example 31 Production of intermediate (1E-20)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｃ−３）（６６８ｍｇ,０．９５９ｍｍｏｌ）と３−アミノ−３−メチルブタノール（１２９ｍｇ,１．２５ｍｍｏｌ,参考例１４）を出発原料として、参考例１２の工程１および工程２に記載されている方法に準拠して、黄色アモルファスとして中間体（１Ｅ−２０）（３２９ｍｇ,２工程４４％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J=7.0 Hz, 3 H) 1.14 (d, J=7.0 Hz, 3 H) 1.33 (s, 6 H) 1.36 (s, 6 H) 1.76 (s, 3 H) 1.98 (s, 3 H) 2.02 - 2.06 (m, 6 H) 2.33 (s, 3 H) 2.90 - 2.95 (m, 3 H) 3.76 - 3.84 (m, 1 H) 3.84 - 3.90 (m, 5 H) 4.06 - 4.14 (m, 1 H) 4.18 - 4.26 (m, 1 H) 4.79 - 4.85 (m, 1 H) 5.13 - 5.23 (m, 1 H) 5.26 - 5.36 (m, 2 H) 5.74 (s, 1 H) 6.26 (d, J=16.3 Hz, 1 H) 6.48 (d, J=16.3 Hz, 1 H) 6.65 (d, J=7.9 Hz, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.09 (d, J=7.9 Hz, 1 H) 7.23 (s, 1 H) 9.72 (t, J=2.2 Hz, 1 H).
MS ESI/APCI Dual posi : 781[M+H]+.
参考例３２ 中間体（１Ｅ−２１）の製造 Step 1 and Step 2
Described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-3) (668 mg, 0.959 mmol) and 3-amino-3-methylbutanol (129 mg, 1.25 mmol, Reference Example 14) as starting materials The intermediate (1E-20) (329 mg, 2 steps 44%) was obtained as a yellow amorphous based on the described method.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 7.0 Hz, 3 H) 1.14 (d, J = 7.0 Hz, 3 H) 1.33 (s, 6 H) 1.36 (s, 6 H ) 1.76 (s, 3 H) 1.98 (s, 3 H) 2.02-2.06 (m, 6 H) 2.33 (s, 3 H) 2.90-2.95 (m, 3 H) 3.76-3.84 (m, 1 H) 3.84 -3.90 (m, 5 H) 4.06-4.14 (m, 1 H) 4.18-4.26 (m, 1 H) 4.79-4.85 (m, 1 H) 5.13-5.23 (m, 1 H) 5.26-5.36 (m, 2 H) 5.74 (s, 1 H) 6.26 (d, J = 16.3 Hz, 1 H) 6.48 (d, J = 16.3 Hz, 1 H) 6.65 (d, J = 7.9 Hz, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.09 (d, J = 7.9 Hz, 1 H) 7.23 (s, 1 H) 9.72 (t, J = 2.2 Hz, 1 H).
MS ESI / APCI Dual posi: 781 [M + H] + .
Reference Example 32 Production of intermediate (1E-21)

Figure 2013224263
Figure 2013224263

工程１、工程２、工程３
中間体（１Ｂ−３）（１．００ｇ,１．４８ｍｍｏｌ）を出発原料として、参考例８、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−２１）（１７５ｍｇ,３工程１５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 - 1.18 (m, 6 H) 1.32 (s, 6 H) 1.38 (s, 6 H) 1.47 (t, J=6.9 Hz, 3 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.33 (s, 3 H) 2.85 - 3.03 (m, 1 H) 3.72 - 3.97 (m, 3 H) 4.01 - 4.16 (m, 3 H) 4.17 - 4.28 (m, 1 H) 4.72 - 4.91 (m, 1 H) 5.11 - 5.21 (m, 1 H) 5.27 - 5.37 (m, 2 H) 6.11 (s, 1 H) 6.26 - 6.35 (m, 1 H) 6.48 - 6.57 (m, 1 H) 6.67 (d, J=7.9 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.10 (d, J=7.9 Hz, 1 H) 7.25 (s, 1 H) 9.33 (s, 1 H).
MS ESI/APCI Dual posi : 780[M+H]+, 802[M+Na]+.
MS ESI/APCI Dual nega : 778[M-H]-, 814[M+Cl]-.
参考例３３ 中間体（１Ｅ−２２）の製造 Step 1, Step 2, Step 3
Intermediate (1B-3) (1.00 g, 1.48 mmol) was used as a starting material, and the intermediate was converted to colorless amorphous according to the methods described in Steps 1 and 2 of Reference Example 8 and Reference Example 12. (1E-21) (175 mg, 3 steps 15%) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.18 (m, 6 H) 1.32 (s, 6 H) 1.38 (s, 6 H) 1.47 (t, J = 6.9 Hz, 3 H) 1.77 ( s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.33 (s, 3 H) 2.85-3.03 (m, 1 H) 3.72-3.97 (m, 3 H ) 4.01-4.16 (m, 3 H) 4.17-4.28 (m, 1 H) 4.72-4.91 (m, 1 H) 5.11-5.21 (m, 1 H) 5.27-5.37 (m, 2 H) 6.11 (s, 1 H) 6.26-6.35 (m, 1 H) 6.48-6.57 (m, 1 H) 6.67 (d, J = 7.9 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.10 (d , J = 7.9 Hz, 1 H) 7.25 (s, 1 H) 9.33 (s, 1 H).
MS ESI / APCI Dual posi: 780 [M + H] + , 802 [M + Na] + .
MS ESI / APCI Dual nega: 778 [MH] - , 814 [M + Cl] - .
Reference Example 33 Production of intermediate (1E-22)

Figure 2013224263
Figure 2013224263

工程１、工程２、工程３
中間体（１Ｂ−６）（４８０ｍｇ,０．６５３ｍｍｏｌ）を出発原料として、参考例８、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−２２）（２５０ｍｇ,３工程４６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.33 (s, 6 H) 1.39 (s, 6 H) 1.76 (s, 3 H) 1.98 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.18 (s, 3 H) 2.32 (s, 3 H) 2.88 - 3.01 (m, 1 H) 3.76 - 3.91 (m, 3 H) 4.05 - 4.13 (m, 1 H) 4.15 - 4.30 (m, 3 H) 4.37 - 4.48 (m, 1 H) 4.53 - 4.63 (m, 1 H) 4.73 (br. s., 1 H) 5.18 (t, J=9.2 Hz, 1 H) 5.30 (t, J=9.2 Hz, 1 H) 5.41 (br. s., 1 H) 6.11 (s, 1 H) 6.34 (d, J=16.0 Hz, 1 H) 6.55 (d, J=16.0 Hz, 1 H) 6.67 (d, J=7.8 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.11 (d, J=7.8 Hz, 1 H) 7.25 (s, 1 H) 9.33 (s, 1 H).
MS ESI/APCI Dual posi : 838[M+H]+, 860[M+Na]+.
MS ESI/APCI Dual nega : 872[M+Cl]-.
参考例３４ 中間体（１Ｅ−２３）の製造 Step 1, Step 2, Step 3
Intermediate (1B-6) (480 mg, 0.653 mmol) was used as a starting material, and intermediate (1E) was obtained as colorless amorphous according to the methods described in Steps 1 and 2 of Reference Example 8 and Reference Example 12. -22) (250 mg, 46% for 3 steps).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.33 (s, 6 H) 1.39 (s, 6 H ) 1.76 (s, 3 H) 1.98 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.18 (s, 3 H) 2.32 (s, 3 H) 2.88-3.01 (m, 1 H) 3.76-3.91 (m, 3 H) 4.05-4.13 (m, 1 H) 4.15-4.30 (m, 3 H) 4.37-4.48 (m, 1 H) 4.53-4.63 (m, 1 H) 4.73 (br s., 1 H) 5.18 (t, J = 9.2 Hz, 1 H) 5.30 (t, J = 9.2 Hz, 1 H) 5.41 (br. s., 1 H) 6.11 (s, 1 H) 6.34 ( d, J = 16.0 Hz, 1 H) 6.55 (d, J = 16.0 Hz, 1 H) 6.67 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.11 ( d, J = 7.8 Hz, 1 H) 7.25 (s, 1 H) 9.33 (s, 1 H).
MS ESI / APCI Dual posi: 838 [M + H] + , 860 [M + Na] + .
MS ESI / APCI Dual nega: 872 [M + Cl] - .
Reference Example 34 Production of intermediate (1E-23)

Figure 2013224263
Figure 2013224263

工程１、工程２、工程３
中間体（１Ｂ−４）（２００ｍｇ,０．２９ｍｍｏｌ）を出発原料として、参考例８、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−２３）（１８５ｍｇ,３工程５７％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 - 1.18 (m, 6 H) 1.30 - 1.35 (m, 6 H) 1.39 (s, 6 H) 1.79 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.89 - 3.04 (m, 1 H) 3.74 - 4.01 (m, 3 H) 4.06 - 4.15 (m, 1 H) 4.16 - 4.25 (m, 1 H) 4.75 - 4.84 (m, 1 H) 5.12 - 5.36 (m, 3 H) 5.61 - 5.68 (m, 1 H) 5.79 - 5.86 (m, 1 H) 6.12 (s, 1 H) 6.27 - 6.36 (m, 1 H) 6.48 - 6.57 (m, 1 H) 6.67 (d, J=8.0 Hz, 1 H) 7.04 (s, 1 H) 7.06 (s, 1 H) 7.12 (dd, J=8.0, 1.5 Hz, 1 H) 7.24 - 7.26 (m, 1 H) 9.33 (s, 1 H).
MS ESI/APCI Dual posi : 784[M+H]+, 806[M+Na]+.
MS ESI/APCI Dual nega : 818[M+Cl]-.
参考例３５ 中間体（１Ｅ−２４）の製造 Step 1, Step 2, Step 3
Intermediate (1B-4) (200 mg, 0.29 mmol) as a starting material, intermediate (1E) as colorless amorphous, according to the methods described in steps 1 and 2 of Reference Example 8 and Reference Example 12. -23) (185 mg, 57% over 3 steps).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.18 (m, 6 H) 1.30-1.35 (m, 6 H) 1.39 (s, 6 H) 1.79 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.89-3.04 (m, 1 H) 3.74-4.01 (m, 3 H) 4.06-4.15 (m, 1 H) 4.16-4.25 (m, 1 H) 4.75-4.84 (m, 1 H) 5.12-5.36 (m, 3 H) 5.61-5.68 (m, 1 H) 5.79-5.86 (m, 1 H) 6.12 (s, 1 H) 6.27-6.36 (m, 1 H) 6.48-6.57 (m, 1 H) 6.67 (d, J = 8.0 Hz, 1 H) 7.04 (s, 1 H) 7.06 (s, 1 H) 7.12 (dd, J = 8.0, 1.5 Hz, 1 H) 7.24-7.26 (m, 1 H) 9.33 (s, 1 H).
MS ESI / APCI Dual posi: 784 [M + H] + , 806 [M + Na] + .
MS ESI / APCI Dual nega: 818 [M + Cl] - .
Reference Example 35 Production of intermediate (1E-24)

Figure 2013224263
Figure 2013224263

工程１、工程２、工程３
中間体（１Ｂ−５）（１０．６ｇ,１５．２ｍｍｏｌ）を出発原料として、参考例８、参考例１２の工程１および工程２に記載されている方法に準拠して、無色アモルファスとして中間体（１Ｅ−２４）（６．６２ｇ,３工程５６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 - 1.19 (m, 6 H) 1.35 (s, 6 H) 1.39 (s, 6 H) 1.80 (s, 3 H) 1.99 (s, 3 H) 2.01 - 2.09 (m, 6 H) 2.31 (s, 3 H) 2.93 - 3.06 (m, 1 H) 3.75 - 4.02 (m, 3 H) 4.07 - 4.25 (m, 2 H) 4.64 - 4.74 (m, 1 H) 5.10 - 5.22 (m, 1 H) 5.26 - 5.39 (m, 2 H) 6.15 (s, 1 H) 6.25 - 6.78 (m, 4 H) 7.02 (s, 1 H) 7.08 (s, 1 H) 7.13 (d, J=7.8 Hz, 1 H) 7.27 (s, 1 H) 9.34 (s, 1 H).
MS ESI/APCI Dual posi : 802[M+H]+, 824[M+Na]+.
MS ESI/APCI Dual nega : 836[M+Cl]-.
参考例３６ 中間体（２Ｃ−１）の製造 Step 1, Step 2, Step 3
Intermediate (1B-5) (10.6 g, 15.2 mmol) was used as a starting material, and the intermediate was converted to colorless amorphous according to the methods described in steps 1 and 2 of Reference Example 8 and Reference Example 12. (1E-24) (6.62 g, 3 steps 56%) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.19 (m, 6 H) 1.35 (s, 6 H) 1.39 (s, 6 H) 1.80 (s, 3 H) 1.99 (s, 3 H) 2.01-2.09 (m, 6 H) 2.31 (s, 3 H) 2.93-3.06 (m, 1 H) 3.75-4.02 (m, 3 H) 4.07-4.25 (m, 2 H) 4.64-4.74 (m, 1 H) 5.10-5.22 (m, 1 H) 5.26-5.39 (m, 2 H) 6.15 (s, 1 H) 6.25-6.78 (m, 4 H) 7.02 (s, 1 H) 7.08 (s, 1 H) 7.13 (d, J = 7.8 Hz, 1 H) 7.27 (s, 1 H) 9.34 (s, 1 H).
MS ESI / APCI Dual posi: 802 [M + H] + , 824 [M + Na] + .
MS ESI / APCI Dual nega: 836 [M + Cl] - .
Reference Example 36 Production of intermediate (2C-1)

Figure 2013224263
Figure 2013224263

工程１
窒素雰囲気下、中間体（１Ｂ−１）（２．５０ｇ,３．６１ｍｍｏｌ）、アクリル酸（６２５ｍｇ,８．６７ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（８１．０ｍｇ,０．３６１ｍｍｏｌ）、トリ−ｏ−トリルホスフィン（２２０ｍｇ,０．７２２ｍｍｏｌ）、トリエチルアミン（２．５０ｍＬ,１８．１ｍｍｏｌ）のアセトニトリル（１０ｍＬ）懸濁液を、マイクロウェーブ照射下１２０℃で３０分間撹拌した。反応液をセライトろ過した後、ろ液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１→酢酸エチル）で精製し、淡黄色油状物として中間体（２Ｂ−１）（１．２８ｇ,５２％）を得た。 Process 1
Under a nitrogen atmosphere, intermediate (1B-1) (2.50 g, 3.61 mmol), acrylic acid (625 mg, 8.67 mmol), palladium (II) acetate (81.0 mg, 0.361 mmol), tri-o- A suspension of trilylphosphine (220 mg, 0.722 mmol) and triethylamine (2.50 mL, 18.1 mmol) in acetonitrile (10 mL) was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to give an intermediate (2B-1) as a pale yellow oil. ) (1.28 g, 52%).

工程２
中間体（２Ｂ−１）（１．１３ｇ,１．６５ｍｍｏｌ）、０．９３Ｍ ボラン−テトラヒドロフラン錯体・テトラヒドロフラン溶液（２．６７ｍＬ,２．４８ｍｍｏｌ）のテトラヒドロフラン（２０ｍＬ）溶液を、室温で一晩撹拌した。メタノールを加えた後、溶媒を減圧下留去し、残渣をＮＨシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１→１：１）で精製し、中間体（２Ｃ−１）（６５０ｍｇ,５９％）を得た。
1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.7 Hz, 3 H) 1.14 (d, J=6.7 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 6 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.94 - 3.04 (m, 1 H) 3.72 - 3.77 (m, 1 H) 3.88 - 3.94 (m, 3 H) 4.05 (dd, J=12.4, 2.1 Hz, 1 H) 4.26 (dd, J=12.4, 4.6 Hz, 1 H) 4.29 - 4.32 (m, 2 H) 4.44 - 4.49 (m, 1 H) 5.12 - 5.16 (m, 1 H) 5.23 - 5.28 (m, 2 H) 6.34 (dt, J=15.6, 6.0 Hz, 1 H) 6.57 (d, J=15.6 Hz, 1 H) 6.69 (d, J=7.8 Hz, 1 H) 6.95 (s, 1 H) 6.99 (s, 1 H) 7.11 (d, J=7.8 Hz, 1 H) 7.22 (s, 1 H)．
参考例３７ 中間体（２Ｅ−１）の製造 Process 2
A solution of intermediate (2B-1) (1.13 g, 1.65 mmol), 0.93 M borane-tetrahydrofuran complex-tetrahydrofuran solution (2.67 mL, 2.48 mmol) in tetrahydrofuran (20 mL) was stirred overnight at room temperature. . After adding methanol, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to obtain intermediate (2C-1) (650 mg, 59 %).
1 H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.7 Hz, 3 H) 1.14 (d, J = 6.7 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H ) 2.03 (s, 3 H) 2.04 (s, 6 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.94-3.04 (m, 1 H) 3.72-3.77 (m, 1 H) 3.88-3.94 (m, 3 H) 4.05 (dd, J = 12.4, 2.1 Hz, 1 H) 4.26 (dd, J = 12.4, 4.6 Hz, 1 H) 4.29-4.32 (m, 2 H) 4.44-4.49 (m, 1 H) 5.12-5.16 (m, 1 H) 5.23-5.28 (m, 2 H) 6.34 (dt, J = 15.6, 6.0 Hz, 1 H) 6.57 (d, J = 15.6 Hz, 1 H) 6.69 (d, J = 7.8 Hz, 1 H) 6.95 (s, 1 H) 6.99 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.22 (s, 1 H).
Reference Example 37 Production of intermediate (2E-1)

Figure 2013224263
Figure 2013224263

工程１
中間体（１Ｃ−２）（０．５９ｇ,０．８７ｍｍｏｌ）のテトラヒドロフラン（１．７ｍＬ）溶液に−７８℃で０．９３Ｍ ボラン−テトラヒドロフラン錯体・テトラヒドロフラン溶液（１．０ｍＬ、０．９３ｍｍｏｌ）を滴下した。反応温度を０℃に昇温後、同温で３時間撹拌し、メタノールを加えた。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィー（クロロホルム：メタノール＝１００：０→９６：４）にて精製し、中間体（２Ｄ−１）（０．３３ｇ,８２％）を得た。 Process 1
To a solution of intermediate (1C-2) (0.59 g, 0.87 mmol) in tetrahydrofuran (1.7 mL), 0.93 M borane-tetrahydrofuran complex-tetrahydrofuran solution (1.0 mL, 0.93 mmol) was added dropwise at -78 ° C. did. After raising the reaction temperature to 0 ° C., the mixture was stirred at the same temperature for 3 hours, and methanol was added. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 100: 0 → 96: 4) to obtain intermediate (2D-1) (0.33 g, 82%).

