CN103030646A

CN103030646A - Benzodioxane derivative, and preparation method thereof and application of derivative in medicines

Info

Publication number: CN103030646A
Application number: CN2012103009827A
Authority: CN
Inventors: 吕贺军; 董庆; 费洪博; 蒋宏健; 宋鹏
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Ruishi biomedical Co., Ltd
Priority date: 2011-09-29
Filing date: 2012-08-22
Publication date: 2013-04-10
Anticipated expiration: 2032-08-22
Also published as: CN103030646B

Abstract

The invention relates to a benzodioxane derivative, a preparation method thereof and application of the derivative in medicines. Specifically, the invention relates to a novel benzodioxane derivative shown as a formula (I), medial salt thereof or a medicine composition containing the derivative, and a preparation method of the derivative. The invention further relates to a use of the benzodioxane derivative and the medial salt thereof or the medicine composition containing the derivative in preparing therapeutic agent, especially GPR 40 agonist, and a drug for treating the diseases such as diabetes, metabolic disorders and the like, wherein each substituent group in the formula (I) is as defined in the description.

Description

Benzodioxane analog derivative, its preparation method and in pharmaceutically application

Technical field

The present invention relates to a kind of new benzodioxane analog derivative and pharmaceutically useful salt thereof or contain its pharmaceutical composition, and preparation method thereof.The pharmaceutical composition that the invention further relates to described benzodioxane analog derivative and pharmaceutically useful salt thereof or contain it is at preparation therapeutical agent, particularly GPR40 agonist, and the purposes in the medicine of the diseases such as preparation treatment diabetes and metabolic disorder.

Background technology

Type ii diabetes claims again non insulin dependent diabetes or maturity-onset diabetes, main manifestations be in the patient amount of insulin secretion very little or body can not effectively utilize Regular Insulin (insulin resistant).The whole world has diabetic subject about 1.85 hundred million at present, and wherein the type ii diabetes patient accounts for 90 ~ 95% of diabetic subject's sum, rises with 6% rate of increase continuation simultaneously.Among the crowds of China more than 20 years old in 2010, the overall morbidity of type ii diabetes has reached 9.7%.

At present, the methods for the treatment of of type ii diabetes comprises: Regular Insulin succagoga such as sulfonylurea, impel pancreatic beta cell to generate more Regular Insulin; Hypoglycemic agent such as N1,N1-Dimethylbiguanide class reduce the formation of glucose in the liver; Oxide compound enzyme body proliferator activated receptor γ (PPAR-γ) activator such as thiazolidinediones improve insulin sensitivity, strengthen the Purificatiou of Regular Insulin; Alpha-glucosidase inhibitor disturbs the production of glucose in the enteron aisle.But the methods for the treatment of of present has certain defective.For example sulfonylurea and injection of insulin agent may increase with hypoglycemic episodes and body weight.In addition, patient's body often loses sulfonylureas and replys in the course of time, produces tolerance.N1,N1-Dimethylbiguanide class and alpha-glucosidase inhibitor usually can cause gastrointestinal problems, and the PPAR-gamma agonist causes that easily body weight increases and oedema.

For the research well afoot in a plurality of fields, in the hope of bring more effective novel ofhypoglycemic medicine for market.For example, it is too much that the inventor is exploring the production of minimizing liver glucose at present, strengthen the conduction that Regular Insulin causes this signal path of glucose absorption, improve the insulin secretion (GSIS) that glucose stimulates in the pancreatic beta cell, for fat and metabolism of fat, accumulate the research of the aspect such as unusual.

Free fatty acids (FFA) is in metabolic many aspects performance keying action, is included under the fasting state to strengthen " safety fuse " that Regular Insulin is replied glucose as pancreatic beta cell, and as the starting point of lipid synthesis.At first, GPR40 finds from human genome with the form of an orphan receptor first.GPR40 is high expression level in the clone of pancreatic beta cell and excreting insulin.GPR40 claims again Fatty Acid Receptors 1 (FFAR1), is a member of g protein coupled receptor (" GPCRs ") gene superfamily.GPCRs is the membranin that a class has seven membrane spaning domains, can produce different kinds of molecules to reply, thereby the signal transduction pathway in the activating cells, most important to realizing multiple physiological function.The activation of GPR40 is related to regulates intracellular signal Protein G q family, and attends by with inducing calcium ion level to raise.GPR40 is first lipid acid cell surface receptor of identifying, can be in conjunction with such as Palmiticacid, and oleic acid, stearic acid, the most general lipid acid in the blood plasma such as linoleic acid plus linolenic acid.GPR40 also can think " nutrition sensing " acceptor, brings into play a plurality of tissue dependence effects, may affect total glucose utilization and/or lipid fat metabolism therebetween.For example, long-chain free fatty acids activates by GPR40, amplifies GSIS in the pancreatic beta cell.

GPR40 modulator performance incretin is used for promoting GSIS, also can unite use by multiple treatment diabetes medicament in addition.Based on more than, the GPR40 agonist can be treated diabetes and relevant indication, especially type ii diabetes, obesity, glucose intolerance, insulin resistant, metabolism syndrome X, hyperlipidemia, hypercholesterolemia, atherosclerosis, nerve degenerative diseases (such as Alzheimer's disease), and other indications such as apoplexy.Take GPR40 as potential treatment target spot, the compound of finding and transform GPR40 has very important researching value and application prospect.

The patent application of a series of GPR40 agonist is disclosed at present, comprising WO2005087710, WO2007106469, WO2004106276 and WO2010143733 etc.

Although disclose the GPR40 agonist of the diseases such as a series for the treatment of diabetes and metabolic disease at present, but still need exploitation new have better drug effect, a compound more the long half-lift, through continuous effort, the compound that the present invention's design has the structure shown in the general formula (I), and find that the compound with this class formation shows excellent effect and effect.

Summary of the invention

The object of the present invention is to provide the compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof.

Wherein:

R ¹And R ²Be selected from independently of one another hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷,-NR ⁷R ⁸,-OC (O) NR ⁷R ⁸,-NHC (O) NR ⁷R ⁸Or-S (O) _mR ⁷, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, carboxyl, cyano group, nitro, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷,-NR ⁷R ⁸,-OC (O) NR ⁷R ⁸,-NHC (O) NR ⁷R ⁸Or-S (O) _mR ⁷Substituting group replace;

Perhaps, R ¹And R ²Condense into a cycloalkyl or heterocyclic radical with phenyl, wherein said cycloalkyl or heterocyclic radical are optional further by one or more R that are selected from ⁶Substituting group replace;

R ³, R ⁴And R ⁵Be selected from independently of one another hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷,-NR ⁷R ⁸,-OC (O) NR ⁷R ⁸,-NHC (O) NR ⁷R ⁸Or-S (O) _mR ⁷, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷,-NR ⁷R ⁸,-OC (O) NR ⁷R ⁸,-NHC (O) NR ⁷R ⁸Or-S (O) _mR ⁷Substituting group replace;

Perhaps, R ³, R ⁴And R ⁵Both of middle arbitrary neighborhood are such as R ³And R ⁴Perhaps R ⁴And R ⁵, condensing into a cycloalkyl or heterocyclic radical with phenyl, wherein said cycloalkyl or heterocyclic radical are optional further by one or more R that are selected from ⁶Substituting group replace;

R ⁶Be selected from independently of one another halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷,-NR ⁷R ⁸,-OC (O) NR ⁷R ⁸,-NHC (O) NR ⁷R ⁸Or-S (O) _mR ⁷, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷,-NR ⁷R ⁸,-OC (O) NR ⁷R ⁸,-NHC (O) NR ⁷R ⁸Or-S (O) _mR ⁷Substituting group replace;

R ⁷And R ⁸Be selected from independently of one another hydrogen atom, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical or-S (O) _mR ⁹Substituting group replace;

R ⁹Be alkyl; And

M is 0,1 or 2.

In one embodiment of the invention, compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the described compound of general formula (II) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:

Wherein:

Y is C, O, N or S atom;

L is cycloalkyl, heterocyclic radical, aryl or heteroaryl;

R ⁹Be alkyl;

M is 0,1 or 2; And

N is 0,1,2,3 or 4.

In one embodiment of the invention, compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the described compound of general formula (III) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:

Wherein:

L is cycloalkyl, heterocyclic radical, aryl or heteroaryl;

R ⁹Be alkyl;

M is 0,1 or 2; And

N is 0,1,2,3 or 4.

In another embodiment of the present invention, compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the described compound of general formula (IV) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:

Wherein: ring L, R ³~ R ⁵Definition such as general formula (I) described in.

In another embodiment of the present invention, compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the logical described compound of formula V or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:

In another embodiment of the present invention, compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein L is aryl, preferably phenyl.

In another embodiment of the present invention, the compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein:

R ³Be selected from hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or-OR ⁷Substituting group replace;

R ⁴, R ⁵Be hydrogen atom or halogen;

R ⁷Be hydrogen atom or alkyl, wherein said alkyl is optional further by one or more-S (O) _mR ⁹Replace;

R ⁹Be alkyl.

In another embodiment of the present invention, the compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein: R ¹And R ²Be selected from independently of one another hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further to be replaced by one or more groups that are selected from halogen, hydroxyl, carboxylic acid group, cyano group, nitro, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.

In another embodiment of the present invention, the compound shown in a kind of general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt, wherein R ⁶Be alkyl, wherein said alkyl is further by one or more-C (O) OR ⁷Replace R ⁷Be hydrogen atom or alkyl.

Typical compound of the present invention includes, but are not limited to:

Or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof.

The invention further relates to a kind of method for preparing the compound shown in the general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmacologically acceptable salt thereof, the method may further comprise the steps:

With compound (IA) catalysis in the presence of catalyzer under the alkaline condition, with the optional further hydrolysis of the product that obtains, obtain general formula compound (I);

Wherein: X is halogen, is preferably bromine or iodine; R ¹～R ⁵, L definition such as general formula (I) described in.

The invention further relates to a kind of pharmaceutical composition, it contains the compound shown in the general formula (I) for the treatment of significant quantity or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof and pharmaceutically acceptable carrier.

Another aspect of the present invention relates to the compound shown in the general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, or comprises its purposes of pharmaceutical composition in preparation GPR40 agonist.

Another aspect of the present invention relates to the compound shown in the general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, or the pharmaceutical composition that comprises it in the medicine of the disease of preparation treatment diabetes and metabolic syndrome purposes, wherein said diabetes are preferably type ii diabetes.

The invention still further relates to a kind of method for the treatment of the disease of diabetes and metabolic syndrome, the method comprises compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and the pharmaceutically useful salt thereof shown in the general formula (I) of patient treatment significant quantity that needs treatment or comprises its pharmaceutical composition.

Another aspect of the present invention relates to as compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and the pharmaceutically useful salt thereof shown in the general formula (I) of the medicine of the disease for the treatment of diabetes and metabolic syndrome, and wherein said diabetes are preferably type ii diabetes.

Another aspect of the present invention relates to a kind of method of regulating Regular Insulin, and the method comprises compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and the pharmaceutically useful salt thereof shown in the general formula (I) of the effective therapeutic dose of patient of needs treatments.

Another aspect of the present invention relates to as compound or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and the pharmaceutically useful salt thereof shown in the general formula (I) of the medicine of regulating Regular Insulin.

Detailed description of the invention

Unless the phase counter-statement is arranged, otherwise the following term that is used in specification sheets and claims has following implication." alkyl " refers to saturated aliphatic hydrocarbon group, comprises straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom more preferably contains the alkyl of 1 to 6 carbon atom.Non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1, the 1-dimethyl propyl, 1, the 2-dimethyl propyl, 2, the 2-dimethyl propyl, the 1-ethyl propyl, the 2-methyl butyl, the 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-trimethylammonium propyl group, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 2, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, the 2-ethyl-butyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 2, the 3-dimethylbutyl, n-heptyl, 2-methyl hexyl, 3-methyl hexyl, 4-methyl hexyl, 5-methyl hexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, the 2-ethyl pentyl group, the 3-ethyl pentyl group, n-octyl, 2,3-dimethyl hexyl, 2,4-dimethyl hexyl, 2,5-dimethyl hexyl, 2,2-dimethyl hexyl, 3,3-dimethyl hexyl, 4,4-dimethyl hexyl, the 2-ethylhexyl, the 3-ethylhexyl, the 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl group, positive decyl, 3, the 3-diethylhexyl, 2, the 2-diethylhexyl, and various branched chain isomers etc.The low alkyl group that more preferably contains 1 to 6 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1, the 1-dimethyl propyl, 1, the 2-dimethyl propyl, 2, the 2-dimethyl propyl, the 1-ethyl propyl, the 2-methyl butyl, the 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-trimethylammonium propyl group, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 2, the 2-dimethylbutyl, 1,3-dimethylbutyl, the 2-ethyl-butyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 2,3-dimethylbutyl etc.Alkyl can be that replace or unsubstituted, when being substituted, substituting group can be substituted at any spendable tie point, be preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷Or-S (O) _mR ⁸

" alkylidene group " refers to that saturated aliphatic hydrocrbon from two formed groups of hydrogen atom of formal elimination, comprises straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom more preferably contains the alkyl of 1 to 6 carbon atom.The non-limiting example of alkylidene group comprises methylene radical, ethylidene, isopropylidene, 1-methyl propylidene, butylidene, pentylidene, hexylidene, ethylene, trimethylene, hexamethylene etc.Alkylidene group can be that replace or unsubstituted, when being substituted, substituting group can be substituted at any spendable tie point, be preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷Or-S (O) _mR ⁸

" cycloalkyl " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, it comprises 3 to 20 carbon atoms, preferably include 3 to 12 carbon atoms, more preferably cycloalkyl ring comprises 3 to 10 carbon atoms, most preferably cycloalkyl ring comprises 3 to 6 carbon atoms, for example can be 3,4,5,6 yuan of rings.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.The polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring.

" spiro cycloalkyl group " refers to 5 to 20 yuan, shares many cyclic groups of a carbon atom (title spiro atom) between the monocycle, and these can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number that shares spiro atom between ring and the ring spiro cycloalkyl group is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises

" condensed ring alkyl " refers to 5 to 20 yuan, each ring in the system and other rings in the system are shared the many cyclic groups of full carbon of a pair of carbon atom that adjoins, wherein one or more rings can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of condensed ring alkyl comprises

" bridge ring alkyl " refers to 5 to 20 yuan, and any two rings share two not many cyclic groups of full carbon of direct-connected carbon atom, and these can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises

Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring that wherein links together with precursor structure is cycloalkyl, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.Cycloalkyl can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷Or-S (O) _mR ⁸

" heterocyclic radical " refers to saturated or the unsaturated monocycle of part or encircle the cyclic hydrocarbon substituting group more, and it comprises 3 to 20 annular atomses, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _mThe heteroatoms of (wherein m is integer 0 to 2), but do not comprise-O-O-,-O-S-or-loop section of S-S-, all the other annular atomses are carbon.Preferably include 3 to 12 annular atomses, wherein 1～4 is heteroatoms, and more preferably heterocycloalkyl ring comprises 3 to 10 annular atomses, most preferably 5 yuan of rings or 6 yuan of rings.The non-limiting example of monocyclic heterocycles base comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc.Many ring heterocyclic radicals comprise the heterocyclic radical of volution, condensed ring and bridged ring." spiro heterocyclic radical " refers to 5 to 20 yuan, shares many rings heterocyclic group of an atom (title spiro atom) between the monocycle, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _mThe heteroatoms of (wherein m is integer 0 to 2), all the other annular atomses are carbon.These can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.According to the number that shares spiro atom between ring and the ring spiro cycloalkyl group is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises

" fused heterocycle base " refers to 5 to 20 yuan, each ring in the system and other rings in the system are shared many rings heterocyclic group of a pair of atom that adjoins, one or more rings can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _mThe heteroatoms of (wherein m is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle the fused heterocycle alkyl more, is preferably dicyclo or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of fused heterocycle base comprises

" bridge heterocyclic radical " refers to 5 to 14 yuan, any two rings share two not many rings heterocyclic groups of direct-connected atom, these can contain one or more pairs of keys, but the neither one ring has the π-electron system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _mThe heteroatoms of (wherein m is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.Number according to makeup ring can be divided into dicyclo, three rings, Fourth Ring or encircle bridge ring alkyl more, is preferably dicyclo, three ring or Fourth Rings, more elects dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:

Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring that wherein links together with precursor structure is heterocyclic radical, and non-limiting example comprises:

Deng.Heterocyclic radical can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio, oxo ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷Or-S (O) _mR ⁸

" cycloalkylidene " refers to saturated or the unsaturated monocycle of part or encircle cyclic hydrocarbon from two formed groups of hydrogen atom of formal elimination more, it comprises 3 to 20 carbon atoms, preferably include 3 to 12 carbon atoms, more preferably monocycle cycloalkylidene ring comprises 3 to 10 carbon atoms.The non-limiting example of monocycle cycloalkylidene comprises cyclopropylidene, inferior cyclobutyl, cyclopentylidene, cyclohexylidene, inferior suberyl, inferior ring octyl group, 1,2-cyclopropylidene, 1, the inferior cyclobutyl of 3-, Isosorbide-5-Nitrae-cyclohexylidene etc.Many ring cycloalkylidenes comprise the cycloalkylidene of inferior volution, inferior condensed ring and inferior bridged ring.

" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely share and adjoin the right ring of carbon atom) group, many rings (being that it is with the ring of phase adjacency pair carbon atom) group with π-electron system of conjugation, be preferably 6 to 10 yuan, for example phenyl and naphthyl, most preferably phenyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is aryl rings, and non-limiting example comprises:

Aryl can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷Or-S (O) _mR ⁸

" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 to 10 yuan.More preferably heteroaryl is 5 yuan or 6 yuan, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl etc., preferred thienyl, pyridyl, pyrimidyl, isoxazolyl.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring that wherein links together with precursor structure is heteroaryl ring, and non-limiting example comprises:

Heteroaryl can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷Or-S (O) _mR ⁸

" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl), wherein alkyl is described as defined above.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from into alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷Or-S (O) _mR ⁸

Term " thiazolinyl " refers to the as defined above alkyl that is comprised of two carbon atoms and at least one carbon-to-carbon double bond by at least, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.Preferred C _2-10Thiazolinyl, more preferably C _2-6Thiazolinyl, most preferably C _2-4Thiazolinyl.Thiazolinyl can be that replace or non-substituted, when being substituted, substituting group is preferably one or more following groups, its be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) R ⁷,-C (O) OR ⁷,-S (O) _mR ⁷,-NR ⁸R ⁹,-C (O) NR ⁸R ⁹,-NR ⁸C (O) R ⁹,-NR ⁸S (O) _mR ⁹Or-S (O) _mNR ⁸R ⁹

Term " alkynyl " refers at least the as defined above alkyl that is comprised of two carbon atoms and at least one carbon-to-carbon triple bond, such as ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Preferred C _2-10Alkynyl, more preferably C _2-6Alkynyl, most preferably C _2-3Alkynyl.Alkynyl can be that replace or non-substituted, when being substituted, substituting group is preferably one or more following groups, its be independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycle alkoxyl group, cycloalkylthio, heterocycle alkylthio ,-C (O) R ⁷,-C (O) OR ⁷,-S (O) _mR ⁷,-NR ⁸R ⁹,-C (O) NR ⁸R ⁹,-NR ⁸C (O) R ⁹,-NR ⁸S (O) _mR ⁹Or-S (O) _mNR ⁸R ⁹

" haloalkyl " refers to that alkyl is replaced by one or more halogens.

" hydroxyl " refers to-the OH group.

" halogen " refers to fluorine, chlorine, bromine or iodine.

" amino " refers to-NH ₂

" cyano group " refers to-CN.

" nitro " refers to-NO ₂

" benzyl " refers to-CH ₂-phenyl.

" oxo " refers to=O.

" carboxylic acid group " refers to-C (O) OH.

" carboxylic acid ester groups " refers to-C (O) O (alkyl) or (cycloalkyl), and wherein alkyl is described as defined above.

" choose wantonly " or " randomly " mean describe subsequently ground event or environment can but needn't occur, this explanation comprises that this event or environment occur or spot occasion not.For example, " the optional heterocyclic group that is replaced by alkyl " mean alkyl can but must not exist, this explanation comprises the situation that situation that heterocyclic group is replaced by alkyl and heterocyclic group are not replaced by alkyl.

" replacement " refers to the one or more hydrogen atoms in the group, is preferably maximum 5, and more preferably 1～3 hydrogen atom is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group only is in their possible chemical position, those skilled in the art can in the situation of not paying too much effort, determine (by experiment or theoretical) may or impossible replacement.For example, the amino or the hydroxyl that have a free hydrogen may be unsettled when the carbon atom with unsaturated (such as olefinic) key is combined.

" pharmaceutical composition " expression contains on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components physiology/pharmaceutically useful carrier and vehicle for example.The purpose of pharmaceutical composition is the administration that promotes organism, is beneficial to absorption and then the performance biological activity of activeconstituents.

M and R ⁷～R ⁸Definition such as general formula (I) compound described in.

The synthetic method of the compounds of this invention

In order to finish purpose of the present invention, the present invention adopts following technical scheme:

The preparation method of the described compound of general formula of the present invention (I) or its pharmaceutically useful salt may further comprise the steps:

Wherein: PG is the silica-based protecting group of hydroxyl, and that the silica-based protecting group of wherein said hydroxyl is selected from is trimethyl silicon based, triethyl is silica-based, t-Butyldimethylsilyl, triisopropylsilyl or tert-butyl diphenyl are silica-based;

X is selected from halogen, is preferably bromine or iodine; R ¹～R ⁵, L definition identical with the definition of general formula (I).

