CN103524466A - Dihydrobenzofuran derivative as well as preparation method, intermediate and application thereof - Google Patents

Dihydrobenzofuran derivative as well as preparation method, intermediate and application thereof Download PDF

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CN103524466A
CN103524466A CN201210227590.2A CN201210227590A CN103524466A CN 103524466 A CN103524466 A CN 103524466A CN 201210227590 A CN201210227590 A CN 201210227590A CN 103524466 A CN103524466 A CN 103524466A
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dihydrobenzofuranes
alkyl
tautomer
enantiomer
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许祖盛
张农
吴添智
钱苏
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SHANGHAI YUNYI HEALTH ADMINISTRATION CONSULTING Co Ltd
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SHANGHAI YUNYI HEALTH ADMINISTRATION CONSULTING Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/247—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C43/253—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

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Abstract

The invention discloses a dihydrobenzofuran derivative as shown by formula I in the specification, a tautomer, a racemate, an enantiomer, a diastereoisomer and a hydrate thereof, or a pharmaceutically acceptable salt or medicament precursor thereof. The invention also discloses a preparation method, an intermediate and an application of the dihydrobenzofuran derivative. The dihydrobenzofuran derivative disclosed by the invention is a very effective agonist to GPR40.

Description

Dihydrobenzofuranes analog derivative, its preparation method, intermediate and application thereof
Technical field
The present invention is specifically related to Dihydrobenzofuranes analog derivative, its preparation method, intermediate and application thereof.
Background technology
Regular Insulin is a kind of hormone of being secreted by beta Cell of islet in human pancreas, and it has a lot of important physiological functions, and wherein of paramount importance is exactly to reduce blood sugar, regulates sugared metabolism.It can promote the utilization of sugar in tissue, makes glucose be transformed into glycogen and fat, suppresses glyconeogenesis.It also regulates the metabolism of fat and protein, is a kind of very important biologically active substance in human body.Defect of insulin secretion and insulin resistant (IR) are the pathogenetic basic link of type ii diabetes and feature.Result of study shows, type ii diabetes patient's early stage metabolic characteristics be the not enough and islet beta cell function obstacle of insulin action (J Clin.Invest.1998,101,86-96.).Fat and hyperlipidaemia type ii diabetes sickness rate in recent years risen in rising rapidly vital role (Ann.Clin.Lab.Sci.1999,29,33-42.).It is to cause one of insulin resistant and the impaired important factor of beta Cell of islet secreting function that free fatty acids (Free Fatty Acid, FFA) concentration raises.
Free fatty acids is a kind of significant energy source in animal body, is also a kind of important signaling molecule simultaneously.Free fatty acids can be divided into short chain according to the length of carbochain in molecular structure, medium chain and longer chain fatty acid.Large quantity research in recent years shows, these free fatty acidies are regulating and controlling Regular Insulin hormone secretion (Endocr.Rev. as signaling molecule, 2001, 22 (5), 565-604.), lipid metabolism (Proc.Natl.Acad.Sci.USA, 2004, 101 (4), 1045-1050.), cell proliferation and differentiation (Biochem Biophys.Res.Commun., 2004, 314 (3), 805-809.), apoptosis (J.Biol.Chem., 2005, 280 (20), 1507-1515.) and immune response (J.Diary Sci.1991, 74 (8), 2507-2514.) etc. brought into play vital role in biological procedures.Free fatty acids can be receptor-mediated by certain films, signal path in active cell, thereby performance biological action.
On cytolemma, have a series of free fatty acids specific receptorss, these acceptors all belong to g protein coupled receptor (G protein-coupled receptor, GPCR), GPR40 most importantly wherein, and it is seven transmembrane receptors of recent findings.Result of study shows, GPR40 is the acceptor of medium chain fatty acid and longer chain fatty acid, the assignment of genes gene mapping is in about 4kb place, CD22 downstream, main great expression in human pancreatic islet β cell, this has shown that GPR40 and diabetes have close relationship (Nature, 2003,422 (6928), 173-176.).
The signal path of GPR40 mediation is main relevant with the release of Regular Insulin.Free fatty acids is by a kind of brand-new mechanism of action, to amplify the secretion of Regular Insulin: glucose concn raises and accelerates the metabolism of glucose in cell, cause that in cytosol, ATP/ADP level rises, thereby close the potassium-channel (KATP) that ATP regulates, cause cytolemma depolarize, activation voltage dependency L-type calcium channel (L-type Ca 2+channel, LTCC), cause that calcium ion discharges, and then impel Regular Insulin secretion (Diabetes Metab.Res.Rev.2002,18 (6), 451-463.).When FFA is by activating Gq albumen in conjunction with GPR40 induction, and then activation Phospholipase C (Phospholipase C, PLC), generate InsP3 (inositol triphosphate, IP3) and triglyceride (diacylglycerol, DAG), then induce calcium channel in endoplasmic reticulum to open.In endoplasmic reticulum, voltage-controlled L-type calcium channel will be further opened in the release of calcium ion, make stream in extracellular calcium, promote outer row (Biochem Biophys.Res.Commun., 2005 of Regular Insulin in cell, 335 (1), 97-104.).
Research shows, free fatty acids has two property to the impact of islet beta cell function: short-term acute effect can strengthen the insulin secretion (GSIS) that glucose stimulates on the one hand; Long-term chronic free fatty acid levels raises on the other hand, can produce fat toxicity, causes islet beta cell function obstacle, even islet beta-cell apoptosis.This fat toxicity is promoting the generation of type ii diabetes, in development, play an important role (Chin.J.Postgrad.Med.2007,30,66-73.).
The discovery of GPR40 agonist and exploitation concerning those because of significant the patient of the type ii diabetes of insulin secretion scarce capacity, GPR40 agonist can be in the situation that high concentration glucose exists, by stimulating the GPR40 on beta Cell of islet film to amplify the insulin secretion that glucose stimulates, and then reduction blood sugar concentration, blood sugar concentration is remained in a normal scope.On the other hand, because of the patient of obesity or hyperlipidemia, GPR40 antagonist can be blocked the fat toxicity stimulation of beta Cell of islet being produced because of long-term high concentration freing acid, can eliminate insulin resistant, recover islet beta cell function, thereby reduce the onset risk of type ii diabetes.
Although existing patent discloses compound as GPR40 receptor stimulant or antagonist and preparation method thereof at present, as WO2003099793, WO2004022551, WO2004041266, WO2004106276, WO2005063725, WO2005063729, WO2005087710, WO2005095338, WO2006011615, WO2007013689, WO2005086661, WO2006127503, WO2008065409, WO2007033002, WO2007106469, WO2008030520, WO2008030618, WO2008130514, WO2009111056, WO2010045258, but also still there is not medicine listing, and also there is the active deficiency that waits on the low side in the compound that the existing GPR40 of take is target spot, therefore be starved of have more effective, safer GPR40 agonist research and development listing.
Summary of the invention
Technical problem to be solved by this invention has been to provide a kind of and the diverse a kind of Dihydrobenzofuranes analog derivative of prior art, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, its pharmacy acceptable salt or its prodrug, its preparation method, intermediate and application.Dihydrobenzofuranes analog derivative of the present invention is that a class is for the very effective agonist of GPR40.
Therefore, the invention provides a kind of suc as formula the Dihydrobenzofuranes analog derivative shown in I, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug;
Wherein:
R 1be selected from hydroxyl or amino, wherein said hydroxyl or amino can further replacement by one or more substituting groups that are selected from alkyl, cycloalkyl or alkylsulfonyl;
R 2, R 3and R 4be selected from independently of one another hydrogen atom, D atom, halogen, hydroxyl, cyano group, carboxyl, alkylsulfonyl, alkyl (as C 1～C 3alkyl), alkoxyl group is (as C 3～C 6cycloalkyloxy or C 1～C 3straight or branched alkoxyl group, described C 3～C 6cycloalkanes oxygen can be cyclopropane oxygen base, pentamethylene oxygen base or tetramethylene oxygen base; Described C 1～C 3straight or branched alkoxyl group can be by C 3～C 6cycloalkyloxy or C 1～C 3the C that alkyl sulphonyl replaces 1～C 3straight or branched alkoxyl group), one or more in thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;
R 2, R 3and R 4in have a substituting group that is selected from cycloalkyloxy or contains cycloalkyloxy at least;
M is 0,1,2, or 3;
N is 0,1,2,3 or 4;
P is 0,1,2,3,4 or 5;
When m is 2 or 3, R 2be same to each other or different to each other;
When n is 2,3 or 4 o'clock, R 3be same to each other or different to each other;
When p is 2,3,4 or 5 o'clock, R 4be same to each other or different to each other.
In compound shown in above-mentioned general formula (I), preferably:
R 1be selected from hydroxyl;
R 2, R 3and R 4be selected from independently of one another hydrogen atom, halogen, hydroxyl, alkyl (as C 1～C 3alkyl) and alkoxyl group (as C 3～C 6cycloalkyloxy or C 1～C 3straight or branched alkoxyl group, described C 3～C 6cycloalkanes oxygen can be cyclopropane oxygen base, pentamethylene oxygen base or tetramethylene oxygen base; Described C 1～C 3straight or branched alkoxyl group can be by C 3～C 6cycloalkyloxy or C 1～C 3the C that alkyl sulphonyl replaces 1～C 3straight or branched alkoxyl group) one or more in;
R 2, R 3and R 4in have a substituting group that is selected from alkoxyl group or contains alkoxyl group at least;
M is 0,1,2 or 3;
N is 0,1,2,3 or 4;
P is 0,1,2,3,4 or 5.
In the present invention, what described Dihydrobenzofuranes analog derivative I was better is as shown in the formula the general formula compound shown in II:
Figure BSA00000743196200051
Wherein, R 1, R 2and R 3definition all the same described in, preferably, R 1for hydroxyl, R 2for hydrogen, halogen (as fluorine, chlorine, bromine or iodine) or C 3～C 6cycloalkyloxy, R 3for C 3～C 6cycloalkyloxy; R 4aand R 4bbe independently C 1～C 3alkyl or C 3～C 6cycloalkyloxy, R 4cfor C 4～C 5the C of cycloalkyl or replacement 1～C 3alkyl, the C of replacement 1～C 3substituting group in alkyl is C 3～C 6cycloalkyloxy or C 1～C 3alkyl sulphonyl; R 4dfor hydrogen or halogen (as fluorine, chlorine, bromine or iodine).
