CN1922165A - 3-(4-benzyloxyphenyl)propanoic acid derivative - Google Patents

3-(4-benzyloxyphenyl)propanoic acid derivative Download PDF

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CN1922165A
CN1922165A CN 200480042139 CN200480042139A CN1922165A CN 1922165 A CN1922165 A CN 1922165A CN 200480042139 CN200480042139 CN 200480042139 CN 200480042139 A CN200480042139 A CN 200480042139A CN 1922165 A CN1922165 A CN 1922165A
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compound
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methoxyl group
replaces
salt
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安间常雄
北村周治
根来伸行
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Abstract

The present invention provides a novel compound represented by the formula (I) wherein each symbol is as defined in the specification, a salt thereof and a prodrug thereof having a superior GPR40 receptor function modulating action, which can be used as an insulin secretagogue, an agent for the prophylaxis or treatment of diabetes and the like. They unexpectedly show superior GPR40 receptor agonist activity, and also show superior properties as a pharmaceutical product, such as stability and the like. Thus, they can be safe and useful pharmaceutical agents for the prophylaxis or treatment of GPR40 receptor related diseases in mammals.

Description

3-(4-benzyloxy phenyl) propanoic derivatives
Technical field
The present invention relates to have the new compound of GPR40 function of receptors regulating effect, it is as the medicament of prevention or treatment diabetes.
Background technology
Recent years report be lipid acid as the part of the GPR40 of a kind of G albumen-coupled receptor (GPCR), and the GPR40 in the pancreatic beta cell relates to insulin secretion effect (Nature, 2003, the 422 volumes, 173-176 page or leaf) consumingly.Thereby, the GPR40 agonist promotes insulin secretion, the GPR40 antagonist suppresses insulin secretion, and this agonist and antagonist are as the medicament (WO03/068959 and WO02/057783) of prevention or treatment type ii diabetes, obesity, impaired glucose tolerance, insulin resistance, neurodegenerative disease (Alzheimer ' s disease) or the like.
On the other hand, reported the medicament of chemical compound lot as prevention or treatment diabetes.
For example, WO02/092590 discloses by (PPAR) conditioning agent of the peroxisome proliferative activity acceptor (peroxisome proliferator activated) of following formula representative:
Figure A20048004213900061
X wherein 1: C 1-3Alkyl or the like; R 1, R 2: H or the like; R 3, R 4, R 5: H, CH 3Or the like; R 26, R 27: H or the like; M:0-3; X 2: O or the like; R 6, R 7: H or the like; Y, Z: one is CH, and another is S or O; R 8: phenyl or the like; R 9: C 1-6Alkyl or the like,
It is as the medicament of prevention or treatment PPAR disease mediated (for example diabetes).
WO02/053547 discloses the alkane acid derivative by the following formula representative:
Figure A20048004213900062
R wherein 1: optional substituted 5 membered aromatic heterocycle groups; X: chemical bond, O, S ,-NR 6-(R 6: H, optional substituted hydrocarbyl group or the like) or the like; Q: divalence C1-20 hydrocarbyl group; Y: chemical bond, O, S ,-NR 7-(R 7: H, optional substituted hydrocarbyl group or the like) or the like; A ring: optional further have 1 to 3 substituent aromatic nucleus; Z:-(CH 2) n-Z 1-(n:1-8, Z 1: O or the like) or the like; B ring: optional further have 1 to 3 substituent phenyl ring or the like; U: chemical bond or the like; W: divalence C 1-20Hydrocarbyl group; R 3:-OR 8-(R 8: H, optional substituted hydrocarbyl group) or-NR 9R 10-(R 9, R 10: H, optional substituted hydrocarbyl group or the like) or the like; Condition is, when the B ring is optional when further having 1 to 3 substituent phenyl ring, U is a chemical bond so,
It is as the medicament that prevents or treat diabetes, hyperlipidemia, impaired glucose tolerance or the like.
WO99/11255 discloses the compound by the following formula representative:
R wherein 1: C 1-8Alkyl, C 1-8Alkoxyl group, halogen atom, trifluoromethyl or the like; R 2:-COOR 3(R 3: H, C 1-4Alkyl) or the like; A:C 1-8Alkylidene group or the like; G: optional by C 1-8Alkyl, C 1-8Carbocyclic ring that alkoxyl group, halogen atom, trifluoromethyl or nitro replace or the like; E 1: C 1-8Alkylidene group or the like; E 2:-O-or the like; E 3: singly-bound or the like; N:0,1; The Cyc1 ring: do not exist or the like,
It has PPAR acceptor regulating effect, and as preventing or treat for example medicament of diabetes, obesity, X syndromes, hypercholesterolemia, hyperlipoproteinemia or the like of metabolic disturbance diseases.
WO00/64876 discloses the compound by the following formula representative:
Figure A20048004213900072
Wherein ArI ring, ArII ring, ArIII encircle: optional substituted aryl or the like; A:-O-,-S-, chemical bond ,-NR 13-(R 13: H, alkyl or the like) or the like; B:-O-or the like; D: chemical bond, vinyl; E: chemical bond, vinyl; Z:R 21O 2C-, (R 21) 2NCO-(R 21: H, alkyl or the like) or the like; A, b, c, e:0-4; D:0-5; F:0-6; R 1-R 12: H or the like,
It is used as PPAR ligand receptor wedding agent, PPAR receptor stimulant or PPAR receptor antagonist, and can be used as the medicament of treatment diabetes.
WO01/00603 discloses the compound by the following formula representative:
X:COOH (comprising ester) or the like wherein; X 1: CH 2Or the like; Have only when X1 is CH, dotted line is represented two keys; X 2: O or the like; R 1, R 2: H, Me or the like; N:1,2; Y, Z: one is N, and another is S or O; The integer of y:0-5; R 3: CF 3Or the like,
Can be used for the PPAR delta agonists, and as the medicament that prevents or treat PPAR δ disease mediated (for example blood fat matter is too much, arteriosclerosis, I type or type ii diabetes or the like).
WO97/31907 discloses the compound by the following formula representative:
Figure A20048004213900082
A wherein: optional phenyl that is replaced by halogen or the like or the like; B:C 1-6Alkylidene group or the like; ALK:C 1-3Alkylidene group; R 1: H, C 1-3Alkyl; Z: optional by halogen or the like replace-(C 1-3Alkylidene group) phenyl,
It is as the PPAR gamma agonist, can be used as too much or the like the medicament of prevention or treatment hyperglycemia, I type or type ii diabetes, blood fat matter.
WO02/083616 discloses the compound by the following formula representative:
Figure A20048004213900083
Ar wherein: the phenyl that is replaced by 1 to 5 identical or different halogen atom or the like, or the like; R 1: halogen atom or the like; R 2: H or the like; R 3, R 4: H, halogen atom; M:1,2; N:2-7,
It has higher Regular Insulin activation, hypoglycemic activity, the effect of falling serum lipid, anti-inflammatory action, immunoregulation effect, lipid oxide product inhibition and PPAR activation, and as the medicament for the treatment of diabetes.
WO01/55085 discloses the compound by the following formula representative:
Figure A20048004213900084
A wherein: the optional aryl that is replaced by OH or the like; X 1, X 2: H or the like; Y, Z:H or the like; N:0-3; M:0,1; Q:O or the like; Ar: arylidene or the like; R 1-R 4: H or the like,
It is used as the medicament that treatment PPAR relates to disease, and as treating for example medicament of type ii diabetes, impaired glucose tolerance, insulin resistance, hypertriglyceridemia or the like.
Yet, for these known Remedies for diabetes, do not disclose it at all and have GPR40 function of receptors regulating effect, and do not have the relevant compound of report with GPR40 function of receptors regulating effect (as GPR40 agonist or GPR40 antagonist).In the case, needed to develop compound with GPR40 function of receptors regulating effect.
Summary of the invention
The object of the invention is to provide the new compound with GPR40 function of receptors regulating effect, and it is as the Regular Insulin succagoga or the medicament of prevention or treatment diabetes or the like.
The inventor has in depth carried out various researchs, and find, compound by following formula (I) representative unexpectedly has higher GPR40 receptor agonist activity, shown for example stability or the like of higher pharmaceutical product performance, and can be safety and the efficacious agents that prevention or the GPR40 acceptor of treatment in the Mammals relate to morbid state or disease, and therefore finish the present invention.
Correspondingly, the invention provides following invention.
(1) compound or its salt of formula (I) representative,
Wherein
R 1, R 3, R 4And R 5Be identical or different, and each is hydrogen atom, halogen atom, the optional alkyl that replaces or the optional hydroxyl that replaces;
R 2Be halogen atom, nitro, the optional hydrocarbyl group that replaces, the optional hydroxyl that replaces, the optional amino that replaces, the optional sulfydryl that replaces, optional acyl group that replaces or the optional heterocyclic group that replaces;
R 10And R 11Be identical or different, and each is hydrogen atom, halogen atom or C 1-6Alkoxyl group;
E is a chemical bond, the optional C that replaces 1-4Alkylidene group ,-W 1-O-W 2-,-W 1-S-W 2-or-W 1-N (R 6)-W 2-(W wherein 1And W 2Be identical or different, and each is chemical bond or the optional C that replaces 1-3Alkylidene group, R 6Be hydrogen atom, optional acyl group that replaces or the optional alkyl that replaces);
S 1Ring is the optional substituent phenyl ring that is selected from halogen atom, the optional alkyl that replaces, the optional hydroxyl that replaces and the optional amino that replaces that further has;
R is optional hydroxyl that replaces or the optional amino that replaces;
Condition is R 1And R 3Not hydrogen atom simultaneously.
(2) compound or its salt of (1), wherein R above 2Be halogen atom, the optional alkyl that replaces, the optional hydroxyl that replaces, the optional amino that replaces, optional sulfydryl that replaces or the optional heterocyclic group that replaces, and R 10And R 11Two all is hydrogen atom.
(3) prodrug or its salt of the compound of (1) above.
(4) compound or its salt of (1), wherein R above 4And R 5Be identical or different, and each is hydrogen atom or halogen atom.
(5) compound or its salt of (1) above, wherein E is a chemical bond.
(6) compound or its salt of (1) above, wherein R is a hydroxyl.
(7) compound or its salt of (1), wherein R above 1And R 3Be identical or different, and each is C 1-6Alkyl.
(8) compound or its salt of (1), wherein R above 2It is the optional hydroxyl that replaces.
(9) compound or its salt of (1), wherein R above 10And R 11Two all is hydrogen atom.
(10) compound or its salt of (1), wherein S above 1Ring is the optional C that further has 1-6The phenyl ring of alkoxyl group.
(11) 3-[4-[[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl base-3-yl] methoxyl group] phenyl] propionic acid;
3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } phenyl)-2,2-difluoro propionic acid;
3-[4-(4 '-[2-(ethylsulfonyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[4-(2 ', 6 '-dimethyl-4 '-[3-(2-oxo-pyrrolidine-1-yl) propoxy-] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[2-fluoro-4-(4 '-[(4-hydroxyl-1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] propionic acid;
3-[4-(2 ', 6 '-dimethyl-4 '-[(methyl sulphonyl) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[4-(4 '-[(1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[4-(2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-4-base oxygen base) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid;
3-[4-(4 '-[3-(diethoxy phosphoryl) propoxy-]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[2-fluoro-4-(6-isopropoxy-2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group) phenyl] propionic acid;
Or its salt.
(12) comprise above the GPR40 function of receptors conditioning agent of (1) compound or its salt or its prodrug.
(13) comprise above the medicament of (1) compound or its salt or its prodrug.
(14) medicament of (13) above, it is the medicament of prevention or treatment diabetes.
(15) (1) compound or its salt or its prodrug purposes in preparation GPR40 function of receptors conditioning agent above.
(16) (1) compound or its salt or its prodrug purposes in preparation prevention or treatment diabetes medicament above.
(17) method of adjusting GPR40 function of receptors in Mammals comprises top (1) compound or its salt or its prodrug that give described Mammals significant quantity.
(18) method of prevention or treatment diabetes in Mammals comprises compound or its salt or its prodrug of top (1) that gives described Mammals significant quantity.
(19) preparation method of the compound or its salt of formula (Ib) representative:
Figure A20048004213900111
R wherein 1, R 2, R 3, R 4, R 5, R 10, R 11, E and S 1The ring such as top (1) definition,
This method comprises the compound or its salt that makes formula (X) representative,
Figure A20048004213900121
Wherein each symbol as defined above,
With the compound or its salt reaction of formula (II) representative,
R wherein 4, R 5, R 10And R 11As defined above, R ' is the optional C that replaces 1-6Alkoxyl group obtains the compound or its salt that formula (Ib ') is represented,
Figure A20048004213900123
Wherein each symbol as defined above,
To the reaction that is hydrolyzed of this compound or its salt.
(20) preparation method of the compound or its salt of formula (Id) representative:
R wherein 1, R 3, R 4, R 5, R 10, R 11, E and S 1Ring as top (1) middle definition, Y is-O-or-S-, and R 2' be substituting group,
This method comprises the compound or its salt that makes formula (Ie ') representative,
R wherein 1, R 3, R 4, R 5, R 10, R 11, E and S 1Ring is as top definition, R ' such as top (19) definition,
With the compound or its salt reaction of following formula representative,
R 2′-OH
R wherein 2' as defined above,
Obtain the compound of formula (If ') representative:
Figure A20048004213900131
Wherein each symbol as defined above,
And to the reaction that is hydrolyzed of this compound or its salt.
Compound of the present invention has higher GPR40 function of receptors regulating effect, can be used as the medicament of prevention or treatment diabetes or the like.
Preferred forms of the present invention
Unless otherwise mentioned, fluorine atom, chlorine atom, bromine atoms iodine atom can be mentioned in term in this manual " halogen atom ".
Unless otherwise mentioned, for " the optional hydrocarbyl group that replaces " in this specification sheets, for example can mention " the optional C that replaces 1-6Alkyl ", " the optional C that replaces 2-6Alkenyl ", " the optional C that replaces 2-6Alkynyl ", " the optional C that replaces 3-8Cycloalkyl ", " the optional C that replaces 6-14Aryl ", " the optional C that replaces 7-16Aralkyl " or the like.
Unless otherwise mentioned, for " the C in this specification sheets 1-6Alkyl ", can mention for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl or the like.
Unless otherwise mentioned, for " the C in this specification sheets 2-6Alkenyl ", can mention for example vinyl, propenyl, pseudoallyl, 2-butylene-1-base, 4-amylene-1-base, 5-hexene-1-base or the like.
Unless otherwise mentioned, for " the C in this specification sheets 2-6Alkynyl ", can mention for example 2-butyne-1-base, 4-pentyne-1-base, 5-hexin-1-base or the like.
Unless otherwise mentioned, for " the C in this specification sheets 3-8Cycloalkyl ", can mention for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
Unless otherwise mentioned, for " the C in this specification sheets 6-14Aryl ", can mention for example phenyl, 1-naphthyl, 2-naphthyl, 2-xenyl, 3-xenyl, 4-xenyl, 2-anthryl or the like.C 6-14Aryl is can optional part saturated, and for the C of fractional saturation 6-14Aryl can be mentioned for example tetralyl or the like.
Unless otherwise mentioned, for " the C in this specification sheets 7-16Aralkyl ", can mention for example benzyl, styroyl, diphenyl-methyl, 1-naphthyl methyl, 2-naphthyl methyl, 2,2-diphenyl-ethyl, 3-hydrocinnamyl, 4-phenyl butyl, 5-phenylpentyl, 2-xenyl methyl, 3-xenyl methyl, 4-xenyl methyl or the like.
Unless otherwise mentioned, for " the optional hydroxyl that replaces " in this specification sheets, for example can mention " hydroxyl ", " the optional C that replaces 1-10Alkoxyl group ", " the optional heterocyclyloxy base that replaces ", " the optional C that replaces 6-14Aryloxy ", " the optional C that replaces 7-16Aralkoxy ", " three-C 1-6Alkyl-silyl oxygen base ", " the optional C that replaces 1-6Alkyl sulphonyl oxygen base ", " optional heterocyclic radical alkylsulfonyl oxygen base that replaces " or the like.
Unless otherwise mentioned, for " the C in this specification sheets 1-6Alkoxyl group ", can mention for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, pentyloxy, hexyloxy or the like.For " the C in this specification sheets 1-10Alkoxyl group ", except that the C of the above 1-6Outside the alkoxyl group, can mention oxygen base in heptan, octyloxy, nonyl oxygen base, the last of the ten Heavenly stems oxygen base or the like.
For " the heterocyclyloxy base " in this specification sheets, can mention the hydroxyl that is replaced by following " heterocyclic group ".Preferred example for the heterocyclyloxy base, can mention THP trtrahydropyranyl oxygen base, thiazolyl oxygen base, pyridyl oxygen base, pyrazolyl oxygen base,  azoles base oxygen base, thienyl oxygen base, furyl oxygen base, tetrahydro thiapyran base oxygen base, 1-oxo tetrahydro thiapyran base oxygen base (1-oxidotetrahydrothiopyranyloxy), 1,1-dioxo tetrahydro thiapyran base oxygen base or the like.
Unless otherwise mentioned, for " the C in this specification sheets 6-14Aryloxy ", can mention for example phenoxy group, 1-naphthyloxy, 2-naphthyloxy or the like.
Unless otherwise mentioned, for " the C in this specification sheets 7-16Aralkoxy ", can mention for example benzyloxy, styroyl oxygen base or the like.
Unless otherwise mentioned, for " three-the C in this specification sheets 1-16Alkyl-silyl oxygen base ", can mention for example trimethyl silyl oxygen base, the tertiary butyl (dimethyl) silyl oxygen base or the like.
For " the C in this specification sheets 1-6Alkyl sulphonyl oxygen base ", can mention for example methyl sulphonyl oxygen base, ethylsulfonyl oxygen base or the like.
For " the heterocyclic radical alkylsulfonyl oxygen base " in this specification sheets, can mention the alkylsulfonyl oxygen base that is replaced by following " heterocyclic group ".For the preferred example of heterocyclic radical alkylsulfonyl oxygen base, can mention thienyl sulphonyl base oxygen base, furyl alkylsulfonyl oxygen base or the like.
Unless otherwise mentioned,, for example can mention " sulfydryl ", " the optional C that replaces for " the optional sulfydryl that replaces " in this specification sheets 1-10Alkylthio ", " the optional heterocyclic radical sulfenyl that replaces ", " the optional C that replaces 6-14Arylthio ", " the optional C that replaces 7-16Aromatic alkyl sulfurio " or the like.
Unless otherwise mentioned, for " the C in this specification sheets 1-6Alkylthio ", can mention for example methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, the second month in a season-butylthio, uncle's butylthio or the like.For " the C in this specification sheets 1-10Alkylthio ", except that the C of the above 1-6Outside the alkylthio, can mention the sulfenyl in heptan, hot sulfenyl, the ninth of the ten Heavenly Stems sulfenyl, the last of the ten Heavenly stems sulfenyl or the like.
Unless otherwise mentioned, for " heterocyclic radical sulfenyl (the heterocyclythio group) " in this specification sheets, can mention the sulfydryl that is replaced by following " heterocyclic group ".Preferred example for the heterocyclic radical sulfenyl, can mention the THP trtrahydropyranyl sulfenyl, thiazolyl sulfenyl, pyridyl sulfenyl, the pyrazolyl sulfenyl,  azoles base sulfenyl, thienyl sulfenyl, furyl sulfenyl, the tetrahydro thiapyran base sulfenyl, 1-oxo tetrahydro thiapyran base sulfenyl, 1,1-dioxo tetrahydro thiapyran base sulfenyl or the like.
Unless otherwise mentioned, for " the C in this specification sheets 6-14Arylthio ", can mention for example thiophenyl, 1-naphthyl sulfenyl, 2-naphthyl sulfenyl or the like.
Unless otherwise mentioned, for " the C in this specification sheets 7-16Aromatic alkylthio ", can mention for example benzylthio, styroyl sulfenyl or the like.
Unless otherwise mentioned, for " heterocyclic group " in this specification sheets, can mention for example 4-to 14-unit (monocycle, dicyclo or trinucleated) heterocyclic group, except that carbon atom, it comprise 1 to 4 be selected from nitrogen-atoms, sulphur atom and the Sauerstoffatom heteroatomic one or two kind as ring atom, preferred (i) 5-to 14-unit (preferred 5-to 10-unit) aromatic heterocycle group, (ii) 4-to 10-unit nonaromatic heterocycles group or the like.In the middle of these, preferred 5-or 6-membered aromatic heterocycle group.
Especially, aromatic heterocycle group thienyl (for example, 2-thienyl for example, the 3-thienyl), furyl (for example, 2-furyl, the 3-furyl), pyridyl (for example, 2-pyridyl, the 3-pyridyl, the 4-pyridyl), thiazolyl is (for example, the 2-thiazolyl, 4-thiazolyl, 5-thiazolyl),  azoles base (for example, 2- azoles base, 4- azoles base, 5- azoles base), quinolyl (for example, 2-quinolyl, the 3-quinolyl, 4-quinolyl, 5-quinolyl, the 8-quinolyl), isoquinolyl (for example, 1-isoquinolyl, the 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), pyrazinyl, pyrimidyl (for example, 2-pyrimidyl, the 4-pyrimidyl), pyrryl (for example, 1-pyrryl, the 2-pyrryl, the 3-pyrryl), imidazolyl is (for example, the 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (for example, 1-pyrazolyl, 3-pyrazolyl, the 4-pyrazolyl), pyridazinyl (for example, 3-pyridazinyl, the 4-pyridazinyl), isothiazolyl (for example, 3-isothiazolyl, the 4-isothiazolyl, the 5-isothiazolyl), different  azoles base is (for example, the different  azoles of 3-base, the different  azoles of 4-base, the different  azoles of 5-base), indyl (for example, 1-indyl, 2-indyl, the 3-indyl), the 2-[4-morpholinodithio base, 2-benzoxazol base, benzimidazolyl-is (for example, the 1-benzimidazolyl-, the 2-benzimidazolyl-), benzo [b] thienyl (for example, 2-benzo [b] thienyl, 3-benzo [b] thienyl), benzo [b] furyl (for example, 2-benzo [b] furyl, 3-benzo [b] furyl) or the like;
The nonaromatic heterocycles group is pyrrolidyl (for example, 1-pyrrolidyl, 2-pyrrolidyl for example, the 3-pyrrolidyl),  oxazolidinyl (for example, 2- oxazolidinyl), imidazolinyl (for example, 1-imidazolinyl, 2-imidazolinyl, the 4-imidazolinyl), piperidyl (for example, piperidino, the 2-piperidyl, 3-piperidyl, 4-piperidyl), piperazinyl (for example, 1-piperazinyl, 2-piperazinyl), morpholinyl (for example, 2-morpholinyl, morpholinyl, the 4-morpholinyl), parathiazan base (for example, 2-parathiazan base, 3-parathiazan base, 4-parathiazan base), THP trtrahydropyranyl, tetrahydro thiapyran base, 1-oxo tetrahydro thiapyran base, 1,1-dioxo tetrahydro thiapyran base, oxo-pyrrolidine base, oxetanyl are (for example, or the like 2-oxetanyl, 3-oxetanyl) or the like, can be mentioned.
Unless otherwise mentioned, for " the C in this specification sheets 1-6Alkyl sulphonyl ", can mention for example methylsulfonyl, ethylsulfonyl or the like.
Unless otherwise mentioned, for " the C in this specification sheets 1-6Alkyl sulphinyl ", can mention for example methylsulfinyl, ethyl sulfinyl or the like.
Unless otherwise mentioned, for " the C in this specification sheets 6-14Aryl sulfonyl ", can mention for example benzenesulfonyl, 1-naphthyl alkylsulfonyl, 2-naphthyl alkylsulfonyl or the like.
Unless otherwise mentioned, for " the C in this specification sheets 6-14Aryl sulfonyl kia ", can mention for example phenyl sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl or the like.
Unless otherwise mentioned, for " carboxyl of optionally esterify " in this specification sheets, can mention for example carboxyl, C 1-6Alkoxyl group-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, tertbutyloxycarbonyl or the like), C 6-14Aryloxy-carbonyl (for example, carbobenzoxy or the like), C 7-16Aralkoxy-carbonyl (for example, carbobenzoxy-(Cbz), styroyl oxygen base carbonyl or the like) or the like.
Unless otherwise mentioned, for " the optional halogenated C in this specification sheets 1-6Alkyl ", can mention the above-mentioned optional " C that is replaced by 1 to 5 above-mentioned " halogen atom " 1-6Alkyl ".For example, can mention methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, trifluoromethyl or the like.
Unless otherwise mentioned, for " the optional halogenated C in this specification sheets 1-6Alkoxyl group ", can mention the above-mentioned optional " C that is replaced by 1 to 5 above-mentioned " halogen atom " 1-6Alkoxyl group ".For example, can mention methoxyl group, oxyethyl group, isopropoxy, tert.-butoxy, trifluoromethoxy or the like.
Unless otherwise mentioned, for " the single or two-C in this specification sheets 1-6Alkyl-amino ", can mention by above-mentioned " C 1-6Alkyl " single or two-amino that replaces.For example, can mention methylamino, ethylamino, propyl group amino, dimethylamino, diethylamino or the like.
Unless otherwise mentioned, for " the single or two-C in this specification sheets 6-14Aryl-amino ", can mention by above-mentioned " C 1-14Aryl " single or two-amino that replaces.For example, can mention phenyl amino, diphenyl amino (diphenylamino), 1-naphthyl amino, 2-naphthyl amino or the like.
Unless otherwise mentioned, for " the single or two-C in this specification sheets 7-16Aralkyl-amino ", can mention by above-mentioned " C 7-16Aralkyl " single or two-amino that replaces.For example, can mention benzylamino, styroyl amino or the like.
Unless otherwise mentioned, for " the N-C in this specification sheets 1-6Alkyl-N-C 6-14Aryl-amino ", can mention by above-mentioned " C 1-6Alkyl " and above-mentioned " C 6-14Aryl " amino that replaces.For example, can mention N-methyl-N-phenyl amino, N-ethyl-N-phenyl amino or the like.
Unless otherwise mentioned, for " the N-C in this specification sheets 1-6Alkyl-N-C 7-16Aralkyl-amino ", can mention by above-mentioned " C 1-6Alkyl " and above-mentioned " C 7-16Aralkyl " amino that replaces.For example, can mention N-methyl-N-benzylamino, N-ethyl-N-benzylamino or the like.
Unless otherwise mentioned, for " the single or two-C in this specification sheets 1-6Alkyl-formamyl ", can mention by above-mentioned " C 1-6Alkyl " single or two-formamyl that replaces.For example, can mention the methylamino formyl radical, ethylamino formyl radical, formyl-dimethylamino, diethylamino formyl radical, ethylmethylamino formyl radical or the like.
Unless otherwise mentioned, for " the N-C in this specification sheets 1-6Alkyl-N-C 1-6Alkyl-carbonyl-amino ", can mention by above-mentioned " C 1-6Alkyl " and C 1-6The amino that alkyl-carbonyl (for example, ethanoyl, isobutyryl, isovaleryl) replaces.For example, can mention N-methyl-N-kharophen, N-ethyl-N-kharophen or the like.
Unless otherwise mentioned, for " the single or two-C in this specification sheets 6-14Aryl-formamyl ", can mention by above-mentioned " C 6-14Aryl " single or two-formamyl that replaces.For example, can mention carbaniloyl,phenylcarbamoyl, 1-naphthyl formamyl, 2-naphthyl formamyl or the like.
Unless otherwise mentioned, for " single or two-5 to the 7 yuan of heterocyclic radical-formamyls " in this specification sheets, can mention the formamyl that is replaced by 5 to 7 yuan of heterocyclic groups.For 5 to 7 yuan of heterocyclic groups, can mention that 1 to 4 of comprising except that carbon atom is selected from heteroatomic one in nitrogen-atoms, sulphur atom and the Sauerstoffatom or two kind of heterocyclic group as ring atom.For the preferred example of " single or two-5 to 7-unit's heterocyclic radical-formamyls ", can mention 2-pyridinylamino formyl radical, 3-pyridinylamino formyl radical, 4-pyridinylamino formyl radical, 2-thienyl formamyl, 3-thienyl formamyl or the like.
Unless otherwise mentioned, for " the single or two-C in this specification sheets 1-6Alkyl-sulfamyl ", can use by above-mentioned " C 1-6Alkyl " single or two-sulfamyl that replaces, for example can mention the methyl sulfamyl, ethyl sulfamyl, dimethylamino alkylsulfonyl, diethyl amino alkylsulfonyl or the like.
Unless otherwise mentioned, for " the single or two-C in this specification sheets 6-14Aryl-sulfamyl ", can use by above-mentioned " C 6-14Aryl " single or two-sulfamyl that replaces, for example can mention phenylsulfamoyl, phenylbenzene sulfamyl, 1-naphthyl sulfamyl, 2-naphthyl sulfamyl or the like.
For " the single or two-C in this specification sheets 1-6Alkyl-phosphono ", can mention by above-mentioned " C 1-6Alkyl " single or two-phosphono that replaces.For example, can mention the dimethyl phosphine acyl group, diethyl phosphonyl, di-isopropyl phosphono, dibutyl phosphono or the like.
Unless otherwise mentioned, for " the optional C that replaces in this specification sheets 1-6Alkyl ", " the optional C that replaces 2-6Alkenyl ", " the optional C that replaces 2-6Alkynyl ", " the optional C that replaces 1-10Alkoxyl group (comprises the optional C that replaces 1-6Alkoxyl group) " " the optional C that replaces, 1-6Alkyl sulphonyl oxygen base " and " the optional C that replaces 1-10Alkylthio (comprises the optional C that replaces 1-6Alkylthio) ", for example.
