TW201300394A - C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to C-aryl glucoside derivatives, preparation process and pharmaceutical use thereof, especially C-aryl glucoside derivatives presented by formula (I), pharmaceutical salts thereof or stereoisomers thereof, methods for their preparation, pharmaceutical compositions containing the same and their use as a therapeutic agent, especially use as drugs for treating diabetes and related diseases, in which each substituent group of formula (I) is defined in the specification.

Description

C-aryl glucoside derivative, preparation method thereof and application thereof in medicine

The present invention relates to a C-aryl glucoside derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, a process for producing the same, and a pharmaceutical composition containing the same, and as a pharmaceutical composition thereof Therapeutic agents are particularly useful as inhibitors of sodium-dependent glucose transporters (SGLTs).

In the early stages of diabetes treatment, diet control and exercise therapy are the preferred glycemic control programs. When these methods are difficult to control blood sugar, insulin or oral hypoglycemic drugs are needed for treatment. A variety of hypoglycemic drugs have been used for clinical treatment, including biguanide compounds, sulfonium urea compounds, insulin resistance improvers, and alpha-glucosidase inhibitors. However, these drugs cannot meet the needs of long-term treatment due to their different side effects. For example, biguanide compounds are prone to lactic acidosis; sulfonylureas cause hypoglycemia; insulin resistance improvers are prone to edema and heart failure, while alpha-glucosidase inhibitors cause abdominal pain, bloating, and diarrhea And other symptoms. In view of the above, people are eager to develop a new safer and more effective hypoglycemic agent to meet the therapeutic needs of diabetes.

The study found that the regulation of glucose transport by cells is mainly achieved by members of the two protein families, glucose-promoting protein (GLUTs) (passive transport) and sodium-dependent glucose co-transporters (SGLTs) (active transport). Among them, the members of the SGLTs family with glucose transport function are mainly distributed in the proximal tubules of the intestines and kidneys, and it is inferred that they play a key role in the absorption of intestinal glucose and the reuptake of renal glucose, thus It is one of the ideal potential targets for the treatment of diabetes.

Specifically, the family member SGLT-1 protein is mainly distributed in the intestinal mucosal cells of the small intestine, and is also slightly expressed in the myocardium and kidney. It mainly cooperates with GLUTs protein to regulate the intestinal absorption process of glucose. Another member, SGLT-2, is responsible for the regulation of the glucose kidney reuptake process because of its high level of expression in the kidney. That is, the glucose in the urine can actively attach to the renal tubular epithelial cells when it is filtered through the glomerulus. It is re-utilized by SGLT-2 protein transport into the cell. In this process, SGLT-2 is responsible for 90% of the resorption process, and the remaining 10% is done by SGLT-1. The theory that SGLT-2 is the main transporter has been further confirmed in animal experiments. Inhibition of renal glucose reuptake in rats was achieved by inhibiting SGLT-2 mRNA levels in rat renal cortical cells using specific SGLT-2 antisense oligonucleotides. Based on these findings, it can be inferred that if a SGLTs (SGLT-1/SGLT-2) protein inhibitor is developed, by regulating its glucose transport function, on the one hand, it can control the absorption of intestinal glucose, on the other hand, it can inhibit Re-uptake of renal glucose, strengthen the discharge of glucose from the urine, play a more systematic hypoglycemic effect, and thus become an ideal drug for the treatment of diabetes.

In addition, the study found that SGLTs protein inhibitors can be used for the treatment of diabetes-related complications. Such as retinopathy, neuropathy, kidney disease, insulin resistance caused by glucose metabolism disorders, hyperinsulinemia, hyperlipidemia, obesity and so on. At the same time, SGLTs protein inhibitors can also be used in combination with existing therapeutic drugs, such as sulfonamide, thiazolidinedione, metformin and insulin, to reduce the dose without affecting the efficacy, thereby avoiding or reducing adverse reactions. The occurrence of the patient's compliance with the treatment.

In summary, SGLTs protein inhibitors, especially SGLT-2 protein inhibitors, have good prospects for development as new therapeutic drugs for diabetes. Although a series of patents relating to the use of C-aryl glucosides and their derivatives as inhibitors of SGLT-2 protein such as CN1989132A, CN1671682A, CN1829729A and WO2010023594A1 have been disclosed, there is still a need to develop therapeutic effects and drug metabolism properties. Better, safer compounds are used in the treatment of diabetes and related metabolic disorders. Through continuous efforts, the present invention discloses a compound having a structure represented by the general formula (I), and has found that a compound having such a structure exhibits an excellent SGLT-2 protein inhibitory effect and a hypoglycemic action.

The object of the present invention is to provide a compound represented by the formula (I), and their tautomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and before metabolism. Body or prodrug.

Wherein: Ring A is selected from aryl or heteroaryl, wherein each of the aryl or heteroaryl is independently further optionally one or more selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle. Base, aryl, heteroaryl, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR Substituted by a substituent of ⁸ R ⁹ wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group may each independently be further optionally one or more selected from the group consisting of a halogen atom, a halogen, an alkenyl group, Alkynyl, nitro, cyano, alkoxy, cycloalkyl, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R Substituted with a substituent of ⁹ or -C(O)NR ⁸ R ⁹ ; each of R ¹ , R ² , R ³ or R ^{4 is} independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amine group, an alkyl group, and an alkyl group. An oxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently further optionally one by one Or substituted with a plurality of substituents selected from the group consisting of a halogen atom, a halogen, a hydroxyl group, an amine group, an alkyl group, an alkoxy group, a carboxylic acid or a carboxylic acid ester; or , R ² and R ³ may be fused to a phenyl group to form a ring which is optionally a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein a cycloalkyl group, a heterocyclic group, an aryl group or The heteroaryl groups are each independently optionally one or more selected from the group consisting of halogen, hydroxy, amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl. Substituting a substituent of a carboxylic acid or a carboxylic acid ester; provided that when ring A is a phenyl group, R ² , R ³ and R ⁴ are a hydrogen atom, and R ^{1 is} selected from a hydrogen atom, a C _1-4 alkyl group, F , Cl, cyano or -OR ¹⁰ when the ring a can be selected from a C _1-4 alkyl, F., Cl, cyano, hydroxy, -OR ^11, F a C _1-2 substituted alkyl, -S (O) ₂ R ¹¹ , C _3-6 cycloalkyl, substituted with a substituent of 1-2 N, O or S C _5-6 saturated heterocyclic groups; R ⁵ and R ⁶ are each independently selected from a hydrogen atom or a halogen atom; R ^{7 is} selected from a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or The heteroaryl groups may each independently be further optionally one or more selected from the group consisting of a halogen atom, an alkyl group, and a halogen. Substituted with a substituent of a hydroxyl group, an amino group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a cycloalkoxy group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ⁸ or R ⁹ are each independently selected From a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently further optionally one by one Or substituted with a plurality of substituents selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amine group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or, R ⁸ Or R ⁹ forms a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group is further optionally one or more Substituted by a substituent selected from alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid; R ¹⁰ is C _1-4 alkyl ; R ^{11 is} selected from C _1-4 alkyl, ; and m is 0, 1, or 2.

A preferred embodiment of the invention, a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, which comprises a compound of the formula (II) or a pharmaceutically acceptable salt thereof:

Wherein ring A, R ¹ to R ⁶ are as defined in formula (I).

A preferred embodiment of the invention, a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the ring A is an aryl group, wherein the aryl group is further further one or more One selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ , wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is each independently further optionally One or more selected from the group consisting of a halogen atom, a halogen, an alkenyl group, an alkynyl group, a nitro group, a cyano group, an alkoxy group, a cycloalkyl group, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ^{7, -C (O) oR 7} , -NR 8 R 9 or -C (O) NR ⁸ R ^9, substituted by a substituent.

A preferred embodiment of the invention, a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the ring A is an aryl group, wherein the aryl group is further further one or more One selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ , wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is each independently further optionally One or more selected from the group consisting of a halogen atom, a halogen, an alkenyl group, an alkynyl group, a nitro group, a cyano group, an alkoxy group, a cycloalkyl group, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ^{7, -C (O) oR 7} , -NR 8 R 9 or -C (O) NR ⁸ R ⁹ being substituted with a substituent; R ^2, R ³ or R ⁴ are each independently a hydrogen atom; and R ¹ is halogen.

A preferred embodiment of the invention, a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the ring A is a phenyl group, wherein the phenyl group is further further 1 to 5 as needed Substituted by a substituent selected from halogen or -OR ⁷ ; R ⁷ is an alkyl group, wherein the alkyl group may be further substituted by 1 to 3 substituents selected from a halogen atom, a halogen, an alkoxy group or a cycloalkoxy group. Replace.

A preferred embodiment of the invention, a compound of the formula (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the ring A is a heteroaryl group, wherein the heteroaryl group may be optionally one Or a plurality selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , —C(O)OR ⁷ , —NR ⁸ R ⁹ or —C(O)NR ⁸ R ⁹ , wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently required Further one or more selected from the group consisting of a halogen atom, a halogen, an alkenyl group, an alkynyl group, a nitro group, a cyano group, an alkoxy group, a cycloalkyl group, -OR ⁷ , -S(O) _m R ⁷ , -C(O Substituting a substituent of R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

A preferred embodiment of the invention, a compound of the formula (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the ring A is a heteroaryl group, wherein the heteroaryl group is optionally one or A plurality selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ , wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group are each independently further optionally One or more selected from the group consisting of a halogen atom, a halogen, an alkenyl group, an alkynyl group, a nitro group, a cyano group, an alkoxy group, a cycloalkyl group, -OR ⁷ , -S(O) _m R ⁷ , -C(O) Substituents of R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ are substituted; R ² , R ³ or R ⁴ are each independently a hydrogen atom; R ¹ is halogen.

A preferred embodiment of the invention, a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the ring A is Or thienyl.

A preferred embodiment of the invention, a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the ring A is optionally selected from one or more selected from the group consisting of aryl halides or Substituted by a substituent of OR ⁷ wherein the aryl group is further optionally substituted with one or more halogens; provided that ring A is substituted with a substituent of -OR ⁷ wherein R ⁷ is C _1-4 In the case of an alkyl group, ring A must be substituted at the same time by one or more halogens.

A preferred embodiment of the invention is a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R ⁵ or R ⁶ is a halogen atom.

A preferred embodiment of the invention, a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R ⁷ is an alkyl group, wherein the alkyl group is further selected from one or more selected from the group consisting of hydrazine Substituted by an atomic substituent.

The compounds of the formula (I) may contain asymmetric carbon atoms and may therefore exist in the form of optically pure diastereomers, diastereomeric mixtures, diastereomeric racemates, mixtures of diastereomeric racemates. Or exist as a meso compound. The invention includes all of these forms. Mixtures of diastereomeric mixtures, diastereomeric racemates or diastereomeric racemates can be separated by conventional methods, for example by column chromatography, thin layer chromatography and HPLC.

Preferred compounds of the formula (I) of the present invention include, but are not limited to:

Or a pharmaceutically acceptable salt thereof or all stereoisomers thereof.

The invention relates to a process for the preparation of a compound of the formula (I), which process comprises:

Converting a compound of formula (IA) to a compound of formula (IB);

Deprotection of a compound of formula (IB) further provides a compound of formula (I); wherein: R ¹ to R ⁶ and ring A are as defined in formula (I); X, Y is a hydroxy protecting group It is preferably an alkyl group or a benzyl group.

The invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or all stereoisomers thereof, for the preparation of a sodium-dependent glucose transporter inhibitor.

Further, the present invention relates to the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or all stereoisomers thereof, for the manufacture of a medicament for the treatment or delay of the development or onset of a disease selected from the group consisting of Diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia , X syndrome, diabetic complications or atherosclerosis or hypertension.

The invention also relates to a treatment for diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, A method of hypertriglyceridemia, X syndrome, diabetic complications, or atherosclerosis or hypertension, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof Or a stereoisomer thereof.

The present invention also relates to a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, as a medicament for treating or delaying the progression or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetes Sexual neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications Or atherosclerosis or high blood pressure.

Still further, the invention relates to a pharmaceutical composition comprising an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or all stereoisomers thereof, and a pharmaceutically acceptable carrier. The use of the pharmaceutical composition for the preparation of a medicament for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, Hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, or atherosclerosis or hypertension.

The invention also relates to a treatment for diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, A method of hypertriglyceridemia, X syndrome, diabetic complications, or atherosclerosis or hypertension, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a pharmaceutical composition of formula (I).

The present invention also relates to a pharmaceutical composition comprising the general formula (I) as a medicament for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance Sexual, hyperglycemic, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications or atherosclerosis or hypertension.

Detailed description of the invention

Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

"Alkyl" means a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group preferably having 1 to 12 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, and t-butyl groups. , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2 ,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3 - dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl , 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl 2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl , and its various branched isomers. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Second butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methyl Butyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2 - dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4- Methyl amyl, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl. , alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy , heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

"Cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises 3 Up to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

"Spirocycloalkyl" means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include

"Fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more Two double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5 member/5 member or 5 member/6 member bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include

"Bridge cycloalkyl" refers to 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The π-electron system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, heterocycloalkylthio, oxo, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

"Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) _m ( Wherein m is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains from 3 to 10 ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like. Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups. "Spirocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, sharing a single atom (called a spiro atom) between the monocyclic rings, wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O) _p The hetero atom (where p is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a dispiroheterocyclic group or a polyspiroheterocyclic group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include

"Fused heterocyclyl" refers to 5 to 20 members, each ring in the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more a bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _p (where p is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member double ring heterogeneous Ring base. Non-limiting examples of fused heterocyclic groups include

"Bridge heterocyclyl" refers to a 5 to 14 member, any two rings sharing two polycyclic heterocyclic groups of atoms that are not directly bonded, these may contain one or more double bonds, but none of the rings are fully conjugated A π-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:

Wait. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, heterocycloalkylthio, oxo, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

"Aryl" means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms), a polycyclic ring having a conjugated π-electron system (ie, having adjacent pairs) The ring of a carbon atom is preferably a 6 to 10 member such as a phenyl group and a naphthyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O )NR ⁸ R ⁹ .

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 5 to 10 members. The heteroaryl group is preferably 5 or 6 members such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, heterocycloalkylthio, oxo, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ .

"Alkoxy" means -O-(alkyl) wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy groups. , alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , cycloalkylthio, heterocycloalkylthio, oxo, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ Or -C(O)NR ⁸ R ⁹ .

"Cycloalkoxy" refers to -O-(unsubstituted cycloalkyl) wherein cycloalkyl is as defined above. Non-limiting examples include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy groups. , alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy , cycloalkylthio, heterocycloalkylthio, oxo, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ Or -C(O)NR ⁸ R ⁹ .

"Hydroxy" refers to an -OH group.

"Halogen" means fluoro, chloro, bromo or iodo.

"Amino" means -NH _2.

"Cyano" means -CN.

"Nitro" means -NO ₂ .

"Benzyl" refers to -CH ₂ - phenyl.

"Oxo group" means =0.

"Carboxylic acid" means -C(O)OH.

"Carboxylic acid ester" means -C(O)O(alkyl) or (cycloalkyl).

"Thienyl" means .

"As needed" or "as needed" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group. situation.

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active ingredient to exert biological activity.

"X Syndrome", also known as the disease, disease and condition of metabolic syndrome, is described in Johannsson J. Clin. Endocrinol. Metab., 1997; 82, 727-734.

m and R ⁷ to R ⁹ are as defined in the compound of the formula (I).

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

The preparation method of the compound of the formula (I) or a pharmaceutically acceptable salt thereof or all the stereoisomers thereof of the present invention comprises the following steps:

The compound a is reacted with a decane reagent under basic conditions to obtain a decyl-protected compound b, and the compound b is sequentially added with sodium hydride and benzyl bromide in an alkaline reagent to obtain a benzyl-protected compound c, a compound c. In a methanol solution, reacting with hydrazine chloride to remove the hydrazine protecting group to obtain hydroxy compound d, compound d is oxidized to obtain aldehyde compound e, and compound e is reacted with sodium hydroxide in formaldehyde solution to obtain bishydroxy compound f, compound (IA) Reaction with trifluoroacetic acid to give compound (IB), which is hydrogenated under palladium on carbon catalysis to remove the benzyl protecting group to give the compound of formula (I).

Wherein: R ¹ to R ⁶ are as defined in the formula (I); and X and Y are a protecting group for a hydroxyl group, preferably an alkyl group or a benzyl group.

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl hydrazine (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four. Methyl decane (TMS).

The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

HPLC measurements were performed using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatography (Gimini C18 150 x 4.6 mm chromatography column).

The thin layer chromatography tantalum sheet uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet, and the thin layer chromatography (TLC) used for the tantalum sheet is 0.15mm to 0.2mm. The specification for thin layer chromatography separation and purification is 0.4. Mm to 0.5mm.

Pipe column chromatography generally uses Yantai Huanghai Silicone 200 to 300 mesh silicone as a carrier.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.

Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere or an argon atmosphere.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature.

The room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and the volume ratio of the solvent was based on the compound. Adjust with different polarity.

The system for the eluent of the column chromatography and the developer system for the thin layer chromatography using the purified compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, the volume ratio of the solvent is based on the compound The polarity is adjusted differently, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.

Example 1 (1 S , 2 S , 3 S , 4 R , 5 R )-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]benzene 1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

first step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[4 -[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol

(2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl] Phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 1a (prepared by the known method "WO2010022313") (3.0 g, 6.06 mmol) Dissolved in 20 mL of pyridine, and then added 4-dimethylaminopyridine (148 mg, 1.21 mmol) and tert-butyldimethylchloromethane (1.1 g, 7.27 mmol), and reacted for 16 hours. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The title compound (2 S , 3 R , 4 S , 5 S , 6 R )-6 was obtained. -[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]- Phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 1b (3.0 g, yellow solid), yield: 81.1%.

¹ H NMR (400 MHz, CD ₃ OD): δ 7.50 (dd, 1H), 7.38 (m, 2H), 7.08 (d, 2H), 6.82 (d, 2H), 4.04 (m, 5H), 3.88 (m, 1H), 3.82 (m, 2H), 3.75 (m, 1H), 3.59 (m, 1H), 3.40 (m, 2H), 3.07 (m, 1H), 3.06 (s, 3H), 0.90 ( s, 9H), 0.53 (m, 4H), 0.10 (s, 3H), 0.07 (s, 3H).

