CN108203432B

CN108203432B - Glucopyranosyl derivative and application thereof in medicine

Info

Publication number: CN108203432B
Application number: CN201711372486.1A
Authority: CN
Inventors: 顾峥; 伍武勇; 康盼盼; 覃浩雄; 曲桐; 黄伟明
Original assignee: Yichang Hec Changjiang Pharmaceutical Co ltd
Current assignee: YICHANG HEC CHANGJIANG PHARMACEUTICAL Co.,Ltd.
Priority date: 2016-12-20
Filing date: 2017-12-19
Publication date: 2021-03-02
Anticipated expiration: 2037-12-19
Also published as: CN108203432A

Abstract

The invention relates to a glucopyranosyl derivative serving as a sodium-dependent glucose transporter (SGLTs) inhibitor, a pharmaceutical composition containing the derivative and application thereof in medicine, in particular to the glucopyranosyl derivative shown in a formula (I) or pharmaceutically acceptable salt or all stereoisomers thereof, or the pharmaceutical composition containing the derivative and application of the derivative and the pharmaceutical composition in preparing medicines for treating diabetes and diabetes-related diseases.

Description

Glucopyranosyl derivative and application thereof in medicine

Technical Field

The invention relates to glucopyranosyl derivatives as sodium-dependent glucose transporter (SGLTs) inhibitors, a method for preparing the same, a pharmaceutical composition containing the derivatives and application of the derivatives and the composition thereof in medicines. More specifically, the compound shown in the general formula (I) or pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition containing the compound and the application of the compound and the pharmaceutical composition in preparing medicines for treating diabetes and diabetes-related diseases.

Background

Diabetes mellitus is a common chronic disease characterized by hyperglycemia, which occurs with decreased insulin resistance in peripheral tissues, decreased insulin secretion in vivo, and increased hepatic gluconeogenesis. When the condition cannot be effectively controlled by diet and exercise, it is required to additionally use insulin or an oral hypoglycemic agent for treatment. The current hypoglycemic agents include biguanides, sulfonylureas, insulin sensitizers, glinides, alpha-glucosidase inhibitors, DPP-IV (dipeptidyl peptidase IV) inhibitors, and the like. However, these hypoglycemic agents are deficient at present, biguanides cause lactic acidosis, sulfonylureas cause severe hypoglycemia, meglitinides cause hypoglycemia due to improper use, insulin sensitizers cause edema, heart failure and weight gain, alpha-glucosidase inhibitors cause abdominal distension and diarrhea, and DPP-IV inhibitors need to be combined with metformin to achieve ideal hypoglycemic effects. Therefore, development of a novel hypoglycemic agent which is safer and more effective is urgently required.

It has been found that glucose transporters are a class of carrier proteins that are embedded in cell membranes to transport glucose, which must pass through the lipid bilayer structure of the cell membrane. Glucose transporters fall into two broad categories, one being sodium-dependent glucose transporters (SGLTs); another class is glucose transporters (GLUTs). The two major family members of SGLTs are SGLT1 and SGLT 2. SGLT1 is distributed mainly in the small intestine, kidney, heart and trachea, expressed mainly at the brush border of the small intestine and in the distant S3 stage of the renal proximal convoluted tubule, expressed in small amounts in the heart and trachea, and transports glucose and galactose in the sodium-glucose 2:1 ratio. While SGLT2 is distributed primarily in the kidney, expressed primarily in the distal S1 segment of the kidney proximal convoluted tubule, transporting glucose at a sodium-glucose 1:1 ratio. In organisms, SGLTs transport glucose against a concentration gradient in an active manner while consuming energy, whereas GLUTs transport glucose along a concentration gradient in a manner that facilitates diffusion, without consuming energy for the transport process. Studies have shown that plasma glucose is normally filtered in the glomeruli of the kidney and 90% of the glucose is actively transported to the epithelial cells by SGLT2 at the proximal S1 segment of the kidney tubule, and 10% of the glucose is actively transported to the epithelial cells by SGLT1 at the distal S3 segment of the kidney tubule and is transported to the surrounding capillary network by GLUT on the basal membrane side of the epithelial cells, completing reabsorption of glucose by the kidney tubules. Therefore, SGLTs are the first pass for regulating the carbohydrate metabolism of cells and are ideal targets for effectively treating diabetes. It has been found that patients deficient in SGLT2 have a large urinary sugar excretion, which provides a basis for the treatment of diabetes by reducing glucose absorption through inhibition of SGLT2 activity. Therefore, the activity of SGLTs transporters is inhibited, the reabsorption of glucose by renal tubules can be blocked, and the excretion of glucose in urine is increased, so that the concentration of glucose in blood plasma is normalized, and the conditions of diabetes and diabetic complications are controlled. Inhibition of SGLTs does not affect normal glucose counterregulation mechanisms, thereby causing a risk of hypoglycemia; and simultaneously, the blood sugar is reduced by increasing the excretion of the glucose in the kidney, and the weight of the obese patient can be reduced. It has also been found that the mechanism of action of SGLTs inhibitors is independent of islet β -cell dysfunction or the degree of insulin resistance, and therefore, its effectiveness does not decrease with β -cell failure or severe insulin resistance. It can be used alone or in combination with other hypoglycemic agents, and has better hypoglycemic effect through mechanism complementation. Therefore, SGLTs inhibitors are ideal novel hypoglycemic agents.

In addition, SGLTs inhibitors have been found to be useful in the treatment of complications associated with diabetes. Such as retinopathy, neuropathy, nephropathy, insulin resistance caused by glucose metabolism disorder, hyperinsulinemia, hyperlipidemia, obesity, etc. Meanwhile, the SGLTs inhibitor can be used together with the existing therapeutic drugs, such as sulfonamide, thiazolidinedione, metformin, insulin and the like, and the dosage is reduced under the condition of not influencing the drug effect, so that the occurrence of adverse reactions is avoided or reduced, and the compliance of patients to treatment is improved.

According to the current research, the effect of the medicament with both SGLT1 inhibitory activity and SGLT2 inhibitory activity on the clinical efficacy of reducing the blood sugar level in the body of a diabetic patient is better than that of a pure selective SGLT2 inhibitor. On the one hand, the SGLT1/SGLT2 dual inhibitor can reduce glucose absorbed into the blood via the gastrointestinal tract by inhibiting SGLT1 and can increase glucose excretion by inhibiting SGLT2, thereby more effectively lowering blood glucose levels; on the other hand, the SGLT1/SGTL2 dual inhibitor can also intervene in multiple cardiovascular disease risk factors, such as lowering postprandial blood glucose, lowering blood pressure, reducing body weight, lowering triacylglycerol and the like, thereby reducing the risk of cardiovascular disease onset. Evidence shows that the SGLT1/SGLT2 dual-inhibitor Sotagliflozin which is currently in the clinical III stage can greatly reduce postprandial blood sugar, obviously increase GLP-1 (glucagon-like peptide-1) and PYY (intestinal tract derived hormone casein peptide) levels, moderately promote urine sugar excretion, and reduce the urogenital infection rate compared with the high-selectivity SGLT2 inhibitor. In addition, the Sotagliflozin can also generate obvious hypoglycemic effect on type II diabetes patients with renal function impairment by inhibiting SGLT1, and more importantly, the hypoglycemic effect mechanism is independent of insulin, so that the risk of hypoglycemia is low, and gastrointestinal adverse reactions such as SGLT 1-related diarrhea and the like are not found at present, so that the Sotagliflozin has better safety, tolerance and Clinical compliance (B Zambrowicz1et al, Clinical trial,2012,92(2) 158-169; Zhou Tanixing and the like, modern medicine and clinic, 30(4),2015, 465-469).

In conclusion, the SGLTs inhibitor, particularly the compound with SGLT1 and SGLT2 double inhibitory activities has good development prospect as a novel diabetes treatment drug.

Disclosure of Invention

The invention provides a compound which has both obvious SGLT2 inhibition activity and better SGLT1 inhibition activity and is used for treating diabetes, insulin resistance, hyperglycemia, hyperinsulinemia, elevation of fatty acid or glycerol levels in blood, hyperlipidemia, obesity, syndrome X, diabetic complications, atherosclerosis or hypertension and complications thereof. The invention also provides a method for preparing the compounds, a pharmaceutical composition containing the compounds and a method for preparing medicaments for treating the diseases of mammals, particularly human beings by using the compounds and the compositions, wherein the compounds have better pharmacological activity and better in-vivo metabolic kinetic property and in-vivo pharmacodynamic property compared with the existing similar compounds. Specifically, the compound of the present invention has not only an excellent SGLT2 inhibitory activity but also an appropriate SGLT1 inhibitory activity, and therefore has more excellent hypoglycemic and urine glucose excretion-promoting effects. Therefore, compared with the existing similar compounds, the compound provided by the invention has better drugability.

Specifically, the method comprises the following steps:

in one aspect, the invention relates to a compound having a structure shown in formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound having the structure shown in formula (I),

wherein R is¹、R²、R³、R⁴、R⁵、R⁶And ring A has the meaning as described in the present invention.

In some embodiments, R¹Is H, D, F, Cl, Br, I, hydroxyl, cyano, nitro, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₄Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₄Haloalkoxy, C₁-C₄Alkylamino radical, C₁-C₄Alkylthio or C₃-C₆Cycloalkyl, wherein each of said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₄Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₄Haloalkoxy, C₁-C₄Alkylamino radical, C₁-C₄Alkylthio and C₃-C₆Cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, carboxy, mercapto, nitro, C₁-C₆Alkyl and amino;

each R²And R³Independently H, D, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino or 3-6-membered heterocyclic group, wherein each of said C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy radical, C ₁-C₄Alkylthio radical, C₁-C₄Alkylamino and 3-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, carboxyl, mercapto, C₁-C₄Hydroxyalkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino radical, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₆-C₁₀Aryl radical C₁-C₂Alkyl, 5-10 membered heteroaryl C₁-C₂Alkyl radical, C₆-C₁₀Aryl radical C₁-C₂Alkoxy, 5-to 10-membered heteroaryl C₁-C₂Alkoxy, -SR¹³、-C(＝O)R¹³、-C(＝O)OR¹³、-OC(＝O)R¹³、-OC(＝O)OR¹³、-NHC(＝O)R¹³、-NHS(＝O)₂R¹³、-C(＝O)NHR¹³Trifluoromethyl, -S (═ O)₂NHR¹³、-S(＝O)₂R¹³and-S (═ O) R¹³Substituted with the substituent(s);

or R²、R³Together with the carbon atom to which they are attached form C₃-C₆Cycloalkyl or 3-6 membered heterocyclyl, wherein each of said C₃-C₆Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, nitro, mercapto and amino;

R⁴is-OR^4a、-NR^4aR^4bor-SR^4c；

Each R^4a、R^4bAnd R^4cIndependently H, D, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₆-C₁₀Aryl radical C₁-C₂Alkyl or 5-10 membered heteroaryl C₁-C₂Alkyl, wherein each of said C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl, 5-to 10-membered heteroaryl, C₆-C₁₀Aryl radical C₁-C₂Alkyl and 5-10 membered heteroaryl C₁-C₂Alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino 、C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₄Hydroxyalkyl, carboxy, mercapto, -SR¹³、-C(＝O)R¹³、-C(＝O)OR¹³、-OC(＝O)R¹³、-OC(＝O)OR¹³、-NHC(＝O)R¹³、-NHS(＝O)₂R¹³、-C(＝O)NHR¹³Trifluoromethyl, -S (═ O)₂NHR¹³、-S(＝O)₂R¹³and-S (═ O) R¹³Substituted with the substituent(s);

each R⁵And R⁶Independently H, D, F, Cl, Br, I, cyano, nitro, C₂-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkoxy, 3-to 6-membered heterocyclic group, C₆-C₁₀Aryl, 5-10 membered heteroaryl, -SR¹³、-S(＝O)R¹³、-S(＝O)₂R¹³、-C(＝O)R¹³、-NR¹³R¹⁴or-C (═ O) NHR¹³Wherein each of C₂-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkoxy, 3-to 6-membered heterocyclic group, C₆-C₁₀Aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, amino, cyano and nitro, provided that when R is⁵And R⁶While being H, R²And R³At least 1 is not H;

or R⁵、R⁶And the carbon atom to which each is attached forms a 5-membered heterocyclic group or a 6-membered heterocyclic group, wherein each of the 5-membered heterocyclic group and the 6-membered heterocyclic group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from H, D, F, Cl, Br, I, hydroxy, oxo (═ O), C, and₁-C₆alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, cyano and nitro, provided thatWhen R is⁵And R⁶Form a 5-membered heterocyclic group or a 6-membered heterocyclic group with the carbon atom to which each is attached, and R ²And R³While being H, R^10a、R^10b、R^10cAnd R^10dNot H at the same time;

ring A is

X is-CR^7aR^7b-, -O-or-NR^7a-；

Y is-CR^8aR^8b-, -O-or-NR^8a-；

Z is-CR^9aor-N ═ or;

each R^7a、R^7b、R^8a、R^8bAnd R^9aIndependently H, D, F, Cl, Br, I, hydroxyl, cyano, nitro, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino radical, C₆-C₁₀Aryl or 5-to 10-membered heteroaryl, wherein each C is₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, C₁-C₆Alkyl, carboxyl, mercapto, C₁-C₄Hydroxyalkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio and C₁-C₄Substituted by alkylamino;

each R^10a、R^10b、R^10c、R^10d、R^11a、R^11b、R^12a、R^12bAnd R^12cIndependently H, D, F, Cl, Br, I, hydroxyl, cyano, nitro, C₁-C₆Alkyl radical, C₁-C₄Alkoxy radicalBase, C₁-C₄Alkylamino radical, C₁-C₄Alkylthio radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkoxy, C₆-C₁₀Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -C (═ O) R¹³、-C(＝O)OR¹³、-S(＝O)₂R¹³、-S(＝O)R¹³、-C(＝O)NR¹³R¹⁴or-NR¹³R¹⁴Wherein each of C₁-C₆Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylamino radical, C₁-C₄Alkylthio radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkoxy, C₆-C₁₀Aryl, 5-10 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, nitro, C ₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, carboxyl, mercapto, C₁-C₄Hydroxyalkyl radical, C₁-C₄Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, -C (═ O) R¹³、-C(＝O)OR¹³、-S(＝O)₂R¹³、-S(＝O)R¹³、-C(＝O)NR¹³R¹⁴and-NR¹³R¹⁴Substituted with the substituent(s);

or R^10a、R^10bAnd the carbon atoms to which they are attached together form a carbonyl group;

or R^10c、R^10dAnd the carbon atoms to which they are attached together form a carbonyl group;

or R^12a、R^12bAnd the carbon atoms to which they are attached together form a carbonyl group;

each R¹³And R¹⁴Independently H, D, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 3-6 membered heterocyclyl, C₆-C₁₀Aryl or 5-to 10-membered heteroaryl, wherein each C is₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 3-to 6-membered heterocyclic group、C₆-C₁₀Aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, carboxyl, mercapto, C₁-C₄Hydroxyalkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino radical, C₆-C₁₀Aryl and 5-10 membered heteroaryl.

In still other embodiments, the invention relates to a compound of formula (II) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (II),

wherein R is ¹、R²、R³、R⁴、R⁵、R⁶And ring A has the meaning as described in the present invention.

In still other embodiments, the invention relates to compounds of the structure shown in formula (I-a), or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of compounds of the structure shown in formula (I-a),

In still other embodiments, the invention relates to compounds of the structure shown in formula (I-b), or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of compounds of the structure shown in formula (I-b),

In still other embodiments, the invention relates to compounds of the structure of formula (II-a), or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of compounds of the structure of formula (II-a),

In still other embodiments, the invention relates to compounds of the structure of formula (II-b), or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs of compounds of the structure of formula (II-b),

In some embodiments, wherein each R is²And R³Independently H, D, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio group、C₁-C₄Alkylamino or 5-6-membered heterocyclic group, wherein each of said C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkylthio radical, C₁-C₄Alkylamino and 5-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, C₁-C₄Alkyl, carboxyl, mercapto, C₁-C₂Hydroxyalkyl radical, C₁-C₂Alkoxy radical, C₁-C₂Alkylthio radical, C₁-C₂Alkylamino, -SR¹³、-C(＝O)R¹³、-C(＝O)OR¹³、-OC(＝O)R¹³、-OC(＝O)OR¹³、-NHC(＝O)R¹³、-NHS(＝O)₂R¹³、-C(＝O)NHR¹³Trifluoromethyl, -S (═ O)₂NHR¹³、-S(＝O)₂R¹³and-S (═ O) R¹³Substituted with the substituent(s);

or R²、R³Together with the carbon atom to which they are attached form C₃-C₆Cycloalkyl or 5-6 membered heterocyclyl, wherein each of said C₃-C₆The cycloalkyl and 5-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, nitro, mercapto and amino.

In some embodiments, wherein each R is²And R³Independently H, D, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, or a 5-6 membered heterocyclyl group, wherein each of said methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, and 5-6 membered heterocyclyl groups is optionally substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, carboxy, and hydroxymethyl;

Or R²、R³And together with the carbon atom to which they are attached form a cyclopropyl group, a cyclobutyl group or a 5-6 membered heterocyclic group, wherein each of the cyclopropyl group, the cyclobutyl groupAnd 5-6 membered heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of D, F, Cl, Br, I, hydroxy, cyano, amino, mercapto, carboxy and hydroxymethyl.

In some embodiments, R⁴is-OR^4a、-NR^4aR^4bor-SR^4c；

Each R^4a、R^4bAnd R^4cIndependently H, D, C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl, 5-6 membered heterocyclyl, C₆-C₁₀Aryl and 5-6 membered heteroaryl, wherein each C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 5-6 membered heterocyclyl, C₆-C₁₀Aryl and 5-6 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₁-C₂Hydroxyalkyl, carboxy, mercapto, -SR¹³、-C(＝O)R¹³、-C(＝O)OR¹³、-OC(＝O)R¹³、-OC(＝O)OR¹³、-NHC(＝O)R¹³、-NHS(＝O)₂R¹³、-C(＝O)NHR¹³Trifluoromethyl, -S (═ O)₂NHR¹³、-S(＝O)₂R¹³and-S (═ O) R¹³Substituted with the substituent(s).

In some embodiments, wherein R⁴is-OR^4a、-NR^4aR^4bor-SR^4c；

Each R^4a、R^4bAnd R^4cIndependently H, D, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, wherein each of said methyl, ethyl, propyl, cyclopropyl, and cyclobutyl is optionally substituted with 1, 2, 3, 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, methyl, ethyl, ethylene, propylene, acetylene, carboxy, mercapto, hydroxymethyl, and trifluoromethyl.

In some embodiments, wherein ring a is

In some embodiments, each R is^7a、R^7b、R^8a、R^8bAnd R^9aIndependently H, D, F, Cl, Br, I, hydroxyl, cyano, nitro, C₁-C₄Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₂Alkoxy radical, C₁-C₂Alkylthio radical, C₁-C₂Alkylamino radical, C₆-C₁₀Aryl or 5-6 membered heteroaryl, wherein each C is₁-C₄Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₂Alkoxy radical, C₁-C₂Alkylthio radical, C₁-C₂Alkylamino radical, C₆-C₁₀Aryl and 5-6 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, C₁-C₄Alkyl, carboxyl, mercapto, C₁-C₂Hydroxyalkyl radical, C₁-C₂Alkoxy radical, C₁-C₂Alkylthio and C₁-C₂Substituted by alkylamino.

In some embodiments, each R is^7aAnd R^8aIndependently H, D, F, Cl, Br, I, hydroxy, cyano, nitro, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, or methylamino, wherein each of said methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, methylthio, and methylamino is optionally substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, methyl, ethyl, carboxy, mercapto, hydroxymethyl, methoxy, ethoxy, methylthio, and methylamino.

In some embodiments, each R is^10a、R^10b、R^10c、R^10d、R^11a、R^11b、R^12a、R^12bAnd R^12cIndependently H, D, F, Cl, Br, I, hydroxyl, cyano, nitro, C₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₂Alkylamino radical, C₁-C₂Alkylthio radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkoxy, C₆-C₁₀Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, -C (═ O) R¹³、-C(＝O)OR¹³、-S(＝O)₂R¹³、-S(＝O)R¹³、-C(＝O)NR¹³R¹⁴or-NR¹³R¹⁴Wherein each of C₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₂Alkylamino radical, C₁-C₂Alkylthio radical, C₃-C₆Cycloalkyl radical, C₃-C₆Cycloalkoxy, C₆-C₁₀Aryl, 5-6 membered heteroaryl and 5-6 membered heterocyclyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, nitro, C₁-C₄Alkyl radical, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, carboxyl, mercapto, C₁-C₂Hydroxyalkyl radical, C₁-C₄Alkoxy radical, C₆-C₁₀Aryl, 5-10 membered heteroaryl, -C (═ O) R¹³、-C(＝O)OR¹³、-S(＝O)₂R¹³、-S(＝O)R¹³、-C(＝O)NR¹³R¹⁴and-NR¹³R¹⁴Substituted with the substituent(s);

or R^12a、R^12bAnd together with the carbon atom to which they are attached form a carbonyl group.

In some embodiments, each R is^10a、R^10b、R^10c、R^10d、R^11a、R^11b、R^12a、R^12bAnd R^12cIndependently H, D, F, Cl, Br, I, hydroxy, cyano, nitro, methyl, ethyl, propyl, methoxy, ethoxy, methylthio, methylamino, cyclopropyl, cyclobutyl, or 5-6 membered heterocyclyl, wherein each of said methyl, ethyl, propyl, methoxy, ethoxy, methylthio, methylamino, cyclopropyl, cyclobutyl, and 5-6 membered heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, nitro, methyl, ethyl, propyl, carboxy, mercapto, hydroxymethyl, methoxy, and ethoxy;

In some embodiments, wherein R¹Is H, D, F, Cl, Br, I, hydroxyl, cyano, nitro, C₁-C₄Alkyl, methoxy, ethoxy, C₁-C₄Haloalkyl, C₁-C₂Haloalkoxy, cyclopropyl or cyclobutyl, wherein each of said C₁-C₄Alkyl, methoxy, ethoxy, C₁-C₄Haloalkyl, C₁-C₂Haloalkoxy, cyclopropyl and cyclobutyl are optionally substituted with 1,2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, carboxy, mercapto, nitro, methyl, ethyl and amino.

In some embodiments, R¹Is H, D, F, Cl, Br, I, hydroxy, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2-difluoroethyl, 1, 2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoroethoxy, difluoroethoxy, monofluoroethoxy, cyclopropyl or cyclobutyl, wherein Each of said methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2-difluoroethyl, 1, 2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoroethoxy, difluoroethoxy, monofluoroethoxy, cyclopropyl, and cyclobutyl is optionally substituted with 1,2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, carboxy, mercapto, nitro, methyl, ethyl, and amino.

In some embodiments, each R is¹³And R¹⁴Independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, 3-6 membered heterocyclyl, phenyl, or 5-10 membered heteroaryl, wherein each of said methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, 3-6 membered heterocyclyl, phenyl, and 5-10 membered heteroaryl is optionally substituted with 1,2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, amino, methyl, ethyl, n-propyl, isopropyl, carboxy, mercapto, hydroxymethyl, methoxy, and ethoxy.

In some embodiments, the present invention relates to structures of one of the following, or stereoisomers, tautomers, nitrogen oxides, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof, but is not limited to these compounds:

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention, and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition of the invention further comprises an additional therapeutic agent, wherein the additional therapeutic agent is selected from an antidiabetic agent other than SGLT2 inhibitors, an antihyperglycemic agent, an antiobesity agent, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic agent, a lipid-lowering agent, an anti-inflammatory agent, or a combination thereof.

In some embodiments, the antidiabetic agent and the antihyperglycemic agent that is a non-SGLT 2 inhibitor described herein are each independently selected from biguanide agents, sulfonylurea agents, glucosidase inhibitors, PPAR agonists (peroxisome proliferator activated receptor agonists), α P2 inhibitors (inhibitors of adipocyte fatty acid binding protein), PPAR α/γ dual activators (peroxisome proliferator activated receptor α/γ dual activators), dipeptidyl peptidase IV inhibitors, glinide agents, insulin, glucagon-like peptide-1 inhibitors, PTP1B inhibitors (protein tyrosine phosphatase 1B inhibitors), glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, or combinations thereof.

In some embodiments, the lipid-lowering drug of the invention is selected from the group consisting of MTP inhibitors (microsomal triglyceride transfer protein inhibitors), HMGCoA reductase inhibitors (hydroxymethylglutaryl coa reductase inhibitors), squalene synthetase inhibitors, bexateine hypolipidemic drugs (also known as fibrate hypolipidemic drugs), ACAT inhibitors (acetylcholinesterase inhibitors), lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal sodium/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, nicotinic acid hypolipidemic drugs, bile acid chelates, and combinations thereof.

In other embodiments, the lipid lowering drug of the present invention is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin, or a combination thereof.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament, wherein the medicament is for inhibiting SGLT 2.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition of the invention in the manufacture of a medicament, wherein the medicament is for inhibiting SGLT 1.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition according to the invention for the preparation of a medicament for increasing the level of high density lipoprotein.

In another aspect, the invention also relates to the use of a compound or pharmaceutical composition according to the invention in the manufacture of a medicament for the prevention or treatment of a disease, alleviating a symptom of a disease or delaying the progression or onset of a disease, wherein the disease is diabetes, a diabetic complication such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, an increase in the level of fatty acids or glycerol in the blood, hyperlipidemia such as triglyceridemia, obesity, syndrome X, atherosclerosis or hypertension.

In another aspect, the invention relates to a method of inhibiting SGLT2 activity using a compound or pharmaceutical composition described herein, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition.

In another aspect, the invention relates to a method of inhibiting SGLT1 activity using a compound or pharmaceutical composition described herein, the method comprising administering to a patient a therapeutically effective amount of the compound or pharmaceutical composition.

In another aspect, the present invention relates to a method for preventing or treating diabetes, diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension, using a compound or a pharmaceutical composition according to the present invention, for alleviating the symptoms of, or delaying the progression or onset of, or for increasing the levels of high density lipoprotein, in a patient, comprising administering a therapeutically effective amount of a compound or a pharmaceutical composition according to the present invention.

In another aspect, the invention relates to the use of a compound or pharmaceutical composition described herein for inhibiting the activity of SGLT2 or the activity of SGLT 1.

In another aspect, the present invention relates to the use of a compound or a pharmaceutical composition according to the present invention for the prevention or treatment of diabetes, diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia such as hypertriglyceridemia, obesity, syndrome X, atherosclerosis or hypertension, for alleviating the symptoms of, or delaying the progression or onset of, or for increasing the levels of high density lipoproteins.

In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.

The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for the preparation and/or purification of the compounds of the present invention and/or for the isolation of enantiomers of the compounds of the present invention.

Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.

Furthermore, the compounds of the present invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form solvates, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include both solvated and unsolvated forms.

Any formulae given herein are also intended to represent unlabeled forms of these compounds as well as isotopically labeled forms. Isotopically-labeled compounds have the structure depicted in the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H，³H，¹¹C，¹³C，¹⁴C，¹⁵N，¹⁸F，³¹P，³²P，³⁶S，³⁷Cl or¹²⁵I。

In another aspect, the compounds of the invention include compounds defined herein which are labelled with various isotopes, for example where a radioactive isotope is present, such as³H，¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³C. the isotope labeled compound can be used for metabolism research (use)¹⁴C) Reaction kinetics study (using, for example ²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-labelled compounds are particularly desirable for PET or SPECT studies. Isotopically-labelled compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using suitable isotopically-labelled reagents in place of the original used unlabelled reagents.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in this context is to be taken as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D ₂O, acetone-d₆Or DMSO-d₆Those solvates of (a).

The foregoing has outlined, rather broadly, certain aspects of the present invention in order that the detailed description of the invention that follows may be better understood, and in order that the present contribution to the art may be better appreciated.

Description

The invention provides a glucopyranosyl derivative, a preparation method thereof and application thereof in medicine, and a person skilled in the art can realize the preparation by appropriately improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention.

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein, and in cases where one or more of the incorporated documents, patents, and similar materials is different from or contradictory to the present application (including but not limited to defined terms, application of terms, described techniques, and the like), the present application shall control.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

Unless otherwise indicated, the terms used in the specification and claims have the following definitions.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

In general, the terms "substituted" or "substitution" mean that one or more hydrogen atoms in a given structure that may be substituted is replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.

The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including, but not limited to, D, F, Cl, Br, I, hydroxy, oxo (═ O), cyano, nitro, amino, alkyl, alkenyl, alkynyl, carboxy, mercapto, hydroxyalkyl, alkoxy, alkylthio, alkylamino, haloalkyl, haloalkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, heteroaryl, -SR ¹³、-C(＝O)R¹³、-C(＝O)OR¹³、-OC(＝O)R¹³、-OC(＝O)OR¹³、-NHC(＝O)R¹³、-NHS(＝O)₂R¹³、-C(＝O)NHR¹³Trifluoromethyl, -S (═ O)₂NHR¹³、-S(＝O)₂R¹³、-S(＝O)R¹³、-NR¹³R¹⁴、-C(＝O)NR¹³R¹⁴Arylalkyl, heteroarylalkyl, aryloxy, heteroaryloxy, arylalkoxy or heteroarylalkoxy, wherein R is¹³And R¹⁴Have the meaning according to the invention.

The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the scenario where the heterocyclic group is substituted with an alkyl and the scenario where the heterocyclic group is not substituted with an alkyl.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… … independently" and "… … independently" and "… … independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C ₁-C₈Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl radical, C₆Alkyl radical, C₇Alkyl and C₈And "3-to 8-membered heterocyclic group" means a heterocyclic group consisting of 3 ring atoms, a heterocyclic group consisting of 4 ring atoms, a heterocyclic group consisting of 5 ring atoms, a heterocyclic group consisting of 6 ring atoms, a heterocyclic group consisting of 7 ring atoms or a heterocyclic group consisting of 8 ring atoms.

The term "halogen" refers to F, Cl, Br, I.

The term "alkyl" refers to a saturated, straight or branched chain, monovalent or multivalent hydrocarbon radical containing from 1 to 20 carbon atoms. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms; in some embodiments, the alkyl group contains 1 to 10 carbon atoms; in other embodiments, the alkyl group contains 1 to 8 carbon atoms; in still other embodiments, the alkyl group contains 1 to 6 carbon atoms; in still other embodiments, the alkyl group contains 1 to 4 carbon atoms; in still other embodiments, the alkyl group contains 1 to 2 carbon atoms. The alkyl group having 1 to 6 carbon atoms is referred to as a lower alkyl group in the present invention.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH) ₂CH₃) Propyl (including n-propyl (n-Pr, -CH)₂CH₂CH₃) And isopropyl (i-Pr, -CH (CH)₃)₂) Butyl (including n-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH) (-)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like. The alkyl group may be optionally substituted with one or more substituents described herein.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one site of unsaturation is a carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In some embodiments, alkenyl groups contain 2 to 8 carbon atoms; in other embodiments, alkenyl groups contain 2 to 6 carbon atoms; in still other embodiments, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH) ₂) Allyl (-CH)₂CH＝CH₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one site of unsaturation is a carbon-carbon sp triple bond. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms; in still other embodiments, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), 1-propynyl (-C.ident.CH-CH)₃) Propargyl (-CH)₂C.ident.CH), 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 1-hexynyl, 1-heptynyl, 1-octynyl, and the like. The alkynyl group may be independently optionally substituted with one or more substituents described herein.

The term "heteroalkyl" means that one or more heteroatoms may be inserted in the alkyl chain, wherein the alkyl group and the heteroatoms have the meaning as described herein. Unless otherwise specified, a heteroalkyl group contains from 1 to 10 carbon atoms, in some embodiments from 1 to 8 carbon atoms, in other embodiments from 1 to 6 carbon atoms, In still other embodiments, the heteroalkyl group contains from 1 to 4 carbon atoms, and in still other embodiments, the heteroalkyl group contains from 1 to 3 carbon atoms. Examples of heteroalkyl groups include, but are not limited to, CH₃OCH₂-、CH₃CH₂OCH₂-、CH₃SCH₂-、(CH₃)₂NCH₂-、(CH₃)₂CH₂OCH₂-、CH₃OCH₂CH₂-、CH₃CH₂OCH₂CH₂-and the like. The heteroalkyl group may be optionally substituted with one or more substituents described herein.