" C 1-6Alkyl ", " C 2-6Alkenyl ", " C 2-6Alkynyl ", " C 1-10Alkoxyl group (comprises C 1-6Alkoxyl group) " " C, 1-6Alkyl sulphonyl oxygen base " and " C 1-10Alkylthio (comprises C 1-6Alkylthio) ", each randomly has 1 to 5 in its commutable position and is selected from following substituting group:
(1) halogen atom;
(2) hydroxyl;
(3) amino;
(4) nitro;
(5) cyano group;
(6) optional by 1 to 3 heterocyclic group (preferred furyl, pyridyl, thienyl, pyrazolyl that is selected from following substituting group replacement, thiazolyl,  azoles base, pyrrolidyl, the oxo-pyrrolidine base, THP trtrahydropyranyl, tetrahydro thiapyran base, 1-oxo tetrahydro thiapyran base, 1,1-dioxo tetrahydro thiapyran base, oxetanyl): halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aromatic yl group, single or two-C 6-14Aryl-amino, C 3-8Group of naphthene base, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl (thiocarbamoyl), single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(7) single or two-C 1-6Alkyl-amino;
(8) single or two-C 6-14Aryl-amino;
(9) single or two-C 7-16Aralkyl-amino;
(10) N-C 1-6Alkyl-N-C 6-4Aryl-amino;
(11) N-C 1-6Alkyl-N-C 7-16Aralkyl-amino;
(12) C 3-8Cycloalkyl;
(13) optional halogenated C 1-6Alkoxyl group;
(14) C 1-6Alkylthio;
(15) C 1-6Alkyl sulphinyl;
(16) C 1-6Alkyl sulphonyl
(17) carboxyl of optionally esterify;
(18) formamyl;
(19) thiocarbamyl;
(20) single or two-C 1-6Alkyl-formamyl;
(21) single or two-C 6-14Aryl-formamyl;
(22) single or two-5-to 7-unit heterocyclic radical-formamyl;
(23) optional by the C of carboxyl substituted 1-6Alkyl-carbonylamino (for example, kharophen, propionyl amino);
(24) optional by 1 to 3 C that is selected from following substituting group replacement 6-14Aryloxy: halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aromatic yl group, single or two-C 6-14Aryl-amino, C 3-8Group of naphthene base, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl, single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(25) optional by 1 to 3 C that is selected from following substituting group replacement 6-14Aryl: halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aryl, single or two-C 6-14Aryl-amino, C 3-8Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl, single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(26) optional by 1 to 3 heterocyclyloxy base that is selected from following substituting group replacement: halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aryl, single or two-C 6-14Aryl-amino, C 3-8Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl, single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(27) sulfamyl;
(28) single or two-C 1-6Alkyl-sulfamyl;
(29) single or two-C 6-14Aryl-sulfamyl;
(30) optional by 1 to 3 C that is selected from following substituting group replacement 7-16Aralkoxy: halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aryl, single or two-C 6-14Aryl-amino, C 3-8Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl, single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(31) N-C 1-6Alkyl-N-C 1-6Alkyl-carbonyl-amino;
(32) single or two-C 1-6Alkyl-phosphono; Or the like,
Can be mentioned.
For " the optional C that replaces in this specification sheets 3-8Cycloalkyl ", " the optional C that replaces 6-14Aryl ", " the optional C that replaces 7-16Aralkyl ", " optional replace heterocyclic group ", " the optional heterocyclyloxy base that replaces ", " the optional C that replaces 6-14Aryloxy ", " the optional C that replaces 7-16Aralkoxy ", " optional replace heterocyclic radical alkylsulfonyl oxygen base ", " the optional heterocyclic radical sulfenyl that replaces ", " the optional C that replaces 6-14Arylthio " and " the optional C that replaces 7-16Aromatic alkyl sulfurio ", " C for example 3-8Cycloalkyl ", " C 6-14Aryl ", " C 7-16Aralkyl ", " heterocyclic group ", " heterocyclyloxy base ", " C 6-14Aryloxy ", " C 7-16Aralkoxy ", " heterocyclic radical alkylsulfonyl oxygen base ", " heterocyclic radical sulfenyl ", " C 6-14Arylthio " and " C 7-16Aromatic alkyl sulfurio ", each is optional in its commutable position to have 1 to 5 and is selected from following substituting group:
(1) halogen atom;
(2) hydroxyl;
(3) amino;
(4) nitro;
(5) cyano group;
(6) the optional C that replaces 1-6Alkyl;
(7) the optional C that replaces 2-6Alkenyl;
(8) the optional C that replaces 2-6Alkynyl;
(9) optional by 1 to 3 C that is selected from following substituting group replacement 6-14Aryl: halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aryl, single or two-C 6-14Aryl-amino, C 3-8Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl, single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(10) optional by 1 to 3 C that is selected from following substituting group replacement 6-14Aryloxy: halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aryl, single or two-C 6-14Aryl-amino, C 3-8Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl, single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(11) optional by 1 to 3 C that is selected from following substituting group replacement 7-16Aralkoxy: halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aryl, single or two-C 6-14Aryl-amino, C 3-8Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl, single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(12) optional by 1 to 3 heterocyclic group (preferred furyl, pyridyl, thienyl, pyrazolyl that is selected from following substituting group replacement, thiazolyl,  azoles base, pyrrolidyl, the oxo-pyrrolidine base, THP trtrahydropyranyl, tetrahydro thiapyran base, 1-oxo tetrahydro thiapyran base, 1,1-dioxo tetrahydro thiapyran base, oxetanyl): halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aryl, single or two-C 6-14Aryl-amino, C 3-8Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl, single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(13) single or two-C 1-6Alkyl-amino;
(14) single or two-C 6-14Aryl-amino;
(15) single or two-C 7-16Aralkyl-amino;
(16) N-C 1-6Alkyl-N-C 6-14Aryl-amino;
(17) N-C 1-6Alkyl-N-C 7-16Aralkyl-amino;
(18) C 3-8Cycloalkyl;
(19) the optional C that replaces 1-6Alkoxyl group;
(20) C 1-6Alkylthio;
(21) C 1-6Alkyl sulphinyl;
(22) C 1-6Alkyl sulphonyl
(23) carboxyl of optionally esterify;
(24) formamyl;
(25) thiocarbamyl;
(26) single or two-C 1-6Alkyl-formamyl;
(27) single or two-C 6-14Aryl-formamyl;
(28) single or two-5-to 7-unit heterocyclic radical-formamyl;
(29) sulfamyl;
(30) single or two-C 1-6Alkyl-sulfamyl;
(31) single or two-C 6-14Aryl-sulfamyl;
(32) N-C 1-6Alkyl-N-C 1-6Alkyl-carbonyl-amino;
(33) optional by 1 to 3 heterocyclyloxy base that is selected from following substituting group replacement: halogen atom, hydroxyl, amino, nitro, cyano group, optional halogenated C 1-6Alkyl, single or two-C 1-6Alkyl-amino, C 6-14Aryl, single or two-C 6-14Aryl-amino, C 3-8Cycloalkyl, C 1-6Alkoxyl group, C 1-6Alkylthio, C 1-6Alkyl sulphinyl, C 1-6Alkyl sulphonyl, the carboxyl of optionally esterify, formamyl, thiocarbamyl, single or two-C 1-6Alkyl-formamyl, single or two-C 6-14Aryl-formamyl, sulfamyl, single or two-C 1-6Alkyl-sulfamyl and single or two-C 6-14Aryl-sulfamyl;
(34) single or two-C 1-6Alkyl-phosphono; Or the like can be mentioned.
Unless otherwise mentioned, for " the optional amino that replaces " in this specification sheets, can mention optional by 1 or 2 amino that is selected from following substituting group replacement:
(1) the optional C that replaces 1-6Alkyl;
(2) the optional C that replaces 2-6Alkenyl;
(3) the optional C that replaces 2-6Alkynyl;
(4) the optional C that replaces 3-8Cycloalkyl;
(5) the optional C that replaces 6-14Aryl;
(6) the optional C that replaces 1-6Alkoxyl group;
(7) the optional acyl group that replaces;
(8) the optional heterocyclic group that replaces (preferred furyl, pyridyl, thienyl, pyrazolyl, thiazolyl,  azoles base);
(9) sulfamyl;
(10) single or two-C 1-6Alkyl-sulfamyl;
(11) single or two-C 6-14Aryl-sulfamyl; Or the like can be mentioned.
When " optional replace amino " by 2 substituting groups replace amino the time, these substituting groups can form with contiguous nitrogen-atoms and form nitrogen heterocyclic ring.For " nitrogen heterocyclic ring ", what can mention is for example, to comprise at least one nitrogen-atoms except that carbon atom and choose wantonly further comprising 1 or 25 to 7 member heterocyclic ring containing nitrogen that are selected from the heteroatoms of Sauerstoffatom, sulphur atom and nitrogen-atoms as ring atom.For nitrogenous heterocyclic preferred example, can mention tetramethyleneimine, imidazolidine, pyrazolidine, piperidines, piperazine, morpholine, parathiazan, thiazolidine,  azoles alkane or the like.
Unless otherwise mentioned, for " the optional acyl group that replaces " in this specification sheets, can mention the group of following formula representative :-COR 8,-CO-OR 8,-SO 2R 8,-SOR 8,-PO (OR 8) (OR 9) ,-CO-NR 8aR 9aWith-CS-NR 8aR 9a, R wherein 8And R 9Be identical or different, and each is hydrogen atom, the optional hydrocarbyl group that replaces or choose the heterocyclic group that replaces, R wantonly 8aAnd R 9aBe identical or different, and each is hydrogen atom, the optional hydrocarbyl group that replaces or the optional heterocyclic group that replaces, or R 8aAnd R 9aCan form optional nitrogen heterocyclic ring that replaces or the like with contiguous nitrogen-atoms.
For R wherein 8aAnd R 9aForm " nitrogen heterocyclic ring " in " the optional nitrogen heterocyclic ring that replaces " with contiguous nitrogen-atoms, what can mention is for example to comprise at least one nitrogen-atoms except that carbon atom and choose wantonly further comprising 1 or 25 to 7 member heterocyclic ring containing nitrogen that are selected from the heteroatoms of Sauerstoffatom, sulphur atom and nitrogen-atoms as ring atom.For the preferred example of " nitrogen heterocyclic ring ", can mention tetramethyleneimine, imidazolidine, pyrazolidine, piperidines, piperazine, morpholine, parathiazan, thiazolidine,  azoles alkane or the like.
This nitrogen heterocyclic ring is chosen wantonly in its commutable position has 1 to 2 substituting group.For these substituting groups, can mention hydroxyl, optional halogenated C 1-6Alkyl, C 6-14Aryl, C 7-16Aralkyl or the like.
For the preferred example of " the optional acyl group that replaces ", can mention formyl radical, carboxyl, formamyl, C 1-6Alkyl-carbonyl (for example, ethanoyl, isobutyryl, isovaleryl), C 1-6Alkoxyl group-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, tertbutyloxycarbonyl), C 3-8Cycloalkyl-carbonyl (for example, cyclopentylcarbonyl, cyclohexyl-carbonyl), C 6-14Aryl-carbonyl (for example, benzoyl, 1-naphthoyl, 2-naphthoyl), C 7-16Aralkyl-carbonyl (for example, phenylacetyl, 2-phenyl propionyl), C 6-14Aryloxy-carbonyl (for example, phenyloxycarbonyl, naphthyloxy carbonyl), C 7-16Aralkoxy-carbonyl (for example, benzyloxycarbonyl, styroyl oxygen base carbonyl), single or two-C 1-6Alkyl-carbamoyl, single or two-C 6-14Aryl-formamyl, C 3-8Cycloalkyl-formamyl (for example, the cyclopropyl formamyl), C 7-16Aralkyl-formamyl (for example, the benzylamino formyl radical), C 1-6Alkyl sulphonyl, C 6-14Aryl sulfonyl, nitrogen heterocycle-carbonyl (for example, pyrrolidyl carbonyl, piperidino carbonyl), C 1-6Alkyl sulphinyl, C 6-14Aryl sulfonyl kia, thiocarbamoyl group, single or two-C 1-6Alkyl-phosphono (for example, dimethyl phosphine acyl group, diethyl phosphonyl, di-isopropyl phosphono, dibutyl phosphono) or the like.
" the optional C that replaces in this specification sheets 1-4Alkylidene group " " C 1-4Alkylidene group " be straight or branched, and for example can mention methylene radical, ethylidene, 1-methyl ethylidene, propylidene, 1-ethyl ethylidene, 1-methyl propylidene, 2-methyl propylidene, butylidene or the like.C 1-4Alkylidene group is chosen wantonly on its commutable position has 1 to 3 substituting group.For these substituting groups, for example, can mention halogen atom, hydroxyl, amino, single or two-C 1-6Alkyl-amino, single or two-C 6-14Aryl-amino, single or two-C 7-16Aralkyl-amino, nitro, cyano group, C 1-6Alkoxyl group, C 1-6Alkylthio or the like.
For " the optional C that replaces in this specification sheets 1-3Alkylidene group " " C 1-3Alkylidene group ", can mention above-mentioned " C with 1 to 3 carbon atom 1-4Alkylidene group ".C 1-3Alkylidene group is chosen wantonly in its commutable position has 1 to 3 substituting group.For these substituting groups, can mention above-mentioned as C 1-4The substituent example of alkylidene group.
The following describes compound (being abbreviated as compound (I) hereinafter sometimes) and its salt by formula of the present invention (I) representative.
R in the formula (I) 2Be halogen atom, nitro, the optional alkyl that replaces; the optional hydroxyl that replaces; the optional amino that replaces, the optional sulfydryl that replaces, optional acyl group that replaces or the optional heterocyclic group that replaces; preferred halogen atom; the optional alkyl that replaces, the optional hydroxyl that replaces, the optional amino that replaces; optional sulfydryl that replaces or the optional heterocyclic group that replaces, more preferably optional alkyl that replaces or the optional hydroxyl that replaces.In the middle of these, the preferred optional hydroxyl that replaces.For the preferred object lesson of the optional hydroxyl that replaces, can mention:
(1) hydroxyl,
(2) optional by 1 to 3 C that is selected from following substituting group replacement 1-10Alkoxyl group:
(a) 4 to 7 yuan of heterocyclic groups, except that carbon atom, it comprises that one in 1 to 4 heteroatoms that is selected from nitrogen-atoms, sulphur atom and Sauerstoffatom or two kind are as ring atom (preferred pyridyl, thiazolyl, pyrrolidyl, oxo-pyrrolidine base, THP trtrahydropyranyl, tetrahydro thiapyran base, 1-oxo tetrahydro thiapyran base, 1,1-dioxo tetrahydro thiapyran base, oxetanyl), optional being selected from by 1 to 3 chosen halogenated C wantonly 1-6Alkyl, hydroxyl and C 1-6The substituting group of alkoxyl group-carbonyl replaces,
(b) C 3-8Cycloalkyl,
(c) hydroxyl,
(d) optional halogenated C 1-6Alkoxyl group,
(e) amino,
(f) single or two-C 1-6Alkyl-amino,
(g) N-C 1-6Alkyl-N-C 1-6Alkyl-carbonyl-amino,
(h) C 7-16Aralkoxy,
(i) C 1-6Alkylthio,
(j) C 1-6Alkyl sulphinyl,
(k) C 1-6Alkyl sulphonyl and
(l) single or two-C 1-6Alkyl-phosphono,
(3) optional by optional halogenated C 1-6The heterocyclyloxy base that alkyl replaces (preferred THP trtrahydropyranyl oxygen base, pyridyl oxygen base, tetrahydro thiapyran base oxygen base, 1-oxo tetrahydro thiapyran base oxygen base, 1,1-dioxo tetrahydro thiapyran base oxygen base),
(4) C 7-16Aralkoxy,
(5) optional by 1 to 3 C 1-6The silyl oxygen base that alkyl replaces,
(6) C 1-6Alkyl sulphonyl oxygen base and
(7) heterocyclic radical alkylsulfonyl oxygen base (preferred thienyl sulphonyl base oxygen base, furyl alkylsulfonyl oxygen base).
R in the formula (I) 1And R 3Be identical (except when R 1And R 3Two when all being hydrogen atom) or it is different, and each is hydrogen atom, halogen atom, optional hydrocarbyl group that replaces or the optional hydroxyl that replaces, preferred hydrogen atom, halogen atom or C 1-6Alkyl, more preferably halogen atom or C 1-6Alkyl.In the middle of these, preferred C 1-6Alkyl (preferable methyl).
R in the formula (I) 4And R 5Be identical or different, and each is hydrogen atom, halogen atom, optional hydrocarbyl group that replaces or the optional hydroxyl that replaces, preferred hydrogen atom or halogen atom (preferred fluorine atom).
R in the formula (I) 10And R 11Be identical or different, and each is hydrogen atom, halogen atom or C 1-6Alkoxyl group, preferred two all is hydrogen atom.
E in the formula (I) is a chemical bond, the optional C that replaces 1-4Alkylidene group ,-W 1-O-W 2,-W 1-S-W 2-or-W 1-N (R 6)-W 2-(W 1And W 2Be identical or different, and each is chemical bond or the optional C that replaces 1-3Alkylidene group, R 6Be hydrogen atom, optional acyl group that replaces or the optional hydrocarbyl group that replaces), preferred chemical bond.
S in the formula (I) 1Ring is the optional substituent phenyl ring that is selected from halogen atom, chooses the amino of the hydrocarbyl group that replaces, the hydroxyl of choosing replacement wantonly and optional replacement wantonly that further has, and preferred phenyl ring is chosen wantonly further has C 1-6Alkoxyl group.Substituent number is for example 1 or 2.
R in the formula (I) is optional hydroxyl that replaces or the optional amino that replaces, the preferred optional hydroxyl that replaces, more preferably hydroxyl or C 1-6Alkoxyl group.In the middle of these, preferred hydroxyl.
For " preferred example of compound (I) ", can mention following compounds.
[compd A]
A kind of compound, wherein
R 2Be
(1) halogen atom,
(2) optional by C 6-14The C that aryloxy replaces 1-6Alkyl, wherein C 6-14Aryloxy is optional to be replaced by halogen atom,
(3) hydroxyl,
(4) optional by 1 to 3 C that is selected from following substituting group replacement 1-10Alkoxyl group:
(a) 5 to 7 yuan of heterocyclic groups, except that carbon atom, it comprises that 1 to 4 is selected from heteroatomic one in nitrogen-atoms, sulphur atom and the Sauerstoffatom or two kind as ring atom (preferred pyridyl, thiazolyl), and is optional by optional halogenated C 1-6Alkyl replaces,
(b) C 3-8Cycloalkyl,
(c) hydroxyl,
(d) optional halogenated C 1-6Alkoxyl group,
(e) amino and
(f) single or two-C 1-6Alkyl-amino,
(5) heterocyclyloxy base (preferred THP trtrahydropyranyl oxygen base), or
(6) C 7-16Aralkoxy;
R 1And R 3Be identical (except when R 1And R 3Two when all being hydrogen atom) or different, and each is hydrogen atom, halogen atom or C 1-6Alkyl;
R 4And R 5Be identical or different, and each is hydrogen atom or halogen atom;
R 10And R 11Two all is hydrogen atom;
E is a key;
S 1Ring is the optional C that further has 1-6The phenyl ring of alkoxyl group; With
R is hydroxyl or C 1-6Alkoxyl group (preferred hydroxyl).
[compd B]
A kind of compound, wherein
R 2Be
(1) halogen atom,
(2) optional by C 6-14The C that aryloxy replaces 1-6Alkyl, wherein C 6-14Aryloxy is optional to be replaced by halogen atom,
(3) hydroxyl,
(4) optional by 1 to 3 C that is selected from following substituting group replacement 1-10Alkoxyl group:
(a) 5 to 7 yuan of heterocyclic groups, except that carbon atom, it comprises that one in 1 to 4 heteroatoms that is selected from nitrogen-atoms, sulphur atom and Sauerstoffatom or two kind are as ring atom (preferred pyridyl, thiazolyl, pyrrolidyl, oxo-pyrrolidine base, tetrahydro thiapyran base, 1,1-dioxo tetrahydro thiapyran base), optional being selected from by 1 to 3 chosen halogenated C wantonly 1-6Alkyl, hydroxyl and C 1-6The substituting group of alkoxyl group-carbonyl replaces,
(b) C 3-8Cycloalkyl,
(c) hydroxyl,
(d) optional halogenated C 1-6Alkoxyl group,
(e) amino
(f) single or two-C 1-6Alkyl-amino,
(g) N-C 1-6Alkyl-N-C 1-6Alkyl-carbonyl-amino,
(h) C 7-16Aralkoxy,
(i) C 1-6Alkylthio and
(j) C 1-6Alkyl sulphonyl,
(5) optional by optional halogenated C 1-6The heterocyclyloxy base that alkyl replaces (preferred THP trtrahydropyranyl oxygen base, pyridyl oxygen base, tetrahydro thiapyran base oxygen base, 1,1-dioxo tetrahydro thiapyran base oxygen base),
(6) C 7-16Aralkoxy,
(7) optional by 1 to 3 C 1-6The silyl oxygen base that alkyl replaces,
(8) C 1-6Alkyl sulphonyl oxygen base, or
(9) heterocyclic radical alkylsulfonyl oxygen base (preferred thienyl sulphonyl base oxygen base, furyl alkylsulfonyl oxygen base);
R 1, R 3, R 4, R 5, R 10, R 11, E, S 1Ring and R such as above-mentioned [compd A] middle definition.
[Compound C]
A kind of compound, wherein
R 2Be
(1) halogen atom,
(2) optional by C 6-14The C that aryloxy replaces 1-6Alkyl, wherein C 6-14Aryloxy is optional to be replaced by halogen atom,
(3) hydroxyl,
(4) optional by 1 to 3 C that is selected from following substituting group replacement 1-10Alkoxyl group:
(a) 4 to 7 yuan of heterocyclic groups, except that carbon atom, it comprises that one in 1 to 4 heteroatoms that is selected from nitrogen-atoms, sulphur atom and Sauerstoffatom or two kind are as ring atom (preferred pyridyl, thiazolyl, pyrrolidyl, oxo-pyrrolidine base, THP trtrahydropyranyl, tetrahydro thiapyran base, 1-oxo tetrahydro thiapyran base, 1,1-dioxo tetrahydro thiapyran base, oxetanyl), optional being selected from by 1 to 3 chosen halogenated C wantonly 1-6Alkyl, hydroxyl and C 1-6The substituting group of alkoxyl group-carbonyl replaces,
(b) C 3-8Cycloalkyl,
(c) hydroxyl,
(d) optional halogenated C 1-6Alkoxyl group,
(e) amino
(f) single or two-C 1-6Alkyl-amino,
(g) N-C 1-6Alkyl-N-C 1-6Alkyl-carbonyl-amino,
(h) C 7-16Aralkoxy,
(i) C 1-6Alkylthio,
(j) C 1-6Alkyl sulphinyl,
(k) C 1-6Alkyl sulphonyl and
(l) single or two-C 1-6Alkyl-phosphono,
(5) optional by optional halogenated C 1-6The heterocyclyloxy base that alkyl replaces (preferred THP trtrahydropyranyl oxygen base, pyridyl oxygen base, tetrahydro thiapyran base oxygen base, 1-oxo tetrahydro thiapyran base oxygen base, 1,1-dioxo tetrahydro thiapyran base oxygen base),
(6) C 7-16Aralkoxy,
(7) optional by 1 to 3 C 1-6The silyl oxygen base that alkyl replaces,
(8) C 1-6Alkyl sulphonyl oxygen base, or
(9) heterocyclic radical alkylsulfonyl oxygen base (preferred thienyl sulphonyl base oxygen base, furyl alkylsulfonyl oxygen base);
R 1, R 3, R 4, R 5, R 10, R 11, E, S 1Ring and R such as above-mentioned [compd A] middle definition.In this compound, R 1And R 3Preferably identical or different, and each is C 1-6Alkyl.
[Compound D]
3-[4-[[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl base-3-yl] methoxyl group] phenyl] propionic acid (embodiment 39);
3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } phenyl)-2,2-difluoro propionic acid (embodiment 75);
3-[4-(4 '-[2-(ethylsulfonyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid (embodiment 86);
3-[4-(2 ', 6 '-dimethyl-4 '-[3-(2-oxo-pyrrolidine-1-yl) propoxy-] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid (embodiment 90);
3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid (embodiment 97);
3-[2-fluoro-4-(4 '-[(4-hydroxyl-1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] propionic acid (embodiment 100);
3-[4-(2 ', 6 '-dimethyl-4 '-[(methyl sulphonyl) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid (embodiment 102);
3-[4-(4 '-[(1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid (embodiment 114);
3-[4-(2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid (embodiment 116);
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-4-base oxygen base) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid (embodiment 118);
3-[4-(4 '-[3-(diethoxy phosphoryl) propoxy-]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid (embodiment 121);
3-[2-fluoro-4-(6-isopropoxy-2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group) phenyl] propionic acid (embodiment 125);
Or its salt (preferably salt hydrochlorate or the like).
For the salt of the compound that uses among the present invention, for example metal-salt, ammonium salt, the salt that becomes with organic bases, the salt that becomes with mineral acid, the salt that becomes with organic acid, salt of becoming with alkalescence or acidic amino acid or the like.The preferred example of metal-salt comprises an alkali metal salt for example sodium salt, sylvite or the like; Alkaline earth salt is calcium salt, magnesium salts, barium salt or the like for example; Aluminium salt or the like.The preferred example of the salt that becomes with organic bases comprises and Trimethylamine 99, triethylamine, pyridine, picoline, 2,6-lutidine, thanomin, diethanolamine, trolamine, hexahydroaniline, dicyclohexylamine, N, salt that the N-dibenzyl-ethylenediamin becomes or the like.The preferred example of the salt that becomes with mineral acid comprises the salt that becomes with hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid or the like.The preferred example of the salt that becomes with organic acid comprises the salt that becomes with formic acid, acetate, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartrate, toxilic acid, citric acid, succsinic acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid or the like.The preferred example of the salt that becomes with basic aminoacids comprises the salt that becomes with arginine, cytolysin (lysin), ornithine or the like.The preferred example of the salt that becomes with acidic amino acid comprises the salt that becomes with aspartic acid, L-glutamic acid or the like.
In the middle of these, the preferred acceptable salt of pharmacology.For example, when compound has acidic functionality, preferable alloy salt is an alkali metal salt (sodium salt for example for example, sylvite or the like), alkaline earth salt (calcium salt for example, magnesium salts, barium salt or the like) or the like, ammonium salt or the like, when compound has basic functionality, preferably with the mineral acid salt that becomes of hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid or the like for example; Or with the organic acid salt that becomes of acetate, phthalic acid, fumaric acid, oxalic acid, tartrate, toxilic acid, citric acid, succsinic acid, methylsulfonic acid, tosic acid or the like for example.
The prodrug of compound (I) and its salt is under the intravital physiological condition of machine, owing to can be transformed into the compound of compound (I) by the reaction of enzyme, hydrochloric acid in gastric juice or the like; That is to say, can be transformed into the compound of compound (I) and can be transformed into the compound of compound (I) by enzymatic oxidation, reduction, hydrolysis or the like by hydrochloric acid in gastric juice or the like hydrolysis or the like.
The example of the prodrug of compound (I) comprises following compounds: wherein the amino of compound (I) by acidylate, alkylation or phosphorylation (for example, wherein the amino of compound (I) by eicosane acidylate, propylene acidylate, amylamine base carbonylation, (5-methyl-2-oxo-1,3-dioxo cyclopentenes (dioxolen)-4-yl) methoxycarbonylization, tetrahydrofuran ization, pyrrolidyl methylate, oxy acid methyl neopentylization, tert-butylation or the like); Compound wherein the hydroxyl of compound (I) by acidylate, alkylation, phosphorylation or boration (for example, compound wherein the hydroxyl of compound (I) be acetylation, palmitoylation, propionylization, pivalylization, succinylation, fumarylization, alanylization, dimethylaminomethyl carbonylation or the like); The wherein esterified or amidation of the carboxyl of compound (I) of compound (for example, compound wherein the carboxyl of compound (I) by C 1-6The alkyl esterification, the phenyl esterification, the carboxymethyl esterification, dimethylaminomethyl esterification, oxy acid methyl neopentyl esterification, the esterification of ethoxy carbonyl oxygen base ethyl, the phthalidyl esterification, (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl-esterified, the esterification of cyclohexyl oxygen base carbonyl ethyl, methyl nitrosoureaization or the like) or the like.In these compounds, preferably wherein the carboxyl of compound (I) by C 1-6Alkyl is the compound of methyl, ethyl, tertiary butyl or the like esterification for example.These compounds can be prepared by compound (I) by known method itself.
The prodrug of compound (I) can be as Development of Pharmaceutical Products, vol.7, Molecule Design, 163-198 is transformed into the compound of compound (I) under the physiological condition described in the Hirokawa Shoten (1990).
The preparation method of compound of the present invention (I) or its salt is described hereinafter.
Each symbol of compound in the synoptic diagram of following reaction scheme as defined above, unless special the description.Each compound of describing in reaction scheme can form salt, as long as its inhibited reaction not, and for this salt, can mention those salt like the salt face with compound (I).
Compound (I) can be for example according to the represented method preparation of following reaction scheme 1-4.
Wherein E is E 1(E 1Be chemical bond, the optional C that replaces 1-4Alkylidene group ,-W 1-N (R 6)-(W 1And R 6As defined above) or-O-) (by the formula (Ia ') and (Ia) compound of representative) (being abbreviated as compound (Ia ') and compound (Ia) respectively)) compound (I), can be for example prepare according to method or its similar method of following reaction scheme 1 expression.
Reaction scheme 1
Figure A20048004213900311
Wherein R ' is the optional C that replaces 1-6Alkoxyl group, L are leavings group or hydroxyl, and L ' is a leavings group, and M is metal (for example, potassium, sodium, lithium, magnesium, copper, mercury, zinc, thallium, boron, tin or the like, it can form complex compound), G 1Be chemical bond or the optional C that replaces 1-4Alkylidene group is (with the C of the optional replacement of E 1-4Alkylidene group is identical), another symbol is as defined above.
For " leavings group " L and L ', for example can mention halogen atom (for example fluorine, chlorine, bromine, iodine), optional halogenated C 1-6Alkyl sulphonyl oxygen base (for example methylsulfonyl oxygen base, ethylsulfonyl oxygen base, trichlorine methylsulfonyl oxygen base, trifyl oxygen base), optional have a substituent C 6-10Aryl sulfonyl oxygen base (for example, optionally has 1 to 3 and is selected from C 1-6Alkyl (for example methyl, ethyl), C 1-6Alkoxyl group (for example methoxyl group, oxyethyl group) and nitro or the like substituent C 6-10Aryl sulfonyl oxygen base (for example phenyl sulfonyl oxygen base, naphthyl alkylsulfonyl oxygen base); For object lesson, phenyl sulfonyl oxygen base, m-nitro base alkylsulfonyl oxygen base, p-toluenesulfonyl oxygen base or the like) or the like.
By formula (II), (III), (V-1), (V-2) and (V-3) compound of representative (be abbreviated as respectively compound (II), (III), (V-1), (V-2) and (V-3)) can commercially buy, and also can prepare according to known method itself or its similar method.
Compound (being abbreviated as compound (IV)) by formula (IV) representative can prepare by compound (II) and compound (III) reaction.
(i) when L is hydroxyl, compound (IV) can carry out Mitsunobu reaction (Synthesis, 1981,1-27 page or leaf) by compound (II) and compound (III) and prepare.In this reaction, compound (II) and compound (III) be the azodicarboxylate for example diethylazodicarboxylate, diisopropyl azo-2-carboxylic acid, 1,1 '-for example existence reaction down of triphenylphosphine, tributylphosphine or the like of (azo dicarbapentaborane) connection piperidines or the like and phosphine.