The ring L compound a that aldehyde radical replaces reacts with wittig reagent (Wei Dixi reagent) under alkaline condition, obtains the ring L compound b of vinyl substituted; Ring L compound b and the oxidant reaction of vinyl substituted obtain dihydroxy compound c; Dihydroxy compound c is under alkaline condition, and the chlorosilane reaction with replacing obtains the siloxy compound d;

The phenyl compound e that hydroxyl replaces and halogenating agent react, and obtain the phenyl compound f of hydroxyl, halogen replacement; The phenyl compound f that hydroxyl, halogen replace and siloxy compound d obtain compound g with generation Mitsunobu reactions such as phosphine part and azodicarbonic acid ester or azoformamides in solvent; Compound g is under acid reagent or fluorizating agent condition, and silylation is taken off in hydrolysis in the solvent, obtains compound (IA); Compound (IA) catalysis in the presence of catalyzer under alkaline condition with the optional further hydrolysis of the product that obtains, obtains general formula compound (I).

Provide the acid of acidic conditions to include but not limited to formic acid, acetic acid, hydrochloric acid, sulfuric acid, methylsulfonic acid, tetrabutylammonium chloride.

Provide the alkali of alkaline condition to comprise organic bases and inorganic base, described organic bases includes but not limited to triethylamine, DMAP, imidazoles, DIPEA, n-Butyl Lithium, potassium tert.-butoxide, and Tetrabutyl amonium bromide is preferably triethylamine; Described inorganic base includes but not limited to sodium hydride, yellow soda ash, sodium bicarbonate, salt of wormwood, saleratus or cesium carbonate, is preferably salt of wormwood or cesium carbonate.

Wittig reagent includes but not limited to first base three phenyl phosphonium bromides or methyl triphenyl phosphonium iodide.

Catalyzer includes but not limited to tetra-triphenylphosphine palladium, triphenylphosphine, palladium chloride, palladium, 1,1 '-two (dibenzyl phosphorus) dichloro diamyl iron palladium, three (dibenzalacetones), two palladiums, palladium/carbon or Raney Ni.

The phosphine part that relates in the Mitsunobu reaction is three substituent phosphine parts, includes but not limited to triphenylphosphine, tributylphosphine or methyldiphenyl base phosphine, triphenylphosphine.

The azodicarbonic acid ester or the azoformamide that relate in the Mitsunobu reaction include but not limited to azo acid dimethyl ester, diethyl azodiformate or Cellmic C 121 two piperidines.

Oxygenant comprises but is not limited to perosmic anhydride, phosphorus oxychloride.

Halogenating agent includes but not limited to bromine water or halogenide; Be preferably iodine chloride.

Solvent for use includes but not limited to: acetic acid, methyl alcohol, ethanol, acetone, the trimethyl carbinol, ether, tetrahydrofuran (THF), methylene dichloride, dimethyl sulfoxide (DMSO), toluene, Isosorbide-5-Nitrae-dioxane, water or DMF.

Embodiment

Be used for further describing the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.

Embodiment

The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS).The mensuration of NMR is that measuring solvent is deuterated dimethyl sulfoxide (DMSO-d with Bruker AVANCE-400 nuclear magnetic resonance spectrometer ₆), deuterochloroform (CDCl ₃), deuterated methanol (CD ₃OD), in be designated as tetramethylsilane (TMS), chemical shift is with 10 ^-6(ppm) provide as unit.

The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

The mensuration of HPLC is used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 * 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150 * 4.6mm chromatographic column).

The average inhibiting rate of kinases and IC ₅₀The mensuration of value is with NovoStar microplate reader (German BMG company).

The tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm silica-gel plate.

The column chromatography normal operation Yantai Huanghai Sea 200 ~ 300 order silica gel are carrier.

Known starting raw material of the present invention can adopt or synthesize according to methods known in the art, maybe can buy the GmbH﹠amp from ABCR; Co.KG, Acros Organnics, Aldrich Chemical Company, reaches the company such as auspicious chemical at splendid chemistry science and technology far away (Accela ChemBio Inc).

If no special instructions, reaction is all carried out under argon atmospher or nitrogen atmosphere among the embodiment.

Argon atmospher or nitrogen atmosphere refer to that reaction flask connects argon gas or the nitrogen balloon of an about 1L volume.

Nitrogen atmosphere refers to that reaction flask connects the hydrogen balloon of an about 1L volume.

Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument are used in the pressure hydration reaction.

Hydrogenation vacuumizes usually, is filled with hydrogen, repeatable operation 3 times.

Microwave reaction uses CEM Discover-S 908860 type microwave reactors.

If no special instructions, the solution in the reaction refers to the aqueous solution among the embodiment.

If no special instructions, the temperature of reaction is room temperature among the embodiment, and temperature range is 20 ℃～30 ℃.

Tlc (TLC) is adopted in the monitoring of the reaction process among the embodiment, the system of reacting employed developping agent has: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: sherwood oil and ethyl acetate system, D: acetone, the volume ratio of solvent is according to different adjusting of polarity of compound.

The system of the system of the eluent of the column chromatography that purifying compounds adopts and the developping agent of tlc comprises: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: normal hexane and acetone system, D: normal hexane, E: ethyl acetate, the volume ratio of solvent also can add a small amount of triethylamine and acidity or alkaline reagents etc. and regulate according to different adjusting of polarity of compound.

Embodiment 1

2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2,6-dimethyl-4-(3-(methylsulfonyl) propoxy-)-3 '-vinyl biphenyl

With 2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-formaldehyde 1a (10g, 28.90mmol, adopt known method " patent WO2008001931 " preparation and get) be dissolved in 155mL dioxane and water (V/V=30:1) mixed solvent, add salt of wormwood (10g, 72.30mmol) and methyl triphenyl phosphonium iodide (23.40g, 57.80mmol), be warming up to 100 ℃, stirring reaction 12 hours.Pour in the 200mL water, with ethyl acetate extraction (150mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2,6-dimethyl-4-(3-(methylsulfonyl) propoxy-)-3 '-vinyl biphenyl 1b (8g, white solid), productive rate: 80.0%.

Second step

1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethane-1, the 2-glycol

With N-methyl morpholine oxide (3.10g, 26.10mmol) and perosmic anhydride (112mg, 0.44mmol) be dissolved in the mixed solvent of 40mL water, acetone and the trimethyl carbinol (V/V/V=5:2:1), add 13mL 2,6-dimethyl-4-(3-(methylsulfonyl) propoxy-)-3 '-vinyl biphenyl 1b (3g, 8.70mmol) acetone and the mixed solvent of methylene dichloride (V/V=10:3), stirring reaction 2 hours.Add 100mL Sulfothiorine, with ethyl acetate extraction (100mL * 3), merge organic phase, use successively Sulfothiorine (100mL * 2), saturated nacl aqueous solution washing (50mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, obtain crude product title product 1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethane-1,2-glycol 1c (3g, gray solid), product is not purified directly carries out next step reaction.

MS m/z(ESI):361.1[M-18]

The 3rd step

2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethanol

With crude product 1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethane-1,2-glycol 1c (2.80g, 7.40mmol), imidazoles (136mg, 14.80mmol) and DMAP (90mg, 0.74mmol) be dissolved in 20mLN, in the dinethylformamide, add TERT-BUTYL DIMETHYL CHLORO SILANE (1.20g, 7.77mmol), stirring reaction 1 hour.Add 100mL water, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethanol 1d (2.60g, white oily matter), productive rate: 72.2%.

The 4th step

(S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1e (1g, 4.80mmol, adopt known method " patent CN101616913 " preparation and get) carry out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column Chiralpak IA with Preparation equipment, moving phase: normal hexane: tetrahydrofuran (THF)=80:20, flow velocity: 1.0mL/ minute), collect its respective components, the rotary evaporation desolventizing, obtain (S)-2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-yl) methyl acetate (500mg, 2.40mmol) is under the ice bath, with reactants dissolved in the 15mL ether, add iodine chloride (390mg, 2.40mmol), stirring reaction 12 hours.Add 20mL water and 20mL ethyl acetate, add again the 30mL Sodium Thiosulfate Pentahydrate aqueous solution, separatory, with ethyl acetate extraction (50mL * 3), merge organic phase, use successively sodium thiosulfate solution (20mL * 3), water (20mL * 3), saturated nacl aqueous solution washing (20mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1f (530mg, yellow oil), productive rate: 66.0%.

MS m/z(ESI):333.0[M-1]

The 5th step

2-((3S)-6-(2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1f (200mg, 0.60mmol), 2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethanol 1d (295mg, 0.60mmol) and azo two formyls two piperidines (242mg, 0.96mmol) be dissolved in the 10mL toluene, add tri-butyl phosphine (194mg, 0.96mmol), be heated to 50 ℃, stirring reaction 12 hours.Add 5mL methyl alcohol, the concentrating under reduced pressure reaction solution, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1g (410mg, yellow liquid), productive rate: 84.7%.

MS m/z(ESI):826.6[M+18]

The 6th step

2-((3S)-6-(1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-the 2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((3S)-6-(2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1g (390mg, 0.48mmol) be dissolved in the 10mL tetrahydrofuran (THF), add 1M tetrabutyl ammonium fluoride (0.5mL, 0.50mmol) tetrahydrofuran solution, stirring reaction 2 hours.The concentrating under reduced pressure reaction solution, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-the 2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1h (260mg, white solid), productive rate: 77.6%.

MS m/z(ESI):712.4[M+18]

The 7th step

2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((3S)-6-(1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-the 2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1h (215mg, 0.31mmol), acid chloride (10mg, 0.05mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (37mg, 0.09mmol) and cesium carbonate (201mg, 0.62mmol) be dissolved in the 10mL toluene, be heated to 50 ℃, stirring reaction 12 hours.Filter, concentrating under reduced pressure filtrate, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 1j (80mg, yellow liquid), productive rate: 45.7%.

MS m/z(ESI):584.2[M+18]

The 8th step

With 2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 1j (80mg, 0.14mmol) is dissolved in 6mL tetrahydrofuran (THF) and methyl alcohol (V/V=1:5) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 68 ℃, stirring reaction 1 hour.Add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with the HPLC preparative chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 1 (54mg, white solid), productive rate: 64.1%.

MS m/z(ESI):551.5[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.45-7.49(m,1H),7.37-7.38(m,1H),7.14-7.18(m,2H),6.77(s,1H),6.66(s,2H),6.47(s,1H),5.12-5.14(m,1H),4.71-4.76(m,1H),4.31-4.34(m,1H),4.23-4.27(m,1H),4.12-4.15(m,2H),3.94-3.99(m,1H),3.81(m,1H),3.26-3.30(m,2H),2.98(s,3H),2.78-2.83(m,1H),2.60-2.66(m,1H),2.33-2.39(m,2H),2.02(s,3H),2.00(s,3H).

Embodiment 2

2-((3R, 8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(2 '; 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2; 3; 7; 8-tetrahydrochysene benzfuran also [5; 6-b] [1; 4] dioxin-8-yl) acetic acid 1 (0.19g, 0.35mmol) carries out chiral separation, adopts the HPLC method; with chiral column chiral isomer is separated (separation condition: chiral column Chiralpak IA with Preparation equipment; moving phase: ethanol: vinyl cyanide: acetic acid=85:15:0.1, flow velocity: 1.0mL/ minute), collect its respective components; the rotary evaporation desolventizing; obtain title product 2-((3R, 8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2; 3; 7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also; 4] dioxin-8-yl) acetic acid 2 (0.09g, white solid).

Embodiment 3

2-((3S, 8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(2 '; 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2; 3; 7; 8-tetrahydrochysene benzfuran also [5; 6-b] [1; 4] dioxin-8-yl) acetic acid 1 (0.19g, 0.35mmol) carries out chiral separation, adopts the HPLC method; with chiral column chiral isomer is separated (separation condition: chiral column Chiralpak IA with Preparation equipment; moving phase: ethanol: vinyl cyanide: acetic acid=85:15:0.1, flow velocity: 1.0mL/ minute), collect its respective components; the rotary evaporation desolventizing; obtain title product 2-((3S, 8S)-3-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl)-2; 3; 7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also; 4] dioxin-8-yl) acetic acid 3 (0.10g, white solid).

Embodiment 4

2-(3-(2'-chlorodiphenyl-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

1-bromo-3-vinyl benzene

With 3-bromobenzaldehyde 4a (10g, 54.05mmol) be dissolved in 102mL dioxane and water (V/V=50:1) mixed solvent, add salt of wormwood (18.64g, 135mmol) with methyl triphenyl phosphonium iodide (43.70g, 108.11mmol), be warming up to 100 ℃, stirring reaction 12 hours.Filter, filter cake washs with 200mL normal hexane and ethyl acetate (V/V=50:1) mixed solvent, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-bromo-3-vinyl benzene 4b (10g, yellow liquid), productive rate: 100.0%.

Second step

1-(3-bromophenyl) ethane-1, the 2-glycol

With N-methyl morpholine oxide (9.59g, 81.90mmol) and perosmic anhydride (350mg, 1.37mmol) be dissolved in the mixed solvent of 40mL water, acetone and the trimethyl carbinol (V/V/V=5:2:1), add 13mL 1-bromo-3-vinyl benzene 4b (5g, 27.30mmol) acetone and the mixed solvent of methylene dichloride (V/V=10:3), stirring reaction 30 minutes.Add 30mL saturated sodium thiosulfate solution, stirred 30 minutes, with ethyl acetate extraction (30mL * 3), merge organic phase, water (20mL * 2) successively, saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains crude product title product 1-(3-bromophenyl) ethane-1,2-glycol 4c (4.70g, yellow solid), product is not purified directly carries out next step reaction.

MS m/z(ESI):236.34[M+18]

The 3rd step

1-(3-bromophenyl)-2-((tertiary butyl dimethylsilane) oxygen) ethanol

With crude product 1-(3-bromophenyl) ethane-1,2-glycol 4c (4.50g, 20.73mmol), imidazoles (2.82g, 41.46mmol) and DMAP (253mg, 2.07mmol) are dissolved in 30mL N, in the dinethylformamide, add again TERT-BUTYL DIMETHYL CHLORO SILANE (3.75g, 24.88mmol), stirring reaction 1 hour.Add 100mL water and 100mL ethyl acetate, the extraction separatory, organic phase is water (30mL * 3) successively, saturated nacl aqueous solution washing (30mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 1-(3-bromophenyl)-2-((tertiary butyl dimethylsilane) oxygen) ethanol 4d (5g with silica gel column chromatography, yellow liquid), productive rate: 72.8%.

MS m/z(ESI):329.1[M-1]

The 4th step

2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

Under the ice bath, 2-(6-hydroxyl-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1e (12g, 57.70mmol) is dissolved in the 100mL ether, adds iodine chloride (9.40g, 57.70mmol), rise to room temperature, stirring reaction 2 hours.Add 100mL water, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with normal hexane and ethyl acetate system recrystallization purifying gained resistates, obtain crude product title product 2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 4e (8.50g, gray solid), product is not purified directly to carry out next step reaction.

The 5th step

2-(6-(1-(3-bromophenyl)-2-((tertiary butyl dimethyl-silicon) oxygen) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 1-(3-bromophenyl)-2-((tertiary butyl dimethylsilane) oxygen) ethanol 4d (3.70g, 11.18mmol), crude product 2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 4e (3.73g, 11.18mmol) and azo two formyls two piperidines (4.51g, 17.89mmol) are dissolved in the 50mL toluene, add tri-butyl phosphine (4.5mL, 17.89mmol), be heated to 50 ℃, stirring reaction 30 minutes.Add 20mL methyl alcohol, the reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-(6-(1-(3-bromophenyl)-2-((tertiary butyl dimethyl-silicon) oxygen) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 4f (8g, yellow liquid), productive rate: 100.0%.

The 6th step

2-(6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-(6-(1-(3-bromophenyl)-2-((tertiary butyl dimethyl-silicon) oxygen) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 4f (8g, 12.36mmol) be dissolved in the 50mL tetrahydrofuran (THF), add tetrabutyl ammonium fluoride (13.6mL, 13.60mmol), stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-(6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 4g (5g, yellow liquid), productive rate: 75.9%.

MS m/z(ESI):552.1[M-1]

The 7th step

2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-(6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 4g (1g, 1.87mmol), acid chloride (63mg, 0.28mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (224mg, 0.56mmol) and cesium carbonate (1.22g, 3.74mmol) are dissolved in the 6mL toluene, microwave heating to 130 ℃, stirring reaction 3 hours.Filter, filter cake concentrates with ethyl acetate washing (5mL * 3), filtrate decompression, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 4h (310mg, yellow liquid), productive rate: 40.8%.

MS m/z(ESI):424.2[M+18]

The 8th step

2-(3-(2'-chlorodiphenyl-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 4h (150mg, 0.37mmol), (2-chloro-phenyl-) boric acid (69mg, 0.44mmol), tetra-triphenylphosphine palladium (21.40mg, 0.02mmol) and cesium carbonate (361mg, 1.11mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 3 hours.Filter, filter cake washs (5mL * 3), anhydrous magnesium sulfate drying with ethyl acetate, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-(3-(2'-chlorodiphenyl-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 4i (100mg, yellow liquid), productive rate: 62.1%.

MS m/z(ESI):454.3[M+18]

The 9th step

With 2-(3-(2'-chlorodiphenyl-3-yl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) methyl acetate 4i (100mg, 0.23mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add sodium hydroxide (92mg, 2.30mmol), be heated to 50 ℃, stirring reaction 30 minutes.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (10mL * 2) successively, saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-(3-(2'-chlorodiphenyl-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 4 (100mg, white solid), productive rate: 100.0%.

MS m/z(ESI):440.2[M+18]

¹H NMR(400MHz,CDCl ₃)δ7.42-7.50(m,5H),7.29-7.38(m,3H),6.79(s,1H),6.49(s,1H),5.15-5.18(m,1H),4.72-4.76(m,1H),4.35-4.38(m,1H),4.24-4.28(m,1H),3.99-4.04(m,1H),3.78-3.84(m,1H),2.78-2.84(m,1H),2.60-2.67(m,1H).

Embodiment 5

2-(3-(3-(3-chloropyridine-4-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

Methyl esters

With 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 4h (130mg, 0.32mmol), (3-chloropyridine-4-yl) boric acid (61mg, 0.39mmol), tetra-triphenylphosphine palladium (19mg, 0.02mmol) and cesium carbonate (312mg, 0.96mmol) are dissolved in 4.5mL dioxane and water (V/V=8:1) mixed solvent, be heated to 95 ℃, stirring reaction 12 hours.Filter, filter cake washs (5mL * 3), anhydrous magnesium sulfate drying with ethyl acetate, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-(3-(3-(3-chloropyridine-4-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 5a (28mg, yellow liquid), productive rate: 20.0%.

MS m/z(ESI):438.3[M+1]

Second step

With 2-(3-(3-(3-chloropyridine-4-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) methyl acetate 5a (28mg, 0.23mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add sodium hydroxide (2.60mg, 0.64mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, dripping 1M hydrochloric acid is 3 ~ 4 to reaction solution pH, separatory, water ethyl acetate extraction (5mL * 3), merge organic phase, water (10mL * 3) successively, saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-(3-(3-(3-chloropyridine-4-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 5 (25mg, white solid), productive rate: 92.6%.

MS m/z(ESI):422.2[M-1]

¹H NMR(400MHz,CDCl ₃)δ8.70(s,1H),8.55-8.56(m,1H),7.51-7.57(m,4H),7.32-7.33(m,1H),6.80(s,1H),6.49(s,1H),5.18-5.20(m,1H),4.73-4.77(m,1H),4.35-4.38(m,1H),4.25-4.29(m,1H),3.98-4.03(m,1H),3.83(m,1H),2.78-2.84(m,1H),2.61-2.67(m,1H).

Embodiment 6

2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((3S)-6-(1-(3-brooethyl)-2-(tertiary butyl dimethyl Si base) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1f (4.50g, 13.47mmol), 1-(3-brooethyl)-2-(tertiary butyl dimethyl Si base) ethanol 4d (4.46g, 13.47mmol) and azo two formyls two piperidines (25.43g, 21.56mmol) are dissolved in the 60mL toluene, add tri-butyl phosphine (4.36g, 21.56mmol), be heated to 50 ℃, stirring reaction 12 hours.Add 5mL methyl alcohol, the concentrating under reduced pressure reaction solution, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(1-(3-brooethyl)-2-(tertiary butyl dimethyl Si base) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 6a (4.80g, yellow liquid), productive rate: 55.2%.

MS m/z(ESI):666.3[M+18]

Second step

2-((3S)-6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((3S)-6-(1-(3-brooethyl)-2-(tertiary butyl dimethyl Si base) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 6a (4.80g, 7.42mmol) be dissolved in the 50mL tetrahydrofuran (THF), add 1M tetrabutyl ammonium fluoride (8.2mL, 8.16mmol) tetrahydrofuran solution, stirring reaction 2 hours.The concentrating under reduced pressure reaction solution, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 6b (2.53g, yellow liquid), productive rate: 64.1%.

