HK1165413B - 4-isopropylphenyl glucitol compounds as sglt1 inhibitors - Google Patents

Description

4-cumyl sorbitol compounds as SGLT1 inhibitors

Technical Field

The present invention relates to 4-cumyl sorbitol compounds having specific inhibitory activity of sodium ion-dependent glucose transporter 1 (hereinafter, for convenience, simply referred to as "SGLT 1") involved in the absorption of glucose and galactose in the small intestine.

Background

Blood glucose levels are commonly used as biomarkers for metabolic signs and people are diagnosed with diabetes if their fasting blood glucose levels exceed 126 mg/dL. Furthermore, even if fasting blood glucose levels are within the normal range, some people may have blood glucose levels up to 140-200 mg/dL 2 hours after meal and be diagnosed as impaired glucose tolerance (or postprandial hyperglycemia). Recent epidemiological studies report that impaired glucose tolerance increases the risk of cardiovascular disease (see NPL 1 and NPL 2). Further, it has been reported that exercise therapy and/or drug therapy not only inhibits the progression of impaired glucose tolerance to type II diabetes but also significantly inhibits the onset of hypertension (see NPL 3).

As mentioned previously, inhibition of postprandial hyperglycemia is important in inhibiting the onset of diabetes and/or metabolic syndrome, and will correspondingly increase the need for drugs to control postprandial hyperglycemia.

As an agent for improving postprandial hyperglycemia, α -glucosidase inhibitors are widely used, which can inhibit glucohydrolase and thus delay absorption of sugar from the small intestine. In addition to these agents, other agents having a new mechanism for improving postprandial hyperglycemia have been studied.

On mammalian small intestine epithelial tissue, sodium ion dependent glucose transporter 1(SGLTl) is expressed at high frequency. SGLTl is known to act depending on sodium, and plays an important role in the activity of the small intestine or in galactose transport. Based on these findings, pyrazole derivatives are reported to have an effect of inhibiting SGLT1 activity and thus inhibiting absorption of glucose from foods, and can be used for the prevention or treatment of postprandial hyperglycemia (see PTL 1 to PTL 6). On the other hand, sodium-ion-dependent glucose transporter 2(SGLT2) is expressed at a high frequency in the kidney, and glucose filtered through the glomerulus is reabsorbed through SGLT2 pathway (see NPL 4). In addition, it has been reported that by inhibiting the activity of SGLT2, the sugar excretion into urine induces a hypoglycemic effect (see NPL 5). SGLT2 inhibitors have good hypoglycemic properties to lower temporary blood glucose levels, but unlike SGLT1 inhibitors, they have a lower effect in controlling postprandial hyperglycemia. Further, it has been reported that C-phenyl sorbitol derivatives can inhibit not only the activity of SGLT1 but also the activity of SGLT2 at the same time (see PTL 7).

On the other hand, when a drug containing an agent for improving postprandial hyperglycemia is to be administered continuously, it is important that a wide safety margin should be secured between the therapeutic dose and the toxic side effect dose of the drug. Particularly those that tend to remain in the body, it is difficult to control the dosage of the desired treatment, and thus the drug residue in the body may progress to an excessive drug effect, resulting in undesirable toxicity or side effects. For example, cationic drug molecules are known to have hydrophilic groups (such as tertiary amines) and hydrophobic groups (such as aromatic rings) which are bound to phospholipids through hydrophobic bonds and taken up by lysosomes, and thus accumulate in various organs in the body. As a typical example, chloroquine is shown to cause retinopathy, while perhexiline causes neuropathy problems due to its induction of changes in the lungs and cerebellum (see NPL 6).

Therefore, it is desirable that drugs be excreted from the body as soon as possible after releasing their potency. In particular, it is required that drugs for ameliorating postprandial hyperglycemia, which must be continuously administered, do not accumulate in the body.

Reference list

Patent document

[ PTL 1] International publication No. WO2002/098893

[ PTL 2] International publication No. WO2004/014932

[ PTL 3] International publication No. WO2004/018491

[ PTL 4] International publication No. WO2004/019958

[ PTL 5] International publication No. WO2005/121161

[ PTL 6] International publication No. WO2004/050122

[ PTL 7] International publication No. WO 2007/136116.

Non-patent document

[NPL 1] Pan XR, et al. Diabets Care, vol. 20, p. 537, 1997

[NPL 2] M Tominaga, et al. Diabets Care, vol. 22, p. 920, 1999

[NPL 3] J.-L.Chiasson, et al. Lancent, vol. 359, p. 2072, 2002

[NPL 4] E. M.Wright, Am.J. Physiol. Renal.Physiol.,vol.280, p. FlO, 2001

[NPL 5] G. Toggenburger, et al. Biochem. Biophys. Acta., vol.688, p. 557, 1982

[NPL 6] Folia Pharmacol. Jpn. vol. 113, p. 19, 1999。

Summary of The Invention

Technical problem

The object of the present invention is to provide a compound or a salt thereof having an inhibitory effect against SGLT1, which has a wide safety margin between the therapeutic dose and the toxic side effect dose of the drug, and a pharmaceutical preparation containing the same.

Technical scheme

The C-phenyl sorbitol derivative disclosed in PTL 7 was found to have a tendency to remain in the kidney without excretion. Based on this fact, the present inventors made many efforts to investigate those compounds that do not accumulate in vivo. As a result, the present inventors have found that 4-cumyl sorbitol compounds represented by the following general formula (I), particularly compounds obtained by introducing an isopropyl group to a benzene ring directly attached to a sugar group and introducing a butene group having an amino group to other benzene rings, surprisingly have no residual body tendency in the kidney. This finding has led to the completion of the present invention.

Specific examples of the 4-cumyl sorbitol compound of the present invention (herein referred to as "the present compound") are given below.

(1) A 4-cumyl sorbitol compound represented by the following general formula (I):

[ solution 1]

Wherein

R¹Represents a hydrogen atom or C_1-4The alkyl group of (a) is,

R²represents a hydrogen atom or a methyl group,

R³denotes "by an amino group or di-C_1-4Alkylamino radical substituted C_1-4An alkyl group "or a piperidine group of (a), and

R⁴represents a hydrogen atom, or alternatively, R³And R⁴Together with the adjacent nitrogen atom form a piperidino or piperazino group, which may be substituted by C_1-4Alkyl radical orDimethylamino group substitution.

(2) 4-cumyl sorbitol compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof.

[ solution 2]

(3) 4-cumyl sorbitol compound selected from the group consisting of the following or a pharmaceutically acceptable salt thereof.

[ solution 3]

(4) A pharmaceutical preparation comprising the 4-cumyl sorbitol compound according to any one of the above (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.

(5) A sodium-dependent glucose transporter 1(SGLT 1) activity inhibitor comprising the 4-cumyl sorbitol compound according to any one of the above (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.

(6) An agent for improving postprandial hyperglycemia, which comprises the 4-cumyl sorbitol compound according to any one of the above (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.

(7) An agent for preventing or treating diabetes, which comprises the 4-cumyl sorbitol compound according to any one of the above (1) to (3) or a pharmaceutically acceptable salt thereof as an active ingredient.

(8) Use of the 4-cumyl sorbitol compound according to any one of (1) to (3) above or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of diabetes.

(9) A method for preventing or treating diabetes, which comprises administering a therapeutically effective amount of the 4-cumyl sorbitol compound according to any one of (1) to (3) above or a pharmaceutically acceptable salt thereof to a mammal.

Advantageous effects of the invention

The present invention can provide a 4-cumyl sorbitol compound which can inhibit SGLT1 activity and has no tendency to accumulate in vivo.

Description of the embodiments

The terms and phrases used herein are defined as follows.

The term "C_1-4Alkyl group "means a straight or branched chain alkyl group having 1 to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl groups.

The term "di-C_1-4Alkylamino "refers to a group consisting of two C_1-4An alkyl group substituted amino group. Examples include dimethylamino and diethylamino groups.

In addition, the term "pharmaceutically acceptable salt" refers to, for example, an alkali metal salt, an alkaline earth metal salt, an ammonium salt or an alkylammonium salt, or a salt of an inorganic acid or an organic acid. Examples include sodium, potassium, calcium, ammonium, aluminum, triammonium, formate, acetate, propionate, butyrate, hexanoate, octanoate, trifluoroacetate, maleate, tartrate, citrate, stearate, succinate, ethylsuccinate, lactobionate, gluconate, glucuronate, glucoheptonate, glutarate, pimelate, suberate, azelate, sebacate, 1, 9-nonyldihydroxy acid, dodecanodiate, tridecanedioate, tetradecanedioate, pentadecanedioate, hexadecanedioate, heptadecanediate, benzoate, 2-hydroxybenzoate, methanesulfonate, ethylsulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, 1, 5-naphthalenesulfonate, lauryl sulfate, lactate, heptadecanediate, benzoate, 2-hydroxybenzoate, methanesulfonate, ethylsulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, 1, 5-naphthalenesulfonate, lauryl sulfate, lactate, Hippurate, fumarate, malonate, trans-cinnamate, malate, aspartate, glutamate, adipate, cysteine, N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylate polymer, and carbopol salt.

The phrase "an agent for improving postprandial hyperglycemia" refers to a drug that inhibits postprandial hyperglycemia and thus inhibits postprandial hyperglycemia-related diseases (e.g., diabetes, metabolic syndrome) or treats these diseases. As used herein, the term "postprandial hyperglycemia" refers to a state of abnormally elevated blood glucose levels after a meal, and particularly to a state of blood glucose levels exceeding 140 mg/dl for two hours after a meal.

The usefulness of the compounds of the present invention will be described in detail below (for a detailed description, see the detection examples described later).

The compound of the invention has strong SGLT1 inhibitory activity and certain SGLT2 inhibitory activity at the same time, although weak. Furthermore, the compounds of the present invention have as strong a hypoglycemic effect as the compounds disclosed in WO 2007/136116. Further, the compound disclosed in WO2007/136116 remained in the kidney after 7 days of oral administration of 1 mg/kg without being excreted, whereas the compound of the present invention showed the property of surprisingly not remaining in the kidney for the next 2 days even at a dose of 3 mg/kg for 3 consecutive days of administration.

Therefore, the compound of the present invention has no tendency to accumulate in vivo, and hardly causes toxic or side effects due to continuous administration, and thus exhibits particularly good characteristics as a pharmaceutical preparation.

When the compound of the present invention is provided in the form of a pharmaceutical preparation, various dosage forms such as solid and solution can be suitably used. In this case, pharmaceutically acceptable carriers may also be used in combination. Examples of such carriers include commonly used excipients, fillers, binders, disintegrants, coatings, sugar coatings, pH adjusters, solubilizers or aqueous or non-aqueous solvents. The compounds of the present invention and these carriers can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions or other dosage forms.

For example, the compounds of the present invention can be formulated into oral tablets using conventional methods for preparing solid preparations and excipients for mixing and tableting.

Furthermore, the compounds of the invention may also include, for example, alpha-, beta-or gamma-cyclodextrins or methylcyclodextrins to improve their solubility.

The dosage of the compound of the present invention may vary depending on the condition of the disease or disorder, body weight, age, sex, administration route, and the like. The daily dose for an adult is 0.1 to 1000 mg/kg body weight, preferably 0.1 to 200 mg/kg body weight, more preferably 0.1 to 10 mg/kg body weight, and is administered in a single dose form or divided dose form.

As a preferred embodiment of the present invention, the following compounds are prepared in the examples section.

[ solution 4]

How the compound (I) of the present invention is prepared is further illustrated in detail by the following examples, but is not limited to the specific cases illustrated below.

Preparation Process 1

The compound (I) of the present invention is synthesized in the following manner.

In the following synthetic schemes, X represents acetyl or C_1-4Alkyl radical, R⁵Represents R³Or R with the amino group protected by butyl versatate (Boc)³And the other groups are as defined above.

[ solution 5]

(1) Step 1 (Heck reaction)

The compound (II) and the alkene carboxylic acid (III) are subjected to Heck reaction in the presence of a palladium catalyst, a phosphine ligand and a suitable base to obtain the compound (IV). Examples of the palladium catalyst used include palladium acetate, tetrakis (triphenylphosphine) palladium, palladium diphenyleneacetonate, bis (triphenylphosphine) palladium chloride, bis (tricyclohexylmethylenephosphine) palladium chloride, and activated carbon palladium. Examples of phosphine ligands include triphenylphosphine and tri-O-tolylphosphine. Likewise, suitable bases for use include triethylamine, N-ethyl-N, N-diisopropylamine, potassium carbonate, calcium carbonate, cesium carbonate and potassium tert-butoxide. Examples of suitable solvents for the reaction include acetonitrile, toluene and tetrahydrofuran. The reaction temperature ranges from 0 ℃ to reflux temperature, or microwave heating may also be used.

(2) Step 2 (conversion to amino group)

The compound (IV) may be prepared by reacting with an amine (R)⁵R⁴NH) to obtain compound (V). Examples of preferred solvents for the reaction include chloroform, dichloromethane and N, N-dimethylformamide. Preferred dehydration condensing agents for use in the reaction include N, N ' -Dicyclohexylcarbodiimide (DCC), N-ethyl-N ' -3-dimethylaminopropyl carbodiimide hydrochloride (EDC-HCl), 1' -Carbonyldiimidazole (CDI), and EDC HC 1/1-hydroxybenzotriazole monohydrate (HOBt H)₂O). The reaction temperature ranges from 0 ℃ to 60 ℃.

(3) Step 3 (deprotection)

The Boc group in the compound (V) can be removed under acidic conditions and the acetyl (Ac) group can be removed under basic conditions, thereby obtaining the compound (I). The Boc group is treated with hydrochloric acid or trifluoroacetic acid with or without a solvent (e.g., dichloromethane, chloroform, dioxane). For the acetyl group, a base treatment such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, or triethylamine may be used. Examples of preferred solvents include methanol, ethanol and aqueous methanol. The reaction temperature ranges from 0 ℃ to 60 ℃.

Preparation Process 2

The compounds (I) of the present invention can also be synthesized by other routes shown below. In the following design, all definitions are as above.