In the present invention, described Dihydrobenzofuranes analog derivative II is preferably arbitrary compound as follows:
Figure BSA00000743196200052
Figure BSA00000743196200061
The present invention also provides the preparation method of above-mentioned Dihydrobenzofuranes analog derivative, and it is following either method:
Method one: work as R 1for being selected from alkyl, cycloalkyl or hydroxyl that alkylsulfonyl replaced or when amino, Compound I-I and Compound I-D being carried out to nucleophilic substitution reaction as follows by one or more;
Figure BSA00000743196200062
Method two: as the R of final Compound I 1for hydroxyl or when amino, by Compound I (R wherein 1for by one or more alkyl, cycloalkyl or hydroxyl or amino that alkylsulfonyl replaced of being selected from) reaction that is hydrolyzed (sloughing hydroxyl or amino substituent reaction);
Figure BSA00000743196200071
In method one and two, except specified otherwise, described in each group and alphabetical definition are all the same.
In method one, the method of described nucleophilic substitution reaction and condition all can be ordinary method and the condition of this type of reaction of this area, the present invention is following method and condition particularly preferably: in solvent, Compound I-I and Compound I-D are carried out to nucleophilic substitution reaction under alkaline condition.Wherein said preferred solvents be acetonitrile, methyl-sulphoxide and DMF, preferably acetonitrile.Alkali in described alkaline condition is preferably cesium carbonate, salt of wormwood, sodium carbonate and Quilonum Retard, preferably cesium carbonate.Solvent is 10～100mL/g with the volume mass of Compound I-I than preferably.The consumption of Compound I-D is preferably 0.5～2 times of molar weight of Compound I-I, and better is 0.9～1.2 times.The consumption of described alkali is preferably 1～10 times of molar weight of Compound I-I, and better is 2～3 times.Described temperature of reaction is preferably 20～120 ℃, and better is 50～90 ℃.The time of described reaction preferably with detection reaction completely till, be generally 5～20 hours.
In method two, the method of the described substitution reaction of sloughing hydroxyl or amino and ordinary method and the condition that condition all can be this type of reaction of this area, the present invention is following method and condition particularly preferably: in solvent, and the Compound I reaction that is hydrolyzed under alkaline condition.Wherein said preferred solvents be methyl alcohol, ethanol, tetrahydrofuran (THF), methyl-sulphoxide, one or more in Isosorbide-5-Nitrae-dioxane, ethylene glycol and water, particular methanol.Alkali in described alkaline condition is preferably lithium hydroxide aqueous solution, aqueous sodium hydroxide solution and potassium hydroxide aqueous solution, preferably aqueous sodium hydroxide solution.Solvent is 10～100mL/g with the volume mass of Compound I than preferably.The concentration of aqueous solution of described alkali is preferably 0.1M～5M, and that better is 1～2M.The consumption of described alkali is preferably 1～10 times of molar weight of Compound I, and better is 2～3 times.Described temperature of reaction is preferably 0～100 ℃, and better is 20～60 ℃.The time of described reaction preferably with detection reaction completely till, be generally 1～20 hour.
In method one, described I-I can be made by following method: Compound I-H is carried out to bromo or the chlorination of hydroxyl;
Figure BSA00000743196200081
Wherein, the method for the bromo-reaction of described hydroxyl and condition all can be ordinary method and the condition of this type of reaction of this area, and the present invention is following method and condition particularly preferably: in solvent, Compound I-H and triphenyl phosphorus and carbon tetrabromide react.Wherein said preferred solvents be tetrahydrofuran (THF), methylene dichloride, trichloromethane, one or more in acetonitrile and Isosorbide-5-Nitrae-dioxane, preferably tetrahydrofuran (THF) and methylene dichloride.Solvent is 10～100mL/g with the volume mass of Compound I-H than preferably.The consumption of triphenyl phosphorus is preferably 1～3 times of molar weight of Compound I-H, and better is 1.2～1.5 times.The consumption of carbon tetrabromide is preferably 1～3 times of molar weight of Compound I-H, and better is 1.2～1.5 times.Described temperature of reaction is preferably 0～50 ℃, and better is 20～30 ℃.The time of described reaction preferably with detection reaction completely till, be generally 1～20 hour.
The method of the chlorination of described hydroxyl and condition all can be ordinary method and the condition of this type of reaction of this area, and the present invention is following method and condition particularly preferably: in solvent, Compound I-H reacts with sulfur oxychloride.Wherein said preferred solvents be tetrahydrofuran (THF), methylene dichloride, trichloromethane, one or more in acetonitrile and Isosorbide-5-Nitrae-dioxane, preferably methylene dichloride.Solvent is 10～100mL/g with the volume mass of Compound I than preferably.The consumption of sulfur oxychloride is preferably 10～60 times of molar weight of Compound I-H.Described temperature of reaction is preferably 0～50 ℃, and better is 20～30 ℃.The time of described reaction preferably with detection reaction completely till, be generally 1～20 hour.
In the present invention, described Compound I-H can be made by following method: Compound I-G is carried out to the reaction that aldehyde radical is reduced to hydroxyl;
Figure BSA00000743196200091
Wherein, described aldehyde radical is reduced to the method for reaction of hydroxyl and ordinary method and the condition that condition all can be this type of reaction of this area, and the present invention is following method and condition particularly preferably: in solvent, and Compound I-G and sodium borohydride reaction.Wherein said preferred solvents be tetrahydrofuran (THF), methylene dichloride, methyl alcohol, one or more in acetonitrile and Isosorbide-5-Nitrae-dioxane, preferably tetrahydrofuran (THF).Solvent is 10～100mL/g with the volume mass of Compound I-G than preferably.The consumption of sodium borohydride is preferably 0.5～5 times of molar weight of Compound I-G, and better is 1～2 times.Described temperature of reaction is preferably 0～70 ℃, and better is 0～30 ℃.The time of described reaction preferably with detection reaction completely till, be generally 1～20 hour.
In the present invention, described Compound I-G can be made by following method: Compound I-E and Compound I-F are carried out to linked reaction as follows;
Figure BSA00000743196200101
Wherein, the method for described linked reaction and condition all can be ordinary method and the condition of this type of reaction of this area, and the present invention is following method and condition particularly preferably: in solvent, under protection of inert gas, under the effect of alkali and palladium catalyst, Compound I-E and I-F are carried out to linked reaction; Wherein, described rare gas element can be argon gas and/or nitrogen; Described preferred solvents be one or more in tetrahydrofuran (THF), toluene, Isosorbide-5-Nitrae-dioxane, glycol dimethyl ether and water, preferred toluene; Solvent is 20～100mL/g with the volume mass of Compound I-F than preferably; Described alkali is preferably one or more in salt of wormwood, cesium carbonate, sodium carbonate and potassiumphosphate; The consumption of alkali is preferably 1～10 times of molar weight of Compound I-F, and better is 3～5 times; Described palladium catalyst is preferably the conventional catalyzer of this type of linked reaction, as palladium, two (tri-butyl phosphine) palladium, tetrakis triphenylphosphine palladium and [1,1 '-bis-(diphenylphosphino) ferrocene] one or more in palladium chloride, preferably two (tri-butyl phosphine) palladium; The consumption of catalyzer is preferably 0.005～0.5 times of molar weight of Compound I-F, and better is 0.01～0.10 times; Described reactant I-G and the mol ratio of I-F are preferably 0.5～2, and better is 0.9～1.5; The temperature of described reaction is preferably 20～120 ℃, and better is 70～90 ℃; The time of described reaction preferably with detection reaction completely till.
In the present invention, described Compound I-D can be made by following method: Compound I-C is carried out to the reduction reaction of ethylene linkage as follows;
Figure BSA00000743196200111
Wherein, the method of described reduction reaction and condition all can be ordinary method and the condition of this type of reaction of this area, and the present invention is following method and condition particularly preferably: under nitrogen atmosphere condition, in solvent, Compound I-C is carried out to the two key hydrogenations under palladium catalyst effect; Wherein, described preferred solvents be methyl alcohol, ethanol or ethyl acetate, particular methanol; Described palladium catalyst can be Pd/C or Pd (OH) 2/ C, preferably Pd/C; Solvent is 20～200mL/g with the volume mass of Compound I-C than preferably; The temperature of described reaction is preferably 0～50 ℃, and better is 20～30 ℃; The pressure of described hydrogen is preferably 1～2 normal atmosphere, and better is 1 normal atmosphere; The time of described reaction preferably with detection reaction completely till.
In the present invention, described Compound I-C can be made by following method: Compound I-B is carried out to reaction as follows;
Figure BSA00000743196200112
Wherein, the method for described reaction and condition all can be ordinary method and the condition of this type of reaction of this area, and the present invention is following method and condition particularly preferably: in solvent, Compound I-B reacts under alkaline condition.Wherein said preferred solvents be tetrahydrofuran (THF), methyl alcohol, ethanol, methyl-sulphoxide, one or more in Isosorbide-5-Nitrae-dioxane, ethylene glycol and water, preferably water.Alkali in described alkaline condition is preferably sodium hydroxide, potassium hydroxide and lithium hydroxide, preferably sodium hydroxide.Solvent is 10～100mL/g with the volume mass of Compound I-B than preferably.The consumption of described alkali is preferably 1～10 times of molar weight of Compound I-B, and better is 1.5～2.5 times.Described temperature of reaction is preferably 20～150 ℃, and better is 90～110 ℃.The time of described reaction preferably with detection reaction completely till, be generally 1～10 hour.
In the present invention, described Compound I-B can be made by following method: Compound I-A is carried out to reaction as follows;
Figure BSA00000743196200121
Wherein, the method for described reaction and condition all can be ordinary method and the condition of this type of reaction of this area, and the present invention is following method and condition particularly preferably: Compound I-A reacts under concentrated acid condition with 4-chloroacetyl acetacetic ester.Wherein said concentrated acid is the vitriol oil, and its consumption is preferably 0.1～1 times of molar weight of Compound I-A, and better is 0.3～0.6 times.The consumption of 4-chloroacetyl acetacetic ester is preferably 1～5 times of molar weight of Compound I-A, and better is 1～1.5 times.Described temperature of reaction is preferably-10～50 ℃, and better is 0～30 ℃.The time of described reaction preferably with detection reaction completely till, be generally 1～10 hour.
In the present invention, the preferably reaction scheme of described Compound I is as follows:
Figure BSA00000743196200122
Those skilled in the art should understand, after the structure of cicada the compounds of this invention, can be by multiple method well known in the art, utilize known raw material, obtain compound of the present invention, such as chemosynthesis or the method extracted from plant, these methods all comprise in the present invention.Unless otherwise indicated or preparation method is provided, prepare compound of the present invention or its intermediate raw material used and be all known in the art maybe can be by commercially available.
In the present invention, each optimum condition in described preparation method can arbitrary combination, obtains each preferred embodiments of the present invention.
