CN111840271A - New application of glycoside derivatives - Google Patents

Abstract

The invention belongs to the field of chemical medicines, and particularly relates toA new use of glycoside derivatives is provided. The glucoside derivative is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:

formula I. The novel glycoside derivative provided by the invention has a treatment effect on type II diabetes, and compared with the prior art, the glycoside derivative has an excellent treatment effect on type II diabetes no matter in high, medium and low doses.

Description

New application of glycoside derivatives

Technical Field

The invention belongs to the field of chemical medicines, and particularly relates to a new application of a glycoside derivative.

Background

Diabetes mellitus is an endocrine metabolic disease in which the metabolism of sugar, fat and protein is disturbed due to insufficient relative or absolute secretion of insulin in the body or a decrease in its biological effects. The international diabetes association (IDF) predicts that the number of diabetics will reach 5.9 billion worldwide in 2035 years. Diabetes is classified into type I diabetes and type II diabetes; type I diabetes, an organ-specific autoimmune disease, exists for a lifetime, and the existing treatment methods mainly involve daily insulin injection and diet control, which causes great pain to patients; in recent years, many new breakthroughs are made for the treatment of type I diabetes, such as chemical drug therapy and the like; type II diabetes is a chronic metabolic disease characterized primarily by relative insufficiency of insulin and hyperglycemia, and can induce a series of complications. Because the pathogenesis is complex and the course of disease is long, the current therapeutic drugs are difficult to control the blood sugar level, so that a novel hypoglycemic drug with a brand-new action mechanism is urgently needed clinically. At present, common II type diabetes mellitus treatment medicines comprise sulfonylureas, alpha-carbon glycosidase inhibitors, biguanides, insulin and the like, and although the effects of the sulfonylureas, the alpha-carbon glycosidase inhibitors, the biguanides, the insulin and the like on controlling blood sugar are good, a plurality of adverse reactions exist. Therefore, researchers are still searching for and developing therapeutic drugs with novel action mechanisms and small toxic and side effects.

Studies have shown that healthy adults have about 180g of glucose per day filtered by the glomeruli, with > 99% of the glucose reabsorbed from the tubules. Under the condition of hyperglycemia, sodium-glucose cotransporters (SGLTs) are saturated, a large amount of glucose is discharged with urine, the SGLTs are currently used as hot treatment targets of diabetes, and the number of human SGLT protein families is expanded to 12: SGLT 1-SGLT 6 and another 6 SLC5A proteins, of which SGLT-1 and SGLT-2 play a dominant role. The main function of SGLT2 is to reabsorb glucose in renal tubules, while the main function of SGLT1 is to absorb glucose from the stomach and intestine and distribute it in multiple organs such as heart and brain, but the inhibition of SGLT1 may cause serious side effects such as gastrointestinal problems such as diarrhea, so that the research of SGLT1 inhibitors is slow and the development of SGLT-2 inhibitors is rapid until now. There are 6 SGLT-2 inhibitors already on the market abroad, but the study is in clinical research stage at home. In view of the above, the market is in need of developing novel and highly effective drugs as SGLT-2 target inhibitors for treating type I and type II diabetes.

Disclosure of Invention

In order to solve the technical problems, the invention provides a glucoside derivative, and a preparation method and application thereof.

The first purpose of the invention is to provide a glycoside derivative, which is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:

wherein A is oxygen, - (CH)₂)_m-, or-NH-; m is 1, 2, or 3;

b is oxygen atom or sulfur atom;

R₁，R₂，R₃，R₄，R₅，R₆independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH₂-aryl, -OCH₂Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen, -CN, alkoxyalkoxy or-NR₇R_7aOr contains 1-4 of N, O, S, SO and/or SO₂3-14 membered heterocyclic ring of the heteroatom(s);

wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxy, cyano, alkoxy, or nitro;

the R is₇、R_7aIndependently a hydrogen atom or an alkyl group.

Among the above glycoside derivatives, as a preferred embodiment, in the compound represented by the formula I, the R group₂Is hydrogen, hydroxy, -O-aryl, -OCH₂Aryl, alkoxy, alkyl, aryl, heteroaryl, -CF₃Or a halogen.

Among the above glycoside derivatives, as a preferred embodiment, in the compound represented by the formula I, the R group₄，R₅Independently hydrogen, hydroxy, alkoxy, -O-aryl, -OCH₂Aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen, or-CN; r₄，R₅The same or different.

Among the above glycoside derivatives, as a preferred embodiment, in the compound represented by the formula I, the R group₆Is hydrogen, hydroxy, carboxy, alkoxy, alkyl, cycloalkyl, -CF₃、-OCHF₂、-OCF₃Halogen, or-CN.

Among the glycoside derivatives, as a preferred embodiment, the compound represented by formula I is (2S,3R,4R,5S,6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol -3,4, 5-triol, (2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxyethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4- (2,4, 5-trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-isopropoxybenzyl) -2- (trifluoromethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol, or (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol.

The second purpose of the invention is to provide a preparation method of the glycoside derivative, wherein the compound shown in the formula I is prepared by the deprotection reaction of the compound shown in the formula II;

wherein A is oxygen, - (CH)₂)_m-, or-NH-; m is 1, 2, or 3;

b is oxygen atom or sulfur atom;

R₁，R₂，R₃，R₄，R₅，R₆independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH₂-aryl, -OCH₂Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen, -CN, alkoxyalkoxy or-NR₇R_7aOr contains 1-4 of N, O, S, SO and/or SO₂3-14 membered heterocyclic ring of the heteroatom(s);

R₉is TMS-, Bn-, Ac-, THP-, MOM-, or TBDMS-;

wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxy, cyano, alkoxy, or nitro;

the R is₇、R_7aIndependently a hydrogen atom or an alkyl group.

In the above production method, as a preferred embodiment, the compound represented by the formula II is produced from a compound represented by the formula III;

wherein A is oxygen, - (CH)₂)_m-, or-NH-; m is 1, 2, or 3;

b is oxygen atom or sulfur atom;

R₁，R₂，R₃，R₄，R₅，R₆Independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH₂-aryl, -OCH₂Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen, -CN, alkoxyalkoxy or-NR₇R_7aOr contains 1-4 of N, O, S, SO and/or SO₂3-14 membered heterocyclic ring of the heteroatom(s);

R₉is TMS-, Bn-, Ac-, THP-, MOM-, or TBDMS-;

wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxy, cyano, alkoxy, or nitro;

the R is₇、R_7aIndependently a hydrogen atom or an alkyl group.

In the above preparation method, as a preferred embodiment, the compound represented by the formula III is prepared by reacting the compound represented by the formula IV with the compound represented by the formula V;

wherein A is oxygen, - (CH)₂)_m-, or-NH-; m is 1, 2, or 3;

b is oxygen atom or sulfur atom;

R₁，R₂，R₃，R₄，R₅，R₆independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH₂-aryl, -OCH₂Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen, -CN, alkoxyalkoxy or-NR₇R_7aOr contains 1-4 of N, O, S, SO and/or SO₂3-14 membered heterocyclic ring of the heteroatom(s);

R₈is-H, -F, -Cl, -Br, -I, -OMs, -OTs, -OTf;

R₉is TMS-, Bn-, Ac-, THP-, MOM-, or TBDMS-;

wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxy, cyano, alkoxy, or nitro;

the R is₇、R_7aIndependently a hydrogen atom or an alkyl group.

The third purpose of the invention is to provide the application of the glucoside derivative in the preparation of medicines for preventing and/or treating type II diabetes.

The fourth purpose of the invention is to provide an application of the glucoside derivative in preparing a medicament for preventing and/or treating high-fat high-sugar food-induced type II diabetes.

The fifth object of the present invention is to provide a pharmaceutical composition of the above glycoside derivatives, which comprises: the compound shown in the formula I or pharmaceutically acceptable salt thereof is used as an active ingredient and at least one pharmaceutically acceptable auxiliary material; preferably, the composition is administered orally, by injection, transdermally, nasally, mucosally, and by inhalation; more preferably, the composition is in a general dosage form, sustained release, controlled release, localized or immediate release dosage form.

Compared with the prior art, the invention has the following technical effects:

1. the invention provides a novel glycoside derivative which has a treatment effect on type II diabetes mellitus, and compared with the prior art, the glycoside derivative has an excellent treatment effect on type II diabetes mellitus no matter in high, medium and low doses.

2. The preparation method of the glycoside derivative adopts cheap and easily-obtained chemical products as starting raw materials, and has higher synthesis yield in each step, so the preparation method has lower production cost and is more suitable for industrial production.

Drawings

FIG. 1 is a hydrogen spectrum of (2S,3R,4R,5S,6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 1);

FIG. 2 is a hydrogen spectrum of (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 2);

FIG. 3 is a hydrogen spectrum of (2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 3);

FIG. 4 is a hydrogen spectrum of (2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 4).

Detailed Description

The glycoside derivatives of the present invention, and the preparation and use thereof, will be described with reference to the following examples. It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. It should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.

A glycoside derivative is a compound represented by formula I or a pharmaceutically acceptable salt thereof:

wherein A is oxygen, - (CH)₂)_m-, or-NH-; m is 1, 2, or 3;

b is oxygen atom or sulfur atom;

R₁，R₂，R₃，R₄，R₅，R₆independently hydrogen, hydroxy, carboxy, alkoxy (illustratively, alkoxy is C1-C6 alkyloxy; C1-C6 alkyloxy is illustratively methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy, etc.), -O-aryl (illustratively, -O-aryl is

Etc.), -O-heteroaryl (-O-heteroaryl is illustratively

Etc.), -OCH₂-aryl (-OCH)₂Aryl is illustratively PhCH₂O-、

Etc.), -OCH₂-heteroaryl (-OCH)₂Heteroaryl is illustratively

Etc.), alkyl groups (illustratively, alkyl groups are C1-C6 chain alkyl groups; C1-C6 chain alkyl groups include straight or branched chain alkyl groups, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl, and the like), cycloalkyl groups (illustratively, cycloalkyl groups are C3-C6 cycloalkyl groups; C3-C6 cycloalkyl includes substituted or unsubstituted cycloalkyl, illustratively cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like,

Cyclopentyl, or cyclohexyl, etc.), aryl (illustratively, aryl is phenyl, p-methylphenyl, p-fluorophenyl, o-chlorophenyl, m-methoxyphenyl, or

Etc.), heteroaryl (illustratively, heteroaryl is

Etc.), -CF₃、-OCHF₂、-OCF₃Halogen (illustratively, halogen is fluorine, chlorine, bromine, or iodine), -CN, alkoxyalkoxy (illustratively, alkoxyalkoxy is methoxymethoxy, ethoxymethoxy, ethoxyethoxy, n-propoxymethoxy,isopropoxymethoxy, n-propoxyethoxy, isopropoxyethoxy, or

Etc.), an ester group (illustratively, an ester group is

Etc.) or-NR₇R_7a(illustratively, -NR)₇R_7aIs amino,

Etc.) or contain 1 to 4 radicals of N, O, S, SO and/or SO₂The heteroatom of (a) is a 3-to 14-membered heterocyclic ring (illustratively, is

Etc.);

the R is₇、R_7aIndependently a hydrogen atom or an alkyl group (illustratively, an alkyl group is a C1-C6 chain alkyl group; C1-C6 chain alkyl group includes a straight-chain or branched-chain alkyl group, illustratively, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, or an isohexyl group, etc.);

wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxy, cyano, alkoxy, or nitro.

Preferably, R₂Is hydrogen, hydroxy, -O-aryl, -OCH₂Aryl, alkoxy, alkyl, aryl, heteroaryl, -CF₃Or a halogen.

Preferably, R₄，R₅Independently hydrogen, hydroxy, alkoxy, -O-aryl, -OCH₂Aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen, or-CN; r₄，R₅The same or different.