[ solution 6]

(4) Step 4 (Heck reaction)

Compound (II) and alkene carboxylic acid (VI) can be reacted with Heck as shown in preparation Process 1 to give compound (VII).

(5) Step 5 (conversion to amino group)

Compound (VII) and amine (VIII) can be concentrated by dehydration as shown in step 2 of preparation Process 1 to give Compound (V).

(6) Step 6 (deprotection)

The compound (V) obtained above can be converted into the compound (I) by a deprotection reaction as shown in step 3 in production process 1.

Preparation Process 3

Process for the preparation of intermediate (II)

The preparation of the intermediate (II) required for the preparation of the compound (I) of the present invention is illustrated below.

In the following design, X¹Represents a benzyl group or C_1-4Alkyl radical, X²Represents a trimethylsilyl group or C_1-4Alkyl radicals, the other definitions being as above.

[ solution 7]

(7) Step 7 (coupling)

Compound (IX) can be treated with an organometallic reagent (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium) to produce an aromatic lithium reagent. Gluconolactone (X) may be added to the reagent to give compound (XI). Examples of solvents that can be used in this reaction include tetrahydrofuran, diethyl ether and toluene. The reaction temperature ranges from-80 ℃ to room temperature, preferably from-78 ℃ to-25 ℃.

(8) Step 8 (acid hydrolysis)

While the silyl group of compound (XI) is removed in methanol under acidic conditions, the 1-position of the sugar group may be converted to a methyl ether to give compound (XII). Examples of the acid used include hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid monohydrate, pyridine p-toluenesulfonic acid, hydrogen fluoride pyridine and n-Bu₄NF (carbon fiber). Although the reaction temperature varies depending on the type of acid used, it is in the range of 0 ℃ to 100 ℃, preferably 25 ℃ to 80 ℃.

(9) Step 9 (acetylation)

The hydroxyl group of compound (XII) may be protected with an acetyl group to give compound (XIII). Compound (XII) may be reacted with, for example, acetic anhydride or acetyl chloride in a solvent in the presence of a suitable base to give compound (XIII). Examples of suitable solvents for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran and N, N-dimethylformamide. Examples of preferred bases include triethylamine, collidine and pyridine. As the reaction catalyst, 4-dimethylaminopyridine can be used. The reaction temperature ranges from 0 ℃ to room temperature.

(10) Step 10 (reduction)

Compound (XIII) can be reacted with Et₃SiH、i-Pr₃SiH、t-BuMe₂SiH or Ph₂SiHCl is reacted in the presence of a Lewis acid to give compound (XIV). Examples of Lewis acids useful for the reaction include BF₃·Et₂O、CF₃COOH、InCl₃、TiCl₄TMSOTf, p-toluenesulfonic acid and methanesulfonic acid. Examples of the solvent include chloroform, dichloromethane, toluene, tetrahydrofuran, acetonitrile or a mixed solvent thereof, and preferred mixed solvents are mixed with acetonitrile such as acetonitrile/chloroform, acetonitrile/dichloromethane, acetonitrile/tetrahydrofuran/toluene, and the like. The reaction temperature ranges from-60 ℃ to 25 ℃, preferably from-30 ℃ to 25 ℃.

(11) Step 11 (deprotection)

When X in Compound (XIV)¹The group is benzyl and the debenzylation can be accomplished by catalytic hydrogenation using hydrogen gas, a catalyst such as palladium on activated carbon, palladium hydroxide or platinum palladium on activated carbon. Among them, activated carbon palladium or palladium hydroxide is a preferred catalyst. Examples of the solvent used for the reaction include methanol, ethanol, isopropanol, ethyl acetate, acetic acid and a mixture thereof. The temperature range of the reaction is from room temperature to reflux temperature, with room temperature being preferred.

(12) Step 12 (bromination)

Compound (XIV) or the compound obtained in step 11 above may be reacted with bromine, N-bromosuccinimide, hydrogen bromide or the like in a solvent to obtain compound (XV). Examples of the solvent used for the reaction include chloroform, dichloromethane, acetic acid, methanol and N, N-dimethylformamide. The reaction temperature ranges from 0 ℃ to room temperature.

(13) Step 13 (deprotection)

The acetyl group in compound (XV) may be removed under basic conditions to give compound (XVI). Examples of the base used include sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate and triethylamine. Examples of preferred solvents include methanol, ethanol and aqueous methanol. The temperature range of the reaction is 0 ℃ to 60 ℃.

(14) Step 14 (silylation)

The hydroxyl group in compound (XVI) may be protected with a silyl group (e.g., a trimethylsilyl group) to give compound (XVII). Compound (XVI) can be obtained in a solvent with trimethylsilyl chloride, triethylsilane chloride, tert-butylsilane chloride, or the like in the presence of an appropriate base to give compound (XVII). Examples of the solvent used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran and N, N-dimethylformamide. Examples of preferred bases include triethylamine, collidine and pyridine. The reaction temperature is preferably in the range of 0 ℃ to room temperature.

(15) Step 15 (coupling reaction)

Compound (XVII) can be treated with an organometallic reagent (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium) to prepare an aryllithium reagent. Acetaldehyde (XVIII) may be added to the reagent to give compound (XIX). Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether and toluene. The reaction temperature ranges from-80 ℃ to room temperature, preferably from-78 ℃ to-25 ℃.

(16) Step 16 (acid hydrolysis)

The compound (XIX) obtained above can be converted into the compound (XX) by an acid hydrolysis reaction as shown in step 8 of preparation Process 3.

(17) Step 17 (acetylation)

The compound (XX) obtained above can be converted into compound (XXI) by the method shown in step 9 of preparation Process 3.

(18) Step 18 (reduction)

The compound (XXI) obtained above can be converted into the intermediate (II) by a reduction method shown in step 10 of preparation process 3.

Preparation Process 4

Process for the preparation of intermediate (II)

Intermediate (II) can also be synthesized by another route shown below. In this approach, steps 19 to 21 may be performed in one reaction tank to reduce the number of reaction steps.

In the following design, all definitions are as described above.

[ solution 8]

(19) Step 19 (coupling)

Compound (XXII) can be treated with an organometallic reagent (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium) to prepare an aryllithium reagent. Gluconolactone (X) may be added to the reagent to obtain compound (XXIII). Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether and toluene. The reaction temperature ranges from-80 ℃ to room temperature, preferably from-78 ℃ to-25 ℃.

(20) Step 20 (silylation)

Following step 19 above, the hydroxyl group at position 1 in compound (XXIII) may be protected with a silyl group (e.g., trimethylsilyl group). The reaction solution of step 19 may be reacted with trimethylsilyl chloride to obtain compound (XXIV). The solvent used for the reaction and the preferred reaction temperature are the same as in step 19.

(21) Step 21 (coupling)

Following step 20 above, the resulting compound (XXIV) can be treated with an organometallic reagent (e.g., n-butyllithium, sec-butyllithium, tert-butyllithium) to prepare an aryllithium reagent. Acetaldehyde (XXIII) may be added to this reagent to obtain compound (XXV). The solvent and temperature used for the reaction are the same as in step 19.

(22) Step 22 (acid hydrolysis)

The compound (XXV) obtained above can be converted into compound (XXVI) by acid hydrolysis as shown in step 8 of preparation process 3.

(23) Step 23 (acetylation)

The compound (XXVI) obtained above can be converted into the compound (XXVII) by acetylation as shown in step 9 of preparation process 3.

(24) Step 24 (reduction)

The compound (XXVII) obtained above may be reduced to be converted into the compound (XXVIII) as shown in step 10 of preparation Process 3.

(25) Step 25 (acetylation or alkylation)

The hydroxyl group of compound (XXVIII) may be protected with acetyl group, or alkylated (e.g., methylated) to prepare intermediate (II). Compound (XXVIII) can be reacted with, for example, acetic anhydride or acetyl chloride in a solvent in the presence of a suitable base to give intermediate (II). Examples of the solvent used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran and N, N-dimethylformamide. Examples of the base used include triethylamine, collidine and pyridine. As the catalyst, 4-dimethylaminopyridine and the like can be used. The reaction temperature range is preferably from 0 ℃ to room temperature. Alternatively, compound (XXVIII) may be reacted with methyl iodide, ethyl iodide, 2-iodopropane or the like in a solvent in the presence of an appropriate base to give intermediate (II). Examples of the solvent used for the reaction include chloroform, dichloromethane, tetrahydrofuran, N-dimethylformamide and acetone. Examples of preferred bases include potassium carbonate and cesium carbonate.

Examples

The present invention will be further illustrated in more detail by the following comparative examples, examples and test examples, but the present invention will not be limited thereby.

Comparative example 1 preparation of intermediate (A)

[ solution 9]

(1) Comparative example 1-1 Compound (Al)

[ solution 10]

To a solution of 3-isopropylphenol (25.0 g, 0.184 mol) in acetic acid (200 mL) was added a suspension of potassium iodate (7.88 g, 0.0368 mol) in water (75 mL) and iodine (18.7 g,0.0736 mol). The reaction mixture was stirred at room temperature for 20 hours. Diethyl ether (400 mL) and water (300 mL) were added again, and the organic layer was separated. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 95:5) to obtain compound (Al) (27.6 g, 57%) as a colorless oil.

¹H NMR (200 MHz, chloroform-d) δ ppm 1.16-1.25 (m, 6H) 2.64-2.98 (m,1H) 5.21 (s, 1H) 6.57 (dd, J =8.13, 2.20 Hz,1H) 6.88 (d, J =2.20 Hz,1H) 7.54 (d, J =8.13 Hz, 1H).

(2) COMPARATIVE EXAMPLES 1-2 Compound (A2)

[ solution 11]

To a suspension of compound (Al) (26.5 g, 0.101 mol) and potassium carbonate (20.9 g, 0.152 mol) in acetonitrile was added benzyl bromide (14.4 mL, 0.121 mol) and stirred at room temperature for 2 hours, followed by addition of methanol (1.0 mL) and stirring continued for 30 minutes. Insoluble matter was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5) to obtain compound (a2) (30.2 g,85%) as a colorless oil.

¹H NMR (200 MHz, chloroform-d) δ ppm 1.21 (d, J =7.03 Hz, 6H) 2.84 (sept, J =7.03 Hz,1H) 5.14 (s, 2H) 6.62 (dd, J =8.35, 2.20 Hz,1H) 6.74 (d, J =2.20 Hz,1H) 7.23-7.58 (m, 5H) 7.68 (d, J =8.35 Hz, 1H).

(3) Comparative examples 1 to 3 Compound (A3)

[ solution 12]

To a solution of compound (A2) (30.2 g, 85.7 mmol) in THF (450 mL) was added dropwise a 2.6M solution of n-butyllithium in hexane (33 mL, 85.7 mmol) at-78 deg.C under nitrogen and stirred at the same temperature for 15 minutes. Then, a solution of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucono-l, 5-lactone (40.0 g, 85.7 mmol) in THF (230 mL) was added dropwise over 15 minutes, followed by stirring at the same temperature for 20 minutes. To the reaction mixture was added saturated aqueous ammonium chloride (150 mL) and water (100 mL). The mixture was warmed to room temperature and then extracted twice with ethyl acetate. The organic layers were combined, washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure.

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

The resulting residue (46.4 g) was dissolved in pyridine (125 mL) and cooled to 4 ℃. Acetic anhydride (75 mL) and 4-dimethylaminopyridine (102 mg, 0.835 mmol) were added to the solution and stirred at room temperature for 19 hours. After addition of ice water (500 mL), the mixture was extracted twice with ethyl acetate (500 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to obtain a crude product compound (53 g).

Et was added to a solution of the crude compound in chloroform (250 mL) and acetonitrile (250 mL) at 4 ℃ under nitrogen₃SiH (13.7 mL, 85.7 mmol) and BF₃-Et₂O (10.9 mL, 85.7 mmol), was stirred at the same temperature for 1.5 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5:1 → 2:1) to obtain compound (a3) (19.1 g, 40%; 4 steps) as a pale yellow amorphous substance.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.21 (d, J =6.99 Hz, 6H) 1.78 (s, 3H) 2.01 (s, 6H) 2.05 (s, 3H) 2.86 (sept, J =6.99 Hz,1H) 3.80 (ddd, J =9.95, 4.59, 2.25 Hz,1H) 4.06-4.13 (m,1H) 4.19-4.27 (m,1H) 4.96 (d, J =9.95 Hz,1H) 5.10 (s, 2H) 5.16-5.25 (m,1H) 5.33 (t, J =9.17 Hz,1H) 5.40-5.49 (m,1H) 6.79 (d, J =1.40 Hz,1H) 6.85 (dd, J =7.93, 1H) 1.93, 26.52 Hz, 26-5.52 Hz, 6H) In that respect

MS ESI/APCI Dual posi: 579[M+Na]⁺。

(4) Comparative examples 1 to 4 Compound (A4)

[ solution 13]

To a solution of compound (A3) (19.1 g, 34.3 mmol) in methanol (200 mL) was added 10% activated palladium carbonate (1.8 g), and the mixture was stirred under hydrogen at room temperature for 2 hours. The reaction mixture was filtered through celite, the solvent was then removed by distillation under the reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2:1 → 1:1) to give compound (a4) (12.3 g, 77%) as a colorless amorphous form.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.20 (d, J =6.89 Hz, 6H) 1.83 (s, 3H) 2.01 (s, 3H) 2.06 (s, 3H) 2.12 (s, 3H) 2.82 (sept, J =6.89 Hz,1H) 3.87 (ddd, J =9.60, 3.85, 2.25 Hz,1H) 4.14-4.21 (m,1H) 4.27-4.36 (m,1H) 4.59 (d, J =9.33 Hz,1H) 5.23-5.39 (m, 3H) 6.70 (dd, J =7.93, 1.71 Hz,1H) 6.77 (d, J =1.71 Hz,1H) 6.80 (s, 1H) 6.91 (d, J =7.93, 1H).