The present invention also provides following arbitrary midbody compound of preparing above-mentioned Dihydrobenzofuranes analog derivative;
Figure BSA00000743196200141
Figure BSA00000743196200151
A kind of pharmaceutical composition is also provided in the present invention, it contains above-mentioned Dihydrobenzofuranes analog derivative, its tautomer, racemic modification, enantiomer, diastereomer, its hydrate for the treatment of effective dose, its pharmacy acceptable salt or its prodrug, with and pharmaceutically acceptable carrier and/or thinner.
The present invention also provides above-mentioned Dihydrobenzofuranes analog derivative, its tautomer, racemic modification, enantiomer, diastereomer, its hydrate, its pharmacy acceptable salt or its prodrug, or the application of aforementioned pharmaceutical compositions in preparing g protein coupled receptor 40 (GPR40) agonist.
Above-mentioned Dihydrobenzofuranes analog derivative, its tautomer, racemic modification, enantiomer, diastereomer, its hydrate have been the present invention further provides, its pharmacy acceptable salt or its prodrug, or the purposes of aforementioned pharmaceutical compositions in treating and/or preventing the medicine of metabolic disorder.
Wherein, described metabolic disorder can be I type or type ii diabetes, insulin resistance, glucose metabolism illness, metabolic acidosis or ketoacidosis, diabetic neuropathy, diabetic retinopathy, obesity, hypoglycemia, hypertension, hyperinsulinemia, insulin allergy disease or nesidioblastoma.
Except as otherwise noted, the following term occurring in specification sheets of the present invention and claims has following implication:
Mean to comprise the side chain of 1～20 carbon atom and the radical of saturated aliphatic alkyl of straight chain " alkyl " as used herein (comprising while using separately and being included in other group), preferred 1～10 carbon atom, more preferably 1～8 carbon atom, such as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, 4,4-dimethyl amyl group, 2,2,4-tri-methyl-amyl, undecyl, dodecyl, and their various isomer etc., and comprise the substituent abovementioned alkyl of following any 1-4 kind: deuterium, halogen (preferred F, Br, Cl or I), alkyl, alkoxyl group, aryl, aryloxy, aryl or diaryl that aryl replaces, aralkyl, aralkoxy, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, cycloalkyl alkoxy, optional substituted amino, hydroxyl, hydroxyalkyl, acyl group, aldehyde radical, heteroaryl, heteroaryloxy, Heterocyclylalkyl, heterocycle alkoxyl group, aryl heteroaryl, aryl alkyl carbonyl oxygen, heteroarylalkyl, heteroaryl alkoxyl group, aryloxyalkyl group, aryl aryloxycarboxylic, alkylamino, amido, aryl-amino-carbonyl, C 1～C 3alkyl sulphonyl, nitro, itrile group, sulfydryl, haloalkyl, three alkylhalide groups and/or alkylthio.
Mean to comprise the side chain of 1～20 carbon atom and the sub-saturated aliphatic hydrocarbyl of straight chain " alkylidene group " as used herein (comprising while using separately and being included in other group), preferred 1～10 carbon atom, more preferably 1～8 carbon atom, such as methylene radical, ethylidene, propylidene, isopropylidene, sub-normal-butyl, the sub-tertiary butyl, isobutylidene, pentylidene, hexylidene, sub-heptyl, octylene, nonamethylene, sub-decyl, sub-(4, 4-dimethyl amyl group), sub-(2, 2, 4-tri-methyl-amyl), sub-undecyl, sub-dodecyl, and their various isomer etc., and comprise the substituent above-mentioned alkylidene group of following any 1-4 kind: deuterium, halogen (preferred F, Br, Cl or I), alkyl, alkoxyl group, aryl, aryloxy, aryl or diaryl that aryl replaces, aralkyl, aralkoxy, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, cycloalkyl alkoxy, optional substituted amino, hydroxyl, hydroxyalkyl, acyl group, aldehyde radical, heteroaryl, heteroaryloxy, Heterocyclylalkyl, heterocycle alkoxyl group, aryl heteroaryl, aryl alkyl carbonyl oxygen, heteroarylalkyl, heteroaryl alkoxyl group, aryloxyalkyl group, aryl aryloxycarboxylic, alkylamino, amido, aryl-amino-carbonyl, nitro, itrile group, sulfydryl, haloalkyl, three alkylhalide groups and/or alkylthio, one or more in above-mentioned substituting group also can connect into ring with alkylidene group, thus formation ring or volution.
The ring-type hydrocarbon group that comprises 1-3 ring that term " alicyclic ring " or " cycloalkyl " (comprising while using separately and being included in other group) comprise saturated or part is unsaturated (comprising 1 or 2 two key), it comprises monocycle alkyl, bicyclic alkyl and tricyclic alkyl, it comprises 3-20 the carbon that can form ring, preferred 3-10 carbon, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclodecane and cyclo-dodecyl, cyclohexenyl; Cycloalkyl can be replaced by following any 1-4 kind substituting group: deuterium, halogen, alkyl, alkoxyl group, hydroxyl, aryl, aryloxy, aralkyl, cycloalkyl, alkylamino, amido, oxygen, acyl group, aryl-amino-carbonyl, amino, nitro, itrile group, sulfydryl and/or alkylthio and/or arbitrarily alkyl substituent.
Term " alkoxyl group " represents to connect by oxo bridge has described carbonatoms object ring-type or non-annularity alkyl.Thus, the definition that " alkoxyl group " comprises above alkyl and cycloalkyl.
Term " thiazolinyl " refers to and contains the non-aromatic alkyl of straight chain, side chain or ring-type that specifies number carbon atom and at least one carbon-carbon double bond.Preferably there is a carbon-carbon double bond, and can exist up to four non-aromatic carbon-carbon double bonds.Thus, " C2-12 thiazolinyl " refers to the thiazolinyl with 2-12 carbon atom." C2-6 thiazolinyl " refers to the thiazolinyl with 2-6 carbon atom, comprises vinyl, propenyl, butenyl, 2-methyl butene base and cyclohexenyl.The straight chain of thiazolinyl, side chain or loop section can contain two keys, and if be indicated as substituted alkenyl, can be substituted so.
Term " alkynyl " refers to and contains straight chain, side chain or the cyclic hydrocarbon group that specifies number carbon atom and at least one carbon carbon triple bond.Wherein can exist up to three carbon carbon triple bonds.Thus, " C2-12 alkynyl " refers to the alkynyl with 2-12 carbon atom." C2-6 alkynyl " refers to the alkynyl with 2-6 carbon atom, comprises ethynyl, proyl, butynyl and 3-methyl butynyl etc.
As used herein " aryl " refer to any stable can be up to monocycle or the bicyclic carbocyclic of 7 atoms in each ring, wherein at least one ring is aromatic nucleus.The example of above-mentioned aryl unit comprises phenyl, naphthyl, tetralyl, 2,3-indanyl, xenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).Be appreciated that at aryl substituent be two ring substituents, and one of them ring is in the situation of non-aromatic ring, connection is undertaken by aromatic ring.And comprise the substituent above-mentioned aryl of following any 1-4 kind: deuterium, halogen (F, Br, Cl or I), alkyl, alkoxyl group, aryl, aryloxy, aryl or diaryl that aryl replaces, aralkyl, aralkoxy, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkylalkyl, cycloalkyl alkoxy, optional substituted amino, hydroxyl, hydroxyalkyl, acyl group, aldehyde radical, heteroaryl, heteroaryloxy, Heterocyclylalkyl, heterocycle alkoxyl group, aryl heteroaryl, aryl alkyl carbonyl oxygen, heteroarylalkyl, heteroaryl alkoxyl group, aryloxyalkyl group, aryl aryloxycarboxylic, alkylamino, amido, aryl-amino-carbonyl, nitro, itrile group, sulfydryl, haloalkyl, three alkylhalide groups and/or alkylthio.
Term " halogen " represents fluorine, chlorine, bromine, iodine or astatine.
Term " hydroxyl " expression-OH.
Term " amino " expression-NH 2.
Term " cyano group " expression-CN.
Term " carboxyl " expression-COOH.
Term " alkylsulfonyl " expression-SO 2-alkyl.
Term " haloalkyl " represents the alkyl that halogen optional position replaces.Thus, the definition that " haloalkyl " comprises above halogen and alkyl.
Term " halogenated alkoxy " represents the alkoxyl group that halogen optional position replaces.Thus, the definition that " halogenated alkoxy " comprises above halogen and alkoxyl group.
Term " aryloxy " represents the described carbonatoms object aryl that has connecting by oxo bridge.Thus, the definition that " aryloxy " comprises above aryl.
Term " heterocyclic base " or " heteroaryl " represent can to encircle up to the stable monocycle or two of 7 atoms in each ring as used herein, and wherein at least one ring is aromatic nucleus and contains 1-4 heteroatoms that is selected from O, N and S.Heteroaryl in this range of definition includes but not limited to: acridyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrahydroquinoline.As the definition of following heterocycle, " heteroaryl " it should also be understood that to be the N-oxide derivative that comprises any nitrogen-containing hetero aryl.Heteroaryl substituting group is that two ring substituents and a ring are non-aromatic rings or do not comprise in heteroatomic situation therein, is appreciated that connection carries out by aromatic ring or by the heteroatoms that comprises ring respectively.Heteroaryl can be replaced by following any 1-4 kind substituting group: deuterium, halogen, alkyl, alkoxyl group, hydroxyl, aryl, aryloxy, aralkyl, cycloalkyl, alkylamino, amido, acyl group, aryl-amino-carbonyl, amino, nitro, itrile group, sulfydryl and/or alkylthio and/or arbitrarily alkyl substituent.
Term " heterocycle " or " heterocyclic radical " represent to contain 1-4 heteroatomic 5-10 unit's fragrance or nonaromatic heterocycles that is selected from O, N and S as used herein, and comprise bicyclic groups.Therefore, " heterocyclic radical " comprise above-mentioned heteroaryl with and dihydro or tetrahydrochysene analogue.Other example of " heterocyclic radical " includes but not limited to following: benzimidazolyl-, benzofuryl, benzofuraxan base, benzopyrazoles base, benzotriazole base, benzothienyl, benzoxazolyl, carbazyl, carbolinyl, cinnolines base, furyl, imidazolyl, indolinyl, indyl, indazolyl, isobenzofuran-base, pseudoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalene pyrimidyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxygen cyclobutyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridine base, pyridazinyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, quinoxalinyl, THP trtrahydropyranyl, tetrazyl, tetrazolo pyridyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, azetidinyl, Isosorbide-5-Nitrae-alkyl dioxins, six hydrogen azatropylidene bases, piperazinyl, piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, dihydrobenzo imidazolyl, dihydro benzo furyl, dihydrobenzo thienyl, Er hydrogen benzoxazolyl, dihydrofuran base, glyoxalidine base, indolinyl, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyl, dihydro-oxazole base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydroquinoline base, dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, methylenedioxyphenyl formyl radical, tetrahydrofuran base and tetrahydro-thienyl and N-oxide compound thereof.Heterocyclic radical substituting group can be connected with other groups through carbon atom or heteroatoms wherein.
