CN108218928B - Bicyclic derivatives of glucoside, preparation method and application thereof - Google Patents

Bicyclic derivatives of glucoside, preparation method and application thereof Download PDF

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CN108218928B
CN108218928B CN201611142602.6A CN201611142602A CN108218928B CN 108218928 B CN108218928 B CN 108218928B CN 201611142602 A CN201611142602 A CN 201611142602A CN 108218928 B CN108218928 B CN 108218928B
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tetrahydro
hydroxymethyl
pyrano
oxazole
diol
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CN108218928A (en
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翟建国
何阳
朱英杰
周宜遂
马红敏
宋萌
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China Resources Double Crane Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/06—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing nitrogen as ring hetero atoms

Abstract

The invention relates to a bicyclic derivative of glucoside, a preparation method and application thereof, in particular to a compound shown as a formula I, a stereoisomer or pharmaceutically acceptable salt or ester thereof, a pharmaceutical composition thereof and application thereof in preparing a medicament for treating diabetes or related diseases thereof,

Description

Bicyclic derivatives of glucoside, preparation method and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a bicyclic derivative of glucoside, a preparation method and application thereof.
Background
Diabetes mellitus is a metabolic disease characterized by hyperglycemia, which is caused by defects in insulin secretion, or impaired biological action, or both, and most of them are type ii diabetics. Prolonged hyperglycemia is very harmful to the patient's body and can cause a variety of complications. At present, the diabetes treatment drugs mainly comprise sulfonylureas, thiazolidinediones, metformin, insulin and the like, but the drugs have potential side effects. The clinical application of the SGLT2 inhibitor opens up another treatment mode and provides a new choice for diabetic patients to overcome hyperglycemia.
SGLT2 is the predominant Na in epithelial cells of the proximal tubule S1 segment+The/glucose cotransporter, responsible for 90% of glucose reabsorption in the kidney.SGLT2 inhibitors inhibit renal glucose reabsorption, bringing diabetic patients to normal plasma glucose levels through urinary glucose excretion, thereby increasing insulin sensitivity and delaying the development of diabetic complications.
WO01/27128A1 discloses C-aryl glucoside SGLT2 inhibitors having the following general molecular structural formula:
Figure BDA0001178173000000011
among them, Dapagliflozin (Dapagliflozin) has been proven to be clinically useful for the treatment of diabetes, and its molecular structure is as follows:
Figure BDA0001178173000000012
since diabetes is a high-grade disease which endangers human health, the search for new drugs for treating diabetes is of great significance.
Disclosure of Invention
The inventor of the invention finds a compound which is derived from glucoside and has a novel structure, namely a bicyclic derivative of glucoside. The compounds have the function of inhibiting reabsorption of renal glucose of mammals or reducing blood sugar values of the mammals, and have the potential of becoming candidate therapeutic drugs for patients with type I diabetes or type II diabetes, or providing a new choice for treatment of diabetes-related diseases.
The invention relates to a compound shown as a formula I, a stereoisomer or pharmaceutically acceptable salt or ester thereof,
Figure BDA0001178173000000021
wherein R is1Selected from hydrogen, halogen and C1-6An alkyl group;
R2selected from hydrogen, halogen, C1-6Alkyl, -OR, -NRR' and-SR;
R3selected from C unsubstituted or substituted by one or more (e.g. 1,2, 3 or 4) substituents selected from1-6Alkyl groups: hydroxy, halogen, C1-6Alkoxy and C1-6An alkylamino group;
r and R' are each independently selected from C1-6Alkyl radical, C3-8Cycloalkyl and C3-8Lipoheterocyclyl, wherein said C1-6Alkyl radical, C3-8Cycloalkyl and C3-8The heterocyclylene group is unsubstituted or substituted with 1 or more (e.g., 2,3 or 4) substituents selected from: hydroxy, halogen, C1-6Alkoxy and C1-6An alkylamino group.
In certain preferred embodiments of the present application, R1Selected from halogen and C1-4An alkyl group.
In certain preferred embodiments of the present application, R1Selected from the group consisting of fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and isobutyl.
In certain preferred embodiments of the present application, R2Selected from hydrogen, halogen, C1-4Alkyl, -OR, -NRR' and-SR;
r and R' are each independently selected from C1-4Alkyl radical, C3-6Cycloalkyl and C3-6Lipoheterocyclyl, wherein said C1-4Alkyl radical, C3-6Cycloalkyl and C3-6The heterocyclylene group is unsubstituted or substituted with 1 or more (e.g., 2,3 or 4) substituents selected from: hydroxy, halogen, C1-4Alkoxy and C1-4An alkylamino group.
In certain preferred embodiments of the present application, R2Selected from hydrogen, halogen, C1-4Alkyl, -OR, -NRR' and-SR;
r and R' are each independently selected from C1-4Alkyl radical, C3-6Cycloalkyl and C with hetero atoms O or N3-6A lipoheterocyclic group.
In certain preferred embodiments of the present application, R2Selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-butyl, sec-butyl, tert-butyl, isobutyl, methoxy, ethoxy, n-propyloxy, isopropoxy, cyclopropylOxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuryloxy, pyrrolidinyloxy, methylamino, ethylamino, dimethylamino, diethylamino, methylthio, ethylthio, and isopropylthio.
In certain preferred embodiments of the present application, R3Selected from C unsubstituted or substituted by 1 or more (e.g. 2,3 or 4) substituents selected from1-4Alkyl groups: hydroxy, halogen, C1-4Alkoxy and C1-4An alkylamino group.
In certain preferred embodiments of the present application, R3Is selected from C1-4Alkyl and C substituted by one or two substituents selected from1-2Alkyl groups: hydroxy, halogen, C1-2Alkoxy and C1-2An alkylamino group.
In certain preferred embodiments of the present application, R3Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, hydroxymethyl and hydroxyethyl.
In certain preferred embodiments of the present application, R1Selected from fluorine, chlorine and methyl;
R2selected from the group consisting of hydrogen, fluoro, methyl, ethyl, n-butyl, methoxy, ethoxy, isopropoxy, dimethylamino, diethylamino, isopropylthio, cyclopentyloxy, and 3-tetrahydrofuryloxy;
R3selected from the group consisting of methyl, n-propyl, n-butyl, isobutyl and hydroxyethyl.
In certain preferred embodiments of the present application, R1Selected from halogens (e.g., fluorine and chlorine);
R2is selected from-OR; wherein R is selected from C1-4Alkyl and C with hetero atoms O3-6A lipoheterocyclic group;
R3is selected from C1-4Alkyl and hydroxy substituted C1-4An alkyl group.
In certain preferred embodiments of the present application, R1Selected from fluorine and chlorine;
R2selected from the group consisting of methoxy, ethoxy, isopropoxy, and 3-tetrahydrofuryloxy;
R3selected from methyl, n-propyl and hydroxyethyl.
In certain preferred embodiments of the present application, the compound is selected from:
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-1);
(5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-2);
(5R,6S,7S) -3a- (4-chloro-3- (4-methoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-3);
(5R,6S,7S) -3a- (4-chloro-3- (4-methylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-4);
(5R,6S,7S) -3a- (4-chloro-3- (4-butylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-5);
(5R,6S,7S) -3a- (4-fluoro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-6);
(5R,6S,7S) -3a- (4-methyl-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-7);
(5R,6S,7S) -3a- (4-methyl-3- (4-methoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-8);
(5R,6S,7S) -3a- (4-methyl-3- (4-methylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-9);
(5R,6S,7S) -3a- (4-methyl-3- (4-butylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-10);
(5R,6S,7S) -3a- (4-chloro-3- (4-ethylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-11);
(5R,6S,7S) -3a- (4-chloro-3- (4-dimethylaminobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-12);
(5R,6S,7S) -3a- (4-chloro-3- (4-diethylaminobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-13);
(5R,6S,7S) -3a- (4-chloro-3- (4-isopropoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-14);
(5R,6S,7S) -3a- (4-fluoro-3- (4-methoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-15);
(5R,6S,7S) -3a- (4-fluoro-3- (4-methylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-16);
(5R,6S,7S) -3a- (4-fluoro-3- (4-ethylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-17);
(5R,6S,7S) -3a- (4-chloro-3- (4-cyclopentyloxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-18);
(5R,6S,7S) -3a- (4-fluoro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-19);
(5R,6S,7S) -3a- (4-fluoro-3-benzylphenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-20);
(5R,6S,7S) -3a- (4-fluoro-3- (4-diethylaminobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-21);
(5R,6S,7S) -3a- (4-chloro-3- (4-fluorobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-22);
(5R,6S,7S) -3a- (4-fluoro-3- (4-isopropoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-23);
(5R,6S,7S) -3a- (4-chloro-3- (4-isopropylsulfanylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-24);
(5R,6S,7S) -3a- (4-methyl-3- (4-dimethylaminobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-25);
(5R,6S,7S) -3a- (4-fluoro-3- (4-isopropylsulfanylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-26);
(5R,6S,7S) -3a- (4-methyl-3- (4-ethylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-27);
(5R,6S,7S) -3a- (4-fluoro-3- (4-cyclopentyloxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-28);
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-29);
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-hydroxyethyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-30);
(5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-31);
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-32);
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-isobutyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-33);
(5R,6S,7S) -3a- (4-fluoro-3- (4-diethylaminobenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-34);
(5R,6S,7S) -3a- (4-methyl-3- (4-dimethylaminobenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-35);
(5R,6S,7S) -3a- (4-chloro-3- (4-isopropylsulfanylbenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-36);
(5R,6S,7S) -3a- (4-chloro-3- (4-cyclopentyloxybenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-37);
(5R,6S,7S) -3a- (4-methyl-3- (4-methoxybenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-38);
(5R,6S,7S) -3a- (4-chloro-3- (4-isopropoxybenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-39);
(5R,6S,7S) -3a- (4-fluoro-3- (4-methylbenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-40);
(5R,6S,7S) -3a- (4-fluoro-3- (4-ethylbenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-41);
(5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-42); and the combination of (a) and (b),
(5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-isobutyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-43).