MS ESI/APCI Dual posi: 489[M+Na]⁺。

MS ESI/APCI Dual nega: 501[M+Cl]^-。

(5) Comparative examples 1 to 5 Compound (A5)

[ solution 14]

To a solution of compound (A4) (12.3 g, 26.3 mmol) in acetic acid (120 mL) was added dropwise bromine (4.2 g, 26.3 mmol) at room temperature. The reaction mixture was stirred for 1.5 hours, and ice water (150 mL) was added. The reaction mixture was extracted twice with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium bicarbonate, 10% aqueous sodium thiosulfate solution, and brine, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 2-propanol (20 mL), followed by dropwise addition of hexane (50 mL). The mixture was stirred at 4 ℃ for 1 hour, and the resulting precipitate was filtered to give compound (a5) (9.8 g, 68%) as a colorless powder.

¹H NMR (300 MHz, chloroform-d) delta ppm 1.12-1.26 (m, 6H) 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+C1]^-, 581[M+2+Cl]^-。

(6) Comparative examples 1 to 6 Compound (A6)

[ solution 15]

To a solution of compound (A5) (12.2 g, 22.3 mmol) in methanol (120 mL) was added triethylamine (24 mL) and water (24 mL). The reaction mixture was stirred at room temperature for 15 hours, and further stirred at 50 ℃ for 10 hours, and then the solvent was distilled off under reduced pressure.

The resulting residue was dissolved in N, N-dimethylformamide (106 mL), followed by addition of triethylamine (18.6 mL, 134 mmol) and chlorotrimethylsilane (14.3 mL, 112 mmol) at 4 ℃ under nitrogen. The reaction mixture was stirred at 4 ℃ for 1 hour, followed by addition of ice water (150 mL). The mixture was extracted three times with toluene, and the organic layers were combined, washed with water, saturated aqueous sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. After the drying agent was removed by filtration, the solvent was distilled off under reduced pressure to give compound (a6) (17.4 g) as an oil. The compound was used in the next reaction without purification.

¹H NMR (300 MHz, chloroform-d) δ ppm-0.28 (s, 9H) 0.08 (s, 9H) 0.19 (s, 9H) 0.20 (s, 9H) 0.29 (s, 9H) 1.16 (d, J =6.84 Hz, 3H) 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) Comparative examples 1 to 7 Compound (A7)

[ solution 16]

To a solution of compound (A6) (13.4 g, 15.9 mmol) in THF (140 mL) was added dropwise a 2.6M solution of n-butyllithium in hexane (7.7 mL, 20.0 mmol) at-78 ℃ over 10 minutes under nitrogen, and the mixture was 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 stirred at the same temperature for 45 minutes. To the reaction mixture were added saturated aqueous ammonium chloride (100 mL) and water (100 mL). The mixture was warmed to room temperature and extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure.

The resulting residue was dissolved in a solution containing methanesulfonic acid (0.9 g) in methanol (200 mL), and the solution was stirred at room temperature for 0.5 hour. After neutralization with triethylamine, the mixture was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1-8: 1) to obtain compound (a7) (5.75 g, 73%) as a colorless amorphous substance.

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.01 and 1.04 (each d, J =6.88 Hz, 3H) 1.18 and 1.19 (each d, J =6.88 Hz, 3H) 2.24 and 2.26 (each s, 3H) 2.95-3.07 (m,1H) 3.35-3.69 (m, 5H) 3.78-3.87 (m,1H) 4.37-4.50 (m,1H) 5.59 (s, 1H) 6.80 (s, 1H) 6.98-7.10 (m, 2H) 7.24-7.30 (m,1H) 7.33 (s, 1H).

MS ESI/APCI Dual posi: 479[M-OH]⁺, 481[M+2-OH]⁺。

(8) Comparative examples 1 to 8 intermediate (A)

[ solution 17]

Compound (A7) (5.7 g, 11.5 mmol) was dissolved in pyridine (34 mL). To the solution were added acetic anhydride (17 mL) and 4-dimethylaminopyridine (10 mg), and the mixture was stirred at room temperature for 0.5 hour. Ice water (500 mL) was then added and the mixture was extracted twice with ethyl acetate (500 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After drying by filtration, the solvent was distilled off under reduced pressure to give a crude product compound (8.5 g).

To a solution of the crude compound (8.5 g) in chloroform (80 mL) and acetonitrile (80 mL) was added Et at 4 ℃ under nitrogen₃SiH (2.7 mL, 17.0 mmol) and BF₃-Et₂O (2.2 mL, 17.0 mmol). The reaction mixture was warmed to room temperature and stirred at the same temperature for 0.5 hour. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was crystallized from a 4:1 mixture of hexane and ethyl acetate, and the resulting precipitate was filtered to give intermediate (A) (5.3 g, 68%) as a colorless powder.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.12 (d, J =6.68 Hz, 3H) 1.14 (d, J =6.68 Hz, 3H) 1.76 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.06 (s, 3H) 2.27 (s, 3H) 2.37 (s, 3H) 2.93 (sept, J =6.68 Hz,1H) 3.76 (ddd, J =9.87, 4.51, 2.25 Hz,1H) 3.87 (s, 2H) 4.06 (dd, J =12.51, 2.25 Hz,1H) 4.27 (dd, J =12.51, 4.51 Hz,1H) 4.49 (d, J =9.64 Hz,1H =9.64 Hz,1H =9.64 Hz,1H, 2H, and d =9.64 HzH) 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]⁺。

Alternatively, the intermediate (A) can also be synthesized by the following comparative examples 1 to 9, 1 to 10 and 1 to 11.

(9) Comparative examples 1 to 9 Compound (A8)

[ solution 18]

To a solution of 3-isopropylphenol (160 g, 1.18 mol) in acetic acid (1.6L) was added dropwise a solution of bromine (469 g, 2.94 mol) in acetic acid (320 mL) over 32 minutes while cooling on ice, the reaction internal temperature did not exceed 19 ℃, and then stirred at room temperature for 1 hour. After toluene (1.6L) was added, a 10% aqueous sodium sulfite solution (1.0L) was added dropwise in an ice bath, and the internal temperature of the reaction was not more than 20 ℃. The organic layer was separated, washed twice with 10% aqueous sodium sulfite (1.0L) and 10% aqueous sodium chloride (1.0L), and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give compound (A8) (342 g, 99%) as a pale yellow oil.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.21 (d, J =6.84 Hz, 6H) 3.25 (sept, J =6.84 Hz,1H) 5.40 (s, 1H) 6.96 (s, 1H) 7.61 (s, 1H).

(10) Comparative examples 1 to 10 Compound (A9)

[ solution 19]

To a chloroform (1.74L) solution of the compound (A8) (512 g, 1.74 mol) was added diisopropylethylamine (364 mL, 2.09 mol), and the mixture was cooled with ice. Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 60 minutes and stirred at room temperature for 1 hour. The reaction mixture was cooled with ice, and a 1M aqueous solution (1.5L) of sodium hydroxide was added dropwise. The organic layer was separated, washed with 1M aqueous sodium hydroxide (1.5L) and water (1.5L), and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by distillation under the reduced pressure (0.93 to 1.5 hpa, 122 ℃ to 137 ℃) to give compound (a9) (548 g, 96%) as a pale yellow oil.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.22 (d, J =6.84 Hz, 6H) 3.28 (sept, J =6.84 Hz,1H) 3.52 (s, 3H) 5.23 (s, 2H) 7.06 (s, 1H) 7.69 (s, 1H).

MS ESI/APCI Dual posi: 339[M+H]⁺, 341[M+2+H]⁺。

(11) Comparative examples 1 to 11 intermediate (A)

To a solution of compound (A9) (210 g, 0.621 mol) in THF (3.1L) was added dropwise a 2.76M solution of n-butyllithium in hexane (236 mL, 0.652 mol) over 20 minutes at-86 to-74 ℃ under an argon atmosphere, and stirred at the same temperature for 35 minutes. Then, a solution of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucono-l, 5-lactone (305 g, 0.652 mol) in THF (890 mL) was added dropwise over 38 minutes and stirred at the same temperature for 50 minutes. Trimethylchlorosilane (82.8 mL, 0.652 mmol) was further added dropwise over 4 minutes and stirred at the same temperature for 3 hours. Then, a 2.76M solution of n-butyllithium in hexane (326 mL, 0.901 mol) was added dropwise over a period of 23 minutes, and 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. The reaction mixture was diluted with water (3.1L) and warmed to room temperature. After toluene (3.1L) was added thereto, the organic layer was separated, and the solvent was distilled off under reduced pressure.

The resulting residue (633 g) was dissolved in methanol (3.1L), and methanesulfonic acid (4.03 mL, 0.0621 mol) was added, followed by heating and refluxing for 1 hour. The reaction mixture was cooled to room temperature, neutralized with triethylamine (17.3 mL, 0.124 mol) and concentrated. The concentrated product (413 g) was dissolved in toluene (1.1L) and washed three times with water (1.65L). The organic layer was diluted with toluene (0.55L) and extracted with 1M aqueous sodium hydroxide (0.55L). The aqueous layer was washed with toluene (1.65L) and acidified with 2M aqueous hydrochloric acid (0.43L). The resulting aqueous layer was extracted with toluene (1.1L). The Giardia layer was washed with 10% aqueous sodium chloride (1.1L), and then the solvent was distilled off under reduced pressure.

The resulting residue (273 g) was dissolved in THF (1.01L). To the solution were added diisopropylethylamine (776 mL, 4.53 mol), acetic anhydride (381 mL, 4.03 mol), and 4-dimethylaminopyridine (615 mg, 5.04 mmol), and the mixture was stirred at room temperature for 21 hours. The reaction mixture was cooled with ice, and water (1.0L) and toluene (1.0L) were added. The organic layer was separated, washed with saturated aqueous sodium bicarbonate (1.0L), and the solvent was distilled off under reduced pressure.

The resulting residue (390 g) was dissolved in acetonitrile (3.85L). To this solution was added water (9.07 mL, 0.504 mol) and t-BuMe₂SiH (334 mL, 2.02 mol), was ice-cooled, followed by addition of TMSOTf (392 mL, 2.17 mol) 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 stirred at the same temperature for 15 minutes. Toluene (3.85 mL) and 3% aqueous sodium bicarbonate (1.92L) were added to the reaction mixture. The organic layer was separated and washed with 3% aqueous sodium bicarbonate (1.92L) and 10% aqueous sodium chloride (1.92L), then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was crystallized from 2-propanol (1.42L). The resulting precipitate was filtered to give intermediate (A) (201 g, 47%; 4 steps) as a colorless powder.

Comparative example 2 preparation of intermediate (B)

[ solution 20]

(1) Comparative example 2-1 Compound (Bl)

[ solution 21]

To a suspension of compound (Al) (27.4 g, 0.104 mol) and potassium carbonate (21.7 g, 0.156 mol) in acetonitrile (200 mL) was added methyl iodide (9.8 mL, 0.156 mol), and stirred at 40 ℃ for 2.5 hours. Further methyl iodide (3.5 mL, 0.052 mol) was added and 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 brine, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 95:5) to give compound (Bl) (24.5 g,85%) as a light yellow oil.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.24 (d, J =6.84 Hz, 6H) 2.87 (sept, J =6.84 Hz,1H) 3.88 (s, 3H) 6.58-6.65 (m,1H) 6.70 (d, J =1.87 Hz,1H) 7.65 (d, J =8.08 Hz, 1H).

MS ESI/APCI Dual posi: 277[M+H]⁺。

(2) COMPARATIVE EXAMPLE 2-2 Compound (B2)

[ solution 22]

To a solution of compound (Bl) (24.5 g, 88.6 mmol) in THF (100 mL) was added dropwise a 2.6M solution of n-butyllithium in hexane (34 mL, 88.6 mmol) at-78 ℃ under nitrogen, and stirred at the same temperature for 5 minutes. Then, a solution of 2,3,4, 6-tetra-O-trimethylsilyl-D-glucono-l, 5-lactone (37.6 g, 80.5 mmol) in THF (60 mL) was added dropwise over 25 minutes and stirred at the same temperature 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 brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure.

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

The resulting residue (30.2 g) was dissolved in pyridine (100 mL). To the solution was added acetic anhydride (100 mL) and stirred at room temperature for 14 hours. After additional ice-water (400 mL) was added, the mixture was extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by distillation under the reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 6:4) to give compound (B2) (32.8 g, 80%; 3 steps) as a pale yellow oil.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.23 (d, J =6.92 Hz, 6H) 1.84 (s, 3H) 1.97 (s, 3H) 2.06 (s, 3H) 2.10 (s, 3H) 2.87 (sept, J =6.92 Hz,1H) 3.32 (s, 3H) 3.87 (s, 3H) 4.04 (ddd, J =10.18, 4.74, 2.41 Hz,1H) 4.17-4.23 (m,1H) 4.28-4.36 (m,1H) 5.25 (dd, J =10.18, 9.40 Hz,1H) 5.36 (d, J =10.18 Hz,1H) 5.60 (dd, J =10.18, 9.40, 1H) 6.74 (d, 1.55H) 6.79 (dd, 1H), j =8.08, 1.55 Hz,1H) 7.26-7.33 (m, 1H).

MS ESI/APCI Dual posi: 533[M+Na]⁺。

(3) Comparative examples 2 to 3 Compound (B3)

[ solution 23]

To a solution of compound (B2) (32.8 g, 64.0 mmol) in chloroform (150 mL) and acetonitrile (150 mL) was added Et at 4 ℃ under nitrogen₃SiH (21 mL, 128 mmol) and BF₃ Et₂O (49 mL, 385 mmol) and stirred at the same temperature for 1 hour. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2:1) to obtain compound (B3) (22.9 g, 74%) as a pale yellow gum.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.22 (d, J =6.99 Hz, 6H) 1.77 (s, 3H) 2.01 (s, 3H) 2.05 (s, 3H) 2.07 (s, 3H) 2.87 (sept, J =6.96 Hz,1H) 3.80-3.87 (m,1H) 3.84 (s, 3H) 4.09-4.16 (m,1H) 4.22-4.29 (m,1H) 4.88-4.95 (m,1H) 5.18-5.27 (m,1H) 5.32-5.38 (m, 2H) 6.71 (d, J =1.55 Hz,1H) 6.83 (dd, J =7.93, 1.55 Hz,1H) 7.23-7.30 (m, 1H).