Term " heterolipid ring " or " Heterocyclylalkyl " separately or while using as a part for another group, refer to the first saturated or undersaturated ring of part of the 4-12 that comprises 1-4 heteroatoms (as nitrogen, oxygen and/or sulphur) at this.Described heterocycloalkyl can comprise 1-4 substituting group, as alkyl, halogen, oxo base and/or any alkyl substituent listed above.In addition, any heterocycloalkyl ring can condense on cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.Heterocyclylalkyl substituting group can be connected with other groups through carbon atom or heteroatoms wherein.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Except specified otherwise, agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: Dihydrobenzofuranes analog derivative of the present invention is that a class is for the very effective agonist of GPR40.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or selects according to catalogue.
The structure of compound determined by nucleus magnetic resonance (NMR) or mass spectrum (MS), and nuclear magnetic resonance spectrum is to obtain by Bruker Avance-500 instrument, deuterated DMSO, and deuterochloroform and deuterated methanol etc. is solvent, TMS is interior mark.Mass spectrum is to be obtained by liquid chromatography-mass spectrography (LC-MS) combined instrument Agilent Technologies6110, adopts ESI ion source.
Preparation Example:
Compound T-01's is synthetic
Synthetic route
Figure BSA00000743196200211
Compound 1-h's is synthetic
Under ice-water bath, to 4-chloroacetyl acetacetic ester (28.0g, 0.17mol) and the vitriol oil (98%, in mixture 60mL), slowly add Resorcinol (17.6g, 0.16mol), mixture was in stirring at room 2 hours.Reaction solution is poured in frozen water, has throw out to separate out, and filters to obtain compound 1-h (28g, the productive rate: 84%) of yellow solid shape.Product, without purifying, directly drops into next step reaction.
Compound 1-g's is synthetic
In aqueous sodium hydroxide solution (1N, 600mL), add compound 1-h (28.0g, 133mmol), mixture reflux 4 hours to raw material disappears.Be chilled to room temperature, to slowly dripping dilute sulphuric acid in reaction solution, make PH < 2, ethyl acetate extraction (100mL * 3), merge organic phase, water (60mL * 3) and saturated aqueous common salt (60mL) are washed successively, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resulting solid suspension, in methyl alcohol (150mL), and adds the vitriol oil (15mL).Mixed solution reflux 4 hours, underpressure distillation is except desolventizing, resistates is used saturated sodium bicarbonate solution (150mL * 3) successively, water (60mL * 3) and saturated aqueous common salt (60mL) are washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains compound 1-g (18.6g), and thick product directly drops into next step reaction.LC-MS(ESI)：m/z＝207[M+H] +.
Compound 1-f's is synthetic
To compound 1-g (4.9g, in methyl alcohol 24mmol) (120mL) solution, add palladium carbon (10%, 0.49g), reaction system hydrogen exchange secondary, mixture stirring at room 24 hours under atmosphere of hydrogen, filters concentrating under reduced pressure filtrate, resistates obtains compound 1-f (4.5g, productive rate: 91%) through purification by silica gel column chromatography (petrol ether/ethyl acetate=4: 1 to 1: 1).LC-MS(ESI)：m/z＝209[M+H] +.
Compound 1-e's is synthetic
By 3; 5-dimethyl-4-bromophenol (10.3g; 51.0mmol), 3-formylphenylboronic acid (7.67g, 51.2mmol); aqueous sodium carbonate (1M; 150mL, 150mmol), four (triphenyl phosphorus) palladium (2.95g; 2.55mmol), the mixture of ethanol (50mL) and toluene (150mL) is heated to 80 ℃ of reactions 24 hours under nitrogen protection.Be chilled to room temperature, add water (100mL) and ethyl acetate (100mL) dilution, filter, organic phase in filtrate is separated, with saturated aqueous common salt (60mL), wash anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=8: 1) obtain compound 1-e (7g, productive rate: 60.7%).LC-MS(ESI)：m/z＝225[M-H] -.
Compound 1-d's is synthetic
Under ice-water bath and nitrogen protection; to compound 1-e (2.3g; in anhydrous tetrahydro furan 10mmol) (25mL) solution, slowly add two (trimethyl silicon based) sodium amide (ethane solution of 2M; 7.5mL; 15mmol), mixture after 10 minutes, slowly adds TERT-BUTYL DIMETHYL CHLORO SILANE (2.3g in 0 ℃ of stirring; tetrahydrofuran (THF) 15mmol) (5mL) solution, mixture was in stirring at room 2 hours.In reaction solution, add water (10mL) cancellation reaction, ethyl acetate extraction (30mL * 3), the organic phase of merging, through anhydrous sodium sulfate drying, is filtered, concentrating under reduced pressure filtrate, the crude product that obtains compound 1-d directly drops into next step.LC-MS(ESI)：m/z＝341[M+H] +.
Compound 1-c's is synthetic
By compound 1-d (270mg, 0.79mmol) be dissolved in the mixed solvent of methyl alcohol (2mL) and tetrahydrofuran (THF) (6mL), ice-water bath is cooling, slowly add sodium borohydride (45mg, 1.19mmol), mixture was in stirring at room 1 hour, add dilute hydrochloric acid (1M, 5mL) and water (15mL), ethyl acetate (10mL * 3) extraction, saturated aqueous common salt for organic phase (50mL) is washed, anhydrous sodium sulfate drying, filters concentrating under reduced pressure filtrate, obtain compound 1-c (260mg), thick product directly drops into next step reaction.
Compound 1-b's is synthetic
By triphenyl phosphorus (178mg, 0.68mmol) and carbon tetrabromide (225mg, 0.68mmol) be dissolved in tetrahydrofuran (THF) (8mL), mixture was in stirring at room 30 minutes, in reaction solution, add compound 1-c (155mg, tetrahydrofuran (THF) 0.45mmol) (5mL) solution, reaction solution is in stirred overnight at room temperature.Filter, filtrate decompression is concentrated, and resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=30: 1) obtain compound 1-b (40mg, productive rate: 21.8%).
Compound 1-a's is synthetic
By compound 1-b (100mg, 0.25mmol), 1-e (71mg, 0.34mmol), the mixture of cesium carbonate (336mg, 1.02mmol) and acetonitrile (15mL) flows through night next time in nitrogen atmosphere.Be chilled to room temperature, add water (15mL), ethyl acetate extraction (15mL * 3), saturated aqueous common salt for organic phase (15mL) is washed, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=3: 1) obtain compound 1-a (60mg, productive rate: 58%).LC-MS(ESI)：m/z＝419[M+H] +.
Synthesizing of compound 1
By compound 1-a (120mg, 0.28mmol), compd A (100mg, 0.34mmol), the mixture of cesium carbonate (122mg, 0.37mmol) and DMF (6mL) is heated to 90 ℃ of reactions and spends the night.Reaction solution is chilled to room temperature, pour in 10mL water, ethyl acetate extraction (30mL * 3), the saturated aqueous common salt for organic phase (10mL) merging is washed, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=5: 1) obtain compound 1 (50mg, productive rate: 34%).LC-MS(ESI)：m/z＝545[M+H] +.
Compound T-01's is synthetic
By compound 1 (50mg, 0.09mmol) be dissolved in the mixed solvent of methyl alcohol (3mL) and tetrahydrofuran (THF) (0.5mL), add aqueous sodium hydroxide solution (2M, 0.2mL), mixture was in room temperature reaction 3 hours, add water (5mL) dilution, with 1M hydrochloric acid acid for adjusting pH to 2-3, ethyl acetate extraction (20mL * 3), saturated aqueous common salt for organic phase (10mL) is washed, and anhydrous sodium sulfate drying filters, filtrate decompression concentrates to obtain compound T-01 (34mg, productive rate: 71%).LC-MS(ESI)：m/z＝531[M+H] +. 1HNMR(500MHz，CDCl 3)δ：7.37-7.43(m，2H)，7.17(s，1H)，7.08(d，J＝7.0Hz，1H)，7.05(d，J＝8.0Hz，1H)，6.69(s，2H)，6.50(dd，J＝2.0Hz，8.0Hz，1H)，6.47(d，J＝7.5Hz，1H)，5.06(s，2H)，4.76(t，J＝9.0Hz，1H)，4.28(dd，J＝6.0Hz，9.0Hz，1H)，4.13(t，J＝5.0Hz，2H)，3.84(t，J＝5.5Hz，2H)，3.77-3.82(m，1H)，3.35-3.40(m，1H)，2.80(dd，J＝5.0Hz，7.0Hz，1H)，2.61(dd，J＝9.5Hz，17.0Hz，1H)，1.99(s，6H)，1.95-1.97(m，2H)，1.75-1.78(m，2H)，1.54-1.57(m，1H)，1.20-1.38(m，5H).
Compound T-02's is synthetic
Synthetic route
Figure BSA00000743196200241
Synthesizing of compound 2
By compound 1-a (130mg, 0.31mmol), compd B (105mg, 0.37mmol), the mixture of cesium carbonate (132mg, 0.41mmol) and DMF (6mL) is heated to 90 ℃ of reactions 18 hours.Reaction solution is chilled to room temperature, pour in 30mL water, ethyl acetate (30mL * 3) extraction, the saturated aqueous common salt for organic phase (30mL) merging is washed, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=4: 1) obtain compound 2 (65mg, productive rate: 39%).LC-MS(ESI)：m/z＝531[M+H] +.
