CN111471032B - Synthesis method of glycoside derivative, intermediate and application thereof - Google Patents

Synthesis method of glycoside derivative, intermediate and application thereof Download PDF

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CN111471032B
CN111471032B CN201910065991.4A CN201910065991A CN111471032B CN 111471032 B CN111471032 B CN 111471032B CN 201910065991 A CN201910065991 A CN 201910065991A CN 111471032 B CN111471032 B CN 111471032B
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triol
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CN111471032A (en
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张保献
张宏武
胡杰
康志云
薛春美
李文慧
宋艳威
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Beijing Increase Innovative Drug Co ltd
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Beijing Increase Innovative Drug Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the field of compound preparation and intermediates thereof, and particularly relates to a synthesis method of a glycoside derivative, an intermediate and application thereof. The intermediate compound is a compound shown in a formula II or a salt thereof:the novel intermediate compound provided by the invention is used for synthesizing the glycoside derivative shown in the formula I, and the glycoside derivative with high purity can be prepared.

Description

Synthesis method of glycoside derivative, intermediate and application thereof
Technical Field
The invention belongs to the field of compound preparation and intermediates thereof, and particularly relates to a synthesis method of a glycoside derivative, an intermediate and application thereof.
Background
Diabetes is an endocrine and metabolic disease that causes disturbances in the metabolism of sugar, fat and proteins due to relative or absolute hyposecretion of insulin in the body, or a decrease in its biological effects. The international diabetes association (IDF) predicts that the worldwide number of diabetics will reach 5.9 billion by 2035. Diabetes mellitus is classified into type I diabetes mellitus and type II diabetes mellitus; type I diabetes is an organ-specific autoimmune disease, and because of the life-long existence of the diabetes, the existing treatment method mainly comprises daily insulin injection and diet control, and patients are very painful; in recent years, a plurality of new breakthroughs are made for treating type I diabetes, such as chemical drug treatment and the like. Because of complex pathogenesis and long course of disease, the current therapeutic drugs are difficult to control blood sugar level, so that a novel hypoglycemic drug with a brand new action mechanism is urgently needed clinically.
Studies have shown that healthy adults have approximately 180 g glucose per day filtered through the glomeruli, with > 99% of the glucose being reabsorbed from the tubules. Under the condition of hyperglycemia, sodium-glucose cotransporters (SGLTs) are saturated, a large amount of glucose is excreted with urine, the SGLTs are currently hot targets for treating diabetes, and the number of human SGLT protein families is expanded to 12: SGLT1 to SGLT6 and another 6 SLC5A proteins, of which SGLT-1 and SGLT-2 play a dominant role. SGLT2 has a main function of reabsorption of glucose by the renal tubules, whereas SGLT1 has a main function of absorption of glucose from the gastrointestinal tract and distribution in various organs such as the heart and brain. In view of this, there is a need in the market to develop novel high-efficiency hypoglycemic agents for the treatment of type I diabetes.
Disclosure of Invention
In order to solve the technical problems, the invention provides a synthesis method of glycoside derivatives, an intermediate thereof and application thereof.
The first object of the present invention is to provide a preparation method of a glycoside derivative, wherein the glycoside derivative is a compound shown in formula I or a pharmaceutically acceptable salt thereof:
a formula I;
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 Independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
In the above preparation method, as a preferred embodiment, in the compound represented by the formula I, the R 2 Is hydrogen, hydroxy, -O-aryl, -OCH 2 -aryl, alkoxy, alkyl, aryl, heteroaryl, -CF 3 Or halogen.
In the above preparation method, as a preferred embodiment, in the compound represented by the formula I, the R 4 ，R 5 Independently hydrogen, hydroxy, alkoxy, -O-aryl, -OCH 2 -aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, or —cn; r is R 4 ，R 5 The same or different.
In the above preparation method, as a preferred embodiment, in the compound represented by the formula I, the R 6 Is hydrogen, hydroxy, carboxy, alkoxy, alkyl, cycloalkyl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, or —cn.
Further, R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 Independently hydrogen, hydroxy, carboxy, alkoxy (illustratively alkoxy is C1-C6 alkyloxy; C1-C6 alkyloxy is illustratively methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy, and the like), -O-aryl (illustratively, -O-aryl is、/>、/>、/>、/>、/>、/>Or->Etc.), the-O-heteroaryl (-O-heteroaryl is illustratively +.>、/>、/>、/>、/>、/>Or->Etc. -OCH 2 -aryl (-OCH) 2 The aryl group is illustratively PhCH 2 O-、、/>、/>、/>Or->Etc. -OCH 2 Heteroaryl (-OCH) 2 The heteroaryl group is illustratively +.>、/>、/>、/>、/>、、/>、/>Or->Etc.), alkyl (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.), cycloalkyl (illustratively cycloalkyl is C3-C6 cycloalkyl; C3-C6 cycloalkyl includes substituted cycloalkyl or unsubstituted cycloalkyl, illustratively cyclopropyl, cyclobutyl,/- >Cyclopentyl, cyclohexyl, or the like), aryl (illustratively, arylThe radicals are phenyl, p-methylphenyl, p-fluorophenyl, o-chlorophenyl, m-methoxyphenyl or +.>Etc.), heteroaryl (illustratively, heteroaryl is +.>、/>、/>、/>、/>、/>、/>、/>、/>、/>、/>Or->Etc. -CF) 3 、-OCHF 2 、-OCF 3 Halogen (illustratively, halogen is fluorine, chlorine, bromine, or iodine), -CN, alkoxyalkoxy (illustratively, alkoxyalkoxy is methoxymethoxy, ethoxymethoxy, ethoxyethoxy, n-propoxymethoxy, isopropoxymethoxy, n-propoxyethoxy)Radical, isopropoxyethoxy, or +.>Etc.), an ester group (illustratively, an ester group is +>、/>、/>、/>、/>Or->Etc.) or-NR 7 R 7a (illustratively, -NR) 7 R 7a Amino group, & lt>、/>Or->Etc.) or contain 1 to 4N, O, S, SO and/or SO 2 3-14 membered heterocyclic ring (exemplified by +.>、/>、/>、/>Or (b)Etc.);
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched chain alkyl, illustratively, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.);
wherein the alkyl, cycloalkyl, aryl, heteroaryl groups may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro.
In the above preparation method, as a preferred embodiment, the compound shown in the formula I is (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4-ethoxyphenoxy) -2H-pyran-3, 4, 5-triol, (2S, 5S, 6R) -2- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 4R, 6R) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 6- (4-ethoxybenzyl) -6R (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxy ethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4- (2, 4, 5-trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 5S, 6R) -2- (4-isobutoxy) phenyl) -6- (4-trifluoro-methyl) tetrahydro-2H-pyran-3, 5-triol, (2S, 3R,4R,5S, 6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol, or (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol.
In the above preparation method, as a preferred embodiment, the compound shown in formula I is prepared by deprotection reaction of an intermediate compound shown in formula II;
a formula II;
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
further, R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 Independently hydrogen, hydroxy, carboxy, alkoxy (illustratively alkoxy is C1-C6 alkyloxy; C1-C6 alkyloxy is illustratively methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy, and the like), -O-aryl (illustratively, -O-aryl is、/>、/>、/>、/>、/>、/>Or->Etc.), the-O-heteroaryl (-O-heteroaryl is illustratively +.>、/>、/>、/>、/>、/>Or->Etc. -OCH 2 -aryl (-OCH) 2 The aryl group is illustratively PhCH 2 O-、、/>、/>、/>Or->Etc. -OCH 2 Heteroaryl (-OCH) 2 The heteroaryl group is illustratively +.>、/>、/>、/>、/>、、/>、/>Or->Etc.), alkyl (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.), cycloalkyl (illustratively cycloalkyl is C3-C6 cycloalkyl; C3-C6 cycloalkyl includes substituted cycloalkyl or unsubstituted cycloalkyl, illustratively cyclopropyl, cyclobutyl,/->Cyclopentyl, cyclohexyl, or the like), aryl (illustratively, aryl is phenyl, p-methylphenyl, p-fluorophenyl, o-chlorophenyl, m-methoxyphenyl, or +.>Etc.), heteroaryl (illustratively, heteroaryl is +.>、/>、/>、/>、/>、/>、/>、/>、/>、/>、/>Or->Etc. -CF) 3 、-OCHF 2 、-OCF 3 Halogen (illustratively halogen is fluorine, chlorine, bromine, or iodine), -CN, alkoxyalkoxy (illustratively alkoxyalkoxy is methoxymethoxy, ethoxymethoxy, ethoxyethoxy, n-propoxymethoxy, isopropoxymethoxy, n-propoxyethoxy, isopropoxyethoxy, or +.>Etc.), an ester group (illustratively, an ester group is + >、/>、/>、/>、/>Or->Etc.) or-NR 7 R 7a (illustratively, -NR) 7 R 7a Amino group, & lt>、/>Or->Etc.) or contain 1 to 4N, O, S, SO and/or SO 2 3-14 membered heterocyclic ring (exemplified by +.>、/>、/>、/>Or (b)Etc.);
R 9 alkyl (illustratively, alkyl is C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched chain alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl, etc.), TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (t-butyldimethylsilyl);
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
Illustratively, when R is 9 In the case of TMS-or TBDMS-, the deprotecting reagent is TBAF; when R is 9 When Bn-, the deprotection reaction condition is H 2 /Pd-C、H 2 /Pt-C, or H 2 /Pd(OH) 2 -C, etc.; when R is 9 In the case of Ac-, the deprotection reaction conditions are strong base conditions (e.g., hydrogen oxidation Sodium aqueous solution, potassium hydroxide aqueous solution, etc.) or strong acid conditions; when R is 9 In the case of THP-or MOM-, the deprotection reaction conditions are acidic conditions (e.g., aqueous hydrochloric acid, ethyl hydrogen chloride (HCl (g)/EtOAc), methanolic hydrogen chloride (HCl (g)/CH) 3 OH), a hydrogen chloride ethanol solution (HCl (g)/EtOH), or a hydrogen chloride dioxane solution (HCl (g)/dioxane)); when R is 9 The deprotection reagent is concentrated hydrochloric acid, hydrobromic acid, concentrated sulfuric acid or boron tribromide.
In the above preparation method, as a preferred embodiment, the compound represented by formula II is prepared from a compound represented by formula III;
a compound of formula III;
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
R 9 alkyl (illustratively, alkyl is C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched chain alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl, etc.), TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (t-butyldimethylsilyl);
Wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
Illustratively, the reaction conditions for preparing a compound of formula II from a compound of formula III are BF 3 .Et 2 O。
In the above preparation method, as a preferred embodiment, the compound represented by formula III is prepared by reacting a compound represented by formula IV with a compound represented by formula V;
a compound of formula IV;
a compound of formula V;
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
R 8 is-H, -F, -Cl, -Br, -I, -OMs, -OTs, -OTf;
R 9 is alkyl (illustratively, alkyl is C1-C6 chain alkyl; C1-C6 chain alkyl includes straight chain alkyl or branched alkyl, illustratively, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl, etc.) ) TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (t-butyldimethylsilyl); the method comprises the steps of carrying out a first treatment on the surface of the
Wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
Illustratively, the reagent for preparing the compound of formula III from the compound of formula IV and the compound of formula V is LDA (lithium diisopropylamide), n-BuLi (n-butyllithium), or the like.