Second step [[(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy) Ethyl]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]t-butyldimethyl decane

(2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[ 4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 1b (3.0 g, 4.92 Ment) dissolved in 50 mL of N,N-dimethylformamide, cooled to 0 ° C, added 60% sodium hydride (984 mg, 24.6 mmol), added to room temperature for 15 minutes, added benzyl bromide ( 2.95 mL, 24.6 mmol), reacted for 16 hours. 5 mL of methanol was added, and the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The title product [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-() Propoxy)ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyldimethyloxane 1c (4.26 g, Yellow oil), used directly in the next reaction without isolation.

third step [(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy) Ethoxy]phenyl]methoxy]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol

The crude product [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-() Propoxy)ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]t-butyldimethylmethane 1c (4.26 g, 4.92 mmol) was dissolved in 30 mL of methanol, and acetonitrile (52 μL, 0.74 mmol) was added and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5 -tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methoxy]phenyl]-6-methoxy-tetra Hydropyran-2-yl]methanol 1d (2.3 g, yellow oil), yield: 62.2%.

¹ H NM R (400 MHz, CDCl ₃ ): δ 7.35 (m, 13H), 7.20 (m, 3H), 7.03 (m, 4H), 6.80 (d, 2H), 4.92 (m, 3H), 4.70 (m, 1H), 4.50 (m, 1H), 4.17 (m, 1H), 4.05 (m, 3H), 3.85 (m, 6H), 3.70 (m, 2H), 3.40 (m, 1H), 3.30 ( m, 1H), 3.07 (s, 3H), 0.63 (m, 2H), 0.48 (m, 2H).

the fourth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)) Ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde

The grass chloroform (0.19 mL, 2.2 mmol) was dissolved in 10 mL of dichloromethane, cooled to -78 ° C, and then 5 mL of dimethyl hydrazine in dichloromethane and 10 mL [(2 R , 3 R , 4) were added dropwise. S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]- A solution of oxy]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 1d (1.3 g, 1.7 mmol) in dichloromethane was reacted at -78 ° C for 30 min. 1.18 mL, 8.5 mmol), and added to room temperature for 1-2 hours. Was added 10mL 1M hydrochloric acid solution, and liquid separation, the organic phase is washed with saturated sodium chloride solution (10 mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title product (2 S, 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy] Phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 1e (1.3 g, colorless oil) was used in the next step without isolation.

MS m/z (ESI): 780.3 [M+18]

the fifth step [(3 S ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy) Phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol

The crude product (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy) Ethyl]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 1e (1.3 g, 1.7 mmol) was dissolved in 15 mL of 1,4-dioxane, added 37 A solution of formaldehyde (2.6 mL, 34 mmol) was dissolved in 5.1 mL of water, and the mixture was added dropwise to the reaction mixture, and reacted at 70 ° C for 4 hours and at 50 ° C for 16 hours. Add 20 mL of a saturated sodium chloride solution, and extract with ethyl acetate (20 mL × 3). The organic phase is washed sequentially with saturated sodium hydrogen carbonate solution (20 mL), washed with saturated sodium chloride solution (20 mL), Dry, filter and concentrate the filtrate under reduced pressure. A mixed solution of 20 mL of tetrahydrofuran and methanol (v: v = 1:1) was added to the residue, and sodium borohydride (130 mg, 3.4 mmol) was added and reacted for 30 minutes. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product [(3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4 -Chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran 2-yl]methanol 1f (320 mg, colorless oil), yield: 23.7%.

Step 6 [(1 S , 2 S , 3 S , 4 R , 5 R )-2,3,4-Tribenzyloxy-5-[4-chloro-3-[[4-[2-(cyclopropoxy) Ethoxy]phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol

[(3 S ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)) Oxy]phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 1f (320 mg, 0.4 mmol) was dissolved in 10 mL of dichloromethane The mixture was cooled to -10 ° C, and trifluoroacetic acid (62 mL, 0.8 mmol) was added and reacted for 1 hour. After adding 10 mL of a saturated sodium hydrogencarbonate solution, the mixture was separated, the aqueous phase was extracted with dichloromethane (10 mL), and the organic phase was washed with saturated sodium chloride (10 mL). , column chromatography using silica gel in the eluent system B resulting residue, to give the title product [(1 S, 2 S, 3 S, 4 R, 5 R) -2,3,4- three benzyloxy -5-[4-Chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1 ] octyl-1-yl]methanol 1 g (230 mg, colorless oil), yield: 75.3%.

MS m/z (ESI): 780.3 [M+18]

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.33 (m, 12H), 7.15 (m, 4H), 7.05 (m, 2H), 6.86 (d, 2H), 6.76 (d, 2H), 4.77 ( m, 4H), 4.27 (m, 2H), 4.00 (m, 6H), 3.83 (m, 3H), 3.70 (m, 4H), 3.38 (m, 1H), 0.63 (m, 2H), 0.48 (m) , 2H).

Seventh step (1 S , 2 S , 3 S , 4 R , 5 R )-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]benzene 1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

[(1 S , 2 S , 3 S , 4 R , 5 R )-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-[2-(cyclopropoxy) Ethyl]phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 1 g (220.3 mg, 0.29 mmol) dissolved in 10 mL of tetrahydrofuran a mixed solution with methanol (v: v = 1:1), 1,2-dichlorobenzene (0.34 mL, 3 mmol) and palladium/carbon (90 mg, 10%) were added, and the hydrogen was replaced three times, reacted for 3 hours, and filtered. The filtrate was concentrated under reduced pressure, column chromatography using silica gel A to the resulting residue was purified eluent system, to give the title product (1 S, 2 S, 3 S, 4 R, 5 R) -5- [4- chloro - 3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1 Octane-2,3,4-triol 1 (140 mg, white solid), yield: 100%.

MS m/z (ESI): 510.2 [M+18] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.45 (d, 1H), 7.36 (m, 2H), 7.10 (d, 2H), 6.82 (m, 2H), 4.14 (d, 1H), 4.05 (m, 4H), 3.83 (m, 3H), 3.78 (m, 1H), 3.66 (m, 2H), 3.57 (m, 2H), 3.40 ( m, 1H), 0.56 (m, 2H), 0.48 (m, 2H).

Example 2 (1 R , 2 R , 3 S , 4 S , 5 S )-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl] Phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

First step (5-bromo-2-chloro-phenyl)-(2,3-difluoro-4-methoxy-phenyl)one 5-bromo-2-chloro-benzoguanidine chloride 2a (7.22 g, 28.45 mmol) and 1,2-difluoro-3-methoxy-benzene 2b (prepared according to CN2003468A) (4.1 g, 28.45 mmol) dissolved in 50 mL of dichloromethane, cooled to 0 ° C, batch Aluminum trichloride (3.4 g, 25.6 mmol) was added and the reaction was carried out for 16 hours. Add 20 mL of 1 M hydrochloric acid, separate the liquid, extract with dichloromethane (50 mL×2), wash the organic phase with saturated sodium carbonate solution (50 mL), wash with saturated sodium chloride solution (50 mL), dried, filtered, and the filtrate was concentrated under reduced pressure to give the title product (5-bromo-2-chloro - phenyl) - (2,3-difluoro-4-methoxy - phenyl) ketone 2c (5.1g, as a yellow solid ), yield: 49.5%. MS m/z (ESI): 362.9 [M+18]

The second step (5-bromo-2-chloro-phenyl)-(2,3-difluoro-4-methoxy-phenyl)methanol (5-bromo-2-chloro-phenyl)-(2 , 3-difluoro-4-methoxy-phenyl)one 2c (5.1 g, 14.1 mmol) was dissolved in 40 mL of a mixed solution of tetrahydrofuran and methanol (v: v = 1:1), and cooled to 0 ° C. Sodium borohydride (1.07 g, 28.2 mmol) was added in portions and allowed to react for 30 min. After adding 10 mL of acetone, the reaction mixture was concentrated under reduced pressure. The residue was evaporated, evaporated, evaporated, evaporated Product (5-Bromo-2-chloro-phenyl)-(2,3-difluoro-4-methoxy-phenyl)methanol 2d (5.1 g, yellow oil).

The third step 1-[(5-bromo-2-chloro-phenyl)methyl]-2,3-difluoro-4-methoxy-benzene (5-bromo-2-chloro-phenyl)- (2,3-Difluoro-4-methoxy-phenyl)methanol 2d (5.1 g, 14.1 mmol) was dissolved in 40 mL of dichloromethane, and triethyl decane (6.75 mL, 42.3 mmol) was added dropwise. Boron fluoride ether (3.57 mL, 28.2 mmol) was reacted for 16 hours. Add 20 mL of saturated sodium carbonate solution, separate the liquid, and extract the aqueous phase with dichloromethane (20 mL×3). The organic phase is combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue was purified to give the title compound 1-[(5-bromo-2-chloro-phenyl)methyl]-2,3-difluoro-4-methoxy-benzene 2e (3.55 g, white solid ), yield: 72.4%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.36-7.33 (m, 1H), 7.30-7.27 (m, 2H), 6.81-6.79 (m, 1H), 6.73-6.69 (m, 1H), 4.00 (s, 2H), 3.92 (s, 3H).

The fourth step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl] Phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 1-[(5-bromo-2-chloro-phenyl)methyl] -2,3-Difluoro-4-methoxy-benzene 2e (3.55 g, 10.2 mmol) was dissolved in 30 mL of a mixed solution of tetrahydrofuran and toluene (v:v = 1:2), cooled to -78 ° C, and dropped. Add n-hexane solution of n-butyllithium (4.9 mL, 12.26 mmol), react at -78 ° C for 1 hour, add 30M1 (3 R , 4 S , 5 R , 6 R )-3,4,5-three (three Methyl decyloxy)-6-(trimethyldecyloxymethyl)tetrahydropyran-2-one 2f (prepared according to patent document WO2010048358) (5.24 g, 11.22 mmol) in toluene solution, at - After reacting at 78 ° C for 3 hours, 30 mL of saturated sodium carbonate solution was added, and the reaction mixture was concentrated under reduced pressure. To the residue was added 30 mL of saturated sodium chloride solution, ethyl acetate (50 mL×3), dried, filtered, and the filtrate was concentrated under reduced pressure, column chromatography using silica gel A to the resulting residue was purified eluent system, to give the title product (2 S, 3 R, 4 S, 5 S, 6 R) -2- [ 4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl) 2-methoxy-tetrahydropyran-3,4,5-triol 2 g (1.31 g, white solid), yield: 27.9%. MS m/z (E S I): 429.1 [M-31]

The fifth step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl] Phenyl]-2-methoxy-6-(trimethyldecyloxymethyl)tetrahydropyran-3,4,5-triol (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy - tetrahydropyran-3,4,5-triol 2 g (1.31 g, 2.84 mmol) was dissolved in 15 mL of pyridine, followed by 4-dimethylaminopyridine (70 mg, 0.57 mmol) and trimethylchloromethane ( 514 mg, 3.4 mmol), reacted for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Filtration and concentrating the filtrate under reduced pressure afforded the title product ( 2S , 3R , 4S , 5S , 6R )-2-[4-chloro-3-[(2,3-difluoro-4-methoxy) -phenyl)methyl]phenyl]-2-methoxy-6-(trimethyldecyloxymethyl)tetrahydropyran-3,4,5-triol 2h (1.63g, pale yellow solid ), yield: 100%.

The sixth step [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro) 4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]trimethylnonane (2 S ,3 R ,4 S ,5 S ,6 R )-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-methoxy-6- (Trimethyldecyloxymethyl)tetrahydropyran-3,4,5-triol 2h (1.63g, 2.84mmol) was dissolved in 30mL of N,N-dimethylformamide and cooled to 0°C 60% sodium hydride (570 mg, 14.2 mmol) was added, and the reaction was allowed to warm to room temperature for 45 minutes, and benzyl bromide (1.7 mL, 14.2 mmol) was added, and the reaction was added overnight. 5 mL of methanol was added, and the reaction mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title product [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro)] 4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]trimethylnonane 2i (2.4 g, yellow oil) , Yield: 100%.

The seventh step [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-) 4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol [[(2 R , 3 R , 4 S , 5 R , 6 S -3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-A Oxy-tetrahydropyran-2-yl]methoxy]trimethylnonane 2i (2.4 g, 2.84 mmol) was dissolved in 20 mL of methanol, and ethyl acetate (30 μL, 0.43 mmol) was added and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5 -tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran 2-yl]methanol 2j (1.25 g, yellow solid), yield: 60.4%.

The eighth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4) -Methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde Dissolve the grass chloroform in 5 mL of dichloromethane, cool to -78 ° C, add 3 mL Dimethylhydrazine (0.26 mL, 3.59 mmol) in dichloromethane, reacted for 15 minutes, and added 5 mL [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-three Benzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2 A solution of methanol 2j (1.25 g, 1.71 mmol) in dichloromethane was reacted for 40 min, triethylamine (1.19 mL, 8.55 mmol) was added dropwise, and the mixture was allowed to react to room temperature for 1.5 hours. The reaction solution was washed with 5mL 1M hydrochloric acid, the organic phase was collected, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S, 5 R, 6 S) -3,4,5- Tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran- 2-Formaldehyde 2k (1.24 g, yellow solid) was used in the next step without isolation.

The ninth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro 4- Methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6 -Methoxy-tetrahydropyran-2-carbaldehyde 2k (1.24 g, 1.71 mmol) was dissolved in 15 mL of 1,4-dioxane, followed by the addition of 37% to 40% aqueous formaldehyde (2.8 mL, 34.2 mmol) It was reacted with 1.5 mL of sodium hydroxide solution (205 mg, 5.13 mmol) at 70 ° C overnight. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. to give the title product (2 S, 3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4-chloro-3 - [(2,3-difluoro - 4-methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 2m (1.29 g, yellow oil), It was directly used for the next reaction by separation.

The tenth step [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-benzene) Methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol (2 S , 3 S , 4 S , 5 R , 6 S ) -3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-(hydroxyl) 6-methoxy-tetrahydropyran-2-carbaldehyde 2m (1.29 g, 1.71 mmol) was dissolved in a mixed solution of 15 mL of tetrahydrofuran and methanol (v: v = 1:2), and sodium borohydride was added. 129 mg, 3.42 mmol), reacted for 20 minutes. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj column chromatography with silica gel to purify the resultant residue was eluent B system, to give the title product [(3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [ 4-Chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran- 2-Base]methanol 2n (520 mg, white solid), yield: 40%.

The eleventh step [(1 R , 2 R , 3 S , 4 S , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro) 4-(methoxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol [[3 S ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]- 2-(Hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 2n (500 mg, 0.66 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (0.2 mL, 2. ), the reaction was 1.5 hours. The reaction mixture was washed with EtOAc EtOAc (EtOAc m. [(1 R , 2 R , 3 S , 4 S , 5 S )-2,3,4-Tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methyl) Oxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 2p (360 mg, white solid), yield: 75.3%. MS m/z (ESI): 746.2 [M+18]

Step 12 (1 R , 2 R , 3 S , 4 S , 5 S )-5-[4-Chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl ]Phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol will [(1 R , 2 R , 3 S , 4 S ,5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl a mixed solution of 6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 2p (350 mg, 0.48 mmol) dissolved in 10 mL of tetrahydrofuran and methanol (v: v = 1:1) Among them, o-dichlorobenzene (0.55 mL, 4.8 mmol) and palladium/carbon (300 mg, 10%) were successively added, and hydrogen was replaced three times for 3 hours. The title compound (1 R , 2 R , 3 S , 4 S , 5 S )-5-[ 4-Chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2 .1] Octane-2,3,4-triol 2 (210 mg, white solid), yield: 95.5%. MS m/z (ESI): 459.1 [M+1] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.42 (m, 3H), 6.81 (m, 2H), 4.16 (d, 1H), 4.10 (s, 2H), 3.87 (s, 3H), 3.82 (m, 2H), 3.68 (m, 2H), 3.55 (m, 1H), 3.61 (m, 1H).

Example 3 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl] Phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

The first step 1-ethoxy-2,-difluoro-benzene 2,3-difluorophenol 3a (4 g, 30.7 mmol) was dissolved in 60 mL of acetone, followed by potassium carbonate (6.36 g, 46.1 mmol) and Iodoethane (3.19 mL, 39.9 mmol) was reacted at 70 ° C for 5 hours. The reaction mixture was filtered, and the filtrate was evaporated.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The title product 1-ethoxy-2,3-difluoro-benzene 3b (4.82 g, yellow oil) was obtained, yield: 99.4%. ¹ H NMR (400 MHz, CDC1 ₃ ): δ 6.95-6.89 (m, 1H), 6.78-6.71 (m, 1H), 4.12 (q, 2H), 1.45 (t, 3H)

The second step (5-bromo-2-chloro-phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanone 5-bromo-2-chloro-benzoguanidine chloride 2a ( 7.74 g, 30.5 mmol) was dissolved in 200 mL of dichloromethane, and 1-ethoxy-2,3-difluoro-benzene 3b (4.82 g, 30.5 mmol) and aluminum trichloride (4.07 g, 30.5 mmol) were added. , the reaction was carried out for 16 hours. After adding 100 mL of a 2M hydrochloric acid solution, the mixture was separated, and the organic phase was washed with EtOAc (EtOAc) -Phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanone 3c (8.0 g, yellow oil), yield: 70.2%. MS m/z (ESI): 376.9 [M+1]

The third step (5-bromo-2-chloro-phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanol (5-bromo-2-chloro-phenyl)-(4 -Ethoxy-2,3-difluoro-phenyl)methanone 3c (8.0 g, 21.3 mmol) was dissolved in a mixed solution of 240 mL of methanol and tetrahydrofuran (v:v = 2:1), and boron was added in an ice bath. Potassium hydride (1.73 g, 32.0 mmol) was reacted at room temperature for 16 hours. 50 mL of a 1 M hydrochloric acid solution was added, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Chloro-phenyl)-(4-ethoxy-2,3-difluoro-phenyl)methanol 3d (8.0 g, yellow oil) was used for the next step without isolation.

The fourth step 1-[(5-bromo-2-chloro-phenyl)methyl]-4-ethoxy-2,3-difluoro-benzene (5-bromo-2-chloro-phenyl)- (4-Ethoxy-2,3-difluoro-phenyl)methanol 3d (8.0g, 21.2mmol) was dissolved in 150mL of a mixed solution of acetonitrile and dichloromethane (v:v=2:1), added three Ethyl decane (10.1 mL, 63.6 mmol) and boron trifluoride diethyl ether (5.3 mL, 42.4 mmol) were reacted for 3 hours. 100 mL of 2M potassium hydroxide solution was added, and the combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. 5-Bromo-2-chloro-phenyl)methyl]-4-ethoxy-2,3-difluoro-benzene 3e (5.5 g, white solid), yield: 72.4%. MS m / z (ESI): 360.5 [M + 1] 1 H NMR (400 MHz, CDCl 3): δ 7.36-7.27 (m, 3H), 6.81-6.76 (dd, 1H), 6.72-6.68 (dd, 1H), 4.17-4.13 (q, 2H), 4.10 (s, 2H), 1.50-1.47 (t, 3H)

The fifth step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl] Phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 1-[(5-bromo-2-chloro-phenyl)methyl] -4-Ethoxy-2,3-difluoro-benzene 3e (5.5 g, 15.3 mmol) was dissolved in 20 mL of tetrahydrofuran, cooled to -78 ° C, and n-hexane solution of n-butyllithium (7.3 mL, 18.3). Methyl), react at -78 ° C for 1 hour, control temperature -78 ° C, add 30 mL (3 R , 4 S , 5 R , 6 R )-3,4,5-tris(trimethyldecyloxy)- 6-(Trimethyldecyloxymethyl)tetrahydropyran-2-one 2f (7.5 g, 16.1 mmol) in tetrahydrofuran, reacted at -78 ° C for 2 hours, then added 51 mL of 0.6 M methanesulfonic acid in methanol The reaction was carried out at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue obtained was purified to give the title product ( 2S , 3R , 4S , 5S , 6R )-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-benzene Methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 3f (3.05 g, white solid), yield: 45.5% .