Preferably, R₆Is hydrogen, hydroxy, carboxy, alkoxy, alkyl, cycloalkyl, -CF₃、-OCHF₂、-OCF₃Halogen, or-CN.

The preparation method of the glycoside derivative comprises the following steps that the compound shown in the formula I is prepared from the compound shown in the formula II through deprotection reaction;

Wherein A is oxygen, - (CH)₂)_m-, or-NH-; m is 1, 2, or 3;

b is oxygen atom or sulfur atom;

R₁，R₂，R₃，R₄，R₅，R₆independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH₂-aryl, -OCH₂Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen, -CN, alkoxyalkoxy or-NR₇R_7aOr contains 1-4 of N, O, S, SO and/or SO₂3-14 membered heterocyclic ring of the heteroatom(s);

R₉is TMS- (trimethylsilyl), Bn- (benzyl), Ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (t-butyldimethylsilyl);

the R is₇、R_7aIndependently a hydrogen atom or an alkyl group;

wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxy, cyano, alkoxy, or nitro.

Illustratively, when R is₉When TMS-or TBDMS-, the deprotection reagent is TBAF; when R is₉When Bn-, the deprotection reaction condition is H₂/Pd-C、H₂Pt-C, or H₂/Pd(OH)₂-C, etc.; when R is₉When Ac-, the deprotection reaction condition is strong alkali condition (such as sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, etc.) or strong acid condition; when R is₉When THP-or MOM-, take off The reaction conditions are acidic conditions (e.g., aqueous hydrochloric acid, ethyl hydrogen chloride acetate solution (HCl (g)/EtOAc), and methanol hydrogen chloride solution (HCl (g)/CH)₃OH), ethanolic hydrogen chloride solution (HCl (g)/EtOH), or dioxane hydrogen chloride solution (HCl (g)/dioxane).

Further, the compound shown in the formula II is prepared from the compound shown in the formula III:

wherein A is oxygen, - (CH)₂)_m-, or-NH-; m is 1, 2, or 3;

b is oxygen atom or sulfur atom;

R₁，R₂，R₃，R₄，R₅，R₆independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH₂-aryl, -OCH₂Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen, -CN, alkoxyalkoxy or-NR₇R_7aOr contains 1-4 of N, O, S, SO and/or SO₂3-14 membered heterocyclic ring of the heteroatom(s);

R₉is TMS-, Bn-, Ac-, THP-, MOM-, or TBDMS-;

wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxy, cyano, alkoxy, or nitro;

the R is₇、R_7aIndependently a hydrogen atom or an alkyl group.

Illustratively, the reaction conditions for preparing the compound of formula II from the compound of formula III are BF₃.Et₂O。

Further, the compound shown in the formula III is prepared by reacting the compound shown in the formula IV with the compound shown in the formula V;

wherein A is oxygen, - (CH)₂)_m-, or-NH-; m is 1, 2, or 3;

b is oxygen atom or sulfur atom;

R₁，R₂，R₃，R₄，R₅，R₆independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -OCH₂Aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen, -CN, or-NR₇R_7aOr contains 1-4 of N, O, S, SO and/or SO₂3-14 membered heterocyclic ring of the heteroatom(s);

R₈is-H, -F, -Cl, -Br, -I, -OMs, -OTs, -OTf;

R₉is TMS-, Bn-, Ac-, THP-, MOM-, or TBDMS-;

wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxy, cyano, alkoxy, or nitro;

the R is₇、R_7aIndependently a hydrogen atom or an alkyl group.

Illustratively, the reaction reagent for preparing the compound shown in the formula III from the compound shown in the formula IV and the compound shown in the formula V is LDA (lithium diisopropylamide), n-BuLi (n-butyllithium) or the like.

The reaction was carried out under conventional reaction conditions, although the conditions in the examples are not specified. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

Example 1 preparation of compound 1: (2S,3R,4R,5S,6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 1-3(1- (4-Ethoxyphenoxy) -3, 5-difluorobenzene)

100g of p-bromophenylether (compound 1-1, 496mmol,1eq) and 97g of 3, 5-difluorophenol (compound 1-2, 746mmol,1.5eq) were added to 1000mL of dioxane, and Cs was added to the above solution in this order at 20 ℃₂CO₃324g (994mmol,2eq), CuI 28.4g (149.2mmol,0.3eq), isobutyl nitrite 30.8g (298mmol,0.6eq), and stirring at 100 ℃ for 12 h. Cooling to 20 ℃ after complete reaction, then carrying out reduced pressure distillation to obtain a concentrate, extracting the concentrate by using water-petroleum ether, collecting petroleum ether phase, and carrying out reduced pressure distillation to obtain a crude product; the crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 61.6g of pure compounds 1-3 as colorless oil in 24.8% yield.

(2) Preparation of intermediate Compounds 1-5

Collecting compound 1-323.8 g (95.1mmol,1.0eq), adding 165.0mL redistilled tetrahydrofuran, at-70 deg.C under N₂71.3mL (2.0M,1.5eq) of a solution of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution, and the above mixture was stirred at-70 ℃ for 0.5h under nitrogen, followed by addition of 1-451.2 g (95.1mmol,1.0eq) of a solution of compound in tetrahydrofuran (redistilled THF, 100.0mL) dropwise and stirring at-70 ℃ for 1h under nitrogen. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 46.0g of pure compound 1-5 as a colorless oil in a yield of 61.3%.

(3) Preparation of intermediate Compounds 1-6

Weighing 1-546.0 g (59.2mmol,1.0eq) of compound, adding 320.0mL of dichloromethane, and adding into the solution at 20 deg.C under nitrogenEt was added₃SiH 8.2g (70.0mmol,1.2 eq); cooling to 0 deg.C, then adding BF dropwise₃.Et₂O5.0g (70.0mmol,1.2eq), heated to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 200.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 1:0 to 10:1 gave 26.0g of pure compound 1-6 as a colorless oil in a yield of 57.7%.

(4) Preparation of the aimed Compound 1((2S,3R,4R,5S,6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

Weighing 1-626.0 g (33.6mmol,1.0eq), adding 200.0mL methanol, adding 15.0g Pd/C (active substance content 10%) into the solution under argon, vacuumizing the reaction system, filling hydrogen, and reacting at 50 ℃ under 50psi hydrogen for 24 h. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 50mm 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 30% -80%, 20min) to give 4.6g of thetitle compound 1 as a white solid in a yield of 33.3%.

1H NMR(400MHz，CD₃OD)，：6.96-7.03(m,4H),6.45-6.49(m,2H),4.53(d,1H),4.06(q,2H),3.85-3.88(m,2H),3.65-3.75(m,1H),3.34-3.44(m,3H),1.41(t,3H)。

Example 2 preparation of compound 2: (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compounds 2-3

Weighing and combining2-153 g (213.4mmol,1.0eq) of the product were added 265mL of redistilled tetrahydrofuran at-70 ℃ under N₂106.6mL (2.0M,1.0eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under-70 ℃ with stirring for 0.5h under nitrogen, and then 2-2115 g (213.4mmol,1.0eq) of the compound in tetrahydrofuran (106.0 mL) was added dropwise with stirring for 1h under-70 ℃ with nitrogen after completion of the addition. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 105.0g of pure compound 2-3 as a colorless oil in a yield of 62.5%.

(2) Preparation of intermediate Compounds 2-4

Weighing 2-3105.0 g (133.4mmol,1.0eq) of compound, adding 735.0mL of dichloromethane, and adding Et to the solution at 20 ℃ under nitrogen₃SiH 18.6g (160mmol,1.2eq), cooling to 0 ℃ and dropwise adding BF₃.Et₂O22.75g (160mmol,1.2eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 500.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 5:1 gave 68.0g of pure compound 2-4 as a white solid with a yield of 66.1%.

(3) Preparation of the aimed Compound 2((2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

Weighing 2-468.0 g (88.2mmol,1.0eq), adding 500.0mL of methanol, adding 22.0g of Pd/C (active ingredient content is 10%) into the solution under the condition of argon, vacuumizing the reaction system, filling hydrogen, and reacting for 24h under the condition of 50psi of hydrogen at 50 ℃. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250: 100 mm: 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 25% -53%, 30min) to obtain 15g of the objective compound 2 as a white solid with a yield of 41.5%.

1H NMR(400MHz，CD₃OD)，：7.08(dd,J＝8.8Hz,2H),6.82(dd,J＝8.4Hz,2H),6.76(d,2H),4.54(d,1H),3.99(q,2H),3.84-3.87(m,4H),3.61-3.63(m,1H),3.30-3.45(m,3H),1.35(t,3H)。

Example 3 preparation of compound 3: (2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 3-3(4- (4-bromo-2-chlorophenoxy) benzaldehyde)

The compound (3-160.0 g, 289.2mmol,1.00eq) was weighed, 650.0mL of DMA (dimethylacetamide), the compound (3-235.90 g, 289.2mmol,1.00eq), and the potassium carbonate (42.37 g, 306.6mmol,1.06eq) were added, and the mixture was reacted at 100 ℃ under nitrogen for 12 hours. After the reaction is finished, cooling to room temperature, extracting by using MTBE (methyl tert-butyl ether) (1.00L), extracting an organic phase MTBE by using saturated saline solution (1.00L), collecting the organic phase, distilling under reduced pressure to obtain a concentrate, passing the concentrate through a silica gel column, and obtaining a mobile phase of petroleum ether: ethyl acetate 40:1 to 3:1 gave 67.0g of compound 3-3 as a pale yellow oil with a yield of 72.1%.

1HNMR(400MHz，CDCl3)：9.66(s,1H),7.89(d,J＝8.8Hz,2H),7.69(d,J＝2.4Hz,1H),7.46(dd,J＝2.4Hz,J＝8.8Hz,1H),7.04(d,J＝0.8Hz,J＝8.8Hz,3H)。

(2) Preparation of intermediate Compounds 3-4

To the solution 3-367.0 g (215.1mmol,1.00eq) of the compound and 670.0mL of dichloromethane were added 58.0g (268.8mmol, 80% purity, 1.25eq) of m-CPBA, and the reaction system was reacted at 20 ℃ for 10 hours. After the TLC detection reaction is completed, adding the mixture into the reaction solution at 10 DEG CInto 200.0mL of saturated Na₂SO₃The aqueous solution was extracted with MTBE (300.0mL), then the organic phase was extracted with saturated aqueous sodium carbonate and saturated brine, respectively, the organic phase was collected and concentrated to give 70.0g of crude compound 3-4, which was used in the next step without purification.

(3) Preparation of intermediate Compounds 3-5

70.0g of the crude compound 3-4 prepared in step (2) was taken, and 350mL of methanol and 0.5mL of concentrated hydrochloric acid (12M) were added and stirred at 20 ℃ for 2 hours. After the reaction is finished, carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 67.0g of compound 3-5 as a pale yellow oil.

1HNMR(400MHz CDCl3)：7.60(d,J＝2.4Hz,1H),7.29(d,J＝2.4Hz,J＝8.8Hz,1H),6.91-6.93(m,2H),6.83-6.86(m,2H),6.75(d,J＝8.8Hz,1H)。

(4) Preparation of intermediate Compounds 3-6

Taking 3-567.0 g (1.00eq) of compound, adding 450.0mL tetrahydrofuran, cooling to 0 ℃, adding 16.5g NaH (purity 60%, 2.4eq) in batches, then adding 40.3g iodoethane (258.3mmol,1.50eq) dropwise, heating to 60 ℃ and reacting for 12 h. After the reaction is finished, the temperature is reduced to 0 ℃, and 300.0mL of saturated NH is added into the reaction solution₄Adding MTBE into Cl aqueous solution for extraction, collecting organic phase, and concentrating to obtain crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 10:1 gave 55.0g of compound 3-6 as a pale yellow oil in 74.8% yield.