In certain preferred embodiments of the present application, the pharmaceutically acceptable ester is an acetate ester of a compound of formula I.
In certain preferred embodiments of the present application, the pharmaceutically acceptable ester is (5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol triacetate (I-1 a).
In a second aspect, the invention relates to a process for the preparation of a compound of formula I, as illustrated in process a:
Figure BDA0001178173000000061
the first step is as follows: reacting the compound VI with an acylating reagent to obtain a corresponding acyl halide compound; then the acyl halide compound and a compound VII are subjected to Friedel-crafts reaction in the presence of Lewis acid to generate a compound V;
the second step is that: reacting the compound V with an alkyl silane reagent in the presence of a Lewis acid to generate a compound III;
the third step: reacting the compound III with a metal organic compound; carrying out condensation reaction on the obtained product and a compound IV; the reaction product continuously reacts with a mixture of methanol and methanesulfonic acid to generate a compound II;
the fourth step: reacting the compound II with R3CN is subjected to cyclization reaction to generate a compound shown in a formula I;
wherein X represents a halogen, such as bromine or iodine; the remaining atoms and substituents are as defined above.
In certain preferred embodiments of the present invention, the acylating agent in the first step is selected from the group consisting of oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, and the like.
In certain preferred embodiments of the invention, the acylating agent is oxalyl chloride.
In certain preferred embodiments of the invention, the first step is carried out in a solvent such as dichloromethane or 1, 2-dichloroethane.
In certain preferred embodiments of the invention, the first step is carried out in a dichloromethane solvent.
In certain preferred embodiments of the present invention, the lewis acid in the first step is selected from aluminum chloride, ferric chloride, trifluoroacetic acid, boron trifluoride, and the like.
In certain preferred embodiments of the invention, the alkylsilane reagent in the second step is triethylsilane.
In certain preferred embodiments of the present invention, the lewis acid in the second step is selected from aluminum chloride, ferric chloride, trifluoroacetic acid, boron trifluoride, and the like.
In certain preferred embodiments of the present invention, the organometallic compound in the third step is an organolithium reagent or a grignard reagent.
In certain preferred embodiments of the present invention, the organolithium reagent is selected from n-butyllithium, isopropyllithium, and the like.
In certain preferred embodiments of the present invention, the organolithium reagent is n-butyllithium.
In certain preferred embodiments of the present invention, the cyclization reaction in the fourth step is carried out in a solvent such as dichloromethane, acetonitrile, tetrahydrofuran, chloroform, 1, 2-dichloroethane or N-methylpyrrolidone.
In certain preferred embodiments of the present invention, the ring closure reaction in the fourth step is carried out in dichloromethane or acetonitrile.
In certain preferred embodiments of the present invention, the cyclization reaction in the fourth step is carried out in the presence of water and boron trifluoride diethyl etherate.
In certain preferred embodiments of the invention, the compound v may be prepared by:
1.0 equivalent of Compound VI is dissolved in methylene chloride (W, calculated as weight/volume ratio)Compound VI:VMethylene dichloride1 ═ 2 to 10)), and then 1.0 to 1.5 equivalents of oxalyl chloride were added. And (3) uniformly stirring the obtained reaction mixture, reacting at room temperature for 2-4 hours, and distilling under reduced pressure to remove the solvent to obtain the acyl chloride compound. The resulting acid chloride compound was dissolved in methylene chloride (W calculated as weight/volume ratio)Compound VI:VMethylene dichloride1- (1-10)), and adding a compound VII. The obtained reaction mixture is stirred uniformly, cooled to 0-10 ℃ (for example, the temperature can be reduced through ice-water bath), added with 1.0-1.5 equivalent of aluminum chloride, and reacted for 1-2 hours at 0-25 ℃. After the reaction is completed, the reaction product is poured into ice water, liquid separation is carried out, the separated water phase is extracted by dichloromethane (for example, 3 times), the organic phase is washed by 1M hydrochloric acid, water, 1M sodium hydroxide and saturated sodium chloride solution in sequence, anhydrous sodium sulfate is dried, a drying agent is filtered, and then the solvent is removed by reduced pressure distillation to obtain oily matter. What is needed isAnd recrystallizing and purifying the obtained oily substance by using methanol/water or ethanol/water, or separating and purifying by using silica gel column chromatography (an eluant is petroleum ether/ethyl acetate with the ratio of 500: 1-10: 1), and evaporating the solvent to obtain the compound shown in the formula V.
In certain preferred embodiments of the present invention, several drops of N, N-dimethylformamide may also be added to the reaction mixture as a reaction aid in the preparation of the acid chloride compound.
In certain preferred embodiments of the present application, the compound of formula iii may be prepared by:
the compound of formula V is dissolved in dichloromethane and acetonitrile (W calculated as weight/volume ratio)Compound V:VMethylene dichloride＝1:(2～5)；WCompound V:VAcetonitrile1, (2-10)). And (2) uniformly stirring the obtained reaction mixture, cooling to 0-10 ℃ (for example, cooling through an ice water bath), adding 2.0-5.0 equivalents of triethylsilane and 1.0-3.0 equivalents of boron trifluoride diethyl etherate, or a proper amount of trifluoroacetic acid, reacting for 5-15 hours at 20-50 ℃, and supplementing 1.0-2.0 equivalents of triethylsilane and 0.5-1.0 equivalents of boron trifluoride diethyl etherate according to the reaction condition in the reaction process. After the reaction is finished, pouring the reaction product into ice water, and adding sodium bicarbonate to neutralize the water phase until the water phase is neutral to alkaline. The organic phase was washed successively with saturated sodium bicarbonate and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The drying agent is filtered off, and then the solvent is removed by reduced pressure distillation to obtain oily matter. And (3) separating and purifying the obtained oily substance by silica gel column chromatography (an eluent is petroleum ether/ethyl acetate with the ratio of 500: 1-10: 1), and evaporating the solvent to obtain the compound shown in the formula III.
In certain preferred embodiments of the present application, the compound of formula ii may be prepared by:
in reaction flask A, compound III and dry toluene (first portion) are added and anhydrous tetrahydrofuran (W/v) is added under a stream of nitrogenCompound III:VToluene＝1:(4～20)；WCompound III:VTetrahydrofuran (THF)1, (2-10)). The reaction mixture is stirred uniformly and cooled to-50 to-78 deg.C (for example, the temperature can be reduced toCooling by dry ice-acetone). Dropwise adding 1.0-1.5 equivalent of n-butyllithium or isopropyllithium, and continuously keeping the temperature for reaction for 0.5-1 hour.
In a further reaction vessel B, compound IV and dry toluene (second portion) (calculated as weight/volume ratio, W)Compound III:VToluene1, (4-20)). The obtained reaction mixture is stirred uniformly and cooled to-50 to-78 ℃ (for example, the temperature can be reduced by dry ice-acetone). Transferring the reaction product in the reaction bottle A to the reaction bottle B under the nitrogen flow, and keeping the temperature of the formed reaction mixture for continuously reacting for 2-3 hours. Methanol and methanesulfonic acid (in weight/volume ratio, W) were addedCompound III:VMethanol＝1:(1～15)；WCompound III:VMethanesulfonic acid1, (0.3-10)) and then naturally raising the temperature. The reaction mixture is reacted for 5 to 20 hours at a temperature of between 25 and 35 ℃.
Saturated sodium bicarbonate solution was added to the resulting reaction product and neutralized until the aqueous phase was neutral to basic. The phases were separated, the aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The drying agent is filtered off, and then the solvent is removed by reduced pressure distillation to obtain oily matter. And (3) separating and purifying the obtained oily substance by silica gel column chromatography (the eluent is petroleum ether/ethyl acetate, the ratio of the petroleum ether/ethyl acetate is usually 4: 1-1: 4, the eluent can also be ethyl acetate or a mixture of ethyl acetate/methanol, and the solvent is evaporated to obtain a compound II.
