JP5817317B2 - A prophylactic or therapeutic agent for diabetes comprising a 4-isopropylphenylglucitol compound as an active ingredient - Google Patents

Description

  The present invention specifically describes 4-isopropyl having an inhibitory activity on sodium-dependent glucose cotransporter 1 (hereinafter abbreviated as “SGLT1” as appropriate) that is involved in the absorption of glucose and galactose in the small intestine. The present invention relates to a phenyl glucitol compound.

  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).

  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.

  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.

  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 and galactose. Thus, pyrazole derivatives that inhibit SGLT1 activity have been reported (see Patent Documents 1 to 6), which suppresses dietary glucose absorption and prevents or treats postprandial hyperglycemia. In addition to SGLT1, there is also a report on a C-phenyl glucitol derivative that simultaneously inhibits SGLT2 activity expressed in the kidney (see Patent Document 7).

International Publication No. WO2002 / 098893 Pamphlet International Publication No. WO2004 / 014932 Pamphlet International Publication No. WO2004 / 018491 Pamphlet International Publication No. WO2004 / 019958 Pamphlet International Publication No. WO2005 / 121161 Pamphlet International Publication No. WO2004 / 050122 Pamphlet International Publication No. WO2007 / 136116 Pamphlet

Pan XR, et al. Diabetes Care, 20, 537, 1997 M Tominaga, et al. Diabetes Care, 22, 920, 1999 J.-L. Chiasson, et al. Lancent, 359, 2072, 2002

  The object of the present invention is to provide a 4-isopropylphenyl glucitol compound that inhibits SGLT1 activity and is expected as a new type of therapeutic agent for diabetes having an inhibitory action on glucose absorption from the digestive tract.

  The present inventors introduced an isopropyl group or a methyl group as a substituent on the benzene ring of the C-phenyl glucitol compound. Furthermore, a substituted butenyl group having an amino group was introduced at the end of the substituent extending from the benzene ring. The introduction of these substituents led to the discovery of 4-isopropylphenyl glucitol compound that inhibits SGLT1 activity and does not remain in major organs such as the kidney.

  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) A prophylactic or therapeutic agent for diabetes comprising a 4-isopropylphenyl glucitol compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient:

式中、
Ｒ^１は水素原子、又はＣ_１−４アルキル基であり、
Ｒ^２は水素原子、又はメチル基であり、
Ｒ^３は“アミノ基若しくはジＣ_１−４アルキルアミノ基で置換されたＣ_１−４アルキル基”、又はピペリジル基であり、
Ｒ^４は水素原子であり、
又はＲ^３とＲ^４は隣接する窒素原子と共にピペリジノ基若しくはピペラジニル基を形成し、それらはＣ_１−４アルキル基若しくはジメチルアミノ基で置換されていてもよい。

Where
R ¹ is a hydrogen atom or a C _1-4 alkyl group,
R ² is a hydrogen atom or a methyl group,
R ³ is “an amino group or a C _1-4 alkyl group substituted with a _{diC 1-4} alkylamino group”, or a piperidyl group;
R ⁴ is a hydrogen atom,
Alternatively, R ³ and R ⁴ together with the adjacent nitrogen atom form a piperidino group or piperazinyl group, which may be substituted with a C _1-4 alkyl group or a dimethylamino group.

(2) A prophylactic or therapeutic agent for diabetes comprising a 4-isopropylphenyl glucitol compound selected from the following group or a pharmaceutically acceptable salt thereof as an active ingredient.

(3) A prophylactic or therapeutic agent for diabetes comprising a 4-isopropylphenyl glucitol compound selected from the following group or a pharmaceutically acceptable salt thereof as an active ingredient.

  According to the present invention, it has become possible to provide a 4-isopropylphenyl glucitol compound that inhibits SGLT1 activity.

1 shows a powder X-ray diffraction pattern of an ethanol solvate. The infrared absorption spectrum (KBr method) of an ethanol solvate is shown. The differential thermal analysis / thermal mass measurement curve of an ethanol solvate is shown. The powder X-ray diffraction pattern of A-form crystal is shown. The differential thermal analysis / thermal mass measurement curve of A-form crystal is shown.

  The terms used in the present invention are defined below.

The “C _1-4 alkyl group” means a linear or branched alkyl group having 1-4 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl and the like can be mentioned.

The “di-C _1-4 alkylamino group” means an amino group substituted with two identical or different C _1-4 alkyl groups. For example, a dimethylamino group, a diethylamino group, etc. are mentioned.

  In addition, the “pharmaceutically acceptable salt” is a salt with an alkali metal, an alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, such as a sodium salt, Potassium salt, calcium salt, ammonium salt, aluminum salt, triethylammonium salt, formate, acetate, propionate, butyrate, hexanoate, octanoate, trifluoroacetate, maleate, tartrate, Citrate, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucuronic acid, glucoheptonate, glutarate, pimelate, suberate, azelate, sebacate 1,9-nonanedicarboxylate, dodecanedioate, tridecanedioate, tetradecanedioate, pentadecanedioate Hexadecanedioate, heptadecanedate, 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.

  “Hydrate” is a pharmaceutically acceptable hydrate of the compound of the present invention or a salt 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.

  The compound of the present invention can inhibit SGLT1 and suppress absorption of sugar from the small intestine to improve IGT.

  Therefore, the compound of the present invention can be used as an active ingredient of a SGLT1 inhibitor or a preventive or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.

  Here, “diabetes” includes type 1 diabetes, type 2 diabetes, and other types of diabetes caused by a specific cause.

  Here, “diabetes-related disease” means hyperinsulinemia, glucose metabolism abnormality, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality, hypertension, congestive heart failure, edema, hyperuricemia Symptoms and gout.

  Here, “diabetic complications” are classified into acute complications and chronic complications.

  “Acute complications” include hyperglycemia (such as ketoacidosis), infections (such as skin, soft tissue, biliary system, respiratory system, urinary tract infection) and the like.

  “Chronic complications” include microangiopathy (nephropathy, retinopathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, lower limb arterial occlusion, etc.), neuropathy (sensory, motor, Autonomic nerves) and foot gangrene.

  The main complications are diabetic retinopathy, diabetic nephropathy, diabetic neuropathy.

The compound of the present invention can be administered orally or parenterally as a pharmaceutical systemically or locally.
Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.

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. From the compound of the present invention and these carriers, tablets, pills, capsules, granules, powders, powders, liquids, emulsions, suspensions, injections, etc., all of which are conventional pharmaceutical techniques (for example, No. 15 It can be manufactured by the method prescribed in the revised Japanese Pharmacopoeia. These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.

  The dose of the compound of the present invention varies depending on the disease, symptom, body weight, age, sex, route of administration and the like. For example, when orally administered to an adult diabetic patient, the dose is usually 0.001 mg to 1000 mg, Preferably it is 0.01 mg-200 mg, and 0.1-10 mg / kg body weight is more preferable. This amount can be administered once to several times a day.

  The superiority of the compound of the present invention over the similar structure compound is shown below.

  Table 2 below shows the blood glucose lowering action and the renal concentration of the similar compounds of the present application after sugar loading. Compounds 4, 10, 11 and 33 showed a strong hypoglycemic effect in a glucose tolerance test after oral administration of 1 mg / kg. On the other hand, 7 days after oral administration of 1 mg / kg, the compound tended to remain in the kidney without being excreted. The target organ is the small intestine where SGLT1 is distributed a lot. Therefore, unexpected side effects may occur when the compound remains for a long time other than the target organ. For example, a compound having a hydrophilic group such as a tertiary amine and a hydrophobic group such as an aromatic ring in the molecule is called a cationic drug. They are hydrophobically bound to phospholipids and can be taken up into lysosomes and accumulated in systemic organs. Depending on the drug, the organs that accumulate are different, with chloroquine showing retinal damage and perhexiline with changes in the lungs and cerebellum (Nippon Pharmacology Folia Pharmacol. Jpn. 113, 19-30, 1999).

  For this reason, it is desirable that the compound is rapidly excreted from the body after showing its medicinal properties.

  Next, Table 3 below shows the blood glucose lowering action and the renal concentration after the sugar load of the compound of the present invention. Examples 1-2, 5-2, 6-2, 13-2, and 15-2 had a strong hypoglycemic effect similar to the above similar compounds. However, surprisingly, the compound was characterized by the fact that it did not remain in the kidney after 2 days, even though the compound was administered continuously at a dose of 3 mg / kg for 3 days. Compared with the similar compounds shown in Table 2, this is considered to be an important property related to the utility of the present compound as a pharmaceutical product.

  In addition, the following Example compounds can be expected to have low toxicity concerns due to continuous casting.

  Accordingly, preferred embodiments of the present invention are the following example compounds.

  Although the manufacturing method of this invention compound (I) is demonstrated in detail below by giving an example, it is not specifically limited to what was illustrated.

Manufacturing method 1
The compound (I) of the present invention can be synthesized by the following method.

However, X is shows an acetyl group or a _{C 1-4} alkyl group, ^{R 5} represents a ^{R 3 wherein R 3} or an amino group is protected with tert- butyl carbonate (Boc), and other symbols are as defined above .

(1) Step 1 (Heck reaction)
Compound (IV) can be obtained by subjecting compound (II) and olefin carboxylic acid (III) 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 from 0 ° C. to reflux temperature, but a microwave may be used.

(2) Step 2 (Conversion to amide group)
Compound (IV) can be dehydrated and condensed with amine (R ⁵ R ⁴ NH) to obtain compound (V). Examples of the solvent used in this reaction include chloroform, dichloromethane, N, N-dimethylformamide, and examples of the dehydrating condensing agent include N, N′-dicyclohexylcarbodiimide (DCC) and N-ethyl-N′-3-. Dimethylaminopropylcarbodiimide hydrochloride (EDC-HCl), 1,1′-carbonyldiimidazole (CDI), EDC-HCl / 1-hydroxybenzotriazole monohydrate (HOBt · H ₂ O), etc. Is mentioned. The reaction temperature here is 0 ° C to 60 ° C.

(3) Step 3 (deprotection)
Compound (I) can be obtained by removing the Boc group in compound (V) 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 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.

Manufacturing method 2
The compound (I) of the present invention can also be synthesized by another route shown below. However, the symbols are as defined above.

(4) Step 4 (Heck reaction)
Compound (VII) can be obtained by performing Heck reaction described in Step 1 of Production Method 1 using Compound (II) and olefin carboxylic acid (VI).

(5) Step 5 (Conversion to amide group)
Compound (V) can be obtained by performing the dehydration condensation reaction described in Step 2 of Production Method 1 using Compound (VII) and amine (VIII).

(6) Step 6 (deprotection)
The compound (V) obtained above can be led to the compound (I) by the deprotection reaction described in Step 3 of Production Method 1.

Production method 3
Production method of intermediate (II) The production method of intermediate (II) necessary for the production of the compound (I) of the present invention is shown below.

However, X ¹ represents a benzyl group or a C _1-4 alkyl group, X ² represents a trimethylsilyl group or a C _1-4 alkyl group, and other symbols are as defined above.

(7) Step 7 (coupling)
An aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for compound (IX). Compound (XI) can be obtained by adding gluconolactone (X) to this. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C.

(8) Step 8 (acid hydrolysis and methyl etherification)
The silyl group in compound (XI) can be removed in methanol under acidic conditions, and the 1-position of sugar can be methyletherified to obtain compound (XII). 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.

(9) Step 9 (acetylation)
Compound (XIII) can be obtained by protecting the hydroxyl group in compound (XII) with an acetyl group. Compound (XIII) can be obtained by reacting compound (XII) with acetic anhydride, acetyl chloride or the like in a solvent in the presence of a suitable base. Solvents used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. As the base, triethylamine, collidine, pyridine and the like can be used. 4-Dimethylaminopyridine can also be used as a catalyst for the reaction. The reaction temperature here is 0 ° C. to room temperature.

(10) Step 10 (reduction)
Compound (XIII) and _{Et 3 SiH, i-Pr 3} SiH, a t-BuMe ₂ SiH or _Ph 2 SiHCl, are reacted in the presence of a Lewis acid, it is possible to obtain compound (XIV). Examples of the Lewis acid used in this reaction include BF ₃ .OEt ₂ , CF ₃ COOH, InCl ₃ , TiCl ₄ , TMSOTf, p-toluenesulfonic acid, methanesulfonic acid, and the like. Solvents include chloroform, dichloromethane, Examples include toluene, tetrahydrofuran, acetonitrile, or a mixed solvent thereof, and a preferable solvent is a mixed solvent of acetonitrile and another solvent such as acetonitrile / chloroform, acetonitrile / dichloromethane, acetonitrile / tetrahydrofuran, acetonitrile / tetrahydrofuran / toluene, and the like. The reaction temperature here is −60 ° C. to 25 ° C., preferably −30 ° C. to 25 ° C.

(11) Step 11 (deprotection)
When X ¹ in compound (XIV) is a benzyl group, debenzylation is performed by catalytic hydrogenation under a hydrogen atmosphere using a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-palladium activated carbon. be able to. Of these, palladium activated carbon and palladium hydroxide are preferred as the catalyst. Examples of the solvent used in this reaction include methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and a mixed solvent thereof. The reaction temperature is from room temperature to reflux temperature, but room temperature is preferred.

(12) Step 12 (bromination)
Compound (XV) can be obtained by reacting Compound (XIV) or the compound obtained in Step 11 above with bromine, N-bromosuccinimide, hydrogen bromide or the like in a solution. Examples of the solvent used for the reaction include chloroform, dichloromethane, acetic acid, methanol, N, N-dimethylformamide and the like. The reaction temperature here is 0 ° C. to room temperature.

(13) Step 13 (deprotection)
Compound (XVI) can be obtained by removing the acetyl group in compound (XV) under basic conditions. As the base, a base such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine or the like can be used. As the solvent, methanol, ethanol, hydrous methanol, or the like can be used. The reaction temperature here is 0 ° C to 60 ° C.

(14) Step 14 (silylation)
Compound (XVII) can be obtained by protecting the hydroxyl group in compound (XVI) with a silyl group such as a trimethylsilyl group. Compound (XVII) can be obtained by reacting compound (XVI) with trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride and the like in a solvent in the presence of an appropriate base. Examples of the solvent used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. As the base, triethylamine, collidine, pyridine and the like can be used. The reaction temperature here is 0 ° C. to room temperature.