MS ESI/APCI Dual posi: 503[M+H]⁺。

MS ESI/APCI Dual nega: 515[M+C1]^-。

(4) Comparative examples 2 to 4 Compound (B4)

[ solution 24]

The procedure shown in comparative examples 1 to 5 was repeated to give compound (B4) (25.5 g, 96%) as a pale yellow amorphous, except that compound (a4) in the procedure was replaced with compound (B3).

¹H NMR (300 MHz, chloroform-d) δ ppm 1.20 (d, J =6.84 Hz, 3H) 1.23 (d, J =6.84 Hz, 3H) 1.80 (s, 3H) 2.01 (s, 3H) 2.05 (s, 3H) 2.09 (s, 3H) 3.31 (sept, J =6.84 Hz,1H) 3.77-3.82 (m,1H) 3.83 (s, 3H) 4.10-4.17 (m,1H) 4.22-4.30 (m,1H) 4.83 (d, J =9.48 Hz,1H) 5.17-5.38 (m, 3H) 6.75 (s, 1H) 7.49 (s, 1H).

MS ESI/APCI Dual posi: 581[M+Na]⁺,583[M+2+Na]⁺。

(5) Comparative examples 2 to 5 Compound (B5)

[ solution 25]

The procedure shown in comparative examples 1 to 6 was repeated to give compound (B5) (30.3 g) as a brown oil by replacing compound (A5) in the procedure with compound (B4). This compound was used in the following reaction without purification.

¹H NMR (300 MHz, chloroform-d) δ ppm-0.32 (s, 9H) 0.09 (s, 9H) 0.18 (s, 9H) 0.20 (s, 9H) 1.19 (d, J =6.84 Hz, 3H) 1.23 (d, J =6.84 Hz, 3H) 3.26-3.44 (m, 3H) 3.52-3.58 (m, 2H) 3.65-3.75 (m, 3H) 3.76-3.83 (m,1H) 3.80 (s, 3H) 4.60 (d, J =8.55 Hz,1H) 6.72 (s, 1H) 7.51 (s, 1H).

MS ESI/APCI Dual posi: 701[M+Na]⁺, 703[M+2+Na]⁺。

(6) Comparative examples 2 to 6 Compound (B6)

[ solution 26]

The procedure shown in comparative examples 1 to 7 was repeated to give compound (B6) (14.7 g, 60%) as a brown amorphous substance by replacing compound (a6) in the procedure with compound (B5).

¹H NMR (300 MHz, chloroform-d) δ ppm 1.23 and 1.25 (each d, J =6.84 Hz, 6H) 1.80 (s, 2H) 2.27 and 2.29 (each s, 3H) 2.30-2.58 (m, 2H) 2.82-3.06 (m, 2H) 3.34 and 3.35 (each s, 3H) 3.38-3.86 (m, 6H) 4.56-4.73 (m,1H) 5.53 (d, J =3.11 Hz,1H) 6.75-7.35(m, 5H).

MS ESI/APCI Dual posi: 493[M-OH]⁺, 495[M+2-OH]⁺。

(7) Comparative examples 2 to 7 intermediate (B)

[ solution 27]

The procedure shown in comparative examples 1 to 8 was repeated to obtain intermediate (B) (14.2 g, 88%) as a colorless amorphous substance, except that compound (A7) in the procedure was replaced with compound (B6).

¹H NMR (300 MHz, chloroform-d) δ ppm 1.11 (d, J =6.68 Hz, 3H) 1.14 (d, J =6.68 Hz, 3H) 1.75 (s, 3H) 1.99 (s, 3H) 2.04 (s, 3H) 2.05 (s, 3H)) 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]⁺。

Comparative example 3 preparation of intermediate (C)

[ solution 28]

The procedures shown in comparative examples 1 to 7 and 1 to 8 were repeated to give compound (C) (2.26 g) as a pale yellow amorphous substance by replacing compound (A6) in the procedure with compound (B5) and 4-bromo-2-methylbenzaldehyde with 4-bromobenzaldehyde.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.04 (d, J =6.84 Hz, 3H) 1.09 (d, J =6.84 Hz, 3H) 1.76 (s, 3H) 2.01 (s, 3H) 2.05 (s, 3H) 2.06 (s, 3H) 2.91-3.06 (m,1H) 3.80-3.88 (m, 4H) 3.91 (d, J =5.13 Hz, 2H) 4.06-4.18 (m,1H) 4.20-4.31 (m,1H) 4.82-4.93(m, 1H) 5.15-5.43 (m, 3H) 6.77 (s, 1H) 6.92 (d, J =8.55 Hz, 2H) 7.11 (s, 1H) 7.36 (d, J =8.55 Hz, 2 H) In that respect

Comparative example 4 preparation of intermediate (D)

[ solution 29]

(1) Comparative example 4-1 Compound (Dl)

[ solution 30]

To a solution of 2, 2-dimethyl-3-butenoic acid (j. org. chem., vol. 65, p. 8402, 2000) (5.42 g, 47.5 mmol) in chloroform (250 mL) under nitrogen was added oxalyl chloride (4.43 mL, 49.9 mmol) and N, N-dimethylformamide (3 drops) and stirred at room temperature for 1.5 hours. The reaction mixture was then cooled with ice, and triethylamine (19.9 mL, 143 mmol) and the hydrochloride of methyl α -aminoisobutyrate (10.9 g, 71.2 mmol) were added, followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was washed with 3M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 4:1) to obtain compound (Dl) (9.38 g, 93%) as a colorless powder.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.27 (s, 6H) 1.51 (s, 6H) 3.73 (s, 3H) 5.17-5.32 (m, 2H) 6.02 (dd, J =17.56, 10.57 Hz,1H) 6.25 (br. s, 1H).

MS ESI/APCI Dual posi: 214[M+H]⁺。

(2) Comparative example 4-2 intermediate (D)

[ solution 31]

To a solution of compound (Dl) (9.38 g, 43.9 mmol) in methanol (20 mL) was added a 4M aqueous solution of sodium hydroxide (16.5 mL, 66.0 mmol), and the mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated. The resulting residue was dissolved in water and neutralized with 3M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After drying by filtration, the solvent was removed by distillation under the reduced pressure to give intermediate (D) (8.19 g, 94%) as a colorless powder.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.29 (s, 6H) 1.54 (s, 6H) 5.16-5.36 (m, 2H) 6.01 (dd, J =17.49, 10.65 Hz,1H) 6.14 (s, 1H).

MS ESI/APCI Dual posi: 200[M+H]⁺, 222[M+Na]⁺。

MS ESI/APCI Dual nega: 198[M-H]^-。

Comparative example 5 preparation of intermediate (E)

[ solution 32]

A suspension of 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-tolylphosphine (880 mg, 2.89 mmol) and triethylamine (3.0 mL, 9.00 mmol) in acetonitrile (24 mL) under argon was stirred under microwave irradiation at 120 ℃ for 20 min. The reaction mixture 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 give intermediate (E) (4.59 g, 78%) as a pale yellow powder.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.16, 1.18 (each d, J =6.84 Hz, each 3H) 1.40 (s, 6H) 1.54-1.58 (m, 6H) 1.76 (s, 3H) 1.99 (s, 6H), 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]^-。

Comparative example 6 preparation of intermediate (F)

[ solution 33]

The same procedure as in comparative example 5 was repeated to obtain intermediate (F) (2.03 g, 87%) as a yellow powder, and intermediate (a) in the procedure was replaced with intermediate (B).

¹H NMR (300 MHz, chloroform-d) δ ppm 1.17, 1.14 (each d, J =6.99 Hz, 3H) 1.38 (s, 6H) 1.55 (s, 6H) 1.76 (s, 3H) 1.98 (s, 3H) 2.04 (s, 6H) 2.30 (s, 3H) 2.94-3.03 (m,1H) 3.76-3.83 (m,1H) 3.84-3.95 (m, 4H) 4.06-4.15 (m,1H) 4.16-4.25 (m,1H) 4.81 (d, J =9.79 Hz,1H) 5.12-5.20 (m,1H) 5.23-5.35 (m, 2H) 6.29 (s, 1H) 6.31 (d, J =16.32, 1H) 6.52 (d, J = 16.32H) 52 (d, 2H), j =16.32 Hz,1H) 6.67 (d, J =8.08 Hz,1H) 6.81 (s, 1H) 6.94 (s, 1H) 7.06-7.14 (m,1H) 7.24 (s, 1H).

MS ESI/APCI Dual posi: 782[M+H]⁺, 804[M+Na]⁺。

MS ESI/APCI Dual nega: 780[M-H]^-。

Comparative example 7 preparation of intermediate (G)

[ chemical 34]

The same procedure as in comparative example 5 was repeated to obtain intermediate (G) (854 mg, 60%) as a pale yellow amorphous, except that intermediate (a) in the procedure was replaced with intermediate (C).

¹H NMR (300 MHz, chloroform-d) δ ppm 1.08 (d, J =6.84 Hz, 3H) 1.12 (d, J =6.84 Hz, 3H) 1.38 (s, 6H) 1.53 (s, 6H) 1.77 (s, 3H) 2.00 (s, 3H) 2.05 (s, 6H) 3.06 (sept, J =6.84 Hz,1H) 3.78-3.83 (m,1H) 3.84 (s, 3H) 3.97 (s, 2H) 4.07-4.18 (m,1H) 4.17-4.27 (m,1H) 4.87 (dd, J =6.76, 2.88 Hz,1H) 5.16-5.25 (m,1H) 5.27-5.40 (m, 2H) 6.18-6.33 (m, 2H), 2 H) 6.54 (d, J =16.48 Hz,1H) 6.77 (s, 1H) 7.03 (d, J =8.08 Hz, 2H) 7.10 (s, 1H) 7.29 (d, J =8.08 Hz, 2H).

MS ESI/APCI Dual posi: 768[M+H]⁺, 790[M+Na]⁺。

MS ESI/APCI Dual nega: 766[M-H]^-。

Comparative example 8 preparation of intermediate (H)

[ solution 35]

A suspension of 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) was heated under reflux for 3 hours under argon. 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 (1.32L). The solution was washed with 1M aqueous hydrochloric acid (0.96L) and 10% aqueous sodium chloride (1.2L), and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was further diluted with ethyl acetate (1.2L) and isopropylamine (28.2 mL, 0.327 mol) was added. The mixture was stirred for 1 hour under ice bath. The resulting precipitate was filtered to give the isopropylamine salt of intermediate (H). This salt was dissolved in ethyl acetate (1.2L) and 1M aqueous hydrochloric acid (500 mL) and stirred for 30 minutes. The organic layer was separated and washed with 10% aqueous sodium chloride (500 mL) and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure to give intermediate (H) (207 g, 88%) as a colorless amorphous substance.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.13 (d, J =6.80 Hz, 3H) 1.14 (d, J =6.80 Hz, 3H) 1.43 (s, 6H) 1.76 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.28 (s, 3H) 2.37 (s, 3H) 2.98 (sept, J =6.80 Hz,1H) 3.70-3.80 (m,1H) 3.91 (s, 2H) 4.05 (dd, J =12.43, 2.18 Hz,1H) 4.28 (dd, J =12.43, 4.35 Hz,1H) 4.43-4.50 (m,1H) 5.11-5.20 (m,1H) 5.22-5.33.33 (m,1H), 2 H) 6.33-6.49 (m, 2H) 6.68 (d, J =7.93 Hz,1H) 6.96 (s, 1H) 6.99 (s, 1H) 7.06-7.14 (m,1H) 7.23 (d, J =1.40 Hz, 1H).

MS ESI/APCI Dual posi: 747[M+Na]⁺。

Comparative example 9 preparation of intermediate (I)

[ solution 36]

2-Aminoisobutyric acid (150 g, 1.45 mol) was dissolved in water (2.2L), and sodium carbonate (465 g, 4.39 mol) was added. The reaction mixture was cooled with ice, and then a solution of benzyl chloroformate (227 mL, 1.60 mol) in 1, 4-dioxane (0.63L) was added dropwise over 45 minutes, with an internal temperature of not more than 10 ℃. After stirring at room temperature overnight, water (3.5L) and toluene (1.0L) were added to the reaction mixture. The aqueous layer was separated and concentrated hydrochloric acid (700 mL) was added dropwise until the pH of the system reached 1. Ethyl acetate (1.0L) was added and stirred for 1 hour. The organic layer was separated and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure.

The resulting residue (338 g) was dissolved in chloroform (1.7L). To this solution was added N, N' -Carbonyldiimidazole (CDI) (253 g, 1.56 mol) in portions under ice cooling, with an internal temperature of not more than 20 ℃. After stirring at room temperature for 30 minutes, the reaction mixture was again cooled with ice and l, 2-diamino-2-methylpropane (138 g, 1.56 mol) was added dropwise over a period of 25 minutes. After stirring overnight at room temperature, 10% aqueous potassium carbonate (1.7L) was added. The organic layer was separated and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure.

The resulting residue (417 g) was dissolved in THF (2.0L). Adding Boc to the solution₂O (355 g, 1.63 mol), and stirred at room temperature for 1.5 hours. Then, a saturated aqueous sodium hydrogencarbonate solution (1.0L) was added to the reaction mixture, and the organic layer was separated and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure.

The resulting residue (549 g) was dissolved in methanol (2.75L). To the solution was added 10% palladium hydroxide (27.5 g), and the mixture was stirred at room temperature under hydrogen gas for 4.5 hours. After the reaction mixture was filtered through Celite, the solvent was removed by distillation under the reduced pressure, and the resulting residue was crystallized from a 2:1 heptane-ethyl acetate mixed solvent (1.75L). The resulting precipitate was filtered to give intermediate (I) (193 g, 53%; 4 steps) as a colorless powder.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.27 (s, 6H) 1.37 (s, 6H) 1.43 (s, 9H) 1.53 (br. s, 2H) 3.39 (d, J =6.53 Hz, 2H) 4.78 (br. s, 1H) 8.04 (br. s, 1H).

