CN111471031B - Glycoside derivative and preparation method and application thereof - Google Patents

Glycoside derivative and preparation method and application thereof Download PDF

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CN111471031B
CN111471031B CN201910065981.0A CN201910065981A CN111471031B CN 111471031 B CN111471031 B CN 111471031B CN 201910065981 A CN201910065981 A CN 201910065981A CN 111471031 B CN111471031 B CN 111471031B
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triol
tetrahydro
hydroxymethyl
pyran
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CN111471031A (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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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • 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
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    • 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
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    • 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
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    • 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
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Abstract

The invention belongs to the field of chemical medicines, and particularly relates to a glycoside derivative, and a preparation method and application thereof. The glycoside derivative is a compound shown in a formula I or pharmaceutically acceptable salt thereof:
Figure DDA0001955660600000011
compared with the prior art, the novel glycoside derivative has excellent treatment effect on the type I diabetes no matter in high, medium and low doses.

Description

Glycoside derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of chemical medicines, and particularly relates to a glycoside derivative, and a preparation method 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 180g glucose per day filtered through the glomeruli, with > 99% of the glucose reabsorbed from the tubules. Under the condition of hyperglycemia, sodium-glucose cotransporters (SGLTs) are saturated, a large amount of glucose is 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 glycoside derivative, and a preparation method and application thereof.
The first object of the present invention is to provide a glycoside derivative, which is a compound represented by formula I or a pharmaceutically acceptable salt thereof:
Figure BDA0001955660580000011
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 glycoside derivative, 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 glycoside derivative, 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 glycoside derivative, 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.
Among the glycoside derivatives, 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.
The second object of the present invention is to provide a preparation method of the glycoside derivative, wherein the compound shown in the formula I is prepared by deprotection reaction of the compound shown in the formula II;
Figure BDA0001955660580000021
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 is TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, 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, the compound represented by formula II is prepared from a compound represented by formula III;
Figure BDA0001955660580000031
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 is TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, 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, the compound represented by formula III is prepared by reacting a compound represented by formula IV with a compound represented by formula V;
Figure BDA0001955660580000032
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 (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 TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, carboxyl, cyano, alkoxy, or nitro;
the R is 7 、R 7a Independently a hydrogen atom or an alkyl group.
The third object of the invention is to provide an application of the glycoside derivative in the medicine for preventing and/or treating type I diabetes.
The fourth object of the invention is to provide an application of the glycoside derivative in medicines for preventing and/or treating type I diabetes induced by tetraoxypyrimidine and the like.
A fifth object of the present invention is to provide a pharmaceutical composition of the above glycoside derivative, which comprises: the compound shown in the formula I or pharmaceutically acceptable salt thereof is used as an active ingredient and at least one pharmaceutically acceptable auxiliary material; preferably, the composition is administered orally, by injection, transdermally, nasally, mucosally, by inhalation; more preferably, the composition is in a conventional dosage form, a slow release, controlled release, localized or immediate release dosage form.
Compared with the prior art, the invention has the following technical effects:
1. compared with the prior art, the glycoside derivative has excellent treatment effect on the type I diabetes no matter in high, medium and low doses.
2. The preparation method of the glycoside derivative adopts cheap and easily available chemical products as the starting materials, and the synthesis yield of each step is higher, so that the preparation method has lower production cost and is more suitable for industrial production.
Drawings
FIG. 1 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (compound 1);
FIG. 2 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (compound 2);
FIG. 3 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 3);
FIG. 4 is a hydrogen spectrum of (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol (Compound 4).
Detailed Description
The glycoside 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.
A glycoside derivative is a compound shown in a formula I or pharmaceutically acceptable salt thereof:
Figure BDA0001955660580000051
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 (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, etc.), O-aryl (illustratively, -O-aryl is
Figure BDA0001955660580000052
Figure BDA0001955660580000053
Etc.), the-O-heteroaryl (-O-heteroaryl is illustratively +.>
Figure BDA0001955660580000054
Figure BDA0001955660580000055
Etc. -OCH 2 -aryl (-OCH) 2 The aryl group is illustratively PhCH 2 O-、
Figure BDA0001955660580000056
Etc. -OCH 2 Heteroaryl (-OCH) 2 The heteroaryl group is illustratively +.>
Figure BDA0001955660580000057
Figure BDA0001955660580000058
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,/->
Figure BDA0001955660580000059
Cyclopentyl, or cyclohexyl, etc.), aryl (illustratively, aryl is phenyl, p-methylphenyl, p-fluorophenyl, o-chlorophenyl, m-methoxyphenyl, or +.>
Figure BDA00019556605800000510
Etc.), heteroaryl (illustratively, heteroaryl is
Figure BDA00019556605800000511
Figure BDA00019556605800000512
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 +.>
Figure BDA00019556605800000513
Etc.), an ester group (illustratively, an ester group is
Figure BDA0001955660580000061
Etc.) or-NR 7 R 7a (illustratively, -NR) 7 R 7a Amino group, & lt>
Figure BDA0001955660580000062
Etc.) or contain 1 to 4N, O, S, SO and/or SO 2 3-14 membered heterocyclic ring (exemplified by +.>
Figure BDA0001955660580000063
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.
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.
The preparation method of the glycoside derivative is as follows, and the compound shown in the formula I is prepared by deprotection reaction of the compound shown in the formula II;
Figure BDA0001955660580000064
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 TMS- (trimethylsilyl), bn- (benzyl), ac- (acetyl), THP- (tetrahydropyranyl), MOM- (methoxymethyl), or TBDMS- (t-butyldimethylsilyl);
the R is 7 、R 7a Independently isA hydrogen atom or an alkyl group;
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.
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 alkali conditions (such as aqueous sodium hydroxide solution, aqueous potassium hydroxide 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 solution of hydrogen chloride in ethanol (HCl (g)/EtOH), or a solution of hydrogen chloride in dioxane (HCl (g)/dioxane)).
Further, the compound shown in the formula II is prepared from a compound shown in the formula III:
Figure BDA0001955660580000071
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 is TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, 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。
Further, the compound shown in the formula III is prepared by reacting a compound shown in the formula IV with a compound shown in the formula V;
Figure BDA0001955660580000072
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, -OCH 2 -aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 、-OCHF 2 、-OCF 3 Halogen, -CN, 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 TMS-, bn-, ac-, THP-, MOM-, or TBDMS-;
wherein the alkyl, cycloalkyl, aryl, heteroaryl may be further substituted with one or more substituents including halogen, hydroxy, amino, 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.
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
Figure BDA0001955660580000081
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Figure BDA0001955660580000082
(1) Preparation of intermediate compound 1-3 (1- (4-ethoxyphenoxy) -3, 5-difluorobenzene)
100g of p-bromophenyl ethyl ether (compound 1-1, 496mmol,1 eq) and 97g of 3, 5-difluorophenol (compound 1-2, 746mmol,1.5 eq) were taken, 1000mL of dioxane was added, and Cs was added to the above solution in sequence at 20 ℃ 2 CO 3 324g (994 mmol,2 eq), cuI 28.4g (149.2 mmol,0.3 eq), isobutyl nitrite 30.8g (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 was passed through a silica gel column with petroleum ether as the mobile phase to give 61.6g of pure compound 1-3 as a colorless oil in a yield of 24.8%.