(15) Step 15 (coupling)
An aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for compound (XVII). Compound (XIX) can be obtained by adding aldehyde (XVIII) to this. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C.

(16) Step 16 (acid hydrolysis)
Compound (XIX) obtained above can be converted to compound (XX) by the acid hydrolysis reaction described in Step 8 of Production Method 3.

(17) Step 17 (acetylation)
Compound (XX) obtained above can be led to compound (XXI) by the acetylation reaction described in Step 9 of Production Method 3.

(18) Step 18 (reduction)
Compound (XXI) obtained above can be led to intermediate (II) by the reduction reaction described in Step 10 of Production Method 3.

Manufacturing method 4
Production Method of Intermediate (II) Intermediate (II) can also be synthesized by another route shown below. Here, steps 19 to 21 can be performed in one pot to reduce the number of steps.

  However, the symbols are as defined above.

(19) Step 19 (coupling)
An aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for compound (XXII). Compound (XXIII) can be obtained by adding gluconolactone (X) to this. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C.

(20) Step 20 (silylation)
Subsequent to step 19, the 1-position hydroxyl group of compound (XXIII) can be protected with a silyl group such as a trimethylsilyl group. The reaction solution in Step 19 can be reacted with trimethylsilyl chloride to obtain compound (XXIV). The solvent and reaction temperature used for the reaction are the same as in Step 19.

(21) Step 21 (coupling)
Subsequent to the step 20, an aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, tert-butyllithium or the like for the produced compound (XXIV). Compound (XXV) can be obtained by adding aldehyde (XVIII) to this. At this time, the solvent used in the reaction and the reaction temperature are the same as in Step 19.

(22) Step 22 (acid hydrolysis)
Compound (XXV) obtained above can be led to compound (XXVI) by the acid hydrolysis reaction described in Step 8 of Production Method 3.

(23) Step 23 (acetylation)
Compound (XXVI) obtained above can be led to compound (XXVII) by the acetylation reaction described in Step 9 of Production Method 3.

(24) Step 24 (reduction)
Compound (XXVII) obtained above can be converted to compound (XXVIII) by the reduction reaction described in Step 10 of Production Method 3.

(25) Step 25 (acetylation or alkylation)
Intermediate (II) can be produced by protecting the hydroxyl group of compound (XXVIII) with an acetyl group or alkylating such as methylation. Intermediate (II) can be obtained by reacting compound (XXVIII) with acetic anhydride or acetyl chloride in a solvent in the presence of a suitable base. Solvents 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 or the like can also be used as a catalyst. The reaction temperature here is 0 ° C. to room temperature. On the other hand, intermediate (II) can be obtained by reacting compound (XXVIII) with methyl iodide, ethyl iodide, isopropyl 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. As the base, potassium carbonate, cesium carbonate, or the like can be used.

  Hereinafter, the present invention will be described in more detail with reference examples, examples and test examples.

  Reference Example 1 Production of Intermediate (A)

（１）参考例１−１ 化合物（Ａ１）

(1) Reference Example 1-1 Compound (A1)

An aqueous suspension (75 mL) of potassium iodate (7.88 g, 0.0368 mol) and iodine (18.7 g, 0.0736 mol) were added to a solution of 3-isopropylphenol (25 g, 0.184 mol) in acetic acid (200 mL). In addition, the reaction solution was stirred at room temperature for 20 hours. After adding diethyl ether (400 mL) and water (300 mL), the organic layer was separated. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then 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: ethyl acetate = 95: 5) to give a colorless oily compound (A1) (27.6 g, 57%).
¹ H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.16-1.25 (m, 6 H) 2.64-2.98 (m, 1 H) 5.21 (s, 1 H) 6.57 (dd, J = 8.13, 2.20 Hz, 1 H) 6.88 (d, J = 2.20 Hz, 1 H) 7.54 (d, J = 8.13 Hz, 1 H).
(2) Reference Example 1-2 Compound (A2)

Benzyl bromide (14.4 mL, 0.121 mol) was added to an acetonitrile suspension of compound (A1) (26.5 g, 0.101 mol) and potassium carbonate (20.9 g, 0.152 mol), and the mixture was stirred at room temperature for 2 hours. did. Methanol (1.0 mL) was added and stirred for 30 minutes. Insoluble matters were filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to obtain a colorless oily compound (A2) (30.2 g, 85%).
¹ H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J = 7.03 Hz, 6 H) 2.84 (sept, J = 7.03 Hz, 1 H) 5.14 (s, 2 H) 6.62 (dd, J = 8.35, 2.20 Hz, 1 H) 6.74 (d, J = 2.20 Hz, 1 H) 7.23-7.58 (m, 5 H) 7.68 (d, J = 8.35 Hz, 1 H).
(3) Reference Example 1-3 Compound (A3)

  To a THF (450 mL) solution of compound (A2) (30.2 g, 85.7 mmol), 2.6 M n-butyllithium hexane solution (33 mL, 85.7 mmol) was added dropwise at −78 ° C. in a nitrogen atmosphere. Stir for 15 minutes at the same temperature. Next, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (40 g, 85.7 mmol) in THF (230 mL) was added dropwise over 15 minutes. Stir for minutes. A saturated aqueous ammonium chloride solution (150 mL) and water (100 mL) were added to the reaction solution. The mixture was warmed to room temperature and extracted twice 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.

  The obtained residue was dissolved in a methanol (840 mL) solution containing methanesulfonic acid (2.9 g) and stirred at room temperature for 14.5 hours. Neutralized with triethylamine (2.5 mL) and the reaction mixture was concentrated.

  The obtained residue (46.4 g) was dissolved in pyridine (125 mL) and cooled to 4 ° C. Acetic anhydride (75 mL) and 4-dimethylaminopyridine (102 mg, 0.835 mmol) were added to this solution, and the mixture was stirred at room temperature for 19 hours. Ice water (500 mL) was added and the mixture was extracted twice with ethyl acetate (500 mL). The combined organic layers were 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 a crude compound (53 g).

A solution of this crude compound in chloroform (250 mL) and acetonitrile (250 mL) was added to Et ₃ SiH (13.7 mL, 85.7 mmol) and BF ₃ .Et ₂ O (10.9 mL, 85.7 mmol) at 4 ° C. in a nitrogen atmosphere. ) And stirred at the same temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 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: ethyl acetate = 5: 1 → 2: 1) to give the compound ( A3) (19.1 g, 40%; 4 steps) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J = 6.99 Hz, 6 H) 1.78 (s, 3 H) 2.01 (s, 6 H) 2.05 (s, 3 H) 2.86 (sept, J = 6.99 Hz, 1 H) 3.80 (ddd, J = 9.95, 4.59, 2.25 Hz, 1 H) 4.06-4.13 (m, 1 H) 4.19-4.27 (m, 1 H) 4.96 (d, J = 9.95 Hz , 1 H) 5.10 (s, 2 H) 5.16-5.25 (m, 1 H) 5.33 (t, J = 9.17 Hz, 1 H) 5.40-5.49 (m, 1 H) 6.79 (d, J = 1.40 Hz, 1 H) 6.85 (dd, J = 7.93, 1.40 Hz, 1 H) 7.26-7.52 (m, 6 H).
MS ESI / APCI Dual posi: 579 [M + Na] ⁺ .
(4) Reference Example 1-4 Compound (A4)

To a solution of compound (A3) (19.1 g, 34.3 mmol) in methanol (200 mL) was added 10% palladium activated carbon (1.8 g), and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to give the compound (A4) as a colorless amorphous product. (12.3 g, 77%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (d, J = 6.89 Hz, 6 H) 1.83 (s, 3 H) 2.01 (s, 3 H) 2.06 (s, 3 H) 2.12 (s, 3 H) 2.82 (sept, J = 6.89 Hz, 1 H) 3.87 (ddd, J = 9.60, 3.85, 2.25 Hz, 1 H) 4.14-4.21 (m, 1 H) 4.27-4.36 (m, 1 H) 4.59 (d, J = 9.33 Hz, 1 H) 5.23-5.39 (m, 3 H) 6.70 (dd, J = 7.93, 1.71 Hz, 1 H) 6.77 (d, J = 1.71 Hz, 1 H) 6.80 (s, 1 H) 6.91 (d, J = 7.93 Hz, 1 H).
MS ESI / APCI Dual posi: 489 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 501 [M + Cl] ⁻ .
(5) Reference Example 1-5 Compound (A5)

Bromine (4.2 g, 26.3 mmol) was added dropwise at room temperature to a solution of compound (A4) (12.3 g, 26.3 mol) in acetic acid (120 mL). The reaction mixture was stirred for 1.5 hours and ice water (150 mL) was added. This mixture was extracted twice with ethyl acetate, and the combined organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, a 10% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 2-propanol (20 mL), and hexane (50 mL) was added dropwise. The mixture was stirred at 4 ° C. for 1 hour, and the deposited precipitate was filtered to obtain a colorless powder of compound (A5) (9.8 g, 68%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12-1.26 (m, 6 H) 1.89 (s, 3 H) 2.01 (s, 3 H) 2.07 (s, 3 H) 2.13 (s, 3 H) 3.22 (sept, J = 6.74 Hz, 1 H) 3.87 (ddd, J = 9.48, 3.73, 2.18 Hz, 1 H) 4.14-4.22 (m, 1 H) 4.28-4.36 (m, 1 H) 4.53 (d, J = 9.33 Hz, 1 H) 5.16-5.39 (m, 3 H) 6.82 (s, 1 H) 7.14 (s, 1 H).
MS ESI / APCI Dual posi: 567 [M + Na] ⁺ , 569 [M + 2 + Na] ⁺ .
MS ESI / APCI Dual nega: 579 [M + Cl] ⁻ , 581 [M + 2 + Cl] ⁻ .
(6) Reference Example 1-6 Compound (A6)

Triethylamine (24 mL) and water (24 mL) were added to a solution of compound (A5) (12.2 g, 22.3 mol) in methanol (120 mL). The reaction mixture was stirred at room temperature for 15 hours and further at 50 ° C. for 10 hours, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (106 mL), and triethylamine (18.6 mL) and chlorotrimethylsilane (14.3 mL) were added at 4 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at 4 ° C. for 1 hour and ice water (150 mL) was added. The mixture was extracted three times with toluene, and the combined organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to obtain an oily compound (A6) (17.4 g). This was used in the next reaction without purification.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm -0.28 (s, 9 H) 0.08 (s, 9 H) 0.19 (s, 9 H) 0.20 (s, 9 H) 0.29 (s, 9 H) 1.16 (d, J = 6.84 Hz, 3 H) 1.21 (d, J = 6.84 Hz, 3 H) 3.17-3.37 (m, 1 H) 3.41-3.56 (m, 3 H) 3.62-3.72 (m, 1 H) 3.76-3.86 (m, 1 H) 4.46 (d, J = 8.24 Hz, 1 H) 6.64 (s, 1 H) 7.47 (s, 1 H).
(7) Reference Example 1-7 Compound (A7)

  To a solution of compound (A6) (13.4 g, 15.9 mmol) in THF (140 mL) at −78 ° C. in a nitrogen atmosphere was added 2.6 M n-butyllithium hexane solution (7.7 mL, 20.0 mmol). The solution was added dropwise over a period of time and stirred at the same temperature for 5 minutes. Then, a solution of 4-bromo-2-methylbenzaldehyde (3.2 g, 15.9 mmol) in THF (24 mL) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 45 minutes. A saturated aqueous ammonium chloride solution (100 mL) and water (100 mL) were added to the reaction solution. The mixture was warmed to room temperature and extracted twice 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.

The obtained residue was dissolved in a methanol (200 mL) solution containing methanesulfonic acid (0.9 g) and stirred at room temperature for 0.5 hour. Neutralized with triethylamine and the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1 → 8: 1) to obtain a colorless amorphous compound (A7) (5.75 g, 73%).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.01 and 1.04 (each d, J = 6.88 Hz, 3 H) 1.18 and 1.19 (each d, J = 6.88 Hz, 3 H) 2.24 and 2.26 (each s , 3 H) 2.95-3.07 (m, 1 H) 3.35-3.69 (m, 5 H) 3.78-3.87 (m, 1 H) 4.37-4.50 (m, 1 H) 5.59 (s, 1 H) 6.80 (s , 1 H) 6.98-7.10 (m, 2 H) 7.24-7.30 (m, 1 H) 7.33 (s, 1 H).
MS ESI / APCI Dual posi: 479 [M-OH] ⁺ , 481 [M + 2-OH] ⁺ .
(8) Reference Example 1-8 Intermediate (A)

  Compound (A7) (5.7 g, 11.5 mmol) was dissolved in pyridine (34 mL). Acetic anhydride (17 mL) and 4-dimethylaminopyridine (10 mg) were added to this solution, and the mixture was stirred at room temperature for 0.5 hr. Ice water (500 mL) was added and the mixture was extracted twice with ethyl acetate (500 mL). The combined organic layers were 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 a crude compound (8.5 g).