工程２
中間体（２Ｄ−１）（０．３３ｇ,０．４８ｍｍｏｌ）、四臭化炭素（０．２５ｇ,０．７３ｍｍｏｌ）のクロロホルム溶液（１．６ｍＬ）にトリフェニルホスフィン（０．１８ｇ,０．６８ｍｍｏｌ）を加え、同温で３時間撹拌した。反応液にクロロホルムを加え、水で洗浄後、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別し、減圧濃縮後、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝３０：７０→５３：４７）にて精製し、中間体（２Ｅ−１）（０．３０ｇ,８２％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.71 - 2.82 (m, 2 H) 2.91 - 3.05 (m, 1 H) 3.47 (t, J=7.1 Hz, 2 H) 3.71 - 3.78 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J=12.4, 2.1 Hz, 1 H) 4.27 (dd, J=12.4, 4.4 Hz, 1 H) 4.43 - 4.50 (m, 1 H) 5.10 - 5.30 (m, 3 H) 6.09 - 6.21 (m, 1 H) 6.44 (d, J=15.9 Hz, 1 H) 6.68 (d, J=7.9 Hz, 1 H) 6.96 (s, 1 H) 6.99 (s, 1 H) 7.05 - 7.11 (m, 1 H) 7.18 - 7.22 (m, 1 H).
参考例３８ 中間体（３Ａ−１）の製造
工程１ Process 2
Triphenylphosphine (0.18 g, 0.68 mmol) was added to a chloroform solution (1.6 mL) of intermediate (2D-1) (0.33 g, 0.48 mmol) and carbon tetrabromide (0.25 g, 0.73 mmol). ) And stirred at the same temperature for 3 hours. Chloroform was added to the reaction solution, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: hexane = 30: 70 → 53: 47) to obtain intermediate (2E-1) (0.30 g, 82%). Got.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H ) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.71-2.82 (m, 2 H) 2.91-3.05 (m, 1 H) 3.47 (t , J = 7.1 Hz, 2 H) 3.71-3.78 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J = 12.4, 2.1 Hz, 1 H) 4.27 (dd, J = 12.4, 4.4 Hz, 1 H) 4.43-4.50 (m, 1 H) 5.10-5.30 (m, 3 H) 6.09-6.21 (m, 1 H) 6.44 (d, J = 15.9 Hz, 1 H) 6.68 (d, J = 7.9 Hz , 1 H) 6.96 (s, 1 H) 6.99 (s, 1 H) 7.05-7.11 (m, 1 H) 7.18-7.22 (m, 1 H).
Reference Example 38 Production process 1 of intermediate (3A-1)

Figure 2013224263
２,２−ジメチル−３−ブテノイックアシッド（５．４２ｇ,４７．５ｍｍｏｌ,Ｊｏｕｒｎａｌ ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ（２０００）,６５,８４０２）のクロロホルム（２５０ｍＬ）溶液に窒素雰囲気下、塩化オキサリル（４．４３ｍＬ,４９．９ｍｍｏｌ）とＮ,Ｎ−ジメチルホルムアミド（３滴）を加え、室温で１．５時間撹拌した。その後反応液を氷冷し、トリエチルアミン（１９．９ｍＬ,１４３ｍｍｏｌ）とα−アミノイソブチリックアシッドメチルエステル塩酸塩（１０．９ｇ,７１．２ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液に水を加え、クロロホルムで抽出後、有機層を３Ｍ塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン→ヘキサン：酢酸エチル＝４：１）にて精製し、無色粉末として中間体（４Ｆ−１）（９．３８ｇ,９３％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.51 (s, 6 H) 3.73 (s, 3 H) 5.17 - 5.32 (m, 2 H) 6.02 (dd, J=17.6, 10.6 Hz, 1 H) 6.25 (br. s., 1 H).
MS ESI/APCI Dual posi : 214[M+H]+.
工程２
Figure 2013224263
 A solution of 2,2-dimethyl-3-butenoic acid (5.42 g, 47.5 mmol, Journal of Organic Chemistry (2000), 65,8402) in chloroform (250 mL) under a nitrogen atmosphere and oxalyl chloride (4.43 mL). , 49.9 mmol) and N, N-dimethylformamide (3 drops) were added and stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was ice-cooled, triethylamine (19.9 mL, 143 mmol) and α-aminoisobutyric acid methyl ester hydrochloride (10.9 g, 71.2 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 3M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 4: 1) to give an intermediate (4F-1) as a colorless powder. ) (9.38 g, 93%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.51 (s, 6 H) 3.73 (s, 3 H) 5.17-5.32 (m, 2 H) 6.02 (dd, J = 17.6 , 10.6 Hz, 1 H) 6.25 (br. S., 1 H).
MS ESI / APCI Dual posi: 214 [M + H] + .
Process 2

Figure 2013224263
中間体（４Ｆ−１）（９．３８ｇ,４３．９ｍｍｏｌ）のメタノール（２０ｍＬ）溶液に４Ｍ水酸化ナトリウム水溶液（１６．５ｍＬ,６６．０ｍｍｏｌ）を加え、室温で１時間撹拌した。その後、反応混合物を濃縮した。得られた残渣を水に溶解し、３Ｍ塩酸を加えて中和した。この混合物を酢酸エチルで抽出し、合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、無色粉末として中間体（４Ｆ−２）（８．１９ｇ,９４％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.54 (s, 6 H) 5.16 - 5.36 (m, 2 H) 6.01 (dd, J=17.5, 10.7 Hz, 1 H) 6.14 (s, 1 H).
MS ESI/APCI Dual posi : 200[M+H]+, 222[M+Na]+.
MS ESI/APCI Dual nega : 198[M-H]-.
工程３
Figure 2013224263
 To a solution of intermediate (4F-1) (9.38 g, 43.9 mmol) in methanol (20 mL) was added 4M aqueous sodium hydroxide solution (16.5 mL, 66.0 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated. The obtained residue was dissolved in water and neutralized by adding 3M hydrochloric acid. This mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain Intermediate (4F-2) (8.19 g, 94%) as a colorless powder.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.54 (s, 6 H) 5.16-5.36 (m, 2 H) 6.01 (dd, J = 17.5, 10.7 Hz, 1 H) 6.14 (s, 1 H).
MS ESI / APCI Dual posi: 200 [M + H] + , 222 [M + Na] + .
MS ESI / APCI Dual nega: 198 [MH] - .
Process 3

Figure 2013224263
アルゴン雰囲気下、中間体（１Ｂ−１）（５．００ｇ,７．２３ｍｍｏｌ）、中間体（４Ｆ−２）（２．５９ｇ,１３．０ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（３２８ｍｇ,１．４５ｍｍｏｌ）、トリ−ｏ−トリルホスフィン（８８０ｍｇ,２．８９ｍｍｏｌ）、トリエチルアミン（３．０ｍＬ,９．００ｍｍｏｌ）のアセトニトリル（２４ｍＬ）懸濁液を、マイクロウェーブ照射下１２０℃で２０分間撹拌した。反応液をセライトろ過し、酢酸エチルで洗浄した。ろ液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝１：１→酢酸エチル）にて精製し、淡黄色粉末として中間体（３Ａ−１）（４．５９ｇ,７８％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16, 1.18 (each d J=6.8 Hz, 3 H) 1.40 (s, 6 H) 1.54 - 1.58 (m, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.98 - 3.10 (m, 1 H) 3.71 - 3.79 (m, 1 H) 3.94 (s, 2 H) 4.01 - 4.08 (m, 1 H) 4.24 (dd, J=12.4, 4.5 Hz, 1 H) 4.47 (d, J=9.2 Hz, 1 H) 5.07 - 5.32 (m, 3 H) 6.31 (d, J=16.3 Hz, 1 H) 6.35 (s, 1 H) 6.55 (d, J=16.3 Hz, 1 H) 6.77 (d, J=7.6 Hz, 1 H) 6.92 (s, 1 H) 6.99 (s, 1 H) 7.12 - 7.18 (m, 1 H) 7.26 (s, 1 H).
MS ESI/APCI Dual posi : 810[M+H]+, 832[M+Na]+ .
MS ESI/APCI Dual nega : 808[M-H]-.
参考例Ａ−１ アミン中間体（４Ｃ−１）の製造
Figure 2013224263
 Under an argon atmosphere, intermediate (1B-1) (5.00 g, 7.23 mmol), intermediate (4F-2) (2.59 g, 13.0 mmol), palladium (II) acetate (328 mg, 1.45 mmol) , A suspension of tri-o-tolylphosphine (880 mg, 2.89 mmol) and triethylamine (3.0 mL, 9.00 mmol) in acetonitrile (24 mL) was stirred at 120 ° C. for 20 minutes under microwave irradiation. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to give intermediate (3A-1) (4.59 g) as a pale yellow powder. 78%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16, 1.18 (each d J = 6.8 Hz, 3 H) 1.40 (s, 6 H) 1.54-1.58 (m, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.98-3.10 (m, 1 H) 3.71-3.79 (m, 1 H) 3.94 (s, 2 H) 4.01-4.08 (m, 1 H) 4.24 (dd, J = 12.4, 4.5 Hz, 1 H) 4.47 (d, J = 9.2 Hz, 1 H) 5.07-5.32 (m , 3 H) 6.31 (d, J = 16.3 Hz, 1 H) 6.35 (s, 1 H) 6.55 (d, J = 16.3 Hz, 1 H) 6.77 (d, J = 7.6 Hz, 1 H) 6.92 (s , 1 H) 6.99 (s, 1 H) 7.12-7.18 (m, 1 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 810 [M + H] + , 832 [M + Na] + .
MS ESI / APCI Dual nega: 808 [MH] - .
Reference Example A-1 Production of amine intermediate (4C-1)

Figure 2013224263
Figure 2013224263

工程１
Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−１,２−ジアミノエタン（１．００ｇ,６．２４ｍｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド（２５ｍＬ）溶液へＣＤＩ（１．５２ｇ,９．３６ｍｍｏｌ）を加え、室温で３時間撹拌した。ここへ２８％アンモニア水溶液（２５ｍＬ）を加え、加熱還流下にて３時間撹拌した。反応液を室温へ冷却後、減圧下濃縮した。得られた残渣へ酢酸エチルを加え、水で洗浄した。水層を酢酸エチル／ヘキサンの混合溶媒で抽出し、得られた有機層と先の有機層を合わせ、硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して、残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノール＝９５：５→８５：１５）で精製し、無色固体として中間体（４Ｃ−１ａ）（１．１９ｇ,９４％）を得た。 Process 1
CDI (1.52 g, 9.36 mmol) was added to a solution of N- (tert-butoxycarbonyl) -1,2-diaminoethane (1.00 g, 6.24 mmol) in N, N-dimethylformamide (25 mL) at room temperature. For 3 hours. A 28% aqueous ammonia solution (25 mL) was added thereto, and the mixture was stirred for 3 hours under reflux with heating. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added to the resulting residue and washed with water. The aqueous layer was extracted with a mixed solvent of ethyl acetate / hexane, and the obtained organic layer and the previous organic layer were combined and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5 → 85: 15) to obtain intermediate (4C-1a) ( 1.19 g, 94%).

工程２
中間体（４Ｃ−１ａ）（１．１９ｇ,５．８６ｍｍｏｌ）の酢酸エチル（３０ｍＬ）溶液へ４Ｍ塩化水素／酢酸エチル（３０ｍＬ）を加え、室温で一晩撹拌した。反応液を減圧下濃縮した後、得られた残渣を酢酸エチルで洗浄し、淡黄色油状物としてアミン中間体（４Ｃ−１）（１．１９ｇ）を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 2.72 - 2.88 (m, 2 H) 3.13 - 3.25 (m, 2 H).
MS ESI/APCI Dual posi : 104[M+H]+, 126[M+Na]+.
参考例Ａ−２ アミン中間体（４Ｃ−２）の製造 Process 2
To a solution of intermediate (4C-1a) (1.19 g, 5.86 mmol) in ethyl acetate (30 mL) was added 4M hydrogen chloride / ethyl acetate (30 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate to obtain amine intermediate (4C-1) (1.19 g) as a pale yellow oil.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 2.72-2.88 (m, 2 H) 3.13-3.25 (m, 2 H).
MS ESI / APCI Dual posi: 104 [M + H] + , 126 [M + Na] + .
Reference Example A-2 Production of amine intermediate (4C-2)

Figure 2013224263
Figure 2013224263

工程１
Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−１,２−ジアミノエタン（５００ｍｇ,３．１２ｍｍｏｌ）、トリエチルアミン（６５０μＬ,４．６８ｍｍｏｌ）のテトラヒドロフラン（１６ｍＬ）溶液へ、氷冷下にてメタンスルホニルクロリド（２９０μＬ,３．７５ｍｍｏｌ）を加えた。氷浴をはずした後、３時間撹拌を行い、ここへ水を加えて酢酸エチルで抽出し、得られた有機層を硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して、残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノール＝９８：２→９０：１０）で精製し、無色固体として中間体（４Ｃ−２ａ）（６０６ｍｇ,８２％）を得た。 Process 1
To a solution of N- (tert-butoxycarbonyl) -1,2-diaminoethane (500 mg, 3.12 mmol) and triethylamine (650 μL, 4.68 mmol) in tetrahydrofuran (16 mL) was added methanesulfonyl chloride (290 μL, 3.75 mmol) was added. After removing the ice bath, the mixture was stirred for 3 hours, water was added thereto, extraction was performed with ethyl acetate, and the obtained organic layer was dried over sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 → 90: 10) to obtain the intermediate (4C-2a) ( 606 mg, 82%).

工程２
中間体（４Ｃ−２ａ）（５９９ｍｇ,２．５１ｍｍｏｌ）から、参考例Ａ−１の工程２と同様の方法により、淡褐色固体としてアミン中間体（４Ｃ−２）（３３８ｍｇ）を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 2.84 - 2.96 (m, 2 H) 2.96 (s, 3 H) 3.15 - 3.28 (m, 2 H).
MS ESI/APCI Dual posi : 139[M+H]+, 161[M+Na]+.
参考例Ａ−３ アミン中間体（４Ｃ−３）の製造 Process 2
Amine intermediate (4C-2) (338 mg) was obtained as a light brown solid from intermediate (4C-2a) (599 mg, 2.51 mmol) by the same method as in step 2 of Reference Example A-1.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 2.84-2.96 (m, 2 H) 2.96 (s, 3 H) 3.15-3.28 (m, 2 H).
MS ESI / APCI Dual posi: 139 [M + H] + , 161 [M + Na] + .
Reference Example A-3 Production of amine intermediate (4C-3)

Figure 2013224263
Figure 2013224263

工程１
（２−アミノ−２−メチル−プロピル）−カルバミックアシッド−ｔｅｒｔブチルエステル（４．３９ｇ,２３．３ｍｍｏｌ）、炭酸水素ナトリウム（２．９４ｇ,３５．０ｍｍｏｌ）の酢酸エチル−水混合懸濁液（１：２,４５ｍＬ）に室温でクロロギ酸ベンジル（５．１８ｇ,３０．３ｍｍｏｌ）を加え,同温で一晩撹拌した。反応液をろ過後、ろ液を酢酸エチルで抽出し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝８０：２０→５０：５０）で精製し、無色固体として中間体（４Ｃ−３ａ）（７．３４ｇ,９８％）を得た。 Process 1
(2-Amino-2-methyl-propyl) -carbamic acid-tertbutyl ester (4.39 g, 23.3 mmol), sodium bicarbonate (2.94 g, 35.0 mmol) in ethyl acetate-water mixed suspension (1: 2, 45 mL) was added benzyl chloroformate (5.18 g, 30.3 mmol) at room temperature, and the mixture was stirred overnight at the same temperature. After filtering the reaction solution, the filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 50: 50) to obtain intermediate (4C-3a) (7.34 g, 98%) as a colorless solid.

工程２
中間体（４Ｃ−３ａ）（７．３４ｇ,２２．８ｍｍｏｌ）の酢酸エチル溶液（３０ｍＬ）へ４Ｍ塩化水素／酢酸エチル（３０ｍＬ）を加え、室温で一晩撹拌した。反応液を減圧下濃縮し、中間体（４Ｃ−３ｂ）（６．１７ｇ）を得た。 Process 2
4M Hydrogen chloride / ethyl acetate (30 mL) was added to an ethyl acetate solution (30 mL) of intermediate (4C-3a) (7.34 g, 22.8 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain Intermediate (4C-3b) (6.17 g).

工程３
中間体（４Ｃ−３ｂ）（１．０ｇ,３．８６ｍｍｏｌ）のクロロホルム（１６ｍＬ）溶液へトリエチルアミン（８００μＬ,５．７９ｍｍｏｌ）を加えた後、氷冷下にてメタンスルホニルクロリド（３６０μＬ,４．６４ｍｍｏｌ）を加えた。氷浴をはずした後、一晩撹拌した。反応液へ水を加えてクロロホルムで抽出し、得られた有機層を硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して、残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝５０：５０→３３：６７）で精製し、無色油状物として中間体（４Ｃ−３ｃ）（１．０８ｇ,９３％）を得た。 Process 3
Triethylamine (800 μL, 5.79 mmol) was added to a solution of intermediate (4C-3b) (1.0 g, 3.86 mmol) in chloroform (16 mL), and then methanesulfonyl chloride (360 μL, 4.64 mmol) was cooled with ice. ) Was added. After removing the ice bath, the mixture was stirred overnight. Water was added to the reaction solution, followed by extraction with chloroform, and the resulting organic layer was dried over sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50 → 33: 67) to give the intermediate (4C-3c) as a colorless oil. ) (1.08 g, 93%).

工程４
中間体（４Ｃ−３ｃ）（１．０８ｇ,３．５９ｍｍｏｌ）、２０％水酸化パラジウムカーボン（２１６ｍｇ）のメタノール（１８ｍＬ）懸濁液を、水素雰囲気下にて室温で一晩撹拌した。反応液をセライトろ過後、溶媒を減圧下留去し、アミン中間体（４Ｃ−３）（５９６ｍｇ）を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.01 (s, 6 H) 2.79 (s, 2 H) 2.91 (s, 3 H).
MS ESI/APCI Dual posi : 167[M+H]+.
MS ESI/APCI Dual nega : 165[M-H]-.
参考例Ａ−４ アミン中間体（４Ｃ−４）の製造 Process 4
A suspension of intermediate (4C-3c) (1.08 g, 3.59 mmol), 20% palladium hydroxide on carbon (216 mg) in methanol (18 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was evaporated under reduced pressure to obtain an amine intermediate (4C-3) (596 mg).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.01 (s, 6 H) 2.79 (s, 2 H) 2.91 (s, 3 H).
MS ESI / APCI Dual posi: 167 [M + H] + .
MS ESI / APCI Dual nega: 165 [MH] - .
Reference Example A-4 Production of amine intermediate (4C-4)

Figure 2013224263
Figure 2013224263

工程１
Ｎ−カルボベンゾキシ−１,２−ジアミノエタン塩酸塩（１．０ｇ,４．３３ｍｍｏｌ）、２−（ｔｅｒｔ−ブトキシカルボニルアミノ）イソ酪酸（１．１５ｇ,５．６４ｍｍｏｌ）、ＥＤＣ−ＨＣｌ（７６２ｍｇ,５．６４ｍｍｏｌ）、ＨＯＢｔ・Ｈ2Ｏ（１．０８ｇ,５．６４ｍｍｏｌ）、トリエチルアミン（１．８ｍＬ,１３ｍｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド（２２ｍＬ）溶液を室温で一晩撹拌した。反応液へ酢酸エチルを加えた後、水で洗浄を行い、硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝５０：５０→２０：８０）で精製し、無色固体として中間体（４Ｃ−４ａ）（１．６６ｇ）を得た。 Process 1
N-carbobenzoxy-1,2-diaminoethane hydrochloride (1.0 g, 4.33 mmol), 2- (tert-butoxycarbonylamino) isobutyric acid (1.15 g, 5.64 mmol), EDC-HCl (762 mg) , 5.64 mmol), HOBt · H 2 O (1.08 g, 5.64 mmol), triethylamine (1.8 mL, 13 mmol) in N, N-dimethylformamide (22 mL) was stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, washed with water, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50 → 20: 80) to obtain intermediate (4C-4a) ( 1.66 g) was obtained.

工程２
中間体（４Ｃ−４ａ）（１．６６ｇ,４．３８ｍｍｏｌ）を出発原料として、参考例Ａ−３の工程４に記載されている方法に準拠して、無色油状物としてアミン中間体（４Ｃ−４）（１．１ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 1.48 (s, 6 H) 2.54 (br. s., 2 H) 2.89 - 2.95 (m, 2 H) 3.33 - 3.45 (m, 2 H) 4.99 (br. s., 1 H) 6.96 (br. s., 1 H).
MS ESI/APCI Dual posi : 246[M+H]+.
MS ESI/APCI Dual nega : 280[M+Cl]-.
参考例Ａ−５ アミン中間体（４Ｃ−５）の製造 Process 2
The intermediate (4C-4a) (1.66 g, 4.38 mmol) was used as a starting material in accordance with the method described in Step 4 of Reference Example A-3, and the amine intermediate (4C- 4) (1.1 g) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 1.48 (s, 6 H) 2.54 (br. S., 2 H) 2.89-2.95 (m, 2 H) 3.33-3.45 ( m, 2 H) 4.99 (br. s., 1 H) 6.96 (br. s., 1 H).
MS ESI / APCI Dual posi: 246 [M + H] + .
MS ESI / APCI Dual nega: 280 [M + Cl] - .
Reference Example A-5 Production of amine intermediate (4C-5)

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（４Ｃ−３ｂ）（１．０ｇ,３．８６ｍｍｏｌ）を出発原料として、参考例Ａ−４の工程１および工程２に記載されている方法に準拠して、無色アモルファスとしてアミン中間体（４Ｃ−５）（４９０ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (s, 6 H) 1.43 (s, 9 H) 1.52 (s, 6 H) 3.34 (d, J=5.8 Hz, 2 H).
MS ESI/APCI Dual posi : 274[M+H]+, 296[M+Na]+.
MS ESI/APCI Dual nega : 308[M+Cl]-.
参考例Ａ−６ アミン中間体（４Ｃ−６）の製造 Step 1 and Step 2
The intermediate (4C-3b) (1.0 g, 3.86 mmol) was used as a starting material, and the amine intermediate (as colorless amorphous) was prepared according to the method described in Step 1 and Step 2 of Reference Example A-4. 4C-5) (490 mg) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (s, 6 H) 1.43 (s, 9 H) 1.52 (s, 6 H) 3.34 (d, J = 5.8 Hz, 2 H).
MS ESI / APCI Dual posi: 274 [M + H] + , 296 [M + Na] + .
MS ESI / APCI Dual nega: 308 [M + Cl] - .
Reference Example A-6 Production of amine intermediate (4C-6)

Figure 2013224263
Figure 2013224263

工程１、工程２
１−カルボベンゾキシピペラジン（１．００ｇ,４．５４ｍｍｏｌ）を出発原料として、参考例Ａ−４の工程１および工程２に記載されている方法に準拠して、無色油状物としてアミン中間体（４Ｃ−６）（１．０５ｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 1.50 (s, 6 H) 2.82 - 2.90 (m, 4 H) 3.63 - 3.75 (m, 4 H).
MS ESI/APCI Dual posi : 272[M+H]+, 284[M+Na]+.
参考例Ａ−７ アミン中間体（４Ｃ−７）の製造 Step 1 and Step 2
Starting from 1-carbobenzoxypiperazine (1.00 g, 4.54 mmol) as a starting material, according to the method described in Step 1 and Step 2 of Reference Example A-4, the amine intermediate ( 4C-6) (1.05 g) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 1.50 (s, 6 H) 2.82-2.90 (m, 4 H) 3.63-3.75 (m, 4 H).
MS ESI / APCI Dual posi: 272 [M + H] + , 284 [M + Na] + .
Reference Example A-7 Production of amine intermediate (4C-7)

Figure 2013224263
Figure 2013224263

工程１
Ｃｂｚ−グリシン（１００ｍｇ,０．３５８ｍｍｏｌ）のテトラヒドロフラン（２ｍＬ）溶液にＣＤＩ（１．４ｇ,８．９ｍｍｏｌ）を室温で加え、同温で３０分間撹拌した。これに、２−メチルプロパン−１,２−ジアミン（６３．２ｍｇ,０．７１７ｍｍｏｌ）を加え、さらに同温で一晩撹拌した。反応液を減圧濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９７：３→２５：７５）で精製し、白色固体として中間体（４Ｃ−７ａ）（１００ｍｇ,５９％）を得た。 Process 1
To a solution of Cbz-glycine (100 mg, 0.358 mmol) in tetrahydrofuran (2 mL) was added CDI (1.4 g, 8.9 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To this, 2-methylpropane-1,2-diamine (63.2 mg, 0.717 mmol) was added and further stirred overnight at the same temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3 → 25: 75) to give intermediate (4C-7a) (100 mg, 59%) as a white solid. Obtained.