The term "haloalkyl" refers to an alkyl group having one or more halo substituents. In some embodiments, haloalkyl groups contain 1 to 8 carbon atoms, in other embodiments, haloalkyl groups contain 1 to 6 carbon atoms, in yet other embodiments, haloalkyl groups contain 1 to 4 carbon atoms, in still other embodiments, haloalkyl groups contain 1 to 3 carbon atoms, and in still other embodiments, haloalkyl groups contain 1 to 2 carbon atoms. Examples of haloalkyl groups include, but are not limited to, fluoromethyl (-CH)₂F) Difluoromethyl (-CHF)₂) Trifluoromethyl (-CF)₃) Fluoroethyl (-CHFCH)₃,-CH₂CH₂F) Difluoroethyl (-CF)₂CH₃,-CFHCFH₂,-CH₂CHF₂) Trifluoroethyl, perfluoroethyl, fluoropropyl (-CHFCH)₂CH₃,-CH₂CHFCH₃,-CH₂CH₂CH₂F) Difluoropropyl (-CF)₂CH₂CH₃,-CFHCFHCH₃,-CH₂CH₂CHF₂,-CH₂CF₂CH₃,-CH₂CHFCH₂F) Trifluoropropyl, 1-dichloroethyl, 1, 2-dichloropropyl, and the like. The haloalkyl group can be optionally substituted with one or more substituents described herein.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, i.e., alkyl-O-, wherein the alkyl group has the meaning as described herein. In some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. In still other embodiments, alkoxy groups contain 1-2 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, 2-methylpropoxy, neopentyloxy, and the like. The alkoxy group may be optionally substituted with one or more substituents described herein.

The term "alkylthio" means an alkyl group attached to the rest of the molecule through a sulfur atom, i.e., alkyl-S-, wherein the alkyl group has the meaning as described herein. In some embodiments, the alkylthio group contains 1 to 6 carbon atoms; in other embodiments, the alkylthio group contains 1 to 4 carbon atoms; in still other embodiments, the alkylthio group contains 1 to 3 carbon atoms; in still other embodiments, the alkylthio group contains 1-2 carbon atoms. Examples of alkylthio include, but are not limited to, methylthio, ethylthio, and the like. The alkylthio group may be optionally substituted with one or more substituents described herein.

The term "haloalkoxy" refers to an alkoxy group having one or more halogen substituents. Wherein the alkoxy group has the meaning as described in the present invention. In some embodiments, haloalkoxy groups contain 1 to 6 carbon atoms; in other embodiments, haloalkoxy groups contain 1 to 4 carbon atoms; in still other embodiments, haloalkoxy groups contain 1-3 carbon atoms; in still other embodiments, haloalkoxy groups contain 1-2 carbon atoms. Examples of haloalkoxy include, but are not limited to, monofluoromethoxy, difluoromethoxy (-OCF)₂) Trifluoromethoxy (-OCF)₃) Fluoroethoxy (-OCHFCH)₃,-OCH₂CH₂F) Difluoroethoxy (-OCF)₂CH₃,-OCFHCFH₂,-OCH₂CHF₂) Trifluoroethoxy, and the like. The haloalkoxy group may optionally be substitutedSubstituted with one or more substituents as described herein.

The term "hydroxyalkyl" or "hydroxyalkyl" refers to an alkyl group having one or more hydroxyl substituents, wherein the alkyl group has the meaning as described herein. In some embodiments, the hydroxyalkyl group contains 1 to 6 carbon atoms; in other embodiments, the hydroxyalkyl group contains 1 to 4 carbon atoms; in still other embodiments, the hydroxyalkyl group contains 1 to 3 carbon atoms; in still other embodiments, the hydroxyalkyl group contains 1-2 carbon atoms. Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl (-CH) ₂CH₂OH), 1-hydroxyethyl (-CHOHCH)₃) 1, 2-dihydroxyethyl (-CHOHCH)₂OH), 2, 3-dihydroxypropyl (-CH)₂CHOHCH₂OH), 1-hydroxypropyl (-CH)₂CH₂CH₂OH), 2-hydroxypropyl, 3-hydroxypropyl, hydroxybutyl, and the like. The hydroxyalkyl group may be optionally substituted with one or more substituents described herein.

The term "alkylamino" refers to an amino group having one or two alkyl substituents. In some embodiments, the alkylamino group contains 1 to 6 carbon atoms; in other embodiments, the alkylamino group contains 1 to 4 carbon atoms; in still other embodiments, the alkylamino group contains 1 to 3 carbon atoms; in still other embodiments, the alkylamino group contains 1-2 carbon atoms. Examples of alkylamino include, but are not limited to, methylamino, ethylamino, N-propylamino, isopropylamino, N-butylamino, N-pentylamino, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-N-propyl-amino, and the like. The alkylamino group can be optionally substituted with one or more substituents described herein.

The term "cycloalkyl" refers to a mono-or polyvalent, saturated monocyclic, bicyclic, or tricyclic ring system (including fused, bridged, and/or spiro ring systems) containing 3 to 12 carbon atoms. In some embodiments, cycloalkyl is a saturated carbocyclyl containing 3 to 12 carbon atoms; in other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.

The term "cycloalkoxy" means that a cycloalkyl group is attached to the rest of the molecule through an oxygen atom, i.e. cycloalkyl-O-, wherein the cycloalkyl group has the meaning as described herein. In some embodiments, cycloalkoxy groups contain 3 to 12 ring carbon atoms; in yet other embodiments, cycloalkoxy groups contain 3 to 8 ring carbon atoms; in still other embodiments, cycloalkoxy groups contain 3 to 6 ring carbon atoms. Examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, and the like. The cycloalkoxy group may be optionally substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, nonaromatic, monocyclic, bicyclic or tricyclic ring containing from 3 to 12 ring atoms wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms, wherein the heterocyclyl is nonaromatic and does not contain any aromatic ring and wherein the ring system has one or more points of attachment to the remainder of the molecule. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂The group may optionally be replaced by-C (═ O) -, the sulfur atom of the ring may optionally be oxidized to S-oxide, and the nitrogen atom of the ring may optionally be oxidized to N-oxygen compound. The heterocyclic group includes a saturated heterocyclic group (heterocycloalkyl group) and a partially unsaturated heterocyclic group. In some embodiments, heterocyclyl is a 3-8 membered heterocyclyl; in some embodiments, heterocyclyl is a 3-6 membered heterocyclyl; in some embodiments, heterocyclyl is a 5-6 membered heterocyclyl; in some embodiments, heterocyclyl is a 3-4 membered heterocyclyl; in other embodiments, the heterocyclyl is a 4-membered heterocyclyl; in other embodiments, the heterocyclyl is a 5-membered heterocyclyl; in other embodiments, heterocyclyl is a 6 membered heterocyclyl; in still other embodiments, the heterocyclic ring The radical is a 7-membered heterocyclic radical.

Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, 1, 3-dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, azacycloheptyl, oxazepanyl, thiazepanyl, pyrazolinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiofuranyl, dihydrothienyl, 1, 3-dioxanyl, 1,3-

Radicals (e.g. 1, 4-oxaza)

1, 2-oxaza

Alkyl), diazepine

Radicals (e.g. 1, 4-diazepine)

1, 2-diazepines

Basic), dioxa

Radicals (e.g. 1, 4-dioxa)

1, 2-dioxan

Basic), a sulfur aza

Radicals (e.g. 1, 4-thiazepine)

1, 2-thiaza radical

Yl), 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, 2-azaspiro [4.4]Nonanyl, 1, 6-dioxaspiro [4.4 ]]Nonanyl, 2-azaspiro [4.5 ]]Decyl, 8-azaspiro [4.5 ]]Decyl, 7-azaspiro [4.5 ] ]Decyl, 3-azaspiro [5.5 ]]Undecyl, 2-azaspiro [5.5]Undecyl, octahydro-1H-isoindolyl, octahydrocyclopenta [ c]Pyrrolyl, hexahydrofuro [3,2-b ] groups]Furyl and dodecahydroisoquinolinyl, and the like. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl and 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "aryl" may be used alone or as a majority of "arylalkyl", "arylalkoxy", "aryloxy", or "aryloxyalkyl", to refer to monocyclic, bicyclic, and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more points of attachment are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups include, but are in no way limited to, phenyl, naphthyl, anthracenyl, and the like. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl", "heteroaryloxy", or "heteroarylalkoxy",represent monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. when-CH is present in the heteroaryl group₂When it is a group, -CH₂The-group may optionally be replaced by-C (═ O) -. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic", "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a 5-12 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is a 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In other embodiments, heteroaryl is a 5-6 membered heteroaryl comprising 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The heteroaryl group is optionally substituted with one or more substituents described herein.

Examples of heteroaryl groups include, but are in no way limited to, the following bicyclic heteroaryls: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), indazolyl (e.g., 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyridyl, pyrazolo [4,3-c ] pyridyl, pyrazolo [3,4-b ] pyridyl, pyrazolo [1,5-a ] pyrimidyl, pyrazolyl, and the like, Imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridinyl, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxole, and the like. Examples of heteroaryl groups also include monocyclic heteroaryl groups, examples of which include, but are not limited to, monocyclic, furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridonyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), Pyrimidineonyl, pyrimidinedione, pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g. 2-pyrazinyl, 3-pyrazinyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazolyl and 5-triazolyl), thienyl (e.g. 2-thienyl, 3-thienyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), pyrazolonyl, isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiodiazolyl, pyridazinyl (e.g. 2-pyrazinyl, 3-pyrazinyl), thiazolyl (e.g. 2-triazolyl), thiazolyl (e.g, 1,3, 4-thiooxadiazolyl, 1,2, 5-thiooxadiazolyl, pyrazinyl and 1,3, 5-triazinyl, and the like.

The term "aryloxy" means that the aryl group is attached to the rest of the molecule through an oxygen atom, i.e. aryl-O-, wherein said aryl group has the meaning as described herein. Such examples include, but are not limited to, phenoxy, and the like.

The term "heteroaryloxy" means that the heteroaryl group is attached to the rest of the molecule through an oxygen atom, i.e., heteroaryl-O-, wherein said aryl has the meaning as described herein. Such examples include, but are not limited to, pyridine-3-oxy, pyrimidine-4-oxy, and the like.

The term "arylalkyl" refers to an alkyl group having an aryl substituent. In some of these embodiments, an arylalkyl group refers to a "lower arylalkyl" group, i.e., the aryl group is attached to C₁-C₆On the alkyl group of (a). In other embodiments, the aryl group is attached to C₁-C₄On the alkyl group of (a). In other embodiments, the aryl group is attached to C₁-C₂On the alkyl group of (a). Examples include, but are not limited to, benzyl, diphenylmethyl, phenethyl, p-tolylmethyl, phenylpropyl, and the like. Aryl alkyl radicalThe groups may be further substituted with halogen, alkyl, alkoxy, haloalkyl and haloalkoxy.

The term "heteroarylalkyl" means that an alkyl group is substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl have the meaning described herein. Examples include, but are not limited to, pyridin-2-ylmethyl, thiazol-2-ylethyl, imidazol-2-ylethyl, pyrimidin-2-ylpropyl, pyrimidin-2-ylmethyl, and the like.

The terms "arylalkoxy" and "aralkoxy" are used interchangeably herein to mean an alkoxy group substituted with one or more aryl groups, wherein aryl and alkoxy have the meaning described herein, and such examples include, but are not limited to, phenylmethoxy, phenylethoxy, p-tolylmethoxy, phenylpropoxy, and the like.

The terms "heteroarylalkoxy" and "heteroarylalkoxy" are used interchangeably herein and include heteroarylalkyl groups containing an oxygen atom attached to another group through an oxygen atom, wherein heteroarylalkyl has the meaning as described herein, examples of which include, but are not limited to, pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethoxy, and the like.

The term "heteroatom" refers to O, S, N, P and any oxidation state form of Si, including S, N, and P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The term "nitro" means-NO₂。

The term "mercapto" refers to-SH.

The term "hydroxy" refers to-OH.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "carboxylic acid" or "carboxyl" refers to-C (═ O) OH.

The term "carbonyl" refers to — C (═ O).

The term "D" refers to deuteration, i.e.²H。

As described herein, a ring system formed by drawing a bond connecting a substituent to the center of the ring (as shown in formula a) represents that the substituent may be substituted at any substitutable position on the ring system. For example, formula a represents a substituent that may be substituted at any possible position on the phenyl ring, as shown in formulas b through d:

as described herein, a ring system formed by a bond to the center of the ring represents that the bond can be attached to the rest of the molecule at any point on the ring system that is attachable. For example, formula e represents that ring a can be attached to the rest of the molecule through any possible attachment position on the ring, and when ring a is a bicyclic structure, ring a can be attached to the rest of the molecule through any possible attachment position on any of the rings; for another example, formula f represents a pyrimidine ring which may be attached to the rest of the molecule via any possible attachment position, as shown in formulae g to j:

The term "protecting group" or "PG" refers to a substituent group that blocks or protects a particular functionality when other functional groups in a compound are reacted. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality of a substituent of a hydroxy group to block or protect the hydroxy group, and suitable protecting groups include, but are not limited to, acetyl, benzoyl, benzyl, p-methoxybenzyl, silyl, and the like. "carboxyl protecting group"refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, typical carboxyl protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley &Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "leaving group" or "LG" refers to an atom or functional group that is removed from a larger molecule in a chemical reaction, a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms cleaved away from the substrate molecule with a pair of electrons is called the leaving group. Common leaving groups are, for example, but not limited to, halogen atoms, ester groups, sulfonate groups, nitro groups, azide groups, hydroxyl groups, or the like.

The term "pharmaceutical composition" means a mixture of one or more compounds described herein or physiologically/pharmaceutically acceptable salts or prodrugs thereof with other chemical components such as physiologically/pharmaceutically acceptable carriers, excipients, diluents, binders, fillers and like excipients, and additional therapeutic agents such as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerotic agents or lipid-lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

The term "syndrome X", also referred to as a condition, disease of metabolic syndrome, the condition of which is described in detail in Johannsson et al, j.clin.endocrinol.metab.,1997,82, 727-.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. Hair brushThe prodrug compound may be ester, and in the present invention, the ester may be phenyl ester or aliphatic (C)₁-C₂₄) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: higuchi et al, Pro-drugs as Novel Delivery Systems, vol.14, a.c.s.symposium Series; roche et al, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; rautio et al, primers: Design and Clinical Applications, Nature Reviews Discovery,2008,7, 255-.

The term "metabolite" refers to the product of the metabolism of a particular compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: parker et al, McGraw-Hill Dictionary of Chemical Terms,1984, McGraw-Hill Book Company, New York and Eliel et al, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Diastereomers may be separated into individual diastereomers on the basis of their physicochemical differences by chromatography, crystallization, distillation, sublimation, or the like. Enantiomers can be separated, such that a chiral isomeric mixture is converted into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers. The intermediates and compounds of the invention may also exist in different tautomeric forms and all such forms are included within the scope of the invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The atoms or groups of these stereoisomers are attached to each other in the same order, but they differ in their steric structure. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The term "racemic mixture" or "racemate" refers to a mixture of two enantiomers in equimolar amounts, lacking optical activity.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons. Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomers, diastereomers, and geometric isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers thereof are intended to be within the scope of the present invention.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

Percentages stated throughout this specification are weight/weight (w/w) percentages, unless otherwise stated.

In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.

The term "pharmaceutically acceptable salts" refers to both organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, describe the description of the descriptive pharmaceutical acceptable salts in detail in J. Pharmacol Sci,1997,66, 1-19. Examples of pharmaceutically acceptable, non-limiting salts include salts of inorganic acids formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, metaphosphate, sulfate, nitrate, perchlorate, and salts of organic acids such as methanesulfonate, ethanesulfonate, acetate, trifluoroacetate, glycollate, isethionate, oxalate, maleate, tartrate, citrate, succinate, malonate, benzenesulfonate, p-toluenesulfonate, malate, fumarate, lactate, lactobionate, or obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, laurates, lauryl sulfates, malonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, picrates, pivalate, propionates, stearates, thiocyanates, undecanoates, monophenolates, benzoates, bisulfates, and mixtures thereof, Valeric acid salts, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N ⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali metals or basesThe earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Non-limiting examples of solvents that form solvates include water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, or aminoethanol, and the like.

The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The invention relates to a pharmaceutical composition, which comprises a compound with a structure shown in formula (I) or formula (II) or a compound with a structure shown in an embodiment, or a stereoisomer, a tautomer, a racemate, a nitrogen oxide, a solvate, a metabolite and a pharmaceutically acceptable salt or prodrug thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical composition further comprises an effective amount of other additional therapeutic agents. The amount of compound in the pharmaceutical composition of the present invention is effective to detectably inhibit sodium-dependent glucose transporters (SGLTs) activity in a biological sample or patient.

The compounds of the invention exist in free form or, where appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adduct or derivative that can be administered directly or indirectly in accordance with the needs of the patient, compounds described in other aspects of the invention, metabolites thereof, or residues thereof.

As described herein, the pharmaceutically acceptable pharmaceutical compositions of the present invention further comprise pharmaceutically acceptable adjuvants such as carriers, diluents, fillers, binders, flavoring agents or excipients, as used herein, including any solvent, diluent or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickening agent, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular target dosage form. As described in the following documents: in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different excipients may be used In The preparation of pharmaceutically acceptable Pharmaceutical compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable pharmaceutical composition, their use is contemplated by the present invention.

Substances which may be used as pharmaceutically acceptable adjuvants include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol, phosphate buffered solutions, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, coloring agents, releasing agents, coating materials, sweetening, flavoring and perfuming agents, preservatives and antioxidants.

The compounds of the present invention may be administered as the sole pharmaceutical agent or in combination with one or more other additional therapeutic (pharmaceutical) agents, where the combined administration results in acceptable adverse effects, of particular significance in the treatment of diabetes, diabetic complications and other related diseases, including, but not limited to, type I diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis, hypertension and the like. As used herein, "additional therapeutic agents" include known antidiabetic agents other than SGLT2 inhibitors, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, lipid-lowering agents, or anti-inflammatory agents, or combinations thereof.

Among the antidiabetic agents described herein that are not SGLT2 inhibitors include, but are not limited to, biguanide drugs (e.g., phenformin, metformin), sulfonylurea drugs (e.g., acesulfame (acetohexamide), chlorpropamide (chlorpropamide), glibenclamide (glibenclamide), glipizide (glipizide, pyrithiocyclamide), gliclazide (gliclazide), glimepiride (glimepiride), glimepiride (glipienide), gliquidone (gliquidone), tolazamide (tolazamide), tolbutamide (tolbutamide), meglitinide (meglitinide), gane drugs (e.g., repaglinide and nateglinide)), alpha-glucosidase inhibitors (e.g., acarbose inhibitors), alpha-glucosidase inhibitors (e.g., glicotigosamide), glimepigosamide (glimepigosamide), gliclazide (gliclazide), gliclazide (e.g., glibenclamide), gliclazide (gliclazide), glibenclamide (e), glibenclamide (e), glibenclamide), gliben, Voglibose (voglibose), pradimicin (pradimicin) and saxagliptin (salbutatin)), PPAR agonists (e.g., balaglitazone (balaglitazone), ciglitazone (ciglitazone), darglitazone (daglitazone), englitazone (englitazone), isglitazone (isglitazone), pioglitazone (pioglitazone), rosiglitazone (rosiglitazone) and troglitazone (troglitazone)), PPAR α/γ dual activators (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), sitagliptin (sitagliptin), vildagliptin (vildagliptin), alogliptin (vildagliptin), agogliptin (vildagliptin)), agogliptin (gliptin (glgliptin), gliptin (glgliptin-3), and saxagliptin (glglitazotin (trogliptin-4)), and saxagliptin (saxatin (SAgliptin-3), and saxaglitazone (SALTP-4, SALT-4), SALT-3), SALTP-1-4, SALT-X-0940, SALT-F) and, Protein tyrosine phosphatase-1B (PTP1B) inhibitors (quinuclidine, petasisol extract and compounds disclosed by Zhang, s. et al, modern drug discovery, 12(9/10), 373-381 (2007)), insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, glycogen phosphorylase inhibitors or glucose-6-phosphatase inhibitors; an α P2 inhibitor, an acetyl-CoA carboxylase-2 (ACC-2) inhibitor, a Phosphodiesterase (PDE) -10 inhibitor, a diacylglycerol acyltransferase (DGAT)1 or 2 inhibitor, a glucose transport vector 4(GLUT4) modulator, and a glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitor.

Among them, the antihyperglycemic agents of the present invention include, but are not limited to, biguanide drugs (e.g., phenformin, metformin, or metformin)), sulfonylurea drugs (e.g., acetohexamide, chlorpropamide, glibenclamide, glipizide, pyrocyclamide, gliclazide, glimepiride, gliquidone, tolazamide, tolbutamide, meglitinide, alpha-glucosidase inhibitors (e.g., arbacin), alpha-glucosidase inhibitors (e.g., alpha-glucosidase inhibitors), alpha-glucosidase inhibitors (e.g., glipizide), glimepiride, glipizide, and the like, Voglibose (voglibose), pradimicin (pradimicin) and saxagliptin (salbutatin)), PPAR agonists (e.g., balaglitazone (balaglitazone), ciglitazone (ciglitazone), darglitazone (darglitazone), englitazone (englitazone), isglitazone (pioglitazone), rosiglitazone (rosiglitazone) and troglitazone (troglitazone)), PPAR α/γ dual activators (e.g., CLX-0940, GW-1536, GW-1929, GW-2433, KRstatin P-297, L-796449, LR-90, MK-0767 and SB-219994), dipeptidyl peptidase IV (e.g., sitagliptin (sitagliptin), vildagliptin (vildagliptin), alogliptin (glgliptin), glgliptin (glgliptin) (glgliptin-3), and exendin (glglitazobactin (trogliptin-4-3)), and glucagon-1-4-like (e-4-analog (glstatin (gliptin (glstatin, glcne, glcn-4-3, glitazobactam), and saxatin (e, glcne, glcn-4-pro-agonist (e, glcne, e, glcn-4-e, protein tyrosine phosphatase-1B (PTP1B) inhibitors (quinuclidine, petasisol extract and compounds disclosed by Zhang, s. et al, modern drug discovery, 12(9/10), 373-381 (2007)), insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists, glucokinase activators, glycogen phosphorylase inhibitors or glucose-6-phosphatase inhibitors; α P2 inhibitors, acetyl-CoA carboxylase-2 (ACC-2 inhibitors), Phosphodiesterase (PDE) -10 inhibitors, diacylglycerol acyltransferase (DGAT)1 or 2 inhibitors, glucose transporter 4(GLUT4) modulators, and glutamine-fructose-6-phosphate amidotransferase (GFAT) inhibitors.

Wherein, the invention is describedLipid agents include, but are not limited to, MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibrates (fibrates), ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal sodium/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, bile acid chelates, or nicotinic acid antilipemic agents. In some embodiments, the lipid lowering agent is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atorvastatin, or rosuvastatin. Wherein the anti-obesity agent is selected from CB-1 antagonists (e.g., rimonabant (rimonabant), tylonabant (taranabant), bromoetabant (surinabant), otentab (otentab), SLV319 and AVE1625), gut-selective MTP inhibitors (e.g., deslorapide, mitratapide and inputade), CCKa agonists, 5HT2c agonists (e.g., lorcaserin), MCR4 agonists, lipase inhibitors (e.g., Cetilistat), PYY agonists_3-36Opioid antagonists (e.g., naltrexone), oleoyl-estrone, obinepitide, pramlintide, tesofensine, lepartine, liraglutide, bromocriptine, orlistat, exenatide, AOD-9604, and sibutramine.

Among the suitable anti-inflammatory agents described herein are those which are prophylactic and therapeutic drugs for genital/urinary tract infections, such as cranberry (Vaccinium macrocarpon) and cranberry derivatives, such as cranberry juice, cranberry extract or cranberry flavonols. In addition, other suitable anti-inflammatory agents include, but are not limited to, aspirin, non-steroidal anti-inflammatory drugs, glucocorticosteroids, sulfasalazine, cyclooxygenase II selective inhibitors, and the like.

The pharmaceutical composition of the present invention may be administered orally, by injection, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable kit. The term "administration by injection" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial (intracavitary), intrasternal, intramembranous, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferred pharmaceutical compositions are oral, intraperitoneal or intravenous. The pharmaceutical compositions of the present invention may be injected in a sterile manner in the form of an aqueous or oleaginous suspension. These suspensions may be formulated according to the known art using suitable dispersing, wetting and suspending agents. Sterile injectable preparations can be sterile injectable solutions or suspensions, in the form of non-toxic acceptable diluents or solvents, such as solutions in 1, 3-butanediol. These acceptable excipients and solvents may be water, ringer's solution and isotonic sodium chloride solution. Further, sterile, nonvolatile oils may conventionally be employed as a solvent or suspending medium.

For this purpose, any bland non-volatile oil may be a synthetic mono-or diglucosoyl diglyceride. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene derivatives. These oil solutions or suspensions may contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, and pharmaceutical preparations typically used in pharmaceutically acceptable dosage forms include emulsions and suspensions. Other commonly used surfactants, such as tweens, spans and other emulsifiers or enhancers of bioavailability, are commonly used in pharmaceutically acceptable solid, liquid, or other dosage forms, and may be used in the preparation of targeted pharmaceutical formulations.

Use of the Compounds and pharmaceutical compositions of the invention

The amount of the compound or the compound in the pharmaceutical composition can effectively and detectably inhibit the activity of sodium-dependent glucose transporters (SGLTs), not only can inhibit the activity of SGLT2, but also has a good inhibition effect on the activity of SGLT 1. SGLT2 is responsible for reabsorbing D-glucose from glomerular filtrate from the kidney, SGLT1 is responsible for reabsorbing glucose from the distal S3 segment of the renal tubules, and together inhibiting reabsorption of glucose is beneficial for lowering blood glucose concentration. Accordingly, the compounds of the present invention will find application in the prevention, treatment, or amelioration of the symptoms of diabetes and related diseases.

The compounds of the present invention will find use in, but are in no way limited to, the administration to a patient of an effective amount of a compound or pharmaceutical composition of the present invention for the prevention or treatment of diabetes and related diseases, or for the alleviation of symptoms of diabetes and related diseases, or the delay of progression or onset of diabetes and related diseases or for the increase of high density lipoprotein levels in a patient. Such diseases include, but are not limited to, diabetes, particularly type II diabetes, as well as insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol in the blood, obesity, hyperlipidemia, such as hypertriglyceridemia, syndrome X, diabetic complications, such as diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy, and the like, atherosclerosis, or hypertension.

Furthermore, the compounds or pharmaceutical compositions according to the invention are also suitable for the prophylaxis and treatment of diabetic late damage, such as nephropathy, retinopathy, neuropathy, and myocardial infarction, peripheral arterial occlusive disease, thrombosis, arteriosclerosis, inflammation, immune disorders, autoimmune disorders, such as AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer's disease, schizophrenia, and infectious diseases.

In addition to being beneficial for human therapy, the compounds of the present invention may also find use in veterinary therapy for pets, animals of the introduced species and animals in farms, including mammals, rodents, and the like. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

An "effective amount," "therapeutically effective amount," or "effective dose" of a compound of the invention or a pharmaceutically acceptable pharmaceutical composition refers to an effective amount to treat or reduce the severity of one or more of the conditions referred to herein. The compounds or pharmaceutically acceptable pharmaceutical compositions of the present invention are effective over a relatively wide dosage range. For example, the daily dosage may be in the range of about 0.1mg to about 1000mg per person, divided into one or more administrations. The methods, compounds and pharmaceutical compositions according to the present invention can be of any amount administered and any route of administration effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compounds or pharmaceutical compositions of the present invention may be administered in combination with one or more other therapeutic agents, as discussed herein.

General Synthesis and detection methods

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known drugs other than those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The structure of the compound is determined by nuclear magnetic resonance ¹H-NMR、¹³C-NMR).¹H-NMR、¹³The C-NMR chemical shifts (. delta.) are given in parts per million (ppm).¹H-NMR、¹³C-NMR was measured using a Bruker Ultrashield-400 NMR spectrometer and a Bruker Avance III HD 600 NMR spectrometer using deuterated chloroform (CDCl) as the solvent₃) Deuterated methanol (CD)₃OD or MeOH-d₄) Or deuterated dimethyl sulfoxide (DMSO-d)₆). Tetramethylsilane (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singlets, singlet), d (doublets ), t (triplets, triplets), m (multiplets ), br (broadcasters, broad), dd (doublets of doublets), dt (doublets of triplets, doublets), td (triplets of doublets, triplet), brs (broad singlets). Coupling constant J, in Hertz (Hz).

HPLC preparative purification typically uses a Novasep pump 250 high performance liquid chromatograph.

MS was determined using an Agilen-6120Quadrupole LC/MS mass spectrometer.

The thin layer chromatography silica gel plate is prepared from HSGF254 silica gel plate of Taiwan yellow sea.

The column chromatography generally uses 300-400 mesh silica gel in Qingdao ocean chemical industry as a carrier.

The starting materials of the present invention are known and commercially available, purchased from Shanghai Accela Company, Annage Company, Bailingwei Company (J & K), Tianjin Afaha Angel Company (Alfa Company), Guangzhou Zeyuan trading Co., LTD., Shanghai Demo Medical technology Co., LTD., Shanghai Araldin Biochemical technology Co., Ltd. (Aladdin), and the like, or may be synthesized using or according to methods known in the art.

In the examples, the reaction is carried out under nitrogen, unless otherwise specified;

the nitrogen atmosphere refers to that the reaction bottle is connected with a nitrogen balloon or a steel kettle with the volume of about 1L;

the hydrogen atmosphere refers to a reaction bottle connected with a hydrogen balloon with the volume of about 1L or a stainless steel high-pressure reaction kettle with the volume of about 1L;

in the examples, unless otherwise specified, the solution means an aqueous solution;

in the examples, the reaction temperature is room temperature unless otherwise specified;

in the examples, the room temperature is 20 ℃ to 30 ℃ unless otherwise specified.

The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a developing solvent system of: dichloromethane and methanol system, dichloromethane and ethyl acetate system, petroleum ether and ethyl acetate system, and the volume ratio of the solvent is adjusted according to the polarity of the compound.

The system of eluent for column chromatography comprises: a: petroleum ether and ethyl acetate system, B: dichloromethane and ethyl acetate system, C: dichloromethane and methanol system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of ammonia water, acetic acid and the like can be added for adjustment.

HPLC refers to high performance liquid chromatography;

HPLC was performed using an Agilent 1200 high pressure liquid chromatograph (PLUS C18,4.6 μm,150X 5mm column);

HPLC test conditions: operating time: 25 min; column temperature: 35 ℃; detection wavelength: 210 nm; flow rate: 1.0 ml/min;

mobile phase: phase A: acetonitrile; phase B: water;

elution procedure:

the following acronyms are used throughout the invention:

DMSO-d₆deuterated dimethyl sulfoxide;

CDCl₃deuterated chloroform;

CD₃OD is deuterated methanol;

THF, tetrahydrofuran;

DMF is N, N-dimethylformamide amide;

DBU is 1, 8-diazabicyclo [5.4.0] undec-7-ene;

TMSCl is trimethylchlorosilane;

TBSCl is tert-butyldimethylsilyl chloride;

DMAP 4-dimethylaminopyridine;

NBS is N-bromosuccinimide;

AIBN azobisisobutyronitrile;

TEMPO 2,2,6, 6-tetramethylpiperidine oxide;

percent by mass;

TBS is tert-butyl dimethyl silicon base;

bn is benzyl;

PMB is p-methoxybenzyl;

TMS is trimethylsilyl;

m, mol/L is mol/L;

ac is acetyl;

et is ethyl.

General synthetic methods

Typical synthetic procedures for preparing the disclosed compounds are shown in the following synthetic schemes 1-10. Unless otherwise stated, each R¹、R²、R³、R⁵、R⁶、R^7a、R^10a、R^10b、R^10c、R^10dAnd ring a has the definition as described in the present invention.