To a solution of the crude compound (8.5 g) in chloroform (80 mL) and acetonitrile (80 mL), Et ₃ SiH (2.7 mL, 17.0 mmol) and BF ₃ .Et ₂ O (2. 2 mL, 17.0 mmol) was added. The reaction solution was warmed to room temperature and then stirred at the same temperature for 0.5 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from a mixture of hexane: ethyl acetate = 4: 1, and the deposited precipitate was filtered to obtain colorless powder intermediate (A) (5.3 g, 68%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 6.68 Hz, 3 H) 1.14 (d, J = 6.68 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) 2.37 (s, 3 H) 2.93 (sept, J = 6.68 Hz, 1 H) 3.76 (ddd, J = 9.87, 4.51 , 2.25 Hz, 1 H) 3.87 (s, 2 H) 4.06 (dd, J = 12.51, 2.25 Hz, 1 H) 4.27 (dd, J = 12.51, 4.51 Hz, 1 H) 4.49 (d, J = 9.64 Hz , 1 H) 5.10-5.33 (m, 3 H) 6.59 (d, J = 8.39 Hz, 1 H) 6.97 (s, 1 H) 7.00 (s, 1 H) 7.20 (dd, J = 8.39, 2.49 Hz, 1 H) 7.34 (d, J = 2.49 Hz, 1 H).
MS ESI / APCI Dual posi: 713 [M + Na] ⁺ , 715 [M + 2 + Na] ⁺ .
Intermediate (A) can also be synthesized by the methods described in Reference Examples 1-9, 10, and 11.
(9) Reference Example 1-9 Compound (A8)

To a solution of 3-isopropylphenol (160 g, 1.18 mol) in acetic acid (1.6 L) was added ice-cooled bromine (469 g, 2.94 mol) in acetic acid (320 mL) for 32 minutes so that the internal temperature did not exceed 19 ° C. The mixture was added dropwise 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 a 10% aqueous sodium sulfite solution (1.0 L) and a 10% aqueous sodium chloride solution (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 a pale yellow oily compound (A8) (342 g, 99%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J = 6.84 Hz, 6 H) 3.25 (sept, J = 6.84 Hz, 1 H) 5.40 (s, 1 H) 6.96 (s, 1 H ) 7.61 (s, 1 H).
(10) Reference Example 1-10 Compound (A9)

N, N-diisopropylethylamine (364 mL, 2.09 mol) was added to a solution of compound (A8) (512 g, 1.74 mol) in chloroform (1.74 L), and the mixture was ice-cooled. Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 60 minutes, 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 (A9) (548 g, 96%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J = 6.84 Hz, 6 H) 3.28 (sept, J = 6.84 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] ⁺ .

(11) Reference Example 1-11 Intermediate (A)
To a THF (3.1 L) solution of the compound (A9) (210 g, 0.621 mol), a 2.76 M n-butyllithium hexane solution (236 mL, 0.652 mol) was added at −86 to −74 ° C. in an argon atmosphere. The solution was added dropwise over 20 minutes and stirred at the same temperature for 35 minutes. Then, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (305 g, 0.652 mol) in THF (890 mL) was added dropwise at the same temperature over 38 minutes. Stir at temperature for 50 minutes. Further, trimethylchlorosilane (82.8 mL, 0.652 mmol) was added dropwise over 4 minutes, and the mixture was stirred at the same temperature for 3 hours. Subsequently, 2.76M n-butyllithium hexane solution (326 mL, 0.901 mol) was added dropwise over 23 minutes, and the mixture was stirred at the same temperature for 40 minutes. Finally, a solution of 4-bromo-2-methylbenzaldehyde (136 g, 0.683 mmol) in THF (890 mL) was added dropwise over 43 minutes and stirred at the same temperature for 35 minutes. Water (3.1 L) was added to the reaction solution and warmed to room temperature. Toluene (3.1 L) was added to separate the organic layer, and the solvent was distilled off under reduced pressure.

  The obtained residue (633 g) was dissolved in methanol (3.1 L), methanesulfonic acid (4.03 mL, 0.0621 mol) was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, neutralized with triethylamine (17.3 mL, 0.124 mol), and the reaction mixture was concentrated. The concentrate (413 g) was dissolved in toluene (1.1 L) and washed 3 times with water (1.65 L). A 1M aqueous sodium hydroxide solution (0.55 L) and toluene (0.55 L) were added to the organic layer to perform extraction, and the aqueous layer was separated. The aqueous layer was washed with toluene (1.65 L). The aqueous layer was extracted with 2M hydrochloric acid (0.43 L) and toluene (1.1 L), and the organic layer was separated. The organic layer was washed with a 10% aqueous sodium chloride solution (1.1 L), and the solvent was distilled off under reduced pressure.

The obtained residue (273 g) was dissolved in THF (1.01 L), and N, N-diisopropylethylamine (776 mL, 4.53 mol), acetic anhydride (381 mL, 4.03 mol) and 4-dimethylaminopyridine (615 mg, 5.04 mmol) was added, and the mixture was stirred at room temperature for 21 hours. The reaction solution was ice-cooled, water (1.0 L) and toluene (1.0 L) were added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (1.0 L), and the solvent was distilled off under reduced pressure.
The obtained residue (390 g) was dissolved in acetonitrile (3.85 L), water (9.07 mL, 0.504 mol), t-BuMe ₂ SiH (334 mL, 2.02 mmol) were added, and after ice cooling, TMSOTf (392 mL). , 2.17 mmol) was added dropwise over 30 minutes. After stirring at the same temperature for 1 hour, acetic anhydride (95.2 mL, 1.01 mol) was added dropwise over 10 minutes, and the mixture was further stirred at the same temperature for 15 minutes. Toluene (3.85 L) and 3% aqueous sodium hydrogen carbonate solution (1.92 L) were added to the reaction solution, and the organic layer was separated. The organic layer was washed with 3% aqueous sodium hydrogen carbonate solution (1.92 L), 10% aqueous sodium chloride solution (1.92 L), 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 crystallized from 2-propanol (1.42 L). The deposited precipitate was filtered to obtain colorless powder of intermediate (A) (201 g, 47 %; 4 steps).

  Reference Example 2 Production of Intermediate (B)

（１）参考例２−１ 化合物（Ｂ１）

(1) Reference Example 2-1 Compound (B1)

Methyl iodide (9.8 mL, 0.156 mol) was added to an acetonitrile suspension (200 mL) of compound (A1) (27.4 g, 0.104 mol) and potassium carbonate (21.7 g, 0.156 mol) at 40 ° C. For 2.5 hours. Methyl iodide (3.5 mL, 0.052 mol) was further added, and the mixture was stirred at the same temperature for 1 hour. Insoluble matter was filtered off, and the filtrate was diluted with ethyl acetate. The organic layer was washed with water, 10% aqueous sodium thiosulfate solution and saturated brine, 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 silica gel column chromatography (hexane → hexane: ethyl acetate = 95: 5) to obtain a light yellow oily compound (B1) (24.5 g, 85%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (d, J = 6.84 Hz, 6 H) 2.87 (sept, J = 6.84 Hz, 1 H) 3.88 (s, 3 H) 6.58-6.65 (m, 1 H) 6.70 (d, J = 1.87 Hz, 1 H) 7.65 (d, J = 8.08 Hz, 1 H).
MS ESI / APCI Dual posi: 277 [M + H] ⁺ .
(2) Reference Example 2-2 Compound (B2)

  To a THF (100 mL) solution of the compound (B1) (24.5 g, 88.6 mmol), a 2.6 M n-butyllithium hexane solution (34 mL, 88.6 mmol) was added dropwise at −78 ° C. in a nitrogen atmosphere. Stir at the same temperature for 5 minutes. Next, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (37.6 g, 80.5 mmol) in THF (60 mL) was added dropwise over 25 minutes to the same temperature. And stirred for 10 minutes. Ice and water were added to the reaction mixture, and the mixture was warmed to room temperature and 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.

  The obtained residue was dissolved in a methanol (380 mL) solution containing methanesulfonic acid (1.55 g, 16.1 mmol) and stirred at room temperature for 2 hours. Neutralized with triethylamine (11.2 mL, 80.5 mmol) and the reaction mixture was concentrated.

The obtained residue (30.2 g) was dissolved in pyridine (100 mL), acetic anhydride (100 mL) was added, and the mixture was stirred at room temperature for 14 hours. Ice water (400 mL) was added and the mixture was extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with 1M 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 = 6: 4) to give a pale yellow oily compound (B2) (32 8 g, 80%; 3 steps).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.92 Hz, 6 H) 1.84 (s, 3 H) 1.97 (s, 3 H) 2.06 (s, 3 H) 2.10 (s, 3 H) 2.87 (sept, J = 6.92 Hz, 1 H) 3.32 (s, 3 H) 3.87 (s, 3 H) 4.04 (ddd, J = 10.18, 4.74, 2.41 Hz, 1 H) 4.17-4.23 (m , 1 H) 4.28-4.36 (m, 1 H) 5.25 (dd, J = 10.18, 9.40 Hz, 1 H) 5.36 (d, J = 10.18 Hz, 1 H) 5.60 (dd, J = 10.18, 9.40 Hz, 1 H) 6.74 (d, J = 1.55 Hz, 1 H) 6.79 (dd, J = 8.08, 1.55 Hz, 1 H) 7.26-7.33 (m, 1 H).
MS ESI / APCI Dual posi: 533 [M + Na] ⁺ .
(3) Reference Example 2-3 Compound (B3)

A solution of compound (B2) (32.8 g, 64.0 mmol) in chloroform (150 mL) and acetonitrile (150 mL) was added Et ₃ SiH (21 mL, 128 mmol) and BF ₃ .Et ₂ O (49 mL) at 4 ° C. under a nitrogen atmosphere. , 385 mmol), and stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 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: ethyl acetate = 2: 1) to give a pale yellow gum-like compound (B3) (22 0.9 g, 74%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J = 6.99 Hz, 6 H) 1.77 (s, 3 H) 2.01 (s, 3 H) 2.05 (s, 3 H) 2.07 (s, 3 H) 2.87 (sept, J = 6.96 Hz, 1 H) 3.80-3.87 (m, 1 H) 3.84 (s, 3 H) 4.09-4.16 (m, 1 H) 4.22-4.29 (m, 1 H) 4.88 -4.95 (m, 1 H) 5.18-5.27 (m, 1 H) 5.32-5.38 (m, 2 H) 6.71 (d, J = 1.55 Hz, 1 H) 6.83 (dd, J = 7.93, 1.55 Hz, 1 H) 7.23-7.30 (m, 1 H).
MS ESI / APCI Dual posi: 503 [M + H] ⁺ .
MS ESI / APCI Dual nega: 515 [M + Cl] ⁻ .
(4) Reference Example 2-4 Compound (B4)

A pale yellow amorphous compound (B4) (25.5 g, 96%) was obtained in the same manner as in Reference Example 1-5 using compound (B3) instead of compound (A4).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (d, J = 6.84 Hz, 3 H) 1.23 (d, J = 6.84 Hz, 3 H) 1.80 (s, 3 H) 2.01 (s, 3 H ) 2.05 (s, 3 H) 2.09 (s, 3 H) 3.31 (sept, J = 6.84 Hz, 1 H) 3.77-3.82 (m, 1 H) 3.83 (s, 3 H) 4.10-4.17 (m, 1 H) 4.22-4.30 (m, 1 H) 4.83 (d, J = 9.48 Hz, 1 H) 5.17-5.38 (m, 3 H) 6.75 (s, 1 H) 7.49 (s, 1 H).
MS ESI / APCI Dual posi: 581 [M + Na] ⁺ , 583 [M + 2 + Na] ⁺ .
(5) Reference Example 2-5 Compound (B5)

Using a compound (B4) instead of the compound (A5), a brown oily compound (B5) (30.3 g) was obtained in the same manner as in Reference Example 1-6. This was used in the next reaction without purification.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm -0.32 (s, 9 H) 0.09 (s, 9 H) 0.18 (s, 9 H) 0.20 (s, 9 H) 1.19 (d, J = 6.84 Hz , 3 H) 1.23 (d, J = 6.84 Hz, 3 H) 3.26-3.44 (m, 3 H) 3.52-3.58 (m, 2 H) 3.65-3.75 (m, 3 H) 3.76-3.83 (m, 1 H) 3.80 (s, 3 H) 4.60 (d, J = 8.55 Hz, 1 H) 6.72 (s, 1 H) 7.51 (s, 1 H).
MS ESI / APCI Dual posi: 701 [M + Na] ⁺ , 703 [M + 2 + Na] ⁺ .
(6) Reference Example 2-6 Compound (B6)

Using the compound (B5) instead of the compound (A6), a brown amorphous compound (B6) (14.7 g, 60%) was obtained in the same manner as in Reference Example 1-7.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 and 1.25 (each d, J = 6.84 Hz, 6 H) 1.80 (s, 2 H) 2.27 and 2.29 (each s, 3 H) 2.30-2.58 (m , 2 H) 2.82-3.06 (m, 2 H) 3.34 and 3.35 (each s, 3 H) 3.38-3.86 (m, 6 H) 4.56-4.73 (m, 1 H) 5.53 (d, J = 3.11 Hz, 1 H) 6.75-7.35 (m, 5 H).
MS ESI / APCI Dual posi: 493 [M-OH] ⁺ , 495 [M + 2-OH] ⁺
(7) Reference Example 2-7 Intermediate (B)

Using the compound (B6) instead of the compound (A7), a colorless amorphous intermediate (B) (14.2 g, 88%) was obtained in the same manner as in Reference Example 1-8.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J = 6.68 Hz, 3 H) 1.14 (d, J = 6.68 Hz, 3 H) 1.75 (s, 3 H) 1.99 (s, 3 H ) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.90 (sept, J = 6.68 Hz, 1 H) 3.71-3.90 (m, 3 H) 3.86 (s, 3H) 3.85 -3.87 (m, 1 H) 4.05-4.15 (m, 1 H) 4.19-4.28 (m, 1 H) 4.77-4.85 (m, 1 H) 5.11-5.23 (m, 1 H) 5.26-5.37 (m, 2 H) 6.54 (d, J = 8.24 Hz, 1 H) 6.81 (s, 1 H) 6.96 (s, 1 H) 7.17 (dd, J = 8.24, 2.64 Hz, 1 H) 7.32 (d, J = 2.64 Hz, 1 H).
MS ESI / APCI Dual posi: 685 [M + Na] ⁺ , 687 [M + 2 + Na] ⁺ .
Reference Example 3 Production of Intermediate (C)

Using 4-bromobenzaldehyde instead of 4-bromo-2-methylbenzaldehyde, Compound (C) (2.26 g) was obtained as a pale yellow amorphous product in the same manner as in Reference Examples 1-7 and 1-8. It was.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J = 6.84 Hz, 3 H) 1.09 (d, J = 6.84 Hz, 3 H) 1.76 (s, 3 H) 2.01 (s, 3 H ) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.91-3.06 (m, 1 H) 3.80-3.88 (m, 4 H) 3.91 (d, J = 5.13 Hz, 2 H) 4.06-4.18 (m , 1 H) 4.20-4.31 (m, 1 H) 4.82-4.93 (m, 1 H) 5.15-5.43 (m, 3 H) 6.77 (s, 1 H) 6.92 (d, J = 8.55 Hz, 2 H) 7.11 (s, 1 H) 7.36 (d, J = 8.55 Hz, 2 H).
MS ESI / APCI Dual posi: 671 [M + Na] ⁺ , 683 [M + 2 + Na] ⁺
Reference Example 4 Production of intermediate (D)