(2) Preparation of intermediate Compounds 1-5
Figure BDA0001955660580000083
Taking compound 1-3.8 g (95.1 mmol,1.0 eq), adding 165.0mL of redistilled tetrahydrofuran at-70℃under N 2 71.3mL (2.0M, 1.5 eq) of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.5hThen a solution of compound 1-4.2 g (95.1 mmol,1.0 eq) in tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise and stirred under nitrogen at-70℃for 1h. 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 46.0g of pure compound 1-5 as a colorless oil with a yield of 61.3%.
(3) Preparation of intermediate Compounds 1-6
Figure BDA0001955660580000084
Compound 1-5.0 g (59.2 mmol,1.0 eq) was weighed out, 320.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 8.2g (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 then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of a 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 26.0g of pure compound 1-6 as a colorless oil 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, 200.0mL of methanol was added, 15.0g 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 at 50℃under 50psi of hydrogen for 24 hours. 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, 10um; mobile phase water (0.1% tfa) -ACN, B%:30% -80%,20 min) to give 4.6g of the title compound 1 as a white solid in 33.3% yield.
1H NMR(400MHz，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)。
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
Figure BDA0001955660580000091
Figure BDA0001955660580000092
(1) Preparation of intermediate Compounds 2-3
Figure BDA0001955660580000093
Compound 2-1 53g (213.4 mmol,1.0 eq) was weighed out, 265mL of redistilled tetrahydrofuran was added, and the mixture was taken at-70℃under N 2 106.6mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃for 0.5h with stirring, then 2-2 115g (213.4 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,106.0 mL) was added dropwise, and after the addition was completed, the mixture was stirred under nitrogen at-70℃for 1h. 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 105.0g of pure compound 2-3 as a colorless oil in 62.5% yield.
(2) Preparation of intermediate Compounds 2-4
Figure BDA0001955660580000101
Compound 2-3.0 g (133.4 mmol,1.0 eq) was weighed out, 735.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 18.6g (160 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O22.75 g (160 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction is completed, the reaction solution is poured into 500.0mL of saturated sodium chloride aqueous solution, extracted, methylene dichloride phase is collected, and reduced pressure distillation is carried out 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 68.0g of pure compound 2-4 as a white solid with a yield of 66.1%.
(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, 500.0mL of methanol was added, 22.0g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated and filled with hydrogen, and reacted at 50℃under 50psi of hydrogen for 24 hours. 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, 10um; mobile phase water (0.1% tfa) -ACN, 25% -53% B%: 30 min) to give 15g of the objective compound 2 as a white solid in 41.5% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.08(dd,J＝8.8Hz,2H),6.82(dd,J＝8.4Hz,2H),6.76(d,2H),4.54(d,1H),3.99(q,2H),3.84-3.87(m,4H),3.61-3.63(m,1H),3.30-3.45(m,3H),1.35(t,3H)。
Example 3 preparation of compound 3: (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxyphenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Figure BDA0001955660580000102
Figure BDA0001955660580000103
(1) Preparation of intermediate compound 3-3 (4- (4-bromo-2-chlorophenoxy) benzaldehyde)
Compound 3-1.0 g (289.2 mmol,1.00 eq) was weighed out, 650.0mL of DMA (dimethylacetamide), compound 3-2.35.90 g (289.2 mmol,1.00 eq) and potassium carbonate 42.37g (306.6 mmol,1.06 eq) were added and reacted under nitrogen at 100deg.C for 12h. After the reaction is completed, the temperature is reduced to room temperature, MTBE (methyl tert-butyl ether) (1.00L) is adopted for extraction, the organic phase MTBE is further adopted for extraction by saturated saline (1.00L), the organic phase is collected, the concentrate is obtained through reduced pressure distillation, the concentrate passes through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=40:1 to 3:1, giving 67.0g of compound 3-3 as a pale yellow oil in a yield of 72.1%.
1HNMR(400MHz，CDCl3)δ：9.66(s,1H),7.89(d,J＝8.8Hz,2H),7.69(d,J＝2.4Hz,1H),7.46(dd,J＝2.4Hz,J＝8.8Hz,1H),7.04(d,J＝0.8Hz,J＝8.8Hz,3H)。
(2) Preparation of intermediate Compounds 3-4
Figure BDA0001955660580000111
To the solution was added 58.0g (268.8 mmol, purity 80%,1.25 eq) of m-CPBA from 3-3.0 g (215.1 mmol,1.00 eq) of methylene chloride (670.0 mL), and the reaction system was reacted at 20℃for 10 hours. After completion of TLC detection, 200.0mL of saturated Na was added to the reaction solution at 10 ℃ 2 SO 3 The aqueous solution was extracted with MTBE (300.0 mL), and 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
Figure BDA0001955660580000112
70.0g of crude compound 3-4 prepared in the step (2) is taken, 350mL of methanol and 0.5mL of concentrated hydrochloric acid (12M) are added, and the mixture is stirred for 2h 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 67.0g of compound 3-5 as a pale yellow oil.
1HNMR(400MHz CDCl3)δ：7.60(d,J＝2.4Hz,1H),7.29(d,J＝2.4Hz,J＝8.8Hz,1H),6.91-6.93(m,2H),6.83-6.86(m,2H),6.75(d,J＝8.8Hz,1H)。
(4) Preparation of intermediate Compounds 3-6
Figure BDA0001955660580000113
Taking compound 3-5.0 g (1.00 eq), adding 450.0mL tetrahydrofuran, reducing16.5g NaH (purity 60%,2.4 eq) was added in portions at 0℃and then 40.3g 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 300.0mL of saturated NH is added into the reaction solution 4 The Cl aqueous solution is added with MTBE 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 55.0g of compound 3-6 as a pale yellow oil in 74.8% yield.
1HNMR(400MHz，CDCl 3 )δ：7.50(d,J＝2.4Hz,1H),7.17-7.20(m,1H),6.85-6.87(m,2H),6.79-6.85(m,2H),6.64(d,J＝8.4Hz,1H),3.94(q,J＝7.2Hz,J＝14.4Hz,2H),1.34(t,J＝7.2Hz,3H)。
(5) Preparation of intermediate Compounds 3-8
Figure BDA0001955660580000114
Compound 3-6.0 g (122.10 mmol,1.00 eq) was weighed out, 700mL THF was added and redistilled at-70℃under N 2 48.84mL (2.5M, 1.00 eq) of n-BuLi (n-butyllithium) in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.2h, followed by dropwise addition of a solution of compound 3-6.77 g (122.10 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,100.0 mL) and stirring at-70℃for 1h under nitrogen. 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 75.0g of pure compound 3-8 as a colorless oil.
1HNMR(400MHz，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＝6.8Hz,3H)。
(6) Preparation of intermediate Compounds 3-9
Figure BDA0001955660580000121
Compound 3-8.0 g (95.3 mmol,1.00 eq) was weighed and 525.0mL of dichloromethane was addedAlkane, et was added to the above solution under nitrogen at 20deg.C 3 SiH (13.3 g,114.3mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O6.5 g (45.7 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After completion of the reaction, the reaction mixture was poured into a saturated solution of 200.0mL 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 52.0g of 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, 880.0mL of 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 and filled with hydrogen, and reacted at 20℃under 30psi of hydrogen for 12 hours. 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%; the flow rate is 73g/min; the detection wavelength is 220nm; column temperature is 40 ℃; pressure 100 bar) to give 9.22g of the title compound 3 as a white solid.