工程２
中間体（４Ｃ−７ａ）（１００ｍｇ,０．３５８ｍｍｏｌ）、Ｂｏｃ2Ｏ（０．１２ｍＬ,０．５３７ｍｍｏｌ）、およびトリエチルアミン（０．０７５ｍＬ,０．５３７ｍｍｏｌ）のクロロホルム（１．５ｍＬ）溶液を室温下一晩撹拌した。溶媒を減圧下留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８５：１５→２０：８０）により精製し、無色油状物として中間体（４Ｃ−７ｂ）（１３６ｍｇ,１００％）を得た。 Process 2
A solution of intermediate (4C-7a) (100 mg, 0.358 mmol), Boc 2 O (0.12 mL, 0.537 mmol), and triethylamine (0.075 mL, 0.537 mmol) in chloroform (1.5 mL) at room temperature. Stir overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15 → 20: 80) to obtain intermediate (4C-7b) (136 mg, 100%) as a colorless oil. Obtained.

工程３
中間体（４Ｃ−７ｂ）（６３ｍｇ,０．１６６ｍｍｏｌ）を出発原料として、参考例Ａ−３の工程４に記載されている方法に準拠して、無色油状物としてアミン中間体（４Ｃ−７）（４０ｍｇ,９８％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.44 (s, 9 H) 3.39 (s, 2 H) 3.45 (d, J=6.4 Hz, 2 H) 4.84 (br. s., 1 H) 7.72 (br. s., 1 H).
MS ESI/APCI Dual posi : 246[M+H]+, 268[M+Na]+.
参考例Ａ−８ アミン中間体（４Ｃ−８）の製造 Process 3
Starting from intermediate (4C-7b) (63 mg, 0.166 mmol) as a starting material, the amine intermediate (4C-7) was obtained as a colorless oil according to the method described in Step 4 of Reference Example A-3. (40 mg, 98%) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.44 (s, 9 H) 3.39 (s, 2 H) 3.45 (d, J = 6.4 Hz, 2 H) 4.84 (br. s., 1 H) 7.72 (br. s., 1 H).
MS ESI / APCI Dual posi: 246 [M + H] + , 268 [M + Na] + .
Reference Example A-8 Production of amine intermediate (4C-8)

Figure 2013224263
Figure 2013224263

工程１
Ｃｂｚ−Ａｉｂ−ＯＨ（２．０ｇ,８．４ｍｍｏｌ）のテトラヒドロフラン（８４ｍＬ）溶液にＣＤＩ（１．４ｇ,８．９ｍｍｏｌ）を室温で加え、同温で１時間撹拌した。これに、グリシンアミド・塩酸塩（０．９８ｇ,８．９ｍｍｏｌ）を加え、さらに同温で３日間撹拌した。反応液を減圧濃縮後、４％炭酸水素ナトリウム水溶液を加えて２時間撹拌後、生じた結晶をろ取し、よく水洗し、減圧乾燥した。得られた結晶をシリカゲルクロマトグラフィー（クロロホルム：メタノール＝２０：１→８７：１３）で精製し、中間体（４Ｃ−８ａ）（１．２ｇ、４７％）を得た。 Process 1
CDI (1.4 g, 8.9 mmol) was added to a solution of Cbz-Aib-OH (2.0 g, 8.4 mmol) in tetrahydrofuran (84 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To this was added glycinamide hydrochloride (0.98 g, 8.9 mmol), and the mixture was further stirred at the same temperature for 3 days. The reaction mixture was concentrated under reduced pressure, 4% aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for 2 hr. The resulting crystals were collected by filtration, washed well with water and dried under reduced pressure. The obtained crystals were purified by silica gel chromatography (chloroform: methanol = 20: 1 → 87: 13) to obtain an intermediate (4C-8a) (1.2 g, 47%).

工程２
中間体（４Ｃ−８ａ）を出発原料として、参考例Ａ−３の工程４に記載されている方法に準拠して、アミン中間体（４Ｃ−８）（０．６７ｇ）を得た。これは目的物以外の化合物を含んでいたが、これ以上精製せずに次の反応に用いた。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (s, 6 H) 3.63 (s, 2 H) 7.08 (br. s., 2 H) 8.17 (br. s, 1 H).
MS ESI/APCI Dual posi : 160[M+H]+.
MS ESI/APCI Dual nega : 158[M-H]-, 194[M+Cl]-.
参考例Ａ−９ アミン中間体（４Ｃ−９）の製造 Process 2
Based on the method described in Step 4 of Reference Example A-3, using Intermediate (4C-8a) as a starting material, amine intermediate (4C-8) (0.67 g) was obtained. This contained a compound other than the desired product, but was used in the next reaction without further purification.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.21 (s, 6 H) 3.63 (s, 2 H) 7.08 (br. S., 2 H) 8.17 (br. S, 1 H).
MS ESI / APCI Dual posi: 160 [M + H] + .
MS ESI / APCI Dual nega: 158 [MH] - , 194 [M + Cl] - .
Reference Example A-9 Production of amine intermediate (4C-9)

Figure 2013224263
Figure 2013224263

工程１、工程２
Ｃｂｚ−Ａｉｂ−ＯＨ（１．０ｇ,４．２１ｍｍｏｌ）と２−アミノ−２−メチルプロパンアミド（５１６ｍｇ,５．０５ｍｍｏｌ）を出発原料として、参考例Ａ−４の工程１および工程２に記載されている方法に準拠して、無色油状物としてアミン中間体（４Ｃ−９）（６６８ｍｇ）を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.22 (s, 6 H) 1.39 (s, 6 H).
MS ESI/APCI Dual posi : 188[M+H]+.
MS ESI/APCI Dual nega : 186[M-H]-, 222[M+Cl]-.
参考例Ａ−１０ アミン中間体（４Ｃ−１０）の製造 Step 1 and Step 2
It is described in Step 1 and Step 2 of Reference Example A-4 using Cbz-Aib-OH (1.0 g, 4.21 mmol) and 2-amino-2-methylpropanamide (516 mg, 5.05 mmol) as starting materials. According to the above method, amine intermediate (4C-9) (668 mg) was obtained as a colorless oil.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.22 (s, 6 H) 1.39 (s, 6 H).
MS ESI / APCI Dual posi: 188 [M + H] + .
MS ESI / APCI Dual nega: 186 [MH] - , 222 [M + Cl] - .
Reference Example A-10 Production of amine intermediate (4C-10)

Figure 2013224263
Figure 2013224263

工程１、工程２
Ｃｂｚ−Ａｉｂ−ＯＨ（５００ｍｇ,２．１１ｍｍｏｌ）とｔｅｒｔ−ブチル（１−アミノ−２−メチルプロパン−２−イル）カーバメート（４７６ｍｇ,２．５３ｍｍｏｌ）を出発原料として、参考例Ａ−４の工程１および工程２に記載されている方法に準拠して、無色アモルファスとしてアミン中間体（４Ｃ−１０）（４７７ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.44 (s, 9 H) 1.57 (s, 6 H) 3.39 (d, J=5.8 Hz, 2 H) 7.99 - 8.38 (m, 1 H).
MS ESI/APCI Dual posi : 274[M+H]+.
MS ESI/APCI Dual nega : 308[M+Cl]-.
参考例Ａ−１１ アミン中間体（４Ｃ−１１）の製造 Step 1 and Step 2
Process of Reference Example A-4 using Cbz-Aib-OH (500 mg, 2.11 mmol) and tert-butyl (1-amino-2-methylpropan-2-yl) carbamate (476 mg, 2.53 mmol) as starting materials According to the method described in 1 and Step 2, amine intermediate (4C-10) (477 mg) was obtained as colorless amorphous.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.44 (s, 9 H) 1.57 (s, 6 H) 3.39 (d, J = 5.8 Hz, 2 H) 7.99-8.38 ( m, 1 H).
MS ESI / APCI Dual posi: 274 [M + H] + .
MS ESI / APCI Dual nega: 308 [M + Cl] - .
Reference Example A-11 Production of amine intermediate (4C-11)

Figure 2013224263
Figure 2013224263

工程１、工程２
Ｃｂｚ−Ａｉｂ−ＯＨ（３．００ｇ,１２．６ｍｍｏｌ）とトリス（ヒドロキシメチル）アミノメタン（１．６０ｇ,１３．３ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色固体としてアミン中間体（４Ｃ−１１）（６３４ｍｇ）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 6 H) 3.69 (s, 6 H).
MS ESI/APCI Dual posi : 207[M+H]+.
MS ESI/APCI Dual nega : 205[M-H]-, 241[M+Cl]-.
参考例Ａ−１２ アミン中間体（４Ｃ−１２）の製造 Step 1 and Step 2
Described in Step 1 and Step 2 of Reference Example A-8 using Cbz-Aib-OH (3.00 g, 12.6 mmol) and tris (hydroxymethyl) aminomethane (1.60 g, 13.3 mmol) as starting materials. According to the method, amine intermediate (4C-11) (634 mg) was obtained as a colorless solid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 6 H) 3.69 (s, 6 H).
MS ESI / APCI Dual posi: 207 [M + H] + .
MS ESI / APCI Dual nega: 205 [MH] - , 241 [M + Cl] - .
Reference Example A-12 Production of amine intermediate (4C-12)

Figure 2013224263
Figure 2013224263

工程１、工程２
Ｃｂｚ−Ａｉｂ−ＯＨ（１．０ｇ,４．２ｍｍｏｌ）とグリシンメチルエステル・塩酸塩（１．６ｇ,１３ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、アミン中間体（４Ｃ−１２）（１．３ｇ,２工程８７％）を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.21 (s, 6 H) 3.64 (s, 3 H) 3.81 - 3.89 (m, 2 H) 8.31 (br. s, 1 H).
MS ESI/APCI Dual posi : 175[M+H]+.
参考例Ａ−１３ アミン中間体（４Ｃ−１３）の製造 Step 1 and Step 2
The method described in steps 1 and 2 of Reference Example A-8 using Cbz-Aib-OH (1.0 g, 4.2 mmol) and glycine methyl ester / hydrochloride (1.6 g, 13 mmol) as starting materials. To obtain an amine intermediate (4C-12) (1.3 g, 87% for 2 steps).
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.21 (s, 6 H) 3.64 (s, 3 H) 3.81-3.89 (m, 2 H) 8.31 (br. S, 1 H).
MS ESI / APCI Dual posi: 175 [M + H] + .
Reference Example A-13 Production of amine intermediate (4C-13)

Figure 2013224263
Figure 2013224263

工程１、工程２
Ｃｂｚ−Ａｉｂ−ＯＨ（１．０ｇ,４．２ｍｍｏｌ）と３−アミノプロパノール（０．９６ｍＬ,１３ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色液体としてアミン中間体（４Ｃ−１３）（０．３１ｇ,２工程４６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 6 H) 1.62 - 1.72 (m, 2 H) 3.35 - 3.44 (m, 2 H) 3.57 (t, J=5.4 Hz, 2 H).
MS ESI/APCI Dual posi : 161[M+H]+.
MS ESI/APCI Dual nega : 159[M-H]-.
参考例Ａ−１４ アミン中間体（４Ｃ−１４）の製造 Step 1 and Step 2
Conforms to the methods described in steps 1 and 2 of Reference Example A-8 using Cbz-Aib-OH (1.0 g, 4.2 mmol) and 3-aminopropanol (0.96 mL, 13 mmol) as starting materials. Thus, an amine intermediate (4C-13) (0.31 g, 46% for 2 steps) was obtained as a colorless liquid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 6 H) 1.62-1.72 (m, 2 H) 3.35-3.44 (m, 2 H) 3.57 (t, J = 5.4 Hz, 2 H) .
MS ESI / APCI Dual posi: 161 [M + H] + .
MS ESI / APCI Dual nega: 159 [MH] - .
Reference Example A-14 Production of amine intermediate (4C-14)

Figure 2013224263
Figure 2013224263

工程１、工程２
Ｃｂｚ−Ａｉｂ−ＯＨ（１．０ｇ,４．２ｍｍｏｌ）と４−アミノブタノール（１．２ｍＬ,１３ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色液体としてアミン中間体（４Ｃ−１４）（０．５２ｇ,２工程７１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 6 H) 1.56 - 1.64 (m, 4 H) 3.27 (q, J=6.6 Hz, 2 H) 3.64 - 3.72 (m, 2 H) 7.72 (br. s., 1 H).
MS ESI/APCI Dual posi : 175[M+H]+, 197[M+Na]+.
MS ESI/APCI Dual nega : 173[M-H]-.
参考例Ａ−１５ アミン中間体（４Ｃ−１５）の製造 Step 1 and Step 2
Conforms to the methods described in steps 1 and 2 of Reference Example A-8 using Cbz-Aib-OH (1.0 g, 4.2 mmol) and 4-aminobutanol (1.2 mL, 13 mmol) as starting materials. Thus, an amine intermediate (4C-14) (0.52 g, 2 steps 71%) was obtained as a colorless liquid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 6 H) 1.56-1.64 (m, 4 H) 3.27 (q, J = 6.6 Hz, 2 H) 3.64-3.72 (m, 2 H) 7.72 (br. S., 1 H).
MS ESI / APCI Dual posi: 175 [M + H] + , 197 [M + Na] + .
MS ESI / APCI Dual nega: 173 [MH] - .
Reference Example A-15 Production of amine intermediate (4C-15)

Figure 2013224263
Figure 2013224263

工程１、工程２
Ｃｂｚ−Ａｉｂ−ＯＨ（１．０ｇ,４．２ｍｍｏｌ）と５−アミノペンタノール（１．４ｍＬ,１３ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色液体としてアミン中間体（４Ｃ−１５）（０．５２ｇ,２工程８２％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 6 H) 1.37 - 1.47 (m, 2 H) 1.49 - 1.70 (m, 4 H) 3.23 (q, J=6.8 Hz, 2 H) 3.65 (t, J=6.4 Hz, 2 H) 7.65 (br. s., 1 H).
MS ESI/APCI Dual posi : 189[M+H]+, 211[M+Na]+.
MS ESI/APCI Dual nega : 187[M-H]-.
参考例Ａ−１６ アミン中間体（４Ｃ−１６）の製造 Step 1 and Step 2
Using Cbz-Aib-OH (1.0 g, 4.2 mmol) and 5-aminopentanol (1.4 mL, 13 mmol) as starting materials, the methods described in steps 1 and 2 of Reference Example A-8 were used. Based on the above, amine intermediate (4C-15) (0.52 g, 2 steps 82%) was obtained as a colorless liquid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 6 H) 1.37-1.47 (m, 2 H) 1.49-1.70 (m, 4 H) 3.23 (q, J = 6.8 Hz, 2 H) 3.65 (t, J = 6.4 Hz, 2 H) 7.65 (br. S., 1 H).
MS ESI / APCI Dual posi: 189 [M + H] + , 211 [M + Na] + .
MS ESI / APCI Dual nega: 187 [MH] - .
Reference Example A-16 Production of amine intermediate (4C-16)

Figure 2013224263
Figure 2013224263

工程１、工程２
３−（ベンジルオキシカルボニルアミノ）−２,２−ジメチルプロパノイックアシッド（０．８０ｇ,３．２ｍｍｏｌ,ＷＯ２００４０１８４９１）とグリシンアミド・塩酸塩（０．３５ｇ,３．２ｍｍｏｌ））を出発原料として、参考例Ａ−４の工程１および工程２に記載されている方法に準拠して、アミン中間体（４Ｃ−１６）（０．４９ｇ,２工程８９％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.25 (s, 6 H) 2.88 (s, 2 H) 3.86 (s, 2 H).
MS ESI/APCI Dual posi : 174[M+H]+, 196[M+Na]+.
MS ESI/APCI Dual nega : 172[M-H]-, 208[M+Cl]-.
参考例Ａ−１７ アミン中間体（４Ｃ−１７）の製造 Step 1 and Step 2
3- (Benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.80 g, 3.2 mmol, WO2004018491) and glycinamide hydrochloride (0.35 g, 3.2 mmol)) as starting materials, Based on the method described in Step 1 and Step 2 of Reference Example A-4, amine intermediate (4C-16) (0.49 g, 2 steps 89%) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.25 (s, 6 H) 2.88 (s, 2 H) 3.86 (s, 2 H).
MS ESI / APCI Dual posi: 174 [M + H] + , 196 [M + Na] + .
MS ESI / APCI Dual nega: 172 [MH] - , 208 [M + Cl] - .
Reference Example A-17 Production of amine intermediate (4C-17)

Figure 2013224263
Figure 2013224263

工程１、工程２
３−（ベンジルオキシカルボニルアミノ）−２,２−ジメチルプロパノイックアシッド（１．０ｇ,４．０ｍｍｏｌ,ＷＯ２００４０１８４９１）とグリシンメチルエステル・塩酸塩（０．７９ｇ,６．３ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、アミン中間体（４Ｃ−１７）（０．５８ｇ,２工程７７％）を得た。
1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 6 H) 2.56 (s, 2 H) 3.62 (s, 3 H) 3.80 (d, J=5.9 Hz, 2 H) 8.34 - 8.46 (m, 1 H).
MS ESI/APCI Dual posi : 189[M+H]+.
MS ESI/APCI Dual nega : 187[M-H]-.
参考例Ａ−１８ アミン中間体（４Ｃ−１８）の製造 Step 1 and Step 2
Using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (1.0 g, 4.0 mmol, WO2004018491) and glycine methyl ester hydrochloride (0.79 g, 6.3 mmol) as starting materials, Based on the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-17) (0.58 g, 2 steps 77%) was obtained.
1 H NMR (300 MHz, DMSO-d 6 ) δ ppm 1.03 (s, 6 H) 2.56 (s, 2 H) 3.62 (s, 3 H) 3.80 (d, J = 5.9 Hz, 2 H) 8.34-8.46 (m, 1 H).
MS ESI / APCI Dual posi: 189 [M + H] + .
MS ESI / APCI Dual nega: 187 [MH] - .
Reference Example A-18 Production of amine intermediate (4C-18)