The sixth step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3- [(4-Ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol (2 S ,3 R , 4 S , 5 S , 6 R ) -2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-(hydroxyl Methyl)-2-methoxy-tetrahydropyran-3,4,5-triol 3f (3.0 g, 6.8 mmol) was dissolved in 30 mL of pyridine, followed by 4-dimethylaminopyridine (166 mg, 1.36). Methyl) and tert-butyldimethylchloromethane (1.23 g, 8.2 mmol) were reacted for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Product (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[( 3-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 3 g (3.75 g, white solid) , Yield: 99.7%.

The seventh step [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-) 2,3-Difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy] tert-butyl-dimethyl-decane (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxy) Base-2,3-difluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 3 g (3.75 g, 6.8 mmol) dissolved in 30 mL of N To N-dimethylformamide, 60% sodium hydride (1.36 g, 34 mmol) was added at 0 ° C, and reacted at room temperature for 45 minutes, followed by the addition of tetrabutylammonium iodide (125 mg, 0.34 mmol) and bromine. Benzyl (4.01 mL, 34 mmol) was reacted at room temperature for 16 hours. After adding 10 mL of methanol, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The product [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2, 3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy] tert-butyl-dimethyl-decane 3h (4.2g, colorless Oil), Yield: 75.0%.

The eighth step [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2) ,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol [[(2 R , 3 R , 4 S , 5 R , 6 S -3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-A Oxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-decane 3h (4.7 g, 5.46 mmol) was dissolved in 50 mL of methanol and ethyl acetate (80 mg, 0.82 mmol) It was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5 -tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran 2-yl]methanol 3i (2.5 g, yellow oil), yield: 61.4%.

The ninth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2, 3-Difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde oxalic acid chloride (0.37 mL, 4.37 mmol) was dissolved in 20 mL of dichloromethane and cooled to -78 ° C, 10 mL of dimethyl hydrazine (0.5 mL, 7.05 mmol) in dichloromethane was added dropwise, 20 mL [(2 R , 3 R , 4 S , 5 R , 6S)-3,4,5- Tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran- A solution of 2-yl]methanol 3i (2.5 g, 3.36 mmol) in methylene chloride was reacted at -78 ° C for 30 min, and triethylamine (2.33 mL, 16.8 mmol) was added and allowed to react at room temperature for 16 hours. Was added 15mL 1M hydrochloric acid solution, and liquid separation, the organic phase is washed with saturated sodium chloride solution (20 mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl) Methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 3j (2.4 g, yellow oil), yield: 96.0%.

The tenth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2, 3-Difluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde (2 S , 3 S , 4 S , 5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]- 6-Methoxy-tetrahydropyran-2-carbaldehyde 3j (2.4 g, 3.23 mmol) was dissolved in 20 mL of 1,4-dioxane, and 5 mL of 37% formaldehyde solution and 13 mL of 1 M sodium hydroxide solution were added. The reaction was carried out at 70 ° C for 21 hours. Was added 20mL of saturated sodium chloride solution, and extracted with ethyl acetate (50mL × 3), combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S, 5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]- 2-(Hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 3k (1.6 g, yellow oil), yield: 64.0%.

The eleventh step [(3 S ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3) -difluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol (2 S ,3 S ,4 S ,5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl] 2-(Hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 3k (1.6 g, 2.1 mmol) dissolved in 35 mL of tetrahydrofuran and methanol (v:v=2:5) mixed solvent Sodium borohydride (78 mg, 4.2 mmol) was added and the mixture was reacted for 2 hours. The reaction solution was concentrated under reduced pressure, column chromatography with silica gel and the obtained residue was purified B eluent system, to give the title product [(3 S, 4 S, 5 R, 6 S) -3,4,5- tribenzyl Oxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy - tetrahydropyran-2-yl]methanol 3 m (1.0 g, yellow oil), yield: 62.5%.

The twelfth step [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-) 2,3-Difluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol [[3 S ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]- 2-(Hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 3 m (1.0 g, 1.29 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (0.19 mL, 2.58 mmol) ), reacted for 4 hours. The reaction solution was concentrated, dried under reduced pressure to silica gel column chromatography eluent systems B resulting residue, to give the title product [(1 S, 2 S, 3 S, 4 R, 5 S) -2,3,4 -tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[ 3.2.1] Octane-1-yl]methanol 3n (500 mg, yellow oil), yield: 52.1%. MS m/z (ESI): 760.3 [M + 18] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.37-7.30 (m, 13H), 7.23-7.18 (m, 3H), 6.91-6.89 ( m, 2H), 6.68 (dd, 1H), 6.55 (dd, 1H), 4.93-4.90 (m, 2H), 4.79-4.56 (m, 4H), 4.30-4.28 (m, 2H), 4.18-4.05 ( m,4H),3.83-3.49(m,5H),1.33(t,3H)

Step 13 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl ]Phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol will [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl -6,8-Dioxabicyclo[3.2.1]octane-1-yl]methanol 3n (550 mg, 0.74 mmol) dissolved in 20 mL of tetrahydrofuran and methanol (v: v = 1:1) Among them, o-dichlorobenzene (0.84 mL, 7.4 mmol) and palladium/carbon (300 mg, 10%) were added, and hydrogen was replaced three times for 3 hours. To the reaction mixture was added a small amount of ethyl acetate, filtered, the filtrate was concentrated under reduced pressure, column chromatography using silica gel A to the resulting residue was purified eluent system, to give the title product (1 S, 2 S, 3 S, 4 R ,5 S )-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8 - Dioxabicyclo[3.2.1]octane-2,3,4-triol 3 (160 mg, white solid), yield: 45.7%. MS m/z (ESI): 472.2 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.43-7.37 (m, 3H), 6.80-6.76 (m, 2H), 4.16-4.07 (m) , 5H), 3.85-3.70 (m, 2H), 3.70-3.51 (m, 4H), 1.34 (t, 3H)

Example 4 (1 S , 2 S , 3 S , 4R, 5 S )-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]- 1-(Hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

First Step 1-Ethoxy-2-Fluoro-Benzene 2-Fluorophenol 4a (6.7 g, 60 mmol) was dissolved in 66 mL of acetone, ethyl iodide (6.3 mL, 78 mmol) and potassium carbonate (12.4 g, 90 mmol) The reaction was refluxed for 5 hours in an oil bath. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjl 1-ethoxy-2-fluoro-benzene 4b (6.9 g, red oil), yield: 82.1%. MS m/z (ESI): 280.2 [2M+1]

The second step (5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanone 5-bromo-2-chloro-benzoguanidine chloride 2a (12.4 g, 48.8 mmol) was dissolved in 100 mL of dichloromethane, 1-ethoxy-2-fluoro-benzene 4b (6.84 g, 48.8 mmol) was added, cooled to 0 ° C, and added aluminum trichloride (5.86 g, 44 mmol). ), the reaction was carried out for 16 hours. 20 mL of 2M hydrochloric acid solution was added dropwise to the reaction mixture under ice-cooling, and the mixture was evaporated. 2-Chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanone 4c (12.7 g, yellow solid), yield: 72.6%. MS m/z (ESI): 358.9 [M+1]

The third step (5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanol (5-bromo-2-chloro-phenyl)-(4-ethoxy Base-3-fluoro-phenyl)methanone 4c (12.7 g, 35.5 mmol) was dissolved in 100 mL of a mixed solvent of tetrahydrofuran and methanol (v: v = 1:1), and sodium borohydride (2.68) was added portionwise in an ice bath. g, 70 mmol), react at room temperature for 30 minutes. After adding 15 mL of acetone, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The title product (5-bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanol 4d (12.7 g, orange oil) was obtained. One step reaction.

The fourth step 4-[(5-bromo-2-chloro-phenyl)methyl]-1-ethoxy-2-fluoro-benzene (5-bromo-2-chloro-phenyl)-(4- Ethoxy-3-fluoro-phenyl)methanol 4d (12.7g, 35.3mmol) was dissolved in 100mL of dichloromethane, triethyl decane (16.9mL, 106mmol) was added, and boron trifluoride etherate (8.95mL) was added dropwise. , 70.6 mmol), reacted for 3 hours. After adding 50 mL of a saturated sodium hydrogencarbonate solution, the mixture was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×2), and the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The resulting residue was purified to give the title product 4-[(5-bromo-2-chloro-phenyl)methyl]-1-ethoxy-2-fluoro-benzene 4e (10 g, pale yellow oil ), yield: 82.4%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.33 - 7.27 (m, 3H), 6.95-6.90 (m, 3H), 4.14 (q, 2H), 4.01 (s, 2H), 1.49 (t, 3H) )

The fifth step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl] -6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 4-[(5-bromo-2-chloro-phenyl)methyl]-1- Ethoxy-2-fluoro-benzene 4e (7.36g, 21.4mmol) was dissolved in 30mL of tetrahydrofuran, cooled to -78 ° C, n-hexane solution of n-butyllithium (10.27mL, 25.7mmol) was added dropwise, at -78 The reaction was carried out at ° C for 1 hour, and 20 mL of (3 R , 4 S , 5 R , 6 R )-3,4,5-tris(trimethyldecyloxy)-6-(trimethyldecyloxymethyl) was added dropwise. A solution of tetrahydropyran-2-one 2f (11 g, 23.6 mmol) in tetrahydrofuran was reacted at -78 °C for 2 hours, and 2.8 mL of methanesulfonic acid and 71 mL of methanol were added and reacted at room temperature for 16 hours. After adding 100 mL of a saturated sodium carbonate solution, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The filtrate by silica gel column chromatography eluent A to the resulting residue system, to give the title product (2 S, 3 R, 4 S, 5 S, 6 R) -2- [4- chloro-3- [ (4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 4f ( 5.7 g, white solid), yield: 58.3%. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.56 (s, 1H), 7.48 (dd, 1H), 7.37 (dd, 1H), 6.95-6.87 (m, 3H), 4.08-4.07 (m, 4H), 3.91 (m, 1H), 3.93-3.73 (m, 2H), 3.56-3.53 (m, 1H), 3.45-3.43 (m, 1H), 3.30 (s, 2H), 3.08 (s, 3H) , 1.35 (t, 3H)

The sixth step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3- [(4-Ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol (2 S ,3 R ,4 S ,5 S ,6 R )-2-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2- Methoxy-tetrahydropyran-3,4,5-triol 4f (5.7 g, 12.5 mmol) was dissolved in 50 mL of pyridine, followed by the addition of tert-butyldimethylchloromethane (2.26 g, 15 mmol) and 4 Dimethylaminopyridine (305 mg, 2.5 mmol) was reacted for 16 hours. The reaction solution was concentrated under reduced pressure, was added 200mL ethyl acetate, washed with saturated copper sulfate solution (50mL × 3) and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 R, 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxy-3- Fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 4g (7.14g, colorless oil), used in the next step without isolation reaction.

The seventh step [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-) 3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyldecane (2 S ,3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxy-3) -Fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 4 g (7.14 g, 12.5 mmol) dissolved in 100 mL of N,N-dimethyl To the methamine, 60% sodium hydride (2.5 g, 62.5 mmol) was added under ice-cooling, and the mixture was reacted at room temperature for 40 minutes, and benzyl bromide (7.5 mL, 62.5 mmol) was added and reacted for 16 hours. Add 20 mL of methanol, concentrate the reaction mixture under reduced pressure, add 200 mL of ethyl acetate and 50 mL of water to dissolve the residue, and separate the residue. The mixture is extracted with ethyl acetate (50 mL). The organic phase is washed with water (50 mL) (50 mL), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product [[(2 R, 3 R , 4 S, 5 R, 6 S) -3,4,5- tribenzyl Oxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]- Oxy]-tert-butyl-dimethyldecane 4h (10.5 g, yellow oil), yield: 99.8%.

The eighth step [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3) -Fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol [[(2 R , 3 R , 4 S , 5 R , 6 S )-3 ,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyridyl Silan-2-yl]methoxy]-tert-butyl-dimethyldecane 4h (10.52g, 12.5mmol) was dissolved in 50mL of methanol, and ethyl acetate (0.13mL, 1.9mmol) was added dropwise for 1 hour. . The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5 -tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2- Methanol] 4i (7.6 g, yellow oil), yield: 83.6%.

The ninth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3- Fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde. Lysoquinone chloride (1.17 mL, 13.6 mmol) was dissolved in 20 mL dichloromethane and cooled to -78 ° C. , 20 mL of dimethyl hydrazine (1.56 mL, 21.9 mmol) in dichloromethane and 50 mL of [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy] 6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 4i A solution of (7.6 g, 10.45 mmol) in methylene chloride was reacted at -78 ° C for 30 min, then triethylamine (7.25 mL, 52.3 mmol) was added and allowed to react at room temperature for 2 hours. 50 mL of 1 M hydrochloric acid solution was added, and the organic layer was washed with a saturated sodium chloride solution (50 mL×2), and the aqueous phase was extracted with dichloromethane (50 mL). The filtrate, to give the title product (2 S, 3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4-chloro-3 - [(4-ethoxy - 3-Fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 4j (7.58 g, colorless oil) was used for the next step without isolation.

Step 10 (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3- Fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde (2 S , 3 S , 4 S , 5 R , 6 S -3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy- Tetrahydropyran-2-carbaldehyde 4j (7.6 g, 10.45 mmol) was dissolved in 80 mL of 1,4-dioxane, followed by 15.8 mL of 37% aqueous formaldehyde solution and sodium hydroxide solution (31.35 mL, 31.35 mmol). The reaction was carried out at 70 ° C for 16 hours. Add 50 mL of a saturated sodium chloride solution, and extract with ethyl acetate (50 mL×4). The organic phase is washed with saturated sodium hydrogen carbonate (50 mL) , filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4-chloro-3 - [( 4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 4k (7.9 g, colorless oil ()), used directly in the next reaction without separation.

The eleventh step [(3 S ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro) -Phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxyl) 6-methoxy-tetrahydropyran-2-carbaldehyde 4k (7.9 g, 10.45 mmol) was dissolved in 50 mL of a mixed solvent of tetrahydrofuran and methanol (v:v = 2:3), and sodium borohydride was added. 794 mg, 20.9 mmol), reacted for 30 minutes. Small amount of acetone was added, the reaction was concentrated under reduced pressure, column chromatography using silica gel A to the resulting residue was purified eluent system, to give the title product [(3 S, 4 S, 5 R, 6 S) -3,4, 5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy Base-tetrahydropyran-2-yl]methanol 4 m (1.11 g, colorless oil), yield: 14.1%.

The twelfth step [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-) 3-(fluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol [[3 S ,4 S ,5 R ,6 S -3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl) 6-Methoxy-tetrahydropyran-2-yl]methanol 4m (1.11g, 1.46mmol) was dissolved in 20mL of dichloromethane, cooled to -10 ° C, then added trifluoroacetic acid (0.23mL, 3mmol) The reaction was carried out at room temperature for 2 hours. After adding 20 mL of a saturated sodium hydrogencarbonate solution, the mixture was separated and the aqueous phase was extracted with dichloromethane (20 mL×2). The organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified initiator system B, to give the title product [(1 S, 2 S, 3 S, 4 R, 5 S) -2,3,4- three-benzyloxy-5- [4-chloro-3- [ (4-Ethoxy-3-fluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 4n (830 mg, colorless oil ()), yield: 78.3%. MS m/z (ESI): 742.3 [M+18]

Step 13 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl ]-1-(Hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol will [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6,8- Dioxabicyclo[3.2.1]octane-1-yl]methanol 4n (830 mg, 1.14 mmol) was dissolved in 20 mL of a mixed solvent of tetrahydrofuran and methanol (v: v = 1:1), and o-dichlorobenzene was added. (1.3 mL, 11.4 mmol) and palladium on carbon (500 mg, 10%) were replaced with hydrogen three times for 3 hours. The reaction solution was filtered, rinsed with a small amount of ethyl acetate, and the filtrate was concentrated under reduced pressure, column chromatography using silica gel A to the resulting residue was purified eluent system, to give the title product (1 S, 2 S, 3 S, 4 R ,5 S )-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxo Heterobicyclo[3.2.1]octane-2,3,4-triol 4 (420 mg, white solid), yield: 81.0%. MS m/z (ESI): 472.2 [M+18] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.47 (s, 1H), 7.42-7.35 (m, 2H), 6.95-6.87 (m, 3H), 4.16-4.14 (m, 1H), 4.06-4.02 (m, 4H), 3.85-3.70 (m, 2H), 3.67-3.54 (m, 4H), 1.37 (t, 3H)

Example 5 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]- 1-(Hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

The first step (5-bromo-2-chloro-phenyl)-(2,3-dihydrobenzofuran-5-yl)methanone 5-bromo-2-chloro-benzoguanidine chloride 2a (10.8 g , 42.5 mmol) was dissolved in 100 mL of dichloromethane, 2,3-dihydrobenzofuran 5a (5.I1g, 42.5 mmol) was added, and aluminum trichloride (6.8 g, 51.0 mmol) was added in portions for 2 hours. . The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjj -5-yl)methanone 5b (10.47 g, white solid), yield: 72.9%. MS m / z (ESI): 339.0 [M + 1] 1 H NMR (400 MHz, CDCl 3): δ 7.73 (d, 1H), 7.58 (dd, 1H), 7.53 (dd, 1H), 7.47 (d , 1H), 7.32 (d, 1H), 6.81 (d, 1H), 4.68 (t, 2H), 3.26 (t, 2H)

The second step (5-bromo-2-chloro-phenyl)-(2,3-dihydrobenzofuran-5-yl)methanol (5-bromo-2-chloro-phenyl)-(2,3 -Dihydrobenzofuran-5-yl)methanone 5b (10.47 g, 31.0 mmol) was dissolved in 100 mL of a mixed solvent of tetrahydrofuran and methanol (v: v = 1:1), cooled to 0 ° C, and boron was added in portions. Sodium hydride (2.35 g, 62.0 mmol) was reacted at 0 ° C for 30 min. After adding 20 mL of acetone, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. (5-Bromo-2-chloro-phenyl)-(2,3-dihydrobenzofuran-5-yl)methanol 5c (10.5 g,yield of pale yellow oil). ¹ H NMR (400 MHz, CDC1 ₃ ): δ 7.88 (d, 1H), 7.34 (dd, 1H), 7.18 (d, 1H), 7.16 (s, 1H), 7.11 (dd, 1H), 6.73 ( d, 1H), 6.05 (s, 1H), 4.56 (t, 2H), 3.18 (t, 2H), 2.27 (s, 1H)

