KR101837488B1

KR101837488B1 - Optically pure benzyl-4-chlorophenyl-c-glucoside derivative

Info

Publication number: KR101837488B1
Application number: KR1020140037632A
Authority: KR
Inventors: 프랭크 우
Original assignee: 수안주 파마 코포레이션 리미티드
Priority date: 2014-01-03
Filing date: 2014-03-31
Publication date: 2018-03-12
Also published as: CN106349201A; JP2015129106A; KR20150081220A; JP6008892B2; CN104761522B; CN104761522A; HK1207626A1; CN106349201B

Abstract

The present invention relates to optically pure benzyl-4-chlorophenyl-C-glucoside derivatives or pharmaceutically acceptable salts thereof, represented by the following Formulas (II) and (III) Methods for the preparation of medicaments for the treatment and / or prevention of diabetes (including insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus) or diabetes-related diseases (insulin resistant disease and obesity), pharmaceutical formulations and pharmaceutical compositions containing said compounds, 4-chlorophenyl-C-glucoside < / RTI > derivative as an inhibitor of sodium glucose transporters (SGLT)
(II)

or
(III)

Description

Optically pure benzyl-4-chlorophenyl-C-glucoside derivative {OPTICALLY PURE BENZYL-4-CHLOROPHENYL-C- GLUCOSIDE DERIVATIVE}

The present invention belongs to the field of pharmacy, and more particularly to an optically pure benzyl-4-chlorophenyl-C-glucoside derivative or a pharmaceutically acceptable salt thereof, a process for the preparation of said compound and its intermediates, Formulations and pharmaceutical compositions for the manufacture of medicaments for the treatment and / or prevention of diabetes (including insulin dependent diabetes and non-insulin dependent diabetes) or diabetes-related diseases (insulin resistant disease and obesity), and sodium glucose co- 4-chlorophenyl-C-glucoside derivative or a pharmaceutically acceptable salt thereof as an < RTI ID = 0.0 > pharmaceutically < / RTI >

Approximately 100,000,000 people worldwide are afflicted with type II diabetes, which is characterized by hyperglycemia caused by excessive hepatic glucose production and peripheral insulin resistance. The hyperglycemia is considered to be an important risk factor for the development of diabetic complications and is likely to be directly related to insulin secretory disturbances in the late stage of type II diabetes. Thus, normalization of insulin may be expected to improve blood glucose in patients with type II diabetes. Currently known diabetes therapeutic agents are usually insulin secretagogues or blood glucose normalizers such as sulfonylureas, glynides, thiazolidinediones and dimethylbiguanides, which tend to increase body weight, hypoglycemia and lactate acidosis And therefore there is a need to urge the development of safe and effective diabetic therapeutic drugs with new mechanisms of action.

In the kidney, glucose is freely filtered through the gonadal sphere (approximately 180 g / d), but can be transported and resorbed almost proactively in the proximal tubule. Among other things, two sodium-glucose transporters, SGLT-1 and SGLT-2, in particular SGLT-2, have a significant effect on glucose reabsorption. SGLT-2 is a transmembrane protein that is specifically expressed only in the S1 section of proximal tubules. One of his main physiological functions is to absorb blood glucose flowing through the renal tubules, accounting for 90% of the reabsorption. SGLT-2 transports at a ratio of 1: 1 sodium-glucose. The SGLT-2 inhibitor may inhibit the absorption of blood glucose in the renal tubule so that a large amount of glucose is excreted through the urine. SGLT-1 is expressed mainly in distal gut tubules, accounting for 10% of the reabsorption. SGLT-1 transports at a ratio of 2: 1 sodium-glucose. SGLT-1 is also found in ministers and other organizations. These transporters exert their function through Na + / ATPase pumps and transport them to the blood via Glucose transporter-2 (GLUT2). This indicates that the most potent drug target is the SGLT-2 transporter, on the one hand due to absolute reabsorption of glucose and on the other hand only in the kidney. In studies of urinary glucose from familial forms of nephropathy, the possibility of this pathway has been confirmed. Although urinary sugars from the familial nephrotic syndrome appear primarily as non-quantitative urinary glucose (about 10 to 120 g / d), patients have a good general condition and no chronic side effects to health are found. Such benign prostatic hyperplasia is mainly caused by genetic mutation of the SGLT-2 transporter, indicating that selective pharmacologic inhibition of SGLT-2 will not produce side effects except induction of urine sugar. One significant clinical benefit of the SGLT-2 inhibitor has been demonstrated to be low hypoglycemia potential. However, inhibition of SGLT-1 will lead to glucose-galactose uptake syndrome, which may also cause dehydration. It has also been demonstrated that the SGLT-1 inhibitor will delay the absorption of carbohydrates and induce gastrointestinal symptoms that are difficult for individuals to tolerate. Highly selective adult SGLT-2 inhibitors will not block the action of SGLT-1 that absorbs the glucose in intestinal transit and are therefore not prone to gastrointestinal symptoms. In addition, SGLT-1 is highly expressed in human myocardial tissue, and blockade of SGLT-1 may induce new or structural disease in cardiac function. Thus, the development of compounds with a high selectivity for SGLT-2 has significant implications for diabetes therapeutic drug studies.

The inhibitor of SGLT-2 acts on SGLT-2 transporter to inhibit reabsorption of renal glucose to treat hyperglycemia, thus providing a new therapeutic pathway for diabetes. Although this pathway can not act directly on the pathophysiology of type II diabetes, a decrease in blood glucose by increasing glucose excretion in the kidney may induce a net energy deficit, thereby promoting weight loss and indirectly improving obesity status . In these studies, these drugs have been found to have the potential effects of low hypoglycemia and weight loss when used in combination with existing blood glucose or insulin-reducing drugs. The SGLT-2 inhibitor is independent of the action of? -Cells and insulin resistance, and is therefore also effective in patients with general diabetes as well as in patients with experience of failing drug treatment such as beta-guanidine and DPP-4 inhibitors It has a therapeutic effect. Thus, the SGLT-2 inhibitor may be used in combination with a hypoglycemic drug such as a biguanide and a DPP-4 inhibitor in the future.

Among other things, patent documents such as WO 0127128 and US 2005209166 disclose a series of compounds as SGLT-2 inhibitors.

Applicants also disclosed a series of C-glucoside derivatives as SGLT-2 inhibitors in PCT application WO2013 / 000275A1, wherein compound 4 had a good inhibitory effect on SGLT-2 and good selectivity and had the following structure:

The compound 4 is a mixture of stereoisomers and has an asymmetric center. Thus, there are a number of optical isomers. Considering that many chiral compound drugs in the prior art have potential problems such as easily generated and unknown toxicity and side effects, reduced drug effectiveness, and difficulty in controlling quality, the risk for research and development of such chiral compound drugs Will increase significantly. Compared to the above chiral mixtures, the optically pure stereoisomers have advantages such as safer safety, lower probability of occurrence of toxicity and side effects, better stability, and ease of quality control, , Pharmacokinetics and toxicology, the development of single stereoisomers with high selectivity for SGLT-2, rapid onset, high efficacy, good safety, and good stability has led to subsequent drug research and development, Which is important in the quality control of production.