MS ESI/APCI Dual posi: 274[M+H]⁺, 296[M+Na]⁺。

MS ESI/APCI Dual nega: 3O8[M+C1]^-。

Examples 1 to 1

[ solution 37]

To intermediate (E) (200 mg, 0.25 mmol), 1-hydroxybenzotriazole monohydrate (HOBt. H)₂O) (57 mg, 0.37 mmol) and N, N-dimethylethylenediamine (65 mg, 0.74 mmol) in N, N-dimethylformamide (3.0 mL) were added N-ethyl-N' -3-dimethylaminopropylcarbodiimide hydrochloride (EDC. HC1) (71 mg, 0.37 mmol), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. After the drying agent 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 give compound (1-1) (132 mg, 61%) as a colorless amorphous form.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.13, 1.15 (each d, J =6.92 Hz, each 3H) 1.38 (s, 6H) 1.53 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.23 (s, 6H) 2.31 (s, 3H) 2.37 (s, 3H) 2.41 (t, J =5.67 Hz, 2H) 2.90-3.03 (m,1H) 3.25-3.34 (m, 2H) 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+C1]^-。

Examples 1 to 2

[ solution 38]

To a solution of compound (1-1) (127 mg, 0.14 mmol) in methanol (2.0 mL) was added sodium methoxide (4.88M/MeOH, 10. mu.L), and the mixture was stirred at room temperature for 1 hour. A small amount of dry ice was added to neutralize the reaction mixture, 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 give compound (1-2) (77 mg, 80%) as a colorless amorphous form.

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.10 (d, J =6.92 Hz, 6H) 1.36 (s, 6H) 1.45 (s, 6H) 2.23 (s, 6H) 2.31 (s, 3H) 2.40 (t, J =6.88 Hz, 2H) 2.87-2.96 (m,1H) 3.28 (t, J =6.88 Hz, 2H) 3.34-3.41 (m, 2H) 3.43-3.50 (m,1H) 3.51-3.57 (m,1H) 3.67 (dd, J =12.15, 2.52 Hz,1H) 3.84 (d, J =11.46 Hz,1H) 3.89 (s, 2H) 4.47 (d, J =9.63 Hz,1H) 6.39 (J =16.05, 1H) 6.50 (d, J =16.05 Hz,1H) 6.75 (d, J =8.25 Hz,1H) 6.80 (s, 1H) 6.97 (s, 1H)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[M-H]^-, 7O4[M+C1]^-。

C₃₇H₅₅N₃O₈·1.4H₂The analytically calculated values of O are C, 63.94, H, 8.38 and N, 6.05. Found C, 64.13, H, 8.39, N, 5.88.

Example 2-1

[ solution 39]

The same procedures as in example 1-1 were repeated to give compound (2-1) (103 mg, 47%) as a colorless amorphous substance in which N, N-dimethylethylenediamine was replaced with piperazine.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.14, 1.16 (each d, J =6.99 Hz, each 3H) 1.38 (s, 6H) 1.61 (s, 6H) 1.71 (s, 3H) 1.99 (s, 3H) 2.05 (s, 3H) 2.12 (s, 3H) 2.27 (s, 3H) 2.79-2.87 (m, 4H) 2.87-2.99 (m,1H) 3.56-3.66 (m, 4H) 3.75-3.94 (m, 3H) 4.12-4.20 (m,1H) 4.25-4.34 (m,1H) 4.44-4.52 (m,1H) 5.23-5.32 (m, 3H) 6.30 (d, J =16.32, 1H) 6.48 Hz, j =16.32 Hz,1H) 6.53 (s, 1H) 6.68 (d, J =7.77 Hz,1H) 6.88 (s, 1H) 6.97 (s, 1H) 7.05-7.12 (m,1H) 7.22 (s, 1H).

MS ESI/APCI Dual posi: 836[M+H]⁺, 858[M+Na]⁺。

MS ESI/APCI Dual nega: 834[M-H]^-, 87O[M+C1]^-。

Examples 2 to 2

[ solution 40]

The same procedures as in example 1-2 were repeated to give compound (2-2) (52 mg, 66%) as a colorless amorphous substance, except that compound (1-1) in the procedure was replaced with compound (2-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.10 (d, J =6.42 Hz, 6H) 1.36 (s, 6H) 1.44 (s, 6H) 2.31 (s, 3H) 2.70 (br. s, 4H) 2.90-2.95 (m,1H) 3.36-3.39 (m, 2H) 3.43-3.61 (m, 7H) 3.65-3.69 (m,1H) 3.84 (d, J =11.92 Hz,1H) 3.88 (s, 2H) 4.46 (d, J =9.63 Hz,1H) 6.38 (d, J =16.05 Hz,1H) 6.47 (d, J =16.05 Hz,1H) 6.76 (d, J =7.79, 1H) 6.80 (s, 1H) 6.95 (s, 95H), 1H) 7.10 (d, J =7.79 Hz,1H) 7.22 (s, 1H).

MS ESI/APCI Dual posi: 668[M+H]⁺, 690[M+Na]⁺。

MS ESI/APCI Dual nega: 666[M-H]^-, 7O2[M+C1]^-。

Example 3-1

[ solution 41]

The same procedures as in example 1-1 were repeated to give compound (3-1) (135 mg, 61%) as a colorless amorphous substance in which N, N-dimethylethylenediamine was replaced with 1-methylpiperazine.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.13, 1.15 (each d, J =6.84 Hz, each 3H) 1.37 (s, 6H) 1.60 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.27 (s, 3H) 2.30 (s, 3H) 2.33-2.41 (m, 7H) 2.88-3.04 (m,1H) 3.60-3.70 (m, 4H) 3.72-3.80 (m,1H) 3.92 (s, 2H) 4.05 (dd, J =12.59, 2.33 Hz,1H) 4.27 (dd, J =12.59, 4.51 Hz,1H) 4.43.4.54 (m,1H) 5.10-5.20 (m,1H), 1H) 5.22-5.32 (m, 2H) 6.31 (d, J =16.48 Hz,1H) 6.49 (d, J =16.48 Hz,1H) 6.68 (d, J =8.08 Hz,1H) 6.86 (s, 1H) 7.00 (s, 2H) 7.08-7.14 (m,1H) 7.24 (s, 1H).

MS ESI/APCI Dual posi: 892[M+H]⁺，914[M+Na]⁺。

MS ESI/APCI Dual nega: 926[M+C1]^-。

Examples 3 to 2

[ solution 42]

The same procedures as in example 1-2 were repeated to give compound (3-2) (79 mg, 79%) as a colorless amorphous substance by substituting compound (1-1) in the procedure with compound (3-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.10 (d, J =6.88 Hz, 6H) 1.37 (s, 6H) 1.44 (s, 6H) 2.16 (s, 3H) 2.22-2.38 (m, 7H) 2.87-2.96 (m,1H) 3.35-3.41 (m, 2H) 3.42-3.51 (m, 2H) 3.51-3.56 (m,1H) 3.56-3.71 (m, 5H) 3.84 (d, J =12.38 Hz,1H) 3.88 (s, 2H) 4.47 (d, J =9.63 Hz,1H) 6.38 (d, J =16.51 Hz,1H) 6.46 (d, J =16.51 Hz,1H) 6.75 (d, J =8.25 Hz,1H) 6.80 (s, 1H) 6.97 (s, 1H) 7.09 (d, J =8.25 Hz,1H) 7.22 (s, 1H) H)。

MS ESI/APCI Dual posi: 682[M+H]⁺, 704[M+Na]⁺。

MS ESI/APCI Dual nega: 680[M-H]^-, 716[M+C1]^-。

Example 4-1

[ solution 43]

The same procedures as in example 1-1 were repeated to give compound (4-1A) (87.9 mg, 38%) as a colorless gum and compound (4-1B) (42.9 mg, 19%) as a colorless gum by substituting N, N-dimethylethylenediamine in step with 1-ethylpiperazine.

Compound (4-1A)

¹H NMR (300 MHz, chloroform-d) δ ppm 1.07 (t, J =7.23 Hz, 3H) 1.12-1.16 (m, 6H) 1.37 (s, 6H) 1.61 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.30 (s, 3H) 2.34-2.44 (m, 9H) 2.90-3.05 (m,1H) 3.60-3.72 (m, 4H) 3.72-3.80 (m,1H) 3.92 (s, 2H) 4.05 (dd, J =12.36, 1.94 Hz,1H) 4.27 (dd, J =12.36, 4.43 Hz,1H) 4.48 (d, J =9.79 Hz,1H) 5.15 (t, J =9.79 Hz,1H) 5.22-5.31 (m, 2H) 6.31 (d, J =16.2 Hz,1H) 6.49 (d, J =16.2 Hz,1H) 6.68 (d, J =8.08 Hz,1H) 6.86-6.93 (m,1H) 7.00 (s, 2H) 7.11 (d, J =8.08 Hz,1H) 7.24 (s, 1H).

MS ESI/APCI Dual posi: 907[M+H]⁺, 929[M+Na]⁺。

MS ESI/APCI Dual nega: 941[M+C1]^-。

Compound (4-1B)

¹H NMR (300 MHz, chloroform-d) δ ppm 1.03-1.19 (m, 9H) 1.37 (s, 6H) 1.62 (s, 6H) 1.71 (s, 3H) 1.99 (s, 3H) 2.05 (s, 3H) 2.12 (s, 3H) 2.27 (s, 3H) 2.33-2.46 (m, 6H) 2.93 (sept, J =6.76 Hz,1H) 3.58-3.71 (m, 4H) 3.73-3.91 (m, 3H) 4.12-4.21 (m,1H) 4.24-4.34 (m,1H) 4.48 (d, J =9.17 Hz,1H) 5.21-5.34 (m, 3H) 6.30 (d, J =16.1, 1H) 6.48 (d, j =16.1 Hz,1H) 6.53 (s, 1H) 6.68 (d, J =7.93 Hz,1H) 6.88 (s, 1H) 6.99 (s, 1H) 7.08 (d, J =7.93 Hz,1H) 7.22 (s, 1H).

MS ESI/APCI Dual posi: 865[M+H]⁺, 887[M+Na]⁺。

MS ESI/APCI Dual nega: 899[M+C1]^-。

Example 4 to 2

[ solution 44]

To compound (4-1A) (87.9 mg, 0.0973 mmol) and compound (4-1B) (42.9 mg, 0.0486 mmol) was added triethylamine/water/methanol (1/1/5, 5 mL). The reaction mixture was stirred at room temperature overnight, and the solvent was removed by distillation under the reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 8:2) to give compound (4-2) (79.2 mg, 78%) as a colorless amorphous substance.

¹H NMR (600 MHz, methanol-d 4) δ ppm 0.98 (t, J =7.23 Hz, 3H) 1.10 (d, J =6.88Hz, 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[M-H]^-。

C₃₉H₅₇N₃O₈·1,2H₂The analytically calculated values of O are C, 65.3, H, 8.34 and N, 5.86. Found C, 65.3, H, 8.36 and N, 5.68.

Example 5-1

[ solution 45]

To intermediate (E) (205 mg, 0.253 mmol), HOBt-H₂To a solution of O (68 mg, 0.506 mmol) and 4-dimethylaminopiperidine (65 mg, 0.506 mmol) in N, N-dimethylformamide (2.0 mL) was added EDC-HCl (97 mg, 0.506 mmol) and the mixture was stirred at 70 ℃ 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 brine (20 mL) and dried over anhydrous magnesium sulfate. After the drying agent 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 give compound (5-1) (80 mg, 34%) as a colorless amorphous substance.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.13 (d, J =6.76 Hz, 3H) 1.15 (d, J =6.76 Hz, 3H) 1.30-1.49 (m, 2H) 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+C1]^-。

Examples 5 and 2

[ solution 46]

The same procedures as in example 1-2 were repeated to give compound (5-2) (33 mg, 53%) as a colorless amorphous substance, except that compound (1-1) in the procedure was replaced with compound (5-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.08 (d, J =6.42 Hz, 6H) 1.21-1.32 (m, 2H) 1.35 (s, 6H) 1.43 (s, 6H) 1.73 (br. s, 2H) 2.16 (s, 6H) 2.28 (s, 3H) 2.28-2.37 (m,1H) 2.89 (sept, J =6.42 Hz,1H) 3.31-3.33 (m, 2H) 3.44 (t, J =8.71 Hz,1H) 3.48-3.56 (m,1H) 3.66 (dd, J =11.92, 2.75 Hz,1H) 3.83 (d, J =11.92 Hz,1H) 3.86 (s, 2H) 4.45 (d =9.63, J = 9.35H) 6.41 (m, 6H), 1H) 6.43-6.47 (m,1H) 6.72 (d, J =7.79 Hz,1H) 6.78 (s, 1H) 6.96 (s, 1H) 7.08 (d, J =7.79 Hz,1H)7.21 (s, 1 H)。

MS ESI/APCI Dual posi: 710[M+H]⁺。

MS ESI/APCI Dual nega: 708[M-H]^-。

C₄₀H₅₉N₃O₈·1.5H₂The analytically calculated values of O are C, 65.19, H, 8.50 and N, 5.70. Found C, 64.81, H, 8.46 and N, 5.61.

Example 6-1

[ solution 47]

To a solution of intermediate (E) (680 mg, 0.746 mmol) in chloroform (5.0 mL) was added CDI (182 mg, 1.12 mmol), 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 the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate. After the drying agent 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 give compound (6-1) (140 mg, 21%) as a colorless amorphous substance.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.11-1.17 (m, 6H) 1.11 (s, 6H) 1.39 (s, 6H) 1.53 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.31 (s, 3H) 2.37 (s, 3H) 2.89-3.05 (m,1H) 3.14 (d, J =5.91 Hz, 2H) 3.76 (ddd, J =9.71, 4.51, 2.10 Hz,1H) 3.93 (s, ddh) 4.05 (J =12.51, 2.10 Hz,1H) 4.27 (dd, J =12.51, 4.51, 1H) 4.49 (d =7.46 Hz,1H) 5.11-5.20 (m,1H) 5.23-5.31 (m, 2H) 6.26 (s, 1H) 6.29-6.38 (m,1H) 6.48-6.57 (m,1H) 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 to 2

[ solution 48]

The same procedure as in example 1-2 was repeated to give compound (6-2) (104 mg, 98%) as a colorless amorphous substance, except that compound (1-1) in the procedure was replaced with compound (6-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.02 (s, 6H) 1.05-1.10 (m, 6H) 1.35 (s, 6H) 1.44 (s, 6H) 2.29 (s, 3H) 2.85-2.93 (m,1H) 3.09 (s, 2H) 3.34-3.39 (m, 2H) 3.42-3.47 (m,1H) 3.52 (t, J =9.40 Hz,1H) 3.63-3.69 (m,1H) 3.80-3.85 (m,1H) 3.86 (s, 2H) 4.46 (d, J =9.63 Hz,1H) 6.35-6.41 (m,1H) 6.44-6.51 (m,1H) 6.73 (d, J =7.79 Hz,1H) 6.78 (s, 1H), 1H) 6.96 (s, 1H) 7.06-7.10 (m,1H) 7.23 (s, 1H).