It is that the inert solvent carries out that this reaction is preferably used for reaction.Do not limit simultaneously solvent especially, as long as reaction, for example, solvent is ether (for example, ether, diisopropyl ether, diphenyl ether, tetrahydrofuran (THF), 1,4-two  alkane, 1,2-glycol dimethyl ether or the like) for example; Aromatic hydrocarbons (for example, benzene, toluene or the like); Saturated hydrocarbons (for example, hexanaphthene, hexane or the like); Acid amides (for example, N, dinethylformamide, N,N-dimethylacetamide, HMPA or the like); Halohydrocarbon (for example, methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride or the like); Nitrile (for example, acetonitrile, propionitrile or the like); Ketone (for example, acetone, ethyl methyl ketone or the like); Sulfoxide (for example, methyl-sulphoxide or the like), or the like, or its mixed solvent or the like is preferred.
About 5 minutes to about 48 hours usually reaction times, preferred about 10 minutes to about 24 hours.About-20 ℃ to about 200 ℃ usually of temperature of reaction, preferred about 0 to about 100 ℃.
Compound with respect to 1 mole (II), the usage quantity of compound (III) are about 1 to about 5 moles, preferred about 1 to about 2 moles.
Compound with respect to 1 mole (II), the usage quantity about respectively 1 of " azodicarboxylate " and " phosphine " be to about 5 moles, preferred about 1 to about 2 moles.
(ii) when L was leavings group, compound (IV) can react with compound (III) in the presence of alkali, by compound (II) and prepare.
For alkali, for example, can mention for example sodium hydroxide of alkali metal hydroxide, potassium hydroxide, lithium hydroxide or the like; Alkaline earth metal hydroxides is hydrated barta or the like for example; Alkaline carbonate is yellow soda ash for example, salt of wormwood, cesium carbonate or the like; Alkali metal hydrocarbonate is sodium bicarbonate or the like for example; Second hydrochloric acid is sodium acetate for example, ammonium acetate or the like; Aromatic amine is pyridine for example, lutidine or the like; Tertiary amine is triethylamine for example, tripropylamine, tributylamine, ethyl diisopropyl amine, cyclohexyl dimethyl amine, 4-dimethylaminopyridine, N, accelerine, N-methyl piperidine, N-crassitude, N-methylmorpholine or the like; Alkalimetal hydride is sodium hydride for example, potassium hydride KH or the like; Amination metal (metal amides) is sodium amide for example, lithium diisopropylamine, hexamethl disilamine base lithium (lithium hexamethyldisilazide) or the like; Alkali metal alcoholates with 1 to 6 carbon atom is sodium methylate for example, sodium ethylate, and sodium tert-butoxide, potassium tert.-butoxide or the like, or the like.
It is that the inert solvent carries out that this reaction is preferably used for reaction.Do not limit simultaneously solvent especially, as long as reaction, for example, solvent is ether (for example, ether, diisopropyl ether, diphenyloxide, tetrahydrofuran (THF), 1,4-two  alkane, 1,2-glycol dimethyl ether or the like) for example; Aromatic hydrocarbons (for example, benzene, toluene or the like); Saturated hydrocarbons (for example, hexanaphthene, hexane or the like); Acid amides (for example, N, dinethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide or the like); Halohydrocarbon (for example, methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride or the like); Nitrile (for example, acetonitrile, propionitrile or the like); Ester (for example, methyl acetate, ethyl acetate, butylacetate or the like); Sulfoxide (for example, methyl-sulphoxide or the like); Water or the like, or its mixed solvent or the like is preferred.
Compound with respect to 1 mole (II), the usage quantity of compound (III) are about 0.8 to 10 mole, preferred about 0.9 to 2 mole.About 1 to 10 mole usually of compound with respect to 1 mole (II), the usage quantity of alkali, preferred 1 to 3 mole.
About 10 minutes to about 12 hours usually reaction times, preferred about 20 minutes to about 6 hours.About-50 ℃ to about 150 ℃ usually of temperature of reaction, preferred-20 to about 100 ℃ approximately.
Compound (Ia ') can pass through compound (IV) and compound (V-1) or compound (V-2) or compound (V-3) (unless otherwise mentioned, these are called compound (V) together) reaction and prepare.
Compound (IV) carries out in the presence of alkali usually with the reaction of compound (V).For alkali, can mention alkalimetal hydride (for example, sodium hydride, potassium hydride KH or the like); Alkali metal hydroxide (for example, lithium hydroxide, sodium hydroxide, potassium hydroxide or the like); Alkaline earth metal hydroxides (for example, magnesium hydroxide, calcium hydroxide or the like); Alkaline carbonate (for example, yellow soda ash, salt of wormwood or the like); Alkali metal hydrocarbonate (for example, sodium bicarbonate, saleratus or the like); Alkali metal alcoholate (for example, sodium methylate, sodium ethylate, sodium tert-butoxide or the like) with 1 to 6 carbon atom; Organic bases (for example, Trimethylamine 99, triethylamine, diisopropylethylamine, pyridine, picoline, N-crassitude, N-methylmorpholine, 1,5-diazabicyclo [4.3.0]-5-nonene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]-7-undecylene or the like); Organolithium (for example, lithium methide, n-Butyl Lithium, the second month in a season-butyllithium, tert-butyl lithium or the like); Lithamide (for example, lithium diisopropylamine or the like), or the like.
It is that the inert solvent carries out that compound (IV) preferably uses for this reaction with the reaction of compound (V).Do not limit simultaneously solvent especially, as long as reaction, solvent is alcohol (for example, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, trimethyl carbinol or the like) for example; Ether (for example, 1,4-two  alkane, tetrahydrofuran (THF), ether, t-butyl methyl ether, diisopropyl ether, ethylene glycol-dme or the like); Ester (for example, ethyl formate, ethyl acetate, n-butyl acetate or the like); Halohydrocarbon (for example, methylene dichloride, chloroform, tetracol phenixin, trieline or the like); Hydrocarbon (for example, normal hexane, benzene, toluene, dimethylbenzene or the like); Acid amides (for example, methane amide, N, dinethylformamide, N,N-dimethylacetamide or the like); Nitrile (for example, acetonitrile, propionitrile or the like); Sulfoxide (for example, methyl-sulphoxide or the like); Tetramethylene sulfone; Hexamethylphosphoric triamide; Water or the like, its mixed solvent or the like are preferred.
Compound (IV) utilizes metal catalyst to promote with the reaction of compound (V) usually.For metal catalyst, can use metal complex with various parts, for example can mention, palladium compound [for example, acid chloride (II), tetrakis triphenylphosphine palladium (0), chlorination two (triphenylphosphine) palladium (II), two (triethyl phosphine) palladiums (0) of dichloro, three (dibenzalacetone) two palladiums-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene, acid chloride (II) and 1, the complex compound of 1 '-two (diphenylphosphino) ferrocene, or the like], nickel compound is [for example, four (triphenylphosphine) nickel (0), two (triethylphosphine) nickel (II) muriate, two (triphenylphosphine) nickel (II) muriate or the like], rhodium compound is [for example, three (triphenylphosphine) rhodium (III) muriate or the like], cobalt compound, copper compound [for example, cupric oxide, cupric chloride (II) or the like], platinic compound or the like.In the middle of these, preferred palladium compound, nickel compound and copper compound.Compound with respect to 1 mole (IV), the usage quantity of metal catalyst are approximately 0.000001 to 5 mole, preferred 0.0001 to 1 mole.When the metal catalyst that is used for this reaction was unstable to oxygen, preferred reaction was carried out under rare gas element (for example argon gas or nitrogen) atmosphere.
Compound with respect to 1 mole (IV), the usage quantity of compound (V) are about 0.8 to 10 mole, preferred about 0.9 to 2 mole.Compound with respect to 1 mole (IV), the usage quantity of alkali are about 1 to about 20 moles, preferred about 1 to 5 mole.
Temperature of reaction is approximately-10 ℃ to about 250 ℃, preferred about 0 ℃ to about 150 ℃.
Although the reaction times changes according to compound (IV), compound (V), metal catalyst, alkali and solvent types, temperature of reaction or the like, it is about about 1 minute to about 200 hours usually, preferred about 5 minutes to about 100 hours.
Compound (Ia) can prepare by reaction that compound (Ia ') is hydrolyzed.According to ordinary method, use the reaction that is hydrolyzed of acid or alkali.
For acid, for example can mention mineral acid (for example hydrochloric acid, sulfuric acid or the like); Lewis acid (Lewis acid) (for example boron trichloride, boron tribromide or the like); Organic acid (for example trifluoroacetic acid, tosic acid or the like), or the like.Lewis acid can use simultaneously with mercaptan or thioether.
For alkali, can mention for example alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, hydrated barta or the like); Alkaline carbonate (for example, yellow soda ash, salt of wormwood or the like); Alkali metal alcoholate (for example, sodium methylate, sodium ethylate, potassium tert.-butoxide or the like) with 1 to 6 carbon atom; Organic bases (for example, triethylamine, imidazoles, carbonamidine or the like), or the like.Compound with respect to 1 mole (Ia '), the usage quantity of bronsted lowry acids and bases bronsted lowry are typically about 0.5 to 10 mole, preferred about 0.5 to 6 mole.
Do not having the reaction that is hydrolyzed under the condition of solvent, or use is the inert solvent for reaction.Do not limit simultaneously solvent especially, as long as reaction, for example, solvent is alcohol (for example, methyl alcohol, ethanol, propyl alcohol or the like) for example; Aromatic hydrocarbons (for example, benzene, toluene or the like); Saturated hydrocarbons (for example, hexanaphthene, hexane or the like); Organic acid (for example, formic acid, acetate or the like); Ether (for example, tetrahydrofuran (THF), 1,4-two  alkane, 1,2-glycol dimethyl ether or the like); Acid amides (for example, N, dinethylformamide, N,N-dimethylacetamide or the like); Halohydrocarbon (for example, methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride or the like); Nitrile (for example, acetonitrile, propionitrile or the like); Ketone (for example, acetone, ethyl methyl ketone or the like); Sulfoxide (for example, methyl-sulphoxide or the like); Water or the like, or its mixed solvent or the like is preferred.
Reaction times is generally 10 minutes to 60 hours, preferred 10 minutes to 12 hours.Temperature of reaction is generally-10 to 200 ℃, preferred 0 to 120 ℃.
Wherein R is the optional C that replaces 1-6The compound of alkoxyl group or hydroxyl (I) (by the formula (Ib ') or (Ib) compound (being abbreviated as compound (Ib ') or compound (Ib) respectively) of representative), method or its similar method preparation that can be for example represent according to following reaction scheme.
Reaction scheme 2
R wherein 7Be the optional C that replaces 1-4Alkoxyl group-carbonyl or formyl radical, other symbols as defined above.For R 7" the optional C that replaces 1-4Alkoxyl group-carbonyl ", can mention optional have 1 to 3 substituting group for example phenyl, halogen atom, C 1-6The C of alkoxyl group or the like 1-4Alkoxyl group-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, carbobenzoxy-(Cbz), 2-(oxyethyl group) ethoxycarbonyl) or the like.
The compound (being abbreviated as compound (X)) of formula (X) representative can carry out reduction reaction by the compound (being abbreviated as compound (IX)) to formula (IX) representative and prepare.
Carry out reduction reaction according to ordinary method, use reductive agent.For reductive agent, can mention for example metal hydride (for example, aluminum hydride, diisobutyl aluminium hydride, tri-butyl tin hydride or the like); Metal hydride complex compound (for example, lithium aluminum hydride, sodium borohydride or the like); Borane complex compound (for example, borane tetrahydrofuran complex, borane dimethyl sulphide complex compound or the like); Boron alkyl (for example, thexylborane, disiamylborane or the like); Diboron hexahydride; Metal (for example, zinc, aluminium, tin, iron or the like); Basic metal (for example, sodium, lithium or the like)/liquefied ammonia (Birch reduction) or the like.Determine the usage quantity of reductive agent rightly according to the kind of reductive agent.For example, compound with respect to 1 mole (IX), the usage quantity of metal hydride or metal hydride complex compound is approximately 0.25 to about 10 moles, preferred about 0.5 to about 5 moles, compound with respect to 1 mole (IX), the usage quantity of borane complex, alkyl borane or diboron hexahydride is approximately 1 to about 10 moles, preferred about 1 to about 5 moles, with respect to 1 normal compound (IX), the usage quantity of metal (comprise and be used for Birch reductive basic metal) is about 1 to about 20 equivalents, and preferred about 1 to about 5 equivalents.
It is that the inert solvent carries out that this reduction reaction is preferably used for reaction.Do not limit simultaneously solvent especially, as long as reaction, for example, solvent is alcohol (for example, methyl alcohol, ethanol, propyl alcohol, trimethyl carbinol or the like) for example; Ether (for example, ether, diisopropyl ether, diphenyloxide, tetrahydrofuran (THF), 1,4-two  alkane, 1,2-glycol dimethyl ether or the like); Aromatic hydrocarbons (for example, benzene, toluene or the like); Saturated hydrocarbons (for example, hexanaphthene, hexane or the like); Acid amides (for example, N, dinethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide or the like); Organic acid (for example, formic acid, acetate, propionic acid, trifluoroacetic acid, methylsulfonic acid or the like), or the like, its mixed solvent or the like is preferred.
Although the reaction times changes according to the kind of reductive agent and quantity or activity of such catalysts and quantity, it is about about 1 hour to about 100 hours usually, preferred about 1 hour to about 50 hours.About-20 to about 120 ℃ usually of temperature of reaction, preferred about 0 to about 80 ℃.
Compound (Ib ') can according to reaction scheme 1 in the Mitsunobu reaction similar methods of compound (II) and compound (III), react by compound (II) and compound (X) and to prepare.
Compound (Ib) can according to reaction scheme 1 in compound (Ia ') the hydrolysis reaction similar methods, prepare by compound (Ib ').
Wherein E is E 2(E 2Be G 1(G 1As defined above) ,-N (R 6)-W 2-(R 6And W 2As defined above) or-O-) compound (IX), (being abbreviated as compound (IX ')) can be for example prepares according to method or its similar method of following reaction scheme 2 ' expression.
By formula (VII), (VIII-1), (VIII-2) and (VIII-3) compound of representative (be abbreviated as compound (VII) respectively, compound (VIII-1), compound (VIII-2) and compound (VIII-3)) be commercial easy acquisition, and also can be according to itself known method or its similar method preparation.
Reaction scheme 2 '
Figure A20048004213900371
Compound (IX ') can according to reaction scheme 1 in compound (IV) and compound (V) reaction similar methods, prepare by compound (VII) and compound (VIII-1), compound (VIII-2) or compound (VIII-3) (unless otherwise mentioned, these are called compound (VIII) together) reaction.
Wherein E is E 3(E 3Be-W 1-O-W 2-,-W 1-S-W 2-or-W 1-N (R 6)-W 2-(W 1, W 2And R 6Compound as defined above)) (I) (by the formula (Ic ') and (Ic) compound (being abbreviated as compound (Ic ') and compound (Ic) respectively) of representative, can be for example prepares according to method or its similar method of following reaction scheme 3 expressions.
Reaction scheme 3
Figure A20048004213900372
Wherein PG is a protecting group, and X is-O-,-S-or-N (R 6)-(R 6As defined above), other symbol as defined above.
For protecting group PG, can use hydroxyl protecting group, amino protecting group and the sulfhydryl protected base mentioned later.
Formula (XI), (XIV-1) and the compound of (XIV-2) representing (are abbreviated as compound (XI) respectively, compound (XIV-1) and compound (XIV-2)) be commercial easy acquisition, and also can be according to itself known method or its similar method preparation.
The compound (being abbreviated as compound (XII)) of formula (XII) representative can according to reaction scheme 1 in compound (II) react with compound (XI) with compound (III) reaction similar methods, by compound (II) and prepare.
The compound (being abbreviated as compound (XIII)) of formula (XIII) representative can be according to itself known deprotection reaction or its similar method, prepare by compound (XII) is gone to protect.
E wherein 3Be-W 1-O-W 2-,-W 1-S-W 2-or-W 1-N (R 6)-W 2-compound (Ic '), W 2And R 6As defined above, W 1Be the optional C that replaces 1-3Alkylidene group, can according to reaction scheme 1 in wherein L be compound (II) and compound (III) the reaction similar methods of leavings group, prepare by compound (XIII) and compound (XIV-1) reaction.
E wherein 3Be-W 1-O-W 2-or-W 1-S-W 2-and W 1And W 2In at least one be the compound (Ic ') of chemical bond, also can according to reaction scheme 1 in the Mitsunobu reacting phase of compound (II) and compound (III) like react, by X wherein be-O-or-compound (XIII) and compound (XIV-2) reaction of S-prepare.
Compound (Ic) can according to reaction scheme 1 in the hydrolysis reaction similar methods of compound (Ia '), (Ic ') prepares by compound.
R wherein 2Be the compound (I) of the amino of the hydroxyl that replaces, replacement or the sulfydryl that replaces, i.e. R wherein 2Be R 2'-Y-[Y is-O-,-S-or-N (R A)-(R ABe that the amino substituting group that occupies of hydrogen atom or quilt is (specifically, by R 2" optional replace amino " in the substituting group that occupies of amino) and R 2' be substituting group (specifically, when Y be-during O-, it is by R 2" optional replace hydroxyl " in the substituting group that occupies of hydroxyl, when Y be-during S-, it is by R 2" optional replace sulfydryl " in the substituting group that occupies of sulfydryl, when Y is-N (R A)-time its by R 2" optional replace amino " in the substituting group that occupies of amino)] compound (I) (by the formula (If ') and (Id) compound (being abbreviated as compound (If ') and compound (Id) respectively) of representative, method or its similar method that can for example represent according to following reaction scheme 4 prepare.
Reaction scheme 4
Wherein each symbol as defined above.
The compound (being abbreviated as compound (Id ')) of formula (Id ') representative can be according to preparing with above-claimed cpd (Ia '), compound (Ib ') or compound (Ic ') similar methods.
The compound (being abbreviated as compound (Ie ')) of formula (Ie ') representative can prepare by compound (Id ') being carried out known deprotection reaction own.
Compound (If ') can according to reaction scheme 1 in wherein L be the compound (II) of leavings group and compound (III) reaction similar methods, by compound (Ie ') and formula R 2The compound of '-L ' representative reacts and prepares.
Wherein Y be-O-or-compound (If ') of S-, can according to reaction scheme 1 in compound (II) and compound (III) Mitsunobu reaction similar methods, by Y wherein be-O-or-compound (Ie ') and the formula R of S- 2The compound of '-OH representative reacts and prepares.
Compound (Id) can according to reaction scheme 1 in compound (Ia ') the hydrolysis reaction similar methods, prepare by compound (If ').
In each above-mentioned reaction, when starting compound had amino, carboxyl, hydroxyl or sulfydryl as substituting group, the protecting group of using in chemistry of peptides or the like can be introduced in these groups usually.Remove protecting group as required after the reaction, can obtain title compound.
For amino-protecting group, can mention for example formyl radical; C 1-6Alkyl-carbonyl (for example ethanoyl, ethyl carbonyl or the like), phenylcarbonyl group, C 1-6Alkoxyl group-carbonyl (for example, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl (Boc) or the like), allyloxy carbonyl (Alloc), phenyloxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc), C 7-10Aralkyl-carbonyl (for example, benzyloxycarbonyl group or the like), C 7-10Aralkoxy-carbonyl (for example carbobenzoxy-(Cbz) (Z) or the like), C 7-10Aralkyl (for example benzyl or the like), trityl, phthaloyl, dithia succinyl or N, N-dimethylamino methylene group, each randomly has substituting group.For substituting group, can use phenyl, halogen atom, C 1-6Alkyl-carbonyl (for example ethanoyl, ethyl carbonyl, butyl carbonyl or the like), the optional C that is replaced by halogen atom 1-6Alkoxyl group (for example methoxyl group, oxyethyl group, trifluoromethoxy or the like), nitro or the like.Substituent number is approximately 1 to 3.
For carboxyl-protecting group, can mention for example C 1-6Alkyl, allyl group, benzyl, phenyl, trityl or trialkylsilkl or the like, each randomly has substituting group.For substituting group, can use halogen atom, formyl radical, C 1-6Alkyl-carbonyl (for example, ethanoyl, ethyl carbonyl, butyl carbonyl or the like), the optional C that is replaced by halogen atom 1-6Alkoxyl group (for example, methoxyl group, oxyethyl group, trifluoromethoxy or the like), nitro or the like.Substituent number is approximately 1 to 3.
For hydroxyl-protecting group, can mention for example C 1-6Alkyl, C 7-20Aralkyl (for example, benzyl, trityl or the like), formyl radical, C 1-6Alkyl-carbonyl (for example, ethanoyl, ethyl carbonyl or the like), benzoyl, C 7-10Aralkyl-carbonyl (for example, benzyloxycarbonyl group or the like), the 2-THP trtrahydropyranyl, tetrahydrofuran base or trialkylsilkl (for example, trimethyl silyl, t-butyldimethylsilyl, di-isopropyl ethyl silicane base or the like) or the like, each randomly has substituting group.For substituting group, can use halogen atom, C 1-6Alkyl, phenyl, C 7-10Aralkyl (for example, benzyl or the like), C 1-6Alkoxyl group, nitro or the like.Substituent number is approximately 1 to 4.
For sulfhydryl protected base, can mention for example C 1-6Alkyl, C 1-6Alkyl-carbonyl (for example, ethanoyl, ethyl carbonyl or the like), C 7-20Aralkyl (for example, benzyl, trityl or the like) or the like, each randomly has substituting group.For substituting group, can use halogen atom, C 1-6Alkyl, phenyl, C 7-10Aralkyl (for example, benzyl or the like), C 1-6Alkoxyl group, nitro or the like.Substituent number is approximately 1 to 4.
For removing protecting group, known method of use itself or method similar with it.For example, can use acid, alkali, reduction, ultraviolet ray, hydrazine, phenylhydrazine, sodium N methyl dithiocarbamate, tetrabutylammonium fluoride, acid chloride or the like to handle.
Compound (I), other reaction intermediate and its starting compound that this mode can be obtained is by known method itself, for example extract, concentrate, neutralization, filtration, distillation, recrystallization, column chromatography, thin-layer chromatography, preparation high pressure liquid chromatography (preparation HPLC), middle compacting be equipped with liquid chromatography (middle compacting is equipped with LC) or the like, isolated or purified comes out from reaction mixture.
The salt that can prepare compound (I) according to known method itself.For example,, can prepare salt, or, prepare salt by adding organic bases or mineral alkali when compound (I) when being acidic cpd by adding mineral acid or organic acid when compound (I) when being basic cpd.
When compound (I) when having optically active isomer, these corresponding optically active isomers and its mixture comprise within the scope of the present invention naturally, and can be as required, these isomer are carried out optical resolution or prepare respectively according to known method itself.
When compound (I) exists with constitutional isomer (steric isomer), diastereomer, conformer or the like form, can be undertaken each by above-mentioned separation and method of purification as requested and separate.In addition, when compound (I) is the raceme form, can they be separated into S-and R-form by the optical resolution of any routine.
When compound (I) when comprising steric isomer, isomer and each mixture of isomers both are included in the scope of the present invention separately.
In addition, compound (I) can be hydrate or non-hydrate.
Compound (I) can be with isotropic substance (for example 3H, 14C, 35S or the like) or the like come mark.
Compound (I), its salt and its prodrug (being abbreviated as compound of the present invention hereinafter sometimes) have shown GPR40 function of receptors regulating effect (GPR40 receptor agonist activity and GPR40 receptor antagonist activity), especially GPR40 receptor agonist activity, shown low toxicity and less side effect (acute toxicity for example, chronic toxicity, genotoxicity, development toxicity, cardiac toxic, drug interaction, cancinogenicity).Therefore, they are used as the GPR40 function of receptors conditioning agent of safety, preferred GPR40 agonist.
The medicament that comprises The compounds of this invention is Mammals (mouse for example, rat, hamster, rabbit, cat, dog, ox, sheep, monkey, mankind or the like) show higher GPR40 function of receptors regulating effect in, and be used as the physiological function regulator that the GPR40 acceptor relates to, or as the morbid state that prevents or treat the GPR40 acceptor to relate to or the medicament of disease.
Specifically, comprise that the medicament of The compounds of this invention is as insulin secretion conditioning agent (preferred Regular Insulin succagoga), hypoglycemic drug and pancreatic beta cell protective material.
And the medicament that comprises The compounds of this invention is as the medicament that prevents or treat following disease, for example: diabetes, impaired glucose tolerance, ketosis, oxypathy, diabetic neuropathy, diabetogenous ephrosis, diabetic retinopathy, macular edema, hyperlipidaemia, reproduction illness, tetter, joint disease, osteopenia, arteriosclerosis, thrombotic disease, maldigestion, memory and learning disorder, depression, depression and mania, schizophrenia, attention deficit superfunction illness (attention deficithyperactivity disorder), visual disorder, appetite center illness (for example, hyperorexia), obesity, hypoglycemia, vascular hypertension, oedema, insulin resistance, unstable diabetes, lipoatrophy, insulin allergy, nesidioblastoma, fat toxicity (lipotoxicity), pancreas fatigue (pancreatic fatigue), hyperinsulinemia (hyperinsulinemia), cancer is (for example, mammary cancer), the metabolic syndromes, Immunological diseases (for example, immune deficiency), inflammatory diseases (for example, enteritis, sacroiliitis, allergy), multiple cerebral sclerosis, acute renal failure or the like; Especially disease diabetes for example, impaired glucose tolerance, ketosis, oxypathy, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macular edema, hyperlipidaemia, the reproduction illness, tetter, joint disease, osteopenia, arteriosclerosis, thrombotic disease, maldigestion, memory and learning disorder or the like.In this article, diabetes comprise 1 type, type ii diabetes and can mention gestational diabetes.In addition, hyperlipidaemia too much comprises hypertriglyceridemia, high blood lipidol of gallbladder, hypoHDL-emia, hyperlipidaemia (postprandial hyperlipidemia) or the like after the meal.
For the diagnosis of diabetes standard, Japan Diabetes Society reported new Case definition in 1999.
According to these reports, diabetes are to show following each illness: be no less than the fasting blood glucose level (glucose concn of intravenously blood plasma) of 126mg/dl, the non-fasting blood glucose level (glucose concn of intravenously blood plasma) that is no less than 2 hours levels (glucose concn of intravenously blood plasma) of 75g oral glucose tolerance test (75g OGTT) of 200mg/dl and is no less than 200mg/dl.Do not list the illness in the above-mentioned diabetes in and be different from " demonstration is no less than the fasting blood glucose level (glucose concn of intravenously blood plasma) of 110mg/dl or is no less than the illness of 75g oral glucose tolerance test (75gOGTT) the 2 hours level (glucose concn of intravenously blood plasma) of 140mg/dl " (normal type), be called " critical adjacent boundary type ".
In addition, ADA (American Diabetes Association) reported the new Case definition of diabetes in 1998, WHO in 1997.
According to this report, diabetes are to show following illness: be no less than 126mg/dl fasting blood glucose level (glucose concn of intravenously blood plasma), be no less than 2 hours levels (glucose concn of intravenously blood plasma) of 75g oral glucose tolerance test of 200mg/dl.
According to above-mentioned report, impaired glucose tolerance is to show following illness: less than the fasting blood glucose level (glucose concn of intravenously blood plasma) of 126mg/dl, be no less than 140mg/dl and less than 2 hours levels (glucose concn of intravenously blood plasma) of 75g oral glucose tolerance test of 200mg/dl.According to the report of ADA, show that fasting blood glucose level (glucose concn of intravenously blood plasma) is no less than 110mg/dl and less than the illness of 126mg/dl, is called IFG (fasting glucose impaired (Impaired FastingGlucose)).Report according to WHO, in the middle of IFG (fasting glucose is impaired), show that 75g oral glucose tolerance test 2 hours level (glucose concn of intravenously blood plasma) less than the illness of 140mg/dl, is called IFG (impaired fasting glucose (IFG) (Impaired Fasting Glycemia)).
According to above-mentioned definite new Case definition, compound of the present invention also can be as the medicament of prevention or treatment diabetes, critical types, impaired glucose tolerance, IFG (fasting glucose reduction) and IFG (fasting plasma glucose reduction).And compound of the present invention can prevent that critical types, impaired glucose tolerance, IFG (impaired fasting glucose (IFG)) or IFG (impaired fasting glucose (IFG)) from developing into diabetes.
Compound of the present invention also can be used as for the invalid treatment of diabetes agent of two generation sulfonylureas, and the insulin secretion effect can not be provided, also therefore can not provide the diabetic subject of enough blood sugar decreasing effects to obtain higher insulin secretion effect and blood sugar decreasing effect for sulfonyl urea compound and quick insulin secretagogue agent.
For sulfonyl urea compound herein, can mention compound or derivatives thereof (for example, tolbutamide, Glyburide with sulfonylurea skeleton, gliclazide, P-607, tolazamide, Acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole or the like).
For quick Regular Insulin succagoga, it is used and the same mode of sulfonyl urea compound promotes Regular Insulin to secrete from pancreatic beta cell, yet it does not have the sulfonylurea skeleton, can mention that for example row naphthalene (glinide) compound (for example, repaglinide (repaglinide), senaglinide, Na Gelie naphthalene (nateglinide), mitiglinide, its calcium salt hydrate or the like) or the like.
The medicament that comprises The compounds of this invention has shown low toxicity, and can according to original state with the form of The compounds of this invention oral safely or parenteral admin (for example local, rectum, intravenous administration or the like), or mixing obtain administration after the pharmaceutical preparation according to the conventional preparation method's who is used for pharmaceutical preparation known method own, with the pharmacology acceptable carrier.
The formulation of said medicine preparation is for example tablet (comprising sublingual tablet and Orally disintegrating tablet), capsule (comprising soft capsule and microcapsule), granule, powder, lozenge (troches), syrup, emulsion, suspension or the like of medicinal preparation for oral administration for example; Or for example injection (for example subcutaneous injection of parenteral medicament, intravenous injection, intramuscular injection, peritoneal injection, drip transfusion or the like), external medicine (for example, preparation capable of permeating skin, ointment or the like), suppository (for example rectal suppository, vaginal suppository or the like), piller (pellets), nasal formulations, lung's preparation (suction), ophthalmic preparation or the like.
These medicaments can be control-delivery formulations, for example quick-release formulation and sustained release preparation (for example slow-release microcapsule).
The compounds of this invention in pharmaceutical preparation of the present invention is approximately 0.01 to about 100% weight with respect to the content of whole preparations.The dosage of The compounds of this invention changes according to the patient of administration, route of administration, disease, illness or the like.When this compound of oral administration maturity-onset diabetes patient (the about 60kg of body weight), every day about 0.01 is to about 30mg/kg body weight, preferred every day, more preferably every day about 1, it can be with the form administration of instant or one day several part to about 20mg/kg body weight approximately o.1 to about 20mg/kg body weight.