The present invention relates to optically pure benzyl-4-chlorophenyl-C-glucoside derivatives or a pharmaceutically acceptable salt thereof, a process for the preparation of said compound and its intermediates, pharmaceutical formulations and pharmaceutical compositions containing said compound, (SGLT) inhibitor in the manufacture of a medicament for the treatment and / or prophylaxis of diabetes-related diseases (including insulin-dependent diseases and obesity), such as diabetes-related diabetes and non-insulin dependent diabetes mellitus, 4-chlorophenyl-C-glucoside derivative or a pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

The present invention provides the following technical solutions:

1. A stereostructured compound of a compound represented by the formula (I): wherein the stereostructural compound is selected from the following formulas II, III, IV and V:

Formula I

(II)

(The above compound is obtained by reacting (2S, 3R, 4R, 5S, 6R) -2- (3- (4- ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)

(III)

(This compound was synthesized in the same manner as (1S, 3R, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)

Formula IV

(This compound was synthesized in the same manner as (1R, 3S, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)

Formula V

(The compound was prepared from (2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3R, 5S) -bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)

2. A process for the preparation of a compound represented by formula (II) as defined in technical solution 1, said process comprising the steps of:

In the above,

X represents fluoro, chloro, bromo or iodo,

G is a hydroxy protecting group selected from trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, Preferably trimethylsilyl.

The step

(1R, 3r, 5S) -bicyclo [3.1.0] hexan-3-ylmethanesulfonate) in an organic solvent (N-methylpyrrolidone, N, N- dimethylformamide, &Lt; / RTI > tetrahydrofuran, dioxane and acetonitrile); Adding the compound of formula a to the resulting mixture; The resulting mixture is then reacted at a temperature of from 0 캜 to 70 캜 to yield a compound of formula c;

The compound of formula (c)

To give a compound of formula d-1 and deprotecting it to produce a compound of formula d-2;

Reacting the compound of formula d-2 at a temperature between -78 [deg.] C and 30 [deg.] C to yield a compound of formula e;

The compound of formula e is purified to produce the compound represented by formula II.

As mentioned above, the compound of formula e can be purified, for example, according to the following method to produce the compound represented by formula II:

Subjecting the compound of formula e to a hydroxy protecting reaction to produce a compound of formula f;

The compound of formula (f) is deprotected to give the compound represented by formula (II): < EMI ID =

Formula f

In this formula,

G 'is selected from the group consisting of acetyl, trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, Butyryl, benzoyl and the like, preferably acetyl, pivaloyl, propionyl, isobutyryl or benzoyl.

The compounds represented by formula II above may be prepared according to methods as illustrated in the above schemes and / or according to other techniques well known to those skilled in the art, but it should be noted that these methods are not exclusive.

3. A process for the preparation of a compound represented by formula (III) as defined in technical solution 1, said process comprising the steps of:

In the above,

X represents fluoro, chloro, bromo or iodo,

The step

Dissolving the compound of formula a in an organic solvent (toluene, N, N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile, preferably toluene); Adding the compound of formula b to the product mixture; The resulting mixture is then reacted at a temperature of 0 ° C to 70 ° C to yield a compound of formula c ';

The compound of formula c '

To give a compound of formula d'-1 and deprotecting it to produce a compound of formula d'-2;

Reacting said compound of formula (D-2) at a temperature of from -78 [deg.] C to 30 [deg.] C to give a compound of formula e ';

The compound of formula e ' is purified to produce the compound represented by formula III.

As mentioned above, the compound of formula e 'can be purified, for example, according to the following method to produce the compound represented by formula III:

Subjecting the compound of formula e 'to a hydroxy protecting reaction to produce a compound of formula f';

The compound of formula f 'is deprotected to give the compound represented by formula III:

The formula f '

In this formula,

The compounds represented by formula III above may be prepared according to methods as illustrated in the above schemes and / or according to other techniques well known to those skilled in the art, but it should be noted that these methods are not exclusive.

4. An intermediate for a compound represented by formula II, wherein said intermediate is:

5. An intermediate for a compound represented by formula II, wherein said intermediate is:

In the above formula, X represents bromo or iodo.

6. An intermediate for a compound represented by formula III, wherein said intermediate is:

7. An intermediate for a compound represented by formula III, wherein said intermediate is:

In the above formula, X represents bromo or iodo.

As used herein, the "pharmaceutically acceptable salts" are alkali metal salts such as Na salts, K salts, Li salts and the like; Alkaline earth metal salts such as Ca salts, Mg salts and the like; Other metal salts such as Al salts, Fe salts, Zn salts, Cu salts, Ni salts, Co salts and the like; Inorganic base salts such as ammonium salts; Organic base salts such as tertiary-octylamine salts, dibenzylamine salts, morpholine salts, glucamineamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethyl Amine salts, triethylamine salts, dicyclohexylamine salts, N, N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenylethylamine salts, Tetramethylammonium salts, tris (hydroxymethyl) aminomethane salts and the like; Halides, such as hydrofluoride, hydrochloride, hydrobromide, hydroiodate and the like; Inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate and the like; Lower alkanesulfonates such as mesylate, trifluoromesylate, ethanesulfonate and the like; Aryl sulfonates such as benzene sulfonate, para-benzene sulfonate and the like; Organic acid salts such as acetate, maleate, fumarate, succinate, citrate, tartrate, oxalate, maleate, etc .; Amino acid salts such as glycine salts, trimethylglycine salts, arginine salts, ornithine salts, glutamate salts, aspartate salts and the like.

The invention also encompasses a pharmaceutical composition comprising a compound represented by formula (II) and / or a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or diluents , And may be prepared in any pharmaceutically acceptable dosage form. The pharmaceutical composition may be administered orally, parenterally, rectally, or pulmonally to a patient in need of such a composition. For oral administration, the compositions may be presented in conventional solid dosage forms, such as tablets, capsules, pills, granules, and the like; Or oral liquid formulations, for example, oral solutions, oral suspensions, syrups, and the like. In preparing the oral dosage form, suitable fillers, binders, disintegrants, lubricants, and the like may be added. In the case of parenteral administration, the composition may be formulated into a injectable preparation, for example, as an injection, as a sterile injectable powder, and as a concentrated injection. For the preparation of injectable preparations, additives may optionally be added depending on the nature of the drug. For rectal administration, the composition may be prepared as a suppository or the like. For pulmonary administration, the composition may be formulated as an inhalant, a spray, or the like. A physiologically effective amount per unit of the formulation, for example, 0.005g-10g, such as 0.005g, 0.01g, 0.05g, 0.1g, 0.125g, 0.2g, 0.25g, 0.3g, 0.4g, 0.5g And / or a compound represented by formula (III), such as a compound represented by formula (III), such as, for example, Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable salts.

The present invention also encompasses a pharmaceutical combination comprising a compound represented by formula (II) and / or a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, and another pharmaceutically active ingredient (s). The other pharmaceutically active ingredient may be one or more hypoglycemic agents. The hypoglycemic agent may be selected from the group consisting of citagliptine phosphate, valdagliptin, saxagliptin, allogliptin benzoate, linagliptin, teneligliptin, gemigliptin, metformin, penformin, exenatide, &Lt; / RTI >

The present invention also encompasses the use of a compound represented by formula (II) and / or a compound represented by formula (III) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of diabetes or a diabetes related disease. The diabetes includes insulin-dependent diabetes mellitus (type I) and non-insulin dependent diabetes mellitus (type II). The diabetes-related diseases include insulin-resistant diseases, obesity, and the like.