（１）参考例４−１ 化合物（Ｄ１）

(1) Reference Example 4-1 Compound (D1)

A solution of 2,2-dimethyl-3-butenoic acid (J. Org. Chem., 65, 8402, 2000) (5.42 g, 47.5 mmol) in chloroform (250 mL) under a nitrogen atmosphere, Oxalyl chloride (4.43 mL, 49.9 mmol) and N, N-dimethylformamide (3 drops) were added, and the mixture was 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 compound (D1) (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 = 17.56 , 10.57 Hz, 1 H) 6.25 (br. S., 1 H).
MS ESI / APCI Dual posi: 214 [M + H] ⁺ .
(2) Reference Example 4-2 Intermediate (D)

To a solution of compound (D1) (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 colorless powder intermediate (D) (8.19 g, 94%).
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 = 17.49, 10.65 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] ⁻ .
Reference Example 5 Production of intermediate (E)

Under an argon atmosphere, intermediate (A) (5.0 g, 7.23 mmol), intermediate (D) (2.59 g, 13.0 mmol), palladium (II) acetate (328 mg, 1.45 mmol), tri-o -A suspension of 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 resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to obtain a pale yellow powder intermediate (E) (4.59 g, 78 %).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16, 1.18 (each d J = 6.84 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 = 12.43, 4.51 Hz, 1 H) 4.47 (d, J = 9.17 Hz, 1 H) 5.07-5.32 (m , 3 H) 6.31 (d, J = 16.32 Hz, 1 H) 6.35 (s, 1 H) 6.55 (d, J = 16.32 Hz, 1 H) 6.77 (d, J = 7.62 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] ⁻ .
Reference Example 6 Production of intermediate (F)

Under an argon atmosphere, intermediate (B) (2.0 g, 3.0 mmol), intermediate (D) (1.08 g, 5.4 mmol), palladium (II) acetate (136 mg, 0.6 mmol), tri-o -A suspension of tolylphosphine (370 mg, 1.2 mmol) and triethylamine (1.26 mL, 9.0 mmol) in acetonitrile (10 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 resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to obtain a pale yellow powder intermediate (F) (2.03 g, 87 %).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14, 1.17 (each d, J = 6.99 Hz, 3 H) 1.38 (s, 6 H) 1.55 (s, 6 H) 1.76 (s, 3 H) 1.98 (s, 3 H) 2.04 (s, 6 H) 2.30 (s, 3 H) 2.94-3.03 (m, 1 H) 3.76-3.83 (m, 1 H) 3.84-3.95 (m, 4 H) 4.06-4.15 (m, 1 H) 4.16-4.25 (m, 1 H) 4.81 (d, J = 9.79 Hz, 1 H) 5.12-5.20 (m, 1 H) 5.23-5.35 (m, 2 H) 6.29 (s, 1H ) 6.31 (d, J = 16.32 Hz, 1 H) 6.52 (d, J = 16.32 Hz, 1 H) 6.67 (d, J = 8.08 Hz, 1 H) 6.81 (s, 1 H) 6.94 (s, 1 H ) 7.06-7.14 (m, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 782 [M + H] ⁺ , 804 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 780 [MH] ⁻ .
Reference Example 7 Production of intermediate (G)

A light yellow amorphous intermediate (G) (854 mg, 60%) was obtained in the same manner as in Reference Example 5 using the intermediate (C) instead of the intermediate (A).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08 (d, J = 6.84 Hz, 3 H) 1.12 (d, J = 6.84 Hz, 3 H) 1.38 (s, 6 H) 1.53 (s, 6 H ) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 6 H) 3.06 (sept, J = 6.84 Hz, 1 H) 3.78-3.83 (m, 1 H) 3.84 (s, 3 H) 3.97 (s, 2 H) 4.07-4.18 (m, 1 H) 4.17-4.27 (m, 1 H) 4.87 (dd, J = 6.76, 2.88 Hz, 1 H) 5.16-5.25 (m, 1 H) 5.27- 5.40 (m, 2 H) 6.18-6.33 (m, 2 H) 6.54 (d, J = 16.48 Hz, 1 H) 6.77 (s, 1 H) 7.03 (d, J = 8.08 Hz, 2 H) 7.10 (s , 1 H) 7.29 (d, J = 8.08 Hz, 2 H).
MS ESI / APCI Dual posi: 768 [M + H] ⁺ , 790 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 766 [MH] ⁻ .
Reference Example 8 Production of intermediate (H)

Under an argon atmosphere, intermediate (A) (216 g, 0.312 mol), 2,2-dimethyl-3-butenoic acid (53.4 g, 0.467 mol), palladium (II) acetate (3.50 g, 15 .6 mmol), tri-o-tolylphosphine (9.48 g, 31.2 mmol) and triethylamine (86.9 mL, 0.623 mol) in acetonitrile (623 mL) were 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% aqueous sodium chloride solution (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 (H). 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% aqueous sodium chloride solution (500 mL) and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain Intermediate (H) (207 g, 88%) as a colorless amorphous substance.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.80 Hz, 3 H) 1.14 (d, J = 6.80 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 (sept, J = 6.80 Hz, 1 H) 3.70- 3.80 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J = 12.43, 2.18 Hz, 1 H) 4.28 (dd, J = 12.43, 4.35 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 = 7.93 Hz, 1 H) 6.96 (s, 1 H) 6.99 (s , 1 H) 7.06-7.14 (m, 1 H) 7.23 (d, J = 1.40 Hz, 1 H).
MS ESI / APCI Dual posi: 747 [M + Na] ⁺ .
Reference Example 9 Production of Intermediate (I)

  2-Aminoisobutyric acid (150 g, 1.45 mol) was dissolved in water (2.2 L) and sodium carbonate (465 g, 4.39 mol) was added. The reaction solution was ice-cooled, and a 1,4-dioxane (0.63 L) solution of benzyl chloroformate (227 mL, 1.60 mol) was added dropwise over 45 minutes so that the internal temperature did not exceed 10 ° C. After stirring overnight at room temperature, water (3.5 L) and toluene (1.0 L) were added to the reaction solution, and the aqueous layer was separated. Concentrated hydrochloric acid (700 mL) was added dropwise to the aqueous layer until pH = 1. Ethyl acetate (1.0 L) was added and stirred for 1 hour, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure.

  The obtained residue (338 g) was dissolved in chloroform (1.7 L), and N, N′-carbonyldiimidazole (253 g, 1.56 mol) was added little by little so that the internal temperature did not exceed 20 ° C. under ice cooling. It was. After stirring at room temperature for 30 minutes, the mixture was ice-cooled again and 1,2-diamino-2-methylpropane (138 g, 1.56 mol) was added dropwise over 25 minutes. After stirring at room temperature overnight, 10% aqueous potassium carbonate solution (1.7 L) was added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure.

The obtained residue (417 g) was dissolved in THF (2.0 L), Boc ₂ O (355 g, 1.63 mol) was added, and the mixture was stirred at room temperature for 1.5 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (1.0 L) was added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure.

The obtained residue (549 g) was dissolved in methanol (2.75 L), 10% palladium hydroxide (27.5 g) was added, and the mixture was stirred at room temperature in a hydrogen atmosphere for 4.5 hours. After the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was crystallized from a heptane: ethyl acetate = 2/1 mixture (1.75 L), and the deposited precipitate was filtered to obtain an intermediate of colorless powder. Body (I) (193 g, 53%; 4 steps) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.37 (s, 6 H) 1.43 (s, 9 H) 1.53 (br. S, 2 H) 3.39 (d, J = 6.53 Hz, 2 H) 4.78 (br.s, 1 H) 8.04 (br.s, 1 H).
MS ESI / APCI Dual posi: 274 [M + H] ⁺ , 296 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 308 [M + Cl] ⁻ .
Example 1-1

Intermediate (E) (200 mg, 0.25 mmol), 1-hydroxybenzotriazole monohydrate (HOBt.H ₂ O) (57 mg, 0.37 mmol), N, N-dimethylethylenediamine (65 mg, 0 .74 mmol) in N, N-dimethylformamide (3.0 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride (EDC-HCl) (71 mg, 0.37 mmol). Stir for hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL) 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 silica gel column chromatography (chloroform → chloroform: methanol = 9: 1) to obtain a colorless amorphous compound (1-1) (132 mg, 61%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13, 1.15 (each d, J = 6.92Hz, each 3 H) 1.38 (s, 6 H) 1.53 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.23 (s, 6 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.41 (t, J = 5.67 Hz , 2 H) 2.90-3.03 (m, 1 H) 3.25-3.34 (m, 2 H) 3.71-3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J = 12.59, 2.18 Hz, 1 H) 4.23-4.32 (m, 1 H) 4.44-4.52 (m, 1 H) 5.11-5.20 (m, 1 H) 5.22-5.33 (m, 2 H) 6.33 (d, J = 16.63 Hz, 1 H) 6.41 (br. S., 1 H) 6.51 (d, J = 16.63 Hz, 1 H) 6.68 (d, J = 7.77 Hz, 1 H) 6.77 (br. S., 1 H) 7.00 (s, 2 H ) 7.12 (d, J = 7.77 Hz, 1 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 880 [M + H] ⁺ , 902 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 914 [M + Cl] ⁻ .
Example 1-2

  Sodium methoxide (4.88 M / MeOH, 10 μL) was added to a methanol (2.0 mL) solution of the compound (1-1) (127 mg, 0.14 mmol), and the mixture was stirred at room temperature for 1 hour. A small amount of dry ice was added to neutralize the reaction solution, and the solvent was distilled off under reduced pressure.

The obtained residue was purified by NH-type silica gel column chromatography (chloroform: methanol = 9: 1 → 6: 4) to obtain a colorless amorphous compound (1-2) (77 mg, 80%).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10 (d, J = 6.92 Hz, 6 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.23 (s, 6 H) 2.31 (s , 3 H) 2.40 (t, J = 6.88 Hz, 2 H) 2.87-2.96 (m, 1 H) 3.28 (t, J = 6.88 Hz, 2 H) 3.34-3.41 (m, 2 H) 3.43-3.50 ( m, 1 H) 3.51-3.57 (m, 1 H) 3.67 (dd, J = 12.15, 2.52 Hz, 1 H) 3.84 (d, J = 11.46 Hz, 1 H) 3.89 (s, 2 H) 4.47 (d , J = 9.63 Hz, 1 H) 6.39 (d, J = 16.05 Hz, 1 H) 6.50 (d, J = 16.05 Hz, 1 H) 6.75 (d, J = 8.25 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.11 (d, J = 8.25 Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 670 [M + H] ⁺ .
MS ESI / APCI Dual nega: 668 [MH] ⁻ , 704 [M + Cl] ⁻ .
Anal. Calcd for C ₃₇ H ₅₅ N ₃ O ₈ · 1.4H ₂ O: C, 63.94; H, 8.38; N, 6.05. Found: C, 64.13; H, 8.39; N, 5.88.
Example 2-1

A colorless amorphous compound (2-1) (103 mg, 47%) was obtained in the same manner as in Example 1-1 using piperazine instead of N, N-dimethylethylenediamine.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14, 1.16 (each d, J = 6.99 Hz, each 3 H) 1.38 (s, 6 H) 1.61 (s, 6 H) 1.71 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.27 (s, 3 H) 2.79-2.87 (m, 4 H) 2.87-2.99 (m, 1 H) 3.56-3.66 ( m, 4 H) 3.75-3.94 (m, 3 H) 4.12-4.20 (m, 1 H) 4.25-4.34 (m, 1 H) 4.44-4.52 (m, 1 H) 5.23-5.32 (m, 3 H) 6.30 (d, J = 16.32 Hz, 1 H) 6.48 (d, J = 16.32 Hz, 1 H) 6.53 (s, 1 H) 6.68 (d, J = 7.77 Hz, 1 H) 6.88 (s, 1 H) 6.97 (s, 1 H) 7.05-7.12 (m, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 836 [M + H] ⁺ , 858 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 834 [MH] ⁻ , 870 [M + Cl] ⁻ .
Example 2-2

A colorless amorphous compound (2-2) (52 mg, 66%) was obtained in the same manner as in Example 1-2 using the compound (2-1) instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10 (d, J = 6.42 Hz, 6 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.31 (s, 3 H) 2.70 (br s, 4 H) 2.90-2.95 (m, 1 H) 3.36-3.39 (m, 2 H) 3.43-3.61 (m, 7 H) 3.65-3.69 (m, 1 H) 3.84 (d, J = 11.92 Hz , 1 H) 3.88 (s, 2 H) 4.46 (d, J = 9.63 Hz, 1 H) 6.38 (d, J = 16.05 Hz, 1 H) 6.47 (d, J = 16.05 Hz, 1 H) 6.76 (d , J = 7.79 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.10 (d, J = 7.79 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 668 [M + H] ⁺ , 690 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 664 [MH] ⁻ , 702 [M + Cl] ⁻ .
Example 3-1

A colorless amorphous compound (3-1) (135 mg, 61%) was obtained in the same manner as in Example 1-1 using 1-methylpiperazine instead of N, N-dimethylethylenediamine.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13, 1.15 (each d, J = 6.84 Hz, each 3 H) 1.37 (s, 6 H) 1.60 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.27 (s, 3 H) 2.30 (s, 3 H) 2.33-2.41 (m, 7 H) 2.88-3.04 (m, 1 H) 3.60-3.70 (m, 4 H) 3.72-3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J = 12.59, 2.33 Hz, 1 H) 4.27 (dd, J = 12.59, 4.51 Hz, 1 H) 4.43-4.54 (m, 1 H) 5.10-5.20 (m, 1 H) 5.22-5.32 (m, 2 H) 6.31 (d, J = 16.48 Hz, 1 H) 6.49 (d, J = 16.48 Hz, 1 H) 6.68 (d, J = 8.08 Hz, 1 H) 6.86 (s, 1 H) 7.00 (s, 2 H) 7.08-7.14 (m, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 892 [M + H] ⁺ , 914 [M + Na] ⁺ _.
MS ESI / APCI Dual nega: 926 [M + Cl] ⁻ .
Example 3-2

A colorless amorphous compound (3-2) (79 mg, 79%) was obtained in the same manner as in Example 1-2 using the compound (3-1) instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10 (d, J = 6.88 Hz, 6 H) 1.37 (s, 6 H) 1.44 (s, 6 H) 2.16 (s, 3 H) 2.22-2.38 (m, 7 H) 2.87-2.96 (m, 1 H) 3.35-3.41 (m, 2 H) 3.42-3.51 (m, 2 H) 3.51-3.56 (m, 1 H) 3.56-3.71 (m, 5 H ) 3.84 (d, J = 12.38 Hz, 1 H) 3.88 (s, 2 H) 4.47 (d, J = 9.63 Hz, 1 H) 6.38 (d, J = 16.51 Hz, 1 H) 6.46 (d, J = 16.51 Hz, 1 H) 6.75 (d, J = 8.25 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.09 (d, J = 8.25 Hz, 1 H) 7.22 (s, 1 H ).
MS ESI / APCI Dual posi: 682 [M + H] ⁺ , 704 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 680 [MH] ⁻ , 716 [M + Cl] ⁻ .
Example 4-1

  A colorless gum compound (4-1A) (87.9 mg, 38%) and a colorless gum compound in the same manner as in Example 1-1 using 1-ethylpiperazine instead of N, N-dimethylethylenediamine (4-1B) (42.9 mg, 19%) was obtained.