1HNMR(400MHz，CD 3 OD)δ：7.55(d,J＝2.0Hz,1H),7.28(dd,J＝2.0Hz,J＝8.4Hz,1H),6.83-6.89(m,5H),4.11(d,J＝8.8Hz,1H),4.06(q,2H),3.88(dd,J＝2.0Hz,J＝8.0Hz,1H),3.71(dd,J＝5.2Hz,J＝11.6Hz,1H),3.40-3.44(m,3H),3.30-3.31(m,1H),1.37(t,J＝6.8Hz,3H)。
Example 4 preparation of compound 4: (2S, 3R,4R,5S, 6R) -2- (3-chloro-4- (4-ethoxybenzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Figure BDA0001955660580000122
Figure BDA0001955660580000123
(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, 17.8g (140.2 mmol,1.10 eq) oxalyl chloride was added dropwise at 0deg.C, and after the addition was completed, the temperature was raised to 20deg.C for 3h. 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
Figure BDA0001955660580000131
To a dichloromethane solution of compound 4-2 obtained in step (1) at 0deg.C under nitrogen, 15.5g (127.4 mmol,1.00 eq) of ethoxybenzene was added followed by the addition of AlCl in portions 3 17.0g (127.4 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to 20℃and reacted for 3h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted 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, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and dried under reduced pressure to give 35.0g of Compound 4-3 as a white solid in 80.9% yield.
1HNMR(400MHz，CDCl 3 )δ：7.74(dd,J＝7.2Hz,J＝9.2Hz,2H),7.63(m,1H),7.50(d,J＝2.0Hz,J＝8.0Hz,1H),7.23(d,J＝8.0Hz,1H),6.92(d,J＝8.8Hz,2H),4.11(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H)。
(3) Preparation of intermediate Compounds 4-4
Figure BDA0001955660580000132
Compound 4-3.0 g (103.1 mmol,1.00 eq) was taken, 350.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 59.9g (515.3 mmol,5.00 eq) and BF were then added dropwise under nitrogen at 25 ℃ 3 .Et 2 O29.3 g (206.1 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 30 was added to the reaction solution0.0mL saturated NaHCO 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 was passed through a silica gel column with petroleum ether as the mobile phase to give 33.0g of compound 4-4 as a pale yellow oil in 92.0% yield.
1HNMR(400MHz，CDCl 3 )δ：7.53(d,J＝2.0Hz,1H),7.29(d,J＝2.0Hz,J＝8.4Hz,1H),7.06(d,J＝8.8Hz,2H),6.98(d,J＝8.0Hz 1H),6.83(d,J＝8.4Hz,2H),3.98(q,J＝6.8Hz,2H),1.40(t,J＝6.8Hz,3H)。
(4) Preparation of intermediate Compounds 4-6
Figure BDA0001955660580000133
Compound 4-4.0 g (86.0 mmol,1.00 eq) was weighed out, 560mL of redistilled THF was added at-70℃under N 2 34.4mL (2.5M, 1.00 eq) of an n-BuLi solution in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.2h, followed by dropwise addition of a solution of compound 4-5.3 g (86.0 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,100.0 mL) and stirring at-70℃for 1h under nitrogen. 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 56.0g of pure compound 4-6 as a colorless oil with a yield of 72.8%.
(5) Preparation of intermediate Compounds 4-7
Figure BDA0001955660580000134
Compound 4-6.0 g (71.3 mmol,1.00 eq) was weighed out, 390.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.95g (85.6 mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O12.1 g (85.6 mmol,1.20 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of a saturated aqueous sodium hydrogencarbonate solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to give a crude productThe product is obtained. 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 55.0g of pure compound 4-7 as a colorless oil in 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)
41.2g (53.6 mmol,1.00 eq) of compound 4-7 and 800.0mL 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℃for 12 hours under 30psi of hydrogen. 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, 10um; mobile phase: water (0.1% tfa) -ACN, B%:26% -46%,20 min) to give 7.7g of the title compound 4 as a white solid in 35.1% yield.
1HNMR(400MHz，DMSO)δ：7.37(s,1H),7.23(d,2H),7.08(d,J＝8.4Hz,2H),6.81(d,J＝8.4Hz,2H),4.7(br.s,4H),3.92-4.00(m,5H),3.60-3.66(m,1H),3.40-3.50(m,1H),3.05-3.24(m,4H),1.27(t,J＝7.2Hz,3H)。
Example 5 preparation of compound 5: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxyphenoxy) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Figure BDA0001955660580000141
/>
Figure BDA0001955660580000142
(1) Preparation of intermediate Compounds 5-3
Figure BDA0001955660580000143
69.4g (5-1, 496mmol,1 eq) of p-bromophenyl ethyl ether and 152.5g (744 mmol,1.5 eq) of compound 5-2 were taken, 500mL of dimethylformamide was added, cs was added to the above solution in sequence at 20 ℃ 2 CO 3 323g (992 mmol,2 eq) then under nitrogen at 100 DEG CStirring was carried out 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
Figure BDA0001955660580000151
Taking 5-3.3 g (124 mmol,1.0 eq) of compound, adding 180.0mL of redistilled tetrahydrofuran at-70 ℃ under N 2 148.8mL (2.5M, 3 eq) of a tetrahydrofuran solution of n-butyllithium were added dropwise to the above solution under nitrogen at-70℃for 0.5h, followed by dropwise addition of a solution of 5-4.7 g (124 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,150.0 mL) of the compound under nitrogen at-70℃for 1h. 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 32.5% yield.
(3) Preparation of intermediate Compounds 5-6
Figure BDA0001955660580000152
Compound 5-5.6 g (40.3 mmol,1.0 eq) was weighed out, 350.0mL of dichloromethane was added, et was added to the above solution under nitrogen at 20 ℃ 3 SiH 5.6g (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) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into a saturated 200.0mL aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. 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, 200.0mL of methanol was added, 17.0g 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 at 50℃under 50psi of hydrogen for 24 hours. 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, 10um; mobile phase water (0.1% tfa) -ACN, B%:30% -80%,20 min) to give 3.0g of the target compound 5 as a white solid in a yield of 30.1%.
1H NMR(400MHz，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
Figure BDA0001955660580000153
Figure BDA0001955660580000161
(1) Preparation of intermediate Compound 6-2
Figure BDA0001955660580000162
Compound 6-1 60g (230.4 mmol,1.00 eq) was taken, 200.0mL DCM and 0.1mL DMF were added, 132.2g (253.4 mmol,1.10 eq) oxalyl chloride was added dropwise at 0deg.C, and after the addition was completed, the temperature was raised to 20deg.C for 3h. 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
Figure BDA0001955660580000163
At 0℃under nitrogen28.0g (230.4 mmol,1.00 eq) of ethoxybenzene was added to the dichloromethane solution of compound 6-2 obtained in step (1), followed by the addition of AlCl in portions 3 30.7g (230.4 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to 20℃and reacted for 3h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted 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 the mixture was stirred at 20℃for 2 hours, 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
Figure BDA0001955660580000164
Compound 6-3 68g (186.4 mmol,1.00 eq) was taken, 350.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 108.3g (932 mmol,5.00 eq) and BF were then added dropwise under nitrogen at 25 ℃ 3 .Et 2 O106 g (745.6 mmol,4.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 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 55.4g of compound 6-6 in 92.0% yield.