Usually as the various organic or inorganic carriers of pharmaceutical preparation raw material, as the pharmacology acceptable carrier, for solid preparation, its form with vehicle, lubricant, tackiness agent and disintegrating agent adds; For liquid preparation, with the form adding of solvent, dissolution aids, suspension agent, isotonic agent, damping fluid and comfort placebo.In case of necessity, can make used additives for example sanitas, antioxidant, tinting material, sweeting agent, sorbent material, wetting agent or the like.
For vehicle, can mention for example lactose, sucrose, D-N.F,USP MANNITOL, starch, W-Gum, crystalline cellulose, light silicic anhydride (light silicic anhydride) or the like.
For lubricant, can mention for example Magnesium Stearate, calcium stearate, talcum, colloid silica or the like.
For tackiness agent, can mention for example crystalline cellulose, sucrose, D-N.F,USP MANNITOL, dextrin, hydroxypropylcellulose, Vltra tears, polyvinylpyrrolidone, starch, sucrose, gel, methylcellulose gum, Xylo-Mucine or the like.
For disintegrating agent, can mention for example starch, carboxymethyl cellulose, calcium carboxymethylcellulose, sodium starch glycolate, L-hydroxypropylcellulose or the like.
For solvent, can mention for example water for injection, alcohol, propylene glycol, polyoxyethylene glycol, sesame oil, Semen Maydis oil, sweet oil or the like.
For dissolution aids, can mention for example polyoxyethylene glycol, propylene glycol, D-N.F,USP MANNITOL, peruscabin, ethanol, Trisaminomethane, cholesterol, trolamine, yellow soda ash, Trisodium Citrate or the like.
For suspension agent, for example can mention for example stearyl trolamine of tensio-active agent, sodium lauryl sulphate, lauryl aminopropionate, Yelkin TTS, benzalkonium chloride, Solamin, glyceryl monostearate or the like; Hydrophilic polymer is polyvinyl alcohol for example, polyvinylpyrrolidone, and Xylo-Mucine, methylcellulose gum, Walocel MT 20.000PV, Natvosol, hydroxypropylcellulose or the like, or the like.
For isotonic agent, can mention for example glucose, D-Sorbitol Powder, sodium-chlor, glycerine, D-mannitol or the like.
For damping fluid, for example can mention for example phosphoric acid salt of damping fluid, acetate, carbonate, Citrate trianion or the like.
For placebo, can mention for example phenylcarbinol or the like.
For sanitas, can mention for example p-Hydroxybenzoate, trichloro-butyl alcohol, phenylcarbinol, phenylethyl alcohol, dehydroacetic acid (DHA), Sorbic Acid or the like.
For antioxidant, can mention for example sulphite, xitix, alpha-tocopherol or the like.
For tinting material, can mention for example water miscible edible tar colorant (food dye for example, for example food dye is red No. 2 and No. 3, yellow No. 4 and No. 5 of food dye, No. 1, food dye indigo plant and No. 2 or the like), water-fast pigment lake (for example aluminium salt of above-mentioned water miscible edible tar colorant or the like), natural pigment (for example, beta-carotene, chlorophyll, red iron oxide or the like) or the like.For sweeting agent, can mention for example soluble saccharin, glycyrrhizin dipotassium, aspartame, Stevia rebaudiana (stevia) or the like.
Compound of the present invention can for example Remedies for diabetes, diabetes complicated Remedies, the too much therapeutical agent of hyperlipidaemia, antihypertensive drug, antiobestic agent, diuretic(s), chemotherapeutics, immunotherapeutic agent, antiphlogiston, antithrombotic drug agent, osteoporosis treatment agent, VITAMIN, anti-dementia drug, incontinence or frequent micturition therapeutical agent, misnicturition therapeutical agent be used in combination (being called as medicine X hereinafter) with medicine.
For Remedies for diabetes, can mention insulin preparation (for example, the animal insulin preparation that extracts from the pancreas of ox and pig; Use intestinal bacteria, yeast heredity synthetic human insulin preparation; Zinc insulin; Insulinum protaminatum cumzinco; The fragment of Regular Insulin or derivative are (for example, INS-1 or the like), Macrulin or the like), insulin sensitizer (for example, pioglitazone or its salt (preferably salt hydrochlorate), rosiglitazone or its salt (preferred maleate), Reglixane (JTT-501), Netoglitazone (MCC-555), GI-262570, FK-614, Rivoglitazone (CS-011), Muraglitazar (BMS-298585), the compound of describing in WO99/58510 is (for example, (E)-4-[4-(5-methyl-2-phenyl-4- azoles ylmethoxy) benzyloxy imido grpup]-the 4-benzenebutanoic acid), be described in the compound among the WO01/38325, Tesaglitazar (AZ-242), BM-13-1258, LM-4156, MBX-102, LY-519818, MX-6054, LY-510929, Balaglitazone (NN-2344), T-131 or its salt, THR-0921 or the like), alpha-glucosidase inhibitor (for example, voglibose (voglibose), acarbose, miglitol, emiglitate or the like), biguanides (for example, phenformin, N1,N1-Dimethylbiguanide, buformin or salt its (for example, hydrochloride, fumarate, succinate) or the like), [sulfonylurea (for example in the insulin secretagogue agent, tolbutamide, Glyburide, gliclazide, P-607 (chlorpropamide), tolazamide, Acetohexamide, glyclopyramide, glimepiride or the like), repaglinide, senaglinide, mitiglinide or its calcium salt hydrate, the Na Gelie naphthalene, or the like], GLP-1 receptor stimulant [GLP-1 for example, GLP-1MR medicament, NN-2211, AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH 2CJC-1131 or the like], inhibitors of dipeptidyl IV (for example, NVP-DPP-278, PT-100, P32/98, P93/01, NVP-DPP-728, LAF237, TS-021 or the like), β 3 agonist (e.g., CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140 or the like), dextrin agonist (for example, tripro-amylin or the like), the phosphotyrosine phosphatase inhibitor (for example, vanadic acid sodium or the like), glyconeogenesis inhibitor (for example, glycogen phosphorylase inhibitors, the glucose-6-phosphatase inhibitor, glucagon antagonist or the like), SGLT (sodium glucose co-transporter 2 is white) inhibitor (for example, T-1095 or the like), 11 beta-hydroxysteroid dehydrogenase inhibitor (for example, BVT-3498 or the like), adiponectin or its agonist, the IKK inhibitor is (for example, AS-2868 or the like), the Leptin tolerance is improved medicine, and somatostatin agonist (is described in WO01/25228, WO03/42204, WO98/44921, WO98/45285, compound among WO99/22735 or the like), activators of glucokinase (for example Ro-28-1675) or the like.
The example of the therapeutical agent of diabetic complication comprises that aldose reductase inhibitor (for example, Tuo Ruisita, epalrestat, zenarestat, zopolrestat, method ground department he (SNK-860), AS-3201, Minalrestat (ARI-509), CT-112 or the like), neurotrophic factor and its enhancing medicine (for example, NGF, NT-3, BDNF is described in neurotrophin product-secernent (for example, 4-(4-chloro-phenyl-)-2-(2-methyl isophthalic acid-imidazolyl)-5-[3-(2-methylphenoxy) propyl group] oxazole or the like) among the WO 01/14372 or the like), protein kinase C (PKC) inhibitor (for example, ruboxistaurin mesylate; LY-333531 or the like), AGE inhibitor (for example, ALT-945, pimagedine, pyratoxanthine, N-phenacyl thiazole  bromide (N-phenacylthiazolium bromide) is (ALT-766), EXO-226, ALT-711, Pyridorin, Pyridoxylamine or the like), active oxygen scavenger (for example, Thioctic Acid or the like), cerebral vasodilator is (for example, tiapride or the like), somatostatin receptor agonist (BIM23190) and apoptosis signal regulating kinase-1 (ASK-1) inhibitor.
The example of the too much therapeutical agent of hyperlipidaemia comprises HMG-CoA reductase inhibitor (Pravastatin for example; simvastatin; lovastatin, Ah appropriate cuts down his spit of fland, fluvastatin; pitavastatin; Rosuvastatin and its salt (for example sodium salt, calcium salt) or the like), inhibitor for squalene synthetic enzyme (for example is described in the compound among the WO97/10224; N-[[(3R for example; 5S)-1-(3-acetoxyl group-2,2-dimethyl propyl)-7-chloro-5-(2, the 3-Dimethoxyphenyl)-2-oxo-1; 2; 3,5-tetrahydrochysene-4,1-benzo oxazapine (benzoxazepin)-3-yl] ethanoyl]-piperidines-4-acetate or the like); fibrate (bezafibrate for example; clofibrate, simifibrate, S-8527 or the like); antioxidant (for example Thioctic Acid, probucol) or the like.
The example of antihypertensive drug comprises that angiotensin-convertion enzyme inhibitor (for example, captopril, enalapril, delapril or the like), angiotensin II receptor antagonists (losartan for example, Candesartan ring plug in heptan (candesartan cilexetil), eprosartan, the third penta husky smooth, telmisartan, Irb, Olmesartan (olmesartan medoxomil), Tasosartan, 1-[[2 '-(2,5-dihydro-5-oxo-4H-1,2,4- diazole-3-yl) biphenyl-4-yl] methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylic acid or the like), calcium channel blocker is (for example, Manidipine, nifedipine, amlodipine, efonidipine, nicardipine or the like), clonidine or the like.
The example of (antiobestic) medicament of anti-obesity comprises anti-obesity agents (for example, dexfenfluramine, fenfluramine, phentermine, sibutramine, Diethylpropion, dextrorotation Diethylpropion, Mazindol, Phenylpropanolamine, the clobenzorex that acts on central nervous system; MCH receptor antagonist (for example, SB-568849; SNAP-7941; Be included in the compound among WO 01/82925 and WO 01/87834 or the like); Neuropeptide tyrosine antagonist (for example, CP-422935 or the like); Cannabinoid receptor antagonists (for example, SR-141716, SR-147778 or the like); The ghrelin antagonist; 11 beta-hydroxysteroid dehydrogenase inhibitor (for example, BVT-3498 or the like) or the like), pancreatic lipase inhibitor (for example, orlistat, ATL-962 or the like), β 3 agonists are (for example, CL-316243, SR-58611-A, UL-TG-307, AJ-9677, AZ40140 or the like), the peptide anorexigenic is (for example, Leptin, CNTF (Ciliary Neurotropic Factor) or the like), the cholecystokinin agonist is (for example, Lintitript, FPL-15849 or the like), antifeedant (for example P-57 or the like) or the like.
The example of diuretic(s) comprises xanthine derivative (for example, sodium salicylate and Theobromine, calcium salicylate and Theobromine or the like), thiazine preparation (for example, P-2105, cyclopenthiazide, trichloromethyl triazo-compound (trichloromethyazide), hydrochlorothiazide, Hydroflumethiazide, the benzylic hydrogens chlorothiazide, Pentylhydroflumethiazide, many thiazines, Methyclothiazide or the like), aldosterone antagonist preparation (for example, spironolactone, triamterene or the like), carbonanhydrase inhibitor (for example, acetazolamide or the like), chlorobenzene sulfonamide preparation (for example, chlorthalidone, mefruside, indapamide or the like), azosemide, Isosorbide, Ethacrynic Acid, piretanide, bumetanide, Furosemide or the like.
The example of chemotherapeutics comprises alkylating agent (for example, endoxan, ifosfamide or the like), antimetabolite (for example, Rheumatrex, 5 FU 5 fluorouracil or derivatives thereof, or the like), anticancer disease microbiotic (for example, mitomycin, Zorubicin or the like), anticancer disease medicament (for example, the vincristine(VCR) of plant-deutero-, vindesine, taxol or the like), cis-platinum, carboplatin, etoposide or the like.In the middle of these, doxifluridine and neofurtulon in the preferred 5 FU 5 fluorouracil derivative.
The example of immunotherapeutic agent (for example comprises microorganism or cell component, the Muramyl dipeptide derivative, Picibanil (picibanil) or the like), have immunity and (for example strengthen active polysaccharide, lentinan, sizofiran, krestin (krestin) or the like), cytokine (for example, Interferon, rabbit, interleukin (IL) or the like) by the gene engineering acquisition, clone's stimulating factor (for example, granulocyte colony-stimulating factor, erythropoietin or the like) or the like, preferred interleukin is IL-1, IL-2, IL-12 or the like for example.
The on-steroidal for example of antiphlogiston can mention to(for) antiphlogiston is Asprin, acetyl aminophenol (acetoaminofen), indomethacin or the like for example.
The example of antithrombotic drug agent comprises heparin (for example, heparin sodium, calciparine, dalteparin sodium or the like), warfarin (for example, potassium warfarin or the like), antithrombotic drug is (for example, argatroban or the like), thrombus medicament (for example, urokinase, Tisokinase, alteplase, Nateplase, Monteplase, pamiteplase or the like), anticoagulant (for example, Ticlopidine Hydrochloride, Cilostazole, 26 alkane pentaene acetoacetic ester (ethyl icosapentate), beraprost sodium, Sarpogrelatehydrochloride or the like) or the like.
The example of osteoporosis treatment agent comprises alfacalcidol, calcitriol, Turbocalcin, salmon calcitonin see calcimar, estriol, ipriflavone, Risedronate disodium salt, Pamidronate (pamidronatedisodium), di 2 ethylhexyl phosphonic acid sodium hydrate (alendronate sodium hydrate), Incadronate (incadronate disodium) or the like.
For VITAMIN, can mention for example vitamins B 1, vitamins B 12Or the like.
The example of anti-dementia drug comprises tacrine, E2020, and Li Fansi's is bright, lycoremine or the like.
The example of the urinary incontinence or frequent micturition therapeutical agent comprises Flavoxate hydrochloride, oxybutynin chloride, hydrochloric acid third piperazine dimension flat (propiverine hydrochloride) or the like.
The example of the odynuria therapeutical agent that can mention comprises acetylcholine esterase inhibitor (for example this is bright) or the like.
In addition, under animal model and clinical state, confirm, medicine with emaciation-improved action, cyclooxygenase inhibitors (for example, indomethacin or the like) for example, the Progesterone derivative is (for example, the acetate megestrol), sugar steroid class (glucosteroid) (for example, dexamethasone or the like), the metoclopramide medicament, the tetrahydrocannabinol medicament, metabolism of fat improves medicament (for example, timnodonic acid or the like), tethelin, IGF-1, or the antibody of emaciation-risk factor TNF-α for example, LIF, IL-6, oncostatin M or the like can be used in combination with compound of the present invention.
Further, glycosylation inhibitor (for example, ALT-711, or the like), neurotization promotes medicament (Y-128 for example, VX853, prosaptide or the like), thymoleptic (for example, Desipramine, amitriptyline, imipramine, or the like), anticonvulsive agent (lamotrigine (lamotrigine) for example, Qu Lai (trileptal), Levetiracetam (Keppra), zonisamide, Pregabalin, Harkoseride, Carbamzepine), anti-arrhythmic (for example mexiletine), acetylcholine receptor ligands (for example ABT-594), endothelin-receptor antagonists (for example ABT-627), monoamine uptake inhibitor (for example U-26225A), narcotic analgesic (for example morphine), the GABA receptor stimulant (for example, gabapentin, gabapentin MR medicament), α 2Receptor stimulant (for example clonidine), Bangesic's (for example capsaicine), anxiolytic (for example benzimidazole thiophanate nitrogen  class), phosphodiesterase inhibitor (for example Virga), dopamine-receptor stimulant (for example apomorphine) or the like also can be used in combination with compound of the present invention.
Two or more said medicine X can appropriate combination use.
By with compound of the present invention and medicine X combination, can obtain higher effect, for example
(1) compare with individually dosed The compounds of this invention or medicine X, the dosage of The compounds of this invention or medicine X can reduce,
(2) by from The compounds of this invention, selecting to have the not medicine X of same-action and mechanism, can set the long course of treatment,
(3) by from The compounds of this invention, selecting to have the not medicine X of same-action and mechanism, can design lasting result of treatment,
(4) by The compounds of this invention and medicine X are used in combination, can obtain synergistic effect, or the like.
When The compounds of this invention and medicine X are used in combination, the administration time of The compounds of this invention and medicine X without limits, and The compounds of this invention and the medicine X time administration patient that can simultaneously, maybe can stagger.The dosage of medicine X can determine according to using dosage clinically, and can select rightly according to the patient of institute's administration, route of administration, disease, composition or the like.
The mode of administration of The compounds of this invention and medicine X is not particularly limited, as long as The compounds of this invention and medicine X combination medicine-feeding.The example of this mode of administration comprises following method: (1) is cofabrication with The compounds of this invention and medicine X, obtains the unitary agent (single preparation) of administration.(2) The compounds of this invention and medicine X are prepared respectively, are obtained two kinds of preparations, with two kinds of preparations by the administration simultaneously of identical route of administration.(3) The compounds of this invention and medicine X are prepared respectively, are obtained two kinds of preparations, with two kinds of preparations by the identical route of administration time administration that staggers.(4) The compounds of this invention and medicine X are prepared respectively, are obtained two kinds of preparations, with two kinds of preparations by the administration simultaneously of different route of administration.(5) The compounds of this invention and medicine X are prepared respectively, are obtained two kinds of preparations, with two kinds of preparations by different route of administration stagger time administration (for example, with this order or with anti-order administration compound of the present invention and medicine X), or the like.
Embodiment
Further describe the present invention with reference to following reference example, embodiment, example of formulations and EXPERIMENTAL EXAMPLE, it only plays embodiment, should not be construed restrictively, and can change under the condition that does not deviate from the scope of the invention.
Below the term " room temperature " among reference example and the embodiment show usually from about 10 ℃ to about 35 ℃ scope.For " % ", productive rate is used for the stratographic solvent in volume % in mol/mol%, and other " % " is in weight %.Can not be included in the data by the definite OH proton of proton N MR spectrum, NH proton or the like owing to broad peak.
Other symbol used herein is meant following:
S: unimodal
D: bimodal
T: triplet
Q: quartet
M: multiplet
Br: broad peak
J: coupling constant
Hz: hertz
CDCl 3: deuterochloroform
1H NMR: proton magnetic resonance (PMR)
Among reference example and the embodiment, mass spectrum (MS) and NMR (Nuclear Magnetic Resonance) spectrum (NMR) are measured under following condition below.
MS metering equipment: Waters Corporation ZMD, Waters Corporation ZQ2000 or Micromass Ltd., platform II.
Ionization method: electronic spraying ionization (ESI) or atmospheric chemical ionization (APCI).Unless specifically show, otherwise use ESI.
NMR metering equipment: Varian Gemini 200 (200MHz), Varian Gemini 300 (300MHz), Varian, AVANCE 300, Bruker BioSpin Corp.
In reference example and embodiment, under following condition, carry out by preparation HPLC purifying.
Preparation HPLC equipment: Gilson, Inc., high throughput purification system
Post: YMC Combiprep ODS-A S-5 μ m, 20 * 50mm
Solvent:
Solution A; The water that contains 0.1% trifluoroacetic acid,
Solution B; The acetonitrile that contains 0.1% trifluoroacetic acid
Gradient circulation A: 0.00min (solution A/solution B=90/10), (1.20min solution A/solution B=90/10), (4.75min solution A/solution B=0/100), (7.30min solution A/solution B=0/100), (7.40min solution A/solution B=90/10), 7.50min (solution A/solution B=90/10).
Gradient circulation B:0.00min (solution A/solution B=95/5), (1.00min solution A/solution B=95/5), (5.20min solution A/solution B=5/95), (6.40min solution A/solution B=5/95), (6.50min solution A/solution B=95/5), 6.60min (solution A/solution B=95/5).
Flow velocity: 25ml/min,
Detection method: UV 220nm
In this manual, fusing point (m.p.) is meant for example little fusing point surveying instrument of use (B ü chi, B-545) fusing point of Ce Dinging or the like.
Usually, fusing point changes according to determining instrument, measuring condition or the like.Crystal in this manual can show and the described different fusing point of this specification sheets, as long as it is within general limit of error (generalerror range).
Reference example 1
2-(4-bromo-3-methylphenoxy) tetrahydrochysene-2H-pyrans
With 4-bromo-3-cresols (4.72 grams, 25.2mmol), 3,4-dihydro-2H-pyrans (3.18 grams, 37.8mmol) and right-toluenesulphonic acids pyridine  (0.628 gram, methylene dichloride 2.50mmol) (100 milliliters) solution at room temperature stirred 24 hours.Wash reaction mixture with water, and use anhydrous sodium sulfate drying.Solvent evaporated under reduced pressure, obtain yellow oil title compound (7.11g, comprise unreacted 3,4-dihydro-2H-pyrans).
1H NMR(CDCl 3)δ：1.58-2.06(6H，m)，2.35(3H，s)，3.56-3.63(1H，m)，3.83-3.91(1H，m)，5.37(1H，t，J＝3.1Hz)，6.77(1H，dd，J＝8.8，3.0Hz)，6.95(1H，d，J＝3.0Hz)，7.39(1H，d，J＝8.8Hz)。
Reference example 2
2 '-methyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) xenyl-3-formaldehyde
With 2-(4-bromo-3-methylphenoxy) tetrahydrochysene-2H-pyrans (7.11 grams; 25.2mmol; comprise 3; 4-dihydro-2H-pyrans) and (3-formyl radical phenyl) boric acid (4.50 the gram; 30.0mmol) be dissolved in the mixture of 1M sodium carbonate solution (60 milliliters), ethanol (30 milliliters) and toluene (60 milliliters); after the argon replaces, (1.73 restrain, 1.50mmol) to add tetrakis triphenylphosphine palladium (0).With reaction mixture under argon atmosphere, stirred 15 hours at 80 ℃.Reaction mixture adds entry and ethyl acetate, and (celite) leaches insoluble substance by celite.With the organic layer of saturated brine wash filtrate, use anhydrous sodium sulfate drying, concentrating under reduced pressure.Resistates by silica gel column chromatography (5%-30% ethyl acetate/hexane) purifying, is obtained title compound (6.16g, 82%, 2 step of productive rate), be light yellow oil.
1H NMR(CDCl 3)δ：1.53-1.77(3H，m)，1.86-1.91(2H，m)，1.98-2.09(1H，m)，2.25(3H，s)，3.61-3.68(1H，m)，3.91-3.99(1H，m)，5.48(1H，t，J＝3.2Hz)，6.95-7.00(2H，m)，7.15(1H，d，J＝8.3Hz)，7.53-7.60(2H，m)，7.82-7.86(2H，m)，10.06(1H，s)。
Reference example 3
[2 '-methyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methyl alcohol
Figure A20048004213900521
With 2 '-methyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) xenyl-3-formaldehyde (13.6 grams, 45.9mmol) be dissolved in 1, in the mixture of 2-glycol dimethyl ether (70 milliliters) and tetrahydrofuran (THF) (70 milliliters), and (0.870 restrains, 23.0mmol) to add sodium borohydride under ice-cooling.Mixture was stirred 3 hours under uniform temp.In this reaction mixture, add aqueous ammonium chloride solution, and use the ethyl acetate extraction mixture.Wash extract with saturated brine, use anhydrous sodium sulfate drying, concentrating under reduced pressure.Resistates by silica gel column chromatography (15%-50% ethyl acetate/hexane) purifying, is obtained title compound (12.2g, productive rate 89%), be colorless oil.
1H NMR(CDCl 3)δ：1.59-1.76(4H，m)，1.85-1.90(2H，m)，1.97-2.11(1H，m)，2.25(3H，s)，3.60-3.67(1H，m)，3.91-3.99(1H，m)，4.73(2H，d，J＝5.8Hz)，5.46(1H，t，J＝3.1Hz)，6.92-6.97(2H，m)，7.14(1H，d，J＝8.1Hz)，7.22-7.41(4H，m)。
Reference example 4
2-(4-bromo-3,5-dimethyl phenoxy) tetrahydrochysene-2H-pyrans
With 4-bromo-3, the 5-xylenol (10.5 grams, 52.2mmol), 3,4-dihydro-2H-pyrans (8.83 grams, 105mmol) and right-toluenesulphonic acids pyridine  (2.64 grams, methylene dichloride 10.5mmol) (160 milliliters) solution at room temperature stirred 80 hours.Solvent evaporated under reduced pressure is carried out silica gel column chromatography (hexane-20% ethyl acetate/hexane) purifying to resistates, obtains title compound (11.5g, productive rate 77%), is colorless oil.
1H NMR(CDCl 3)δ：1.56-1.75(3H，m)，1.80-2.07(3H，m)，2.37(6H，s)，3.55-3.64(1H，m)，3.83-3.93(1H，m)，5.37(1H，t，J＝3.1Hz)，6.80(2H，s)。
Reference example 5
2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) xenyl-3-formaldehyde
Figure A20048004213900531
According to reference example 2 similar methods, obtain the title compound (productive rate 83%) of yellow oil by 2-(4-bromo-3,5-dimethyl phenoxy) tetrahydrochysene-2H-pyrans and (3-formyl radical phenyl) boric acid.
1H NMR(CDCl 3)δ：1.57-1.78(3H，m)，1.82-1.93(2H，m)，1.99(6H，s)，2.04(1H，m)，3.65(1H，m)，3.97(1H，m)，5.47(1H，t，J＝3.0Hz)，6.84(2H，s)，7.42(1H，m)，7.58(1H，t，J＝7.5Hz)，7.67(1H，s)，7.86(1H，m)，10.05(1H，s)。
Reference example 6
[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methyl alcohol
Figure A20048004213900532
According to reference example 3 similar methods, by 2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) xenyl-3-formaldehyde obtains the title compound (productive rate 83%) of colorless oil.
1H NMR(CDCl 3)δ：1.55-1.79(4H，m)，1.80-1.93(2H，m)，2.00(6H，s)，2.03(1H，m)，3.64(1H，m)，3.97(1H，m)，4.73(2H，d，J＝5.7Hz)，5.45(1H，t，J＝3.0Hz)，6.81(2H，s)，7.07(1H，d，J＝7.5Hz)，7.13(1H，s)，7.33(1H，d，J＝7.5Hz)，7.40(1H，t，J＝7.8Hz)。
Reference example 7
2,6-dimethyl-3 '-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] xenyl-4-alcohol
Figure A20048004213900533
With 2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) xenyl-3-formaldehyde (9.05 grams, 29.2mmol) be dissolved in 1, in the mixture of 2-glycol dimethyl ether (50 milliliters) and tetrahydrofuran (THF) (50 milliliters), and (0.567 restrains, 15.0mmol) to add sodium borohydride under ice-cooling.Mixture was stirred 3 hours under uniform temp.10% aqueous citric acid solution is joined in the reaction mixture, and use the ethyl acetate extraction mixture.Wash extract with saturated brine, use anhydrous sodium sulfate drying, concentrating under reduced pressure.Resistates by silica gel column chromatography (15%-50% ethyl acetate/hexane) purifying, is obtained title compound (3.24g, productive rate 36%), be clear crystal.
1H NMR(CDCl 3)δ：1.47-1.93(6H，m)，1.98(3H，s)，1.99(3H，s)，3.50-3.58(1H，m)，3.88-3.96(1H，m)，4.54(1H，d，J＝12.1Hz)，4.68(1H，s)，4.73(1H，t，J＝3.4Hz)，4.83(1H，d，J＝12.1Hz)，6.59(2H，s)，7.04(1H，d，J＝7.3Hz)，7.13(1H，s)，7.30-7.34(1H，m)，7.38(1H，t，J＝7.3Hz)。
Reference example 8
2-{[4 '-(benzyloxy)-2,6-dimethyl diphenyl-3-yl] methoxyl group } tetrahydrochysene-2H-pyrans
With 2,6-dimethyl-3 '-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] xenyl-4-alcohol (1.78 grams, 5.70mmol), (0.885 milliliter of phenylcarbinol, 8.55mmol) and (2.13 milliliters of tributylphosphines, 8.55mmol) toluene (80 milliliters) solution under ice-cooling, stir, and divide little part (by small portions) add 1,1 '-(azo dicarbapentaborane (azodicarbonyl)) connection piperidines (2.16 grams, 8.55mmol).Mixture is warming up to room temperature, and stirred 24 hours.(40mL) joins in the reaction mixture with hexane, and leaches sedimentary insoluble substance.Concentrating under reduced pressure filtrate, and use silica gel column chromatography (hexane-10% ethyl acetate/hexane) purifying resistates, obtain the title compound (1.71g, productive rate 75%) of colorless oil.
1H NMR(CDCl 3)δ：1.47-1.93(6H，m)，2.01(3H，s)，2.02(3H，s)，3.50-3.57(1H，m)，3.88-3.96(1H，m)，4.54(1H，d，J＝12.2Hz)，4.73(1H，t，J＝3.5Hz)，4.83(1H，d，J＝12.2Hz)，5.07(2H，s)，6.75(2H，s)，7.05(1H，d，J＝7.2Hz)，7.14(1H，s)，7.30-7.48(7H，m)。
Reference example 9
[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol
Figure A20048004213900551
With 2-{[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } tetrahydrochysene-2H-pyrans (1.71 grams, 4.25mmol) and the tosic acid monohydrate (80.8 milligrams, methyl alcohol 0.425mmol) (15 milliliters) solution at room temperature stirred 20 hours.The reduction vaporization reaction solvent, and dilute resistates with ethyl acetate, with the saturated brine washing, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.Resistates by silica gel column chromatography (20%-50% ethyl acetate/hexane) purifying, is obtained title compound (1.13g, productive rate 84%), be colorless oil.
1H NMR(CDCl 3)δ：1.65(1H，t，J＝5.9Hz)，2.01(6H，s)，4.73(2H，d，J＝5.9Hz)，5.07(2H，s)，6.75(2H，s)，7.07(1H，d，J＝7.3Hz)，7.13(1H，s)，7.30-7.48(7H，m)。
Reference example 10
2-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } tetrahydrochysene-2H-pyrans
According to reference example 8 similar methods, by 2,6-dimethyl-3 '-[(tetrahydrochysene-2H-pyrans-2-base oxygen base) methyl] pure and mild cellosolvo of xenyl-4-obtains colorless oil title compound (productive rate 74%).
1H NMR(CDCl 3)δ：1.25(3H，t，J＝7.1Hz)，1.48-1.94(6H，m)，2.00(3H，s)，2.01(3H，s)，3.50-3.57(1H，m)，3.62(2H，q，J＝7.1Hz)，3.80(2H，t，J＝5.0Hz)，3.88-3.96(1H，m)，4.14(2H，t，J＝5.0Hz)，4.54(1H，d，J＝12.1Hz)，4.72(1H，t，J＝3.5Hz)，4.82(1H，d，J＝12.1Hz)，6.69(2H，s)，7.04(1H，d，J＝7.3Hz)，7.13(1H，s)，7.32(1H，d，J＝7.3Hz)，7.38(1H，t，J＝7.3Hz)。
Reference example 11
[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol
Figure A20048004213900553
According to reference example 9 similar methods, by 2-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group tetrahydrochysene-2H-pyrans obtains colorless oil title compound (productive rate 82%).