The present invention also relates to the use of the compounds of formula I in the treatment and / or prophylaxis of such diseases in mammals (including humans) which require the treatment and / or prevention of diabetes (including insulin dependent diabetes mellitus and non-insulin dependent diabetes mellitus) or diabetes related diseases (including insulin resistant diseases and obesity) Comprising administering to such mammal a therapeutically effective amount of a compound represented by formula (II) and / or a compound represented by formula (III) or a pharmaceutically acceptable salt thereof.

The compounds of the present invention have the following characteristics:

(1) The compounds of the present invention have a high selectivity for SGLT-2 and can be safely used for the above treatment and / or prophylaxis in mammals (including humans) in need of treatment and / or prevention of diabetes or diabetes related diseases .

(2) The compounds of the present invention have very-effective inhibition and significant hypoglycemic activity, rapid onset, low toxicity and low side effects, and high safety for SGLT-2.

(3) The compounds of the present invention have good physical-chemical properties, high purity, good stability and easily adjustable quality, and are industrially large-scale productions.

For convenience, well-known abbreviations used in this specification are included:

Me: methyl;

Et: ethyl;

Ms: methylsulfonyl;

Ac: acetyl;

TBS: tert-butyldimethylsilyl;

THF: tetrahydrofuran;

DMAP: 4-dimethylaminopyridine;

DIPEA: N, N-diisopropylethylamine;

n-BuLi: n-butyllithium;

TMS: trimethylsilyl.

In the present invention, room temperature refers to a temperature of from 10 캜 to 30 캜.

Hereinafter, the beneficial effects of the compounds of the present invention will be illustrated by analysis of pharmacological activity. However, it goes without saying that the beneficial effects of the present invention are not limited to the effects illustrated below.

Analysis 1: In vitro analysis of the pharmacological activity of the compounds of the present invention

Analysis sample:

Compounds represented by formulas (II), (III), (IV) and (V) as defined above in the present invention and as lab-produced, their chemical names and methods of preparation are disclosed in the following preparations.

Comparative compound 1: Laboratory-prepared (with reference to PCT application WO2013 / 000275A1), compound 4 as disclosed in PCT application WO2013 / 000275A1, the structure of which is as follows:

Compound 4, i.e. a compound represented by formula I.

The abbreviation (s) used in the following analysis has the following meanings:

NMG N-methyl-glucoseamine

KRH Krebs-Ringer-Henseleit

In in vitro analysis of the pharmacological activity of the compounds of the present invention, human SGLT-2 and SGLT-1 sequences were stably transfected into Chinese hamster ovary cells. The half-inhibitory concentration IC ₅₀ was determined by measuring the inhibition of sodium-dependent adsorption of [ ¹⁴ C] -labeled R-methyl-D-glucopyranoside (AMG) into cells.

Buffer ^{A (KRH-Na +):} 120 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl 2, 2.2 mM CaCl 2, 10 mM HEPES (1 pH 7.4 by tris mM).

Buffer A- (KRH-NMG): 120 mM NMG, 4.7 mM KCl, 1.2 mM MgCl 2, 2.2 mM CaCl 2, 10 mM HEPES (1 pH 7.4 by tris mM).

Buffer D: 120 mM NaCl, 4.7 mM KCl, 1.2 mM MgCl 2, 2.2 mM CaCl 2, 10 mM HEPES, 0.5 mM (1 pH 7.4 by tris mM).

Assay: Human SGLT-2 and SGLT-1 sequences were stably expressed in CHO cells. The cell culture was performed in a 96-well plate for 12 hours. The plate was washed three times with KRH-Na + (Buffer A) or KRH-NMG (Buffer A-) buffer, 200 μl / well. Buffer A or Buffer A-plus [ ¹⁴ C] -AMG (10 μCi / ml), buffer solution containing 100 μl / well was then added to the plate. The cell culture was performed at 37 캜 for 1 hour. The assay was then terminated by adding 100 [mu] l ice-cold buffer (Buffer D). The plate was washed five times. Followed by ice-cold lysis buffer (100 mM NaOH solution, 20 [mu] l / well) and centrifugation at 600 rpm for 5 minutes. Subsequently, a solution of Microscint 40 (80 [mu] l / well) was added, and centrifugation was performed at 600 rpm for 5 minutes. Finally, the radioactivity of [< ¹⁴ > C] -AMG was detected with MicroBeta Trilux (purchased from PerkinElmer Co. Ltd.) according to the flash counting method and the half- IC ₅₀ was calculated.

Results and Conclusion:

Inhibitory effect of the compounds of the present invention number SGLT-1 IC ₅₀ (nM) SGLT-2 IC ₅₀ (nM) Selectivity Comparative compound 1 2397.69 3.63 660.52 Compounds of formula II 17217.33 2.50 6886.93 The compound of formula III 3075.36 7.83 392.77 Compounds of formula IV 111470.59 1110.95 100.34 Compounds of formula V 75465.18 281.83 267.77

From the above Table 1, it was found that the compound represented by the formula (II) according to the present invention has a remarkable advantage with good selectivity as well as an inhibitory effect on SGLT-2 better than the comparative compound 1.

Analysis 2: In vivo pharmacokinetic analysis of the compounds of the invention in vivo

Anal animal: 6-8 week old male SD rats (purchased from Vital River Laboratories), 3 rats per compound, weight 200-240 g.

Analysis sample:

The compounds, as previously defined herein and as lab-produced, represented by formula II, their chemical names and methods of preparation are set forth in Example 1 below.

Compound 4, i.e. a compound represented by formula I.

COMPARATIVE COMPOUND 2: LABORATORY - COMPOUND 22 (as described in PCT Application WO2013 / 000275A1), PCT Application WO2013 / 000275A1, the structure of which is as follows:

Compound 22.

Solvent: 0.5% MC (methylcellulose) solution + 0.1% SDS (sodium dodecyl sulfate).

Analysis method:

Intragastric (PO): See Table 2

Administration of compounds in rat PK (pharmacokinetic) assays Animal sheep gender Route Dose (mg / kg) Volume (ml / kg) Concentration (mg / ml) 3 cock PO 10 5 2

Blood collection: 200 쨉 l of whole blood was collected at 0.17 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hr, 30 hr, 48 hr, 54 hr and 72 hr. The collected blood samples were centrifuged at 8000 rpm for 6 minutes at 4 DEG C in a low-temperature high-speed centrifuge (5415R, Eppendorf) to separate plasma. The separated plasma was stored in a refrigerator at -80 占 폚.

Plasma Sample Analysis:

20 [mu] l of plasma was carefully taken and 600 [mu] l of an internal standard MTBE (methyl tert-butyl ether) solution (containing 25 ng / ml of internal standard dipalmitoylphosphate) was added. The plasma was vortexed at 1500 rpm for 10 minutes and then centrifuged at 12000 rpm for 5 minutes. 400 [mu] l of the supernatant was taken and blown-dried with nitrogen gas. The dried material was redissolved in 200 [mu] l of redissolving solution (acetonitrile: water = 7: 3). The solution was vortexed for 10 minutes and analyzed by LC-MS / MS (API4000, Applied Biosystems).

The rat PK (pharmacokinetic) evaluation results (PO) PK parameters (units) T _1/2
(h) Tmax
(h) Cmax
(ng / ml) AUC _last
(h * ng / ml) AUC _inf
(h * ng / ml) Comparative compound 1 10.26 2 4143 69582 70279 Comparative compound 2 8.18 2 4977 69297 69392 Compounds of formula II 8.98 One 6383 92064 92123

T _1/2 represents half-life.

Tmax represents the time to maximum plasma concentration.

Cmax represents the maximum concentration in plasma.