Figure 2013224263
Figure 2013224263

工程１、工程２
３−（ベンジルオキシカルボニルアミノ）−２,２−ジメチルプロパノイックアシッド（０．５０ｇ,２．０ｍｍｏｌ,ＷＯ２００４０１８４９１）と３−アミノプロパノール（０．４６ｍＬ,６．０ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色固体としてアミン中間体（４Ｃ−１８）（０．３０ｇ,２工程８７％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 (s, 6 H) 1.61 - 1.71 (m, 2 H) 1.98 (br. s., 2 H) 2.79 (s, 2 H) 3.41 (s, 2 H) 3.55 - 3.61 (m, 2 H) 8.18 (br. s., 1 H).
MS ESI/APCI Dual posi : 175[M+H]+, 197[M+Na]+.
MS ESI/APCI Dual nega : 209[M+Cl]-.
参考例Ａ−１９ アミン中間体（４Ｃ−１９）の製造 Step 1 and Step 2
Reference example using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and 3-aminopropanol (0.46 mL, 6.0 mmol) as starting materials Based on the method described in Step 1 and Step 2 of A-8, amine intermediate (4C-18) (0.30 g, 87% for 2 steps) was obtained as a colorless solid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 (s, 6 H) 1.61-1.71 (m, 2 H) 1.98 (br. S., 2 H) 2.79 (s, 2 H) 3.41 (s, 2 H) 3.55-3.61 (m, 2 H) 8.18 (br.s., 1 H).
MS ESI / APCI Dual posi: 175 [M + H] + , 197 [M + Na] + .
MS ESI / APCI Dual nega: 209 [M + Cl] - .
Reference Example A-19 Production of amine intermediate (4C-19)

Figure 2013224263
Figure 2013224263

工程１、工程２
３−（ベンジルオキシカルボニルアミノ）−２,２−ジメチルプロパノイックアシッド（０．５０ｇ,２．０ｍｍｏｌ,ＷＯ２００４０１８４９１）と４−アミノブタノール（０．５６ｍＬ,６．０ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色液体としてアミン中間体（４Ｃ−１９）（０．２３ｇ,２工程６１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.55 - 1.66 (m, 4 H) 2.78 (s, 2 H) 3.24 - 3.33 (m, 2 H) 3.64 - 3.72 (m, 2 H) 7.90 (br. s., 1 H).
MS ESI/APCI Dual posi : 189[M+H]+, 211[M+Na]+.
MS ESI/APCI Dual nega : 187[M-H]-.
参考例Ａ−２０ アミン中間体（４Ｃ−２０）の製造 Step 1 and Step 2
Reference example using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and 4-aminobutanol (0.56 mL, 6.0 mmol) as starting materials According to the method described in Steps 1 and 2 of A-8, an amine intermediate (4C-19) (0.23 g, 2 steps 61%) was obtained as a colorless liquid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.55-1.66 (m, 4 H) 2.78 (s, 2 H) 3.24-3.33 (m, 2 H) 3.64-3.72 (m , 2 H) 7.90 (br. S., 1 H).
MS ESI / APCI Dual posi: 189 [M + H] + , 211 [M + Na] + .
MS ESI / APCI Dual nega: 187 [MH] - .
Reference Example A-20 Production of amine intermediate (4C-20)

Figure 2013224263
Figure 2013224263

工程１、工程２
３−（ベンジルオキシカルボニルアミノ）−２,２−ジメチルプロパノイックアシッド（０．５０ｇ,２．０ｍｍｏｌ,ＷＯ２００４０１８４９１）と５−アミノペンタノール（０．６ｍｇ,６．０ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色液体としてアミン中間体（４Ｃ−２０）（０．３６ｇ,２工程８７％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.34 - 1.47 (m, 2 H) 1.48 - 1.66 (m, 4 H) 2.77 (s, 2 H) 3.21 - 3.29 (m, 2 H) 3.64 (t, J=6.4 Hz, 2 H) 7.80 (br. s., 1 H).
MS ESI/APCI Dual posi : 203[M+H]+, 225[M+Na]+.
MS ESI/APCI Dual nega : 201[M-H]-.
参考例Ａ−２１ アミン中間体（４Ｃ−２１）の製造 Step 1 and Step 2
Reference was made using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and 5-aminopentanol (0.6 mg, 6.0 mmol) as starting materials. According to the method described in Step 1 and Step 2 of Example A-8, amine intermediate (4C-20) (0.36 g, 87% for 2 steps) was obtained as a colorless liquid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.34-1.47 (m, 2 H) 1.48-1.66 (m, 4 H) 2.77 (s, 2 H) 3.21-3.29 (m , 2 H) 3.64 (t, J = 6.4 Hz, 2 H) 7.80 (br.s., 1 H).
MS ESI / APCI Dual posi: 203 [M + H] + , 225 [M + Na] + .
MS ESI / APCI Dual nega: 201 [MH] - .
Reference Example A-21 Production of amine intermediate (4C-21)

Figure 2013224263
Figure 2013224263

工程１、工程２
３−（ベンジルオキシカルボニルアミノ）−２,２−ジメチルプロパノイックアシッド（０．５０ｇ,２．０ｍｍｏｌ,ＷＯ２００４０１８４９１）とＮ,Ｎ−ジメチルエチレンジアミン（０．６６ｍＬ,６．０ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色液体としてアミン中間体（４Ｃ−２１）（０．３４ｇ,２工程９１％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15 (s, 6 H) 2.24 (s, 6 H) 2.42 (t, J=6.3 Hz, 2 H) 2.76 (s, 2 H) 3.29 - 3.37 (m, 2 H) 7.45 (br. s., 1 H).
MS ESI/APCI Dual posi : 188[M+H]+.
参考例Ａ−２２ アミン中間体（４Ｃ−２２）の製造 Step 1 and Step 2
Using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and N, N-dimethylethylenediamine (0.66 mL, 6.0 mmol) as starting materials, Based on the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-21) (0.34 g, 2 steps 91%) was obtained as a colorless liquid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15 (s, 6 H) 2.24 (s, 6 H) 2.42 (t, J = 6.3 Hz, 2 H) 2.76 (s, 2 H) 3.29-3.37 ( m, 2 H) 7.45 (br.s., 1 H).
MS ESI / APCI Dual posi: 188 [M + H] + .
Reference Example A-22 Production of amine intermediate (4C-22)

Figure 2013224263
Figure 2013224263

工程１、工程２
３−（ベンジルオキシカルボニルアミノ）−２,２−ジメチルプロパノイックアシッド（０．５０ｇ,２．０ｍｍｏｌ,ＷＯ２００４０１８４９１）とＮ,Ｎ−ジメチルプロピレンジアミン（０．７６ｍＬ,６．０ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色液体としてアミン中間体（４Ｃ−２２）（０．２３ｇ,２工程５９％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 6 H) 1.60 - 1.72 (m, 2 H) 2.25 (s, 6 H) 2.40 (t, J=6.5 Hz, 2 H) 2.76 (s, 2 H) 3.32 - 3.37 (m, 2 H) 8.28 (br. s., 1 H).
MS ESI/APCI Dual posi : 202[M+H]+.
参考例Ａ−２３ アミン中間体（４Ｃ−２３）の製造 Step 1 and Step 2
Using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and N, N-dimethylpropylenediamine (0.76 mL, 6.0 mmol) as starting materials Based on the method described in Step 1 and Step 2 of Reference Example A-8, an amine intermediate (4C-22) (0.23 g, 2 steps 59%) was obtained as a colorless liquid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 6 H) 1.60-1.72 (m, 2 H) 2.25 (s, 6 H) 2.40 (t, J = 6.5 Hz, 2 H) 2.76 ( s, 2 H) 3.32-3.37 (m, 2 H) 8.28 (br.s., 1 H).
MS ESI / APCI Dual posi: 202 [M + H] + .
Reference Example A-23 Production of amine intermediate (4C-23)

Figure 2013224263
Figure 2013224263

工程１、工程２
３−（ベンジルオキシカルボニルアミノ）−２,２−ジメチルプロパノイックアシッド（０．５０２ｇ,２．００ｍｍｏｌ,ＷＯ２００４０１８４９１）と４−（ジメチルアミノ）ブチルアミン・二塩酸塩（１．１３ｇ,６．００ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色液体としてアミン中間体（４Ｃ−２３）（０．３７５ｇ,２工程８７％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 6 H) 1.49 - 1.57 (m, 4 H) 2.00 (br. s., 2 H) 2.25 (s, 6 H) 2.30 - 2.38 (m, 2 H) 2.76 (s, 2 H) 3.19 - 3.30 (m, 2 H) 7.98 (br. s., 1 H).
MS ESI/APCI Dual posi : 216[M+H]+, 228[M+Na]+.
参考例Ａ−２４ アミン中間体（４Ｃ−２４）の製造 Step 1 and Step 2
3- (Benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.502 g, 2.00 mmol, WO2004018491) and 4- (dimethylamino) butylamine dihydrochloride (1.13 g, 6.00 mmol) Based on the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-23) (0.375 g, 87% for 2 steps) was obtained as a colorless liquid. It was.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 6 H) 1.49-1.57 (m, 4 H) 2.00 (br. S., 2 H) 2.25 (s, 6 H) 2.30-2.38 ( m, 2 H) 2.76 (s, 2 H) 3.19-3.30 (m, 2 H) 7.98 (br. s., 1 H).
MS ESI / APCI Dual posi: 216 [M + H] + , 228 [M + Na] + .
Reference Example A-24 Production of amine intermediate (4C-24)

Figure 2013224263
Figure 2013224263

工程１、工程２
３−（ベンジルオキシカルボニルアミノ）−２,２−ジメチルプロパノイックアシッド（０．５０２ｇ,２．００ｍｍｏｌ,ＷＯ２００４０１８４９１）と５−（ジメチルアミノ）ペンチルアミン（０．７８ｇ,６．００ｍｍｏｌ）を出発原料として、参考例Ａ−８の工程１および工程２に記載されている方法に準拠して、無色液体としてアミン中間体（４Ｃ−２４）（０．５０５ｇ,２工程１００％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.30 - 1.40 (m, 2 H) 1.45 - 1.59 (m, 4 H) 2.26 (s, 6 H) 2.27 - 2.35 (m, 2 H) 2.77 (s, 2 H) 3.19 - 3.26 (m, 2 H) 7.88 (br. s., 1 H).
MS ESI/APCI Dual posi : 230[M+H]+.
MS ESI/APCI Dual nega : 228[M-H]-.
参考例Ａ−２５ アミン中間体（４Ｃ−２５）の製造 Step 1 and Step 2
Starting material: 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.502 g, 2.00 mmol, WO2004018491) and 5- (dimethylamino) pentylamine (0.78 g, 6.00 mmol) Based on the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-24) (0.505 g, 2 steps 100%) was obtained as a colorless liquid.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.30-1.40 (m, 2 H) 1.45-1.59 (m, 4 H) 2.26 (s, 6 H) 2.27-2.35 (m , 2 H) 2.77 (s, 2 H) 3.19-3.26 (m, 2 H) 7.88 (br. S., 1 H).
MS ESI / APCI Dual posi: 230 [M + H] + .
MS ESI / APCI Dual nega: 228 [MH] - .
Reference Example A-25 Production of amine intermediate (4C-25)

Figure 2013224263
Figure 2013224263

工程１
Ｂｏｃ−Ａｉｂ−ＯＨ（３．００ｇ,１４．８ｍｍｏｌ）と１−ベンジルピペリジン−４−アミン（２．９５ｇ,１５．５ｍｍｏｌ）を出発原料として、参考例Ａ−７の工程１に記載されている方法に準拠して、無色結晶として中間体（４Ｃ−２５ａ）（１．５６ｇ,２８％）を得た。 Process 1
It is described in Step 1 of Reference Example A-7 using Boc-Aib-OH (3.00 g, 14.8 mmol) and 1-benzylpiperidin-4-amine (2.95 g, 15.5 mmol) as starting materials. According to the method, intermediate (4C-25a) (1.56 g, 28%) was obtained as colorless crystals.

工程２
中間体（４Ｃ−２５ａ）（４２９ｍｇ,１．１４ｍｍｏｌ）のクロロホルム溶液（１．５ｍＬ）を０℃に冷却し、トリフルオロ酢酸（１．５ｍＬ）をゆっくり加えた後、混合液を室温下２時間撹拌した。溶媒を減圧下留去し、アミン中間体（４Ｃ−２５）の二トリフルオロ酢酸塩（５７４ｍｇ,１００％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.54 (s, 6 H) 1.77 - 1.86 (m, 2 H) 2.09 - 2.16 (m, 2 H) 3.09 - 3.16 (m, 2 H) 3.51 - 3.57 (m, 2 H) 3.93 - 4.00 (m, 1 H) 4.31 (s, 2 H) 7.50 (s, 5 H).
MS ESI/APCI Dual posi : 276[M+H]+, 298[M+Na]+.
参考例Ａ−２６ アミン中間体（４Ｃ−２６）の製造 Process 2
A chloroform solution (1.5 mL) of intermediate (4C-25a) (429 mg, 1.14 mmol) was cooled to 0 ° C., trifluoroacetic acid (1.5 mL) was slowly added, and the mixture was stirred at room temperature for 2 hours. Stir. The solvent was distilled off under reduced pressure to obtain the ditrifluoroacetate salt (574 mg, 100%) of the amine intermediate (4C-25).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.54 (s, 6 H) 1.77-1.86 (m, 2 H) 2.09-2.16 (m, 2 H) 3.09-3.16 (m, 2 H) 3.51- 3.57 (m, 2 H) 3.93-4.00 (m, 1 H) 4.31 (s, 2 H) 7.50 (s, 5 H).
MS ESI / APCI Dual posi: 276 [M + H] + , 298 [M + Na] + .
Reference Example A-26 Production of amine intermediate (4C-26)

Figure 2013224263
Figure 2013224263

工程１
３−（（ｔｅｒｔ−ブトキシカルボニル）アミノ）−２,２−ジメチルプロパン酸（２２０ｍｇ,１．０１ｍｍｏｌ）と１−ベンジルピペリジン−４−アミン（２８９ｍｇ,１．５２ｍｍｏｌ）を出発原料として、参考例Ａ−４の工程１に記載されている方法に準拠して、無色結晶として中間体（４Ｃ−２６ａ）（２１０ｍｇ,５３％）を得た。 Process 1
Reference Example A using 3-((tert-butoxycarbonyl) amino) -2,2-dimethylpropanoic acid (220 mg, 1.01 mmol) and 1-benzylpiperidin-4-amine (289 mg, 1.52 mmol) as starting materials According to the method described in Step 1 of -4, intermediate (4C-26a) (210 mg, 53%) was obtained as colorless crystals.

工程２
中間体（４Ｃ−２６ａ）（１８４ｍｇ,０．４７２ｍｍｏｌ）を出発原料として、参考例Ａ−２５の工程２に記載されている方法に準拠して、アミン中間体（４Ｃ−２６）の二トリフルオロ酢酸塩（２４４ｍｇ,１００％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.28 (s, 6 H) 1.75 - 1.85 (m, 2 H) 2.06 - 2.13 (m, 2 H) 3.00 (s, 2 H) 3.07 - 3.15 (m, 2 H) 3.49 - 3.56 (m, 2 H) 3.92 - 4.00 (m, 1 H) 4.31 (s, 2 H) 7.50 (s, 5 H).
MS ESI/APCI Dual posi : 290[M+H]+.
実施例１−１ Process 2
Starting from intermediate (4C-26a) (184 mg, 0.472 mmol) as a starting material, ditrifluoromethane of amine intermediate (4C-26) was prepared according to the method described in Step 2 of Reference Example A-25. Acetic acid salt (244 mg, 100%) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.28 (s, 6 H) 1.75-1.85 (m, 2 H) 2.06-2.13 (m, 2 H) 3.00 (s, 2 H) 3.07-3.15 ( m, 2 H) 3.49-3.56 (m, 2 H) 3.92-4.00 (m, 1 H) 4.31 (s, 2 H) 7.50 (s, 5 H).
MS ESI / APCI Dual posi: 290 [M + H] + .
Example 1-1

Figure 2013224263
Figure 2013224263

工程１
中間体（１Ｅ−１）（１４５ｍｇ,０．１８２ｍｍｏｌ）、３−アミノプロパノール（１６．５ｍｇ,０．２１９ｍｍｏｌ）、ＮａＢＨ（ＯＡｃ）3（４６．３ｍｇ,０．２１９ｍｍｏｌ）のクロロホルム溶液（５ｍＬ）を室温で３０分間撹拌した。溶媒を減圧下留去した後、飽和炭酸水素ナトリウム水溶液を加えて、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、粗精製の中間体（１−１ａ）（１０２ｍｇ）を得た。 Process 1
A chloroform solution (5 mL) of intermediate (1E-1) (145 mg, 0.182 mmol), 3-aminopropanol (16.5 mg, 0.219 mmol), NaBH (OAc) 3 (46.3 mg, 0.219 mmol). Stir at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain crude intermediate (1-1a) (102 mg).

工程２
中間体（１−１ａ）（１０１ｍｇ,０．１１９ｍｍｏｌ）、ナトリウムメトキシド（４．８８Ｍメタノール溶液,０．２４２ｍＬ,１．１９ｍｍｏｌ）のメタノール溶液（２ｍＬ）を室温で１時間撹拌した。溶媒を減圧下留去し、残渣をＮＨシリカゲルカラムクロマトグラフィ−（クロロホルム→クロロホルム：メタノール＝７：３）で精製し、無色アモルファスの化合物（１−１）（２５ｍｇ,２工程２１％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 (d, J=6.5 Hz, 6 H) 1.29 (s, 6 H) 1.33 (s, 6 H) 1.55 (quin, J=6.5 Hz, 2 H) 2.32 (s, 3 H) 2.59 - 2.65 (m, 4 H) 2.87 - 2.96 (m, 1 H) 3.37 - 3.41 (m, 2 H) 3.43 - 3.50 (m, 3 H) 3.52 - 3.57 (m, 1 H) 3.68 (dd, J=12.2, 4.8 Hz, 1 H) 3.84 (dd, J=12.2, 1.6 Hz, 1 H) 3.89 (s, 2 H) 4.47 (d, J=9.6 Hz, 1 H) 6.34 (d, J=16.1 Hz, 1 H) 6.49 (d, J=16.1 Hz, 1 H) 6.74 (d, J=7.8 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.10 (d, J=7.8 Hz, 1 H) 7.23 (s, 1 H)．
MS ESI/APCI Dual posi : 643[M+H]+, 675[M+Na]+.
MS ESI/APCI Dual nega : 641[M-H]-, 677[M+Cl]-.
実施例１−２ Process 2
A methanol solution (2 mL) of intermediate (1-1a) (101 mg, 0.119 mmol) and sodium methoxide (4.88 M methanol solution, 0.242 mL, 1.19 mmol) was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (chloroform → chloroform: methanol = 7: 3) to obtain a colorless amorphous compound (1-1) (25 mg, 21% for 2 steps). .
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10 (d, J = 6.5 Hz, 6 H) 1.29 (s, 6 H) 1.33 (s, 6 H) 1.55 (quin, J = 6.5 Hz, 2 H) 2.32 (s, 3 H) 2.59-2.65 (m, 4 H) 2.87-2.96 (m, 1 H) 3.37-3.41 (m, 2 H) 3.43-3.50 (m, 3 H) 3.52-3.57 (m , 1 H) 3.68 (dd, J = 12.2, 4.8 Hz, 1 H) 3.84 (dd, J = 12.2, 1.6 Hz, 1 H) 3.89 (s, 2 H) 4.47 (d, J = 9.6 Hz, 1 H ) 6.34 (d, J = 16.1 Hz, 1 H) 6.49 (d, J = 16.1 Hz, 1 H) 6.74 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H ) 7.10 (d, J = 7.8 Hz, 1 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 643 [M + H] + , 675 [M + Na] + .
MS ESI / APCI Dual nega: 641 [MH] - , 677 [M + Cl] - .
Example 1-2

Figure 2013224263
Figure 2013224263

工程１
中間体(１Ｅ−１)（３００ｍｇ,０．５１ｍｍｏｌ）、６−アミノヘキサンアミド（８７ｍｇ,０．６７ｍｍｏｌ）のメタノール（５ｍＬ）溶液へＮａＢＨ3ＣＮ（４２ｍｇ、０．６７ｍｍｏｌ）を加え、室温で一晩撹拌した。反応液を減圧下濃縮し、残渣に飽和炭酸水素ナトリウム水溶液を加えて酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して、残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノール＝９８：２→８５：１５）で精製し、淡褐色アモルファスとして中間体（１−２ａ）（２４３ｍｇ,５２％）を得た。 Process 1
To a solution of intermediate (1E-1) (300 mg, 0.51 mmol) and 6-aminohexanamide (87 mg, 0.67 mmol) in methanol (5 mL), NaBH 3 CN (42 mg, 0.67 mmol) was added, Stir overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 → 85: 15) to obtain an intermediate (1-2a) as a light brown amorphous (243 mg, 52%) was obtained.