MS ESI/APCI Dual posi: 670[M+H]⁺, 692[M+Na]⁺。

MS ESI/APCI Dual nega: 668[M-H]^-，7O4[M+C1]^-。

Alternatively, the compound (6-2) can also be synthesized by the following examples 6-3 and 6-4.

Examples 6 to 3

[ solution 49]

To intermediate (H) (205 g, 0.273 mol), intermediate (I) (97.0 g, 0.355 mol), HOBt. H₂EDC-HCl (78.5 g, 0.410 mol) was added to a solution of O (62.7 g, 0.410 mol) and triethylamine (114 mL, 0.819 mol) in N, N-dimethylformamide (1.98L) and stirred at room temperature for 11 h. Toluene (1.0L) and 10% aqueous sodium chloride (2.0L) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with toluene (1.0L), and the combined organic layers were washed with 5% aqueous sodium chloride (1.0L) and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 2-propanol (300 mL) at 50 ℃ and heptane (2.7L) was added dropwise. The mixture was stirred under ice-cooling for 1 hour, and the resulting precipitate was filtered to give compound (6-3) (221 g, 83%) as a colorless powder.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.13 (d, J =6.88 Hz, 3H) 1.14 (d, J =6.88 Hz, 3H) 1.26 (s, 6H) 1.39 (s, 6H) 1.44 (s, 9H) 1.55 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.30 (s, 3H) 2.37 (s, 3H) 2.97 (sept, J =6.88 Hz,1H) 3.41 (d, J =5.60 Hz, 2H) 3.72-3.80 (m,1H) 3.92 (s, 2H) 4.05 (dd, J =12.43, 2.02, 1H) 4.28 (dd =12.43, 2.02 Hz,1H) 4.28 (dd =12.43, dd), 4.51 Hz,1H) 4.45-4.52 (m,1H) 4.65 (s, 1H) 5.11-5.19 (m,1H) 5.22-5.33 (m, 2H) 6.29-6.39 (m,1H) 6.46-6.57 (m, 2H) 6.69 (d, J =8.00 Hz,1H) 6.96-7.03 (m, 2H) 7.11 (dd, J =8.00, 1.63 Hz,1H) 7.24-7.26 (m,1H) 7.59 (br. s, 1H).

Examples 6 to 4

Trifluoroacetic acid (297 mL, 3.88 mol) was added dropwise to a chloroform (3.0L) solution of compound (6-3) (220 g, 0.225 mol) over 10 minutes at room temperature, and stirred at the same temperature for 20 hours. The reaction mixture was diluted with toluene (3.0L) and concentrated. The concentrated product was dissolved in ethyl acetate (3.0L), washed with 10% aqueous sodium carbonate (1.2L) and brine (1.0L), and then the solvent was distilled off under reduced pressure.

The resulting residue (240 g) was dissolved in methanol (1.5L), cooled with ice, and triethylamine (0.3L) and water (0.3L) were added thereto. After stirring at room temperature for 13 hours, methanol (1.5L), triethylamine (0.3L) and water (0.3L) were further added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and co-evaporated with methanol. The obtained residue was purified by NH-type silica gel column chromatography (ethyl acetate: ethanol: water = 15:2:1 → 10:2:1) to obtain compound (6-2) (129 g, 86%; 2 steps) as a colorless amorphous substance.

Example 7-1

[ solution 50]

The same procedure as in example 1-1 was repeated to give compound (7-1) (112 mg, 74%) as a colorless amorphous substance by substituting intermediate (E) in the procedure with intermediate (F).

¹H NMR (300 MHz, chloroform-d) delta ppm 1.12, 1.14 (each d, J =6.84 Hz, each 3H) 1.37 (s, 6H) 1.51 (s, 6H) 1.76 (s, 3H) 1.99 (s, 3H) 2.04 (s, 3H) 2.04 (s, 3H) 2.23 (s, 6H) 2.32 (s, 3H) 2.41 (t, J =6.22 Hz, 2H) 2.86-2.99 (m,1H) 3.25-3.33 (m, 2H) 3.76-3.90 (m, 6H) 4.07-4.15 (m,1H) 4.18-4.26 (m,1H) 4.76-4.85 (m,1H) 5.13-5.22 (m,1H) 5.26-5.36 (m,1H), 2 H) 6.31 (d, J =16.48 Hz,1H) 6.37 (s, 1H) 6.50 (d, J =16.48 Hz,1H) 6.61-6.67 (m,1H) 6.81 (s, 1H) 6.99 (s, 1H) 7.06-7.12 (m,1H) 7.24 (s, 1H).

MS ESI/APCI Dual posi: 852[M+H]⁺。

MS ESI/APCI Dual nega: 886[M+C1]^-。

Example 7-2

[ solution 51]

The same procedure as in example 1-2 was repeated to give compound (7-2) (69 mg, 78%) as a colorless amorphous substance, except that compound (1-1) in the procedure was replaced with compound (7-1).

¹HNMR (600 MHz, methanol-d 4) δ ppm 1.13, 1.15 (each d, J =6.84 Hz, each 3H) 1.36 (s, 6H) 1.45 (s, 6H) 2.21 (s, 6H) 2.32 (s, 3H) 2.39 (t, J =6.88 Hz, 2H) 2.93-3.02 (m,1H) 3.24-3.39 (m, 4H) 3.42-3.48 (m,1H) 3.49-3.54 (m,1H) 3.58-3.65 (m,1H) 3.80-3.87 (m, 4H) 3.91 (s, 2H) 4.61 (d, J =9.63 Hz,1H) 6.39 (d, J =16.51 Hz,1H) 6.50 (d, J =16.51, 1H) 6.73 (d, J =16.51 Hz, j =7.80 Hz,1H) 6.92 (s, 1H) 7.08 (s, 1H) 7.10 (d, J =7.80 Hz,1H) 7.25 (s, 1H).

MS ESI/APCI Dual posi: 684[M+H]⁺。

MS ESI/APCI Dual nega: 682[M-H]^-，718[M+C1]^-。

C₃₈H₅₇N₃O₈·1.7H₂The analytically calculated values of O are C, 63.88, H, 8.52 and N, 5.88. Found C, 63.84, H, 8.41, N, 5.75.

Example 8-1

[ solution 52]

The same procedures as in example 1-1 were repeated to give compound (8-1) (145 mg, 89%) as a colorless amorphous substance by substituting intermediate (E) in the procedure with intermediate (F) and N, N-dimethylethylenediamine with N-t-butoxycarbonylethylenediamine.

MS ESI/APCI Dual posi: 924[M+H]⁺, 946[M+Na]⁺。

MS ESI/APCI Dual nega: 958[M+C1]^-。

Example 8 to 2

[ Hua 53]

To a chloroform (3.0 ml) solution of the compound (8-1), trifluoroacetic acid (600. mu.L) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and then purified by silica gel column chromatography (chloroform: methanol = 95:5 → 60:40) to give compound (8-2) (68 mg, 55%) as a colorless amorphous substance.

¹H NMR (300 MHz, chloroform-d) delta ppm 1.14, 1.16 (each d, J =6.37 Hz, each 3H) 1.32 (s, 6H) 1.42 (s, 6H) 1.77 (s, 3H) 1.98 (s, 3H) 2.03 (s, 3H) 2.04 (s, 3H) 2.32 (s, 3H) 2.90-3.02 (m,1H) 3.22-3.34 (m, 2H) 3.48-3.57 (m, 2H) 3.76-3.96 (m, 6H) 4.07-4.14(m, 1H) 4.17-4.25 (m,1H) 4.79-4.87 (m,1H) 5.12-5.22 (m,1H) 5.24-5.36 (m, 2H) 6.32(s), 1H) 6.40 (d, J =16.63 Hz,1H) 6.51 (d, J =16.63 Hz,1H) 6.65 (d, J =8.55 Hz,1H) 6.82 (s, 1H) 6.96 (s, 1H) 7.07-7.13 (m,1H) 7.28-7.31 (m,1H) 8.04 (br.s., 2H).

MS ESI/APCI Dual posi: 824[M+H]⁺, 846[M+Na]⁺。

MS ESI/APCI Dual nega: 858[M+C1]^-。

Examples 8 to 3

[ solution 54]

The same procedure as in example 1-2 was repeated to give compound (8-3) (22 mg, 44%) as a colorless amorphous substance, except that compound (1-1) in the procedure was replaced with compound (8-2).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.13, 1.15 (each d, J =6.84 Hz, each 3H) 1.36 (s, 6H) 1.45 (s, 6H) 2.32 (s, 3H) 2.63-2.71 (m, 2H) 2.94-3.03 (m,1H) 3.23 (t, J =5.96 Hz, 2H) 3.28-3.39 (m, 4H) 3.43-3.48 (m,1H) 3.48-3.54 (m,1H) 3.62 (dd, J =12.15, 5.73 Hz,1H) 3.79-3.88 (m, 2H) 3.92 (s, 2H) 4.61 (d, J =9.63, 1H) 6.40 (d, J =16.51, 6.51H) 50 (d, 1H), j =16.51 Hz,1H) 6.74 (d, J =7.79 Hz,1H) 6.92 (s, 1H) 7.07 (s, 1H) 7.11 (d, J =7.79 Hz,1H) 7.26 (s, 1H).

MS ESI/APCI Dual posi: 656[M+H]⁺。

MS ESI/APCI Dual nega: 654[M-H]^-，69O[M+C1]^-。

Example 9-1

[ solution 55]

The same procedure as in example 1-1 was repeated to give compound (9-1) (42 mg, 38%) as a colorless amorphous substance, except that intermediate (E) in the procedure was replaced with intermediate (F), and N, N-dimethylethylenediamine was replaced with piperazine.

¹H NMR (300 MHz, chloroform-d) delta ppm 1.12, 1.14 (each d, J =6.99 Hz, each 3H) 1.37 (s, 6H) 1.58 (s, 6H) 1.76 (s, 3H) 1.99 (s, 3H) 2.04 (s, 3H) 2.04 (s, 3H) 2.32 (s, 3H) 2.79-2.86 (m, 4H) 2.88-2.99 (m,1H) 3.57-3.64 (m, 4H) 3.76-3.95 (m, 6H) 4.07-4.14(m, 1H) 4.18-4.26 (m,1H) 4.77-4.84 (m,1H) 5.13-5.22 (m,1H) 5.26-5.37 (m, 2H) 6.29 d (d, 29 Hz), j =16.16 Hz,1H) 6.49 (d, J =16.16 Hz,1H) 6.64 (d, J =7.93 Hz,1H) 6.77-6.83 (m, 2H) 6.99 (s, 1H) 7.05-7.11 (m,1H) 7.22 (br.s., 1H).

MS ESI/APCI Dual posi: 850[M+H]⁺, 872[M+Na]⁺。

MS ESI/APCI Dual nega: 884[M+C1]^-。

Example 9-2

[ solution 56]

The same procedure as in example 1-2 was repeated to give compound (9-2) (27 mg, 94%) as a colorless amorphous substance, except that compound (1-1) in the procedure was replaced with compound (9-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.14, 1.16 (each d, J =6.42 Hz, each 3H) 1.36 (s, 6H) 1.44 (s, 6H) 2.32 (s, 3H) 2.69 (br. s, 4H) 2.95-3.03 (m,1H) 3.28-3.38 (m, 2H) 3.42-3.52 (m, 2H) 3.53-3.65 (m, 5H) 3.80-3.84 (m,1H) 3.84 (s, 3H) 3.92 (s, 2H) 4.61 (d, J =9.17 Hz,1H) 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[M-H]^-，716[M+C1]^-。

example 10-1

[ solution 57]

The same procedure as in example 1-1 was repeated to give a crude product, compound (10-1) (100 mg), as a colorless amorphous substance, obtained by substituting intermediate (E) in the procedure with intermediate (F), and N, N-dimethylethylenediamine with N-methylpiperazine. The product was used in the following reaction without purification.

¹H NMR (300 MHz, chloroform-d) delta ppm 1.12 (d, J =8.5 Hz, 3H) 1.15 (d, J =8.5 Hz, 3H) 1.36 (s, 6H) 1.56 (s, 6H) 1.77 (s, 3H) 1.99 (s, 3H) 2.04 (s, 6H) 2.30 (s, 3H) 2.32 (s, 3H) 2.38-2.50 (m, 4H) 2.85-3.02 (m,1H) 3.61-3.74 (m, 4H) 3.76-3.84 (m,1H) 3.81-3.96 (m,1H) 3.86 (s, 3H) 4.07-4.15 (m,1H) 4.18-4.27 (m,1H) 4.75-4.88 (m,1H) 5.11-5.24 (m,1H) 5.26-5.37 (m, 2H) 6.22-6.38 (m,1H) 6.43-6.54 (m,1H) 6.59-6.70 (m, 2H) 6.81 (s, 1H) 6.96-7.02 (m,1H) 7.04-7.12 (m,1H) 7.20-7.26 (m, 1H).