MS m/z(ESI):533.0[M+1]

The 3rd step

2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((3S)-6-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 6b (1g, 1.87mmol), acid chloride (63mg, 0.28mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (224mg, 0.56mmol) and cesium carbonate (1.22g, 3.74mmol) are dissolved in the 6mL toluene, microwave heating to 130 ℃, stirring reaction 3 hours.Filter, with ethyl acetate washing (5mL * 4), concentrating under reduced pressure filtrate, use silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 6c (390mg, yellow liquid), productive rate: 51.3%.

MS m/z(ESI):422.2[M+18]

The 4th step

With 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) methyl acetate 6c (90mg, 0.22mmol) be dissolved in 5mL tetrahydrofuran (THF) and methyl alcohol (V/V=1:4) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The concentrating under reduced pressure reaction solution, add 15mL water and 15mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, with ethyl acetate extraction (5mL * 2), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate uses the HPLC preparative chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 6 (35mg, white solid), productive rate: 40.2%.

MS m/z(ESI):389.0[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.58(s,1H),7.50-7.52(m,1H),7.29-7.35(m,2H),6.79(s,1H),6.48(s,1H),5.07-5.09(m,1H),4.72-4.77(m,1H),4.25-4.32(m,2H),3.90-3.96(m,1H),3.78-3.86(m,1H),2.78-2.85(m,1H),2.61-2.68(m,1H).

Embodiment 7

2-((8S)-3-(3-cyclopropyl phenyl)-2,3,7, the 8-tetrahydrochysene benzfuran is [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl also) acetic acid

The first step

2-((8S)-3-(3-cyclopropyl phenyl)-2,3,7, the 8-tetrahydrochysene benzfuran is [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl also) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 6c (150mg, 0.37mmol), cyclopropylboronic acid (38mg, 0.44mmol), tetra-triphenylphosphine palladium (21mg, 0.02mmol) and cesium carbonate (361g, 1.11mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 95 ℃, stirring reaction 2 hours.Filter, with ethyl acetate washing (5mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate uses the HPLC preparative chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(3-cyclopropyl phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 7a (59mg, yellow liquid), productive rate: 43.4%.

MS m/z(ESI):367.2[M+1]

Second step

With 2-((8S)-3-(3-cyclopropyl phenyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) methyl acetate 7a (59mg, 0.16mmol) be dissolved in 5mL tetrahydrofuran (THF) and methyl alcohol (V/V=1:4) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The concentrating under reduced pressure reaction solution, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, with ethyl acetate extraction (5mL * 2), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate uses the HPLC preparative chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(3-cyclopropyl phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 7 (35mg, white solid), productive rate: 61.4%.

MS m/z(ESI):353.0[M+1]

¹H NMR(400MHz,CDCl ₃)δ7.28-7.32(m,1H),7.17-7.19(m,1H),7.13(s,1H),7.05-7.07(m,1H),6.78(s,1H),6.49(s,1H),5.05-5.07(m,1H),4.72-4.76(m,1H),4.24-4.31(m,2H),3.93-3.98(m,1H),3.80-3.84(m,1H),2.78-2.84(m,1H),2.61-2.67(m,1H),1.90-1.96(m,1H),0.97-1.01(m,2H),0.70-0.75(m,2H).

Embodiment 8

2-((8S)-3-(2', 4', 6'-trimethylammonium-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((8S)-3-(2', 4', 6'-trimethylammonium-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 6c (50mg, 0.12mmol), Three methyl Benzene boric acid (20mg, 0.12mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) and cesium carbonate (120mg, 0.37mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 2 hours.Filter, with ethyl acetate washing (5mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(2', 4', 6'-trimethylammonium-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 8a (40mg, yellow liquid), productive rate: 72.4%.

MS m/z(ESI):445.4[M+1]

Second step

With 2-((8S)-3-(2', 4', 6'-trimethylammonium-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran [5,6-b] [1 also, 4] dioxin-8-yl) methyl acetate 8a (40mg, 0.09mmol) be dissolved in 3mL tetrahydrofuran (THF) and methyl alcohol (V/V=1:2) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 0.5 hour.The concentrating under reduced pressure reaction solution, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (10mL * 3) successively, saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate uses silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(2', 4', 6'-trimethylammonium-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 8 (35mg, white solid), productive rate: 92.1%.

MS m/z(ESI):429.1[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.37-7.49(m,3H),7.16-7.20(m,1H),6.96(s,2H),6.78(s,1H),6.48(s,1H),5.13-5.15(m,1H),4.72-4.76(m,1H),4.26-4.35(m,2H),3.95-4.00(m,1H),3.82(m,1H),2.79-2.84(m,1H),2.61-2.67(m,1H),2.34(s,3H),2.00-2.02(m,6H).

Embodiment 9

2-((8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 6c (50mg, 0.12mmol), (2,6-dimethyl benzene) boric acid (19mg, 0.12mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) and cesium carbonate (120mg, 0.37mmol) are dissolved in 3.3mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 2 hours.Filter, with ethyl acetate washing (2mL * 2), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate with eluent system B purifying gained resistates, obtains title product 2-((8S)-3-(2' with silica gel column chromatography, 6'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 9a (33mg, yellow liquid), productive rate: 62.3%.

Second step

With 2-((8S)-3-(2', 6'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 9a (33mg, 0.08mmol) is dissolved in 4mL tetrahydrofuran (THF) and methyl alcohol (V/V=1:3) mixed solvent, add 1M sodium hydroxide solution (0.5mL, 0.50mmol), be heated to 50 ℃, stirring reaction 0.5 hour.The concentrating under reduced pressure reaction solution, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (10mL * 3) successively, saturated nacl aqueous solution washing (10mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate with eluent system A purifying gained resistates, obtains title product 2-((8S)-3-(2' with silica gel column chromatography, 6'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 9 (28mg, white solid), productive rate: 87.5%.MS m/z(ESI):415.1[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.47-7.50(m,1H),7.38-7.42(m,2H),7.13-7.21(m,4H),6.78(s,1H),6.48(s,1H),5.13-5.15(m,1H),4.71-4.76(m,1H),4.24-4.35(m,2H),3.95-4.00(m,1H),3.82(m,1H),2.79-2.83(m,1H),2.61-2.67(m,1H),2.02-2.05(m,6H).

Embodiment 10

2-(3-([1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-(3-([1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-(3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 4h (90mg, 0.22mmol), phenyl-boron dihydroxide (27mg, 0.22mmol), tetra-triphenylphosphine palladium (13mg, 0.01mmol) and cesium carbonate (215mg, 0.66mmol) be dissolved in 5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 2 hours.Filter, filter cake washs (5mL * 3) with ethyl acetate, and anhydrous magnesium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtain title product 2-(3-([1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5 with silica gel column chromatography, 6-b] [1,4] dioxin-8-yl) methyl acetate 10a (60mg, colourless liquid), productive rate: 67.4%.

MS m/z(ESI):420.3[M+18]

Second step

(3-([1 with 2-, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 10a (60mg, 0.15mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (10mL * 3) successively, saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtain title product 2-(3-([1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5 with silica gel column chromatography, 6-b] [1,4] dioxin-8-yl) acetic acid 10 (60mg, white solid), productive rate: 100.0%.

MS m/z(ESI):387.1[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.58-7.62(m,3H),7.38-7.50(m,6H),6.80(s,1H),6.51(s,1H),5.17-5.19(m,1H),4.72-4.77(m,1H),4.25-4.38(m,2H),4.00-4.05(m,1H),3.83(m,1H),2.79-2.85(m,1H),2.62-2.68(m,1H).

Embodiment 11

2-(3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-(3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-(3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 4h (90mg, 0.22mmol), o-methyl-benzene boric acid (30mg, 0.22mmol), tetra-triphenylphosphine palladium (13mg, 0.01mmol) and cesium carbonate (215mg, 0.66mmol) be dissolved in 5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 2 hours.Filter, filter cake washs (5mL * 3) with ethyl acetate, and anhydrous magnesium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtain title product 2-(3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5 with silica gel column chromatography, 6-b] [1,4] dioxin-8-yl) methyl acetate 11a (48mg, yellow liquid), productive rate: 52.2%.

MS m/z(ESI):434.3[M+18]

Second step

With 2-(3-(2'-methyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 11a (48mg, 0.12mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (10mL * 3) successively, saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtain title product 2-(3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5 with silica gel column chromatography, 6-b] [1,4] dioxin-8-yl) acetic acid 11 (42mg, white solid), productive rate: 91.3%.

MS m/z(ESI):401.1[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.26-7.47(m,8H),6.79(s,1H),6.49(s,1H),5.15(m,1H),4.74-4.76(m,1H),4.26-4.37(m,2H),4.01-4.03(m,1H),3.82(m,1H),2.79-2.83(m,1H),2.61-2.67(m,1H),2.28(s,3H).

Embodiment 12

2-(3-(2', 4'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-(2,4-3,5-dimethylphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring

With 1-bromo-2,4-dimethyl benzene 12a (1.0g, 5.40mmol), two valeryl two boron (1.90g, 8.10mmol), 1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride (198mg, 0.27mmol) and Potassium ethanoate (1.30g, 13.50mmol) be dissolved in the 50mL glycol dimethyl ether, be heated to return stirring reaction 3 hours.Filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-(2 with silica gel column chromatography, the 4-3,5-dimethylphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxy boron, penta ring 12b (700mg, yellow oil), productive rate: 56.0%.

Second step

2-(3-(2', 4'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 4h (90mg, 0.22mmol), 2-(2, the 4-3,5-dimethylphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring 12b (62mg, 0.27mmol), tetra-triphenylphosphine palladium (13mg, 0.01mmol) and yellow soda ash (47mg, 0.44mmol) be dissolved in 5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 2 hours.Filter, filter cake washs (5mL * 3), anhydrous magnesium sulfate drying with ethyl acetate, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-(3-(2' with silica gel column chromatography, 4'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 12c (50mg, yellow liquid), productive rate: 52.1%.Generate by product 2-(3-phenyl-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 12d (20mg, yellow liquid).

MS m/z(ESI):448.3[M+18]

The 3rd step

With 2-(3-(2', 4'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 12c (50mg, 0.12mmol) is dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (5mL * 3) successively, saturated nacl aqueous solution washing (5mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtains title product 2-(3-(2' with silica gel column chromatography, 4'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 12 (45mg, white solid), productive rate: 93.7%.

MS m/z(ESI):415.1[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.27-7.58(m,6H),7.08-7.15(m,1H),6.78(s,1H),6.48(s,1H),5.07-5.16(m,1H),4.72-4.76(m,1H),4.25-4.36(m,2H),3.91-4.03(m,1H),3.82(m,1H),2.79-2.84(m,1H),2.61-2.68(m,1H),2.37(s,3H),2.25(s,3H).

Embodiment 13

2-(3-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2,5-, two chloro-2, the 5-dimethylhexane

With 2,5-dimethylhexane-2,5-glycol 13a (102.20g, 0.70mol) is added in the 700mL concentrated hydrochloric acid, adds the 50mL normal hexane again, stirring reaction 12 hours.Filter, filter cake washes (50mL * 3) with water, and filtrate is used ethyl acetate extraction (200mL * 3), merge organic phase, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, merge filter cake, obtain title product crude product 2,5-two chloro-2,5-dimethylhexane 13b (124.20g, white powder), product is not purified directly carries out next step reaction.

Second step

6-bromo-1, Isosorbide-5-Nitrae, 4-tetramethyl--1,2,3,4-naphthane

Under the ice bath, with crude product 2,5-two chloro-2,5-dimethylhexane 13b (5.0g, 27.30mmol) is dissolved in the 50mL methylene dichloride, add bromobenzene (8.45g, 53.80mmol), add again aluminum chloride (728mg, 5.46mmol) in batches, stirred 10 minutes, and naturally rose to again stirring at room reaction 0.5 hour.Pour reaction solution into the 100mL frozen water, add the 50mL ethyl acetate, extraction separatory, water ethyl acetate extraction (50mL * 3), merge organic phase, water (30mL * 3) successively, saturated nacl aqueous solution washing (30mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 6-bromo-1 with silica gel column chromatography, 1,4,4-tetramethyl--1,2,3,4-naphthane 13c (7.10g, yellow liquid), productive rate: 97.4%.

The 3rd step

5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-formaldehyde

Under-78 ℃, with 6-bromo-1,1,4,4-tetramethyl--1,2,3,4-naphthane 13c (7.0g, 26.20mmol) is dissolved in the 70mL tetrahydrofuran (THF), drip the 12.6mL2.5M n-Butyl Lithium, stirred 30 minutes, and dripped again DMF (2.87g, 39.30mmol), stirring reaction 0.5 hour.Pour reaction solution into the 50mL saturated ammonium chloride solution, add 50mL ethyl acetate and 50mL water, the extraction separatory, organic phase is water (30mL * 3) successively, saturated nacl aqueous solution washing (30mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-formaldehyde 13d (2.97g, yellow liquid), productive rate: 52.5%.

MS m/z(ESI):217.2[M+1]

The 4th step

1, Isosorbide-5-Nitrae, 4-tetramethyl--6-vinyl-1,2,3,4-naphthane

With 5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-formaldehyde 13d (2.82g, 13.06mmol) be dissolved in 51mL dioxane and water (V/V=50:1) mixed solvent, add salt of wormwood (4.50g, 32.65mmol) and triphenylphosphine methyl iodide (10.55g, 26.11mmol), be warming up to 100 ℃, stirring reaction 12 hours.Filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 1, Isosorbide-5-Nitrae, 4-tetramethyl--6-vinyl-1,2,3,4-naphthane 13e (2.60g, colourless liquid), productive rate: 93.2% with silica gel column chromatography.

The 5th step

1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethane-1, the 2-glycol

N-methyl morpholine oxide (2.46g, 21.02mmol) and perosmic anhydride (89mg, 0.35mmol) are dissolved in 20mL water, in acetone and the trimethyl carbinol (V/V/V=5:2:1) mixed solvent, add 13mL 1, Isosorbide-5-Nitrae, 4-tetramethyl--6-vinyl-1,2,3,4-naphthane 13e (1.50g, acetone 7mmol) and methylene dichloride (V/V=10:3) mixed solvent, stirring reaction 1.5 hours.Add 30mL saturated sodium thiosulfate solution, stirred 30 minutes, with ethyl acetate extraction (30mL * 3), merge organic phase, use successively saturated sodium carbonate solution (20mL * 2), water (20mL * 2), saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethane-1,2-glycol 13f (1.53g, white solid), productive rate: 88.0%.

The 6th step

2-((tertiary butyl dimethylsilane) oxygen)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethanol

With 1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethane-1,2-glycol 13f (1.53g, 6.17mmol), imidazoles (839mg, 12.34mmol) and DMAP (75mg, 0.62mmol) are dissolved in 30mLN, in the dinethylformamide, add again TERT-BUTYL DIMETHYL CHLORO SILANE (1.12g, 7.40mmol), stirring reaction 0.5 hour.Add 30mL water and 30mL ethyl acetate, the extraction separatory, organic phase is water (20mL * 3) successively, saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((tertiary butyl dimethylsilane) oxygen)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethanol 13g (1.99g, yellow liquid), productive rate: 89.2%.

The 7th step

2-(6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((tertiary butyl dimethylsilane) oxygen)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethanol 13g (250mg, 0.69mmol), crude product 2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 4e (230mg, 0.69mmol) and azo two formyls two piperidines (278mg, 1.10mmol) are dissolved in the 10mL toluene, add tri-n-butyl phosphine (0.27mL, 1.10mmol), be heated to 50 ℃, stirring reaction 30 minutes.Add 10mL methyl alcohol, the reaction solution concentrating under reduced pressure uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-(6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-and 5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 13h (430mg, yellow liquid), productive rate: 91.9%.

MS m/z(ESI):696.5[M+18]

The 8th step

2-(6-(2-hydroxyl-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-(6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-and 5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 13h (390mg, 0.57mmol) be dissolved in the 10mL tetrahydrofuran (THF), add tetrabutyl ammonium fluoride (0.63mL, 0.63mmol), stirring reaction 0.5 hour.The reaction solution concentrating under reduced pressure, with eluent system B purifying gained resistates, obtain title product 2-(6-(2-hydroxyl-1-(5,5 with silica gel column chromatography, 8,8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 13i (240mg, yellow liquid), productive rate: 74.0%.

The 9th step

2-(3-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

((2-hydroxyl-1-(5,5,8 for 6-with 2-, 8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-and 5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 13i (190mg, 0.34mmol), acid chloride (11mg, 0.05mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (40mg, 0.10mmol) and cesium carbonate (219mg, 0.68mmol) be dissolved in the 10mL toluene, be heated to 50 ℃ of stirring reactions 16 hours.Filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, (3-(5,5,8 to obtain title product 2-, 8-tetramethyl--5,6,7,8-naphthane-2-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 13j (115mg, white solid), productive rate: 78.2%.

MS m/z(ESI):454.3[M+18]

The tenth step

(3-(5,5,8 with 2-, 8-tetramethyl--5,6,7,8-naphthane-2-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 13j (135mg, 0.31mmol) is dissolved in 7.5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1.5M sodium hydroxide solution (2mL, 3mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure adds 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (15mL * 3) successively, saturated nacl aqueous solution washing (15mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, and with eluent system A purifying gained resistates, (3-(5 to obtain title product 2-with silica gel column chromatography, 5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 13 (130mg, white solid), productive rate: 100.0%.

MS m/z(ESI):421.2[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.34-7.36(m,1H),7.31(m,1H),7.15-7.17(m,1H),6.78(s,1H),6.48(s,1H),5.03-5.05(m,1H),4.71-4.76(m,1H),4.24-4.31(m,2H),3.96-4.01(m,1H),3.80-3.81(m,1H),2.79-2.84(m,1H),2.60-2.67(m,1H),1.70(s,4H),1.29(s,12H).

Embodiment 14

2-(3-(2', 5'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-(2,5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring

With 2-bromo-1,4-dimethyl benzene 14a (1.02g, 5.50mmol), two valeryl two boron (1.95g, 8.30mmol), 1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride (202mg, 0.30mmol) and Potassium ethanoate (1.35g, 13.80mmol) be dissolved in the 20mL glycol dimethyl ether, be heated to return stirring reaction 3 hours.Filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-(2 with silica gel column chromatography, the 5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxy boron, penta ring 14b (538mg, colorless oil), productive rate: 42.1%.

Second step

2-(3-(2', 5'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 4h (150mg, 0.37mmol), 2-(2, the 5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring 14b (103mg, 0.44mmol), tetra-triphenylphosphine palladium (21mg, 0.021mmol) and yellow soda ash (78mg, 0.74mmol) be dissolved in 5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 3 hours.Filter, filter cake washs (10mL * 3), anhydrous sodium sulfate drying with ethyl acetate, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-(3-(2' with silica gel column chromatography, 5'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 14c (80mg, yellow liquid), productive rate: 50.3%.

MS m/z(ESI):448.2[M+18]

The 3rd step

With 2-(3-(2', 5'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 14c (80mg, 0.19mmol) is dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (10mL * 2) successively, saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtains title product 2-(3-(2' with silica gel column chromatography, 5'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 14 (70mg, white solid), productive rate: 90.9%.

MS m/z(ESI):415.5[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.33-7.48(m,4H),7.16-7.18(m,1H),7.08-7.10(m,1H),7.06(m,1H),6.79(s,1H),6.49(s,1H),5.14-5.16(m,1H),4.72-4.76(m,1H),4.24-4.37(m,2H),3.98-4.03(m,1H),3.81-3.84(m,1H),2.78-2.84(m,1H),2.61-2.67(m,1H),2.36(s,3H),2.23(s,3H).

Embodiment 15

2-(3-(3', 5'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-(3,5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring

With 2-bromo-3,5-dimethyl benzene 15a (1.06g, 5.70mmol), two valeryl two boron (2.0g, 8.60mmol), 1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride (210mg, 0.20mmol) and Potassium ethanoate (1.40g, 14.30mmol) be dissolved in the 20mL glycol dimethyl ether, be heated to return stirring reaction 3 hours.Filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-(3 with silica gel column chromatography, the 5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxy boron, penta ring 15b (538mg, colorless oil), productive rate: 42.1%.

Second step

2-(3-(3', 5'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 4h (150mg, 0.37mmol), 2-(3, the 5-3,5-dimethylphenyl)-4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring 15b (103mg, 0.44mmol), tetra-triphenylphosphine palladium (21mg, 0.021mmol) and yellow soda ash (78mg, 0.74mmol) be dissolved in 5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 3 hours.Filter, filter cake washs (10mL * 3), anhydrous sodium sulfate drying with ethyl acetate, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-(3-(3' with silica gel column chromatography, 5'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 15c (77mg, yellow liquid), productive rate: 48.4%.

MS m/z(ESI):448.2[M+18]

The 3rd step

With 2-(3-(3', 5'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 15c (77mg, 0.18mmol) is dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 0.5 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (10mL * 2) successively, saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtains title product 2-(3-(3' with silica gel column chromatography, 5'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 15 (75mg, white solid), productive rate: 100.0%.

MS m/z(ESI):415.5[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.58-7.60(m,2H),7.45-7.49(m,1H),7.37-7.38(m,1H),7.21(s,2H),7.02(s,1H),6.80(s,1H),6.51(s,1H),5.16-5.18(m,1H),4.72-4.77(m,1H),4.25-4.37(m,2H),3.99-4.04(m,1H),3.81-3.84(m,1H),2.79-2.85(m,1H),2.61-2.68(m,1H),2.40(s,6H).