A second object of the present invention is to provide an intermediate compound which is a compound represented by formula II:
a formula II;
wherein A is oxygen, - (CH) 2 ) m -, or-NH-; m is 1, 2, or 3;
b is an oxygen atom or a sulfur atom;
R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, alkoxyalkoxy or-NR 7 R 7a Or contains 1 to 4 of N, O, S, SO and/or SO 2 3-14 membered heterocycle of heteroatoms of (2);
R 9 alkyl, TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (tert-butyldimethylsilyl);
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
Preferably, R 2 Is hydrogen, hydroxy, -O-aryl, -OCH 2 -aryl, alkoxy, alkyl, aryl, heteroaryl, -CF 3 Or halogen.
Preferably, R 4 ，R 5 Independently hydrogen, hydroxy, alkoxy, -O-aryl, -OCH 2 -aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, or —cn; r is R 4 ，R 5 The same or different.
Preferably, R 6 Is hydrogen, hydroxy, carboxy, alkoxy, alkyl, cycloalkyl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, or —cn.
Further, R 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 Independently hydrogen, hydroxy, carboxy, alkoxy (illustratively alkoxy is C1-C6 alkyloxy; C1-C6 alkyloxy is illustratively methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, n-pentyloxy, isopentyloxy, n-hexyloxy, and the like), -O-aryl (illustratively, -O-aryl is 、/>、/>、/>、/>、/>、/>Or->Etc.), the-O-heteroaryl (-O-heteroaryl is illustratively +.>、/>、/>、/>、/>、/>Or->Etc. -OCH 2 -aryl (-OCH) 2 The aryl group is illustratively PhCH 2 O-、、/>、/>、/>Or->Etc. -OCH 2 Heteroaryl (-OCH) 2 The heteroaryl group is illustratively +.>、/>、/>、/>、/>、、/>、/>Or->Etc.), alkyl (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.), cycloalkyl (illustratively cycloalkyl is C3-C6 cycloalkyl; C3-C6 cycloalkyl includes substituted cycloalkyl or unsubstituted cycloalkyl, illustratively cyclopropyl, cyclobutyl,/->Cyclopentyl, cyclohexyl, or the like), aryl (illustratively, aryl is phenyl, p-methylphenyl, p-fluorophenyl, o-chlorophenyl, m-methoxyphenyl, or +.>Etc.), heteroaryl (illustratively, heteroaryl is +.>、/>、/>、/>、/>、/>、/>、/>、/>、/>、/>Or->Etc. -CF) 3 、-OCHF 2 、-OCF 3 Halogen (illustratively halogen is fluorine, chlorine, bromine, or iodine), -CN, alkoxyalkoxy (illustratively alkoxyalkoxy is methoxymethoxy, ethoxymethoxy, ethoxyethoxy, n-propoxymethoxy, isopropoxymethoxy, n-propoxyethoxy, isopropoxyethoxy, or +. >Etc.), an ester group (illustratively, an ester group is/>、/>、/>、/>、/>Or->Etc.) or-NR 7 R 7a (illustratively, -NR) 7 R 7a Amino group, & lt>、/>Or->Etc.) or contain 1 to 4N, O, S, SO and/or SO 2 3-14 membered heterocyclic ring (exemplified by +.>、/>、/>、/>Or (b)Etc.);
R 9 is alkyl (illustratively, alkylIs C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched alkyl, illustratively methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.), TMS- (trimethylsilyl), bn- (benzyl), formyl, ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (t-butyldimethylsilyl);
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group (illustratively, alkyl is a C1-C6 chain alkyl; C1-C6 chain alkyl includes straight or branched chain alkyl, illustratively, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, etc.);
wherein the alkyl, cycloalkyl, aryl, heteroaryl groups may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro.
Further, the compound shown in the formula II is:、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、/>、/>、/>、、/>or->。
The third object of the invention is to provide an application of an intermediate compound in preparing the glycoside derivative, wherein the glycoside derivative is a compound shown in a formula I or a pharmaceutically acceptable salt thereof, the intermediate compound is a compound shown in a formula II, and the compound shown in the formula II is prepared into the compound shown in the formula I or the pharmaceutically acceptable salt thereof through deprotection reaction.
Compared with the prior art, the invention has the following technical effects:
1. the invention provides a novel intermediate compound, which is used for synthesizing a glycoside derivative shown in a formula I and can prepare the glycoside derivative with high purity.
2. The preparation method of the novel intermediate compound adopts cheap and easily available chemical products as the initial raw materials, and the synthesis yield of each step is higher, so that the production cost is lower and the method is more suitable for industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (compound 1);
FIG. 2 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (compound 2);
FIG. 3 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 3);
FIG. 4 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 4);
FIG. 5 is a High Performance Liquid Chromatography (HPLC) of intermediate compounds 4-7 of example 4.
Detailed Description
The glycoside derivative of the present invention, and the preparation method and application thereof are described below with reference to examples. It is to be understood that these examples are for the purpose of illustrating the invention only and are not to be construed as limiting the scope of the invention. It is to be understood that various changes and modifications may be made by one skilled in the art after reading the disclosure herein, and that such equivalents are intended to fall within the scope of the claims appended hereto.
The examples were conducted under conventional reaction conditions, where no specific conditions were noted. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1 preparation of compound 1: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Route 1:
(1) Preparation of intermediate compound 1-3 (1- (4-ethoxyphenoxy) -3, 5-difluorobenzene)
Parobromophenetole 100 g (1-1, 496 mmol, 1 eq), 3, 5-difluorophenol 97 g (1-2, 746 mmol, 1.5 eq) were taken, 1000 mL dioxane was added, cs was added sequentially to the above solution at 20 ℃C 2 CO 3 324 g (994 mmol, 2 eq), cuI 28.4g (149.2 mmol, 0.3 eq), isobutyl nitrite 30.8 g (298 mmol, 0.6 eq) and then stirred at 100 ℃ for 12h. Cooling to 20 ℃ after the reaction is completed, then distilling under reduced pressure to obtain a concentrate, extracting the concentrate by adopting water-petroleum ether, collecting a petroleum ether phase, and distilling under reduced pressure to obtain a crude product; the crude product is passed through a silica gel column, and the mobile phase is stoneThe oil ether gave 61.6g of pure compound 1-3 as a colorless oil in 24.8% yield.
(2) Preparation of intermediate Compounds 1-5
Taking compound 1-3.8 g (95.1 mmol, 1.0 eq), adding 165.0 mL to restille tetrahydrofuran at-70℃under N 2 To the above solution was added dropwise a solution of 71.3 mL (2.0M, 1.5 eq) LDA (lithium diisopropylamide) in tetrahydrofuran under nitrogen at-70 ℃ below zero, the above mixture was stirred for 0.5 h, then a solution of 1-4.2 g (95.1 mmol, 1.0 eq) of compound in tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise, and stirred for 1 h under nitrogen at-70 ℃. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 46.0. 46.0 g pure compound 1-5 as colorless oil with a yield of 61.3%.
(3) Preparation of intermediate Compounds 1-6
Compound 1-5.0 g (59.2 mmol, 1.0 eq) was weighed out, 320.0 mL dichloromethane was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 8.2 g (70.0 mmol, 1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O5.0 g (70.0 mmol, 1.2 eq), was warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0. 200.0 mL saturated aqueous sodium chloride solution, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=1:0 to 10:1, yielding 26.0. 26.0 g pure compounds 1 to 6 as colorless oils with a yield of 57.7%.
(4) Preparation of the target Compound 1 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
1-6.0 g (33.6 mmol, 1.0 eq) of the compound was weighed, 200.0 mL methanol was added, 15.0 g Pd/C (active material content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 50 psi hydrogen at 50℃for 24 h. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 50mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:30% -80%,20 min) to give 4.6 g of the target compound 1 as a white solid in a yield of 33.3%.
1H NMR（400 MHz，CD 3 OD），δ：6.96-7.03 (m, 4H), 6.45-6.49 (m, 2H), 4.53 (d, 1H), 4.06 (q, 2H), 3.85-3.88 (m, 2H), 3.65-3.75 (m, 1H), 3.34-3.44 (m, 3H), 1.41 (t, 3H)。
Route 2:
(1) Preparation of intermediate Compounds 1-8
Synthesis of 1-3 g (20 mmol) as illustrated in FIG. 1.
Compound 1-3.5 g (10 mmol, 1.0 eq) was taken, to which was added 20 mL g of tetrahydrofuran distilled at-70℃under N 2 To the above solution was added dropwise a solution of 7.5 mL (2.0M, 1.5 eq) LDA (lithium diisopropylamide) in tetrahydrofuran under nitrogen at-70 ℃ and stirring the above mixture for 0.5 h, followed by dropwise a solution of 1-7.34 g (10 mmol, 1.0 eq) of the compound in tetrahydrofuran (redistilled THF,10 mL) under nitrogen at-70 ℃ and stirring for 1 h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 4:1, yielding 3.4. 3.4 g pure compound 1-8 with a yield of 71%.
(2) Preparation of intermediate Compounds 1-9
1-8.4 g (7.1 mmol, 1.0 eq) of Compound 1-8 was weighed, 30 mL methylene chloride was added, et was added to the above solution under nitrogen at 20 ℃ 3 SiH 1.0 g (8.52 mmol, 1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O0.6 g (8.52 mmol, 1.2 eq), and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a 20.0. 20.0 mL saturated aqueous sodium chloride solution, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=1:0 to 6:1, yielding 2.16 g pure compound 1-9 in 65% yield.
(3) Preparation of the target Compound 1 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
2.16 g (4.6 mmol, 1.0 eq) of compound 1-9 was weighed, 20 mL methylene chloride was added, boron tribromide 5.75 g (23 mmol) was added dropwise at 0℃and stirred for 2h at 0 ℃. Pouring the mixture into ice water after the reaction is finished, adding dichloromethane for extraction, collecting an organic phase, and distilling under reduced pressure to obtain a concentrate; the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 18, 250, 50mm, 10 um; mobile phase: water (0.1% TFA) -ACN, B%:30% -80%,20 min) to give 0.6, g of the title compound 1 as a white solid in 32% yield.
Route 3:
(1) Preparation of intermediate Compounds 1-11
Synthesis of Compound 1-3.5 g (10 mmol, 1.0 eq) by the preparation method of scheme 2, 20 mL g of tetrahydrofuran are added thereto and distilled at-70℃under N 2 To the above solution was added dropwise a tetrahydrofuran solution of 7.5 mL (2.0M, 1.5 eq) LDA (lithium diisopropylamide) under nitrogen at-70 ℃ C. With stirring 0.5 h, followed by dropwise addition of 1-10.7 g (10 mmol, 1.0 eq) of tetrahydrofuran of the compoundThe solution of the furan (redistilled THF,10 mL) was stirred under nitrogen at-70 ℃ for 1 h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 4.4. 4.4 g pure compounds 1-11 with a yield of 62%.
(2) Preparation of intermediate Compounds 1-12
Compound 1-11.4 g (6.2 mmol, 1.0 eq) was weighed out, 40 mL dichloromethane was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 0.87 g (7.44 mmol, 1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O0.5 g (7.44 mmol, 1.2 eq), and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a 20.0. 20.0 mL saturated aqueous sodium chloride solution, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=1:0 to 8:1, yielding 2.74-g pure compound 1-12 with a yield of 63%.
(3) Preparation of the target Compound 1 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
2.74 g (3.9 mmol, 1.0 eq) of compound 1-12 was weighed, 40 mL tetrahydrofuran was added, TBAF (tetrabutylammonium fluoride) 4.07 g (15.6 mmol, 4 eq) was added and reacted at 40℃for 6h. After the reaction is finished, adding dichloromethane-saturated saline for extraction, collecting an organic phase, and distilling under reduced pressure to obtain a concentrate; the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 18, 250, 50mm, 10 um; mobile phase: water (0.1% TFA) -ACN, B%:30% -80%,20 min) to give 0.67-g of the title compound 1 as a white solid in 42% yield.