AUC _last represents the area under the curve at time = 0 → t.

AUC _inf shows the area under the curve when time = 0 → ∞.

Conclusion: From the results shown in Table 3, it was found that the compound represented by Formula II according to the present invention had time to maximum concentration in short plasma and fast onset. Compared with the comparative compound 1 and the comparative compound 2, the compound represented by the formula II according to the present invention exhibited higher exposure and had a considerable difference, indicating that the compound represented by formula II according to the present invention has remarkable improvement .

The following preparations are intended to illustrate the invention and are not to be construed as limitations thereof. All technical solutions that can be performed on the basis of the above specification are within the scope of the present invention.

In the preparation examples, the starting materials used are commercially available, for example, from Alfa Aesar China (Tianjin) Co., Ltd., Sinopharm Chemical Co., Reagent Co., Ltd., Tianjin Fuyu Fine Chemical Co., Ltd., Shanghai Bangchen Chemical Co. Ltd., Ltd., Tianjin Guangxi Chemical Reagent Co., Ltd., Tianjin Guangfu Fine Chemical Co., Ltd., Tianjin Kemiou Chemical Reagent Co., Ltd. ). &Lt; / RTI >

Example 1: Preparation of (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S) -bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (Formula II)

(1) Preparation of 5-bromo-2-chlorobenzoyl chloride

5-Bromo-2-chlorobenzoic acid (270 g, 1.15 mol) was suspended in methylene chloride (2700 mL). To the resulting mixture was added N, N-dimethylformamide (1 mL), followed by dropwise addition of oxalyl chloride (288 mL, 3.46 mol) at 0 ° C. After completion of the dropwise addition, the mixture was warmed to 20 < 0 > C and reacted for 3 hours. The reaction mixture became clear and TLC (thin layer chromatography) indicated the completion of the reaction. The reaction mixture was evaporated by rotation at 30-35 [deg.] C to give the product which was used directly in the next reaction.

(2) Preparation of (5-bromo-2-chlorophenyl) (4-methoxyphenyl)

Anhydrous aluminum trichloride (155 g, 1.16 mol) was suspended in methylene chloride (2050 mL) under nitrogen protection. To the resulting mixture was added anisole (125 mL, 1.15 mol) in one batch at -5 ° C. After stirring for 20 min, a solution of 5-bromo-2-chlorobenzoyl chloride in methylene chloride (300 mL) was added dropwise to the mixture. The resulting mixture was allowed to react at -5 DEG C for 3 hours. TLC indicated completion of the reaction. The reaction mixture was poured into 2N hydrochloric acid. The product mixture was separated into an organic phase and an aqueous phase. The organic phase was washed twice with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to give a solid. Ethanol (150 mL) was added to the solid, and the resulting mixture was washed, starved for 30 minutes, and filtered. The filter cake was oven dried to yield 265 g of product in 71% yield.

(3) Preparation of 4-bromo-1-chloro-2- (4-methoxybenzyl) benzene

Methoxyphenyl) methanone (265 g, 0.81 mol) was dissolved in methylene chloride (515 mL) and acetonitrile (1030 mL). To the resultant mixture was added triethylsilane (352 mL, 2.22 mol). Boron trifluoride-diethyl etherate (273 mL, 2.22 mol) was then added dropwise to the resulting mixture at 0 < 0 > C under nitrogen protection. After completion of the dropwise addition, the resulting mixture was stirred for 20 minutes, allowed to warm to room temperature and reacted for 2 hours. TLC indicated completion of the reaction. Methyl tertiary-butyl ether (1.5 L) and saturated sodium bicarbonate solution (1.5 L) were added to the reaction mixture. The mixture was stirred for 30 minutes. The organic phase was separated, washed four times with saturated sodium bicarbonate solution, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to give an oily material. Ethanol was added to the oily material. The resulting mixture was stirred at room temperature for 30 minutes and then in an ice bath for 30 minutes. A large amount of solid was separated and filtered. The filter cake was dried to yield 226 g of product in 89% yield.

(4) Preparation of 4- (5-bromo-2-chlorobenzyl) phenol

4-Bromo-1-chloro-2- (4-methoxybenzyl) benzene (226 g, 0.73 mol) was dissolved in methylene chloride (2240 mL) under nitrogen protection with interception of light. The resulting mixture was slowly added dropwise to a solution of boron tribromide (357 g, 1.42 mol) in methylene chloride (1416 mL) at -78 <0> C. After completion of the dropwise addition, the reaction mixture was allowed to warm to room temperature and reacted for 2 hours. TLC indicated completion of the reaction. Water was slowly added dropwise to the reaction mixture in an ice-water bath. The methylene chloride phase was collected. The residual aqueous phase was extracted twice with methylene chloride (1 L). The organic phases were combined, washed three times with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to yield 210 g of product in 97% yield.

(5) Preparation of (lR, 3r, 5S) -bicyclo [3.1.0] hexan-3-ol

Diethylzinc (7.16 L, 7.14 mol) was added dropwise at 0 < 0 > C to methylene chloride (9 L). When the white vapors disappeared after completion of the dropwise addition, a solution of triflu or o acetic acid (816 g, 7.16 mol) in methylene chloride (1 L) was slowly added dropwise to the resulting mixture. After completion of the dropwise addition, the resulting mixture was stirred for 30 minutes. To this mixture was added dropwise a solution of methylene iodide (1918 g, 7.14 mol) in methylene chloride (1 L). After completion of the dropwise addition, the resulting mixture was stirred for 30 minutes. To this mixture was added dropwise a solution of cyclopent-3-en-1-ol (200 g, 2.38 mol) in methylene chloride (800 mL). After completion of the dropwise addition, the resulting mixture was allowed to warm to room temperature and reacted for 30 minutes. TLC indicated completion of the reaction. The reaction mixture was poured into saturated ammonium chloride. After stirring for 10 minutes, the mixture was separated into an organic phase and an aqueous phase. The aqueous phase was extracted once with methylene chloride (2 L). The organic phase was washed with saturated sodium sulphite, saturated sodium bicarbonate, and saturated sodium chloride and dried over anhydrous sodium sulfate. The residue was purified by column chromatography to give 112 g of product in 48% yield.

(6) Preparation of (lR, 3r, 5S) -bicyclo [3.1.0] hexan-3-ylmethanesulfonate

(112 g, 1.14 mol) was dissolved in methylene chloride (1250 mL) in an ice-water bath. To the resultant mixture was added triethylamine (174 g, 1.69 mol), followed by the slow addition of methylsulfonyl chloride (197 g, 1.72 mol). After completion of the dropwise addition, the resulting mixture was reacted at 0 占 폚 for 30 minutes. TLC indicated completion of the reaction. The reaction mixture was poured into water, which was separated into an organic phase and an aqueous phase. The organic phase was washed once with diluted hydrochloric acid, twice with water, and then with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to yield 138 g of product in 68% yield.

(7) Preparation of (lR, 3s, 5S) -3- (4- (5-bromo-2- chlorobenzyl) phenyloxy) bicyclo [3.1.0] hexane

(138 mg, 0.78 mol) was dissolved in N-methylpyrrolidone (2.1 L). To the resulting mixture was added 210 g (0.71 mol), cesium carbonate (462 g, 1.42 mol) and benzyltriethylammonium chloride (5.46 g, 24 mmol) Respectively. The resulting mixture was then stirred at room temperature for 10 minutes, warmed to 50 < 0 > C and allowed to react overnight. TLC indicated completion of the reaction. Water was added to the reaction mixture. The resulting mixture was then extracted twice with a mixed solution of petroleum ether and methyl tertiary-butyl ether (petroleum ether: methyl tert-butyl ether = 1: 1). The organic phases were combined, washed twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated by rotary evaporation. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 50: 1) to give 135 g of product in a yield of 50%.