Embodiment 16

(S)-2-(3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

(S)-2-(3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 6c (150mg, 0.37mmol), o-methyl-benzene boric acid (60mg, 0.44mmol), tetra-triphenylphosphine palladium (21mg, 0.021mmol) and cesium carbonate (361mg, 1.11mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 3 hours.Filter, filter cake washs (5mL * 3) with ethyl acetate, and anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtain title product (S)-2-(3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5 with silica gel column chromatography, 6-b] [1,4] dioxin-8-yl) methyl acetate 16a (115mg, yellow liquid), productive rate: 74.6%.

MS m/z(ESI):434.3[M+18]

Second step

With (S)-2-(3-(2'-methyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 16a (115mg, 0.28mmol) be dissolved in 7.5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (10mL * 3) successively, saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtain title product (S)-2-(3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5 with silica gel column chromatography, 6-b] [1,4] dioxin-8-yl) acetic acid 16 (105mg, white solid), productive rate: 94.6%.

MS m/z(ESI):401.3[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.29-7.59(m,8H),6.80(s,1H),6.50(s,1H),5.16(m,1H),4.75(m,1H),4.28-4.38(m,2H),4.02(m,1H),3.83(m,1H),2.81-2.85(m,1H),2.67-2.69(m,1H),2.29(s,3H).

Embodiment 17

2-((3R, 8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(2', 6'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 9 (90mg, 0.22mmol) carry out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column AD-s Chiralpak 4.6, moving phase: ethanol/vinyl cyanide/acetic acid=90/10/0.1 with Preparation equipment, flow velocity: 0.5mL/ minute), collect its respective components, the rotary evaporation desolventizing obtains title product 2-((3R, 8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 17 (39mg, white solid).

¹H NMR(400MHz,CDCl ₃)δ7.41-7.49(m,3H),7.13-7.21(m,4H),6.78(s,1H),6.48(s,1H),5.14(m,1H),4.74(m,1H),4.26-4.35(m,2H),3.98(m,1H),3.82(m,1H),2.79(m,1H),2.65(m,1H),2.02-2.05(m,6H).

Embodiment 18

2-((3R, 8S)-3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With (S)-2-(3-(2'-methyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 16 (105mg, 0.26mmol) carry out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column AD-H Chiralpak 4.6 with Preparation equipment, moving phase: ethanol: vinyl cyanide: acetic acid=90/10/0.1 (v/v/v), flow velocity: 0.5mL/ minute), collect its respective components, the rotary evaporation desolventizing, obtain title product 2-((3R, 8S)-3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 18 (34mg, white solid).

¹H NMR(400MHz,CDCl ₃)δ7.27-7.58(m,8H),6.78(s,1H),6.48(s,1H),5.14(m,1H),4.73(m,1H),4.26-4.36(m,2H),4.00(m,1H),3.81(m,1H),2.79-2.83(m,1H),2.65-2.67(m,1H),2.27(s,3H).

Embodiment 19

2-(3-phenyl-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-(3-phenyl-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 12d (20mg, 0.06mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (5mL * 3) successively, saturated nacl aqueous solution washing (5mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-(3-phenyl-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 19 (10mg, white solid), productive rate: 52.6%.

MS m/z(ESI):313.3[M+1]

¹H NMR(400MHz,CDCl ₃)δ7.42(m,5H),6.78(s,1H),6.49(s,1H),5.10-5.12(m,1H),4.72-4.76(m,1H),4.24-4.33(m,2H),3.95-4.00(m,1H),3.82(m,1H),2.79-2.83(m,1H),2.61-2.67(m,1H).

Embodiment 20

2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) methyl acetate 4h (30mg, 0.07mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (5mL * 3) successively, saturated nacl aqueous solution washing (5mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-(3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 20 (20mg, white solid), productive rate: 74.1%.

MS m/z(ESI):389.1[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.58(m,1H),7.50-7.52(m,1H),7.29-7.35(m,2H),6.78(s,1H),6.48(s,1H),5.07-5.09(m,1H),4.72-4.77(m,1H),4.24-4.32(m,2H),3.91-3.96(m,1H),3.82(m,1H),2.79-2.83(m,1H),2.60-2.67(m,1H).

Embodiment 21

2-((3S, 8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(2', 6'-dimethyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 9 (90mg, 0.22mmol) carry out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column AD-s Chiralpak 4.6, moving phase: ethanol/vinyl cyanide/acetic acid=90/10/0.1 with Preparation equipment, flow velocity: 0.5mL/ minute), collect its respective components, the rotary evaporation desolventizing obtains title product 2-((3S, 8S)-3-(2', 6'-dimethyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 21 (54mg, white solid).

¹H NMR(400MHz,CDCl ₃)δ7.42-7.49(m,3H),7.13-7.21(m,4H),6.78(s,1H),6.48(s,1H),5.14(m,1H),4.74(m,1H),4.26-4.35(m,2H),3.98(m,1H),3.82(m,1H),2.79(m,1H),2.65(m,1H),2.05(s,3H),2.02(s,3H).

Embodiment 22

2-((3S, 8S)-3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With (S)-2-(3-(2'-methyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 16 (105mg, 0.26mmol) carry out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column AD-H Chiralpak 4.6 with Preparation equipment, moving phase: ethanol: vinyl cyanide: acetic acid=90/10/0.1 (v/v/v), flow velocity: 0.5mL/ minute), collect its respective components, the rotary evaporation desolventizing, obtain title product 2-((3S, 8S)-3-(2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 22 (39mg, white solid).

¹H NMR(400MHz,CDCl ₃)δ7.27-7.58(m,8H),6.79(s,1H),6.49(s,1H),5.15(m,1H),4.74(m,1H),4.26-4.37(m,2H),4.01(m,1H),3.82(m,1H),2.80-2.83(m,1H),2.65-2.68(m,1H),2.28(s,3H).

Embodiment 23

2-(3-(4'-fluoro-2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-(3-(4'-fluoro-2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-(3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 4h (100mg, 0.25mmol), (4-fluoro-2-methylbenzene base) boric acid (46mg, 0.30mmol), tetra-triphenylphosphine palladium (14mg, 0.01mmol) and cesium carbonate (241mg, 0.74mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 95 ℃, stirring reaction 2 hours.Filter, filter cake washs (10mL * 2) with ethyl acetate, and anhydrous magnesium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtain title product 2-(3-(4'-fluoro-2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5 with silica gel column chromatography, 6-b] [1,4] dioxin-8-yl) methyl acetate 23a (74mg, yellow liquid), productive rate: 69.2%.

MS m/z(ESI):452.2[M+18]

Second step

With 2-(3-(4'-fluoro-2'-methyl-[1, the 1'-xenyl]-the 3-yl)-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 23a (74mg, 0.17mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 3M sodium hydroxide solution (0.5mL, 1.5mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (10mL * 2) successively, saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtain title product 2-(3-(4'-fluoro-2'-methyl-[1,1'-xenyl]-3-yl)-tetrahydrochysene benzfuran also [5 with silica gel column chromatography, 6-b] [1,4] dioxin-8-yl) acetic acid 23 (62mg, white solid), productive rate: 86.6%.

MS m/z(ESI):419.3[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.45-7.49(m,1H),7.38-7.42(m,1H),7.29-7.33(m,2H),7.17-7.21(m,1H),6.93-7.00(m,2H),6.79(s,1H),6.48(s,1H),5.14-5.16(m,1H),4.72-4.76(m,1H),4.24-4.37(m,2H),3.98-4.03(m,1H),3.82(m,1H),2.78-2.84(m,1H),2.61-2.67(m,1H),2.26(s,3H).

Embodiment 24

2-((8S)-3-(2 '-methyl-4 '-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

3-(methyl sulphonyl) propyl group toluenesulfonate

Under the ice bath, 3-(methylthio group) propyl group toluenesulfonate 24a (10.0g, 38.40mmol) is dissolved in the 100mL methyl alcohol, drips 100mL and contain Oxone reagent (35.42g, 57.60mmol) the aqueous solution, naturally rose to stirring at room reaction 2 hours.The reaction solution concentrating under reduced pressure adds 100mL water and 100mL ethyl acetate, the extraction separatory; water ethyl acetate extraction (50mL * 2); merge organic phase, water (30mL * 3) successively, saturated nacl aqueous solution washing (30mL * 3); anhydrous sodium sulfate drying; filter, filtrate decompression is concentrated, obtains crude product title product 3-(methyl sulphonyl) propyl group toluenesulfonate 24b (8.0g; white solid), product is not purified directly carries out next step reaction.

MS m/z(ESI):310.1[M+18]

Second step

1-bromo-2-methyl-4-(3-(methylsulfonyl) propoxy-) benzene

With crude product 3-(methyl sulphonyl) propyl group toluenesulfonate 24b (1.87g; 6.42mmol); 4-bromo-3-methylphenol (1.0g; 5.34mmol) and salt of wormwood (1.47g; 10.68mmol) be dissolved in 20mLN; in the dinethylformamide, be heated to 95 ℃, stirring reaction 2 hours.Add 50mL water and 50mL ethyl acetate; stirred 30 minutes; the extraction separatory; water ethyl acetate extraction (30mL * 2); merge organic phase; water (30mL * 3) successively; saturated nacl aqueous solution washing (30mL * 3); anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 1-bromo-2-methyl-4-(3-(methylsulfonyl) propoxy-) benzene 24c (1.27g, yellow solid), productive rate: 77.4%.

The 3rd step

4,4,5,5-tetramethyl--2-(2-methyl-4-(3-(methylsulfonyl) propoxy-) phenyl)-1,3,2-dioxy boron penta ring

With 1-bromo-2-methyl-4-(3-(methylsulfonyl) propoxy-) benzene 24c (640mg; 2.08mmol), two valeryl two boron (738mg; 3.12mmol), 1; two (diphenylphosphine) ferrocene of 1'-] palladium chloride (76mg; 0.10mmol) and Potassium ethanoate (510mg; 5.20mmol) be dissolved in the 15mL glycol dimethyl ether, be heated to 90 ℃, stirring reaction 3 hours.Filter; filtrate decompression is concentrated; with eluent system B purifying gained resistates, obtain title product 4,4 with silica gel column chromatography; 5; 5-tetramethyl--2-(2-methyl-4-(3-(methylsulfonyl) propoxy-) phenyl)-1,3,2-dioxy boron penta ring 24d (930mg; brown liquid), productive rate: 100.0%.

MS m/z(ESI):372.2[M+18]

The 4th step

2-((8S)-3-(2 '-methyl-4 '-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2; 3; 7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also; 4] dioxin-8-yl) methyl acetate 6c (150mg; 0.37mmol), 4,4; 5; 5-tetramethyl--2-(2-methyl-4-(3-(methylsulfonyl) propoxy-) phenyl)-1,3,2-dioxy boron penta ring 24d (157mg; 0.44mmol); tetra-triphenylphosphine palladium (21mg, 0.021mmol) and yellow soda ash (118mg, 1.11mmol) are dissolved in 4.5mL dioxane and water (V/V=8:1) mixed solvent; be heated to 90 ℃, stirring reaction 12 hours.Filter, filter cake washs (5mL * 4) with ethyl acetate, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(2 '-methyl-4 '-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 24e (170mg, yellow liquid), productive rate: 83.3%.

MS m/z(ESI):570.3[M+18]

The 5th step

With 2-((8S)-3-(2 '-methyl-4 '-(3-(methylsulfonyl) propoxy-)-[1, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 24e (65mg, 0.12mmol) is dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, dripping 1M hydrochloric acid is 3 ~ 4 to reaction solution pH, the extraction separatory, and organic phase is water (5mL * 3) successively, saturated nacl aqueous solution washing (5mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(2 '-methyl-4 '-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 24 (24mg, white solid), productive rate: 38.1%.

MS m/z(ESI):537.4[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.42-7.45(m,1H),7.30-7.38(m,3H),7.16-7.18(m,1H),6.79-6.82(m,3H),6.48(s,1H),5.13-5.15(m,1H),4.72-4.76(m,1H),4.24-4.36(m,2H),4.14-4.17(m,2H),3.98-4.03(m,1H),3.82(m,1H),3.27-3.31(m,2H),2.98(s,3H),2.78-2.82(m,1H),2.60-2.67(m,1H),2.38-2.39(m,2H),2.26(s,3H).

Embodiment 25

2-((8S)-3-(2 '-chloro-4 '-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

1-bromo-2-chloro-4-(3-(methylsulfonyl) propoxy-) benzene

With crude product 3-(methyl sulphonyl) propyl group toluenesulfonate 24b (676mg; 2.31mmol); 4-bromo-3-chlorophenol (400mg; 1.93mmol) and salt of wormwood (532mg; 3.86mmol) be dissolved in 10mLN; in the dinethylformamide, be heated to 90 ℃, stirring reaction 2 hours.Add 50mL water and 50mL ethyl acetate; the extraction separatory; water ethyl acetate extraction (30mL * 3); merge organic phase; water (30mL * 3) successively; saturated nacl aqueous solution washing (30mL * 3); anhydrous sodium sulfate drying; filter; filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 1-bromo-2-chloro-4-(3-(methylsulfonyl) propoxy-) benzene 25a (540mg with silica gel column chromatography; white solid), productive rate: 85.6%.

Second step

4,4,5,5-tetramethyl--2-(2-chloro-4-(3-(methylsulfonyl) propoxy-) phenyl)-1,3,2-dioxy boron penta ring

With 1-bromo-2-chloro-4-(3-(methylsulfonyl) propoxy-) benzene 25a (300mg; 0.92mmol), two valeryl two boron (324mg; 1.37mmol), 1; two (diphenylphosphine) ferrocene of 1'-] palladium chloride (34mg; 0.05mmol) and Potassium ethanoate (225mg; 2.29mmol) be dissolved in the 10mL glycol dimethyl ether, be heated to 90 ℃, stirring reaction 3 hours.Filter; filtrate decompression is concentrated; with eluent system B purifying gained resistates, obtain title product 4,4 with silica gel column chromatography; 5; 5-tetramethyl--2-(2-chloro-4-(3-(methylsulfonyl) propoxy-) phenyl)-1,3,2-dioxy boron penta ring 25b (190mg; yellow liquid), productive rate: 55.4%.

MS m/z(ESI):392.0[M+18]

The 3rd step

2-((8S)-3-(2 '-chloro-4 '-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2; 3; 7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also; 4] dioxin-8-yl) methyl acetate 6c (85mg; 0.21mmol), 4,4; 5; 5-tetramethyl--2-(2-chloro-4-(3-(methylsulfonyl) propoxy-) phenyl)-1,3,2-dioxy boron penta ring 25b (94mg; 0.25mmol); tetra-triphenylphosphine palladium (12mg, 0.01mmol) and yellow soda ash (67mg, 0.63mmol) are dissolved in 4.5mL dioxane and water (V/V=8:1) mixed solvent; be heated to 90 ℃, stirring reaction 12 hours.Filter, filter cake washs (5mL * 2) with ethyl acetate, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(2 '-chloro-4 '-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 25c (82mg, yellow liquid), productive rate: 68.3%.

MS m/z(ESI):590.5[M+18]

The 4th step

With 2-((8S)-3-(2 '-chloro-4 '-(3-(methylsulfonyl) propoxy-)-[1, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 25c (82mg, 0.14mmol) is dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, dripping 1M hydrochloric acid is 3 ~ 4 to reaction solution pH, the extraction separatory, and organic phase is water (5mL * 3) successively, saturated nacl aqueous solution washing (5mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(2 '-chloro-4 '-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 25 (66mg, white solid), productive rate: 82.5%.

MS m/z(ESI):557.3[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.40-7.49(m,4H),7.27-7.29(m,1H),7.02-7.03(m,1H),6.86-6.89(m,1H),6.79(s,1H),6.49(s,1H),5.14-5.16(m,1H),4.72-4.76(m,1H),4.24-4.37(m,2H),4.15-4.18(m,2H),3.98-4.03(m,1H),3.82(m,1H),3.26-3.30(m,2H),2.99(s,3H),2.78-2.84(m,1H),2.61-2.67(m,1H),2.36-2.42(m,2H).

Embodiment 26

3-(3-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid

The first step

3-(4-hydroxyl-3-iodophenyl) methyl propionate

Under the ice bath, with 3-(4-hydroxy phenyl) methyl propionate 26a (1.0g, 5.60mmol) be dissolved in the 15mL Glacial acetic acid, add the 0.5mL vitriol oil, drip again 5mL and contain N-N-iodosuccinimide (1.2g, 5.60mmol) glacial acetic acid solution, naturally rose to stirring at room reaction 12 hours.Reaction solution is poured in the 100mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, use successively saturated sodium thiosulfate solution (100mL * 2), saturated nacl aqueous solution washing (100mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 3-(4-hydroxyl-3-iodophenyl) methyl propionate 26b (700mg, white solid), productive rate: 41.0%.

Second step

2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl) oxyethane

With 2,6-dimethyl-4-(3-(methylsulfonyl) propoxy-)-3 '-vinyl biphenyl 1b (3.10g, 9mmol) be dissolved in the 50mL methylene dichloride, add sodium bicarbonate (3.0g, 36mmol) and metachloroperbenzoic acid (5.40g, 31.50mmol), stirring reaction 12 hours.Pour reaction solution into 100mL saturated sodium thiosulfate solution, with dichloromethane extraction (100mL * 2), merge organic phase, with saturated nacl aqueous solution washing (100mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl) oxyethane 26c (980mg, the white oily), productive rate: 30.6%.

The 3rd step

3-(4-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2-hydroxyl-oxethyl)-3-iodophenyl) methyl propionate

With 2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1, the 1'-xenyl]-the 3-yl) oxyethane 26c (400mg, 1.10mmol), 3-(4-hydroxyl-3-iodophenyl) methyl propionate 26b (440mg, 1.10mmol), Red copper oxide (24mg, 0.17mmol), cesium carbonate (720mg, 2.20mmol) and 1,10-phenanthrolene (59mg, 0.33mmol) is dissolved in 10mLN, in the dinethylformamide, be warming up to 110 ℃, stirring reaction 12 hours.Reaction solution is poured in the 100mL water; with ethyl acetate extraction (80mL * 2); merge organic phase; with saturated nacl aqueous solution washing (50mL * 3); anhydrous magnesium sulfate drying; filter; concentrating under reduced pressure filtrate; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 3-(4-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2-hydroxyl-oxethyl)-3-iodophenyl) methyl propionate 26d (200mg; yellow oily), productive rate: 41.0%.

The 4th step

3-(4-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2-hydroxyl-oxethyl)-3-iodophenyl) propionic acid

With 3-(4-(2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-the 2-hydroxyl-oxethyl)-the 3-iodophenyl) methyl propionate 26d (150mg; 0.30mmol) be dissolved in the 10mL methyl alcohol; add lithium hydroxide (72mg; 3mmol), be warming up to return stirring reaction 3 hours.Be cooled to room temperature; with the reaction solution concentrating under reduced pressure; pour in the 50mL water; drip 1M hydrochloric acid to reaction solution pH be 1 ~ 2; with ethyl acetate extraction (50mL * 3); merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous magnesium sulfate drying; filter; concentrating under reduced pressure filtrate with eluent system A purifying gained resistates, obtains title product 3-(4-(2-(2' with silica gel column chromatography; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-the 2-hydroxyl-oxethyl)-the 3-iodophenyl) propionic acid 26e (70mg, yellow oily), productive rate: 50.0%.

The 5th step

With 3-(4-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2-hydroxyl-oxethyl)-3-iodophenyl) propionic acid 26e (70mg; 0.11mmol); Red copper oxide (3mg, 0.02mmol), cesium carbonate (72mg; 0.22mmol) and 1; 10-phenanthrolene (5.40mg, 0.03mmol) is dissolved in 10mLN, in the dinethylformamide; be warming up to 110 ℃, stirring reaction 12 hours.Reaction solution is poured in the 100mL water; with ethyl acetate extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 3); anhydrous magnesium sulfate drying; filter; concentrating under reduced pressure filtrate with eluent system A purifying gained resistates, obtains title product 3-(3-(2' with silica gel column chromatography; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid 26 (8mg; white solid), productive rate: 14.0%.

MS m/z(ESI):523.2[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.49-7.45(m,1H),7.39-7.38(m,1H),7.27(s,1H)，7.19(s,1H),7.16-7.14(d,1H),6.85(s,1H),6.74-6.72(d,1H),6.66(s,2H),5.15-5.14(m,1H),4.38-4.35(m,1H),4.15-4.12(m,2H),4.04-3.99(m,1H),3.30-3.26(m,2H),2.97(s,3H),2.90-2.86(m,2H),2.67-2.63(m,2H),2.39-2.32(m,2H),2.02-1.99(d,6H).

Embodiment 27

3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid

The first step

(E)-3-(3-hydroxy phenyl) ethyl propenoate

With 3-bromophenol 27a (3.46g, 20.0mmol), acid chloride (220mg, 1mmol), triphenylphosphine (1.05g, 4mmol) be dissolved in 50mLN, in the dinethylformamide, add again ethyl propenoate (6.0g, 60mmol) and triethylamine (7.07g, 70mmol), be warming up to 100 ℃, stirring reaction 12 hours.Add 20mL water and 100mL ethyl acetate, the extraction separatory, organic phase is water (50mL * 3) successively, saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate with eluent system B purifying gained resistates, obtains title product (E)-3-(3-hydroxy phenyl) ethyl propenoate 27b (2.97g with silica gel column chromatography, yellow solid), productive rate: 77.3%.