MS m/z 301(MH +)
Reference example 12
(2E)-3-(2-fluoro-4-p-methoxy-phenyl) ethyl propenoate
To ice-refrigerative diethyl phosphonyl ethyl acetate (9.45 grams, add in tetrahydrofuran (THF) 42.1mmol) (50 milliliters) solution sodium hydride (60% oil suspension, 1.54 grams, 38.5mmol) and, and stirred this mixture 15 minutes.Dropwise add 2-fluoro-4-methoxybenzaldehyde (5.00g, tetrahydrofuran (THF) 32.4mmol) (30mL) solution.Mixture was at room temperature stirred 2 hours and add entry.Use the ethyl acetate extraction mixture.Wash extract with saturated brine, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.Resistates by silica gel column chromatography (20% ethyl acetate/hexane) purifying, is obtained title compound (7.07g, productive rate 97%), be colorless oil.
1H NMR(CDCl 3)δ：1.33(3H，t，J＝7.1Hz)，3.83(3H，s)，4.26(2H，q，J＝7.1Hz)，6.41(1H，d，J＝16.2Hz)，6.61-6.73(2H，m)，7.45(1H，t，J＝8.6Hz)，7.75(1H，d，J＝16.2Hz)。
Reference example 13
3-(2-fluoro-4-p-methoxy-phenyl) ethyl propionate
With (2E)-3-(2-fluoro-4-p-methoxy-phenyl) ethyl propenoate (7.07 grams, 31.5mmol), the mixture of tetrahydrofuran (THF) (50 milliliters), ethanol (5 milliliters) and platinum oxide (300 milligrams) under atmosphere of hydrogen, stirring at room temperature spends the night.Leach catalyzer, and filtrate is concentrated.Resistates by silica gel column chromatography (20% ethyl acetate/hexane) purifying, is obtained colorless oil title compound (5.97g, productive rate 84%).
1H NMR(CDCl 3)δ：1.23(3H，t，J＝7.2Hz)，2.58(2H，t，J＝7.6Hz)，2.90(2H，t，J＝7.6Hz)，3.77(3H，s)，4.12(2H，q，J＝7.2Hz)，6.57-6.63(2H，m)，7.07-7.13(1H，m)。
Reference example 14
3-(2-fluoro-4-hydroxy phenyl) ethyl propionate
To 3-(2-fluoro-4-p-methoxy-phenyl) ethyl propionate (57.4 grams, 254mmol) and aluminum chloride (101 the gram, (74.3 grams 508mmol), and at room temperature stirred this mixture 2 hours dropwise to add the 1-spicy thioalcohol in methylene dichloride 761mmol) (250 milliliters) solution.Reaction mixture is poured in the frozen water, and this mixture was stirred 30 minutes.Separate organic layer,, use anhydrous magnesium sulfate drying, concentrating under reduced pressure with the saturated brine washing.Resistates by silica gel column chromatography (20% ethyl acetate/hexane) purifying, is obtained colorless oil title compound (44.6g, productive rate 83%).
1H NMR(CDCl 3)δ：1.23(3H，t，J＝7.2Hz)，2.58(2H，t，J＝8.1Hz)，2.89(2H，t，J＝8.1Hz)，4.12(2H，q，J＝7.2Hz)，6.51-6.56(2H，m)，7.01-7.06(1H，m)。
Reference example 15
2 ', 4 '-dimethyl diphenyl base-3-carboxylic acid, ethyl ester
With (2, the 4-3,5-dimethylphenyl) boric acid (3.0 grams, 20.0mmol), 3-bromo-benzoic acid ethyl ester (4.3 the gram, 18.8mmol) and cesium carbonate (9.8 grams, 30.0mmol) join in the mixture of ethanol (20 milliliters) and toluene (80 milliliters), after the argon replaces, (0.30 restrains, 0.26mmol) to add tetrakis triphenylphosphine palladium (0).With reaction mixture under argon atmosphere, stirred 18 hours at 70 ℃.Reaction mixture leaches insoluble substance by celite.Concentrating under reduced pressure filtrate, and (ethyl acetate: purifying resistates hexane=1: 10) obtains colorless oil title compound (5.0g, productive rate 100%) to use silica gel column chromatography.
1H NMR(CDCl 3)δ：1.39(3H，t，J＝7.0Hz)，2.23(3H，s)，2.37(3H，s)，4.38(2H，q，J＝7.0Hz)，7.02-7.54(5H，m)，8.00-8.05(2H，m)。
Reference example 16
(2 ', 4 '-dimethyl diphenyl-3-yl) methyl alcohol
Figure A20048004213900573
Under ice-cooling, to 2 ', 4 '-(5.0 grams, (0.91 gram 24.0mmol), and at room temperature stirred this mixture 3 hours to dimethyl diphenyl base-3-carboxylic acid, ethyl ester to add lithium aluminium hydride in anhydrous tetrahydro furan 19.7mmol) (50 milliliters) solution.With reaction soln with ice-cooled, and add sodium sulfate 10 hydrates (8.0g, 24.8mmol).At room temperature stirred the mixture 1 hour.Leach sedimentary insoluble substance by celite, concentrating under reduced pressure filtrate obtains colorless oil title compound (productive rate 96%).
1H NMR(CDCl 3)δ：2.24(3H，s)，2.36(3H，s)，4.73(2H，d，J＝6.0Hz)，7.00-7.45(7H，m)。
Reference example 17
2 ', 4 ', 6 '-trimethylammonium xenyl-3-formaldehyde
Figure A20048004213900581
According to reference example 15 similar methods, obtain colorless oil title compound (productive rate 76%) by (2,4, the 6-trimethylphenyl) boric acid and 3-bromobenzaldehyde.
MS m/z 225(MH +)
Reference example 18
(2 ', 4 ', 6 '-trimethylammonium biphenyl-3-yl) methyl alcohol
Figure A20048004213900582
With 2 ', 4 ', 6 '-(2.36 grams 10.5mmol) are dissolved in the ethanol (20 milliliters) trimethylammonium xenyl-3-formaldehyde, and (0.40 gram 10.6mmol) joins in this solution with sodium borohydride.After ice-cooled stirring down 3 hours, aqueous citric acid solution is joined in the reaction soln.With the mixture ethyl acetate extraction,, use dried over mgso, concentrating under reduced pressure with the saturated brine washing.The resistates that obtains is passed through silica gel column chromatography, and (ethyl acetate: hexane=1: 5-1: 2) purifying obtains colorless oil title compound (1.66g, productive rate 70%).
1H NMR(CDCl 3)δ：2.00(6H，s)，2.33(3H，s)，4.73(2H，d，J＝6.2Hz)，6.94(2H，s)，7.00-7.42(4H，m)。
Reference example 19
6-methoxyl group-2 ', 4 '-dimethyl diphenyl base-3-formaldehyde
According to reference example 15 similar methods, by 1-bromo-2,4-dimethylbenzene and (5-formyl radical-2-p-methoxy-phenyl) boric acid obtain colorless oil title compound (productive rate 87%).
MS m/z 241(MH +)
Reference example 20
(6-methoxyl group-2 ', 4 '-dimethyl diphenyl-3-yl) methyl alcohol
According to reference example 18 similar methods, by 6-methoxyl group-2 ', 4 '-dimethyl diphenyl base-3-formaldehyde obtains colorless oil title compound (productive rate 88%).
1H NMR(CDCl 3)δ：2.01(6H，s)，3.74(3H，s)，4.65(2H，d，J＝5.2Hz)，6.97(1H，d，J＝8.4Hz)，7.03(1H，d，J＝2.2Hz)，7.06-7.24(3H，m)，7.35(1H，dd，J＝2.6，8.4Hz)。
Reference example 21
2 ', 4 ', 6 '-trimethylammonium xenyl-3-carboxylic acid, ethyl ester
Figure A20048004213900592
According to reference example 15 similar methods, obtain colorless oil title compound (productive rate 80%) by (2,4, the 6-trimethylphenyl) boric acid and 3-bromo-benzoic acid ethyl ester.
MS m/z 269(MH +)
Reference example 22
4 '-brooethyl-2 ', 6 '-dimethyl diphenyl base-3-carboxylic acid, ethyl ester and 2 '-brooethyl-4 ', 6 '-dimethyl diphenyl base-3-carboxylic acid, ethyl ester
Figure A20048004213900593
Mixture
With 2 ', 4 ', 6 '-trimethylammonium xenyl-3-carboxylic acid, ethyl ester (1.0 grams, 3.73mmol), N-bromosuccinimide (0.70 the gram, 3.93mmol) and 2,2 '-(65 milligrams, tetracol phenixin 0.40mmol) (30 milliliters) solution stirred 5 hours at 80 ℃ two (isopropyl cyanide) (azobis (isobutyronitrile)) of azo.Cooled reaction solution is to room temperature, and leaches sedimentary insoluble substance.Concentrating under reduced pressure filtrate, and (ethyl acetate: hexane=1: 10-1: the 5) resistates that obtains of purifying obtains the mixture (0.82g, productive rate 64%) of colorless oil title compound to use silica gel column chromatography.Mixture just need not be separated to be used for subsequent reactions.
MS m/z 348(MH +)
Reference example 23
[4 '-[(4-fluorophenoxy) methyl]-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol and [2 '-[(4-fluorophenoxy) methyl]-4 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol
Figure A20048004213900601
Mixture
With right-fluorophenol (0.32 gram, 2.85mmol) and sodium hydride (89 milligrams, 2.60mmol) at anhydrous tetrahydro furan (20 milliliters)-N, the mixing solutions in the dinethylformamide (10 milliliters) was ice-cooled down stirring 20 minutes.(0.82g 2.36mmol), and at room temperature stirred this mixture 18 hours to be added in the reference example 22 mixture that obtains in this solution.With ethyl acetate diluting reaction solution, with aqueous citric acid solution, water and saturated brine washing, use dried over mgso, concentrating under reduced pressure successively.The light yellow oil that obtains is dissolved in the anhydrous tetrahydro furan (30mL), and with this mixture with ice-cooled.In this solution, dropwise add 1.5mol/l the diisobutylaluminium hydride toluene solution (5.0mL, 7.5mmol).Solution was stirred 5 hours down ice-cooled, and dilute hydrochloric acid is joined in this reaction soln.With the mixture ethyl acetate extraction,, use dried over mgso, concentrating under reduced pressure with the saturated brine washing.(ethyl acetate: hexane=1: 10-1: 5-1: 3-1: 1) purifying obtains the colorless oil (0.74g, productive rate 93%) of the mixture of title compound by silica gel column chromatography with the resistates that obtains.Mixture just need not be separated to be used for subsequent reactions.
MS m/z 319(M-OH)
Reference example 24
The 3-[4-[(3-bromobenzyl) oxygen base] phenyl] methyl propionate
Figure A20048004213900602
At 0 ℃, (0.3 gram, N 1.67mmol) add 60% sodium hydride (0.073 gram in dinethylformamide (4.0 milliliters) solution to 3-(4-hydroxy phenyl) methyl propionate to be accompanied by stirring, 1.83mmol), and under uniform temp, stirred this mixture 15 minutes.Then, be accompanied by at 0 ℃ that (0.44g 1.75mmol) joins in this mixture, and at room temperature stirs this mixture 2 hours with 3-bromobenzyl bromination thing.Reaction mixture is diluted with ethyl acetate, and wash with 5% aqueous potassium hydrogen sulfate and saturated brine.Use the dried over mgso ethyl acetate layer, concentrating under reduced pressure obtains title compound colourless powder (0.84g, productive rate 72%).
1H NMR(CDCl 3)δ：2.60(2H，t，J＝7.8Hz)，2.90(2H，t，J＝7.8Hz)，3.67(3H，s)，5.01(2H，s)，6.88(2H，d，J＝8.4Hz)，7.12(2H，d，J＝8.4Hz)，7.25(1H，m)，7.35(1H，d，J＝7.5Hz)，7.45(1H，d，J＝7.5Hz)，7.59(1H，s)。
Reference example 25
4 '-(methoxymethoxy)-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde
At 70 ℃, with 4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde (4.5 grams, 19.9mmol), (2.3 milliliters of chloromethyl methyl ethers, 30.3mmol), salt of wormwood (5.5 the gram, 39.8mmol) and potassiumiodide (0.66 gram, 3.98mmol) at N, the mixture stirring in the dinethylformamide (50 milliliters) 20 hours.With ethyl acetate diluting reaction solution, with aqueous citric acid solution, water and saturated brine washing, use dried over mgso, concentrating under reduced pressure successively.With the resistates that obtains by silica gel column chromatography (ethyl acetate: hexane=3: 97-1: 9) purifying, obtain title compound (1.7g, productive rate 32%), be colorless oil.
MS m/z 271(MH+)
Reference example 26
[4 '-(methoxymethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol
According to reference example 3 similar methods, by 4 '-(methoxymethoxy)-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde obtains the title compound (productive rate 89%) of colorless oil.
MS m/z 255(MH+)
Reference example 27
2,2-two fluoro-3-(4-hydroxy phenyl) ethyl propionate
To according to Synthesis, vol.13, the method synthetic of describing among the pp.1917-1924 (2000) 2,2-two fluoro-3-(4-p-methoxy-phenyl) ethyl propionate (1.72 grams, 7.05mmol) and aluminum chloride (2.82 grams, 21.2mmol) methylene dichloride (50 milliliters) solution in dropwise add the 1-spicy thioalcohol (2.06 the gram, 14.1mmol), and at room temperature stirred this mixture 2 hours.Reaction mixture is poured in the frozen water, and this mixture was stirred 30 minutes.Separate organic layer,, use anhydrous magnesium sulfate drying, concentrating under reduced pressure with the saturated brine washing.Resistates by silica gel column chromatography (8%-60% ethyl acetate/hexane) purifying, is obtained title compound (0.90g, productive rate 56%), be colorless oil.
1H NMR(CDCl 3)δ：1.26(3H，t，J＝7.1Hz)，3.30(2H，t，J＝16.3Hz)，4.25(2H，q，J＝7.2Hz)，4.84(1H，s)，6.74-6.82(2H，m)，7.13(2H，d，J＝8.3Hz)。
Reference example 28
2-(4-bromo-3,5-dimethyl phenoxy)-6-picoline
(0.23 gram adds 4-bromo-3 in methyl alcohol 5.81mmol) (50 milliliters) solution, 5-xylenol (1.17 grams to sodium hydroxide, 5.81mmol), and at room temperature this mixture was left standstill 10 minutes, be concentrated into dried, obtain 4-bromo-3,5-xylenol sodium salt (1.30g).Then, with the 4-bromo-3 that obtains, 5-xylenol sodium salt (1.30 gram), 2-bromo-6-picoline (1.0 grams, 5.81mmol) and copper powder (11 milligrams, mixture 0.17mmol) was 185 ℃ of stirrings 1 hour.Reaction mixture, with the ethyl acetate dilution, water and saturated brine washing, dry and concentrating under reduced pressure.Resistates with silica gel column chromatography (hexane-hexane/ethyl acetate=5/1) purifying, is obtained title compound (1.25g, productive rate 74%), be light yellow oil.
MS(ESI+)：292(M+H)，294
Reference example 29
2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) oxygen base] xenyl-3-formaldehyde
According to the title compound (productive rate 94%) that obtains colorless oil with reference example 2 similar methods, by 2-(4-bromo-3,5-dimethyl phenoxy)-6-picoline and (3-formyl radical phenyl) boric acid.
MS(ESI+)：318(M+H)
Reference example 30
2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) oxygen base] biphenyl-3-yl } methyl alcohol
According to reference example 3 similar methods, by 2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) oxygen base] xenyl-3-formaldehyde obtain colorless oil title compound (productive rate 98%].
MS(ESI+)：320(M+H)
Reference example 31
2-bromo-5-(2-ethoxy ethoxy)-1,3-dimethylbenzene
Figure A20048004213900633
At room temperature be accompanied by stirring to 4-bromo-3,5-xylenol (12 grams, 59.7mmol), potassiumiodide (1.5 the gram, 9.0mmol) and salt of wormwood (9.9 grams, 71.6mmol) N, (9.7 grams 89.3mmol), and stirred these mixtures 2 days at 70 ℃ to add 2-chloroethyl ether in dinethylformamide (80 milliliters) solution.With reaction mixture cooling and concentrating under reduced pressure.Resistates is distributed between ethyl acetate and water.Wash organic layer with saturated brine, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.Resistates with silica gel column chromatography (hexane/ethyl acetate=19/1) purifying, is obtained title compound (15.9g, productive rate 98%), be yellow oil.
MS(ESI+)：274(M+H)
Reference example 32
[4-(2-ethoxy ethoxy)-2,6-3,5-dimethylphenyl] boric acid
Be accompanied by stirring to 2-bromo-5-(2-ethoxy ethoxy)-1 at-78 ℃, 3-dimethylbenzene (10.0 grams, and adding n-Butyl Lithium hexane solution in tetrahydrofuran (THF) 36.6mmol) (100 milliliters) solution (1.6M, 25.1 milliliters, 40.2mmol).Reaction mixture was stirred 30 minutes under uniform temp, and adding triisopropyl boric acid ester (10.5 milliliters, 45.5mmol).Reaction mixture is warming up to room temperature, and stirred 3 hours.(20mL) joins in the reaction mixture with 5N hydrochloric acid, and mixture is distributed between ethyl acetate and water.With the organic layer dried over mgso, and concentrating under reduced pressure.Resistates is washed and drying with hexane/ether, obtain the title compound (5.9g, productive rate 68%) of pale yellow crystals.
1H NMR(CDCl 3)δ：1.24(3H，t，J＝7.0Hz)，2.36(6H，s)，3.60(2H，q，J＝7.0Hz)，3.77(2H，t，J＝5.0Hz)，4.09(2H，t，J＝5.0Hz)，4.52(2H，s)，6.58(2H，s)。
Reference example 33
4 '-(2-ethoxy ethoxy)-6-methoxyl group-2 ', 6 '-dimethyl diphenyl base-3-carboxylate methyl ester
Figure A20048004213900642
With 3-bromo-4-methoxyl methyl benzoate (0.90 gram, 3.67mmol), [4-(2-ethoxy ethoxy)-2, the 6-3,5-dimethylphenyl] boric acid (0.87 gram, 3.67mmol), three (dibenzalacetones), two palladiums (0) (0.13 the gram, 0.15mmol), (79 milligrams in 2-(dicyclohexyl phosphino-) biphenyl, 0.22mmol), Tripotassium phosphate (1.56 the gram, 7.34mmol) and the mixture of toluene (20 milliliters) under nitrogen atmosphere 90 ℃ stirrings 18 hours.Reaction mixture, and leach insoluble substance.Concentrating under reduced pressure filtrate, and use silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=1/1) purifying resistates, obtain the title compound (0.71g, productive rate 54%) of yellow oil.
MS(ESI+)：359(M+H)
Reference example 34
[4 '-(2-ethoxy ethoxy)-6-methoxyl group-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol
According to reference example 16 similar methods, by 4 '-(2-ethoxy ethoxy)-6-methoxyl group-2 ', 6 '-dimethyl diphenyl base-3-carboxylate methyl ester obtains the title compound (productive rate 100%) of colorless oil.
MS(ESI+)：331(M+H)
Reference example 35
4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde
According to reference example 2 similar methods, by 4-bromo-3,5-xylenol and (3-formyl radical phenyl) boric acid obtain the title compound (productive rate 83%) of pale yellow crystals.
MS(ESI+)：227(M+H)
Reference example 36
4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde
Figure A20048004213900653
At room temperature be accompanied by stirring to 4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde (9.0 grams, 39.8mmol) and imidazoles (2.98 grams, 43.8mmol) N, add TERT-BUTYL DIMETHYL CHLORO SILANE (6.6 grams in dinethylformamide (100 milliliters) solution, 43.8mmol), and at room temperature stirred this mixture 4 hours.Use the ethyl acetate diluted reaction mixture, water and saturated brine washing, dry and concentrating under reduced pressure.Resistates by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) purifying, is obtained the title compound (10.5g, productive rate 77%) of yellow oil.
1H NMR(CDCl 3)δ：0.25(6H，s)，1.02(9H，s)，1.97(6H，s)，6.62(2H，s)，7.44(1H，dt，J＝1.5，7.5Hz)，7.59(1H，t，J＝7.5Hz)，7.68(1H，t，J＝1.5Hz)，7.86(1H，dt，J＝1.5，7.5Hz)，10.06(1H，s)。
Reference example 37
(4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-2 ', 6 '-dimethyl diphenyl-3-yl) methyl alcohol
Figure A20048004213900661
According to reference example 3 similar methods, by 4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde obtains title compound clear crystal (productive rate 89%).
1H NMR(CDCl 3)δ：0.23(6H，s)，1.00(9H，s)，1.96(6H，s)，4.73(2H，s)，6.58(2H，s)，7.07(1H，d，J＝7.5Hz)，7.13(1H，s)，7.32(1H，d，J＝7.5Hz)，7.40(1H，t，J＝7.5Hz)。
Reference example 38
(2E)-and 3-[4-(benzyloxy) phenyl] tert-butyl acrylate
Figure A20048004213900662
According to reference example 12 similar methods, obtain title compound clear crystal (productive rate 94%) by 4-(benzyloxy) phenyl aldehyde and diethyl phosphonyl tert.-butyl acetate.
1H NMR(CDCl 3)δ：1.53(9H，s)，5.09(2H，s)，6.24(1H，d，J＝15.9Hz)，6.96(2H，d，J＝9.0Hz)，7.32-7.49(7H，m)，7.54(1H，d，J＝15.9Hz)。
Reference example 39
3-(4-hydroxy phenyl) the propionic acid tert-butyl ester
Figure A20048004213900663
With (2E)-3-[4-(benzyloxy) phenyl] (13.3 grams, 42.8mmol), 10% palladium carbon (1.3 gram), the mixture of ethanol (100 milliliters) and ethyl acetate (30 milliliters) is under atmosphere of hydrogen, at room temperature stirred 19 hours for tert-butyl acrylate.Leach catalyzer, and filtrate decompression is concentrated, obtain title compound clear crystal (7.5g, productive rate 79%).
1H NMR(CDCl 3)δ：1.41(9H，s)，2.50(2H，t，J＝7.8Hz)，2.83(2H，t，J＝7.8Hz)，6.74(2H，d，J＝8.7Hz)，7.06(2H，d，J＝8.7Hz)。
Reference example 40
2,6-dimethyl-4-nitrophenyl triflate
Figure A20048004213900671
Be accompanied by stirring to 2 at 0 ℃, ((60%, 1.44 gram 35.9mmol), and stirred this mixture 10 minutes to 6-dimethyl-nitrophenol to add sodium hydride in dinethylformamide (50 milliliters) solution for 5.0 grams, N 29.9mmol).(12.8 grams 35.9mmol), and stirred this mixture 2 hours under uniform temp to add N-phenyl two (fluoroform sulfimides).Use the ethyl acetate diluted reaction mixture, water and saturated brine washing, dry and concentrating under reduced pressure.Resistates by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=5/1) purifying, is obtained title compound yellow oil (9.2g, productive rate 100%).
1H NMR(CDCl 3)δ：2.50(6H，s)，8.03(2H，s)。
Reference example 41
(2 ', 6 '-dimethyl-4 '-nitrobiphenyl-3-yl) methyl alcohol
With 2; 6-dimethyl-4-nitrophenyl triflate (9.2 grams; 29.9mmol), 3-(formyl radical phenyl) boric acid (4.7 the gram; 31.4mmol), three (dibenzalacetones), two palladiums (0) (1.10 the gram; 1.20mmol), rac-2,2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (1.12 the gram; 1.80mmol), cesium carbonate (14.6 the gram, 44.9mmol) and the mixture of toluene (150 milliliters) under nitrogen atmosphere 90 ℃ stirrings 18 hours.Reaction mixture, and leach insoluble substance.Concentrating under reduced pressure filtrate, and use silica gel column chromatography (hexane/ethyl acetate=9/1-hexane/ethyl acetate=2/1) purifying resistates, obtain yellow oil (1.0g).Be accompanied by stirring at 0 ℃ and in the mixture of the yellow oil that obtains (1.0 gram), methyl alcohol (10 milliliters) and tetrahydrofuran (THF) (10 milliliters), add sodium borohydride (74 milligrams 1.96mmol), and were stirred this mixture 2 hours under uniform temp.In reaction mixture, add entry and ethyl acetate, to distribute mixture.With the organic layer dried over mgso, and concentrating under reduced pressure.Use silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/1) purifying resistates, obtain title compound pale yellow crystals (0.44g, productive rate 6%).
1H NMR(CDCl 3)δ：1.74(1H，t，J＝5.7Hz)，2.11(6H，s)，4.77(2H，d，J＝5.7Hz)，7.04(1H，m)，7.12(1H，s)，7.41(1H，d，J＝7.8Hz)，7.48(1H，t，J＝7.5Hz)，7.97(2H，s)。
Reference example 42
1-oxa--6-thia spiral shell [2.5] octane
Figure A20048004213900681
Under nitrogen atmosphere, at room temperature, to trimethylammonium sulfoxonium iodide (37.1 grams, 165.1mmol) methyl-sulphoxide (120 milliliters) suspension in add at leisure sodium hydride (6.10 the gram, 152.4mmol), after stirring 1 hour, (14.8 restrain methyl-sulphoxide 127.0mmol) (60 milliliters) solution dropwise to add tetrahydrochysene-4H-thiapyran-4-ketone with 20 minutes.Reaction soln was at room temperature further stirred 14 hours, and dilute with water is also used ether extraction.Water and saturated brine washing organic layer are used anhydrous sodium sulfate drying, concentrating under reduced pressure.At room temperature leave standstill resistates,, obtain title compound colourless acicular crystal (8.22g, productive rate 50%) with the crystal that a small amount of hexane wash obtained, drying.
1H NMR(CDCl 3)δ：1.69-1.82(2H，m)，1.93-2.09(2H，m)，2.56-2.73(4H，m)，2.85-3.01(2H，m)。
Reference example 43
4 '-[(4-hydroxy tetrahydro-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde
At room temperature be accompanied by stirring to 1-oxa--6-thia spiral shell [2.5] octane (6.33 grams, 48.6mmol) and 4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde (10.0 grams, 44.2mmol) N, add salt of wormwood (6.11 grams in dinethylformamide (150 milliliters) solution, 44.2mmol), and stirred these mixtures 12 hours at 100 ℃.With the reaction mixture concentrating under reduced pressure.In resistates, add 1M hydrochloric acid, with this solution that neutralizes, and with this mixture of ethyl acetate extraction.Use the anhydrous sodium sulfate drying extract, concentrating under reduced pressure carries out crystallization by add diisopropyl ether in the oily matter that is obtained.Filter and collect crystal, obtain title compound clear crystal (12.3g, productive rate 78%).
1H NMR(CDCl 3)δ：1.76-1.91(2H，m)，2.00(6H，s)，2.06-2.17(2H，m)，2.19(1H，s)，2.41-2.55(2H，m)，3.03-3.19(2H，m)，3.81(2H，s)，6.69(2H，s)，7.37-7.46(1H，m)，7.55-7.71(2H，m)，7.83-7.92(1H，m)，10.05(1H，s)。
Reference example 44
4-([3 '-(methylol)-2,6-dimethyl diphenyl-4-yl] the oxygen base } methyl) tetrahydrochysene-2H-thiapyran-4-alcohol
According to reference example 3 similar methods, by 4 '-[(4-hydroxy tetrahydro-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl base-3-formaldehyde obtains title compound clear crystal (productive rate 100%).
1H NMR(CDCl 3)δ：1.70(1H，t，J＝5.8Hz)，1.76-1.90(2H，m)，2.01(6H，s)，2.05-2.16(2H，m)，2.20(1H，s)，2.40-2.53(2H，m)，3.03-3.18(2H，m)，3.80(2H，s)，4.73(2H，d，J＝5.8Hz)，6.67(2H，s)，7.02-7.09(1H，m)，7.12(1H，s)，7.31-7.37(1H，m)，7.41(1H，t，J＝7.4Hz)。
Reference example 45
3-bromo-4-methyl hydroxybenzoate
Figure A20048004213900692
With 3-bromo-4-hydroxy-benzoic acid (50.4 grams, 232mmol) and methyl alcohol (330 milliliters) the solution reflux of the vitriol oil (17 milliliters) 24 hours.This reaction mixture is neutralized with aqueous sodium hydroxide solution.Methyl alcohol is removed in decompression, and uses the ethyl acetate extraction resistates.With sodium bicarbonate aqueous solution and saturated brine washing extract, use anhydrous sodium sulfate drying, concentrating under reduced pressure.The crystal that obtains is washed with ether/hexane, obtain title compound (45.5g, productive rate 85%), be the baby pink crystal.
MS m/z 231(MH +)
Reference example 46
3-bromo-4-isopropoxy methyl benzoate
Figure A20048004213900701
To 3-bromo-4-methyl hydroxybenzoate (15.0 grams, 64.9mmol), (7.68 milliliters of 2-N-PROPYLE BROMIDEs, 77.9mmol) and potassiumiodide (1.0 grams, 6.49mmol) N, add salt of wormwood (13.5 grams in dinethylformamide (200 milliliters) solution, 97.4mmol), and stirred these mixtures 2 hours at 80 ℃.With the reaction mixture concentrating under reduced pressure.In the resistates that obtains, add salt solution, and use the ethyl acetate extraction mixture.Use the anhydrous sodium sulfate drying extract, concentrating under reduced pressure.Resistates with silica gel column chromatography (hexane-hexane/ethyl acetate=9/1) purifying, is obtained title compound (14.6g, productive rate 83%), be colorless oil.
1H NMR(CDCl 3)δ：1.41(6H，d，J＝6.0Hz)，3.89(3H，s)，4.59-4.75(1H，m)，6.90(1H，d，J＝8.9Hz)，7.94(1H，dd，J＝8.7，2.1Hz)，8.23(1H，d，J＝2.1Hz)。
Reference example 47
(4-bromo-3,5-dimethyl phenoxy) (tertiary butyl) dimethylsilane
Figure A20048004213900702
According to reference example 36 similar methods, by 4-bromo-3, the 5-xylenol obtains title compound colorless oil (productive rate 97%).
1H NMR(CDCl 3)δ：0.18(6H，s)，0.97(9H，s)，2.34(6H，s)，6.57(2H，s)。
Reference example 48
(the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2, the 6-3,5-dimethylphenyl) boric acid
Figure A20048004213900711
According to reference example 32 similar methods, obtain the light yellow prismatic crystal of title compound (productive rate 53%) by (4-bromo-3,5-dimethyl phenoxy) (tertiary butyl) dimethylsilane.