The third step is 5-[(5-bromo-2-chloro-phenyl)methyl]-2,3-dihydrobenzofuran (5-bromo-2-chloro-phenyl)-(2,3- Dihydrobenzofuran-5-yl)methanol 5c (10.5 g, 30.9 mmol) was dissolved in 100 mL of dichloromethane, triethyl decane (14.8 mL, 92.7 mmol) was added, and boron trifluoride diethyl ether (7.8 mL) was added dropwise. , 61.8 mmol), reacted for 16 hours. The reaction mixture was concentrated under reduced pressure and purified mjjjjjjjlili Dihydrobenzofuran 5d (10.0 g, pale yellow oil), yield: 100%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.29-7.21 (m, 3H), 7.00 (s, 1H), 6.93 (d, 1H), 6.73 (d, 1H), 4.56 (t, 2H), 3.98(s,2H), 3.18(t,2H)

The fourth step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]- 6-(Hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 5-[(5-bromo-2-chloro-phenyl)methyl]-2,3 -Dihydrobenzofuran 5d (10.0 g, 30.9 mmol) was dissolved in a mixed solvent of 90 mL of tetrahydrofuran and toluene (v:v = 1:2), cooled to -78 ° C, and n-hexane solution of n-butyllithium was added dropwise. (14.83 mL, 37.1 mmol), reacted at -78 ° C for 1 hour, and added 90 mL (3 R , 4 S , 5 R , 6 R )-3,4,5-tris(trimethyldecyloxy)-6 dropwise. -(Trimethylmethoxymethyl)tetrahydropyran-2-one 2f (15.87 g, 33.9 mmol) in toluene, reacted at -78 ° C for 3 hours, and added 103 mL of 0.6 M methanesulfonic acid in methanol. The reaction was carried out for 16 hours at room temperature. After adding 100 mL of a saturated sodium carbonate solution, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Column chromatography to purify the residue obtained in eluent system E to give the title product ( 2S , 3R , 4S , 5S , 6R )-2-[4-chloro-3-(2,3- Dihydrobenzofuran-5-ylmethyl)phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 5e (6.3 g, white solid ), yield: 46.7%. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.53 (d, 1H), 7.45 (dd, 1H), 7.35 (d, 1H), 7.03 (s, 1H), 6.91 (d, 1H), 6.60 (d,1H), 4.48(t,2H), 4.13-3.91(m,3H),3.84-3.73(m,2H),3.61-3.56(m,1H),3.44-3.39(m,1H),3.11 (dd, 3H), 3.07 (s, 3H)

The fifth step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3- (2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol (2 S ,3 R ,4 S ,5 S ,6 R )-2-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-(hydroxymethyl)-2-methoxy Base-tetrahydropyran-3,4,5-triol 5e (6.3 g, 14.44 mmol) was dissolved in 60 mL of pyridine, followed by 4-dimethylaminopyridine (353 mg, 2.89 mmol) and tert-butyl Methylchlorodecane (2.61 g, 17.32 mmol) was reacted for 16 hours. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The filtrate gave the title product ( 2S , 3R , 4S , 5S , 6R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro- 3-(2,3-Dihydrobenzofuran-5-ylmethyl)phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 5f (7.96 g, pale yellow solid ), used directly in the next reaction without separation.

The sixth step [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzene) And furan-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyloxane (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-(2,3-dihydrobenzofuran) -5-ylmethyl)phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 5f (7.96 g, 14.4 mmol) was dissolved in 80 mL of N,N-dimethylformamidine The amine was cooled to 0 ° C, 60% sodium hydride (2.89 g, 72.21 mmol) was added, and the mixture was reacted for 15 minutes at room temperature, and benzyl bromide (8.58 mL, 72.21 mmol) was added and reacted for 16 hours. 10mL of methanol was added, the reaction solution was concentrated under reduced pressure, was added 200mL ethyl acetate, washed with water (50mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product [[(2 R, 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)benzene 6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyldecane 5g (11.86g, black oil), used directly without isolation One step reaction.

The seventh step [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzo) Furan-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol [[(2 R , 3 R , 4 S , 5 R , 6 S )-3, 4,5-Tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran- 2-Gytyl]methoxy]-tert-butyl-dimethyldecane 5 g (11.86 g , 14.4 mmol) was dissolved in 100 mL of methanol, and ethyl acetate (152 μL, 2.17 mmol) was added and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to D resulting residue was purified eluent system, to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5 -tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-yl Methanol 5 h (9.0 g, yellow liquid), yield: 88.1%.

Step 8 (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran) -5-Methylmethyl)phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde. The hydrazine chloride (0.76 mL, 8.91 mmol) was dissolved in 10 mL dichloromethane and cooled to -78 °C. A mixed solution of 10 mL of dichloromethane and dimethyl hydrazine (v: v = 10: 0.85) was added dropwise, and the reaction was carried out for 15 minutes, and 25 mL of [(2 R , 3 R , 4 S , 5 R , 6 S )-3 was added dropwise. ,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydropyran A solution of 2-yl]methanol in 5h (4.2 g, 5.94 mmol) in methylene chloride was reacted for 40 min, and triethylamine (4.29 mL, 29.69 mmol) was added dropwise and allowed to react at room temperature for 2 hours. Was added 35mL 1M hydrochloric acid solution, and liquid separation, the organic phase is washed with saturated sodium chloride solution (35mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl ]-6-Methoxy-tetrahydropyran-2-carbaldehyde 5i (4.19 g, light yellow oil) was used for the next reaction without isolation.

The ninth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran) -5-ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde (2 S , 3 S , 4 S , 5 R , 6 S ) -3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6-methoxy-tetrahydro Pyran-2-carbaldehyde 5i (4.19g, 5.9mmol) was dissolved in 45mL of 1,4-dioxane, 9.6mL of 37% formaldehyde solution was added, 17.82mL of 1M sodium hydroxide solution was added dropwise, and the reaction was carried out at 70 °C. 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The filtrate, to give the title product (2 S, 3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4-chloro-3- (2,3-dihydrobenzo And furan-5-ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 5j (4.36 g, yellow oil), without isolation Used for the next reaction.

The tenth step [(3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5 -ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol (2 S , 3 S , 4 S , 5 R , 6 S ) -3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-(hydroxymethyl)- 6-Methoxy-tetrahydropyran-2-carbaldehyde 5j (4.36 g, 5.93 mmol) was dissolved in 50 mL of a mixed solvent of tetrahydrofuran and methanol (v: v = 1:1), and sodium borohydride (0.45) was added in portions. g, 11.9 mmol), react for 30 minutes. The reaction solution was concentrated under reduced pressure, column chromatography with silica gel and the obtained residue was purified D eluent system, to give the title product [(3 S, 4 S, 5 R, 6 S) -3,4,5- tribenzyl Oxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyridyl M--2-yl]methanol 5k (1.26 g, white solid), yield: 28.8%. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.53 (dd, 1H), 7.44 (d, 1H), 7.35 (d, 1H), 7.31-7.26 (m, 5H), 7.25-7.18 (m, 8H), 7.04-7.02 (m, 2H), 6.90 (s, 1H), 6.80 (d, 1H), 6.54 (d, 1H), 4.90-4.79 (m, 4H), 4.73 (d, 1H), 4.54 (d,1H), 4.46-4.41 (m, 2H), 4.20 (t, 1H), 4.10-4.00 (m, 5H), 3.88 (dd, 2H), 3.74 (d, 1H), 3.15 (s, 3H) ), 3.06-3.00 (m, 2H)

The eleventh step [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-(2,3-dihydrobenzene And furan-5-ylmethyl)phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol [[3 S ,4 S ,5 R ,6 S ) -3,4,5-tribenzyloxy-6-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-2-(hydroxymethyl)- 6-Methoxy-tetrahydropyran-2-yl]methanol 5k (1.2 g, 1.63 mmol) was dissolved in dichloromethane (25 mL), and trifluoroacetic acid (0.5 mL, 6. The reaction solution was concentrated, dried under reduced pressure to silica gel column chromatography eluent systems D resulting residue, to give the title product [(1 S, 2 S, 3 S, 4 R, 5 S) -2,3,4 -tribenzyloxy-5-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6,8-dioxabicyclo[3.2.1] Octane-1-yl]methanol 5m (580 mg, white solid), yield: 50.4%. M S m/z (E S I): 722.3 [M+18] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.48-7.39 (m, 3H), 7.35-7.23 (m, 10H), 7.21. -7.11(m,3H), 6.97(s,1H), 6.90(d,1H), 6.84(d,2H),6.57(d,1H),4.83(d,4H),4.44(t,2H), 4.23 (m, 2H), 4.07-4.00 (m, 3H), 3.95 (dd, 1H), 3.87 (d, 1H), 3.79 (d, 1H), 3.73-3.69 (m, 2H), 3.56 (d, 1H), 3.01 (t, 2H)

The twelfth step (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl] 1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [[1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-6,8-dioxo Heterobicyclo[3.2.1]octane-1-yl]methanol 5m (100mg, 0.14mmol) was dissolved in a mixed solvent of 5mL of tetrahydrofuran and methanol (v:v=1:1), followed by o-dichlorobenzene ( 208 mg, 1.42 mmol) and palladium on carbon (10 mg, 10%) were replaced with hydrogen three times for 1.5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (1 S, 2 S, 3 S, 4 R, 5 S) -5- [4- Chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane- 2,3,4-triol 5 (58 mg, white solid), yield: 93.5%. MS m/z (ESI): 435.1 [M+1] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.47 (d, 1H), 7.39-7.35 (m, 2H), 7.04 (s, 1H) , 6.93 (d, 1H), 6.62 (d, 1H), 4.50 (t, 2H), 4.17 (d, 1H), 4.03 (s, 2H), 3.88-3.79 (m, 2H), 3.71-3.65 (m , 2H), 3.62-3.56 (m, 2H), 3.15 (t, 2H)

Example 6 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-(2,3-dihydrobenzofuran-5-ylmethyl)phenyl]- 1-(Hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

First step 5-bromo-2-chloro-N-methoxy-N-methyl-benzamide The N-methyl-N-methoxyamine hydrochloride (3.41 g, 35 mmol) was dissolved in 140 mL Triethylamine (14.6 mL, 105 mmol) was added to dichloromethane, and the reaction was carried out for 10 minutes, followed by the addition of 5-bromo-2-chloro-benzoic acid 6a (8.24 g, 35 mmol) and bis(2-oxoyl-3-) Oxazolidinylphosphinium chloride (10.69 g, 42 mmol) was reacted for 16 hours. After adding 120 mL of water, it was extracted with ethyl acetate (80 mL × 3), and the organic phase was washed with saturated sodium chloride (60 mL). method B in the resulting residue was purified eluent system, to give the title product 5-bromo-2-chloro -N- methoxy -N- methyl - benzoyl-amine 6b (7.50g, pale yellow solid), yield : 76.9%. MS m/z (ESI): 280.0 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.46-7.44 (m, 2H), 7.29-7.26 (m, 1H), 3.49 (s, 3H) ), 3.37(s, 3H)

The second step 1-bromo-4-(trifluoromethoxy)benzene Trifluoromethoxybenzene 6c (11.35 g, 70 mmol) was dissolved in 3.57 mL of liquid bromine, 0.24 g of iron was added, and reacted at 100 ° C for 16 hours. . After adding 450 mL of dichloromethane, the organic phase was washed successively with 6M hydrochloric acid (140 mL), 10% sodium hydrogensulfite solution (140 mL) and saturated sodium chloride solution (140 mL). The filtrate was concentrated to give the title product, 1-bromo-4-(trifluoromethoxy)benzene 6d (14.1 g,yel. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.54 - 7.50 (m, 2H), 7.11-7.09 (m, 2H)

The third step 1-magnesium bromide-4-(trifluoromethoxy)benzene Magnesium (0.12g, 5mmol) and catalytic amount of iodine were placed in the reaction flask, and 5mL 1-bromo-4-(trifluoro) was added dropwise A solution of methoxy)benzene 6d (1.2 g, 5 mmol) in tetrahydrofuran was refluxed for 1 hour. The title product 1-magnesium bromide-4-(trifluoromethoxy)benzene 6e (1.32 g) was obtained.

The fourth step (5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanone 5-bromo-2-chloro-N-methoxy-N-methyl - Benzylamine 6b (5.16 g, 18.5 mmol) was dissolved in 50 mL of tetrahydrofuran, and 1-Bromomagnesium bromide-4-(trifluoromethoxy)benzene 6e (13.21 g, 49.8 mmol) was added dropwise for 2 hours. . After adding 200 mL of a saturated sodium chloride solution, 200 mL of water and 150 mL of ethyl acetate, the mixture was separated, the aqueous phase was extracted with ethyl acetate (150 mL), and the organic phase was washed with saturated sodium chloride solution (200 mL). The title compound (5-bromo-2-chloro-phenyl)-[4-(trifluoromethyl) was obtained after purification. Oxy)phenyl]methanone 6f (4.08 g, pale yellow solid), yield: 58.1%. MS m/z (ESI): 380.9 [M+1] ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.78-7.84 (m, 2H), 7.58 (dd, 1H), 7.51 (d, 1H), 7.35 (d, 1H), 7.32-7.30 (m, 2H)

The fifth step (5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanol (5-bromo-2-chloro-phenyl)-[4-(trifluoro Methoxy)phenyl]methanone 6f (4.35 g, 11.5 mmol) was dissolved in 40 mL of a mixed solvent of tetrahydrofuran and methanol (v: v = 1:1), cooled to 0 ° C, and sodium borohydride (0.87) was added portionwise. g, 23.0 mmol), reacted at 0 ° C for 30 minutes. Add 10 mL of acetone, concentrate the reaction mixture under reduced pressure, add 100 mL of ethyl acetate and 50 mL of water, and separate the mixture. The organic phase is washed with saturated sodium chloride solution (50 mL×2). The filtrate was concentrated to give the title product (5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanol 6 g (4.4 g, pale yellow oil). In the next step. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.80 (d, 1H), 7.43-7.40 (m, 2H), 7.36 (dd, 1H), 7.20 (t, 3H), 6.16 (s, 1H)

The sixth step 4-bromo-1-chloro-2-[[4-(trifluoromethoxy)phenyl]methyl]benzene will be (5-bromo-2-chloro-phenyl)-[4-(three 6 g (4.37 g, 11.5 mmol) of fluoromethoxy)phenyl]methanol was dissolved in 35 mL of dichloromethane, triethyl decane (5.49 mL, 34.4 mmol) was added, and boron trifluoride etherate (2.9 mL, 22.9) was added dropwise. Methyl), reaction for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The residue obtained was purified by EtOAc EtOAc (EtOAc) Colorless oil), Yield: 71.6%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.33 - 7.29 (m, 2H), 7.26-7.24 (m, 1H), 7.21-7.18 (m, 2H), 7.15 (d, 2H), 4.06 (s) , 2H)

Step 7 (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]- 6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 4-bromo-1-chloro-2-[[4-(trifluoromethoxy)benzene 6 ]methyl]benzene 6h (2.33g, 6.38mmol) was dissolved in a mixed solvent of 40mL of tetrahydrofuran and n-hexane (v:v=1:3), cooled to -78 ° C, n-hexane of n-butyllithium was added dropwise The solution (3.83 mL, 9.57 mmol) was reacted at -78 ° C for 1.5 hours, and 30 mL (3 R , 4 S , 5 R , 6 R )-3,4,5-tris(trimethyldecyloxy) was added dropwise. -6-(Trimethyldecyloxymethyl)tetrahydropyran-2-one 2f (4.47 g, 9.57 mmol) in tetrahydrofuran and n-hexane (v: v = 1:3) solution, reacted at -78 ° C After 2 hours, 32 mL of 0.6 M methanesulfonic acid in methanol was added and reacted at room temperature for 16 hours. Add 150 mL of saturated sodium carbonate solution, separate the liquid, and extract the aqueous phase with ethyl acetate (100 mL × 3), and the organic phase is combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The resulting residue was purified to give the title product ( 2S , 3R , 4S , 5S , 6R )-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl] Methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 6i (1.38 g, white solid), yield: 45.2%. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.61 (d, 1H), 7.51 (dd, 1H), 7.40 (d, 1H), 7.31-7.29 (m, 2H), 7.17 (d, 2H) , 4.3-4.12 (m, 2H), 3.94 (d, 1H), 3.86-3.75 (m, 2H), 3.95-3.59 (m, 2H), 3.47-3.42 (m, 1H), 3.10 (s, 3H)

The eighth step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3- [[4-(Trifluoromethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol will (2 S ,3 R ,4 S ,5 S ,6 R )-2-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy Base-tetrahydropyran-3,4,5-triol 6i (1.33 g, 2.78 mmol) was dissolved in 12 mL of pyridine, followed by 4-dimethylaminopyridine (67.93 mg, 0.55 mmol) and tributyl Dimethylchloromethane (0.50 g, 3.34 mmol) was reacted for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjj (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[4 -(Trifluoromethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 6j (1.60 g, white solid), yield: 97.6 %. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.55 (d, 1H), 7.46 (d, 1H), 7.41 (d, 1H), 7.26 (d, 2H), 7.17 (d, 2H), 4.17 (s, 2H), 4.04 (d, 1H), 3.92-3.88 (m, 1H), 3.77 (t, 1H), 3.61-3.59 (m, 1H), 3.09 (s, 3H)

The ninth step [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethyl) Oxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyldecane (2 S ,3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[4-(trifluoromethoxy) Phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 6j (1.60 g, 2.69 mmol) dissolved in 15 mL of N,N-dimethylformamidine The amine was cooled to 0 ° C, 60% sodium hydride (0.54 g, 13.5 mmol) was added, and the mixture was reacted at room temperature for 15 minutes, and benzyl bromide (1.6 mL, 13.5 mmol) was added and reacted for 16 hours. 5mL of methanol was added, the reaction solution was concentrated under reduced pressure, was added 100mL ethyl acetate, washed with water (50mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product [[(2 R, 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]benzene 6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyldecane 6k (2.32 g, yellow oil), used directly without isolation One step reaction.