MS m/z(ESI):193.0[M+1]

Second step

3-(3-hydroxy phenyl) ethyl propionate

(E)-3-(3-hydroxy phenyl) ethyl propenoate 27b (500mg, 2.60mmol) is dissolved in the 20mL ethanol, adds palladium/carbon (50mg, 10%), hydrogen exchange three times, stirring reaction 12 hours.Filter, filtrate decompression is concentrated, obtains crude product title product 3-(3-hydroxy phenyl) ethyl propionate 27c (470mg, yellow oil), and product is not purified directly to carry out next step reaction.

MS m/z(ESI):193.1[M-1]

The 3rd step

3-(3-hydroxyl-4-iodophenyl) ethyl propionate

Under the ice bath, with crude product 3-(3-hydroxy phenyl) ethyl propionate 27c (460mg, 2.37mmol) be dissolved in the 10mL Glacial acetic acid, drip 5mL and contain N-N-iodosuccinimide (533mg, 2.37mmol) glacial acetic acid solution, add again 10 vitriol oils, naturally rise to stirring at room reaction 12 hours.Reaction solution is poured in the 100mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, use successively saturated sodium thiosulfate solution (20mL * 3), saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 3-(3-hydroxyl-4-iodophenyl) ethyl propionate 27d (270mg, yellow liquid), productive rate: 35.6%.

MS m/z(ESI):318.9[M-1]

The 4th step

With 2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1, the 1'-xenyl]-the 3-yl) oxyethane 26c (563mg, 1.56mmol), 3-(3-hydroxyl-4-iodophenyl) ethyl propionate 27d (250mg, 0.78mmol), Red copper oxide (18mg, 0.12mmol), cesium carbonate (477mg, 1.56mmol) and 1,10-phenanthrolene (42mg, 0.23mmol) is dissolved in 10mLN, in the dinethylformamide, be warming up to 110 ℃, stirring reaction 12 hours.Add 30mL water and 30mL ethyl acetate; the extraction separatory; water ethyl acetate extraction (15mL * 3); merge organic phase; water (20mL * 3) successively, saturated nacl aqueous solution washing (20mL * 3), anhydrous magnesium sulfate drying; filter; concentrating under reduced pressure filtrate with eluent system A purifying gained resistates, obtains title product 3-(2-(2' with silica gel column chromatography; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid 27 (15mg; yellow solid), productive rate: 3.6%.

MS m/z(ESI):523.26[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.46-7.49(m,1H),7.38-7.40(m,1H),7.14-7.19(m,2H),6.79-6.92(m,2H),6.72-6.74(m,1H),6.66(s,2H),5.13-5.15(m,1H),4.36-4.39(m,1H),4.12-4.15(m,2H),4.00-4.06(m,1H),3.26-3.30(m,2H),2.98(s,3H),2.87-2.91(m,2H),2.64-2.68(m,2H),2.33-2.40(m,2H),2.03(s,3H),2.00(s,3H).

Embodiment 28

2-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) cyclopropanecarboxylic acid

The first step

(E)-3-(3-p-methoxy-phenyl) ethyl propenoate

With 1-bromo-4-anisole 28a (10.0g, 57.80mmol), acid chloride (649mg, 2.89mmol), triphenylphosphine (3.03g, 11.56mmol) be dissolved in 50mLN, in the dinethylformamide, add again ethyl propenoate (17.34g, 173.40mmol) and triethylamine (20.43g, 202.30mmol), be warming up to 90 ℃, stirring reaction 12 hours.Reaction solution is poured in the 100mL water, with ethyl acetate extraction (100mL * 2), merge organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate with eluent system B purifying gained resistates, obtains title product (E)-3-(3-p-methoxy-phenyl) ethyl propenoate 28b (6.50g with silica gel column chromatography, the white oily), productive rate: 58.5%.

Second step

2-(4-p-methoxy-phenyl) cyclopropanecarboxylic acid ethyl ester

With sodium hydride (464mg, 11.60mmol) and Trimethylsulfoxonium Iodide (2.60g, 11.60mmol) be dissolved in the 20mL dimethyl sulfoxide (DMSO), stirred 1 hour, add (E)-3-(3-p-methoxy-phenyl) ethyl propenoate 28b (1.20g, 5.80mmol), stirring reaction 1 hour.Reaction solution is poured in the 100mL water, with ethyl acetate extraction (50mL * 2), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate with eluent system B purifying gained resistates, obtains title product 2-(4-p-methoxy-phenyl) cyclopropanecarboxylic acid ethyl ester 28c (160mg with silica gel column chromatography, white solid), productive rate: 12.7%.

The 3rd step

2-(4-hydroxy phenyl) cyclopropanecarboxylic acid ethyl ester

Under-78 ℃, 2-(4-p-methoxy-phenyl) cyclopropanecarboxylic acid ethyl ester 28c (160mg, 0.77mmol) is dissolved in the 20mL methylene dichloride, drips the dichloromethane solution of 0.8mL2M boron tribromide, stirring reaction 15 minutes rises to 0 ℃ of stirring reaction 12 hours again.Reaction solution is poured in the 100mL saturated ammonium chloride solution, with ethyl acetate extraction (50mL * 2), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate with eluent system B purifying gained resistates, obtains title product 2-(4-hydroxy phenyl) cyclopropanecarboxylic acid ethyl ester 28d (195mg with tlc, white solid), productive rate: 57.8%.

The 4th step

2-(4-hydroxyl-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

Under the ice bath, 2-(4-hydroxy phenyl) cyclopropanecarboxylic acid ethyl ester 28d (195mg, 0.95mmol) is dissolved in the 20mL Glacial acetic acid, add N-N-iodosuccinimide (202mg, 0.90mmol), add again the 1mL vitriol oil, naturally rise to stirring at room reaction 12 hours.Reaction solution is poured in the 50mL water, with ethyl acetate extraction (50mL * 2), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-(4-hydroxyl-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28e (230mg with silica gel column chromatography, white liquid), productive rate: 73.0%.

The 5th step

2-(4-(2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl) oxyethyl group)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

With 2-(4-hydroxyl-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28e (230mg, 0.69mmol), 2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethanol 1d (340mg, 0.69mmol) and azo two formyls two piperidines (277mg, 1.10mmol) be dissolved in the 10mL toluene, add tri-n-butyl phosphine (222mg, 1.10mmol), be heated to 50 ℃, stirring reaction 12 hours.Reaction solution is poured in the 50mL water; with ethyl acetate extraction (50mL * 2); merge organic phase; with saturated nacl aqueous solution washing (50mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression is concentrated; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 2-(4-(2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl) oxyethyl group)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28f (320mg; white liquid), productive rate: 57.0%.

The 6th step

2-(4-(1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2-hydroxyl-oxethyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

With 2-(4-(2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl) oxyethyl group)-the 3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28f (320mg; 0.40mmol) be dissolved in the 10mL tetrahydrofuran (THF); the tetrahydrofuran solution that adds the 0.44mL1M tetrabutyl ammonium fluoride, stirring reaction 2 hours.The reaction solution concentrating under reduced pressure; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 2-(4-(1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-the 2-hydroxyl-oxethyl)-the 3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28g (220mg; white solid), productive rate: 80.3%.

The 7th step

2-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) the cyclopropanecarboxylic acid ethyl ester

With 2-(4-(1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-the 2-hydroxyl-oxethyl)-the 3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28g (215mg; 0.31mmol); acid chloride (11mg; 0.05mmol); 2-(di-t-butyl phosphorus)-1; 1'-dinaphthalene (37mg; 0.09mmol) and cesium carbonate (302mg; 0.93mmol) be dissolved in the 10mL toluene, be heated to 50 ℃, stirring reaction 12 hours.Reaction solution is poured in the 50mL water; with ethyl acetate extraction (50mL * 2); merge organic phase; with saturated nacl aqueous solution washing (50mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-(2-(2' with tlc; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) cyclopropanecarboxylic acid ethyl ester 28h (130mg; white liquid), productive rate: 74.3%.

MS m/z(ESI):582.54[M+18]

The 8th step

With 2-(2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) cyclopropanecarboxylic acid ethyl ester 28h (130mg, 0.23mmol) is dissolved in 16mL tetrahydrofuran (THF) and methyl alcohol (V/V=1:15) mixed solvent; add 1M sodium hydroxide solution (1mL; 1mmol), be heated to 70 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure; add 50mL water; drip 1M hydrochloric acid to reaction solution pH be 1 ~ 2; with ethyl acetate extraction (50mL * 2); merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous magnesium sulfate drying; filter; concentrating under reduced pressure filtrate with eluent system A purifying gained resistates, obtains title product 2-(2-(2' with tlc; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) cyclopropanecarboxylic acid 28 (85mg; white solid), productive rate: 69.0%.

MS m/z(ESI):535.49[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.49-7.46(m,1H),7.39-7.37(m,1H),7.18-7.14(m,2H),6.91-6.89(d,1H),6.68-6.65(m,4H),5.14-5.11(m,1H),4.39-4.35(m,1H),4.15-4.12(m,2H),4.04-4.02(m,1H),3.30-3.26(m,2H),2.98(s,3H),2.54-2.52(m,1H),2.38-2.34(m,2H),2.02-1.99(d,6H),1.83-1.82(m,1H),1.64-1.59(m,1H),1.36-1.33(m,1H).

Embodiment 29

(R)-3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid

With 3-(2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [1; 4] dioxin-6-yl) propionic acid 27 (95mg; 0.18mmol) carry out chiral separation; adopt the HPLC method; with chiral column chiral isomer is separated (separation condition: chiral column AD-H Chiralpak 4.6 with Preparation equipment; moving phase: (methyl alcohol: ethanol 1:1) (0.1%TFA): normal hexane=60:40; flow velocity: 0.5mL/ minute); collect its respective components; the rotary evaporation desolventizing obtains title product (R)-3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid 29 (40mg, white solid).

Embodiment 30

(S)-3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid

With 3-(2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [1; 4] dioxin-6-yl) propionic acid 27 (95mg; 0.18mmol) carry out chiral separation; adopt the HPLC method; with chiral column chiral isomer is separated (separation condition: chiral column AD-H Chiralpak 4.6 with Preparation equipment; moving phase: (methyl alcohol: ethanol 1:1) (0.1%TFA): normal hexane=60:40; flow velocity: 0.5mL/ minute); collect its respective components; the rotary evaporation desolventizing obtains title product (S)-3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid 30 (32mg, colourless liquid).

Embodiment 31

3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-7-fluoro-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid

The first step

(E)-3-(2-fluoro-4-hydroxy phenyl) ethyl propenoate

With 4-bromo-3-fluorophenol 31a (5.0g, 26.18mmol), acid chloride (588mg, 2.62mmol), triphenylphosphine (1.37g, 5.24mmol) be dissolved in 30mLN, in the dinethylformamide, add again ethyl propenoate (5.23g, 52.36mmol) and triethylamine (7.93g, 78.54mmol), be warming up to 100 ℃, stirring reaction 72 hours.Add 100mL water and 100mL ethyl acetate, the extraction separatory, water ethyl acetate extraction (50mL * 3), merge organic phase, water (50mL * 3) successively, saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate with eluent system B purifying gained resistates, obtains title product (E)-3-(2-fluoro-4-hydroxy phenyl) ethyl propenoate 31b (4.80g with silica gel column chromatography, yellow solid), productive rate: 87.3%.

MS m/z(ESI):209.1[M-1]

Second step

3-(2-fluoro-4-hydroxy phenyl) ethyl propionate

(E)-3-(2-fluoro-4-hydroxy phenyl) ethyl propenoate 31b (2.0g, 9.52mmol) is dissolved in 15mL methyl alcohol and tetrahydrofuran (THF) (V/V=2:1) mixed solvent, add palladium/carbon (200mg, 10%), hydrogen exchange three times, stirring reaction 12 hours.Filter, filtrate decompression is concentrated, obtains crude product title product 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate 31c (2.0g, yellow oil), and product is not purified directly to carry out next step reaction.

MS m/z(ESI):211.45[M-1]

The 3rd step

3-(2-fluoro-4-hydroxyl-5-iodophenyl) ethyl propionate

Under the ice bath, with crude product 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate 31c (500mg, 2.36mmol) be dissolved in the 10mL Glacial acetic acid, drip 5mL and contain N-N-iodosuccinimide (530mg, 2.36mmol) glacial acetic acid solution, add again 4 vitriol oils, naturally rise to stirring at room reaction 12 hours.Add 150mL water and 150mL ethyl acetate, the extraction separatory, organic phase is used saturated sodium bicarbonate solution (100mL * 3) successively, water (100mL * 3), saturated nacl aqueous solution washing (100mL * 3), anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 3-(2-fluoro-4-hydroxyl-5-iodophenyl) ethyl propionate 31d (600mg, yellow liquid), productive rate: 75.3%.

The 4th step

3-(4-(2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl) oxyethyl group)-2-fluoro-5-iodophenyl) ethyl propionate

With 3-(2-fluoro-4-hydroxyl-5-iodophenyl) ethyl propionate 31d (150mg, 0.44mmol), 2-(tertiary butyl dimethyl Si base)-1-(2 ', 6 '-dimethyl-4 '-(3-(methylsulfonyl) propoxy-) biphenyl-3-yl) ethanol 1d (218mg, 0.44mmol) and azo two formyls two piperidines (179mg, 0.71mmol) be dissolved in the 15mL toluene, add tri-n-butyl phosphine (143mg, 0.71mmol), be heated to 50 ℃, stirring reaction 1.5 hours.Add 20mL methyl alcohol cancellation reaction; the reaction solution concentrating under reduced pressure; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 3-(4-(2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl) oxyethyl group)-2-fluoro-5-iodophenyl) ethyl propionate 31e (220mg, yellow liquid), productive rate: 61.1%.

MS m/z(ESI):830.2[M+18]

The 5th step

3-(4-(1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2-hydroxyl-oxethyl)-2-fluoro-5-iodophenyl) ethyl propionate

With 3-(4-(2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl) oxyethyl group)-2-fluoro-5-iodophenyl) ethyl propionate 31e (210mg; 0.26mmol) be dissolved in the 3mL tetrahydrofuran (THF); the tetrahydrofuran solution that adds the 0.28mL1M tetrabutyl ammonium fluoride, stirring reaction 2 hours.The reaction solution concentrating under reduced pressure; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 3-(4-(1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-the 2-hydroxyl-oxethyl)-2-fluoro-5-iodophenyl) ethyl propionate 31f (110mg; yellow liquid), productive rate: 61.1%.

The 6th step

3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-7-fluoro-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) ethyl propionate

With 3-(4-(1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-the 2-hydroxyl-oxethyl)-2-fluoro-5-iodophenyl) ethyl propionate 31f (110mg; 0.16mmol); acid chloride (5mg; 0.02mmol); 2-(di-t-butyl phosphorus)-1; 1'-dinaphthalene (19mg; 0.05mmol) and cesium carbonate (102mg; 0.31mmol) be dissolved in the 10mL toluene, be heated to 80 ℃, stirring reaction 12 hours.Filter; filtrate decompression is concentrated; with silica gel column chromatography with eluent system B purifying gained resistates; obtain title product 3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-7-fluoro-2; 3-dihydrobenzo [b] [1; 4] dioxin-6-yl) ethyl propionate 31g (70mg, yellow liquid), productive rate: 77.8%.

MS m/z(ESI):588.57[M+18]

The 7th step

With 3-(2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-7-fluoro-2; 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) ethyl propionate 31g (70mg, 0.12mmol) is dissolved in 6mL tetrahydrofuran (THF) and methyl alcohol (V/V=1:5) mixed solvent; add 1M sodium hydroxide solution (1mL; 1mmol), be heated to 70 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure; add 30mL water and 30mL ethyl acetate; drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4; with ethyl acetate extraction (10mL * 2); merge organic phase; water (10mL * 3) successively; saturated nacl aqueous solution washing (10mL * 3); anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product 3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-7-fluoro-2; 3-dihydrobenzo [b] [1; 4] dioxin-6-yl) propionic acid 31 (80mg, white solid), productive rate: 100.0%.

MS m/z(ESI):541.3[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.46-7.49(m,1H),7.36-7.38(m,1H),7.15-7.17(m,2H),6.76-6.782(m,1H),6.68-6.71(m,1H),6.66(s,2H),5.12-5.15(m,1H),4.34-4.37(m,1H),4.12-4.15(m,2H),3.97-4.02(m,1H),3.26-3.30(m,2H),2.98(s,3H),2.88-2.92(m,2H),2.64-2.68(m,2H),2.33-2.40(m,2H),2.02(s,3H),2.00(s,3H).

Embodiment 32

3-((S)-2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl)-the 4-acetylenic acid

The first step

4-hydroxyl-3-benzaldehyde iodine

4-hydroxy benzaldehyde 32a (5.0g, 40.90mmol) is dissolved in the 30mL Glacial acetic acid, adds the glacial acetic acid solution of N-N-iodosuccinimide (9.20g, 40.90mmol), add again the 1mL vitriol oil, stirring reaction 12 hours.Reaction solution is poured in the 50mL water, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate with eluent system A purifying gained resistates, obtains title product 4-hydroxyl-3-benzaldehyde iodine 32b (5.0g with silica gel column chromatography, yellow liquid), productive rate: 49.0%.

Second step

5-(4-hydroxyl-3-iodine benzylidene)-2,2-dimethyl-1,3-diox-4,6-diketone

4-hydroxyl-3-benzaldehyde iodine 32b (2.0g, 8.10mmol) is dissolved in the 20mL water, is warming up to 75 ℃, add 10mL and contain 2,2-dimethyl-1,3-diox-4, the aqueous solution of 6-diketone (1.20g, 40.98.50mmol), stirring reaction 2 hours.Reaction solution is poured in the 50mL water, regulated pH value to 1～2 with the 1M sulphuric acid soln, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains crude product title product 5-(4-hydroxyl-3-iodine benzylidene)-2,2-dimethyl-1,3-diox-4,6-diketone 32c (2.60g, yellow solid), product is not purified directly to carry out next step reaction.

The 3rd step

5-(1-(4-hydroxyl-3-iodophenyl)-2-butyne-1-yl)-2,2-dimethyl-1,3-diox-4,6-diketone

With crude product 5-(4-hydroxyl-3-iodine benzylidene)-2,2-dimethyl-1,3-diox-4,6-diketone 32c (1.0g, 2.70mmol) are dissolved in the 20mL tetrahydrofuran (THF), add 20mL2M1-proyl magnesium bromide, stirring reaction 2 hours.Reaction solution is poured in the 50mL water, regulate pH value to 1～2 with the 1M sulphuric acid soln, ethyl acetate extraction (50mL * 2), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, obtains crude product title product 5-(1-(4-hydroxyl-3-iodophenyl)-2-butyne-1-yl)-2,2-dimethyl-1,3-diox-4,6-diketone 32d (1.10g, yellow solid), product is not purified directly to carry out next step reaction.

MS m/z(ESI):413.1[M-1]

The 4th step

3-(4-hydroxyl-3-iodophenyl)-4-hexin ethyl ester

With crude product 5-(1-(4-hydroxyl-3-iodophenyl)-2-butyne-1-yl)-2,2-dimethyl-1,3-diox-4,6-diketone 32d (1.10g, 2.70mmol) is dissolved in the 1.5mL ethanol, adds the 4.5mL pyridine, be warming up to 80 ℃, stirring reaction 12 hours.The reaction solution concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product 3-(4-hydroxyl-3-iodophenyl)-4-hexin ethyl ester 32e (600mg, yellow liquid), productive rate: 63.0% with silica gel column chromatography.

The 5th step

(R)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl) ethane-1; under 0 ℃ of the 2-glycol; 2,6-dimethyl-4-(3-(methylsulfonyl) propoxy-)-3 '-vinyl biphenyl 1b (3.0g, 8.70mmol) is dissolved in the 200mL trimethyl carbinol and water (V/V=1:1) mixed solvent; add again AD-mix-beta (13.0g), stirring reaction 3 hours.Reaction solution is poured in the 100mL saturated sodium thiosulfate solution; with ethyl acetate extraction (100mL * 2); merge organic phase; with saturated nacl aqueous solution washing (50mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; with eluent system B purifying gained resistates, obtain title product (R)-1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1 with silica gel column chromatography; the 1'-xenyl]-the 3-yl) ethane-1; 2-glycol 32f (1.20g, white solid), productive rate: 36.0%.

The 6th step

(R)-2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl) ethanol

With (R)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl) ethane-1,2-glycol 32f (1.10g; 2.90mmol); imidazoles (395mg, 5.80mmol) and DMAP (26mg, 0.29mmol) are dissolved in 20mLN; in the dinethylformamide; add TERT-BUTYL DIMETHYL CHLORO SILANE (482mg, 3.20mmol), stirring reaction 2 hours.Add 100mL water; with ethyl acetate extraction (50mL * 2); merge organic phase; with saturated nacl aqueous solution washing (50mL * 2); anhydrous magnesium sulfate drying; filter; concentrating under reduced pressure filtrate; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (R)-2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl) ethanol 32g (900mg; white oily matter), productive rate: 62.9%.