Example 2 preparation of compound 2: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula/>
(1) Preparation of intermediate Compounds 2-3
Weighing compound 2-1 53g (213.4 mmol, 1.0 eq), adding 265 mL g tetrahydrofuran, steaming at-70deg.C under N 2 106.6 mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under conditions, and stirred under nitrogen at-70℃for 0.5 h, then 2-2 g (213.4 mmol, 1.0 eq) of tetrahydrofuran (redistilled THF,106.0 mL) solution of compound 2-2 g was added dropwise, and after the addition was completed, stirred under nitrogen at-70℃for 1 h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 105.0. 105.0 g pure compound 2-3 as colorless oil with a yield of 62.5%.
(2) Preparation of intermediate Compounds 2-4
Compound 2-3.0 g (133.4 mmol, 1.0 eq) was weighed out, 735.0 mL dichloromethane was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 18.6 g (160 mmol, 1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O22.75 g (160 mmol, 1.2 eq) was then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0. 500.0 mL saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, giving 68.0 g pure compound 2-4 as a white solid in 66.1% yield.
(3) Preparation of target Compound 2 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
2-4.0 g (88.2 mmol, 1.0 eq) of the compound was weighed, 500.0 mL methanol was added, 22.0 g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 50 psi hydrogen at 50℃for 24 h. After the reaction was completed, the filtrate was suction filtered and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 100mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:25% -53%,30 min) to give 15 g of the target compound 2 as a white solid in a yield of 41.5%.
1H NMR（400 MHz，CD 3 OD），δ：7.08 (dd, J = 8.8 Hz, 2H), 6.82 (dd, J = 8.4 Hz, 2H), 6.76 (d, 2H), 4.54 (d, 1H), 3.99 (q, 2H), 3.84-3.87 (m, 4H), 3.61-3.63 (m, 1H), 3.30-3.45 (m, 3H), 1.35 (t, 3H)。
Example 3 preparation of compound 3: (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate compound 3-3 (4- (4-bromo-2-chlorophenoxy) benzaldehyde)
Weigh 3-1.0 g (289.2 mmol, 1.00 eq) of compound, add 650.0mL DMA (dimethylacetamide), 3-2.90 g (289.2 mmol, 1.00 eq) of compound, 42.37g (306.6 mmol, 1.06 eq) of potassium carbonate, and react 12 h under nitrogen at 100deg.C. After the reaction was completed, the temperature was lowered to room temperature, MTBE (methyl tert-butyl ether) (1.00L) was used for extraction, the organic phase MTBE was further extracted with saturated brine (1.00L), the organic phase was collected, and the concentrate was obtained by distillation under reduced pressure, and the concentrate was passed through a silica gel column, and the mobile phase was petroleum ether: ethyl acetate=40:1 to 3:1, 67.0g of compound 3-3 was obtained as a pale yellow oil, and the yield was 72.1%.
1HNMR（400 MHz，CDCl3）δ： 9.66 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 7.04 (d, J = 0.8 Hz, J = 8.8 Hz, 3H)。
(2) Preparation of intermediate Compounds 3-4
To the above solution was added m-CPBA 58.0 g (268.8 mmol, purity 80%, 1.25 eq) from 3-3.0 g (215.1 mmol, 1.00 eq), 670.0 mL dichloromethane, and the above reaction system was reacted at 20℃with 10 h. After completion of TLC detection, 200.0. 200.0 mL saturated Na was added to the reaction solution at 10 ℃ 2 SO 3 The aqueous solution was extracted with MTBE (300.0. 300.0 mL), then the organic phase was extracted with saturated aqueous sodium carbonate and saturated brine, respectively, and the organic phase was collected and concentrated to give 70.0g of crude compound 3-4, which was used in the next step without purification.
(3) Preparation of intermediate Compounds 3-5
70.0 g crude compound 3-4 prepared in the step (2) is taken, 350. 350 mL methanol and 0.5. 0.5 mL concentrated hydrochloric acid (12M) are added, and 2h is stirred at 20 ℃. After the reaction is finished, the crude product is obtained by reduced pressure distillation. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 67.0 g compound 3-5 as a pale yellow oil.
1HNMR（400 MHz CDCl3）δ：7.60 (d, J = 2.4 Hz, 1H), 7.29 (d, J = 2.4 Hz, J = 8.8 Hz, 1H), 6.91-6.93 (m, 2H), 6.83-6.86 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H)。
(4) Preparation of intermediate Compounds 3-6
Compound 3-5.0 g (1.00 eq) was taken, added with 450.0 mL tetrahydrofuran, cooled to 0 ℃, 16.5 g NaH (purity 60%, 2.4 eq) was added in portions, then 40.3 g iodoethane (258.3 mmol, 1.50 eq) was added dropwise, and the temperature was raised to 60 ℃ for reaction for 12h. After the reaction is completed, the temperature is reduced to 0 ℃ and 300.0 mL saturated NH is added into the reaction liquid 4 Aqueous Cl solution, thenMTBE is added for extraction, the organic phase is collected and concentrated to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 10:1, giving 55.0 of g compound 3-6 as a pale yellow oil in 74.8% yield.
1HNMR（400 MHz，CDCl 3 ）δ：7.50 (d, J = 2.4 Hz, 1H), 7.17-7.20 (m, 1H), 6.85-6.87 (m, 2H), 6.79-6.85 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 3.94 (q, J = 7.2 Hz, J = 14.4 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H)。
(5) Preparation of intermediate Compounds 3-8
Weigh compound 3-6.0 g (122.10 mmol, 1.00 eq), add re-distilled 700 mL THF at-70℃under N 2 To the above solution was added dropwise a solution of 48.84 mL (2.5M, 1.00 eq) n-BuLi (n-butyllithium) in tetrahydrofuran under nitrogen at-70℃with stirring 0.2 h, followed by dropwise a solution of 3-6.77 g (122.10 mmol, 1.00 eq) of tetrahydrofuran (redistilled THF,100.0 mL) and then stirring 1 h under nitrogen at-70 ℃. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 75.0. 75.0 g pure compound 3-8 as colorless oil.
1HNMR（400 MHz，DMSO）δ： 7.64 (s, 1H), 7.34-7.32 (d, J = 6.8Hz, 1H), 7.20-7.29 (m, 15H), 6.92-6.93 (m, 6H), 6.85 (s, 1H), 4.75-4.80 (m, 3H), 4.8-4.58 (m, 5H), 3.96-4.02 (m, 4H), 3.64-3.78 (m, 4H), 1.30 (t, J = 6.8 Hz, 3H)。
(6) Preparation of intermediate Compounds 3-9
Compound 3-8.0 g (95.3 mmol, 1.00, eq) was weighed out, 525.0 mL dichloromethane was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH (13.3 g, 114.3 mmol, 1.20 eq), cooled to 0℃and BF was added dropwise 3 .Et 2 O6.5 g (45.7 mmol, 1.2 eq) then warmed to 20℃and stirred for 2h. After completion of the reaction, the reaction mixture was poured into a saturated solution of 200.0 mL NaHCO 3 Extracting in aqueous solution, collecting dichloromethane phase, and distilling under reduced pressure to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 52.0. 52.0 g pure compound 3-9 as a white solid with a yield of 70.7%.
(7) Preparation of the target Compound 3 ((2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
3-9.0 g (57.0 mmol, 1.00 eq) of the compound was weighed, 880.0 mL ethanol was added, pd/C11.0 g (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 30 psi hydrogen at 20℃for 12 h. After the reaction is completed, suction filtration is carried out, the filtrate is concentrated, and the concentrate is subjected to prep. SFC (preparation type SFC) (column: chiralpak IC-H250 x 30mm i.d.5u; mobile phase: A phase CO) 2 Phase B IPA (isopropylamine) (0.1% NH) 3. H 2 O); gradient B% = 45%, flow rate 73g/min, detection wavelength 220 nm, column temperature 40% o C, performing operation; 100 bar) to give 9.22. 9.22 g of the title compound 3 as a white solid.
1HNMR(400 MHz，CD 3 OD)δ：7.55 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 2.0 Hz, J = 8.4 Hz, 1H), 6.83-6.89 (m, 5H), 4.11 (d, J = 8.8 Hz, 1H), 4.06 (q, 2H), 3.88 (dd, J = 2.0 Hz, J = 8.0 Hz, 1H), 3.71 (dd, J = 5.2 Hz, J = 11.6 Hz, 1H), 3.40-3.44 (m, 3H), 3.30-3.31 (m, 1H), 1.37 (t, J = 6.8 Hz, 3H )。
Example 4 preparation of compound 4: (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate compound 4-2 (4-bromo-2-chlorobenzoyl chloride)
Compound 4-1.0 g (127.41 mmol, 1.00 eq) was taken, 180.0mL DCM and 0.1mL DMF were added, oxalyl chloride 17.8 g (140.2 mmol, 1.10 eq) was added dropwise at 0deg.C, and the temperature was raised to 20deg.C after the addition was complete to react 3 h. After the reaction was completed, a dichloromethane solution of compound 4-2 was obtained and used directly in the next step without post-treatment.
(2) Preparation of intermediate Compounds 4-3
Ethoxybenzene 15.5 g (127.4 mmol, 1.00 eq) was added to the dichloromethane solution of compound 4-2 obtained in step (1) at 0deg.C under nitrogen, followed by the addition of AlCl in portions 3 17.0 g (127.4 mmol, 1.00 eq) and after addition, the reaction mixture was warmed to 20℃for reaction 3 h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, then 200 mL dilute hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate and stirred at 20℃for 2 h, the solid was precipitated, collected by filtration, and dried under reduced pressure to give 35.0. 35.0 g of compound 4-3 as a white solid in 80.9% yield.
1HNMR（400 MHz，CDCl 3 ）δ：7.74 (dd, J = 7.2 Hz, J = 9.2 Hz, 2H), 7.63 (m, 1H), 7.50 (d, J = 2.0 Hz, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz,1H), 6.92 (d, J = 8.8 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H)。
(3) Preparation of intermediate Compounds 4-4
Compound 4-3.0 g (103.1 mmol, 1.00, eq) was taken, 350.0 mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 59.9g (515.3 mmol, 5.00 eq) and then BF were added dropwise under nitrogen at 25 ℃ 3 .Et 2 O29.3 g (206.1 mmol, 2.00. Eq), the above mixture was reacted at 25℃with 12. 12 h. After the reaction, 300.0. 300.0 mL saturated NaHCO is added into the reaction solution 3 Water-solubleThe solution was then extracted with MTBE, the organic phase was extracted with saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 33.0. 33.0 g of compound 4-4 as a pale yellow oil in 92.0% yield.
1HNMR（400 MHz，CDCl 3 ）δ：7.53 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 2.0 Hz, J = 8.4 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.0 Hz 1H), 6.83 (d, J = 8.4 Hz, 2H), 3.98 (q, J = 6.8 Hz, 2H), 1.40 (t, J = 6.8 Hz, 3H)。
(4) Preparation of intermediate Compounds 4-6
Compound 4-4.0 g (86.0 mmol, 1.00. 1.00 eq) was weighed out and 560 mL g of THF was added to evaporate at-70℃under N 2 34.4 mL (2.5M, 1.00 eq) n-BuLi in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃with stirring for 0.2 h, then 4-5.3 g (86.0 mmol, 1.00 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise, followed by stirring for 1 h under nitrogen at-70 ℃. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 56.0. 56.0g pure compound 4-6 as a colorless oil in a yield of 72.8%.