1HNMR(400MHz，CDCl₃)：7.50(d,J＝2.4Hz,1H),7.17-7.20(m,1H),6.85-6.87(m,2H),6.79-6.85(m,2H),6.64(d,J＝8.4Hz,1H),3.94(q,J＝7.2Hz,J＝14.4Hz,2H),1.34(t,J＝7.2Hz,3H)。

(5) Preparation of intermediate Compounds 3-8

Weighing 3-640.0 g (122.10mmol,1.00eq) of compound, adding 700mL THF, and heating at-70 deg.C under N₂To the above solution was added dropwise 48.84mL (2.5M,1.00eq) of a solution of n-BuLi (n-butyllithium) in tetrahydrofuran under stirring at-70 ℃ under nitrogen for 0.2h, followed by dropwise addition of a solution of compound 3-665.77 g (122.10mmol,1.00eq) in tetrahydrofuran (redistilled THF, 100.0mL) under nitrogen at-70 ℃ for 1 h. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by adopting MTBE, collecting an organic phase, and distilling the organic phase under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 75.0g of pure compound 3-8 as a colorless oil.

1HNMR(400MHz，DMSO)：7.64(s,1H),7.34-7.32(d,J＝6.8Hz,1H),7.20-7.29(m,15H),6.92-6.93(m,6H),6.85(s,1H),4.75-4.80(m,3H),4.8-4.58(m,5H),3.96-4.02(m,4H),3.64-3.78(m,4H),1.30(t,J＝6.8Hz,3H)。

(6) Preparation of intermediate Compounds 3-9

3-875.0 g (95.3mmol,1.00eq) of the compound was weighed, 525.0mL of dichloromethane was added, and Et was added to the solution at 20 ℃ under nitrogen₃SiH (13.3g,114.3mmol,1.20eq), cooled to 0 ℃ and BF added dropwise₃.Et₂O6.5g (45.7mmol,1.2eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction was poured into saturated 200.0mL NaHCO₃Extracting in water solution, collecting dichloromethane phase, and distilling under reduced pressure to obtain crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 52.0g of pure compound 3-9 as a white solid with a yield of 70.7%.

(7) Preparation of the title compound 3((2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

Weighing 3-944.0 g (57.0mmol,1.00eq) of compound, adding 880.0mL of ethanol, and adding 11.0g (effective component) of Pd/C to the solution under argonContent 10%) and the reaction system is vacuumized, charged with hydrogen and reacted at 20 ℃ for 12h under 30psi of hydrogen. After the reaction was completed, suction filtration was carried out, the filtrate was concentrated, and the concentrate was passed through prep. SFC (preparative SFC) (column: Chiralpak IC-H250 x 30mm i.d.5 u; mobile phase: A phase CO₂B phase IPA (isopropylamine) (0.1% NH)₃.H₂O); gradient, B% ═ 45%; the flow rate is 73 g/min; the detection wavelength is 220 nm; the column temperature is 40 ℃; pressure 100bar) to yield 9.22g of the title compound 3 as a white solid.

1HNMR(400MHz，CD₃OD)：7.55(d,J＝2.0Hz,1H),7.28(dd,J＝2.0Hz,J＝8.4Hz,1H),6.83-6.89(m,5H),4.11(d,J＝8.8Hz,1H),4.06(q,2H),3.88(dd,J＝2.0Hz,J＝8.0Hz,1H),3.71(dd,J＝5.2Hz,J＝11.6Hz,1H),3.40-3.44(m,3H),3.30-3.31(m,1H),1.37(t,J＝6.8Hz,3H)。

Example 4 preparation of compound 4: (2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 4-2 (4-bromo-2-chlorobenzoyl chloride)

The compound 4-130.0 g (127.41mmol,1.00eq) was taken, 180.0mL DCM and 0.1mL DMF were added, 17.8g (140.2mmol,1.10eq) of oxalyl chloride was added dropwise at 0 deg.C, and after the addition was complete, the temperature was raised to 20 deg.C for reaction for 3 h. After the reaction was completed, a dichloromethane solution of compound 4-2 was obtained and used in the next step without further treatment.

(2) Preparation of intermediate Compound 4-3

15.5g (127.4mmol,1.00eq) of ethoxybenzene was added to a dichloromethane solution of the compound 4-2 obtained in step (1) at 0 ℃ under nitrogen, followed by addition of AlCl in portions₃17.0g (127.4mmol,1.00eq), after the addition is complete,the temperature of the reaction solution is raised to 20 ℃ for reaction for 3 h. After the reaction is finished, cooling the reaction liquid to 0 ℃, adding 200mL of dilute hydrochloric acid, adding saturated salt solution for extraction, collecting an organic phase, and adding anhydrous Na₂SO₄Drying, filtering, and concentrating the filtrate by vacuum distillation to obtain concentrate. MeOH (100mL) was added to the concentrate, and the mixture was stirred at 20 ℃ for 2 hours to precipitate a solid, which was collected by filtration and dried under reduced pressure to obtain 35.0g of compound 4-3 as a white solid with a yield of 80.9%.

1HNMR(400MHz，CDCl₃)：7.74(dd,J＝7.2Hz,J＝9.2Hz,2H),7.63(m,1H),7.50(d,J＝2.0Hz,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),6.92(d,J＝8.8Hz,2H),4.11(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H)。

(3) Preparation of intermediate Compound 4-4

Taking 4-335.0 g (103.1mmol,1.00eq) of compound, adding 350.0mL of acetonitrile, adding Et under nitrogen at 20 deg.C₃SiH 59.9g (515.3mmol,5.00eq) was added dropwise to BF at 25 ℃ under nitrogen₃.Et₂O29.3 g (206.1mmol,2.00eq), and the mixture was reacted at 25 ℃ for 12 h. After the reaction was complete, 300.0mL of saturated NaHCO was added to the reaction mixture₃And adding MTBE into the aqueous solution for extraction, extracting the organic phase by using saturated saline solution, collecting the organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and concentrating the organic phase under reduced pressure to obtain a crude product. The crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 33.0g of compound 4-4 as a pale yellow oil in 92.0% yield.

1HNMR(400MHz，CDCl₃)：7.53(d,J＝2.0Hz,1H),7.29(d,J＝2.0Hz,J＝8.4Hz,1H),7.06(d,J＝8.8Hz,2H),6.98(d,J＝8.0Hz 1H),6.83(d,J＝8.4Hz,2H),3.98(q,J＝6.8Hz,2H),1.40(t,J＝6.8Hz,3H)。

(4) Preparation of intermediate Compounds 4-6

Weighing 4-428.0 g (86.0mmol,1.00eq) of compound, adding 560mL of redistilled THF at-70 deg.C in N₂34.4mL (2.5M,1.00eq) of n-BuLi in tetrahydrofuran was added dropwise to the above solution under-70 ℃ with stirring for 0.2h under nitrogen, followed by addition of 4-546.3 g (86.0mmol,1.00eq) of the compound in tetrahydrofuran (redistilled THF, 100.0mL) dropwise and stirring for 1h under-70 ℃ with nitrogen. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by adopting MTBE, collecting an organic phase, and distilling the organic phase under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 56.0g of pure compound 4-6 as a colorless oil in a yield of 72.8%.

(5) Preparation of intermediate Compounds 4-7

Weighing 4-656.0 g (71.3mmol,1.00eq) of compound, adding 390.0mL of dichloromethane, and adding Et to the solution at 20 ℃ under nitrogen₃SiH 9.95g (85.6mmol,1.20eq), cooling to 0 deg.C and dropwise adding BF₃.Et₂O12.1g (85.6mmol,1.20eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 200.0mL of a saturated aqueous sodium bicarbonate solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 55.0g of pure compound 4-7 as a colorless oil in a yield of 64.6%.

(6) Preparation of the title compound 4((2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

41.2g (53.6mmol,1.00eq) of the compound 4-7 and 800.0mL of ethyl acetate are taken, mixed uniformly under stirring, then 8.00g of Pd/C (active ingredient content is 10%) is added under the condition of argon, the reaction system is vacuumized and filled with hydrogen, and reacted for 12 hours at 20 ℃ under the condition of 30psi of hydrogen. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 26% -46%, 20min) to give 7.7g of the title compound 4 as a white solid with a yield of 35.1%.

1HNMR(400MHz，DMSO)：7.37(s,1H),7.23(d,2H),7.08(d,J＝8.4Hz,2H),6.81(d,J＝8.4Hz,2H),4.7(br.s,4H),3.92-4.00(m,5H),3.60-3.66(m,1H),3.40-3.50(m,1H),3.05-3.24(m,4H),1.27(t,J＝7.2Hz,3H)。

Example 5 preparation of compound 5: (2S,3R,4R,5S,6R) -2- (4- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 5-3

To the p-bromophenylether 69.4g (compound 5-1, 496mmol,1eq) and the compound 5-2(744mmol,1.5eq) 152.5g were added 500mL of dimethylformamide, and Cs was added to the above solutions in this order at 20 ℃₂CO₃323g (992mmol,2eq), and then stirred at 100 ℃ under nitrogen for 12 h. Cooling to room temperature after complete reaction, then distilling under reduced pressure to obtain a concentrate, extracting the concentrate by using water-ethyl acetate, collecting an organic phase, and distilling under reduced pressure to obtain a crude product; passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 40:1 to 5:1 gave 40.3g of pure compound 5-3 as a colorless oil in a yield of 25%.

(2) Preparation of intermediate Compounds 5-5

5-340.3 g (124mmol,1.0eq) of the compound was taken, 180.0mL of redistilled tetrahydrofuran was added, and the mixture was heated at-70 ℃ under N₂148.8mL (2.5M,3eq) of a solution of n-butyllithium in tetrahydrofuran was added dropwise to the above solution, the above mixture was stirred at-70 ℃ for 0.5h under nitrogen, then a solution of compound 5-466.7 g (124mmol,1.0eq) in tetrahydrofuran (redistilled THF, 150.0mL) was added dropwise to the solution Stirring at-70 ℃ for 1h under nitrogen. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 31.6g of pure compound 5-5 in 32.5% yield.

(3) Preparation of intermediate Compounds 5-6

5-531.6 g (40.3mmol,1.0eq) of the compound was weighed, 350.0mL of dichloromethane was added, and Et was added to the above solution at 20 ℃ under nitrogen₃SiH 5.6g (48.36mmol,1.2 eq); cooling to 0 deg.C, then adding BF dropwise₃.Et₂O3.5 g (48.36mmol,1.2eq), heated to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into a saturated 200.0mL aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 1:0 to 10:1 gave 18.8g of pure compound 5-6 in a yield of 61%.

(4) Preparation of the title compound 5((2S,3R,4R,5S,6R) -2- (4- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

5 to 618.8 g (24.5mmol,1.0eq) of the compound was weighed, 200.0mL of methanol was added, 17.0g of Pd/C (active material content: 10%) was added to the above solution under argon, the reaction system was evacuated and charged with hydrogen, and reacted at 50 ℃ under 50psi of hydrogen for 24 hours. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 50mm 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 30% -80%, 20min) to obtain 3.0g of the title compound 5 as a white solid with a yield of 30.1%.

1H NMR(400MHz，CD₃OD)，：6.96-7.03(m,4H),6.18(dd,2H),5.35(d,1H),4.53(q,2H),4.03-4.09(m,1H),3.85-3.88(m,2H),3.63-3.65(m,1H),3.34-3.44(m,3H),1.42(t,3H)。

Example 6 preparation of compound 6: (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 6-2

The compound (6-160 g, 230.4mmol,1.00eq) was taken, 200.0mL DCM and 0.1mL DMF were added, 132.2g oxalyl chloride (253.4mmol,1.10eq) was added dropwise at 0 deg.C, and after the addition was complete, the temperature was raised to 20 deg.C for reaction for 3 h. After the reaction was completed, a dichloromethane solution of compound 6-2 was obtained and used in the next step without further treatment.