Compound (4-1A)
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 (t, J = 7.23 Hz, 3 H) 1.12-1.16 (m, 6 H) 1.37 (s, 6 H) 1.61 (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) 2.34-2.44 (m, 9 H) 2.90-3.05 (m, 1 H ) 3.60-3.72 (m, 4 H) 3.72-3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J = 12.36, 1.94 Hz, 1 H) 4.27 (dd, J = 12.36, 4.43 Hz , 1 H) 4.48 (d, J = 9.79 Hz, 1 H) 5.15 (t, J = 9.79 Hz, 1 H) 5.22-5.31 (m, 2 H) 6.31 (d, J = 16.2 Hz, 1 H) 6.49 (d, J = 16.2 Hz, 1 H) 6.68 (d, J = 8.08 Hz, 1 H) 6.86-6.93 (m, 1 H) 7.00 (s, 2 H) 7.11 (d, J = 8.08 Hz, 1 H ) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 907 [M + H] ⁺ , 929 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 941 [M + Cl] ⁻ .

Compound (4-1B)
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.03-1.19 (m, 9 H) 1.37 (s, 6 H) 1.62 (s, 6 H) 1.71 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.27 (s, 3 H) 2.33-2.46 (m, 6 H) 2.93 (sept, J = 6.76 Hz, 1 H) 3.58-3.71 (m, 4 H ) 3.73-3.91 (m, 3 H) 4.12-4.21 (m, 1 H) 4.24-4.34 (m, 1 H) 4.48 (d, J = 9.17 Hz, 1 H) 5.21-5.34 (m, 3 H) 6.30 (d, J = 16.1 Hz, 1 H) 6.48 (d, J = 16.1 Hz, 1 H) 6.53 (s, 1 H) 6.68 (d, J = 7.93 Hz, 1 H) 6.88 (s, 1 H) 6.99 (s, 1 H) 7.08 (d, J = 7.93 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 865 [M + H] ⁺ , 887 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 899 [M + Cl] ⁻ .
Example 4-2

Triethylamine / water / methanol (1/1/5, 5 mL) was added to the compound (4-1A) (87.9 mg, 0.0973 mmol) and the compound (4-1B) (42.9 mg, 0.0486 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 8: 2) to obtain a colorless amorphous compound (4-2) (79.2 mg, 78%).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 0.98 (t, J = 7.23 Hz, 3 H) 1.10 (d, J = 6.88 Hz, 6 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.23-2.42 (m, 9 H) 2.85-2.99 (m, 1 H) 3.35-3.41 (m, 2 H) 3.42-3.48 (m, 1 H) 3.50-3.56 (m, 1 H) 3.55-3.71 (m, 5 H) 3.81-3.90 (m, 3 H) 4.47 (d, J = 9.63 Hz, 1 H) 6.39 (d, J = 16.1 Hz, 1 H) 6.46 (d, J = 16.1 Hz, 1 H ) 6.71-6.77 (m, 1 H) 6.80 (s, 1 H) 6.98 (s, 1 H) 7.09 (d, J = 7.79 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 696 [M + H] ⁺ , 718 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 694 [MH] ⁻ .
Anal. Calcd for C ₃₉ H ₅₇ N ₃ O ₈・ 1.2H ₂ O: C, 65.3; H, 8.34; N, 5.86. Found: C, 65.3; H, 8.36; N, 5.68.
Example 5-1

Intermediate (E) (205 mg, 0.253 mmol), HOBt · H ₂ O (68 mg, 0.506 mmol), 4-dimethylaminopiperidine (65 mg, 0.506 mmol) in N, N-dimethylformamide (2.0 mL) To the solution, EDC-HCl (97 mg, 0.506 mmol) was added and stirred at 70 ° C. for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL) 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 silica gel column chromatography (chloroform → chloroform: methanol = 3: 1) to obtain a colorless amorphous compound (5-1) (80 mg, 34%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.76 Hz, 3 H) 1.15 (d, J = 6.76 Hz, 3 H) 1.30-1.49 (m, 2 H) 1.38 (s, 6 H) 1.61 (s, 6 H) 1.77 (s, 3 H) 1.84 (d, J = 12.75 Hz, 2 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.27 (s, 6 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.81 (t, J = 12.28 Hz, 2 H) 2.97 (sept, J = 6.76 Hz, 1 H) 3.76 (ddd, J = 10.03, 4.66, 2.25 Hz, 1 H) 3.92 (s, 2 H) 4.05 (dd, J = 12.43, 2.25 Hz, 1 H) 4.28 (dd, J = 12.43, 4.66 Hz, 1 H) 4.33-4.53 ( m, 3 H) 5.10-5.34 (m, 3 H) 6.31 (d, J = 15.00 Hz, 1 H) 6.50 (d, J = 15.00 Hz, 1 H) 6.68 (d, J = 8.08 Hz, 1 H) 6.97-7.04 (m, 2 H) 7.11 (d, J = 8.08 Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 920 [M + H] ⁺ .
MS ESI / APCI Dual nega: 954 [M + Cl] ⁻ .
Example 5-2

A colorless amorphous compound (5-2) (33 mg, 53%) was obtained in the same manner as in Example 1-2 except that the compound (5-1) was used instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.08 (d, J = 6.42 Hz, 6 H) 1.21-1.32 (m, 2 H) 1.35 (s, 6 H) 1.43 (s, 6 H) 1.73 (br. s., 2 H) 2.16 (s, 6 H) 2.28 (s, 3H) 2.28-2.37 (m, 1 H) 2.89 (sept, J = 6.42 Hz, 1 H) 3.31-3.33 (m, 2 H) 3.44 (t, J = 8.71 Hz, 1 H) 3.48-3.56 (m, 1 H) 3.66 (dd, J = 11.92, 2.75 Hz, 1 H) 3.83 (d, J = 11.92 Hz, 1 H) 3.86 (s, 2 H) 4.45 (d, J = 9.63 Hz, 1 H) 6.35-6.41 (m, 1 H) 6.43-6.47 (m, 1 H) 6.72 (d, J = 7.79 Hz, 1 H) 6.78 ( s, 1 H) 6.96 (s, 1 H) 7.08 (d, J = 7.79 Hz, 1 H) 7.21 (s, 1 H).
MS ESI / APCI Dual posi: 710 [M + H] ⁺ .
MS ESI / APCI Dual nega: 708 [MH] ⁻ .
Anal.Calcd for C ₄₀ H ₅₉ N ₃ O ₈・ 1.5H ₂ O: C, 65.19; H, 8.50; N, 5.70. Found: C, 64.81; H, 8.46; N, 5.61.
Example 6-1

N, N′-carbonyldiimidazole (182 mg, 1.12 mmol) was added to a solution of intermediate (E) (680 mg, 0.746 mmol) in chloroform (5.0 mL), and the mixture was stirred at room temperature for 1 hour. Then, 1,2-diamino-2-methylpropane (79 mg, 0.895 mmol) was added and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 85: 15) to obtain a colorless amorphous compound (6-1) (140 mg, 21%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.17 (m, 6 H) 1.11 (s, 6 H) 1.39 (s, 6 H) 1.53 (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) 2.89-3.05 (m, 1 H) 3.14 (d, J = 5.91 Hz, 2 H) 3.76 (ddd, J = 9.71, 4.51, 2.10 Hz, 1 H) 3.93 (s, 2 H) 4.05 (dd, J = 12.51, 2.10 Hz, 1 H) 4.27 (dd, J = 12.51 , 4.51 Hz, 1 H) 4.49 (d, J = 7.46 Hz, 1 H) 5.11-5.20 (m, 1 H) 5.23-5.31 (m, 2 H) 6.26 (s, 1 H) 6.29-6.38 (m, 1 H) 6.48-6.57 (m, 1 H) 6.69 (d, J = 7.93 Hz, 1 H) 6.97-7.03 (m, 3 H) 7.12 (d, J = 7.93 Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 880 [M + H] ⁺ .
Example 6-2

A colorless amorphous compound (6-2) (104 mg, 98%) was obtained in the same manner as in Example 1-2 using the compound (6-1) instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.02 (s, 6 H) 1.05-1.10 (m, 6 H) 1.35 (s, 6 H) 1.44 (s, 6 H) 2.29 (s, 3 H ) 2.85-2.93 (m, 1 H) 3.09 (s, 2 H) 3.34-3.39 (m, 2 H) 3.42-3.47 (m, 1 H) 3.52 (t, J = 9.40 Hz, 1 H) 3.63-3.69 (m, 1 H) 3.80-3.85 (m, 1 H) 3.86 (s, 2 H) 4.46 (d, J = 9.63 Hz, 1 H) 6.35-6.41 (m, 1 H) 6.44-6.51 (m, 1 H) 6.73 (d, J = 7.79 Hz, 1 H) 6.78 (s, 1 H) 6.96 (s, 1 H) 7.06-7.10 (m, 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] ⁻ .

Compound (6-2) can also be synthesized by the methods described in Examples 6-3 and 6-4 below.
Example 6-3

Intermediate (H) (205 g, 0.273 mol), Intermediate (I) (97.0 g, 0.355 mol), HOBt · H ₂ O (62.7 g, 0.410 mol), triethylamine (114 mL, 0.819 mol) ) In N, N-dimethylformamide (1.98 L) was added EDC-HCl (78.5 g, 0.410 mol), and the mixture was stirred at room temperature for 11 hours. Toluene (1.0 L) and 10% aqueous sodium chloride solution (2.0 L) were added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted from toluene (1.0 L), and the combined organic layers were washed with 5% aqueous sodium chloride solution (1.0 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 dissolved in 2-propanol (300 mL) at 50 ° C., and heptane (2.7 L) was added dropwise. The mixed solution was stirred with ice cooling for 1 hour, and the deposited precipitate was filtered to obtain a colorless powder of compound (6-3) (221 g, 83%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.88 Hz, 3 H) 1.14 (d, J = 6.88 Hz, 3 H) 1.26 (s, 6 H) 1.39 (s, 6 H ) 1.44 (s, 9 H) 1.55 (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) 2.97 (sept, J = 6.88 Hz, 1 H) 3.41 (d, J = 5.60 Hz, 2 H) 3.72-3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd , J = 12.43, 2.02 Hz, 1 H) 4.28 (dd, J = 12.43, 4.51 Hz, 1 H) 4.45-4.52 (m, 1 H) 4.65 (s, 1 H) 5.11-5.19 (m, 1 H) 5.22-5.33 (m, 2 H) 6.29-6.39 (m, 1 H) 6.46-6.57 (m, 2 H) 6.69 (d, J = 8.00 Hz, 1 H) 6.96-7.03 (m, 2 H) 7.11 ( dd, J = 8.00, 1.63 Hz, 1 H) 7.24-7.26 (m, 1 H) 7.59 (br. s, 1 H).
Example 6-4

  To a chloroform (3.0 L) solution of the compound (6-3) (220 g, 0.225 mol) is added dropwise trifluoroacetic acid (297 mL, 3.88 mol) at room temperature over 10 minutes, followed by stirring at the same temperature for 20 hours. did. The reaction solution was diluted with toluene (3.0 L) and concentrated. The concentrate was dissolved in ethyl acetate (3.0 L), washed with 10% aqueous sodium carbonate solution (1.2 L) and saturated brine (1.0 L), and the solvent was evaporated under reduced pressure.