The 7th step

3-(4-((S)-2-((t-Butyldimethylsilyl) oxygen base)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl) oxyethyl group)-the 3-iodophenyl)-4-hexin ethyl ester

With 3-(4-hydroxyl-3-iodophenyl)-4-hexin ethyl ester 32e (240mg; 0.67mmol); (R)-2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl) ethanol 32g (300mg; 0.61mmol) and azo two formyls two piperidines (247mg; 0.98mmol) be dissolved in the 10mL toluene; add tri-n-butyl phosphine (198mg; 0.98mmol); be heated to 50 ℃, stirring reaction 12 hours.Add 50mL water; with ethyl acetate extraction (25mL * 2); merge organic phase; with saturated nacl aqueous solution washing (25mL * 3); anhydrous magnesium sulfate drying; filter; concentrating under reduced pressure filtrate; obtain crude product title product 3-(4-((S)-2-((t-Butyldimethylsilyl) oxygen base)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl) oxyethyl group)-the 3-iodophenyl)-4-hexin ethyl ester 32h (500g, yellow liquid), product is not purified directly to carry out next step reaction.

The 8th step

3-(4-((S)-1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2-hydroxyl-oxethyl-3-iodophenyl)-4-hexin ethyl ester

With crude product 3-(4-((S)-2-((t-Butyldimethylsilyl) oxygen base)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl) oxyethyl group)-the 3-iodophenyl)-4-hexin ethyl ester 32h (500mg; 0.60mmol) be dissolved in the 10mL tetrahydrofuran (THF); add 1M tetrabutyl ammonium fluoride (0.66mL; 0.66mmol) tetrahydrofuran solution, stirring reaction 1 hour.Add 25mL water; with ethyl acetate extraction (20mL * 2); merge organic phase; with saturated nacl aqueous solution washing (20mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated; with tlc with eluent system B purifying gained resistates; obtain title product 3-(4-((S)-1-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2-hydroxyl-oxethyl-3-iodophenyl)-4-hexin ethyl ester 32i (300mg; yellow oily), productive rate: 77.9%.

MS m/z(ESI):736.4[M+18]

The 9th step

3-((S)-2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl)-4-acetylenic acid ethyl ester

With 3-(4-((S)-1-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2-hydroxyl-oxethyl-3-iodophenyl)-4-hexin ethyl ester 32i (300mg; 0.42mmol); acid chloride (14mg; 0.06mmol); 2-(di-t-butyl phosphorus)-1; 1'-dinaphthalene (52mg; 0.13mmol) and cesium carbonate (409mg; 1.26mmol) be dissolved in the 10mL toluene, be heated to 50 ℃, stirring reaction 12 hours.Add 20mL water; with ethyl acetate extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 3); anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 3-((S)-2-(2' with tlc; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl)-4-acetylenic acid ethyl ester 32j (180mg; yellow oily), productive rate: 72.9%.

The tenth step

With 3-((S)-2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl)-4-acetylenic acid ethyl ester 32j (180mg, 0.31mmol) is dissolved in 16mL tetrahydrofuran (THF) and methyl alcohol (V/V=1:15) mixed solvent; add 1M sodium hydroxide solution (1mL; 1mmol), be heated to 70 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure; add 25mL water; drip 1M hydrochloric acid to reaction solution pH be 1 ~ 2; with ethyl acetate extraction (25mL * 2); merge organic phase, with saturated nacl aqueous solution washing (25mL * 2), anhydrous magnesium sulfate drying; filter; filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtains title product 3-((S)-2-(2' with silica gel column chromatography; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl)-4-acetylenic acid 32 (140mg; white solid), productive rate: 81.9%.

MS m/z(ESI):580.4[M+18]

¹H NMR(400MHz,CDCl ₃)δ7.49-7.45(m,1H),7.39-7.37(m,1H),7.18-7.14(m,2H),7.00-6.99(m,1H),6.92-6.89(m,2H),6.65(s,2H),5.15-5.13(m,1H),4.39-4.36(m,1H),4.15-4.10(m,2H),4.04-4.00(m,2H),3.30-3.26(m,2H),2.97(s,3H),2.83-2.69(m,2H),2.39-2.34(m,2H),2.02-1.99(m,6H),1.84(m,3H).

Embodiment 33

(R)-3-((S)-2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl)-the 4-acetylenic acid

With 3-((S)-2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [1; 4] dioxin-6-yl)-4-acetylenic acid 32 (140mg; 0.25mmol) carry out chiral separation; adopt the HPLC method; with chiral column chiral isomer is separated (separation condition: chiral column ADH CHIRALPAK4.6 with Preparation equipment; moving phase: ethanol/vinyl cyanide/acetic acid=95/5/0.1; flow velocity: 0.8mL/ minute); collect its respective components; the rotary evaporation desolventizing obtains title product (R)-3-((S)-2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl)-4-acetylenic acid 33 (60mg, white solid).

Embodiment 34

(S)-3-((S)-2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl)-the 4-acetylenic acid

With 3-((S)-2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [1; 4] dioxin-6-yl)-4-acetylenic acid 32 (140mg; 0.25mmol) carry out chiral separation; adopt the HPLC method; with chiral column chiral isomer is separated (separation condition: chiral column ADH CHIRALPAK 4.6 with Preparation equipment; moving phase: ethanol/vinyl cyanide/acetic acid=95/5/0.1; flow velocity: 0.8mL/ minute); collect its respective components; the rotary evaporation desolventizing obtains title product (S)-3-((S)-2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-2; 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl)-4-acetylenic acid 34 (76mg, white solid).

Embodiment 35

2-(2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) cyclopropanecarboxylic acid

The first step

2-(4-(2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

With 2-(4-hydroxyl-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28e (230mg, 0.69mmol), 2-((tertiary butyl dimethylsilane) oxygen)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) ethanol 13g (250mg, 0.69mmol) and azo two formyls two piperidines (277mg, 1.10mmol) be dissolved in the 10mL toluene, add tri-butyl phosphine (223mg, 1.10mmol), be heated to 50 ℃, stirring reaction 2 hours.The reaction solution concentrating under reduced pressure, obtain crude product title product 2-(4-(2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-and the 3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 35a (460mg, white liquid), product is not purified directly to carry out next step reaction.

Second step

2-(4-(2-hydroxyl-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

With crude product 2-(4-(2-((tertiary butyl dimethyl-silicon) oxygen base)-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-and the 3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 35a (500mg, 0.74mmol) be dissolved in the 10mL tetrahydrofuran (THF), add the tetrahydrofuran solution of 0.82mL1M tetrabutyl ammonium fluoride, stirring reaction 2 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, ((2-hydroxyl-1-(5,5,8 for 4-to obtain title product 2-, 8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-and the 3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 35b (170mg, the white oily), productive rate: 41.0%.

The 3rd step

2-(2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) the cyclopropanecarboxylic acid ethyl ester

((2-hydroxyl-1-(5,5,8 for 4-with 2-, 8-tetramethyl--5,6,7,8-naphthane-2-yl) oxyethyl group)-and the 3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 35b (170mg, 0.30mmol), acid chloride (11mg, 0.05mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (36mg, 0.09mmol) and cesium carbonate (195mg, 0.60mmol) be dissolved in the 10mL toluene, be heated to 50 ℃, stirring reaction 12 hours.Filter, filtrate decompression is concentrated, uses tlc with eluent system B purifying gained resistates, (2-(5,5,8 to obtain title product 2-, 8-tetramethyl--5,6,7,8-naphthane-2-yl)-2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) cyclopropanecarboxylic acid ethyl ester 35c (120mg, white liquid), productive rate: 90.0%.

MS m/z(ESI):452.2[M+18]

The 4th step

(2-(5,5,8 with 2-, 8-tetramethyl--5,6,7,8-naphthane-2-yl)-2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) cyclopropanecarboxylic acid ethyl ester 35c (120mg, 0.30mmol) is dissolved in the 15mL methyl alcohol, adds 1M sodium hydroxide solution (1mL, 1mmol), be heated to return stirring reaction 0.5 hour.The reaction solution concentrating under reduced pressure adds 25mL water, drip 1M hydrochloric acid to reaction solution pH be 1 ~ 2, with ethyl acetate extraction (25mL * 2), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with eluent system B purifying gained resistates, (2-(5 to obtain title product 2-with tlc, 5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) cyclopropanecarboxylic acid 35 (70mg, white solid), productive rate: 62.5%.

MS m/z(ESI):405.3[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.36-7.32(m,2H),7.17-7.15(m,1H),6.91-6.89(m,1H),6.69-6.65(m,2H),5.04-5.02(m,1H),4.35-4.32(m,1H),4.06-4.01(m,1H),2.57-2.53(m,1H),1.86-1.84(m,1H),1.70(s,4H),1.64-160(m,1H),1.36-1.25(m,13H).

Embodiment 36

(R)-3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-7-fluoro-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid

With 3-(2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-7-fluoro-2; 3-dihydrobenzo [b] [1; 4] dioxin-6-yl) propionic acid 31 (80mg; 0.15mmol) carry out chiral separation; adopt the HPLC method; with chiral column chiral isomer is separated (separation condition: chiral column OJ-H CHIRALCEL4.6 with Preparation equipment; moving phase: ethanol: normal hexane: methyl alcohol=45:10:45; flow velocity: 0.5mL/ minute); collect its respective components; the rotary evaporation desolventizing obtains title product (R)-3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-7-fluoro-2; 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid 36 (40mg, brown solid).

Embodiment 37

(S)-3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1,1'-xenyl]-3-yl)-7-fluoro-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid

With 3-(2-(2'; 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-7-fluoro-2; 3-dihydrobenzo [b] [1; 4] dioxin-6-yl) propionic acid 31 (80mg; 0.15mmol) carry out chiral separation; adopt the HPLC method; with chiral column chiral isomer is separated (separation condition: chiral column OJ-H CHIRALCEL4.6 with Preparation equipment; moving phase: ethanol: normal hexane: methyl alcohol=45:10:45; flow velocity: 0.5mL/ minute); collect its respective components; the rotary evaporation desolventizing obtains title product (S)-3-(2-(2', 6'-dimethyl-4'-(3-(methylsulfonyl) propoxy-)-[1; the 1'-xenyl]-the 3-yl)-7-fluoro-2; 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) propionic acid 37 (44mg, brown solid).

Embodiment 38

2-(2-(2'-methyl-[1,1'-xenyl]-3-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) cyclopropanecarboxylic acid

The first step

2-(4-(1-(3-bromophenyl)-2-((tertiary butyl dimethyl-silicon) oxygen base) oxyethyl group)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

With 1-(3-bromophenyl)-2-((tertiary butyl dimethylsilane) oxygen) ethanol 4d (745mg, 2.25mmol), 2-(4-hydroxyl-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 28e (750mg, 2.25mmol) and azo two formyls two piperidines (907mg, 3.60mmol) be dissolved in the 20mL toluene, add tri-n-butyl phosphine (728mg, 3.60mmol), be heated to 50 ℃, stirring reaction 30 minutes.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-(4-(1-(3-bromophenyl)-2-((tertiary butyl dimethyl-silicon) oxygen base) oxyethyl group)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 38a (1.25g, yellow liquid), productive rate: 86.2%.

Second step

2-(4-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester

With 2-(4-(1-(3-bromophenyl)-2-((tertiary butyl dimethyl-silicon) oxygen base) oxyethyl group)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 38a (1.25g, 1.93mmol) be dissolved in the 10mL tetrahydrofuran (THF), the tetrahydrofuran solution that adds the 2.1mL1M tetrabutyl ammonium fluoride, stirring reaction 2 hours.Add 20mL water, with ethyl acetate extraction (20mL * 2), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-(4-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 38b (600mg with silica gel column chromatography, colorless oil), productive rate: 58.3%.

The 3rd step

2-(2-(3-bromophenyl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) the cyclopropanecarboxylic acid ethyl ester

With 2-(4-(1-(3-bromophenyl)-2-hydroxyl-oxethyl)-3-iodophenyl) cyclopropanecarboxylic acid ethyl ester 38b (200mg, 0.38mmol), acid chloride (15mg, 0.06mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (48mg, 0.12mmol) and cesium carbonate (123mg, 0.38mmol) be dissolved in the 10mL toluene, be heated to 50 ℃, stirring reaction 12 hours.Add 20mL water, with ethyl acetate extraction (20mL * 2), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with tlc with eluent system B purifying gained resistates, obtain title product 2-(2-(3-bromophenyl)-2,3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) cyclopropanecarboxylic acid ethyl ester 38c (120mg, colourless liquid), productive rate: 59.2%.

MS m/z(ESI):405.1[M+1]

The 4th step

2-(2-(2'-methyl-[1,1'-xenyl]-3-yl)-2, and 3-dihydrobenzo [b] [Isosorbide-5-Nitrae] dioxin-6-yl) the cyclopropanecarboxylic acid ethyl ester

With 2-(2-(3-bromophenyl)-2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) cyclopropanecarboxylic acid ethyl ester 38c (85mg, 0.21mmol), 2-toluene boric acid (35mg, 0.25mmol), tetra-triphenylphosphine palladium (14mg, 0.01mmol) and cesium carbonate (204mg, 0.63mmol) are dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 3 hours.Add 30mL water, with ethyl acetate extraction (20mL * 2), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtain title product 2-(2-(2'-methyl-[1,1'-xenyl]-3-yl)-2 with silica gel column chromatography, 3-dihydrobenzo [b] [1,4] dioxin-6-yl) cyclopropanecarboxylic acid ethyl ester 38d (80mg, yellow liquid), productive rate: 90.0%.

MS m/z(ESI):432.5[M+18]

The 5th step

With 2-(2-(2'-methyl-[1, the 1'-xenyl]-the 3-yl)-2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) cyclopropanecarboxylic acid ethyl ester 38d (80mg, 0.19mmol) be dissolved in 5.5mL methyl alcohol and tetrahydrofuran (THF) (V/V=10:1) mixed solvent, add 1M sodium hydroxide solution (2mL, 2mmol), be heated to return stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 20mL water, drip 1M hydrochloric acid to reaction solution pH be 1 ~ 2, with ethyl acetate extraction (25mL * 2), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtain title product 2-(2-(2'-methyl-[1,1'-xenyl]-3-yl)-2 with tlc, 3-dihydrobenzo [b] [1,4] dioxin-6-yl) cyclopropanecarboxylic acid 38 (20mg, white solid), productive rate: 26.6%.

MS m/z(ESI):385.1[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.49-7.47(m,1H),7.40-7.36(m,3H),7.28-7.25(m,4H),6.92-6.90(m,1H),6.70-6.66(m,2H),5.16-5.13(m,1H),4.41-4.38(m,1H),4.08-4.03(m,1H),2.55-2.52(m,1H),2.27(s,3H),1.84(m,1H),1.65-1.60(m,1H),1.36-1.33(m,1H).

Embodiment 39

2-((8S)-3-(3-(3 methyl thiophene-2-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((8S)-3-(3-(3 methyl thiophene-2-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 6c (85mg, 0.21mmol), (3 methyl thiophene-2-yl) boric acid (36mg, 0.25mmol), tetra-triphenylphosphine palladium (12mg, 0.01mmol) and cesium carbonate (205mg, 0.63mmol) be dissolved in 4.5mL dioxane and water (V/V=8:1) mixed solvent, be heated to 90 ℃, stirring reaction 12 hours.Filter, filter cake washs (5mL * 2), anhydrous magnesium sulfate drying with ethyl acetate, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(3-(3 methyl thiophene-2-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 39a (60mg, yellow liquid), productive rate: 68.2%.

MS m/z(ESI):440.3[M+18]

Second step

With 2-((8S)-3-(3-(3 methyl thiophene-2-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) methyl acetate 39a (60mg, 0.14mmol) be dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, organic phase is water (5mL * 3) successively, saturated nacl aqueous solution washing (5mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(3-(3 methyl thiophene-2-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 39 (26mg, white solid), productive rate: 44.8%.

MS m/z(ESI):407.3[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.44-7.50(m,3H),7.36-7.37(m,1H),7.23-7.27(m,1H),6.94-6.95(m,1H),6.79(s,1H),6.50(s,1H),5.15-5.17(m,1H),4.72-4.77(m,1H),4.25-4.37(m,2H),3.99-4.04(m,1H),3.79-3.86(m,1H),2.79-2.85(m,1H),2.62-2.69(m,1H),2.33(s,3H).

Embodiment 40

2-((8S)-3-(3-bromo-5-fluorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

3-bromo-5-fluorobenzaldehyde

Under the ice bath, 2M isopropylmagnesium chloride (10mL, 20mmol) is dissolved in the 5mL tetrahydrofuran (THF), drips the tetrahydrofuran solution that 5mL contains 1,3-, two bromo-5-fluorobenzene 40a (4.0g, 15.70mmol), stirred 2 hours, be warming up to again 20 ℃ of reactions 30 minutes.Be cooled to 0 ℃, drip DMF (2.5mL, 31.50mmol), stirring reaction 1.5 hours rises to stirring at room reaction 12 hours.Add 20mL saturated ammonium chloride solution cancellation reaction, with ethyl acetate extraction (50mL * 3), merge organic phase, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 3-bromo-5-fluorobenzaldehyde 40b (2.57g, yellow liquid), productive rate: 81.0%.

Second step

1-bromo-3-fluoro-5-vinyl benzene

With methyltriphenylphospbromide bromide phosphorus (3.70g, 10.30mmol) and potassium tert.-butoxide (867mg, 7.70mmol) be dissolved in the 40mL tetrahydrofuran (THF), stirred 1 hour, ice bath is cooled to 0 ℃, drip the tetrahydrofuran solution that 20mL contains 3-bromo-5-fluorobenzaldehyde 40b (1.50g, 7.40mmol), rise to stirring at room reaction 3.5 hours.Add 20mL saturated ammonium chloride solution cancellation reaction, with normal hexane extraction (50mL * 3), merge organic phase, anhydrous magnesium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-bromo-3-fluoro-5-vinyl benzene 40c (680mg, colourless liquid), productive rate: 46.0%.

The 3rd step

1-(3-bromo-5-fluorophenyl) ethane-1, the 2-glycol

With N-methyl morpholine oxide (2.55g, 21.70mmol) and perosmic anhydride (500mg, 1.96mmol) be dissolved in 30mL water, in acetone and the trimethyl carbinol (V/V/V=19:8:3) mixed solvent, add 13mL and contain 1-bromo-3-fluoro-5-vinyl benzene 40c (1.45g, 7.25mmol) methylene dichloride and acetone (V/V=10:3) mixed solvent, stirring reaction 2 hours.Add 30mL saturated sodium thiosulfate solution cancellation reaction, with ethyl acetate extraction (50mL * 3), merge organic phase, anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtain title product 1-(3-bromo-5-fluorophenyl) ethane-1,2-glycol 40d (1.25g with silica gel column chromatography, colourless liquid), productive rate: 73.0%.

The 4th step

1-(3-bromo-5-fluorophenyl)-2-((tertiary butyl dimethylsilane) oxygen) ethanol

With 1-(3-bromo-5-fluorophenyl) ethane-1,2-glycol 40d (1.25g, 5.30mmol), imidazoles (0.54g, 7.90mmol) is dissolved in the 30mL methylene dichloride, adds TERT-BUTYL DIMETHYL CHLORO SILANE (0.84g again, 5.60mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-(3-bromo-5-fluorophenyl)-2-((tertiary butyl dimethylsilane) oxygen) ethanol 40e (1.0g, colourless liquid), productive rate: 54.0%.

The 5th step

2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-2-((tertiary butyl dimethyl-silicon) oxygen) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 1-(3-bromo-5-fluorophenyl)-2-((tertiary butyl dimethylsilane) oxygen) ethanol 40e (172mg, 0.49mmol), (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1f (150mg, 0.45mmol) and azo two formyls two piperidines (181mg, 0.72mmol) are dissolved in the 5mL toluene, add tri-n-butyl phosphine (145mg, 0.72mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-2-((tertiary butyl dimethyl-silicon) oxygen) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 40f (260mg, colourless liquid), productive rate: 87.0%.

The 6th step

2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-2-((tertiary butyl dimethyl-silicon) oxygen) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 40f (260mg, 0.39mmol) be dissolved in the 20mL tetrahydrofuran (THF), add 1M tetrabutyl ammonium fluoride (0.6mL, 0.60mmol), stirring reaction 0.5 hour.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 40g (178mg, white liquid), productive rate: 82.7%.

The 7th step

2-((8S)-3-(3-bromo-5-fluorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((3S)-6-(1-(3-bromo-5-fluorophenyl)-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 40g (178mg, 0.32mmol), acid chloride (22mg, 0.10mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (77mg, 0.19mmol) and cesium carbonate (210mg, 0.65mmol) are dissolved in the 5mL toluene, be heated to 50 ℃, stirring reaction 12 hours.Filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(3-bromo-5-fluorophenyl)-2,3 with tlc, 7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 40h (26mg, colourless liquid), productive rate: 19.0%.

The 8th step

With 2-((8S)-3-(3-bromo-5-fluorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 40h (26mg, 0.06mmol) is dissolved in 5mL methyl alcohol, in tetrahydrofuran (THF) and water (V/V/V=1:3:1) mixed solvent, add lithium hydroxide (13mg, 0.31mmol), be heated to 50 ℃, stirring reaction 1.5 hours.The reaction solution concentrating under reduced pressure adds 10mL water, drip 1M hydrochloric acid to reaction solution pH be 1, with dichloromethane extraction (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-((8S)-3-(3-bromo-5-fluorophenyl)-2 with tlc, 3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 40 (16mg, white solid), productive rate: 64.0%.

MS m/z(ESI):409.1[M+1]

¹H NMR(400MHz,CDCl ₃)δ7.40(s,1H),7.29(d,1H),7.13(d,1H),6.81(s,1H),6.51(s,1H),5.12(d,1H),4.78(t,1H),4.28-4.36(m,2H),3.94-3.97(m,1H),3.84-3.86(m,1H),2.81-2.87(m,1H),2.64-2.71(m,1H).