(2) Preparation of intermediate Compound 6-3

28.0g (230.4mmol,1.00eq) of ethoxybenzene was added to a dichloromethane solution of compound 6-2 obtained in step (1) at 0 ℃ under nitrogen, followed by addition of AlCl in portions₃30.7g (230.4mmol,1.00eq), and after the addition, the reaction solution was heated to 20 ℃ for reaction for 3 hours. After the reaction is finished, cooling the reaction liquid to 0 ℃, adding 200mL of dilute hydrochloric acid, adding saturated salt solution for extraction, collecting an organic phase, and adding anhydrous Na₂SO₄Drying, filtering, and concentrating the filtrate by vacuum distillation to obtain concentrate. MeOH (100mL) was added to the concentrate, and the mixture was stirred at 20 ℃ for 2 hours to precipitate a solid, which was collected by filtration and dried under reduced pressure to obtain 68g of compound 6-3 in a yield of 80.9%.

(3) Preparation of intermediate Compound 6-4

Taking 6-368 g (186.4mmol,1.00eq) of the compound, adding 350.0mL of acetonitrile, adding Et under the condition of nitrogen at 20 DEG C₃SiH 108.3g (932mmol,5.00eq), followed by dropwise addition of BF at 25 ℃ under nitrogen₃.Et₂O106 g (745.6mmol,4.00eq), and the mixture was reacted at 25 ℃ for 12 h. After the reaction was complete, 300.0mL of saturated NaHCO was added to the reaction mixture₃And adding MTBE into the aqueous solution for extraction, extracting the organic phase by using saturated saline solution, collecting the organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and concentrating the organic phase under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 50:1 to 5:1 gave 55.4g of compound 6-6 in 92.0% yield.

(4) Preparation of intermediate Compound 6-6

Weighing 6-455.4 g (171.5mmol,1.0eq) of compound, adding 300mL of redistilled tetrahydrofuran at-70 deg.C under N₂To the above solution was added dropwise 205.8mL (2.5M,3.0eq) of a solution of n-butyllithium in tetrahydrofuran under conditions of-70 ℃ under nitrogen for 0.5h, followed by dropwise addition of a solution of compound 6-592 g (171.5mmol,1.0eq) in tetrahydrofuran (redistilled THF, 100.0mL) under nitrogen at-70 ℃ for 1 h. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 40.3g of pure compound 6-6 in a yield of 30%.

(5) Preparation of intermediate Compounds 6-7

6-640.3 g (51.45mmol,1.0eq) of the compound was weighed, 300.0mL of dichloromethane was added, and Et was added to the solution at 20 ℃ under nitrogen₃SiH 7.16g (61.74mmol,1.2eq), cooled to 0 ℃ and BF added dropwise₃.Et₂O8.8g (61.74mmol,1.2eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 200.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Crude product is passed through silica gelColumn, mobile phase petroleum ether: ethyl acetate 100:1 to 5:1 gave 23.7g of pure compound 6-7 as a white solid with a yield of 60%.

(6) Preparation of the title compound 6((2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

The compound 6-723.7 g (30.87mmol,1.0eq) was weighed, 200.0mL of methanol was added, 12g of Pd/C (active ingredient content 10%) was added to the above solution under argon, the reaction system was evacuated and charged with hydrogen, and reacted at 50 ℃ under 50psi of hydrogen for 24 hours. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250: 100 mm: 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 20% -60%, 30min) to obtain 3.7g of the objective compound 6 as a white solid with a yield of 30%.

1H NMR(400MHz，DMSO)，：7.08(d,J＝8.8Hz,2H),6.82(d,J＝8.4Hz,2H),6.47(s,2H),4.53-4.56(m,1H),3.95-4.01(q,2H),3.84-3.87(m,4H),3.61-3.63(m,1H),3.30-3.35(m,3H),1.36(t,3H)。

Example 7 preparation of compound 7: (2S,3R,4R,5S,6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxyethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 7-3

100g of p-bromophenol (compound 7-1, 578mmol,1eq), 7-296.5 g (578mmol,1eq), and 95.7g of potassium carbonate were added to 1000mL of dioxane, and the mixture was stirred at 60 ℃ for 12 hours. After the reaction is completed, carrying out reduced pressure distillation on the reaction liquid to obtain a concentrate, extracting the concentrate by using saturated saline-ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product; passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 gave 104.8g of pure compound 7-3 in 70% yield.

(2) Preparation of intermediate Compound 7-5

Adding 800mL of dioxane into 7-3100 g (386mmol,1eq) of compound and 60.2g (7-4, 463.2mmol,1.2eq) of 3, 5-difluorophenol, and adding Cs into the above solution at 20 deg.C₂CO₃252g (772mmol,2eq), CuI 22g (115.8mmol,0.3eq), isobutyl nitrite 23.9g (231.6mmol,0.6eq), and stirring at 100 deg.C for 12 h. Cooling to 20 ℃ after complete reaction, then carrying out reduced pressure distillation to obtain a concentrate, extracting the concentrate by using water-ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product; passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 50:1 gave 59.4g of pure compound 7-5 in 50% yield.

(3) Preparation of intermediate Compounds 7-7

Collecting 7-759.4 g (193mmol,1.0eq), adding 200.0mL redistilled tetrahydrofuran, and heating at-70 deg.C under N₂144.6mL (2.0M,1.5eq) of a solution of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution, and the above mixture was stirred at-70 ℃ under nitrogen for 0.5h, then a solution of compound 7-6103.9 g (193mmol,1.0eq) in tetrahydrofuran (redistilled THF, 200.0mL) was added dropwise and stirred at-70 ℃ under nitrogen for 1 h. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 95.1g of pure compound 7-7 in 58.3% yield.

(4) Preparation of intermediate Compounds 7-8

Weighing 7-895.1 g (112.5mmol,1.0eq) of compound, adding 500.0mL of dichloromethane, and adding Et to the solution at 20 ℃ under nitrogen₃SiH 15.6g (135mmol,1.2 eq); cooling to 0 deg.C, then adding BF dropwise₃.Et₂O9.6g (135mmol,1.2eq), heated to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into a saturated 200.0mL aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 10:0 to 2:1 gave 52.1g of pure compound 7-8 in 55.8% yield.

(5) Preparation of the aimed Compound 7((2S,3R,4R,5S,6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxyethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

Weighing 7-852.1 g (62.8mmol,1.0eq), adding 500.0mL of methanol, adding 28.0g of Pd/C (active substance content is 10%) into the solution under the condition of argon, vacuumizing the reaction system, filling hydrogen, and reacting for 24h under the condition of 50psi of hydrogen at 50 ℃. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 10 um; mobile phase: water (0.1% HCOOH) -ACN ], B%: 30% -80%, 20min) to give 10.3g of the title compound 7 as a white solid with a yield of 35%.

1H NMR(400MHz，CD₃OD)，：7.30(dd,2H),6.96(d,2H),6.87(dd,2H),4.54(d,1H),4.29(t,2H),4.03-4.09(m,2H),3.85(t,2H),3.65(m,1H),3.34-3.44(m,3H),3.11-3.13(m,1H),1.08(d,6H)。

Example 8 preparation of compound 8: (2S,3R,4R,5S,6R) -2- (4- (4-acetoxy benzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 8-3

8-150 g (227mmol,1.0eq) of the compound was weighed, 300mL of redistilled tetrahydrofuran was added, and the mixture was heated at-70 ℃ under N₂226.8mL (2.0M,2.0eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under-70 ℃ with stirring for 0.5h under nitrogen, followed by dropwise addition of compound 8-2122.3 g (227mmol,1.0eq) of tetrahydrofuran (redistilled THF, 100.0mL) solution under nitrogen at-70 ℃ with stirring for 1 h. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 1:1 gave 101.5g of pure compound 8-3 in 59% yield.

(2) Preparation of intermediate Compound 8-4

8-3101.5 g (133.9mmol,1.0eq) of the compound was weighed, 800.0mL of dichloromethane was added, and Et was added to the solution at 20 ℃ under nitrogen₃SiH 18.7g (160.7mmol,1.2eq), cooled to 0 ℃ and BF added dropwise₃.Et₂O22.8g (160.7mmol,1.2eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 500.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: 59.6g of pure compound 8-4 was obtained with an ethyl acetate ratio of 100:1 to 2:1, and the yield was 60%.

(3) Preparation of intermediate Compounds 8-5

8-459.6 g (80.3mmol,1.0eq) of the compound was weighed, 500mL of dichloromethane, 20.7g (160.6mmol, 2eq) of DIPEA and 35.5g (93.4mmol, 1.2eq) of HATU were added, 4.3g (93.4mmol, 1.2eq) of formic acid was added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 2 hours. Extracting with saturated salt solution, collecting organic phase, and distilling under reduced pressure to obtain crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 10:1 gave 45.3g of pure compound 8-5 in a yield of 72%.

(4) Preparation of the aimed compound 8((2S,3R,4R,5S,6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

8 to 568.0 g (57.8mmol,1.0eq) of the compound was weighed, 500.0mL of ethanol was added, 22.0g of Pd/C (active ingredient content: 10%) was added to the above solution under argon, the reaction system was evacuated and charged with hydrogen, and reacted at 50 ℃ under 50psi of hydrogen for 24 hours. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250: 100 mm: 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 25% -70%, 30min) to obtain 9.5g of the objective compound 8 as a white solid in 39% yield.

1H NMR(400MHz，CD₃OD)，：7.16(d,J＝8.8Hz,2H),6.87(d,J＝8.4Hz,2H),6.42(d,2H),4.57(d,1H),3.98(s,2H),3.86-3.89(m,4H),3.61(m,1H),3.30-3.35(m,1H),2.23(s,3H)。

Example 9 preparation of compound 9: (2S,3R,4R,5S,6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 9-3

9-150 g (171.2mmol,1.0eq) of the compound was weighed, 200mL of redistilled tetrahydrofuran was added, and the mixture was heated at-70 ℃ under N₂85.5mL (2.0M,1.0eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under conditions and stirred at-70 ℃ for 0.5h under nitrogen, then 9-292.3 g (171.2mmol,1.0eq) of tetrahydrofuran (redistilled THF, 100.0mL) was added dropwise and stirred at-70 deg.C under nitrogen for 1 h. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 2:1 gave 92.3g of pure compound 9-3 as a colorless oil in a yield of 65%.

(2) Preparation of intermediate Compound 9-4

9-392.3 g (111.3mmol,1.0eq) of the compound was weighed, 700.0mL of dichloromethane was added, and Et was added to the solution at 20 ℃ under nitrogen₃SiH 15.6g (133.6mmol,1.2eq), cooling to 0 deg.C and dropwise adding BF₃.Et₂O19g (133.6mmol,1.2eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 500.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 5:1 gave 60.7g of pure compound 9-4 as a white solid with a yield of 67%.

(3) Preparation of the aimed compound 9((2S,3R,4R,5S,6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

9-460.7 g (74.5mmol,1.0eq) of the compound was weighed, 500.0mL of methanol was added, 18.6g of Pd/C (active ingredient content: 10%) was added to the above solution under argon, the reaction system was evacuated and charged with hydrogen, and reacted at 50 ℃ under 50psi of hydrogen for 24 hours. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250: 100 mm: 10 um; mobile phase: water (0.1% HCOOH) -ACN ], B%: 25% -60%, 30min) to give 15.2g of the title compound 9 as a white solid with a yield of 45%.

1H NMR(400MHz，CD₃OD)，：7.05(s,1H),6.79(d,1H),6.70(d,1H),6.56(d,2H),4.53-4.56(m,1H),4.06(q,4H),3.97(s,2H),3.84-3.87(m,4H),3.60-3.63(m,2H),1.35(t,6H)。

Example 10 preparation of compound 10: (2S,3R,4R,5S,6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 10-3

Weighing 10-150 g (182.4mmol,1.0eq) of the compound, adding 200mL of redistilled tetrahydrofuran, and heating at-70 deg.C under N₂91.1mL (2.0M,1.0eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under-70 ℃ with stirring for 0.2h under nitrogen, followed by addition of 10-298.2 g (182.4mmol,1.0eq) of the compound in tetrahydrofuran (redistilled THF, 100.0mL) dropwise, and stirring for 1h under-70 ℃ with nitrogen after completion of the addition. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 2:1 gave 86.5g of pure compound 10-3 as a colorless oil in a yield of 58.4%.