The tenth step [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy) Phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol [[(2 R , 3 R , 4 S , 5 R , 6 S )-3, 4,5-Tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran- 2-Based]methoxy]-tert-butyl-dimethyldecane 6k (2.32 g, 2.69 mmol) was dissolved in 12 mL of methanol, and ethyl acetate (16 μL, 0.40 mmol) was added and reacted for 1.5 hours. The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5 -tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl Methanol 6 m (1.22 g, light yellow oil), yield: 60.7%. ¹ H NMR (400 MHz, CD ₃ 0D): δ 7.54-7.52 (m, 2H), 7.41 (d, 1H), 7.32-7.22 (m, 13H), 7.18 (d, 2H), 7.08-7.04 (m) , 4H), 4.91-4.85 (m, 3H), 4.75 (d, 1H), 4.52 (d, 1H), 4.17-4.09 (m, 3H), 4.00 (d, 1H), 3.94-3.83 (m, 3H) ), 3.75-3.69 (m, 2H), 3.09 (s, 3H)

The eleventh step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy) Phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde oxalic acid chloride (0.21 mL, 2.45 mmol) was dissolved in 5 mL dichloromethane and cooled to -78 ° C 5 mL of dimethyl hydrazine (0.24 mL, 3.26 mmol) in dichloromethane was added dropwise, and the reaction was carried out for 15 minutes, and 10 mL of [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4 was added dropwise. 5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2- A solution of methanol ( 6 m (1.22 g, 1.63 mmol) in methylene chloride was reacted for 40 minutes, triethylamine (1.18 mL, 8.15 mmol) was added dropwise, and the mixture was reacted at room temperature for 1.5 hours. Was added 10mL 1M hydrochloric acid solution, and liquid separation, the organic phase is washed with saturated sodium chloride solution (10 mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]benzene 6-methoxy-tetrahydropyran-2-carbaldehyde 6n (1.21 g, yellow oil) was used in the next step without isolation.

Step 12 (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy) Phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde (2 S , 3 S , 4 S , 5 R , 6 S -3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetra Hydropyran-2-carbaldehyde 6n (1.21 g, 1.63 mmol) was dissolved in 12 mL of 1,4-dioxane, 2.65 mL of 37% formaldehyde solution was added, and 4.89 mL of 1 M sodium hydroxide solution was added dropwise at 70 ° C. The reaction was continued for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. 2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl] Methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 6p (1.27 g, light yellow oil), used for next step without isolation .

Step 13 [(3 S ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)) Phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol (2 S , 3 S , 4 S , 5 R , 6 S -3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl) 6-methoxy-tetrahydropyran-2-carbaldehyde 6p (1.27 g, 1.63 mmol) was dissolved in 10 mL of a mixed solvent of tetrahydrofuran and methanol (v: v = 1:1), and sodium borohydride was added in portions ( 0.12 g, 3.26 mmol), reacted for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. in E chromatography eluent systems resulting residue was the title product [(3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4-chloro - 3-[[4-(Trifluoromethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 6q (400 mg , white solid), Yield: 31.5%. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.58 (dd, 1H), 7.54 (d, 1H), 7.39 (d, 1H), 7.31-7, 24 (m, 13H), 7.16 (d, 2H), 7.11-7.06 (m, 4H), 4.92 (d, 1H), 4.76 (d, 1H), 4.66-4.59 (m, 1H), 4.27-4.22 (m, 2H), 4.17-4.10 (m, 2H), 4.07-4.04 (m, 3H), 3.99-3.95 (m, 2H), 3.77 (d, 1H), 3.65-3.60 (m, 2H), 3.35 (s, 2H), 3.18 (s, 3H)

Fourteenth step [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethyl) Oxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol [[3 S ,4 S ,5 R ,6 S ) -3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)- 6-Methoxy-tetrahydropyran-2-yl]methanol 6q (400 mg, 0.51 mmol) was dissolved in 10 mL of dichloromethane, and trifluoroacetic acid (0.15 mL, 2.05 mmol) was added dropwise and reacted for 1.5 hours. The reaction solution was concentrated, dried under reduced pressure to silica gel column chromatography eluent systems B resulting residue, to give the title product [(1 S, 2 S, 3 S, 4 R, 5 S) -2,3,4 -tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1] Octane-1-yl]methanol 6r (290 mg, white solid), yield: 76.1%. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.59 (dd, 1H), 7.50-7.44 (m, 2H), 7.34-7.15 (m, 17H), 6.83 (d, 2H), 5.22 (t, 1H), 4.81-4.74 (m, 4H), 4.32 (d, 1H), 4.11-4.08 (m, 3H), 4.07-4.04 (m, 1H), 3.93 (d, 1H), 3.87 (t, 1H) , 3.79-3.71 (m, 3H), 3.59 (dd, 1H), 3.52 (d, 1H)

The fifteenth step (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl] 1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [[1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-6,8-dioxo Heterobicyclo[3.2.1]octane-1-yl]methanol 6r (150 mg, 0.20 mmol) was dissolved in 10 mL of a mixed solvent of tetrahydrofuran and methanol (v: v = 1:1), and then o-dichlorobenzene was added sequentially. 0.23 mL, 2 mmol) and palladium on carbon (60 mg, 10%) were replaced with hydrogen three times for 1 hour. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, by silica gel column chromatography to E resulting residue was purified eluent system, to give the title product (1 S, 2 S, 3 S, 4 R, 5 S) -5- [ 4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1] octane Alkano-2,3,4-triol 6 (82 mg, white solid), yield: 86.0%. MS m/z (ESI): 477.1 [M+1] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.54 (d, 1H), 7.46-7.39 (m, 2H), 7.30 (d, 2H), 7.17 (d, 2H), 4.17 (d, 3H), 3.86 (d, 1H), 3.80 (d, 1H), 3.72-3.68 (m, 2H), 3.62 (dd, 1H), 3.58 (d, 1H)

Example 7 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]- Phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

First step 2,2,2-trifluoromethyl-4-methylbenzenesulfonate 2,2,2-trifluoromethylethanol 7a (7.2 mL, 100 mmol) was dissolved in 300 mL of dichloromethane and added Triethylamine (28 mL, 200 mmol) was cooled to 0 ° C, and a solution of 100 mL of p-toluenesulfonium chloride (30 g, 150 mmol) in dichloromethane was added dropwise, and the mixture was reacted at room temperature for 16 hours. After adding 100 mL of water, it was extracted with dichloromethane (100 mL×3), and the organic phase was washed with saturated sodium chloride (50 mL). method D in the resulting residue was purified eluent system, to give the title product 2,2,2-trifluoro-4-methyl benzenesulfonate ester 7b (25g, colorless liquid), yield: 98.4%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.88-7.76 (m, 2H), 7.44 - 7.33 (m, 2H), 4.35 (d, 2H), 2.47 (s, 3H)

The second step is 4-bromo-1-chloro-2-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]benzene 4-[(5-bromo-2-chloro- Phenyl)methyl]phenol 7c (prepared according to WO2009026537) (14.5 g, 48.7 mmol) was dissolved in 300 mL of N,N-dimethylformamide, and cesium carbonate (31.7 g, 97.5 mmol) was added and stirred 10 In a minute, 2,2,2-trifluoromethyl-4-methylbenzenesulfonate 7b (12.4 g, 48.7 mmol) was added, and the mixture was reacted at 80 ° C for 8 hours. The reaction mixture was filtered, washed with EtOAc EtOAc (EtOAc)EtOAc.EtOAc. The mixture was washed with a saturated sodium chloride solution (100 mL), EtOAcjjjjjjjjjjjjjj Bromo-1-chloro-2-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]benzene 7d (7.26 g, white solid), yield: 39.2%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.32 (s, 1H), 7.30-7.24 (m, 2H), 7.21-7.14 (m, 2H), 6.98-6.87 (m, 2H), 4.38 (d, 2H), 4.06 (s, 2H)

The third step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]- 4-phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 4-bromo-1-chloro-2-[[4-(2 , 2,2-Trifluoroethoxy)phenyl]methyl]benzene 7d (6.15 g, 16.2 mmol) was dissolved in 150 mL of a mixed solvent of tetrahydrofuran and n-hexane (v:v = 2:3), cooled to - Add n-hexane solution of n-butyllithium (10 mL, 24.3 mmol) at 78 ° C, and react at -78 ° C for 1 hour, add 35 mL (3 R , 4 S , 5 R , 6 R )-3,4,5 - a solution of tris(trimethyldecyloxy)-6-(trimethyldecyloxymethyl)tetrahydropyran-2-one 2f (8.32 g, 17.8 mmol) in n-hexane, reacted at -78 °C 2 In an hour, 50 mL of methanol and 3.2 mL of methanesulfonic acid were added and reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (3 mL) (EtOAc) dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, by silica gel column chromatography to D resulting residue was purified eluent system, to give the title product (2 S, 3 R, 4 S, 5 S, 6 R) - 2-[4-Chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy- Tetrahydropyran-3,4,5-triol 7e (3.93 g, white solid), yield: 49.2%. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.57 (d, 1H), 7.49 (dd, 1H), 7.38 (d, 1H), 7.18 (d, 2H), 6.99-6.88 (m, 2H) , 4.49 (q, 2H), 4.19-4.01 (m, 3H), 3.99-3.91 (m, 1H), 3.89-3.71 (m, 2H), 3.66-3.55 (m, 1H), 3.49-3.39 (m, 1H), 3.14-3.04 (s, 3H)

The fourth step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3- [[4-(2,2,2-Trifluoroethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]- 6-(Hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 7e (3.8 g, 7.71 mmol) was dissolved in 100 mL of N,N-dimethylformamide. 4-Dimethylaminopyridine (188 mg, 1.54 mmol), tert-butyldimethylchloromethane (1.39 g, 9.25 mmol) and 50 mL of pyridine were added, and the mixture was reacted for 36 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The filtrate was concentrated under reduced pressure, by silica gel column chromatography to D resulting residue was purified eluent system, to give the title product (2 S, 3 R, 4 S, 5 S, 6 R) -6 - [( t-butoxide (dimethyl)decyloxymethyl]-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]- 2-methoxy-tetrahydropyran-3,4,5-triol 7f (2.94 g, yellow oil), yield: 62.8%. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.94 (s, 2H), 7.45 (d, 1H), 7.40 (d, 1H), 7.35-7.28 (m, 1H), 7.17-7.05 (m) , 2H), 7.01-6.90 (m, 2H), 5.00 (d, 1H), 4.84-4.74 (m, 2H), 4.68 (q, 2H), 4.11-3.87 (m, 3H), 3.73 (dd, 1H) ), 3.60-3.46 (m, 1H), 3.42 (ddd, fH), 3.14 (td, 1H), 2.92 (s, 3H), 0.05-0.02 (m, 3H)

The fifth step [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2) ,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[4 -(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 7f (2.90 g, 4.78 mmol Dissolved in 70 mL of N,N-dimethylformamide, cooled to 0 ° C, added 60% sodium hydride (955 mg, 23.9 mmol), reacted for 1 hour at room temperature, and added benzyl bromide (3.0 mL, 23.9 mmol) ), react for 3 hours. Add 5 mL of methanol and 10 mL of water, add 100 mL of water and 30 mL of saturated sodium chloride solution, separate the liquid, extract the aqueous phase with ethyl acetate (50 mL × 3), wash the organic phase with saturated sodium chloride solution (30 mL), and combine the organic phase , dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product [[(2 R, 3 R , 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4 -Chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy ]-T-butyl-dimethyl-decane 7 g (4.60 g, pale yellow liquid) was used in the next reaction without isolation.

The sixth step [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2, 2-[Trifluoroethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl] -6-Methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane 7g (4.19g, 4.78mmol) was dissolved in 30mL of methanol and added with acetonitrile ( 51 μL, 0.72 mmol), and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to D resulting residue was purified eluent system, to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5 -Tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydro Pyr-2-yl]methanol 7h (1.1g, white oil), yield: 30.1%. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ 7.55-7.43 (m, 2H), 7.39-7.28 (m, 6H), 7.28-7.16 (m, 9H), 7.11-7.03 (m, 1H), 7.01 (dd, 2H), 6.90 (d, 2H), 4.91-4.73 (m, 4H), 4.73-4.58 (m, 3H), 4.42 (d, 1H), 4.17-3.87 (m, 4H), 3.83 3.62 (m, 4H), 3.53 (dd, 1H), 3.24 (d, 1H), 3.08-2.86 (m, 3H)

The seventh step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2 -Trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde The oxaloquinone chloride (0.16 mL, 1.87 mmol) was dissolved in 5 mL dichloromethane. Cool to -78 ° C, add 3 mL of dimethyl hydrazine (0.2 mL, 2.88 mmol) in dichloromethane, react for 15 minutes, add 10 mL [(2 R , 3 R , 4 S , 5 R , 6 S ) -3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6- A solution of methoxy-tetrahydropyran-2-yl]methanol in 7h (1.10g, 1.44mmol) in dichloromethane, 40 min, triethylamine (1.0 mL, 7.21 mmol). . 5mL 1M hydrochloric acid solution was added, and liquid separation, the aqueous phase was extracted with ethyl acetate (10mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]- Phenyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 7i (1.06 g, yellow oil) was used in the next step without isolation.

The eighth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2 -Trifluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde (2 S , 3 S , 4 S , 5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl] Phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 7i (1.06 g, 1.39 mmol) was dissolved in 20 mL of 1,4-dioxane, and 2.3 mL of 37% formaldehyde solution was added, 4 mL was added dropwise. A 2.9 M sodium hydroxide solution was reacted at 70 ° C for 25 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy) Phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 7j (1.1 g, yellow oil), used without isolation In the next step.

The ninth step [(3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-3) Fluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol (2 S , 3 S , 4 S , 5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl] Phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 7j (1.1 g, 1.39 mmol) was dissolved in 30 mL of tetrahydrofuran and methanol (v: v = 1:2) In a mixed solvent, sodium borohydride (106 mg, 2.78 mmol) was added portionwise and reacted for 30 minutes. Add 20 mL of water, add 30 mL of water, and extract with ethyl acetate (50 mL×3). The organic phase is washed with saturated sodium chloride solution (30 mL). D to column chromatography eluting agent system resulting residue, to give the title product [(3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4- Chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran- 2-Base]methanol 7k (100 mg, yellow oil), yield: 9.1%.

The tenth step [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2, 2-(Trifluoroethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol [[3 S ,4 S ,5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]benzene 4-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 7k (100 mg, 0.13 mmol) was dissolved in 10 mL of dichloromethane, and 0.1 mL of trifluoroacetic acid was added dropwise. Reaction for 1 hour. The reaction solution was concentrated, dried under reduced pressure to silica gel column chromatography eluent systems D resulting residue, to give the title product [(1 S, 2 S, 3 S, 4 R, 5 S) -2,3,4 -Tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo And [3.2.1] octane-1-yl]methanol 7m (22 mg, white solid), yield: 22.9%. MS m/z (ESI): 778.3 [M+18]

The eleventh step (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl] Methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol will [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]- Phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 7m (20mg, 0.03mmol) was dissolved in 10mL of tetrahydrofuran and methanol (v:v=1:1) In a mixed solvent, o-dichlorobenzene (31 μL, 0.27 mmol) and palladium/carbon (20 mg, 10%) were successively added, and hydrogen was replaced three times for 2 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (1 S, 2 S, 3 S, 4 R, 5 S) -5- [4- Chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2 .1] Octane-2,3,4-triol 7 (9 mg, white solid), yield: 69.2%. MS m/z (ESI): 491.1 [M+1] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.48 (m, 1H), 7.40-7.38 (m, 2H), 7.18-7.16 (d, 2H) ), 6.93-6.91 (d, 2H), 4.51-4.45 (q, 2H), 4.17-4.15 (d, 1H), 4.08 (s, 2H), 3.81-3.78 (d, 1H), 3.78-3.71 (d) , 1H), 3.69-3.67 (m, 2H), 3.62-3.57 (m, 2H)

Example 8 (1S, 2S, 3S, 4R, 5S)-5-[4-chloro-3-[[3-fluoro-4-(tridemethoxymethoxy)phenyl]methyl]phenyl]- 1-(Hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

First step 4-[(5-bromo-2-chloro-phenyl)methyl]-2-fluoro-phenol 4-((5-bromo-2-chloro-phenyl)methyl]-1-ethyl Oxy-2-fluoro-benzene 4e (31.7 g, 92.3 mmol) was dissolved in 300 mL of dichloromethane, and boron tribromide (11.4 mL, 120 mmol) was added under ice-cooling, and reacted at room temperature for 4 hours. The organic phase was washed with a saturated sodium chloride solution (30 mL), and the organic phase was dried over anhydrous magnesium sulfate. The filtrate by silica gel column chromatography to D resulting residue was purified eluent system, to give the title product 4 - [(5-bromo-2-chloro - phenyl) methyl] -2-fluoro - phenol 8a (28.1 g, white solid), Yield: 96.7%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.36-7.18 (m, 3H), 7.01-6.80 (m, 3 H), 5.08 (br, 1 H), 3.99 (s, 2 H)

The second step is 4-[(5-bromo-2-chloro-phenyl)methyl]-2-fluoro-1-(tridemethoxy)benzene 4-[(5-bromo-2-chloro- Phenyl)methyl]-2-fluoro-phenol 8a (10.0 g, 31.75 mmol) was dissolved in 150 mL of tetrahydrofuran, and triphenylphosphine (16.6 g, 63.5 mmol) and diisopropyl azodicarboxylate (12.6 mL) were added. , 63.5 mmol), react for 30 minutes. Add 3 mL of deuterated methanol and react for 18 hours. The reaction solution was concentrated under reduced pressure, and then crystallised from petroleum ether, filtered, and then filtered, and then filtered, and then taken in 50 mL of methanol, and then added to 2 mL of hydrogen peroxide. After stirring for 1 minute, 5 g of sodium thiosulfate, 40 mL of water and 50 mL of ethyl acetate were added. The liquid and the aqueous phase were extracted with ethyl acetate (30 mL×3), and the organic phase was washed with saturated sodium chloride (30 mL). The residue obtained was purified by eluent D to give the title product 4-[(5-bromo-2-chloro-phenyl)methyl]-2-fluoro-1-(tridecylmethoxy)benzene. 8b (8.2 g, white solid), yield: 77.4%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.37-7.32 (m, 1 H), 7.32-7.28 (m, 2 H), 6.99-6.89 (m, 3 H), 4.02 (s, 2 H)

The third step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[3-fluoro-4-(tridemethoxy)phenyl]methyl Phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 4-((5-bromo-2-chloro-phenyl)methyl ]-2-fluoro-1-(tridemethoxy)benzene 8b (8.2 g, 24.6 mmol) was dissolved in 150 mL of a mixed solvent of tetrahydrofuran and n-hexane (v:v=2:3), and cooled to -78 °C, n-hexane solution of n-butyllithium (14.8 mL, 36.9 mmol) in n-hexane was added dropwise, and the mixture was reacted at -78 ° C for 2 hours, and 40 mL (3 R , 4 S , 5 R , 6 R )-3 was added dropwise. , 4,5-tris(trimethyldecyloxy)-6-(trimethyldecyloxymethyl)tetrahydropyran-2-one 2f (12.6 g, 27.1 mmol) in n-hexane, The reaction was carried out at 78 ° C for 3 hours, and 40 mL of methanol and 4.79 mL of methanesulfonic acid were added, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The filtrate was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue obtained was purified by eluent D to give the title product ( 2S , 3R , 4S , 5S , 6R )-2-[4-chloro-3-[[3-fluoro-4-(tris) Methoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 8c (8.2 g, white solid) , Yield: 83.6%. _{^{1 H NMR (400MHz, CDC1 3}} ): δ 7.47-7.29 (m, 3H), 6.93-6.78 (m, 3H), 4.08-3.98 (m, 2H), 3.98-3.78 (m, 5H), 3.73 (d , 1H), 3.47 (s, 6H)

The fourth step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3- [[3-Fluoro-4-(tridemethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[3-fluoro-4-(tris-methoxy)phenyl]methyl]phenyl]-6- (Hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 8c (9.2g, 20.6mmo1) was dissolved in 80 mL of pyridine, followed by 4-dimethylaminopyridine (502 mg) , 4.11 mmol) and tert-butyldimethylchloromethane (3.72 g, 24.7 mmol) were reacted for 24 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The residue obtained was purified by column chromatography eluting to afford the title product ( 2S , 3R , 4S , 5S , 6R )-6-[(t-butyl(dimethyl)decylalkyl) Oxymethyl]-2-[4-chloro-3-[[3-fluoro-4-(tridecylmethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyridyl M--3,4,5-triol 8d (2.4 g, yellow liquid), yield: 20.9%.