In certain preferred embodiments of the present application, the compound II can also be prepared by the following method b (see examples 5-8):
Figure BDA0001178173000000091
in certain preferred embodiments of the present application, the compound II can also be prepared by the following method c (see examples 10-12):
Figure BDA0001178173000000092
in certain preferred embodiments of the present application, the compound i may be prepared by:
dissolving Compound II in acetonitrile (calculated as weight/volume ratio, W)Compound II:VAcetonitrile1, (5 to 50), preferably 1, (5 to 10)). And adding a small amount of water as a reaction auxiliary agent into the mixture, then adding 1-10 equivalents of boron trifluoride diethyl etherate, and reacting the formed reaction mixture at 15-55 ℃ for 1-16 hours. After the reaction is finished, saturated sodium bicarbonate solution is added for neutralization until the solution is neutral to alkaline. The phases were separated, the aqueous phase was extracted 1 time with ethyl acetate and the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filtering to remove the drying agent, distilling under reduced pressure to remove the solvent, separating and purifying the obtained residue by silica gel column chromatography (the eluent is petroleum ether/ethyl acetate with the ratio of 5: 1-1: 5, the eluent can also be ethyl acetate or a mixture of 20: 1-10: 1 of ethyl acetate/methanol), and evaporating the solvent to obtain a compound I which is a foamy solid powder.
In certain preferred embodiments of the present application, pharmaceutically acceptable esters of the compounds of formula I can be prepared by process d (see example 21 for a specific implementation):
Figure BDA0001178173000000101
another aspect of the invention relates to a pharmaceutical composition comprising a compound as described hereinbefore, a stereoisomer or pharmaceutically acceptable salt or ester thereof, and one or more carriers or diluents.
In certain preferred embodiments of the present invention, the pharmaceutically acceptable carrier or diluent may be a filler, wetting agent, binder, disintegrant, lubricant or coating material. Wherein the filler is selected from starch, pregelatinized starch, dextrin mannitol, microcrystalline cellulose MCC, and calcium sulfate; the wetting agent can be selected from distilled water and 30-70% ethanol; the binder is selected from hydroxypropyl methylcellulose HPMC, polyvidone PVP, starch slurry, and mucilage; the disintegrant is selected from croscarmellose sodium CCNa, hydroxypropyl starch HPS, crospovidone PVPP, surfactant Tween 80, and sodium lauryl sulfate; the lubricant is selected from magnesium stearate, pulvis Talci, hydrogenated vegetable oil, polyethylene glycol PEG, and silica gel micropowder; the coating material, such as film coating material, can be selected from cellulose derivatives, PEG, PVP; the enteric coating material is selected from CAP and HPMCP.
In certain preferred embodiments of the present invention, the pharmaceutical composition may further comprise other antidiabetic agents or/and antihyperlipidemic agents. The other antidiabetic drug can be biguanide antidiabetic drug such as metformin, or sulfonylurea antidiabetic drug such as glibenclamide and glipizide, or glucosidase inhibitor such as acarbose, or oxazolidinedione insulin sensitizer such as pioglitazone. Wherein the antihyperlipidemic drug can be HMG CoA reductase inhibitor such as Atorvastatin (Atorvastatin), Pitavastatin (Pitavastatin), Rosuvastatin (Rosuvastatin).
Depending on the mode of administration, the compounds of formula I, their stereoisomers or pharmaceutically acceptable salts or esters thereof, together with conventional solid or liquid carriers or diluents and other pharmaceutical additives, may be formulated in the form of tablets, capsules, granules or powders, or in the form of injections, or in the form of transdermal patches.
In certain preferred embodiments of the invention, the effectiveness of the compositions of the invention and whether administration is suitable for treating a disease or medical condition in an individual may be determined by performing appropriate in vitro or in vivo assays. Generally, an effective amount of a composition of the invention sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day. Suitably, the dose is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day. Exemplary treatment regimens are once every two days or once a week or once a month. The agent is typically administered multiple times, and the interval between single doses may be daily, weekly, monthly or yearly. The amount effective for therapeutic use will depend on the severity of the disease to be treated, the general state of the patient's own immune system, the general condition of the patient, e.g. age, weight and sex, the mode of administration of the drug, and other treatments administered concurrently, etc.
Another aspect of the present invention relates to the use of a compound as described hereinbefore, a stereoisomer or a pharmaceutically acceptable salt or ester thereof, for the manufacture of a medicament for the treatment of diabetes or a disease associated therewith.
In certain preferred embodiments of the present invention, the diabetes is selected from the group consisting of insulin-dependent diabetes (type i diabetes) and non-insulin-dependent diabetes (type ii diabetes).
In certain preferred embodiments of the present invention, the diabetes-related disease is selected from diabetic nephropathy, diabetic retinopathy, hyperglycemia, hyperinsulinemia, diabetic cardiovascular complications, diabetic cerebrovascular disease, diabetic peripheral neuropathy, and the like.
In the present invention, unless otherwise specified, scientific and technical terms used herein have the meanings that are commonly understood by those skilled in the art. For a better understanding of the present invention, the following provides definitions and explanations of relevant terms.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
As used herein, the term "C1-6Alkyl "means a straight or branched chain saturated hydrocarbon radical containing from 1 to 6 carbon atoms, e.g. C1-4Alkyl radical, C1-2An alkyl group. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
As used herein, the term "C1-6Alkoxy "means having C1-6A group of alkyl-O-structure wherein said "C" is1-6Alkyl is as previously definedThe above-mentioned processes are described. C1-6Preferred examples of alkoxy groups include C1-4Alkoxy radical, C1-2Alkoxy, and the like. Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, and the like.
As used herein, the term "C1-6Alkylamino means having C1-6A group of alkyl-NH-structure wherein "C" is1-6Alkyl "is as defined above. C1-6Preferred examples of alkylamino include C1-4Alkylamino radical, C1-2Alkylamino, and the like. Specific examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, isobutylamino, tert-butylamino, and the like.
As used herein, the term "C3-8Cycloalkyl "refers to a monocyclic saturated hydrocarbon group containing 3-8 ring members, e.g. C3-6Cycloalkyl radical, C3Cycloalkyl radical, C4Cycloalkyl radical, C5Cycloalkyl or C6A cycloalkyl group. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
As used herein, the term "C3-8"Lipocyclyl" refers to a monocyclic saturated hydrocarbon group containing 3-8 ring members, at least one of which is a heteroatom selected from N, O and S. E.g. C with the heteroatom N3-8Lipoheterocyclic radicals, e.g. C with hetero atom being O3-8Lipoheterocyclic radicals, e.g. C, with hetero atoms N and O3-8A lipoheterocyclic group. E.g. C3-6Lipoheterocyclic group, C3Lipoheterocyclic group, C4Lipoheterocyclic group, C5Lipoheterocyclyl or C6A lipoheterocyclic group. Specific examples include, but are not limited to, oxiranyl, pyrrolidinyl, tetrahydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like.
As used herein, the term "pharmaceutically acceptable ester" refers to an ester formed by esterification of a carboxyl group in a compound of the present invention with an alcohol; or an ester formed by esterification reaction of a hydroxyl group in the compound of the present invention with an organic acid, an inorganic acid, an organic acid salt, or the like. For example, pharmaceutically acceptable esters of the compounds of formula I, typically carboxylic acid esters, carbonic acid esters, or phosphoric acid esters, such as methyl, ethyl, benzyl, allyl, and the like, in certain preferred embodiments herein, the pharmaceutically acceptable ester is an ethyl ester, can be prepared by reacting one or more hydroxyl groups of the compound of formula I with an alkyl, alkoxy, or aryl substituted acylating agent. The pharmaceutically acceptable esters can be converted in vivo as prodrugs to release the active drug.
As used herein, the term "pharmaceutically acceptable salts" refers to compounds of formula i, when present with basic functional groups (e.g., amino groups, etc.), which can form pharmaceutically acceptable salts with acids, including inorganic acid salts such as phosphate, hydrochloride, or sulfate, and organic acid salts such as formate, acetate, malate, fumarate, or citrate, and the like; when an acidic functional group is present in a compound of formula I, for example when it contains a carboxyl group, it may form a pharmaceutically acceptable amine salt with an amine or alkali metal ion or an alkali metal salt, for example an amine salt with methylamine, ethylamine, triethylamine, diisopropylethylamine, amantadine, phenylmethylamine, or an alkali metal salt with a sodium, potassium, calcium, magnesium ion.
As used herein, the term "stereoisomer" refers to isomers formed as a result of the different spatial arrangement of atoms or groups of atoms in a molecule. The compounds of the invention may have a plurality of asymmetric centers and, therefore, the compounds of formula I of the invention may exist in a single configuration or in a mixture with an enantiomer or diastereomer thereof.
The english abbreviations in the present invention have the following meanings:
AC acetyl group;
ACN acetonitrile;
an Allyl group;
benzyl;
i-Bu isobutyl;
n-Bu n-butyl;
n-BuLi n-butyllithium;
CCNa croscarmellose sodium;
DCM dichloromethane;
DMF N, N-dimethylformamide;
DMSO dimethyl sulfoxide;
et ethyl;
HMG CoA 3-hydroxy-3-methylglutaryl coenzyme a;
HPLC high performance liquid chromatography;
HPMC hypromellose;
HPMCP hypromellose phthalate;
HPS hydroxypropyl starch;
MCC microcrystalline cellulose;
me methyl group;
MS mass spectrometry;
MSA methanesulfonic acid;
NMP N-methylpyrrolidone;
NMR nuclear magnetic resonance;
PEG polyethylene glycol;
iPr isopropyl group;
nPr n-propyl;
PVPP crospovidone;
PVP povidone;
SGLT2 Na+glucose cotransporter 2;
TFA trifluoroacetic acid;
THF tetrahydrofuran;
TLC thin layer chromatography.