(2) Preparation of intermediate Compound 10-4

10-386.5 g (106.6mmol,1.0eq) of the compound was weighed, 700.0mL of dichloromethane was added, and Et was added to the solution at room temperature under nitrogen₃SiH 14.9g (127.9mmol,1.2eq), cooling to 0 ℃ and dropwise adding BF₃.Et₂O18.2g (127.9mmol,1.2eq), then warmed to room temperature and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 500.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate ═ 100:1 to 3:1, 56.8g of pure compound 10-4 was obtained as a white solid with a yield of 67%.

(3) Preparation of the aimed Compound 10((2S,3R,4R,5S,6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

10-456.8 g (71.4mmol,1.0eq) of the compound was weighed, 500.0mL of ethyl acetate was added, 17.8g of Pd/C (wet palladium on carbon, active ingredient content 5%) was added to the above solution under argon, the reaction system was evacuated and charged with hydrogen, and reacted at 50 ℃ under 50psi of hydrogen for 12 hours. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250: 100 mm: 10 um; mobile phase: water (0.1% HCOOH) -ACN ], B%: 25% -70%, 30min) to obtain 13g of the objective compound 10 as a white solid with a yield of 42%.

1H NMR(400MHz，CD₃OD)，：7.55(d,J＝8.8Hz,2H),7.32(d,J＝8.4Hz,2H),6.88(d,2H),4.53-4.56(m,1H),3.87-3.90(m,1H),3.80-3.82(m,2H),3.61-3.63(m,3H)。

Example 11 preparation of compound 11: (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 11-2 (4-bromo-2-fluorobenzoyl chloride)

The compound 11-130.0 g (137mmol,1.00eq) was taken, 200.0mL DCM and 0.1mL DMF were added, 19.1g (150.7mmol,1.10eq) of oxalyl chloride was added dropwise at 0 deg.C, and after the dropwise addition was completed, the reaction was warmed to room temperature for 5 h. After the reaction was completed, a dichloromethane solution of compound 11-2 was obtained and used in the next step without further treatment.

(2) Preparation of intermediate Compound 11-3

16.7g (137mmol,1.00eq) of ethoxybenzene was added to a dichloromethane solution of the compound 11-2 obtained in step (1) at 0 ℃ under nitrogen, followed by addition of AlCl in portions₃18.3g (137mmol,1.00eq), and after the addition was complete, the reaction mixture was warmed to room temperature for 3 h. After the reaction is finished, cooling the reaction liquid to 0 ℃, adding 200mL of dilute hydrochloric acid, adding saturated salt solution for extraction, collecting an organic phase, and adding anhydrous Na₂SO₄Drying, filtering, distilling under reduced pressure, and concentrating to obtain concentrate. MeOH (100mL) was added to the concentrate, and the mixture was stirred at 20 ℃ for 2h to precipitate a solid, which was collected by filtration and dried under reduced pressure to give 33.3g of Compound 11-3 as a white solid in a yield of 75.2%.

(3) Preparation of intermediate Compound 11-4

Taking 11-333.3 g (103.1mmol,1.00eq) of the compound, adding 350.0mL of acetonitrile, adding Et under nitrogen at 20 deg.C₃SiH 18g (154.65mmol,1.5eq), followed by dropwise addition of BF at 25 ℃ under nitrogen₃.Et₂O29.3 g (206.1mmol,2.00eq), and the mixture was reacted at 25 ℃ for 12 h. After the reaction was complete, 300.0mL of saturated NaHCO was added to the reaction mixture₃And (3) adding MTBE into the aqueous solution for extraction, extracting the organic phase by using saturated saline solution, collecting the organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was passed through a silica gel column and the mobile phase was petroleum ether to give 28.4g of compound 11-4 in 89% yield.

(4) Preparation of intermediate Compound 11-6

Weighing 11-428.4 g (91.8mmol,1.00eq) of compound, adding 600mL of redistilled THF at-70 deg.C in N₂36.7mL (2.5M,1.00eq) of a solution of n-BuLi in tetrahydrofuran was added dropwise to the above solution under conditions of stirring at-70 ℃ for 0.2h under nitrogen, followed by the dropwise addition of compound 10-549.4 g (91.8mmol,1.00eq) of tetrahydrofuran (redistilled THF, 1.00eq)00.0mL) was added and the mixture was stirred at-70 deg.C under nitrogen for 1 h. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by adopting MTBE, collecting an organic phase, and distilling the organic phase under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 3:1 gave 52.9g of pure compound 11-6 in a yield of 75%.

(5) Preparation of intermediate Compound 11-7

Weighing 11-652.9 g (68.85mmol,1.00eq) of compound, adding 400.0mL of dichloromethane, and adding Et to the solution at 20 ℃ under nitrogen₃SiH 9.6g (82.62mmol,1.20eq), cooling to 0 ℃ and dropwise adding BF₃.Et₂O11.7g (82.62mmol,1.20eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 200.0mL of a saturated aqueous sodium bicarbonate solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 4:1 gave 35.3g of pure compound 11-7 in a yield of 68%.

(6) Preparation of the title compound 11((2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

35.3g (46.8mmol,1.00eq) of the compound 11-7 and 600.0mL of ethyl acetate are taken, mixed uniformly under stirring, then 7.00g of Pd/C (active ingredient content is 10%) is added under the condition of argon, the reaction system is vacuumized and filled with hydrogen, and reacted for 12 hours at 20 ℃ under the condition of 30psi of hydrogen. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 20% -60%, 20min) to give 6.8g of the title compound 11 as a white solid with a yield of 37%.

1HNMR(400MHz，DMSO)：7.15(d,1H),7.14(d,2H),7.02(d,1H),6.89(d,2H),6.79(d,1H),4.7(br.s,4H),3.94-4.02(m,5H),3.61-3.67(m,1H),3.41-3.51(m,1H),3.06-3.25(m,4H),1.34D(t,3H)。

Example 12 preparation of compound 12: (2S, 3R)4R,5S,6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula

(1) Preparation of intermediate Compound 12-2 (4-bromo-2-fluorobenzoyl chloride)

Taking 12-130.0 g (137mmol,1.00eq) of the compound, adding 200.0mL DCM and 0.1mL DMF, dropwise adding 19.1g (150.7mmol,1.10eq) of oxalyl chloride at 0 ℃, after the dropwise adding is finished, heating to 20 ℃ for reaction for 3 h. After the reaction was completed, a dichloromethane solution of compound 12-2 was obtained and used in the next step without further treatment.

(2) Preparation of intermediate Compound 12-3

To a dichloromethane solution of the compound 12-2 obtained in the step (1) at 0 ℃ under nitrogen atmosphere, 25.7g (137mmol,1.00eq) of p-fluorophenoxybenzene was added, followed by addition of AlCl in portions₃18.3g (137mmol,1.00eq), and after the addition was complete, the reaction mixture was heated to 20 ℃ for 5 h. After the reaction is finished, cooling the reaction liquid to 0 ℃, adding 200mL of dilute hydrochloric acid, adding saturated salt solution for extraction, collecting an organic phase, and adding anhydrous Na₂SO₄Drying, filtering, and concentrating the filtrate by vacuum distillation to obtain concentrate. MeOH (100mL) was added to the concentrate, and the mixture was stirred at 20 ℃ for 2h to precipitate a solid, which was collected by filtration and dried under reduced pressure to obtain 45.3g of compound 12-3 as a white solid with a yield of 85%.

(3) Preparation of intermediate Compound 12-4

Taking 12-345.3 g (116.4mmol,1.00eq), adding 400.0mL acetonitrile, adding Et under nitrogen at 20 deg.C₃SiH 40.6g(349.2mmol,3.00eq)Then adding BF dropwise at 25 ℃ under nitrogen₃.Et₂O33 g (232.8mmol,2.00eq), and the mixture was reacted at 25 ℃ for 12 hours. After the reaction was complete, 300.0mL of saturated NaHCO was added to the reaction mixture₃And adding MTBE into the aqueous solution for extraction, extracting the organic phase by using saturated saline solution, collecting the organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and concentrating the organic phase under reduced pressure to obtain a crude product. The crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 39.7g of compound 12-4 in 91.0% yield.

(4) Preparation of intermediate Compound 12-6

Weighing 12-439.7 g (105.9mmol,1.00eq) of compound, adding 600mL of redistilled THF at-70 deg.C in N₂42.4mL (2.5M,1.00eq) of n-BuLi in tetrahydrofuran was added dropwise to the above solution under-70 ℃ with stirring for 0.2h under nitrogen, followed by addition of 12-557 g (105.9mmol,1.00eq) of the compound in tetrahydrofuran (redistilled THF, 150.0mL) dropwise and stirring for 1h under-70 ℃ with nitrogen. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by adopting MTBE, collecting an organic phase, and distilling the organic phase under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 4:1 gave 66.2g of pure compound 12-6 in a yield of 75%.

(5) Preparation of intermediate Compounds 12-7

Weighing 12-666.2 g (79.4mmol,1.00eq) of compound, adding 400.0mL of dichloromethane, and adding Et to the solution at 20 ℃ under nitrogen₃SiH 11g (95.3mmol,1.20eq), cooling to 0 ℃ and dropwise adding BF₃.Et₂O13.5g (95.3mmol,1.20eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 200.0mL of a saturated aqueous sodium bicarbonate solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 4:1, 39.6g of pure chemical compound was obtainedSubstance 12-7, yield 61%.

(6) Preparation of the aimed compound 12((2S,3R,4R,5S,6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

39.6g (48.4mmol,1.00eq) of the compound 12-7 and 800.0mL of ethyl acetate were taken, mixed uniformly with stirring, then 7.2g (10% of active ingredient content) of Pd/C was added under argon, the reaction system was evacuated and charged with hydrogen, and reacted at room temperature under 30psi of hydrogen for 12 hours. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 50mm 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 20% -60%, 30min) to give 8.2g of the title compound 12 as a white solid with a yield of 37%.

1HNMR(400MHz，DMSO)：7.41(dd,2H),7.25(dd,2H),7.18(dd,2H),7.16(dd,2H),7.13(d,1H),6.99(d,1H),6.75(d,1H),3.95(s,2H),4.6(br.s,4H),3.91-4.04(m,3H),3.63-3.68(m,1H),3.42-3.51(m,3H),3.05-3.24(m,2H)。

Example 13 preparation of compound 13: (2S,3R,4R,5S,6R) -2- (4- (4- (2,4, 5-trifluoro-phenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 13-2 (4-bromo-benzoyl chloride)

13 to 127.5 g (137mmol,1.00eq) of the compound was taken, 200.0mL of DCM and 0.1mL of DMF were added, 19.1g (150.7mmol,1.10eq) of oxalyl chloride was added dropwise at 0 ℃, and after the addition was completed, the temperature was raised to 20 ℃ for reaction for 3 hours. After the reaction was completed, a dichloromethane solution of compound 13-2 was obtained and used in the next step without further treatment.

(2) Preparation of intermediate Compound 13-4

At 0 ℃ inAdding 13-330.7g (137mmol,1.00eq) of compound 13-2 obtained in step (1) into dichloromethane solution under nitrogen, and then adding AlCl in batches₃18.3g (137mmol,1.00eq), and after the addition was complete, the reaction mixture was heated to 20 ℃ for 5 h. After the reaction is finished, cooling the reaction liquid to 0 ℃, adding 200mL of dilute hydrochloric acid, adding saturated salt solution for extraction, collecting an organic phase, and adding anhydrous Na₂SO₄Drying, filtering, and concentrating the filtrate by vacuum distillation to obtain concentrate. MeOH (100mL) was added to the concentrate, and the mixture was stirred at 20 ℃ for 2h to precipitate a solid, which was collected by filtration and dried under reduced pressure to obtain 45.7g of compound 13-4 as a white solid in 82% yield.