Synthesis scheme 1

The compounds having the structure shown in general formula (I-A) can be prepared by general synthetic methods described in scheme 1, and specific procedures can be referred to examples. Wherein X is Br or I, each PG ₁、PG₂And PG₃Independently, a suitable hydroxy protecting group. The compound of the general formula (I-a) reacts with a hydroxyl protecting group PG under the action of 4-methylmorpholine₁React to obtainTo compounds of general formula (I-b); reacting the halide fragment compound with the general formula (I-c) with n-butyllithium, and then coupling the halide fragment compound with the general formula (I-b) to obtain a compound of the general formula (I-d); reacting the compound of the general formula (I-d) with methanol under an acidic condition to obtain a compound of the general formula (I-e); reducing the compound of the general formula (I-e) by a reducing agent (such as triethylsilane) to obtain a compound of the general formula (I-f); the compound of the general formula (I-f) reacts with a hydroxyl protecting group PG under alkaline conditions₂Reacting to obtain a compound shown in a general formula (I-g); the compound of the general formula (I-g) is reacted with a hydroxyl protecting group PG under alkaline conditions₃Reacting to obtain a compound shown in a general formula (I-h); the compound of the general formula (I-h) reacts with tetrabutylammonium fluoride to remove the hydroxyl protecting group PG₂To obtain a compound of the general formula (I-I); carrying out oxidation reaction on the general formula (I-I) to obtain a compound of the general formula (I-j); carrying out esterification reaction on the compound of the general formula (I-j) and methanol under an acidic condition to obtain a compound of the general formula (I-k); reacting the compound of the general formula (I-k) with a Grignard reagent (such as methyl magnesium bromide or ethyl magnesium bromide) at a low temperature to obtain a compound of the general formula (I-l); hydrogenation of the compound of formula (I-l) in the presence of a catalyst (e.g. palladium on carbon) to remove the protecting group PG ₁To obtain the target compound shown in the general formula (I-A).

Synthesis scheme 2:

compounds having the structure shown in general formula (I-B) can be prepared by general synthetic methods described in scheme 2, with reference to the examples for specific procedures. Wherein each PG₂And PG₃Independently, a suitable hydroxy protecting group. The compound of the general formula (I-e) is reacted with a hydroxyl protecting group PG under suitable basic (e.g. imidazole) conditions₂Reacting to obtain a compound shown in a general formula (I-m); a compound of formula (I-m) is reacted with a hydroxy protecting group PG under suitable basic conditions, such as sodium hydride₃Reacting to obtain a compound of a general formula (I-n); reacting the compound of the general formula (I-n) with tetrabutylammonium fluoride to remove the protective group PG₂To obtain a compound of the general formula (I-o); oxidizing the compound of the general formula (I-o) to obtain a compound of a general formula (I-p); formula (I-p) formulaReacting the compound with formaldehyde in a polar solvent under the action of DBU to obtain a compound with a general formula (I-q); reducing the compound with the general formula (I-q) by sodium borohydride to obtain a compound with the general formula (I-r); the compound of the general formula (I-r) is subjected to ring closure under an acidic condition to obtain a compound of the general formula (I-s); hydrogenation of compounds of general formula (I-s) in the presence of a catalyst (e.g. palladium on carbon) to remove the protecting group PG₃To obtain the target compound shown as the general formula (I-B).

Synthesis scheme 3

Compounds having a structure represented by general formula (I-C) can be prepared by general synthetic methods described in scheme 3, with reference to the examples for specific procedures. Wherein PG₃Are suitable hydroxyl protecting groups. Carrying out oxidation reaction on the compound with the general formula (I-s) to obtain a compound with a general formula (I-t); carrying out esterification reaction on the compound with the general formula (I-t) and methanol under an acidic condition to obtain a compound with the general formula (I-u); reacting the compound of the general formula (I-u) with a Grignard reagent (such as methyl magnesium bromide, ethyl magnesium bromide and the like) at low temperature to obtain a compound of the general formula (I-v); the compound of the general formula (I-v) is hydrogenated to remove the protective group PG under the action of a catalyst (such as palladium/carbon and the like)₃To obtain the target compound shown as the general formula (I-C).

Synthesis scheme 4

Compounds having the structure shown in general formula (I-D) can be prepared by general synthetic methods described in scheme 4, with reference to the examples for specific procedures. Wherein X is Br or I, L is C₂-C₆Alkyl or C₃-C₆Cycloalkyl of (2), PG₃Are suitable hydroxy protecting groups. Reacting the compound of the general formula (I-w) with a compound of the general formula (I-aa) or a compound of the general formula (I-bb) under the action of a catalyst (such as palladium acetate) to obtain a compound of the general formula (I-x); the compound of formula (I-x) is used as a catalyst (e.g. palladium on carbon) By removing the protecting group PG₃To obtain the target compound shown in the general formula (I-D).

Synthesis scheme 5

Compounds having the structure shown in general formula (I-E) can be prepared by general synthetic methods described in FIG. 5, with reference to the examples for specific procedures. Wherein PG₃Is a hydroxyl protecting group. Reacting the compound of the general formula (I-s) with methane sulfonyl chloride under alkaline conditions to obtain a compound of the general formula (I-y); reacting the compound of the general formula (I-y) with sodium methyl mercaptide to obtain a compound of the general formula (I-z); removing hydroxyl protecting group PG from compound of general formula (I-z) under catalysis of catalyst (such as palladium/carbon)₃To obtain the target compound shown in the general formula (I-D).

Synthesis scheme 6

Compounds having the structure shown by the general formula (I-F) can be prepared by general synthetic methods as depicted in scheme 6, with reference to the examples for specific procedures. Wherein X is Br or I, each PG₁、PG₃And PG₄Is a hydroxyl protecting group, p is 1, 2, 3, 4, 5 or 6. Is represented by the general formula (I-c)₁) Starting with the compound and the compound of the general formula (I-b), the compound of the general formula (I-c) can be obtained by referring to FIG. 1 or FIG. 2₂) A compound; general formula (I-c)₂) Removing protecting group PG by one-step or multi-step reaction of compound under action of catalyst (such as palladium/carbon) ₃And PG₄To obtain the target compound shown in the general formula (I-F).

Synthesis scheme 7

Has the general formulaThe compounds of the structures shown in (II-A) and general formula (II-B) can be prepared by general synthetic methods described in FIG. 7, and the specific procedures can be referred to in the examples. Wherein X is Br or I, PG₃Is a hydroxyl protecting group, and t is 1, 2, 3, 4 or 5. Reacting the compound of the general formula (II-a) with a compound of the general formula (II-z) to obtain a compound of the general formula (II-b); reducing the compound of the general formula (II-b) by a reducing agent (such as iron powder), and then self-cyclizing the obtained product to obtain a compound of the general formula (II-c); removing the protecting group PG of the compound of the general formula (II-c) under proper alkaline conditions₃Obtaining a target compound shown by a pyranyl glucose derivative (II-A); compounds of the general formula (II-A) and R^7aReacting the obtained product with the intermediate to obtain a target compound shown by another pyranyl glucose derivative (II-B).

Synthesis scheme 8

Compounds having structures represented by general formula (II-C) and general formula (II-D) can be prepared by general synthetic methods as described in FIG. 8, with reference to the examples for specific procedures. Wherein X is Br or I, PG₃Is a hydroxyl protecting group. Reacting the compound of the general formula (II-a) with a compound of the general formula (II-y) to obtain a compound of the general formula (II-d); reducing the compound of the general formula (II-d) by a reducing agent (such as tin dichloride) to obtain a compound of the general formula (II-e); the compound of the general formula (II-e) is condensed to form a ring under the alkaline condition to obtain a compound of the general formula (II-f); removing the protecting group PG of the compound of the general formula (II-f) under proper alkaline conditions ₃Obtaining a target compound shown as a pyranoglucosan derivative (II-C); compounds of the general formula (II-C) and R^7aThe reaction of the intermediate compound and the compound of formula (I) to obtain another pyranyl glucose derivative (II-D).

Synthesis scheme 9

Compounds having the structure shown by the general formula (II-E) can be prepared by general synthetic methods as depicted in FIG. 9, with reference to the examples for specific procedures. Wherein PG is a protecting group. Reacting the compound of the general formula (II-A) with a protecting group PG under alkaline conditions to obtain a compound of the general formula (II-g) with the hydroxyl and the amido protected by the protecting group; reacting the ethyl magnesium bromide with tetraisopropyl titanate and then with a compound of a general formula (II-g) to obtain a compound of a general formula (II-h); and (3) under the catalysis of a catalyst (such as palladium dichloride), removing a protective group PG and simultaneously opening a ring to obtain a target compound shown in a general formula (II-E).

Synthesis scheme 10

Compounds of formula (II-G) can be prepared by general synthetic methods as depicted in scheme 10, with reference to the examples for specific procedures. Wherein PG₃Is a hydroxyl protecting group, and t is 1, 2, 3, 4 or 5. Reacting the compound of the general formula (II-i) with paraformaldehyde under a suitable alkaline condition to obtain a compound of the general formula (II-j); carrying out wittig reaction on the compound with the general formula (II-j) and a corresponding wittig reagent (such as carbethoxy methylene triphenylphosphine) to obtain a compound with a general formula (II-k); carrying out microwave reaction on the compound of the general formula (II-k), and carrying out self-cyclization to obtain a compound of the general formula (II-l); removing the protective group PG from the compound of the general formula (II-l) under suitable alkaline conditions ₃To obtain the target compound represented by the general formula (II-G).

Examples

Example 1(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 1

Step 15-bromo-2-fluoro-benzoyl chloride 1b

N, N-dimethylformamide (0.1mL,1.2mmol) was added dropwise to a solution of 5-bromo-2-fluoro-benzoic acid 1a (1.0g,4.57mmol) in thionyl chloride (10mL) at room temperature, and the mixture was heated to 75 ℃ for reaction for 4 hours. After the reaction was completed, concentration was performed under reduced pressure to remove the organic solvent, to obtain the title compound 1b (1.1g, brown oil), yield: 100 percent. The product was used directly in the next reaction.

Step 2 (5-bromo-2-fluoro-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 1c

The crude 5-bromo-2-fluoro-benzoyl chloride 1b (1.1g,4.62mmol) obtained above was dissolved in dichloromethane (10mL) at room temperature, 2, 3-dihydro-1, 4-benzodioxin (0.62g,4.57mmol) was added, and after the mixture was cooled to 0 ℃ under a nitrogen atmosphere, aluminum chloride (0.79g,5.92mmol) was added thereto in portions, and then slowly warmed to room temperature and stirred for 12 hours. After the reaction was completed, the mixture was poured into crushed ice, extracted with dichloromethane (20mL × 2), and the combined organic phases were washed with saturated brine (30mL), dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 1c (1.6g, yellow solid), yield: 100 percent. The product was used directly in the next reaction.

Step 36- [ (5-bromo-2-fluoro-phenyl) methyl]-2, 3-dihydro-1, 4-benzodioxin 1d

Triethylsilane (6.5mL,39mmol) and trifluoromethanesulfonic acid (6.0mL,77.5mmol) were added dropwise to a solution of (5-bromo-2-fluoro-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 1c (1.6g,4.76mmol) in trifluoroacetic acid (6mL) at 0 ℃ and the resulting mixture was reacted at room temperature for 30 minutes. After completion of the reaction, concentration under reduced pressure was carried out to remove the organic solvent, ethyl acetate (60mL) was added to the residue, which was then washed with water (50mL), a saturated sodium bicarbonate solution (50mL) and a saturated saline solution (50mL) in this order, dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% petroleum ether ] to obtain the title compound 1d (0.75g, yellow oily substance), yield: 49.4 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.50(m,1H),7.46-7.40(m,1H),7.15(t,1H),6.77(d,1H),6.72(s,1H),6.69-6.63(m,1H),4.19(s,4H),3.83(s,2H)。

Step 4(3R,4S,5R,6R) -3,4, 5-tris (trimethylsiloxy) -6- (trimethylsiloxymethyl) tetrakis Hydro furan-2 one 1f

To a solution of gluconolactone 1e (30g,168.4mmol) in anhydrous tetrahydrofuran (200mL) was added 4-methylmorpholine (150mL,1.40mol) at room temperature, followed by the slow dropwise addition of TMSCl (125mL,985mmol) at-5 ℃ for a total period of 1 hour, after the addition was complete, stirring was continued for 30 minutes, and then moved to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was added to petroleum ether (300mL), followed by washing with water (300mL) and a saturated disodium hydrogenphosphate solution (300mL × 2) in this order, drying over anhydrous sodium sulfate, suction filtration, concentration of the filtrate under reduced pressure, and purification of the residue by flash silica gel column chromatography [ 100% petroleum ether ] to give the title compound 1f (65.4g, a colorless transparent oily liquid) in yield: 83.2 percent.

Step 5(2S,3R,4S,5R,6R) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-benzene Base of]1g of (E) -3,4, 5-tris (trimethylsiloxy) -6- (trimethylsiloxymethyl) tetrahydropyran-2-ol

A solution of n-butyllithium in n-hexane (26mL,62mol,2.4M) was added dropwise to a solution of 6- [ (5-bromo-2-fluoro-phenyl) methyl ] -2, 3-dihydro-1, 4-benzodioxin 1d (18.0g,55.7mmol) in anhydrous tetrahydrofuran (300mL) at-78 deg.C, with stirring for 1 hour, and then a solution of (3R,4S,5R,6R) -3,4, 5-tris (trimethylsilyloxy) -6- (trimethylsilyloxymethyl) tetrahydropyran-2-one 1f (28.6g,61.3mmol) in anhydrous tetrahydrofuran (100mL) was slowly added dropwise, with stirring, and the reaction was continued for 5 hours. After the reaction was completed, the reaction was quenched with water (5mL), and the resulting mixture was used directly in the next reaction.

Step 6(2S,3R,4S,5S,6R) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-benzene Base of]-6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 1h

Methanol (200mL) and p-toluenesulfonic acid monohydrate (12.7g,67mmol) were added to the reaction mixture in the first step at room temperature, and the mixture was stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, ethyl acetate (200mL) was added to the residue, which was then washed with water (100mL), a saturated sodium bicarbonate solution (100mL) and a saturated saline solution (100mL) in this order, dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to give the title compound 1h (7.1g, pale yellow solid) in total yield in two steps: 29 percent.

Step 7(2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl]Oxymethyl radical]-2- [3- (2, 3-dihydro-) 1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl]-2-methoxy-tetrahydropyran-3, 4, 5-triol 1i

Imidazole (0.87g,13.0mmol), TBSCl (1.92g,12.7mmol) and 4-dimethylaminopyridine (0.08g,0.63mmol) were added sequentially to a solution of (2S,3R,4S,5S,6R) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol in dichloromethane (20mL) for 1h (2.74g,6.28mmol) at 0 ℃ and stirred for 2 hours. After the reaction was completed, concentration was performed under reduced pressure to remove the organic solvent, water (20mL) was added to the residue, followed by extraction with ethyl acetate (20mL × 2), the combined extracts were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1i (3.46g, colorless oil), yield: 100 percent.

Step 8 tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro- 1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl]-6-methoxy-tetrahydropyran-2-yl]Methoxy radical]Silane 1j

Sodium hydride (0.95g,38.0mmol) was added portionwise to a solution of (2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -2-methoxy-tetrahydropyran-3, 4, 5-triol 1i (3.46g,6.10mmol) in anhydrous tetrahydrofuran (20mL) at 0 ℃ and stirred for 1h, followed by benzyl bromide (4.5mL,38.0mmol) and tetrabutylammonium iodide (0.01g,0.03mmol), and the resulting mixture was heated to 40 ℃ and stirred for 18 h. After completion of the reaction, the reaction mixture was cooled to 0 ℃, quenched by dropwise addition of water (1mL), then concentrated under reduced pressure to remove the organic solvent, and the residue was dissolved in ethyl acetate (30mL), washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to give the title compound 1j (5.11g, yellow oil), yield: 100 percent.

Step 9[ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-fluoro-phenyl]-6-methoxy-tetrahydropyran-2-yl]Methanol 1k

A solution of tetrabutylammonium fluoride in tetrahydrofuran (12.5mL,12.5mmol,1M) was added to a solution of tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methoxy ] silane 1j (5.11g,6.10mmol) in tetrahydrofuran (30mL) at room temperature and stirred at room temperature for 32 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was dissolved in ethyl acetate (60mL), washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 2/1] to give the title compound 1k (0.38g, yellow oil) in yield: 8.66 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.48-7.06(m,17H),6.99(s,1H),6.70(d,1H),6.61(s,1H),6.57(d,1H),5.40(d,1H),4.93(d,1H),4.78-4.71(m,1H),4.66(d,1H),4.52(d,1H),4.17(s,5H),4.03(m,1H),3.87(d,1H),3.81(d,1H),3.78-3.71(m,2H),3.66(d,1H),3.49(d,2H),3.03(d,1H),2.94(s,3H)。

Step 10(2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-fluoro-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 1l

A sodium bicarbonate solution (0.51g,6.1mmol, 10mL), potassium bromide (0.04g,0.34mmol), TEMPO (0.01g,0.06mmol) and a sodium hypochlorite solution (690mg, 0.68mmol of available chlorine, 3.5% of available chlorine) were added to a solution of [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methanol 1k (0.38g,0.54mmol) in dichloromethane (10mL) at 0 ℃ in that order and stirred for 10 minutes. After completion of the reaction, liquid separation was performed, and the separated organic phase was washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 1l (0.38g, yellow oil), yield: 100 percent.

Step 11(2R,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-fluoro-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 1m

Formaldehyde solution (1.2mL,16mmol, wt.%: 37%), DBU (0.07mL,0.5mmol) were added in sequence to a solution of (2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -6-methoxy-tetrahydropyran-2-carbaldehyde 1l (0.38g,0.53mmol) in N, N-dimethylformamide (5mL) at room temperature and stirred for 40 h. After the reaction was completed, water (20mL) was added to dilute the reaction solution, followed by extraction with ethyl acetate (20mL × 2), and the combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain the title compound 1m (0.40g, yellow oil), yield: 100 percent.

Step 12[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-fluoro-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl]Methanol 1n

Sodium borohydride (32mg,0.83mmol) was added to a solution of (2R,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 1m (0.40g,0.54mmol) in methanol (10mL) at 0 ℃ and stirred for 5 minutes. After the reaction was completed, water (20mL) was added to dilute the reaction solution, followed by extraction with ethyl acetate (20mL × 2), and the combined organic phases were washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain the title compound 1n (0.40g, yellow oil), yield: 100 percent.

Step 13[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-fluoro-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methanol 1o

P-toluenesulfonic acid monohydrate (0.15g,0.79mmol) was added to a solution of [ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl ] methanol 1n (0.40g,0.54mmol) in tetrahydrofuran (10mL) at room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and ethyl acetate (20mL) was added to the residue, which was washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 5/1] to give the title compound 1o (0.12g, yellow oil), yield: 32 percent.

Step 14(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro- Phenyl radical]-1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 1

To a solution of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 1o (80mg,0.11mmol) in methanol/tetrahydrofuran (v/v ═ 3/1,12mL) was added 10% palladium on carbon (20mg,0.02mmol) at room temperature, and the mixture was stirred under a hydrogen atmosphere for 5 hours. After the reaction was completed, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 1(41mg, white solid) in yield: 84 percent.

MS(ESI,pos.ion):m/z 479.1[M+HCOO]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)：7.37(d,1H),7.35-7.29(m,1H),7.14-7.07(m,1H),6.75(d,1H),6.66(d,2H),5.18(d,1H),4.96(d,1H),4.87(d,1H),4.75(t,1H),4.19(s,3H),3.98(d,1H),3.83(s,1H),3.63(m,1H),3.56-3.51(m,1H),3.50-3.44(m,2H),3.42(d,2H)。

Example 2(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 2

Step 1(1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-fluoro-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 2a

Dess-martin oxidizer (0.56g,1.3mmol) was added to a solution of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 1o (227mg,0.32mmol) in dichloromethane (10mL) at 0 ℃ and the resulting mixture was heated to 40 ℃ and stirred for 16 hours. After the completion of the reaction, concentration under reduced pressure was performed to remove the organic solvent, a saturated sodium bicarbonate solution (30mL) was added to the residue, extraction was performed with ethyl acetate (10mL × 3), the organic phases were combined, concentration under reduced pressure was performed, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1] to give the title compound 2a (193mg, yellow oil), yield: 83 percent.

Step 2 methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) -4-fluoro-phenyl ]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 2b

Concentrated sulfuric acid (50mg,0.50mmol) was added to a solution of (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 2a (193mg,0.26mmol) in methanol (10mL) at room temperature, and the resulting mixture was heated to 40 ℃ and stirred for 8 hours. After completion of the reaction, concentration under reduced pressure was carried out to remove the organic solvent, and the residue was dissolved in ethyl acetate (10mL), washed with saturated sodium bicarbonate solution (10mL) and saturated brine (10mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1] to give the title compound 2b (113mg, yellow oil) in yield: 57 percent.

Step 32- [ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) -4-fluoro-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 2c

A solution of methylmagnesium bromide in diethyl ether (0.2mL,0.6mmol,3M) was added dropwise to a solution of methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 2b (113mg,0.15mmol) in anhydrous tetrahydrofuran (5mL) at 0 deg.C, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction was quenched by adding water (0.5mL) dropwise, concentrated under reduced pressure, the organic solvent was removed, the residue was dissolved in ethyl acetate (10mL), washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 6/1] to give the title compound 2c (48mg, colorless oil) in yield: 42 percent.

Step 4(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-benzene Base of]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 2

To a solution of 2- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-fluoro-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 2c (48mg,0.07mmol) in methanol/tetrahydrofuran (v/v ═ 4/1,5mL) was added 10% palladium/carbon (100mg,0.09mmol) at room temperature, and the mixture was stirred under hydrogen atmosphere for 2 hours. After the completion of the reaction, concentration under reduced pressure was carried out to remove the organic solvent, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 2(29mg, white solid) in yield: 88 percent.

MS(ESI,pos.ion):m/z 507.1[M+HCOO]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.39(d,1H),7.32(m,1H),7.13(t,1H),6.75(d,1H),6.67(s,1H),6.65(d,1H),5.69(d,1H),5.20(d,1H),5.06(d,1H),4.27(d,1H),4.18(s,4H),3.92(d,1H),3.84(s,1H),3.82(s,2H),3.76(t,1H),3.51(t,1H),3.44(m,1H),1.24(s,6H)。

Example 3(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 3

Step 1(2S,3R,4S,5R,6R) -2- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) benzene Base of]-3,4, 5-tris (trimethylsiloxy) -6- (trimethylsiloxymethyl) tetrahydropyran-2-ol 3b

6- [ (5-bromo-2-chloro-phenyl) methyl ] -2, 3-dihydro-1, 4-benzodioxin 3a (30.0g,88.3mmol) was dissolved in anhydrous tetrahydrofuran (200mL) under a nitrogen atmosphere and cooled to-78 ℃, and then an n-hexane solution of n-butyllithium (37mL,89mol,2.4M) was slowly added dropwise, and after completion of the dropwise addition, stirring was carried out for 40 minutes, and a solution of (3R,4S,5R,6R) -3,4, 5-tris (trimethylsilyloxy) -6- (trimethylsilyloxymethyl) tetrahydropyran-2-one 1f (37.8g,81.0mmol) in anhydrous tetrahydrofuran (400mL) was slowly added dropwise to the reaction solution, and stirring was continued for 16 hours. After the reaction was completed, the reaction was quenched by slowly dropping water (5mL), then naturally warmed to room temperature, and then the mixture was diluted with ethyl acetate (300mL), washed with a saturated ammonium chloride solution (200mL × 2) and a saturated saline solution (200mL × 2) in this order, dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 3b (59.2g, yellow syrup) in yield: 100 percent.

Step 2(2S,3R,4S,5S,6R) -2- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) benzene Base of]-6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 3c

P-toluenesulfonic acid monohydrate (17.2g,98.9mmol) was added to a solution of (2S,3R,4S,5R,6R) -2- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -3,4, 5-tris (trimethylsiloxy) -6- (trimethylsiloxymethyl) tetrahydropyran-2-ol 3b (59.2g,81.4mmol) in methanol (400mL) at room temperature, and the resulting mixture was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was washed with a saturated sodium bicarbonate solution (200mL), concentrated under reduced pressure, the organic solvent was removed, the obtained residue was extracted with ethyl acetate (500mL), washed with a saturated saline solution (150mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the filtrate was crystallized from the residue with ethyl acetate/petroleum ether (v/v ═ 1/10, 300mL), and the title compound 3c (20.0g, yellow solid) was obtained in yield: 51 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm)：7.52(s,1H),7.39(s,2H),6.75(d,1H),6.63(d,2H),4.97(d,1H),4.75(m,2H),4.55(t,1H),4.19(d,4H),3.93(t,2H),3.75(m,1H),3.56(m,3H),3.23(m,1H),2.93(s,3H),2.88(d,

1H)。

Step 3(2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl]Oxymethyl-2- [ 4-chloro-3- (2, 3-di) Hydro-1, 4-benzodioxin-6-ylmethyl) phenyl]-2-methoxy-tetrahydropyran-3, 4, 5-triol 3d

Imidazole (6.1g,89.0mmol), TBSCl (13.5g,89.6mmol) and 4-dimethylaminopyridine (0.54g,4.42mmol) were added sequentially to a solution of (2S,3R,4S,5S,6R) -2- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 3c (20.0g,44.2mmol) in dichloromethane (200mL) at 0 ℃ and stirred for 2 hours. After completion of the reaction, concentration under reduced pressure was carried out to remove the organic solvent, and water (100mL) was added to the residue, followed by extraction with ethyl acetate (100mL × 2), and the combined extracts were washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to give the title compound 3d (25.0g, reddish brown oily substance), yield: 100 percent.

Step 4 tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- (2,3- Dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl]-6-methoxy-tetrahydropyran-2-yl]Methoxy radical]Silane 3e

Sodium hydride (7.7g,300mmol) was added in portions to a solution of (2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl-2- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -2-methoxy-tetrahydropyran-3, 4, 5-triol 3d (25.0g,44.2mmol) in anhydrous tetrahydrofuran (200mL) at 0 ℃, after stirring for 1 hour, benzyl bromide (32mL,269mmol) and tetrabutylammonium iodide (0.01g,0.03mmol) were added, and the resulting mixture was heated to 40 ℃ and stirred for 18 hours. After the reaction was completed, it was cooled to 0 ℃, the reaction was quenched by adding water (5mL) dropwise, concentrated under reduced pressure, the organic solvent was removed, and the residue was dissolved in ethyl acetate (200mL), washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to give the title compound 3e (37.0g, yellow oil), yield: 100 percent.

Step 5[ (2R,3R,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodi) Oxazolin-6-ylmethyl) phenyl]-6-methoxy-tetrahydropyran-2-yl]Methanol 3f

A solution of tetrabutylammonium fluoride in tetrahydrofuran (90mL,90mmol,1M) was added to a solution of tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methoxy ] silane 3e (37.0g,44.2mmol) in tetrahydrofuran (200mL) at room temperature and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was dissolved in ethyl acetate (200mL), washed with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 5/1] to give the title compound 3f (5.7g, yellow oil) in yield: 18 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm)：7.50(s,1H),7.45(s,2H),7.34(s,7H),7.33-7.29(m,4H),7.25(m,7H),6.99(m,2H),6.68(d,1H),6.60-6.53(m,2H),4.91(m,1H),4.79(d,3H),4.68(d,1H),4.39(d,1H),4.16(s,4H),4.05-3.90(m,2H),3.84(d,J＝15.2Hz,1H),3.78-3.59(m,4H),3.56-3.48(m,1H),3.23(d,1H),2.98(s,3H)。

Step 6(2S,3S,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 3g

An aqueous solution (100mL) of sodium bicarbonate (5.8g,68.2mmol), potassium bromide (0.52g,4.34mmol), TEMPO (0.2g,1.24mmol) and a sodium hypochlorite solution (9.13g, 9.0mmol, 3.5% available chlorine) were added to a solution of [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methanol 3f (4.8g,6.6mmol) in dichloromethane (50mL) at 0 ℃ in that order, and stirred for 5 minutes. After completion of the reaction, the organic phase was separated, washed with saturated brine (30mL × 2), dried over anhydrous sodium sulfate, suction-filtered, and the filtrate was concentrated under reduced pressure to obtain 3g (5.0g, yellow oil) of the title compound in yield: 100 percent.

Step 7(2R,3S,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 3h

A formaldehyde solution (13mL,173.5mmol, wt.%: 37%), DBU (0.64mL,4.2mmol) were added in sequence to a solution of (2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6-methoxy-tetrahydropyran-2-carbaldehyde 3g (5.0g,6.9mmol) in N, N-dimethylformamide (50mL) at room temperature and the reaction was stirred at room temperature for 40 hours. After the reaction was completed, the mixture was diluted with water (100mL), extracted with ethyl acetate (100mL × 2), and the combined organic phases were washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to give the title compound 3h (5.2g, yellow oil), yield: 100 percent.

Step 8[ (3S,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [ 4-chloro-3- (2, 3-dihydro-1, 4-Benzodioxol) En-6-ylmethyl) phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl]Methanol 3i

Sodium borohydride (0.37g,9.6mmol) was added to a solution of (2R,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde in dry methanol (50mL) for 3h (5.2g,6.91mmol) at 0 ℃ and stirred for 5 min. After completion of the reaction, concentration under reduced pressure was carried out, and the residue was dissolved in ethyl acetate (50mL), washed with saturated brine (30 mL. times.2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to give the title compound 3i (5.2g, yellow oil), yield: 100 percent.

Step 9[ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methanol 3j

P-toluenesulfonic acid monohydrate (1.5g,7.89mmol) was added to a solution of [ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl ] methanol 3i (5.2g,6.9mmol) in tetrahydrofuran (30mL) at room temperature and stirred for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, ethyl acetate (50mL) was added to the residue, followed by washing with a saturated sodium bicarbonate solution (30mL) and a saturated brine (30mL), followed by drying over anhydrous sodium sulfate, suction filtration, and concentration of the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 5/1] to give the title compound 3j (2.15g, yellow oily substance) in yield: and 43 percent.

Step 10(1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodi Oxazolin-6-ylmethyl) phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 3k

A sodium hydrogencarbonate solution (1.2g,14.0mmol, 20mL), potassium bromide (0.1g,0.8mmol), TEMPO (0.02g,0.1mmol) and a sodium hypochlorite solution (3.41g, 3.36mmol of available chlorine, 3.5% of available chlorine) were added to a solution of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy 5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxobicyclo [3.2.1] octane-1-yl ] methanol 3j (0.97g,1.3mmol) in dichloromethane (10mL) in this order at 0 ℃ and stirred for 10 minutes. After the reaction was completed, the organic phase was separated, washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, suction-filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 3k (0.31g, yellow solid), yield: 31 percent.

Step 11 methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzene) Dioxin-6-ylmethyl) phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 3l

Concentrated sulfuric acid (50mg,0.50mmol) was added to a solution of (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 3k (310mg,0.42mmol) in methanol (20mL) at room temperature, and the resulting mixture was heated to 40 ℃ and stirred for 15 hours. After the reaction was completed, the reaction was quenched with saturated sodium bicarbonate solution (10mL), concentrated under reduced pressure to remove the organic solvent, the residue was extracted with ethyl acetate (10mL × 2), the combined extracts were washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to give the title compound 3l (316mg, yellow oil) in yield: 100 percent.

Step 122- [ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 3m

A solution of methylmagnesium bromide in diethyl ether (1.2mL,3.6mmol,3M) was added dropwise to a solution of methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 3l (310mg,0.41mmol) in anhydrous tetrahydrofuran (10mL) at 0 deg.C, the mixture was allowed to warm to room temperature and stirred for 1 hour. After the reaction was completed, the reaction was cooled to 0 ℃, and water (1mL) was added dropwise to quench the reaction, and concentrated under reduced pressure, the organic solvent was removed, ethyl acetate (20mL) was added to the residue, which was washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 5/1] to obtain the title compound 3m (180mg, white solid) in yield: 58 percent.

Step 13(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl)) Benzene and its derivatives Base of]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 3

O-dichlorobenzene (0.1mL,0.9mmol) and 10% palladium on carbon (26mg,0.02mmol) were added to a solution of 2- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 3m (180mg,0.24mmol) in methanol/tetrahydrofuran (v/v ═ 3/1,5mL) at room temperature, and stirred under a hydrogen atmosphere for 5 hours. After the reaction was completed, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 3(100mg, white solid) in yield: 95 percent.