Advantageous effects of the invention
The invention obtains a class of bicyclic derivatives of glucoside with a brand new structure as shown in formula I by derivatization of glucoside, the compounds have the function of inhibiting reabsorption of renal glucose of mammals or the function of reducing blood sugar values of the mammals, and can be used for treating type I or type II diabetes mellitus or related diseases thereof. The pharmacological activity of the compound of formula I is tested by two pharmacological models, rat blood glucose inhibition test and rat urine glucose excretion test, and the specific implementation method is shown in example 25 and example 26.
In the blood sugar suppression experiment of rats, rats respectively administered with 10mg/kg or 20mg/kg of I-01, I-03, I-07, I-30, I-31 and the like show a significant or significant reduction in blood sugar values relative to the blood sugar values of the blank control group. In additional cohort experiments, rats administered I-02 and I-04 at 10mg/kg, or I-15, I-21, I-24 and I-25 at 20mg/kg also showed a significant or significant decrease in blood glucose values relative to the control blank.
In the experiment of urinary sugar excretion in rats, rats respectively give a dose of I-01 of 10mg/kg or 20mg/kg to show significant urinary sugar excretion. In a separate group of experiments, rats were given I-03, I-07, I-21, I-24, I-30, and I-32, respectively, and showed significant glucose excretion at a dose of 20 mg/kg.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
In the following examples, the reagents used are generally of analytical grade unless otherwise specified. The animals used in the pharmacological test were SPF grade SD rats purchased from China food and drug testing research institute. Dapagliflozin (pharmacologically active control drug) used in the pharmacological test was prepared by Huarun Erianthus pharmaceutical Co., Ltd according to the methods of examples A to D and F to G in WO 2003/099836.
In the following examples, the solvent is concentrated or evaporated to dryness in
Figure BDA0001178173000000142
On a rotary evaporator of type R-200; the HPLC chromatogram is measured on a waters e2695 high performance liquid chromatograph; mass spectra were determined on a JEOL AccutoFCS (JMS T100CS) type mass spectrometer or an Agilent 6230TOF LC/MS LC-MS; nuclear magnetic resonance1H spectrum and13the C spectra were determined on a Bruker AVANCEIII model 400 or Bruker Biospin II nuclear magnetic resonance apparatus. Blood glucose values were measured on a prominent splendid-type glucometer from roche, and urine glucose values were measured on a μ Quant-type full-wavelength microplate reader from BIOTEK, usa.
Example 1 preparation of 5-bromo-2-chloro-4' -ethoxybenzophenone (V-1)
Figure BDA0001178173000000141
5-bromo-2-chlorobenzoic acid (20.0g, 0.085mol) was added to a 2.0M solution of oxalyl chloride in dichloromethane (50ml, 0.1mol), stirred to a suspension, then 8 drops of DMF solution were added dropwise with bubbling, and after 3h of reaction, the reaction was essentially complete, placed on a rotary evaporator to spin dry the solvent, then 15ml of dichloromethane was added, and the solvent was spun dry. After spin-drying, adding 30ml of dichloromethane, stirring, cooling to 0-5 ℃, adding phenetole (10.9g, 0.089mol), adding anhydrous aluminum trichloride (12.5g, 0.093mol) in batches, controlling the temperature to be not more than 5 ℃, continuing to stir at 4 ℃ for 1h after the addition is finished, monitoring by TLC to ensure that the reaction is basically complete, placing the reactant on an ice-water mixture to quench the reaction, separating an organic phase, extracting the aqueous phase with dichloromethane, washing the organic phase twice with 1mol/L hydrochloric acid, washing with purified water once, washing twice with 1mol/L NaOH solution, washing twice with saturated sodium chloride, and drying with anhydrous sodium sulfate. Suction filtration, spin drying of the solvent gave an off-white solid which was recrystallized from absolute ethanol to give 20.2g (70.0%) of a white solid.
1H-NMR(400MHz，CDCl3，ppm-1)δ:7.76(m,2H),7.52(m,1H),7.47(d,1H),7.31(d,1H),6.93(m,2H),4.11(q,2H),1.44(t,3H)。
ESI MS(m/z):339/341(Br+Cl)[M+2]+/[M+4]+。
Example 2, 5-bromo-2-chloro-4' -ethoxydiphenylmethanePreparation of (III-1)
Figure BDA0001178173000000151
Adding 5-bromo-2-chloro-4' -ethoxy benzophenone (V-1) (18.0g, 0.053mol) into 135ml of acetonitrile/dichloromethane mixed solvent (volume ratio is 2:1), cooling to 5-10 ℃, adding triethylsilane (18.6ml, 0.117mol), then dropwise adding boron trifluoride diethyl etherate (9.4ml, 0.074mol), removing the ice bath after dropwise adding is finished, and naturally raising the temperature to room temperature for reaction overnight. TLC to monitor the reaction was almost complete, saturated sodium bicarbonate solution was added to adjust the pH to neutral, ethyl acetate was extracted, the organic phase was washed twice with saturated sodium chloride and dried over anhydrous sodium sulfate. Filtering, and spin-drying the solvent to obtain oily substance. Column chromatography gave 13.2g (76.5%) of an oil.
1H-NMR(400MHz，CDCl3，ppm-1)δ:7.23(m,3H),7.08(m,2H),6.83(m,2H),4.01(q,2H),3.97(s,2H),1.39(t,3H)。
Example 3 methyl 1-C- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl]Phenyl radical]- α -D-glucopyranoside (II-1) preparation of
Figure BDA0001178173000000152
Adding 5-bromo-2-chloro-4' -ethoxydiphenylmethane (III-1) (12.5, 0.038mol) into a 250ml three-necked flask (numbered flask A) under the protection of nitrogen, adding 40ml absolute tetrahydrofuran and 80ml toluene (dried by calcium chloride), stirring, drying acetone, cooling to-72 ℃, dropwise adding 2.5M n-BuLi in n-hexane (18.4ml, 0.046mol), ensuring the temperature is not higher than-60 ℃, stirring for 30min, preparing a 500ml three-necked flask (numbered flask B), protecting with nitrogen, adding 2,3,4, 6-tetra-O-trimethylsilyl- β -D-gluconolactone (19.7g, 0.042mol) and 110ml toluene (dried by calcium chloride), cooling acetone to-72 ℃, when the reaction time in the flask A is up, introducing the solution in the flask A into the flask B, continuing the reaction for 2 hours at low temperature, adding methanesulfonic acid (14.8g, 0.154mol) and 110ml dry sodium bicarbonate, removing the solvent, filtering, removing the saturated aqueous phase, removing the water, filtering, and obtaining a saturated aqueous phase, after the saturated aqueous phase is saturated sodium bicarbonate solution is dried.
1H-NMR(400MHz，DMSO-d6，ppm-1)δ:7.51(1H,s),7.40(2H,m),7.05(2H,d),6.80(2H,d),3.92-4.04(4H,m),3.71-3.74(1H,m),3.50-3.61(2H,m),3.33-3.37(1H,m),3.20-3.32(1H,m),2.86-2.91(4H,m),1.29(3H,t)。
ESI MS(m/z):461[M+Na]+。
Example 4, (5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ]]Preparation of oxazole-6, 7-diol (I-1)
Figure BDA0001178173000000161
Adding methyl 1-C- [ 4-chloro-3- [ (4-ethoxyphenyl) methyl ] phenyl ] - α -D-glucopyranoside (II-1) (10.0g, 0.023mol) into a 500ml three-necked flask, dissolving with 120ml acetonitrile, adding a small amount of water with stirring, then adding boron trifluoride diethyl ether (5.6ml, 0.045mol), reacting at room temperature for 1-16 hours after dropwise adding, monitoring by TLC for complete reaction, adding saturated sodium bicarbonate solution to adjust the pH to be neutral, extracting with ethyl acetate, washing an organic phase twice with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering out a drying agent, separating and purifying a residue formed after concentration by silica gel column chromatography (an eluent is ethyl acetate/petroleum ether 1/5-5/1), evaporating to dryness to obtain 6.4g of a white solid, and detecting the yield by an HPLC method, wherein the content is 98.10% by a peak area normalization method.
1H-NMR(400MHz,DMSO-d6,ppm-1)δ:7.42(1H,d),7.40(1H,s),7.35(1H,dd),7.04(2H,d),6.81(2H,d),5.48(1H,s),4.80(1H,s),4.50(1H,s),4.40(1H,s),4.18(1H,s),3.92-4.01(4H,m),3.87(1H,m),3.57(1H,d),3.45(1H,dd),3.35(1H,dd),2.03(3H,s),1.28(3H,t).
13C-NMR(400MHz,CD3OD，ppm-1)δ:166.8,156.9,140.63,138.1,132.6,131.0,129.4,129.0,126.1,114.3,109.0,91.0,79.7,73.5,68.4,63.7,62.9,37.7,14.7,13.5.