(3) Preparation of intermediate Compound 13-5

Taking 13-445.7 g (112.3mmol,1.00eq) of compound, adding 400.0mL of acetonitrile, adding Et under nitrogen at 20 deg.C₃SiH 39g (336.9mmol,3.00eq), followed by dropwise addition of BF at 25 ℃ under nitrogen₃.Et₂O31.8 g (224.6mmol,2.00eq), and the mixture was reacted at 25 ℃ for 12 h. After the reaction was complete, 300.0mL of saturated NaHCO was added to the reaction mixture₃And (3) adding MTBE into the aqueous solution for extraction, extracting the organic phase by using saturated saline solution, collecting the organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and concentrating the filtrate under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 50:1 gave 40.6g of compound 13-5 in 92% yield.

(4) Preparation of intermediate Compound 13-7

Weighing 13-540.6 g (103.3mmol,1.00eq) of compound, adding 600mL of redistilled THF at-70 deg.C in N₂41.4mL (2.5M,1.00eq) of a solution of n-BuLi in tetrahydrofuran was added dropwise to the above solution under stirring at-70 ℃ for 0.2h under nitrogen, followed by addition of a solution of compound 13-655.6 g (103.3mmol,1.00eq) in tetrahydrofuran (redistilled THF, 150.0mL) dropwise and then to the solutionStirring at-70 ℃ for 1h under nitrogen. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by adopting MTBE, collecting an organic phase, and distilling the organic phase under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 50:1 to 3:1 gave 59g of pure compound 13-7 in 67% yield.

(5) Preparation of intermediate Compound 13-8

13-759 g (69.2mmol,1.00eq) of the compound was weighed, 400.0mL of dichloromethane was added, and Et was added to the above solution at 20 ℃ under nitrogen₃SiH 9.6g (83mmol,1.20eq), cooling to 0 ℃ and dropwise adding BF₃.Et₂O11.8g (83mmol,1.20eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 200.0mL of a saturated aqueous sodium bicarbonate solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 50:1 to 4:1 gave 34.2g of pure compound 13-8 in 59% yield.

(6) Preparation of the titled compound 13((2S,3R,4R,5S,6R) -2- (4- (4- (2,4, 5-Trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

34.2g (40.8mmol,1.00eq) of the compound 13-8 and 800.0mL of ethyl acetate are mixed uniformly with stirring, then 6.1g (10% of active ingredient content) of Pd/C is added under the condition of argon, the reaction system is vacuumized and filled with hydrogen, and the reaction is carried out for 12 hours under the condition of 30psi of hydrogen pressure and room temperature. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 50mm 10 um; mobile phase: water (0.1% TFA) -MeOH ], B%: 20% -40%, 30min) to obtain 5.8g of the title compound 13 as a white solid in a yield of 30%.

1HNMR(400MHz，DMSO)：7.29(dd,2H),7.26(d,1H),7.25(dd,J＝8.4Hz,2H),7.19(dd,2H),7.16(dd,J＝8.4Hz,2H),6.68(t,1H),4.6(br.s,4H),4.05(d,1H),3.97(s,2H),3.63-3.68(m,1H),3.42-3.51(m,3H),3.05-3.24(m,2H)。

EXAMPLE 14 preparation of Compound 14: (2S,3R,4R,5S,6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula

(1) Preparation of intermediate Compound 14-3

Taking 17.2g (150mmol,1.00eq) of 2-chloropyrimidine, adding 100mL of DMF, 15.5g (165mmol,1.100eq) of phenol and 73.4g (225mmol,1.5eq) of cesium carbonate, and reacting at 60 ℃ for 12 h; after the reaction is finished, extracting by using ethyl acetate and saturated salt water, collecting an organic phase, and concentrating to obtain a crude product; passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 50:1 gave 23.7g of compound 14-3 in a yield of 92%.

(2) Preparation of intermediate Compound 14-2 (4-bromo-benzoyl chloride)

14-127.5g (137mmol,1.00eq) of the compound was taken, 200.0mL of DCM and 0.1mL of DMF were added, 19.1g (150.7mmol,1.10eq) of oxalyl chloride was added dropwise at 0 ℃, and after the addition was completed, the temperature was raised to 20 ℃ for reaction for 3 h. After the reaction was completed, a dichloromethane solution of compound 14-2 was obtained and used in the next step without further treatment.

(3) Preparation of intermediate Compound 14-4

Adding 14-323.7g (137mmol,1.00eq) of compound 13-2 obtained in step (2) in dichloromethane at 0 ℃ under nitrogen, and then adding AlCl in portions₃18.3g (137mmol,1.00eq), and after the addition was complete, the reaction mixture was heated to 20 ℃ for 5 h. After the reaction is finished, cooling the reaction liquid to 0 ℃, adding 200mL of dilute hydrochloric acid, adding saturated salt solution for extraction, collecting an organic phase, and adding anhydrous Na₂SO₄Drying, filtering, vacuum distilling the filtrate, concentrating,a concentrate is obtained. MeOH (100mL) was added to the concentrate, and the mixture was stirred at 20 ℃ for 2h to precipitate a solid, which was collected by filtration and dried under reduced pressure to obtain 41.3g of compound 14-4 as a white solid with a yield of 85%.

(4) Preparation of intermediate Compound 14-5

14-441.3 g (116.4mmol,1.00eq) of the compound was taken, 400.0mL of acetonitrile was added, and Et was added under nitrogen at 20 ℃ to₃SiH 40.4g (349.2mmol,3.00eq) was added dropwise to BF at 25 ℃ under nitrogen₃.Et₂O33 g (224.6mmol,2.00eq), and the mixture was reacted at 25 ℃ for 12 h. After the reaction was complete, 300.0mL of saturated NaHCO was added to the reaction mixture₃And (3) adding MTBE into the aqueous solution for extraction, extracting the organic phase by using saturated saline solution, collecting the organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and concentrating the filtrate under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 50:1 gave 35.2g of compound 14-5 in 88.7% yield.

(5) Preparation of intermediate Compounds 14-7

Weighing 14-535.2 g (103.3mmol,1.00eq) of compound, adding 600mL of redistilled THF at-70 deg.C in N₂41.4mL (2.5M,1.00eq) of a solution of n-BuLi in tetrahydrofuran was added dropwise to the above solution under conditions of stirring at-70 ℃ for 0.2h under nitrogen, followed by dropwise addition of a solution of compound 14-655.6 g (103.3mmol,1.00eq) in tetrahydrofuran (redistilled THF, 150.0mL) and then stirring at-70 ℃ for 1h under nitrogen. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by adopting MTBE, collecting an organic phase, and distilling the organic phase under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 50:1 to 2:1 gave 53.7g of pure compound 14-7 in a yield of 65%.

(6) Preparation of intermediate Compound 14-8

14-753.7 g (67mmol,1.00eq) of the compound was weighed, 400.0mL of dichloromethane was added, and Et was added to the above solution at 20 ℃ under nitrogen₃SiH 9.3g (80.4mmol,1.20eq), cooling to 0 deg.C and dropwise adding BF₃.Et₂O11.4g (80.4mmol,1.20eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 200.0mL of a saturated aqueous sodium bicarbonate solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 50:1 to 3:1 gave 33g of pure compound 14-8 in a yield of 63%.

(7) Preparation of the title compound 14((2S,3R,4R,5S,6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

33g (42.2mmol,1.00eq) of the compound 14-8 and 800.0mL of ethyl acetate are mixed uniformly with stirring, then 6.3g (active ingredient content: 10%) of Pd/C is added under the condition of argon, the reaction system is vacuumized and filled with hydrogen, and the reaction is carried out for 12 hours at room temperature under the condition of 30psi of hydrogen pressure. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 50mm 10 um; mobile phase: water (0.1% TFA) -MeOH ], B%: 20% -50%, 30min) to obtain 6.3g of the title compound 14 as a white solid in a yield of 35%.

1HNMR(400MHz，DMSO)：8.35(d,2H),7.22(dd,2H),7.14(dd,J＝8.4Hz,2H),7.09(dd,2H),7.06(dd,J＝8.4Hz,2H),6.75(t,1H),4.5(br.s,4H),3.90-4.02(m,3H),3.61-3.66(m,1H),3.42-3.51(m,3H),3.03-3.21(m,2H)。

Example 15 preparation of compound 15: (2S,3R,4R,5S,6R) -2- (2-hydroxy-4- (4- (thiophene-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation ofIntermediate compound 15-2

15-120 g (86.6mmol,1.00eq) of the compound was taken, 200.0mL of DCM and 0.1mL of DMF were added, 12.1g (95.3mmol,1.10eq) of oxalyl chloride was added dropwise at 0 ℃, and after the dropwise addition was completed, the reaction was warmed to room temperature for 2 h. After the reaction was completed, a dichloromethane solution of compound 15-2 was obtained and used in the next step without further treatment.

(2) Preparation of intermediate Compound 15-4

Adding 15-313.8g (86.6mmol,1.00eq) of compound 15-2 obtained in step (1) in dichloromethane at 0 ℃ under nitrogen, and then adding AlCl in portions₃11.6g (86.6mmol,1.00eq) was added, and after completion of the addition, the reaction mixture was allowed to warm to room temperature for 6 hours. After the reaction is finished, cooling the reaction liquid to 0 ℃, adding 200mL of dilute hydrochloric acid, adding saturated salt solution for extraction, collecting an organic phase, and adding anhydrous Na₂SO₄Drying, filtering, and concentrating the filtrate by vacuum distillation to obtain concentrate. Ethanol was added to the concentrate to precipitate a solid, which was collected by filtration and dried under reduced pressure to give 25.8g of compound 15-4 as a white solid in 80% yield.

(3) Preparation of intermediate Compound 15-5

15-425.8 g (69.3mmol,1.00eq) of the compound was taken, 200.0mL of acetonitrile was added, and Et was added under nitrogen at 20 ℃ to₃SiH 24g (207.9mmol,3.00eq), followed by dropwise addition of BF at 25 ℃ under nitrogen₃.Et₂O39.2 g (277.2mmol,4.00eq), and the mixture was reacted at 25 ℃ for 12 h. After the reaction was complete, 100.0mL of saturated NaHCO was added to the reaction mixture₃And (3) adding MTBE into the aqueous solution for extraction, extracting the organic phase by using saturated saline solution, collecting the organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and concentrating the filtrate under reduced pressure to obtain a crude product. Crude product is used Silica gel column, mobile phase petroleum ether: ethyl acetate 50:1 to 10:1 gave 20.3g of compound 15-5 in 85% yield.

(4) Preparation of intermediate Compound 15-7

Weighing 15-520.3 g (58.9mmol,1.00eq) of compound, adding 300mL of redistilled THF at-70 deg.C in N₂To the above solution was added dropwise 47.2mL (2.5M,2.00eq) of a solution of n-BuLi in tetrahydrofuran under conditions of-70 ℃ under nitrogen stirring for 0.3h, followed by dropwise addition of a solution of compound 15-631.7 g (58.9mmol,1.00eq) in tetrahydrofuran (redistilled THF, 50.0mL) under nitrogen stirring for 1h at-70 ℃. The reaction solution was poured into saturated NH₄And (3) extracting with dichloromethane in a Cl aqueous solution, collecting an organic phase, and distilling under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 10:1 to 1:1 gave 24.6g of pure compound 15-7 in 52% yield.

(5) Preparation of intermediate Compound 15-8

15-724.6 g (30.6mmol,1.00eq) of the compound was weighed, 200.0mL of dichloromethane was added, and Et was added to the solution at 20 ℃ under nitrogen₃SiH 4.2g (36.7mmol,1.20eq), cooling to 0 deg.C and dropwise adding BF₃.Et₂O13g (91.8mmol,3.0eq), then warmed to room temperature and stirred for 6 h. After completion of the reaction, the reaction mixture was poured into 100.0mL of a saturated aqueous sodium bicarbonate solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 10:1 to 3:1 gave 11.6g of pure compound 15-8 in 48% yield.