(5) Preparation of intermediate Compounds 4-7
Compound 4-6.0 g (71.3 mmol, 1.00 eq) was weighed out, 390.0 mL dichloromethane was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.95 g (85.6 mmol, 1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O12.1 g (85.6 mmol, 1.20 g eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0. 200.0 mL saturated aqueous sodium bicarbonate solution, extracted, and the dichloromethane phase was collected and evaporated under reduced pressureAnd (5) distilling to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 55.0. 55.0 g pure compound 4-7 as a colorless oil with a yield of 64.6%.
(6) Preparation of the target Compound 4 ((2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
41.2. 41.2 g (53.6 mmol, 1.00 eq) of compound 4-7 and 800.0 mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C8.00 g (active ingredient content 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at 20℃under 30 psi of hydrogen to 12 h. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 50mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:26% -46%,20 min) to give 7.7. 7.7 g of the target compound 4 as a white solid in a yield of 35.1%.
1HNMR（400 MHz，DMSO）δ：7.37 (s, 1H), 7.23 (d, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.7 (br.s, 4H), 3.92-4.00 (m, 5H), 3.60-3.66 (m, 1H), 3.40-3.50 (m, 1H), 3.05-3.24 (m, 4H), 1.27(t, J = 7.2Hz, 3H)。
Example 5 preparation of compound 5: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula/>
(1) Preparation of intermediate Compounds 5-3
69.4g of p-bromophenyl ethyl ether (5-1, 496 mmol, 1 eq) and 152.5 g of 5-2 (744 mmol, 1.5 eq) were taken, 500 mL dimethylformamide was added, and Cs was added to the above solution in sequence at 20 ℃ 2 CO 3 323 g (992 mmol, 2eq) and then stirred under nitrogen at 100 ℃ for 12h. Cooling to room temperature after the reaction is completed, then distilling under reduced pressure to obtain a concentrate, extracting the concentrate by adopting water-ethyl acetate, collecting an organic phase, and distilling under reduced pressure to obtain a crude product; the crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=40:1 to 5:1, giving 40.3g of pure compound 5-3 as a colorless oil in 25% yield.
(2) Preparation of intermediate Compounds 5-5
Taking 5-3.3 g (124 mmol, 1.0 eq) of compound, adding 180.0 mL g of tetrahydrofuran, steaming at-70deg.C under N 2 To the above solution was added dropwise a solution of 148.8 mL (2.5M, 3 eq) of n-butyllithium in tetrahydrofuran under nitrogen at-70 ℃ with stirring for 0.5 h, then a solution of 5-4.7 g (124 mmol, 1.0 eq) of the compound in tetrahydrofuran (redistilled THF,150.0 mL) was added dropwise with stirring for 1 h under nitrogen at-70 ℃. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 31.6g of pure compound 5-5 in a yield of 32.5%.
(3) Preparation of intermediate Compounds 5-6
Compound 5-5.6 g (40.3 mmol, 1.0 eq) was weighed out, 350.0 mL dichloromethane was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 5.6 g (48.36 mmol, 1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O3.5 g (48.36 mmol, 1.2 eq) was warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a saturated aqueous solution of 200.0. 200.0 mL sodium chloride, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=1:0 to 10:1, yielding 18.8g of pure compound 5-6 in 61% yield.
(4) Preparation of the target Compound 5 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
5-6.8 g (24.5 mmol, 1.0 eq) of the compound was weighed, 200.0 mL methanol was added, 17.0 g Pd/C (active material content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 50 psi hydrogen at 50℃for 24 h. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 50mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:30% -80%,20 min) to give 3.0 g of the target compound 5 as a white solid in a yield of 30.1%.
1H NMR（400 MHz，CD 3 OD），δ：6.96-7.03 (m, 4H), 6.18 (dd, 2H), 5.35 (d, 1H), 4.53 (q, 2H), 4.03-4.09 (m, 1H), 3.85-3.88 (m, 2H), 3.63-3.65 (m, 1H), 3.34-3.44 (m, 3H), 1.42 (t, 3H)。
Example 6 preparation of compound 6: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 6-2
Compound 6-1 60g (230.4 mmol, 1.00 eq) was taken, 200.0mL DCM and 0.1mL DMF were added, oxalyl chloride 132.2g (253.4 mmol, 1.10 eq) was added dropwise at 0℃and after the addition was completed, the temperature was raised to 20℃for 3h of reaction. After the reaction was completed, a dichloromethane solution of compound 6-2 was obtained and used directly in the next step without post-treatment.
(2) Preparation of intermediate Compound 6-3
To a dichloromethane solution of compound 6-2 obtained in step (1) was added ethoxybenzene 28.0 g (230.4 mmol, 1.00 eq) at 0 ℃ under nitrogen, followed by the addition of AlCl in portions 3 30.7g (230.4 mmol, 1.00. 1.00 eq) and after addition, the reaction mixture was warmed to 20℃for reaction 3. 3h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, then 200 mL dilute hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate and stirred at 20℃for 2h, the solid was precipitated, collected by filtration, and dried under reduced pressure to give 68g of Compound 6-3 in 80.9% yield.
(3) Preparation of intermediate Compounds 6-4
Compound 6-3 68g (186.4 mmol, 1.00 eq) was taken, 350.0 mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 108.3g (932 mmol, 5.00. 5.00 eq) followed by dropwise addition of BF under nitrogen at 25 ℃ 3 .Et 2 O106 g (745.6mmol,4.00 eq), the above mixture was reacted at 25℃with 12 h. After the reaction, 300.0. 300.0 mL saturated NaHCO is added into the reaction solution 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated brine, the organic phase is collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 5:1, yielding 55.4 g compound 6-6 in 92.0% yield.
(4) Preparation of intermediate Compounds 6-6
6-4.4 g (171.5 mmol, 1.0 eq) of compound was weighed out, 300. 300 mL g of tetrahydrofuran was added and distilled at-70℃under N 2 To the above solution was added dropwise a tetrahydrofuran solution of 205.8 mL (2.5M, 3.0 eq) n-butyllithium under nitrogen at-70℃with stirring 0.5 h, followed by dropwise addition of 6-5 g (171.5 mmol, 1.0 eq) of tetrahydrofuran (re-distilled THF, 1)00.0 mL) and after the addition was completed, 1 was stirred under nitrogen at-70 ℃ for h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving pure compound 6-6 of 40.3 g in 30% yield.
(5) Preparation of intermediate Compounds 6-7
Compound 6-6.3 g (51.45 mmol, 1.0 eq) was weighed out, 300.0 mL methylene chloride was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 7.16 g (61.74 mmol, 1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O8.8 g (61.74 mmol, 1.2 eq) then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0. 200.0 mL saturated aqueous sodium chloride solution, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, yielding 23.7g of pure compound 6-7 as a white solid with a yield of 60%.
(6) Preparation of the target Compound 6 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
Compound 6-7.7 g (30.87 mmol, 1.0 eq) was weighed, 200.0 mL methanol was added, 12g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50 psi hydrogen atmosphere for 24 h. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 100mm, 10 um; mobile phase water (0.1% tfa) -ACN, B%:20% -60%,30 min) to give 3.7. 3.7g of the target compound 6 as a white solid in 30% yield.
1H NMR（400 MHz，DMSO），δ：7.08 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 6.47 (s, 2H), 4.53-4.56 (m, 1H), 3.95-4.01 (q, 2H), 3.84-3.87 (m, 4H), 3.61-3.63 (m, 1H), 3.30-3.35 (m, 3H), 1.36 (t, 3H)。
Example 7 preparation of compound 7: (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxy ethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula/>
(1) Preparation of intermediate Compound 7-3
100. 100 g (compound 7-1, 578 mmol, 1 eq), 7-2.5 g (578 mmol, 1 eq) and 95.7g of potassium carbonate were added to 1000 mL dioxane and stirred at 60℃for 12 hours. After the reaction is completed, the reaction liquid is distilled under reduced pressure to obtain a concentrate, the concentrate is extracted by adopting saturated saline water-ethyl acetate, an organic phase is collected, and a crude product is obtained through reduced pressure distillation; the crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1, giving 104.8g of pure compound 7-3 in 70% yield.
(2) Preparation of intermediate Compounds 7-5
Taking 7-3 g (386 mmol, 1 eq) of compound, 60.2 g (7-4, 463.2 mmol, 1.2 eq) of 3, 5-difluorophenol, adding 800 mL dioxane, adding Cs sequentially to the above solution at 20deg.C 2 CO 3 252 g (772 mmol, 2 eq), cuI 22g (115.8 mmol, 0.3 eq), isobutyl nitrite 23.9g (231.6 mmol, 0.6 eq) and then stirred at 100 ℃ for 12h. Cooling to 20 ℃ after the reaction is completed, then distilling under reduced pressure to obtain a concentrate, extracting the concentrate by adopting water-ethyl acetate, collecting an organic phase, and distilling under reduced pressure to obtain a crude product; the crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, yielding 59.4g of pure compound 7-5 in 50% yield.
(3) Preparation of intermediate Compounds 7-7
59.4 g (193 mmol, 1.0 eq) of compound 7-7 was taken, 200.0 mL g tetrahydrofuran was added to the mixture, and the mixture was distilled at-70℃under N 2 144.6 mL (2.0M, 1.5 eq) of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃with stirring for 0.5 h, followed by dropwise addition of 7-6.9 g (193 mmol, 1.0 eq) of tetrahydrofuran (redistilled THF,200.0 mL) with stirring for 1 h under nitrogen at-70 ℃. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 95.1 g pure compound 7-7 with a yield of 58.3%.
(4) Preparation of intermediate Compounds 7-8
Compound 7-8.1 g (112.5 mmol, 1.0 eq) was weighed out, 500.0 mL methylene chloride was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 15.6 g (135 mmol, 1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O9.6 g (135 mmol, 1.2 eq) was warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a saturated aqueous solution of 200.0. 200.0 mL sodium chloride, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=10:0 to 2:1, yielding 52.1 g pure compound 7-8 with a yield of 55.8%.
(5) Preparation of the target Compound 7 ((2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxyethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
To the above solution was weighed 7-8.1 g (62.8 mmol, 1.0 eq), 500.0 mL methanol was added, 28.0 g Pd/C (active material content 10%) was added under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 50 psi hydrogen at 50℃for 24 h. After the reaction was completed, the filtrate was suction filtered, concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 50mm, 10 um; mobile phase water (0.1% hcooh) -ACN, 30% -80%,20 min) to give 10.3 g of the target compound 7 as a white solid in 35% yield.
1H NMR（400 MHz，CD 3 OD），δ：7.30 (dd, 2H), 6.96 (d, 2H), 6.87 (dd, 2H), 4.54 (d, 1H), 4.29 (t, 2H), 4.03-4.09 (m, 2H), 3.85 (t, 2H), 3.65 (m, 1H), 3.34-3.44 (m, 3H), 3.11-3.13 (m, 1H), 1.08 (d, 6H)。
Example 8 preparation of compound 8: (2S, 3R,4R,5S, 6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 8-3
Weighing compound 8-1 50g (227 mmol, 1.0 eq), adding 300 mL g tetrahydrofuran, steaming at-70deg.C under N 2 226.8mL (2.0M, 2.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃with stirring for 0.5 h, then 8-2.3 g (227 mmol, 1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise, and after the addition was completed, 1 h was stirred under nitrogen at-70 ℃. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 1:1, yielding 101.5g of pure compound 8-3 with a yield of 59%.
(2) Preparation of intermediate Compounds 8-4
Compound 8-3.5 g (133.9 mmol, 1.0 eq) was weighed out, 800.0 mL dichloromethane was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 18.7 g (160.7 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O22.8 g (160.7 mmol,1.2 eq) was then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0. 500.0 mL saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 2:1, yielding 59.6g of pure compound 8-4 with a yield of 60%.