The fifth step [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4- (trideuteromethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane 2 S ,3 R ,4 S ,5 S ,6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[3- Fluoro-4-(tridemethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 8d (2.4g, 4.29mmol) dissolved In 70 mL of N,N-dimethylformamide, cooled to 0 ° C, 60% sodium hydride (857 mg, 21.4 mmol) was added and allowed to react at room temperature for 1 hour, and benzyl bromide (2.56 mL, 21.4 mmol) was added. Reaction for 3 hours. 5 mL of methanol and 100 mL of water were added, and the mixture was extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated sodium chloride (30 mL). [[(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(tris) Methoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane 8e (3.56 g, Yellow liquid), used directly in the next reaction without separation.

The sixth step [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-( Triterpene methoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(tridemethyloxy)phenyl]methyl]phenyl]-6 -Methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane 8e (3.56 g, 4.29 mmol) was dissolved in 30 mL of methanol and added with ethyl acetate (95.5 μL) , 1.34 mmol), reacted for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The obtained residue was purified to give the title product [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3- Fluoro-4-(tridemethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 8f (2.2 g, yellow liquid), yield: 73.3%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.42 - 7.27 (m, 13 H), 7.24 - 7.14 (m, 3 H), 6.98 (d, 2 H), 6.89-6.72 (m, 3 H) , 4.96-4.87 (m, 3 H), 4.71-4.67 (m, 1 H), 4.51 (d, 1 H), 4.18 (t, 1 H), 4.07 (d, 1 H), 3.95-3.84 (m) , 3 H), 3.83-3.77 (m, 1 H), 3.76-3.64 (m, 2 H), 3.30 (d, 1 H), 3.07 (s, 3 H)

The seventh step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(three Deuterated methoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde oxalic acid chloride (0.34 mL, 3.93 mmol) was dissolved in 5 mL of dichloromethane, cold To -78 ° C, 10 mL of a solution of dimethyl hydrazine (0.43 mL, 6.04 mmol) in dichloromethane was added dropwise, and reacted for 15 minutes, and 15 mL of [(2 R , 3 R , 4 S , 5 R , 6 S )- 3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(tridemethoxy)phenyl]methyl]phenyl]-6-methoxy A solution of benzyl-tetrahydropyran-2-yl]methanol 8f (2.2 g, 3.02 mmol) in methylene chloride was reacted for 45 min, and triethylamine (2.1 mL, 15.1 mmol) was added dropwise, and the mixture was reacted at room temperature for 2.5 hours. Was added 5mL 1M hydrochloric acid solution and extracted with dichloromethane (15mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S, 5 R, 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(tris-methoxy)phenyl]methyl]phenyl]- 6-Methoxy-tetrahydropyran-2-carbaldehyde 8 g (2.1 g, yellow liquid) was used in the next reaction without isolation.

The eighth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(three Deuterated methoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(tridemethoxy)phenyl]methyl]phenyl 6-methoxy-tetrahydropyran-2-carbaldehyde 8 g (2.1 g, 2.94 mmol) was dissolved in 50 mL of 1,4-dioxane, and formaldehyde (5.4 mL, 72.2 mmol) and 3.94 mL of 3M were added. The sodium hydroxide solution was reacted at 50 ° C for 6 hours. 20 mL of water and extracted with ethyl acetate (20mL × 3), combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S, 5 R, 6 S -3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(tridemethoxymethoxy)phenyl]methyl]phenyl]-2- (Hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 8 h (2.5 g, yellow liquid) was used in the next step without isolation.

The ninth step [(3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(tris) Methoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol (2 S ,3 S ,4 S ,5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(tridemethoxy)phenyl]methyl]phenyl ]-2-(Hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 8h (2.5g, 3.36mmol) was dissolved in 30mL of tetrahydrofuran and methanol (v:v=1:2) mixed solvent In the middle, sodium borohydride (269 mg, 6.72 mmol) was added in portions and the mixture was reacted for 2 hours. The reaction was quenched by the addition of EtOAc (EtOAc) (EtOAc (EtOAc) D to column chromatography eluting agent system resulting residue, to give the title product [(3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4-chloro -3-[[3-fluoro-4-(tridemethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2- Base] methanol 8i (350 mg, yellow liquid), yield: 15.9%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.41-7.19 (m, 16 H), 7.04 (dd, 2 H), 6.86-6.76 (m, 3 H), 5.01-4.87 (m, 3 H), 4.71-4.59 (m, 2 H), 4.44-4.31 (m, 2 H), 4.06-3.92 (m, 3 H), 3.87-3.76 (m, 3 H), 3.68 (d, 1 H), 3.25 ( d,1 H),3.07(s,3 H)

The tenth step [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[[3-fluoro-4-( Tris(methoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol [[3 S ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(tridemethoxymethoxy)phenyl]methyl]phenyl] 2-(Hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 8i (350 mg, 0.47 mmol) was dissolved in 20 mL of dichloromethane, and 0.5 mL of trifluoroacetic acid was added dropwise. hour. The reaction solution was concentrated, dried under reduced pressure to silica gel column chromatography eluent systems D resulting residue, to give the title product [(1 S, 2 S, 3 S, 4 R, 5 S) -2,3,4 -Tribenzyloxy-5-[4-chloro-3-[[3-fluoro-4-(tridemethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo [3.2.1] Octane-1-yl]methanol 8j (200 mg, colorless liquid), yield: 59.7%. MS m/z (ESI): 731.3 [M+18]

The eleventh step (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[[3-fluoro-4-(tridemethoxy)phenyl]- Phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [[1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[[3-fluoro-4-(tridemethoxymethoxy)phenyl]methyl] Phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 8j (190 mg, 0.27 mmol) was dissolved in 30 mL of tetrahydrofuran and methanol (v: v = 1:1) In the mixed solvent, o-dichlorobenzene (391 mg, 2.66 mmol) and palladium/carbon (20 mg, 10%) were successively added, and hydrogen was replaced three times for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, separation by reverse-phase column to elute the surfactant system F The resulting residue was purified to give the title product (1 S, 2 S, 3 S, 4 R, 5 S) -5- [ 4-chloro-3-[[3-fluoro-4-(tridemethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[ 3.2.1] Octane-2,3,4-triol 8 (74 mg, white solid), yield: 62.7%. MS m/z (ESI): 461.1 [M+18] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.59-7.45 (m, 1 H), 7.45-7.33 (m, 2 H), 7.06-6.84 (m, 3 H), 4.16 (d, 1 H), 4.05 (d, 2 H), 3.93-3.76 (m, 2 H), 3.75-3.52 (m, 4 H)

Example 9 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl -phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

First step 2-(4-fluorophenyl)thiophene 2-iodothiophene (1.05 g, 5 mmol) was dissolved in 6 mL of a mixed solution of dimethyl ether and water (v:v=2:1), and 1-fluoro 4-Methyl-benzene 9a (700 mg, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(triphenylphosphine)palladium (173 mg, 0.15 mmol) were reacted at 100 ° C for 30 min. Add 10 mL of water, extract with ethyl acetate (20 mL×3), EtOAc (EtOAc) in method C eluant system resulting residue was purified to give the title product 2- (4-fluorophenyl) thiophene-9B (767 mg, white solid), yield: 86.1%.

The second step (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl]methanone dissolves aluminum trichloride (1.5 g, 11 mmol) in 10 mL of dichloro In methane, cooled to -10 ° C, and added 5-bromo-2-chloro-benzoguanidine chloride 2a (2.54 g, 10 mmol) and 2-(4-fluorophenyl)thiophene 9b (1.78 g, 10 mmol), reaction 30 In minutes, the reaction was allowed to rise to room temperature for 16 hours. The reaction solution was cooled to -10 ° C, a small amount of water was added, 20 mL of 1 M hydrochloric acid, and ethyl acetate (50 mL × 2), the organic phase was combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by eluent B to give the title product (5-bromo-2-chloro-phenyl)-[5-(4-fluorophenyl)-2-thienyl] ketone 9c (1.5 g, yellow solid), Yield: 37.9%.

The third step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl -Phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol (5-bromo-2-chloro-phenyl)-[5-( 4-Fluorophenyl)-2-thienyl]methanone 9c (3.7 g, 10.4 mmol) was dissolved in 40 mL of tetrahydrofuran, cooled to -78 ° C, and n-butyl lithium (5 mL, 12.5 mmol) was added dropwise at -78 The reaction was carried out at ° C for 1 hour, and 30 mL of (3 R , 4 S , 5 R , 6 R )-3,4,5-tris(trimethyldecyloxy)-6-(trimethyldecyloxymethyl) was added dropwise. A solution of tetrahydropyran-2-one 2f (4.85 g, 10.4 mmol) in tetrahydrofuran was reacted at -78 °C for 2 hours, and 60 mL of a 0.6 M solution of methanesulfonic acid in methanol was added and allowed to react at room temperature for 16 hours. After adding 30 mL of a saturated sodium carbonate solution, the reaction mixture was evaporated, evaporated, evaporated, evaporated, evaporated. The residue obtained was purified to give the title product ( 2S , 3R , 4S , 5S , 6R )-2-[3-[[5-(4-fluorophenyl)-2-thienyl] Methyl]-4-methyl-phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 9d (1.8 g, orange solid) Yield: 36.7%.

The fourth step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[3-[[5- (4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol (2 S , 3 R ,4 S ,5 S ,6 R )-2-[3-[[5-(4-Fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6- (Hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 9d (1.8 g, 3.8 mmol) was dissolved in 20 mL of pyridine, followed by the addition of 4-dimethylaminopyridine ( 93 mg, 0.76 mmol) and tert-butyldimethylchloromethane (686 mg, 4.55 mmol) were reacted for 16 hours. The reaction mixture was concentrated under reduced vacuol~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ to column chromatography using silica gel eluting A surfactant system resulting residue, to give the title product (2 S, 3 R, 4 S, 5 S, 6 R) -6 - [( tert-butyl (dimethyl矽alkyl)oxymethyl]-2-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy- Tetrahydropyran-3,4,5-triol 9e (2.0 g, orange solid), Yield: 89.7%.

The fifth step [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-) 2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane 2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[3-[[5-(4-fluoro) Phenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 9e (2.0 g, 3.4 mmol) dissolved In 20 mL of N,N-dimethylformamide, cool to 0 ° C, add 60% sodium hydride (680 mg, 17 mmol), react at room temperature for 30 minutes, add benzyl bromide (2.0 mL, 17 mmol), react for 16 hours . After adding 10 mL of methanol, the reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. , the title product [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)) -2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane 9f (2.9 g, yellow oil) was used in the next step without isolation.

The sixth step [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2 -thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6 -Methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane 9f (2.9 g, 3.37 mmol) was dissolved in 20 mL of methanol and added with ethyl acetate (38 μL) , 0.5 mmol), reacted for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj B to column chromatography eluting agent system resulting residue, to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [ 3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 9g ( 1.9 g, yellow solid), yield: 76.0%.

The seventh step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2- Thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde oxalic acid chloride (0.27 mL, 3.12 mmol) was dissolved in 8 mL dichloromethane. To a solution of 4 mL of dimethyl hydrazine (0.36 mL, 5.04 mmol) in dichloromethane was added dropwise to -78 ° C for 15 minutes, and 8 mL [(2 R , 3 R , 4 S , 5 R , 6 S )- 3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy A solution of 9 g (1.8 g, 2.4 mmol) of m -tetrahydropyran-2-yl]methanol in methylene chloride was reacted for 30 min, and triethylamine (1.66 mL, 12 mmol) was added dropwise, and the mixture was reacted at room temperature for 1 hour. 12mL 1M hydrochloric acid was added, liquid separation, the organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S, 5 R, 6 S) -3,4,5- Tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-6-methoxy-tetrahydropyran 2-carbaldehyde 9h (1.8 g, yellow oil) was used in the next step without isolation.

The eighth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2- Thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl ]-6-Methoxy-tetrahydropyran-2-carbaldehyde 9h (1.53g, 2.1mmol) was dissolved in 15mL of 1,4-dioxane, adding 3.4mL of 37% formaldehyde solution, adding 6.3mL 1M The sodium hydroxide solution was reacted at 70 ° C for 16 hours. Was added 50mL of saturated sodium chloride solution, separated, the aqueous phase was extracted with ethyl acetate (50mL × 3), combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl Phenyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 9i (2.0 g, pale yellow oil) was used in the next step without isolation.

The ninth step [(3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl) ]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol (2 S ,3 S ,4 S ,5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl ]-2-(Hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 9i (2.0 g, 2.1 mmol) was dissolved in 30 mL of a mixed solvent of tetrahydrofuran and methanol (v: v = 1:20) Medium, sodium borohydride (238 mg, 6.3 mmol) was added in portions and allowed to react for 1 hour. The reaction solution was concentrated under reduced pressure, silica gel column chromatography with eluant System B to E, and the resulting residue was purified to give the title product [(3 S, 4 S, 5 R, 6 S) -3,4,5- Tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6- Methoxy-tetrahydropyran-2-yl]methanol 9j (420 mg, pale yellow solid), yield: 25.8%. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.55 (d, 2H), 7.48-7.45 (m, 3H), 7.32-7.28 (m, 5H), 7.25-7.21 (m, 9H), 7.16 ( d, 2H), 7.07-7.03 (m, 3H), 6.63 (d, 1H), 4.91 (d, 1H), 4.83 (d, 1H), 4.75 (d, 1H), 4.54 (d, 1H), 4.26 -4.17 (m, 2H), 4.10-4.04 (m, 5H), 3.94 (d, 1H), 3.78 (d, 1H), 3.36 (d, 1H), 3.26 (s, 3H), 2.34 (s, 3H) )

Step 10 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[3-[[5-(4-Fluorophenyl)-2-thienyl]methyl]-4-methyl -Phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol [[3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]- 2-(Hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 9j (130 mg, 0.17 mmol) was dissolved in 10 mL of methanol, and 4 mL of 2M hydrogen chloride in ethyl acetate Palladium (260 mg, 20%) was replaced with hydrogen three times for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the resulting residue was purified preparation by HPLC, and the title product (1 S, 2 S, 3 S, 4 R, 5 S) -5- [3 - [[5- (4- fluoro Phenyl)-2-thienyl]methyl]-4-methyl-phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3 , 4-triol 9 (11 mg, white solid), yield: 13.8%. MS m/z (ESI): 473.2 [M+1] ¹ H NMR (400 MHz, CD ₃ OD): δ 7.57-7.56 (m, 2H), 7.48 (d, 1H), 7.39-7.37 (m, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 7.10-7.06 (m, 2H), 6.67 (d, 1H), 4.18 (d, 3H), 3.88-3.81 (m, 2H), 3.73 -3.68 (m, 2H), 3.65-3.62 (m, 2H), 2.33 (s, 3H)

Example 10 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[[3-fluoro-4-(1,1,2,2,2-quinone ethoxy) Phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

first step 4-[(5-Bromo-2-chloro-phenyl)methyl]-2-fluoro-1-(1,1,2,2,2-pentamethoxy)benzene

4-[(5-Bromo-2-chloro-phenyl)methyl]-2-fluoro-phenol 8a (6.0 g, 19.05 mmol) was dissolved in 100 mL of tetrahydrofuran, and triphenylphosphine (9.98 g, 38.1 mmol) was added. And diisopropyl azodicarboxylate (7.7 mL, 38.1 mmol), and reacted for 30 minutes. 2.5 mL of deuterated ethanol was added and the reaction was carried out for 18 hours. The reaction solution was concentrated under reduced pressure, and then recrystallized from petroleum ether, filtered, and filtered, and the mixture was collected, dissolved in 50 mL of methanol, and added to 2 mL of hydrogen peroxide. After stirring for 1 minute, 5 g of sodium thiosulfate, 40 mL of water and 50 mL of ethyl acetate were added. The aqueous phase is extracted with ethyl acetate (30 mL×3), and the organic phase is washed with saturated sodium chloride (30 mL). The obtained residue was purified with EtOAc EtOAc (EtOAc). Pentadecyl methoxy)benzene 10a (5.78 g, colorless liquid), yield: 86%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.38-7.24 (m, 3H), 6.99-6.83 (m, 3H), 4.02 (s, 2H)

Second step (2 S ,3 R ,4 S ,5 S ,6 R )-2-[4-chloro-3-[[3-fluoro-4-(1,1,2,2,2-quinone methoxy) Phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol

4-[(5-Bromo-2-chloro-phenyl)methyl]-2-fluoro-1-(1,1,2,2,2-pentamethoxy)benzene 10a (5.78 g, 16.6 mmol) was dissolved in a mixed solvent of 125 mL of tetrahydrofuran and n-hexane (v:v = 2:3), cooled to -78 ° C, and n-butyllithium (8.53 g, 18.26 mmol) in n-hexane was added dropwise. The reaction was carried out at 78 ° C for 2 hours, and 40 mL of (3 R , 4 S , 5 R , 6 R )-3,4,5-tris(trimethyldecyloxy)-6-(trimethyldecyloxymethyl) was added dropwise. A solution of tetrahydropyran-2-one 2f (12.6 g, 27.1 mmol) in n-hexane was reacted at -78 ° C for 3 hours, and 40 mL of methanol and 4.79 mL of methanesulfonic acid were added and allowed to react at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The filtrate was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. The residue obtained was purified by eluent D to afford the title product ( 2S , 3R , 4S , 5S , 6R )-2-[4-chloro-3-[[3-fluoro-4-(1, 1,2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5- Triol 10b (1.6 g, yellow solid), Yield: 20.9%.

third step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[3 -fluoro-4-(1,1,2,2,2-pentamethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5- Triol

(2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[3-fluoro-4-(1,1,2,2,2- quinone Oxy)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 10b (1.6 g, 3.47 mmol) was dissolved in In 40 mL of pyridine, 4-dimethylaminopyridine (64 mg, 0.52 mmol) and tert-butyldimethylchloromethane (0.57 g, 3.8 mmol) were sequentially added and reacted for 24 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The residue obtained was purified by column chromatography eluting to afford the title product ( 2S , 3R , 4S , 5S , 6R )-6-[(t-butyl(dimethyl)decylalkyl) Oxymethyl]-2-[4-chloro-3-[[3-fluoro-4-(1,1,2,2,2-pentamethoxy)phenyl]methyl]phenyl] 2-methoxy-tetrahydropyran-3,4,5-triol 10c (1.7 g, yellow liquid), yield: 85%.

the fourth step [[(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1, 1,2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl- Dimethyl-decane

(2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[ 3-fluoro-4-(1,1,2,2,2-pentamethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5 - Triol 10c (1.7g, 2.90mmo1) was dissolved in 50mL of N,N-dimethylformamide, cooled to 0 ° C, added 60% sodium hydride (620mg, 14.0mmol), reacted at room temperature for 1 hour, added Benzyl bromide (1.90 mL, 14 mmol) was reacted for 3 hours. 5 mL of methanol and 100 mL of water were added, and the mixture was extracted with ethyl acetate (50 mL × 3), and the organic phase was washed with saturated sodium chloride (30 mL). [[(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1, 1,2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl- Dimethyl-decane 10d (2.45 g, yellow liquid) was used in the next reaction without isolation.

the fifth step [(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1,1 ,2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol

[[(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1) ,1,2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-t-butyl M-dimethyl-decane 10d (2.45 g, 2.90 mmol) was dissolved in 30 mL of methanol, and ethyl acetate (50 μL, 0.4 mmol) was added and reacted for 4 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The obtained residue was purified to give the title product [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3- Fluorine-4-1,1,2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 10e (1.2 g, yellow liquid), yield: 56.8%.