Example 10-2

[ solution 58]

The same procedures as in example 1-2 were repeated to give compound (10-2) (8.0 mg, 9%; 2 steps) as a colorless amorphous form in which compound (1-1) in the step was replaced with compound (10-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.09-1.16 (m, 6H) 1.35 (s, 6H) 1.42 (s, 6H) 2.12-2.16 (m, 3H) 2.23-2.33 (br. s, 4H) 2.30 (s, 3H) 2.92-3.01 (m,1H) 3.28 (s, 2H) 3.30-3.38 (m,1H) 3.41-3.51 (m, 2H) 3.55-3.66 (m, 5H) 3.78-3.86 (m, 4H) 3.90 (s, 2H) 4.59 (d, J =9.17 Hz,1H) 6.33-6.39 (m,1H) 6.42-6.47 (m,1H) 6.72 (d, J =7.79 Hz,1H) 6.90 (s, 1H) 7.04-7.11 (m, 2H) 7.19-7.24 (m, 1H).

MS ESI/APCI Dual posi: 696[M+H]⁺, 718[M+Na]⁺。

MS ESI/APCI Dual nega: 694[M-H]^-，73O[M+C1]^-。

Example 11-1

[ chemical 59]

The same procedure as in example 1-1 was repeated to give compound (11-1) (200 mg, 89%) as a pale yellow amorphous substance, except that intermediate (E) in the procedure was replaced with intermediate (F), and N, N-dimethylethylenediamine was replaced with 1-ethylpiperazine.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.07 (t, J =7.23 Hz, 3H) 1.11 (d, J =6.84 Hz, 3H) 1.14 (d, J =6.84 Hz, 3H) 1.36 (s, 6H) 1.59 (s, 6H) 1.76 (s, 3H) 1.99 (s, 3H) 2.04 (s, 3H) 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+C1]^-。

Example 11-2

[ solution 60]

The same procedures as in example 4-2 were repeated to give compound (11-2) (118 mg, 73%) as a colorless amorphous substance by substituting compounds (4-1A) and (4-1B) in the procedure with compound (11-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 0.97 (t, J =7.11 Hz, 3H) 1.10-1.19 (m, 6H) 1.37 (s, 6H) 1.45 (s, 6H) 2.26-2.42 (m, 9H) 2.97 (sept, J =6.76 Hz,1H) 3.32-3.40 (m, 2H) 3.43-3.48 (m,1H) 3.48-3.55 (m,1H) 3.55-3.72 (m, 5H) 3.79-3.89 (m, 4H) 3.91 (s, 2H) 4.61 (d, J =9.17 Hz,1H) 6.39 (d, J =16.5 Hz,1H) 6.46 (d, J =16.5 Hz,1H) 6.73J =7.79 Hz,1H) 6.92 (s, 1H) 7.04-7.14 (m, 2H) 7.23 (s, 1H).

MS ESI/APCI Dual posi: 710[M+H]⁺, 732[M+Na]⁺。

MS ESI/APCI Dual nega: 744[M+C1]^-。

C₄₀H₅₉N₃O₈·1.5H₂The analytically calculated values of O are C, 65.2, H, 8.48 and N, 5.70. Found C, 65.1, H, 8.38, N, 5.64.

Example 12-1

[ solution 61]

The same procedure as in example 5-1 was repeated to give compound (12-1) (55 mg, 40%) as a colorless amorphous substance by substituting intermediate (E) in the procedure with intermediate (F).

¹H NMR (300 MHz, chloroform-d) delta ppm 1.12, 1.14 (each d, J =6.92 Hz, each 3H) 1.28-1.47 (m, 8H) 1.60 (s, 6H) 1.73-1.89 (m, 5H) 1.99 (s, 3H) 2.04 (s, 3H) 2.04 (s, 3H) 2.22-2.35 (m, 10H) 2.73-2.99 (m, 3H) 3.76-3.84 (m,1H) 3.84-3.90 (m, 5H) 4.07-4.15 (m,1H) 4.18-4.26 (m,1H) 4.34-4.50 (m, 2H) 4.75-4.86 (m,1H) 5.13-5.23 (m,1H) 5.26-39.39 (m,1H), 2 H) 6.30 (d, J =16.48 Hz,1H) 6.48 (d, J =16.48 Hz,1H) 6.63 (d, J =8.39 Hz,1H) 6.81 (s, 1H) 6.94-7.01 (m, 2H) 7.04-7.11 (m,1H) 7.23 (s, 1H).

MS ESI/APCI Dual posi: 892[M+H]⁺, 914[M+Na]⁺。

Example 12-2

[ solution 62]

The same procedures as in example 1-2 were repeated to give compound (12-2) (55 mg, 82%) as a colorless amorphous substance by substituting compound (1-1) in the procedure with compound (12-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.13, 1.15 (each d, J =6.84 Hz, each 3H) 1.24-1.33 (m, 2H) 1.37 (s, 6H) 1.44 (s, 6H) 1.75 (br. s, 2H) 2.17 (s, 6H) 2.30-2.39 (m, 4H) 2.93-3.01 (m,1H) 3.28-3.38 (m, 5H) 3.43-3.47 (m,1H) 3.47-3.53 (m,1H) 3.62 (dd, J =12.15, 5.73 Hz,1H) 3.80-3.86 (m, 3H) 3.91 (s, 2H) 4.48 (br. s., 2H) 4.61 (d, J =9.63, J = 9.40H) (d, 6H) 3.40 Hz, j =16.05 Hz,1H) 6.47 (d, J =16.05 Hz,1H) 6.73 (d, J =7.79 Hz,1H) 6.92 (s, 1H) 7.06-7.11 (m, 2H) 7.23 (s, 1H).

MS ESI/APCI Dual posi: 724[M+H]⁺, 746[M+Na]⁺。

MS ESI/APCI Dual nega: 722[M-H]^-，758[M+C1]^-。

C₄₁H₆₁N₃O₈·2.5H₂The analytically calculated values of O are C, 64.04, H, 8.65 and N, 5.46. Found C, 64.01, H, 8.38, N, 5.49.

Example 13-1

[ solution 63]

The same procedure as in example 6-1 was repeated to give compound (13-1) (1.98 g, 99%) as a colorless amorphous substance by substituting intermediate (E) in the procedure with intermediate (F).

¹H NMR (300 MHz, chloroform-d) delta ppm 1.10 (s, 6H) 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

[ solution 64]

The same procedure as in example 1-2 was repeated to give compound (13-2) (1.0 g, 65%) as a colorless amorphous substance by substituting compound (1-1) in the procedure with compound (13-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.01 (s, 6H) 1.09-1.15 (m, 6H) 1.35 (s, 6H) 1.43 (s, 6H) 2.31 (s, 3H) 2.91-3.00 (m,1H) 3.08 (s, 2H) 3.27-3.36 (m, 5H) 3.41-3.46 (m,1H) 3.47-3.52 (m,1H) 3.60 (dd, J =11.92, 5.96 Hz,1H) 3.80-3.84 (m, 4H) 3.90 (s, 2H) 4.59 (d, J =9.63 Hz,1H) 6.36-6.41 (m,1H) 6.45-6.50 (m,1H) 6.71 (d, J =7.79, 1H) 6.90 (s, 1H) 7.06 (s, 1H) 7.07-7.10 (m,1H) 7.20-7.25 (m, 1H).

MS ESI/APCI Dual posi: 684[M+H]⁺。

MS ESI/APCI Dual nega: 682[M-H]^-，718[M+C1]^-。

Example 14-1

[ solution 65]

The same procedure as in example 1-1 was repeated to give compound (14-1) (200 mg, quant.) as a pale yellow oil by substituting intermediate (E) in the procedure with intermediate (F) and N, N-dimethylethylenediamine with 4-amino-l-tert-butoxycarbonylpiperidine.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.11 (d, J =6.99 Hz, 3H) 1.14 (d, J =6.99 Hz, 3H) 1.25-1.33 (m, 2H) 1.36 (s, 6H) 1.45 (s, 9H) 1.48 (s, 6H) 1.77 (s, 3H) 1.79-1.93 (m, 2H) 1.99 (s, 3H) 2.04 (s, 3H) 2.32 (s, 3H) 2.90-2.98 (m, 3H) 3.75-4.00 (m, 9H) 4.07-4.15 (m,1H) 4.18-4.27 (m,1H) 4.79-4.86 (m,1H) 5.19 (d, J =10.10 Hz,1H) 5.26-5.35 (m, 2H) 6.09 (s, 1H) 6.26 (d, J =16.48 Hz,1H) 6.50 (d, J =16.48 Hz,1H) 6.65 (d, J =8.32 Hz,1H) 6.74-6.83 (m, 2H) 6.99 (s, 1H) 7.08 (dd, J =8.32, 2.72 Hz,1H) 7.22 (d, J =2.72 Hz, 1H).

MS ESI/APCI Dual posi: 965[M+H]⁺, 987[M+Na]⁺。

MS ESI/APCI Dual nega: 999[M+C1]^-。

Example 14-2

[ solution 66]

To a solution of compound (14-1) (185 mg, 0.192 mmol) in chloroform (2 mL) was added trifluoroacetic acid (450. mu.L). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was removed by distillation under the reduced pressure. To the resulting residue was added triethylamine/water/methanol (1/1/5, 4 mL), and the reaction mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 8:2) to give compound (14-2) (103 mg, 77%) as a colorless amorphous substance.

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.14 (d, J =5.50 Hz, 3H) 1.15 (d, J =5.50 Hz, 3H) 1.27-1.35 (m, 2H) 1.37 (s, 6H) 1.45 (s, 6H) 1.78 (d, J =11.46 Hz, 2H) 2.33 (s, 3H) 2.56-2.68 (m, 2H) 2.95-3.03 (m, 3H) 3.33-3.37 (m, 2H) 3.43-3.48 (m,1H) 3.49-3.53 (m,1H) 3.57-3.66 (m,1H) 3.68-3.75 (m,1H) 3.81-3.84 (m,1H) 3.85 (s, 3H) 3.92(s), 2 H) 4.61 (d, J =9.17 Hz,1H) 6.34-6.43 (m,1H) 6.45-6.56 (m,1H) 6.74 (d, J =7.79 Hz,1H) 6.92 (s, 1H) 7.04-7.16 (m, 2H) 7.26 (s, 1H).

MS ESI/APCI Dual posi: 696[M+H]⁺, 718[M+Na]⁺。

Example 15-1

[ solution 67]

The same procedure as in example 1-1 was repeated to give compound (15-1) (103 mg, 94%) as a colorless amorphous substance by substituting intermediate (E) in the procedure with intermediate (G).

¹H NMR (300 MHz, chloroform-d) δ ppm 1.05 (d, J =6.84 Hz, 3H) 1.10 (d, J =6.84 Hz, 3H) 1.38 (s, 6H) 1.49 (s, 6H) 1.77 (s, 3H) 2.00 (s, 3H) 2.05 (s, 3H) 2.06 (s, 3H) 2.46 (s, 6H) 2.64-2.78 (m, 2H) 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+C1]^-。

Example 15-2

[ solution 68]

The same procedures as in example 4-2 were repeated to give compound (15-2) (62.1 mg, 75%) as a colorless amorphous substance by substituting compounds (4-1A) and (4-1B) in the procedures with compound (15-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.07 (d, J =6.76 Hz, 3H) 1.09 (d, J =6.76 Hz, 3H) 1.36 (s, 6H) 1.44 (s, 6H) 2.23 (s, 6H) 2.41 (t, J =6.88 Hz, 2H) 3.10 (sept, J =6.76 Hz,1H) 3.26-3.30 (m, 2H) 3.35-3.45 (m, 2H) 3.45-3.52 (m,1H) 3.54-3.60 (m,1H) 3.62-3.69 (m,1H) 3.79-3.89 (m, 4H) 3.99 (s, 2H) 4.65 (d, J =9.63, 1H) 6.39 (d =16.51, 1H) 6.52 (d, J =16.51 Hz,1H) 6.88 (s, 1H) 7.07 (d, J =8.25 Hz, 2H) 7.23 (s, 1H) 7.31 (d, J =8.25 Hz, 2H).

MS ESI/APCI Dual posi: 670[M+H]⁺。

MS ESI/APCI Dual nega: 7O4[M+C1]^-。

C₃₇H₅₅N₃O₈·1.0H₂The analytically calculated values of O are C, 64.6, H, 8.36 and N, 6.11. Found C, 64.5, H, 8.31, N, 6.02.

Example 16-1

[ solution 69]

The same procedure as in example 1-1 was repeated to give compound (16-1) (90 mg, 55%) as a colorless amorphous substance, except that intermediate (E) in the procedure was replaced with intermediate (G) and N, N-dimethylethylenediamine was replaced with piperazine.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.06 (d, J =6.6 Hz, 3H) 1.11 (d, J =6.6 Hz, 3H) 1.35 (s, 6H) 1.77 (s, 6H) 2.00 (s, 3H) 2.04 (s, 3H) 2.06 (s, 3H) 2.25 (br. s., 2H) 2.78-2.88 (m, 4H) 2.96-3.12 (m,1H) 3.55-3.65 (m, 4H) 3.78-3.88 (m,1H) 3.85 (s, 3H) 3.88-4.04 (m, 2H) 4.09-4.18 (m,1H) 4.20-4.30 (m,1H) 4.88 (d, J =9.48, 1H) 5.15-5 Hz (m, 27H) 27.27 Hz,1H) 5.28-5.44 (m, 2H) 6.22-6.33 (m,1H) 6.41-6.55 (m,1H) 6.72-6.85 (m, 2H) 6.96-7.06 (m, 2H) 7.14 (s, 1H) 7.23-7.32 (m, 2H).

MS ESI/APCI Dual posi: 836[M+H]⁺。

Example 16-2

[ solution 70]

The same procedure as in example 1-2 was repeated to give compound (16-2) (52 mg, 70%) as a colorless amorphous substance, except that compound (1-1) in the procedure was replaced with compound (16-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.06 (d, J =6.80 Hz, 3H) 1.07 (d, J =6.80 Hz, 3H) 1.34 (s, 6H) 1.42 (s, 6H) 2.67 (br. s, 4H) 3.04-3.12 (m,1H) 3.27-3.30 (m, 2H) 3.33-3.38 (m, 2H) 3.43-3.49 (m,1H) 3.50-3.61 (m, 3H) 3.61-3.66 (m,1H) 3.80 (s, 3H) 3.83 (d, J = I1.92 Hz,1H) 3.92-4.00 (m, 2H) 4.63 (d, J =9.63, 1H) 6.33-6.39 (m, 6H) 6.39-49 (m, 49H), 1H) 6.86 (s, 1H) 7.06 (d, J =8.25 Hz, 2H) 7.21 (s, 1H) 7.27 (d, J =8.25 Hz, 2H).