(3) Preparation of intermediate Compounds 8-5
Compound 8-4.6 g (80.3 mmol, 1.0 eq) was weighed, 500. 500 mL dichloromethane, DIPEA 20.7g (160.6 mmol,2 eq), HATU 35.5g (93.4 mmol,1.2 eq) then formic acid 4.3g (93.4 mmol,1.2 eq) was added dropwise and after the addition was completed, 2h was stirred at room temperature. Extracting with saturated saline, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 10:1, yielding 45.3 g pure compound 8-5 with a yield of 72%.
(4) Preparation of target Compound 8 ((2S, 3R,4R,5S, 6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
8-5.0 g (57.8 mmol, 1.0 eq) of the compound was weighed, 500.0 mL ethanol was added, 22.0 g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 50 psi hydrogen at 50℃for 24 h. After the reaction was completed, the filtrate was filtered by suction, and concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 100mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:25% -70%,30 min) to give 9.5 g of the target compound 8 as a white solid in 39% yield.
1H NMR（400 MHz，CD 3 OD），δ：7.16 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.42 (d, 2H), 4.57 (d, 1H), 3.98 (s, 2H), 3.86-3.89 (m, 4H), 3.61 (m, 1H), 3.30-3.35 (m, 1H), 2.23 (s, 3H)。
Example 9 preparation of compound 9: (2S, 3R,4R,5S, 6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 9-3
Weighing compound 9-1 50g (171.2 mmol, 1.0 eq), adding 200 mL g tetrahydrofuran, steaming at-70deg.C under N 2 85.5 mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under conditions, and stirred under nitrogen at-70℃for 0.5 h, then 9-2.3 g (171.2 mmol, 1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise, and after the addition was completed, 1 h was stirred under nitrogen at-70 ℃. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 2:1, giving 92.3 g pure compound 9-3 as a colorless oil in 65% yield.
(2) Preparation of intermediate Compounds 9-4
Compound 9-3.3 g (111.3 mmol, 1.0 eq) was weighed out, 700.0 mL dichloromethane was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 15.6 g (133.6 mmol, 1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O19 g (133.6 mmol, 1.2 eq) was then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction mixture was poured into 500.0. 500.0 mL to be saturatedExtracting in sodium chloride aqueous solution, collecting dichloromethane phase, and distilling under reduced pressure to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, giving 60.7. 60.7 g pure compound 9-4 as a white solid in 67% yield.
(3) Preparation of target Compound 9 ((2S, 3R,4R,5S, 6R) -2- (4- (3, 4-diethyloxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
To the above solution was weighed compound 9-4.7 g (74.5 mmol, 1.0 eq), added 500.0 mL methanol, 18.6 g Pd/C (active ingredient content 10%) under argon atmosphere, and the reaction system was evacuated to fill hydrogen and reacted at 50℃under 50 psi hydrogen atmosphere for 24 h. After the reaction was completed, the filtrate was filtered by suction, and concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 100mm, 10 um; mobile phase: water (0.1% hcooh) -ACN, 25% -60% B%, 30 min) to give 15.2 g of the objective compound 9 as a white solid in 45% yield.
1H NMR（400 MHz，CD 3 OD），δ：7.05 (s, 1H), 6.79 (d, 1H), 6.70 (d, 1H), 6.56 (d, 2H), 4.53-4.56 (m, 1H), 4.06 (q, 4H), 3.97 (s, 2H), 3.84-3.87 (m, 4H), 3.60-3.63 (m, 2H), 1.35 (t, 6H)。
Example 10 preparation of compound 10: (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 10-3
Weighing compound 10-1 50g (182.4 mmol, 1.0 eq), adding 200 mL redistilled tetrahydrofuran at-70deg.C under N 2 Under the condition of adding 91.1 mL (2.0M, 1.0 eq) LDA tetrad dropwise into the above-mentioned solutionA solution of tetrahydrofuran was stirred under nitrogen at-70 ℃ for 0.2. 0.2 h, then a solution of compound 10-2.2 g (182.4 mmol, 1.0 eq) in tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise, and after the addition was stirred under nitrogen at-70 ℃ for 1 h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 2:1, giving 86.5. 86.5 g pure compound 10-3 as a colorless oil in 58.4% yield.
(2) Preparation of intermediate Compound 10-4
10-3.5 g (106.6 mmol, 1.0 eq) of Compound 10-3 was weighed, 700.0 mL methylene chloride was added, and Et was added to the above solution under nitrogen at room temperature 3 SiH 14.9 g (127.9 mmol, 1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O18.2 g (127.9 mmol, 1.2 eq) then warmed to room temperature and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0. 500.0 mL saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 3:1, giving 56.8 g pure compound 10-4 as a white solid in 67% yield.
(3) Preparation of target Compound 10 ((2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
10-4.8 g (71.4 mmol, 1.0 eq) of the compound was weighed, 500.0 mL ethyl acetate was added, 17.8 g Pd/C (wet palladium on carbon, active ingredient content 5%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50 psi hydrogen atmosphere for 12 h. After the reaction was completed, the filtrate was filtered by suction, and concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 100mm, 10 um; mobile phase: water (0.1% hcooh) -ACN, B%:25% -70%,30 min) to give 13 g of the objective compound 10 as a white solid in 42% yield.
1H NMR（400 MHz，CD 3 OD），δ：7.55 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 6.88 (d, 2H), 4.53-4.56 (m, 1H), 3.87-3.90 (m, 1H), 3.80-3.82 (m, 2H), 3.61-3.63 (m, 3H)。
Example 11 preparation of compound 11: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 11-2 (4-bromo-2-fluorobenzoyl chloride)
Compound 11-1.0 g (137 mmol, 1.00 eq) was taken, 200.0 mL DCM and 0.1 mL DMF were added, oxalyl chloride 19.1 g (150.7 mmol, 1.10 eq) was added dropwise at 0deg.C, and after the addition was complete, the reaction was warmed to room temperature and allowed to proceed to 5 h. After the reaction was completed, a methylene chloride solution of the compound 11-2 was obtained, which was used in the next step without post-treatment.
(2) Preparation of intermediate Compound 11-3
To a dichloromethane solution of compound 11-2 obtained in step (1) was added ethoxybenzene 16.7 g (137 mmol, 1.00 eq) at 0℃under nitrogen, followed by the addition of AlCl in portions 3 18.3 g (137 mmol, 1.00, eq), and after the addition, the reaction mixture was warmed to room temperature and reacted for 3 h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, then 200 mL dilute hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate and stirred at 20℃for 2 h to precipitate a solid, which was collected by filtration and dried under reduced pressure to give 33.3 g of compound 11-3 as a white solid in 75.2% yield.
(3) Preparation of intermediate Compound 11-4
Compound 11-3.3 g (103.1 mmol, 1.00. 1.00 eq) was taken, 350.0 mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 18 g (154.65 mmol,1.5 eq) followed by dropwise addition of BF under nitrogen at 25 ℃ 3 .Et 2 O29.3 g (206.1 mmol, 2.00 eq), the above mixture was reacted at 25℃with 12 h. After the reaction, 300.0. 300.0 mL saturated NaHCO is added into the reaction solution 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product was passed through a silica gel column with petroleum ether as the mobile phase to give 28.4g of compound 11-4 in 89% yield.
(4) Preparation of intermediate Compounds 11-6
Weigh 11-4.4 g (91.8 mmol, 1.00, eq) of compound, add 600 mL g of distilled THF at-70℃under N 2 36.7 mL (2.5M, 1.00 eq) n-BuLi in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃with stirring for 0.2 h, then 10-5.4 g (91.8 mmol, 1.00 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise, followed by stirring for 1 h under nitrogen at-70 ℃. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 3:1, giving 52.9 g pure compound 11-6 in 75% yield.
(5) Preparation of intermediate Compounds 11-7
Compound 11-6.9 g (68.85 mmol, 1.00 eq) was weighed out, 400.0 mL methylene chloride was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.6 g (82.62 mmol, 1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O 11.7 g(82.62 mmol, 1.20, eq), then warmed to 20 ℃ and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0. 200.0 mL saturated aqueous sodium bicarbonate solution, extracted, and the dichloromethane phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 4:1, giving 35.3 g pure compound 11-7 in 68% yield.
(6) Preparation of the target Compound 11 ((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
35.3. 35.3 g (46.8 mmol, 1.00. 1.00 eq) of 11-7 ethyl acetate and 600.0. 600.0 mL ethyl acetate were taken and mixed uniformly under stirring, then Pd/C7.00 g (active ingredient content 10%) was added under argon, the reaction system was evacuated to fill hydrogen, and reacted at 20℃under 30 psi of hydrogen to 12 h. After the reaction was completed, the filtrate was suction filtered and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 50mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:20% -60%,20 min) to give 6.8 g of the target compound 11 as a white solid in 37% yield.
1HNMR（400 MHz，DMSO）δ：7.15 (d, 1H), 7.14 (d, 2H), 7.02 (d, 1H), 6.89 (d, 2H), 6.79 (d, 1H), 4.7 (br.s, 4H), 3.94-4.02 (m, 5H), 3.61-3.67 (m, 1H), 3.41-3.51 (m, 1H), 3.06-3.25 (m, 4H), 1.34 D(t, 3H)。
Example 12 preparation of compound 12: (2S, 3R,4R,5S, 6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate compound 12-2 (4-bromo-2-fluorobenzoyl chloride)
12-1.0 g (137 mmol, 1.00 eq) of compound was taken, 200.0 mL of DCM and 0.1 mL of DMF were added, oxalyl chloride 19.1 g (150.7 mmol, 1.10 eq) was added dropwise at 0℃and after the addition was completed, the temperature was raised to 20℃for reaction 3 h. After the reaction was completed, a dichloromethane solution of compound 12-2 was obtained, which was used directly in the next step without post-treatment.
(2) Preparation of intermediate Compound 12-3
Parafluorophenoxybenzene 25.7. 25.7 g (137 mmol, 1.00. 1.00 eq) was added to the dichloromethane solution of compound 12-2 obtained in step (1) at 0deg.C under nitrogen, followed by the addition of AlCl in portions 3 18.3 g (137 mmol, 1.00, eq), and after the addition, the reaction mixture was warmed to 20 ℃ and reacted 5. 5 h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, then 200 mL dilute hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate and stirred at 20℃for 2h to precipitate a solid, which was collected by filtration and dried under reduced pressure to give 45.3 g of compound 12-3 as a white solid in 85% yield.
(3) Preparation of intermediate Compound 12-4
Compound 12-3.3 g (116.4 mmol, 1.00. 1.00 eq) was taken, 400.0 mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 40.6 g (349.2 mmol, 3.00 eq) and then BF were added dropwise under nitrogen at 25 ℃ 3 .Et 2 O33 g (232.8 mmol, 2.00. Eq), the above mixture was reacted at 25℃with 12 h. After the reaction, 300.0. 300.0 mL saturated NaHCO is added into the reaction solution 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated brine, the organic phase is collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product is passed through a silica gel column, the mobile phase is petroleum ether, and 39.7 g of compound 12-4 is obtained, and the yield is 91.0%.
(4) Preparation of intermediate Compound 12-6
Weigh compound 12-4.7 g (105.9 mmol, 1.00, eq), 600: 600 mL g of THF were added, distilled at-70℃under N 2 To the above solution was added dropwise a solution of 42.4. 42.4 mL (2.5M, 1.00 eq) n-BuLi in tetrahydrofuran under nitrogen at-70℃with stirring 0.2 h, then a solution of 12-5 g (105.9 mmol, 1.00 eq) of the compound in tetrahydrofuran (re-distilled THF,150.0 mL) was added dropwise, followed by stirring 1 h under nitrogen at-70 ℃. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 4:1, yielding 66.2 g pure compound 12-6 in 75% yield.