Step 6 (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1,1, 2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde

The grass chloroform (0.36 mL, 3.93 mmol) was dissolved in 5 mL of dichloromethane, cooled to -78 ° C, and 10 mL of a solution of dimethyl hydrazine (0.35 mL, 4.92 mmol) in dichloromethane was added dropwise for 15 minutes. Add 15 mL [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1) ,1,2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 10e (1.2 g, 1.64 mmol) The methylene chloride solution was reacted for 45 minutes, and triethylamine (1.2 mL, 8.2 mmol) was added dropwise, and the mixture was reacted at room temperature for 2.5 hours. Was added 5mL 1M hydrochloric acid solution and extracted with dichloromethane (15mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S, 5 R, 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1,1,2,2,2-pentamethoxy) Phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 10f (1.2 g, yellow liquid) was used in the next step without isolation.

Seventh step [(3 S ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1,1,2, 2,2-quinolinomethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol

(2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1,1) , 2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 10f (1.2 g, 1.64 mmol) dissolved in 40 mL 1 To the 4-dioxane, formaldehyde (2.2 mL, 7.54 mmol) and potassium hydroxide (0.27 g, 4.92 mmol) were added, and benzyl alcohol (177 mg, 1.64 mmol) was added and reacted at 50 ° C for 6 hours. 20mL of water was added, extracted with ethyl acetate (20 mL × 3), combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product [(3 S, 4 S, 5 R, 6 S) - 3,4,5-tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(1,1,2,2,2-pentamethoxy)phenyl]- yl] phenyl] -2- (hydroxymethyl) -6-methoxy - tetrahydropyran-2-yl] methanol 10g (0.64g, yellow liquid), without isolation directly used for the next reaction.

Eighth step [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[[3-fluoro-4-(1,1) ,2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol

[(3 S ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[3-fluoro-4-(-pentamethine) Oxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 10 g (640 mg, 0.83 mmol) dissolved in 20 mL of dichloromethane Medium, 0.5 mL of trifluoroacetic acid was added dropwise, and the reaction was carried out for 2 hours. The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to D resulting residue was purified eluent system, to give the title product [(1 S, 2 S, 3 S, 4R, 5 S) -2,3,4- Tribenzyloxy-5-[4-chloro-3-[[3-fluoro-4-(1,1,2,2,2-pentamethoxy)phenyl]methyl]phenyl]- 6,8-Dioxabicyclo[3.2.1]octane-1-yl]methanol 10h (300 mg, pale yellow solid), yield: 41.0%.

MS m/z (ESI): 747.3 [M+18]

Step 9 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[[3-fluoro-4-(1,1,2,2,2-quinone methoxy) Phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

[(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[[3-fluoro-4-(1, 1,2,2,2-quinodimethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 10h (300mg , 0.41 mmol) dissolved in 30 mL of a mixed solvent of tetrahydrofuran and methanol (v: v = 1:1), followed by the addition of o-dichlorobenzene (600 mg, 4.10 mmol) and palladium/carbon (30 mg, 10%). Three times, the reaction was carried out for 3 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, separation by reverse-phase column to elute the surfactant system F The resulting residue was purified to give the title product (1 S, 2 S, 3 S, 4 R, 5 S) -5- [ 4-Chloro-3-[[3-fluoro-4-(1,1,2,2,2-pentamethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)- 6,8-Dioxabicyclo[3.2.1]octane-2,3,4-triol 10 (134 mg, white solid), yield: 70.0%.

MS m/z (ESI): 477.1 [M+18]

¹ H NMR (400 MHz, CD ₃ OD): δ 7.49 (d, 1H), 7.46-7.30 (m, 2H), 7.05-6.81 (m, 3H), 4.17 (d, 1H), 4.06 (s, 2H) ), 3.86 (d, 1H), 3.79 (s, 1H), 3.75-3.51 (m, 4H)

Example 11 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[di-deutero-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl ]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

first step (5-bromo-2-chloro-phenyl)-deutero-(4-ethoxy-3-fluoro-phenyl)methanol

(5-Bromo-2-chloro-phenyl)-(4-ethoxy-3-fluoro-phenyl)methanone 4c (15.0 g, 41.96 mmol) was dissolved in 120 mL of tetrahydrofuran. Aluminum (12.3 g, 92 mmol) was added in portions with sodium tetrahydroborohydride (7.00 g, 167.2 mmol) and 150 mL of trifluoroacetic acid. The reaction was quenched by the addition of 15 mL of EtOAc. EtOAc (EtOAc m. The title product (5-bromo-2-chloro-phenyl)-deutero-(4-ethoxy-3-fluoro-phenyl)methanol 11a (15.6 g, orange oil) was obtained without isolation Used directly in the next step.

Second step 4-[(5-bromo-2-chloro-phenyl)-di-deutero-methyl]-1-ethoxy-2-fluoro-benzene

(5-Bromo-2-chloro-phenyl)-deutero-(4-ethoxy-3-fluoro-phenyl)methanol 11a (6.4 g, 18.3 mmol) was dissolved in 40 mL of trifluoroacetic acid and added to Deuterated sodium borohydride (1.6 g, 38 mmol) was reacted for 3 hours. The reaction was quenched by the addition of 50 mL of EtOAc EtOAc (EtOAc m. The resulting eluent B in the residue system, to give the title product 4 - [(5-bromo-2-chloro - phenyl) - dideutero - methyl] -1-ethoxy-2-fluoro - benzene 11b (4.3 g, colorless oil), yield: 67.8%. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.43-7.23 (m, 3H), 7.03-6.85 (m, 3H), 4.21-4.08 (m, 2H), 1.54-1.44 (m, 3H)

third step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[di-deutero-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl ]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol

4-[(5-Bromo-2-chloro-phenyl)-di-deutero-methyl]-1-ethoxy-2-fluoro-benzene 11b (5.00 g, 16.4 mmol) was dissolved in 50 mL of tetrahydrofuran and 75 mL In a mixed solvent of n-hexane, cooled to -78 ° C, n-butyllithium (9.00 mL, 21.6 mmol) was added dropwise, and reacted at -78 ° C for 2 hours, and 30 mL (3 R , 4 S , 5 R , 6 R ) was added dropwise. a solution of -3,4,5-tris(trimethyldecyloxy)-6-(trimethyldecyloxymethyl)tetrahydropyran-2-one 2f (7.4 g, 15.8 mmol) in n-hexane The reaction was carried out at -78 ° C for 2 hours, and 3.5 mL of methanesulfonic acid and 40 mL of methanol were added thereto, and the mixture was reacted at room temperature for 16 hours. The reaction was quenched by the addition of EtOAc EtOAc (EtOAc) The filtrate was concentrated under reduced pressure, column chromatography using silica gel A to the resulting residue was purified eluent system, to give the title product (2 S, 3 R, 4 S, 5 S, 6 R) -2- [4- chloro - 3-[Di-deutero-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4 , 5-triol 11c (2.4 g, colorless liquid), yield: 36.4%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.57-7.34 (m, 3H), 7.04-6.81 (m, 3H), 4.20-3.80 (m, 8H), 3.52 (s, 3H), 2.54 (br. s., 4H), 1.41-1.24 (m, 3H)

the fourth step (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[diindole -(4-Ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol

(2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[di-deutero-(4-ethoxy-3-fluoro-phenyl)methyl]benzene 6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 11c (2.4 g, 5.24 mmol) was dissolved in 40 mL of dichloromethane and then added 4- Dimethylaminopyridine (97 mg, 0.79 mmol) and imidazole (1.07 mg, 15.7 mmol) were added to butyl dimethyl chloro decane (0.87 g, 5.76 mmol) for 16 hr. The reaction solution was concentrated under reduced pressure, was added 200mL ethyl acetate, washed with saturated copper sulfate solution (50mL × 3) and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 R, 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[dioxin-(4-ethoxy) 3-fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 11d (2.87 g, pale yellow solid), used without isolation In the next step.

the fifth step [[(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-diindole-[(4-ethoxyl) 3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyldecane

(2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[ Deuterated-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 11d (2.87g, 5.02mmol Dissolved in 60 mL of N,N-dimethylformamide, 60% sodium hydride (1.00 g, 25.1 mmol) was added to the ice bath, added, and reacted at room temperature for 40 minutes, and benzyl bromide (3.00 mL, 25.1 mmol), react for 3 hours. The reaction was quenched by the addition of 20 mL of EtOAc. EtOAc was evaporated. EtOAc EtOAc. washed with a solution of sodium (50 mL), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product [[(2 R, 3 R , 4 S, 5 R, 6 S) -3,4,5 -tribenzyloxy-6-[4-chloro-3-[dioxin-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyridyl M--2-yl]methoxy]-tert-butyl-dimethylnonane 11e (3.00 g, yellow oil), yield: 99.8%.

Step 6 [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[di-deutero-(4-ethoxy- 3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol

[[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[di-deutero-(4-ethoxy) 3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyldecane 11e (4.22 g, 5.02 mmol) was dissolved in 30 mL of methanol, and acetonitrile (0.05 mL, 0.75 mmol) was added dropwise, and the mixture was reacted for 1 hour. The reaction solution was concentrated under reduced pressure, by silica gel column chromatography to B the resulting residue was purified eluent system, to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5 -tribenzyloxy-6-[4-chloro-3-[dioxin-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyridyl Methyl-2-yl]methanol 11f (1.45 g, yellow oil), yield: 55.0%.

Seventh step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[di-deutero-(4-ethoxy-3) -fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde

The grass chloroform (0.3 mL, 3.57 mmol) was dissolved in 20 mL of dichloromethane, cooled to -78 ° C, and 10 mL of dimethyl hydrazine (0.39 mL, 5.48 mmol) in dichloromethane and 15 mL [(2) R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[di-deutero-(4-ethoxy-3-fluoro) -Phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 11f (2 g, 2.74 mmol) in methylene chloride, react at -78 ° C for 30 min, add three Ethylamine (1.9 mL, 13.7 mmol) was reacted at room temperature for 2 hours. The reaction was quenched by the addition of 5 mL of 1M EtOAc. EtOAc (EtOAc m. The filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4-chloro-3- [dideuterio - (4-Ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 11 g (2.00 g, yellow oil), without isolation Used for the next reaction.

Eighth step (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[di-deutero-(4-ethoxy-3) -fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde

(2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[dioxin-(4-ethoxy- 3-Fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carboxaldehyde 11g (2.00g, 2.74mmol) was dissolved in 30mL of 1,4-dioxane, added sequentially 4.1 mL of a 37% aqueous solution of formaldehyde and sodium hydroxide solution (330 mg, 2.74 mmol) were reacted at 70 ° C for 6 hours. After adding 20 mL of a saturated sodium chloride solution and extracting with ethyl acetate (20 mL × 4), the organic phase was washed with saturated sodium hydrogen sulfate (20 mL) , filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4-chloro-3- [bis Deuterated-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 11h (2.1g , yellow oil), used directly in the next reaction without isolation.

Step 9 [(3 S ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[di-deutero-(4-ethoxy-3-fluoro) -phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol

(2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[dioxin-(4-ethoxy- 3-Fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 11h (2.07 g, 2.74 mmol) dissolved in 30 mL of tetrahydrofuran and methanol In a mixed solvent of (v: v = 2: 3), sodium borohydride (200 mg, 5.48 mmol) was added, and the mixture was reacted for 2 hours. The reaction was quenched with small amount of acetone was added, the reaction solution was concentrated under reduced pressure, column chromatography using silica gel A to the resulting residue was purified eluent system, to give the title product [(3 S, 4 S, 5 R, 6 S) -3 ,4,5-tribenzyloxy-6-[4-chloro-3-[diindole-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxyl) 6-methoxy-tetrahydropyran-2-yl]methanol 11i (0.20 g, colorless oil), yield: 10%.

¹ H NMR (400 MHz, CDCl ₃ ): δ 7.39-7.19 (m, 16H), 7.04 (dd, 2H), 6.89-6.74 (m, 3H), 5.03-4.86 (m, 3H), 4.72-4.59 ( m, 2H), 4.45-4.30 (m, 2H), 4.05 (q, 2H), 3.98 (dd, 2H), 3.90-3.80 (m, 2H), 3.75-3.62 (m, 1H), 3.25 (d, 1H), 3.06 (s, 3H), 1.42 (t, 3H)

Step 10 [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-Tribenzyloxy-5-[4-chloro-3-[di-deutero-(4-ethoxy- 3-fluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol

[(3 S ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[di-deutero-(4-ethoxy-3- Fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 11i (0.50 g, 6.60 mmol) was dissolved in dichloromethane (2 mL) The mixture was cooled to -10 ° C, and 1 mL of trifluoroacetic acid was added thereto, and the mixture was reacted at room temperature for 2 hours. The reaction was quenched by the addition of 5 mL of EtOAc EtOAc (EtOAc m. The resulting eluent B in the residue system, to give the title product [(1 S, 2 S, 3 S, 4 R, 5 S) -2,3,4- three benzyloxy-5- [4-chloro - 3-[Di-deutero-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 11j (300 mg, white solid), yield: 62.6%.

MS m/z (ESI): 744.0 [M+18]

The eleventh step (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[di-deutero-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl ]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

[(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-tribenzyloxy-5-[4-chloro-3-[di-deutero-(4-ethoxy) 3-fluoro-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 11j (300 mg, 0.41 mmol) dissolved in 10 mL of tetrahydrofuran and methanol In a mixed solvent of (v: v = 1:1), o-dichlorobenzene (600 mg, 0.41 mmol) and palladium/carbon (30 mg, 10%) were added, and hydrogen was replaced three times for 3 hours. The reaction solution was filtered, rinsed with a small amount of ethyl acetate, and the filtrate was concentrated under reduced pressure, column chromatography using silica gel A to the resulting residue was purified eluent system, to give the title product (1 S, 2 S, 3 S, 4 R , 5 S )-5-[4-chloro-3-[di-deutero-(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-1-(hydroxymethyl)-6, 8-Dioxabicyclo[3.2.1]octane-2,3,4-triol 11 (143 mg, white solid), yield: 76.0%.

MS m/z (ESI): 474.1 [M+18]

¹ H NMR (400 MHz, CD ₃ OD): δ 7.49 (d, 1H), 7.45-7.36 (m, 2H), 7.00-6.88 (m, 3H), 4.17 (d, 1H), 4.08 (q, 2H) ), 3.89-3.77 (m, 2H), 3.73 - 3.54 (m, 4H), 1.40 (t, 3H)

Example 12 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl] -1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

first step 2,2-difluoroethoxybenzene

Under nitrogen protection, 60% NaH (10.2g, 254.27mmol) and 40mL DMF were added to a 500mL reaction flask, cooled to 0 ° C, 2,2-difluoroethanol 12a (23g, 280.3mmol) was dissolved in 40mL DMF Add dropwise to the reaction flask, control the temperature at 0 ° C, complete the dropwise addition for 4 hours, raise the room temperature, react for 30 minutes, and then add bromobenzene (39.92 g, 254.25 mmol) in DMF (40 mL) and CuBr (0.35 g, 2.43mmol), after the addition, the temperature was raised to 160 ° C, the reaction was stirred for 16 hours, cooled to room temperature, filtered, and the filter cake was washed with n-hexane, and 5% hydrochloric acid (160 mL) was added to the filtrate, and n-hexane (160 mL×3) was used. The combined organic phases were washed with saturated sodium chloride solution (50mL) and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product ethoxy-2,2-difluoro-benzene 12c (32.97g , yellow liquid), yield: 82.0%.

Second step 2-chloro-5-bromo-benzylguanidine chloride

2-Chloro-5-bromo-benzoic acid (35 g, 148.6 mmol) was dissolved in toluene (230 mL) under argon, and DMF (0.5 mL) was added at room temperature, and then cooled to 0 ° C.碸(44g, 372mmol), after the dropwise addition, the mixture was warmed to 100 ° C, and the reaction was carried out for 5 hours, and concentrated under reduced pressure to give the title product 2-chloro-5-bromo-benzopyridinium chloride 12n (35.5 g, pale yellow oil). Yield: 94.0%.

third step (5-bromo-2-chlorophenyl)(4-difluoroethoxyphenyl)methanone

2-Chloro-5-bromo-benzoguanidine chloride 12n (37.7 g, 148.6 mmol) was dissolved in 350 mL of dichloromethane at room temperature under the protection of argon, and 2,2-difluoroethoxybenzene 12c (25 g) was added. , 158.6mmol), stirred and dissolved, cooled to 0 ° C, added aluminum trichloride (19.1g, 142.4mmol) in portions, added, temperature control 0 ° C, reaction for 2 hours, the reaction solution was poured into 300mL ice water, stirred After 30 minutes, the layers were separated and evaporated with w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 200 mL), dried combined organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title product (5-bromo-2-chlorophenyl) (4-fluoro-ethoxyphenyl) methanone 12o (56g , yellow oil), yield: 99.0%.

the fourth step 4-bromo-1-chloro-2-[[4-(2,2-difluoroethoxy)phenyl]methyl]benzene

(5-Bromo-2-chlorophenyl)(4-difluoroethoxyphenyl)methanone 12o (55.7 g, 148.6 mmol) was dissolved in 400 mL of acetonitrile under argon and triethyldecane was added (46.54). g, 401.22mmol), cooled to 0 ° C, slowly drip boron trifluoride etherate (57g, 401.22mmol), add, heat to 50 ° C, reaction for 16 hours, cooled to room temperature, add 200mL methyl third The ether was added dropwise, 300 mL of a saturated aqueous solution of sodium bicarbonate, and the organic layer was washed with 200 mL of brine. 1-Chloro-2-[[4-(2,2-difluoroethoxy)phenyl]methyl]benzene 12p (20 g, colourless oil), yield: 20.0%.