MS(ESI,pos.ion):m/z 523.1[M+HCOO]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm)：7.43(d,1H),7.39(d,1H),7.33(m,1H),6.75(d,1H),6.65(d,2H),5.49(d,1H),5.03(d,1H),4.98(d,1H),4.24(s,1H),4.19(s,4H),3.94(s,2H),3.81(d,1H),3.74-3.68(m,1H),3.49-3.44(m,1H),3.41-3.36(m,2H),1.21(s,3H),1.16(s,3H)。

Example 4(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 4

Step 15-bromo-2-methyl-benzoyl chloride 4b

To a solution of 5-bromo-2-methyl-benzoic acid 4a (21.5g,100mmol) in dichloromethane (200mL) at 0 deg.C was added oxalyl chloride (50.4g,397mmol) slowly, followed by N, N-dimethylformamide (0.5mL,6.4mmol) dropwise and the resulting mixture stirred at room temperature for 6 h. After the reaction was completed, concentration was performed under reduced pressure to obtain the title compound 4b (23.3g, pale yellow liquid), yield: 100 percent.

Step 2 (5-bromo-2-methyl-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 4c

2, 3-dihydro-1, 4-benzodioxin (14.96g,109.9mmol) was added to a solution of 5-bromo-2-methyl-benzoyl chloride 4b (23.3g,100.0mmol) in dichloromethane (400mL) at 0 deg.C, aluminum trichloride (52.9g,397mmol) was added in portions, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction was completed, the mixture was poured into crushed ice, extracted with dichloromethane (400mL × 2), the combined organic phases were washed successively with water (100mL × 2), a saturated sodium bicarbonate solution (200mL × 2) and a saturated brine (100mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by crystallization from n-hexane (300mL) to give the title compound 4c (31.6g, a grayish brown powder) in yield: 95 percent.

Step 36- [ (5-bromo-2-methyl-phenyl) methyl]-2, 3-dihydro-1, 4-benzodioxin 4d

Trifluoroacetic acid (30mL,391mmol), triethylsilane (51mL,310mmol) and trifluoromethanesulfonic acid (3.0mL,38.4mmol) were added in this order to a solution of (5-bromo-2-methyl-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 4c (31.6g,94.8mmol) in dichloromethane (200mL) at room temperature, and reacted for 2 hours at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, the residue was extracted with ethyl acetate (200mL × 2), the organic phase was separated, the organic phase was washed with saturated sodium bicarbonate solution (200mL × 2), water (200mL × 2) and saturated brine (200mL × 2) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═

20/1], to give the title compound 4d (29.0g, white solid), yield: 95 percent.

Step 4(2S,3R,4S,5S,6R) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl- Phenyl radical]-6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 4e

A solution of n-butyllithium in n-hexane (50mL,120mmol,2.4M) was slowly added dropwise to a solution of 6- [ (5-bromo-2-methyl-phenyl) methyl ] -2, 3-dihydro-1, 4-benzodioxin 4d (34.7g,109mmol) in anhydrous tetrahydrofuran (200mL) at-78 ℃ under a nitrogen atmosphere, and after stirring for 40 minutes, (3R,4S,5R,6R) -3,4, 5-tris (trimethylsilyloxy) -6- (trimethylsilyloxymethyl) tetrahydropyran-2-one 1f (56.1g,120mmol) in anhydrous tetrahydrofuran (50mL) was slowly added dropwise and stirring was continued for 5 hours. After the reaction was completed, the reaction was quenched by slowly dropping a saturated ammonium chloride solution (50mL), then naturally warmed to room temperature, a saturated aqueous ammonium chloride solution (150mL) was added, followed by extraction with ethyl acetate (150 mL. times.2), the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, the resulting residue was dissolved again in methanol (300mL), p-toluenesulfonic acid monohydrate (29.0g,152.0mmol) was added, and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, sodium hydrogencarbonate solid (15g) was added, and the mixture was concentrated under reduced pressure to remove the organic solvent, ethyl acetate (300mL) was added to the residue, which was then washed with water (200mL) and saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ], to give the title compound 4e (23.6g, yellow solid) in yield: 50 percent.

Step 5(2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl]Oxymethyl radical]-2- [3- (2, 3-dihydro-) 1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl]-2-methoxy-tetrahydropyran-3, 4, 5-triol 4f

Imidazole (1.50g,22.0mmol) and tert-butyldimethylsilyl chloride (3.41g,22.0mmol) were added sequentially to a solution of (2S,3R,4S,5S,6R) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 4e (4.8g,11.0mmol) in dichloromethane (100mL) at 0 deg.C and stirred for 2 hours. After completion of the reaction, the reaction mixture was washed with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 4f (4.3g, yellow oil), yield: 71 percent.

Step 6 t-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro- 1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]Methoxy radical]Silane 4g

A solution of (2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -2-methoxy-tetrahydropyran-3, 4, 5-triol 4f (4.3g,7.9mmol) in anhydrous tetrahydrofuran (20mL) is slowly added to a suspension of sodium hydride (60% dispersed in mineral oil) (1.78g,44.5mmol) in anhydrous tetrahydrofuran (100mL) at 0 deg.C, after stirring for 30 minutes, benzyl bromide (5.7mL,47.0mmol) and tetrabutylammonium iodide (0.3g,0.8mmol) were added in this order, and the mixture was stirred at room temperature for 3 hours, then heated to 40 ℃ and stirred for 12 hours. After the reaction was completed, the reaction was quenched by dropwise addition of water (1mL) at 0 ℃, concentrated under reduced pressure to remove the organic solvent, ethyl acetate (100mL) was added to the residue, washed with water (100mL) and saturated brine (100mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 10/1] to obtain 4g of the title compound (5.1g, yellow oily substance), yield: 79 percent.

Step 7[ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]Methanol for 4h

A solution of tetrabutylammonium fluoride in tetrahydrofuran (12mL,12mmol,1M) was added to a solution of tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methoxy ] silane 4g (5.1g,6.2mmol) in tetrahydrofuran (50mL) at room temperature and stirred for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was dissolved in ethyl acetate (100mL), washed with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 10/1] to give the title compound 4h (2.1g, yellow oil), yield: 48 percent.

Step 8(2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 4i

[ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxinn-6-ylmethyl) -4-methyl-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methanol 4h (1.25g,1.78mmol) was dissolved in dichloromethane (20mL), then a saturated sodium bicarbonate solution (33mL) was added, and after the resulting mixture was cooled to 0 ℃ potassium bromide (0.1g,0.8mmol), TEMPO (0.13g,0.82mmol) and a sodium hypochlorite solution (5.6mL, 3.57mmol of available chlorine, 1.81%) were sequentially added and the resulting mixture was stirred for 1 hour. After completion of the reaction, the reaction mixture was separated, and the organic phase was washed with saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 4i as a crude product (1.27g, yellow oil).

Step 9(2R,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-methyl-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 4j

Formaldehyde solution (2.0mL, 27mmol, wt.%: 37%), DBU (0.2g,1.0mmol) were added sequentially to a solution of (2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -6-methoxy-tetrahydropyran-2-carbaldehyde 4i (1.27g,1.78mmol) in N, N-dimethylformamide (15mL) at room temperature and stirred for 40 hours. After completion of the reaction, water (50mL) was added, followed by extraction with ethyl acetate (30 mL. times.3), and the organic phases were combined, washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 4j as a crude product (1.35g, yellow oil).

Step 10[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-methyl-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl]Methanol 4k

Sodium borohydride (0.1g,2mmol) was added to a solution of (2R,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 4j (1.35g,1.78mmol) in anhydrous methanol (15mL) at 0 ℃ and stirred for 10 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and ethyl acetate (50mL) was added to the residue, which was washed with water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 4k as a crude product (1.33g, yellow oil).

Step 11[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-methyl-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methanol 4l

P-toluenesulfonic acid monohydrate (0.46g,2.6mmol) was added to a solution of [ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl ] methanol 4k crude product (1.33g,1.78mmol) in tetrahydrofuran (15mL) at room temperature and stirred for 16 hours. After completion of the reaction, ethyl acetate (50mL) was added, and the mixture was washed with a saturated sodium bicarbonate solution (30mL) and a saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the title compound 4l (0.19g, yellow oil). The total yield of the four steps is as follows: 15 percent.

Step 12(1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-methyl-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 4m

Dess-martin oxidizer (0.36g,0.82mmol) was added to a solution of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 4l (0.15g,0.21mmol) in dichloromethane (10mL) at room temperature, and the resulting mixture was heated to 40 ℃ and stirred for 8 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was washed with ethyl acetate (10mL × 3), filtered with suction, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 4m (141mg, yellow oil) in yield: 97 percent.

Step 13 methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) -4-methyl-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 4n

Concentrated sulfuric acid (15mg,0.15mmol) was added to a solution of (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 4m (84mg,0.12mmol) in methanol (5mL) at room temperature, heated to 40 ℃, and stirred for reaction for 12 hours. After completion of the reaction, sodium hydrogencarbonate solid (30mg) was added, and the mixture was concentrated under reduced pressure to remove the organic solvent, and ethyl acetate (10mL) was added to the residue, which was then washed with water (10mL) and saturated brine (10mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1] to give the title compound 4n (64mg, yellow oil) in yield: 75 percent.

Step 142- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) -4-methyl-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 4o

A solution of methylmagnesium bromide in diethyl ether (0.12mL,0.36mmol,3M) was added dropwise to a solution of methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 4n (64mg,0.09mmol) in anhydrous tetrahydrofuran (5mL) at 0 deg.C, and the resulting mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction was quenched by adding water (0.1mL) dropwise, and concentrated under reduced pressure to remove the organic solvent, and ethyl acetate (10mL) was added to the residue, which was then washed with a saturated ammonium chloride solution (5mL) and a saturated saline solution (5mL) in this order, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 6/1] to give the title compound 4o (41mg, colorless oil), yield: and 64 percent.

Step 15(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 4

To a solution of 4o (41mg,0.06mmol) of 2- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol (10% palladium/carbon (100mg,0.09mmol) in methanol/tetrahydrofuran (v/v ═ 4/1,5mL) was added at room temperature, and the resulting mixture was stirred under a hydrogen atmosphere for 2 hours. After the reaction was completed, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 4(17mg, white solid) in yield: 66 percent.

MS(ESI,pos.ion):m/z 503.1[M+HCOO]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.24(d,1H),7.20(d,1H),7.11(d,1H),6.73(d,1H),6.57(d,1H),6.55(s,1H),5.65(d,1H),5.15(d,1H),4.99(d,1H),4.26(d,1H),4.18(s,4H),3.92(d,1H),3.83(s,2H),3.82(s,1H),3.76(t,1H),3.52(t,1H),3.45(m,1H),2.17(s,3H),1.23(s,6H)。

Example 5(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-ethyl-phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 5

Step 12-bromo-5-iodobenzoyl chloride 5b

2-bromo-5-iodobenzoic acid 5a (40.0g,122mmol) was dissolved in dichloromethane (350mL) and then cooled to-5 ℃ under nitrogen, oxalyl chloride (16.4mL,194mmol) and N, N-dimethylformamide (1.5mL,19mmol) were added dropwise, and the mixture was allowed to stir at room temperature for 4 hours. After the reaction was completed, concentration was performed under reduced pressure to remove the organic solvent, to obtain the title compound 5b (46.0g, yellow solid) in yield: 100 percent.

Step 2 (2-bromo-5-iodo-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 5c

2-bromo-5-iodobenzoyl chloride 5b (46.0g,133mmol) was dissolved in dichloromethane (460mL), cooled to-5 ℃ under nitrogen, benzodioxan (20.0g,147mmol) was added, then anhydrous aluminum trichloride (71.0g,532mmol) was added in portions, and the resulting mixture was allowed to stir at room temperature for 4 hours. After the reaction was completed, the mixture was poured into crushed ice, extracted with dichloromethane (400mL × 2), the combined organic phases were washed successively with saturated sodium bicarbonate solution (300mL) and saturated brine (300mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and heptane (100mL) was added to the residue, and after standing in a refrigerator for 2 days, suction filtration was carried out to obtain the title compound 5c (53.1g, white solid), yield: 90 percent.

Step 36- [ (2-bromo-5-iodo-phenyl) methyl]-2, 3-dihydro-1, 4-benzodioxin 5d

(2-bromo-5-iodo-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 5c (53.0g,121mmol) was dissolved in trifluoroacetic acid (200mL), cooled to-5 ℃ under a nitrogen atmosphere, triethylsilane (160mL,972mmol) and trifluoromethanesulfonic acid (12mL,132mmol) were added, and the resulting mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, ethyl acetate (300mL) was added to the residue, which was washed with water (300mL), a saturated sodium bicarbonate solution (300mL) and a saturated brine (300mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/20] to give the title compound 5d (52.1g, yellow oily substance) in yield: 95 percent.

Step 4(2S,3R,4S,5S,6R) -2- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) benzene Base of]-6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 5e

6- [ (2-bromo-5-iodo-phenyl) methyl ] -2, 3-dihydro-1, 4-benzodioxin 5d (18.0g,42mmol) was dissolved in tetrahydrofuran (100mL), cooled to-78 ℃ under a nitrogen atmosphere, and then an n-hexane solution of n-butyllithium (18mL,45mmol) was added dropwise, after the addition was completed, the mixture was stirred for 1 hour, and then a tetrahydrofuran (50mL) solution of (3R,4S,5R,6R) -3,4, 5-tris (trimethylsilyloxy) -6- (trimethylsilyloxymethyl) tetrahydrofuran-2 one 1f (18.2g,39mmol) was added dropwise, and after the addition was completed, the mixture was stirred and reacted for 3 hours. After the reaction was completed, the reaction was quenched by adding methanol (10mL) dropwise, then warmed to room temperature, methanol (300mL) and methanesulfonic acid (10.0g,101mmol) were added, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction was completed, sodium hydrogencarbonate solid (10g) was added, followed by concentration under reduced pressure to remove the organic solvent, and ethyl acetate (200mL) was added to the residue, which was then washed with water (200mL) and saturated brine (200mL) in this order, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to give the title compound 5e (7.23g, yellow solid) in yield: 37 percent.

Step 5(2S,3R,4S,5S,6R) -2- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) benzene Base of]-6- [ [ tert-butyl (dimethyl) silyl ] group]Oxymethyl radical]-2-methoxy-tetrahydropyran-3, 4, 5-triol 5f

(2S,3R,4S,5S,6R) -2- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 5e (7.2g,14mmol) was dissolved in dichloromethane (70mL) and cooled to 0 ℃ before imidazole (2.0g,29mmol) and tert-butyldimethylchlorosilane (4.5g,29mmol) were added and the resulting mixture was stirred at 0 ℃ for 1 hour. After completion of the reaction, the reaction mixture was washed with water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/1] to give the title compound 5f (7.8g, white solid) in yield: 88 percent.

Step 6 tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2,3- Dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl]-6-methoxy-tetrahydropyran-2-yl]Methoxy radical]Silane 5g

(2S,3R,4S,5S,6R) -2- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] -2-methoxy-tetrahydropyran-3, 4, 5-triol 5f (7.8g,13mmol) was dissolved in tetrahydrofuran (80mL) and cooled to 0 deg.C, sodium hydride (60% dispersed in mineral oil) (3.1g,78mmol) was added in portions, stirred for 30 minutes, then benzyl bromide (9.0mL,76mmol) and tetrabutylammonium iodide (0.48g,1.3mmol) were added, the resulting mixture was stirred for 0.5 hour, then warmed to 40 deg.C and stirred for 18 hours. After completion of the reaction, the reaction was quenched by dropwise addition of water (2mL) at 0 ℃, concentrated under reduced pressure, and ethyl acetate (100mL) was added to the residue, which was then washed with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/20] to give the title compound 5g (10.6g, colorless oily substance), yield: 95 percent.

Step 7[ [ (2R,3R,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodi-o-l) Oxazolin-6-ylmethyl) phenyl]-6-methoxy-tetrahydropyran-2-yl]Methanol for 5h

Tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methoxy ] silane 5g (3.0g,3.4mmol) was dissolved in tetrahydrofuran (20mL) at room temperature, tetrabutylammonium fluoride (7.0mL,7.0mmol,1.0M) was added, and stirring was carried out for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and ethyl acetate (50mL) was added to the residue, which was then washed with water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/5] to give the title compound 5h (2.48g, colorless oil) in yield: 95 percent.

Step 8(2R,3R,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 5i

Dissolve [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methanol 5h (2.48g,3.23mmol) in dichloromethane (20mL), add saturated sodium bicarbonate solution (40mL), cool to 0 deg.C, add potassium bromide (0.25g,2.1mmol) and TEMPO (80mg,0.5mmol), stir for 1 min, add sodium hypochlorite solution (5.5mL, 8.3mmol, 4.3% available chlorine), stir for 10 min. After completion of the reaction, liquid separation was performed, and the organic phase was washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 5i (2.50g, yellow oil), yield: 99 percent.

Step 9(2R,3R,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 5j

(2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6-methoxy-tetrahydropyran-2-carbaldehyde 5i (2.50g,3.41mmol) was dissolved in N, N-dimethylformamide (20mL) at room temperature, and a formaldehyde solution (6.3mL, 84mmol, wt.: 37%) and DBU (0.34g,2.2mmol) were added and stirred for 21 hours. After completion of the reaction, ethyl acetate (60mL) was added, and the mixture was washed with water (50mL × 2) and saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 5j (2.58g, red oil), yield: 99 percent.

Step 10[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-methanol 5k

(2R,3R,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 5k (2.58g,3.24mmol) was dissolved in ethyl acetate (20mL) and cooled to 0 ℃ before sodium borohydride (0.2g,5.3mmol) was added and the resulting mixture was stirred for 10 minutes. After completion of the reaction, the reaction mixture was washed with saturated brine (20mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound 5k (2.59g, yellow oil) in yield: 99 percent.

Step 11[ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodi) Oxazolin-6-ylmethyl) phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methanol 5l

[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-methanol 5k (2.59g,3.25mmol) was dissolved in tetrahydrofuran (20mL) at room temperature, p-toluenesulfonic acid (0.75g,3.9mmol) was added, and the resulting mixture was stirred for 36 hours. After the reaction was completed, a saturated sodium bicarbonate solution (50mL) was added, followed by extraction with ethyl acetate (50mL), the combined organic phases were washed with a saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/6] to give the title compound 5l (1.10g, white solid) in yield: 68 percent.

Step 12(1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodi Oxazolin-6-ylmethyl) phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 5m

5l (1.70g,2.2mmol) of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol was dissolved in methylene chloride (20mL), and dess-martin oxidant (6.8g,16mmol) was added to stir the resulting mixture at 40 ℃ for 1.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 5m (1.70g, yellow oil), yield: 98 percent.

Step 13 methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzene) Dioxin-6-ylmethyl) phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 5n

(1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 5m (0.21g,0.27mmol) was dissolved in anhydrous methanol (10mL), concentrated sulfuric acid (20mg,0.2mmol) was added, and the resulting mixture was heated to 40 ℃ and stirred for 12 hours. After completion of the reaction, concentration under reduced pressure was carried out to remove the organic solvent, and ethyl acetate (30mL) was added to the residue, which was washed with a saturated sodium bicarbonate solution (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 5n (0.22g, yellow oil), yield: 99 percent.

Step 142- [ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzene) Dioxin-6-ylmethyl) phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 5o

Methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 5n (0.22g,0.27mmol) was dissolved in tetrahydrofuran (6mL), cooled to 0 ℃ under a nitrogen atmosphere, a methyl magnesium bromide solution (0.6mL,1.2mmol,2.0M) was added dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 5 hours. After completion of the reaction, the reaction was quenched by dropwise addition of a saturated ammonium chloride solution (1mL) at 0 ℃, ethyl acetate (20mL) was further added, followed by washing with water (20mL) and saturated brine (20mL) in this order, drying over anhydrous sodium sulfate, concentration under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/10], to give the title compound 5o (165mg, colorless oil) in yield: 75 percent.

Step 152- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxan) ININ-6-YLMETHYL) -4-ETHYL-PHENYL]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 5p

2- [ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 5o (160mg,0.20mmol) was dissolved in toluene (10mL) at room temperature, water (2mL) was added, and tricyclohexylphosphine (23mg,0.08mmol), potassium phosphate (180mg,0.83mmol), ethylboronic acid (50mg,0.65mmol), and palladium acetate (7mg,0.03mmol) were sequentially added under a nitrogen atmosphere, and the resulting mixture was heated to 110 ℃ and stirred for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, and the residue was purified directly by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/10] to give the title compound 5p (148mg, colorless oil) in yield: 98 percent.

Step 16(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-ethane Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 5

2- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-ethyl-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 5p (100mg,0.13mmol) was dissolved in tetrahydrofuran (2mL) at room temperature, methanol (8mL) and 10% palladium on carbon (10mg, 10. mu. mol) were sequentially added, and the resulting mixture was stirred under a hydrogen atmosphere for 12 hours. After the completion of the reaction, concentration under reduced pressure was performed to remove the organic solvent, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 3/1] to give the title compound 5(60mg, white solid) in yield: 90 percent.

MS(ESI,pos.ion):m/z 473.5[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm)：7.32(m,2H),7.17(d,1H),6.75(d,1H),6.62-6.55(m,2H),4.23(d,1H),4.17(q,5H),4.04(t,2H),3.90(s,2H),3.85(t,1H),3.76(d,1H),2.58(q,2H),1.35(s,3H),1.28(s,3H),1.13(t,3H)。

Example 6(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-propyl-phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 6

Step 12- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-cyclopropyl-3- (2, 3-dihydro-1, 4-) Benzodioxodioxin-6-ylmethyl) phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 6a

2- [ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 5o (600mg,0.75mmol) was dissolved in toluene (10mL) at room temperature, water (2mL) was added, and tricyclohexylphosphine (85mg,0.30mmol), potassium phosphate (660mg,3.0mmol), cyclopropylboronic acid (210mg,2.3mmol), and palladium acetate (27mg,0.11mmol) were sequentially added under a nitrogen atmosphere, and the resulting mixture was heated to 90 ℃ and stirred for 15 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/10] to give the title compound 6a (501mg, colorless oil) in yield: 90 percent.

Step 2(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-propyl- Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 6

2- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-cyclopropyl-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 6a (130mg,0.17mmol) was dissolved in tetrahydrofuran (2mL) at room temperature, methanol (8mL) and 10% palladium on carbon (10mg, 10. mu. mol) were sequentially added, and the resulting mixture was stirred under a hydrogen atmosphere for 13 hours. After the completion of the reaction, concentration under reduced pressure was performed to remove the organic solvent, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 3/1] to give the title compound 6(70mg, white solid) in yield: 83 percent.

MS(ESI,pos.ion):m/z 487.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.29(m,2H),7.13(d,1H),6.74(d,1H),6.62-6.54(m,2H),4.40(s,1H),4.23(d,2H),4.16(q,4H),4.03(t,2H),3.91-3.82(m,3H),3.76(s,1H),3.23(s,1H),3.15(s,1H),2.56-2.47(m,2H),1.50(m,2H),1.34(s,3H),1.27(s,3H),0.93(t,3H)。

Example 7(1S,2S,3S,4R,5S) -5- [ 4-cyclopropyl-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 7

2- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-cyclopropyl-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 6a (62mg,0.08mmol) was dissolved in tetrahydrofuran (2mL) at room temperature, methanol (8mL) and 10% palladium on carbon (10mg, 10. mu. mol) were sequentially added, and the resulting mixture was stirred under a hydrogen atmosphere for 1 hour. After completion of the reaction, concentration under reduced pressure was performed to remove the organic solvent, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 3/1] to give the title compound 7(30mg, white solid) in yield: 73 percent.

MS(ESI,pos.ion)m/z:485.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.33(d,2H),7.03(d,1H),6.79-6.75(m,1H),6.62(m,2H),4.28-4.22(m,5H),4.15-4.04(m,4H),3.95-3.83(m,2H),3.76(d,1H),3.14(s,1H),2.97(s,1H),2.87(s,1H),1.85(m,1H),1.41(s,3H),1.33(s,3H),0.90(m,4H)。

Example 8(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 8

Step 15-bromo-2-methoxybenzoyl chloride 8b

5-bromo-2-methoxybenzoic acid 8a (30.0g,130mmol) was dissolved in dichloromethane (300mL), cooled to-5 ℃ under a nitrogen atmosphere, oxalyl chloride (16mL,189mmol) and N, N-dimethylformamide (1.0mL,12.9mmol) were added, and the resulting mixture was allowed to warm to room temperature and stirred for 4 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain the title compound 8b (34.1g, yellow oil), yield: 100 percent.

Step 2 (5-bromo-2-methoxy-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 8c

5-bromo-2-methoxybenzoyl chloride 8b (34.1g,130mmol) was dissolved in dichloromethane (400mL), cooled to-5 ℃ under a nitrogen atmosphere, benzodioxan (19.0g,140mmol) was added, anhydrous aluminum trichloride (65.0g,487mmol) was added in portions, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was poured into crushed ice, extracted with dichloromethane (300mL × 2), the combined organic phases were washed successively with a saturated sodium bicarbonate solution (300mL) and a saturated brine (300mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/20] to give the title compound 8c (13.2g, pale yellow solid), yield: 29 percent.

Step 36- [ (5-bromo-2-methoxy-phenyl) methyl]-2, 3-dihydro-1, 4-benzodioxin 8d

(5-bromo-2-methoxy-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 8c (13.2g,37.8mmol) was dissolved in trifluoroacetic acid (50mL), cooled to-5 ℃ under a nitrogen atmosphere, triethylsilane (18mL,113mmol) and trifluoromethanesulfonic acid (1.0mL,11mmol) were added, and the resulting mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, ethyl acetate (100mL) was added to the residue, which was washed with water (100mL), a saturated sodium bicarbonate solution (100mL) and a saturated brine (100mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/20] to give the title compound 8d (11.0g, yellow oily substance) in yield: 86 percent.

Step 4(2S,3R,4S,5S,6R) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy Phenyl radical]-6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 8e

6- [ (5-bromo-2-methoxy-phenyl) methyl ] -2, 3-dihydro-1, 4-benzodioxin 8d (11.0g,32.8mmol) was dissolved in tetrahydrofuran (100mL), cooled to-78 ℃ under a nitrogen atmosphere, and a solution of n-butyl lithium in n-hexane (14mL,33.6mmol, 2.4M) was added dropwise, followed by stirring for 1 hour. After completion of the stirring, a solution of (3R,4S,5R,6R) -3,4, 5-tris (trimethylsiloxy) -6- (trimethylsiloxymethyl) tetrahydrofuran-2-one 1f (14.0g,30mmol) in THF (50mL) was added dropwise, and after completion of the addition, the reaction was continued for 3 hours, after completion of the reaction, the reaction was quenched by adding methanol (3mL) dropwise, the mixture was allowed to warm to room temperature, methanol (200mL) and methanesulfonic acid (5.0mL,77mmol) were added, and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, the residue was added to ethyl acetate (200mL), washed with water (100mL), a saturated sodium bicarbonate solution (100mL) and a saturated brine (100mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 8e (7.01g, yellow solid) in yield: 52 percent.

Step 5(2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl]Oxymethyl radical]-2- [3- (2, 3-dihydro-) 1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl]-2-methoxy-tetrahydropyran-3, 4, 5-triol 8f

(2S,3R,4S,5S,6R) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 8e (7.01g,15.6mmol) was dissolved in dichloromethane (50mL) at room temperature, cooled to 0 ℃ and imidazole (2.2g,32mmol) and TBSCl (4.9g,32mmol) were added and stirring was continued for 1 hour after the addition was complete. After completion of the reaction, the reaction mixture was washed with water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/1] to give the title compound 8f (6.22g, white solid) in yield: 71 percent.

Step 6 t-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro- 1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl]-6-methoxy-tetrahydropyran-2-yl]Methoxy radical]Silane 8g

(2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -2-methoxy-tetrahydropyran-3, 4, 5-triol 8f (6.22g,11mmol) was dissolved in tetrahydrofuran (50mL) at room temperature, cooled to 0 deg.C, and after addition of sodium hydride (2.6g,65mmol) in portions, stirring was carried out for 30 minutes, then benzyl bromide (8.0mL,67mmol) and tetrabutylammonium iodide (0.42g,1.1mmol) were added, stirring was carried out for 0.5 hour, heating was continued to 40 deg.C, and stirring was carried out for 18 hours. After the reaction was completed, the mixture was cooled to 0 ℃, the reaction was quenched by adding water (2mL) dropwise, concentrated under reduced pressure, the organic solvent was removed, ethyl acetate (80mL) was added, washed with water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/20] to obtain 8g of the title compound (7.70g, colorless oil), yield: 84 percent.

Step 7[ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-methoxy-phenyl]-6-methoxy-tetrahydropyran-2-yl]Methanol for 8h

At room temperature, 8g (7.70g,9.2mmol) of t-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methoxy ] silane was dissolved in tetrahydrofuran (70mL), tetrabutylammonium iodide (18mL,18mmol,1.0M) was added, and the resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, ethyl acetate (80mL) was added, the mixture was washed with water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/5] to give the title compound 8h (5.52g, colorless oil) in yield: 83 percent.

Step 8(2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-methoxy-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 8i

[ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxine-6-ylmethyl) -4-methoxy-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methanol 8h (4.80g,6.7mmol) was dissolved in dichloromethane (50mL), a saturated sodium bicarbonate solution (100mL) was added, cooling was carried out to 0 ℃ and then potassium bromide (0.52g,4.4mmol) and TEMPO (0.16g,0.97mmol) were added, stirring was carried out for 1 minute, a sodium hypochlorite solution (16.2mL, 17.4mmol of available chlorine, 3.05% of available chlorine) was added, and stirring was carried out for 10 minutes. After completion of the reaction, the reaction solution was separated, and the organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 8i (4.79g, yellow oil), yield: 99 percent.

Step 9(2R,3S,4S,5R,6S) -3,4, 5-Tribenzyloxy6- [3- (2, 3-dihydro-1, 4-benzodioxin-6- Ylmethyl) -4-methoxy-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 8j

(2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -6-methoxy-tetrahydropyran-2-carbaldehyde 8i (4.79g,6.7mmol) was dissolved in N, N-dimethylformamide (35mL) at room temperature, a formaldehyde solution (14mL,188mmol, wt.%: 37%) and DBU (0.7g,4.6mmol) were added, and the reaction was stirred for 21 hours. After completion of the reaction, ethyl acetate (200mL) was added, and the mixture was washed with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 8j (5.01g, red oil), yield: 99 percent.

Step 10[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-methoxy-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl]Methanol 8k

(2R,3S,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 8j (5.01g,6.7mmol) was dissolved in ethyl acetate (50mL) at room temperature and cooled to 0 ℃ before adding sodium borohydride (0.52g,13mmol) and stirring for 10 minutes. After completion of the reaction, the reaction mixture was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 8k (4.80g, yellow oil) in yield: 96 percent.

Step 11[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-methoxy-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methanol 8l

[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxine-6-ylmethyl) -4-methoxy-phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl ] methanol 8k (4.8g,6.4mmol) was dissolved in tetrahydrofuran (40mL) at room temperature, p-toluenesulfonic acid (1.20g,6.3mmol) was added, and the mixture was stirred for 42 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was extracted with ethyl acetate (60mL), washed with saturated sodium bicarbonate solution (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/4] to give the title compound 8l (2.42g, white solid) in yield: and 63 percent.

Step 12[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-methoxy-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Formic acid 8m

8l (1.55g,2.16mmol) of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol was dissolved in methylene chloride (20mL), and dess-martin oxidant (3.7g,8.5mmol) was added to heat the resulting mixture to 40 ℃ and stir it for 1.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 8m (1.42g, yellow oil), yield: 90 percent.

Step 13 methyl [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodi) Oxazolin-6-ylmethyl) -4-methoxy-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Formic acid 8n

[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxine-6-ylmethyl) -4-methoxy-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] carboxylic acid 8m (1.42g,1.94mmol) was dissolved in anhydrous methanol (20mL), concentrated sulfuric acid (20mg,0.2mmol) was added, and the resulting mixture was heated to 40 ℃ and stirred for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, and ethyl acetate (50mL) was added to the residue, which was washed with saturated sodium bicarbonate solution (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 8n (1.45g, yellow oil), yield: 100 percent.

Step 142- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethylYl) -4-methoxy-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 8o

Methyl [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] carboxylic acid 8n (300mg,0.40mmol) was dissolved in tetrahydrofuran (8mL), cooled to 0 ℃ under a nitrogen atmosphere, and methyl magnesium bromide (1.0mL,3.0mmol,3.0M) was added dropwise, and the resulting mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was quenched by dropwise addition of a saturated ammonium chloride solution (1mL) at 0 ℃, ethyl acetate (30mL) was further added, followed by washing with water (30mL) and saturated brine (30mL), drying over anhydrous sodium sulfate, concentration under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/10] to give the title compound 8o (270mg, colorless oil) in yield: 90 percent.