(4) Preparation of intermediate Compounds 6-6
Figure BDA0001955660580000165
Weighing 6-4.4 g (171.5 mmol,1.0 eq) of the compound, adding 300mL of redistilled tetrahydrofuran at-70deg.C under N 2 205.8mL (2.5M, 3.0 eq) of a tetrahydrofuran solution of n-butyllithium was added dropwise to the above solution under nitrogen at-70℃for 0.5h, followed by dropwise addition of a tetrahydrofuran (redistilled THF,100.0 mL) solution of 6-5 g (171.5 mmol,1.0 eq) of the compound under nitrogen at-70℃after the completion of the dropwise additionStirring for 1h. 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 40.3g of pure compound 6-6 in 30% yield.
(5) Preparation of intermediate Compounds 6-7
Figure BDA0001955660580000171
Compound 6-6.3 g (51.45 mmol,1.0 eq) was weighed out, 300.0mL of dichloromethane was added, et was added to the above solution under nitrogen at 20 ℃ 3 SiH 7.16g (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) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of a 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 in 60% yield.
(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, 200.0mL of 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 50psi of hydrogen for 24 hours. 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, 10um; mobile phase water (0.1% tfa) -ACN, B%:20% -60%,30 min) to give 3.7g of the target compound 6 as a white solid in 30% yield.
1H NMR(400MHz，DMSO)，δ：7.08(d,J＝8.8Hz,2H),6.82(d,J＝8.4Hz,2H),6.47(s,2H),4.53-4.56(m,1H),3.95-4.01(q,2H),3.84-3.87(m,4H),3.61-3.63(m,1H),3.30-3.35(m,3H),1.36(t,3H)。
Example 7 preparation of compound 7: (2S, 3R,4R,5S, 6R) -2- (2, 6-difluoro-4- (4- (2-)Isopropoxy ethoxy) phenoxy) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Figure BDA0001955660580000172
/>
Figure BDA0001955660580000173
(1) Preparation of intermediate Compound 7-3
Figure BDA0001955660580000174
100g of p-bromophenol (compound 7-1, 578mmol,1 eq), compound 7-2.5 g (578 mmol,1 eq) and potassium carbonate 95.7g were taken, 1000mL of dioxane was added, and stirred at 60℃for 12h. 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
Figure BDA0001955660580000181
Taking 100g (383 mmol,1 eq) of compound 7-3, 60.2g (compound 7-4, 463.2mmol,1.2 eq) of 3, 5-difluorophenol, adding 800mL of dioxane, adding Cs sequentially to the above solution at 20deg.C 2 CO 3 252g (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
Figure BDA0001955660580000182
59.4g (193 mmol,1.0 eq) of Compound 7-7 was taken, 200.0mL of redistilled tetrahydrofuran was added at-70℃under N 2 144.6mL (2.0M, 1.5 eq) of LDA (lithium diisopropylamide) in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.5h, followed by dropwise addition of a solution of compound 7-6.9 g (193 mmol,1.0 eq) in tetrahydrofuran (redistilled THF,200.0 mL) under nitrogen at-70℃for 1h. 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 95.1g of pure compound 7-7 with a yield of 58.3%.
(4) Preparation of intermediate Compounds 7-8
Figure BDA0001955660580000183
Compound 7-8.1 g (112.5 mmol,1.0 eq) was weighed, 500.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 15.6g (135 mmol,1.2 eq); cooling to 0 ℃, then adding BF dropwise 3 .Et 2 O9.6 g (135 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 saturated 200.0mL aqueous solution of sodium chloride, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. 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 52.1g of 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 compound 7-8.1 g (62.8 mmol,1.0 eq), added 500.0mL of methanol, 28.0g Pd/C (active material content 10%) under argon atmosphere, and the reaction system was evacuated to fill hydrogen and reacted under 50psi hydrogen at 50℃for 24 hours. 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, 10um; mobile phase: water (0.1% hcooh) -ACN, B%:30% -80%,20 min) to give 10.3g of the objective compound 7 as a white solid in 35% yield.
1H NMR(400MHz，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
Figure BDA0001955660580000191
Figure BDA0001955660580000192
(1) Preparation of intermediate Compound 8-3
Figure BDA0001955660580000193
Weighing compound 8-1 50g (227 mmol,1.0 eq), adding 300mL of redistilled tetrahydrofuran 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℃for 0.5h with stirring, and then 8-2.122.3 g (227 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise with stirring at-70℃for 1h 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 1:1, yielding 101.5g of pure compound 8-3 in 59% yield.
(2) Preparation of intermediate Compounds 8-4
Figure BDA0001955660580000194
Compound 8-3.5 g (133.9 mmol,1.0 eq) was weighed out, 800.0mL of dichloromethane was added,et is added to the above solution under nitrogen at 20 ℃ 3 SiH 18.7g (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) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0mL of 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 in 60% yield.
(3) Preparation of intermediate Compounds 8-5
Figure BDA0001955660580000201
Compound 8-4.6 g (80.3 mmol,1.0 eq) was weighed, 500mL of dichloromethane, 20.7g of DIPEA (160.6 mmol,2 eq), 35.5g of HATU (93.4 mmol,1.2 eq) were added, then 4.3g of formic acid (93.4 mmol,1.2 eq) was added dropwise, and after the addition was completed, stirring was carried out at room temperature for 2h. 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 45.3g of pure compound 8-5 in 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, 500.0mL of ethanol was added, 22.0g Pd/C (active ingredient content 10%) was added to the above solution under argon atmosphere, the reaction system was evacuated and filled with hydrogen, and reacted at 50℃under 50psi of hydrogen for 24 hours. 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, 10um; mobile phase water (0.1% tfa) -ACN, B%:25% -70%,30 min) to give 9.5g of the title compound 8 as a white solid in 39% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.16(d,J＝8.8Hz,2H),6.87(d,J＝8.4Hz,2H),6.42(d,2H),4.57(d,1H),3.98(s,2H),3.86-3.89(m,4H),3.61(m,1H),3.30-3.35(m,1H),2.23(s,3H)。
Example 9 preparation of compound 9: (2S, 3R,4R,5S, 6R) -2- (4- (3, 4-diethoxybenzyl) -2, 6-difluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Figure BDA0001955660580000202
Figure BDA0001955660580000203
(1) Preparation of intermediate Compound 9-3
Figure BDA0001955660580000204
50g (171.2 mmol,1.0 eq) of Compound 9-1 was weighed, 200mL of redistilled tetrahydrofuran was added, and the mixture was taken at-70℃under N 2 85.5mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70deg.C for 0.5h with stirring, 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, the mixture was stirred at-70deg.C for 1h 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 2:1, yielding 92.3g of pure compound 9-3 as a colorless oil in 65% yield.
(2) Preparation of intermediate Compounds 9-4
Figure BDA0001955660580000211
Compound 9-3.3 g (111.3 mmol,1.0 eq) was weighed out, 700.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 15.6g (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 solution was poured into 500.0mL of 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: second stepEthyl acetate=100:1 to 5:1, giving 60.7g of 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 500.0mL of methanol, 18.6g Pd/C (active ingredient content 10%) under argon atmosphere, and the reaction system was evacuated to fill hydrogen and reacted at 50℃under 50psi of hydrogen for 24 hours. 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, 10um; mobile phase water (0.1% hcooh) -ACN, B%:25% -60%,30 min) to give 15.2g of the objective compound 9 as a white solid in 45% yield.