1H NMR(CDCl 3)δ：0.19(6H，s)，0.98(9H，s)，2.32(6H，s)，4.58(2H，s)，6.47(2H，s)。
Reference example 49
4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-6-isopropoxy-2 ', 6 '-dimethyl diphenyl base-3-carboxylate methyl ester
Figure A20048004213900712
Will (the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2, the 6-3,5-dimethylphenyl) boric acid is (500 milligrams, 1.83mmol) and (667 milligrams of 3-bromo-4-isopropoxy methyl benzoate, 2.38mmol) mixture be dissolved in the mixture of the 2M aqueous sodium carbonate aqueous solution (2.38 milliliters) and toluene (20 milliliters), after the argon replaces, adding 2-dicyclohexyl phosphino--2 '-(N, the N-dimethylamino) biphenyl is (118 milligrams, 0.29mmol) and three (dibenzalacetones), two palladiums (0) (67.0 milligrams, 0.07mmol).With reaction mixture reflux 1 day under argon atmospher.Reaction mixture adds salt solution.Use the ethyl acetate extraction mixture, use the anhydrous sodium sulfate drying organic layer, concentrating under reduced pressure.With resistates silica gel chromatography (hexane-hexane/ethyl acetate=10/1) purifying, obtain the title compound (642mg, productive rate 82%) of yellow oil.
1H NMR(CDCl 3)δ：0.19-0.26(6H，m)，1.00(9H，s)，1.17(6H，d，J＝6.0Hz)，1.92(6H，s)，3.87(3H，s)，4.42-4.57(1H，m)，6.57(2H，s)，6.95(1H，d，J＝8.7Hz)，7.74(1H，d，J＝2.3Hz)，7.99(1H，dd，J＝8.7，2.4Hz)。
Reference example 50
(4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-6-isopropoxy-2 ', 6 '-dimethyl diphenyl-3-yl) methyl alcohol
Figure A20048004213900721
According to reference example 16 similar methods, by 4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-6-isopropoxy-2 ', 6 '-dimethyl diphenyl base-3-carboxylate methyl ester obtains the title compound (productive rate 85%) of colorless oil.
1H NMR(CDCl 3)δ：0.22(6H，s)，1.00(9H，s)，1.10(6H，d，J＝6.2Hz)，1.94-1.98(6H，m)，4.16-4.31(1H，m)，4.64(2H，d，J＝3.6Hz)，6.57(2H，s)，6.94(1H，d，J＝8.5Hz)，7.04(1H，d，J＝2.1Hz)，7.24-7.31(1H，m)。
Embodiment 1
3-(4-{[2 '-methyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methoxyl group } phenyl) methyl propionate
Figure A20048004213900722
With 3-(4-hydroxy phenyl) methyl propionate (1.43 grams, 7.94mmol), [2 '-methyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methyl alcohol (2.37 grams, 7.94mmol) and (2.97 milliliters of tributylphosphines, 11.9mmol) toluene (120 milliliters) solution under ice-cooling, stir, and divide little part to add 1,1 '-(azo dicarbapentaborane) connection piperidines (3.00 grams, 11.9mmol).Mixture is warming up to room temperature, and stirred 24 hours.(60mL) joins in the reaction mixture with hexane, and leaches sedimentary insoluble substance.Concentrating under reduced pressure filtrate, and use silica gel column chromatography (hexane-20% ethyl acetate/hexane) purifying resistates, obtain the title compound (3.05g, productive rate 83%) of colorless oil.
1H NMR(CDCl 3)δ：1.58-1.75(3H，m)，1.85-1.90(2H，m)，1.97-2.08(1H，m)，2.23(3H，s)，2.60(2H，t，J＝7.8Hz)，2.89(2H，t，J＝7.8Hz)，3.61-3.66(4H，m)，3.91-3.99(1H，m)，5.07(2H，s)，5.46(1H，t，J＝3.1Hz)，6.88-6.97(4H，m)，7.08-7.16(3H，m)，7.24-7.27(1H，m)，7.35-7.43(3H，m)。
Embodiment 2
3-(4-{[2 '-methyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methoxyl group } phenyl) propionic acid
To 3-(4-{[2 '-methyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methoxyl group phenyl) methyl propionate (0.599 gram, 1.30mmol) methyl alcohol (6 milliliters) and tetrahydrofuran (THF) (6 milliliters) solution in add 2M aqueous sodium hydroxide solution (2 milliliters), and at room temperature stirred this mixture 24 hours.Water is joined in the reaction mixture, and, use ethyl acetate extraction with 10% aqueous citric acid solution neutralise mixt.Wash extract with saturated brine, use anhydrous sodium sulfate drying, concentrating under reduced pressure.Resistates with ethyl acetate-hexane recrystallization, is obtained the colourless needle crystals of title compound (0.436g, productive rate 75%).
1H NMR(CDCl 3)δ：1.58-1.76(3H，m)，1.85-1.90(2H，m)，1.97-2.10(1H，m)，2.23(3H，s)，2.65(2H，t，J＝7.6Hz)，2.91(2H，t，J＝7.6Hz)，3.60-3.66(1H，m)，3.91-3.99(1H，m)，5.08(2H，s)，5.46(1H，t，J＝3.1Hz)，6.89-6.97(4H，m)，7.11-7.16(3H，m)，7.24-7.27(1H，m)，7.35-7.43(3H，m)。
Embodiment 3
3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl } methyl propionate
Figure A20048004213900732
With 3-(4-{[2 '-methyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methoxyl group phenyl) methyl propionate (3.78 grams, 8.21mmol) and the tosic acid monohydrate (0.156 the gram, methyl alcohol 0.821mmol) (60 milliliters) solution at room temperature stirred 2 hours.The reduction vaporization reaction solvent, and dilute resistates with ethyl acetate, with the saturated brine washing, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.Resistates by silica gel column chromatography (20%-60% ethyl acetate/hexane) purifying, is obtained the title compound (3.04g, productive rate 98%) of colourless viscosity oily matter.
MS m/z 377(MH +)
Embodiment 4
3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid
Figure A20048004213900741
According to embodiment 2 similar methods, by 3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate obtains the colourless prismatic crystal of title compound (productive rate 31% is with hexane-re-crystallizing in ethyl acetate).
1H NMR(CDCl 3)δ：2.21(3H，s)，2.65(2H，t，J＝7.7Hz)，2.91(2H，t，J＝7.7Hz)，5.07(2H，s)，6.69-6.75(2H，m)，6.92(2H，d，J＝8.7Hz)，7.09-7.15(3H，m)，7.23-7.26(1H，m)，7.35-7.43(3H，m)。
Embodiment 5
3-{4-[(4 '-methoxyl group-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl } methyl propionate
Figure A20048004213900742
According to embodiment 1 similar methods, by 3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and methyl alcohol obtains the title compound (productive rate 92%) of light yellow oil.
1H NMR(CDCl 3)δ：2.24(3H，s)，2.60(2H，t，J＝7.8Hz)，2.89(2H，t，J＝7.8Hz)，3.66(3H，s)，3.83(3H，s)，5.07(2H，s)，6.77-6.82(2H，m)，6.91(2H，d，J＝8.7Hz)，7.10-7.17(3H，m)，7.24-7.27(1H，m)，7.35-7.43(3H，m)。
Embodiment 6
3-{4-[(4 '-methoxyl group-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid
Figure A20048004213900743
According to embodiment 2 similar methods, by 3-{4-[(4 '-methoxyl group-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate obtains the colourless needle crystals of title compound (productive rate 56% is with hexane-re-crystallizing in ethyl acetate).
1H NMR(CDCl 3)δ：2.24(3H，s)，2.65(2H，t，J＝7.7Hz)，2.91(2H，t，J＝7.7Hz)，3.83(3H，s)，5.08(2H，s)，6.77-6.81(2H，m)，6.92(2H，d，J＝8.7Hz)，7.11-7.18(3H，m)，7.24-7.27(1H，m)，7.36-7.44(3H，m)。
Embodiment 7
3-(4-{[4 '-(cyclo propyl methoxy)-2 '-methyl diphenyl-3-yl] methoxyl group } phenyl) methyl propionate
Figure A20048004213900751
According to embodiment 1 similar methods, by 3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and cyclopropyl-carbinol obtain the title compound (productive rate 85%) of colorless oil.
MS m/z 431(MH +)
Embodiment 8
3-(4-{[4 '-(cyclo propyl methoxy)-2 '-methyl diphenyl-3-yl] methoxyl group } phenyl) propionic acid
Figure A20048004213900752
According to embodiment 2 similar methods, by 3-(4-{[4 '-(cyclo propyl methoxy)-2 '-methyl diphenyl-3-yl] methoxyl group phenyl) methyl propionate obtains the colourless needle crystals of title compound (productive rate 43% is with hexane-re-crystallizing in ethyl acetate).
MS m/z 417(MH +)
Embodiment 9
3-{4-[(4 '-isopropoxy-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl } methyl propionate
According to embodiment 1 similar methods, by 3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and 2-Virahol obtain the title compound (productive rate 78%) of colorless oil.
MS m/z 419(MH +)
Embodiment 10
3-{4-[(4 '-isopropoxy-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid
Figure A20048004213900761
According to embodiment 2 similar methods, by 3-{4-[(4 '-isopropoxy-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate obtains the colourless needle crystals of title compound (productive rate 56% is with hexane-re-crystallizing in ethyl acetate).
MS m/z 405(MH +)
Embodiment 11
3-(4-{[4 '-(benzyloxy)-2 '-methyl diphenyl-3-yl] methoxyl group } phenyl) methyl propionate
Figure A20048004213900762
According to embodiment 1 similar methods, by 3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and phenylcarbinol obtain the title compound (productive rate 79%) of colorless oil.
MS m/z 467(MH +)
Embodiment 12
3-(4-{[4 '-(benzyloxy)-2 '-methyl diphenyl-3-yl] methoxyl group } phenyl) propionic acid
According to embodiment 2 similar methods, by 3-(4-{[4 '-(benzyloxy)-2 '-methyl diphenyl-3-yl] methoxyl group phenyl) methyl propionate obtains the colourless needle crystals of title compound (productive rate 45% is with hexane-re-crystallizing in ethyl acetate).
MS m/z 453(MH +)
Embodiment 13
3-[4-(2 '-methyl-4 '-[2-(4-methyl isophthalic acid, 3-thiazole-5-yl) oxyethyl group] biphenyl-3-yl } methoxyl group) phenyl] methyl propionate
According to embodiment 1 similar methods, by 3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and 2-(4-methyl isophthalic acid, 3-thiazole-5-yl) ethanol obtains the title compound (productive rate 62%) of brown oil.
MS m/z 502(MH +)
Embodiment 14
3-[4-(2 '-methyl-4 '-[2-(4-methyl isophthalic acid, 3-thiazole-5-yl) oxyethyl group] biphenyl-3-yl } methoxyl group) phenyl] propionic acid
According to embodiment 2 similar methods, by 3-[4-(2 '-methyl-4 '-[2-(4-methyl isophthalic acid, 3-thiazole-5-yl) oxyethyl group] biphenyl-3-yl } methoxyl group) phenyl] the colourless tabular crystal of methyl propionate acquisition title compound (productive rate 77% is with hexane-re-crystallizing in ethyl acetate).
MS m/z 488(MH +)
Embodiment 15
3-(4-{[2 '-methyl-4 '-(3-(pyridine-2-yl) propoxy-) biphenyl-3-yl] methoxyl group } phenyl) methyl propionate
Figure A20048004213900773
With 3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate (0.602 the gram, 1.60mmol), 3-(pyridine-2-yl) third-1-alcohol (0.822 the gram, 6.00mmol) and triphenylphosphine (1.57 grams, 6.00mmol) tetrahydrofuran (THF) (20 milliliters) solution under ice-cooling, stir, and adding azo-2-carboxylic acid diethyl ester (40% toluene solution, 2.72 milliliter, 6.00mmol).Mixture is warming up to room temperature, and stirred 42 hours.The concentrating under reduced pressure reaction mixture, and use silica gel column chromatography (20%-60% ethyl acetate/hexane) and preparation HPLC purifying resistates, obtain the title compound (0.446g, productive rate 56%) of yellow viscous oil shape thing.
MS m/z 496(MH +)
Embodiment 16
3-(4-{[2 '-methyl-4 '-(3-(pyridine-2-yl) propoxy-) biphenyl-3-yl] methoxyl group } phenyl) propionic acid
Figure A20048004213900781
To 3-(4-{[2 '-methyl-4 '-(3-(pyridine-2-yl) propoxy-) biphenyl-3-yl] methoxyl group phenyl) methyl propionate (0.401 the gram, 0.809mmol) methyl alcohol (5 milliliters) and tetrahydrofuran (THF) (5 milliliters) solution in add 2M aqueous sodium hydroxide solution (1.5 milliliters), and at room temperature stirred this mixture 75 hours.Water is joined in the reaction mixture, and, use ethyl acetate extraction with 10% aqueous citric acid solution neutralise mixt.Wash extract with saturated brine, use anhydrous sodium sulfate drying, concentrating under reduced pressure.Resistates is passed through silica gel column chromatography (50% ethyl acetate/hexane-ethyl acetate) purifying, and, obtain the colourless prismatic crystal of title compound (0.186g, productive rate 48%) with ethyl acetate-hexane recrystallization.
MS m/z 482(MH +)
Embodiment 17
3-(4-{[2 '-methyl-4 '-(1-propyl group butoxy) biphenyl-3-yl] methoxyl group } phenyl) methyl propionate
Figure A20048004213900782
According to embodiment 1 similar methods, by 3-{4-[(4 '-hydroxyl-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and 4-enanthol obtain the title compound (productive rate 65%) of colorless oil.
1H NMR(CDCl 3)δ：0.94(6H，t，J＝7.2Hz)，1.31-1.81(8H，m)，2.22(3H，s)，2.60(2H，t，J＝7.8Hz)，2.89(2H，t，J＝7.8Hz)，3.66(3H，s)4.23-4.31(1H，m)，5.07(2H，s)，6.74-6.80(2H，m)，6.88-6.93(2H，m)，7.10-7.16(3H，m)，7.25-7.28(1H，m)，7.36-7.43(3H，m)。
Embodiment 18
3-(4-{[2 '-methyl-4 '-(1-propyl group butoxy) biphenyl-3-yl] methoxyl group } phenyl) propionic acid
According to embodiment 2 similar methods, by 3-(4-{[2 '-methyl-4 '-(1-propyl group butoxy) biphenyl-3-yl] methoxyl group phenyl) methyl propionate obtains the colourless needle crystals of title compound (productive rate 77% is with hexane-re-crystallizing in ethyl acetate).
1H NMR(CDCl 3)δ：0.94(6H，t，J＝7.3Hz)，1.33-1.76(8H，m)，2.22(3H，s)，2.65(2H，t，J＝7.7Hz)，2.91(2H，t，J＝7.7Hz)，4.23-4.31(1H，m)，5.07(2H，s)，6.73-6.80(2H，m)，6.92(2H，d，J＝8.6Hz)，7.13(3H，d，J＝8.6Hz)，7.24-7.28(1H，m)，7.35-7.43(3H，m)。
Embodiment 19
3-(4-{[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) ethyl propionate
Figure A20048004213900792
According to embodiment 1 similar methods, by 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate and [4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol obtains title compound colorless oil (productive rate 76%).
MS m/z 513(MH +)
Embodiment 20
3-(4-{[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid
Figure A20048004213900793
According to embodiment 2 similar methods, by 3-(4-{[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group-the 2-fluorophenyl) ethyl propionate obtains the colourless prismatic crystallization of title compound (productive rate 57% is with heptane-re-crystallizing in ethyl acetate).
MS m/z 485(MH +)
Embodiment 21
3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) ethyl propionate
According to embodiment 1 similar methods, by 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate and [4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol obtains the title compound (productive rate 93%) of colorless oil.
MS m/z 495(MH +)
Embodiment 22
3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid
According to embodiment 2 similar methods, by 3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) the colourless prismatic crystallization of ethyl propionate acquisition title compound (productive rate 77% is with hexane-re-crystallizing in ethyl acetate).
MS m/z 467(MH +)
Embodiment 23
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) ethyl propionate
According to embodiment 1 similar methods, by 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate and [2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methyl alcohol obtains the title compound (productive rate 89%) of colorless oil.
MS m/z 507(MH +)
Embodiment 24
3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } ethyl propionate
Figure A20048004213900811
According to embodiment 3 similar methods, by 3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methoxyl group-the 2-fluorophenyl) ethyl propionate obtains the title compound (productive rate 97%) of colorless oil.
MS m/z 423(MH +)
Embodiment 25
3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid
According to embodiment 2 similar methods, by 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate obtains the colourless prismatic crystal of title compound (productive rate 82% is with hexane-re-crystallizing in ethyl acetate).
MS m/z 395(MH +)
Embodiment 26
3-(4-{[2 ', 6 '-dimethyl-4 '-(1-propyl group butoxy) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) ethyl propionate
According to embodiment 1 similar methods, by 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate and 4-enanthol obtain the title compound (productive rate 88%) of colorless oil.
1H NMR(CDCl 3)δ：0.94(6H，t，J＝7.2Hz)，1.23(3H，t，J＝7.2Hz)，1.33-1.76(8H，m)，1.98(6H，s)，2.57(2H，t，J＝7.6Hz)，2.89(2H，t，J＝7.6Hz)，4.12(2H，q，J＝7.2Hz)，4.21-4.29(1H，m)，5.06(2H，s)，6.62-6.70(4H，m)，7.05-7.12(2H，m)，7.18(1H，s)，7.33-7.38(1H，m)，7.42(1H，t，J＝7.5Hz)。
Embodiment 27
3-(4-{[2 ', 6 '-dimethyl-4 '-(1-propyl group butoxy) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid
Figure A20048004213900821
According to embodiment 2 similar methods, by 3-(4-{[2 ', 6 '-dimethyl-4 '-(1-propyl group butoxy) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) the colourless needle crystals of ethyl propionate acquisition title compound (productive rate 62% is with heptane-re-crystallizing in ethyl acetate).
1H NMR(CDCl 3)δ：0.94(6H，t，J＝7.3Hz)，1.33-1.76(8H，m)，1.97(6H，s)，2.64(2H，t，J＝7.6Hz)，2.91(2H，t，J＝7.6Hz)，4.21-4.29(1H，m)，5.06(2H，s)，6.63-6.71(4H，m)，7.06-7.13(2H，m)，7.18(1H，s)，7.33-7.38(1H，m)，7.42(1H，t，J＝7.4Hz)。
Embodiment 28
3-[4-[[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methoxyl group] phenyl] methyl propionate
Be accompanied by stirring to 3-(4-hydroxy phenyl) methyl propionate (3.28 grams at 0 ℃, 18.2mmol), [2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methyl alcohol (5.15 grams, 16.5mmol) and triphenylphosphine (5.63 grams, 21.5mmol) tetrahydrofuran (THF) (100 milliliters) solution in dropwise add diethylazodicarboxylate's (40% toluene solution, 9.7 milliliter), and at room temperature stirred this mixture 48 hours.The concentrating under reduced pressure reaction mixture, and use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) purifying resistates, obtain the title compound (2.92g, productive rate 37%) of yellow oil.
1H NMR(CDCl 3)δ：1.57-1.78(3H，m)，1.82-1.90(2H，m)，1.98(6H，s)，2.02(1H，m)，2.59(2H，t，J＝7.8Hz)，2.89(2H，t，J＝7.8Hz)，3.62(1H，m)，3.66(3H，s)，3.97(1H，m)，5.08(2H，s)，5.45(1H，t，J＝3.0Hz)，6.81(2H，s)，6.89(2H，d，J＝8.4Hz)，7.05-7.14(3H，m)，7.18(1H，s)，7.34-7.47(2H，m)。
Embodiment 29
3-[4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate
Figure A20048004213900831
With 3-[4-[[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-2-base oxygen base) biphenyl-3-yl] methoxyl group] phenyl] methyl propionate (2.92 grams, 6.15mmol), the tosic acid monohydrate (0.12 the gram, 0.62mmol) and the mixture of methyl alcohol (60 milliliters) at room temperature stir 2 hours, and this mixture of concentrating under reduced pressure.Use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/2) purifying resistates, obtain the red oily matter of title compound (2.12g, productive rate 88%).
1H NMR(CDCl 3)δ：1.96(6H，s)，2.59(2H，t，J＝7.8Hz)，2.89(2H，t，J＝7.8Hz)，3.66(3H，s)，4.63(1H，s)，5.08(2H，s)，6.59(2H，s)，6.89(2H，d，J＝8.7Hz)，7.05-7.13(3H，m)，7.17(1H，s)，7.35-7.45(2H，m)。
Embodiment 30
3-[4-[(4 '-methoxyl group-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] propionic acid
0 ℃ be accompanied by stirring to 3-[4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate (0.20 gram, 0.51mmol), (0.041 milliliter of methyl alcohol, 1.02mmol) and triphenylphosphine (0.18 gram, 0.67mmol) tetrahydrofuran (THF) (4.0 milliliters) solution in dropwise add diethylazodicarboxylate's (40% toluene solution, 0.30 milliliter), and at room temperature stirred this mixture 12 hours.The concentrating under reduced pressure reaction mixture, and use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) purifying resistates, obtain yellow oil (0.13g, productive rate 65%).
At room temperature be accompanied by stirring to the product that is obtained, add 1N aqueous sodium hydroxide solution (0.66 milliliter) in the mixture of methyl alcohol (2 milliliters) and tetrahydrofuran (THF) (4 milliliters), and under uniform temp, stirred this mixture 1 hour.To be adjusted to pH3 with 1N hydrochloric acid in the reaction mixture, and use the ethyl acetate extraction mixture.Water and saturated brine washing ethyl acetate layer are used anhydrous magnesium sulfate drying, concentrating under reduced pressure.Use silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/2) purifying resistates, obtain title compound clear crystal (0.12g, productive rate 89%).
MS(APCI-)：389(M-H)
Embodiment 31
3-[4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] propionic acid
Figure A20048004213900841
To 3-[4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate (0.18 gram, 0.46mmol) methyl alcohol (2 milliliters) and tetrahydrofuran (THF) (4 milliliters) solution in add 1N aqueous sodium hydroxide solution (0.91 milliliter), and at room temperature stirred this mixture 1 hour.Concentrated reaction mixture, and resistates diluted with ethyl acetate, with 1N hydrochloric acid and saturated brine washing, dry and concentrating under reduced pressure.With hexane/ethyl acetate=4/1 crystalline residue, obtain title compound clear crystal (0.13g, productive rate 74%).
MS(APCI-)：375(M-H)
Embodiment 32
3-[4-[(4 '-chloro-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate
With the 3-[4-[(3-bromobenzyl) the oxygen base] phenyl] methyl propionate (0.5 gram, 1.43mmol), 4-chloro-2-aminomethyl phenyl boric acid (0.30 the gram, 1.72mmol), tetrakis triphenylphosphine palladium (0) (0.083 the gram, 0.072mmol), yellow soda ash (0.46 gram, 4.29mmol), the mixture of water (5 milliliters), ethanol (5 milliliters) and toluene (25 milliliters) is under argon atmospher, 90 ℃ of stirrings 16 hours.Reaction mixture, with the ethyl acetate dilution, water and saturated brine washing, dry and concentrating under reduced pressure.(the purifying resistates of hexane/ethyl acetate=10/1-4/1) obtains the title compound (0.50g, productive rate 88%) of colorless oil to use silica gel column chromatography.
1H NMR(CDCl 3)δ：2.22(3H，s)，2.60(2H，t，J＝7.8Hz)，2.90(2H，t，J＝7.8Hz)，3.66(3H，s)，5.08(2H，s)，6.91(2H，d，J＝8.7Hz)，7.08-7.28(6H，m)，7.34(1H，br)，7.38-7.46(2H，m)。
Embodiment 33
3-[4-[(4 '-chloro-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl] propionic acid
According to embodiment 31 similar methods, by 3-[4-[(4 '-chloro-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate obtains title compound clear crystal (productive rate 73%).
MS(APCI-)：379(M-H)，381
Embodiment 34
3-[4-[(4 '-fluoro-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate
Figure A20048004213900852
According to embodiment 32 similar methods, by the 3-[4-[(3-bromobenzyl) the oxygen base] phenyl] methyl propionate and 4-fluoro-2-aminomethyl phenyl boric acid obtains title compound clear crystal (productive rate 94%).
1H NMR(CDCl 3)δ：2.23(3H，s)，2.60(2H，t，J＝7.8Hz)，2.90(2H，t，J＝7.8Hz)，3.66(3H，s)，5.08(2H，s)，6.86-7.00(4H，m)，7.07-7.28(4H，m)，7.31-7.46(3H，m)。
Embodiment 35
3-[4-[(4 '-fluoro-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl] propionic acid
Figure A20048004213900853
According to embodiment 31 similar methods, by 3-[4-[(4 '-fluoro-2 '-methyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate obtains title compound clear crystal (productive rate 81%).
MS(APCI-)：363(M-H)
Embodiment 36
3-[4-[[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] methyl propionate
Figure A20048004213900861
0 ℃ be accompanied by stirring to 3-[4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate (0.20 gram, 0.51mmol), (0.099 milliliter of cellosolvo, 1.02mmol) and triphenylphosphine (0.18 gram, 0.67mmol) tetrahydrofuran (THF) (4.0 milliliters) solution in dropwise add azo-2-carboxylic acid's diethyl ester (40% toluene solution, 0.30 milliliter), and at room temperature stirred this mixture 12 hours.The concentrating under reduced pressure reaction mixture, and use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) purifying resistates, obtain title compound colorless oil (0.12g, productive rate 51%).
1H NMR(CDCl 3)δ：1.25(3H，t，J＝6.9Hz)，1.98(6H，s)，2.59(2H，t，J＝7.8Hz)，2.89(2H，t，J＝7.8Hz)，3.62(2H，q，J＝6.9Hz)，3.66(3H，s)，3.80(2H，t，J＝5.1Hz)，4.14(2H，t，J＝5.1Hz)，5.08(2H，s)，6.68(2H，s)，6.89(2H，d，J＝8.4Hz)，7.04-7.14(3H，m)，7.17(1H，s)，7.35-7.45(2H，m)。
Embodiment 37
3-[4-[[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] propionic acid
Figure A20048004213900862
With 3-[4-[[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] methyl propionate (0.12 gram, 0.26mmol) be dissolved in the mixing solutions of methyl alcohol (2 milliliters) and tetrahydrofuran (THF) (4 milliliters), and at room temperature add 1N aqueous sodium hydroxide solution (0.52mL), stir simultaneously.Mixture was stirred 2 hours under uniform temp.Reaction is used the ethyl acetate diluted reaction mixture after finishing, successively with 1N hydrochloric acid, water and saturated brine washing, dry and concentrating under reduced pressure.With hexane/ethyl acetate=4/1 crystalline residue, obtain title compound clear crystal (0.087g, productive rate 75%).
MS(APCI-)：447(M-H)
Embodiment 38
3-[4-[[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] methyl propionate
According to embodiment 36 similar methods, by 3-[4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate obtains the title compound (productive rate 63%) of colorless oil.
1H NMR(CDCl 3)δ：1.99(6H，s)，2.59(2H，t，J＝7.8Hz)，2.89(2H，t，J＝7.8Hz)，3.66(3H，s)，5.07(2H，s)，5.08(2H，s)，6.75(2H，s)，6.89(2H，d，J＝8.7Hz)，7.05-7.13(3H，m)，7.18(1H，s)，7.30-7.49(7H，m)。
Embodiment 39
3-[4-[[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] propionic acid
Figure A20048004213900872
According to embodiment 37 similar methods, by 3-[4-[[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] methyl propionate obtains title compound clear crystal (productive rate 91%).
MS(APCI-)：465(M-H)。
m.p.：123℃.
Embodiment 40
3-[4-[[4 '-(cyclo propyl methoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] methyl propionate
Figure A20048004213900873
According to embodiment 36 similar methods, by 3-[4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate and cyclopropyl-carbinol obtain the title compound (productive rate 69%) of colorless oil.
1H NMR(CDCl 3)δ：0.31-0.39(2H，m)，0.60-0.69(2H，m)，1.27(1H，m)，1.98(6H，s)，2.59(2H，t，J＝7.8Hz)，2.89(2H，t，J＝7.8Hz)，3.66(3H，s)，3.81(2H，d，J＝6.9Hz)，5.08(2H，s)，6.66(2H，s)，6.89(2H，d，J＝8.7Hz)，7.05-7.13(3H，m)，7.18(1H，s)，7.35-7.45(2H，m)。
Embodiment 41
3-[4-[[4 '-(cyclo propyl methoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] propionic acid
According to embodiment 37 similar methods, by 3-[4-[[4 '-(cyclo propyl methoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] methyl propionate obtains title compound clear crystal (productive rate 76%).
MS(APCI-)：429(M-H)
Embodiment 42
3-[4-[[4 '-[2-(dimethylamino) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] methyl propionate
According to embodiment 36 similar methods, by 3-[4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate and N, the N-dimethylethanolamine obtains the title compound (productive rate 38%) of colorless oil.
1H NMR(CDCl 3)δ：1.98(6H，s)，2.35(6H，s)，2.59(2H，t，J＝7.8Hz)，2.75(2H，t，J＝5.7Hz)，2.89(2H，t，J＝7.8Hz)，3.66(3H，s)，4.09(2H，t，J＝5.7Hz)，5.08(2H，s)，6.68(2H，s)，6.89(2H，d，J＝8.7Hz)，7.05-7.13(3H，m)，7.18(1H，s)，7.35-7.45(2H，m)。
Embodiment 43
3-[4-[[4 '-[2-(dimethylamino) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] the propionic acid trifluoroacetate
According to embodiment 37 similar methods, by 3-[4-[[4 '-[2-(dimethylamino) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] methyl propionate obtains title compound clear crystal (productive rate 87%).With this compound preparation HPLC purifying.
MS (APCI-): 446 (M-H is with free forms)
Embodiment 44
3-{4-[(2 ', 4 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } methyl propionate
According to embodiment 1 similar methods, by 3-(4-hydroxy phenyl) methyl propionate and (2 ', 4 '-dimethyl diphenyl-3-yl) methyl alcohol obtains title compound (productive rate 83%).
MS m/z 375(MH +)
Embodiment 45
3-{4-[(2 ', 4 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid
According to embodiment 2 similar methods, by 3-{4-[(2 ', 4 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate obtains title compound (productive rate 91%).