ESI MS(m/z):484(M+H)+。
EXAMPLE 5 preparation of 5-iodo-2-chloro-4' -fluorobenzophenone (V-2)
Figure BDA0001178173000000162
5-iodo-2-chlorobenzoic acid (20.0g, 0.071mol) was added to a 2.0M solution of oxalyl chloride in dichloromethane (39ml, 0.078mol), stirred to a suspension, then 8 drops of DMF solution were added dropwise with bubbling, after 3h of reaction, the solution was clear and substantially complete, placed on a rotary evaporator and the solvent was spin-dried, then 15ml of dichloromethane was added, and the solvent was spin-dried. After spin-drying, adding 30ml of dichloromethane, stirring, cooling to 0-5 ℃, adding fluorobenzene (7.1g, 0.074mol), adding anhydrous aluminum trichloride (9.9g, 0.074mol) in batches, controlling the temperature to be not more than 5 ℃, continuing stirring for 1h at 4 ℃ after the addition is finished, monitoring by TLC to ensure that the reaction is basically complete, placing the reactant on an ice-water mixture to quench the reaction, separating an organic phase, extracting the aqueous phase with dichloromethane, washing the organic phase twice with 1mol/L hydrochloric acid, washing with purified water once, washing twice with 1mol/L NaOH solution, washing twice with saturated sodium chloride, and drying with anhydrous sodium sulfate. Suction filtration, spin-drying of the solvent gave an oil, which was chromatographed to give 20.1g (78.6%) of an off-white solid.
EXAMPLE 6 preparation of (S) -5-iodo-2-chloro-4' - (tetrahydro-3-furanyl) oxybenzophenone (Va-2)
Figure BDA0001178173000000171
Dissolving 5-iodine-2-chlorine-4' -fluorobenzophenone (V-2) (18.5g, 0.051mol) in 50ml of tetrahydrofuran solution, adding (S) -3-hydroxyl tetrahydrofuran (4.9g, 0.056mol) and stirring, finally dropwise adding a potassium tert-butoxide (6.9g, 0.061mol) solution dissolved in 30ml of tetrahydrofuran, controlling the temperature at 16-25 ℃, stirring and reacting at 20 ℃ for 1 hour after the dropwise addition is finished, monitoring by TLC to ensure that the reaction is almost complete, slowly adding purified water, stirring for 30min, standing and separating the liquid, and rotatably drying the organic phase. Column chromatography gave 14.1g (64.3%) of a solid.
Example 7 preparation of (S) -5-iodo-2-chloro-4' - (tetrahydro-3-furanyl) oxydiphenylmethane (IIIa-2)
Figure BDA0001178173000000172
Adding (S) -5-iodine-2-chlorine-4' - (tetrahydro-3-furyl) oxybenzophenone (Va-2) (14.0g, 0.033mol) into 135ml of acetonitrile/dichloromethane mixed solvent (volume ratio is 2:1), cooling to 5-10 ℃, adding triethylsilane (13.0ml, 0.082mol), dropwise adding boron trifluoride diethyl etherate (6.2ml, 0.049mol), removing an ice bath after dropwise adding is finished, and naturally raising the temperature to room temperature for reaction overnight. TLC to monitor the reaction was almost complete, saturated sodium bicarbonate solution was added to adjust the pH to neutral, ethyl acetate was extracted, the organic phase was washed twice with saturated sodium chloride and dried over anhydrous sodium sulfate. Filtering, and spin-drying the solvent to obtain oily substance. Column chromatography gave 10.3g (76.2%) of an oil.
Example 8 methyl 1-C- [ 4-chloro-3- [ (4- ((S) -tetrahydro-3-furanyl) oxyphenyl) methyl]Phenyl radical]-α- Preparation of D-glucopyranoside (II-2)
Figure BDA0001178173000000181
Under the protection of nitrogen, a 250ml three-necked flask (No. flask A) is added with (S) -5-iodine-2-chlorine-4' - (tetrahydro-3-furyl) oxydiphenylmethane (IIIa-2) (10.0g, 0.024mol), 40ml absolute dried tetrahydrofuran and 80ml toluene (dried by calcium chloride), dry ice acetone is stirred and cooled to-72 ℃, a normal hexane solution of 2.5M n-BuLi (11.6ml, 0.029mol) is added dropwise, the temperature is ensured to be not higher than-60 ℃, stirred for 30min, a 500ml three-necked flask (No. B) is prepared, under the protection of nitrogen, 2,3,4, 6-tetra-O-trimethylsilyl- β -D-gluconolactone (12.4g, 0.027mol) and 110ml toluene (dried by calcium chloride) are added, acetone is cooled to-72 ℃, after the reaction time in the flask A reaches the reaction time, the solution in the flask A is added into the flask B, the reaction is continued for 2 hours at low temperature, methanesulfonic acid (14 g, 0.027mol) is added, the solution is dried by a sodium chloride column after the reaction is carried out, the saturated aqueous phase is extracted by a sodium chloride column chromatography, the saturated sodium bicarbonate is added, the solution is added, the saturated sodium chloride phase is separated, the saturated aqueous phase is extracted, the solution is extracted for one time, the saturated sodium bicarbonate phase is added, the saturated sodium bicarbonate is added, the saturated aqueous phase is added.
1H-NMR(400MHz，DMSO-d6，ppm-1)δ:7.52(s,1H),7.38(m,2H),7.07(d,2H),6.81(d,2H),4.92-4.97(m,2H),4.76(m,2H),4.52(m,1H),3.93-4.04(m,2H),3.68-3.86(m,4H),3.50-3.60(m,2H),3.22(m,1H),2.88(s,3H),2.86(m,1H),2.14-2.19(m,1H),1.97(s,1H),1.91(m,1H),1.16(t,1H)；
13C-NMR(400MHz,DMSO-d6，ppm-1)δ:170.3,155.4,138.5,137.3,132.4,131.5,130.7,129.5,128.4,127.4,115.1,100.6,76.9,76.8,74.1,74.0,72.2,70.0,66.3,60.8,59.7,48.2,37.8,32.4,20.7,14.0。
ESI MS(m/z):503[M+Na]+。
Example 9, (5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxy Methyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ]]Preparation of oxazole-6, 7-diol (I-2)
Figure BDA0001178173000000182
Methyl 1-C- [ 4-chloro-3- [ (4- ((S) -tetrahydro-3-furanyl) oxyphenyl) methyl ] phenyl ] - α -D-glucopyranoside (II-2) (5.0g, 0.010mol) and 80ml of acetonitrile are added into a 500ml three-necked flask to be dissolved, a small amount of water is added under stirring, then boron trifluoride diethyl ether (2.6ml, 0.021mol) is added dropwise, the reaction is carried out at room temperature for 1 to 16 hours after the dropwise addition, TLC is used for monitoring the completion of the reaction, saturated sodium bicarbonate solution is added for adjusting the pH to be neutral, ethyl acetate is used for extraction, an organic phase is washed twice by saturated sodium chloride solution, anhydrous sodium sulfate is used for drying, a drying agent is filtered, and a residue formed after concentration is separated and purified by silica gel column chromatography (an eluent is ethyl acetate/petroleum ether ═ 1/5 to 5/1), and a solvent is evaporated to obtain 1.3g of a white solid with the.
1H-NMR(400MHz，DMSO-d6，ppm-1)δ:7.42(m,2H),7.35(m,1H),7.05(d,2H),6.81(d,2H),5.44(d,1H),4.94(m,1H),4.76(d,1H),4.48(t,1H),4.39(s,1H),4.17(t,1H),3.97(s,2H),3.71-3.87(m,5H),3.55(m,1H),3.44(dd,1H),3.34(m,1H),2.15(m,1H),2.03(s,3H),1.93(m,1H)。
13C-NMR(400MHz,DMSO-d6，ppm-1)δ:166.7,155.4,140.6,137.9,132.5,131.3,129.5,128.9,126.0,115.1,108.9,91.0,79.6,76.9,73.4,72.2,68.4,66.3,63.6,37.6,32.4,13.5。
ESI MS(m/z):490[M+H]+。
Example 10 preparation of 5-bromo-2-chloro-4' -hydroxydiphenylmethane (IIIb-14)
Figure BDA0001178173000000191
5-bromo-2-chloro-4' -ethoxydiphenylmethane (III-1) (16g, 4.95mmol) and dichloromethane (200ml) were charged into a 500ml single-neck flask, stirred in an ice bath, and 50ml of a boron tribromide dichloromethane solution (1 mol/l) was added to the reaction system, and after 1 hour of reaction, the raw material exhaustion was observed by TLC, and the reaction was completed. The system was poured into ice water and the pH was adjusted to 7 with sodium bicarbonate, the organic phase was separated, dried and evaporated to dryness to give 15g (95.0%) of the target.
Example 11 preparation of 5-bromo-2-chloro-4' -isopropoxydiphenylmethane (IIIc-14)
Figure BDA0001178173000000192
5-bromo-2-chloro-4' -hydroxydiphenylmethane (IIIb-14) (7.5g,25.2mmol) was charged into a 100ml single-neck flask containing DMF (30ml) and stirred at room temperature, and potassium carbonate (6.8g,50.40mmol), isopropyl iodide (5.14g,30.24mmol) were added to the reaction system, and after completion of the addition, the reaction was allowed to react at 80 ℃ for 5 hours. After TLC monitoring reaction, cooling to room temperature, adding water into the reaction system, extracting with ethyl acetate, separating, spin-drying the organic phase, and purifying by column chromatography to obtain 6.4g (77.0%) of target product.