MS m/z (ESI): 362.0 [M+1]

the fifth step (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl] -6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol

Under the protection of argon, 4-bromo-1-chloro-2-[[4-(2,2-difluoroethoxy)phenyl]methyl]benzene 12p (26.5 g, 73.3 mmol), methyl Tributyl ether (266 mL) and n-hexane (133 mL) were added to a 1 L reaction flask, stirred well, and cooled to -78 ° C. 2.4 M n-butyllithium (52 mL, 124.6 mmol) was added dropwise, and the addition was completed in 30 minutes. Stir at -78 ° C for 50 minutes, add (3 R , 4 S , 5 R , 6 R )-3,4,5-tris(trimethyldecyloxy)-6-(trimethyldecyloxymethyl) a mixture of tetrahydropyran-2-one 2f (55 g, 117.3 mmol) of methyl tert-butyl ether and n-hexane (60 mL: 30 mL), temperature control -78 ° C, 20 minutes dropwise, control After reacting at -78 ° C for 4 hours, adding 130 mL of methanol, stirring for 20 minutes, adding methanesulfonic acid (25 g, 256.55 mmol), raising to room temperature, reacting for 16 hours, adding 500 mL of saturated sodium hydrogencarbonate to the reaction solution. After stirring for 1 hour, the layers were separated, and the aqueous phase was extracted with methyl tert-butyl ether (100 mL × 2). The organic phase was combined and purified by column chromatography (eluent: dichloromethane: methanol = 100:1 to 10: 1) The title product (2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]- Phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydro Pyran-3,4,5-triol 12e (5 g, pale yellow solid), yield 10%.

MS m/z (ESI): 492.46 [M+18]

Step 6 (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[4 -(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol

(2 S , 3 R , 4 S , 5 S , 6 R )-2-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl ]-6-(Hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 12e (4g, 8.43mmol) was dissolved in 40mL of dichloromethane, then added 4-dimethyl Aminopyridine (103 mg, 0.84 mmol), tert-butyldimethylchloromethane (1.4 g, 9.27 mmol) and imidazole (1.72 g, 25.3 mmol) were reacted for 16 hours. 40mL of saturated sodium bicarbonate was added, stirring separated and the organic layer was washed successively with 0.1N hydrochloric acid (20mL) and washed with 40mL saturated aqueous sodium chloride, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the title product (2 S, 3 R , 4 S , 5 S , 6 R )-6-[(t-butyl(dimethyl)decyl)oxymethyl]-2-[4-chloro-3-[[4-(2, 2-Difluoroethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 12f (4.96 g, pale yellow solid), yield: 100%.

Seventh step [[(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoro) Ethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane

60% sodium hydride (1.9 g, 47.21 mmol) and 15 mL of tetrahydrofuran were added to a 100 mL reaction flask, and the temperature was lowered to 0 ° C. (2 S , 3 R , 4 S , 5 S , 6 R )-6-[(third Butyl (dimethyl)nonanyloxymethyl]-2-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2 -Methoxy-tetrahydropyran-3,4,5-triol 12f (4.96g, 8.43mmol) was dissolved in 18mL of tetrahydrofuran, added dropwise to the reaction system, controlled temperature 0 ° C, 10 minutes after the completion of the addition, continue After stirring for 30 minutes, a solution of benzyl bromide (7.21 g, 42.15 mmol) in N,N-dimethylformamide (10 mL) was added dropwise, and the mixture was allowed to react at room temperature for 16 hours. Then, 200 mL of ethyl acetate and saturated were added to the reaction mixture. The sodium bicarbonate solution (70 mL) and water (50 mL) were evaporated, evaporated, evaporated. The product [[(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-) Fluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane 12g (7.25g, Light yellow liquid), used directly in the next reaction without separation

Eighth step [(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoro) Oxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol

[[(2 R ,3 R ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[4-(2,2-) Fluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]-tert-butyl-dimethyl-decane 12g (4.10g, 4.78 mmol) was dissolved in 30 mL of methanol, and acetonitrile (51 μL, 0.72 mmol) was added and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, The resulting residue was purified by column chromatography to give the title product [(2 R, 3 R, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6 [4-Chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 12h ( 1.23 g, white oil), Yield: 34.6%.

Step 9 (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy) Phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde

The grass chloroform (0.18 mL, 2.16 mmol) was dissolved in 5 mL of dichloromethane, cooled to -78 ° C, and 3 mL of dimethyl hydrazine (0.23 mL, 3.31 mmol) in dichloromethane was added dropwise. Add 10 mL [(2 R , 3 R , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-) a solution of fluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol in 12h (1.23 g, 1.66 mmol) in dichloromethane for 40 min. Triethylamine (1.2 mL, 8.31 mmol) was added and allowed to react at room temperature for 3 hours. 5mL 1M hydrochloric acid solution was added, and liquid separation, the aqueous phase was extracted with ethyl acetate (20mL × 2), organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product (2 S, 3 S, 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl] Phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 12i (1.10 g, yellow oil) was used in the next step without isolation.

Step 10 (2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy) Phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde

(2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoro) Oxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 12i (1.10 g, 1.48 mmol) was dissolved in 20 mL of 1,4-dioxane, and 2.5 mL was added. A 37% formaldehyde solution was added dropwise with 4 mL of a 2.9 M sodium hydroxide solution, and reacted at 70 ° C for 25 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy) Phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 12j (1.09 g, yellow oil), used directly without isolation One step reaction.

The eleventh step [(3 S ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy) Phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol

(2 S , 3 S , 4 S , 5 R , 6 S )-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoro) Oxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 12j (1.09 g, 1.42 mmol) was dissolved in 30 mL of tetrahydrofuran and methanol In a mixed solvent of (v: v = 1: 2), sodium borohydride (108 mg, 2.83 mmol) was added portionwise, and the mixture was reacted for 30 minutes. After adding 20 mL of water, adding 30 mL of water, and extracting with ethyl acetate (30 mL × 3), the organic phase was washed with saturated sodium chloride solution (30 mL). The resulting residue was purified by column chromatography to give the title product [(3 S, 4 S, 5 R, 6 S) -3,4,5- three-benzyloxy-6- [4-chloro-3 - [[4- (2,2-Difluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 12k (293mg, yellow Oil), yield: 27.0%.

Step 12 [(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-Tribenzyloxy-5-[4-chloro-3-[[4-(2,2-difluoro) Oxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol

[(3 S ,4 S ,5 R ,6 S )-3,4,5-Tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy) Phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 12k (293 mg, 0.38 mmol) dissolved in 10 mL of dichloromethane The reaction was carried out for 1 hour by dropwise addition of 0.1 mL of trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, The resulting residue was purified by column chromatography to give the title product [(1 S, 2 S, 3 S, 4 R, 5 S) -2,3,4- three benzyloxy-5- [4-Chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1 -Based methanol 12 m (76 mg, white solid), yield: 27.6%.

Step 13 (1 S , 2 S , 3 S , 4 R , 5 S )-5-[4-chloro-3-[[4-(2,2,2-difluoroethoxy)phenyl]methyl]benzene 1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol

[(1 S , 2 S , 3 S , 4 R , 5 S )-2,3,4-Tribenzyloxy-5-[4-chloro-3-[[4-(2,2-difluoro) Ethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]methanol 12m (76 mg, 0.10 mmol) was dissolved in 10 mL of tetrahydrofuran and methanol ( In a mixed solvent of v:v = 1:1), o-dichlorobenzene (103 μL, 0.9 mmol) and palladium/carbon (180 mg, 10%) were successively added, and hydrogen was replaced three times for 2 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, purified by chromatography resulting residue was purified by column to give the title product (1 S, 2 S, 3 S, 4 R, 5 S) -5- [4- chloro-3- [ [4-(2,2,2-Difluoroethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane -2,3,4-triol 12 (17 mg, pale yellow solid, yield: 34.0%).

MS m/z (ESI): 490.24 [M+18]

¹ H NMR (400 MHz, CD ₃ OD): δ 7.48-7.49 (m, 1H), 7.37-7.39 (m, 2H), 7.15-7.17 (d, 2H), 6.88-6.91 (d, 2H), 6.02 -6.29(ddt,1H),4.23-4.24(d,1H), 4.20-4.21(d,1H),4.16-4.17(d,1H),4.08(s,2H),3.78-3.88(m,2H) , 3.67-3.72 (m, 2H), 3.55-3.57 (m, 2H)

Test case: SGLT1 and SGLT2 activity assay

The following method can be used to determine the inhibitory activity of the compounds of the invention against SGLT1 and SGLT2 . The experimental methods are briefly described as follows: SGLT1 or SGLT2 transient transfectants were inoculated in 96-well plates (prepared according to the existing literature "Diabetes, 57, 1723-1729, 2008", in which the cDNAs of SGLT1 and SGLT2 were purchased from Origene), cells The density is from 1 to 1.5x10 ⁴ . The cells were cultured at 37 ° C, 5% CO ₂ for 48 hours, and then washed twice with 200 μL of sodium-free buffer; 90 μL of sodium-containing buffer containing different concentrations of the test compound was added to the well, and the corresponding concentration of each test compound was Make 3 repeating holes. After incubating the compound for 15 minutes at 37 ° C, 10 μL of a total of 0.1 μCi of [ ¹⁴ C]Methyl α-D-glucopyranoside (methyl α-D-glucopyranoside) was added to each well of a 96-well plate. After incubating for 2 hours at 37 ° C, the supernatant was discarded, and the cells were washed twice with pre-cooled sodium-free buffer, and the cells were lysed with 100 μL of 200 mM NaOH, and 100 μL of scintillation fluid was added thereto, followed by mixing. The ¹⁴ C was quantitatively detected by a liquid scintillation meter.

IC ₅₀ values for compounds may be obtained by aggregation rate calculated at different concentrations.

Conclusion: The compounds of the present invention have high selectivity to SGLT2 and have significant inhibitory effects on SGLT2.

Preliminary evaluation of hypoglycemic effect Research purpose

The effects of test compounds on the blood glucose level of glucose-loaded mice were observed. The glucose content in the tail of the mice at different times within 2 hours after the administration of sugar was measured and analyzed by blood glucose meter, and the hypoglycemic effect in vivo was evaluated. .

2. Test compound

Example 1, Example 2, Example 4, Example 5, Example 6, Example 7, and Example 8 compound

3. Test animals

Healthy ICR mice (body weight 20 to 24 g) 56, 28 females and 28 males were purchased from Shanghai Xipuer-Beikai Experimental Animal Co., Ltd., animal production license number: SCXK (Shanghai) 2008-0016.

4. Drug preparation

Weigh an appropriate amount of sample and add water (the water source is pure water produced by the company) to prepare an aqueous solution of 0.1 mg/mL (containing 5% DMSO for solubilization).

5. Test method

5.1 Dose setting

The doses administered were 1 mg/kg, respectively, and the control (Blank) group was given water (both containing 5% DMSO).

5.2 Administration method

The drug was administered by intragastric administration, and after 15 minutes of administration, a 20% glucose solution (0.8 mL per mouse) was administered at 4 g/kg.

5.3 Determination of blood glucose levels

The blood glucose level (-15 minutes) was measured by dosing.

After 15 minutes of administration, a 20% glucose solution was administered at 4 g/kg, and the blood glucose level of each mouse was measured at 0, 15, 30, 45, 60, and 120 minutes using a Roche Rocco whole blood glucose meter, and the drug was calculated. The rate of decline under the curve area (AUC).

6. Test results:

Conclusion: The compounds of the invention showed a significant decrease in blood glucose after 15 minutes of administration.

Claims (18)

A compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof: Wherein: Ring A is selected from aryl or heteroaryl, wherein each of the aryl or heteroaryl is independently further optionally one or more selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle. Base, aryl, heteroaryl, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR Substituted by a substituent of ⁸ R ⁹ wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups may be further optionally, if desired, further selected from one or more selected from the group consisting of a halogen atom, a halogen, an alkenyl group, Alkynyl, nitro, cyano, alkoxy, cycloalkyl, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , -C(O)OR ⁷ , -NR ⁸ R Substituted with a substituent of ⁹ or -C(O)NR ⁸ R ⁹ ; each of R ¹ , R ² , R ³ or R ^{4 is} independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a hydroxyl group, an amine group, an alkyl group, and an alkyl group. An oxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently further optionally one by one Or substituted with a plurality of substituents selected from the group consisting of a halogen atom, a halogen, a hydroxyl group, an amine group, an alkyl group, an alkoxy group, a carboxylic acid or a carboxylic acid ester; or , R ² and R ³ may be fused to a phenyl group to form a ring which is optionally a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein a cycloalkyl group, a heterocyclic group, an aryl group or The heteroaryl groups are each independently optionally one or more selected from the group consisting of halogen, hydroxy, amine, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl. Substituting a substituent of a carboxylic acid or a carboxylic acid ester; provided that when ring A is a phenyl group, R ² , R ³ and R ⁴ are a hydrogen atom, and R ^{1 is} selected from a hydrogen atom, a C _1-4 alkyl group, F , Cl, cyano or -OR ¹⁰ when the ring a can be selected from a C _1-4 alkyl, F., Cl, cyano, hydroxy, -OR ^11, F a C _1-2 substituted alkyl, -S (O) ₂ R ¹¹ , C _3-6 cycloalkyl, substituted with a substituent of 1-2 N, O or S C _5-6 saturated heterocyclic groups; R ⁵ and R ⁶ are each independently selected from a hydrogen atom or a halogen atom; R ^{7 is} selected from a hydrogen atom, a halogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or The heteroaryl groups may each independently be further optionally one or more selected from the group consisting of a halogen atom, an alkyl group, and a halogen. Substituted by a substituent of a hydroxyl group, an amine group, an alkoxy group, a cycloalkyl group, a cycloalkoxy group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; R ⁸ or R ⁹ are each independently selected From a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently further optionally one by one Or substituted with a plurality of substituents selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amine group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxylic acid or a carboxylic acid ester; or, R ⁸ Or R ⁹ forms a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, O or S(O) _m heteroatoms, and the heterocyclic group is further optionally one or more Substituted by a substituent selected from alkyl, halo, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxylic acid; R ¹⁰ is C _1-4 alkyl ; R ^{11 is} selected from C _1-4 alkyl, ; and m is 0, 1, or 2. a compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to the first aspect of the invention, which comprises a compound of the formula (II) or a pharmaceutically acceptable compound thereof salt: A compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 1, wherein the ring A is an aryl group, wherein the aryl group is further further optionally Or a plurality selected from halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ⁷ , -S(O) _m R ⁷ , -C(O)R ⁷ , —C(O)OR ⁷ , —NR ⁸ R ⁹ or —C(O)NR ⁸ R ⁹ , wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently required Further one or more selected from the group consisting of a halogen atom, a halogen, an alkenyl group, an alkynyl group, a nitro group, a cyano group, an alkoxy group, a cycloalkyl group, -OR ⁷ , -S(O) _m R ⁷ , -C(O Substituting a substituent of R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ . a compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 3, wherein: R ² , R ³ or R ⁴ are each independently a hydrogen atom; And R ¹ is a halogen. A compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to the third aspect of the invention, wherein the ring A is a phenyl group, wherein the phenyl group is further further 1 as needed Substituted to 5 substituents selected from halogen or -OR ⁷ ; R ⁷ is alkyl, wherein the alkyl group may be further 1 to 3 selected from the group consisting of a halogen atom, a halogen, an alkoxy group or a cycloalkoxy group. Substituted by a substituent. A compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to the first aspect of the invention, wherein the ring A is a heteroaryl group, wherein the heteroaryl group may be optionally One or more selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁷ , -S(O) _m R ⁷ , -C(O R ⁷ , —C(O)OR ⁷ , —NR ⁸ R ⁹ or —C(O)NR ⁸ R ⁹ , wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Desirably further selected from one or more selected from the group consisting of a halogen atom, a halogen, an alkenyl group, an alkynyl group, a nitro group, a cyano group, an alkoxy group, a cycloalkyl group, -OR ⁷ , -S(O) _m R ⁷ , -C Substituting (O) a substituent of R ⁷ , -C(O)OR ⁷ , -NR ⁸ R ⁹ or -C(O)NR ⁸ R ⁹ . a compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 6 wherein R ² , R ³ or R ⁴ are each independently a hydrogen atom; R ¹ is a halogen. a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described in claim 6 of the patent application, wherein the ring A is Or thienyl. The compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 8, wherein the ring A is optionally one or more Substituted by a substituent selected from halogen or -OR ⁷ ; provided that when ring A is substituted with a substituent of OR ⁷ wherein R ⁷ is C _1-4 alkyl, then ring A must be simultaneously Replaced by multiple halogens. The compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1 to 8, wherein R ⁵ or R ⁶ is a halogen atom. The compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, according to any one of claims 1 to 8, wherein R ⁷ is an alkyl group, the alkyl group further Substituted by one or more substituents selected from ruthenium atoms. The compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of: A method for preparing a compound of the formula (I) according to the first aspect of the patent application, the method comprising: Converting a compound of formula (IA) to a compound of formula (IB); Further deprotecting the compound of formula (IB) gives a compound of formula (I); wherein: R ¹ to R ⁶ and ring A are as defined in claim 1; X, Y is a hydroxy protecting group group. The method of claim 13, wherein X, Y is an alkyl group or a benzyl group. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutically acceptable carrier. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to any one of claims 1 to 12, or a pharmaceutical product according to claim 15 The use of a composition for the preparation of a sodium-dependent glucose transporter inhibitor. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to any one of claims 1 to 12, or a pharmaceutical product according to claim 15 The use of a composition for the preparation of a medicament for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia Hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications or atherosclerosis or hypertension. The compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, according to any one of claims 1 to 12, or as described in claim 15 A pharmaceutical composition for treating or delaying the development or onset of a disease selected from the group consisting of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, Elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, or atherosclerosis or hypertension.