1H NMR(400MHz，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
Figure BDA0001955660580000212
Figure BDA0001955660580000213
(1) Preparation of intermediate Compound 10-3
Figure BDA0001955660580000214
10-1 g (182.4 mmol,1.0 eq) of the compound was weighed, 200mL of redistilled tetrahydrofuran was added, and the mixture was taken at-70℃under N 2 91.1mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70deg.C for 0.2h with stirring, followed by dropwise addition of 10-2.98.2 g (182.4 mmol,1.0 eq) of tetrahydrofuran (redistilled THF, 100.0)mL) and stirring for 1h at-70 ℃ under nitrogen after the 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 2:1, yielding 86.5g of pure compound 10-3 as a colorless oil with a yield of 58.4%.
(2) Preparation of intermediate Compound 10-4
Figure BDA0001955660580000221
Compound 10-3.5 g (106.6 mmol,1.0 eq) was weighed out, 700.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at room temperature 3 SiH 14.9g (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 500.0mL of 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, yielding 56.8g of pure compound 10-4 as a white solid with a yield of 67%.
(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, 500.0mL of ethyl acetate was added, 17.8g Pd/C (wet palladium on carbon, 5% active ingredient content) was added to the above solution under argon atmosphere, the reaction system was evacuated to fill hydrogen, and reacted under 50psi hydrogen at 50℃for 12 hours. 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, 10um; mobile phase water (0.1% hcooh) -ACN, 25% -70% B%, 30 min) to give 13g of the title compound 10 as a white solid in 42% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.55(d,J＝8.8Hz,2H),7.32(d,J＝8.4Hz,2H),6.88(d,2H),4.53-4.56(m,1H),3.87-3.90(m,1H),3.80-3.82(m,2H),3.61-3.63(m,3H)。
Example 11 preparation of compound 11: (2S, 3R,4R,5S, 6R) -2- (4- (4-ethoxybenzyl) -3-fluorophenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Figure BDA0001955660580000222
Figure BDA0001955660580000231
(1) Preparation of intermediate Compound 11-2 (4-bromo-2-fluorobenzoyl chloride)
Compound 11-1.0 g (137 mmol,1.00 eq) was taken, 200.0mL DCM and 0.1mL DMF were added, and oxalyl chloride 19.1g (150.7 mmol,1.10 eq) was added dropwise at 0deg.C and reacted at room temperature for 5h. 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
Figure BDA0001955660580000232
To a dichloromethane solution of compound 11-2 obtained in step (1) at 0deg.C under nitrogen, 16.7g (137 mmol,1.00 eq) of ethoxybenzene was added 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 for 3h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted 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, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and the solid was dried under reduced pressure to give 33.3g of Compound 11-3 as a white solid in 75.2% yield.
(3) Preparation of intermediate Compound 11-4
Figure BDA0001955660580000233
Compound 11-3.3 g (103.1 mmol,1.00 eq) was taken and 350.0mL acetonitrile was added Et is added under nitrogen at 20 DEG C 3 SiH 18g (154.65 mmol,1.5 eq) and BF were then added dropwise under nitrogen at 25 ℃ 3 .Et 2 O29.3 g (206.1 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 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
Figure BDA0001955660580000234
Compound 11-4.4 g (91.8 mmol,1.00 eq) was weighed out, 600mL of redistilled THF was added at-70℃under N 2 36.7mL (2.5M, 1.00 eq) of an n-BuLi solution in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.2h, followed by dropwise addition of a solution of compound 10-5.49.4 g (91.8 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,100.0 mL) and stirring at-70℃for 1h under nitrogen. 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, yielding 52.9g of pure compound 11-6 in 75% yield.
(5) Preparation of intermediate Compounds 11-7
Figure BDA0001955660580000241
Compound 11-6.9 g (68.85 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.6g (82.62 mmol,1.20 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O11.7 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 200.0mL of saturated aqueous sodium bicarbonate, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Crude product of desilicationThe gel column, the mobile phase is petroleum ether: ethyl acetate=20:1 to 4:1, yielding 35.3g of 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)
35.3g (46.8 mmol,1.00 eq) of 11-7 compound and 600.0mL of 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 and filled with hydrogen, and reacted at 20℃under 30psi of hydrogen for 12 hours. 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, 10um; mobile phase: water (0.1% tfa) -ACN, B%:20% -60%,20 min) to give 6.8g of the objective compound 11 as a white solid in 37% yield.
1HNMR(400MHz，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),1.34D(t,3H)。
Example 12 preparation of compound 12: (2S, 3R,4R,5S, 6R) -2- (3-fluoro-4- (4- (4-fluorophenoxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Figure BDA0001955660580000242
Figure BDA0001955660580000243
(1) Preparation of intermediate compound 12-2 (4-bromo-2-fluorobenzoyl chloride)
12-1.0 g (137 mmol,1.00 eq) of the compound was taken, 200.0mL of DCM and 0.1mL of DMF were added, 19.1g (150.7 mmol,1.10 eq) of oxalyl chloride was added dropwise at 0℃and after the addition was completed, the temperature was raised to 20℃for reaction for 3h. 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
Figure BDA0001955660580000251
25.7g (137 mmol,1.00 eq) of p-fluorophenoxybenzene was added to a dichloromethane solution of compound 12-2 obtained in step (1) at 0deg.C under nitrogen, followed by the addition of AlCl in portions 3 18.3g (137 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to 20℃and reacted for 5h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted 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, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and the solid was dried under reduced pressure to give 45.3g of compound 12-3 as a white solid in 85% yield.
(3) Preparation of intermediate Compound 12-4
Figure BDA0001955660580000252
Compound 12-3.45.3 g (116.4 mmol,1.00 eq) was taken, 400.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 40.6g SiH (349.2 mmol,3.00 eq) were then added dropwise under nitrogen at 25℃with BF 3 .Et 2 O33 g (232.8 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 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 was passed through a silica gel column with petroleum ether as the mobile phase to give 39.7g of compound 12-4 in 91.0% yield.
(4) Preparation of intermediate Compound 12-6
Figure BDA0001955660580000253
Compound 12-4.7 g (105.9 mmol,1.00 eq) was weighed out, 600mL of redistilled THF was added at-70℃under N 2 42.4mL (2.5M, 1.00 eq) of n-BuLi in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.2h, followed by dropwise additionA solution of compound 12-5 57g (105.9 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,150.0 mL) was added and then stirred under nitrogen at-70℃for 1h. 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 66.2g of pure compound 12-6 in 75% yield.
(5) Preparation of intermediate Compounds 12-7
Figure BDA0001955660580000254
Compound 12-6.2 g (79.4 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, et was added to the above solution under nitrogen at 20 ℃ 3 SiH 11g (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) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 200.0mL of saturated aqueous sodium bicarbonate, 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=20:1 to 4:1, yielding 39.6g of 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)
39.6g (48.4 mmol,1.00 eq) of the compound 12-7 and 800.0mL of ethyl acetate were taken and mixed uniformly under stirring, then 7.2g (active ingredient content 10%) of Pd/C was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30psi of hydrogen pressure for 12 hours. 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, 10um; mobile phase: water (0.1% tfa) -ACN, B%:20% -60%,30 min) to give 8.2g of the title compound 12 as a white solid in 37% yield.