Compound T-02's is synthetic
By compound 2 (65mg, 0.12mmol) be dissolved in the mixed solvent of methyl alcohol (3mL) and tetrahydrofuran (THF) (2mL), add aqueous sodium hydroxide solution (2M, 0.25mL), mixture was in room temperature reaction 3 hours, add water (5mL) dilution, with 1M hydrochloric acid acid for adjusting pH to 2-3, ethyl acetate extraction (20mL * 3), saturated aqueous common salt for organic phase (10mL) is washed, and anhydrous sodium sulfate drying filters, filtrate decompression concentrates to obtain compound T-02 (15mg, productive rate: 25%).LC-MS(ESI)：m/z＝517[M+H] +. 1HNMR(500MHz，CDCl 3)δ：7.36-7.43(m，2H)，7.17(s，1H)，7.08(d，J＝7.0Hz，1H)，7.05(d，J＝8.5Hz，1H)，6.68(s，2H)，6.50(dd，J＝2.0Hz，8.0Hz，1H)，6.47(d，J＝2.0Hz，1H)，5.06(s，2H)，4.76(t，J＝9.0Hz，1H)，4.28(dd，J＝6.0Hz，9.5Hz，1H)，4.12(t，J＝5.5Hz，2H)，4.01-4.05(m，1H)，3.78-3.82(m，1H)，3.77(t，J＝5.0Hz，2H)，2.80(dd，J＝5.0Hz，17.0Hz，1H)，2.62(dd，J＝4.5Hz，17.0Hz，1H)，1.91(s，6H)，1.70-1.80(m，6H)，1.53-1.55(m，2H).
Compound T-03's is synthetic
Synthetic route
Figure BSA00000743196200251
Synthesizing of compound 3
By compound 1-a (64mg, 0.43mmol), bromo pentane silane (60mg, 0.14mmol), the mixture of cesium carbonate (273mg, 0.84mmol) and DMF (15mL) is heated to 80 ℃ of reactions 18 hours.Be chilled to room temperature, add water (15mL), ethyl acetate (20mL * 3) extraction, organic phase merges, and washes anhydrous sodium sulfate drying with saturated aqueous common salt (15mL), filter, filtrate decompression is concentrated, and resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=5: 1) obtain compound 3 (20mg, productive rate: 28.6%).LC-MS(ESI)：m/z＝509[M+Na] +.
Compound T-03's is synthetic
By compound 1 (20mg, 0.04mmol) be dissolved in the mixed solvent of methyl alcohol (3mL) and tetrahydrofuran (THF) (2mL), add aqueous sodium hydroxide solution (2M, 0.2mL), mixture is heated to 50 ℃ of reactions 1 hour, reaction solution is chilled to room temperature, add water (5mL) dilution, with 1M hydrochloric acid acid for adjusting pH to 2-3, ethyl acetate extraction (10mL * 3), saturated aqueous common salt for organic phase (10mL) is washed, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates to obtain compound T-03.LC-MS(ESI)：m/z＝473[M+H] +. 1HNMR(500MHz，CDCl 3)δ：7.36-7.43(m，2H)，7.19(s，1H)，7.10(d，J＝7.5Hz，1H)，7.05(d，J＝8.5Hz，1H)，6.64(s，2H)，6.50(dd，J＝7.0Hz，8.5Hz，1H，6.47(d，J＝2.0Hz，1H)，5.06(s，2H)，4.75-4.80(m，2H)，4.29(dd，J＝6.0Hz，9.0Hz，1H)，3.78-3.84(m，1H)，2.81(dd，J＝5.0Hz，16.5Hz，1H)，2.62(dd，J＝10.0Hz，16.5Hz，1H)，1.99(s，6H)，1.89-1.96(m，4H)，1.78-1.87(m，2H)，1.60-1.67(m，2H).
Compound T-04's is synthetic
Synthetic route
Figure BSA00000743196200261
Compound 4-g's is synthetic
To 4-HBA methyl esters (6.08g, in chloroform 40mmol) (60mL) solution, add acetic acid (12mL), again to chloroform (10mL) solution that slowly drips bromine (6.4g, 40mmol) in mixture, mixture disappears in stirring at room 24 hours to raw material.Concentrating under reduced pressure reaction solution, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=4: 1) obtain compound 4-g (6.85g, productive rate: 75%).
Compound 4-f's is synthetic
By compound 4-g (2.31g; 10.0mmol); vinyl-acetic ester (3.34g; 40mmol); sodium carbonate (636mg; 6.0mmol), two the mixture of [two (cyclooctadiene) iridium chloride)] (134mg, 0.2mmol) and toluene (30mL) is heated to 100 ℃ of reactions 4 hours to raw material and disappears under nitrogen protection.Concentrating under reduced pressure reaction solution, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=10: 1) obtain compound 4-f (2.24g, productive rate: 87%).
Compound 4-e's is synthetic
To the hexane solution (1M that adds zinc ethyl in 100mL three-necked bottle, 13mL, 13mmol) and methylene dichloride (20mL), be cooled to 0 ℃, slowly drip trifluoroacetic acid (1.42g, 12.5mmol), after 20 minutes, add methylene iodide (3.62g, 13.5mmol), 0 ℃ was stirred after 20 minutes, add compound 4-f (1.30g, 5.0mmol).Reaction solution slowly rises to room temperature, continues to stir 2 hours.In reaction solution, add saturated ammonium chloride solution (20mL) cancellation reaction, by ethyl acetate (40mL * 3), extract, the organic phase merging successively water (40mL * 2) and saturated aqueous common salt (40mL * 1) is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=10: 1) obtain compound 4-e (672mg, productive rate: 50%). 1HNMR(500MHz，CDCl 3)δ：8.21(d，J＝2.0Hz，1H)，7.98(dd，J＝2.0Hz，8.5Hz，1H)，7.29(d，J＝8.5Hz，1H)，3.90(s，3H)，3.84-3.89(m，1H)，0.88(d，J＝4.5Hz，4H).
Compound 4-d's is synthetic
By compound 4-e (542mg, 2.0mmol), pinacol boric acid ester (558mg, 2.2mmol), Pd (dppf) Cl 2(16mg, 0.02mmol), the mixture of Potassium ethanoate (684g, 6.0mmol) and toluene (15mL) is heated to 80 ℃ of reactions 16 hours under nitrogen atmosphere.Reaction solution is cooled to room temperature, filters, and concentrating under reduced pressure filtrate, resistates obtains compound 4-d (500mg, productive rate: 79%) through purification by silica gel column chromatography (petrol ether/ethyl acetate=10: 1 to 5: 1).LC-MS(ESI)：m/z＝319[M+H] +. 1HNMR(500MHz，CDCl 3)δ：8.27(d，J＝2.5Hz，1H)，8.08(dd，J＝2.5Hz，9.0Hz，1H)，7.23(d，J＝8.5Hz，1H)，3.88(s，3H)，3.81-3.83(m，1H)，1.33(s，12H)，0.79(d，J＝6.5Hz，4H).
Compound 4-c's is synthetic
By compound 4-d (200mg, 0.63mmol), Compound C (250mg, 0.77mmol), two (tri-tert phosphorus) palladium (40mg, 0.08mmol), the mixture of potassiumphosphate (424g, 2.0mmol) and toluene (10mL) is heated to 80 ℃ of reactions 16 hours under nitrogen atmosphere.Reaction solution is cooled to room temperature, filters, and concentrating under reduced pressure filtrate, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=2: 1) obtain compound 4-c (200mg, productive rate: 73%).LC-MS(ESI)：m/z＝433[M+H] +.
Compound 4-b's is synthetic
By compound 4-c (180mg, tetrahydrofuran (THF) 0.42mmol) (5mL) solution is cooling by dry ice acetone bath, slowly drip inwards the toluene solution (1M of diisobutyl aluminium hydride, 1.0mL, 1.0mmol), add rear mixture and slowly rise to stirring at room 2 hours, add saturated ammonium chloride solution (20mL) cancellation, ethyl acetate extraction (30mL * 3), the organic phase merging successively water (30mL * 1) and saturated aqueous common salt (30mL * 1) is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=1: 1) obtain compound 4-b (140mg, productive rate: 82%).LC-MS(ESI)：m/z＝405[M+H] +.
Compound 4-a's is synthetic
Under ice-water bath, to compound 4-b (80mg, 2.0mmol) and carbon tetrabromide (132mg, in dry methylene chloride 4.0mmol) (5mL) solution, slowly drip triphenyl phosphorus (105mg, methylene dichloride 4.0mmol) (5mL) solution, adds rear mixture and slowly rises to stirring at room 3 hours to raw material and disappear.Reaction solution concentrating under reduced pressure, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=2: 1) obtain compound 4-a (70mg, productive rate: 76%).
Synthesizing of compound 4
By compound 1-f (60mg, 0.28mmol), the mixture of cesium carbonate (150mg, 0.46mmol) and acetonitrile (8mL) is heated to 60 ℃ of reactions 20 minutes, then add 4-a (67mg, acetonitrile 0.14mmol) (3mL) solution, reaction solution continues to stir 16 hours in 60 ℃, is cooled to room temperature, filter, concentrating under reduced pressure filtrate, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=4: 1) obtain compound 4 (56mg, productive rate: 65%).LC-MS(ESI)：m/z＝595[M+H] +.
Compound T-04's is synthetic
By compound 4 (50mg, 0.084mmol) be dissolved in methyl alcohol (5mL), add aqueous sodium hydroxide solution (4M, 0.5mL, 2mmol), mixture was in room temperature reaction 16 hours, methyl alcohol is removed in underpressure distillation, resistates water (5mL) dilution, and 1M hydrochloric acid acid for adjusting pH is to 2-3, ethyl acetate extraction (20mL * 3), the organic phase merging successively water (20mL) and saturated aqueous common salt (20mL) is washed, anhydrous sodium sulfate drying, filtration, filtrate decompression concentrates to obtain compound T-04 (42mg, productive rate: 86%).LC-MS(ESI)：m/z＝581[M+H] +.1HNMR(500MHz，CDCl 3)δ：7.38(dd，J＝2.0Hz，8.5Hz，1H)，7.32(d，J＝8.0Hz，1H)，7.03-7.06(m，2H)，6.61(s，2H)，6.48(dd，J＝2.0Hz，8.0Hz，1H)，6.46(d，J＝2.0Hz，1H)，4.97(s，2H)，4.76(t，J＝9.0Hz，1H)，4.28(dd，J＝6.0Hz，9.0Hz，1H)，4.12(t，J＝6.0Hz，2H)，3.79-3.83(m，1H)，3.65-3.69(m，1H)，3.27(t，J＝8.0Hz，2H)，2.96(s，3H)，2.80(dd，J＝5.0Hz，16.5Hz，1H)，2.61(dd，J＝9.0Hz，17.0Hz，1H)，2.31-2.37(m，2H)，1.93(s，6H)，0.69-0.73(m，2H)，0.59-0.62(m，2H).
Compound T-05's is synthetic
Synthetic route
Figure BSA00000743196200301
Compound 5-c's is synthetic
By compound 1-e (1.6g, 8.1mmol), cyclobutyl bromine (1.0g, 7.4mmol), the mixture of cesium carbonate (2.9g, 8.9mmol) and DMF (10mL) is heated to 85 ℃ of reactions 20 hours under nitrogen protection.Be chilled to room temperature, reaction solution is poured in water (20mL), ethyl acetate extraction (30mL * 3), the organic phase anhydrous sodium sulfate drying merging, filter, concentrating under reduced pressure filtrate, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=10: 1) obtain compound 5-c (1.0g, productive rate: 55%).LC-MS(ESI)：m/z＝281[M+H] +.