_{Formula: C 19 H 18 BrClO; Mw} : 377.71

^{1 H-NMR (400MHz, CDCl} 3) δ: 7.28-7.21 (m, 3H), 7.07-7.05 (d, 2H), 6.82-6.78 (m, 2H), 4.42-4.35 (m, 1H), 3.98 ( s, 2H), 2.36-2.31 (m, 2H), 1.96-1.90 (m, 2H), 1.40-1.33 (m, 2H), 0.47-0.44 (m, 1H), 0.07-0.02 (m,

((Trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2 - Manufacture of onions

(85 g, 0.47 mol) was dissolved in THF (tetrahydrofuran) in tetrahydrofuran (10 mL) at -78 < 0 > ) (932 mL). To the resulting mixture was added N-methylmorpholine (405 mL, 4.78 mol). The resulting mixture was then cooled to -5 [deg.] C under nitrogen protection and TMSCl (trimethylsilane chloride) (360 mL, 4.78 mol) was added dropwise thereto. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 1 hour and at 35 DEG C for 5 hours. The mixture was then stirred overnight while maintaining the temperature at 25 < 0 > C. TLC indicated completion of the reaction. Toluene (200 mL) was added to the reaction mixture, and water (1 L) was added dropwise in an ice-water bath. The organic phase was collected, washed once with sodium hydrogenphosphate, once with water and once with saturated sodium chloride solution, dried and concentrated to yield 218 g of product in 100% yield.

(9R) -4S, 5S, 6R) -2- (3- (4 - (((1R, 3S, 5S) -Bicyclo [3.1.0] -Chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol

(135 g, 0.358 mol) was added dropwise to a solution of (1R, 3S, 5S) -3- (4- (5- bromo-2- chlorobenzyl) phenyloxy) bicyclo [3.1.0] hexane 813 ml) and toluene (813 ml). The resulting mixture was cooled to -78 < 0 > C and n-butyllithium (194 mL, 0.465 mol) was added dropwise thereto. After completion of the dropwise addition, the reaction mixture was stirred for 2 hours, sucked into the syringe and subsequently treated with (3R, 4S, 5R, 6R) -3,4,5-tri ((trimethylsilyl) Oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro-2H-pyran-2-one (218 g, 0.47 mol). The resulting mixture was stirred for 1 hour and a solution of methyl sulfonic acid (44.9 mL, 2.15 mol) in methanol (1.2 L) was added thereto. The mixture was stirred at -78 < 0 > C for 1 hour, warmed to room temperature and allowed to react overnight. TLC indicated completion of the reaction. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (2 L). The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to yield 173 g of product in 98% yield.

(10) (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3S, 5S) -Bicyclo [3.1.0] -Chlorophenyl) -6- (hydroxymethyl) -tetrahydro-2H-pyran-3,4,5-triol

(3R, 4S, 5S, 6R) -2- (3- (4 - ((lR, 3s, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) Pyrrol-3,4,5-triol (173 g, 0.352 mol) and triethylsilane (180 mL, 1.05 mol) were added to a solution of 2- In methylene chloride (2 L) at -78 < 0 > C. To the resulting mixture was slowly added dropwise boron trifluoride-diethyl etherate (134 mL, 1.05 mol). After completion of the dropwise addition, the mixture was reacted at -78 ° C for 1 hour. The reaction mixture was slowly warmed to room temperature and allowed to react for 1 hour. HPLC indicated completion of the reaction. Saturated sodium bicarbonate solution was added dropwise to the reaction mixture. The resulting mixture was extracted with ethyl acetate (1 L). The organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated by rotary evaporation to yield 143 g of product in 88% yield.

(11R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4 - ((lR, 3s, 5S) -bicyclo [3.1.0] hexane- Yl) oxy) benzyl) -4-chlorophenyl) -tetrahydro-2H-pyran-3,4,5-triyl triacetate

(3R, 4R, 5S, 6R) -2- (3- (4 - ((lR, 3s, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) ) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (143 g, 0.311 mol) was dissolved in methylene chloride (720 mL). To the resulting mixture was added pyridine (252 mL, 3.11 mol) and DMAP (4-dimethylaminopyridine) (1.9 g, 15.6 mmol) followed by dropwise addition of acetic anhydride (292 mL, 3.11 mol) in an ice bath. The reaction mixture was stirred at room temperature for 3 hours, quenched with water and extracted with ethyl acetate (1.5 L). The organic layer was washed three times with diluted hydrochloric acid, once with saturated sodium bicarbonate, with water, and with saturated sodium chloride, dried over anhydrous sodium sulfate and evaporated by rotary evaporation. The residue was recrystallized from ethanol to give 81 g of product in 42% yield.

(12) (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3S, 5S) -Bicyclo [3.1.0] -4-chlorophenyl) - (6-hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

(2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4 - ((lR, 3s, 5S) -bicyclo [3.1.0] (81 g, 0.129 mol) was dissolved in tetrahydrofuran (313 ml), methanol (470 ml), and methanol (470 ml) Was dissolved in a mixed solvent of water (156 ml). To the resultant mixture was added lithium hydroxide monohydrate (6.32 g, 150 mmol). The mixture was stirred at room temperature overnight. TLC indicated completion of the reaction. The solvent was removed from the reaction mixture by rotary evaporation. The residual reaction mixture was dissolved in ethyl acetate (400 mL). The organic phase was washed twice with aqueous saturated sodium chloride solution, aqueous KHSO ₄ solution and water, dried over anhydrous sodium sulfate and evaporated by rotary evaporation. The residue was purified by C18 reverse phase preparative chromatography to yield 54.2 g of the final product in 91% yield.

_{Formula: C 25 H 29 ClO 6 Mw} : 460.95 LC-MS (m / z): 478.3 [M + NH 4] +

^{1 H-NMR (400MHz, MeOD} ) δ: 7.35-7.26 (m, 3H), 7.08-7.06 (d, 2H), 6.76-6.74 (d, 2H), 4.45-4.41 (m, 1H), 4.10-4.00 (m, 3H), 3.31-3. 26 (m, 1H), 2.34-2.29 (m, 2H) , 1.87-1.81 (m, 2H), 1.37-1.33 (m, 2H), 0.43-0.42 (m, 1H), 0.11-0.10 (m, 1H).

Example 2: Preparation of (2S, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3R, 5S) -Bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (Formula III)

Preparation of (1R, 3R, 5S) -3- (4- (5-bromo-2-chlorobenzyl) phenyloxy) bicyclo [3.1.0] hexane

(29.7 g, 0.10 mol) was dissolved in toluene (450 mL) at room temperature under nitrogen atmosphere. To the resulting mixture was added sodium hydroxide (8 g, 0.20 mol), water (27 mL), (lR, 3r, 5S) -bicyclo [3.1.0] hexane- 3- yl methanesulfonate (step 5) - (6) (17.6 g, 0.10 mol) and benzyltriethylammonium chloride (1.05 g, 4.61 mmol) were successively added. The mixture was reacted at 70 DEG C for 2 hours. TLC indicated completion of the reaction. The reaction mixture was extracted with ethyl acetate (500 mL). The organic phase was dried and the solvent was extracted by rotary evaporation. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to give 10.1 g of product in 27% yield.