工程２
中間体（１−２ａ）（２４３ｍｇ,０．２７ｍｍｏｌ）を出発原料として、実施例１−１の工程２に記載されている方法に準拠して、無色アモルファスの化合物（１−２）（１００ｍｇ、５３％）を得た。
1H NMR (600 MHz, MEHTANOL-d4) δ ppm 1.07 - 1.15 (m, 6 H) 1.19 - 1.25 (m, 2 H) 1.29 (s, 6 H) 1.31 - 1.36 (m, 8 H) 1.45 - 1.53 (m, 2 H) 2.12 (t, J=7.6 Hz, 2 H) 2.32 (s, 3 H) 2.49 (t, J=7.3 Hz, 2 H) 2.62 (s, 2 H) 2.87 - 2.94 (m, 1 H) 3.37 - 3.41 (m, 2 H) 3.46 (t, J=8.9 Hz, 1 H) 3.53 - 3.59 (m, 1 H) 3.68 (dd, J=12.2, 4.8 Hz, 1 H) 3.83 - 3.87 (m, 1 H) 3.89 (s, 2 H) 4.47 (d, J=9.6 Hz, 1 H) 6.34 (d, J=16.0 Hz, 1 H) 6.49 (d, J=16.0 Hz, 1 H) 6.74 (d, J=7.8 Hz, 1 H) 6.80 (s, 1 H) 6.99 (s, 1 H) 7.10 (d, J=7.8 Hz, 1 H) 7.23 (s, 1 H).
MS ESI/APCI Dual posi : 698[M+H]+, 720[M+Na]+.
MS ESI/APCI Dual nega : 696[M-H]-, 732[M+Cl]-.
実施例１−３ Process 2
Based on the method described in Step 2 of Example 1-1, using Intermediate (1-2a) (243 mg, 0.27 mmol) as a starting material, colorless amorphous compound (1-2) (100 mg, 53%).
1 H NMR (600 MHz, MEHTANOL-d 4 ) δ ppm 1.07-1.15 (m, 6 H) 1.19-1.25 (m, 2 H) 1.29 (s, 6 H) 1.31-1.36 (m, 8 H) 1.45- 1.53 (m, 2 H) 2.12 (t, J = 7.6 Hz, 2 H) 2.32 (s, 3 H) 2.49 (t, J = 7.3 Hz, 2 H) 2.62 (s, 2 H) 2.87-2.94 (m , 1 H) 3.37-3.41 (m, 2 H) 3.46 (t, J = 8.9 Hz, 1 H) 3.53-3.59 (m, 1 H) 3.68 (dd, J = 12.2, 4.8 Hz, 1 H) 3.83- 3.87 (m, 1 H) 3.89 (s, 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.34 (d, J = 16.0 Hz, 1 H) 6.49 (d, J = 16.0 Hz, 1 H) 6.74 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.99 (s, 1 H) 7.10 (d, J = 7.8 Hz, 1 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 698 [M + H] + , 720 [M + Na] + .
MS ESI / APCI Dual nega: 696 [MH] - , 732 [M + Cl] - .
Example 1-3

Figure 2013224263
Figure 2013224263

工程１
中間体（１Ｅ−１）（８６ｍｇ,０．１１ｍｍｏｌ）、グリシルグリシナミド（１８ｍｇ,０．１４ｍｍｏｌ）およびボラン−２−ピコリン錯体（１５ｍｇ,０．１４ｍｍｏｌ）のメタノール−酢酸溶液（１０：１,１．１ｍＬ）を室温下一晩撹拌した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９８：２→８０：２０）で精製し、無色アモルファスとして中間体（１−３ａ）（９０ｍｇ,９１％）を得た。 Process 1
A solution of intermediate (1E-1) (86 mg, 0.11 mmol), glycylglycinamide (18 mg, 0.14 mmol) and borane-2-picoline complex (15 mg, 0.14 mmol) in methanol-acetic acid (10: 1, 1.1 mL) was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 → 80: 20) to obtain intermediate (1-3a) (90 mg, 91%) as a colorless amorphous substance.

工程２
中間体（１−３ａ）（９０ｍｇ,０．０９９ｍｍｏｌ）のトリエチルアミン−水−メタノール混合懸濁液（１：１：５,２ｍＬ）を室温下一晩撹拌した。溶媒を減圧留去し、残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル：エタノール：水＝１０：２：１）で精製し、無色アモルファスの化合物（１−３）（４４ｍｇ,６４％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.11 (d, J=6.9 Hz, 6 H) 1.32 (s, 6 H) 1.35 (s, 6 H) 2.30 (s, 3 H) 2.69 (s, 2 H) 2.90 - 2.96 (m, 1 H) 3.24 (s, 2 H) 3.37 - 3.40 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.55 (t, J=8.7 Hz, 1 H) 3.65 - 3.70 (m, 1 H) 3.71 (d, J=2.8 Hz, 2 H) 3.83-3.85 (m, 1 H) 3.89 (s, 2 H) 4.47 (d, J=9.6 Hz, 1 H) 6.38 (d, J=16.5 Hz, 1 H) 6.51 (d, J=16.5 Hz, 1 H) 6.75 (d, J=7.8 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.11 (d, J=7.8 Hz, 1 H) 7.22 (s, 1 H).
MS ESI/APCI Dual posi : 699[M+H]+, 721[M+Na]+.
MS ESI/APCI Dual nega : 697[M-H]-, 733[M+Cl]-. Process 2
A mixed suspension of intermediate (1-3a) (90 mg, 0.099 mmol) in triethylamine-water-methanol (1: 1: 5, 2 mL) was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: ethanol: water = 10: 2: 1) to obtain a colorless amorphous compound (1-3) (44 mg, 64%). .
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.11 (d, J = 6.9 Hz, 6 H) 1.32 (s, 6 H) 1.35 (s, 6 H) 2.30 (s, 3 H) 2.69 (s , 2 H) 2.90-2.96 (m, 1 H) 3.24 (s, 2 H) 3.37-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.55 (t, J = 8.7 Hz, 1 H) 3.65-3.70 (m, 1 H) 3.71 (d, J = 2.8 Hz, 2 H) 3.83-3.85 (m, 1 H) 3.89 (s, 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.38 (d, J = 16.5 Hz, 1 H) 6.51 (d, J = 16.5 Hz, 1 H) 6.75 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 699 [M + H] + , 721 [M + Na] + .
MS ESI / APCI Dual nega: 697 [MH] - , 733 [M + Cl] - .

以下の実施例１−４〜１−２５、１−２７〜１−４０も、中間体（１Ｅ−１）と対応するアミンを用いて、実施例１−１、１−２または１−３の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表１−１から表１−１０に示す。   The following Examples 1-4 to 1-25 and 1-27 to 1-40 are also used in Examples 1-1, 1-2, or 1-3 using the intermediate (1E-1) and the corresponding amine. Synthesis was performed according to any method described in the process. The structures, NMR data, and MS data of these compounds are shown in Table 1-1 to Table 1-10.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

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Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例１−４１
Figure 2013224263
 Example 1-41

Figure 2013224263
Figure 2013224263

工程１
中間体（１Ｅ−１）（２００ｍｇ,０．２５ｍｍｏｌ）および１−（エトキシカルボニルメチル）ピペラジン（５６ｍｇ,０．３３ｍｍｏｌ）を出発原料として、実施例１−１の工程１に記載されている方法に準拠して、無色アモルファスとして中間体（１−４１ａ）（８０ｍｇ、３３％）を得た。 Process 1
Using the intermediate (1E-1) (200 mg, 0.25 mmol) and 1- (ethoxycarbonylmethyl) piperazine (56 mg, 0.33 mmol) as starting materials, the method described in Step 1 of Example 1-1 was used. In conformity, intermediate (1-41a) (80 mg, 33%) was obtained as colorless amorphous.

工程２
中間体（１−４１ａ）（８０ｍｇ,０．０８４ｍｍｏｌ）、ナトリウムエトキシド（２０％エタノール溶液,０．１７ｍＬ）のエタノール溶液（１ｍＬ）を室温で３０分間撹拌した。反応液に酢酸（０．０５８ｍＬ,１．０ｍｍｏｌ）を加えた後、溶媒を減圧下留去し、残渣をＮＨシリカゲルカラムクロマトグラフィ−（酢酸エチル：エタノール：水＝３０：２：１→７：２：１）で精製し、無色アモルファスの化合物（１−４１）（８ｍｇ,１０％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.11 - 1.15 (m, 6 H) 1.27 (t, J=6.9 Hz, 3 H) 1.31 (s, 6 H) 1.33 (s, 6 H) 2.03 - 2.25 (m, 4 H) 2.33 (s, 2 H) 2.34 (s, 3 H) 2.47 (br. s., 4 H) 2.70 - 2.78 (m, 2 H) 2.93 - 3.00 (m, 1 H) 3.34 - 3.39 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.51 - 3.56 (m, 1 H) 3.64 - 3.68 (m, 1 H) 3.82 - 3.92 (m, 3 H) 4.16 (q, J=6.9 Hz, 2 H) 4.47 (d, J=9.6 Hz, 1 H) 6.38 (d, J=16.5 Hz, 1 H) 6.54 (d, J=16.5 Hz, 1 H) 6.78 (d, J=7.8 Hz, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.17 (d, J=7.8 Hz, 1 H) 7.28 (s, 1 H).
MS ESI/APCI Dual posi: 740[M+H]+, 762[M+Na]+.
MS ESI/APCI Dual nega: 738[M-H]-. Process 2
Intermediate (1-41a) (80 mg, 0.084 mmol), sodium ethoxide (20% ethanol solution, 0.17 mL) in ethanol (1 mL) was stirred at room temperature for 30 minutes. Acetic acid (0.058 mL, 1.0 mmol) was added to the reaction solution, the solvent was evaporated under reduced pressure, and the residue was subjected to NH silica gel column chromatography (ethyl acetate: ethanol: water = 30: 2: 1 → 7: 2). : 1) to obtain colorless amorphous compound (1-41) (8 mg, 10%).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.11-1.15 (m, 6 H) 1.27 (t, J = 6.9 Hz, 3 H) 1.31 (s, 6 H) 1.33 (s, 6 H) 2.03 -2.25 (m, 4 H) 2.33 (s, 2 H) 2.34 (s, 3 H) 2.47 (br. S., 4 H) 2.70-2.78 (m, 2 H) 2.93-3.00 (m, 1 H) 3.34-3.39 (m, 2 H) 3.43-3.48 (m, 1 H) 3.51-3.56 (m, 1 H) 3.64-3.68 (m, 1 H) 3.82-3.92 (m, 3 H) 4.16 (q, J = 6.9 Hz, 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.38 (d, J = 16.5 Hz, 1 H) 6.54 (d, J = 16.5 Hz, 1 H) 6.78 (d, J = 7.8 Hz, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.17 (d, J = 7.8 Hz, 1 H) 7.28 (s, 1 H).
MS ESI / APCI Dual posi: 740 [M + H] + , 762 [M + Na] + .
MS ESI / APCI Dual nega: 738 [MH] - .

以下の実施例１−４２〜１−５７も、中間体（１Ｅ−１）と対応するアミンを用いて、実施例１−１、１−２、１−３または１−４１の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表１−１１から表１−１４に示す。   Examples 1-42 to 1-57 below are also described in the steps of Examples 1-1, 1-2, 1-3 or 1-41 using the intermediate (1E-1) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 1-11 to 1-14.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例２−１
Figure 2013224263
 Example 2-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−２）（０．３８４ｇ,０．４９２ｍｍｏｌ）とグリシンアミド・塩酸塩（８１．６ｍｇ,０．７３９ｍｍｏｌ）を出発原料として、実施例１−２の工程１および実施例１−３の工程２に記載されている方法に準拠して、無色アモルファスの化合物（２−１）（１３３ｍｇ,２工程４３％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.06 - 1.13 (m, 6 H) 1.35 (s, 6 H) 1.63 - 1.70 (m, 2 H) 2.30 (s, 3 H) 2.56 (t, J=6.9 Hz, 2 H) 2.89 - 2.96 (m, 1 H) 3.16 (s, 2 H) 3.25 (t, J=6.9 Hz, 2 H) 3.36 - 3.41 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.54 (t, J=9.6 Hz, 1 H) 3.65 - 3.70 (m, 1 H) 3.81 - 3.90 (m, 3 H) 4.46 (d, J=9.6 Hz, 1 H) 6.33 (d, J=16.5 Hz, 1 H) 6.45 (d, J=16.5 Hz, 1 H) 6.75 (d, J=8.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.09 (d, J=8.3 Hz, 1 H) 7.22 (s, 1 H).
MS ESI/APCI Dual posi : 628[M+H]+, 650[M+Na]+.
MS ESI/APCI Dual nega : 626[M-H]-, 662[M+Cl]-. Step 1 and Step 2
Using Intermediate (1E-2) (0.384 g, 0.492 mmol) and glycinamide hydrochloride (81.6 mg, 0.739 mmol) as starting materials, Step 1 of Example 1-2 and Example 1-3 In accordance with the method described in Step 2, a colorless amorphous compound (2-1) (133 mg, 43% in 2 steps) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.06-1.13 (m, 6 H) 1.35 (s, 6 H) 1.63-1.70 (m, 2 H) 2.30 (s, 3 H) 2.56 (t, J = 6.9 Hz, 2 H) 2.89-2.96 (m, 1 H) 3.16 (s, 2 H) 3.25 (t, J = 6.9 Hz, 2 H) 3.36-3.41 (m, 2 H) 3.43-3.48 (m , 1 H) 3.54 (t, J = 9.6 Hz, 1 H) 3.65-3.70 (m, 1 H) 3.81-3.90 (m, 3 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.33 (d, J = 16.5 Hz, 1 H) 6.45 (d, J = 16.5 Hz, 1 H) 6.75 (d, J = 8.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.09 (d, J = 8.3 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 628 [M + H] + , 650 [M + Na] + .
MS ESI / APCI Dual nega: 626 [MH] - , 662 [M + Cl] - .

以下の実施例２−２〜２−１２も、中間体（１Ｅ−２）〜中間体（１Ｅ−１０）と対応するアミンを用いて、実施例１−１、１−２または１−３の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表２−１から表２−３に示す。   The following Examples 2-2 to 2-12 were also prepared according to Examples 1-1, 1-2, or 1-3 using amines corresponding to Intermediate (1E-2) to Intermediate (1E-10). Synthesis was performed according to any method described in the process. The structures, NMR data, and MS data of these compounds are shown in Tables 2-1 to 2-3.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例３−１
Figure 2013224263
 Example 3-1

Figure 2013224263
Figure 2013224263

工程１
中間体(１Ｅ−１１)（１５０ｍｇ,０．１７ｍｍｏｌ）、酢酸（１１μＬ,０．１９ｍｍｏｌ）、グリシンアミド・塩酸塩（２５ｍｇ,０．２３ｍｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド（２ｍＬ）懸濁液を７０℃で３０分撹拌した。室温へ放冷後、ＮａＢＨ（ＯＡｃ）3（４８ｍｇ,０．２２５ｍｍｏｌ）を加えて室温で一晩撹拌した。反応液へ酢酸エチルを加え、水、飽和食塩水で順次洗浄を行い、硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して、残渣をシリカゲルカラムクロマトグラフィ−（クロロホルム：メタノール＝９８：２→９１：９）で精製し、無色アモルファスとして中間体（３−１ａ）（１３１ｍｇ,８２％）を得た。 Process 1
A suspension of intermediate (1E-11) (150 mg, 0.17 mmol), acetic acid (11 μL, 0.19 mmol) and glycinamide hydrochloride (25 mg, 0.23 mmol) in N, N-dimethylformamide (2 mL) Stir at 70 ° C. for 30 minutes. After allowing to cool to room temperature, NaBH (OAc) 3 (48 mg, 0.225 mmol) was added and stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, washed successively with water and saturated brine, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 → 91: 9) to give intermediate (3-1a) ( 131 mg, 82%).

工程２
中間体（３−１ａ）（１３０ｍｇ,０．１４ｍｍｏｌ）のテトラヒドロフラン溶液に６Ｍ塩酸（１４０μＬ,０．８５ｍｍｏｌ）を加えて室温で一晩撹拌した。反応液を減圧下濃縮して、中間体（３−１ｂ）（１５０ｍｇ）を得た。
工程３
中間体（３−１ｂ）（１５０ｍｇ）を出発原料として、実施例１−１の工程２に記載されている方法に準拠して、無色アモルファスの化合物（３−１）（８２ｍｇ,５３％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.09 - 1.13 (m, 6 H) 1.38 (s, 6 H) 2.30 (s, 3 H) 2.78 (s, 2 H) 2.90 - 2.96 (m, 1 H) 3.19 (s, 2 H) 3.36 - 3.40 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.51 - 3.56 (m, 1 H) 3.63 - 3.70 (m, 5 H) 3.84 (dd, J=11.9, 1.4 Hz, 1 H) 3.89 (s, 2 H) 4.46 (d, J=9.6 Hz, 1 H) 6.38 (d, J=16.0 Hz, 1 H) 6.55 (d, J=16.0 Hz, 1 H) 6.76 (d, J=7.8 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.11 (d, J=7.8 Hz, 1 H) 7.24 (s, 1 H).
MS ESI/APCI Dual posi : 674[M+H]+, 696[M+Na]+.
MS ESI/APCI Dual nega : 708[M+Cl]-. Process 2
To a tetrahydrofuran solution of intermediate (3-1a) (130 mg, 0.14 mmol) was added 6M hydrochloric acid (140 μL, 0.85 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain Intermediate (3-1b) (150 mg).
Process 3
Based on the method described in Step 2 of Example 1-1, using Intermediate (3-1b) (150 mg) as a starting material, colorless amorphous compound (3-1) (82 mg, 53%) was obtained. Obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.09-1.13 (m, 6 H) 1.38 (s, 6 H) 2.30 (s, 3 H) 2.78 (s, 2 H) 2.90-2.96 (m, 1 H) 3.19 (s, 2 H) 3.36-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.51-3.56 (m, 1 H) 3.63-3.70 (m, 5 H) 3.84 (dd, J = 11.9, 1.4 Hz, 1 H) 3.89 (s, 2 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.38 (d, J = 16.0 Hz, 1 H) 6.55 (d, J = 16.0 Hz, 1 H) 6.76 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 674 [M + H] + , 696 [M + Na] + .
MS ESI / APCI Dual nega: 708 [M + Cl] - .

以下の実施例３−２〜３−１２も、中間体（１Ｅ−１１）と対応するアミンを用いて、実施例１−１、１−２、１−３または３−１の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表３−１から表３−３に示す。   Examples 3-2 to 3-12 below are also described in the steps of Examples 1-1, 1-2, 1-3, or 3-1, using the intermediate (1E-11) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 3-1 to 3-3.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例４−１
Figure 2013224263
 Example 4-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−１２）（３００ｍｇ,０．３９２ｍｍｏｌ）とＮ,Ｎ−ジメチルエチレンジアミン（５１．８ｍｇ,０．５８８ｍｍｏｌ）を出発原料として、実施例１−２の工程１と実施例１−３の工程２に記載されている方法に準拠して、無色アモルファスの化合物（４−１）（２６．８ｍｇ,２工程１１％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 (d, J=6.9 Hz, 6 H) 1.32 (s, 6 H) 2.17 (s, 6 H) 2.30 (s, 3 H) 2.38 (t, J=6.6 Hz, 2 H) 2.67 (t, J=6.6 Hz, 2 H) 2.77 (s, 2 H) 2.88 - 2.94 (m, 1 H) 3.05 (d, J=7.3 Hz, 2 H) 3.36 - 3.40 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.52 - 3.56 (m, 1 H) 3.65 - 3.70 (m, 1 H) 3.84 (d, J=12.4 Hz, 1 H) 3.88 (s, 2 H) 4.47 (d, J=9.6 Hz, 1 H) 6.25 (dt, J=16.0, 7.3 Hz, 1 H) 6.45 (d, J=16.0 Hz, 1 H) 6.73 (d, J=7.8 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.06 (d, J=7.8 Hz, 1 H) 7.19 (s, 1 H).
MS ESI/APCI Dual posi : 628[M+H]+, 650[M+Na]+.
MS ESI/APCI Dual nega : 626[M-H]-. Step 1 and Step 2
Using Intermediate (1E-12) (300 mg, 0.392 mmol) and N, N-dimethylethylenediamine (51.8 mg, 0.588 mmol) as starting materials, steps 1 and 1-3 of Example 1-2 were used. Based on the method described in Step 2, colorless amorphous compound (4-1) (26.8 mg, 2 steps 11%) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10 (d, J = 6.9 Hz, 6 H) 1.32 (s, 6 H) 2.17 (s, 6 H) 2.30 (s, 3 H) 2.38 (t , J = 6.6 Hz, 2 H) 2.67 (t, J = 6.6 Hz, 2 H) 2.77 (s, 2 H) 2.88-2.94 (m, 1 H) 3.05 (d, J = 7.3 Hz, 2 H) 3.36 -3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.52-3.56 (m, 1 H) 3.65-3.70 (m, 1 H) 3.84 (d, J = 12.4 Hz, 1 H) 3.88 (s , 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.25 (dt, J = 16.0, 7.3 Hz, 1 H) 6.45 (d, J = 16.0 Hz, 1 H) 6.73 (d, J = 7.8 Hz , 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.06 (d, J = 7.8 Hz, 1 H) 7.19 (s, 1 H).
MS ESI / APCI Dual posi: 628 [M + H] + , 650 [M + Na] + .
MS ESI / APCI Dual nega: 626 [MH] - .