(5) Preparation of intermediate Compounds 12-7
Compound 12-6.2 g (79.4 mmol, 1.00 eq) was weighed out, 400.0 mL methylene chloride was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 11 g (95.3 mmol, 1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O13.5 g (95.3 mmol, 1.20 eq) was then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0. 200.0 mL saturated aqueous sodium bicarbonate solution, extracted, and the dichloromethane phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 4:1, yielding 39.6 g pure compound 12-7 in 61% yield.
(6) Preparation of the target Compound 12 ((2S, 3R,4R,5S, 6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
39.6. 39.6 g (48.4 mmol, 1.00 eq) of compound 12-7 and 800.0 mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C7.2 g (active ingredient content 10%) was added under argon atmosphere, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30 psi hydrogen pressure to 12 h. After the reaction was completed, the filtrate was suction filtered and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 50mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:20% -60%,30 min) to give 8.2 g of the target compound 12 as a white solid in 37% yield.
1HNMR（400 MHz，DMSO）δ： 7.41 (dd, 2H), 7.25 (dd, 2H), 7.18(dd, 2H), 7.16 (dd, 2H), 7.13 (d, 1H), 6.99 (d, 1H), 6.75 (d, 1H), 3.95 (s, 2H), 4.6 (br.s, 4H), 3.91-4.04 (m, 3H), 3.63-3.68 (m, 1H), 3.42-3.51 (m, 3H), 3.05-3.24 (m, 2H)。
Example 13 preparation of compound 13: (2S, 3R,4R,5S, 6R) -2- (4- (4- (2, 4, 5-Trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
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(1) Preparation of intermediate Compound 13-2 (4-bromo-benzoyl chloride)
Compound 13-1.5 g (137 mmol, 1.00 eq) was taken, 200.0 mL DCM and 0.1 mL DMF were added, oxalyl chloride 19.1 g (150.7 mmol, 1.10 eq) was added dropwise at 0deg.C, and the temperature was raised to 20deg.C after the addition was complete to react 3 h. After the reaction was completed, a methylene chloride solution of the compound 13-2 was obtained, which was used in the next step without post-treatment.
(2) Preparation of intermediate Compound 13-4
To a dichloromethane solution of compound 13-2 obtained in step (1) at 0℃under nitrogen, was added compound 13-3.7 g (137 mmol, 1.00, eq), followed by the addition of AlCl in portions 3 18.3 g (137 mmol, 1.00, eq), and after the addition, the reaction mixture was warmed to 20 ℃ and reacted 5. 5 h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, then 200 mL dilute hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate and stirred at 20℃for 2h to precipitate a solid, which was collected by filtration and dried under reduced pressure to give 45.7. 45.7 g of the compound 13-4 as white solid with a yield of 82%.
(3) Preparation of intermediate Compound 13-5
45.7 g (112.3 mmol, 1.00, eq) of Compound 13-4 was taken, 400.0 mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 39 g (336.9 mmol, 3.00 eq) and then BF were added dropwise under nitrogen at 25 ℃ 3 .Et 2 O31.8 g (224.6 mmol, 2.00. Eq), the above mixture was reacted at 25℃with 12. 12 h. After the reaction, 300.0. 300.0 mL saturated NaHCO is added into the reaction solution 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, yielding 40.6 g compound 13-5 in 92% yield.
(4) Preparation of intermediate Compounds 13-7
Weigh 13-5.6 g (103.3 mmol, 1.00, eq) of compound, add 600 mL g of distilled THF at-70℃under N 2 To the above solution was added dropwise a solution of 41.4 mL (2.5M, 1.00 eq) n-BuLi in tetrahydrofuran under nitrogen at-70℃with stirring 0.2 h, followed by dropwise a solution of compound 13-6.6 g (103.3 mmol, 1.00 eq) in tetrahydrofuran (redistilled THF,150.0 mL) with stirring 1 h under nitrogen at-70 ℃. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 3:1, yielding 59 g pure compound 13-7 in 67% yield.
(5) Preparation of intermediate Compounds 13-8
Weigh compound 13-7 g (69.2 mmol, 1.00 eq) and add 400.0 mL dichloroMethane was added to the above solution at 20℃under nitrogen 3 SiH 9.6 g (83 mmol, 1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O11.8 g (83 mmol, 1.20 eq) then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0. 200.0 mL saturated aqueous sodium bicarbonate solution, extracted, and the dichloromethane phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 4:1, yielding 34.2 g pure compound 13-8 in 59% yield.
(6) Preparation of the target Compound 13 ((2S, 3R,4R,5S, 6R) -2- (4- (4- (2, 4, 5-trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
34.2 parts by weight g (40.8 mmol, 1.00 parts by weight eq) of 13-8 parts by weight and 800.0 parts by weight mL parts by weight of ethyl acetate were mixed with stirring, pd/C6.1 parts by weight g (10% of active ingredient) was added under argon atmosphere, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30 psi of hydrogen under room temperature conditions to obtain h. After the reaction was completed, the filtrate was suction filtered and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 50mm, 10 um; mobile phase: water (0.1% tfa) -MeOH, B%:20% -40%,30 min) to give 5.8 g of the target compound 13 as a white solid in a yield of 30%.
1HNMR（400 MHz，DMSO）δ：7.29 (dd, 2H), 7.26 (d, 1H), 7.25 (dd, J = 8.4 Hz, 2H), 7.19 (dd, 2H), 7.16 (dd, J = 8.4 Hz, 2H), 6.68 (t, 1H), 4.6 (br.s, 4H), 4.05 (d, 1H), 3.97 (s, 2H), 3.63-3.68 (m, 1H), 3.42-3.51 (m, 3H), 3.05-3.24 (m, 2H)。
Example 14 preparation of compound 14: (2S, 3R,4R,5S, 6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 14-3
2-Chloropyrimidine 17.2 g (150 mmol, 1.00 eq) was taken, 100mL of DMF, 15.5g (165 mmol, 1.100 eq) of phenol, 73.4g (225 mmol, 1.5 eq) of cesium carbonate were added and reacted at 60℃for 12 hours; after the reaction is finished, extracting by adopting ethyl acetate and saturated saline water, collecting an organic phase, and concentrating to obtain a crude product; the crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, yielding 23.7g of compound 14-3 in 92% yield.
(2) Preparation of intermediate Compound 14-2 (4-bromo-benzoyl chloride)
Compound 14-1.5 g (137 mmol, 1.00 eq) was taken, 200.0 mL DCM and 0.1 mL DMF were added, oxalyl chloride 19.1 g (150.7 mmol, 1.10 eq) was added dropwise at 0deg.C, and the temperature was raised to 20deg.C after the addition was complete to react 3 h. After the reaction was completed, a dichloromethane solution of compound 14-2 was obtained, which was used directly in the next step without post-treatment.
(3) Preparation of intermediate Compound 14-4
To the dichloromethane solution of compound 13-2 obtained in step (2) was added compound 14-3.7 g (137 mmol, 1.00, eq) at 0℃under nitrogen, followed by the addition of AlCl in portions 3 18.3 g (137 mmol, 1.00, eq), and after the addition, the reaction mixture was warmed to 20 ℃ and reacted 5. 5 h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, then 200 mL dilute hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. MeOH (100 mL) was added to the concentrate and stirred at 20℃for 2 h to precipitate a solid, which was collected by filtration and dried under reduced pressure to give compound 14-4 as a white solid in 85% yield.
(4) Preparation of intermediate Compound 14-5
Compound 14-4.41.3 g (116.4 mmol)1.00 eq), 400.0 mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 40.4 g (349.2 mmol, 3.00 eq) and then BF were added dropwise under nitrogen at 25 ℃ 3 .Et 2 O33 g (224.6 mmol, 2.00. Eq), the above mixture was reacted at 25℃with 12 h. After the reaction, 300.0. 300.0 mL saturated NaHCO is added into the reaction solution 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, yielding 35.2. 35.2 g compound 14-5 in 88.7% yield.
(5) Preparation of intermediate Compounds 14-7
Compound 14-5.2 g (103.3 mmol, 1.00, eq) was weighed out and 600 mL g of THF was added to evaporate at-70℃under N 2 To the above solution was added dropwise a solution of 41.4 mL (2.5M, 1.00 eq) n-BuLi in tetrahydrofuran under nitrogen at-70℃with stirring 0.2 h, followed by dropwise a solution of 14-6.6 g (103.3 mmol, 1.00 eq) of the compound in tetrahydrofuran (redistilled THF,150.0 mL) with stirring 1 h under nitrogen at-70 ℃. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 2:1, yielding 53.7. 53.7 g pure compound 14-7 in 65% yield.
(6) Preparation of intermediate Compounds 14-8
Compound 14-7.7 g (67 mmol, 1.00, eq) was weighed out, 400.0 mL methylene chloride was added, et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.3 g (80.4 mmol, 1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O11.4 g (80.4 mmol, 1.20 eq) then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction mixture was poured into 200.0. 200.0 mL saturated aqueous sodium hydrogencarbonate solutionExtracting, collecting dichloromethane phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 3:1, giving 33 g pure compound 14-8 in 63% yield.
(7) Preparation of the target Compound 14 ((2S, 3R,4R,5S, 6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
33 g (42.2 mmol, 1.00 eq) of 14-8 ethyl acetate and 800.0 mL ethyl acetate were mixed uniformly under stirring, then Pd/C6.3 g (active ingredient content 10%) was added under argon, the reaction system was evacuated to fill hydrogen, and reacted at room temperature under 30 psi hydrogen pressure to 12 h. After the reaction was completed, the filtrate was filtered by suction and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 50mm, 10 um; mobile phase: water (0.1% tfa) -MeOH, B%:20% -50%,30 min) to give 6.3 g of the title compound 14 as a white solid in 35% yield.
1HNMR（400 MHz，DMSO）δ：8.35 (d, 2H), 7.22 (dd, 2H), 7.14 (dd, J = 8.4 Hz, 2H), 7.09 (dd, 2H), 7.06 (dd, J = 8.4 Hz, 2H), 6.75 (t, 1H), 4.5 (br.s, 4H), 3.90-4.02 (m, 3H), 3.61-3.66 (m, 1H), 3.42-3.51 (m, 3H), 3.03-3.21 (m, 2H)。
Example 15 preparation of compound 15: (2S, 3R,4R,5S, 6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 15-2
15-1 g (86.6 mmol, 1.00 eq) of compound was taken, 200.0 mL of DCM and 0.1 mL of DMF were added, oxalyl chloride 12.1 g (95.3 mmol, 1.10 eq) was added dropwise at 0℃and after the addition was completed, the temperature was raised to room temperature for reaction 2 h. After the reaction was completed, a dichloromethane solution of compound 15-2 was obtained, which was used directly in the next step without post-treatment.
(2) Preparation of intermediate Compounds 15-4
To a dichloromethane solution of compound 15-2 obtained in step (1) at 0℃under nitrogen, was added compound 15-3.8 g (86.6 mmol, 1.00, eq), followed by the addition of AlCl in portions 3 11.6 g (86.6 mmol, 1.00, eq), and after the addition, the reaction mixture was warmed to room temperature and reacted for 6.6 h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, then 200 mL dilute hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by distillation under reduced pressure to obtain concentrate. Ethanol was added to the concentrate to precipitate a solid, which was collected by filtration, and the solid was dried under reduced pressure to give 25.8. 25.8 g compound 15-4 as a white solid in 80% yield.