Step 15(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 8

2- [ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 8o (270mg,0.36mmol) was dissolved in tetrahydrofuran (2mL) at room temperature, methanol (8mL) and 10% palladium on carbon (30mg, 28. mu. mol) were added, and the resulting mixture was stirred under a hydrogen atmosphere for 12 hours. After the completion of the reaction, concentration under reduced pressure was performed to remove the organic solvent, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 3/1] to give the title compound 8(140mg, white solid) in yield: 81 percent.

MS(ESI,pos.ion):m/z 475.5[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):7.30-7.27(m,2H),6.73-6.66(m,4H),4.20(d,1H),4.13-4.09(m,4H),

4.02-3.97(m,2H),3.82(s,3H),3.75(m,4H),3.31(s,1H),2.23(t,3H),1.30(s,3H),1.24(s,3H)。

Example 9(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -1- (1-hydroxycyclopropyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 9

Step 11- [ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) -4-methoxy-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Cyclopropanol 9a

Tetraisopropyltitanyl (0.26mL,0.88mmol) and a tetrahydrofuran solution of ethylmagnesium bromide (1.2mL,3.6mmol,3.0M) were sequentially added to a solution of methyl [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] carboxylic acid 8n (460mg,0.62mmol) in anhydrous tetrahydrofuran (20mL) under a nitrogen atmosphere, and the resulting mixture was heated to 40 ℃ and stirred for 18 hours. After completion of the reaction, the reaction mixture was quenched by adding a saturated ammonium chloride solution (10mL), concentrated under reduced pressure, the organic solvent was removed, water (50mL) was added to the residue, followed by extraction with ethyl acetate (50mL), the organic phase was washed with a saturated aqueous salt solution (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 20/1] to give the title compound 9a (55mg, colorless oil) in yield: 12 percent.

Step 2(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy Phenyl radical]-1- (1-hydroxycyclopropyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 9

To 1- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] was added 10% palladium on carbon (200mg,0.19mmol) at room temperature]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]To a solution of cyclopropanol 9a (55mg,0.07mmol) in methanol/tetrahydrofuran (v/v ═ 4/1,5mL), the resulting mixture was stirred under a hydrogen atmosphere for 2 hours. After the reaction is finished, filtering and decompressingThe filtrate was concentrated, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ]]To give title compound 9(16mg, white solid), yield: 38 percent. MS (ESI, pos. ion) M/z 517.8[ M + HCOO]^-；

¹HNMR(400MHz,CD₃OD)δ(ppm):7.26(d,1H),7.19(d,1H),6.91(d,1H),6.72(d,1H),6.64(d,2H),4.18(m,4H),4.05(d,1H),3.99(d,1H),3.80(d,2H),3.78(s,3H),3.76(d,1H),3.52(t,1H),3.45(m,1H),0.47-0.64(m,4H)。

Example 10(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4- (trifluoromethoxy) phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 10

Step 15-bromo-2- (trifluoromethoxy) benzoyl chloride 10b

To a solution of 5-bromo-2- (trifluoromethoxy) benzoic acid 10a (10.0g,35.1mmol) in dichloromethane (100mL) at 0 deg.C were added oxalyl chloride (12mL,138mmol) and N, N-dimethylformamide (0.1mL,1.29mmol), and the resulting mixture was allowed to stir at room temperature for 2 hours. After the reaction was completed, concentration was performed under reduced pressure to remove the organic solvent, to obtain the title compound 10b (10.7g, yellow oil), yield: 100 percent. Directly used for the next reaction.

Step 2[ (5-bromo-2- (trifluoromethoxy) phenyl group)]- (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 10c

To a solution of crude 5-bromo-2- (trifluoromethoxy) benzoyl chloride 10b (10.7g,35.1mmol) obtained in the previous step in dichloromethane (150mL) at 0 ℃ was added 2, 3-dihydro-1, 4-benzodioxin (5.3g,38.8mmol), followed by addition of anhydrous aluminum trichloride (11.7g,86.0mmol) in portions, and the resulting mixture was allowed to stand at room temperature and stirred for 2 hours. After the reaction was completed, the reaction mixture was poured into crushed ice, extracted with dichloromethane (200mL × 2), the combined organic phases were washed successively with a saturated sodium bicarbonate solution (200mL) and a saturated brine (200mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 10/1] to give the title compound 10c (13.2g, yellowish green oil) in yield: 93 percent.

Step 36- [ [ (5-bromo-2- (trifluoromethoxy) phenyl)]Methyl radical]-2, 3-dihydro-1, 4-benzodioxin 10d

Trifluoroacetic acid (20mL) and triethylsilane (14mL,87.1mmol) were added to a solution of [ (5-bromo-2- (trifluoromethoxy) phenyl ] - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 10c (13.2g,32.8mmol) in dichloromethane (100mL) at room temperature, cooled to 0 ℃, trifluoromethanesulfonic (1.0mL, 11mmol) was slowly added dropwise, and the resulting mixture was stirred at room temperature for 3 hours, after completion of the reaction, washed with water (100mL), a saturated sodium bicarbonate solution (100mL × 2), and a saturated saline (100mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 10/1], to give the title compound 10d (10.0g, yellow oily substance), yield: 78 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.53-7.58(m,2H),7.30(d,1H),6.78(d,1H),6.69(s,1H),6.63-6.66(d,1H),4.20(s,4H),3.86(s,2H)。

Step 4(2S,3R,4S,5S,6R) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-trifluoro-l Methoxy-phenyl]-6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 10e

6- [ [ (5-bromo-2- (trifluoromethoxy) phenyl ] methyl ] -2, 3-dihydro-1, 4-benzodioxin 10d (10.0g, 25.7mmol) was dissolved in anhydrous tetrahydrofuran (120mL) at room temperature, cooled to-78 ℃ under a nitrogen atmosphere, and a n-hexane solution of n-butyllithium (12mL,29mmol,2.4M) was slowly added dropwise, followed by stirring for 40 minutes, and then a solution of (3R,4S,5R,6R) -3,4, 5-tris (trimethylsilyloxy) -6- (trimethylsilyloxymethyl) tetrahydrofuran-2 one 1f (13.2g,28.3mmol) in anhydrous tetrahydrofuran (20mL) was added dropwise, and stirring was continued for 3 hours, after completion of the reaction, water (20mL) was added to the reaction mixture to quench the reaction, and concentrated under reduced pressure, the organic solvent was removed, and ethyl acetate (100mL) was added to the residue, which was washed with water (100mL) and saturated brine (100mL) in this order, concentrated under reduced pressure, and the resulting residue was added with methanol (200mL) and concentrated hydrochloric acid (5mL,60mmol) and stirred at 40 ℃ for 3 hours. After completion of the reaction, solid sodium hydrogencarbonate (6.0g) was added to the reaction mixture, which was concentrated under reduced pressure, and ethyl acetate (100mL) was added to the residue, which was washed successively with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 10e as a crude product (11.8g, yellow oil) which was used in the next reaction.

Step 5(2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl]Oxymethyl radical]-2- [3- (2, 3-dihydro-) 1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl]-2-methoxy-tetrahydropyran-3, 4, 5-triol 10f

Imidazole (3.3g,48mmol) was added to a solution of crude (2S,3R,4S,5S,6R) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 10e (11.8g) obtained in the previous step in dichloromethane (150mL), cooled to 0 ℃ and then TMSCl (7.3g,47mmol) and DMAP (70mg,0.57mmol) were added and the resulting mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was washed with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/1-0/1] to give the title compound 10f (5.5g, white solid) in total yield in two steps: 35 percent.

Step 6 t-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro- 1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl]-6-methoxy-tetrahydropyran-2-yl]Methoxy radical]Silicon Alkane 10g

Sodium hydride (60% dispersed in mineral oil) (0.5g,12.5mmol) was added to anhydrous tetrahydrofuran (10mL) at 0 deg.C, a solution of (2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl ] -2-methoxy-tetrahydropyran-3, 4, 5-triol 10f (1.7g,2.76mmol) in anhydrous tetrahydrofuran (10mL) was added under a nitrogen atmosphere, stirring was carried out for 30 minutes, then benzyl bromide (1.5mL,12mmol) and tetrabutylammonium iodide (10mg,0.03mmol) were added, the resulting mixture was moved to room temperature and stirred for 3 hours, heating to 40 deg.C is continued and stirring is carried out for 20 hours. After completion of the reaction, the reaction was quenched with dropwise water (1mL) at 0 ℃, ethyl acetate (50mL) was added to the reaction solution, and then washed with water (50mL) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, the filtrate was reduced in pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 10/1] to give 10g of the title compound (1.3g, pale yellow oily substance), yield: 53 percent.

Step 7[ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-trifluoromethoxy-phenyl]-6-methoxy-tetrahydropyran-2-yl]Methanol for 10h

To a solution of tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methoxy ] silane in 10g (1.3g, 1.47mmol) of tetrahydrofuran (20mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (5.9mL,5.9mmol,1M), and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate (60mL) was added, followed by washing with water (50mL) and saturated brine (50mL), drying over anhydrous sodium sulfate, and concentration under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 10h (1.0g, colorless oil) in yield: 88.0 percent.

Step 8(2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-trifluoromethoxy-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 10i

[ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methanol 10h (1.0g,1.3mmol) was dissolved in dichloromethane (20mL), a saturated sodium bicarbonate solution (20mL) was added, the resulting mixture was cooled to 0 ℃ and then potassium bromide (93mg,0.78mmol), TEMPO (30mg,0.19mmol) and a sodium hypochlorite solution (2.0mL, 3.38mmol of available chlorine, 4.8% of available chlorine) were added in this order and stirred for 10 minutes. After completion of the reaction, liquid separation was performed, and the separated organic phase was washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 10i (1.0g, red syrup), yield: 100 percent.

Step 9(2R,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-trifluoromethoxy-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 10j

To a solution of (2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxine-6-ylmethyl) -4-trifluoromethoxy-phenyl ] -6-methoxy-tetrahydropyran-2-carbaldehyde 10i (1.0g,1.3mmol) in N, N-dimethylformamide (10mL) was added a formaldehyde solution (2.0mL, 27mmol, wt.: 37%) and DBU (0.20g,1.3mmol), and the resulting mixture was stirred at room temperature for 22 hours. After completion of the reaction, ethyl acetate (50mL) was added, and the mixture was washed with water (50 mL. times.2) and saturated brine (50mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 10j as a crude product (1.0g, orange syrup) which was used in the next reaction.

Step 10[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-) Ylmethyl) -4-trifluoromethoxy-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl]Methanol 10k

The crude product (1.0g) of (2R,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxine-6-ylmethyl) -4-trifluoromethoxy-phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 10j obtained in the previous step was dissolved in ethyl acetate (15mL), cooled to 0 ℃, and sodium borohydride (0.1g,2mmol) was added and stirred for 20 minutes. After completion of the reaction, the reaction mixture was washed with water (10mL) and saturated brine (10mL), dried over sodium sulfate, and concentrated under reduced pressure to give the title compound 10k as a crude product (1.0g, yellow oil) which was used in the next reaction.

Step 11[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-methoxy-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methanol 10l

The [ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl group obtained in the previous step is reacted at room temperature]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl]To a solution of crude methanol 10k (1.0g) in tetrahydrofuran (20mL) was added p-toluenesulfonic acid (0.43g,2.5mmol) and the mixture was stirred for 22 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was purified by silica gel column chromatography as it is [ petroleum ether/ethyl acetate (v/v) ═ 4: 1%]To give the title compound 10l (325mg, colorless oil) in three steps in total yield: 32 percent.¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.51-7.56(m,2H),7.30-7.36(m,11H),7.13-7.33(m,3H),6.75(d,2H),6.66-6.70(m,2H),6.57-6.60(d,1H),5.23(t,1H),4.78(s,4H),4.28(d,1H),4.15(s,4H),4.08(d,1H),3.84-3.95(m,4H),3.71-3.79(m,3H),3.56-3.60(d,1H),3.51(d,1H)。

Step 12[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-trifluoromethoxy-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Formic acid 10m

10l (160mg,0.21mmol) of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methoxy-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol was dissolved in methylene chloride (20mL), and dess-martin oxidant (540mg,1.2mmol) was added to stir the resulting mixture at 40 ℃ for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was washed with ethyl acetate (30mL) and a saturated sodium bicarbonate solution (30 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 10m as a crude product (162mg, yellow oil).

Step 13 methyl [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodi) Oxazolin-6-ylmethyl) -4-trifluoromethoxy-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Formic acid 10n

To a solution of crude [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-yl ] carboxylic acid 10m (160mg) in methanol (15mL) obtained in the previous step was added concentrated sulfuric acid (20mg, 0.2mmol), and the resulting mixture was heated to 40 ℃ and stirred for 6 hours. After completion of the reaction, sodium hydrogencarbonate solid (50mg) was added to the reaction solution, concentrated under reduced pressure, the organic solvent was removed, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 8/1] to give the title compound 10n (135mg, colorless syrup) in two-step total yield: 82 percent.

Step 142- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) -4-trifluoromethoxy-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 10o

Methyl [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-yl ] carboxylic acid 10n (135mg,0.17mmol) was dissolved in anhydrous tetrahydrofuran (10mL) under a nitrogen atmosphere, and cooled to 0 ℃, then an anhydrous tetrahydrofuran solution (0.34mL,1.0mmol,3.0M) of methylmagnesium bromide was added dropwise, and the resulting mixture was transferred to room temperature and stirred for reaction for 4 hours. After the reaction was completed, the reaction was quenched by adding water (0.5mL) dropwise to the reaction mixture at 0 ℃, concentrated under reduced pressure, and the organic solvent was removed, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 5/1] to give the title compound 10o (120mg, colorless syrup), yield: 89 percent.

Step 15(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4- (tris Fluoromethoxy) phenyl]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 10

2- [ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-trifluoromethoxy-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 10o (120mg,0.15mmol) was dissolved in tetrahydrofuran (2mL) at room temperature, methanol (8mL) and 10% palladium on carbon (0.3g,0.3mmol) were added, and the resulting mixture was stirred under a hydrogen atmosphere for 4 hours. After the reaction was completed, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 10(60mg, white solid) in yield: 75 percent.

MS(ESI,pos.ion):m/z 573.3[M+HCOO]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.46(s,1H),7.42(d,1H),7.28(d,1H),6.75(d,1H),6.64(s,1H),6.62(d,1H),5.50(d,1H),5.03(d,1H),5.01(d,1H),4.24(s,1H),4.18(s,4H),4.03(m,1H),3.86(s,2H),3.81(d,1H),3.70(t,1H),3.43-3.49(q,1H),3.39(t,1H),1.20(s,3H),1.16(s,3H)。

Example 11(1S,2S,3S,4R,5S) -5- [3- (1, 4-Benzodioxazin-6-ylmethyl) -4-chloro-phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 11

Step 15-bromo-2-chlorobenzoyl chloride 11b

5-bromo-2-chlorobenzoic acid 11a (93.0g,395mmol) was dissolved in dichloromethane (900mL), cooled to-5 ℃ under nitrogen, oxalyl chloride (50mL,590mmol) and N, N-dimethylformamide (1.0mL,12.9mmol) were added, and the resulting mixture was allowed to warm to room temperature and stirred for 4 hours. After the reaction was completed, concentration was performed under reduced pressure to obtain the title compound 11b (107g, yellow oil), yield: 100 percent.

Step 2 (5-bromo-2-chloro-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 11c

5-bromo-2-chlorobenzoyl chloride 11b (107g,424.72mmol) was added to a solution of benzodioxan (63.6g,467mmol) in dichloromethane (800mL) and cooled to-5 deg.C, aluminum trichloride (170g,1.27mol) was added in portions, and the mixture was allowed to warm to room temperature and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into ice water, hydrochloric acid (50mL,2M) was added, the mixture was stirred for 5 minutes, liquid separation was performed, the separated organic phase was washed with saturated brine (300mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 10/1] to obtain the objective compound 11c (76.0g, white solid) in 50% yield.

Step 3 (5-bromo-2-chloro-phenyl) - (2, 3-dibromo-2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 11d

NBS (36.2g, 204mmol) and AIBN (2.79g,17.0mmol) were added to a solution of (5-bromo-2-chloro-phenyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 11c (30.0g,85mmol) in carbon tetrachloride (200mL), heated to 80 ℃ under a nitrogen atmosphere, and stirred for 20 hours. After the reaction was completed, it was cooled to room temperature, suction-filtered, the filtrate was concentrated under reduced pressure, the obtained residue was added to methylene chloride (250mL), stirred, further washed with a 5% sodium thiosulfate solution (120 mL. times.2) and a saturated saline solution (150mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was added to petroleum ether (120mL), stirred overnight, the filter cake was collected by suction-filtration and dried under vacuum to obtain Compound 11d (16.0g, white solid) in 37% yield.

¹H NMR(400MHz,CDCl₃)δ(ppm)：7.64-7.48(m,4H),7.37(d,1H),7.14(d,1H),6.71(d,2H)。

Step 4 (5-bromo-2-chloro-phenyl) - (2, 3-dibromo-2, 3-dihydro-1, 4-benzodioxin-6-yl) methanol 11e

Sodium borohydride (7.25g, 192mmol) was added portionwise to a solution of (5-bromo-2-chloro-phenyl) - (2, 3-dibromo 2, 3-dihydro-1, 4-benzodioxin-6-yl) methanone 11d (32.0g,62.3mmol) in methanol/tetrahydrofuran (v/v ═ 2/1,225mL) at 0 ℃ and stirred for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and ethyl acetate (300mL) was added to the residue, which was washed with water (200mL) and saturated brine (200mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 11e (32.0g, pale yellow oil) in 100% yield.

¹H NMR(400MHz,CDCl₃)δ(ppm)：7.53(m,1H),7.45(d,1H),7.31(d,1H),7.23(m,1H),7.10(d,1H),6.65(d,1H),5.92-5.88(m,2H)。

Step 52, 3-dibromo-6- [ (5-bromo-2-chloro-phenyl) methyl group]-2, 3-dihydro-1, 4-benzodioxin 11f

Boron trifluoride diethyl etherate (4.78mL,81.1mmol) was added dropwise to a solution of triethylsilane (11mL,68.9mmol) and (5-bromo-2-chloro-phenyl) - (2, 3-dibromo-2, 3-dihydro-1, 4-benzodioxin-6-yl) methanol 11e (32g, 62.33mmol) in dichloromethane (200mL) at 0 ℃ and after completion of the addition, the resulting mixture was allowed to stand at room temperature and stirred for 3 hours. After completion of the reaction, the reaction mixture was washed with water (200mL) and saturated brine (200mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% petroleum ether ] to obtain compound 11f (17.6g, pale yellow oily substance) in yield: 57 percent.

Step 66- [ (5-bromo-2-chloro-phenyl) methyl]-1, 4-benzodioxin 11g

Anhydrous sodium iodide (36.0g,240mmol) was added to a solution of 2, 3-dibromo-6- [ (5-bromo-2-chloro-phenyl) methyl ] -2, 3-dihydro-1, 4-benzodioxin 11f (24.0g, 48mmol) in acetone (150mL) at room temperature, heated to reflux, and stirred for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, and 50% sodium thiosulfate solution (150mL) was added to the reaction mixture to quench the reaction, ethyl acetate (200mL × 2) was further added to extract, the combined organic phases were washed with saturated brine (200mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% petroleum ether ] to obtain 11g (12.2g, white solid) of a mixture, yield: 75 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.31(m,1H),7.25(d,2H),6.65(m,1H),6.57(d,1H),6.45(d,1H),5.87(q,2H),3.90(s,2H)。

Step 7(2S,3R,4S,5S,6R) -2- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]-6- (hydroxy) Methyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 11h

A solution of n-butyllithium in n-hexane (16mL,38mmol,2.4M) was added dropwise to a solution of 6- [ (5-bromo-2-chloro-phenyl) methyl ] -1, 4-benzodioxin (11 g (12.0g,36mmol) in anhydrous tetrahydrofuran (120mL) at-78 ℃ under a nitrogen atmosphere, the mixture was stirred for 30 minutes, and a solution of (3R,4S,5R,6R) -3,4, 5-tris (trimethylsiloxy) -6- ((trimethylsiloxy) methyl) -tetrahydropyran-2-one 1f (22.0g,47.1mmol) in anhydrous tetrahydrofuran (80mL) was added dropwise at the same temperature, and stirring was continued for 3 hours. After completion of the reaction, the reaction was quenched by adding methanol (10mL) dropwise, the mixture was allowed to warm to room temperature, methanol (200mL) and concentrated hydrochloric acid (3.0mL,36mmol) were added, and the mixture was heated to 40 ℃ and stirred for 12 hours. After completion of the reaction, the reaction solution was added with sodium hydrogencarbonate solid (5.0g), concentrated under reduced pressure to remove the organic solvent, ethyl acetate (200mL) was added to the residue, which was then washed with water (200mL) and saturated brine (200mL) in this order, concentrated under reduced pressure, and the residue was purified by crystallization [ ethyl acetate/petroleum ether (v/v) ═ 1/10] to give compound 11h (12.5g, pale yellow solid) in yield: 78 percent.

Step 8(2S,3R,4S,5S,6R) -2- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]-6- [ [ tert-butyl (dimethyl) silyl group ]]Oxymethyl radical]-2-methoxy-tetrahydropyran-3, 4, 5-triol 11i

Imidazole (5.7g,83.1mmol) was added to a solution of (2S,3R,4S,5S,6R) -2- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol in dichloromethane (100mL) for 11h (12.5g,27.7mmol), stirred and cooled to 0 ℃, followed by addition of TBSCl (12.5g,82.9mmol) and stirring for 2 hours. After the reaction was completed, the organic phase was separated, washed with water (100mL) and saturated brine (100mL) in turn, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/5] to give a mixture 11i (10.5g, pale yellow solid) in yield: 67%.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.42(d,2H),7.35(m,1H),6.63(dt,2H),6.45(d,1H),6.14(q,2H),5.02(d,1H),4.80(t,2H),3.99-3.87(m,3H),3.75(m,1H),3.54(td,1H),3.48-3.40(m,1H),3.16(td,1H),2.94(s,3H),2.89(m,1H),0.84(s,9H),0.05(s,3H),0.01(s,3H)。

Step 9[ (2R,3R,4S,5R,6S) -6- [3 ]- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]-6-methyl Oxy-3, 4, 5-tris [ (4-methoxyphenyl) methoxy]Tetrahydropyran-2-yl]Methoxy-tert-butyl-dimethyl-silane 11j

A solution of (2S,3R,4S,5S,6R) -2- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] -2-methoxy-tetrahydropyran-3, 4, 5-triol 11i (10.5g,19.6mol) in anhydrous tetrahydrofuran (75mL) was added dropwise to anhydrous tetrahydrofuran (55mL) of sodium hydride (60% dispersed in mineral oil) (5.0g,125.0mol) at 0 ℃ under a nitrogen atmosphere, and stirred for 20 minutes. P-methoxybenzyl bromide (17.2mL,118mmol) and tetrabutylammonium iodide (160mg,0.43mmol) were added successively, and the resulting mixture was heated to 40 ℃ and stirred for 18 hours. After completion of the reaction, the reaction was quenched at 0 ℃ with ice water (10mL) dropwise, ethyl acetate (200mL) was added, followed by washing with water (150mL) and saturated brine (150mL) in this order, drying over anhydrous sodium sulfate, concentration under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 15/1] to give compound 11j (10.3g, yellow oil) in yield: 59 percent.

Step 10[ (2R,3R,4S,5R,6S) -6- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]-6- Methoxy-3, 4, 5-tris [ (4-methoxyphenyl) methoxy group]Tetrahydropyran-2-yl]Methanol 11k

Tetrabutylammonium fluoride tetrahydrofuran solution (45mL,45mmol,1M) was added to a solution of [ (2R,3R,4S,5R,6S) -6- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -6-methoxy-3, 4, 5-tris [ (4-methoxyphenyl) methoxy ] tetrahydropyran-2-yl ] methoxy-tert-butyl-dimethyl-silane 11j (10.2g,11.4mmol) in tetrahydrofuran (100mL) at room temperature and stirred for 20 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, ethyl acetate (100mL) was added to the residue, the combined organic phases were washed successively with water (100mL) and saturated brine (100mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the objective product 11k (6.5g, yellow oil) in 73% yield.

Step 11[ (2R)3R,4S,5R,6S) -6- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]-6- Methoxy-3, 4, 5-tris [ (4-methoxyphenyl) methoxy group]Tetrahydropyran-2-yl]Formaldehyde 11l

Oxalyl chloride (1.4mL,17mmol) in anhydrous dichloromethane (20mL) was added dropwise to a solution of dimethyl sulfoxide (2.3mL,32mmol) in anhydrous dichloromethane (20mL) under nitrogen at-78 ℃ and stirring for 30 minutes, and a solution of [ (2R,3R,4S,5R,6S) -6- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -6-methoxy-3, 4, 5-tris [ (4-methoxyphenyl) methoxy ] tetrahydropyran-2-yl ] methanol 11k (6.4g,7.89mmol) in anhydrous dichloromethane (30mL) was added dropwise. After the addition was complete, the temperature was raised to-60 ℃ and stirring was continued for 1 h, followed by addition of triethylamine (6.6mL,47mmol) and stirring for 1 h. After completion of the reaction, the reaction mixture was warmed to 0 ℃ and water (100mL) was added to the reaction mixture, followed by extraction with dichloromethane (100mL), and the combined organic phases were washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 11l of crude compound (6.4g, yellow solid). Directly used for the next reaction.

Step 12(2S,3S,4S,5R,6S) -6- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]-2- (hydroxymethyl) -6-methoxy-3, 4, 5-tris [ (4-methoxyphenyl) methoxy]Tetrahydropyran-2-carbaldehyde 11m

Formaldehyde solution (15mL, 0.20mol, wt.%: 37%), DBU (1.0mL, 6.6mmol) was added to a solution of 11l crude [ (2R,3R,4S,5R,6S) -6- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -6-methoxy-3, 4, 5-tris [ (4-methoxyphenyl) methoxy ] tetrahydropyran-2-yl ] carbaldehyde (6.4g,8.9mmol) in N, N-dimethylformamide (50mL) at room temperature, and the resulting mixture was heated to 40 ℃ and stirred for 20 hours. After completion of the reaction, ethyl acetate (100mL) was added to the reaction mixture, which was washed with water (100 mL. times.2) and saturated brine (100mL) in this order, and concentrated under reduced pressure to give crude compound 11m (6.6g, red syrup). Directly used for the next reaction.

Step 13[ (3S,4S,5R,6S) -6- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]-2- (hydroxy) Methyl) -6-methoxy-3, 4,5-Tris [ (4-methoxyphenyl) methoxy group]Tetrahydropyran-2 yl radical]-methanol 11n

Sodium borohydride (920mg,24mmol) was added portionwise to a solution of (2S,3S,4S,5R,6S) -6- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -2- (hydroxymethyl) -6-methoxy-3, 4, 5-tris [ (4-methoxyphenyl) methoxy ] tetrahydropyran-2-carbaldehyde 11m crude product (6.6g) in ethyl acetate (80mL) at 0 ℃ and stirred for 20 minutes. After completion of the reaction, the reaction mixture was washed with water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/4] to give compound 11n (4.2g, white solid) in three steps: and 63 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.31(m,4H),7.26-7.19(m,3H),6.97(d,2H),6.89(t,4H),6.77(d,2H),6.57(m,1H),6.52(d,1H),6.40(d,1H),5.85(m,2H),4.91(dt,3H),4.61(m,2H),4.42-4.32(m,2H),3.98(m,3H),3.92-3.74(m,11H),3.68(t,1H),3.24(d,1H),3.08(s,3H),3.00(d,1H)。

Step 14[ (1S,2S,3S,4R,5S) -5- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]-2, 3, 4-tris [ (4-methoxyphenyl) methoxy group]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methanol 11o

Concentrated hydrochloric acid (2mL, 24mmol) was added to a solution of [ (3S,4S,5R,6S) -6- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -2- (hydroxymethyl) -6-methoxy-3, 4, 5-tris [ (4-methoxyphenyl) methoxy ] tetrahydropyran-2 yl ] -methanol 11n (4.0g,4.75mmol) in dichloromethane (50mL) at room temperature and stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was washed with saturated sodium bicarbonate solution (40mL) and saturated brine (40mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/4] to give compound 11o (2.7g, pale yellow viscous substance). Yield: 70 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.40(s,1H),7.38-7.30(m,3H),7.27-7.23(m,3H),6.89(m,4H),6.81(d,2H),6.71(d,2H),6.63(m,1H),6.48(m,2H),5.83(m,2H),4.89-4.76(m,3H),4.73-4.61(m,2H),4.24(m,2H),3.95(m,3H),3.83(m,8H),3.78(s,4H),3.67(d,2H)。

Step 15[ (1S,2S,3S,4R,5S) -5- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]-2, 3, 4-tris [ (4-methoxyphenyl) methoxy group]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Formic acid 11p

Iodophenylenediacetic acid (1.8g,5.5mmol) and TEMPO (59mg,0.37mmol) were added to a solution of [ (1S,2S,3S,4R,5S) -5- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -2,3, 4-tris [ (4-methoxyphenyl) methoxy ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 11o (1.5g,1.9mmol) in dichloromethane (20mL) at room temperature and stirred for 17 hours. After completion of the reaction, the reaction mixture was washed with water (20mL) and saturated brine (20mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 11p (1.5g, pale yellow oil).

Step 16 methyl [ (1S,2S,3S,4R,5S) -5- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-benzene Base of]-2,3, 4-tris [ (4-methoxyphenyl) methoxy group]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Formic acid 11q

Iodomethane (0.28mL,4.5mmol) and potassium carbonate (180mg,1.3mmol) were added to a solution of crude [ (1S,2S,3S,4R,5S) -5- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -2,3, 4-tris [ (4-methoxyphenyl) methoxy ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] carboxylic acid 11p (1.5g,1.8mmol) in N, N-dimethylformamide (20mL) at room temperature, and the resulting mixture was stirred at room temperature overnight. After completion of the reaction, ethyl acetate (50mL) was added, followed by washing with water (50mL) and saturated brine (50mL) in this order, drying over anhydrous sodium sulfate, concentration under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/10] to give the title compound 11q (360mg, white solid) in yield: 24 percent.

Step 172- [ (1S,2S,3S,4R,5S) -5- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl]- 2,3, 4-tris [ (4-methoxyphenyl) methyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 11r

Methyl magnesium bromide in diethyl ether (0.87mL,2.1mmol,2.4M) was added to a solution of methyl [ (1S,2S,3S,4R,5S) -5- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -2,3, 4-tris [ (4-methoxyphenyl) methoxy ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] carboxylic acid 11q (350mg,0.42mmol) in tetrahydrofuran (10mL) at 0 ℃ under a nitrogen atmosphere, and the reaction was stirred for 4 hours. After the reaction was completed, the reaction mixture was poured into ice water (20mL) to quench the reaction, a saturated ammonium chloride solution (5mL) was added, followed by extraction with ethyl acetate (40mL × 2), the combined organic phases were washed with a saturated saline solution (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/4] to obtain the title compound 11r (315mg, white solid) in yield: 90 percent.

Step 18(1S,2S,3S,4R,5S) -5- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 11

2- [ (1S,2S,3S,4R,5S) -5- [3- (1, 4-benzodioxin-6-ylmethyl) -4-chloro-phenyl ] -2,3, 4-tris [ (4-methoxyphenyl) methyl ] -6,8-

Dioxobicyclo [3.2.1] octan-1-yl ] propan-2-ol 11r (295mg,0.35mmol) was dissolved in dichloromethane (15mL), water (6mL) and 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone (400mg,1.76mmol) were added, and the resulting mixture was stirred at room temperature for 42 hours. After the reaction was completed, the solution was separated, the organic phase was washed with a saturated sodium bicarbonate solution (10mL) and a saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound 11s (21mg, white solid) in yield: 12 percent.

MS(ESI,pos.ion):m/z 499.1[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)：7.34(m,2H),7.26(s,1H),6.66-6.58(m,1H),6.51(d,1H),6.41(d,1H),5.81(m,2H),4.37(s,1H),4.26-4.16(m,2H),4.03(d,2H),3.92(d,2H),3.85(s,1H),3.70(t,1H),3.25(d,1H),3.06(s,1H),1.35(s,3H),1.27(s,3H)。

Example 12(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -1- (methylthiomethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 12

Step 1[ (1R,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodi) Oxazolin-6-ylmethyl) phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methyl methanesulfonate ester 12a

[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy 5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 3j (200mg,0.28mmol) was dissolved in dichloromethane (10mL), triethylamine (0.4mL,3.0mmol) was added, cooling was performed to 0 ℃, methanesulfonyl chloride (0.13mL,1.7mmol) was added, and the resulting mixture was allowed to stand at room temperature and stirred for 1 hour. After the completion of the reaction, concentration under reduced pressure was performed to remove the organic solvent, and the residue was purified directly by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the title compound 12a (220mg, white solid) in yield: 97 percent.