Compound 5-b's is synthetic
Under ice-water bath, in tetrahydrofuran (THF) (10mL) solution of compound 5-c (300mg, 1.07mmol), add sodium borohydride (122mg, 3.21mmol), mixture slowly rises to room temperature, stirs and disappears to raw material for 5 hours.Reaction solution is poured in water (10mL), ethyl acetate (30mL * 3) extraction, the organic phase anhydrous sodium sulfate drying of merging, filter, concentrating under reduced pressure filtrate obtain compound 5-b (240mg, productive rate: 79%), thick not purified next step reaction of direct input of product.LC-MS(ESI)：m/z＝283[M+H] +.
Compound 5-a's is synthetic
In methylene dichloride (8mL) solution of compound 5-b (140mg, 0.5mmol), add sulfur oxychloride (0.24g, 20mmol), mixture was in stirring at room 24 hours.Concentrating under reduced pressure reaction solution obtains compound 5-a (130mg, 87%), and thick product directly drops into next step reaction.
Synthesizing of compound 5
By compound 5-a (130mg, 0.46mmol), 1-f (115mg, 0.55mmol), cesium carbonate (300mg, 0.92mmol) and N, the mixture of dinethylformamide (6mL) is heated to 90 ℃ of reactions 20 hours, is chilled to after room temperature, and reaction solution is poured in water (10mL), ethyl acetate (30mL * 3) extraction, the organic phase anhydrous sodium sulfate drying merging, filters concentrating under reduced pressure filtrate, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=5: 1) obtain compound 5 (100mg, productive rate: 49%).LC-MS(ESI)：m/z＝473[M+H] +.
Compound T-05's is synthetic
By compound 5 (50mg, 0.11mmol) be dissolved in tetrahydrofuran (THF) (3mL), in the mixed solvent of methyl alcohol (1mL) and water (0.5mL), add aqueous sodium hydroxide solution (2M, 0.25mL, 0.5mmol), mixture was in room temperature reaction 4 hours, and methyl alcohol is removed in underpressure distillation, resistates water (5mL) dilution, 1M hydrochloric acid acid for adjusting pH is to 2-3, ethyl acetate extraction (20mL * 3), and the organic phase of merging successively water (20mL) and saturated aqueous common salt (20mL) is washed, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates to obtain compound T-05 (23mg, productive rate: 47%).LC-MS(ESI)：m/z＝459[M+H] +. 1HNMR(500MHz，CDCl 3)δ：7.41(t，J＝7.5Hz，1H)，7.36(d，J＝7.5Hz，1H)，7.17(s，1H)，7.08(d，J＝7.5Hz，1H)，7.04(d，J＝8.5Hz，1H)，6.57(s，2H)，6.49(dd，J＝2.5Hz，7.5Hz，1H)，6.45(d，J＝2.0Hz，1H)，5.05(s，2H)，4.76(t，J＝9.0Hz，1H)，4.62-4.68(m，1H)，4.28(dd，J＝6.0Hz，8.5Hz，1H)，3.77-3.83(m，1H)，2.19(dd，J＝4.5Hz，17.0Hz，1H)，2.59(dd，J＝9.0Hz，16.5Hz，1H)，2.43-2.49(m，2H)，2.10-2.23(m，2H)，1.98(s，6H)，1.83-1.89(m，1H)，1.64-1.73(m，1H).
Compound T-06's is synthetic
Synthetic route
Compound 6-g's is synthetic
To 5-methyl isophthalic acid, 3-dihydroxy-benzene (2.48g, in methylene dichloride 20.0mmol) (50mL) and acetic acid (10mL) solution, drip methylene dichloride (6mL) solution of bromine (3.2g, 20.0mmol), mixture disappears in stirring at room 1 hour to raw material.Concentrating under reduced pressure reaction solution, resistates is dissolved in ethyl acetate (50mL), with saturated sodium bicarbonate solution (50mL) washing, separatory.Ethyl acetate for water (50mL * 2) extraction, the organic phase merging successively water (50mL) and saturated aqueous common salt (50mL) is washed, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, resistates is through purification by silica gel column chromatography (sherwood oil/methylene dichloride=4: 1) obtain compound 6-g (2.68g, productive rate: 62%). 1HNMR(500MHz，d 6-DMSO)δ：9.83(s，1H)，9.29(s，1H)，6.24(d，J＝2.5Hz，1H)，6.18(d，J＝2.5Hz，1H)，2.17(s，3H).
Compound 6-f's is synthetic
By compound 6-g (2.02g, 10.0mmol), cesium carbonate (3.25g, 10.0mmol) and N, the mixture of dinethylformamide (20mL) is heated to 60 ℃ of reactions 1 hour, add Compound C (2.92g, 10.0mmol), mixture continues reaction 16 hours in 60 ℃ again.Reaction solution is chilled to after room temperature, pour in water (100mL), ethyl acetate (40mL * 2) extraction, the organic phase merging successively water (50mL) and saturated aqueous common salt (50mL) is washed, anhydrous sodium sulfate drying, filters, and filtrate decompression is concentrated, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=3: 1) obtain compound 6-f (1.36g, productive rate: 42%).LC-MS(ESI)：m/z＝303[M+H] +.
Compound 6-e's is synthetic
By compound 6-f (840mg; 2.6mmol); vinyl-acetic ester (447mg; 5.2mmol); sodium carbonate (165mg; 1.56mmol), two the mixture of [two (cyclooctadiene) iridium chloride)] (35mg, 0.052mmol) and toluene (15mL) is heated to 100 ℃ of reactions 16 hours under nitrogen protection.After concentrating under reduced pressure reaction solution, resistates obtains compound 6-e (2.24g, productive rate: 87%) through purification by silica gel column chromatography (petrol ether/ethyl acetate=5: 1 to 3: 1). 1HNMR(500MHz，CDCl 3)δ：6.58(dd，J＝6.0Hz，14.0Hz，1H)，6.56(d，J＝2.5Hz，1H)，6.40(d，J＝3.0Hz，1H)，4.79(dd，J＝2.0Hz，14.0Hz，1H)，4.47(dd，J＝2.0Hz，6.5Hz，1H)，4.14(t，J＝6.0Hz，2H)，3.45(t，J＝7.5Hz，2H)，2.97(s，3H)，2.36-2.42(m，2H)，2.39(s，3H).
Compound 6-d's is synthetic
To the hexane solution (1M that adds zinc ethyl in 100mL three-necked bottle, 11mL, 11mmol) and methylene dichloride (15mL), be cooled to 0 ℃, slowly drip trifluoroacetic acid (1.14g, 10.0mmol), after 20 minutes, add methylene iodide (2.95g, 11.0mmol), low temperature continues to stir 20 minutes, add compound 6-e (0.6g, 1.7mmol), add rear mixture and slowly rise to stirring at room 16 hours.Add saturated ammonium chloride solution (50mL) cancellation reaction, by ethyl acetate (40mL * 3), extract, the organic phase merging successively water (40mL * 2) and saturated aqueous common salt (40mL * 1) is washed, anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, resistates obtains compound 6-d (410mg, productive rate: 67%) through purification by silica gel column chromatography (petrol ether/ethyl acetate=4: 1 to 2: 1).LC-MS(ESI)：m/z＝363[M+H] +.
Compound 6-c's is synthetic
By compound 6-d (181mg; 0.5mmol); 3-formylphenylboronic acid (90mg; 0.6mmol); two (tri-tert phosphorus) palladium (25mg; 0.05mmol), the mixture of potassiumphosphate (318g, 1.5mmol) and toluene (10mL) is heated to 80 ℃ of reactions 16 hours under nitrogen atmosphere.Reaction solution is cooled to room temperature, filters, and concentrating under reduced pressure filtrate, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=2: 1) obtain compound 6-c (40mg, productive rate: 20%).LC-MS(ESI)：m/z＝389[M+H] +.
Compound 6-b's is synthetic
In tetrahydrofuran (THF) (10mL) solution of compound 6-c (40mg, 0.1mmol), add sodium borohydride (20mg, 0.5mmol), mixture disappears in stirring at room 1 hour to raw material.Concentrating under reduced pressure reaction solution, in resistates, add dilute hydrochloric acid (1M, 20mL), ethyl acetate (30mL * 3) extraction, the organic phase of merging is used saturated sodium bicarbonate solution (20mL) successively, water (20mL) and saturated aqueous common salt (20mL) are washed, anhydrous sodium sulfate drying, filters, and filtrate decompression concentrates to obtain compound 6-b (40mg, productive rate: 100%), thick product is not purified is directly used in next step reaction.
Compound 6-a's is synthetic
In methylene dichloride (5mL) solution of compound 6-b (40mg, 0.1mmol), add sulfur oxychloride (1mL), mixture disappears in stirring at room 3 hours to raw material.Concentrating under reduced pressure reaction solution obtains compound 6-a (41mg, productive rate: 100%), thick product is directly used in next step reaction.
Synthesizing of compound 6
To compound 1-f (42mg, 0.2mmol), cesium carbonate (65mg, 0.2mmol) and in the mixture of acetonitrile (4mL) add 6-a (41mg, acetonitrile 0.1mmol) (2mL) solution, mixture is heated to 60 ℃ of reactions 16 hours, concentrating under reduced pressure reaction solution, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=2: 1) obtain compound 6 (13mg, productive rate: 21%).LC-MS(ESI)：m/z＝615[M+H] +.
Compound T-06's is synthetic
By compound 6 (12mg, 0.02mmol) be dissolved in methyl alcohol (5mL), add aqueous sodium hydroxide solution (4M, 0.5mL, 2mmol), mixture was in room temperature reaction 16 hours, methyl alcohol is removed in underpressure distillation, resistates water (5mL) dilution, and 1M hydrochloric acid acid for adjusting pH is to 2-3, ethyl acetate extraction (20mL * 3), the organic phase merging successively water (20mL) and saturated aqueous common salt (20mL) is washed, anhydrous sodium sulfate drying, filtration, filtrate decompression concentrates to obtain compound T-06 (10mg, productive rate: 83%).LC-MS(ESI)：m/z＝601[M+H] +. 1HNMR(500MHz，CDCl3)δ：7.38-7.45(m，2H)，7.24(s，1H)，7.13(d，J＝8.0Hz，1H)，7.06(d，J＝8.5Hz，1H)，6.84(s，1H)，6.48(d，J＝8.5Hz，1H)，6.45(s，1H)，5.05(d，J＝2.0Hz，2H)，4.76(t，J＝9.0Hz，1H)，4.30(dd，J＝6.0Hz，9.0Hz，1H)，3.97(t，J＝6.0Hz，2H)，3.79-3.83(m，2H)，2.79(dd，J＝5.5Hz，16.5Hz，1H)，2.67-2.72(m，2H)，2.60-2.65(m，1H)，2.63(s，3H)，2.16(s，3H)，2.02-2.08(m，2H)，0.83-0.92(m，4H).