EXAMPLE 12 methyl 1-C- [ 4-chloro-3- (4-isopropoxybenzyl) phenyl]- α -D-glucopyranoside(Ⅱ- 14) Preparation of
Figure BDA0001178173000000201
Adding 5-bromo-2-chloro-4' -isopropoxydiphenylmethane (IIIc-14) (6.4g, 0.019mol) into a 250ml three-necked flask (numbered flask A), 20ml absolute tetrahydrofuran and 40ml toluene (dried by calcium chloride), stirring, drying glacial acetone, cooling to-72 ℃, dropwise adding 2.5M n-BuLi in n-hexane solution (8.3ml,0.021mol), ensuring the temperature to be not higher than-60 ℃, stirring for 30min, preparing a 500ml three-necked flask (numbered flask B), stirring under nitrogen protection, adding 2,3,4, 6-tetra-O-trimethylsilyl- β -D-gluconolactone (10.61g,0.023mol) and 55ml toluene (dried by calcium chloride), cooling acetone to-72 ℃, after the reaction time in the flask A reaches, introducing the solution in the flask A into the flask B, continuing to react for 2 hours under low temperature, adding methanesulfonic acid (4.4g, 0.046mol) and dry ice, removing the dry ice, performing a dry ice separation, removing the pH by a saturated aqueous phase, performing a filtration reaction, adding saturated sodium bicarbonate solution, performing a filtration, and obtaining a saturated aqueous phase, and performing a chromatographic extraction, wherein the pH is 25.7 liters.
1H-NMR(300MHz,CDCl3，ppm-1)δ：7.26-7.43(m,3H)，7.02-7.09(m,2H),6.75-6.80(m,2H)，4.44-4.48(m,1H)，3.93-4.04(m,5H)，3.57-3.74(m,2H)，2.95-3.57(m,4H)，1.22-1.28(m,6H)。
LC-MS(m/z):475[M+Na]+。
Example 13, (5R,6S,7S) -3a- (4-chloro-3- (4-isopropoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl- 5,6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ]]Preparation of oxazole-6, 7-diol (I-14)
Figure BDA0001178173000000202
Adding methyl 1-C- [ 4-chloro-3- (4-isopropoxybenzyl) phenyl ] - α -D-glucopyranoside (II-14) (1.0g, 2.21mmol) and 20ml of acetonitrile into a 250ml three-neck flask for dissolving, adding a small amount of water under stirring, then dropwise adding boron trifluoride diethyl ether (0.5ml, 4.4mmol), reacting at room temperature for 1-16 hours after dropwise adding, monitoring by TLC for complete reaction, adding saturated sodium bicarbonate solution to adjust the pH to be neutral, extracting with ethyl acetate, washing an aqueous organic phase twice with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering out a drying agent, separating and purifying a residue after concentration by silica gel column chromatography (an eluent is ethyl acetate/petroleum ether 1/5-5/1), evaporating the solvent to dryness, and drying in vacuum to obtain 0.68g (66.8%) of white powdery solid.
1H-NMR(400MHz,DMSO-d6，ppm-1)δ7.43(dd,2H),7.37(dd,1H),7.05(d,2H),6.82(d,2H),5.47(d,1H),4.79(d,1H),4.59–4.48(m,2H),4.42(s,1H),4.24–4.15(m,1H),3.98(s,2H),3.93–3.83(m,1H),3.58(m,1H),3.46(dd,1H),3.42–3.37(m,1H),2.05(s,3H),1.22(d,6H).
LC-MS(m/z):462[M+H]+。
Example 14 preparation of 5-bromo-2-fluorobenzophenone (V-20)
Figure BDA0001178173000000211
5-bromo-2-fluorobenzoic acid (15.44g, 0.070mol) was added to a 2.0M solution of oxalyl chloride in dichloromethane (48ml, 0.096mol), stirred to a suspension, then 5 drops of DMF solution were added dropwise with bubbling, after 3h of reaction, the solution was clear and substantially complete, placed on a rotary evaporator and the solvent was spin-dried, then 15ml of dichloromethane was added, and the solvent was spin-dried. After spin-drying, adding 30ml of dichloromethane, stirring, cooling to 0-5 ℃, adding benzene (7.6ml, 0.085mol), adding anhydrous aluminum trichloride (11.28g, 0.092mol) in batches, controlling the temperature to be not more than 5 ℃, continuing stirring for 1h at 4 ℃ after the addition is finished, monitoring by TLC to ensure that the reaction is basically complete, placing the reactant on an ice-water mixture to quench the reaction, separating an organic phase, extracting the aqueous phase with dichloromethane, washing the organic phase twice with 1mol/L hydrochloric acid, washing with purified water once, washing twice with 1mol/L NaOH solution, washing twice with saturated sodium chloride, and drying with anhydrous sodium sulfate. Suction filtration and spin-drying of the solvent gave a yellow oil which was chromatographed over a column to give 16.48g (83.75%) of a colorless liquid.
Example 15 preparation of 5-bromo-2-fluorodiphenylmethane (III-20)
Figure BDA0001178173000000212
18ml of trifluoroacetic acid and 5-bromo-2-fluorobenzophenone (V-20) (5.53g, 19.81mmol) were placed in a 250ml three-necked flask, the temperature was lowered to 5-10 ℃ and triethylsilane (7.84g, 98.9mmol) was added, after the addition, the ice bath was removed and the temperature was raised to 50 ℃. The TLC monitored that the reaction was not complete and 2.2g of triethylsilane was added to continue the reaction. TLC detects the reaction is complete, and 40ml water is added to quench the reaction. Saturated sodium bicarbonate solution was added to adjust the pH to neutral, the aqueous phase was extracted with dichloromethane, the organic phase was washed twice with saturated sodium chloride and dried over anhydrous magnesium sulfate. Filtering, and spin-drying the solvent to obtain oily substance. Column chromatography gave 5.08g (96.71%) of a colourless oil.
EXAMPLE 16 methyl 1- [ 4-fluoro-3-benzylphenyl]Preparation of- α -D-glucopyranoside (II-20)
Figure BDA0001178173000000213
Under the protection of nitrogen, 5-bromo-2-fluorodiphenylmethane (III-20) (4.2g, 0.016mol), 20ml absolute dry tetrahydrofuran and 40ml toluene (dried by calcium chloride) are added into a 250ml three-necked flask (numbered flask A), dry glacial acetone is stirred and cooled to-72 ℃, a normal hexane solution of 2.5M n-BuLi (7.6ml, 0.019mol) is added dropwise under stirring, the temperature is ensured to be not higher than-60 ℃, a 500ml three-necked flask (numbered flask B) is stirred for 30min, nitrogen is protected, 2,3,4, 6-tetra-O-trimethylsilyl- β -D-gluconolactone (8.1g, 0.017mol) and 55ml toluene (dried by calcium chloride) are added, acetone is cooled to-72 ℃, after the reaction time in the flask A is reached, the solution in the flask A is introduced into the flask B, the reaction is continued for 2 hours under low temperature, 3ml of methanesulfonic acid and 55ml of methanol are added, dry ice bath is removed, the dry ice bath is naturally raised to room temperature, the reaction is carried out, the saturated aqueous phase is added with sodium bicarbonate, the saturated sodium bicarbonate solution is filtered, the saturated aqueous phase is extracted, the saturated sodium chloride is extracted, the saturated aqueous phase is 3g is added, and the saturated.
1H-NMR(400MHz，DMSO-d6，ppm-1)δ7.51(dd,1H),7.45–7.38(m,1H),7.32–7.26(m,2H),7.23–7.17(m,3H),7.16–7.08(m,1H),4.97(d,1H),4.76(d,1H),4.73(d,1H),4.54(t,1H),4.00(m,3H),3.79–3.70(m,1H),3.64–3.49(m,2H),3.38(dd,1H),3.22(m,1H),2.97–2.90(m,3H).
LC-MS(m/z):401[M+Na]+。
Example 17, (5R,6S,7S) -3a- (4-fluoro-3-benzylphenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrakis Hydrogen-3 aH-pyrano [2,3-d ]]Preparation of oxazole-6, 7-diol (I-20)
Figure BDA0001178173000000221
Adding methyl 1- [ 4-fluoro-3-benzylphenyl ] - α -D-glucopyranoside (II-20) (1.0g, 2.64mmol) and 30ml of acetonitrile into a 250ml three-neck flask for dissolving, adding a small amount of water while stirring, then dropwise adding boron trifluoride diethyl etherate (0.7ml, 5.3mmol), reacting at room temperature for 1-16 hours after dropwise adding, monitoring the reaction to be complete by TLC, adding saturated sodium bicarbonate solution to adjust the pH to be neutral, adding ethyl acetate for extraction, washing an organic phase twice by saturated sodium chloride solution, drying by anhydrous sodium sulfate, filtering out a drying agent, separating and purifying a residue formed after concentration by silica gel column chromatography (an eluent is ethyl acetate/petroleum ether is 1/5-5/1), evaporating the solvent to dryness, and drying in vacuum to obtain 0.43g (42.0%) of white powdery solid.