Step 26- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3,4, -tribenzyloxy-1- (methylthiomethyl) -6,8- Dioxybicyclo [3.2.1]Octane-5-yl]-phenyl radical]Methyl radical]-2, 3-dihydro-1, 4-benzodioxin 12b

[ (1R,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methyl methanesulfonate 12a (85mg,0.11mmol) was dissolved in DMF (3mL), sodium methyl mercaptide (50mg,0.71mmol) was added, and the resulting mixture was heated to 50 ℃ and stirred for 1 hour. After completion of the reaction, ethyl acetate (10mL) was added, followed by washing with water (10mL × 2) and saturated brine (10mL), drying over anhydrous sodium sulfate, and concentration under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 5/2] to give the title compound 12b (24mg, pale yellow syrup) in yield: 30 percent.

Step 3(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) benzene Base of]-1- (methylthiomethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 12

6- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3,4, -tribenzyloxy-1- (methylthiomethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] -phenyl ] methyl ] -2, 3-dihydro-1, 4-benzodioxin 12b (24mg,0.03mmol) was dissolved in tetrahydrofuran (0.5mL) at room temperature, methanol (2mL), concentrated hydrochloric acid (0.1mL,1mmol) and 10% palladium on carbon (50mg,0.05mmol) were added, and the resulting mixture was stirred under a hydrogen atmosphere for 3 hours. After the reaction was completed, the reaction mixture was suction-filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound 12(6mg, white solid) in yield: 38 percent.

MS(ESI,pos.ion):m/z 503.1[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.29-7.34(m,2H),7.24(d,1H),6.74(d,1H),6.63-6.66(d,2H),4.15(s,5H),4.06(d,2H),3.90-4.00(q,3H),3.76(t,1H),3.65(d,1H),3.61(d,1H),2.85-2.89(d,1H),2.72-2.76(d,1H),2.13(s,3H)。

Example 13(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ [3- (hydroxymethyl) - (2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 13

Step 15-bromo-2-chlorobenzoyl chloride 13b

Oxalyl chloride (50mL,590mmol) was added to a solution of 5-bromo-2-chlorobenzoic acid 13a (60.2g,256mmol) in dichloromethane (300mL) at 0 deg.C, DMF (1.5mL,19mmol) was added dropwise slowly, and after dropping, the mixture was allowed to warm to room temperature and stirred for 1 hour. After the reaction was completed, concentration was performed under reduced pressure to obtain the title compound 13b (65.0g, yellow oil), yield: 100 percent, and is directly used for the next reaction.

Step 23- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin 13d

Sodium hydride (60% dispersed in mineral oil) (8.44g,211mmol) was added to tetrahydrofuran (50mL) at 0 deg.C, and after stirring for 10 minutes, a tetrahydrofuran solution (70mL) of 2, 3-dihydro-1, 4-benzodioxin-3-ylcarbinol 13c (30.4g,183mmol) and benzyl bromide (22mL,185mmol) were gradually added dropwise in this order, and after completion of the dropwise addition, tetrabutylammonium iodide (0.02g,0.05mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 16 hours. After the reaction was completed, the reaction was quenched by dropping water (100mL) to the reaction mixture at 0 ℃, followed by extraction with ethyl acetate (100mL × 2), and the combined organic phases were washed successively with a saturated ammonium chloride solution (200mL), water (200mL) and a saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 13d (50.2g, yellow oil), yield: 100 percent, and is directly used for the next reaction.¹H NMR(400MHz,CDCl₃)δ(ppm):7.41-7.31(m,5H),6.96-6.83(m,4H),4.63(s,2H),4.41-4.31(m,2H),

4.12(m,1H),3.78(m,1H),3.69(m,1H)。

Step 3 (5-bromo-2-chloro-phenyl) - [3- (hydroxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl]Ketone 13e

Aluminum trichloride (52.6g,394mmol) was added to a solution of 5-bromo-2-chlorobenzoyl chloride 13b (65.0g,256.0mmol) and 3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin 13d (50.0g,195.1mmol) in dichloromethane (300mL) at 0 deg.C, and after completion of addition, the mixture was allowed to stand at room temperature for 4 hours. After the reaction was completed, the reaction mixture was poured into crushed ice, adjusted to distinct layers with hydrochloric acid, extracted with dichloromethane (200mL × 2), and the combined organic phases were washed with saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 13e (76.2g, deep red semisolid), yield: 100 percent, and is directly used for the next reaction.

Step 4[3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl]- (5-bromo-2-chloro-phenyl) -methyl Ketone 13f

To tetrahydrofuran (100mL) was added sodium hydride (60% dispersed in mineral oil) (15.2g,380mmol) at 0 ℃, stirred for 10 minutes, a solution of (5-bromo-2 chloro-phenyl) - [3- (hydroxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methanone 13e (76.2g,198mmol) in tetrahydrofuran (200mL) was slowly added dropwise, stirred for 20 minutes, benzyl bromide (28mL,236mmol) was slowly added dropwise, tetrabutylammonium iodide (0.02g,0.05mmol) was added to the mixture after completion of the dropwise addition, and the resulting mixture was allowed to warm to room temperature and stirred for 16 hours. After the reaction was completed, the reaction was quenched by adding water (100mL) dropwise to the reaction mixture at 0 ℃, followed by extraction with ethyl acetate (100mL × 2), and the combined extracts were washed successively with water (200mL × 2) and saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 13f (101g, reddish brown gum), yield: 100 percent, and is directly used for the next reaction.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.54(m,1H),7.48(d,1H),7.40-7.32(m,8H),6.97(m,1H),4.62(d,2H),4.38(m,2H),4.23-4.13(m,1H),3.80-3.74(m,1H),3.70(m,1H)。

Step 5[3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl]- (5-bromo-2-chloro-phenyl) -methyl Alcohol 13g

Sodium borohydride (11.6g,300mmol) was added portionwise to a solution of [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] - (5-bromo-2 chloro-phenyl) -methanone 13f (101g,213mmol) in tetrahydrofuran (70mL) and methanol (210mL) at 0 ℃ and stirred for 30 minutes. After the reaction was completed, the reaction was quenched by adding a saturated ammonium chloride solution (100mL), the organic solvent was removed by concentration under reduced pressure, the residue was extracted with ethyl acetate (200mL × 2), separated, and the separated organic phase was washed with a saturated saline solution (200mL), dried over sodium sulfate and concentrated under reduced pressure to obtain 13g of the title compound (100g, yellow gum), yield: 98 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.48(m,1H),7.37-7.25(m,7H),6.80(m,3H),6.15-6.09(m,1H),5.84(d,1H),4.54(s,2H),4.38-4.28(m,2H),4.00(m,1H),3.66(d,2H)。

Step 63- (benzyloxymethyl) -6-, [ 2 ](5-bromo-2-chloro-phenyl) methyl]-2, 3-dihydro-1, 4-benzodioxin 13h

Triethylsilane (45mL,273mmol) and boron trifluoride diethyl etherate (40mL,324mmol) were added to a solution of [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] - (5-bromo-2 chloro-phenyl) -methanol (13 g (100g,210mmol) in dichloromethane (300mL) at 0 ℃ and after the addition, the resulting mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was quenched by dropwise addition of a saturated sodium bicarbonate solution (100mL) at 0 ℃, separated, and the organic phase was washed with a saturated saline solution (200mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 20/1] to give the title compound 13h (61.0g, yellow oil) in yield: and 63 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.55(m,1H),7.45(m,1H),7.40(d,1H),7.37-7.26(m,5H),6.84-6.77(m,1H),6.76-6.64(m,2H),4.54(s,2H),4.38-4.27(m,2H),4.04-3.97(m,1H),3.94(s,2H),3.66(d,2H)。

Step 7(2S,3R,4S,5S,6R) -2- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin- 6-yl]Methyl radical]-4-chloro-phenyl]-6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 13i

A solution of n-butyllithium in n-hexane (61mL,150mmol,2.4M) was added dropwise to a solution of 3- (benzyloxymethyl) -6- [ (5-bromo-2-chloro-phenyl) methyl ] -2, 3-dihydro-1, 4-benzodioxin in 13h (61.0g,132.7mmol) in anhydrous tetrahydrofuran (210mL) at-78 ℃ and stirred for 40 minutes, followed by addition of a solution of (3R,4S,5R,6R) -3,4, 5-tris (trimethylsilyloxy) -6- ((trimethylsilyloxy) methyl) -tetrahydropyran-2-one 1f (63.0g, 128.5mmol) in tetrahydrofuran (100mL) and stirring for 3 hours. After the reaction was completed, the reaction mixture was quenched by dropping water (100mL) thereto, followed by extraction with ethyl acetate (200mL), separation of the organic phase, concentration of the organic phase under reduced pressure, dissolution of the obtained residue in methanol (300mL), adjustment of the pH of the solution to 2 with concentrated hydrochloric acid, and reaction of the obtained mixture with stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, concentrated under reduced pressure to remove the organic solvent, and the residue was extracted with ethyl acetate (200mL), the organic phase was washed successively with water (200mL) and saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 13i (39.2g, yellow dope) in yield: 35 percent.

Step 8(2S,3R,4S,5S,6R) -2- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin- 6-yl]Methyl radical]-4-chloro-phenyl]-6- [ [ tert-butyl (dimethyl) silyl ] group]Oxymethyl radical]-2-methoxy-tetrahydropyran-3, 4,5- Triol 13j

Imidazole (9.53g,140mmol), TBSCl (21.0g,139mmol) and DMAP (0.18g,1.5mmol) were added to a solution of (2S,3R,4S,5S,6R) -2- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] -4-chloro-phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 13i (39.2g,68.4mmol) in dichloromethane (300mL) at 0 deg.C and the resulting mixture was allowed to warm to room temperature and stirred for 2 hours. After completion of the reaction, the reaction mixture was washed successively with water (200 mL. times.2) and saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 13j as a crude product (55.1g, a brownish red oily substance) which was used in the next reaction.

Step 9 tert-butyldimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- [ [3- (benzyloxy) -group Methyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl]Methyl radical]-4-chloro-phenyl]-6-methoxy-tetrahydropyran-2-yl]First of all Oxy radical]Silane 13k

Sodium hydride (60% dispersed in mineral oil) (15.2g,380mmol) was added to tetrahydrofuran (200mL) at 0 deg.C, stirred for 30 minutes, and then a solution of tetrahydrofuran (100mL) and benzyl bromide (29.5mL,248mmol) of all crude (2S,3R,4S,5S,6R) -2- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] -4-chloro-phenyl ] -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] -2-methoxy-tetrahydropyran-3, 4, 5-triol 13j (55.1g) obtained in the previous step was slowly added dropwise, and tetrabutylammonium iodide (0.02g,0.05mmol) was added after dropwise addition, the resulting mixture was heated to 40 ℃ and stirred for 20 hours. After completion of the reaction, the reaction mixture was quenched by dropwise addition of water (100mL) at 0 ℃ and then extracted with ethyl acetate (200mL), which was then washed with water (200 mL. times.2) and saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 13k as a crude product (78.2g, a reddish brown gum). Directly used for the next reaction.

Step 10[ (2R,3R,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [3- [ [3- (benzyloxymethyl) -2, 3-Bis ] Hydrogen-1, 4-benzodioxin-6-yl]Methyl radical]-4-chloro-phenyl]-6-methoxy-tetrahydropyran-2-yl]Methanol 13l

A tetrabutylammonium fluoride tetrahydrofuran solution (280mL,280mmol,1.0M) was added to a solution of the crude compound of t-butyldimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] -4-chloro-phenyl ] -6-methoxy-tetrahydropyran-2 yl ] methoxy ] silane 13k (78.2g) obtained in the previous step in tetrahydrofuran (200mL) at room temperature, and the mixture was heated to 40 ℃ and stirred for 4 hours. After completion of the reaction, ethyl acetate (200mL) was added, followed by washing with water (200mL) and saturated brine (200mL × 3) in this order, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 2/1] to give the title compound 13l (16.2g, yellow gum), three-step total yield: 28 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.50(s,1H),7.45(s,2H),7.35-7.29(m,10H),7.24(m,8H),6.97(d,2H),6.74-6.68(m,1H),6.64-6.54(m,2H),4.88-4.84(m,1H),4.78(d,3H),4.68(d,1H),4.52(m,2H),4.38(d,1H),4.26(d,2H),4.02-3.92(m,3H),3.85(d,1H),3.77-3.60(m,7H),3.23(d,1H),2.98(s,3H)。

Step 11[ (2R,3R,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [3- [ [3- (benzyloxymethyl) -2, 3-Bis ] Hydrogen-1, 4-benzodioxin-6-yl]Methyl radical]-4-chloro-phenyl]-6-methoxy-tetrahydropyran-2-yl]Formaldehyde 13m

The compound [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] -4-chloro-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methanol 13l (6.01g,7.11mmol) was dissolved in methylene chloride (100mL), a saturated sodium bicarbonate solution (60mL) was further added thereto, the resulting mixture was cooled to 0 ℃ and potassium bromide (0.5g,4.2mmol), TEMPO (0.1g,0.6mmol) and a sodium hypochlorite solution (13.3mL, 19.5mmol of available chlorine, 4.16% of available chlorine) were further added in this order, followed by stirring for 5 minutes. After completion of the reaction, the reaction mixture was separated, and the separated organic phase was washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title crude compound 13m (6.05g, a reddish brown oil). Directly used for the next reaction.

Step 12(2R,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-) 1, 4-benzodioxin-6-yl]Methyl radical]-4-chloro-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 13n

A formaldehyde solution (13mL,7.4mmol, wt.%: 37%) and DBU (0.66mL,4.3mmol) were added to a solution of [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] -4-chloro-phenyl ] -6-methoxy-tetrahydropyran-2-yl ] carboxaldehyde 13m (6.05g,7.11mmol) in N, N-dimethylformamide (40mL) at room temperature and the resulting mixture was stirred at room temperature for 42 hours. After completion of the reaction, ethyl acetate (100mL) was added, and the mixture was washed with water (100 mL. times.2) and saturated brine (100mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 13n as a crude product (6.21g, pale yellow oil). Directly used for the next reaction.

Step 13[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl]Methyl radical]-4-chloro-phenyl]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl]Methanol 13o

Sodium borohydride (0.42g, 11mmol) was added to a mixed solution of (2R,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] -4-chloro-phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 13n (6.21g,7.1mmol) in tetrahydrofuran (20mL) and methanol (80mL) at 0 ℃ and stirred for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was dissolved in ethyl acetate (50mL), which was washed with water (50mL) and saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 13o as a crude product (6.35g, yellow syrup). Directly used for the next reaction.

Step 14[ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [3- [ [3- (benzyloxymethyl) -2, 3-Bis Hydrogen-1, 4-benzodioxin-6-yl]Methyl radical]-4-chloro-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methanol 13p

P-toluenesulfonic acid monohydrate (2.01g,10.5mmol) was added to a solution of [ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] -4-chloro-phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl ] methanol crude 13o (6.35g) in tetrahydrofuran (50mL) obtained in the previous step at room temperature, and the resulting mixture was stirred for 39 hours. After completion of the reaction, the reaction mixture was washed with a saturated sodium bicarbonate solution (20mL), concentrated under reduced pressure to remove the organic solvent, the residue was extracted with ethyl acetate (50mL), the organic phase was washed with a saturated saline solution (50mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 13p (2.27g, white semisolid) in three steps: 38 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.53(s,1H),7.44(m,3H),7.37-7.24(m,15H),7.16(d,2H),6.81(m,2H),6.68(m,3H),5.23(t,1H),4.78-4.74(m,3H),4.54-4.49(m,2H),4.26(d,3H),4.08(d,1H),3.95(m,4H),3.87-3.82(m,1H),3.78-3.69(m,3H),3.66-3.54(m,4H),3.50(d,1H)。

Step 15(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ [3- (hydroxymethyl) -2, 3-dihydro-1, 4-benzodioxan In-6-yl]Methyl radical]Phenyl radical]-1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1 ]Octane-2, 3, 4-triol 13

To a solution of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- [ [3- (benzyloxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] -4-chloro-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 13p (2.25g,2.68mmol) in tetrahydrofuran/methanol (v/v ═ 1/5,60mL) at room temperature was added 10% palladium on carbon (210mg,0.2mmol) and concentrated hydrochloric acid (1.0mL, wt.%: 36%), and the resulting mixture was stirred under a hydrogen atmosphere for 3 hours. After the reaction was completed, it was washed with a saturated sodium bicarbonate solution (20mL), concentrated under reduced pressure, and the organic solvent was removed, and the residue was extracted with ethyl acetate (30mL), the organic phase was washed with water (30mL) and a saturated saline (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 13(1.26g, white solid), yield: 95 percent. Purification by HPLC preparative gave isomer 1(367mg, HPLC: 95.4%, retention time: 5.78min) and isomer 2(525mg, HPLC: 96.2%, retention time: 5.95 min).

Isomer 1:

MS(ESI,pos.ion):m/z 503.4[M+Na]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.45-7.38(m,2H),7.34-7.29(m,1H),6.77(d,1H),6.71-6.60(m,2H),5.19(d,1H),5.02(t,1H),4.97(d,1H),4.91(d,1H),4.76(m,1H),4.28(d,1H),4.11(d,1H),3.98-3.94(m,3H),3.66–3.41(m,9H)。

isomer 2:

MS(ESI,pos.ion):m/z 503.4[M+Na]⁺；

H NMR(400MHz,DMSO-d₆)δ(ppm):7.42-7.38(m,2H),7.34-7.29(m,1H),6.77(d,1H),6.71-6.60(m,2H),5.19(d,1H),5.02(t,1H),4.97(d,1H),4.91(d,1H),4.71(m,1H),4.28(d,1H),4.11(d,1H),3.98-3.95(m,3H),3.66–3.40(m,9H)。

example 146- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -4H-1, 4-benzoxazin-3-one 14

Step 1(1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl group]Benzene and its derivatives Base of]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 14b

A saturated sodium bicarbonate solution (8mL), potassium bromide (12mg,0.10mmol) and TEMPO (8mg,0.05mmol) were added to a solution of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 14a (0.36g,0.51mmol) in dichloromethane (7mL) in this order at 0 ℃ and a sodium hypochlorite solution (6.7mL, available chlorine 13mmol, available chlorine 5.5% or more) was added thereto in one portion, and the resulting mixture was stirred at 0 ℃ for 2 hours. After completion of the reaction, the reaction mixture was adjusted to pH 4 with hydrochloric acid (1M), followed by extraction with ethyl acetate (10 mL. times.2), and the combined extracts were washed with saturated brine (10mL) and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the title compound 14b (0.38g, yellow oil), yield: 100 percent. The crude product was used directly in the next step.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):13.92(s,1H),7.52(s,1H),7.45(m,2H),7.30(m,10H),7.19(t,3H),7.05(d,2H),6.82(d,2H),6.75(d,2H),4.75(m,3H),4.68(d,1H),4.36(d,1H),4.29(d,1H),4.09(d,1H),4.02(m,3H),3.93(m,2H),3.89-3.82(m,2H),3.76(d,1H),1.28(t,3H)。

Step 2 methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl Base of]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 14c

Concentrated sulfuric acid (50mg,0.50mmol) was added to a solution of (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 14b (0.38g,0.53mmol) in methanol (8mL), and the resulting mixture was heated to 40 ℃ and stirred for 12 hours. After completion of the reaction, a saturated sodium bicarbonate solution (2mL) was added, the mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was extracted with ethyl acetate (10mL), washed with saturated brine (10mL), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 10/1] to give the objective compound 14c (155mg, colorless oil), yield: 41 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.48(m,1H),7.39(m,2H),7.38-7.29(m,7H),7.28-7.23(m,3H),7.19(m,3H),7.08(m,2H),6.91-6.86(m,2H),6.80-6.73(m,2H),4.82(m,3H),4.63(d,1H),4.53(d,1H),4.26(d,1H),4.24-4.16(m,2H),4.09(d,1H),4.05-3.94(m,4H),3.87(d,1H),3.75(d,1H),3.71(s,3H),1.41(t,3H)。

Step 32- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl [ ] - Base of]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 14d

A tetrahydrofuran solution of methylmagnesium bromide (0.42mL,1.27mmol,3M) was slowly dropped into a solution of methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylic acid 14c (155mg,0.21mmol) in anhydrous tetrahydrofuran (5mL) at 0 ℃ to obtain a mixture, which was heated to 40 ℃ and stirred for 12 hours. After completion of the reaction, the reaction was quenched with water (2mL), filtered, and the filtrate was concentrated under reduced pressure to remove most of the solvent, followed by extraction with ethyl acetate (5mL × 2), liquid separation, washing of the organic phase with saturated brine (5mL × 2), and drying over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave the title compound 14d (155mg, colorless oil), yield: 100 percent. The crude product was used directly in the next step.

Step 4(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl group]Phenyl radical]-1- (1-hydroxy-) 1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 14e

To a solution of 2- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 14d (155mg,0.21mmol) in methanol/tetrahydrofuran (v/v ═ 4/1,5mL) was added successively o-dichlorobenzene (155mg,1.06mmol) and 10% palladium on carbon (22mg,0.02mmol) at room temperature, and the mixture was stirred under hydrogen atmosphere for 1 hour. After the reaction was completed, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 1/2] to give the title compound 14e (90mg, white solid) in yield: 92 percent.

MS(ESI,pos.ion):m/z 509[M⁺HCOO]^-；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.35(s,2H),7.30(m,1H),7.08(d,2H),6.81(d,2H),5.46(t,1H),5.01(d,1H),4.95(d,1H),4.21(s,1H),3.95(d,5H),3.78(d,1H),3.68(m,1H),3.43(m,1H),3.35(m,1H),1.28(t,3H),1.18(s,3H),1.13(s,3H)。

Step 5[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl group] Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-3-yl]Acetate 14f

(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 14e (50mg,0.11mmol) was dissolved in tetrahydrofuran (5mL), DMAP (5.3mg,0.04mmol), N-diisopropylethylamine (0.15mL,0.85mmol) and acetic anhydride (70. mu.L, 0.75mmol) were added in this order, and the resulting mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and ethyl acetate (15mL) was added to the residue, which was washed with 1M hydrochloric acid (10mL), water (10mL) and saturated brine (10mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 14f (45mg, white solid) in yield: 66 percent.

MS(ESI,pos.ion):m/z 612.3[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.36(d,1H),7.32(d,1H),7.28(m,1H),7.07(d,2H),6.81(d,2H),5.50(m,1H),5.39(t,1H),5.28(d,1H),4.41(d,1H),4.19(m,1H),4.06(t,,1H),4.00(d,2H),3.97(d,1H)2.07(s,3H),1.98(s,3H),1.70(s,3H),1.39(t,3H),1.34(s,3H),1.13(s,3H)。

Step 6[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (4-hydroxyphenyl) methyl group]Benzene and its derivatives Base of]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-3-yl]Acetate 14g

[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-3-yl ] acetate 14f (800mg,1.35mmol) was dissolved in dichloromethane (20mL), cooled to-78 ℃ under a nitrogen atmosphere, boron tribromide (0.65mL,6.9mmol) was added dropwise, and after completion of the addition, the mixture was stirred for 1 hour, then heated to-20 ℃ and stirred for 1 hour. After the reaction was completed, the reaction mixture was poured into crushed ice, extracted with dichloromethane (30mL × 2), the organic phases were combined, washed with water (50mL), a saturated sodium bicarbonate solution (50mL), and a saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to obtain 14g of the title compound (225mg, white solid) in yield: 30 percent.

Step 7[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (4-hydroxy-3-nitro-phenyl) Methyl radical]Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-3-yl]Acetate 14h

14g (420mg,0.75mmol) of [ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (4-hydroxyphenyl) methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-3-yl ] acetate was dissolved in acetic anhydride (20mL) and cooled to-2 ℃ and nitric acid (70. mu.L, 0.91mmol) was further added and the resulting mixture was allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction, ethyl acetate (50mL) was added, followed by washing with water (50mL), a saturated sodium bicarbonate solution (50mL) and a saturated brine (50mL), followed by drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1], to give the title compound 14h (235mg, pale yellow solid) in yield: 52 percent.

¹H NMR(600MHz,CDCl₃)δ(ppm):10.51(s,1H),7.90(d,1H),7.44-7.36(m,4H),7.11(d,1H),5.54(m,1H),5.43(t,1H),5.36(d,1H),4.45(d,1H),4.23(m,1H),4.10(d,2H),2.32(s,1H),2.10(s,3H),2.01(s,3H),1.79(s,3H),1.36(s,3H),1.16(s,3H)。

Step 8 Ethyl 2- [4- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (1-hydroxy- 1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-5-yl]Phenyl radical]Methyl radical]-2-nitro-phenoxy]Ethyl acetate 14i

[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (4-hydroxy-3-nitro-phenyl) methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-3-yl ] acetate 14h (30mg,0.05mmol) was dissolved in acetonitrile (3mL), ethyl 2-bromoacetate (20. mu.L, 0.23mmol) and cesium carbonate (64mg,0.20mmol) were added, and the resulting mixture was heated to 80 ℃ under a nitrogen atmosphere and stirred for 15 hours. After completion of the reaction, ethyl acetate (30mL) was added, followed by washing with saturated brine (30mL), drying over anhydrous sodium sulfate, and concentration under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/3] to give the title compound 14i (18mg, white solid) in yield: 53 percent.

¹H NMR(600MHz,CDCl₃)δ(ppm):7.67(d,1H),7.38(m,1H),7.36(d 1H),7.34(d,1H),7.30(m,1H),6.93(d,1H),5.52(t,1H),5.15(d,1H),4.75(s,2H),4.43(d,1H),4.36(d,1H),4.22-4.12(m,2H),4.10(s,2H),3.96(s,1H),2.09(s,3H),2.01(s,3H),1.78(s,3H),1.39(s,3H),1.32-1.29(m,6H)。

Step 9[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (3-carbonyl-4H-1, 4-benzo- Oxazin-6-yl) methyl]Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-3-yl]Acetic acid Ester 14j

Ethyl 2- [4- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -2-nitro-phenoxy ] acetate 14i (100mg,0.14mmol) was dissolved in acetic acid (5mL), followed by addition of iron powder (80mg,1.43mmol), and the resulting mixture was heated to 60 ℃ and stirred for 16 hours. After completion of the reaction, ethyl acetate (30mL) was added, the mixture was filtered under suction, and the filtrate was washed with water (30mL), a saturated sodium bicarbonate solution (30mL) and a saturated brine (30mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 14j as a crude product (93mg, white solid). Directly used for the next reaction.

Step 106- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethan-yl) 6, 8-Dioxobicyclo [3.2.1] yl]Octane-5-yl]Phenyl radical]Methyl radical]-4H-1, 4-benzoxazin-3-one 14

The crude [ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (3-carbonyl-4H-1, 4-benzoxazin-6-yl) methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-3-yl ] acetate 14j (93mg) was dissolved in tetrahydrofuran (2mL), methanol (1mL), water (1mL) and lithium hydroxide monohydrate (36mg,1.47mmol) were added in this order, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate (20mL) was added, followed by washing with water (20mL) and saturated brine (20mL × 2) in this order, drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by silica gel column chromatography [ 100% ethyl acetate ] to give the title compound 14(23mg, white solid) in total yield in two steps: 32 percent.

MS(ESI,pos.ion):m/z 492.1[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm):9.30(s,1H),7.50(s,1H),7.21(s,2H),7.01(d,1H),6.87(d,1H),6.38(s,1H),4.43(d,1H),4.31(d,1H),4.24(s,1H),4.09(d,1H),4.02(d,1H),4.00(d,1H),3.95(d,2H),3.77(s,1H),3.30(s,1H),1.36(s,3H),1.28(s,3H)。

Example 156- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -4-ethyl-1, 4-benzoxazin-3-one 15

6- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -4H-1, 4-benzoxazin-3-one 14(100mg,0.20mmol) was dissolved in N, N-dimethylformamide (2mL), potassium carbonate (57mg,0.41mmol) and iodoethane (20. mu.L, 0.30mmol) were added, and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate (5mL) was added, the mixture was washed with water (5mL) and saturated brine (5mL) in this order, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ], to give the title compound 15(36mg, white solid) in yield: 34 percent.

MS(ESI,pos.ion):m/z 520.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.41(t,2H),7.36(m,1H),6.91(d,1H),6.87(s,1H),6.83(d,1H),4.58(s,2H),4.26(d,1H),4.11-4.04(m,4H),3.95(q,2H),3.83(t,1H),3.70(d,1H),1.40(s,3H),1.28(s,3H),1.24(t,3H)。

Example 166- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -3, 4-dihydro-1, 4-benzoxazin-2-one 16

Step 1[4- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (1-hydroxy-1-methyl- Ethyl) -6, 8-dioxybicyclo [3.2.1]Octane-5-yl]Phenyl radical ]Methyl radical]-2-nitro-phenyl]2-chloroacetate 16a

Sodium hydride (60% in mineral oil) (30mg,0.75mmol) was added to anhydrous tetrahydrofuran (2mL) and cooled to 0 ℃, then a solution of [ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (4-hydroxy-3-nitro-phenyl) methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-3-yl ] acetate 14h (235mg,0.39mmol) in anhydrous tetrahydrofuran (2mL) was added dropwise, stirred for 15 minutes, 2-chloroacetyl chloride (0.04mL,0.54mmol) was added further, and the resulting mixture was allowed to warm to room temperature and stirred for 1 hour. After completion of the reaction, ice water (20mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20mL), the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the title compound 16a (200mg, pale yellow solid) in yield: 75 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.95(d,1H),7.49(m,1H),7.42(t,3H),7.22(d,1H),5.55(d,1H),5.44(t,1H),5.36(d,1H),4.46(d,1H),4.40(s,2H),4.25-4.18(m,3H),2.10(s,3H),2.01(s,3H),1.77(s,3H),1.36(s,3H),1.28(s,3H)。

Step 2[ 2-amino-4- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (1-hydroxy- 1-methyl-ethyl) -6, 8-dioxybisRing [3.2.1]Octane-5-yl]Phenyl radical]Methyl radical]Phenyl radical]2-chloroacetate 16b

[4- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -2-nitro-phenyl ] 2-chloroacetate 16a (200mg,0.29mmol) and tin dichloride (270mg,1.4mmol) were added to ethanol (5mL), and the resulting mixture was heated to 80 ℃ under a nitrogen atmosphere and stirred for 1 hour. After the completion of the reaction, concentration under reduced pressure was performed to remove the organic solvent, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 2/1] to give the title compound 16b (120mg, white solid) in yield: and 63 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):8.99(s,1H),8.08(s,1H),7.38(s,2H),7.34(s,1H),7.10(m,1H),6.98(d,1H),6.85(d,1H),5.55(d,1H),5.44(t,1H),5.37(d,1H),4.46(d,1H),4.29-4.18(m,3H),4.17-4.11(m,1H),3.96(d,1H),2.10(s,3H),2.01(s,3H),1.77(s,3H),1.37(s,3H),1.16(s,3H)。

Step 3[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (2-oxo-3, 4-dihydro-1, 4-) Benzoxazin-6-yl) methyl]Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-3-yl] Acetic acid ester 16c

[ 2-amino-4- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] phenyl ] 2-chloroacetate 16b (120mg,0.18mmol) was dissolved in acetonitrile (3mL), potassium carbonate (92mg,0.67mmol) was added, and the resulting mixture was heated to 68 ℃ under a nitrogen atmosphere and stirred for 5 hours. After completion of the reaction, it was cooled to room temperature, and then a mixture of ethyl acetate (20mL) was added, which was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 16c (112mg, white solid) in yield: 98 percent.

Step 46- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethan-yl) 6, 8-Dioxobicyclo [3.2.1] yl]Octane-5-yl]Phenyl radical]Methyl radical]-3, 4-dihydro-1, 4-benzoxazin-2-one 16

[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (2-oxo-3, 4-dihydro-1, 4-benzoxazin-6-yl) methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-3-yl ] acetate 16c (112mg,0.18mmol) was dissolved in methanol (6mL), sodium methoxide (50mg,0.93mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, and the residue was directly purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 16(62mg, white solid) in yield: 70 percent.