Compound T-07's is synthetic
Synthetic route
Figure BSA00000743196200351
Compound 7-e's is synthetic
By mono-vinyl glycol ether (2.20g, 25mmoL), triethylamine (5.05g, 50mmoL) and DMAP (305mg, methylene dichloride 2.5mmoL) (100mL) solution is cooled to 0 ℃, adds p-methyl benzene sulfonic chloride (5.23g, 27.5mmoL).Finish, rise to stirring at room reaction 24 hours.Concentrating under reduced pressure reaction solution, residue is through purification by silica gel column chromatography (petrol ether/ethyl acetate=5: 1) obtain compound 7-e (5.30g, productive rate: 88%).
Compound 7-d's is synthetic
In 100mL three-necked bottle, add zinc ethyl (1M, 26mL, 26mmol) and methylene dichloride (30mL), be cooled to 0 ℃, slowly drip trifluoroacetic acid (2.84g, 25mmol), after 20 minutes, add methylene iodide (7.27g, 27mmol), finish, low temperature continues to stir 20 minutes, adds compound 7-e (2.42g, 10mmol), mixture slowly rises to stirring at room 16 hours.Add saturated ammonium chloride solution (50mL) cancellation reaction, ethyl acetate extraction (40mL * 3), the organic phase merging successively water (40mL * 2) and saturated aqueous common salt (40mL * 1) is washed, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, and resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=4: 1) obtain compound 7-d (1.84g, productive rate: 72%).1HNMR(400MHz，CDCl3)：δ7.79(d，J＝8.0Hz，2H)，7.34(d，J＝8.0Hz，2H)，4.15(t，J＝5.2Hz，2H)，3.68(t，J＝5.2Hz，2H)，3.23～3.26(m，1H)，0.47～0.51(m，2H)，0.41～0.45(m，2H).
Compound 7-c's is synthetic
In acetonitrile (20mL) solution of 3-(4-hydroxyl-2,6-3,5-dimethylphenyl)-phenyl aldehyde (452mg, 2.0mmoL), add compound 7-d (564mg, 2.2mmoL) and cesium carbonate (1.62g, 5.0mmoL).At 65 ℃, react 16 hours.Concentrating under reduced pressure reaction solution, residue through purification by silica gel column chromatography (petrol ether/ethyl acetate=3: 1) obtain compound 7-c (140mg, productive rate: 22%) .LC-MS (ESI): m/z=311[M+H]+.
Compound 7-b's is synthetic:
In tetrahydrofuran (THF) (10mL) solution of compound 7-c (120mg, 0.4mmoL), in 0C, add sodium borohydride (38mg, 1.0mmoL), reactant stirs 2 hours at 0 ℃.The hydrochloric acid cancellation reaction that adds 20 milliliters of 1M, ethyl acetate (40mL * 3) extraction.Organic layer uses saturated sodium bicarbonate (10mL) and saturated aqueous common salt (20mL) to wash successively, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, residue is through purification by silica gel column chromatography (petrol ether/ethyl acetate=3: 1) obtain compound 7-b (110mg, productive rate: 91%).LC-MS(ESI)：m/z＝313[M+H]+.
Compound 7-a's is synthetic
Under ice-water bath, to compound 7-b (110mg, 0.35mmol) and carbon tetrabromide (234mg, in dry methylene chloride 0.7mmoL) (5mL) solution, slowly drip triphenyl phosphorus (184mg, methylene dichloride 0.7mmoL) (5mL) solution, mixture slowly rises to stirring at room 3 hours.Concentrating under reduced pressure reaction solution, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=3: 1) obtain compound 7-a (100mg, productive rate: 76%).
Synthesizing of compound 7
By compound 1-f (55mg, 0.27mmol), cesium carbonate (263mg, 0.81mmol) and the mixture of acetonitrile (10mL) be heated to 65 ℃ reaction 20 minutes, add compound 7 (110mg, 0.27mmol), in 65 ℃, continue to stir 16 hours, concentrating under reduced pressure reaction solution, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=3: 1) obtain compound 7 (110mg, productive rate: 81%).LC-MS(ESI)：m/z＝503[M+H]+.
Compound T-07's is synthetic
Compound 7 (100mg, 0.2mmoL) is dissolved in methyl alcohol (5mL), adds aqueous sodium hydroxide solution (4M, 0.5mL, 2mmol), mixture was in room temperature reaction 16 hours.Decompression is revolved except methyl alcohol, resistates water (5mL) dilution, 1N hydrochloric acid acid for adjusting pH is to 2-3, ethyl acetate extraction (20mL * 3), the organic phase merging is water (20mL) and saturated aqueous common salt 20mL successively) to wash, anhydrous sodium sulfate drying, filters, filtrate decompression concentrates to obtain compound T-07 (85mg, productive rate: 81%).LC-MS(ESI)：m/z＝489[M+H]+。1HNMR(400MHz，CDCl3)δ：7.36-7.43(m，2H)，7.16(s，1H)，7.04～7.09(m，2H)，6.67(s，2H)，6.46～6.51(m，2H)，5.06(s，2H)，4.76(t，J＝6.0Hz，2H)，4.26～4.30(m，1H)，4.12(t J＝6.0Hz，2H)，3.84(t，J＝6.0Hz，2H)，3.76-3.82(m，2H)，3.39～3.44(m，1H)，2.81(dd，J＝5.6Hz，16.8Hz，1H)，2.61(dd，J＝9.2Hz，16.8Hz，1H)，1.97(s，6H)，0.62～0.65(m，2H)，0.45～0.52(m，2H).
Synthesizing of several intermediates
1. compd A is synthetic
Figure BSA00000743196200371
Synthesizing of compd A-2
To hexalin (2.0g, in methylene dichloride 20.0mmol) (20mL) solution, add four acetic acid two rhodium (176mg, 0.4mmol), mixture slowly drips ethyl diazoacetate (2.28g after 3 minutes in stirring at room, methylene dichloride 20.0mmol) (5mL) solution, the mixture obtaining disappears in stirring at room 1 hour to raw material.Normal pressure concentration of reaction solution, resistates is through purification by silica gel column chromatography (petrol ether/ethyl acetate=15: 1) obtain compd A-2 (2.24g, productive rate: 60%).
Synthesizing of compd A-1
Under ice-water bath, to tetrahydrofuran (THF) (5mL) solution that is added dropwise to compd A-2 (1.86g, 10mmol) in tetrahydrofuran (THF) (15mL) solution of Lithium Aluminium Hydride (1.1g, 30mmol), add rear mixture in stirring at room 30 minutes, be then heated to 50 ℃ of reactions 2 hours.Question response liquid cooling is to room temperature, add saturated ammonium chloride (10mL) solution cancellation reaction, ethyl acetate for reaction solution (20mL * 3) extraction, the saturated aqueous common salt for organic phase (20mL) merging is washed, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates to obtain compd A-1 (1.2g, productive rate: 83%).LC-MS(ESI)：m/z＝145[M+H] +.
Synthesizing of compd A
By compd A-1 (1.2g, 8.3mmol) and pyridine (2.6g, methylene dichloride 33.2mmol) (30mL) solution stirs 20 minutes under ice-water bath, in reaction solution, add Tosyl chloride (2.4g, methylene dichloride 12.5mmol) (10mL) solution, the mixture obtaining was in stirring at room 16 hours, concentrating under reduced pressure reaction solution, resistates obtains compd A (1.7g, productive rate: 70%) through purification by silica gel column chromatography (petrol ether/ethyl acetate=15: 1 to 10: 1).LC-MS(ESI)：m/z＝321[M+H] +.
2. compd B is synthetic
Figure BSA00000743196200381
Synthesizing of compd B-2
To cyclopentanol (420mg, in methylene dichloride 4.9mmol) (20mL) solution, add four acetic acid two rhodium (44mg, 0.1mmol), mixture slowly drips ethyl diazoacetate (710mg after 3 minutes in stirring at room, methylene dichloride 5.0mmol) (5mL) solution, the mixture obtaining disappears in stirring at room 1 hour to raw material.Concentrating under reduced pressure reaction solution, resistates through purification by silica gel column chromatography (petrol ether/ethyl acetate=15:
1) obtain compd B-2 (500mg, productive rate: 50%). 1HNMR(500MHz，CDCl 3)δ：3.94-3.97(m，1H)，3.89(s，2H)，1.66-1.72(m，4H)，1.46-1.51(m，4H)，1.44(s，9H).
Synthesizing of compd B-1
Under ice-water bath, to tetrahydrofuran (THF) (5mL) solution that adds compd B-2 (1.4g, 0.86mmol) in tetrahydrofuran (THF) (15mL) solution of Lithium Aluminium Hydride (0.86g, 23.2mmol), add rear mixture in stirring at room 30 minutes, be heated to 50 ℃ of reactions 2 hours.Question response liquid cooling is to room temperature, add saturated ammonium chloride (10mL) solution cancellation reaction, ethyl acetate for reaction solution (20mL * 3) extraction, the saturated aqueous common salt for organic phase (20mL) merging is washed, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates to obtain compd B-1 (0.76g, productive rate: 83%).
Synthesizing of compd B
Under ice-water bath, to compd B-1 (260mg, 2.0mmol) and pyridine (474mg, in methylene dichloride 6.0mmol) (15mL) solution, add Tosyl chloride (456mg in batches, 2.4mmol), mixture is in stirring at room 16 hours, concentrating under reduced pressure reaction solution, resistates obtains compd B (398mg, productive rate: 70%) through purification by silica gel column chromatography (petrol ether/ethyl acetate=15: 1 to 10: 1).
Synthesizing of Compound C
Figure BSA00000743196200391
Under ice-water bath, to 3-methylsulfonyl 1-propyl alcohol (5.3g, 50mmol) and triethylamine (10.5mL, in toluene 75mmol) (110mL) solution, add Tosyl chloride (14.3g, toluene 75mmol) (50mL) solution, mixture is in stirring at room 16 hours, concentrating under reduced pressure reaction solution, resistates obtains Compound C (11g, productive rate: 89%) through purification by silica gel column chromatography (petrol ether/ethyl acetate=8: 1 to 3: 1).LC-MS(ESI)：m/z＝261[M+H] +.