The obtained residue (240 g) was dissolved in methanol (1.5 L), and after ice cooling, triethylamine (0.3 L) and water (0.3 L) were added. After stirring at room temperature for 13 hours, methanol (1.5 L), triethylamine (0.3 L) and water (0.3 L) were further added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and azeotroped with methanol. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 15: 2: 1 → 10: 2: 1), and colorless amorphous compound (6-2) (129 g, 86%; 2 steps) )
Example 7-1

A colorless amorphous compound (7-1) (112 mg, 74%) was obtained in the same manner as in Example 1-1 using the intermediate (F) instead of the intermediate (E).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12, 1.14 (each d, J = 6.84 Hz, each 3 H) 1.37 (s, 6 H) 1.51 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.23 (s, 6 H) 2.32 (s, 3 H) 2.41 (t, J = 6.22 Hz, 2 H) 2.86-2.99 (m, 1 H) 3.25-3.33 (m, 2 H) 3.76-3.90 (m, 6 H) 4.07-4.15 (m, 1 H) 4.18-4.26 (m, 1 H) 4.76-4.85 (m, 1 H ) 5.13-5.22 (m, 1 H) 5.26-5.36 (m, 2 H) 6.31 (d, J = 16.48 Hz, 1 H) 6.37 (s, 1 H) 6.50 (d, J = 16.48 Hz, 1 H) 6.61-6.67 (m, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.06-7.12 (m, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 852 [M + H] ⁺ .
MS ESI / APCI Dual nega: 886 [M + Cl] ⁻ .
Example 7-2

A colorless amorphous compound (7-2) (69 mg, 78%) was obtained in the same manner as in Example 1-2 using the compound (7-1) instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.13, 1.15 (each d, J = 6.84 Hz, each 3 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.21 (s, 6 H ) 2.32 (s, 3 H) 2.39 (t, J = 6.88 Hz, 2 H) 2.93-3.02 (m, 1 H) 3.24-3.39 (m, 4 H) 3.42-3.48 (m, 1 H) 3.49-3.54 (m, 1 H) 3.58-3.65 (m, 1 H) 3.80-3.87 (m, 4 H) 3.91 (s, 2 H) 4.61 (d, J = 9.63 Hz, 1 H) 6.39 (d, J = 16.51 Hz, 1 H) 6.50 (d, J = 16.51 Hz, 1 H) 6.73 (d, J = 7.80 Hz, 1 H) 6.92 (s, 1 H) 7.08 (s, 1 H) 7.10 (d, J = 7.80 (Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 684 [M + H] ⁺ .
MS ESI / APCI Dual nega: 682 [MH] ⁻ , 718 [M + Cl] ⁻ .
Anal. Calcd for C ₃₈ H ₅₇ N ₃ O ₈・ 1.7H ₂ O: C, 63.88; H, 8.52, N, 5.88. Found: C, 63.84; H, 8.41; N, 5.75.
Example 8-1

A colorless amorphous compound (8-) was prepared in the same manner as in Example 1-1 except that intermediate (F) was used instead of intermediate (E), and Nt-butoxycarbonylethylenediamine was used instead of N, N-dimethylethylenediamine. 1) (145 mg, 89%) was obtained.
MS ESI / APCI Dual posi: 924 [M + H] ⁺ , 946 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 958 [M + Cl] ⁻ .
Example 8-2

Trifluoroacetic acid (600 μL) was added to a chloroform (3.0 ml) solution of the compound (8-1), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (chloroform: methanol = 95: 5 → 60: 40) to obtain a colorless amorphous compound (8-2) (68 mg, 55%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14, 1.16 (each d, J = 6.37 Hz, each 3 H) 1.32 (br. S., 6 H) 1.42 (s, 6 H) 1.77 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.90-3.02 (m, 1 H) 3.22-3.34 (m, 2 H) 3.48 -3.57 (m, 2 H) 3.76-3.96 (m, 6 H) 4.07-4.14 (m, 1 H) 4.17-4.25 (m, 1 H) 4.79-4.87 (m, 1 H) 5.12-5.22 (m, 1 H) 5.24-5.36 (m, 2 H) 6.32 (s, 1 H) 6.40 (d, J = 16.63 Hz, 1 H) 6.51 (d, J = 16.63 Hz, 1 H) 6.65 (d, J = 8.55 Hz, 1 H) 6.82 (s, 1 H) 6.96 (s, 1 H) 7.07-7.13 (m, 1 H) 7.28-7.31 (m, 1 H) 8.04 (br. S., 2 H).
MS ESI / APCI Dual posi: 824 [M + H] ⁺ , 846 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 858 [M + Cl] ⁻ .
Example 8-3

A colorless amorphous compound (8-3) (22 mg, 44%) was obtained in the same manner as in Example 1-2 using the compound (8-2) instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.13, 1.15 (each d, J = 6.84 Hz, each 3 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.32 (s, 3 H ) 2.63-2.71 (m, 2 H) 2.94-3.03 (m, 1 H) 3.23 (t, J = 5.96 Hz, 2 H) 3.28-3.39 (m, 4 H) 3.43-3.48 (m, 1 H) 3.48 -3.54 (m, 1 H) 3.62 (dd, J = 12.15, 5.73 Hz, 1 H) 3.79-3.88 (m, 2 H) 3.92 (s, 2 H) 4.61 (d, J = 9.63 Hz, 1 H) 6.40 (d, J = 16.51 Hz, 1 H) 6.50 (d, J = 16.51 Hz, 1 H) 6.74 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.07 (s, 1 H) 7.11 (d, J = 7.79 Hz, 1 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 656 [M + H] ⁺ .
MS ESI / APCI Dual nega: 654 [MH] ⁻ , 690 [M + Cl] ⁻ .
Example 9-1

A colorless amorphous compound (9-1) (42 mg, 38) was prepared in the same manner as in Example 1-1 using Intermediate (F) instead of Intermediate (E) and Piperazine instead of N, N-dimethylethylenediamine. %).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12, 1.14 (each d, J = 6.99 Hz, each 3 H) 1.37 (s, 6 H) 1.58 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.79-2.86 (m, 4 H) 2.88-2.99 (m, 1 H) 3.57-3.64 ( m, 4 H) 3.76-3.95 (m, 6 H) 4.07-4.14 (m, 1 H) 4.18-4.26 (m, 1 H) 4.77-4.84 (m, 1 H) 5.13-5.22 (m, 1 H) 5.26-5.37 (m, 2 H) 6.29 (d, J = 16.16 Hz, 1 H) 6.49 (d, J = 16.16 Hz, 1 H) 6.64 (d, J = 7.93 Hz, 1 H) 6.77-6.83 (m , 2 H) 6.99 (s, 1 H) 7.05-7.11 (m, 1 H) 7.22 (br. S., 1 H).
MS ESI / APCI Dual posi: 850 [M + H] ⁺ , 872 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 884 [M + Cl] ⁻ .
Example 9-2

A colorless amorphous compound (9-2) (27 mg, 94%) was obtained in the same manner as in Example 1-2 using the compound (9-1) instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.14, 1.16 (each d, J = 6.42Hz, each 3 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.32 (s, 3 H ) 2.69 (br. S., 4 H) 2.95-3.03 (m, 1 H) 3.28-3.38 (m, 2 H) 3.42-3.52 (m, 2 H) 3.53-3.65 (m, 5 H) 3.80-3.84 (m, 1 H) 3.84 (s, 3 H) 3.92 (s, 2 H) 4.61 (d, J = 9.17 Hz, 1 H) 6.39 (d, J = 16.05 Hz, 1 H) 6.47 (d, J = 16.05 Hz, 1 H) 6.74 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.06 (s, 1 H) 7.10 (d, J = 7.79 Hz, 1 H) 7.22 (s, 1 H ).
MS ESI / APCI Dual posi: 682 [M + H] ⁺ .
MS ESI / APCI Dual nega: 680 [MH] ⁻ , 716 [M + Cl] ⁻ .
Example 10-1

Colorless amorphous crude compound (10-1) in the same manner as in Example 1-1 using intermediate (F) instead of intermediate (E) and N-methylpiperazine instead of N, N-dimethylethylenediamine (100 mg) was obtained. This product was used in the next reaction without further purification.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 8.5 Hz, 3 H) 1.15 (d, J = 8.5 Hz, 3 H) 1.36 (s, 6 H) 1.56 (s, 6 H ) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 6 H) 2.30 (s, 3 H) 2.32 (s, 3 H) 2.38-2.50 (m, 4 H) 2.85-3.02 (m , 1 H) 3.61-3.74 (m, 4 H) 3.76-3.84 (m, 1 H) 3.81-3.96 (m, 1 H) 3.86 (s, 3 H) 4.07-4.15 (m, 1 H) 4.18-4.27 (m, 1 H) 4.75-4.88 (m, 1 H) 5.11-5.24 (m, 1 H) 5.26-5.37 (m, 2 H) 6.22-6.38 (m, 1 H) 6.43-6.54 (m, 1 H 6.59-6.70 (m, 2 H) 6.81 (s, 1 H) 6.96-7.02 (m, 1 H) 7.04-7.12 (m, 1 H) 7.20-7.26 (m, 1 H).
Example 10-2

Using the compound (10-1) instead of the compound (1-1), a colorless amorphous compound (10-2) (8.0 mg, 9%; 2 steps) was obtained in the same manner as in Example 1-2. It was.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.09-1.16 (m, 6 H) 1.35 (s, 6 H) 1.42 (s, 6 H) 2.12-2.16 (m, 3 H) 2.23-2.33 ( br. s., 4 H) 2.30 (s, 3 H) 2.92-3.01 (m, 1 H) 3.28 (s, 2 H) 3.30-3.38 (m, 1 H) 3.41-3.51 (m, 2 H) 3.55 -3.66 (m, 5 H) 3.78-3.86 (m, 4 H) 3.90 (s, 2 H) 4.59 (d, J = 9.17 Hz, 1 H) 6.33-6.39 (m, 1 H) 6.42-6.47 (m , 1 H) 6.72 (d, J = 7.79 Hz, 1 H) 6.90 (s, 1 H) 7.04-7.11 (m, 2 H) 7.19-7.24 (m, 1 H).
MS ESI / APCI Dual posi: 696 [M + H] ⁺ , 718 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 694 [MH] ^- , 730 [M + Cl] ⁻ .
Example 11-1

A pale yellow amorphous compound (11-1) in the same manner as in Example 1-1 using Intermediate (F) instead of Intermediate (E) and 1-ethylpiperazine instead of N, N-dimethylethylenediamine (200 mg, 89%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 (t, J = 7.23 Hz, 3 H) 1.11 (d, J = 6.84 Hz, 3 H) 1.14 (d, J = 6.84 Hz, 3 H) 1.36 (s, 6 H) 1.59 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.36- 2.44 (m, 6 H) 2.93 (sept, J = 6.84 Hz, 1 H) 3.61-3.71 (m, 4 H) 3.77-3.84 (m, 1 H) 3.83-3.94 (m, 5 H) 4.05-4.16 ( m, 1 H) 4.18-4.27 (m, 1 H) 4.76-4.86 (m, 1 H) 5.14-5.23 (m, 1 H) 5.25-5.37 (m, 2 H) 6.29 (d, J = 16.1 Hz, 1 H) 6.48 (d, J = 16.1 Hz, 1 H) 6.64 (d, J = 7.62 Hz, 1 H) 6.77-6.86 (m, 2 H) 6.99 (s, 1 H) 7.08 (d, J = 7.62 (Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 879 [M + H] ⁺ , 901 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 913 [M + Cl] ⁻ .
Example 11-2

The colorless amorphous compound (11-2) (118 mg, 73%) was obtained in the same manner as in Example 4-2 using the compound (4-1A) and the compound (11-1) instead of the compound (4-1A). Got.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 0.97 (t, J = 7.11 Hz, 3 H) 1.10-1.19 (m, 6 H) 1.37 (s, 6 H) 1.45 (s, 6 H) 2.26 -2.42 (m, 9 H) 2.97 (sept, J = 6.76 Hz, 1 H) 3.32-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.48-3.55 (m, 1 H) 3.55-3.72 (m, 5 H) 3.79-3.89 (m, 4 H) 3.91 (s, 2 H) 4.61 (d, J = 9.17 Hz, 1 H) 6.39 (d, J = 16.5 Hz, 1 H) 6.46 (d, J = 16.5 Hz, 1 H) 6.73 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.04-7.14 (m, 2 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 710 [M + H] ⁺ , 732 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 744 [M + Cl] ⁻ .
Anal.Calcd for C ₄₀ H ₅₉ N ₃ O ₈・ 1.5H ₂ O: C, 65.2; H, 8.48; N, 5.70. Found: C, 65.1; H, 8.38; N, 5.64.
Example 12-1

A colorless amorphous compound (12-1) (55 mg, 40%) was obtained in the same manner as in Example 5-1, except that the intermediate (F) was used instead of the intermediate (E).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12, 1.14 (each d, J = 6.92 Hz, each 3 H) 1.28-1.47 (m, 8 H) 1.60 (s, 6 H) 1.73-1.89 (m , 5 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.22-2.35 (m, 10 H) 2.73-2.99 (m, 3 H) 3.76-3.84 (m, 1 H) 3.84-3.90 (m, 5 H) 4.07-4.15 (m, 1 H) 4.18-4.26 (m, 1 H) 4.34-4.50 (m, 2 H) 4.75-4.86 (m, 1 H) 5.13-5.23 (m, 1 H) 5.26-5.39 (m, 2 H) 6.30 (d, J = 16.48 Hz, 1 H) 6.48 (d, J = 16.48 Hz, 1 H) 6.63 (d, J = 8.39 Hz, 1 H ) 6.81 (s, 1 H) 6.94-7.01 (m, 2 H) 7.04-7.11 (m, 1 H) 7.23 (s, 1 H).
MSESI / APCI Dual posi: 892 [M + H] ⁺ , 914 [M + Na] ⁺ .
Example 12-2

A colorless amorphous compound (12-2) (55 mg, 82%) was obtained in the same manner as in Example 1-2 using the compound (12-1) instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.13, 1.15 (each d, J = 6.84 Hz, each 3 H) 1.24-1.33 (m, 2 H) 1.37 (s, 6 H) 1.44 (s, 6 H) 1.75 (br. S, 2 H) 2.17 (s, 6 H) 2.30-2.39 (m, 4 H) 2.93-3.01 (m, 1 H) 3.28-3.38 (m, 5 H) 3.43-3.47 ( m, 1 H) 3.47-3.53 (m, 1 H) 3.62 (dd, J = 12.15, 5.73 Hz, 1 H) 3.80-3.86 (m, 3 H) 3.91 (s, 2 H) 4.48 (br. s. , 2 H) 4.61 (d, J = 9.63 Hz, 1 H) 6.40 (d, J = 16.05 Hz, 1 H) 6.47 (d, J = 16.05 Hz, 1 H) 6.73 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.06-7.11 (m, 2 H) 7.23 (s, 1 H).
MSESI / APCI Dual posi: 724 [M + H] ⁺ , 746 [M + Na] ⁺ .
MSESI / APCI Dual nega: 722 [MH] ⁻ , 758 [M + Cl] ⁻ .
_{. Anal Calcd for C 41 H 61} N 3 O 8 · 2.5H 2 O:. C, 64.04; H, 8.65; N, 5.46 Found: C, 64.01; H, 8.38; N, 5.49.
Example 13-1