以下の実施例４−２〜４−１６も、中間体（１Ｅ−１２）と対応するアミンを用いて、実施例１−１、１−２または１−３の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表４−１から表４−５に示す。   Examples 4-2 to 4-16 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-12) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Tables 4-1 to 4-5.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例５−１
Figure 2013224263
 Example 5-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−１３）（１３５ｍｇ,０．１７４ｍｍｏｌ）とグリシンアミド・塩酸塩（２９．０ｍｇ,０．２６１ｍｍｏｌ）を出発原料として、実施例１−２の工程１と実施例１−３の工程２に記載されている方法に準拠して、無色アモルファスの化合物（５−１）（４６．７ｍｇ,２工程４３％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 (d, J=6.4 Hz, 6 H) 1.32 (s, 6 H) 1.91 (t, J=7.8 Hz, 2 H) 2.30 (s, 3 H) 2.59 (t, J=7.8 Hz, 2 H) 2.89 - 2.95 (m, 1 H) 3.03 (d, J=7.3 Hz, 2 H) 3.17 (s, 2 H) 3.36 - 3.39 (m, 2 H) 3.43 - 3.47 (m, 1 H) 3.54 (t, J=9.4 Hz, 1 H) 3.65 - 3.70 (m, 1 H) 3.82 - 3.86 (m, 1 H) 3.88 (s, 2 H) 4.46 (d, J=10.1 Hz, 1 H) 6.24 (dt, J=16.0, 7.3 Hz, 1 H) 6.44 (d, J=16.0 Hz, 1 H) 6.73 (d, J=8.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.06 (d, J=8.3 Hz, 1 H) 7.18 (s, 1 H).
MS ESI/APCI Dual posi : 628[M+H]+, 650[M+Na]+.
MS ESI/APCI Dual nega : 626[M-H]-, 662[M+Cl]-. Step 1 and Step 2
Step 1 of Example 1-2 and Step of Example 1-3 using intermediate (1E-13) (135 mg, 0.174 mmol) and glycinamide hydrochloride (29.0 mg, 0.261 mmol) as starting materials In accordance with the method described in 2, a colorless amorphous compound (5-1) (46.7 mg, 43% for 2 steps) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10 (d, J = 6.4 Hz, 6 H) 1.32 (s, 6 H) 1.91 (t, J = 7.8 Hz, 2 H) 2.30 (s, 3 H) 2.59 (t, J = 7.8 Hz, 2 H) 2.89-2.95 (m, 1 H) 3.03 (d, J = 7.3 Hz, 2 H) 3.17 (s, 2 H) 3.36-3.39 (m, 2 H ) 3.43-3.47 (m, 1 H) 3.54 (t, J = 9.4 Hz, 1 H) 3.65-3.70 (m, 1 H) 3.82-3.86 (m, 1 H) 3.88 (s, 2 H) 4.46 (d , J = 10.1 Hz, 1 H) 6.24 (dt, J = 16.0, 7.3 Hz, 1 H) 6.44 (d, J = 16.0 Hz, 1 H) 6.73 (d, J = 8.3 Hz, 1 H) 6.80 (s , 1 H) 6.95 (s, 1 H) 7.06 (d, J = 8.3 Hz, 1 H) 7.18 (s, 1 H).
MS ESI / APCI Dual posi: 628 [M + H] + , 650 [M + Na] + .
MS ESI / APCI Dual nega: 626 [MH] - , 662 [M + Cl] - .

以下の実施例５−２〜５−４も、中間体（１Ｅ−１３）と対応するアミンを用いて、実施例１−１、１−２または１−３の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表５−１に示す。   Examples 5-2 to 5-4 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-13) and the corresponding amine. It was synthesized in accordance with the method. The structure, NMR data, and MS data of these compounds are shown in Table 5-1.

Figure 2013224263
実施例６−１
Figure 2013224263
 Example 6-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−１４）（３００ｍｇ,０．３７９ｍｍｏｌ）とグリシンアミド・塩酸塩（６２．８ｍｇ,０．５６８ｍｍｏｌ）を出発原料として、実施例１−２の工程１と実施例１−３の工程２に記載されている方法に準拠して、無色アモルファスの化合物（６−１）（８１．４ｍｇ,２工程３４％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 (d, J=6.9 Hz, 6 H) 1.60 - 1.76 (m, 6 H) 2.01 (m, 2 H) 2.29 (s, 3 H) 2.87 (s, 2 H) 2.92 (spt, J=6.9 Hz, 1 H) 3.08 (d, J=6.9 Hz, 2 H) 3.22 (s, 2 H) 3.36 - 3.41 (m, 2 H) 3.43 - 3.49 (m, 1 H) 3.51 - 3.57 (m, 1 H) 3.67 (dd, J=12.2, 4.8 Hz, 1 H) 3.81 - 3.90 (m, 3 H) 4.46 (d, J=9.6 Hz, 1 H) 6.22 - 6.30 (m, 1 H) 6.45 (d, J=16.0 Hz, 1 H) 6.73 (d, J=7.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.06 (d, J=7.3 Hz, 1 H) 7.19 (s, 1 H).
MS ESI/APCI Dual posi : 640[M+H]+.
MS ESI/APCI Dual nega : 638[M-H]-, 674[M+Cl]-. Step 1 and Step 2
Step 1 of Example 1-2 and Step of Example 1-3 using intermediate (1E-14) (300 mg, 0.379 mmol) and glycinamide hydrochloride (62.8 mg, 0.568 mmol) as starting materials In accordance with the method described in 2, colorless amorphous compound (6-1) (81.4 mg, 34% for 2 steps) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10 (d, J = 6.9 Hz, 6 H) 1.60-1.76 (m, 6 H) 2.01 (m, 2 H) 2.29 (s, 3 H) 2.87 (s, 2 H) 2.92 (spt, J = 6.9 Hz, 1 H) 3.08 (d, J = 6.9 Hz, 2 H) 3.22 (s, 2 H) 3.36-3.41 (m, 2 H) 3.43-3.49 ( m, 1 H) 3.51-3.57 (m, 1 H) 3.67 (dd, J = 12.2, 4.8 Hz, 1 H) 3.81-3.90 (m, 3 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.22 -6.30 (m, 1 H) 6.45 (d, J = 16.0 Hz, 1 H) 6.73 (d, J = 7.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.06 (d, J = 7.3 Hz, 1 H) 7.19 (s, 1 H).
MS ESI / APCI Dual posi: 640 [M + H] + .
MS ESI / APCI Dual nega: 638 [MH] - , 674 [M + Cl] - .

以下の実施例６−２〜６−４も、中間体（１Ｅ−１４）と対応するアミンを用いて、実施例１−１、１−２または１−３の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表６−１に示す。   Examples 6-2 to 6-4 below are also any of those described in the steps of Examples 1-1, 1-2, or 1-3 using the intermediate (1E-14) and the corresponding amine. It was synthesized in accordance with the method. The structure, NMR data, and MS data of these compounds are shown in Table 6-1.

Figure 2013224263
実施例７−１
Figure 2013224263
 Example 7-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−１５）（２００ｍｇ,０．２４ｍｍｏｌ）とグリシンアミド・塩酸塩（３５ｍｇ,０．３２ｍｍｏｌ）を出発原料として、実施例１−１の工程１および工程２に記載されている方法に準拠して、無色アモルファスの化合物（７−１）（６７ｍｇ,２工程４２％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 0.88 (t, J=7.6 Hz, 6 H) 1.09 - 1.13 (m, 6 H) 1.33 (s, 6 H) 1.75 - 1.83 (m, 4 H) 2.31 (s, 3 H) 2.65 (s, 2 H) 2.90 - 2.97 (m, 1 H) 3.18 (s, 2 H) 3.36 - 3.40 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.52 - 3.57 (m, 1 H) 3.65 - 3.70 (m, 1 H) 3.82 - 3.86 (m, 1 H) 3.89 (s, 2 H) 4.46 (d, J=9.6 Hz, 1 H) 6.31 (d, J=16.5 Hz, 1 H) 6.48 (d, J=16.5 Hz, 1 H) 6.77 (d, J=7.8 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.11 (d, J=7.8 Hz, 1 H) 7.23 (s, 1 H).
MS ESI/APCI Dual posi : 670[M+H]+, 692[M+Na]+.
MS ESI/APCI Dual nega : 668[M-H]-, 704[M+Cl]-. Step 1 and Step 2
Using the intermediate (1E-15) (200 mg, 0.24 mmol) and glycinamide hydrochloride (35 mg, 0.32 mmol) as starting materials, the method described in Step 1 and Step 2 of Example 1-1 was used. Based on this, a colorless amorphous compound (7-1) (67 mg, 42% for 2 steps) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 0.88 (t, J = 7.6 Hz, 6 H) 1.09-1.13 (m, 6 H) 1.33 (s, 6 H) 1.75-1.83 (m, 4 H 2.31 (s, 3 H) 2.65 (s, 2 H) 2.90-2.97 (m, 1 H) 3.18 (s, 2 H) 3.36-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.52 -3.57 (m, 1 H) 3.65-3.70 (m, 1 H) 3.82-3.86 (m, 1 H) 3.89 (s, 2 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.31 (d, J = 16.5 Hz, 1 H) 6.48 (d, J = 16.5 Hz, 1 H) 6.77 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 670 [M + H] + , 692 [M + Na] + .
MS ESI / APCI Dual nega: 668 [MH] - , 704 [M + Cl] - .

以下の実施例７−２は、中間体（１Ｅ−１６）とグリシンアミド・塩酸塩を用いて、実施例１−１、１−２、１−３の工程に記載されている何れかの方法に準拠して、実施例７−３は、中間体（１Ｅ−１７）とグリシンアミド・塩酸塩を用いて、実施例１−１、１−２、１−３または３−１の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表７−１に示す。   Example 7-2 below is one of the methods described in the steps of Examples 1-1, 1-2, 1-3 using intermediate (1E-16) and glycinamide hydrochloride. Example 7-3 described in the steps of Example 1-1, 1-2, 1-3 or 3-1 using intermediate (1E-17) and glycinamide hydrochloride. It was synthesized according to any of the methods described. Table 7-1 shows the structures, NMR data, and MS data of these compounds.

Figure 2013224263
実施例８−１
Figure 2013224263
 Example 8-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−１８）（１５０ｍｇ,０．１９６ｍｍｏｌ）とＮ,Ｎ−ジメチルエチレンジアミン（２６．０ｍｇ,０．２９４ｍｍｏｌ）を出発原料として、実施例１−１の工程１と実施例１−３の工程２に記載されている方法に準拠して、無色アモルファスの化合物（８−１）（７７．１ｍｇ,２工程６１％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.15 (d, J=6.4 Hz, 6 H) 1.30 (s, 6 H) 1.33 (s, 6 H) 2.10 (s, 6 H) 2.20 (t, J=6.4 Hz, 2 H) 2.34 (s, 3 H) 2.58 - 2.63 (m, 4 H) 2.94 - 3.02 (m, 1 H) 3.34 - 3.39 (m, 2 H) 3.43 - 3.49 (m, 1 H) 3.48 - 3.54 (m, 1 H) 3.59 - 3.66 (m, 1 H) 3.80 - 3.88 (m, 4 H) 3.92 (s, 2 H) 4.61 (d, J=9.6 Hz, 1 H) 6.35 (d, J=16.0 Hz, 1 H) 6.50 (d, J=16.0 Hz, 1 H) 6.73 (d, J=7.8 Hz, 1 H) 6.93 (s, 1 H) 7.08 (s, 1 H) 7.11 (d, J=7.8 Hz, 1 H) 7.26 (s, 1 H).
MS ESI/APCI Dual posi : 671[M+H]+, 693[M+Na]+.
MS ESI/APCI Dual nega : 669[M-H]-, 705[M+Cl]-. Step 1 and Step 2
Using Intermediate (1E-18) (150 mg, 0.196 mmol) and N, N-dimethylethylenediamine (26.0 mg, 0.294 mmol) as starting materials, steps 1 and 1-3 of Example 1-1 were used. Based on the method described in Step 2, colorless amorphous compound (8-1) (77.1 mg, 2 steps 61%) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.15 (d, J = 6.4 Hz, 6 H) 1.30 (s, 6 H) 1.33 (s, 6 H) 2.10 (s, 6 H) 2.20 (t , J = 6.4 Hz, 2 H) 2.34 (s, 3 H) 2.58-2.63 (m, 4 H) 2.94-3.02 (m, 1 H) 3.34-3.39 (m, 2 H) 3.43-3.49 (m, 1 H) 3.48-3.54 (m, 1 H) 3.59-3.66 (m, 1 H) 3.80-3.88 (m, 4 H) 3.92 (s, 2 H) 4.61 (d, J = 9.6 Hz, 1 H) 6.35 ( d, J = 16.0 Hz, 1 H) 6.50 (d, J = 16.0 Hz, 1 H) 6.73 (d, J = 7.8 Hz, 1 H) 6.93 (s, 1 H) 7.08 (s, 1 H) 7.11 ( d, J = 7.8 Hz, 1 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 671 [M + H] + , 693 [M + Na] + .
MS ESI / APCI Dual nega: 669 [MH] - , 705 [M + Cl] - .

以下の実施例８−２〜８−３１も、中間体（１Ｅ−１８）と対応するアミンを用いて、実施例１−１、１−２、１−３または１−４１の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表８−１から表８−９に示す。   Examples 8-2 to 8-31 below are also described in the steps of Example 1-1, 1-2, 1-3 or 1-41 using the intermediate (1E-18) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 8-1 to 8-9.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例９−１
Figure 2013224263
 Example 9-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−１９）（１００ｍｇ,０．１３６ｍｍｏｌ）とＮ,Ｎ−ジメチルエチレンジアミン（０．０４４ｍＬ,０．４０７ｍｍｏｌ）を出発原料として、実施例１−２の工程１および実施例１−３の工程２に記載されている方法に準拠して、無色アモルファスの化合物（９−１）（５．０ｍｇ,２工程７％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.14 (d, J=6.4 Hz, 6 H) 1.32 (s, 6 H) 2.18 (s, 6 H) 2.32 (s, 3 H) 2.39 (t, J=6.6 Hz, 2 H) 2.68 (t, J=6.6 Hz, 2 H) 2.78 (s, 2 H) 2.95-2.99 (m, 1 H) 3.06 (d, J=6.9 Hz, 2 H) 3.32 - 3.38 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.48 - 3.54 (m, 1 H) 3.59 - 3.64 (m, 1 H) 3.80 - 3.86 (m, 4 H) 3.91 (s, 2 H) 4.61 (d, J=9.6 Hz, 1 H) 6.26 (dt, J=16.5, 6.9 Hz, 1 H) 6.45 (d, J=16.0 Hz, 1 H) 6.71 (d, J=7.8 Hz, 1 H) 6.92 (s, 1 H) 7.06 (d, J=7.8 Hz, 1 H) 7.08 (s, 1 H) 7.20 (s, 1 H).
MS ESI/APCI Dual posi : 642[M+H]+, 664[M+Na]+.
MS ESI/APCI Dual nega : 640[M-H]-, 676[M+Cl]-.
Step 1 and Step 2
Using Intermediate (1E-19) (100 mg, 0.136 mmol) and N, N-dimethylethylenediamine (0.044 mL, 0.407 mmol) as starting materials, Step 1 of Example 1-2 and Example 1-3 Based on the method described in Step 2, a colorless amorphous compound (9-1) (5.0 mg, 2 steps 7%) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.14 (d, J = 6.4 Hz, 6 H) 1.32 (s, 6 H) 2.18 (s, 6 H) 2.32 (s, 3 H) 2.39 (t , J = 6.6 Hz, 2 H) 2.68 (t, J = 6.6 Hz, 2 H) 2.78 (s, 2 H) 2.95-2.99 (m, 1 H) 3.06 (d, J = 6.9 Hz, 2 H) 3.32 -3.38 (m, 2 H) 3.43-3.48 (m, 1 H) 3.48-3.54 (m, 1 H) 3.59-3.64 (m, 1 H) 3.80-3.86 (m, 4 H) 3.91 (s, 2 H ) 4.61 (d, J = 9.6 Hz, 1 H) 6.26 (dt, J = 16.5, 6.9 Hz, 1 H) 6.45 (d, J = 16.0 Hz, 1 H) 6.71 (d, J = 7.8 Hz, 1 H) ) 6.92 (s, 1 H) 7.06 (d, J = 7.8 Hz, 1 H) 7.08 (s, 1 H) 7.20 (s, 1 H).
MS ESI / APCI Dual posi: 642 [M + H] + , 664 [M + Na] + .
MS ESI / APCI Dual nega: 640 [MH] - , 676 [M + Cl] - .

以下の実施例９−２〜９−１５も、中間体（１Ｅ−１９）と対応するアミンを用いて実施例１−１、１−２、１−３または１−４１の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表９−１から表９−５に示す。   Examples 9-2 to 9-15 below are also described in the steps of Examples 1-1, 1-2, 1-3 or 1-41 using the intermediate (1E-19) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 9-1 to 9-5.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例１０−１
Figure 2013224263
 Example 10-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−２０）（０．３２９ｇ,０．４２２ｍｍｏｌ）とグリシンアミド・塩酸塩（６０．６ｍｇ,０．５４８ｍｍｏｌ）を出発原料として、実施例１−１の工程１および実施例１−３の工程２に記載されている方法に準拠して、無色アモルファスの化合物（１０−１）（２１．６ｍｇ,２工程１２％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 - 1.17 (m, 3 H) 1.15 (d, J=6.6 Hz, 3 H) 1.25 - 1.39 (m, 12 H) 1.80 (t, J=7.3 Hz, 2 H) 2.32 (s, 3 H) 2.59 (t, J=7.3 Hz, 2 H) 2.94 - 3.03 (m, 1 H) 3.08 (s, 2 H) 3.31 - 3.38 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.49 - 3.54 (m, 1 H) 3.62 (dd, J=11.9, 5.5 Hz, 1 H) 3.80 - 3.86 (m, 4 H) 3.91 (s, 2 H) 4.61 (d, J=9.2 Hz, 1 H) 6.34 (d, J=16.5 Hz, 1 H) 6.46 (d, J=16.5 Hz, 1 H) 6.73 (d, J=7.8 Hz, 1 H) 6.92 (s, 1 H) 7.04 - 7.12 (m, 2 H) 7.23 (s, 1 H).
MS ESI/APCI Dual posi : 670[M+H]+, 692[M+Na]+.
MS ESI/APCI Dual nega : 704[M+Cl]-. Step 1 and Step 2
Using Intermediate (1E-20) (0.329 g, 0.422 mmol) and glycinamide hydrochloride (60.6 mg, 0.548 mmol) as starting materials, Step 1 and Example 1-3 of Example 1-1 In accordance with the method described in Step 2, a colorless amorphous compound (10-1) (21.6 mg, 12% for 2 steps) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10-1.17 (m, 3 H) 1.15 (d, J = 6.6 Hz, 3 H) 1.25-1.39 (m, 12 H) 1.80 (t, J = 7.3 Hz, 2 H) 2.32 (s, 3 H) 2.59 (t, J = 7.3 Hz, 2 H) 2.94-3.03 (m, 1 H) 3.08 (s, 2 H) 3.31-3.38 (m, 2 H) 3.43-3.48 (m, 1 H) 3.49-3.54 (m, 1 H) 3.62 (dd, J = 11.9, 5.5 Hz, 1 H) 3.80-3.86 (m, 4 H) 3.91 (s, 2 H) 4.61 ( d, J = 9.2 Hz, 1 H) 6.34 (d, J = 16.5 Hz, 1 H) 6.46 (d, J = 16.5 Hz, 1 H) 6.73 (d, J = 7.8 Hz, 1 H) 6.92 (s, 1 H) 7.04-7.12 (m, 2 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 670 [M + H] + , 692 [M + Na] + .
MS ESI / APCI Dual nega: 704 [M + Cl] - .

以下の実施例１０−２〜１０−５も、中間体（１Ｅ−２０）と対応するアミンを用いて、実施例１−１、１−２または１−３の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表１０−１から表１０−２に示す。   Examples 10-2 to 10-5 below are also described in the steps of Examples 1-1, 1-2, or 1-3 using the intermediate (1E-20) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Tables 10-1 to 10-2.

Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例１１−１
Figure 2013224263
 Example 11-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−２１）（１７５ｍｇ,０．２２ｍｍｏｌ）とグリシンアミド・塩酸塩（３２ｍｇ,０．２９ｍｍｏｌ）を出発原料として、実施例１−１の工程１および工程２に記載されている方法に準拠して、無色アモルファスの化合物（１１−１）（８０ｍｇ,２工程５６％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 - 1.16 (m, 6 H) 1.30 (s, 6 H) 1.35 (s, 6 H) 1.41 (t, J=6.9 Hz, 3 H) 2.32 (s, 3 H) 2.66 (s, 2 H) 2.95 - 3.02 (m, 1 H) 3.18 (s, 2 H) 3.33 - 3.38 (m, 2 H) 3.45 (t, J=8.7 Hz, 1 H) 3.55 - 3.64 (m, 2 H) 3.83 (dd, J=11.9, 1.8 Hz, 1 H) 3.92 (s, 2 H) 4.05 - 4.13 (m, 2 H) 4.59 (d, J=9.6 Hz, 1 H) 6.37 (d, J=16.5 Hz, 1 H) 6.50 (d, J=16.5 Hz, 1 H) 6.75 (d, J=7.8 Hz, 1 H) 6.91 (s, 1 H) 7.05 (s, 1 H) 7.11 (d, J=7.8 Hz, 1 H) 7.24 (s, 1 H).
MS ESI/APCI Dual posi : 670[M+H]+, 692[M+Na]+.
MS ESI/APCI Dual nega : 668[M-H]-, 704[M+Cl]-. Step 1 and Step 2
Using the intermediate (1E-21) (175 mg, 0.22 mmol) and glycinamide hydrochloride (32 mg, 0.29 mmol) as starting materials, the method described in Step 1 and Step 2 of Example 1-1 was used. Based on the above, colorless amorphous compound (11-1) (80 mg, 56% in 2 steps) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10-1.16 (m, 6 H) 1.30 (s, 6 H) 1.35 (s, 6 H) 1.41 (t, J = 6.9 Hz, 3 H) 2.32 (s, 3 H) 2.66 (s, 2 H) 2.95-3.02 (m, 1 H) 3.18 (s, 2 H) 3.33-3.38 (m, 2 H) 3.45 (t, J = 8.7 Hz, 1 H) 3.55-3.64 (m, 2 H) 3.83 (dd, J = 11.9, 1.8 Hz, 1 H) 3.92 (s, 2 H) 4.05-4.13 (m, 2 H) 4.59 (d, J = 9.6 Hz, 1 H ) 6.37 (d, J = 16.5 Hz, 1 H) 6.50 (d, J = 16.5 Hz, 1 H) 6.75 (d, J = 7.8 Hz, 1 H) 6.91 (s, 1 H) 7.05 (s, 1 H ) 7.11 (d, J = 7.8 Hz, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 670 [M + H] + , 692 [M + Na] + .
MS ESI / APCI Dual nega: 668 [MH] - , 704 [M + Cl] - .

以下の実施例１１−２、１１−３も、中間体（１Ｅ−２２）、中間体（１Ｅ−２３）とグリシンアミド・塩酸塩を用いて、実施例１−１、１−２または１−３の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表１１−１に示す。   The following Examples 11-2 and 11-3 were also prepared using Examples 1-1, 1-2, or 1-, using Intermediate (1E-22), Intermediate (1E-23), and glycinamide / hydrochloride. Synthesis was performed according to any method described in the step 3. The structure, NMR data, and MS data of these compounds are shown in Table 11-1.

Figure 2013224263
実施例１２−１
Figure 2013224263
 Example 12-1

Figure 2013224263
Figure 2013224263

工程１、工程２
中間体（１Ｅ−２４）（１５０ｍｇ,０．１８７ｍｍｏｌ）とＮ,Ｎ−ジメチルエチレンジアミン（２２ｍｇ,０．２４３ｍｍｏｌ）を出発原料として、実施例１−１の工程１および実施例１−３の工程２に記載されている方法に準拠して、無色アモルファスの化合物（１２−１）（２２ｍｇ,２工程１７％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.12 - 1.17 (m, 6 H) 1.30 (s, 6 H) 1.33 (s, 6 H) 2.11 (s, 6 H) 2.22 (t, J=6.6 Hz, 2 H) 2.32 (s, 3 H) 2.58 - 2.64 (m, 4 H) 3.02 (spt, J=6.7 Hz, 1 H) 3.33 - 3.39 (m, 1 H) 3.42 - 3.47 (m, 1 H) 3.55 - 3.64 (m, 3 H) 3.85 (dd, J=11.9, 2.3 Hz, 1 H) 3.98 (s, 2 H) 4.42 (d, J=9.6 Hz, 1 H) 6.36 (d, J=16.0 Hz, 1 H) 6.50 (d, J=16.0 Hz, 1 H) 6.58 - 6.85 (m, 2 H) 7.08 - 7.18 (m, 3 H) 7.27 (s, 1 H).
MS ESI/APCI Dual posi : 706[M+H]+, 728[M+Na]+.
MS ESI/APCI Dual nega : 704[M-H]-, 740[M+Cl]-. Step 1 and Step 2
Using Intermediate (1E-24) (150 mg, 0.187 mmol) and N, N-dimethylethylenediamine (22 mg, 0.243 mmol) as starting materials, Step 1 of Example 1-1 and Step 2 of Example 1-3 The colorless amorphous compound (12-1) (22 mg, 17% for 2 steps) was obtained according to the method described in 1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.12-1.17 (m, 6 H) 1.30 (s, 6 H) 1.33 (s, 6 H) 2.11 (s, 6 H) 2.22 (t, J = 6.6 Hz, 2 H) 2.32 (s, 3 H) 2.58-2.64 (m, 4 H) 3.02 (spt, J = 6.7 Hz, 1 H) 3.33-3.39 (m, 1 H) 3.42-3.47 (m, 1 H) 3.55-3.64 (m, 3 H) 3.85 (dd, J = 11.9, 2.3 Hz, 1 H) 3.98 (s, 2 H) 4.42 (d, J = 9.6 Hz, 1 H) 6.36 (d, J = 16.0 Hz, 1 H) 6.50 (d, J = 16.0 Hz, 1 H) 6.58-6.85 (m, 2 H) 7.08-7.18 (m, 3 H) 7.27 (s, 1 H).
MS ESI / APCI Dual posi: 706 [M + H] + , 728 [M + Na] + .
MS ESI / APCI Dual nega: 704 [MH] - , 740 [M + Cl] - .

以下の実施例１２−２〜１２−２０も、中間体（１Ｅ−２４）と対応するアミンを用いて、実施例１−１、１−２または１−３の工程に記載されている何れかの方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表１２−１から表１２−６に示す。   Examples 12-2 to 12-20 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-24) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Tables 12-1 to 12-6.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例１３−１
Figure 2013224263
 Example 13-1

Figure 2013224263
Figure 2013224263

工程１
中間体（２Ｃ−１）（０．１５０ｇ,０．２２５ｍｍｏｌ）、トリエチルアミン（４２．０μＬ,０．３３８ｍｍｏｌ）のテトラヒドロフラン（５ｍＬ）溶液に、メタンスルホニルクロリド（１６μＬ,０．２４７ｍｍｏｌ）を加えて、４０℃で２時間撹拌した後、減圧下溶媒を留去した。残渣をＮ,Ｎ−ジメチルホルムアミド（５ｍＬ）に溶かし、アミン中間体（４Ｃ−１０）（１０４ｍｇ,０．６０１ｍｍｏｌ）を加えて、１００℃で一晩撹拌した。減圧下溶媒を留去した後、残渣をＮＨシリカゲルカラムクロマトグラフィー（酢酸エチル）で粗精製し、中間体（１３−１ａ）を得た。 Process 1
To a solution of intermediate (2C-1) (0.150 g, 0.225 mmol) and triethylamine (42.0 μL, 0.338 mmol) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (16 μL, 0.247 mmol), and 40 After stirring at ° C for 2 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (5 mL), amine intermediate (4C-10) (104 mg, 0.601 mmol) was added, and the mixture was stirred at 100 ° C. overnight. After evaporating the solvent under reduced pressure, the residue was roughly purified by NH silica gel column chromatography (ethyl acetate) to obtain an intermediate (13-1a).

工程２
中間体（１３−１ａ）のクロロホルム（１．０ｍＬ）溶液に室温でトリフルオロ酢酸（４２ｍｇ,０．３６７ｍｍｏｌ）を加え、５０℃で４時間撹拌後、反応液を減圧濃縮した。この残渣をメタノール（１ｍＬ）に溶かし、ナトリウムメトキシド（４．８８Ｍメタノール溶液,７２．５μＬ,０．３５４ｍｍｏｌ）を室温で加えて１時間撹拌した。反応液を分取ＨＰＬＣ（Ｗａｔｅｒｓ Ｓｕｎｆｉｒｅ １９×１５０ｍｍ ５μｍ,ｒａｔｅ：２０ｍｌ／ｍｉｎ,ｅｌｕｅｎｔ：Ａ＝アセトニトリル,Ｂ＝０．１％トリフロオロ酢酸水溶液,ｇｒａｄｉｅｎｔ：１０〜９０％）で精製し、無色油状の化合物（１３−１）（２．２ｍｇ,１．５％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.06 - 1.12 (m, 6 H) 1.34 (s, 6 H) 1.67 (s, 6 H) 2.32 - 2.35 (m, 3 H) 2.85 - 2.95 (m, 1 H) 3.36 - 3.40 (m, 2 H) 3.42 (s, 2 H) 3.46 (s, 1 H) 3.50 - 3.56 (m, 1 H) 3.64 - 3.70 (m, 1 H) 3.78 (d, J=7.3 Hz, 1 H) 3.82 - 3.87 (m, 1 H) 3.91 (s, 2 H) 4.47 (d, J=9.6 Hz, 1 H) 6.18 - 6.26 (m, 1 H) 6.77 - 6.84 (m, 3 H) 6.97 (s, 1 H) 7.15 (dd, J=7.8, 1.4 Hz, 1 H) 7.27 (s, 1 H).
MS ESI/APCI Dual posi : 614[M+H]+, 636[M+Na]+ Process 2
To a chloroform (1.0 mL) solution of intermediate (13-1a) was added trifluoroacetic acid (42 mg, 0.367 mmol) at room temperature, and the mixture was stirred at 50 ° C. for 4 hours, and then the reaction mixture was concentrated under reduced pressure. This residue was dissolved in methanol (1 mL), sodium methoxide (4.88 M methanol solution, 72.5 μL, 0.354 mmol) was added at room temperature, and the mixture was stirred for 1 hour. The reaction solution was purified by preparative HPLC (Waters Sunfire 19 × 150 mm 5 μm, rate: 20 ml / min, element: A = acetonitrile, B = 0.1% trifluoroacetic acid aqueous solution, gradient: 10-90%) Compound (13-1) (2.2 mg, 1.5%) was obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.06-1.12 (m, 6 H) 1.34 (s, 6 H) 1.67 (s, 6 H) 2.32-2.35 (m, 3 H) 2.85-2.95 ( m, 1 H) 3.36-3.40 (m, 2 H) 3.42 (s, 2 H) 3.46 (s, 1 H) 3.50-3.56 (m, 1 H) 3.64-3.70 (m, 1 H) 3.78 (d, J = 7.3 Hz, 1 H) 3.82-3.87 (m, 1 H) 3.91 (s, 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.18-6.26 (m, 1 H) 6.77-6.84 (m , 3 H) 6.97 (s, 1 H) 7.15 (dd, J = 7.8, 1.4 Hz, 1 H) 7.27 (s, 1 H).
MS ESI / APCI Dual posi: 614 [M + H] + , 636 [M + Na] +

以下の実施例１３−２〜１３−４も、中間体（２Ｃ−１）と対応するアミンを用いて、実施例１３−１の工程に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表１３−１に示す。   The following Examples 13-2 to 13-4 were also synthesized in accordance with the method described in the step of Example 13-1, using the intermediate (2C-1) and the corresponding amine. The structures, NMR data and MS data of these compounds are shown in Table 13-1.

Figure 2013224263
実施例１４−１
Figure 2013224263
 Example 14-1

Figure 2013224263
Figure 2013224263

工程１
中間体（２Ｅ−１）（０．２０６ｇ,０．２７０ｍｍｏｌ）とアミン中間体（４Ｃ−１０）（０．２２５ｇ,０．８４０ｍｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド（１ｍＬ）溶液を９０℃で５．５時間撹拌した。反応液を室温まで冷却後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧濃縮し、残渣をシリカゲルクロマトグラフィーにて２回（１回目：クロロホルム：メタノール＝９０：１０→８２：１２、２回目：酢酸エチル：ヘキサン＝５０：５０→１００：０）精製し、中間体（１４−１ａ）（５５ｍｇ,２２％）を得た。 Process 1
A solution of intermediate (2E-1) (0.206 g, 0.270 mmol) and amine intermediate (4C-10) (0.225 g, 0.840 mmol) in N, N-dimethylformamide (1 mL) at 90 ° C. Stir for 5 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was subjected to silica gel chromatography twice (first time: chloroform: methanol = 90: 10 → 82: 12, second time: ethyl acetate: hexane = 50: 50 → 100: 0) Purification gave intermediate (14-1a) (55 mg, 22%).

工程２
中間体（１４−１ａ）（５５ｍｇ,０．０５９ｍｍｏｌ）のクロロホルム（０．７ｍＬ）溶液に室温でトリフルオロ酢酸を加え、同温で一晩撹拌後、反応液を減圧濃縮した。この残渣をメタノール（１ｍＬ）に溶かし、ナトリウムメトキシド（４．８８Ｍメタノール溶液,７２．５μＬ,０．３５４ｍｍｏｌ）を室温で加えて２時間撹拌した。反応液に酢酸（４０．５μＬ,０．７０８ｍｍｏｌ）を加えた後、溶媒を減圧下留去し、残渣をＮＨシリカゲルクロマトグラフィーにて２回（１回目：クロロホルム：メタノール＝９５：５→７５：２５,２回目：酢酸エチル：エタノール：水＝３０：２：１→９：２：１）精製し、無色アモルファスの化合物（１４−１）（２６ｍｇ,７０％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.01 (s, 6 H) 1.08 - 1.12 (m, 6 H) 1.30 (s, 6 H) 2.30 (s, 3 H) 2.33 - 2.40 (m, 2 H) 2.60 (t, J=6.7 Hz, 2 H) 2.89 - 2.96 (m, 1 H) 3.09 (s, 2 H) 3.35 - 3.40 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.51 - 3.56 (m, 1 H) 3.64 - 3.70 (m, 1 H) 3.81 - 3.90 (m, 3 H) 4.47 (d, J=9.6 Hz, 1 H) 6.16 - 6.26 (m, 1 H) 6.40 (d, J=15.6 Hz, 1 H) 6.72 (d, J=8.3 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.05 (d, J=8.3 Hz, 1 H) 7.18 (s, 1 H).
MS ESI/APCI Dual posi : 628[M+H]+, 650[M+Na]+.
MS ESI/APCI Dual nega : 626[M-H]-, 662[M+Cl]-. Process 2
To a solution of intermediate (14-1a) (55 mg, 0.059 mmol) in chloroform (0.7 mL) was added trifluoroacetic acid at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was concentrated under reduced pressure. This residue was dissolved in methanol (1 mL), sodium methoxide (4.88 M methanol solution, 72.5 μL, 0.354 mmol) was added at room temperature, and the mixture was stirred for 2 hours. Acetic acid (40.5 μL, 0.708 mmol) was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was subjected to NH silica gel chromatography twice (first time: chloroform: methanol = 95: 5 → 75: 25, 2nd: ethyl acetate: ethanol: water = 30: 2: 1 → 9: 2: 1) Purification was carried out to obtain colorless amorphous compound (14-1) (26 mg, 70%).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.01 (s, 6 H) 1.08-1.12 (m, 6 H) 1.30 (s, 6 H) 2.30 (s, 3 H) 2.33-2.40 (m, 2 H) 2.60 (t, J = 6.7 Hz, 2 H) 2.89-2.96 (m, 1 H) 3.09 (s, 2 H) 3.35-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.51 -3.56 (m, 1 H) 3.64-3.70 (m, 1 H) 3.81-3.90 (m, 3 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.16-6.26 (m, 1 H) 6.40 (d , J = 15.6 Hz, 1 H) 6.72 (d, J = 8.3 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.05 (d, J = 8.3 Hz, 1 H) 7.18 (s , 1 H).
MS ESI / APCI Dual posi: 628 [M + H] + , 650 [M + Na] + .
MS ESI / APCI Dual nega: 626 [MH] - , 662 [M + Cl] - .

以下の実施例１４−２〜１４−１６も、中間体（２Ｅ−１）と対応するアミンを用いて、実施例１４−１の工程に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを１４−１から１４−５に示す。   The following Examples 14-2 to 14-16 were also synthesized according to the method described in the step of Example 14-1 using the amine corresponding to the intermediate (2E-1). The structures, NMR data, and MS data of these compounds are shown in 14-1 to 14-5.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
実施例１５−１
Figure 2013224263
 Example 15-1

Figure 2013224263
Figure 2013224263

工程１
中間体（３Ａ−１）（２５０ｍｇ,０．３０９ｍｍｏｌ）と３−アミノプロパノール（５３ｍｇ,０．７１１ｍｍｏｌ）を出発原料として、参考例１２の工程１に記載されている方法に準拠して、無色アモルファスとして中間体（１５−１ａ）（１８２ｍｇ,６８％）を得た。 Process 1
In accordance with the method described in Step 1 of Reference Example 12, starting from intermediate (3A-1) (250 mg, 0.309 mmol) and 3-aminopropanol (53 mg, 0.711 mmol), colorless amorphous Intermediate (15-1a) (182 mg, 68%) was obtained.

工程２
中間体（１５−１ａ）（１８２ｍｇ,０．２１０ｍｍｏｌ）を出発原料として、実施例１−３の工程２に記載されている方法に準拠して、無色アモルファスの化合物（１５−１）（８０ｍｇ,５８％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 (d, J=6.9 Hz, 6 H) 1.36 (s, 6 H) 1.46 (s, 6 H) 1.63-1.70 (m, 2 H) 2.32 (s, 3 H) 2.90-2.94 (m, 1 H) 3.26 (t, J=6.9 Hz, 2 H) 3.37 - 3.40 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.52 - 3.58 (m, 3 H) 3.68 (dd, J=12.2, 5.3 Hz, 1 H) 3.82 - 3.86 (m, 1 H) 3.89 (s, 2 H) 4.46 (d, J=9.6 Hz, 1 H) 6.38 (d, J=16.5 Hz, 1 H) 6.50 (d, J=16.5 Hz, 1 H) 6.75 (d, J=7.8 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.11 (d, J=7.8 Hz, 1 H) 7.25 (s, 1 H).
MS ESI/APCI Dual posi : 657[M+H]+, 679[M+Na]+.
MS ESI/APCI Dual nega : 655[M-H]-, 691[M+Cl]-. Process 2
According to the method described in Step 2 of Example 1-3, using Intermediate (15-1a) (182 mg, 0.210 mmol) as a starting material, colorless amorphous compound (15-1) (80 mg, 58%).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10 (d, J = 6.9 Hz, 6 H) 1.36 (s, 6 H) 1.46 (s, 6 H) 1.63-1.70 (m, 2 H) 2.32 (s, 3 H) 2.90-2.94 (m, 1 H) 3.26 (t, J = 6.9 Hz, 2 H) 3.37-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.52-3.58 (m , 3 H) 3.68 (dd, J = 12.2, 5.3 Hz, 1 H) 3.82-3.86 (m, 1 H) 3.89 (s, 2 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.38 (d, J = 16.5 Hz, 1 H) 6.50 (d, J = 16.5 Hz, 1 H) 6.75 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 657 [M + H] + , 679 [M + Na] + .
MS ESI / APCI Dual nega: 655 [MH] - , 691 [M + Cl] - .

以下の実施例１５−２〜１５−５も、中間体（３Ａ−１）と対応するアミンを用いて、実施例１５−１の工程に記載されている方法に準拠して合成した。それらの化合物の構造、ＮＭＲデータ、ＭＳデータを表１５−１に示す。   The following Examples 15-2 to 15-5 were also synthesized in accordance with the method described in the step of Example 15-1, using the amine corresponding to the intermediate (3A-1). The structures, NMR data, and MS data of these compounds are shown in Table 15-1.