MS ESI/APCI Dual posi: 668[M+H]⁺, 690[M+Na]⁺。

MS ESI/APCI Dual nega: 666[M-H]^-，7O2[M+C1]^-。

Example 17-1

[ solution 71]

The same procedures as in example 1-1 were repeated to give compound (17-1) (187 mg, 95%) as a colorless amorphous substance by substituting intermediate (E) in the procedure with intermediate (G) and N, N-dimethylethylenediamine with 1-methylpiperazine.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.05 (d, J =6.84 Hz, 3H) 1.10 (d, J =6.84 Hz, 3H) 1.36 (s, 6H) 1.59 (s, 6H) 1.77 (s, 3H) 2.00 (s, 3H) 2.05 (s, 3H) 2.06 (s, 3H) 2.26 (s, 3H) 2.32-2.40 (m, 4H) 2.96-3.12 (m,1H) 3.59-3.71 (m, 4H) 3.79-3.84 (m,1H) 3.85 (s, 3H) 3.9.90-4.05 (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+C1]^-。

Example 17-2

[ chemical formula 72]

The same procedures as in example 4-2 were repeated to give compound (17-2) (127 mg, 84%) as a colorless amorphous substance by substituting compounds (4-1A) and (4-1B) in the procedures with compound (17-1).

¹H NMR (600 MHz, methanol-d 4) δ ppm 1.05 (d, J =6.65 Hz, 3H) 1.07 (d, J =6.65 Hz, 3H) 1.36 (s, 6H) 1.45 (s, 6H) 2.14 (s, 3H) 2.23-2.40 (m, 4H) 3.06-3.16 (m,1H) 3.34-3.42 (m, 2H) 3.46-3.52 (m,1H) 3.51-3.73 (m, 6H) 3.79-3.91 (m, 4H) 3.98 (s, 2H) 4.65 (d, J =9.63 Hz,1H) 6.38 (d, J =16.1 Hz,1H) 6.48 (d, J =16.1 Hz,1H) 6.88 (s, 1H) 7.08 (d, 1H), j =8.25 Hz, 2H) 7.23 (s, 1H) 7.29 (d, J =8.25 Hz, 2H).

MS ESI/APCI Dual posi: 682[M+H]⁺, 704[M+Na]⁺。

MS ESI/APCI Dual nega: 716[M+C1]^-。

C₃₈H-₃O₈·1.6H₂Analysis of OCalculated values of C, 64.2, H, 8.25 and N, 5.91. Found C, 64.3, H, 8.08, N, 5.89.

Detection example 1

(1) Production of CHO-Kl cells stably expressing human SGLT1

Plasmids expressing human SGLTl protein were transfected into CHO-Kl cells using lipofectamine 2000 (Invitrogen). Cells were cultured in the presence of 500. mu.g/mL geneticin to select drug-resistant strains, followed by screening in the system shown below with the sugar uptake capacity as an indication to obtain SGLTl-expressing cells.

(2) Production of CHO-Kl cells stably expressing human SGLT2

Method A (see WO2007/136116) A plasmid expressing human SGLT2 protein modified to have LeuGluSerargGlyProVal attached at the carboxy terminus was transfected into CHO-Kl cells using lipofectamine 2000 (Invitrogen). Cells were cultured in the presence of 500. mu.g/mL of hygromycin B to select drug-resistant strains, followed by screening in the system shown below with the sugar uptake capacity as an indication to obtain SGLT 2-expressing cells. The results calculated using these stably expressing cells are shown in Table 1 as method A.

Method B A plasmid expressing human SGLT2 protein was transfected into CHO-Kl cells using lipofectamine LTX (Invitrogen). Cells were cultured in the presence of 1000. mu.g/mL of geneticin to select drug-resistant strains, followed by screening in the system shown below with the sugar uptake ability as an indication to obtain SGLT 2-expressing cells. The results calculated using these stably expressing cells are shown in table 1, method B.

(3) Inhibition assay for sodium-dependent sugar uptake in stably expressing cells

The stably expressing cells prepared above were used in the following assay.

The pretreatment buffer (140 mM choline chloride, 2 mM KCl, 1 mM CaCl)₂, 1 mM MgCl₂10 mM HEPES/5 mM Tris, pH 7.4) was added in a volume of 200. mu.LStably expressing SGLTl cells, or 2 mL in volume for method A and 200. mu.L in volume for method B, were added to stably expressing SGLT2 cells and incubated for 20 minutes. The pretreatment buffer was removed, and a sample containing a test compound (1 mM methyl α -D-glucopyranoside [ alpha ], [ alpha ] -D-glucopyranoside ] was used¹⁴C]Methyl alpha-D-glucopyranoside), 140 mM NaCl, 2 mM KCl, 1 mM CaCl₂, 1 mM MgCl₂10 mM HEPES/5 mM Tris, p H7.4.4) in a volume of 75. mu.L for SGLT1 and SGLT2 in method B and 200. mu.L for SGLT2 in method A. The uptake reactions were carried out at 37 ℃ for 30 min (SGLTl) or 60 min (SGLT 2). After the reaction, the cells were washed with a washing buffer (10 mM methyl α -D-glucopyranoside, 140 mM choline chloride, 2 mM KCl, 1 mM CaCl)₂, 1 mM MgCl₂10 mM HEPES/5 mM Tris, pH 7.4) in a volume of 200. mu.L for SGLTl and SGLT2 in method B or 2 mL for SGLT2 in method A, followed by dissolution in 0.25M NaOH solution (75. mu.L for SGLTl and SGLT2 in method B or 400. mu.L for SGLT2 in method A). Liquid scintillator (Perkin Elmer) was added and mixed well with each sample before radioactivity was measured using a beta-ray analyzer. In the control group, the uptake buffer contained no test compound. In addition, another uptake buffer containing choline chloride instead of NaCl was prepared for baseline uptake.

For the determination of the IC50 values, the test compounds were prepared at 6 appropriate concentrations, which were used to measure the 50% inhibition of sugar uptake (IC 50 value) calculated relative to the sugar uptake value of the control group (100%). The results of the tests are shown in Table 1.

[ Table 1]

Table 1 shows that the compounds of the present invention have strong SGLT1 inhibitory activity and also have some, albeit weaker, SGLT2 inhibitory activity.

Test example 2 determination of hypoglycemic Effect in streptozotocin-induced diabetes model mice

(1) Preparation of diabetes model mouse

7-week-old SD/IGS mice (male, Charles River Laboratories Japan Inc.) were fasted for about 16 hours, and then 50 mg/kg Streptozotocin (STZ) was injected via tail vein under ether anesthesia to prepare diabetes model mice. Similarly, another group of 7-week-old SD/IGS mice was also injected with a 1.25 mmol/L solution of citric acid in physiological saline (1 mL/kg) via the tail vein under ether anesthesia to prepare normal control group mice. One week after injection of STZ or 1.25 citric acid in physiological saline, the mice were subjected to an oral glucose tolerance test.

(2) Oral Glucose Tolerance Test (OGTT)

After fasting for about 16 hours in diabetic model mice, each of the drug groups was orally administered (1 mg/kg) and dissolved in a 0.5% aqueous solution of sodium carboxymethylcellulose (CMC), while the control group was orally administered only a 0.5% aqueous CMC solution. The drugs used were compounds 10, 11 and 33, disclosed in WO07/136116, and compounds 1-2, 5-2, 6-2, 13-2 and 15-2 according to the invention. After administration, glucose solution (2 g/kg) was taken orally rapidly and blood was collected at 6 points: pre-dose (0 hours) and 0.25, 0.5, 1, 1.5 and 2 hours after oral administration.

Blood samples were collected from the tail vein of each mouse under non-anesthesia using a heparin-coated blood sample collection tube, and plasma was centrifuged. Plasma glucose concentration was measured using glucose CII-Test Wako (Wako Pure Chemical Industries, Ltd., Japan). To determine the extent of hypoglycemic events, the pre-administration blood glucose level was subtracted from each glucose level determined until one hour after oral administration of each drug group, and the results were analyzed by trapezoidal analysis to calculate the increase in area under the glucose curve (Δ AUC), which expresses a decrease in Δ AUC relative to the control group.

The results are shown in tables 2 and 3.

Detection example 3

(1) Change in Kidney concentration of the Compound disclosed in WO07/136116 one week after oral administration

SD/IGS mice (male, non-fasted, Charles River Laboratories Japan Inc.) aged 7 weeks were orally administered a 0.5% aqueous CMC solution prepared from Compound 10 or 33 (1 mg/kg) or Compound 11 (0.3 mg/kg). At 24, 72 and 168 hours post-dose, mice were anesthetized with ether and bled via the inferior vena cava, and the kidneys were excised after sacrifice. The tissue surface was washed with physiological saline, weighed, and homogenized with 4-fold volume of pure water under ice-cooling. Acetonitrile/methanol solution containing an internal standard was added to each homogenate to remove proteins, and the supernatant was then treated with LC-MS/MS (Applied Biosystems API 3000). Drug-derived ions generated by cationic electrospray ionization were detected by a selective reaction monitor. The peak areas of the resulting extracted ion chromatograms were analyzed by applying an internal standard method to calculate the drug concentration in the homogenate.

The internal standard for compounds 10 and 33 was (1S) -1, 5-anhydro-l- [5- (4-ethoxybenzyl) -2-methoxy-4-tolyl]-l-thio-D-sorbitol, ethyl-D₅And the internal standard for Compound 11 is Compound 11 (Trihydroxymethyl-D)₆;-C(CD₂OH)₃)。

The results are shown in Table 2.

(2) Renal concentration of the Compound of the present invention for three days with repeated oral administration

7-week-old SD/IGS mice (male, non-fasted, Charles River Laboratories Japan Inc.) were orally administered once daily with 0.5% aqueous CMC solutions prepared from compounds 1-2, 5-2, 6-2, 13-2 or 15-2 (3 mg/kg) of the present invention for three consecutive days. At the last 48 hours after administration, the mice were anesthetized with isoflurane and bled via the inferior vena cava, and the kidneys were excised after sacrifice. The tissue surface was washed with physiological saline, weighed, and homogenized with 4-fold volume of pure water under ice-cooling. The determination of the drug concentration in each homogenate was carried out by LC-MS/MS using the same method as in detection example 3 (1), using Compound 11 as an internal standard.

The results are shown in Table 3.

TABLE 2

Results of sugar tolerance test and renal concentration of prior art compounds

Denotes mean ± s.d. compound 11 was administered orally at 0.3 mg/kg.

^$Shows the AUC of glucose compared between Streptozotocin (STZ) -induced diabetic mice and control groups_o-1hThe oral dosage is 1 mg/kg.

^#The OGTT was obtained using Sprague-Dawley rats.

Compounds 10, 11 and 33 disclosed in WO2007/136116 are shown below.

[ solution 73]

TABLE 3

Results of sugar tolerance test and renal concentration of the Compound of the present invention

Denotes glucose AUC in comparison between STZ-induced diabetic mice and control group_o-1hThe oral dosage is 1 mg/kg.

^#Meaning of BLQIs lower than the quantitative value (5 ng/g).

The compounds disclosed in WO2007/136116 show a strong hypoglycemic effect in the glucose tolerance test administered orally at 1 mg/kg. However, their concentrations in the kidney did not substantially decrease after 1, 3 and 7 days after 1 mg/kg oral administration, and these compounds tended to accumulate in the kidney without being excreted 7 days after administration (table 2).

On the other hand, the compounds of the present invention were found to have a strong hypoglycemic effect, comparable to the compounds of the prior art described above. Furthermore, the compounds of the present invention showed the property of surprisingly not accumulating in the kidney in the following two days, given a continuous dose of 3 mg/kg for three days (table 3).

One possible reason for this difference is that the compounds of the present invention are hardly absorbed in the small intestine, and the absorbed compounds are also excreted without remaining in the kidney.

Therefore, the compound of the present invention has no tendency to accumulate in vivo, is unlikely to cause toxic or side effects due to continuous administration, and thus exhibits particularly superior properties in terms of pharmaceutical preparation.

Industrial applicability

The present invention can provide an agent for improving postprandial hyperglycemia, which has a strong SGLT1 inhibitory activity and does not tend to accumulate in the body. The present invention also contributes to improvement in human health, and treatment and prevention of postprandial hyperglycemia-induced diseases by effectively inhibiting SGLT1 activity promotes the beneficial development of the pharmaceutical industry.

Claims (7)

1. A 4-cumyl sorbitol compound represented by the following formula (I):

[ solution 1]

Wherein

R¹Represents a hydrogen atom or C_1-4The alkyl group of (a) is,

R²represents a hydrogen atom or a methyl groupThe mass of the balls is obtained by mixing the raw materials,

R³denotes "by an amino group or di-C_1-4Alkylamino radical substituted C_1-4An alkyl group "or a piperidinyl group, and

R⁴represents a hydrogen atom, or alternatively, R³And R⁴Together with the adjacent nitrogen atom form a piperidino or piperazino group, which may be substituted by C_1-4Alkyl groups or dimethylamino groups.

2. 4-cumyl sorbitol compound selected from the following structural formula:

[ solution 2]

。

3. 4-cumyl sorbitol compound selected from the following structural formula:

[ solution 3]

。

4. A pharmaceutical preparation comprising the 4-cumyl sorbitol compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 as an active ingredient.

5. An inhibitor of sodium ion-dependent glucose transporter 1(SGLT 1) activity, which comprises the 4-cumyl sorbitol compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

6. An agent for improving postprandial hyperglycemia, which comprises the 4-cumyl sorbitol compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 as an active ingredient.

7. A prophylactic or therapeutic agent for diabetes, which comprises the 4-cumyl sorbitol compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 as an active ingredient.