(6) Preparation of the target Compound 15((2S,3R,4R,5S,6R) -2- (2-hydroxy-4- (4- (thien-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

11.6g (14.7mmol,1.00eq) of the compound 15-8 and 200.0mL of ethyl acetate are mixed uniformly with stirring, 4.5g (active ingredient content: 10%) of Pd/C is added under the condition of argon, the reaction system is vacuumized and filled with hydrogen, and the reaction is carried out for 12 hours at room temperature under the condition of 30psi of hydrogen pressure. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 50mm 10 um; mobile phase: water (0.1% HCOOH) -MeOH ], B%: 20% -80%, 30min) to give 1.7g of the title compound 15 as a white solid in 27% yield.

1HNMR(400MHz，DMSO)：7.71(d,1H),7.67(dd,2H),7.42(d,1H),7.40(d,1H),7.31(dd,2H),7.18(t,1H),7.08(s,1H),6.75(d,1H),5.60(br.s,1H),4.7(br.s,4H),3.91-4.04(m,3H),3.64-3.69(m,1H),3.41-3.50(m,1H),3.21-3.32(m,3H),3.07-3.20(m,1H)。

Example 16 preparation of compound 16: (2S,3R,4R,5S,6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 16-3

Weighing 16-120 g (67.3mmol,1.0eq) of compound, adding 100mL of redistilled tetrahydrofuran, and heating at-70 deg.C under N₂To the above solution was added dropwise 100.8mL (2.0M,3.0eq) of LDA tetrahydrofuran solution under-70 ℃ nitrogen for 1h, followed by dropwise addition of 16-236.2 g (67.3mmol,1.0eq) of the compound in tetrahydrofuran (redistilled THF, 100.0mL) and stirring at-70 ℃ nitrogen for 1 h. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 16.3g of pure compound 16-3 as a colorless oil with a yield of 32%.

(2) Preparation of intermediate Compound 16-4

16-316.3 g (21.5mmol,1.0eq) of the compound was weighed, 200.0mL of dichloromethane was added, and Et was added to the solution at 20 ℃ under nitrogen₃SiH 3g (25.8mmol,1.2eq), cooling to 0 deg.C and dropwise adding BF₃.Et₂O3.7 g (25.8mmol,1.2eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 100.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 5:1 gave 10.3g of pure compound 16-4 as a white solid with a yield of 65%.

(3) Preparation of the title compound 16((2S,3R,4R,5S,6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

16-410.3 g (14mmol,1.0eq) of the compound was weighed, 100.0mL of methanol was added, 3.5g of Pd/C (active ingredient content 10%) was added to the above solution under argon, the reaction system was evacuated and charged with hydrogen, and reacted at 50 ℃ under 50psi of hydrogen for 24 hours. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250: 100 mm: 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 20% -50%, 30min) to give 2.1g of the title compound 16 as a white solid with a yield of 40%.

1H NMR(400MHz，CD₃OD)，：7.21(dd,2H),7.10(dd,2H),6.50(d,2H),4.57(d,1H),3.98(s,2H),3.82-3.87(m,4H),3.54-3.63(m,2H)。

Example 17 preparation of compound 17: (2S,3R,4R,5S,6R) -2- (4- (4-isopropoxybenzyl) -2- (trifluoromethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with the structural formula

(1) Preparation ofIntermediate compound 17-3

Weighing 17-120 g (68mmol,1.0eq) of the compound, adding 150mL of redistilled tetrahydrofuran, and heating at-70 ℃ under N₂34mL (2.0M,1.0eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under-70 ℃ with stirring for 0.5h under nitrogen, followed by dropwise addition of a solution of compound 17-236.6 g (68mmol,1.0eq) of tetrahydrofuran (redistilled THF, 50.0mL) followed by stirring for 1h under nitrogen at-70 ℃ after completion of the dropwise addition. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 33.4g of pure compound 17-3 in 59% yield.

(2) Preparation of intermediate Compound 17-4

Weighing 17-333.4 g (40.1mmol,1.0eq) of the compound, adding 150.0mL of dichloromethane, and adding Et to the solution at 20 ℃ under nitrogen₃SiH 5.6g (48.1mmol,1.2eq), cooling to 0 deg.C and dropwise adding BF₃.Et₂O6.8g (48.1mmol,1.2eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 100.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 50:1 to 5:1 gave 19.6g of pure compound 17-4 as a white solid with a yield of 60%.

(3) Preparation of the titled compound 17((2S,3R,4R,5S,6R) -2- (4- (4-isopropoxybenzyl) -2- (trifluoromethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

Weighing 17-419.6 g (24mmol,1.0eq), adding 100.0mL methanol, adding 6.0g Pd/C (active ingredient content 10%) into the solution under argon, vacuumizing the reaction system, filling hydrogen, and reacting at 50 deg.C under 50psi hydrogen for 12 h. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250: 100 mm: 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 20% -80%, 30min) to give 4.05g of the title compound 17 as a white solid with a yield of 37%.

1H NMR(400MHz，CD₃OD)，：7.42(s,1H),7.18(d,1H),7.16(d,1H),7.14(dd,2H),6.89(dd,2H),4.68-4.70(m,1H),4.53-4.56(m,1H),3.96(s,2H),3.54-3.79(m,6H),1.36(d,6H)。

Example 18 preparation of compound 18: (2S,3R,4R,5S,6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula

(1) Preparation of intermediate Compound 18-2

The compound (18-130.0 g, 137mmol,1.00eq) was taken, 200.0mL of DCM and 0.1mL of DMF were added, 19.1g of oxalyl chloride (150.7mmol,1.10eq) was added dropwise at 0 deg.C, and after the dropwise addition was completed, the reaction was warmed to room temperature for 3 h. After the reaction was completed, a dichloromethane solution of compound 18-2 was obtained and used in the next step without further treatment.

(2) Preparation of intermediate Compound 18-4

Adding 24g (137mmol,1.00eq) of compound 18-3 into the dichloromethane solution of compound 18-2 obtained in step (1) at 0 ℃ under nitrogen, and adding AlCl in batches₃18.3g (137mmol,1.00eq), and after the addition was complete, the reaction mixture was warmed to room temperature for 5 h. After the reaction is finished, cooling the reaction liquid to 0 ℃, adding 200mL of dilute hydrochloric acid, adding saturated salt solution for extraction, collecting an organic phase, and adding anhydrous Na₂SO₄Drying, filtering, and reducing filtrateAnd (5) performing distillation and concentration under pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 50:1, and dried under reduced pressure to give 42.8g of compound 18-4 as a white solid with a yield of 83%.

(3) Preparation of intermediate Compound 18-5

The compound (18-442.8 g, 113.7mmol,1.00eq) was taken, 350.0mL of acetonitrile was added, and Et was added under nitrogen at 20 ℃ to₃SiH 53g (515.3mmol,4.00eq), followed by dropwise addition of BF at 25 ℃ under nitrogen₃.Et₂O32.3 g (227.4mmol,2.00eq), and the mixture was reacted at 25 ℃ for 12 h. After the reaction was complete, 300.0mL of saturated NaHCO was added to the reaction mixture₃And (3) adding MTBE into the aqueous solution for extraction, extracting the organic phase by using saturated saline solution, collecting the organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering the organic phase, and concentrating the filtrate under reduced pressure to obtain a crude product. The crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 35.9g of compound 18-5 in 87.0% yield.

(4) Preparation of intermediate Compound 18-7

Weighing 18-535.9 g (98.9mmol,1.00eq) of compound, adding 550mL of redistilled THF at-70 deg.C in N₂To the above solution was added dropwise 35.6mL (2.5M,1.00eq) of n-BuLi in tetrahydrofuran under-70 ℃ with stirring for 0.3h under nitrogen, followed by dropwise addition of compound 18-653.2 g (98.9mmol,1.00eq) in tetrahydrofuran (re-evaporated THF, 100.0mL) with stirring for 1h under nitrogen at-70 ℃. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by adopting MTBE, collecting an organic phase, and distilling the organic phase under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 61g of pure compound 18-7 in a yield of 75%.

(5) Preparation of intermediate Compound 18-8

18-761 g (74.2mmol,1.00eq) of the compound was weighed, 400.0mL of dichloromethane was added, and Et was added to the solution at room temperature under nitrogen₃SiH 10.3g (89mmol,1.20eq), cooling to 0 deg.C and dropwise adding BF₃.Et₂O12.6g (89mmol,1.20eq), then warmed to room temperature and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 200.0mL of a saturated aqueous sodium bicarbonate solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 40.1g of pure compound 18-8 in 67% yield.

(6) Preparation of the aimed compound 18((2S,3R,4R,5S,6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)

40.1g (49.7mmol,1.00eq) of the compound 18-8 and 400.0mL of ethyl acetate are mixed uniformly with stirring, then 7.4g (10% of active ingredient content) of Pd/C is added under the condition of argon, the reaction system is vacuumized and filled with hydrogen, and the reaction is carried out for 12 hours at 20 ℃ under the condition of 30psi of hydrogen. After completion of the reaction, filtration was carried out by suction, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250 mm 50mm 10 um; mobile phase: water (0.1% HCOOH) -ACN ], B%: 20% -60%, 30min) to give 7.09g of the title compound 18 as a white solid with a yield of 32%.

1HNMR(400MHz，DMSO)：7.17(d,1H),7.08(dd,2H),6.95(d,1H),6.72(d,1H),6.68(dd,2H),4.7(br.s,4H),3.92-4.00(m,1H),3.98(s,2H),3.60-3.69(m,5H),3.40-3.50(m,1H),3.34(t,4H),2.85(t,4H),2.28(s,3H)。

Example 19 preparation of compound 19: (2S,3R,4R,5S,6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate compoundsSubstance 19-3

Weighing 19-120 g (54.8mmol,1.0eq) of compound, adding 100mL of redistilled tetrahydrofuran, and heating at-70 deg.C under N₂82mL (2.0M,3.0eq) of a solution of n-butyllithium in tetrahydrofuran was added dropwise to the above solution under conditions of-70 ℃ under nitrogen and stirring for 0.5h, and then a solution of compound 19-230.3 g (54.8mmol,1.0eq) in tetrahydrofuran (redistilled THF, 50.0mL) was added dropwise and stirred for 1h under-70 ℃ under nitrogen after completion of the addition. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 26.7g of pure compound 19-3 in a yield of 58%.

(2) Preparation of intermediate Compound 19-4

19-326.7 g (31.8mmol,1.0eq) of the compound was weighed, 200.0mL of dichloromethane was added, and Et was added to the solution at 20 ℃ under nitrogen₃SiH 4.4g (38.2mmol,1.2eq), cooling to 0 deg.C and dropwise adding BF₃.Et₂O5.4g (38.2mmol,1.2eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 100.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 5:1 gave 14.4g of pure compound 19-4 as a white solid with a yield of 55%.

(3) Preparation of the title compound 19((2S,3R,4R,5S,6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol)

19 to 414.4 g (17.5mmol,1.0eq) of the compound was weighed, 100.0mL of methanol was added, 4.3g of Pd/C (active ingredient content: 10%) was added to the above solution under argon, the reaction system was evacuated and charged with hydrogen, and reacted at 50 ℃ under 50psi of hydrogen for 12 hours. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250: 100 mm: 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 20% -80%, 40min) to give 3g of the title compound 19 as a white solid with a yield of 37%.