1H-NMR(400MHz，DMSO-d6，ppm-1)δ7.47–7.37(m,2H),7.33–7.25(m,2H),7.18(m,4H),5.46(d,1H),4.79(d,1H),4.51(t,1H),4.42(s,1H),4.22–4.16(m,1H),3.99(d,2H),3.9–3.84(m,1H),3.58(m,1H),3.45(dd,1H),3.40–3.36(m,1H),2.05(s,3H).
LC-MS(m/z):388,[M+H]+。
Example 18, (5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ]]Preparation of oxazole-6, 7-diol (I-29)
Figure BDA0001178173000000231
Adding methyl 1-C- [ 4-chloro-3- (4-ethoxybenzyl) phenyl ] - α -D-glucopyranoside (II-1) (5.0g, 0.011mol) into a 250ml three-necked bottle, dissolving 80ml butyronitrile, adding a small amount of water under stirring, then dropwise adding boron trifluoride diethyl etherate (2.7ml, 0.022mol), reacting at room temperature for 1-16 hours after dropwise adding, monitoring by TLC for complete reaction, adding saturated sodium bicarbonate solution to adjust the pH to be neutral, extracting with ethyl acetate, washing an organic phase twice with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering out a drying agent, separating and purifying a residue formed after concentration by silica gel column chromatography (an eluent is ethyl acetate/petroleum ether 1/5-5/1), and evaporating the solvent to dryness to obtain 1.2g (22.2%) of white powdery solid.
1H-NMR(400MHz，DMSO-d6，ppm-1)δ:7.41(d,1H),7.35(m,2H),7.03(d,2H),6.82(d,2H),5.44(d,1H),4.77(d,1H),4.47(t,1H),4.36(s,1H),4.15(t,1H),3.95(m,4H),3.86(m,1H),3.55(m,1H),3.42(m,1H),3.35(m,1H),2.30(m,2H),1.58(m,2H),1.28(t,3H),0.90(t,3H)。
13C-NMR(400MHz,DMSO-d6，ppm-1)δ:169.4，156.9,140.7，138.1,132.4，130.8,129.5，128.9，128.6，125.9,114.3,108.7，90.8,79.6,73.5,68.3,63.6,62.8,37.6,28.9,18.9,14.6,13.4。
ESI MS(m/z):476[M+H]+。
Example 19, (5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-hydroxyethyl- 5,6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ]]Preparation of oxazole-6, 7-diol (I-30)
Figure BDA0001178173000000232
Adding methyl 1-C- [ 4-chloro-3- (4-ethoxybenzyl) phenyl ] - α -D-glucopyranoside (II-1) (5.0g, 0.011mol) into a 250ml three-necked flask, dissolving 25ml 3-hydroxypropionitrile, adding a small amount of water while stirring, dropwise adding boron trifluoride diethyl ether (2.7ml, 0.022mol), reacting at room temperature for 1-16 hours after dropwise adding, monitoring by TLC for complete reaction, adding saturated sodium bicarbonate solution to adjust the pH to be neutral, extracting with ethyl acetate, washing an organic phase twice with saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering out a drying agent, separating and purifying a residue after concentration by silica gel column chromatography (an eluent is ethyl acetate/petroleum ether is 1/5-5/1), and evaporating the solvent to obtain 0.5g (9.3%) of white powdery solid.
1H-NMR(400MHz，DMSO-d6，ppm-1)δ:7.40(d,2H),7.34(m,1H),7.04(d,2H),6.82(d,2H),5.42(d,1H),4.76(m,2H),4.47(t,1H),4.36(s,1H),4.16(m,1H),3.98(s,2H),3.94(m,2H),3.87(m,1H),3.67(dd,2H),3.56(m,1H),3.45(m,1H),3.35(m,2H),2.52(m,1H),1.28(t,3H)。
13C-NMR(400MHz,DMSO-d6，ppm-1)δ:167.9,156.9,140.7,138.0,132.5,130.9,129.4,128.9,125.9，114.2,108.7,90.8,79.8,73.5,68.4,63.7,62.8,57.4,37.7,31.2,14.6。
ESI MS(m/z):478[M+H]+。
Example 20, (5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5- Hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ]]Preparation of oxazole-6, 7-diol (I-31)
Figure BDA0001178173000000241
Starting from methyl 1-C- [ 4-chloro-3- [ (4- ((S) -tetrahydro-3-furanyl) oxyphenyl) methyl ] phenyl ] - α -D-glucopyranoside (II-2), reference example 9 gave the target 1.2g of a white powder in 52.2% yield.
1H-NMR(400MHz，DMSO-d6，ppm-1)δ:7.42(d,1H),7.35(m,2H),7.06(d,2H),6.82(d,2H),5.44(d,1H),4.94(dd,1H),4.77(d,1H),4.47(t,1H),4.37(s,1H),4.16(t,1H),3.96(s,2H),3.71-3.87(m,5H),3.57(m,1H),3.42(m,1H),3.35(m,1H),2.30(m,2H),2.16(m,1H),1.93(m,1H),1.58(q,2H),0.90(t,3H)。
13C-NMR(400MHz,DMSO-d6，ppm-1)δ:169.5,155.4,140.7,138.0,132.4,131.1,129.6,128.9,128.8,128.6,125.9,115.1,108.7,90.8,79.6,76.9,73.5,72.5,68.3,66.3,63.6,37.6,32.4,28.9,18.9,13.4。
ESI MS(m/z):518[M+H]+。
Example 21, (5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ]]Preparation of oxazole-6, 7-diol triacetate (I-1 a)
Figure BDA0001178173000000242
Adding (5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol (I-1) (2.0g, 4.47mmol) and 50ml of dichloromethane into a 100ml three-necked flask, cooling to 0-4 deg.C with stirring, adding triethylamine (2.3g, 22.32mmol) and 4-dimethylaminopyridine (0.05g, 0.48mmol), dropwise adding acetic anhydride (1.6g, 16.1mmol), naturally heating to react for 1h after dropwise addition, monitoring by TLC for reaction completion, quenching with 20% phosphoric acid solution, extracting with dichloromethane, adding water to the organic phase, saturated sodium bicarbonate solution, adding water to the organic phase, adding a saturated sodium bicarbonate solution, adding a solvent to the mixture, and stirring, The sodium chloride solutions were washed once each time and dried over anhydrous sodium sulfate. Filtration, evaporation to dryness and column chromatography gave 2.3g of oil in 89.8% yield.
1H-NMR(400MHz,DMSO-d6，ppm-1)δ7.45(d,1H),7.37(d,1H),7.25(dd,1H),7.07(d,2H),6.83(d,2H),5.25(m,2H),4.65(s,1H),4.43(m,1H),4.02(m,6H),2.12(s,3H),2.00(m,9H),1.28(t,3H)。
LC-MS(m/z):574[M+H]+。
Example 22 preparation of Compounds II-3 to 13, II-15 to 19, and II-21 to 28
The above intermediates were prepared according to method a, method b or method c, respectively, as detailed in the following table:
Figure BDA0001178173000000251
Figure BDA0001178173000000252
Figure BDA0001178173000000261
Figure BDA0001178173000000271
Figure BDA0001178173000000281
example 23 preparation of Compounds I-3 to 13, I-15 to 19, I-21 to 28, I-32 to 43
See example 4 or example 18 for the preparation of the above compounds, respectively, detailed in the following table:
Figure BDA0001178173000000291
Figure BDA0001178173000000292
Figure BDA0001178173000000301
Figure BDA0001178173000000311
Figure BDA0001178173000000321
Figure BDA0001178173000000331
Figure BDA0001178173000000341
Figure BDA0001178173000000351
Figure BDA0001178173000000361
Figure BDA0001178173000000371
Figure BDA0001178173000000381
example 24 measurement of blood sugar value after rat administration or sugar administration
Test animals:
SD rats with the specification of SPF grade and the weight of 180-220 g, and the female half and the male half are purchased from China food and drug testing research institute, and the qualification code is SCXK (Jing) 2014-0013.
Pharmacological activity control drug:
dapagliflozin (prepared by Huarun Eriane pharmaceuticals Co., Ltd. according to the methods of examples A to D and F to G in WO 2003/099836).
The preparation method of the test solution comprises the following steps:
taking a proper amount of a sample, adding 10ml of 1% sodium carboxymethylcellulose, and preparing into suspensions with concentrations of 1mg/ml and 2mg/ml respectively.
The test method comprises the following steps:
rats were randomly grouped after acclimatization for 1 week, 10 rats were taken out of each group, and after fasting for 16 hours, the rats were orally gavaged with test drugs at different doses, wherein the blank control group was given no drug and 1 hour after the administration, and then were intraperitoneally injected with 50% glucose injection. The dose of the glucose injection was 4ml/kg (equivalent to 2g/kg), and the dose of the test sample solution was 10ml/kg (equivalent to 10mg/kg in the low dose group and 20mg/kg in the high dose group). Blood is collected from rat tail tip before administration, 30min after administration, 60min after administration, and 120min after administration, and blood glucose is measured with a glucometer for calculating blood glucose value.