A colorless amorphous compound (13-1) (1.98 g, 99%) was obtained in the same manner as in Example 6-1 using the intermediate (F) instead of the intermediate (E).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 (s, 6 H) 1.12 (d, J = 6.84 Hz, 3 H) 1.14 (d, J = 6.84 Hz, 3 H) 1.36 (s, 6 H ) 1.56 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 6 H) 2.30 (s, 3 H) 2.85-3.02 (m, 1 H) 3.13 (d, J = 5.91 Hz, 2 H) 3.76-3.84 (m, 1 H) 3.81-3.96 (m, 1 H) 3.86 (s, 3 H) 4.07-4.15 (m, 1 H) 4.18-4.27 (m, 1 H) 4.75-4.88 (m, 1 H) 5.11-5.24 (m, 1 H) 5.26-5.37 (m, 2 H) 6.22-6.38 (m, 1 H) 6.43-6.54 (m, 1 H) 6.59-6.70 (m , 1 H) 6.81 (s, 1 H) 6.96-7.02 (m, 2 H) 7.04-7.12 (m, 1 H) 7.20-7.26 (m, 1 H).
Example 13-2

A colorless amorphous compound (12-2) (1.0 g, 65%) was obtained in the same manner as in Example 1-2 using the compound (13-1) instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.01 (s, 6 H) 1.09-1.15 (m, 6 H) 1.35 (s, 6 H) 1.43 (s, 6 H) 2.31 (s, 3 H ) 2.91-3.00 (m, 1 H) 3.08 (s, 2 H) 3.27-3.36 (m, 5 H) 3.41-3.46 (m, 1 H) 3.47-3.52 (m, 1 H) 3.60 (dd, J = 11.92, 5.96 Hz, 1 H) 3.80-3.84 (m, 4 H) 3.90 (s, 2 H) 4.59 (d, J = 9.63 Hz, 1 H) 6.36-6.41 (m, 1 H) 6.45-6.50 (m , 1 H) 6.71 (d, J = 7.79 Hz, 1 H) 6.90 (s, 1 H) 7.06 (s, 1 H) 7.07-7.10 (m, 1 H) 7.20-7.25 (m, 1 H).
MS ESI / APCI Dual posi: 684 [M + H] ⁺ .
MS ESI / APCI Dual nega: 682 [MH] ^- , 718 [M + Cl] ⁻ .
Example 14-1

In the same manner as in Example 1-1, intermediate (F) was used instead of intermediate (E), and 4-amino-1-tert-butoxycarbonylpiperidine was used instead of N, N-dimethylethylenediamine. An oily compound (14-1) (200 mg, quant.) Was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J = 6.99 Hz, 3 H) 1.14 (d, J = 6.99 Hz, 3 H) 1.25-1.33 (m, 2 H) 1.36 (s, 6 H) 1.45 (s, 9 H) 1.48 (s, 6 H) 1.77 (s, 3 H) 1.79-1.93 (m, 2 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s , 3 H) 2.32 (s, 3 H) 2.90-2.98 (m, 3 H) 3.75-4.00 (m, 9 H) 4.07-4.15 (m, 1 H) 4.18-4.27 (m, 1 H) 4.79-4.86 (m, 1 H) 5.19 (d, J = 10.10 Hz, 1 H) 5.26-5.35 (m, 2 H) 6.09 (s, 1 H) 6.26 (d, J = 16.48 Hz, 1 H) 6.50 (d, J = 16.48 Hz, 1 H) 6.65 (d, J = 8.32 Hz, 1 H) 6.74-6.83 (m, 2 H) 6.99 (s, 1 H) 7.08 (dd, J = 8.32, 2.72 Hz, 1 H) 7.22 (d, J = 2.72 Hz, 1 H).
MS ESI / APCI Dual posi: 965 [M + H] ⁺ , 987 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 999 [M + Cl] ⁻ .
Example 14-2

Trifluoroacetic acid (450 μL) was added to a solution of compound (14-1) (185 mg, 0.192 mmol) in chloroform (2 mL). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. Triethylamine / water / methanol (1/1/5, 4 mL) was added to the resulting residue, and the reaction mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 0 → 8: 2) to give colorless amorphous compound (14-2) (103 mg, 77%). Obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.14 (d, J = 5.50 Hz, 3 H) 1.15 (d, J = 5.50 Hz, 3 H) 1.27-1.35 (m, 2 H) 1.37 (s , 6 H) 1.45 (s, 6 H) 1.78 (d, J = 11.46 Hz, 2 H) 2.33 (s, 3 H) 2.56-2.68 (m, 2 H) 2.95-3.03 (m, 3 H) 3.33- 3.37 (m, 2 H) 3.43-3.48 (m, 1 H) 3.49-3.53 (m, 1 H) 3.57-3.66 (m, 1 H) 3.68-3.75 (m, 1 H) 3.81-3.84 (m, 1 H) 3.85 (s, 3 H) 3.92 (s, 2 H) 4.61 (d, J = 9.17 Hz, 1 H) 6.34-6.43 (m, 1 H) 6.45-6.56 (m, 1 H) 6.74 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.04-7.16 (m, 2 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 696 [M + H] ⁺ , 718 [M + Na] ⁺ .
Example 15-1

A colorless amorphous compound (15-1) (103 mg, 94%) was obtained in the same manner as in Example 1-1 using the intermediate (G) instead of the intermediate (E).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.05 (d, J = 6.84 Hz, 3 H) 1.10 (d, J = 6.84 Hz, 3 H) 1.38 (s, 6 H) 1.49 (s, 6 H ) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.46 (s, 6 H) 2.64-2.78 (m, 2 H) 3.04 (sept, J = 6.84 Hz, 1 H) 3.38-3.49 (m, 2 H) 3.78-3.83 (m, 1 H) 3.85 (s, 3 H) 3.87-4.04 (m, 2 H) 4.08-4.18 (m, 1 H) 4.18-4.30 (m, 1 H) 4.87 (d, J = 9.48 Hz, 1 H) 5.16-5.27 (m, 1 H) 5.28-5.44 (m, 2 H) 6.35 (s, 1 H) 6.40-6.57 ( m, 2 H) 6.77 (s, 1 H) 7.01 (d, J = 8.24 Hz, 2 H) 7.13 (s, 1 H) 7.32 (d, J = 8.24 Hz, 2 H) 7.40 (s, 1 H) .
MS ESI / APCI Dual posi: 839 [M + H] ⁺ .
MS ESI / APCI Dual nega: 873 [M + Cl] ⁻ .
Example 15-2

A colorless amorphous compound (15-2) (62.1 mg, 75) was prepared in the same manner as in Example 4-2 using the compound (4-1A) and the compound (4-1B) instead of the compound (4-1A). %).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.07 (d, J = 6.76 Hz, 3 H) 1.09 (d, J = 6.76 Hz, 3 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.23 (s, 6 H) 2.41 (t, J = 6.88 Hz, 2 H) 3.10 (sept, J = 6.76 Hz, 1 H) 3.26-3.30 (m, 2 H) 3.35-3.45 (m, 2 H ) 3.45-3.52 (m, 1 H) 3.54-3.60 (m, 1 H) 3.62-3.69 (m, 1 H) 3.79-3.89 (m, 4 H) 3.99 (s, 2 H) 4.65 (d, J = 9.63 Hz, 1 H) 6.39 (d, J = 16.51 Hz, 1 H) 6.52 (d, J = 16.51 Hz, 1 H) 6.88 (s, 1 H) 7.07 (d, J = 8.25 Hz, 2 H) 7.23 (s, 1 H) 7.31 (d, J = 8.25 Hz, 2 H).
MS ESI / APCI Dual posi: 670 [M + H] ⁺ .
MS ESI / APCI Dual nega: 704 [M + Cl] ⁻ .
Anal.Calcd for C ₃₇ H ₅₅ N ₃ O ₈・ 1.0H ₂ O: C, 64.6; H, 8.36; N, 6.11. Found: C, 64.5; H, 8.31; N, 6.02.
Example 15-3

25 mg of colorless amorphous compound (15-2) (purity 99.9%) was dissolved in 0.08 mL of ethanol at room temperature and stirred at room temperature for 1 day to obtain crystals. The crystals were dried under reduced pressure at room temperature to obtain 27 mg of colorless crystals (recovery rate 100%). When the powder X-ray diffraction pattern, differential thermal analysis / thermal mass measurement (TG / DTA) and infrared absorption spectrum of this crystal were measured, it was a crystal of the ethanol solvate of compound (15-2). The obtained crystals had peaks at 2θ = 5.9 degrees, 17.1 degrees, 17.6 degrees, and 21.5 degrees in powder X-ray diffraction (Cu—Kα). In the infrared absorption spectrum, characteristic absorption bands were 3538 cm ⁻¹ , 3357 cm ⁻¹ , 2964 cm ⁻¹ , 1673 cm ⁻¹ , 1634 cm ⁻¹ and 1505 cm ⁻¹ . And melting | fusing point was 108 to 114 degreeC.

The powder X-ray diffraction pattern of the crystal is shown in FIG. 1, the infrared absorption spectrum (KBr method) is shown in FIG. 2, and the differential thermal analysis / thermal mass measurement curve is shown in FIG.
Example 15-4

Further, the above crystal could be obtained by the following method.
After dissolving 56 g of colorless amorphous compound (15-2) (purity 96.0%) in 135 mL of ethanol at 66 ° C., 135 mL of heptane was added with stirring and cooled, and at about 45 ° C., in Example 15-3 After putting the ethanol solvate crystal of the obtained compound (15-2), the temperature was lowered to 1 ° C. The precipitated crystals were collected by filtration and then dried under reduced pressure at 40 ° C. to obtain 46 g of colorless crystals (recovery rate 82%, purity 99.1%). When the powder X-ray diffraction pattern, differential thermal analysis / thermal mass measurement (TG / DTA) and infrared absorption spectrum of this crystal were measured, it was a crystal of the ethanol solvate of compound (15-2).
¹ H NMR (600 MHz, METHANOL- d ₄ ) δ ppm 1.06 (d, J = 5.04 Hz, 3 H) 1.07 (d, J = 5.50 Hz, 3 H) 1.15 (t, J = 6.88 Hz, 3 H) 1.34 (s, 6 H) 1.43 (s, 6 H) 2.20 (s, 6 H) 2.37 (t, J = 6.88 Hz, 2 H) 3.08 (quin, J = 6.88 Hz, 1 H) 3.26 (t, J = 6.88 Hz, 2 H) 3.28-3.30 (m, 4 H) 3.34-3.38 (m, 2 H) 3.43-3.49 (m, 1 H) 3.55 (t, J = 9.17 Hz, 1 H) 3.58 (q, J = 6.88 Hz, 2 H) 3.62-3.66 (m, 1 H) 3.78-3.85 (m, 4 H) 3.96 (s, 2 H) 4.63 (d, J = 9.62 Hz, 1 H) 6.37 (d, J = 16.50 Hz, 1 H) 6.50 (d, J = 16.50 Hz, 1 H) 6.86 (s, 1 H) 7.05 (d, J = 7.80 Hz, 2 H) 7.22 (s, 1 H) 7.29 (d, J = 7.79 Hz, 2 H).
MS ESI / APCI Dual posi: 670 [M + H] ⁺ .
MS ESI / APCI Dual nega: 704 [M + Cl] ^- .
Anal. Calcd for C ₃₉ H ₆₁ N ₃ O ₉ , 0.6H ₂ O: C, 64.94; H, 8.61; N, 5.83. Found: C, 64.75; H, 8.46; N, 5.82.
Example 15-5

Further, by performing the following operation, a crystal different from the above crystal (A-type crystal) was obtained.
To 0.10 g of ethanol solvate of colorless amorphous compound (15-2), 600 μL of phosphate buffer (pH 6.8) was added and suspended at 25 ° C. for 24 hours. After centrifugation (3000 rpm, 25 ° C., 10 minutes), the supernatant was removed and dried at room temperature. When the powder X-ray diffraction pattern and differential thermal analysis / thermal mass measurement (TG / DTA) of this crystal were measured, it was an A-form crystal.
The obtained crystals had peaks at 2θ = 6.1 degrees, 13.7 degrees, 18.0 degrees, and 18.7 degrees in powder X-ray diffraction (Cu—Kα). Moreover, melting | fusing point was 107 to 113 degreeC.