1HNMR(400MHz，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
Figure BDA0001955660580000261
Figure BDA0001955660580000262
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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, 200.0mL DCM and 0.1mL LDMF were added, and 19.1g (150.7 mmol,1.10 eq) oxalyl chloride was added dropwise at 0deg.C, and after the addition was completed, the temperature was raised to 20deg.C for 3h. 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
Figure BDA0001955660580000263
To a dichloromethane solution of compound 13-2 obtained in step (1) at 0deg.C under nitrogen, 13-330.7g (137 mmol,1.00 eq) of compound was added 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 20℃and reacted for 5h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted 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, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and the solid was dried under reduced pressure to give 45.7g of Compound 13-4 as a white solid in 82% yield.
(3) Preparation of intermediate Compound 13-5
Figure BDA0001955660580000264
Taking and combining13-4.7 g (112.3 mmol,1.00 eq) of acetonitrile was added 400.0mL of Et under nitrogen at 20deg.C 3 SiH 39g (336.9 mmol,3.00 eq) and BF were then added dropwise under nitrogen at 25 ℃ 3 .Et 2 O31.8 g (224.6 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 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 40.6g of compound 13-5 in 92% yield.
(4) Preparation of intermediate Compounds 13-7
Figure BDA0001955660580000271
Compound 13-5.6 g (103.3 mmol,1.00 eq) was weighed out, 600mL of redistilled THF was added at-70℃under N 2 41.4mL (2.5M, 1.00 eq) of an n-BuLi solution in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.2h, followed by dropwise addition of a solution of compound 13-6.6 g (103.3 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,150.0 mL) and stirring at-70℃for 1h under nitrogen. 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 59g of pure compound 13-7 in 67% yield.
(5) Preparation of intermediate Compounds 13-8
Figure BDA0001955660580000272
Compound 13-7 59g (69.2 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.6g (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 mixture was poured into 200.0mL of a 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 4:1, yielding 34.2g of 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)
34.2g (40.8 mmol,1.00 eq) of compound 13-8 and 800.0mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C6.1 g (active ingredient content 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30psi hydrogen pressure for 12 hours. After the reaction was completed, the filtrate was suction filtered and concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 50mm, 10um; mobile phase water (0.1% tfa) -MeOH, B%:20% -40%,30 min) to give 5.8g of the title compound 13 as a white solid in 30% yield.
1HNMR(400MHz，DMSO)δ：7.29(dd,2H),7.26(d,1H),7.25(dd,J＝8.4Hz,2H),7.19(dd,2H),7.16(dd,J＝8.4Hz,2H),6.68(t,1H),4.6(br.s,4H),4.05(d,1H),3.97(s,2H),3.63-3.68(m,1H),3.42-3.51(m,3H),3.05-3.24(m,2H)。
Example 14 preparation of compound 14: (2S, 3R,4R,5S, 6R) -2- (4- (4- (pyrimidin-2-yloxy) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Figure BDA0001955660580000273
Figure BDA0001955660580000281
(1) Preparation of intermediate Compound 14-3
Figure BDA0001955660580000282
17.2g (150 mmol,1.00 eq) of 2-chloropyrimidine 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 12h; 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, 200.0mL DCM and 0.1mL DMF were added, and oxalyl chloride 19.1g (150.7 mmol,1.10 eq) was added dropwise at 0deg.C, after which the temperature was raised to 20deg.C for 3h. 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
Figure BDA0001955660580000283
To a dichloromethane solution of compound 13-2 obtained in step (2) at 0deg.C under nitrogen, 14-323.7g (137 mmol,1.00 eq) of compound was added 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 20℃and reacted for 5h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted 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, stirred at 20deg.C for 2h, the solid was precipitated, collected by filtration, and the solid was dried under reduced pressure to give 41.3g of Compound 14-4 as a white solid in 85% yield.
(4) Preparation of intermediate Compound 14-5
Figure BDA0001955660580000284
Compound 14-4.3 g (116.4 mmol,1.00 eq) was taken, 400.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 40.4g of SiH (349.2 mmol,3.00 eq) were then added dropwise under nitrogen at 25℃with BF 3 .Et 2 O33 g (224.6 mmol,2.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 3 Aqueous solution, then MTBE was added for extractionThe organic phase is extracted by saturated saline water, the organic phase is collected, dried by anhydrous sodium sulfate, filtered, and the filtrate is concentrated 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=100:1 to 50:1, yielding 35.2g of compound 14-5 in 88.7% yield.
(5) Preparation of intermediate Compounds 14-7
Figure BDA0001955660580000291
Compound 14-5.2 g (103.3 mmol,1.00 eq) was weighed out, 600mL of redistilled THF was added at-70℃under N 2 41.4mL (2.5M, 1.00 eq) of an n-BuLi solution in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.2h, followed by dropwise addition of a solution of compound 14-6.6 g (103.3 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,150.0 mL) and stirring at-70℃for 1h under nitrogen. 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 53.7g of pure compound 14-7 in 65% yield.
(6) Preparation of intermediate Compounds 14-8
Figure BDA0001955660580000292
Compound 14-7.7 g (67 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 9.3g (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 solution was poured into 200.0mL of saturated aqueous sodium bicarbonate, 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=50:1 to 3:1, giving 33g of 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)
33g (42.2 mmol,1.00 eq) of compound 14-8 and 800.0mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C6.3 g (active ingredient content 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30psi hydrogen pressure for 12 hours. After the reaction was completed, the filtrate was suction filtered and concentrated, and the concentrate was subjected to prep-HPLC (preparative HPLC) (column Phenomenex luna C, 250, 50mm, 10um; mobile phase water (0.1% tfa) -MeOH, B%:20% -50%,30 min) to give 6.3g of the title compound 14 as a white solid in 35% yield.
1HNMR(400MHz，DMSO)δ：8.35(d,2H),7.22(dd,2H),7.14(dd,J＝8.4Hz,2H),7.09(dd,2H),7.06(dd,J＝8.4Hz,2H),6.75(t,1H),4.5(br.s,4H),3.90-4.02(m,3H),3.61-3.66(m,1H),3.42-3.51(m,3H),3.03-3.21(m,2H)。
Example 15 preparation of compound 15: (2S, 3R,4R,5S, 6R) -2- (2-hydroxy-4- (4- (thiophen-2-yl) benzyl) phenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol having the structural formula
Figure BDA0001955660580000293
Figure BDA0001955660580000301
(1) Preparation of intermediate Compound 15-2
Figure BDA0001955660580000302
15-1 g (86.6 mmol,1.00 eq) of compound was taken, 200.0mL of DCM and 0.1mL of DMF were added, 12.1g (95.3 mmol,1.10 eq) of oxalyl chloride was added dropwise at 0℃and the reaction was carried out at room temperature for 2h after the addition was completed. 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
Figure BDA0001955660580000303
At 0 ℃ under nitrogen, to the step(1) To the resulting dichloromethane solution of compound 15-2 was added compound 15-313.8g (86.6 mmol,1.00 eq) followed by the addition of AlCl in portions 3 11.6g (86.6 mmol,1.00 eq) and after the addition, the reaction mixture was warmed to room temperature and reacted for 6h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted 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, and the solid was collected by filtration, and dried under reduced pressure to give 25.8g of compound 15-4 as a white solid in 80% yield.