C ₁₉ H ₁₈ BrClO Mw: 377.71

^{1 H-NMR (400MHz, CDCl} 3) δ: 7.28-7.21 (m, 3H), 7.07-7.05 (d, 2H), 6.76-6.72 (d, 2H), 4.79-4.76 (m, 1H), 3.98 ( s, 2H), 2.22-2.16 (m, 2H), 2.05-2.01 (m, 2H), 1.35-1.31 (m, 2H), 0.62-0.58 (m, 1H), 0.51-0.46 (m,

(3R, 4S, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -Chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol

(1.5 g, 3.97 mmol) was dissolved in tetrahydrofuran (100 ml) and the mixture was stirred at room temperature for 3 hours. &Lt; / RTI > The resulting mixture was cooled to -78 < 0 > C under nitrogen protection. To the mixture was added n-butyllithium (2 mL, 4.8 mmol) dropwise. After completion of the dropwise addition, the resulting mixture was stirred at -78 < 0 > C for 1 hour. To this mixture was added a solution of (3R, 4S, 5R, 6R) -3,4,5-tri ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro -2H-pyran-2-one (3.0 g, 6.4 mmol). The resulting mixture was allowed to react for 1 hour while maintaining the temperature at -78 占 폚. A solution of methanesulfonic acid (3.8 g, 39.6 mmol) in methanol (50 mL) was then added dropwise to the reaction mixture. The resultant mixture was allowed to react for 0.5 hour while maintaining the temperature at -78 占 폚, followed by reaction at room temperature for 18 hours. The reaction mixture was quenched with an aqueous saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent and yield 1.5 g of product in 77% yield.

(3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -Chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

(3R, 4S, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) (1.40 g, 2.86 mmol) was dissolved in methylene chloride (40 mL) and acetonitrile (40 mL) at 0 < 0 & ). &Lt; / RTI > To the resultant mixture was added triethylsilane (1.0 g, 8.6 mmol). The mixture was stirred at room temperature and boron trifluoride-diethyl etherate (1.2 g, 8.45 mmol) was added dropwise thereto. After completion of the addition, the resulting mixture was allowed to react at room temperature for 16 hours. To the reaction mixture was added an aqueous saturated sodium bicarbonate solution (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent and yield 1.0 g of crude product in 76% yield.

(4R, 3R, 5S) -Bicyclo [3.1.0] hexane-3 (2R, 3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- -Yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate

(3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) ) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (1.0 g, 2.2 mmol) was dissolved in methylene chloride (40 mL). Pyridine (1.78 mL) and DMAP (13 mg) were added to the resulting mixture, and acetic anhydride (2.07 mL) was added dropwise in an ice bath. The reaction mixture was stirred at room temperature for 3 hours, quenched with water (10 mL) and separated into an organic and an aqueous phase. The aqueous phase was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to yield 400 mg of product in 29% yield.

(5S, 3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

(3R, 4R, 5S, 6S) -2- (acetoxymethyl) -6- (3- (4- (400 mg, 0.64 mmol) was dissolved in tetrahydrofuran (5 mL), water (5 mL), and methanol (5 mL) (5 mL) in a mixed solvent. To the resultant mixture was added lithium hydroxide monohydrate (107.5 mg, 2.56 mmol). The reaction mixture was stirred at room temperature for 2 hours. TLC indicated completion of the reaction. Solvent was collected by rotary evaporation. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give 200 mg of the final product in a yield of 68%.

The formula: C ₂₅ H ₂₉ ClO ₆ Mw: 460.95

^{1 H-NMR (400MHz, MeOD} ) d: 7.23-7.38 (m, 3H), 7.07 (m, 2H), 6.69 (m, 2H), 4.79 (m, 1H), 4.06-4.11 (m, 1H), 2H), 3.94 (m, 2H), 3.87 (m, 1H), 3.64-3.73 (m, 1.26-1.41 (m, 2H), 0.52-0.60 (m, 1H), 0.39-0.50 (m, 1H).

Example 3: (2R, 3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3s, 5S) -Bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (IV)

(1R, 3R, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl) -4 -Chlorophenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol

(5 g, 13.3 mmol) was dissolved in tetrahydrofuran (100 ml) and the mixture was stirred at room temperature for 3 hours. &Lt; / RTI > The resulting mixture was cooled to -78 < 0 > C under nitrogen protection. N-BuLi (6.7 mL, 15.8 mmol) was added dropwise to the mixture. After completion of the dropwise addition, the resulting mixture was stirred at -78 < 0 > C for 1 hour. To this mixture was added a solution of (3R, 4S, 5R, 6R) -3,4,5-tri ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetrahydro -2H-pyran-2-one (10 g, 21.4 mmol) in dichloromethane was added dropwise. The resulting mixture was allowed to react for 1 hour while maintaining the temperature at -78 占 폚. To the reaction mixture was then added a solution of methanesulfonic acid (12.7 g, 132 mmol) in methanol (60 mL). The resulting mixture was allowed to react at room temperature for 18 hours. The reaction mixture was quenched with an aqueous saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent and yield 4.5 g of product in 69% yield.

(3R, 4S, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) Yl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran-3,4,5-triol (4 g, 8.16 mmol) was dissolved in methylene chloride (30 mL) and acetonitrile ). &Lt; / RTI > To the resultant mixture was added triethylsilane (2.86 g, 24.6 mmol). The mixture was stirred at room temperature and boron trifluoride-diethyl etherate (3.43 g, 24.2 mmol) was added dropwise thereto. After completion of the addition, the resulting mixture was allowed to react at room temperature for 16 hours. To the reaction mixture was added an aqueous saturated sodium bicarbonate solution (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting crude product was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give 2 mg of product in 53% yield.

(3R, 3R, 4R, 5S, 6R) -2- (acetoxymethyl) -6- (3- (4- Yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate

(3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -bicyclo [3.1.0] hexan-3- yl) oxy) benzyl) ) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (1.0 g, 2.17 mmol) was dissolved in methylene chloride (20 mL). N, N-Diisopropylethylamine (2.8 g, 21.7 mmol), acetic anhydride (2.2 g, 21.7 mmol) and a catalytic amount of 4-dimethylaminopyridine (25 mg) were added to the resulting mixture. The reaction mixture was stirred at room temperature for 2 hours, washed with 1 N hydrochloric acid (15 mL) and separated into an organic and an aqueous phase. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 0.55 g of product in 40% yield.

(4R, 3R, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl) -2,3- -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

(2R, 3R, 4R, 5S, 6R) -2- (acetoxymethyl) -6- (3- (4- (0.55 g, 0.87 mmol) was dissolved in a mixed solvent of water, methanol and tetrahydrofuran (25 mL), and the mixture was stirred at room temperature for 2 hours. , 2: 2: 1). To the resultant mixture was added lithium hydroxide monohydrate (0.37 g, 8.7 mmol). The reaction mixture was stirred overnight at room temperature. Solvent was collected by rotary evaporation. The resulting mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting crude product was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give 0.27 mg of the final product in a yield of 67.5%.

The formula: C ₂₅ H ₂₉ ClO ₆ Mw: 460.95

^{1 H-NMR (400MHz, MeOD} ) d: 7.21-7.31 (m, 3H), 6.93-7.09 (m, 2H), 6.74-6.79 (m, 2H), 4.53-4.63 (m, 1H), 4.39-4.48 (m, 2H), 1.84 (m, 2H), 3.84 (m, ), 1.34 (m, 2H), 0.43 (m, IH), 0.10 (m, IH).