Embodiment 41

2-((3S, 8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 6 (212mg, 0.54mmol) carries out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column OJ-RH CHIRALCEL4.6, moving phase: normal hexane/ethanol/acetic acid=80/20/0.1 (V/V/V), flow velocity: 1.0mL/ minute) with Preparation equipment, collect its respective components, the rotary evaporation desolventizing obtains title product 2-((3S, 8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 41 (79mg, white solid).

Embodiment 42

2-((3R, 8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 6 (212mg, 0.54mmol) carries out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column OJ-RH CHIRALCEL4.6, moving phase: normal hexane/ethanol/acetic acid=80/20/0.1 (V/V/V), flow velocity: 1.0mL/ minute) with Preparation equipment, collect its respective components, the rotary evaporation desolventizing obtains title product 2-((3R, 8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 42 (65mg, white solid).

Embodiment 43

2-((8S)-3-(3-(3,5-dimethyl isoxazole-4-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((8S)-3-(3-(3,5-dimethyl isoxazole-4-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 6c (100mg, 0.25mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-base) isoxazole (66mg, 0.30mmol), tetra-triphenylphosphine palladium (14mg, 0.01mmol) and yellow soda ash (79mg, 0.74mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 12 hours.Filter, filter cake washs (5mL * 2), anhydrous magnesium sulfate drying with ethyl acetate, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(3-(3,5-dimethyl isoxazole-4-yl) phenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 43a (70mg, yellow liquid), productive rate: 67.3%.

MS m/z(ESI):422.4[M+1]

Second step

((3-(3 for (8S)-3-with 2-, 5-dimethyl isoxazole-4-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 43a (70mg, 0.17mmol) is dissolved in 5mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, dripping 1M hydrochloric acid is 3 ~ 4 to reaction solution pH, the extraction separatory, and organic phase is water (10mL * 2) successively, saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(3-(3,5-dimethyl isoxazole-4-yl) phenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 43 (63mg, white solid), productive rate: 92.6%.

MS m/z(ESI):406.3[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.48-7.52(m,1H),7.39-7.41(m,1H),7.27-7.30(m,2H),6.79(s,1H),6.49(s,1H),5.16-5.18(m,1H),4.72-4.77(m,1H),4.25-4.37(m,2H),3.98-4.03(m,1H),3.81-3.82(m,1H),2.78-2.84(m,1H),2.61-2.68(m,1H),2.41(s,3H),2.28(s,3H),.

Embodiment 44

2-((8S)-3-(2'-chloro-[1,1'-xenyl]-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((8S)-3-(2'-chloro-[1,1'-xenyl]-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 6c (200mg, 0.50mmol), (2-chloro-phenyl-) boric acid (93mg, 0.60mmol), tetra-triphenylphosphine palladium (29mg, 0.02mmol) and cesium carbonate (482mg, 1.48mmol) be dissolved in 11mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 12 hours.Filter, anhydrous magnesium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-((8S)-3-(2'-chloro-[1 with silica gel column chromatography, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 44a (144mg, yellow liquid), productive rate: 66.7%.

MS m/z(ESI):454.3[M+18]

Second step

With 2-((8S)-3-(2'-chloro-[1, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 44a (144mg, 0.33mmol) is dissolved in 10mL methyl alcohol and tetrahydrofuran (THF) (V/V=4:1) mixed solvent, adds 2M sodium hydroxide solution 1.5mL, be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 20mL water and 20mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, water merges organic phase, successively water (10mL * 3) with ethyl acetate extraction (10mL * 3), saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(2'-chloro-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 44 (112mg, white solid), productive rate: 80.6%.

MS m/z(ESI):421.3[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.43-7.50(m,5H),7.31-7.35(m,3H),6.79(s,1H),6.49(s,1H),5.16-5.18(m,1H),4.72-4.76(m,1H),4.24-4.38(m,2H),3.99-4.04(m,1H),3.82(m,1H),2.79-2.84(m,1H),2.61-2.68(m,1H).

Embodiment 45

2-((8S)-3-(3-(trifluoromethyl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

1-(trifluoromethyl)-3-vinyl benzene

With 3-(trifluoromethyl) phenyl aldehyde 45a (5.0g, 28.70mmol), methyltriphenylphospbromide bromide phosphorus (20.50g, 57.50mmol) and salt of wormwood (9.90g, 71.75mmol) be dissolved in 152mL dioxane and water (V/V=75:1) mixed solvent, be heated to 95 ℃, stirring reaction 12 hours.Add 250mL water and 50mL normal hexane, stirred 10 minutes, the extraction separatory, water merges organic phase, successively water (30mL * 3) with normal hexane extraction (30mL * 3), saturated nacl aqueous solution washing (30mL * 3), anhydrous magnesium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-(trifluoromethyl)-3-vinyl benzene 45b (1.35g, colourless liquid), productive rate: 27.3%.

Second step

1-(3-(trifluoromethyl) phenyl) ethane-1, the 2-glycol

With N-methyl morpholine oxide (2.66g, 22.68mmol) and perosmic anhydride (96mg, 0.38mmol) be dissolved in 40mL water, in acetone and the trimethyl carbinol (V/V/V=5:2:1) mixed solvent, add 13mL and contain 1-(trifluoromethyl)-3-vinyl benzene 45b (1.30g, 7.56mmol) methylene dichloride and acetone (V/V=10:3) mixed solvent, stirring reaction 2 hours.Add 10mL saturated sodium thiosulfate solution cancellation reaction, with ethyl acetate extraction (50mL * 3), merge organic phase, use successively saturated sodium thiosulfate solution (30mL * 3), water (30mL * 3), saturated nacl aqueous solution washing (30mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-(3-(trifluoromethyl) phenyl) ethane-1,2-glycol 45c (1.40g, yellow liquid), productive rate: 90.5%.

The 3rd step

2-((tertiary butyl dimethylsilane) oxygen)-1-(3-(trifluoromethyl) phenyl) ethanol

With 1-(3-(trifluoromethyl) phenyl) ethane-1,2-glycol 45c (1.40g, 6.80mmol), imidazoles (925mg, 13.60mmol) and DMAP (83mg, 0.68mmol) are dissolved in 15mL N, in the dinethylformamide, add again TERT-BUTYL DIMETHYL CHLORO SILANE (1.23g, 8.16mmol), stirring reaction 1 hour.Add 50mL water and 50mL ethyl acetate, stirred 30 minutes, the extraction separatory, water ethyl acetate extraction (20mL * 3), merge organic phase, water (20mL * 3) successively, saturated nacl aqueous solution washing (20mL * 3), anhydrous magnesium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((tertiary butyl dimethylsilane) oxygen)-1-(3-(trifluoromethyl) phenyl) ethanol 45d (1.99g, yellow liquid), productive rate: 91.7%.

MS m/z(ESI):338.3[M+18]

The 4th step

2-((3S)-6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(3-(trifluoromethyl) phenyl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((tertiary butyl dimethylsilane) oxygen)-1-(3-(trifluoromethyl) phenyl) ethanol 45d (144mg, 0.45mmol), (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1f (150mg, 0.45mmol) and azo two formyls two piperidines (181mg, 0.72mmol) are dissolved in the 5mL toluene, add tri-n-butyl phosphine (145mg, 0.72mmol), be heated to 50 ℃, stirring reaction 1 hour.Add 10mL methyl alcohol, the reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(3-(trifluoromethyl) phenyl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 45e (250mg, yellow liquid), productive rate: 87.4%.

MS m/z(ESI):654.4[M+18]

The 5th step

2-((3S)-6-(2-hydroxyl-1-(3-(trifluoromethyl) phenyl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((3S)-6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(3-(trifluoromethyl) phenyl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 45e (250mg, 0.39mmol) be dissolved in the 10mL tetrahydrofuran (THF), add 1M tetrabutyl ammonium fluoride (0.5mL, 0.50mmol), stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(2-hydroxyl-1-(3-(trifluoromethyl) phenyl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 45f (160mg, yellow liquid), productive rate: 78.0%.

MS m/z(ESI):523.1[M+1]

The 6th step

2-((8S)-3-(3-(trifluoromethyl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((3S)-6-(2-hydroxyl-1-(3-(trifluoromethyl) phenyl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 45f (160mg, 0.31mmol), acid chloride (21mg, 0.10mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (73mg, 0.18mmol) and cesium carbonate (199mg, 0.61mmol) are dissolved in the 15mL toluene, be heated to 50 ℃, stirring reaction 12 hours.Add 30mL water and 30mL ethyl acetate, the extraction separatory, water ethyl acetate extraction (10mL * 3), merge organic phase, water (15mL * 3) successively, saturated nacl aqueous solution washing (15mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(3-(trifluoromethyl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 45g (100mg, yellow liquid), productive rate: 82.6%.

MS m/z(ESI):412.1[M+1]

The 7th step

With 2-((8S)-3-(3-(trifluoromethyl) phenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 45g (100mg, 0.25mmol) be dissolved in 6mL methyl alcohol and tetrahydrofuran (THF) (V/V=5:1) mixed solvent, add 2M sodium hydroxide solution 1mL, be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, dripping 1M hydrochloric acid is 3～4 to reaction solution pH, and usefulness ethyl acetate extraction (10mL * 3) merges organic phase, water (10mL * 3) successively, saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(3-(trifluoromethyl) phenyl)-2,3 with silica gel column chromatography, 7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 45 (80mg, white solid), productive rate: 83.3%.

MS m/z(ESI):379.2[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.55-7.69(m,4H),6.79(s,1H),6.50(s,1H),5.17-5.19(m,1H),4.73-4.77(m,1H),4.25-4.35(m,2H),3.93-3.98(m,1H),3.83(m,1H),2.80-2.84(m,1H),2.62-2.69(m,1H).

Embodiment 46

2-((8S)-3-(3-chloro-phenyl-)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

1-chloro-3-vinyl benzene

With 3-chlorobenzaldehyde 46a (10.0g, 71.10mmol), methyltriphenylphospbromide bromide phosphorus (50.80g, 142.20mmol) and salt of wormwood (24.50g, 178mmol) be dissolved in 160mL dioxane and water (V/V=15:1) mixed solvent, be heated to 95 ℃, stirring reaction 12 hours.Add 100mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (100mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 1-chloro-3-vinyl benzene 46b (7.0g with silica gel column chromatography, colourless liquid), productive rate: 71.0%.

Second step

1-(3-chloro-phenyl-) ethane-1, the 2-glycol

With N-methyl morpholine oxide (12.30g, 108.30mmol) and perosmic anhydride (500mg, 1.97mmol) be dissolved in 100mL water, in acetone and the trimethyl carbinol (V/V/V=5:2:1) mixed solvent, add 50mL and contain 1-chloro-3-vinyl benzene 46b (5.0g, 36.10mmol) methylene dichloride and acetone (V/V=10:3) mixed solvent, stirring reaction 2 hours.Add 100mL saturated sodium thiosulfate solution cancellation reaction, with ethyl acetate extraction (50mL * 3), merge organic phase, water (50mL * 3) successively, saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtain title product 1-(3-chloro-phenyl-) ethane-1,2-glycol 46c (4.30g with silica gel column chromatography, colourless liquid), productive rate: 69.4%.

The 3rd step

2-((tertiary butyl dimethylsilane) oxygen)-1-(3-chloro-phenyl-) ethanol

With 1-(3-chloro-phenyl-) ethane-1,2-glycol 46c (4.30g, 24.90mmol), imidazoles (3.40g, 49.80mmol) and DMAP (305mg, 2.50mmol) are dissolved in 30mLN, in the dinethylformamide, add again TERT-BUTYL DIMETHYL CHLORO SILANE (4.50g, 29.90mmol), stirring reaction 2 hours.Add 100mL water, with ethyl acetate extraction (60mL * 2), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-((tertiary butyl dimethylsilane) oxygen)-1-(3-chloro-phenyl-) ethanol 46d (5.0g with silica gel column chromatography, colourless liquid), productive rate: 70.0%.

MS m/z(ESI):288.2[M+1]

The 4th step

2-((3S)-6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(3-chloro-phenyl-) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((tertiary butyl dimethylsilane) oxygen)-1-(3-chloro-phenyl-) ethanol 46d (150mg, 0.52mmol), (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1f (174mg, 0.52mmol) and azo two formyls two piperidines (209mg, 0.83mmol) are dissolved in the 5mL toluene, add tri-n-butyl phosphine (168mg, 0.83mmol), be heated to 50 ℃, stirring reaction 2 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(3-chloro-phenyl-) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 46e (220mg, colourless liquid), productive rate: 69.8%.

MS m/z(ESI):620.4[M+18]

The 5th step

2-((3S)-6-(1-(3-chloro-phenyl-)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((3S)-6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(3-chloro-phenyl-) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 46e (220mg, 0.36mmol) be dissolved in the 20mL tetrahydrofuran (THF), add 1M tetrabutyl ammonium fluoride (0.4mL, 0.40mmol), stirring reaction 2 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(1-(3-chloro-phenyl-)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 46f (130mg, colourless liquid), productive rate: 73.0%.

The 6th step

2-((8S)-3-(3-chloro-phenyl-)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((3S)-6-(1-(3-chloro-phenyl-)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 46f (130mg, 0.27mmol), acid chloride (18mg, 0.08mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (64mg, 0.16mmol) and cesium carbonate (176mg, 0.54mmol) are dissolved in the 15mL toluene, be heated to 50 ℃, stirring reaction 12 hours.Add 50mL water, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (30mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-((8S)-3-(3-chloro-phenyl-)-2 with tlc, 3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 46g (70mg, colourless liquid), productive rate: 72.9%.

The 7th step

With 2-((8S)-3-(3-chloro-phenyl-)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 46g (70mg, 0.19mmol) be dissolved in the 10mL methyl alcohol, add 1M sodium hydroxide solution 1mL, be heated to 60 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 20mL water, drip 1M hydrochloric acid to reaction solution pH be 1～2, with ethyl acetate extraction (20mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses tlc with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(3-chloro-phenyl-)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 46 (50mg, white solid), productive rate: 74.6%.

MS m/z(ESI):345.2[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.42(s,1H),7.36-7.35(m,2H),7.30-7.28(m,1H),6.78(s,1H),6.48(s,1H),5.10-5.08(m,1H),4.76-4.72(m,1H),4.32-4.24(m,2H),3.96-3.92(m,1H),3.82(m,1H),2.85-2.78(m,1H),2.68-2.62(m,1H).

Embodiment 47

2-((8S)-3-(2'-chloro-4'-fluoro-[1,1'-xenyl]-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((8S)-3-(2'-chloro-4'-fluoro-[1,1'-xenyl]-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 6c (100mg, 0.25mmol), (2-chloro-4-fluorophenyl) boric acid (52mg, 0.30mmol), tetra-triphenylphosphine palladium (14mg, 0.01mmol) and cesium carbonate (241mg, 0.74mmol) be dissolved in 11mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 12 hours.Filter, anhydrous magnesium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-((8S)-3-(2'-chloro-4'-fluoro-[1 with silica gel column chromatography, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 47a (100mg, yellow liquid), productive rate: 89.3%.

MS m/z(ESI):472.3[M+18]

Second step

With 2-((8S)-3-(2'-chloro-4'-fluoro-[1, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 47a (100mg, 0.22mmol) is dissolved in 6mL methyl alcohol and tetrahydrofuran (THF) (V/V=5:1) mixed solvent, adds 2M sodium hydroxide solution 1mL, be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 15mL water and 15mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, water merges organic phase, successively water (10mL * 3) with ethyl acetate extraction (10mL * 3), saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(2'-chloro-4'-fluoro-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 47 (90mg, white solid), productive rate: 92.8%.

MS m/z(ESI):438.9[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.45(m,4H),7.27-7.33(m,2H),7.07(m,1H),6.79(s,1H),6.49(s,1H),5.15-5.17(m,1H),4.74(m,1H),4.26-4.37(m,2H),4.01-4.03(m,1H),3.83(m,1H),2.79-2.84(m,1H),2.66-2.68(m,1H).

Embodiment 48

The first step

4,6-dimethyl-5-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) pyrimidine

With 5-bromo-4,6-dimethyl pyrimidine 48a (470mg, 2.51mmol, adopt known method " document Heterocycles, vol, 38; NO.6,1994, " preparation and get), two valeryl two boron (3.56g, 15.06mmol), 1, two (diphenylphosphine) ferrocene of 1'-] palladium chloride (184mg, 0.28mmol) and Potassium ethanoate (617mg, 6.28mmol) be dissolved in the 10mL glycol dimethyl ether, be heated to 90 ℃, stirring reaction 2 hours.Filter, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 4 with silica gel column chromatography, 6-dimethyl-5-(4,4,5,5-tetramethyl--1,3,2-dioxy boron, penta ring-2-yl) pyrimidine 48b (545mg, yellow solid), productive rate: 92.6%.

MS m/z(ESI):235.2[M+1]

Second step

2-((8S)-3-(3-(4,6-dimethyl pyrimidine-5-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 6c (60mg, 0.14mmol), 4,6-dimethyl-5-(4,4,5,5-tetramethyl--1,3,2-dioxy boron penta ring-2-yl) pyrimidine 48b (120mg, 0.52mmol), tetra-triphenylphosphine palladium (40mg, 0.03mmol) and yellow soda ash (70mg, 0.66mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 12 hours.Filter, filter cake washs (5mL * 2), anhydrous sodium sulfate drying with ethyl acetate, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(3-(4,6-dimethyl pyrimidine-5-yl) phenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 48c (60mg, yellow liquid), productive rate: 74.7%.

MS m/z(ESI):433.4[M+1]

The 3rd step

2-((8S)-3-(3-(4,6-dimethyl pyrimidine-5-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

((3-(4 for (8S)-3-with 2-, 6-dimethyl pyrimidine-5-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 48c (80mg, 0.18mmol) is dissolved in 3mL methyl alcohol and tetrahydrofuran (THF) (V/V=5:1) mixed solvent, add 1M sodium hydroxide solution (1mL, 1mmol), be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 10mL water and 10mL ethyl acetate, dripping 2M hydrochloric acid is 2 to reaction solution pH, the extraction separatory, and organic phase is water (5mL * 3) successively, saturated nacl aqueous solution washing (5mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(3-(4,6-dimethyl pyrimidine-5-yl) phenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 48 (28mg, white solid), productive rate: 36.2%.

MS m/z(ESI):417.3[M-1]

¹H NMR(400MHz,CDCl ₃)δ8.96(s,1H),7.51-7.55(m,1H),7.44-7.46(m,1H),7.18-7.23(m,2H),6.76(s,1H),6.44(s,1H),5.11-5.16(m,1H),4.67-4.69(m,1H),4.22-4.32(m,2H),3.92-3.99(m,1H),3.78(m,1H),2.73-2.76(m,1H),2.58(m,1H),2.24-2.29(m,6H).

Embodiment 49

2-((8S)-3-(2'-fluoro-[1,1'-xenyl]-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((8S)-3-(2'-fluoro-[1,1'-xenyl]-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 6c (50mg, 0.12mmol), (2-fluorophenyl) boric acid (21mg, 0.15mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) and cesium carbonate (120mg, 0.37mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 12 hours.Filter, anhydrous magnesium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-((8S)-3-(2'-fluoro-[1 with silica gel column chromatography, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 49a (52mg, yellow liquid), productive rate: 100.0%.

MS m/z(ESI):438.4[M+18]

Second step

With 2-((8S)-3-(2'-fluoro-[1, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 49a (52mg, 0.12mmol) is dissolved in 6mL methyl alcohol and tetrahydrofuran (THF) (V/V=5:1) mixed solvent, adds 1M sodium hydroxide solution 1mL, be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 15mL water and 15mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, water merges organic phase, successively water (10mL * 2) with ethyl acetate extraction (10mL * 2), saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(2'-fluoro-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 49 (47mg, white solid), productive rate: 94.0%.

MS m/z(ESI):405.1[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.42-7.59(m,5H),7.15-7.35(m,3H),6.79(s,1H),6.50(s,1H),5.16-5.18(m,1H),4.72-4.77(m,1H),4.24-4.38(m,2H),3.99-4.04(m,1H),3.82(m,1H),2.79-2.83(m,1H),2.61-2.68(m,1H).

Embodiment 50

2-((8S)-3-(2'-(trifluoromethyl)-[1,1'-xenyl]-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((8S)-3-(2'-(trifluoromethyl)-[1,1'-xenyl]-3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 6c (50mg, 0.12mmol), (2-(trifluoromethyl) phenyl) boric acid (28mg, 0.15mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) and cesium carbonate (120mg, 0.37mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 12 hours.Filter, anhydrous magnesium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtains title product 2-((8S)-3-(2'-(trifluoromethyl)-[1 with silica gel column chromatography, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 50a (57mg, yellow liquid), productive rate: 98.3%.

MS m/z(ESI):488.4[M+18]

Second step

With 2-((8S)-3-(2'-(trifluoromethyl)-[1, the 1'-xenyl]-the 3-yl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 50a (57mg, 0.12mmol) is dissolved in 6mL methyl alcohol and tetrahydrofuran (THF) (V/V=5:1) mixed solvent, adds 1M sodium hydroxide solution 1mL, be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 15mL water and 15mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, water merges organic phase, successively water (10mL * 3) with ethyl acetate extraction (10mL * 3), saturated nacl aqueous solution washing (10mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(2'-(trifluoromethyl)-[1,1'-xenyl]-3-yl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 50 (50mg, white solid), productive rate: 90.9%.