(3) Preparation of intermediate Compounds 15-5
Figure BDA0001955660580000304
Compound 15-4.8 g (69.3 mmol,1.00 eq) was taken, 200.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 24g (207.9 mmol,3.00 eq) followed by dropwise addition of BF under nitrogen at 25 ℃ 3 .Et 2 O39.2 g (277.2 mmol,4.00 eq) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 100.0mL of saturated NaHCO was added to the reaction mixture 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 20.3g of compound 15-5 in 85% yield.
(4) Preparation of intermediate Compounds 15-7
Figure BDA0001955660580000305
Compound 15-5.3 g (58.9 mmol,1.00 eq) was weighed out, 300mL of redistilled THF was added at-70℃under N 2 47.2mL (2.5M, 2.00 eq) of an n-BuLi solution in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.3h, followed by dropwise addition of a solution of 15-6.7 g (58.9 mmol,1.00 eq) of the compound in tetrahydrofuran (redistilled THF,50.0 mL) and stirring at-70℃for 1h under nitrogen. The reaction solution is poured to be fullAnd 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 24.6g of pure compound 15-7 in 52% yield.
(5) Preparation of intermediate Compounds 15-8
Figure BDA0001955660580000311
Compound 15-7.6 g (30.6 mmol,1.00 eq) was weighed out, 200.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 4.2g (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 100.0mL of saturated aqueous sodium hydrogencarbonate, 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=10:1 to 3:1, yielding 11.6g of pure compound 15-8 in 48% yield.
(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)
11.6g (14.7 mmol,1.00 eq) of the compound 15-8 and 200.0mL of ethyl acetate were taken and mixed uniformly under stirring, then Pd/C4.5g (active ingredient content 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at room temperature under 30psi hydrogen pressure for 12 hours. 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, 10um; mobile phase: water (0.1% hcooh) -MeOH, B%:20% -80%,30 min) to give 1.7g of the title compound 15 as a white solid in 27% yield.
1HNMR(400MHz，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, 3)R,4R,5S, 6R) -2- (4- (4-fluorobenzyl) -2, 6-dihydroxyphenyl) -6- (hydroxymethyl) tetrahydro-2H-pyran-3, 4, 5-triol with structural formula
Figure BDA0001955660580000312
Figure BDA0001955660580000313
(1) Preparation of intermediate Compound 16-3
Figure BDA0001955660580000321
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16-1 g (67.3 mmol,1.0 eq) of the compound was weighed, 100mL of redistilled tetrahydrofuran was added, and the mixture was evaporated at-70℃under N 2 100.8mL (2.0M, 3.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃for 1 hour, followed by dropwise addition of a solution of compound 16-2.36.2 g (67.3 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) and stirring at-70℃for 1 hour 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 16.3g of pure compound 16-3 as a colorless oil in a yield of 32%.
(2) Preparation of intermediate Compound 16-4
Figure BDA0001955660580000322
Compound 16-3.3 g (21.5 mmol,1.0 eq) was weighed out, 200.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 3g (25.8 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O3.7 g (25.8 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 100.0mL of 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 10.3g of purified productCompound 16-4 was 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, 100.0mL of methanol was added, 3.5g 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 50psi of hydrogen for 24 hours. 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, 10um; mobile phase water (0.1% tfa) -ACN, B%:20% -50%,30 min) to give 2.1g of the title compound 16 as a white solid in 40% yield.
1H NMR(400MHz，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
Figure BDA0001955660580000323
Figure BDA0001955660580000331
(1) Preparation of intermediate Compound 17-3
Figure BDA0001955660580000332
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17-1 g (68 mmol,1.0 eq) of the compound was weighed, 150mL of redistilled tetrahydrofuran was added, and the mixture was taken at-70℃under N 2 34mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃for 0.5h with stirring, and then 17-2.36.6 g (68 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,50.0 mL) was added dropwise with stirring at-70℃for 1h 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, giving 33.4g of pure compound 17-3 in 59% yield.
(2) Preparation of intermediate Compound 17-4
Figure BDA0001955660580000333
Compound 17-3.4 g (40.1 mmol,1.0 eq) was weighed out, 150.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 5.6g (48.1 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O6.8 g (48.1 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 100.0mL of 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=50:1 to 5:1, yielding 19.6g of pure compound 17-4 as a white solid in 60% yield.
(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, 100.0mL of methanol was added, 6.0g 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 50psi of hydrogen for 12 hours. 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, 10um; mobile phase water (0.1% tfa) -ACN, B%:20% -80%,30 min) to give 4.05g of the title compound 17 as a white solid in 37% yield.
1H NMR(400MHz，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 with structural formula
Figure BDA0001955660580000341
Figure BDA0001955660580000342
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(1) Preparation of intermediate Compound 18-2
Figure BDA0001955660580000343
Compound 18-1.0 g (137 mmol,1.00 eq) was taken, 200.0mL DCM and 0.1mL LDMF were added, and 19.1g (150.7 mmol,1.10 eq) oxalyl chloride was added dropwise at 0deg.C, and after the addition was completed, the reaction was allowed to warm to room temperature for 3h. 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
Figure BDA0001955660580000344
24g (137 mmol,1.00 eq) of compound 18-3 are added to a dichloromethane solution of compound 18-2 obtained in step (1) at 0deg.C 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 for 5h. After the reaction is finished, the temperature of the reaction solution is reduced to 0 ℃, 200mL of diluted 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 42.8g of compound 18-4 as a white solid in 83% yield.
(3) Preparation of intermediate Compound 18-5
Figure BDA0001955660580000345
Compound 18-4.8 g (113.7 mmol,1.00 eq) was taken, 350.0mL acetonitrile was added and Et was added under nitrogen at 20 ℃ 3 SiH 53g (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) and the above mixture was reacted at 25℃for 12h. After the reaction was completed, 300.0mL of saturated NaHCO was added to the reaction mixture 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 35.9g of compound 18-5 in a yield of 87.0%.
(4) Preparation of intermediate Compound 18-7
Figure BDA0001955660580000346
Compound 18-5.9 g (98.9 mmol,1.00 eq) was weighed out, 550mL of redistilled THF was added at-70℃under N 2 35.6mL (2.5M, 1.00 eq) of an n-BuLi solution in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70℃for 0.3h, followed by dropwise addition of a solution of compound 18-6.2 g (98.9 mmol,1.00 eq) in tetrahydrofuran (redistilled THF,100.0 mL) and stirring at-70℃for 1h under nitrogen. 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 61g of pure compound 18-7 in 75% yield.
(5) Preparation of intermediate Compounds 18-8
Figure BDA0001955660580000351
Compound 18-7 61g (74.2 mmol,1.00 eq) was weighed out, 400.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at room temperature 3 SiH 10.3g (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 200.0mL of saturated aqueous sodium bicarbonate, 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 = 20:1-5:1, 40.1g of pure compound 18-8 was obtained, with a yield of 67%.