1H NMR(400MHz，CD₃OD)，：7.12(dd,2H),6.86(dd,2H),6.47(d,2H),4.52-4.54(m,1H),4.28(d,2H),4.12-4.16(m,1H),3.98(s,2H),3.84-3.87(m,4H),3.80-3.82(m,2H),3.61-3.63(m,2H),2.60-2.65(m,2H)。

Example 20 preparation of compound 20: (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol with the structural formula

(1) Preparation of intermediate Compound 20-3

Weighing 20-153 g (213.4mmol,1.0eq) of the compound, adding 265mL of redistilled tetrahydrofuran, and heating at-70 deg.C under N₂106.6mL (2.0M,1.0eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under-70 ℃ with stirring for 0.5h under nitrogen, followed by dropwise addition of 20-2118 g (213.4mmol,1.0eq) of a tetrahydrofuran (redistilled THF, 100.0mL) solution of compound, followed by stirring for 1h under-70 ℃ with nitrogen after completion of the dropwise addition. The reaction solution was poured into saturated NH₄And (3) extracting the solution in the Cl aqueous solution by using ethyl acetate, collecting an organic phase, and carrying out reduced pressure distillation to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 20:1 to 5:1 gave 109.5g of pure compound 20-3 in a yield of 64%.

(2) Preparation of intermediate Compound 20-4

Weighing compounds 20-3109.5g (136.6mmol,1.0eq), 700.0mL of dichloromethane were added and Et was added to the solution at 20 ℃ under nitrogen₃SiH 19g (163.9mmol,1.2eq), cooling to 0 ℃ and dropwise adding BF₃.Et₂O23.3g (163.9mmol,1.2eq), then warmed to 20 ℃ and stirred for 2 h. After completion of the reaction, the reaction mixture was poured into 500.0mL of a saturated aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Passing the crude product through a silica gel column, wherein the mobile phase is petroleum ether: ethyl acetate 100:1 to 5:1 gave 64.5g of pure compound 20-4 as a white solid with a yield of 60%.

(3) Preparation of the titled compound 20(((2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol)

20-464.5 g (82mmol,1.0eq) of the compound is weighed, 500.0mL of methanol is added, 20g of Pd/C (active ingredient content is 10%) is added into the solution under the condition of argon, the reaction system is vacuumized and filled with hydrogen, and the reaction system is reacted for 24 hours under the condition of 50psi of hydrogen at 50 ℃. After completion of the reaction, suction filtration was carried out, the filtrate was concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18250: 100 mm: 10 um; mobile phase: water (0.1% TFA) -ACN ], B%: 25% -53%, 30min) to give 15.02g of the title compound 20 as a white solid in 43% yield.

1H NMR(400MHz，CD₃OD)，：7.09(d,J＝8.8Hz,2H),6.83(d,J＝8.4Hz,2H),6.45(d,2H),4.52-4.54(m,1H),4.02(q,2H),3.98(s,2H),3.84-3.87(m,4H),3.61-3.63(m,2H),1.35(t,3H)。

In order to evaluate the efficacy of the glycoside derivatives of the present invention, the following test examples were conducted.

Test example 1 therapeutic Effect of glycoside derivatives of the present invention on type I diabetes mellitus model of ICR mice induced by Tetraoxypyrimidine

The healthy ICR mice are fed adaptively for 3 days, water is not forbidden in a fasting state for 12-16 hours on the 3 rd day, injection is completed within 30s after 70.0mg/kg and 0.1mL/10g of alloxan ALX (prepared currently) is injected into tail veins at one time, an I type diabetes animal model is induced, and the normal unmolded mice are injected with the same amount of physiological saline into the tail veins. Feeding the mice normally for 2 days after injection, fasting the mice for 12-16 h without water prohibition, taking blood from the tail tips after ALX injection for 72h, determining fasting blood glucose concentration (FGB) by adopting a trinonoxan code-regulation-free fast glucometer (namely the blood glucose concentration before administration), and regarding the mice with the FGB value of 11.1-25.0 mmol/L as successfully modeled diabetic mice for experiment.

After selecting the diabetic mice with successful modeling, the mice are immediately randomly grouped according to the fasting blood glucose value (FGB) of the mice, and the mice are divided into 22 groups, wherein each group comprises 4 mice and half of the mice, wherein the diabetes model group G2, the metformin group G3 (positive control, 200mg/kg) and the glycoside derivatives of the invention are respectively administered in groups G4-G23, and the control group G1 (4 healthy and normal blood glucose mice in the same batch are used as a blank control group G1), and the specific grouping condition is shown in Table 1. The oral gavage administration is started the next day after grouping, 1 time per day, the continuous administration is carried out for 7d, the fasting blood glucose concentration (FGB) (namely the blood glucose value after administration) of the mice is measured by a rapid glucometer after 1 hour of the administration on the 7 th day, and the result is expressed by unit mmol.L^-1The results of the specific tests are shown in Table 1.

Table 1: the glycoside derivative has the treatment effect on ICR mouse type I diabetes mellitus model caused by alloxan

Remarking: the method comprises the following steps: p is less than 0.01 compared with the blank group; secondly, the step of: compared with the model group, P is less than 0.05; ③: compared with the model group, P is less than 0.01.

As can be seen from the table, for the type I diabetes model of an ICR mouse caused by alloxan, compared with a model group, the positive control metformin group and the glycoside derivative administration group have the effect of reducing blood sugar, and have obvious treatment effect, and part of the glycoside derivative administration groups have the effect of reducing blood sugar better than the positive control group, so that the glycoside derivative has the treatment effect on the type I diabetes.

Test example 2 therapeutic Effect of glycoside derivatives of the present invention on type II diabetes

In the experiment, a II-type diabetes rat model is prepared by adopting a method of injecting low-dose Streptozotocin (STZ) to damage pancreatic islets after high-fat diet induces insulin resistance of rats so as to cause blood sugar rise, and the pathogenesis process of human II-type diabetes can be simulated. Streptozotocin has a highly selective toxic effect on islet beta cells, damages the islet beta cells through free radicals, causes dysfunction of the islet beta cells, reduces insulin synthesis, and causes diabetes.

The specific experiment is as follows:

after one week of adaptive feeding, rats were given high-fat and high-sugar diet, and after 4 weeks of feeding, the rats were fasted without water deprivation for 12 hours and were intraperitoneally injected with 2% STZ solution at a dose of 30 mg/kg. After feeding with high-fat high-sugar feed for 3 days, fasting for 12h, collecting blood 200 μ L from rat inner canthus vein with capillary glass tube (or collecting blood 200 μ L from rat tail vein with disposable blood taking needle), measuring rat fasting blood glucose value (FBG) with rapid glucometer (i.e. blood glucose value before administration), and collecting fasting blood glucose value of 16.7 mmol.L^-1～25mmol·L^-1As a judgment standard for judging the success of the model building of the immune model of the type II diabetes.

Randomly selecting II type diabetes model rats successfully molded, and dividing the model rats into 29 groups, wherein each group comprises 4 rats and each half of rats is male and female; the test results are respectively a model group G2, a dapagliflozin group G3 (positive control group) and each administration group G4-G30 of the glycoside derivative of the invention, and a blank control group G1 (4 healthy and normal-blood-sugar mice fed with the same basal feed are used as a blank control group G1). Wherein, the rats of the administration groups G4-G30 and the Dagliflozin group G3 of the glycoside derivative of the invention are gavaged with corresponding doses of drugs (dissolved in 0.4 percent of CMCNa) every day, while the rats of the blank control group G1 and the type II diabetes model group G2 are gavaged with 0.4 percent of CMCNa with the same volume every day, are administrated for 1 time every day and are administrated for 2 weeks continuously, and the blood sugar values after 1 week of administration and 2 weeks of administration are respectively measured, and the measurement results are shown in Table 2:

Table 2: therapeutic action of glycoside derivatives on type II diabetes

Note: compared to the blank group:^◆P＜0.05；^◆◆p is less than 0.01; compared to the model set:^▼P＜0.05；^▼▼P＜0.01。

from the results, it can be seen that a rat type II diabetes model can be constructed by using the high-fat high-sugar feed in combination with streptozotocin, and all rats have high blood sugar rise and very significant difference, and no statistical significance difference exists between groups after grouping. After 1 week and 2 weeks of administration, compared with the model group G2, the glycoside derivative of the invention has significant blood sugar lowering effect in the high, medium and low dose groups; all doses ofcompound 1, compound 2, compound 6, compound 9, compound 3, compound 4, compound 11, compound 12, high and medium blood glucose levels and compound 17 were lower than in thedapagliflozin group 1 weeks after administration compared to the dapagliflozin group G3; after 2 weeks of administration, the blood glucose levels of the high and medium doses of thecompound 1, the medium and low doses of the compound 2, the medium dose of the compound 6, the high and medium doses of the compound 9, the high and medium doses of the compound 11, the high and medium doses of the compound 12 and the high dose of the compound 17 are all lower than those of the dapagliflozin group, which proves that the glycoside derivatives of the present invention have the effect of reducing blood glucose for the blood glucose increase caused by type II diabetes.

Claims (7)

1. The application of a glycoside derivative in a medicine for preventing and/or treating type II diabetes mellitus is that the glycoside derivative is a compound shown as a formula I or a pharmaceutically acceptable salt thereof:

wherein A is oxygen, - (CH)₂)_m-, or-NH-; m is 1, 2, or 3;

b is oxygen atom or sulfur atom;

R₁，R₂，R₃，R₄，R₅，R₆independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH₂-aryl, -OCH₂Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen (fluorine, chlorine, bromine, or iodine), -CN, alkoxyalkoxy, or-NR₇R_7aOr contains 1-4 of N, O, S, SO and/or SO₂3-14 membered heterocyclic ring of the heteroatom(s);

wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen (fluoro, chloro, bromo, or iodo), hydroxy, amino, carboxy, cyano, alkoxy, or nitro;

the R is₇、R_7aIndependently a hydrogen atom or an alkyl group.

2. The use according to claim 1, wherein in the compound of formula I, R is₂Is hydrogen, hydroxy, -O-aryl, -OCH₂Aryl, alkoxy, alkyl, aryl, heteroaryl, -CF₃Or halogen (fluorine, chlorine, bromine, or iodine).

3. Use according to claim 1 or 2, wherein in the compound of formula I, R is₄，R₅Independently hydrogen, hydroxy, alkoxy, -O-aryl, -OCH₂Aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF₃、-OCHF₂、-OCF₃Halogen (fluorine, chlorine, bromine, or iodine), or-CN; r₄，R₅The same or different.

4. Use according to any one of claims 1 to 3, wherein, in said compound of formula I, said R is₆Is hydrogen, hydroxy, carboxy, alkoxy, alkyl, cycloalkyl, -CF₃、-OCHF₂、-OCF₃Halogen (fluorine, chlorine, bromine, or iodine), or-CN.

5. Use according to any one of claims 1 to 4, wherein said alkoxy is C1-C6 alkyloxy; C1-C6 alkyloxy is illustratively methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy; said-O-aryl is

said-O-heteroaryl is

the-OCH₂Aryl is PhCH₂O-、

the-OCH₂-heteroaryl is

The alkyl group is a C1-C6 chain alkyl group including a straight chain alkyl group or a branched alkyl group, illustratively a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, or an isohexyl group; the cycloalkyl group is a C3-C6 cycloalkyl group including substituted or unsubstituted cycloalkyl groups, illustratively cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like,

Cyclopentyl, or cyclohexyl; the aryl group is phenyl, p-methylphenyl, p-fluorophenyl, o-chlorophenyl, m-methoxyphenyl, or

Said heteroaryl is

The alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy, or

The ester group is

6. The use according to any one of claims 1 to 5, wherein the compound of formula I is (2S,3R,4R,5S,6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol -pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxyethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4- (2,4, 5-trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (4- (4-isopropoxybenzyl) -2- (trifluoromethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S,3R,4R,5S,6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol, or (2S,3R,4R,5S,6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol.

7. Use of the glycoside derivative according to any one of claims 1 to 6 for the prophylaxis and/or treatment of high-fat high-carbohydrate food-induced type II diabetes.

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