Example 4: (2R, 3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) -Bicyclo [3.1.0] ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (Formula V)

(1) Preparation of 2-chloro-5-iodobenzoyl chloride

2-Chloro-5-iodobenzoic acid (10.0 g, 35.3 mmol) was suspended in methylene chloride (200 mL). N, N-Dimethylformamide (0.05 mL) was added to the resulting mixture, followed by dropwise addition of oxalyl chloride (11.3 g, 89.0 mmol) at 0 ° C. After completion of the dropwise addition, the resulting mixture was allowed to warm to room temperature and stirred for 4 hours. The resulting clear solution was evaporated by rotary evaporation to remove the solvent and yielded 10.7 g of the product in 100% yield, which was used directly in the next reaction without purification.

(2) Preparation of (2-chloro-5-iodophenyl) (4-methoxyphenyl) methanone

2-Chloro-5-iodobenzoyl chloride (10.7 g, 35.5 mmol) was dissolved in methylene chloride (200 mL). The resulting mixture was cooled in an ice-water bath. Aluminum trichloride (10.4 g, 78.2 mmol) was added to the mixture, followed by the dropwise addition of a solution of anisole (4.2 g, 38.9 mmol) in methylene chloride (50 mL). After completion of the dropwise addition, the resulting mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was poured into ice water and quenched. 3 mol / L hydrochloric acid was added to the reaction mixture. The product mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (150 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 100) to give 12.0 g of product in 91% yield.

(3) Preparation of 1-chloro-4-iodo-2- (4-methoxybenzyl) benzene

Methoxyphenyl) methanone (12.0 g, 32.2 mmol) and triethylsilane (9.86 g, 84.8 mmol) were dissolved in acetonitrile (200 mL). To the resulting mixture was added boron trifluoride-diethyl etherate complex (13.7 g, 96.5 mmol) at 0 < 0 > C. After completion of the dropwise addition, the mixture was warmed to 70 DEG C and stirred for 3 hours. The mixture was then cooled to room temperature. The mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 100) to give 10.0 g of product in 87% yield.

(4) Preparation of 4- (2-chloro-5-iodobenzyl) phenol

(10.0 g, 27.9 mmol) was dissolved in methylene chloride (150 mL). Boron tribromide (21 g, 83.7 mmol) was added dropwise to the resulting mixture under cooling in an ice-water bath. After completion of the dropwise addition, the mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was quenched with saturated sodium bicarbonate solution and separated into an aqueous and an organic phase. The aqueous phase was extracted with methylene chloride (150 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 20) to give 8.5 g of product in 88% yield.

(5) Preparation of (4- (2-chloro-5-iodobenzyl) phenyloxy) tert-butyldimethylsilane

4- (2-Chloro-5-iodobenzyl) phenol (8.5 g, 24.7 mmol) and triethylamine (5.0 g, 49.5 mmol) were dissolved in methylene chloride (200 mL). To the resulting mixture was added tert-butyldimethylsilane chloride (5.6 g, 37.1 mmol) and 4- (dimethylamino) pyridine (305 mg, 2.5 mmol) at 0 ° C. After completion of the addition, the mixture was allowed to warm to room temperature and stirred for 18 hours. Water (100 mL) was added to the mixture. The resulting mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with methylene chloride (100 mL x 2). The organic phases were combined, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 100) to give 10.0 g of product in 88% yield.

(6) Synthesis of (3R, 4S, 5S, 6R) -2- (3- (4- ((tert- butyldimethylsilyl) oxy) benzyl) -4- chlorophenyl) -6- (hydroxymethyl) Preparation of 2-methoxytetrahydro-2H-pyran-3,4,5-triol

A solution of (4- (2-chloro-5-iodobenzyl) phenyloxy) tert-butyldimethylsilane (10.0 g, 21.8 mmol) in anhydrous tetrahydrofuran (80 mL) and toluene (80 mL) Gt; 78 C. < / RTI > To this solution was slowly added dropwise a solution of n-butyllithium in n-hexane (2.4 mol / L, 13.6 mL, 32.6 mmol). The resulting mixture was allowed to react at -78 < 0 > C for 2 hours and then warmed to -60 < 0 > C. To the reaction mixture was added a solution of (3R, 4S, 5R, 6R) -3,4,5-tri ((trimethylsilyl) oxy) -6 - (((trimethylsilyl) oxy) methyl) tetra -2H-pyran-2-one (15.3 g, 32.7 mmol) was added in one batch. The resultant mixture was reacted at -60 DEG C for 2 hours. To the reaction mixture was added dropwise a solution of methanesulfonic acid (14.6 g, 152.1 mmol) in methanol (50 mL). After completion of the dropwise addition, the resulting mixture was reacted at room temperature for 17 hours with stirring. The reaction mixture was quenched with saturated sodium bicarbonate solution and separated into an aqueous and an organic phase. The aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 9.0 g of crude product which was used directly in the next reaction without purification.

(7) Synthesis of (3R, 4S, 5S, 6R) -2- (4-chloro-3- (4- hydroxybenzyl) phenyl) -6- (hydroxymethyl) -2- methoxytetrahydro- -3,4,5-triol

Benzyl) -4-chlorophenyl) -6- (hydroxymethyl) -2- (4-methylpiperazin-1- Methoxytetrahydro-2H-pyran-3,4,5-triol (9.0 g) was dissolved in tetrahydrofuran (70 ml). Tetrabutylammonium fluoride trihydrate (22.1 g, 70 mmol) was added to the resulting solution. The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. Ethyl acetate (400 mL) and water (200 mL) were added to the mixture. The product mixture was separated into an aqueous phase and an organic phase. The organic phase was washed successively with water (200 mL x 3) and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 6.5 g of crude product which was used directly in the next step without purification Respectively.

(8) (3R, 4R, 5S, 6R) -2- (4-Chloro-3- (4- hydroxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro- Preparation of 5-triol

(4-chloro-3- (4-hydroxybenzyl) phenyl) -6- (hydroxymethyl) -2-methoxytetrahydro-2H-pyran- , 4,5-triol (6.5 g) and triethylsilane (4.03 g, 34.7 mmol) were dissolved in a mixed solvent of methylene chloride (100 ml) and acetonitrile (100 ml). To the resulting mixture was added dropwise a boron trifluoride-diethyl etherate complex (5.6 g, 39.5 mmol) at 0 ° C. After completion of the dropwise addition, the resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (250 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (methanol: methylene chloride = 0-1: 15) to give 3.8 g of product in 46% yield (total of 3 steps).

(9R) - (3R, 4R, 5S, 6R) -2- (3- (4- (((1R, 3R, 5S) -Bicyclo [3.1.0] -Chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

(3R, 4R, 5S, 6R) -2- (4-chloro-3- (4- hydroxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro- (3.8 g, 10 mmol) and (lR, 3r, 5S) -bicyclo [3.1.0] hexan-3- yl methanesulfonate (3.5 g, 20 mmol) were dissolved in toluene (100 mL) ). NaOH (1.0 g, 25 mmol) and benzyltriethylammonium chloride (114 mg, 0.5 mmol) were successively added to the resulting suspension. The resulting mixture was heated to 80 < 0 > C and allowed to react for 16 hours. The reaction mixture was cooled to room temperature. Water (50 mL) was added to the reaction mixture. The product mixture was separated into an aqueous phase and an organic phase. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5.0 g of crude product which was used directly in the next step without purification.