(3) Preparation of intermediate Compounds 15-5
Compound 15-4.8 g (69.3 mmol, 1.00, eq) was taken, 200.0, mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 24 g (207.9 mmol, 3.00 eq) and then dropwise addition of BF under nitrogen at 25 ℃ 3 .Et 2 O39.2 g (277.2 mmol,4.00 eq), the above mixture was reacted at 25℃with 12 h. After the reaction, 100.0. 100.0 mL saturated NaHCO is added into the reaction solution 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 10:1, yielding 20.3 g compound 15-5 in 85% yield.
(4) Preparation of intermediate Compounds 15-7
Weighing and combining15-5.3 g (58.9 mmol, 1.00, eq) of the product are added 300 mL g of THF which is distilled at-70℃under N 2 To the above solution was added dropwise a solution of 47.2 mL (2.5M, 2.00 eq) n-BuLi in tetrahydrofuran under nitrogen at-70℃with stirring 0.3 h, followed by dropwise a solution of 15-6.7 g (58.9 mmol, 1.00 eq) of the compound in tetrahydrofuran (redistilled THF,50.0 mL) with stirring 1 h under nitrogen at-70 ℃. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, dichloromethane extraction is then adopted, an organic phase is collected, and reduced pressure distillation is carried out to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=10:1 to 1:1, yielding 24.6 g pure compound 15-7 with a yield of 52%.
(5) Preparation of intermediate Compounds 15-8
Compound 15-7.6 g (30.6 mmol, 1.00, eq) was weighed out, 200.0, mL methylene chloride was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 4.2 g (36.7 mmol, 1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O13 g (91.8 mmol, 3.0 eq) was then warmed to room temperature and stirred for 6h. After the reaction was completed, the reaction solution was poured into a 100.0. 100.0 mL saturated aqueous sodium bicarbonate solution, extracted, and a dichloromethane phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=10:1 to 3:1, yielding 11.6 g pure compound 15-8 with a yield of 48%.
(6) Preparation of target Compound 15 ((2S, 3R,4R,5S, 6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
11.6. 11.6 g (14.7 mmol, 1.00 eq) of 15-8 ethyl acetate and 200.0. 200.0 mL ethyl acetate were taken and mixed uniformly under stirring, then Pd/C4.5 g (active ingredient content 10%) was added under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at room temperature under 30 psi hydrogen pressure to 12 h. After the reaction was completed, the filtrate was filtered by suction and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 50mm, 10 um; mobile phase: water (0.1% hcooh) -MeOH, B%:20% -80%,30 min) to give 1.7. 1.7 g of the target compound 15 as a white solid in 27% yield.
1HNMR（400 MHz，DMSO）δ：7.71 (d, 1H), 7.67 (dd, 2H), 7.42 (d, 1H), 7.40 (d, 1H), 7.31 (dd, 2H), 7.18 (t, 1H), 7.08 (s, 1H), 6.75 (d, 1H), 5.60 (br.s, 1H), 4.7 (br.s, 4H), 3.91-4.04 (m, 3H), 3.64-3.69 (m, 1H), 3.41-3.50 (m, 1H), 3.21-3.32 (m, 3H), 3.07-3.20 (m, 1H)。
Example 16 preparation of compound 16: (2S, 3R,4R,5S, 6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 16-3/>
16-1 g (67.3 mmol, 1.0 eq) of the compound was weighed, 100 mL g of tetrahydrofuran was added thereto, and the mixture was distilled at-70℃under N 2 100.8 mL (2.0M, 3.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃with stirring for 1 h, then 16-2.2 g (67.3 mmol, 1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise, and after the addition was completed, 1 h was stirred under nitrogen at-70 ℃. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 16.3 g pure compound 16-3 as a colorless oil in 32% yield.
(2) Preparation of intermediate Compound 16-4
16-3.3 g (21.5 mmol, 1.0. 1.0 eq) of compound 16-3 was weighed out, 200.0 mL methylene chloride was added thereto, and a nitrogen gas stream was introduced at 20 ℃Et is added to the above solution under the above conditions 3 SiH 3g (25.8 mmol, 1.2. 1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O3.7 g (25.8 mmol, 1.2 eq) then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a 100.0. 100.0 mL saturated aqueous sodium chloride solution, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, giving 10.3 g pure compound 16-4 as a white solid in 65% yield.
(3) Preparation of the target Compound 16 ((2S, 3R,4R,5S, 6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
16-4.3 g (14 mmol, 1.0 eq) of the compound was weighed, 100.0 mL methanol was added, 3.5 g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50 psi hydrogen atmosphere for 24 h. After the reaction was completed, the filtrate was filtered by suction, and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 100mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:20% -50%,30 min) to give 2.1 g of the target compound 16 as a white solid in 40% yield.
1H NMR（400 MHz，CD 3 OD），δ：7.21 (dd, 2H), 7.10 (dd, 2H), 6.50 (d, 2H), 4.57 (d, 1H), 3.98 (s, 2H), 3.82-3.87 (m, 4H), 3.54-3.63 (m, 2H)。
Example 17 preparation of compound 17: (2S, 3R,4R,5S, 6R) -2- (4- (4-isopropoxybenzyl) -2- (trifluoromethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
/>
(1) Preparation of intermediate Compound 17-3
17-1 g (68 mmol, 1.0 eq) of compound was weighed out, 150 mL g of tetrahydrofuran was added thereto, and the mixture was distilled at-70℃under N 2 34 mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under the condition, and stirred under nitrogen at-70℃for 0.5 h, then 17-2.6 g (68 mmol, 1.0 eq) of tetrahydrofuran (redistilled THF,50.0 mL) was added dropwise, and after the addition was completed, stirred under nitrogen at-70℃for 1 h. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving 33.4 g pure compound 17-3 in 59% yield.
(2) Preparation of intermediate Compound 17-4
Compound 17-3.4 g (40.1 mmol, 1.0 eq) was weighed out, 150.0 mL dichloromethane was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 5.6g (48.1 mmol, 1.2. 1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O6.8 g (48.1 mmol, 1.2 eq) then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a 100.0. 100.0 mL saturated aqueous sodium chloride solution, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=50:1 to 5:1, yielding 19.6 g as a white solid with a yield of 60%.
(3) Preparation of target Compound 17 ((2S, 3R,4R,5S, 6R) -2- (4- (4-isopropoxybenzyl) -2- (trifluoromethyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
17-4.6 g (24 mmol, 1.0 eq) of the compound was weighed, 100.0 mL methanol was added, 6.0 g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50 psi hydrogen atmosphere to 12 h. After the reaction was completed, the filtrate was filtered by suction, and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 100mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:20% -80%,30 min) to give 4.05 g of the target compound 17 as a white solid in 37% yield.
1H NMR（400 MHz，CD 3 OD），δ：7.42 (s, 1H), 7.18 (d, 1H), 7.16 (d, 1H), 7.14 (dd, 2H), 6.89 (dd, 2H), 4.68-4.70 (m, 1H), 4.53-4.56 (m, 1H), 3.96 (s, 2H), 3.54-3.79 (m, 6H), 1.36 (d, 6H)。
Example 18 preparation of compound 18: (2S, 3R,4R,5S, 6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula/>
(1) Preparation of intermediate Compound 18-2
Compound 18-1.0 g (137 mmol, 1.00 eq) was taken, 200.0 mL DCM and 0.1 mL DMF were added, oxalyl chloride 19.1 g (150.7 mmol, 1.10 eq) was added dropwise at 0deg.C, and after the addition was complete, the reaction was warmed to room temperature and allowed to react 3 h. After the reaction was completed, a dichloromethane solution of compound 18-2 was obtained, which was used directly in the next step without post-treatment.
(2) Preparation of intermediate Compound 18-4
24g (137 mmol, 1.00, eq) of compound 18-3 was added to the methylene chloride solution of compound 18-2 obtained in step (1) at 0℃under nitrogen, followed by the addition of AlCl in portions 3 18.3g (137 mmol, 1.00, eq) and after the addition, the reaction mixture was warmed to room temperature and reacted 5. 5 h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, then 200 mL dilute hydrochloric acid is added, then saturated saline water is added for extraction, and an organic phase and anhydrous Na are collected 2 SO 4 Drying, filtering, and concentrating the filtrate by reduced pressure distillation to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 50:1, drying under reduced pressure gave 42.8, g compound 18-4 as a white solid in 83% yield.
(3) Preparation of intermediate Compound 18-5
Compound 18-4.8 g (113.7 mmol, 1.00, eq) was taken and 350.0, mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 53 g (515.3 mmol, 4.00 eq) followed by dropwise addition of BF under nitrogen at 25 ℃ 3 .Et 2 O32.3 g (227.4 mmol, 2.00 eq), the above mixture reacted at 25℃12 h. After the reaction, 300.0. 300.0 mL saturated NaHCO is added into the reaction solution 3 The aqueous solution is then extracted with MTBE, the organic phase is extracted with saturated saline, the organic phase is collected, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude product. The crude product is passed through a silica gel column, the mobile phase is petroleum ether, and 35.9 g compound 18-5 is obtained, and the yield is 87.0%.
(4) Preparation of intermediate Compound 18-7
Compound 18-5.9 g (98.9 mmol, 1.00, eq) was weighed out and 550 mL g of THF was added to evaporate at-70℃under N 2 To the above solution was added dropwise a solution of 35.6 mL (2.5M, 1.00 eq) n-BuLi in tetrahydrofuran under nitrogen at-70℃with stirring 0.3 h, followed by dropwise a solution of compound 18-6.2 g (98.9 mmol, 1.00 eq) in tetrahydrofuran (redistilled THF,100.0 mL) with stirring 1 h under nitrogen at-70 ℃. The reaction solution was poured into saturated NH 4 In Cl aqueous solution, MTBE is then used for extraction, the organic phase is collected and distilled under reduced pressure to obtain crude products. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 61 g pure compound 18-7 in 75% yield.
(5) Preparation of intermediate Compounds 18-8
Weighing 18-7 g (74.2 mmo) of the compoundl, 1.00 eq), 400.0. 400.0 mL methylene chloride was added and Et was added to the above solution under nitrogen at room temperature 3 SiH 10.3 g (89 mmol, 1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O12.6 g (89 mmol, 1.20 eq) then warmed to room temperature and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0. 200.0 mL saturated aqueous sodium bicarbonate solution, extracted, and the dichloromethane phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, giving pure compound 18-8 of 40.1 g in 67% yield.
(6) Preparation of the target Compound 18 ((2S, 3R,4R,5S, 6R) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol)
40.1. 40.1 g (49.7 mmol, 1.00 eq) of 18-8 ethyl acetate and 400.0. 400.0 mL ethyl acetate were taken and mixed uniformly under stirring, then Pd/C7.4 g (active ingredient content 10%) was added under argon, the reaction system was evacuated to fill hydrogen, and reacted at 20℃under 30 psi of hydrogen to 12 h. After the reaction was completed, the filtrate was filtered by suction, and concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column: phenomenex luna C, 250, 50mm, 10 um; mobile phase: water (0.1% hcooh) -ACN, B%:20% -60%,30 min) to give 7.09 g of the objective compound 18 as a white solid in 32% yield.
1HNMR（400 MHz，DMSO）δ：7.17 (d, 1H), 7.08 (dd, 2H), 6.95 (d, 1H), 6.72 (d, 1H), 6.68 (dd, 2H), 4.7 (br.s, 4H), 3.92-4.00 (m, 1H), 3.98 (s, 2H), 3.60-3.69 (m, 5H), 3.40-3.50 (m, 1H), 3.34 (t, 4H), 2.85 (t, 4H), 2.28 (s, 3H)。
Example 19 preparation of compound 19: (2S, 3R,4R,5S, 6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol having the structural formula
（1）Preparation of intermediate Compound 19-3
Weigh 19-1 20g (54.8 mmol, 1.0 eq) of compound, add 100 mL g of tetrahydrofuran, and evaporate at-70℃under N 2 82 mL (2.0M, 3.0 eq) of n-butyllithium in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70 ℃ with stirring for 0.5 h, and then 19-2.3 g (54.8 mmol, 1.0 eq) of tetrahydrofuran (redistilled THF,50.0 mL) was added dropwise with stirring for 1 h at-70 ℃ under nitrogen. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 26.7g of pure compound 19-3 in 58% yield.