(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)
40.1g (49.7 mmol,1.00 eq) of 18-8 mL of compound and 400.0mL of ethyl acetate were taken and mixed uniformly under stirring, then 7.4g of Pd/C (active ingredient content: 10%) was added under argon, the reaction system was evacuated and filled with hydrogen, and reacted at 20℃for 12 hours under 30psi of hydrogen. 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, 10um; mobile phase: water (0.1% hcooh) -ACN, B%:20% -60%,30 min) to give 7.09g of the objective compound 18 as a white solid in 32% yield.
1HNMR(400MHz，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
Figure BDA0001955660580000352
Figure BDA0001955660580000353
(1) Preparation of intermediate Compound 19-3
Figure BDA0001955660580000361
Weighing 19-1 g (54.8 mmol,1.0 eq) of the compound, adding 100mL of redistilled tetrahydrofuran at-70deg.C under N 2 82mL (2.0M, 3.0 eq) of n-butyllithium in tetrahydrofuran was added dropwise to the above solution under nitrogen at-70deg.C for 0.5h, followed by dropwise addition of 19-2.3 g (54.8 mmol,1.0 eq) of compound ) Tetrahydrofuran (redistilled THF,50.0 mL) and stirred at-70℃under nitrogen for 1h 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 26.7g of pure compound 19-3 in 58% yield.
(2) Preparation of intermediate Compound 19-4
Figure BDA0001955660580000362
Compound 19-3.7 g (31.8 mmol,1.0 eq) was weighed out, 200.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 4.4g (38.2 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O5.4 g (38.2 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 100.0mL of 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 14.4g of pure compound 19-4 as a white solid with a yield of 55%.
(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 14.4.4 g (17.5 mmol,1.0 eq) of the compound, 100.0mL of methanol was added, 4.3g Pd/C (active ingredient content 10%) was added under argon atmosphere, the reaction system was evacuated and filled with hydrogen, and reacted at 50℃under 50psi of hydrogen for 12 hours. 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, 10um; mobile phase water (0.1% tfa) -ACN, B%:20% -80%,40 min) to give 3g of the title compound 19 as a white solid in 37% yield.
1H NMR(400MHz，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
Figure BDA0001955660580000363
Figure BDA0001955660580000371
(1) Preparation of intermediate Compound 20-3
Figure BDA0001955660580000372
20-1 g (213.4 mmol,1.0 eq) of the compound was weighed out, 265mL of redistilled tetrahydrofuran was added, and the mixture was taken out at-70℃under N 2 106.6mL (2.0M, 1.0 eq) of LDA tetrahydrofuran solution was added dropwise to the above solution under nitrogen at-70℃for 0.5h with stirring, and then 20-2 118g (213.4 mmol,1.0 eq) of tetrahydrofuran (redistilled THF,100.0 mL) was added dropwise with stirring at-70℃for 1h 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 109.5g of pure compound 20-3 in 64% yield.
(2) Preparation of intermediate Compound 20-4
Figure BDA0001955660580000373
Compound 20-3.5 g (136.6 mmol,1.0 eq) was weighed out, 700.0mL of dichloromethane was added, and Et was added to the above solution under nitrogen at 20 ℃ 3 SiH 19g (163.9 mmol,1.2 eq), cooling to 0℃and adding BF dropwise 3 .Et 2 O23.3 g (163.9 mmol,1.2 eq) and then warmed to 20℃and stirred for 2h. After the reaction was completed, the reaction solution was poured into 500.0mL of saturated aqueous sodium chloride solution, extracted, and the methylene chloride phase was collected and distilled under reduced pressure to obtain a crude product. Coarse sizeThe product is passed through a silica gel column, and the mobile phase is petroleum ether: ethyl acetate=100:1 to 5:1, yielding 64.5g of 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, 500.0mL of methanol was added, 20g 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 50psi hydrogen at 50℃for 24 hours. 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, 10um; mobile phase water (0.1% tfa) -ACN, 25% -53%,30 min) to give 15.02g of the title compound 20 as a white solid in 43% yield.
1H NMR(400MHz，CD 3 OD)，δ：7.09(d,J＝8.8Hz,2H),6.83(d,J＝8.4Hz,2H),6.45(d,2H),4.52-4.54(m,1H),4.02(q,2H),3.98(s,2H),3.84-3.87(m,4H),3.61-3.63(m,2H),1.35(t,3H)。
In order to evaluate the efficacy of the glycoside derivative of the present invention, the following test examples were conducted.
Test example 1 therapeutic Effect of the glycoside derivative of the present invention on the model of type I diabetes in ICR mice induced by tetraoxypyrimidine
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 non-modeling mice are injected with the same amount of physiological saline through tail vein injection. After injection, the mice are normally fed 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 the diabetic mice with successful modeling, and the mice are used for experiments.
After selecting diabetic mice with successful modeling, randomly grouping according to fasting blood glucose (FGB) of the mice, and dividing into 22 groups of 4, male and female halvesThe specific grouping conditions of the diabetes model group G2, the metformin group G3 (positive control, 200 mg/kg) and the glycoside derivatives of the present invention in each of the administration groups G4 to G23, the control group G1 (the same batch of 4 healthy and normoglycemic mice were used as the blank control group G1) 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
Figure BDA0001955660580000381
Figure BDA0001955660580000391
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, aiming at the ICR mouse type I diabetes model caused by the tetraoxypyrimidine, compared with a model group, a positive control metformin group and a glycoside derivative administration group have the effect of reducing blood sugar, have remarkable treatment effect, and part of the glycoside derivative administration group has the effect of reducing blood sugar better than the positive control group, so that the glycoside derivative has the treatment effect on type I diabetes.

Claims (9)

1. The glycoside derivative is characterized by being a compound shown in a formula I or pharmaceutically acceptable salt thereof:
Figure FDA0004156006420000011
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.
2. The preparation method of the glycoside derivative of claim 1, which is characterized in that the compound shown in the formula I is prepared by deprotection reaction of the compound shown in the formula II;
Figure FDA0004156006420000021
therein, A, B, R 1 -R 6 A substituent corresponding to the substituent on each of the compounds of claim 1;
R 9 is Bn-.
3. The preparation method according to claim 2, wherein the compound represented by formula II is prepared from a compound represented by formula III;
Figure FDA0004156006420000022
therein, A, B, R 1 -R 6 A substituent corresponding to the substituent on each of the compounds of claim 1;
R 9 is Bn-.
4. The method according to claim 3, wherein the compound represented by formula III is prepared by reacting a compound represented by formula IV with a compound represented by formula V;
Figure FDA0004156006420000023
therein, A, B, R 1 -R 6 A substituent corresponding to the substituent on each of the compounds of claim 1;
R 8 is-H or-Br;
R 9 is Bn-.
5. The use of the glycoside derivative according to claim 1 for preparing a medicament for preventing and/or treating type I diabetes.
6. The use of the glycoside derivative according to claim 1 for preparing a medicament for preventing and/or treating type I diabetes induced by tetraoxypyrimidine.
7. A pharmaceutical composition of the glycoside derivative of claim 1, comprising: the compound shown in the formula I or pharmaceutically acceptable salt thereof is used as an active ingredient and at least one pharmaceutically acceptable auxiliary material.
8. The pharmaceutical composition of the glycoside derivative according to claim 7, wherein: the composition is administered orally, by injection, transdermally, nasally, mucosally, and by inhalation.
9. The pharmaceutical composition of the glycoside derivative according to claim 8, wherein: the composition is in a slow release dosage form, a controlled release dosage form or an immediate release dosage form.
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