(10) (2R, 3R, 4R, 5S, 6R) -2- (acetoxymethyl) -6- (3- (4- Yl) oxy) benzyl) -4-chlorophenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate

(3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, 5S) Phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol (5.0 g) was dissolved in methylene chloride (50 ml). To the resulting mixture was added pyridine (7.9 g, 100 mmol) and 4- (dimethylamino) pyridine (122 mg, 1 mmol) followed by acetic anhydride (10.2 g, 100 mmol) in an ice bath. The mixture was allowed to warm to room temperature and stirred for 4 hours. Water was added to the mixture. The resulting mixture was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed successively with 1 mol / L hydrochloric acid (150 mL x 3), saturated sodium bicarbonate solution (150 mL) and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-1: 4) to give 350 mg of the product in a yield of 5.6% (total of 2 steps).

(11R, 3R, 4R, 5S, 6R) -2- (3- (4 - (((1R, 3R, -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol

(2R, 3R, 4R, 5S, 6R) -2- (acetoxymethyl) -6- (3- (4- (350 mg, 0.56 mmol) was dissolved in water, methanol, and tetrahydrofuran (1: 2: 2, 25 ml) in a mixed solvent. To the resultant mixture was added LiOH 占₂ 2O (118 mg, 2.8 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. Water (20 mL) was added to the resulting concentrate. The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (methanol: methylene chloride = 0-1: 15) to give 140 mg of product in a yield of 54.7%.

The formula: C ₂₅ H ₂₉ ClO ₆ Mw: 460.95

^{1 H-NMR (400MHz, MeOD} ) δ: 7.29-7.31 (m, 3H), 7.04-7.07 (m, 2H), 6.68-6.71 (m, 2H), 4.77-4.81 (m, 1H), 4.57-4.61 (m, 1 H), 3.63-3.68 (m, 1H), 4.15-4.19 (m, 1H), 3.98-4.05 (4H, m), 3.92-3.93 , 2.16-2.21 (m, 2H), 1.94-1.97 (m, 2H), 1.24-1.34 (m, 2H), 0.54-0.56 (m, 1H), 0.39-0.49 (m, 1H).

Claims

Claims 1. A compound represented by the formula < RTI ID = 0.0 > (II) < / RTI &
(II)

(The above compound is obtained by reacting (2S, 3R, 4R, 5S, 6R) -2- (3- (4- ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol.

A process for the preparation of a compound represented by formula (II), comprising the steps of:

(The above compound is obtained by reacting (2S, 3R, 4R, 5S, 6R) -2- (3- (4- ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)
Dissolving the compound of formula b in an organic solvent; Adding the compound of formula a to the resulting mixture; The resulting mixture is then reacted at a temperature of from 0 캜 to 70 캜 to yield a compound of formula c;
The compound of formula (c)

To give a compound of formula d-1 and deprotecting it to produce a compound of formula d-2;
Reacting the compound of formula d-2 at a temperature between -78 [deg.] C and 30 [deg.] C to yield a compound of formula e;
The compound of formula e is purified to give the compound represented by formula II

,

,

,

,

,

In the above,
X represents fluoro, chloro, bromo or iodo,
G represents a hydroxy protecting group selected from trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl and trimethylsilylethyl .

3. The method of claim 2,
Wherein the organic solvent is selected from N-methylpyrrolidone, N, N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile.

3. The method of claim 2,
Process for the preparation of compounds represented by formula (II) wherein the compound of formula (e) is purified by the following steps to produce the compound represented by formula
Subjecting the compound of formula e to a hydroxy protecting reaction to produce a compound of formula f;
The compound of formula (f) is deprotected to give the compound represented by formula (II): < EMI ID =
Formula f

In this formula,
G 'is selected from the group consisting of acetyl, trimethylsilyl, triethylsilyl, benzyl, para-methoxybenzyl, para-nitrobenzyl, pivaloyl, allyl, methoxymethyl, benzyloxymethyl, trimethylsilylethyl, Butyryl, and benzoyl.

A process for the preparation of compounds represented by formula (III), comprising the steps of:

(This compound was synthesized in the same manner as (1S, 3R, 5S) -bicyclo [3.1.0] hexan-3-yl) oxy) benzyl ) -4-chlorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3,4,5-triol)
Dissolving the compound of formula (a) in an organic solvent; Adding the compound of formula b to the product mixture; The resulting mixture is then reacted at a temperature of 0 ° C to 70 ° C to yield a compound of formula c ';
The compound of formula c '

To give a compound of formula d'-1 and deprotecting it to produce a compound of formula d'-2;
Reacting said compound of formula (D-2) at a temperature of from -78 [deg.] C to 30 [deg.] C to give a compound of formula e ';
The compound of formula e ' is purified to produce the compound represented by formula III

,

,

,

,

,

6. The method of claim 5,
Wherein the organic solvent is selected from toluene, N, N-dimethylformamide, tetrahydrofuran, dioxane and acetonitrile.

6. The method of claim 5,
A process for the preparation of compounds represented by formula (III) wherein the compound of formula (e ') is purified by the following steps to yield the compound represented by formula (III)
Subjecting the compound of formula e 'to a hydroxy protecting reaction to produce a compound of formula f';
The compound of formula f 'is deprotected to give the compound represented by formula III:
The formula f '

3. The method of claim 2,
Wherein G is trimethylsilyl. &Lt; RTI ID = 0.0 > 11. < / RTI >

The method of claim 3,
Wherein the organic solvent is N-methyl pyrrolidone.

5. The method of claim 4,
Wherein G 'represents a hydroxy protecting group selected from acetyl, pivaloyl, propionyl, isobutyryl and benzoyl.

6. The method of claim 5,
Wherein G is trimethylsilyl. &Lt; RTI ID = 0.0 > 11. < / RTI >

The method according to claim 6,
RTI ID = 0.0 > (III) < / RTI > wherein said organic solvent is toluene.

8. The method of claim 7,
Wherein G 'represents a hydroxy protecting group selected from acetyl, pivaloyl, propionyl, isobutyryl and benzoyl.

As intermediates for the compounds represented by formula II,

Lt; / RTI >

As intermediates for the compounds represented by formula II,

(Wherein X is bromo or iodo).

A pharmaceutical composition comprising a compound represented by formula (II) as defined in claim 1, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or diluents, A pharmaceutical composition for the treatment or prevention of diabetes related diseases.

17. The method of claim 16,
Wherein the pharmaceutical composition further comprises at least one hypoglycemic agent and wherein the hypoglycemic agent is selected from the group consisting of citagliptin phosphate, valdagliptin, saxagliptin, allogliptin benzoate, linagliptin, teneligliptin, gemigliptin, metformin , &Lt; / RTI > phenorphin, exenatide, and liraglutide, for the treatment or prevention of diabetes or diabetes related diseases.

Use of a compound represented by formula (II) or a pharmaceutically acceptable salt thereof as defined in claim 1 in the manufacture of a medicament for the treatment or prevention of diabetes mellitus or diabetes-related diseases in mammals.

19. The method of claim 18,
Wherein said diabetes is insulin dependent diabetes or non-insulin dependent diabetes.

19. The method of claim 18,
Wherein said diabetes-related disease is insulin-resistant disease or obesity.

19. The method of claim 18,
Wherein said mammal is a human.