MS(ESI,pos.ion):m/z 492.2[M+H]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm):7.46(s,1H),7.43-7.36(m,2H),6.90-6.80(m,2H),6.74(s,1H),4.54(s,2H),4.22(d,1H),4.05(s,2H),3.99(d,1H),3.92(d,1H),3.68(s,1H),3.55(d,1H),1.35(s,3H),1.30(s,3H)。

Example 176- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -4-methyl-3H-1, 4-benzoxazin-2-one 17

Potassium carbonate (57mg,0.41mmol) and iodomethane (15. mu.l, 0.24mmol) were added to a solution of 6- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -3, 4-dihydro-1, 4-benzoxazin-2-one 16(100mg,0.20mmol) in N, N-dimethylformamide (2mL), and the resulting mixture was heated to 55 ℃ and stirred for 3 hours. After the reaction was completed, ethyl acetate (10mL) was added, the mixture was washed with water (10mL) and a saturated sodium bicarbonate solution (10mL) in this order, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ], to obtain the objective compound 17(59mg, white solid) in yield: 57 percent.

MS(ESI,pos.ion):m/z 506.2[M+H]⁺；

¹H NMR(400MHz,MeOD)δ(ppm):7.48(s,1H),7.43-7.37(m,2H),7.01(s,1H),6.93-6.87(m,2H),4.58(s,2H),4.21(d,1H),4.12(s,2H),3.98(d,1H),3.92(d,1H),3.68(t,1H),3.54(d,1H),3.33(s,3H),1.35(s,3H),1.29(s,3H)。

Example 18(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ (3-ethyl-3, 4-dihydro-2H-1, 4-benzoxazin-6-yl) methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 18

Step 14-benzyl-6- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-1- (1-hydroxy-1- Methyl-ethyl) -6, 8-dioxabicyclo [3.2.1 ]Octane-5-yl]Phenyl radical]Methyl radical]-1, 4-benzoxazin-3-one 18a

After sodium hydride (60% dispersed in mineral oil) (640mg,16mmol) was suspended in anhydrous tetrahydrofuran (5mL) and cooled to 0 ℃ under a nitrogen atmosphere, a solution of 6- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -4H-1, 4-benzoxazin-3-one 14(1.2g,2.44mmol) in anhydrous tetrahydrofuran (10mL) was added dropwise, stirred for 15 minutes, benzyl bromide (1.74mL,14.7mmol) was added, and the resulting mixture was heated to 40 ℃ and stirred for 18 hours. After completion of the reaction, ice water (30mL) was added, followed by extraction with ethyl acetate (30mL), liquid separation, washing of the organic phase with saturated brine (30mL), drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 6/1] to give the title compound 18a (620mg, off-white solid) in yield: 30 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.51(s,1H),7.45(m,2H),7.37-7.16(m,18H),6.91(s,1H),6.84(d,

2H),6.79(d,1H),6.73(d,1H),4.97(d,2H),4.76(t,2H),4.66(s,2H),4.61(s,2H),4.23(m,2H),4.12(d,1H),3.99–3.87(m,3H),3.75(m,3H),1.30(s,3H),1.25(s.3H)。

Step 22- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- [ (4-benzylspiro [2H-1, 4-benzoxazole) Oxazine-3, 1' -cyclopropyl]-6-yl) methyl]-4-chloro-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Propane-2-ol 18b

Cooling tetraisopropyl titanate (0.5mL,1.0mmol) in anhydrous tetrahydrofuran (15mL) to-50 ℃ under nitrogen atmosphere, adding dropwise ethyl magnesium bromide (1.2mL,3.6mmol,3M) solution, transferring the resulting mixture to room temperature, stirring for 1 hour, cooling the reaction system to-15 ℃, adding 4-benzyl-6- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-5-yl ] phenyl ] methyl ] -1, 4-benzoxazine-3-one 18a (600mg,0.704mmol) in anhydrous tetrahydrofuran (5mL), the resulting mixture was heated to 60 ℃ and stirred for 24 hours. After completion of the reaction, the reaction solution was poured into ice water (50mL), followed by addition of ethyl acetate (50mL), followed by washing with a saturated ammonium chloride solution (30mL) and saturated brine (30mL), drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 10/1] to give the title compound 18b (240mg, off-white solid) in yield: 39 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.42(s,1H),7.33(m,11H),7.25(d,4H),7.23-7.13(m,5H),6.90(d,2H),6.75(d,1H),6.65(d,1H),6.61-6.54(m,1H),5.06(d,1H),4.96(d,1H),4.77(d,2H),4.33(d,1H),4.26(s,2H),4.17(d,1H),4.12-4.03(m,2H),3.96(m,3H),3.78(d,1H),3.74(s,2H),3.69(d,1H),1.29(s,3H),1.25(s,3H),0.89(t,2H),0.65(t,2H)。

Step 3(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ (3-ethyl-3, 4-dihydro-2H-1, 4-benzoxazine-6-) Radical) methyl]Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 18

Palladium dichloride (85mg,0.48mmol) was added to a solution of 2- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- [ (4-benzylspiro [2H-1, 4-benzoxazine-3, 1' -cyclopropyl ] -6-yl) methyl ] -4-chloro-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] propan-2-ol 18b (600mg,0.70mmol) in tetrahydrofuran (5mL), methanol (20mL) was further added, and the resulting mixture was stirred under an atmosphere of hydrogen for 1 hour. After completion of the reaction, concentration under reduced pressure was performed, ethyl acetate (20mL) was added to the residue, which was then washed with saturated sodium bicarbonate (10mL) and saturated brine (10mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound 18(17mg, off-white solid) in yield: 14 percent.

MS(ESI,pos.ion):m/z 506.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.38(d,1H),7.33(d,1H),7.25(d,1H),6.70(d,1H),6.53(d,1H),6.40(s,1H),4.23(d,1H),4.17(m,1H),4.04(t,2H),3.95(s,2H),3.87-3.72(m,3H),3.68(d,1H),3.27-3.16(m,1H),1.46(m,2H),1.37(s,3H),1.28(s,3H),0.98(t,3H)。

Example 196- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -4H-1, 4-benzoxazin-3-one 19

Step 1(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl group]Phenyl radical]-1- (hydroxymethyl) - 6, 8-Dioxobicyclo [3.2.1]Octane-2, 3, 4-triol 19b

To a solution of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 14a (6.0g,8.48mmol) in tetrahydrofuran/methanol (v/v ═ 1/8,54mL) at room temperature was added 10% palladium on carbon (600mg,0.57mmol) and concentrated hydrochloric acid (3.0mL,36mmol), and the resulting mixture was stirred under hydrogen atmosphere for 3 hours. After the reaction was completed, sodium bicarbonate solid (3.0g) was added, the filtrate was concentrated under reduced pressure, and the residue was directly purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 19b (3.3g, white solid) in yield: 89 percent.

Step 2[ (1R,2S,3S,4 ]R,5S) -2,3, 4-triacetoxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl Base of]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methyl acetate 19c

Pyridine (3.4mL,41mmol), acetic anhydride (4.0mL,41mmol) and DMAP (64mg,0.52mmol) were added sequentially to a solution of (1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 19b (2.2g,5.0mmol) in dichloromethane (40mL), and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with water (40mL), hydrochloric acid (40mL,1M) and a saturated sodium bicarbonate solution (40mL) in this order, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 19c (2.48g, white solid) in yield: 82 percent.

¹H NMR(600MHz,CDCl₃)δ(ppm):7.37-7.34(m,2H),7.31(m,1H),7.08-7.04(m,2H),6.83-6.78(m,2H),5.48(m,1H),5.42-5.37(m,1H),5.28(d,1H),4.55-4.50(m,1H),4.42(d,1H),4.08(d,1H),4.02-3.94(m,4H),3.70(m,1H),2.10(d,3H),2.04(d,3H),1.98(s,3H),1.68(d,3H),1.39(t,3H)。

Step 3[ (1R,2S,3S,4R,5S) -2,3, 4-triacetoxy-5- [ 4-chloro-3- [ (4-ethoxy-3-nitro- Phenyl) methyl]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Acetic acid methyl ester 19d

A nitric acid solution (0.42mL,5.0mmol, wt.: 60%) was added dropwise to a solution of methyl [ (1R,2S,3S,4R,5S) -2,3, 4-triacetoxy-5- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] acetate 19c (2.1g,3.5mmol) in acetic anhydride (10mL) at-5 ℃, stirred for 2 hours, then moved to room temperature and stirred for 12 hours. After completion of the reaction, the reaction solution was poured into ice water (50mL), followed by extraction with ethyl acetate (20mL × 3), the combined organic phases were washed successively with a saturated sodium bicarbonate solution (50mL) and a saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the title compound 19d (2.0g, yellow solid) in yield: 88 percent.

¹H NMR(600MHz,CDCl₃)δ(ppm):7.58(d,1H),7.38(s,3H),7.28(dt,1H),7.00-6.94(m,1H),5.49(m,1H),5.41(t,1H),5.34-5.29(m,1H),4.54(d,1H),4.44(d,1H),4.18-4.11(m,2H),4.07(s,2H),3.96(d,1H),3.72(m,1H),2.10(d,3H),2.05(d,3H),1.99(s,3H),1.75(s,3H),1.47-1.41(m,3H)。

Step 4[ (1R,2S,3S,4R,5S) -2,3, 4-triacetoxy-5- [ 4-chloro-3- [ (4-hydroxy-3-nitro-benzene) Radical) methyl]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Acetic acid methyl ester 19e

Methyl [ (1R,2S,3S,4R,5S) -2,3, 4-triacetoxy-5- [ 4-chloro-3- [ (4-ethoxy-3-nitro-phenyl) methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] acetate 19d (1.84g,2.83mmol) was dissolved in dichloromethane (10mL) and cooled to 0 ℃ and aluminum trichloride (3.77g,28.3mmol) was added in portions, stirred for 30 minutes after completion of the addition, then allowed to stand at room temperature and stirred for 6 hours. After completion of the reaction, the reaction solution was poured into ice water (50mL), followed by extraction with dichloromethane (50mL), liquid separation, washing of the organic phase with saturated brine (50mL), drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification of the residue by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give the title compound 19e (1.29g, pale yellow solid) in yield: 73 percent.

MS(ESI,pos.ion):m/z 622.5[M+H]⁺；

¹H NMR(600MHz,CDCl₃)δ(ppm)：10.48(d,1H),7.87(d,1H),7.45-7.31(m,4H),7.08(d,1H),5.48(d,1H),5.40(t,1H),5.35-5.28(m,1H),4.53(d,1H),4.44(d,1H),4.06(t,2H),3.99-3.93(m,1H),3.72(d,1H),2.08(d,3H),2.04(s,3H),1.98(s,3H),1.74(d,3H)。

Step 52- [4- [ [ 2-chloro-5- [ (1R,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (acetoxymethyl) methyl 6, 8-Dioxobicyclo [3.2.1] yl]Octane-5-yl]Phenyl radical]Methyl radical]-2-nitro-phenoxy]Ethyl acetate 19f

Cesium carbonate (0.32g,0.97mmol) and ethyl bromoacetate (0.14mL,1.27mmol) were added to a solution of methyl [ (1R,2S,3S,4R,5S) -2,3, 4-triacetoxy-5- [ 4-chloro-3- [ (4-hydroxy-3-nitro-phenyl) methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] acetate 19e (0.15g,0.24mmol) in acetonitrile (5mL), and the resulting mixture was heated to 85 ℃ under a nitrogen atmosphere and stirred for 15 hours. After the reaction was completed, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 4/1] to give the title compound 19f (85mg, white solid) in yield: 50 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.64(d,1H),7.37(d,3H),7.33-7.27(m,1H),6.91(d,1H),5.49(d,1H),5.41(t,1H),5.34-5.28(m,1H),4.73(s,2H),4.54(d,1H),4.43(t,1H),4.25(q,2H),4.08(d,2H),3.96(d,1H),3.72(d,1H),2.10(d,3H),2.04(s,3H),1.99(s,3H),1.73(d,3H),1.40-1.18(m,3H)。

Step 6[ (1R,2S,3S,4R,5S) -2,3, 4-triacetoxy-5- [ 4-chloro-3- [ (3-carbonyl-4H-1, 4-benzene) Oxazin-6-yl) methyl]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methyl acetate 19g

Iron powder (154mg,2.76mmol) was added to a solution of ethyl 2- [4- [ [ 2-chloro-5- [ (1R,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (acetoxymethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -2-nitro-phenoxy ] acetate 19f (130mg,0.18mmol) in acetic acid (5mL), and the resulting mixture was heated to 60 ℃ and stirred for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, ethyl acetate (30mL) was then added, and the mixture was washed with water (30mL), a saturated sodium bicarbonate solution (30mL) and a saturated brine (30mL) in this order, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 2/1] to give the title compound 19g (80mg, white solid) in yield: and 69 percent.

¹H NMR(400MHz,CDCl3)δ(ppm):8.27(s,1H),7.36(m,3H),6.97-6.80(m,2H),6.40(d,1H),5.58-5.28(m,3H),4.60-4.40(m,4H),3.96(m,2H),3.71(t,1H),3.24(m,1H),2.12-2.07(m,3H),2.05(d,3H),2.02(s,3H),1.78(d,3H)。

Step 76- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (hydroxymethyl) -6, 8-dioxybis Ring [3.2.1]Octane-5-yl]Phenyl radical]Methyl radical]-4H-1, 4-benzoxazin-3-one 19

Lithium hydroxide monohydrate (270mg,6.44mmol) was added to a solution of methyl [ (1R,2S,3S,4R,5S) -2,3, 4-triacetoxy-5- [ 4-chloro-3- [ (3-carbonyl-4H-1, 4-benzoxazin-6-yl) methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] acetate 19g (401mg,0.63mmol) in methanol (5mL), and the resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, concentration under reduced pressure was performed to remove the organic solvent, and ethyl acetate (20mL) was added to the residue, which was washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the objective compound 19(160mg, white solid) in yield: 54 percent.

MS(ESI,pos.ion):m/z 464.8[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)δ(ppm):10.60(s,1H),7.43-7.38(m,2H),7.32(m,1H),6.85(d,1H),6.74(d,2H),5.19(d,1H),4.99(d,1H),4.89(d,1H),4.76(t,1H),4.51(s,2H),4.02(s,2H),3.98(s,1H),3.64(m,1H),3.53(m,1H),3.48-3.38(m,4H)。

Example 206- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethyl ] -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] chromen-2-one 20

Step 1[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (3-carboxaldehyde-4-hydroxy-phenyl) Methyl radical]Phenyl radical]-1- (1-hydroxy-1-methyl-ethyl)]-6, 8-dioxabicyclo [3.2.1 ]Octane-3-yl]Acetate 20a

Mixing [ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (4-hydroxyphenyl) methyl group]Phenyl radical]-1- (1-hydroxy-1-methylethyl) -6, 8-dioxabicyclo [3.2.1]Octane-3-yl]Acetate 14g (200mg,0.36mmol) was dissolved in acetonitrile (12mL), and paraformaldehyde (73mg,2.4mmol), magnesium chloride (55mg,0.58mmol) and triethylamine (0.17mL,1.21mmol), and the resulting mixture was heated to 90 deg.C and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into hydrochloric acid (20mL,1M), followed by extraction with ethyl acetate (30mL × 2), the combined organic phases were washed successively with a saturated sodium bicarbonate solution (50mL) and a saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1]To give the title compound 20a (65mg, green solid), yield: 31 percent.¹H NMR(400MHz,CDCl₃)δ(ppm):10.94(s,1H),9.88(s,1H),7.43-7.35(m,4H),7.32(d,1H),6.95(d,1H),5.54(m,1H),5.43(t,1H),5.35(d,1H),4.45(d,1H),4.22(m,1H),4.10(d,2H),2.10(s,3H),2.01(s,3H),1.74(s,3H),1.36(s,3H),1.20(s,3H)。

Step 2(E) -3- [5- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (1-hydroxy- 1-methylethyl) -6, 8-dioxabicyclo [3.2.1]Octane-5-yl]Phenyl radical]Methyl radical]-2-hydroxyphenyl]Propane-2-enoic acid ethylene Ester 20b

Ethoxyformylmethylenetriphenylphosphine (230mg,0.66mmol) was added to a solution of [ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (3-carboxaldehyde-4-hydroxy-phenyl) methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl ] -6, 8-dioxabicyclo [3.2.1] octan-3-yl ] acetate 20a (260mg,0.44mmol) in tetrahydrofuran (5mL), the resulting mixture was stirred at room temperature for 30 minutes, after the completion of the reaction, the mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1], to give the title compound 20b (240mg, light green solid), yield: 82 percent.

Step 3[ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (2-oxobenzopyran-6- Radical) methyl]Phenyl radical]-1- (1-hydroxy-1-methylethyl) -6, 8-dioxabicyclo [3.2.1]Octane-3-yl]Acetic ester 20c

Ethyl (E) -3- [5- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-triacetoxy-1- (1-hydroxy-1-methylethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -2-hydroxyphenyl ] propane-2-enoate 20b (50mg,0.08mmol) was dissolved in a solution of o-xylene (3mL) and subjected to a microwave reaction (220 ℃ C.) for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate v/v) ═ 3/1] to give the title compound 20c (16mg, white solid) in yield: 34 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.70(d,1H),7.44-7.36(m,4H),7.30-7.26(m,1H),7.23(s,1H),6.41(d,1H),5.54(d,1H),5.43(t,1H),5.37-5.31(m,1H),4.45(d,1H),4.23(d,1H),4.15(m,2H),2.10(s,3H),2.01(s,3H),1.74(s,3H),1.36(s,3H),1.16(s,3H)。

Step 46- [ [ 2-chloro-5- [ (1S,2S,3S,4R,5S) -2,3, 4-trihydroxy-1- (1-hydroxy-1-methyl-ethan-yl) Base of]-6, 8-dioxabicyclo [3.2.1]Octane-5-yl]Phenyl radical]Methyl radical]Benzopyran-2-one 20

Sodium methoxide (43mg,0.80mmol) was added to a solution of [ (1S,2S,3S,4R,5S) -2, 4-diacetoxy-5- [ 4-chloro-3- [ (2-oxobenzopyran-6-yl) methyl ] phenyl ] -1- (1-hydroxy-1-methylethyl) -6, 8-dioxabicyclo [3.2.1] octan-3-yl ] acetate 20c (100mg,0.16mmol) in methanol (5mL), and the mixture was stirred at room temperature for 20 minutes. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the organic solvent was removed, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the objective compound 20(34mg, white solid) in yield: and 43 percent.

MS(ESI,pos.ion):m/z 489.2[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm)：7.66(d,1H),7.48(m,4H),7.29-7.27(m,2H),6.42(d,1H),4.28(d,1H),4.18(s,2H),4.12(d,1H),4.09(d,1H),3.84(t,1H),3.72(t,1H),1.41(s,3H),1.32(s,3H)。

Example 21(2S,3R,4R,5S,6S) -2- [ 4-cyclopropyl-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6- (1-hydroxy-1-methyl-ethyl) tetrahydropyran-3, 4, 5-triol 21

Step 1(2S,3R,4R,5S,6R) -2- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) benzene Base of]-6- (hydroxymethyl) tetrahydropyran-3, 4, 5-triol 21a

The compound (2S,3R,4S,5S,6R) -2- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 5e (30.0g,60.3mmol) was dissolved in a mixed solvent of dichloromethane/acetonitrile (v/v ═ 1/1,300mL), triethylsilane (38mL,240mmol) was added, the resulting mixture was cooled to 0 ℃ under a nitrogen atmosphere, and then boron trifluoride ether (15mL,122mmol) was added, and the resulting reaction liquid was transferred to room temperature and stirred for 4 hours. After completion of the reaction, the reaction was quenched by dropwise addition of a saturated sodium bicarbonate solution (100mL), concentrated under reduced pressure to remove the organic solvent, extracted with ethyl acetate (500mL), and the organic phase was washed with a saturated saline solution (300mL × 2) and concentrated under reduced pressure to obtain the title compound 21a (27.0g, brown oil), yield: 91 percent.

MS(ESI,pos.ion):m/z 489.2[M+Na]⁺。

Step 2(2S,3R,4R,5S,6R) -2- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) benzene Base of]-6- [ [ tert-butyl (dimethyl) silyl ] group]Oxymethyl radical]Tetrahydropyran-3, 4, 5-triol 21b

The compound (2S,3R,4R,5S,6R) -2- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6- (hydroxymethyl) tetrahydropyran-3, 4, 5-triol 21a (16.0g,34.2mmol) was dissolved in dichloromethane (200mL), cooled to 0 deg.C, then imidazole (5.0g,73mmol) was added, then tert-butyldimethylsilyl chloride (10.5g,69.7mmol) was added, and the resulting mixture was stirred at 0 deg.C for 30 minutes. After completion of the reaction, the reaction mixture was washed with water (200 mL. times.2), a saturated sodium bicarbonate solution (100mL) and a saturated brine (100mL) in this order, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound 21b (21.0g, brown oil) in yield: 100 percent. Directly used for the next reaction.

Step 3 tert-butyldimethyl- [ [ (2R,3R,4R,5S,6S) -34, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-di) Hydro-1, 4-benzodioxin-6-ylmethyl) phenyl]Tetrahydropyran-2-yl]Methoxy radical]Silane 21c

Sodium hydride (60% dispersed in mineral oil) (12.0g,300mmol, wt.%: 60%) was suspended in tetrahydrofuran (200mL) and after cooling to 0 ℃ under nitrogen atmosphere, a solution of (2S,3R,4R,5S,6R) -2- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ] tetrahydropyran-3, 4, 5-triol 21b (29.0g,49.9mmol) in tetrahydrofuran (100mL) was added dropwise and after completion of the addition, the resulting mixture was stirred for a further 30 minutes at 0 ℃. Tetrabutylammonium iodide (0.21g,0.57mmol) was added further, then benzyl bromide (36mL,303mmol) was added dropwise, and after completion of the addition, the resulting mixture was allowed to stand at room temperature for 30 minutes with stirring, then heated to 40 ℃ with stirring overnight. After the reaction was completed, the reaction was quenched by adding methanol (10mL) dropwise. Further, petroleum ether (200mL) was added, and the resulting mixture was washed with a saturated ammonium chloride solution (200mL), water (200mL) and a saturated saline solution (200mL) in this order. Concentration under reduced pressure gave the title compound 21c (61.5g, brown oil), yield: 100 percent. Directly used for the next reaction.

Step 4[ (2R,3R,4R,5S,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodi) Oxazolin-6-ylmethyl) phenyl]Tetrahydropyran-2 yl radical]Methanol 21d

Tert-butyldimethyl- [ [ (2R,3R,4R,5S,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-yl ] methoxy ] silane 21c (61.5g,72.2mmol) was dissolved in tetrahydrofuran (200mL), a solution of tetrabutylammonium fluoride in tetrahydrofuran (220mL,220mmol,1.0M) was added, and the resulting mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the organic solvent, and the residue was dissolved in ethyl acetate (200mL), washed with saturated brine (200mL × 2), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/3] to give the title compound 21d (30.1g, yellow oil) in yield: 56 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.58(d,1H),7.42-7.30(m,10H),7.27-7.20(m,4H),7.17(dd,1H),6.97-6.89(m,2H),6.78(d,1H),6.72(d,1H),6.65(dd,1H),5.00-4.90(m,3H),4.73(d,1H),4.44(d,1H),4.26-4.19(m,5H),4.08(d,1H),4.00-3.93(d,1H),3.91(m,2H),3.83(t,1H),3.73(m,2H),3.50(m,2H),1.95(t,1H)。

Step 5(2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) phenyl]Tetrahydropyran-2-carbaldehyde 21e

[ (2R,3R,4R,5S,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2 yl ] methanol 21d (30.0g,40.7mmol) was dissolved in dichloromethane (200mL), a saturated sodium bicarbonate solution (700mL,600mmol) was added, the resulting mixture was cooled to 0 ℃, potassium bromide (2.90g,24.4mmol) and TEMPO (0.64g,4.1mmol) were added, then a sodium hypochlorite solution (105mL, 122mmol, 3.31% available chlorine) was added all at once, and stirring was continued for 30 minutes. After completion of the reaction, liquid separation was performed, and the organic phase was washed with saturated brine (200mL), and concentrated under reduced pressure to obtain the title compound 21e (30.0g, yellow oil), yield: 100 percent. Directly used for the next reaction.

Step 6(2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) phenyl]Tetrahydropyran-2-carboxylic acid 21f

(2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-carbaldehyde 21e (30.0g,40.8mmol) was dissolved in dichloromethane (200mL), cooled to 0 deg.C, and dessimutane oxidant (26.0g,61.3mmol) was added in portions, and after the addition was completed, the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, suction filtration was performed, and the filtrate was washed with a saturated sodium bicarbonate solution (300mL × 2) and a saturated brine (200mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound 21f (28.2g, a yellow semi-solid), yield: 92 percent. Directly used for the next reaction.

Step 7 methyl (2S,3S,4R,5S,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzo Dioxin-6-ylmethyl) phenyl]Tetrahydropyran-2-carboxylate 21g

(2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-carboxylic acid 21f (28.2g,37.5mmol) was dissolved in dichloromethane (20mL), methanol (200mL) and acetyl chloride (6mL,84.4mmol) were added, and the resulting mixture was heated to 40 ℃ and stirred overnight. After the reaction was completed, the mixture was slowly poured into a saturated sodium bicarbonate solution (200mL), the organic solvent was removed by concentration under reduced pressure, the residue was extracted with ethyl acetate (200mL), the organic phase was washed with a saturated saline solution (200mL), concentrated under reduced pressure, methanol (200mL) was added to the residue, stirred at room temperature for 3 hours, and filtered by suction to obtain 21g (18.8g, white solid) of the title compound, yield: and 64 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.53(d,1H),7.36-7.28(m,7H),7.25-7.12(m,8H),6.93-6.82(m,2H),6.72(d,1H),6.66(d,1H),6.59(dd,1H),4.92-4.84(m,2H),4.81(d,1H),4.63(d,1H),4.38(d,1H),4.19(s,4H),4.18(s,1H),4.04(d,1H),4.00(d,1H),3.97-3.87(m,2H),3.85(d,1H),3.78(t,1H),3.70(s,3H),3.50(t,1H)。

Step 82- [ (2S,3S,4R,5S,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzo Dioxin-6-ylmethyl) phenyl]Tetrahydropyran-2-yl]Propane-2-ol 21h

21g (2.70g,3.64mmol) of methyl (2S,3S,4R,5S,6S) -3,4, 5-tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-carboxylate was dissolved in tetrahydrofuran (30mL), and after cooling to 0 ℃ under a nitrogen atmosphere, a tetrahydrofuran solution of methylmagnesium bromide (7.0mL,21mmol,3.0M) was added dropwise, and after the addition, the reaction mixture was heated to 40 ℃ and stirred overnight. After the reaction was completed, the mixture was cooled to 0 ℃, a saturated ammonium chloride solution (50mL) was added dropwise to quench the reaction, a saturated brine (200mL) was added, followed by extraction with ethyl acetate (200mL), the resulting organic phase was washed 1 time with a saturated brine (200mL), concentrated under reduced pressure, and the residue was purified by a silica gel column [ ethyl acetate/petroleum ether (v/v) ═ 1/4] to obtain the title compound 21h (2.61g, white solid), yield: 96 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.53(d,1H),7.36-7.27(m,9H),7.25-7.16(m,4H),7.16-7.08(m,2H),6.93(dd,2H),6.72(d,1H),6.66(d,1H),6.59(dd,1H),5.07(d,1H),4.97(d,1H),4.84(d,1H),4.72(d,1H),4.38(d,1H),4.19(s,4H),4.17(d,1H),4.02(d,1H),3.92(d,1H),389-3.80(m,2H),3.74(t,1H),3.49(s,1H),3.40(t,1H),3.29(d,1H),1.24(s,3H),1.20(s,3H)。

Step 92- [ (2S,3S,4R,5S,6S) -3,4, 5-tribenzyloxy-6- [ 4-cyclopropyl-3- (2, 3-dihydro-1, 4-) Benzodioxodioxin-6-ylmethyl) phenyl]Tetrahydropyran-2-yl]Propane-2-ol 21i

2- [ (2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-yl ] propan-2-ol 21h (0.60g,0.78mmol) was dissolved in toluene (5mL), tricyclohexylphosphorus (90mg,0.32mmol), tripotassium phosphate (0.66g,3.10mmol), water (1mL), cyclopropylboronic acid (0.30g,3.49mmol), and palladium acetate (30mg,0.13mmol) were added in this order, and the resulting mixture was heated to 90 ℃ under a nitrogen atmosphere and stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, the mixture was filtered with suction through celite, the filtrate was separated, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/4] to give the title compound 21i (0.50g, white solid) in yield: 88 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.35-7.23(m,10H),7.22-7.16(m,4H),7.14(d,1H),7.01(d,1H),6.93(dd,2H),6.71(d,1H),6.65(d,1H),6.58(dd,1H),5.08(d,1H),4.98(d,1H),4.82(d,1H),4.72(d,1H),4.32(d,1H),4.19(m,5H),4.12(d,1H),4.02(d,1H),3.86(t,1H),3.81(d,1H),3.74(t,1H),3.53(s,1H),3.47(t,1H),3.30(d,1H),1.85(m,1H),1.25(s,3H),1.21(s,3H),0.95-0.83(m,2H),0.69-0.59(m,2H)。

Step 10(2S,3R,4R,5S,6S) -2- [ 4-cyclopropyl-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethylol Radical) phenyl]-6- (1-hydroxy-1-methyl-ethyl) tetrahydropyran-3, 4, 5-triol 21

2- [ (2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-cyclopropyl-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-yl ] propan-2-ol 21i (0.30g,0.41mmol) was dissolved in tetrahydrofuran (0.5mL), methanol (3mL) and 10% palladium on carbon (0.20g,0.19mmol) were added, and the resulting mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. After the reaction was complete, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by HPLC to give the title compound 21(67mg, white solid) in yield: 35 percent.

MS(ESI,pos.ion)m/z:479.3[M+Na]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm):7.16(d,1H),7.12(s,1H),6.98(d,1H),6.71(d,1H),6.63(d,2H),4.19(s,4H),4.10-4.02(d,3H),3.63(t,1H),3.50(t,1H),3.29(t,1H),3.20(d,1H),1.85(m,1H),1.28(s,3H),1.24(s,3H),0.87(m,2H),0.58(m,2H)。

Example 22(2S,3R,4R,5S,6S) -2- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] -6- (1-hydroxy-1-methyl-ethyl) tetrahydropyran-3, 4, 5-triol 22

2- [ (2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-yl ] propan-2-ol 21h (0.15g,0.20mmol) was dissolved in tetrahydrofuran (0.5mL), methanol (3mL), triethylamine (60mg,0.6mmol) and 10% palladium on carbon (80mg,0.08mmol) were added, and the resulting mixture was stirred under a hydrogen atmosphere at room temperature overnight. After completion of the reaction, the reaction mixture was filtered by suction, the filtrate was concentrated under reduced pressure, and ethyl acetate (3mL) was added to the residue, which was then washed with water (3mL) and saturated brine (3mL) in this order, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to give the title compound 22(56mg, white solid) in yield: 65 percent.

MS(ESI,pos.ion):m/z 439.9[M+Na]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.24(t,1H),7.17(s,2H),7.10(d,1H),6.77(d,1H),6.66(d,2H),4.73(s,1H),4.57(s,1H),4.17(s,4H),4.10(d,1H),3.85(s,2H),3.72(t,1H),3.66(t,1H),3.57(s,1H),3.40(s,1H),3.36(t,1H),3.23(d,1H),1.29(s,3H),1.25(s,3H)。

Example 23(2S,3R,4R,5S,6S) -2- [ -3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-propyl-phenyl ] -6- (1-hydroxy-1-methyl-ethyl) tetrahydropyran-3, 4, 5-triol 23

2- [ (2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-cyclopropyl-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-yl ] propan-2-ol 21i (0.15g,0.21mmol) was dissolved in tetrahydrofuran (0.5mL), methanol (3mL) and 10% palladium on carbon (90mg,0.08mmol) were added, and the resulting mixture was stirred at room temperature for 5 days under a hydrogen atmosphere. Suction filtration, the filtrate concentrated under reduced pressure, and the residue purified by silica gel column chromatography (100% ethyl acetate) to give the title compound 23(55mg, white solid) in yield: 57 percent.