1H NMR(CDCl 3)δ：2.22(3H，s)，2.36(3H，s)，2.65(2H，t，J＝7.6Hz)，2.91(2H，t，J＝7.6Hz)，5.08(2H，s)，6.91(2H，d，J＝8.4Hz)，7.00-7.46(9H，m)。
Embodiment 46
3-{4-[(2 ', 4 ', 6 '-trimethylammonium biphenyl-3-yl) methoxyl group] phenyl } methyl propionate
Figure A20048004213900893
According to embodiment 1 similar methods, by 3-(4-hydroxy phenyl) methyl propionate and (2 ', 4 ', 6 '-trimethylammonium biphenyl-3-yl) methyl alcohol obtains title compound (productive rate 71%).
1H NMR(CDCl 3)δ：1.98(6H，s)，2.32(3H，s)，2.59(2H，t，J＝7.6Hz)，2.89(2H，t，J＝7.6Hz)，3.66(3H，s)，5.08(2H，s)，6.88(2H，d，J＝8.8Hz)，6.93(2H，s)，7.05-7.48(6H，m)。
Embodiment 47
3-{4-[(2 ', 4 ', 6 '-trimethylammonium biphenyl-3-yl) methoxyl group] phenyl } propionic acid
Figure A20048004213900901
According to embodiment 2 similar methods, by 3-{4-[(2 ', 4 ', 6 '-trimethylammonium biphenyl-3-yl) methoxyl group] phenyl methyl propionate obtains title compound (productive rate 88%).
1H NMR(CDCl 3)δ：1.98(6H，s)，2.32(3H，s)，2.64(2H，t，J＝7.4Hz)，2.90(2H，t，J＝7.4Hz)，5.08(2H，s)，6.89(2H，d，J＝8.8Hz)，6.93(2H，s)，7.04-7.48(6H，m)。
Embodiment 48
3-(4-((6-methoxyl group-2 ', 4 '-dimethyl diphenyl-3-yl) methoxyl group) phenyl) methyl propionate
Figure A20048004213900902
According to embodiment 1 similar methods, by 3-(4-hydroxy phenyl) methyl propionate and (6-methoxyl group-2 ', 4 '-dimethyl diphenyl-3-yl) methyl alcohol obtains title compound (productive rate 68%).
1H NMR(CDCl 3)δ：2.10(3H，s)，2.36(3H，s)，2.59(2H，t，J＝7.6Hz)，2.90(2H，t，J＝7.6Hz)，3.66(3H，s)，3.77(3H，s)，4.98(2H，s)，6.90(2H，d，J＝8.8Hz)，6.95(1H，d，J＝8.4Hz)，7.00-7.17(5H，m)，7.20(1H，d，J＝2.2Hz)，7.39(1H，dd，J＝2.2，8.4Hz)。
Embodiment 49
3-(4-((6-methoxyl group-2 ', 4 '-dimethyl diphenyl-3-yl) methoxyl group) phenyl) propionic acid
According to embodiment 2 similar methods, by 3-(4-((6-methoxyl group-2 ', 4 '-dimethyl diphenyl-3-yl) methoxyl group) phenyl) methyl propionate obtains title compound (productive rate 100%).
1H NMR(CDCl 3)δ：2.10(3H，s)，2.36(3H，s)，2.65(2H，t，J＝7.6Hz)，2.91(2H，t，J＝7.6Hz)，3.77(3H，s)，4.99(2H，s)，6.84-7.18(8H，m)，7.20(1H，d，J＝2.2Hz)，7.39(1H，dd，J＝2.6，8.4Hz)。
Embodiment 50
3-{2-fluoro-4-[(2 ', 4 ', 6 '-trimethylammonium biphenyl-3-yl) methoxyl group] phenyl } ethyl propionate
Figure A20048004213900911
According to embodiment 1 similar methods, by 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate and (2 ', 4 ', 6 '-trimethylammonium biphenyl-3-yl) methyl alcohol obtains title compound (productive rate 74%).
MS m/z 421(MH +)
Embodiment 51
3-{2-fluoro-4-[(2 ', 4 ', 6 '-trimethylammonium biphenyl-3-yl) methoxyl group] phenyl } propionic acid
Figure A20048004213900912
According to embodiment 2 similar methods, by 3-{2-fluoro-4-[(2 ', 4 ', 6 '-trimethylammonium biphenyl-3-yl) methoxyl group] phenyl ethyl propionate obtains title compound (productive rate 77%).
APCI(-)391(M-H)
Embodiment 52 and 53
3-{2-fluoro-4-[(2 '-(4-fluorophenoxy methyl)-4 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } ethyl propionate (embodiment 52) and 3-{2-fluoro-4-[(4 '-(4-fluorophenoxy methyl)-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } mixture of ethyl propionate (embodiment 53)
To the mixture that obtains in reference example 23 (0.74 gram, 2.20mmol), 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate (0.47 the gram, 2.21mmol) and (0.71 milliliter of tributylphosphine, 2.85mmol) in the solution in anhydrous tetrahydro furan (40 milliliters), divide little part to add 1,1 '-(0.72 gram 2.85mmol), and at room temperature stirred mixture 18 hours (azo dicarbapentaborane) connection piperidines.Reaction mixture is diluted with ether (40 milliliters), and, then filtrate decompression is concentrated sedimentation and filtration.(ethyl acetate: hexane=1: 10-1: 5) purifying obtains the mixture light yellow oil (1.08 grams, productive rate 93%) of title compound by silica gel column chromatography with the resistates that obtains.Mixture just need not be separated to be used for subsequent reactions.
MS m/z 531(MH +)
Embodiment 54 and 55
3-{2-fluoro-4-[(2 '-(4-fluorobenzene oxygen methyl)-4 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid (embodiment 54) and 3-{2-fluoro-4-[(4 '-(4-fluorophenoxy methyl)-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid (embodiment 55)
The 3-{2-fluoro-4-[(2 ' that will in embodiment 52 and 53, obtain-(4-fluorophenoxy methyl)-4 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } ethyl propionate and 3-{2-fluoro-4-[(4 '-(4-fluorobenzene oxygen methyl)-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } (1.08 grams 2.04mmol) are dissolved in the mixed solvent of tetrahydrofuran (THF) (10 milliliters) and ethanol (10 milliliters) the ethyl propionate mixture.In this solution, add 85% potassium hydroxide (0.34 gram, the 5.15mmol) aqueous solution (5 milliliters), and mixture at room temperature stirred 18 hours.With ethyl acetate diluting reaction solution, with aqueous citric acid solution, water and saturated brine washing, use dried over mgso, concentrating under reduced pressure successively.The resistates that obtains is applied to chiral column (CHIRALPAK) chromatogram (hexane: Virahol: acetate=94: 6: 0.1) go up with each steric isomer of purifying.
Acquisition 3-{2-fluoro-4-[(2 '-(4-fluorophenoxy methyl)-4 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid (657 milligrams, productive rate 64%), be light yellow oil.
1H NMR(CDCl 3)δ：2.03(3H，s)，2.38(3H，s)，2.63(2H，t，J＝7.4Hz)，2.90(2H，t，J＝7.4Hz)，4.59(2H，s)，5.00(2H，s)，6.57-7.18(9H，m)，7.23(2H，br s)，7.30-7.44(2H，m)。
Figure A20048004213900921
Obtain colourless prismatic crystalline 3-{2-fluoro-4-[(4 '-(4-fluorophenoxy methyl)-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl propionic acid (141 milligrams, productive rate 14%).
1H NMR(CDCl 3)δ：2.02(6H，s)，2.05-3.00(4H，m)，4.97(2H，s)，5.07(2H，s)，6.62-6.72(2H，m)，6.90-7.14(7H，m)，7.16(2H，s)，7.36-7.50(2H，m)。
Figure A20048004213900931
Embodiment 56
3-{4-[(4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } the propionic acid tert-butyl ester
Figure A20048004213900932
By (4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-2 ', 6 '-methyl diphenyl-3-yl) methyl alcohol and 3-(4-hydroxy phenyl) the propionic acid tert-butyl ester, obtain the title compound (productive rate 87%) of light yellow oil according to method similar to Example 1.
1H NMR(CDCl 3)δ：0.23(6H，s)，1.00(9H，s)，1.41(9H，s)，1.95(6H，s)，2.49(2H，t，J＝7.8Hz)，2.84(2H，t，J＝7.8Hz)，5.07(2H，s)，6.58(2H，s)，6.89(2H，d，J＝8.4Hz)，7.01-7.14(3H，m)，7.18(1H，s)，7.33-7.46(2H，m)。
Embodiment 57
3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } the propionic acid tert-butyl ester
Figure A20048004213900933
In room temperature, stir under to 3-{4-[(4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } the propionic acid tert-butyl ester (2.38 grams, 4.35mmol) add four fourth Neutral ammonium fluoride (1M tetrahydrofuran solutions in the solution in tetrahydrofuran (THF) (24 milliliters), 4.79mmol, 4.79 milliliter), and with mixture at room temperature stirred 2 hours.With reaction mixture thing concentrating under reduced pressure, and resistates distributed between water and ethyl acetate.With the organic layer anhydrous magnesium sulfate drying, and concentrating under reduced pressure.Resistates by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) purifying, is obtained the title compound (1.69 grams, productive rate 90%) of colorless oil.
1H NMR(CDCl 3)δ：1.41(9H，s)，1.96(6H，s)，2.50(2H，t，J＝7.8Hz)，2.84(2H，t，J＝7.8Hz)，5.08(2H，s)，6.59(2H，s)，6.89(2H，d，J＝8.7Hz)，7.04-7.14(3H，m)，7.18(1H，s)，7.35-7.45(2H，m)。
Embodiment 58
3-[4-(4 '-[2-oxyethyl group-1-(ethoxyl methyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
By 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate and 1,3-diethoxy propan-2-ol, according to embodiment 1 similar methods, obtain (productive rate 65%) of the title compound of colorless oil.
MS m/z 553(MH +)
Embodiment 59
3-[4-(4 '-[2-oxyethyl group-1-(ethoxyl methyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid
To 3-[4-(4 '-[2-oxyethyl group-1-(ethoxyl methyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate (0.665 gram, 1.20mmol) add 2M aqueous sodium hydroxide solution (2 milliliters) in the mixing solutions in ethanol (6 milliliters) and tetrahydrofuran (THF) (6 milliliters), and mixture was at room temperature stirred 72 hours.Water is joined in the reaction mixture, and, use ethyl acetate extraction with 10% aqueous citric acid solution neutralise mixt.Wash extract with saturated brine, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.Resistates by silica gel column chromatography (20%-80% ethyl acetate/hexane) purifying, is obtained the colourless viscosity oily matter of title compound (0.588g, productive rate 93%).
MS m/z 525(MH +)
Embodiment 60
3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid amide
Figure A20048004213900951
With 3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid (0.233 gram, 0.500mmol), (0.4 milliliter of 7M ammonia/methyl alcohol, 2.80mmol) solution, 1-ethyl-3-(3-aminopropyl) carbodiimide hydrochloride (2.88 grams, 1.50mmol), I-hydroxybenzotriazole (0.230 gram, 1.50mmol), 1, (0.448 milliliter of 8-diazabicyclo [5.4.0]-7-undecylene, 3.00mmol), triethylamine (0.502 milliliter, 3.60mmol) and the mixture of acetonitrile (3 milliliters) at room temperature stirred 27 hours.Reaction mixture is poured in the saturated sodium bicarbonate aqueous solution, and with the mixture ethyl acetate extraction.Wash extract with saturated brine, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.Resistates by alkaline silica gel column chromatography (50% ethyl acetate/hexane-ethyl acetate) purifying, is obtained title compound (0.186g, productive rate 80%), be colorless oil.
MS m/z 466(MH +)
Embodiment 61
1-[3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionyl] tetramethyleneimine
According to embodiment 60 similar methods, by 3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group-the 2-fluorophenyl) propionic acid and tetramethyleneimine obtain the title compound (productive rate 95%) of yellow oil.
MS m/z 520(MH +)
Embodiment 62
3-(4-{[4 '-(methoxymethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } phenyl) propionic acid
Figure A20048004213900961
Room temperature under stirring to 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } methyl propionate (0.50 gram, 1.28mmol), salt of wormwood (0.35 gram, 2.56mmol) and sodium iodide (0.19 the gram, 1.28mmol) at N, add (0.13 milliliter of chloromethyl methyl ether in the solution of dinethylformamide (5.0 milliliters), 1.66mmol), and mixture stirred 24 hours at 50 ℃.Use the ethyl acetate diluted reaction mixture, water and saturated brine washing, dry and concentrating under reduced pressure.Resistates by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) purifying, is obtained colorless oil.Then, in the mixture of this oily matter, methyl alcohol (4 milliliters) and tetrahydrofuran (THF) (8 milliliters), add 1N aqueous sodium hydroxide solution (2.6 milliliters) in room temperature and under stirring, and mixture was stirred 2 hours under uniform temp.With 1N hydrochloric acid conditioned reaction mixture pH to 3, with the ethyl acetate dilution, with the saturated brine washing, dry and concentrating under reduced pressure.Use silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/2) purifying resistates, obtain title compound clear crystal (0.12g, productive rate 22%).
MS(APCI-)：419(M-H)
Embodiment 63
3-{4-[(4 '-oxyethyl group-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid
According to embodiment 62 similar methods, by 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and iodoethane obtain title compound clear crystal (productive rate 14%).
MS(APCI-)：403(M-H)
Embodiment 64
3-(4-{[4 '-(2-butoxy oxyethyl group)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } phenyl) propionic acid
Figure A20048004213900971
According to embodiment 62 similar methods, by 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and 2-chloroethyl n-butyl ether obtain title compound clear crystal (productive rate 66%).
MS(APCI-)：475(M-H)
Embodiment 65
3-[4-(4 '-[2-(benzyloxy) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] propionic acid
Figure A20048004213900972
0 ℃ be accompanied by stirring to 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } methyl propionate (0.50 gram, 1.28mmol), (0.20 milliliter of 2-(benzyloxy) ethanol, 1.41mmol) and (0.48 milliliter of tributylphosphine, 1.92mmol) tetrahydrofuran (THF) (10 milliliters) solution in add 1,1 '-(azo dicarbapentaborane) connection piperidines (0.48 gram, 1.92mmol).This reaction mixture was at room temperature stirred 18 hours, and under uniform temp, add the mentioned reagent (2-(benzyloxy) ethanol, tributylphosphine and 1,1 '-(azo dicarbapentaborane) connection piperidines) of equal quantities, further stirred this mixture 18 hours.Ether is joined in the reaction mixture, and leach insoluble substance.Concentrating under reduced pressure filtrate, and use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) purifying resistates, obtain colorless oil.Then, in the mixture of this oily matter, methyl alcohol (4 milliliters) and tetrahydrofuran (THF) (8 milliliters), add 1N aqueous sodium hydroxide solution (2.6 milliliters) in room temperature and under stirring, and mixture was stirred 2 hours under uniform temp.With 1N hydrochloric acid neutralization reaction mixture, with the ethyl acetate dilution, with the saturated brine washing, dry and concentrating under reduced pressure.Use silica gel column chromatography (hexane/ethyl acetate=4/1-hexane/ethyl acetate=1/2) purifying resistates, obtain title compound clear crystal (0.26g, productive rate 39%).
MS(APCI-)：509(M-H)
Embodiment 66
3-(4-{[2 ', 6 '-dimethyl-4 '-(3-pyridine-2-base propoxy-) biphenyl-3-yl] methoxyl group } phenyl) propionic acid
Figure A20048004213900981
According to embodiment 65 similar methods, by 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and 3-(pyridine-2-yl) third-1-alcohol obtains the title compound (productive rate 28%) of colorless oil.
MS(APCI-)：494(M-H)
Embodiment 67
3-{4-[(4 '-butoxy-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } propionic acid
Figure A20048004213900982
According to embodiment 65 similar methods, by 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and 1-butanols obtain title compound clear crystal (productive rate 45%).
MS(APCI-)：431(M-H)
Embodiment 68
3-[4-(4 '-[2-(ethylmercapto group) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] methyl propionate
Figure A20048004213900983
According to embodiment 1 similar methods, by 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and 2-(ethylmercapto group) ethanol obtains the title compound (productive rate 64%) of light yellow oil.
1H NMR(CDCl 3)δ：1.31(3H，t，J＝7.2Hz)，1.98(6H，s)，2.59(2H，t，J＝7.8Hz)，2.67(2H，q，J＝7.2Hz)，2.85-2.97(4H，m)，3.66(3H，s)，4.15(2H，t，J＝6.9Hz)，5.08(2H，s)，6.66(2H，s)，6.89(2H，d，J＝8.7Hz)，7.04-7.14(3H，m)，7.17(1H，s)，7.35-7.47(2H，m)。
Embodiment 69
3-[4-(4 '-[2-(ethylmercapto group) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] propionic acid
According to embodiment 37 similar methods, by 3-[4-(4 '-[2-(ethylmercapto group) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl methoxyl group) phenyl] methyl propionate is by obtaining title compound clear crystal (productive rate 47%).
MS(APCI-)：463(M-H)。
Embodiment 70
3-[4-(4 '-[2-(ethylmercapto group) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] the propionic acid tertiary butyl ester
Figure A20048004213900992
At room temperature be accompanied by stirring to 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } the propionic acid tert-butyl ester (1.69 grams, 3.91mmol), (0.46 milliliter of 2-(ethylmercapto group) ethanol, 4.30mmol) and (1.46 milliliters of tributylphosphines, 5.86mmol) tetrahydrofuran (THF) (33 milliliters) solution in add 1,1 '-(azo dicarbapentaborane) connection piperidines (1.48 grams, 5.86mmol).This reaction mixture was at room temperature stirred 16 hours, and the mentioned reagent (2-(ethylmercapto group) ethanol, the tributylphosphine and 1 that under uniform temp, add equal quantities, 1 '-(azo dicarbapentaborane) connection piperidines), further under uniform temp, stirred this mixture 16 hours.Ether is joined in the reaction mixture, and leach insoluble substance.Concentrating under reduced pressure filtrate, and use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) purifying resistates, obtain the title compound (1.40g, productive rate 69%) of colorless oil.
1H NMR(CDCl 3)δ：1.31(3H，t，J＝7.2Hz)，1.41(9H，s)，1.99(6H，s)，2.49(2H，t，J＝7.8Hz)，2.67(2H，q，J＝7.2Hz)，2.84(2H，t，J＝7.8Hz)，2.92(2H，t，J＝6.9Hz)，4.15(2H，t，J＝6.9Hz)，5.08(2H，s)，6.66(2H，s)，6.89(2H，d，J＝8.7Hz)，7.05-7.14(3H，m)，7.18(1H，s)，7.35-7.45(2H，m)。
Embodiment 71
3-[4-(4 '-[2-(ethylsulfonyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] the propionic acid tert-butyl ester
0 ℃ be accompanied by stirring to 3-[4-(4 '-[2-(ethylmercapto group) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] the propionic acid tert-butyl ester (0.70 gram, 1.34mmol) methylene dichloride (14 milliliters) solution in add metachloroperbenzoic acid (0.73 the gram, 2.96mmol), and under uniform temp, stirred this mixture 2 hours.With aqueous sodium hydroxide solution and saturated brine washing reaction mixture, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.Use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) purifying resistates, obtain the title compound (0.67g, productive rate 74%) of light yellow oil.
1H NMR(CDCl 3)δ：1.41(9H，s)，1.47(3H，t，J＝7.5Hz)，1.99(6H，s)，2.49(2H，t，J＝7.8Hz)，2.84(2H，t，J＝7.8Hz)，3.19(2H，q，J＝7.5Hz)，3.42(2H，t，J＝5.1Hz)，4.44(2H，t，J＝5.1Hz)，5.08(2H，s)，6.64(2H，s)，6.88(2H，d，J＝8.7Hz)，7.03-7.14(3H，m)，7.17(1H，s)，7.36-7.48(2H，m)。
Embodiment 72
3-[4-(4 '-[2-(ethylsulfonyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] propionic acid
Figure A20048004213901002
At room temperature be accompanied by stirring to 3-[4-(4 '-[2-(ethylsulfonyl) oxyethyl group]-2 '; 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] the propionic acid tert-butyl ester (0.37 gram; 0.67mmol) toluene (3.7 milliliters) solution in add trifluoroacetic acid (3.7 milliliters), and at room temperature stirred this mixture 2 hours.This reaction mixture of concentrating under reduced pressure is collected the crystal that obtains by filtering, and washing is also dry, obtains title compound clear crystal (0.24g, productive rate 72%).
MS(APCI-)：495(M-H)
Embodiment 73
3-[4-(2 ', 6 '-dimethyl-4 '-[3-(6-picoline-2-yl) propoxy-] biphenyl-3-yl } methoxyl group) phenyl] propionic acid
According to embodiment 65 similar methods, by 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and 3-(6-picoline-2-yl) third-1-alcohol obtains the title compound (productive rate 17%) of light yellow oil.
MS(APCI-)：508(M-H)
Embodiment 74
3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } phenyl)-2,2-difluoro ethyl propionate
According to embodiment 1 similar methods, by 2,2-two fluoro-3-(4-hydroxy phenyl) ethyl propionate and [4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol obtains title compound colorless oil (productive rate 51%).
MS m/z 513(MH +)
Embodiment 75
3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } phenyl)-2,2-difluoro propionic acid
According to embodiment 2 similar methods, by 3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group phenyl)-2,2-difluoro ethyl propionate obtains the title compound (productive rate 79%) of colorless oil.
MS m/z 485(MH +)。
1H NMR(CDCl 3)δ：1.21-1.30(3H，m)，1.95(6H，s)，3.25(2H，t，J＝16.7Hz)，3.63(2H，q，J＝7.0Hz)，3.77-3.85(2H，m)，4.07-4.19(2H，m)，5.02(2H，s)，6.66(2H，s)，6.87(2H，d，J＝8.5Hz)，7.02-7.20(4H，m)，7.30-7.43(2H，m)。
Embodiment 76
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-thiapyran-4-base oxygen base) biphenyl-3-yl] methoxyl group } phenyl) methyl propionate
According to embodiment 1 similar methods, by 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl methyl propionate and tetrahydrochysene-2H-thiapyran-4-alcohol obtains the title compound (productive rate 12%) of colorless oil.
1H NMR(CDCl 3)δ：1.98(6H，s)，1.99-2.11(2H，m)，2.15-2.27(2H，m)，2.53-2.65(4H，m)，2.84-3.01(4H，m)，3.66(3H，s)，4.37(1H，m)，5.08(2H，s)，6.65(2H，s)，6.89(2H，d，J＝8.7Hz)，7.05-7.14(3H，m)，7.18(1H，s)，7.35-7.46(2H，m)。
Embodiment 77
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-thiapyran-4-base oxygen base) biphenyl-3-yl] methoxyl group } phenyl) propionic acid
According to embodiment 37 similar methods, by 3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-thiapyran-4-base oxygen base) biphenyl-3-yl] methoxyl group phenyl) methyl propionate obtains title compound clear crystal (productive rate 55%).
MS(ESI+)：477(M+H)
Embodiment 78
3-[4-(4 '-[(1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] propionic acid
Figure A20048004213901031
0 ℃ be accompanied by stirring to 3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-thiapyran-4-base oxygen base) biphenyl-3-yl] methoxyl group } phenyl) methyl propionate (0.11 gram, 0.22mmol) methylene dichloride (2.2 milliliters) solution in add metachloroperbenzoic acid (0.12 the gram, 0.49mmol), and under uniform temp, stirred this mixture 2 hours.With aqueous sodium hydroxide solution and the saturated brine washing reaction mixture of 1N, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.At room temperature be accompanied by stirring and in the mixture of resistates, methyl alcohol (2 milliliters) and tetrahydrofuran (THF) (4 milliliters), add 1N aqueous sodium hydroxide solution (0.44 milliliter), and under uniform temp, stirred this mixture 2 hours.Use the ethyl acetate diluted reaction mixture, with 1N hydrochloric acid and saturated brine washing, dry and concentrating under reduced pressure.Use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) purifying resistates, obtain title compound clear crystal (43mg, productive rate 38%).
MS(ESI+)：509(M+H)。
Embodiment 79
3-[4-(2 ', 6 '-dimethyl-4 '-[3-(6-picoline-2-yl) propoxy-] biphenyl-3-yl } methoxyl group) phenyl] the propionic salt hydrochlorate
Figure A20048004213901032
To 3-[4-(2 ', 6 '-dimethyl-4 '-[3-(6-picoline-2-yl) propoxy-] biphenyl-3-yl } methoxyl group) phenyl] (55 milligrams of propionic acid, 0.11mmol) ethyl acetate (2.2 milliliters) solution in add 4N hydrochloric acid-ethyl acetate solution (81 μ L, 0.32mmol), and this mixture of concentrating under reduced pressure.Collect the crystal that obtains by filtering, washing is also dry, obtains title compound clear crystal (42mg, productive rate 71%).
MS (ESI+): 510 (M+H is with free forms)
Embodiment 80
3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) methoxyl group] biphenyl-3-yl } methoxyl group) phenyl] the propionic salt hydrochlorate
Figure A20048004213901041
At room temperature be accompanied by stirring to 3-{4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } methyl propionate (0.40 gram, 1.03mmol), (6-picoline-2-yl) methyl alcohol (0.14 the gram, 1.13mmol) and triphenylphosphine (0.34 gram, 1.31mmol) tetrahydrofuran (THF) (8.0 milliliters) solution in add diisopropyl azo-2-carboxylic acid's (40% toluene solution, 0.59 milliliter, 1.13mmol).This reaction mixture was at room temperature stirred 12 hours, and the mentioned reagent ((6-picoline-2-yl) methyl alcohol, triphenylphosphine and diisopropyl azo-2-carboxylic acid) that adds equal quantities under uniform temp further stirred this mixture 12 hours under uniform temp.The concentrating under reduced pressure reaction mixture, and use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) purifying resistates, obtain colorless oil.Then, in the mixture of this oily matter, methyl alcohol (4 milliliters) and tetrahydrofuran (THF) (8 milliliters), add 1N aqueous sodium hydroxide solution (2.1 milliliters) in room temperature and under stirring, and mixture was stirred 2 hours under uniform temp.With 1N hydrochloric acid neutralization reaction mixture, with the ethyl acetate dilution, with the saturated brine washing, dry and concentrating under reduced pressure.Resistates by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/4) purifying, is obtained colorless oil.Oily matter is dissolved in the ethyl acetate, and adds 4N hydrochloric acid-ethyl acetate solution.With the mixture concentrating under reduced pressure.Collect the crystal that obtains by filtering, washing is also dry, obtains title compound clear crystal (0.24g, productive rate 44%).
MS (APCI-): 480 (M-H is with free forms)
Embodiment 81
3-[4-(2 ', 6 '-dimethyl-4 '-[2-(6-picoline-2-yl) oxyethyl group] biphenyl-3-yl } methoxyl group) phenyl] the propionic salt hydrochlorate
According to embodiment 80 similar methods, by 3-[4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl] methyl propionate and 2-(6-picoline-2-yl) ethanol obtains title compound clear crystal (productive rate 26%).
MS (APCI-): 494 (M-H, free forms)
Embodiment 82
3-{4-[(2 ', 6 '-dimethyl-4 '-nitrobiphenyl-3-yl) methoxyl group]-the 2-fluorophenyl } ethyl propionate
Figure A20048004213901051
According to embodiment 1 similar methods, by (2 ', 6 '-dimethyl-4 '-nitrobiphenyl-3-yl) methyl alcohol and 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate obtain the title compound (productive rate 97%) of light yellow oil.
MS(ESI+)：452(M+H)
Embodiment 83
3-{4-[(2 ', 6 '-dimethyl-4 '-nitrobiphenyl-3-yl) methoxyl group]-the 2-fluorophenyl } propionic acid
Figure A20048004213901052
According to embodiment 37 similar methods, by 3-{4-[(2 ', 6 '-dimethyl-4 '-nitrobiphenyl-3-yl) methoxyl group]-the 2-fluorophenyl ethyl propionate obtains title compound clear crystal (productive rate 84%).
MS(APCI-)：422(M-H)
Embodiment 84
3-[4-(4 '-[2-(ethylmercapto group) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
Figure A20048004213901053
According to embodiment 70 similar methods, by 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate and 2-(ethylmercapto group) ethanol obtains the title compound (productive rate 79%) of colorless oil.
1H NMR(CDCl 3)δ：1.23(3H，t，J＝7.2Hz)，1.31(3H，t，J＝7.5Hz)，1.98(6H，s)，2.57(2H，t，J＝7.8Hz)，2.67(2H，q，J＝7.5Hz)，2.86-2.96(4H，m)，4.07-4.19(4H，m)，5.06(2H，s)，6.62-6.71(4H，m)，7.04-7.13(2H，m)，7.16(1H，s)，7.33-7.47(2H，m)。
Embodiment 85
3-[4-(4 '-[2-(ethylsulfonyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
Figure A20048004213901061
According to embodiment 71 similar methods, by 3-[4-(4 '-[2-(ethylmercapto group) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl methoxyl group)-the 2-fluorophenyl] ethyl propionate obtains the title compound (productive rate 89%) of colorless oil.
MS(ESI+)：543(M+H)
Embodiment 86
3-[4-(4 '-[2-(ethylsulfonyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid
Figure A20048004213901062
With 3-[4-(4 '-[2-(ethylsulfonyl) oxyethyl group]-2 '; 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] and ethyl propionate (0.19 gram, 0.35mmol), the mixture of acetate (4.5 milliliters), water (4.0 milliliters) and the vitriol oil (0.65 milliliter) is 90 ℃ of stirrings 4 hours.Reaction mixture, with the ethyl acetate dilution, water and saturated brine washing, dry and concentrating under reduced pressure.Use silica gel column chromatography (hexane/ethyl acetate=4/1-ethyl acetate) purifying resistates, obtain title compound clear crystal (0.12g, productive rate 61%).
MS(APCI-)：513(M-H).
m.p.：126-127℃.
Embodiment 87
3-[4-(4 '-[2-(diethylamino) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
According to embodiment 70 similar methods, by 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate and 2-(diethylamino) ethanol obtains the title compound (productive rate 100%) of colorless oil.
MS(ESI+)：522(M+H)
Embodiment 88
3-[4-(4 '-[2-(diethylamino) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] the propionic salt hydrochlorate
Figure A20048004213901072
In room temperature and under stirring, to 3-[4-(4 '-[2-(diethylamino) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate (0.62 gram, 1.18mmol), add 1N aqueous sodium hydroxide solution (2.4 milliliters) in the mixture of methyl alcohol (5 milliliters) and tetrahydrofuran (THF) (10 milliliters), and under uniform temp, stirred this mixture 2 hours.With 1N hydrochloric acid neutralization reaction mixture, with the ethyl acetate dilution, with the saturated brine washing, dry and concentrating under reduced pressure.By preparation HPLC purifying resistates, obtain colorless oil.This oily matter is dissolved in the ethyl acetate, with the saturated sodium bicarbonate aqueous solution neutralization, water and saturated brine washing, dry and concentrating under reduced pressure.Resistates is dissolved in the ethyl acetate, and adds 4N hydrochloric acid-ethyl acetate solution.By filtering the crystal of collecting precipitation, washing is also dry, obtains title compound clear crystal (0.20g, productive rate 32%).