(2) Preparation of intermediate Compound 19-4
Compound 19-3.7 g (31.8 mmol, 1.0 eq) was weighed out, 200.0 mL methylene chloride was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 4.4g (38.2 mmol, 1.2. 1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O5.4 g (38.2 mmol, 1.2 eq) was then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a 100.0. 100.0 mL saturated aqueous sodium chloride solution, extracted, and a methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, yielding 14.4. 14.4 g pure compound 19-4 as a white solid in 55% yield.
(3) Preparation of the target Compound 19 ((2S, 3R,4R,5S, 6R) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol)
To the above solution was weighed 19-4.4 g (17.5 mmol, 1.0 eq), 100.0 mL methanol was added, 4.3 g Pd/C (active ingredient content 10%) was added under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 50 psi hydrogen at 50℃for 12 h. After the reaction was completed, the filtrate was suction filtered and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 100mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:20% -80%,40 min) to give 3 g of the target compound 19 as a white solid in 37% yield.
1H NMR（400 MHz，CD 3 OD），δ：7.12 (dd, 2H), 6.86 (dd, 2H), 6.47 (d, 2H), 4.52-4.54 (m, 1H), 4.28 (d, 2H), 4.12-4.16 (m, 1H), 3.98 (s, 2H), 3.84-3.87 (m, 4H), 3.80-3.82 (m, 2H), 3.61-3.63 (m, 2H), 2.60-2.65 (m, 2H)。
Example 20 preparation of compound 20: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol having the structural formula
(1) Preparation of intermediate Compound 20-3/>
20-1 g (213.4 mmol, 1.0 eq) of the compound was weighed out, 265 mL g of tetrahydrofuran was added and distilled at-70℃under N 2 106.6 mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under conditions, and stirred under nitrogen at-70℃for 0.5 h, followed by dropwise addition of 20-2 118 g (213.4 mmol, 1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) solution of the compound, and stirring under nitrogen at-70℃for 1 h after completion of the dropwise addition. Pouring the reaction solution into saturated NH 4 Extracting with ethyl acetate, collecting organic phase, and vacuum distilling to obtain crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=20:1 to 5:1, yielding 109.5g of pure compound 20-3 in 64% yield.
(2) Preparation of intermediate Compound 20-4
Compound 20-3.5 g (136.6 mmol, 1.0 eq) was weighed out, 700.0 mL methylene chloride was added and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 19 g (163.9 mmol, 1.2 eq), cooling to 0deg.C, adding BF dropwise 3 .Et 2 O23.3 g (163.9 mmol, 1.2 eq) then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0. 500.0 mL saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. The crude product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, yielding 64.5. 64.5 g pure compound 20-4 as a white solid in 60% yield.
(3) Preparation of target Compound 20 (((2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol)
20-4.5 g (82 mmol, 1.0 eq) of the compound was weighed, 500.0 mL methanol was added, 20 g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted at 50℃under 50 psi hydrogen atmosphere for 24 h. After the reaction was completed, the filtrate was filtered by suction, and concentrated, and the concentrate was subjected to prep-HPLC (prep HPLC) (column: phenomenex luna C, 250, 100mm, 10 um; mobile phase: water (0.1% tfa) -ACN, B%:25% -53%,30 min) to give 15.02, g of the title compound 20 as a white solid in 43% yield.
1H NMR（400 MHz，CD 3 OD），δ：7.09 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 6.45 (d, 2H), 4.52-4.54(m, 1H), 4.02 (q, 2H), 3.98 (s, 2H), 3.84-3.87 (m, 4H), 3.61-3.63 (m, 2H), 1.35 (t, 3H)。
In order to evaluate the efficacy of the glycoside derivative of the present invention, the following test examples were conducted.
Test example 1 ICR mice induced by glycoside derivatives of the present invention to tetraoxypyrimidineTherapeutic effects of model of type diabetes
Healthy ICR mice are adaptively fed for 3d, fasted and not forbidden for 12-16 h on day 3, and the tail vein injection of tetraoxypyrimidine ALX (prepared in the prior art) is completed within 70.0mg/kg and 0.1mL/10g for 30s, so that an I-type diabetes animal model is induced, and normal and non-molded mice are injected with the same amount of physiological saline through tail vein injection. After injection, normal feeding is carried out for 2d, the mice are fasted and not forbidden for 12-16 h, blood is taken from the tail tip after ALX is injected for 72h, the fast glucose meter with the trinoantine regulatory code is adopted to measure the fasting blood glucose concentration (FGB) (namely the blood glucose concentration before administration), and the FGB value is 11.1 mmol/L-25.0 mmol/L, which is regarded as a model successful diabetic mice, and the model successful diabetic mice are used for experiments.
Immediately after selecting successfully modeled diabetic mice, randomly grouping the diabetic mice into 22 groups according to fasting blood glucose (FGB) of the mice, wherein each group comprises 4 mice, each half of the mice, wherein the diabetic model group G2, the metformin group G3 (positive control, 200 mg/kg) and the glycoside derivatives of the invention are respectively administered in groups G4-G23, the control group G1 (the same group of 4 healthy and normoglycemic mice are used as a blank control group G1), and the specific grouping conditions are shown in Table 1. Oral gavage administration was started the following day after grouping, 1 time a day, 7d continuously, and the fasting blood glucose concentration (FGB) (i.e., blood glucose value after administration) of mice was measured in mmol.L by using a rapid glucometer 1h after administration on day 7 -1 The specific test results are shown in Table 1.
Table 1: the glycoside derivative has the effect of treating ICR mouse type I diabetes model caused by tetraoxypyrimidine
Group of Test article Dosage (mg- kg） Administration volume (mL- kg） Number of animals (only) Blood glucose level before administration （mmol.L -1 ） Blood glucose level after administration （mmol.L -1 ）
Control group G1 Purified water - 20 mL /kg 2♂+2♀ 5.6±1.2 5.6±1.0
Model group G2 Purified water - 20 mL /kg 2♂+2♀ 22.0±1.8 27.6±0.3 ①
Metformin hydrochloride Group G3 Metformin hydrochloride Sheet 200mg/kg 20 mL /kg 2♂+2♀ 21.3±4.9 14.8±8.3 ②
G4 Compound 1 50 mg/kg 20 mL /kg 2♂+2♀ 22.4±2.4 15.0±11.1 ②
G5 Compound 2 50 mg/kg 20 mL /kg 2♂+2♀ 22.3±2.4 6.5±1.8 ③
G6 Compound 3 50 mg/kg 20 mL /kg 2♂+2♀ 21.3±2.2 9.1±6.7 ③
G7 Compound 4 50 mg/kg 20 mL /kg 2♂+2♀ 21.6±3.5 9.2±5.4 ③
G8 Compound 5 50 mg/kg 20 mL /kg 2♂+2♀ 23.3±2.8 16.1±9.3
G9 Compound 6 50 mg/kg 20 mL /kg 2♂+2♀ 22.6±3.2 8.8±6.2 ③
G10 Compound 7 50 mg/kg 20 mL /kg 2♂+2♀ 21.7±3.9 10.2±5.7 ②
G11 Compound 8 50 mg/kg 20 mL /kg 2♂+2♀ 23.3±2.5 11.8±7.3 ②
G12 Compound 9 50 mg/kg 20 mL /kg 2♂+2♀ 22.8±3.6 8.9±5.2 ③
G13 Compound 10 50 mg/kg 20 mL /kg 2♂+2♀ 23.3±2.1 14.6±5.6
G14 Compound 11 50 mg/kg 20 mL /kg 2♂+2♀ 23.2±2.9 8.6±5.3 ③
G15 Compound 12 50 mg/kg 20 mL /kg 2♂+2♀ 21.5±3.2 9.6±4.8 ③
G16 Compound 13 50 mg/kg 20 mL /kg 2♂+2♀ 22.1±2.6 10.6±6.3 ②
G17 Compound 14 50 mg/kg 20 mL /kg 2♂+2♀ 21.9±2.7 12.1±7.5 ②
G18 Compound 15 50 mg/kg 20 mL /kg 2♂+2♀ 23.5±3.1 10.9±6.9 ②
G19 Compound 16 50 mg/kg 20 mL /kg 2♂+2♀ 22.6±2.8 11.7±7.3 ②
G20 Compound 17 50 mg/kg 20 mL /kg 2♂+2♀ 23.4±3.1 11.6±5.1 ③
G21 Compound 18 50 mg/kg 20 mL /kg 2♂+2♀ 21.6±2.4 12.9±6.5 ②
G22 Compound 19 50 mg/kg 20 mL /kg 2♂+2♀ 22.7±3.2 13.4±5.8 ②
G23 Compound 20 50 mg/kg 20 mL /kg 2♂+2♀ 22.8±2.2 10.1±5.2 ②
Remarks: (1) the method comprises the following steps P < 0.01 compared with the blank group; (2) the method comprises the following steps P < 0.05 compared with the model group; (3) the method comprises the following steps P < 0.01 compared to model group.
As can be seen from the table, ICR mice developed against tetraoxypyrimidineCompared with a model group, the positive control metformin group and the glycoside derivative administration group of the type diabetes model have the effect of reducing blood sugar, have obvious treatment effect, and part of the glycoside derivative administration group of the invention has the effect of reducing blood sugar better than the positive control group, thus proving that the glycoside derivative of the invention has the effect of reducing blood sugar >SugarThe composition has therapeutic effect on urine diseases. />

Claims (2)

1. An intermediate compound, characterized in that the intermediate compound is a compound represented by formula II:
a formula II;
wherein the compound shown in the formula II is:
、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>or (b)。
2. The use of an intermediate compound according to claim 1 in the preparation of the glycoside derivative, wherein the glycoside derivative is a compound shown in formula I or a pharmaceutically acceptable salt thereof, the intermediate compound is a compound shown in formula II, and the compound shown in formula II is prepared into the compound shown in formula I or the pharmaceutically acceptable salt thereof through deprotection reaction; wherein, the liquid crystal display device comprises a liquid crystal display device,
the compound shown in the formula I is: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4-dihydroxyphenyl) -2- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -2- (3R, 4, 5R, 6R) -tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 5R, 6R) -6R-tetrahydro-6- (4-ethoxybenzyl) phenyl) -2H-pyran-3, 4, 5-triol, (2S, 5R, 6R) -6R-tetrahydro-6R-hydroxy-6R-hydroxy-3 (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (2-isopropoxy ethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-acetoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (trifluoromethyl) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4- (2, 4, 5-trifluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 3R,4R,5S, 6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2S, 5S, 6R) -2- (4-isobutoxy) phenyl) -6- (4-trifluoro-methyl) tetrahydro-2H-pyran-3, 5-triol, (2 s,3r,4r,5s,6 r) -2- (2-fluoro-4- (4- (4-methylpiperazin-1-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol, (2 s,3r,4r,5s,6 r) -2- (2, 6-dihydroxy-4- (4- ((tetrahydrofuran-3-yl) oxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol, or (2 s,3r,4r,5s,6 r) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-thiopyran-3, 4, 5-triol;
The compound shown in the formula II is:、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、、/>、/>、or->。
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