The blood glucose measurement data for each test group were as follows:
Figure BDA0001178173000000391
remarking: p < 0.01 compared with blank control group; comparison with blank control group |. P | < 0.05.
Figure BDA0001178173000000392
Remarking: p < 0.01 compared with blank control group; comparison with blank control group |. P | < 0.05.
Figure BDA0001178173000000393
Remarking: p < 0.01 compared with blank control group; comparison with blank control group |. P | < 0.05.
Figure BDA0001178173000000394
Remarking: p < 0.01 compared with blank control group; comparison with blank control group |. P | < 0.05.
Figure BDA0001178173000000395
Figure BDA0001178173000000401
Figure BDA0001178173000000402
Remarking: p < 0.01 compared with blank control group; comparison with blank control group |. P | < 0.05.
Figure BDA0001178173000000403
Remarking: p < 0.01 compared with blank control group; comparison with blank control group |. P | < 0.05.
Figure BDA0001178173000000404
Remarking: p < 0.01 compared with blank control group; comparison with blank control group |. P | < 0.05.
Figure BDA0001178173000000405
Figure BDA0001178173000000411
Remarking: p < 0.01 compared with blank control group; comparison with blank control group |. P | < 0.05.
Figure BDA0001178173000000412
Figure BDA0001178173000000413
Example 25 measurement of glucose concentration in urine 24 hours after administration to rats
Test animals:
SD rats with the specification of SPF grade and the weight of 180-220 g, and the female half and the male half are purchased from China food and drug testing research institute, and the qualification code is SCXK (Jing) 2014-0013.
The preparation method of the test solution comprises the following steps:
taking a proper amount of a sample, adding 10ml of 1% sodium carboxymethylcellulose, and preparing into suspensions with concentrations of 1mg/ml and 2mg/ml respectively.
The test method comprises the following steps:
after the rats are adapted to the environment for 1 week, the rats are randomly grouped, 10 rats in each group are transferred to a rat metabolism cage, after fasting for 16 hours, the rats are orally gavaged to administer the tested drugs with different doses, and after administration, a blank control group does not administer the drugs and 1 hour, and then 50% glucose injection is injected into the abdominal cavity. The dose of the glucose injection was 4ml/kg (equivalent to 2g/kg), and the dose of the test sample solution was 10ml/kg (equivalent to 10mg/kg in the low dose group and 20mg/kg in the high dose group). 4h after dosing, the rats were given feed and returned to free feeding. Separately, 24h urine was collected, the urine volume was recorded, and the glucose concentration in the urine was measured, wherein the urine glucose value was measured on a mu Quant type full-wavelength microplate reader of the company BIOTEK, usa. The data for the determination of the urine glucose values for the test groups are as follows:
Figure BDA0001178173000000421
remarking: comparison with blank control group |. P | < 0.05.
Although specific embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that, based upon the overall teachings of the disclosure, various modifications and alternatives to those details could be developed and still be encompassed by the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.

Claims (16)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,
Figure FDA0002481741370000011
wherein R is1Is fluorine;
R2selected from hydrogen, -OR, -NRR' and-SR;
R3is selected from C1-6An alkyl group;
when R is2When is-OR, R is independently selected from C1-4Alkyl radical, C3-6Cycloalkyl and C3-6A lipoheterocyclic group;
when R is2When it is-NRR ', R and R' are each independently selected from C1-4An alkyl group;
when R is2When is-SR, R is independently selected from C1-4An alkyl group.
2. A compound of formula I or a pharmaceutically acceptable salt thereof,
Figure FDA0002481741370000012
wherein R is1Is chlorine;
R2is selected from C1-4Alkyl, -OR, -NRR' and-SR;
R3selected from C unsubstituted or substituted by 1 hydroxy1-4An alkyl group;
when R is2When is-OR, R is independently selected from C1-2Alkyl radical, C3-6Cycloalkyl and C3-6A lipoheterocyclic group;
when R is2When it is-NRR ', R and R' are each independently selected from C1-2An alkyl group;
when R is2When is-SR, R is independently selected from C1-2An alkyl group.
3. A compound of formula I or a pharmaceutically acceptable salt thereof,
Figure FDA0002481741370000021
wherein R is1Is methyl;
R2selected from-OR, -NRR', and-SR;
R3is selected from C1-4An alkyl group;
r and R' are each independently selected from C1-2An alkyl group.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof,
R2selected from the group consisting of hydrogen, methoxy, ethoxy, n-propyloxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuryloxy, pyrrolidinyloxy, dimethylamino, diethylamino, methylthio, ethylthio and isopropylthio.
5. The compound of claim 2, or a pharmaceutically acceptable salt thereof,
R2selected from the group consisting of methyl, ethyl, methoxy, ethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuryloxy, pyrrolidinyloxy, dimethylamino, diethylamino, methylthio and ethylthio.
6. The compound of claim 3, or a pharmaceutically acceptable salt thereof,
R2selected from methoxy, ethoxy, dimethylamino, diethylamino, methylthio and ethylthio.
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof,
R3selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and isobutyl.
8. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R3Selected from hydroxymethyl and hydroxyethyl.
9. The following compounds or pharmaceutically acceptable salts thereof:
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-methoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-methylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-butylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-methyl-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-methyl-3- (4-methoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-methyl-3- (4-butylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-ethylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-dimethylaminobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-diethylaminobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (4-methoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-cyclopentyloxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3-benzylphenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (4-diethylaminobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-fluorobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (4-isopropoxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-isopropylsulfanylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-methyl-3- (4-dimethylaminobenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (4-isopropylsulfanylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-methyl-3- (4-ethylbenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (4-cyclopentyloxybenzyl) phenyl) -5-hydroxymethyl-2-methyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-hydroxyethyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-ethoxybenzyl) phenyl) -5-hydroxymethyl-2-isobutyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (4-diethylaminobenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-methyl-3- (4-dimethylaminobenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-isopropylsulfanylbenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-cyclopentyloxybenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-methyl-3- (4-methoxybenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (4-isopropoxybenzyl) phenyl) -5-hydroxymethyl-2-propyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (4-methylbenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-fluoro-3- (4-ethylbenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol;
(5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-butyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol; and the combination of (a) and (b),
(5R,6S,7S) -3a- (4-chloro-3- (((S) -tetrahydro-3-furanyl) oxybenzyl) phenyl) -5-hydroxymethyl-2-isobutyl-5, 6,7,7 a-tetrahydro-3 aH-pyrano [2,3-d ] oxazole-6, 7-diol.
10. A process for the preparation of a compound as claimed in any one of claims 1 to 9, comprising the steps of:
the first step is as follows: reacting the compound VI with an acylating reagent to obtain a corresponding acyl halide compound; then the acyl halide compound and a compound VII are subjected to Friedel-crafts reaction in the presence of Lewis acid to generate a compound V;
Figure FDA0002481741370000061
the second step is that: reacting the compound V with an alkyl silane reagent in the presence of Lewis acid to generate a compound III;
Figure FDA0002481741370000062
the third step: reacting the compound III with a metal organic compound; carrying out condensation reaction on the obtained product and a compound IV; the reaction product continuously reacts with a mixture of methanol and methanesulfonic acid to generate a compound II;
Figure FDA0002481741370000063
the fourth step: reacting the compound II with R3CN is subjected to cyclization reaction to generate a compound shown in a formula I;
Figure FDA0002481741370000064
wherein X represents halogen; the remaining atoms and substituents are as defined in any one of claims 1 to 9.
11. The method of claim 10, wherein the halogen is bromine or iodine.
12. The method of claim 10 or 11, characterized by one or more of the following:
(1) in the first step, the acylating agent is selected from oxalyl chloride, thionyl chloride, phosphorus trichloride and phosphorus pentachloride;
(2) the first step is carried out in dichloromethane or 1, 2-dichloroethane;
(3) in the first step the lewis acid is selected from the group consisting of aluminum chloride, ferric chloride, trifluoroacetic acid and boron trifluoride;
(4) in the second step, the alkyl silane reagent is triethylsilane;
(5) in the second step, the Lewis acid is selected from aluminum chloride, ferric trichloride, trifluoroacetic acid and boron trifluoride;
(6) in the third step, the metal organic compound is an organic lithium reagent or a Grignard reagent;
(7) in the fourth step, the cyclization reaction is carried out in dichloromethane, acetonitrile, tetrahydrofuran, chloroform, 1, 2-dichloroethane or N-methylpyrrolidone solvent;
(8) in the fourth step the cyclization is carried out in the presence of water and boron trifluoride diethyl etherate.
13. The process according to claim 12, wherein the organolithium reagent in item (6) is selected from the group consisting of n-butyllithium and isopropyllithium.
14. A pharmaceutical composition comprising a compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, and one or more carriers or excipients.
15. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diabetes or a disease associated therewith selected from diabetic nephropathy, diabetic retinopathy, hyperglycemia, hyperinsulinemia, diabetic cardiovascular complications, diabetic cerebrovascular disease and diabetic peripheral neuropathy.
16. The use of claim 15, wherein the diabetes is selected from the group consisting of insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus.
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