Figure 2013224263
実施例１６−１
Figure 2013224263
 Example 16-1

Figure 2013224263
Figure 2013224263

工程１ Process 1

中間体（１Ｃ−１）（１．００ｇ,１．３８ｍｍｏｌ）のテトラヒドロフラン溶液（２．８ｍＬ）に−４０℃で０．９１Ｍ ボラン−テトラヒドロフラン錯体（１．７ｍＬ,１．５２ｍｍｏｌ）を滴下した。反応温度を０℃に昇温後、同温で１時間撹拌し、反応液にメタノールを加えた。溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ヘキサン＝６５：３５→３５：６５）にて精製し、中間体（１６−１ａ）（０．２２８ｇ,２３％）を得た。   To a tetrahydrofuran solution (2.8 mL) of intermediate (1C-1) (1.00 g, 1.38 mmol), 0.91 M borane-tetrahydrofuran complex (1.7 mL, 1.52 mmol) was added dropwise at −40 ° C. After raising the reaction temperature to 0 ° C., the mixture was stirred at the same temperature for 1 hour, and methanol was added to the reaction solution. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: hexane = 65: 35 → 35: 65) to obtain intermediate (16-1a) (0.228 g, 23%). .

工程２
中間体（１６−１ａ）（０．２３７ｇ,０．３３４ｍｍｏｌ）、３−アミノ−２,２−ジメチルプロパンアミド（５８．２ｍｇ,０．５０１ｍｍｏｌ,ＷＯ２００４０１８４９）のクロロホルム（１．６ｍＬ）溶液にＮａＢＨ（ＯＡｃ）3（２１２ｍｇ,１．００ｍｍｏｌ）を室温で加え、同温で一晩撹拌した。反応液に水を加え、クロロホルムで抽出後、有機層を飽和塩化アンモニウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧濃縮した。この残渣をメタノール（１ｍＬ）に溶解し、ナトリウムメトキシド（４．８８Ｍメタノール溶液,０．４１ｍＬ,２．０ｍｍｏｌ）を室温で加えて３０分間撹拌した。反応液に酢酸（２２９μＬ,４．０１ｍｍｏｌ）を加えた後、溶媒を減圧下留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：エタノール：水＝３０：２：１→１０：２：１）にて精製し、淡黄色アモルファスの化合物（１６−１）（８６ｍｇ,４３％）を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 (s, 6 H) 1.23 (s, 6 H) 1.24 (s, 6 H) 2.30 (s, 3 H) 2.89 (s, 2 H) 2.89 - 2.95 (m, 1 H) 2.95 (s, 2 H) 3.35 - 3.42 (m, 2 H) 3.46 (t, J=8.9 Hz, 1 H) 3.51 - 3.56 (m, 1 H) 3.64 - 3.70 (m, 1 H) 3.81 - 3.91 (m, 3 H) 4.46 (d, J=9.6 Hz, 1 H) 6.19 (d, J=16.5 Hz, 1 H) 6.45 (d, J=16.5 Hz, 1 H) 6.74 (d, J=7.8 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.11 (d, J=7.8 Hz, 1 H) 7.22 (s, 1 H).
MS ESI posi : 599[M+H]+. Process 2
To a solution of intermediate (16-1a) (0.237 g, 0.334 mmol), 3-amino-2,2-dimethylpropanamide (58.2 mg, 0.501 mmol, WO200401849) in chloroform (1.6 mL) was added NaBH ( OAc) 3 (212 mg, 1.00 mmol) was added at room temperature and stirred at the same temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. This residue was dissolved in methanol (1 mL), sodium methoxide (4.88 M methanol solution, 0.41 mL, 2.0 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. Acetic acid (229 μL, 4.01 mmol) was added to the reaction solution, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel chromatography (ethyl acetate: ethanol: water = 30: 2: 1 → 10: 2: 1). To obtain a pale yellow amorphous compound (16-1) (86 mg, 43%).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10 (s, 6 H) 1.23 (s, 6 H) 1.24 (s, 6 H) 2.30 (s, 3 H) 2.89 (s, 2 H) 2.89 -2.95 (m, 1 H) 2.95 (s, 2 H) 3.35-3.42 (m, 2 H) 3.46 (t, J = 8.9 Hz, 1 H) 3.51-3.56 (m, 1 H) 3.64-3.70 (m , 1 H) 3.81-3.91 (m, 3 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.19 (d, J = 16.5 Hz, 1 H) 6.45 (d, J = 16.5 Hz, 1 H) 6.74 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.22 (s, 1 H).
MS ESI posi: 599 [M + H] + .

試験例１
（１）ヒトＳＧＬＴ１を安定に発現するＣＨＯ−Ｋ１細胞の作製
ヒトＳＧＬＴ１蛋白質を発現するプラスミドベクターを、リポフェクトアミン２０００（インビトロジェン社）を用いてＣＨＯ−Ｋ１細胞にトランスフェクションした。ＳＧＬＴ１発現細胞は、５００μｇ／ｍＬの濃度のジェネティシンの存在下で培養し耐性株を選択し、下記に示す系により糖取り込み能を指標に取得した。 Test example 1
(1) Production of CHO-K1 cells stably expressing human SGLT1 Plasmid vectors expressing human SGLT1 protein were transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen). SGLT1-expressing cells were cultured in the presence of geneticin at a concentration of 500 μg / mL, resistant strains were selected, and sugar uptake ability was obtained as an index by the system shown below.

（２）安定発現細胞におけるナトリウム依存的糖取り込み阻害試験
安定発現細胞をナトリウム依存的グルコース取り込み活性阻害試験に用いた。
前処理用緩衝液（１４０ｍＭ 塩化コリン、２ｍＭ ＫＣｌ、１ｍＭ ＣａＣｌ2、１ｍＭ ＭｇＣｌ2、１０ｍＭ ＨＥＰＥＳ／５ｍＭ Ｔｒｉｓ、ｐＨ７．４）を安定発現細胞に加え、２０分間インキュベーションした。前処理用緩衝液を除去し、試験化合物を含む取り込み用緩衝液（［14Ｃ］メチル α−Ｄ−グルコピラノシドを含むメチル α−Ｄ−グルコピラノシド（１ｍＭ）、１４５ｍＭ ＮａＣｌ、２ｍＭ ＫＣｌ、１ｍＭ ＣａＣｌ2、１ｍＭ ＭｇＣｌ2、１０ｍＭ ＨＥＰＥＳ／５ｍＭ Ｔｒｉｓ、ｐＨ７．４）を加え、３７℃にて３０分（ＳＧＬＴ１）または６０分（ＳＧＬＴ２）取り込み反応を行った。反応後細胞を洗浄用緩衝液（１０ｍＭ メチル α−Ｄ−グルコピラノシド、１４０ｍＭ 塩化コリン２ｍＭ ＫＣｌ、１ｍＭ ＣａＣｌ2、１ｍＭ ＭｇＣｌ2、１０ｍＭ ＨＥＰＥＳ／５ｍＭ Ｔｒｉｓ、ｐＨ７．４）で２回洗浄し、０．２５Ｍ ＮａＯＨ溶液に溶かした。液体シンチレーター（パーキンエルマー社）を加えよく混和した後、β 線測定装置を用いて放射活性を測定した。対照群として試験化合物を含まない取り込み用緩衝液を調製した。また基礎取り込み用としてＮａＣｌに代えて塩化コリンを含む取り込み用緩衝液を調製した。
ＩＣ50値を求めるにあたり、適当な６濃度の試験化合物を用い、対照群の糖取り込み量（１００％）に対し、糖取り込み量が５０％阻害される試験化合物濃度（ＩＣ50値）を算出した。試験結果を表１７−１から表１７−３に示す。 (2) Sodium-dependent glucose uptake inhibition test in stably expressing cells The stably expressed cells were used in a sodium-dependent glucose uptake activity inhibition test.
Pretreatment buffer (140 mM choline chloride, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) was added to the stably expressing cells and incubated for 20 minutes. The pretreatment buffer is removed and the uptake buffer containing the test compound ([ 14 C] methyl α-D-glucopyranoside containing methyl α-D-glucopyranoside (1 mM), 145 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) was added, and an uptake reaction was performed at 37 ° C. for 30 minutes (SGLT1) or 60 minutes (SGLT2). After the reaction, the cells were washed twice with a washing buffer (10 mM methyl α-D-glucopyranoside, 140 mM choline chloride 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) and 0.25 M. Dissolved in NaOH solution. After adding a liquid scintillator (Perkin Elmer) and mixing well, the radioactivity was measured using a β ray measuring apparatus. As a control group, an uptake buffer containing no test compound was prepared. For basal uptake, an uptake buffer containing choline chloride instead of NaCl was prepared.
In determining the IC 50 value, the test compound concentration (IC 50 value) at which the sugar uptake amount was inhibited by 50% relative to the sugar uptake amount (100%) of the control group was calculated using appropriate 6 concentrations of the test compound. . The test results are shown in Tables 17-1 to 17-3.

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

Figure 2013224263
Figure 2013224263

なお、本発明化合物のヒトＳＧＬＴ２に対する阻害活性は、下記の試験例２の方法に従って確認することができる。   The inhibitory activity of the compound of the present invention against human SGLT2 can be confirmed according to the method of Test Example 2 below.

試験例２
（１）ヒトＳＧＬＴ２を安定に発現するＣＨＯ−Ｋ１細胞の作製および安定発現細胞におけるナトリウム依存的糖取り込み阻害試験
ヒトＳＧＬＴ２蛋白質を発現するプラスミドベクターを、リポフェクトアミンＬＴＸ（インビトロジェン社）を用いてＣＨＯ−Ｋ１細胞にトランスフェクションする。ＳＧＬＴ２発現細胞は、１０００μｇ／ｍＬの濃度のジェネティシンの存在下で培養し耐性株を選択し、上記試験例１の（２）に示す系により糖取り込み能を指標に取得することができる。 Test example 2
(1) Preparation of CHO-K1 cells that stably express human SGLT2 and sodium-dependent sugar uptake inhibition test in stably expressing cells A plasmid vector that expresses human SGLT2 protein was CHO using Lipofectamine LTX (Invitrogen). -Transfect K1 cells. SGLT2-expressing cells can be obtained by culturing in the presence of geneticin at a concentration of 1000 μg / mL, selecting a resistant strain, and using the system shown in (2) of Test Example 1 as an index, the sugar uptake ability.

また、先行技術化合物（ＷＯ２００７／１３６１１６号に記載された化合物）に対する本発明の化合物の優位性を、薬物の体内残留性から示す。上記文献に記載のＣ−フェニル グルシトール誘導体は、薬物が腎臓に残留する傾向が見られるが、腎臓中の薬物濃度は、下記の試験例３の方法に従って確認することができる。   In addition, the superiority of the compound of the present invention over the prior art compound (the compound described in WO2007 / 136116) is shown from the persistence of the drug in the body. In the C-phenyl glucitol derivative described in the above document, the drug tends to remain in the kidney. The drug concentration in the kidney can be confirmed according to the method of Test Example 3 below.

試験例３
（１）本発明の化合物の３日間反復経口投与後の腎臓中濃度
７週齢のＳＤ／ＩＧＳラット（日本チャールスリバー株式会社,雄性,非絶食）に、０．５％ＣＭＣ水溶液にて調製した本発明の化合物（３ｍｇ／ｋｇ）を１日１回３日間連続経口投与する。最終日の薬物投与後４８時間にイソフルラン麻酔下、後大静脈より全採血し、安楽死確認後に腎臓を摘出する。生理食塩液で組織表面を洗浄後、重量を測定し４倍量の精製水を加え氷冷下ホモジナイズする。ホモジネートに内標準物質を含むアセトニトリル／メタノール溶液を加えて除タンパクした後、上清をＬＣ−ＭＳ／ＭＳ（アプライドバイオシステムズＡＰＩ３０００）に供する。ポジティブイオンモードのエレクトロスプレーイオン化法にて生成した薬物由来のイオンを選択反応モニタリングにて検出し、得られた抽出イオンクロマトグラムのピーク面積から内標準法にてホモジネート中薬物濃度を算出することができる。 Test example 3
(1) Renal concentration after repeated oral administration of the compound of the present invention for 3 days A 7-week-old SD / IGS rat (Nippon Charles River Co., Ltd., male, non-fasted) was prepared in 0.5% CMC aqueous solution. The compound of the present invention (3 mg / kg) is orally administered once a day for 3 consecutive days. At 48 hours after drug administration on the final day, whole blood is collected from the posterior vena cava under isoflurane anesthesia, and the kidney is removed after confirmation of euthanasia. After washing the tissue surface with physiological saline, weigh it, add 4 times the amount of purified water, and homogenize under ice cooling. After deproteinization by adding an acetonitrile / methanol solution containing an internal standard substance to the homogenate, the supernatant is subjected to LC-MS / MS (Applied Biosystems API 3000). It is possible to detect drug-derived ions generated by electrospray ionization in positive ion mode by selective reaction monitoring, and calculate the drug concentration in the homogenate from the peak area of the extracted ion chromatogram obtained by the internal standard method. it can.

本発明により、ＳＧＬＴ１阻害活性が強い食後高血糖改善薬を提供することができ、ＳＧＬＴ１活性を阻害することによって、食後高血糖に由来する疾患に対する有効な治療・予防に貢献することを通じて、人類の健康の増進に寄与し、健全な医薬品産業の発達を図ることができる。   According to the present invention, a postprandial hyperglycemia-improving drug having strong SGLT1 inhibitory activity can be provided, and by inhibiting SGLT1 activity, contributing to effective treatment / prevention for diseases derived from postprandial hyperglycemia, It contributes to the promotion of health and the development of a healthy pharmaceutical industry.

Claims (7)

下記式（Ｉ）で表される４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩：
Figure 2013224263
 式中、
Ｒ1は、水素原子又は“水酸基若しくはハロゲン原子で置換されても良いＣ1-4アルキル基”であり、
Ｒ2及びＲ3は、同一若しくは異なって、水素原子、メチル基、エチル基若しくはヒドロキシメチル基であり、
又は、Ｒ2及びＲ3は、隣接する炭素原子と共にＣ3-6シクロアルキル基を形成し、
Ｒ4及びＲ5は、同一若しくは異なって、水素原子、メチル基若しくはヒドロキシメチル基であり、
又は、Ｒ4及びＲ5は、隣接する炭素原子と共にＣ3-6シクロアルキル基若しくはＣ4-6ヘテロシクリル基を形成し、
ｎは０又は１であり、
Ｒ6は水素原子、“ベンジル基で置換されても良いピペリジル基”若しくは“同一若しくは異なって、水酸基、アミノ基、カルバモイル基、ウレイド基、Ｃ2-7アルコキシカルボニル基、Ｃ1-6アルキルアミノカルボニル基（該Ｃ1-6アルキルアミノカルボニル基は、アミノ基、Ｃ2-7アルコキシカルボニル基、カルバモイル基、ジＣ1-4アルキルアミノ基若しくは水酸基から選ばれる１から３個の基で置換されても良い）、Ｃ2-7アルカノイルアミノ基（該Ｃ2-7アルカノイルアミノ基はアミノ基で置換されても良い）、Ｃ1-6アルキルスルホニルアミノ基、ジＣ1-4アルキルアミノ基、フェニル基（該フェニル基は水酸基で置換されても良い）、ピリジル基若しくはピペリジル基から選ばれる１から３個の基で置換されたＣ1-6アルキル基”であり、
Ｒ7は、水素原子若しくはＣ1-4アルキル基であり、
又は、Ｒ6及びＲ7は、隣接する窒素原子と共に“Ｃ1-6アルキル基（該Ｃ1-6アルキル基はＣ2-7アルコキシカルボニル基若しくは水酸基で置換されても良い）、カルバモイル基若しくはＣ2-7アルカノイル基（該Ｃ2-7アルカノイル基はアミノ基で置換されても良い）から選ばれる１個の基で置換されても良いピペラジニル基”若しくは“水酸基、カルバモイル基、ウレイド基、ジＣ1-4アルキルアミノ基、モルホリノ基、Ｃ2-7アルコキシカルボニル基、Ｃ1-6アルキルスルホニルアミノ基、Ｃ1-6アルキルアミノ基（該Ｃ1-6アルキルアミノ基は、アミノ基、カルバモイル基、ジＣ1-4アルキルアミノ基で置換されても良い）、Ｃ2-7アルカノイルアミノ基（該Ｃ2-7アルカノイルアミノ基はアミノ基で置換されても良い）若しくはＣ1-6アルキルアミノカルボニルアミノ基（該Ｃ1-6アルキルアミノカルボニルアミノ基は１〜３個の水酸基で置換されても良い）から選ばれる１個の基で置換されても良いピペリジノ基“を形成し、
Ｗは単結合、メチレン基（ＣＨ2）又はカルボニル基（Ｃ＝Ｏ）を示し、
ＹはＣ1-4アルキレン基又はカルボニル基（Ｃ＝Ｏ）を示す。 4-Isopropylphenyl glucitol compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
Figure 2013224263
 Where
R 1 is a hydrogen atom or a “C 1-4 alkyl group optionally substituted with a hydroxyl group or a halogen atom”;
R 2 and R 3 are the same or different and are a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group,
Or R 2 and R 3 together with the adjacent carbon atom form a C 3-6 cycloalkyl group,
R 4 and R 5 are the same or different and are a hydrogen atom, a methyl group or a hydroxymethyl group,
Or R 4 and R 5 together with the adjacent carbon atom form a C 3-6 cycloalkyl group or a C 4-6 heterocyclyl group;
n is 0 or 1;
R 6 is a hydrogen atom, “piperidyl group optionally substituted with a benzyl group” or “same or different, hydroxyl group, amino group, carbamoyl group, ureido group, C 2-7 alkoxycarbonyl group, C 1-6 alkylamino group A carbonyl group (the C 1-6 alkylaminocarbonyl group is substituted with 1 to 3 groups selected from an amino group, a C 2-7 alkoxycarbonyl group, a carbamoyl group, a diC 1-4 alkylamino group or a hydroxyl group; C 2-7 alkanoylamino group (the C 2-7 alkanoylamino group may be substituted with an amino group), C 1-6 alkylsulfonylamino group, diC 1-4 alkylamino group, A phenyl group (the phenyl group may be substituted with a hydroxyl group), a pyridyl group or a C 1-6 alkyl group substituted with 1 to 3 groups selected from a piperidyl group;
R 7 is a hydrogen atom or a C 1-4 alkyl group,
Or R 6 and R 7 together with an adjacent nitrogen atom are a “C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with a C 2-7 alkoxycarbonyl group or a hydroxyl group), a carbamoyl group or A piperazinyl group which may be substituted with one group selected from a C 2-7 alkanoyl group (the C 2-7 alkanoyl group may be substituted with an amino group) or a hydroxyl group, a carbamoyl group, a ureido group, Di-C 1-4 alkylamino group, morpholino group, C 2-7 alkoxycarbonyl group, C 1-6 alkylsulfonylamino group, C 1-6 alkylamino group (the C 1-6 alkylamino group is an amino group, A carbamoyl group, which may be substituted with a di-C 1-4 alkylamino group), a C 2-7 alkanoylamino group (the C 2-7 alkanoylamino group may be substituted with an amino group) or C 1-6 Alkylamino Ruboniruamino group (wherein the C 1-6 alkylaminocarbonyl amino group may be substituted with 1 to 3 hydroxyl groups) to form one may piperidino group which may be substituted with a group "chosen from,
W represents a single bond, a methylene group (CH 2 ) or a carbonyl group (C═O),
Y represents a C 1-4 alkylene group or a carbonyl group (C═O). Ｗが単結合又はメチレン基（ＣＨ2）を示す、請求項１に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩：
ただし、式中、
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7、ｎ及びＹは、請求項１で定義した通りである。 The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein W represents a single bond or a methylene group (CH 2 ):
However, in the formula:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and Y are as defined in claim 1. Ｗがカルボニル基（Ｃ＝Ｏ）を示す、請求項１に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩：
ただし、式中、
Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｒ7、ｎ及びＹは、請求項１で定義した通りである。 The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein W represents a carbonyl group (C = O):
However, in the formula:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and Y are as defined in claim 1. 請求項１〜３に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含むナトリウム依存性グルコース共輸送体１（ＳＧＬＴ１）活性阻害剤。   A sodium-dependent glucose cotransporter 1 (SGLT1) activity inhibitor comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 請求項１〜３に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含む食後高血糖改善薬。   The postprandial hyperglycemia improving drug which contains the 4-isopropylphenyl glucitol compound or its pharmaceutically acceptable salt of Claims 1-3 as an active ingredient. 請求項１〜３に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含む糖尿病の予防又は治療薬。   A prophylactic or therapeutic agent for diabetes comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 糖尿病の予防又は治療用の薬剤の製造における、請求項１〜３に記載の４−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩の使用。   Use of the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the manufacture of a medicament for preventing or treating diabetes.
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