Effect embodiment
GPR40 agonist in-vitro screening
1. cell strain: CHO-K1/GPR40
2. reagent consumptive material: DMEM/F12 substratum (containing 10%FBS, 200 μ g/ml G418);
Fluo-4NW Calcium detection kit (Invitrogen, F36205);
384-well plate，black，clear bottom(Corning，3712)；
384-well plate，clear，v-bottom(Costar，3657)；
Detecting instrument: FLIPR tETRA(Molecular Devices).
3. experimental procedure:
3.1CHO-K1/GPR40 kind plate
Digestion process CHO-K1/GPR40 cell, is diluted to 125000 cell/ml.In 384 orifice plates, add 50 μ l/ holes.37 ℃ of incubated overnight.
3.2 reagent are prepared
Fluo-4NW Calcium detection kit comprises component A:Fluo-4NW dye mix (totally 10 bottles); B component: probenecid, water-soluble (Probenecid, water soluble) (1 pipe); Detect damping fluid (assay buffer): 1 * HBSS balanced salt solution (20mM HEPES).
1) preparation 250mM probenecid: add 1ml to detect damping fluid in B component.Fully mix, dissolve, be stored in-20 ℃.
2) preparation Fluo-4 sample-loading buffer: add 10ml to detect damping fluid and 100 μ l probenecids in every bottle of Fluo-4NW dye mix, vortex, fully dissolves.
3.3 compound preparations
With detection damping fluid (assay buffer), prepare positive compound (linolic acid, linoleic acid) and the testing compound of 3 times of final concentrations
3.4 loading
From incubator, take out Tissue Culture Plate, it is 90% left and right that cell converges rate, removes after substratum, adds the Fluo-4 sample-loading buffer in 25 μ l/ holes.Hatch after 30min for 37 ℃, room temperature continues to hatch 30min.
3.5 calcium current signal detection
At FLIPR tETRAon (Molecular Devices), carry out calcium current signal detection.
Excitation LED(nm)：470-495；
Emission Filter(nm)：515-575；
Compound concentration: 3 *final concentration;
Compound application of sample volume: 12.5 μ l.
Table one is that selected compound is for the EC of GPR40 cytoactive 50value:
Table one
Compound number EC 50(μM) Compound number EC 50(μM)
T-01 25.97 T-02 15.94
T-03 13.01 T-04 1.12
T-05 8.83 T-06 7.57
T-07 2.26 Linolic acid 10.22

Claims (15)

1. suc as formula the Dihydrobenzofuranes analog derivative shown in I, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug;
Figure FSA00000743196100011
Wherein:
R 1be selected from hydroxyl or amino, wherein said hydroxyl or amino can further replacement by one or more substituting groups that are selected from alkyl, cycloalkyl or alkylsulfonyl;
R 2, R 3and R 4be selected from independently of one another one or more in hydrogen atom, D atom, halogen, hydroxyl, cyano group, carboxyl, alkylsulfonyl, alkyl, alkoxyl group, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl and heteroaryl;
R 2, R 3and R 4in have a substituting group that is selected from cycloalkyloxy or contains cycloalkyloxy at least;
M is 0,1,2, or 3;
N is 0,1,2,3 or 4;
P is 0,1,2,3,4 or 5;
When m is 2 or 3, R 2be same to each other or different to each other;
When n is 2,3 or 4 o'clock, R 3be same to each other or different to each other;
When p is 2,3,4 or 5 o'clock, R 4be same to each other or different to each other.
2. Dihydrobenzofuranes analog derivative as claimed in claim 1, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug, it is characterized in that: in the compound shown in above-mentioned general formula (I)
R 1be selected from hydroxyl;
R 2, R 3and R 4be selected from independently of one another one or more in hydrogen atom, halogen, hydroxyl, alkyl and alkoxyl group;
R 2, R 3and R 4in have a substituting group that is selected from alkoxyl group or contains alkoxyl group at least;
M is 0,1,2 or 3;
N is 0,1,2,3 or 4;
P is 0,1,2,3,4 or 5.
3. Dihydrobenzofuranes analog derivative as claimed in claim 1 or 2, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug, is characterized in that: work as R 2, R 3and R 4while being selected from alkyl independently of one another, described alkyl is C 1～C 3alkyl;
And/or, work as R 2, R 3and R 4while being selected from alkoxyl group independently of one another, described alkoxyl group is C 3～C 6cycloalkyloxy or C 1～C 3straight or branched alkoxyl group.
4. Dihydrobenzofuranes analog derivative as claimed in claim 3, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug, is characterized in that: work as R 2, R 3and R 4be selected from independently of one another C 3～C 6during cycloalkyloxy, described C 3～C 6cycloalkanes oxygen is cyclopropane oxygen base, pentamethylene oxygen base or tetramethylene oxygen base.
5. Dihydrobenzofuranes analog derivative as claimed in claim 3, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug, is characterized in that: work as R 2, R 3and R 4be selected from independently of one another C 1～C 3during straight or branched alkoxyl group, described C 1～C 3straight or branched alkoxyl group is by C 3～C 6cycloalkyloxy or C 1～C 3the C that alkyl sulphonyl replaces 1～C 3straight or branched alkoxyl group.
6. Dihydrobenzofuranes analog derivative as claimed in claim 1, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug, it is characterized in that: described Dihydrobenzofuranes analog derivative I is as shown in the formula the general formula compound shown in II:
Wherein, R 1, R 2and R 3definition all as described in claim 1～5 any one.
7. Dihydrobenzofuranes analog derivative as claimed in claim 6, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug, is characterized in that: in Compound I I, and R 1for hydroxyl, R 2for hydrogen, halogen or C 3～C 6cycloalkyloxy, R 3for C 3～C 6cycloalkyloxy; R 4aand R 4bbe independently C 1～C 3alkyl or C 3～C 6cycloalkyloxy, R 4cfor C 4～C 5the C of cycloalkyl or replacement 1～C 3alkyl, the C of replacement 1～C 3substituting group in alkyl is C 3～C 6cycloalkyloxy or C 1～C 3alkyl sulphonyl, R 4dfor hydrogen or halogen.
8. Dihydrobenzofuranes analog derivative as claimed in claim 7, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug, is characterized in that: in Compound I I, and R 2during for halogen, described halogen is fluorine, chlorine, bromine or iodine;
And/or, in Compound I I, R 4dduring for hydrogen or halogen, described halogen is fluorine, chlorine, bromine or iodine.
9. Dihydrobenzofuranes analog derivative as claimed in claim 6, tautomer, racemic modification, enantiomer, diastereomer, its hydrate, or its pharmacy acceptable salt or its prodrug, it is characterized in that: described Dihydrobenzofuranes analog derivative II is arbitrary compound as follows:
Figure FSA00000743196100032
Figure FSA00000743196100041
10. the preparation method of the Dihydrobenzofuranes analog derivative as described in claim 1～9 any one, it is following either method:
Method one: work as R 1for being selected from alkyl, cycloalkyl or hydroxyl that alkylsulfonyl replaced or when amino, Compound I-I and Compound I-D being carried out to nucleophilic substitution reaction as follows by one or more;
Figure FSA00000743196100051
Method two: as the R of final Compound I 1for hydroxyl or when amino, by Compound I (R wherein 1for by the one or more hydroxyl that substituting group replaced or amino that is selected from alkyl, cycloalkyl or alkylsulfonyl) reaction that is hydrolyzed;
In method one and two, other each groups and alphabetical definition are all with described in claim 1～9 any one.
11. arbitrary midbody compounds as follows;
Figure FSA00000743196100053
Figure FSA00000743196100061
Figure FSA00000743196100071
12. 1 kinds of pharmaceutical compositions, it contains Dihydrobenzofuranes analog derivative, its tautomer, racemic modification, enantiomer, diastereomer, its hydrate described in claim 1～9 any one for the treatment of effective dose, its pharmacy acceptable salt or its prodrug, with and pharmaceutically acceptable carrier and/or thinner.
13. Dihydrobenzofuranes analog derivative, its tautomer, racemic modification, enantiomer, diastereomer, its hydrates as described in claim 1～9 any one, its pharmacy acceptable salt or its prodrug, or the application of the pharmaceutical composition described in claim 12 in preparing g protein coupled receptor 40 agonists.
14. Dihydrobenzofuranes analog derivative, its tautomer, racemic modification, enantiomer, diastereomer, its hydrates as described in claim 1～9 any one, its pharmacy acceptable salt or its prodrug, or the purposes of the pharmaceutical composition described in claim 12 in treating and/or preventing the medicine of metabolic disorder.
15. Dihydrobenzofuranes analog derivatives as claimed in claim 14, its tautomer, racemic modification, enantiomer, diastereomer, its hydrate, its pharmacy acceptable salt or its prodrug, is characterized in that: described metabolic disorder is I type or type ii diabetes, insulin resistance, glucose metabolism illness, metabolic acidosis or ketoacidosis, diabetic neuropathy, diabetic retinopathy, obesity, hypoglycemia, hypertension, hyperinsulinemia, insulin allergy disease or nesidioblastoma.
CN201210227590.2A 2012-07-03 2012-07-03 Dihydrobenzofuran derivative as well as preparation method, intermediate and application thereof Pending CN103524466A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014187343A1 (en) * 2013-05-22 2014-11-27 四川海思科制药有限公司 Benzofuran derivative, preparation method therefor, and medical application thereof
CN104262330A (en) * 2014-08-27 2015-01-07 广东东阳光药业有限公司 Novel carbamide substituted biphenyl compounds, compositions and applications thereof
CN105418563A (en) * 2015-12-28 2016-03-23 山东大学 TAK-875 analog, and preparation method and application thereof
WO2023134712A1 (en) * 2022-01-14 2023-07-20 Rezubio Pharmaceuticals Co., Ltd Antidiabetic compounds and compositions

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014187343A1 (en) * 2013-05-22 2014-11-27 四川海思科制药有限公司 Benzofuran derivative, preparation method therefor, and medical application thereof
CN104262330A (en) * 2014-08-27 2015-01-07 广东东阳光药业有限公司 Novel carbamide substituted biphenyl compounds, compositions and applications thereof
CN105418563A (en) * 2015-12-28 2016-03-23 山东大学 TAK-875 analog, and preparation method and application thereof
CN105418563B (en) * 2015-12-28 2017-11-10 山东大学 Analogs of TAK 875 and preparation method and application
WO2023134712A1 (en) * 2022-01-14 2023-07-20 Rezubio Pharmaceuticals Co., Ltd Antidiabetic compounds and compositions

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