The powder X-ray diffraction pattern of the crystal is shown in FIG. 4, and the differential thermal analysis / thermal mass measurement curve is shown in FIG.
Example 16-1

A colorless amorphous compound (16-1) (90 mg, 55) was prepared in the same manner as in Example 1-1 except that intermediate (G) was used instead of intermediate (E) and piperazine was used instead of N, N-dimethylethylenediamine. %).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 (d, J = 6.6 Hz, 3 H) 1.11 (d, J = 6.6 Hz, 3 H) 1.35 (s, 6 H) 1.77 (s, 6 H ) 2.00 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.25 (br. S., 2 H) 2.78-2.88 (m, 4 H) 2.96-3.12 (m, 1 H) 3.55-3.65 (m, 4 H) 3.78-3.88 (m, 1 H) 3.85 (s, 3 H) 3.88-4.04 (m, 2 H) 4.09-4.18 (m, 1 H) 4.20-4.30 (m, 1 H) 4.88 (d, J = 9.48 Hz, 1 H) 5.15-5.27 (m, 1 H) 5.28-5.44 (m, 2 H) 6.22-6.33 (m, 1 H) 6.41-6.55 (m, 1 H) 6.72-6.85 (m, 2 H) 6.96-7.06 (m, 2 H) 7.14 (s, 1 H) 7.23-7.32 (m, 2 H).
MS ESI / APCI Dual posi: 836 [M + H] ⁺ .
Example 16-2

A colorless amorphous compound (16-2) (52 mg, 70%) was obtained in the same manner as in Example 1-2 using the compound (16-1) instead of the compound (1-1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.06 (d, J = 6.80 Hz, 3 H) 1.07 (d, J = 6.80 Hz, 3 H) 1.34 (s, 6 H) 1.42 (s, 6 H) 2.67 (br. S., 4 H) 3.04-3.12 (m, 1 H) 3.27-3.30 (m, 2 H) 3.33-3.38 (m, 2 H) 3.43-3.49 (m, 1 H) 3.50- 3.61 (m, 3 H) 3.61-3.66 (m, 1 H) 3.80 (s, 3 H) 3.83 (d, J = 11.92 Hz, 1 H) 3.92-4.00 (m, 2 H) 4.63 (d, J = 9.63 Hz, 1 H) 6.33-6.39 (m, 1 H) 6.44-6.49 (m, 1 H) 6.86 (s, 1 H) 7.06 (d, J = 8.25 Hz, 2 H) 7.21 (s, 1 H) 7.27 (d, J = 8.25 Hz, 2 H).
MS ESI / APCI Dual posi: 668 [M + H] ⁺ , 690 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 666 [MH] ⁻ , 702 [M + Cl] ⁻ .
Example 17-1

A colorless amorphous compound (17-1) (17-1) in the same manner as in Example 1-1 using Intermediate (G) instead of Intermediate (E) and 1-methylpiperazine instead of N, N-dimethylethylenediamine 187 mg, 95%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.05 (d, J = 6.84 Hz, 3 H) 1.10 (d, J = 6.84 Hz, 3 H) 1.36 (s, 6 H) 1.59 (s, 6 H ) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.26 (s, 3 H) 2.32-2.40 (m, 4 H) 2.96-3.12 (m , 1 H) 3.59-3.71 (m, 4 H) 3.79-3.84 (m, 1 H) 3.85 (s, 3 H) 3.90-4.05 (m, 2 H) 4.10-4.16 (m, 1 H) 4.21-4.28 (m, 1 H) 4.87 (d, J = 9.64 Hz, 1 H) 5.16-5.27 (m, 1 H) 5.29-5.44 (m, 2 H) 6.28 (d, J = 16.4 Hz, 1 H) 6.49 ( d, J = 16.4 Hz, 1 H) 6.77 (s, 1 H) 6.83 (s, 1 H) 7.01 (d, J = 8.08 Hz, 2 H) 7.13 (s, 1 H) 7.25-7.32 (m, 2 H).
MS ESI / APCI Dual posi: 850 [M + H] ⁺ .
MS ESI / APCI Dual nega: 884 [M + Cl] ⁻ .
Example 17-2

A colorless amorphous compound (17-2) (127 mg, 84%) was obtained in the same manner as in Example 4-2 using the compound (4-1A) and the compound (4-1B) instead of the compound (4-1B). Got.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.05 (d, J = 6.65 Hz, 3 H) 1.07 (d, J = 6.65 Hz, 3 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.14 (s, 3 H) 2.23-2.40 (m, 4 H) 3.06-3.16 (m, 1 H) 3.34-3.42 (m, 2 H) 3.46-3.52 (m, 1 H) 3.51-3.73 (m , 6 H) 3.79-3.91 (m, 4 H) 3.98 (s, 2 H) 4.65 (d, J = 9.63 Hz, 1 H) 6.38 (d, J = 16.1 Hz, 1 H) 6.48 (d, J = 16.1 Hz, 1 H) 6.88 (s, 1 H) 7.08 (d, J = 8.25 Hz, 2 H) 7.23 (s, 1 H) 7.29 (d, J = 8.25 Hz, 2 H).
MS ESI / APCI Dual posi: 682 [M + H] ⁺ , 704 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 716 [M + Cl] ⁻ .
Anal. Calcd for C ₃₈ H ₅₅ N ₃ O ₈・ 1.6H ₂ O: C, 64.2; H, 8.25; N, 5.91. Found: C, 64.3; H, 8.08; N, 5.89.

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) Production of CHO-K1 cells that stably express human SGLT2 Method A (method described in WO2007 / 136116): A plasmid vector that expresses a protein in which LeuGluSerArgGlyProVal is added to the final residue of the human SGLT2 carboxy terminus, CHO-K1 cells were transfected using Lipofectamine 2000 (Invitrogen). SGLT2-expressing cells were cultured in the presence of hygromycin B at a concentration of 500 μg / mL, resistant strains were selected, and sugar uptake ability was obtained as an index using the system shown below. The results calculated using the stably expressing cells are shown in Table 1 as Method A.

  Method B: A plasmid vector expressing human SGLT2 protein was transfected into CHO-K1 cells using Lipofectamine LTX (Invitrogen). SGLT2-expressing cells were cultured in the presence of geneticin at a concentration of 1000 μg / mL, resistant strains were selected, and sugar uptake capacity was obtained as an index by the system shown below. The results calculated using the stably expressing cells are shown in Table 1 as Method B.

(3) Sodium-dependent sugar uptake inhibition test in stably expressing cells The following tests were conducted using the stably expressing cells prepared above.

Add 200 μL of 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) to SGLT1 stably expressing cells, or 2 mL to each SGLT2 stably expressing cells 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), 140 mM NaCl, 2 mM KCl, 1 mM CaCl ₂ , Add 1 μM MgCl ₂ , 10 mM HEPES / 5 mM Tris, pH 7.4) 75 μL (for SGLT1) or 200 μL (for SGLT2) and perform uptake reaction at 37 ° C. for 30 minutes (SGLT1) or 60 minutes (SGLT2) It was. After reaction, the cells are washed with a buffer for washing (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) 200 μL (for SGLT1), or 2 mL It was washed twice with (in the case of SGLT2) and dissolved in 75 μL of 0.25 M NaOH solution (in the case of SGLT1) or 400 μL (in the case of SGLT2). After adding a liquid scintillator (Perkin Elmer) and mixing well, radioactivity was measured using a β-ray measuring device. 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 Table 1.

From Table 1, it was shown that the compounds of the present invention have strong SGLT1 inhibitory activity and also have some activity although SGLT2 inhibitory activity is weak.
The superiority of the compound of the present invention over the similar structure compound is shown below.

  Table 2 shows the blood glucose lowering effect and intrarenal concentration of the similar compounds of the present application after sugar loading. Compounds 4, 10, 11 and 33 showed a strong hypoglycemic effect in a glucose tolerance test after oral administration of 1 mg / kg. On the other hand, 7 days after oral administration of 1 mg / kg, the compound tended to remain in the kidney without being excreted. The target organ is the small intestine where SGLT1 is distributed a lot. Therefore, unexpected side effects may occur when the compound remains for a long time other than the target organ. For example, a compound having a hydrophilic group such as a tertiary amine and a hydrophobic group such as an aromatic ring in the molecule is called a cationic drug. They are hydrophobically bound to phospholipids and can be taken up into lysosomes and accumulated in systemic organs. Depending on the drug, the organs that accumulate are different, with chloroquine showing retinal damage and perhexiline with changes in the lungs and cerebellum. (Nippon Pharmacology Journal Folia Pharmacol. Jpn. 113, 19-30, 1999)

  For this reason, it is desirable that the compound is rapidly excreted from the body after showing its medicinal properties.

Test Example 2 Test for confirming inhibitory effect on blood glucose level in streptozotocin diabetic model rats (1) Preparation of diabetic model rats 7-week-old SD / IGS rats (Nippon Charles River Co., Ltd., male) were fasted for about 16 hours and then anesthetized with ether. Under the above, streptozotocin (STZ) 50 mg / kg was administered into the tail vein to prepare a diabetes model rat. Similarly, under ether anesthesia, 1.25 mmol / L citrate physiological saline 1 mL / kg was administered into the tail vein to prepare normal control rats. One week after administration of STZ or 1.25 mmol / L citrate physiological saline (8 weeks of age), it was subjected to an oral glucose tolerance test.

(2) Oral glucose tolerance test After fasting rats for about 16 hours, in the drug administration group, a drug (1 mg / kg) dissolved in a 0.5% sodium carboxymethylcellulose (CMC) aqueous solution was added to the control group, and in the control group, the dose was 0. Only 5% CMC aqueous solution was orally administered. Five minutes after drug administration, glucose solution (2 g / kg) was orally administered, and blood was collected at a total of 5 points before drug administration (0 time) and 0.25, 0.5, and 1, 2 hours after oral administration.

  Blood collection was performed using heparin-coated blood collection tubes from the rat tail vein under ether anesthesia, and after centrifugation, plasma was collected. The plasma glucose concentration was measured using Glucose CII Test Wako (Wako Pure Chemical Industries, Ltd.). The blood glucose level increase inhibitory action strength is calculated by calculating the area under the blood glucose level-time curve (AUC) using the trapezoidal method from the blood glucose level from 0 to 1 hour of each drug administration group, and the area of increased blood glucose (ΔAUC) by subtracting basal ) And expressed as a percentage of the drop relative to that of the control group.

  The results are shown in Tables 2 and 3.

Test example 3
(1) Changes in renal concentration up to 1 week after oral administration of compounds 4, 10, 11, 33 described in the pamphlet of International Patent Publication No. WO 2007/136116 7-week-old SD / IGS rats (Nippon Charles River Co., Ltd., male, non- In the fasting, compounds 4, 10, 33 (each 1 mg / kg) and compound 11 (0.3 mg / kg) prepared in 0.5% CMC aqueous solution were orally administered. At 24, 72 and 168 hours after drug administration, whole blood was collected from the posterior vena cava under ether anesthesia, and the kidney was removed after confirmation of euthanasia. After washing the tissue surface with physiological saline, the weight was measured, 4 times the amount of purified water was added, and the mixture was homogenized under ice cooling. After deproteinization by adding an acetonitrile / methanol solution containing an internal standard substance to the homogenate, the supernatant was subjected to LC-MS / MS (Applied Biosystems API3000). Drug-derived ions generated by the electrospray ionization method in the positive ion mode were detected by selective reaction monitoring. The drug concentration in the homogenate was calculated from the peak area of the extracted ion chromatogram obtained by the internal standard method.
Here, the internal standard substances of the compounds 10 and 33 include (1S) -1,5-anhydro-1- [5- (4-ethoxybenzyl) -2-methoxy-4-methylphenyl] -1-thio- D-glucitol and ethyl-D ₅ were used, and compound 11 and compound 11 deuterium labeled (trishydroxymethyl-D ₆ ; -C (CD ₂ OH) ₃ ) were used as internal standard substances of compounds 4 and 11, respectively. Using.

  The experimental results are shown in Table 2.

(2) Renal concentration after repeated oral administration of compounds 1-2, 5-2, 6-2, 13-2, and 15-2 for 3 days SD / IGS rats (Nippon Charles River Co., Ltd., male) , Non-fasted) Compound 1-2, 5-2, 6-2, 13-2, 15-2 (3 mg / kg) prepared in 0.5% CMC aqueous solution was orally administered once a day for 3 consecutive days. Administered. At 48 hours after drug administration on the final day, whole blood was collected from the posterior vena cava under anesthesia with isoflurane, and the kidney was removed after confirmation of euthanasia. After washing the tissue surface with physiological saline, the weight was measured, 4 times the amount of purified water was added, and the mixture was homogenized under ice cooling. The measurement of the drug concentration in the homogenate was performed by LC-MS / MS using the above compound 11 as an internal standard substance in the same manner as in Test Example 3 (1) shown above.

  The experimental results are shown in Table 3.

  The structures of compounds 4, 10, 11, and 33 disclosed in International Patent Publication WO2007 / 136116 are shown below.

  The compound disclosed in the pamphlet of International Patent Publication No. WO2007 / 136116 showed a strong hypoglycemic action in a glucose tolerance test after oral administration of 1 mg / kg. However, after oral administration of 1 mg / kg, the disappearance rate of the compound from the kidney was slow, and even after 7 days, the compound was not excreted and remained in the kidney (Table 2).

  On the other hand, the compound of the present invention had a strong hypoglycemic action like the above prior art compounds. In addition, despite the continuous administration for 3 days at a dose of 3 mg / kg, it was shown that the compound unexpectedly did not remain in the kidney 2 days after administration (Table 3).

  As a cause of this difference, it is considered that the compound of the present invention was rapidly excreted without remaining in the kidney when absorbed into the body.

  Therefore, the compound of the present invention does not tend to remain in the body, and is considered to have a property that is excellent in practicality as a pharmaceutical with few side effects and toxicity due to continuous administration.

Formulation examples of the compound of the present invention are shown below.
Formulation Example 1
A capsule containing the following ingredients is produced.
Component Compound represented by formula (I) 10mg
Mannitol 113mg
L-HPC 15mg
HPC-L 9mg
147mg
The compound of formula (I) is passed through a 30 mesh screen. The other additives are mixed and then passed through a 30 mesh screen. Purified water is added to these and granulated, followed by drying. The obtained dried granules are sieved with a sieve (30 mesh), and 147 mg is filled into a No. 2 capsule.

Formulation Example 2
A tablet containing the following ingredients is produced.
Component Compound represented by formula (I) 10mg
Mannitol 86mg
Crystalline cellulose 21mg
L-HPC 14mg
HPC-L 8mg
Magnesium stearate 1mg
140mg
The compound of formula (I) is passed through a 30 mesh screen. The other additives are mixed and then passed through a 30 mesh screen. Purified water is added to these and granulated, followed by drying. The obtained dried granules are sieved through a sieve (30 mesh) and mixed. Add magnesium stearate to the mixture to obtain tableting granules. The granules for tableting are compressed to obtain 140 mg tablets.

  According to the present invention, SGLT1 (sodium-dependent glucose cotransporter 1) activity expressed in the small intestinal epithelium is inhibited, glucose absorption from the gastrointestinal tract is suppressed, and there is no tendency to retain in the body. It is expected to provide a prophylactic or therapeutic agent for diabetes, which comprises an isopropylphenyl glucitol compound as an active ingredient.

Claims (2)

It contains a 4-isopropylphenyl glucitol compound represented by the following formula ( I ′ ) or a pharmaceutically acceptable salt thereof as an active ingredient , and further includes crystalline cellulose, starch, lactose, mannitol, hydroxypropylcellulose, polyvinylpyrrolidone, An oral preparation for the prevention or treatment of diabetes comprising one or more selected from the group consisting of magnesium stearate, talc and carboxymethylcellulose calcium :

The oral preparation according to claim 1, wherein the dose of the 4-isopropylphenyl glucitol compound represented by the formula (I ') or a pharmaceutically acceptable salt thereof is 0.001 mg to 1000 mg per day.

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