MS m/z(ESI):455.1[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.75-7.77(m,1H),7.57-7.60(m,1H),7.45-7.51(m,3H),7.35-7.38(m,3H),6.78(s,1H),6.48(s,1H),5.14-5.16(m,1H),4.72-4.76(m,1H),4.24-4.36(m,2H),3.96-4.01(m,1H),3.82(m,1H),2.79-2.84(m,1H),2.61-2.67(m,1H).

Embodiment 51

2-((8S)-3-(3-(4-picoline-3-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

2-((8S)-3-(3-(4-picoline-3-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

With 2-((8S)-3-(3-bromophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 6c (50mg, 0.12mmol), (4-picoline-3-yl) boric acid (20mg, 0.15mmol), tetra-triphenylphosphine palladium (7mg, 0.006mmol) and cesium carbonate (120mg, 0.37mmol) be dissolved in 5.5mL dioxane and water (V/V=10:1) mixed solvent, be heated to 90 ℃, stirring reaction 12 hours.Filter, anhydrous magnesium sulfate drying filters, filtrate decompression is concentrated, with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(3-(4-picoline-3-yl) phenyl)-2,3 with silica gel column chromatography, 7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 51a (80mg, yellow liquid), productive rate: 100.0%.

MS m/z(ESI):418.3[M+1]

Second step

With 2-((8S)-3-(3-(4-picoline-3-yl) phenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 51a (80mg, 0.19mmol) be dissolved in 6mL methyl alcohol and tetrahydrofuran (THF) (V/V=5:1) mixed solvent, add 2M sodium hydroxide solution 1mL, be heated to 50 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 15mL water and 15mL ethyl acetate, drip 1M hydrochloric acid to reaction solution pH be 3 ~ 4, the extraction separatory, water ethyl acetate extraction (10mL * 2), merge organic phase, water (10mL * 2) successively, saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(3-(4-picoline-3-yl) phenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 51 (11mg, white solid), productive rate: 14.3%.

MS m/z(ESI):402.2[M-1]

¹H NMR(400MHz,CDCl ₃)δ8.37-8.46(m,2H),7.43-7.54(m,2H),7.33-7.37(m,2H),7.26(m,1H),6.80(s,1H),6.47-6.48(m,1H),5.16-5.22(m,1H),4.72-4.76(m,1H),4.24-4.38(m,2H),3.98-4.07(m,1H),3.82-3.85(m,1H),2.75-2.82(m,1H),2.60-2.68(m,1H),2.32-2.33(m,3H).

Embodiment 52

2-((8S)-3-(3,4-dichlorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

The first step

1,2-, two chloro-4-vinyl benzenes

With 3,4-dichlorobenzaldehyde 52a (5.0g, 28.60mmol), methyltriphenylphospbromide bromide phosphorus (20.40g, 57.20mmol) and salt of wormwood (9.90g, 71.50mmol) be dissolved in 110mL dioxane and water (V/V=10:1) mixed solvent, be heated to 95 ℃, stirring reaction 12 hours.Add 100mL water, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1,2-two chloro-4-vinyl benzene 52b (4.0g, colourless liquid), productive rate: 80.9%.

Second step

1-(3,4-dichlorophenyl) ethane-1, the 2-glycol

With N-methyl morpholine oxide (2.0g, 17.40mmol) and perosmic anhydride (74mg, 0.29mmol) be dissolved in 50mL water, in acetone and the trimethyl carbinol (V/V/V=5:2:1) mixed solvent, add 13mL and contain 1, the methylene dichloride of 2-two chloro-4-vinyl benzene 52b (1.0g, 5.80mmol) and acetone (V/V=10:3) mixed solvent, stirring reaction 12 hours.Add 50mL saturated sodium thiosulfate solution cancellation reaction, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (30mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 1-(3,4-dichlorophenyl) ethane-1,2-glycol 52c (750mg, colourless liquid), productive rate: 62.5%.

The 3rd step

2-((tertiary butyl dimethylsilane) oxygen)-1-(3,4-dichlorophenyl) ethanol

With 1-(3, the 4-dichlorophenyl) ethane-1,2-glycol 52c (750mg, 3.62mmol), imidazoles (492mg, 7.24mmol) and DMAP (45mg, 0.40mmol) be dissolved in the 30mL DMF, add again TERT-BUTYL DIMETHYL CHLORO SILANE (655mg, 4.34mmol), stirring reaction 2 hours.Add 50mL water, with ethyl acetate extraction (30mL * 3), merge organic phase, with saturated nacl aqueous solution washing (30mL * 3), anhydrous magnesium sulfate drying, filter, filtrate decompression is concentrated, uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((tertiary butyl dimethylsilane) oxygen)-1-(3, the 4-dichlorophenyl) ethanol 52d (770mg, colourless liquid), productive rate: 70.0%.

The 4th step

2-((3S)-6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(3,4-dichlorophenyl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((tertiary butyl dimethylsilane) oxygen)-1-(3, the 4-dichlorophenyl) ethanol 52d (211mg, 0.66mmol), (S)-2-(6-hydroxyl-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 1f (220mg, 0.66mmol) and azo two formyls two piperidines (267mg, 1.06mmol) be dissolved in the 5mL toluene, add tri-n-butyl phosphine (214mg, 1.06mmol), be heated to 50 ℃, stirring reaction 3 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 2-((3S)-6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(3, the 4-dichlorophenyl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 52e (350mg, colourless liquid), productive rate: 80.0%.

The 5th step

2-((3S)-6-(1-(3,4-dichlorophenyl)-2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate

With 2-((3S)-6-(2-((tertiary butyl dimethyl-silicon) oxygen)-1-(3, the 4-dichlorophenyl) oxyethyl group)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 52e (350mg, 0.55mmol) be dissolved in the 20mL tetrahydrofuran (THF), add 1M tetrabutyl ammonium fluoride (0.6mL, 0.60mmol), stirring reaction 2 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography with eluent system B purifying gained resistates, ((1-(3 for (3S)-6-to obtain title product 2-, the 4-dichlorophenyl)-the 2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 52f (200mg, colourless liquid), productive rate: 70.0%.

The 6th step

2-((8S)-3-(3,4-dichlorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate

((1-(3 for (3S)-6-with 2-, the 4-dichlorophenyl)-the 2-hydroxyl-oxethyl)-5-iodo-2,3-Dihydrobenzofuranes-3-yl) methyl acetate 52f (200mg, 0.38mmol), acid chloride (26mg, 0.11mmol), 2-(di-t-butyl phosphorus)-1,1'-dinaphthalene (91mg, 0.23mmol) and cesium carbonate (247mg, 0.76mmol) be dissolved in the 20mL toluene, be heated to 50 ℃, stirring reaction 12 hours.Add 30mL water, with ethyl acetate extraction (30mL * 2), merge organic phase, with saturated nacl aqueous solution washing (30mL * 2), anhydrous magnesium sulfate drying filters, and filtrate decompression is concentrated, with tlc with eluent system B purifying gained resistates, obtain title product 2-((8S)-3-(3,4-dichlorophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) methyl acetate 52g (120mg, yellow liquid), productive rate: 79.5%.

The 7th step

With 2-((8S)-3-(3, the 4-dichlorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) methyl acetate 52g (120mg, 0.30mmol) is dissolved in the 10mL methyl alcohol, adds 1.5M sodium hydroxide solution 1mL, be heated to 60 ℃, stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, add 30mL water, dripping 1M hydrochloric acid is 1～2 to reaction solution pH, and usefulness ethyl acetate extraction (30mL * 2) merges organic phase, with saturated nacl aqueous solution washing (20mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, with tlc with eluent system A purifying gained resistates, obtain title product 2-((8S)-3-(3,4-dichlorophenyl)-2,3,7, the 8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 52 (60mg, white solid), productive rate: 51.7%.

MS m/z(ESI):379.2[M-1]

¹H NMR(400MHz,CDCl ₃)δ7.52-7.48(m,2H),7.25-7.24(m,1H),6.77-6.76(m,1H),6.47-6.46(m,1H),5.09-5.06(m,1H),4.76-4.72(m,1H),4.30-4.24(m,2H),3.92-3.81(m,2H),2.82-2.77(m,1H),2.67-2.61(m,1H).

Embodiment 53

2-((3R, 8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 45 (70mg, 0.18mmol) carries out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column AD-H CHIRALPAK4.6, moving phase: methyl alcohol/vinyl cyanide/acetic acid=80/20/0.1, flow velocity: 1.0mL/ minute) with Preparation equipment, collect its respective components, the rotary evaporation desolventizing obtains title product 2-((3R, 8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 53 (25mg, white solid).

MS m/z(ESI):379.2[M-1]

Embodiment 54

2-((3S, 8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 6 (70mg, 0.18mmol) carries out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column AD-H CHIRALPAK 4.6, moving phase: methyl alcohol/vinyl cyanide/acetic acid=80/20/0.1, flow velocity: 1.0mL/ minute) with Preparation equipment, collect its respective components, the rotary evaporation desolventizing obtains title product 2-((3S, 8S)-3-(3-trifluoromethyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 54 (22mg, white solid).

MS m/z(ESI):379.2[M-1]

Embodiment 55

2-((3R, 8S)-3-(3-chloro-phenyl-)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(3-chloro-phenyl-)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 46 (50mg, 0.21mmol) carries out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column AY-H CHIRALPAK 4.6, moving phase: normal hexane/Virahol/acetic acid=80/20/0.1, flow velocity: 1.0mL/ minute) with Preparation equipment, collect its respective components, the rotary evaporation desolventizing obtains title product 2-((3R, 8S)-3-(3-chloro-phenyl-)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 55 (25mg, white solid).

MS m/z(ESI):345.2[M-1]

Embodiment 56

2-((3S, 8S)-3-(3-chloro-phenyl-)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(3-chloro-phenyl-)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid 46 (80mg, 0.21mmol) carries out chiral separation, adopt the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column AY-H CHIRALPAK4.6, moving phase: normal hexane/Virahol/acetic acid=80/20/0.1, flow velocity: 1.0mL/ minute) with Preparation equipment, collect its respective components, the rotary evaporation desolventizing obtains title product 2-((3S, 8S)-3-(3-chloro-phenyl-)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 56 (24mg, white solid).

MS m/z(ESI):345.2[M-1]

Embodiment 57

2-((3R, 8S)-3-(3,4-dichlorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(3, the 4-dichlorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 52 (65mg, 0.16mmol) carries out chiral separation, adopts the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column IA CHIRALPAK 4.6 with Preparation equipment, moving phase: Virahol/vinyl cyanide/acetic acid=80/20/0.1 (v/v/v), flow velocity: 1.0mL/ minute), collect its respective components, the rotary evaporation desolventizing, obtain title product 2-((3R, 8S)-3-(3,4-dichlorophenyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 57 (31mg, white solid).

MS m/z(ESI):379.2[M-1]

Embodiment 58

2-((3S, 8S)-3-(3,4-dichlorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [Isosorbide-5-Nitrae] dioxin-8-yl) acetic acid

With 2-((8S)-3-(3, the 4-dichlorophenyl)-2,3,7,8-tetrahydrochysene benzfuran also [5,6-b] [1,4] dioxin-8-yl) acetic acid 52 (65mg, 0.16mmol) carries out chiral separation, adopts the HPLC method, with chiral column chiral isomer is separated (separation condition: chiral column IA CHIRALPAK 4.6 with Preparation equipment, moving phase: Virahol/vinyl cyanide/acetic acid=80/20/0.1 (v/v/v), flow velocity: 1.0mL/ minute), collect its respective components, the rotary evaporation desolventizing, obtain title product 2-((3S, 8S)-3-(3,4-dichlorophenyl)-2,3,7,8-tetrahydrochysene benzfuran is [5,6-b] [1 also, 4] dioxin-8-yl) acetic acid 58 (33mg, white solid).

MS m/z(ESI):379.2[M-1]

Utilize suitable reactant with reference to the operation steps synthetic example 59-71 of embodiment 9 and 25.

Below be that embodiment numbers, the structure and characterization data:

Utilize suitable reactant with reference to embodiment 9,13,45 and 64 operation steps synthetic example 72-88.

Below be that embodiment numbers, the structure and characterization data:

Test case

Biological assessment

Test case 1 the compounds of this invention is to the agonist activity of CHO-K1/GPR40 cell

Following methods is used for measuring the compounds of this invention to the agonist activity of GPR40.

Experimental technique is summarized as follows:

(by the CHO-K1 clone of Retroviral Transfer method construction expression P2Y12, be called for short the CHO-K1/GPR40 cell, wherein, the CHO-K1 cell is available from Chinese Academy of Sciences's cell bank, catalog number (Cat.No.) GNHa 7 for inoculation CHO-K1/GPR40 cell in 96 orifice plates; GPR40cDNA is available from Guangzhou FulenGen Co., Ltd., catalog number (Cat.No.) EX-U0270-M02), inoculum density is 25000/hole.Cell is at 37 ℃, 5%CO ₂Cultivated 24 hours under the condition.After the experiment, discard cell culture fluid, wash once with damping fluid (1x HBSS+20mM HEPES pH7.4) cell after, in every hole, add rapidly 100 μ L Fluo-4 calcium ion dyestuffs, and hatched 30 minutes 37 ℃ of lucifuges, then continued to hatch 30 minutes in room temperature.During mensuration, read first every hole baseline value, then in the hole, add different concns medicine (50 μ L/ hole), continue to read fluorescent value.Fluorescence madam excitation wavelength is 494nm, and emission wavelength is 516nm.The increase of fluorescence intensity is directly proportional with intracellular calcium ion level.Obtain every porocyte responsiveness=(maximum fluorescence value-minimum fluorescent value)/minimum fluorescent value, computerized compound EC ₅₀Value.

Compound number	EC ₅₀(CHO-K1/GPR40)/(nM)
		Embodiment 2	54
Embodiment 3	156
		Embodiment 4	50
Embodiment 5	46
		Embodiment 6	54
Embodiment 7	36
		Embodiment 8	61
Embodiment 9	25
		Embodiment 10	65
Embodiment 11	11
		Embodiment 12	38
Embodiment 13	56
		Embodiment 14	88
Embodiment 15	132
		Embodiment 16	37
Embodiment 17	52
		Embodiment 18	39
Embodiment 19	85
		Embodiment 20	43
Embodiment 21	30

Embodiment 22	19
		Embodiment 23	35
Embodiment 24	122
		Embodiment 25	64
Embodiment 27	71
		Embodiment 29	45
Embodiment 30	62
		Embodiment 31	80
Embodiment 32	116
		Embodiment 33	64
Embodiment 35	65
		Embodiment 36	35
Embodiment 37	99
		Embodiment 38	35
Embodiment 40	47
		Embodiment 42	32
Embodiment 43	89
		Embodiment 44	31
Embodiment 45	44
		Embodiment 46	37
Embodiment 47	74
		Embodiment 49	73
Embodiment 50	74
		Embodiment 51	136
Embodiment 52	36
		Embodiment 53	11
Embodiment 54	30
		Embodiment 56	23
Embodiment 57	15
		Embodiment 59	128
Embodiment 60	94
		Embodiment 61	81
Embodiment 64	56
		Embodiment 66	95
Embodiment 67	56
		Embodiment 68	46
Embodiment 69	67
		Embodiment 70	82

Embodiment 71	120
		Embodiment 72	66
Embodiment 73	56
		Embodiment 75	62
Embodiment 77	63
		Embodiment 78	100
Embodiment 79	125
		Embodiment 81	101
Embodiment 82	33
		Embodiment 83	44
Embodiment 84	35
		Embodiment 85	98
Embodiment 86	54
		Embodiment 88	125

Conclusion: the compounds of this invention has obvious agonist activity to GPR40.

The pharmacokinetics test

1, summary

Study the drug level in the different constantly blood plasma behind the oral embodiment of the invention compound.Its characteristics of pharmacokinetics is estimated in the pharmacokinetics behavior of research the compounds of this invention in the rat body.

2, testing program

2.1 test drug

Embodiment 1 compound, embodiment 4 compounds, embodiment 5 compounds, embodiment 6 compounds, embodiment 42 compounds, embodiment 53 compounds, embodiment 56 compounds, embodiment 57 compounds and embodiment 60 compounds.

2.2 experimental animal

36 of healthy adult SD rats are divided into 9 groups, and 4 every group, male and female half and half are available from west, Shanghai pul-Bi Kai laboratory animal company limited, animal production licence number: SCXK (Shanghai) 2008-0016.

2.3 medicine preparation

Take by weighing a certain amount of medicine, add 0.5% Xylo-Mucine, the ultrasonic 0.5mg/mL suspension of making.

2.4 administration and sample collecting

Fasting is distinguished gastric infusion after one night, and dosage is 5.0mg/kg, administration volume 10mL/kg.Each constantly blood sampling in 24 hours before administration and after the administration, anticoagulant heparin, separated plasma is preserved in 20 ° of C.Feed in 2 hours after the administration.

3, analytical procedure

Before administration and after the administration 1.0,2.0,3.0,4.0,6.0,8.0,11.0,24.0, the 48.0h 0.1mL that take a blood sample, place the heparinization test tube, 3500 rev/mins of centrifugal 5 minutes separated plasmas are in 20 ° of C preservations.Feed in 2 hours after the administration.

Measure the testing compound content in the rat plasma behind the different compound gastric infusions with the LC/MS/MS method.The linearity range of method is 25.0 ~ 5000ng/mL, and plasma sample is analyzed after methanol extraction albumen is processed.

4, pharmacokinetic parameter result

The pharmacokinetic parameter of the compounds of this invention such as following table:

Conclusion: the compounds of this invention behind oral administration in the rat body Plasma Concentration and exposure level all higher, long half time has good medicine dynamic characteristic.

Claims

1. the compound shown in the general formula (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:

Wherein:

L is cycloalkyl, heterocyclic radical, aryl or heteroaryl;

R ¹And R ²Be selected from independently of one another hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷,-NR ⁷R ⁸,-OC (O) NR ⁷R ⁸,-NHC (O) NR ⁷R ⁸Or-S (O) _mR ⁷, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, alkynyl, carboxyl, cyano group, nitro, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR ⁷,-C (O) OR ⁷,-OC (O) R ⁷,-C (O) R ⁷,-NHC (O) R ⁷,-NR ⁷R ⁸,-OC (O) NR ⁷R ⁸,-NHC (O) NR ⁷R ⁸Or-S (O) _mR ⁷Substituting group replace;

Perhaps, R ³, R ⁴And R ⁵Both of middle arbitrary neighborhood condense into a cycloalkyl or heterocyclic radical with phenyl, and wherein said cycloalkyl or heterocyclic radical are optional further by one or more R that are selected from ⁶Substituting group replace;

R ⁹Be alkyl; And

M is 0,1 or 2.

2. the compound shown in a kind of general formula according to claim 1 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the described compound of general formula (II) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:

Wherein:

Y is C, O, N or S atom;

N is 0,1,2,3 or 4;

Ring L, R ³-R ⁶Definition such as claim 1 described in.

3. the compound shown in a kind of general formula according to claim 2 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the described compound of general formula (III) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:

Wherein:

Ring L, R ³-R ⁶Definition such as claim 1 described in; And

N is 0,1,2,3 or 4.

4. the compound shown in a kind of general formula according to claim 2 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the described compound of general formula (IV) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:

Wherein: ring L, R ³~ R ⁵Definition such as claim 1 described in.

5. the compound shown in a kind of general formula according to claim 2 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, it is the logical described compound of formula V or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof:

Wherein: ring L, R ³~ R ⁵Definition such as claim 1 described in.

6. according to claim 1-5 compound shown in the described general formula of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein L is aryl, preferably phenyl.

7. according to claim 1-5 compound shown in the described general formula of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein:

R ³Be hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or-OR ⁷Substituting group replace;

R ⁴, R ⁵Be hydrogen atom or halogen;

R ⁹Be alkyl.

8. the compound shown in the general formula according to claim 1 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt, wherein R ¹And R ²Be selected from independently of one another hydrogen atom, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further to be replaced by one or more substituting groups that are selected from halogen, hydroxyl, carboxylic acid group, cyano group, nitro, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.

9. according to claim 1-3 compound shown in the described general formula of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein R6 is alkyl, and wherein said alkyl is further by one or more-C (O) OR ⁷Replace R ⁷Be hydrogen atom or alkyl.

10. the compound shown in the general formula according to claim 1 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, wherein this compound is:

11. a method for preparing the compound shown in the general formula according to claim 1 (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmacologically acceptable salt thereof, the method may further comprise the steps:

Compound (IA) is carried out catalysis in the presence of the catalyzer under the alkaline condition, with the optional further hydrolysis of the product that obtains, obtaining general formula (I) compound;

Wherein: X is halogen, is preferably bromine or iodine; R ¹～R ⁵, L definition such as claim 1 described in.

12. a pharmaceutical composition, described pharmaceutical composition contain the compound shown in the described general formula of according to claim 1-10 any one (I) for the treatment of significant quantity or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof and pharmaceutically acceptable carrier, thinner and vehicle.

13. according to claim 1-10 compound shown in the described general formula of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, or the purposes of pharmaceutical composition according to claim 12 in preparation GPR40 agonist.

14. according to claim 1-10 compound shown in the described general formula of any one (I) or its tautomer, mesomeride, racemic modification, enantiomer, diastereomer, its form of mixtures and pharmaceutically useful salt thereof, or the purposes of pharmaceutical composition according to claim 12 in the medicine of the disease of preparation treatment diabetes and metabolic syndrome, wherein said diabetes are type ii diabetes.