MS(ESI,pos.ion):m/z 481.9[M+Na]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm):7.22-7.10(m,3H),6.71(d,1H),6.59(d,2H),4.19(s,4H),4.08(d,1H),3.90(s,2H),3.64(t,1H),3.50(t,1H),3.38-3.27(m,1H),3.20(d,1H),2.56(m,2H),1.50(m,2H),1.28(s,3H),1.24(s,3H),0.93(t,3H)。

Example 24(2S,3R,4R,5S,6S) -2- [ -3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-ethyl-phenyl ] -6- (1-hydroxy-1-methyl-ethyl) tetrahydropyran-3, 4, 5-triol 24

Step 12- [ (2S,3S,4R,5S,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxan) ININ-6-YLMETHYL) -4-ETHYL-PHENYL]Tetrahydropyran-2-yl]Propane-2-ol 24a

2- [ (2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-yl ] propan-2-ol 21h (0.44g,0.57mmol) was dissolved in toluene (4mL), tricyclohexylphosphorus (65mg,0.23mmol), tripotassium phosphate (0.60g,2.82mmol), water (1mL), ethylboronic acid (0.33g,4.47mmol), and palladium acetate (20mg,0.09mmol) were added in this order, and the resulting mixture was heated to 90 ℃ under a nitrogen atmosphere and stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, the mixture was filtered with suction through celite, the filtrate was separated, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/4] to give the title compound 24a (0.34g, white solid) in yield: 80 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.39-7.28(m,10H),7.27-7.18(m,5H),7.17(s,1H),6.97(m,2H),6.73(d,1H),6.63(d,1H),6.57(dd,1H),5.11(d,1H),5.02(d,1H),4.86(d,1H),4.75(d,1H),4.35(d,1H),4.29-4.18(m,5H),3.97(d,1H),3.92(s,1H),3.89(d,1H),3.85(d,1H),3.78(t,1H),3.57(s,1H),3.52(t,1H),3.34(d,1H),2.66(q,2H),1.29(s,3H),1.25(s,3H),1.21(t,3H)。

Step 2(2S,3R,4R,5S,6S) -2- [ -3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-ethane Phenyl radical]-6- (1-hydroxy-1-methyl-ethyl) tetrahydropyran-3, 4, 5-triol 24

2- [ (2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-ethyl-phenyl ] tetrahydropyran-2-yl ] propan-2-ol 24a (0.34g,0.48mmol) was dissolved in tetrahydrofuran (0.5mL), methanol (4mL) and 10% palladium on carbon (0.10g,0.09mmol) were added, and the resulting mixture was stirred at room temperature for 3 days under a hydrogen atmosphere. After the reaction was completed, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 24(0.14g, white solid) in yield: and 64 percent.

MS(ESI,pos.ion):m/z 467.9[M+Na]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm):7.22-7.15(m,2H),7.12(s,1H),6.71(d,1H),6.63-6.56(m,2H),4.19(s,4H),4.08(d,1H),3.91(s,2H),3.64(t,1H),3.51(t,1H),3.29(t,1H),3.21(d,1H),2.61(q,2H),1.29(s,3H),1.24(s,3H),1.12(t,3H)。

Example 25(2S,3R,4R,5S,6S) -2- [ -3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-isopropyl-phenyl ] -6- (1-hydroxy-1-methyl-ethyl) tetrahydropyran-3, 4, 5-triol 25

Step 12- [ (2S,3S,4R,5S,6S) -3,4, 5-tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxan) En-6-ylmethyl) -4-isopropyl-phenyl]Tetrahydropyran-2-yl]Propane-2-ol 25a

2- [ (2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [ 4-bromo-3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) phenyl ] tetrahydropyran-2-yl ] propan-2-ol 21h (0.46g,0.60mmol) was dissolved in toluene (4mL), tricyclohexylphosphorus (65mg,0.23mmol), tripotassium phosphate (0.50g,2.36mmol), water (1mL), isopropenylboronic acid pinacol ester (0.30g,1.79mmol), and palladium acetate (20mg,0.09mmol) were added in this order, and the resulting mixture was heated to 90 ℃ under a nitrogen atmosphere and stirred overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, the mixture was filtered with suction through celite, the filtrate was separated, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/4] to give the title compound 25a (85mg, yellow solid) in yield: 20 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.37-7.29(m,9H),7.26-7.18(m,5H),7.19-7.14(m,2H),6.94(dd,2H),6.71(d,1H),6.62(d,1H),6.56(dd,1H),5.23(s,1H),5.10(d,1H),5.01(d,1H),4.88(s,1H),4.85(d,1H),4.74(d,1H),4.37(d,1H),4.27-4.18(m,5H),3.99(d,1H),3.92-.81(m,3H),3.77(t,1H),3.53(s,1H),3.49(t,1H),3.33(d,1H),2.02(s,3H),1.28(s,3H),1.24(s,3H)。

Step 2(2S,3R,4R,5S,6S) -2- [ -3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-iso-isomer Propyl-phenyl]-6- (1-hydroxy-1-methyl-ethyl) tetrahydropyran-3, 4, 5-triol 25

2- [ (2S,3S,4R,5S,6S) -3,4, 5-Tribenzyloxy-6- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-isopropyl-phenyl ] tetrahydropyran-2-yl ] propan-2-ol 25a (80mg,0.11mmol) was dissolved in tetrahydrofuran (0.5mL), methanol (4mL) and 10% palladium on carbon (50mg,0.05mmol) were added, and the resulting mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. After the reaction was completed, suction filtration was performed, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to obtain the title compound 25(16mg, white solid) in yield: 31 percent.

MS(ESI,pos.ion):m/z 481.9[M+Na]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm):7.35-7.19(m,2H),7.14(s,1H),6.71(d,1H),6.64-6.52(m,2H),4.20(s,4H),4.09(d,1H),3.95(s,2H),3.65(t,1H),3.52(t,1H),3.31(m,1H),3.29-3.09(m,2H),1.30(s,3H),1.26(s,3H),1.14(s,3H),1.12(s,3H)。

Example 26(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -1- (methylthiomethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 26

Step 1[ (1R,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin- 6-ylmethyl) -4-methyl-phenyl]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methylmethanesulfonate 26a

4l (151mg,0.22mmol) of [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxine-6-ylmethyl) -4-methyl-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol and triethylamine (0.3mL,2.0mmol) were dissolved in methylene chloride (20mL), cooled to 0 ℃, methanesulfonyl chloride (0.1mL,2.0mmol) was added, and the mixture was stirred for 3 hours. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 3/1] to give title compound 26a (165mg, yellow oil), yield: 98 percent.

Step 26- [ [ 2-methyl-5- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-1- (methylthiomethyl) -6, 8-dioxybicyclo [3.2.1]]Octane-5-yl]Phenyl radical]Methyl radical]-2, 3-dihydro-1, 4-benzodioxin 26b

[ (1R,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl-phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methyl methanesulfonate 26a (90mg,0.12mmol) was dissolved in N, N-dimethylformamide (10mL), sodium thiomethoxide (80mg,0.46mmol) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (20mL) and water (30mL × 2) were added in this order, washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ petroleum ether/ethyl acetate (v/v) ═ 5/1] to give title compound 26b (45mg, yellow oil), yield: 53 percent.

Step 3(1S,2S,3S,4R,5S) -5- [3- (2, 3-dihydro-1, 4-benzodioxin-6-ylmethyl) -4-methyl- Phenyl radical]-1- (methylthiomethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 26

6- [ [ 2-methyl-5- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-1- (methylmercaptomethyl) -6, 8-dioxabicyclo [3.2.1] octan-5-yl ] phenyl ] methyl ] -2, 3-dihydro-1, 4-benzodioxin 26b (45mg,0.06mmol) was dissolved in tetrahydrofuran (1mL), methanol (4mL) and 10% palladium on carbon (0.30g,0.28mmol) were added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. Suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to give title compound 26(7mg, white solid) in yield: 24.7 percent.

MS(ESI,neg.ion)m/z:459.3[M-H]^-；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.31(m,2H),7.18(d,1H),6.77(d,1H),6.61-6.56(m,2H),4.17(s,5H),4.07(d,2H),3.92-4.03(q,3H),3.77(t,1H),3.65(d,1H),3.62(d,1H),2.88(d,1H),2.73(d,1H),2.15(s,3H)。

Example 27(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 27

Step 1[6- [ (5-bromo-2-chloro-phenyl) methyl]-2, 3-dihydro-1, 4-benzodioxin-3 yl]Methanol 27a

3- (benzyloxymethyl) -6- [ (5-bromo-2-chloro-phenyl) methyl ] -2, 3-dihydro-1, 4-benzodioxin was dissolved in dichloromethane (200mL) for 13h (30.0g,65.2mmol), cooled to 0 ℃, and aluminum trichloride (17.6g,132mmol) was added in portions, and after completion of addition, the mixture was allowed to stand at room temperature and stirred for 2 hours. The reaction solution was poured into ice water (200mL), the organic phase was washed with dilute hydrochloric acid (1M,200mL) and saturated brine (200mL) in this order, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/3] to give title compound 27a (22.0g, red oil), yield: 91 percent.

Step 26- [ (5-bromo-2-chloro-phenyl) methyl]-3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin 27b

Sodium hydride (60% dispersed in mineral oil) (2.84g,71.0mmol, wt.%: 60%) was suspended in tetrahydrofuran (200mL) and cooled to 0 ℃, a solution of [6- [ (5-bromo-2-chloro-phenyl) methyl ] -2, 3-dihydro-1, 4-benzodioxin-3 yl ] methanol 27a (22.0g,59.5mmol) in tetrahydrofuran (60mL) was added dropwise and stirred for 20 min, iodoethane (5.2mL,65mmol) and tetrabutylammonium iodide (10mg,0.03mmol) were added and the mixture was heated to 50 ℃ and stirred overnight. Cooled to 0 ℃, the reaction was quenched by dropwise addition of water (2mL), concentrated under reduced pressure, the residue was dissolved in ethyl acetate (200mL), washed with saturated brine (200mL × 2), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% petroleum ether ] to give the title compound 27b (13.2g, yellow oil) in yield: 56 percent.

¹H NMR(400MHz,CD₃OD)δ(ppm):7.36-7.25(m,3H),6.77(m,1H),6.64(m,2H),4.26(m,2H),3.99(m,1H),3.94(s,2H),3.65(m,2H),3.59-3.53(q,2H),1.18(t,3H)。

Step 3(2S,3R,4S,5S,6R) -2- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodi Oxadin-6-yl]Methyl radical]Phenyl radical]-6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 27c

Dissolving 6- [ (5-bromo-2-chloro-phenyl) methyl ] -3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin 27b (13.2g,33.3mmol) in tetrahydrofuran (110mL), cooling to-78 deg.C, adding n-hexane solution of n-butyllithium (15mL,36mmol,2.4M) dropwise, continuing to stir for 40 minutes after completion of the addition, slowly adding tetrahydrofuran (80mL) solution of (3R,4S,5R,6R) -3,4, 5-tris (trimethylsilyloxy) -6- (trimethylsilyloxymethyl) tetrahydrofuran-2 one 1f (16.9g,36.2mmol) dropwise, stirring for 2 hours, adding water (1mL) dropwise to quench the reaction, concentrating under reduced pressure, adding methanol (200mL) to the residue, adjusting the pH to 2 with concentrated hydrochloric acid, the mixture was heated to 40 ℃ and stirred for 1 hour, sodium bicarbonate solid was added to adjust the pH to 7-8, concentrated under reduced pressure, and ethyl acetate (200mL) was added to the residue, which was washed with water (200mL) and saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 27c (11.6g, yellow solid), yield: 68 percent.

Step 4(2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl ]Oxymethyl radical]2- [ 4-chloro-3- [ [3- (ethyl) ethyl ester Oxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-2-methoxy-tetrahydropyran-3, 4, 5-tris Alcohol 27d

(2S,3R,4S,5S,6R) -2- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -6- (hydroxymethyl) -2-methoxy-tetrahydropyran-3, 4, 5-triol 27c (11.6g,22.7mmol) and imidazole (3.10g,45.6mmol) were dissolved in dichloromethane (200mL), cooled to 0 deg.C, tert-butyldimethylchlorosilane (6.88g,45.6mmol) was added, and the mixture was transferred to room temperature and stirred for 2 hours. Water (200mL) and saturated brine (200mL) were washed in sequence, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 3/1] to give title compound 27d (12.1g, white solid), yield: 85 percent.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.46(s,1H),7.41(d,1H),7.34(dd,1H),6.76(dd,1H),6.66-6.59(m,2H),5.01(d,1H),4.79(t,2H),4.26(d,2H),3.94(dd,4H),3.75(dd,1H),3.60-3.53(m,3H),3.53-3.40(m,4H),3.16(m,1H),2.94(s,3H),1.11(t,3H),0.84(s,9H),0.05(s,3H),0.01(s,3H).

Step 5 tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-6-methoxy-tetrahydropyran-2-yl] Methoxy radical]Silane 27e

Sodium hydride (60% dispersed in mineral oil) (2.52g,63.0mmol, wt.%: 60%) was suspended in tetrahydrofuran (200mL) and cooled to 0 ℃, a solution of (2S,3R,4S,5S,6R) -6- [ [ tert-butyl (dimethyl) silyl ] oxymethyl ]2- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxine-6-yl ] methyl ] phenyl ] -2-methoxy-tetrahydropyran-3, 4, 5-triol 27d (12.1g,19.4mmol) in tetrahydrofuran (60mL) was added dropwise and stirred for 20 minutes, benzyl bromide (7.0mL,59mmol) and tetrabutylammonium iodide (0.01g,0.03mmol) were added and the mixture was heated to 40 ℃ overnight and stirred. Cooled to 0 ℃, the reaction was quenched by dropwise addition of water (2mL), concentrated under reduced pressure, the residue was dissolved in ethyl acetate (200mL), washed with saturated brine (200mL × 2), and concentrated under reduced pressure to give the title compound 27e (20.0g, yellow oil), yield: 100 percent.

Step 6[ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2,3- Dihydro-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-6-methoxy-tetrahydropyran-2-yl]Methanol 27f

Tert-butyl-dimethyl- [ [ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methoxy ] silane 27e (20.0g,22.3mmol) was dissolved in tetrahydrofuran (200mL), a solution of tetrabutylammonium fluoride in tetrahydrofuran (90mL,90mmol,1.0M) was added, and the mixture was stirred at room temperature overnight. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate (150mL), washed with saturated brine (150mL × 2), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/5] to give title compound 27f (14.1g, yellow oil), yield: 81 percent.

Step 7[ (2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2,3- Dihydro-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-6-methoxy-tetrahydropyran-2-yl]Formaldehyde 27g

[ (2R,3R,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -6-methoxy-tetrahydropyran-2-yl ] methanol 27f (14.1g,18.0mmol) was dissolved in dichloromethane (200mL), saturated sodium bicarbonate solution (250mL) was added, the mixture cooled to 0 deg.C, potassium bromide (1.28g,10.8mmol) and 2,2,6, 6-tetramethylpiperidine-nitrogen-oxide (0.28g,1.79mmol) were added and stirred to dissolve, sodium hypochlorite solution (34mL, available chlorine 46.2mol, available chlorine 3.86%) was added and stirred for 10 minutes. The separated organic phase was washed with saturated brine (200mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 27g (14.7g, yellow oil) of the title compound, yield: 100 percent.

Step 8(2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2,3- Dihydro-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 27h

27g (14.7g,18.9mmol) of [ (2S,3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -6-methoxy-tetrahydropyran-2-yl ] carboxaldehyde (14.7g,18.9mmol) was dissolved in N, N-dimethylformamide (200mL,2.58mol), and a solution of formaldehyde (36mL,480mmol, wt.%: 37%) and 1, 8-diazabicycloundecene (1.8mL,12mmol) were added successively, and the mixture was stirred at room temperature for 42 hours. Water (500mL) was added for dilution, ethyl acetate (300mL × 2) was extracted, and the combined organic phases were washed with saturated brine (300mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound 27h (15.3g, pale yellow oil), yield: 100 percent.

Step 9[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-bis Hydrogen-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl]Methanol 27i

(2S,3S,4S,5R,6S) -3,4, 5-Tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-carbaldehyde 27h (15.3g,18.9mmol) was dissolved in tetrahydrofuran (40mL), methanol (160mL) was added, the mixture was cooled to 0 ℃, sodium borohydride (0.92g,24mmol) was added in portions, stirring was carried out for 20 minutes, concentration under reduced pressure was carried out, the residue was dissolved in ethyl acetate (100mL), washing with saturated brine (100mL), drying over anhydrous sodium sulfate, concentration under reduced pressure was carried out to give the title compound 27i (14.4g, yellow oil), yield: 94 percent.

Step 10[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]Methanol 27j

[ (3S,4S,5R,6S) -3,4, 5-tribenzyloxy-6- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -2- (hydroxymethyl) -6-methoxy-tetrahydropyran-2-yl ] -methanol 27i (14.4g,17.7mmol) was dissolved in tetrahydrofuran (200mL), p-toluenesulfonic acid monohydrate (6.92g,36.4mmol) was added, and the mixture was stirred at room temperature overnight. Concentrated under reduced pressure, and the residue was added with ethyl acetate (200mL), washed with saturated sodium bicarbonate solution (100mL) and saturated brine (100mL), concentrated under reduced pressure, and purified by silica gel column chromatography [ ethyl acetate/petroleum ether/(v/v) ═ 1/3] to give title compound 27j (8.8g, red oil), yield: and 64 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.44(s,1H),7.39-7.30(m,12H),7.22-7.14(m,3H),6.89(m,2H),6.80-6.70(m,2H),6.66(d,1H),4.87(m,3H),4.77(d,1H),4.28(m,4H),4.01(m,5H),3.89-3.75(m,3H),3.69(m,3H),3.58(m,4H),1.22(m,3H)。

Step 11(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodi Oxadin-6-yl]Methyl radical]Phenyl radical]-1- (hydroxymethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 27

[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 27j (0.35g,0.45mmol) was dissolved in tetrahydrofuran (4mL), methanol (12mL), 10% palladium on carbon (50mg,0.05mmol) and concentrated hydrochloric acid (0.2mL,2.4mmol) were added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. Suction filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (10mL), washed successively with saturated sodium bicarbonate solution (10mL) and saturated brine (10mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to give title compound 27(70mg, white solid), yield: 31 percent.

MS(ESI,pos.ion)m/z:509.5[M+H]⁺；

¹H NMR(400MHz,CDCl₃)δ(ppm):7.40(s,1H),7.26-7.17(m,2H),6.79-6.70(m,1H),6.67-6.58(m,2H),4.24-4.08(m,3H),4.02(m,1H),3.96-3.86(m,3H),3.85-3.67(m,3H),3.65-3.45(m,5H),3.40(m,1H),3.25(br s,4H),1.17(m,3H)。

Example 28(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1] octane-2, 3, 4-triol 28

Step 1(1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2,3- Dihydro-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 28a

[ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] methanol 27j (0.92g,1.2mmol) was dissolved in dichloromethane (20mL), dess-martin oxidant (3.1g,7.3mmol) was added, and the mixture was heated to 40 ℃ and stirred overnight. After washing with saturated sodium bicarbonate solution (20 mL. times.2) and saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the title compound 28a (1.31g, white solid) was obtained in the following yield: 100 percent. Directly used for the next reaction.

Step 2 methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ [3- (ethoxymethyl) - 2, 3-dihydro-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylate 28b

The crude product obtained in the previous step (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl)]Methyl radical]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-carboxylic acid 28a (1.31g,1.65mmol) was dissolved in methanol (11mL), and concentrated sulfuric acid (20mL) was added_μL,0.4mmol), the mixture was heated to 40 ℃ and stirred overnight. Concentrated under reduced pressure, the residue was dissolved in ethyl acetate (20mL), washed with saturated sodium bicarbonate solution (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether/(v/v) ═ 1/5]The title compound 28b (0.65g, light yellow oil) was obtained in yield: 49 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.48(s,1H),7.38-7.21(m,12H),7.21-7.14(m,3H),6.88(m,2H),6.81-6.68(m,2H),6.65(d,1H),4.85(q,2H),4.78(d,1H),4.63(d,1H),4.53(d,1H),4.29-4.13(m,5H),4.05-3.88(m,4H),3.88(d,1H),3.75(d,1H),3.71(s,3H),3.67-3.49(m,4H),1.22(m,3H).

Step 32- [ (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl]Methyl radical]Phenyl radical]-6, 8-dioxabicyclo [3.2.1]Octane-1-yl]-propan-2-ol 28c

Methyl (1S,2S,3S,4R,5S) -2,3, 4-tribenzyloxy-5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octane-1-carboxylate 28b (0.65g,0.80mmol) was dissolved in tetrahydrofuran (10mL) and cooled to 0 ℃, a solution of methyl magnesium bromide in diethyl ether (1.5mL,4.5mmol,3.0M) was added, and the mixture was allowed to stand at room temperature and stirred overnight. Cooled to 0 ℃, the reaction was quenched by dropwise addition of water (0.5mL), ethyl acetate (10mL) was added, washed successively with saturated ammonium chloride solution (10mL) and saturated brine (10mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ ethyl acetate/petroleum ether (v/v) ═ 1/5] to give title compound 28c (0.57g, white solid), yield: 88 percent.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.45(s,1H),7.43-7.15(m,15H),6.93(m,2H),6.81-6.71(m,2H),6.66(d,1H),5.07(d,1H),4.96(d,1H),4.77(d,2H),4.34(d,1H),4.30-4.18(m,3H),4.17-3.95(m,7H),3.82(d,1H),3.72(d,1H),3.66–3.52(m,4H),1.30(s,3H),1.27(s,3H),1.24–1.19(m,3H)。

Step 4(1S,2S,3S,4R,5S) -5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodi Oxadin-6-yl]Methyl phenyl]-1- (1-hydroxy-1-methyl-ethyl) -6, 8-dioxabicyclo [3.2.1]Octane-2, 3, 4-triol 28

2- [ (1S,2S,3S,4R,5S) -2,3, 4-Tribenzyloxy-5- [ 4-chloro-3- [ [3- (ethoxymethyl) -2, 3-dihydro-1, 4-benzodioxin-6-yl ] methyl ] phenyl ] -6, 8-dioxabicyclo [3.2.1] octan-1-yl ] -propan-2-ol 28c (0.57g,0.71mmol) was dissolved in tetrahydrofuran (4mL), methanol (12mL), 10% palladium on carbon (80mg,0.08mmol), and concentrated hydrochloric acid (0.3mL,3.6mmol) were added, and the mixture was stirred under a hydrogen atmosphere for 5 hours. Suction filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (10mL), washed successively with saturated sodium bicarbonate solution (10mL) and saturated brine (10mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ 100% ethyl acetate ] to afford title compound 28(0.19g, white solid), yield: 50 percent.

MS(ESI,neg.ion)m/z:581.5[M+HCOO]^-；

¹H NMR(400MHz,CD₃OD)δ(ppm):7.42(s,1H),7.35(s,2H),6.72(d,1H),6.65(m,2H),4.22(m,3H),4.03-3.93(m,4H),3.89(d,1H),3.70-3.59(m,3H),3.56(m,3H),1.32(s,3H),1.27(s,3H),1.18(t,3H)。

Test example

First, assay of SGLT2 and SGLT1 inhibitory Activity

The test purpose is as follows:

the following methods were used to determine the inhibitory activity of the compounds of the present invention on SGLT1 and SGLT 2.

Test materials:

¹⁴C-AMG solution was purchased from Perkinelmer, Cat. No. NEZ080001MC;

alpha-methyl glucoside was purchased from Sigma, Cat. No. M9376-100G;

N-methyl-D-glucosamine was purchased from Sigma, cat. No. m 2004-100G;

phlorizin was purchased from Sigma, cat.no. p 3449-1G;

96 well cell culture plates were purchased from Corning, Cat.No. 3903.

The test method comprises the following steps:

will be 3X 10⁴The Mock-transfected FIP-in CHO cells and CHO cells expressing the human SGLT1/SGLT2 gene were inoculated into 96 wells, respectively

A cell culture plate; after 12 hours of culture, 150. mu.L of sodium-free buffer was added to each well to wash the cells 1 time; 50. mu.L of a sodium-containing buffer solution containing the compound at a different concentration and 0.5. mu.M of¹⁴C]AMG and incubated for 1 hour at 37 ℃ in an incubator, 150 μ L of pre-cooled sodium-free buffer per well being added to stop the reaction; continuously washing the cells for 3 times by using a sodium-free buffer solution and removing residual liquid in the holes; add 20. mu.L of pre-cooled 100mM NaOH per well and shake for 5 minutes at 900 rpm; add 80. mu.L of scintillation fluid to each well, after shaking for 5 minutes at 600rpm, read the plate with a liquid scintillation device, the results are shown in Table 1:

note: "-" indicates not measured.

The test results show that: the compound has obvious inhibition effect on SGLT2 and better inhibition activity on SGLT 1. Second, oral glucose tolerance test and urine glucose excretion test

The purpose of the measurement is as follows:

the following methods were used to determine the effect of the compounds of the present invention on improving oral glucose tolerance and promoting urinary glucose excretion.

Test materials:

glucose: chengdu Kelong chemical reagent plant

A Roche biochemical analyzer: for urine glucose detection

Roche excellent blood sugar detector: for blood glucose testing

Test method 1:

weighing C57BL/6 mice after fasting for 15 hours overnight, detecting fasting blood glucose concentration, grouping according to weight and fasting blood glucose, then respectively administering corresponding test compound by single gavage to each administration group, wherein the administration dose is 1mg/kg, administering a solvent to a blank control group, detecting blood glucose value (blood glucose at 0) after 15min administration, immediately administering glucose (2.5g/kg) by single gavage to each group of mice after 0 blood glucose detection, taking blood by tail vein 15min, 30min, 60min and 120min after sugar administration, continuously detecting blood glucose concentration of C57BL/6 mice by a glucometer, and calculating blood glucose Area Under Curve (AUC) within 120min after sugar load_Glu _0-120min) The rate of decrease of (c).

After 120min of blood sugar detection is finished, each group of animals is respectively placed into a metabolism cage, urine of 2.25-6 hours and 6-24 hours after administration is collected by taking the metabolism cage as a unit, the urine volume of each time point is recorded, free diet and drinking water are obtained in the urine collection process, after urine is collected, supernatant is centrifuged, and the urine sugar concentration of C57BL/6 mice at each time point is detected by using a Roche full-automatic biochemical analyzer. The test results are shown in tables 2 and 3 below:

Test method 2:

male SD rats are weighed after being fasted for 15 hours at night, fasting blood glucose concentration is detected, the rats are grouped according to body weight and fasting blood glucose, then each administration group is respectively administered with corresponding test compound by single intragastric gavage, the administration dosage is 1mg/kg, a blank control group is administered with a solvent, the blood glucose value (blood glucose at 0 hour) is detected after administration for 30min, each group of mice immediately administered with blood glucose at 0 hour is administered with glucose (4.0g/kg) by single intragastric gavage, blood is taken by tail veins 15min, 30min and 60min after administration, a blood glucose meter continuously detects the blood glucose concentration of the SD rats, and the area under the blood glucose curve (AUC) within 60min after the glucose load is calculated_Glu _0-60min) The rate of decrease of (c).

After 60min of blood sugar detection is finished, each group of animals is respectively placed into a metabolism cage, urine of 1.5-24 hours and 24-48 hours after administration is collected by taking the metabolism cage as a unit, the urine volume of each time point is recorded, free diet and drinking water are obtained in the urine collection process, after the urine is collected, the supernatant is centrifuged, and the urine sugar concentration of C57BL/6 mice at each time point is detected by using a Roche full-automatic biochemical analyzer. The test results are shown in table 4 below:

table 2: the test result of the influence of the compound provided by the embodiment of the invention on the blood sugar of C57BL/6 mice

Example numbering	Administration dose (mg/kg)	Blood sugar lowering rate (%)
			Example 3	1	43.05
Example 5	1	36.87
			Example 7	1	21.38
Example 8	1	28.88

The test results show that: the compound of the invention has obvious effect on reducing blood sugar level.

Table 3: the compound provided by the embodiment of the invention has the test result of promoting the excretion of urine glucose to C57BL/6 mice at the dose of 1mg/kg

The test results show that: the compound of the present invention has a remarkable effect in promoting the excretion of urine glucose.

Table 4: test results of influence of compounds provided by the embodiment of the invention on SD rat blood sugar

Example numbering	Administration dose (mg/kg)	Blood sugar lowering rate (%)
			Example 11	1	37.59

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

1. A compound having a structure as shown in formula (I-a) or a pharmaceutically acceptable salt of the compound having the structure as shown in formula (I-a),

wherein R is¹Is H, D, F, Cl, Br, I, C₁-C₆Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₆Haloalkyl, C₁-C₄Haloalkoxy, C₁-C₄Alkylthio or C₃-C₆A cycloalkyl group;

each R²And R³Independently is C₁-C₆An alkyl group;

or R²、R³Together with the carbon atom to which they are attached form C₃-C₆A cycloalkyl group;

R⁴is-OR^4aor-SR^4c；

Each R^4aAnd R^4cIndependently H, D or C₁-C₆An alkyl group;

ring A is

X is-O-or-NR^7a-；

Y is-O-;

z is-CR^9a＝；

Each R^7aAnd R^9aIndependently H, D or C₁-C₆An alkyl group;

each R^10a、R^10b、R^10c、R^10d、R^11a、R^11b、R^12a、R^12bAnd R^12cIndependently is H, D, F, Cl, Br, I or C₁-C₆Alkyl, wherein each of said C₁-C₆Alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, nitro, C₁-C₆Alkyl, mercapto, C₁-C₄Hydroxyalkyl and C₁-C₄Substituted by a substituent of alkoxy;

2. The compound of claim 1, having a structure of formula (II-a) or a pharmaceutically acceptable salt of a compound of formula (II-a),

3. a compound according to any one of claims 1 or 2, wherein each R is²And R³Independently methyl, ethyl or propyl;

or R²、R³And together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl group.

4. A compound according to any one of claims 1 or 2, wherein R⁴is-OR^4aor-SR^4c；

Each R^4aAnd R^4cIndependently H, D, methyl, ethyl or propyl.

5. The compound according to any one of claims 1 or 2, wherein,

ring A is

R^7aH, D, methyl, ethyl or propyl;

each R^10a、R^10b、R^10c、R^10d、R^11a、R^11b、R^12a、R^12bAnd R^12cIndependently H, D, F, Cl, Br, I, methyl, ethyl, or propyl, wherein each of said methyl, ethyl, and propyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from D, F, Cl, Br, I, hydroxy, cyano, nitro, methyl, ethyl, propyl, mercapto, hydroxymethyl, methoxy, and ethoxy;

6. A compound according to any one of claims 1 or 2, wherein R¹Is H, D, F, Cl, Br, I, C₁-C₄Alkyl, methoxy, ethoxy, C₁-C₄Haloalkyl, C₁-C₂Haloalkoxy, cyclopropyl or cyclobutyl.

7. The compound according to any one of claims 1 or 2, wherein the compound has the structure of one of:

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, further comprising an additional therapeutic agent, wherein the additional therapeutic agent is selected from an antidiabetic agent other than SGLT2 inhibitors, an antihyperglycemic agent, an antiobesity agent, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic agent, a lipid-lowering agent, an anti-inflammatory agent, or a combination thereof.

10. The pharmaceutical composition of claim 9, wherein said antidiabetic agent other than SGLT2 inhibitor and said antihyperglycemic agent are each independently selected from biguanide agents, sulfonylurea agents, glucosidase inhibitors, PPAR agonists, α P2 inhibitors, PPAR α/γ dual activators, dipeptidyl peptidase IV inhibitors, glinide agents, insulin, glucagon-like peptide-1 inhibitors, PTP1B inhibitors, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, or combinations thereof, and said lipid lowering agent is selected from MTP inhibitors, HMGCoA reductase inhibitors, squalene synthase inhibitors, bebubonic hypolipidemic agents, ACAT inhibitors, lipoxygenase inhibitors, cholesterol absorption inhibitors, ileal sodium/bile acid cotransporter inhibitors, upregulators of LDL receptor activity, Nicotinic acid hypolipidemic agents, bile acid chelates, or combinations thereof; or the lipid-lowering drug is selected from pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin or combination thereof.

11. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 8 to 10 in the manufacture of a medicament for inhibiting SGLT2 or SGLT 1; or for increasing the level of high density lipoproteins; or for preventing or treating a disease, alleviating a symptom of the disease, or delaying the progression or onset of the disease, wherein the disease is diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, syndrome X, atherosclerosis, or hypertension.