MS (ESI+): 494 (M+H is with free forms)
Embodiment 89
3-[4-(2 ', 6 '-dimethyl-4 '-[3-(2-oxo-pyrrolidine-1-yl) propoxy-] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
By 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } ethyl propionate and 1-(3-hydroxypropyl) pyrrolidin-2-one, according to embodiment 1 similar methods, obtain the colorless oil (productive rate 67%) of title compound.
MS(ESI+)：548(M+H)
Embodiment 90
3-[4-(2 ', 6 '-dimethyl-4 '-[3-(2-oxo-pyrrolidine-1-yl) propoxy-] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid
Figure A20048004213901082
According to embodiment 37 similar methods, by 3-[4-(2 ', 6 '-dimethyl-4 '-[3-(2-oxo-pyrrolidine-1-yl) propoxy-] biphenyl-3-yl methoxyl group)-the 2-fluorophenyl] ethyl propionate obtains the clear crystal (productive rate 64%) of title compound.This compound is passed through preparation HPLC purifying (gradient circulation A).
MS(ESI+)：520(M+H)。
m.p.：139-140℃.
Embodiment 91
3-(2-fluoro-4-{[4 '-(methoxymethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } phenyl) ethyl propionate
Figure A20048004213901083
According to embodiment 1 similar methods, by [4 '-(methoxymethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol and 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate obtain title compound colorless oil (productive rate 82%).
1H NMR(CDCl 3)δ：1.23(3H，t，J＝7.2Hz)，1.99(6H，s)，2.57(2H，t，J＝7.6Hz)，2.90(2H，t，J＝7.6Hz)，3.51(3H，s)，4.12(2H，q，J＝7.2Hz)，5.06(2H，s)，5.19(2H，s)，6.60-6.75(2H，m)，6.80(2H，s)，7.02-7.50(5H，m)。
Embodiment 92
3-(2-fluoro-4-{[4 '-(methoxymethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } phenyl) propionic acid
Figure A20048004213901091
According to embodiment 2 similar methods, by 3-(2-fluoro-4-{[4 '-(methoxymethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group phenyl) ethyl propionate obtains the colourless needle crystals of title compound (productive rate 88%).
MS m/z 437(MH+)
Embodiment 93
3-[4-(4 '-[2-(ethylamino-) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
Figure A20048004213901092
In room temperature and under stirring, to 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } ethyl propionate (0.50 gram, 1.18mmol), (0.10 milliliter of 2-ethylaminoethyl alcohol, 1.30mmol) and (0.44 milliliter of tributylphosphine, 1.78mmol) tetrahydrofuran (THF) (10 milliliters) solution in add 1,1 '-(azo dicarbapentaborane) connection piperidines (0.45 gram, 1.78mmol).This reaction mixture was at room temperature stirred 16 hours, add the mentioned reagent (2-ethylaminoethyl alcohol, tributylphosphine and 1,1 '-(azo dicarbapentaborane) connection piperidines) of equal quantities, further under uniform temp, stirred this mixture 16 hours.Ether is joined in the reaction mixture, and leach insoluble substance.Concentrating under reduced pressure filtrate, and use HPLC (gradient circulation A) the purifying resistates for preparing, obtain colorless oil.The oily matter that obtains is dissolved in the ethyl acetate, with the saturated sodium bicarbonate aqueous solution neutralization, water and saturated brine washing, drying is concentrating under reduced pressure also, obtains the title compound (0.52g, productive rate 58%) of colorless oil.
MS(ESI+)：494(M+H)
Embodiment 94
3-{4-[(4 '-and 2-[ethanoyl (ethyl) amino] oxyethyl group }-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group]-the 2-fluorophenyl } ethyl propionate
With 3-[4-(4 '-[2-(ethylamino-) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate (0.27 gram, 0.55mmol), (7 milligrams of 4-dimethylaminopyridines, 55 μ mol), diacetyl oxide (0.10 milliliter, 1.09mmol) and the mixture of pyridine (5.4 milliliters) at room temperature stirred 62 hours.Concentrate this reaction mixture, and use silica gel column chromatography (hexane/ethyl acetate=9/1-ethyl acetate) purifying resistates, obtain the title compound (0.25g, productive rate 85%) of colorless oil.
MS(ESI+)：536(M+H)
Embodiment 95
3-{4-[(4 '-and 2-[ethanoyl (ethyl) amino] oxyethyl group }-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group]-the 2-fluorophenyl } propionic acid
Figure A20048004213901102
According to embodiment 37 similar methods, by 3-{4-[(4 '-{ 2-[ethanoyl (ethyl) amino] oxyethyl group }-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group]-the 2-fluorophenyl ethyl propionate obtains title compound clear crystal (productive rate 51%).
MS(ESI+)：508(M+H)
Embodiment 96
3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
In room temperature and under stirring, to 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } ethyl propionate (1.2 grams, 2.84mmol), (6-picoline-2-yl) methyl alcohol (0.39 the gram, 3.12mmol) and triphenylphosphine (0.95 gram, 3.61mmol) tetrahydrofuran (THF) (24 milliliters) solution in add azo-2-carboxylic acid's diisopropyl ester (40% toluene solution, 1.54 milliliters, 3.12mmol).This reaction mixture was at room temperature stirred 12 hours, and add the mentioned reagent ((6-picoline-2-yl) methyl alcohol, triphenylphosphine and diisopropyl azo-2-carboxylic acid) of equal quantities.This mixture was further stirred 12 hours under uniform temp.The concentrating under reduced pressure reaction mixture, and use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=1/1) purifying resistates, obtain title compound colorless oil (1.3g, productive rate 87%).
MS(ESI+)：528(M+H)
Embodiment 97
3-[4-(2 ', 6-dimethyl-4 '-[(6-picoline-2-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] the propionic salt hydrochlorate
Figure A20048004213901112
In room temperature and under stirring, to 3-[4-(2 ', 6-dimethyl-4 '-[(6-picoline-2-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate (1.30 grams, 2.46mmol), add 1N aqueous sodium hydroxide solution (4.9 milliliters) in the mixture of methyl alcohol (6 milliliters) and tetrahydrofuran (THF) (10 milliliters), and under uniform temp, stirred this mixture 2 hours.With 1N hydrochloric acid neutralization reaction mixture, with the ethyl acetate dilution, with the saturated brine washing, dry and concentrating under reduced pressure.Resistates by silica gel column chromatography (hexane/ethyl acetate=4/1-ethyl acetate) purifying, is obtained colorless oil.Oily matter is dissolved in the ethyl acetate, and adds 4N hydrogenchloride-ethyl acetate solution.By filtering the crystal of collecting precipitation, washing is also dry, obtains title compound clear crystal (1.14g, productive rate 86%).
MS (ESI+): 500 (M+H, free forms).
m.p.：55-56℃。
Embodiment 98
3-[2-fluoro-4-(4 '-[(4-hydroxy tetrahydro-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] ethyl propionate
Figure A20048004213901121
In room temperature and under stirring, to 4-([3 '-(methylol)-2,6-dimethyl diphenyl-4-yl] the oxygen base } methyl) tetrahydrochysene-2H-thiapyran-4-alcohol (0.90 gram, 2.51mmol), 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate (0.56 the gram, 2.64mmol) and tributylphosphine (0.86 milliliter, add 1,1 in tetrahydrofuran (THF) 3.26mmol) (20 milliliters) solution '-(azo dicarbapentaborane) connection piperidines (0.85 gram, 3.26mmol), and stirred this mixture 10 hours.Leach the precipitation that obtains, and filtrate decompression is concentrated.Resistates by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) purifying, is obtained the title compound (1.24 grams, productive rate 89%) of colorless oil.
1H NMR(CDCl 3)δ：1.23(3H，t，J＝7.2Hz)，1.75-1.90(2H，m)，1.99(6H，s)，2.05-2.16(2H，m，J＝13.9Hz)，2.19(1H，s)，2.39-2.52(2H，m)，2.57(2H，t，J＝7.6Hz)，2.89(2H，t，J＝7.6Hz)，3.03-3.19(2H，m)，3.79(2H，s)，4.12(2H，q，J＝7.2Hz)，5.06(2H，s)，6.60-6.73(4H，m)，7.01-7.19(3H，m)，7.33-7.48(2H，m)。
Embodiment 99
3-[2-fluoro-4-(4 '-[(4-hydroxyl-1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] ethyl propionate
According to embodiment 71 similar methods, by 3-[2-fluoro-4-(4 '-[(4-hydroxy tetrahydro-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl-3-yl methoxyl group) phenyl] ethyl propionate obtains title compound clear crystal (productive rate 72%).
MS m/z 585(MH +)
Embodiment 100
3-[2-fluoro-4-(4 '-[(4-hydroxyl-1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] propionic acid
Figure A20048004213901131
According to embodiment 37 similar methods, by 3-[2-fluoro-4-(4 '-[(4-hydroxyl-1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] ethyl propionate obtains title compound clear crystal (productive rate 78%).
MS m/z 557(MH +)。
m.p.：198-199℃.
Embodiment 101
3-[4-(2 ', 6 '-dimethyl-4 '-[(methyl sulphonyl) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
To ice-cooled 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate (310 milligrams, dropwise add in pyridine 0.736mmol) (8 milliliters) solution methylsulfonyl chloride (168 milligrams, 1.47mmol).Mixture was at room temperature stirred 2 days.Add entry, and with this mixture of ethyl acetate extraction.Wash extract with saturated brine, use anhydrous magnesium sulfate drying, concentrating under reduced pressure.(the purifying resistates of hexane/ethyl acetate=10/1-1/1) obtains the title compound (320mg, productive rate 87%) of colorless oil to use silica gel column chromatography.
MS m/z 501(MH +)
Embodiment 102
3-[4-(2 ', 6 '-dimethyl-4 '-[(methyl sulphonyl) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid
According to embodiment 2 similar methods, by 3-[4-(2 ', 6 '-dimethyl-4 '-[(methyl sulphonyl) oxygen base] biphenyl-3-yl methoxyl group)-the 2-fluorophenyl] ethyl propionate obtains title compound colorless oil (productive rate 61%).
MS m/z 473(MH +)。
m.p.：124-125℃。
Embodiment 103
3-[4-(2 ', 6 '-dimethyl-4 '-[(3-thienyl sulphonyl base) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
Figure A20048004213901142
According to embodiment 101 similar methods, by 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate and 3-thiophene SULPHURYL CHLORIDE obtain the title compound (productive rate 57%) of colorless oil.
MS m/z 569(MH +)
Embodiment 104
3-[4-(2 ', 6 '-dimethyl-4 '-[(3-thienyl sulphonyl base) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid
According to embodiment 2 similar methods, by 3-[4-(2 ', 6 '-dimethyl-4 '-[(3-thienyl sulphonyl base) oxygen base] biphenyl-3-yl methoxyl group)-the 2-fluorophenyl] ethyl propionate obtains title compound clear crystal (productive rate 44%).
MS m/z 541(MH +)
Embodiment 105
3-(4-{[4 '-(2-ethoxy ethoxy)-6-methoxyl group-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) ethyl propionate
According to embodiment 1 similar methods, by 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate and [4 '-(2-ethoxy ethoxy)-6-methoxyl group-2 ', 6 '-dimethyl diphenyl-3-yl] methyl alcohol obtains the title compound (productive rate 88%) of light yellow oil.
MS(ESI+)：525(M+H)
Embodiment 106
3-(4-{[4 '-(2-ethoxy ethoxy)-6-methoxyl group-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid
Figure A20048004213901152
In room temperature and under stirring, to 3-(4-{[4 '-(2-ethoxy ethoxy)-6-methoxyl group-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) ethyl propionate (0.45 gram, 0.86mmol), add 1N aqueous sodium hydroxide solution (1.7 milliliters) in the mixture of methyl alcohol (4.5 milliliters) and tetrahydrofuran (THF) (9 milliliters), and under uniform temp, stirred this mixture 2 hours.With 1N hydrochloric acid neutralization reaction mixture, and concentrating under reduced pressure.Dilute resistates with ethyl acetate, water and saturated brine washing, dry and concentrating under reduced pressure.Use silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/2) purifying resistates, obtain the title compound (85mg, productive rate 20%) of colorless oil.
MS(ESI+)：497(M+H)
Embodiment 107
(2S)-and 2-{[(3 '-{ [4-(3-oxyethyl group-3-oxopropyl)-3-fluorophenoxy] methyl }-2,6-dimethyl diphenyl-4-yl) the oxygen base] methyl } tetramethyleneimine-1-carboxylic acid tertiary butyl ester
Figure A20048004213901161
According to embodiment 1 similar methods, by 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate and (2S)-2-(methylol) tetramethyleneimine-1-carboxylic acid tert-butyl ester obtains title compound colorless oil (productive rate 8.6%).
1H NMR(CDCl 3)δ：1.23(3H，t，J＝7.4Hz)，1.48(9H，s)，1.70-2.10(4H，m)，1.98(6H，s)，2.57(2H，t，J＝7.6Hz)，2.90(2H，t，J＝7.6Hz)，3.30-3.50(3H，m)，4.11(2H，q，J＝7.4Hz)，4.00-4.24(2H，m)，5.06(2H，s)，6.60-6.72(4H，m)，7.04-7.48(5H，m)。
Embodiment 108
3-{4-[(4 '-[(2S)-and 1-(tertbutyloxycarbonyl) tetramethyleneimine-2-yl] methoxyl group }-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group]-the 2-fluorophenyl } propionic acid
According to embodiment 2 similar methods, by (2S)-2-{[(3 '-{ [4-(3-oxyethyl group-3-oxopropyl)-3-fluorophenoxy] methyl }-2,6-dimethyl diphenyl-4-yl) the oxygen base] methyl } tetramethyleneimine-1-carboxylic acid tert-butyl ester obtains title compound colorless solid (productive rate 61%).
MS(APCI-)：576(M-H)
Embodiment 109
3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
Figure A20048004213901171
According to embodiment 1 similar methods, by 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate and 2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) oxygen base] biphenyl-3-yl methyl alcohol obtains the title compound (productive rate 94%) of colorless oil.
MS(ESI+)：514(M+H)
Embodiment 110
3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid
According to embodiment 106 similar methods, by 3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) oxygen base] biphenyl-3-yl methoxyl group)-the 2-fluorophenyl] ethyl propionate obtains the title compound (productive rate 62%) of colorless oil.
MS(ESI+)：486(M+H)
Embodiment 111
3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] the propionic salt hydrochlorate
Figure A20048004213901173
According to embodiment 79 similar methods, by 3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) oxygen base] biphenyl-3-yl methoxyl group)-the 2-fluorophenyl] propionic acid obtains title compound (productive rate 83%).
MS (ESI+): 486 (M+H is with free forms)
Embodiment 112
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-thiapyran-4-base oxygen base) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) ethyl propionate
Figure A20048004213901181
In room temperature and under stirring, to 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } ethyl propionate (0.50 gram, 1.18mmol), tetrahydrochysene-2H-thiapyran-4-alcohol (0.15 the gram, 1.30mmol) and triphenylphosphine (0.31 gram, 1.30mmol) tetrahydrofuran (THF) (10 milliliters) solution in add azo-2-carboxylic acid's diethyl ester (40% toluene solution, 0.70 milliliter, 1.53mmol).This reaction mixture was at room temperature stirred 19 hours, and add the mentioned reagent (tetrahydrochysene-2H-thiapyran-4-alcohol, triphenylphosphine and diethylazodicarboxylate) of equal quantities.This mixture was further stirred 6 hours under uniform temp.The concentrating under reduced pressure reaction mixture, and use silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) purifying resistates, obtain this title compound (0.53g, productive rate 91%) of yellow oil.
1H NMR(CDCl 3)δ：1.23(3H，t，J＝7.1Hz)，1.98(6H，s)，1.99-2.11(2H，m)，2.16-2.27(2H，m)，2.53-2.64(4H，m)，2.85-3.01(4H，m)，4.07-4.17(2H，m)，4.32-4.42(1H，m)，5.06(2H，s)，6.62-6.71(4H，m)，7.05-7.12(2H，m)，7.17(1H，s)，7.34-7.46(2H，m)。
Embodiment 113
3-[4-(4 '-[(1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
Except using ethyl acetate to replace methylene dichloride, according to embodiment 71 similar methods, by 3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-thiapyran-4-base oxygen base) biphenyl-3-yl] methoxyl group-the 2-fluorophenyl) ethyl propionate obtains the title compound (productive rate 45%) of light yellow oil.
MS(ESI+)：555(M+H)
Embodiment 114
3-[4-(4 '-[(1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid
Figure A20048004213901191
According to embodiment 37 similar methods, by 3-[4-({ 4 '-[(1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate obtains title compound clear crystal (productive rate 68%).
MS(ESI+)：527(M+H)。
m.p.：148-149℃.
Embodiment 115
3-[4-(2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
Figure A20048004213901192
According to embodiment 70 similar methods, by 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate and 3-methyl-3-oxetane methanol (oxetanemethanol) obtain title compound colorless oil (productive rate 92%).
MS(ESI+)：507(M+H)
Embodiment 116
3-[4-(2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid
Figure A20048004213901193
According to embodiment 37 similar methods, by 3-[4-(2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl methoxyl group)-the 2-fluorophenyl] ethyl propionate obtains title compound clear crystal (productive rate 67%).
MS(ESI+)：479(M+H)。
m.p.：112-113℃.
Embodiment 117
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-4-base oxygen base) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) ethyl propionate
Figure A20048004213901201
According to embodiment 112 similar methods, by 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate and tetrahydrochysene-2H-pyrans-4-alcohol obtains colorless oil d title compound (productive rate 97%).
MS(ESI+)：507(M+H)
Embodiment 118
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-4-base oxygen base) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid
Figure A20048004213901202
According to embodiment 37 similar methods, by 3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-4-base oxygen base) biphenyl-3-yl] methoxyl group-the 2-fluorophenyl) ethyl propionate obtains title compound clear crystal (productive rate 47%).
MS(ESI+)：479(M+H)。
m.p.：123℃。
Embodiment 119
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-thiapyran-4-base oxygen base) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid
According to embodiment 37 similar methods, by 3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-thiapyran-4-base oxygen base) biphenyl-3-yl] methoxyl group-the 2-fluorophenyl) ethyl propionate obtains title compound clear crystal (productive rate 49%).
MS m/z 495(MH +)
Embodiment 120
3-[4-(4 '-[3-(diethoxy phosphoryl) propoxy-]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] ethyl propionate
0 ℃ with stir under, to 3-{2-fluoro-4-[(4 '-hydroxyl-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } (315 milligrams of ethyl propionates, 0.74mmol) N, add sodium hydride (60% in dinethylformamide (4 milliliters) solution, 31 milligrams, 0.78mmol), and at room temperature stirred this mixture 30 minutes.Add (3-bromopropyl) diethyl phosphonate (578 milligrams, 2.23mmol) and potassiumiodide (37 milligrams, 0.22mmol), and 60 ℃ of further these mixture overnight of stirring.With the reaction mixture concentrating under reduced pressure.Salt solution is joined in the resistates, and use the ethyl acetate extraction mixture.Use the anhydrous sodium sulfate drying extract, concentrating under reduced pressure.(hexane/ethyl acetate=pass through preparation HPLC (gradient circulation A) purifying resistates 10/1-1/4), then obtains the title compound (0.22g, productive rate 50%) of colorless oil to use silica gel column chromatography.
MS m/z 601(MH +)
Embodiment 121
3-[4-(4 '-[3-(diethoxy phosphoryl) propoxy-]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid
Figure A20048004213901221
According to embodiment 37 similar methods, by 3-[4-(4 '-[3-(diethoxy phosphoryl) propoxy-]-2 ', 6 '-dimethyl diphenyl-3-yl methoxyl group)-the 2-fluorophenyl] ethyl propionate obtains title compound colorless oil (productive rate 64%).
MS m/z 573(MH +)。
1H NMR(CDCl 3)δ：1.33(6H，t，J＝7.1Hz)，1.85-2.19(10H，m)，2.62(2H，t，J＝7.6Hz)，2.90(2H，t，J＝7.6Hz)，4.03(2H，t，J＝6.1Hz)，4.06-4.22(4H，m)，5.06(2H，s)，6.60-6.72(4H，m)，7.03-7.18(3H，m)，7.32-7.47(2H，m)。
Embodiment 122
3-{4-[(4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-6-isopropoxy-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group]-the 2-fluorophenyl } ethyl propionate
Figure A20048004213901222
According to embodiment 1 similar methods, by (4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-6-isopropoxy-2 ', 6 '-dimethyl diphenyl-3-yl) methyl alcohol and 3-(2-fluoro-4-hydroxy phenyl) ethyl propionate obtain the title compound (productive rate 87%) of colorless oil.
1H NMR(CDCl 3)δ：0.22(6H，s)，1.00(9H，s)，1.11(6H，d，J＝6.0Hz)，1.23(3H，t，J＝7.2Hz)，1.94(6H，s)，2.57(2H，t，J＝7.6Hz)，2.89(2H，t，J＝7.6Hz)，4.12(2H，q，J＝7.2Hz)，4.21-4.34(1H，m)，4.96(2H，s)，6.56(2H，s)，6.61-6.72(2H，m)，6.96(1H，d，J＝8.5Hz)，7.04-7.13(2H，m)，7.31(1H，dd，J＝8.4，2.4Hz)。
Embodiment 123
3-{2-fluoro-4-[(4 '-hydroxyl-6-isopropoxy-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl } ethyl propionate
Figure A20048004213901231
According to embodiment 57 similar methods, by 3-{4-[(4 '-{ [tertiary butyl (dimethyl) silyl] oxygen base }-6-isopropoxy-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group]-the 2-fluorophenyl ethyl propionate obtains the title compound (productive rate 80%) of colorless oil.
MS m/z 481(MH +)
Embodiment 124
3-[2-fluoro-4-(6-isopropoxy-2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group) phenyl] ethyl propionate
According to embodiment 70 similar methods, by 3-{2-fluoro-4-[(4 '-hydroxyl-6-isopropoxy-2 ', 6 '-dimethyl diphenyl-3-yl) methoxyl group] phenyl ethyl propionate and 3-methyl-3-oxetane methanol obtain the title compound (productive rate 72%) of colorless oil.
MS m/z 565(MH +)
Embodiment 125
3-[2-fluoro-4-(6-isopropoxy-2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group) phenyl] propionic acid
Figure A20048004213901233
According to embodiment 37 similar methods, by 3-[2-fluoro-4-(6-isopropoxy-2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl methoxyl group) phenyl] ethyl propionate obtains the colourless amorphous powder of title compound (productive rate 87%).
MS m/z 537(MH +)。
1H NMR(CDCl 3)δ：1.15(6H，d，J＝6.0Hz)，1.45(3H，s)，1.98(6H，s)，2.64(2H，t，J＝7.7Hz)，2.90(2H，t，J＝7.6Hz)，4.04(2H，s)，4.31-4.41(1H，m)，4.47(2H，d，J＝5.8Hz)，4.66(2H，d，J＝5.8Hz)，4.96(2H，s)，6.61-6.72(4H，m)，6.96(1H，d，J＝8.5Hz)，7.03-7.14(2H，m)，7.32(1H，dd，J＝8.5，2.3Hz)。
Example of formulations 1 (capsule product)
1) the compound 30mg of embodiment 1
2) Microcrystalline Cellulose 10mg
3) lactose 19mg
4) Magnesium Stearate 1mg
Add up to 60mg
With above-mentioned 1), 2), 3) and 4) mix and be filled in the capsule.
Example of formulations 2 (tablet product)
1) the compound 30g of embodiment 1
2) lactose 50g
3) W-Gum 15g
4) calcium carboxymethylcellulose 44g
5) Magnesium Stearate 1g
1000, add up to 140g
With above-mentioned 1), 2) and 3) total amount and 30 grams 4) stir vacuum-drying and granulation with water.With prilling powder and 14 grams 4) and 1 gram 5) mix, and make tablet with tabletting machine.In this way, obtain 1000 every tablet tablet that contains 30 milligrams of embodiment 1 compounds.
EXPERIMENTAL EXAMPLE 1
Measure the EC50 value of The compounds of this invention at human GPR40
For measuring the EC50 value, use the Chinese hamster ovary celI system of the human GPR40 of stably express.Unless otherwise stated, otherwise use the α-MEM substratum (Invitrogen) contain 10% foetal calf serum (Invitrogen) to cultivate Chinese hamster ovary celI system.
In the day before yesterday of test, wash with PBS (Invitrogen) being cultured to the cell that almost converges, digest with 0.05%TrypsinEDTA solution (Invitrogen), and collect by centrifugation.Count the quantity of resultant cell, and, can make like this in per 1 milliliter of substratum and contain 3 * 10 cell dilution 5Individual cell is assigned to cell in the 96 hole flat boards (coster) in black hole (black welled), every hole 100 μ L, and at CO 2Overnight incubation in the incubator.Various testing compounds are joined in the Chinese hamster ovary celI of preparation thus, and use FLIPR (Molecular Device) to measure the variation of cellular calcium concentration.The cellular calcium change in concentration of being undertaken by FLIPR is measured in the pre-treatment that use is mentioned below.
Prepared and be used for adding fluorescence dye Fluo3-AM (DOJIN) or being used for before the FLIPR test mensuration damping fluid of washed cell immediately to cell.Join HBSS (Invitrogen to 1M, 1000 milliliters) in HEPES (pH value 7.4, DOJIN, 20 milliliters) add in (being HBSS/HEPES solution hereinafter) solution by with benemid (Sigma, 710 milligrams) be dissolved in the solution (10 milliliters) that obtains among the 1N NaOH (5 milliliters), add and mix HBSS/HEPES solution (5 milliliters), and resulting solution is used as the mensuration damping fluid.Fluo3-AM (50 μ g) is dissolved in the methyl-sulphoxide (Wako, 21 μ L), and (an equivalent amount) the 20% Pluronic acid (pluronic acid) that adds equal quantities (MolecularProbes) also mixes.This solution is joined in the damping fluid to be measured (10.6 milliliters) that is supplemented with foetal calf serum (105 μ L), obtain a kind of fluorescence dye liquor.The test the day before yesterday, the Chinese hamster ovary celI substratum that is inoculated into recently on the plate of 96-hole, black hole is removed, the fluorescence dye liquor is distributed immediately with the every hole of 100 μ L, and with cell at CO 2Cultivated 1 hour in the incubator, take in fluorescence dye by cell.After the cultivation cell is washed with the above damping fluid to be measured, and place on the FLIPR.Test compound in advance with the methyl-sulphoxide dilution, is assigned in the polypropylene 96-hole plate (sample panel) with 2 μ L, and-20 ℃ of following cryopreservations.In the sample panel of melting, add the damping fluid to be measured that contains 0.015%CHAPS (DOJIN) with 198 μ L, and be placed on the FLIPR simultaneously with cell plate.After the above-mentioned pre-treatment, measure the change of cellular calcium concentration when adding various test compound by FLIPR.According to the result, form the dose response curve of each test compound and calculate the EC50 value.The results are shown in Table 1.
Table 1
Function of receptors regulating effect on GPR40
Compound number EC 50(μM)
Embodiment 14 0.010
Embodiment 33 0.0061
Embodiment 39 0.032
Embodiment 49 0.011
Embodiment 54 0.049
Embodiment 75 0.016
Embodiment 86 0.032
Embodiment 90 0.034
Embodiment 97 0.023
Embodiment 100 0.017
Embodiment 102 0.015
Embodiment 114 0.02
Industrial applicibility
Compound (I), its salt and its pro-drug have higher GPR40 function of receptors regulating action, can be as the medicine of prevention or treatment diabetes etc.
The application is based on the number of patent application 431629/2003 and 241484/2004 in Japanese publication, and its content in this combination as a reference.

Claims (20)

1. the compound or its salt of formula (I) representative,
Wherein
R 1, R 3, R 4And R 5Be identical or different, and each is hydrogen atom, halogen atom, the optional alkyl that replaces or the optional hydroxyl that replaces;
R 2Be halogen atom, nitro, the optional alkyl that replaces, the optional hydroxyl that replaces, the optional amino that replaces, the optional sulfydryl that replaces, the optional acyl group that replaces or the optional heterocyclic radical that replaces;
R 10And R 11Be identical or different, and each is hydrogen atom, halogen atom or C 1-6Alkoxyl group;
E is chemical bond, the optional C that replaces 1-4Alkylidene group ,-W 1-O-W 2-,-W 1-S-W 2-or-W 1-N (R 6)-W 2-(W wherein 1And W 2Be identical or different, and each is chemical bond or the optional C that replaces 1-3Alkylidene group, and R 6Be hydrogen atom, the optional acyl group that replaces or the optional alkyl that replaces);
S 1Ring is the optional substituent phenyl ring that is selected from halogen atom, the optional alkyl that replaces, the optional hydroxyl that replaces and the optional amino that replaces that further has;
R is optional hydroxyl that replaces or the optional amino that replaces;
Condition is R 1And R 3Not hydrogen atom simultaneously.
2. the compound or its salt of claim 1, wherein R 2Be halogen atom, the optional alkyl that replaces, the optional hydroxyl that replaces, the optional amino that replaces, the optional sulfydryl that replaces or the optional heterocyclic radical that replaces, and R 10And R 11Two all is hydrogen atom.
3. the prodrug of the compound of claim 1 or its salt.
4. the compound or its salt of claim 1, wherein R 4And R 5Be identical or different, and each is hydrogen atom or halogen atom.
5. the compound or its salt of claim 1, wherein E is a chemical bond.
6. the compound or its salt of claim 1, wherein R is a hydroxyl.
7. the compound or its salt of claim 1, wherein R 1And R 3Be identical or different, and each is C 1-6Alkyl.
8. the compound or its salt of claim 1, wherein R 2It is the optional hydroxyl that replaces.
9. the compound or its salt of claim 1, wherein R 10And R 11Two all is hydrogen atom.
10. the compound or its salt of claim 1, wherein S 1Ring is the optional C that further has 1-6The phenyl ring of alkoxyl group.
11.3-[4-[[4 '-(benzyloxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group] phenyl] propionic acid;
3-(4-{[4 '-(2-ethoxy ethoxy)-2 ', 6 '-dimethyl diphenyl-3-yl] methoxyl group } phenyl)-2,2-difluoro propionic acid;
3-[4-(4 '-[2-(ethylsulfonyl) oxyethyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[4-(2 ', 6 '-dimethyl-4 '-[3-(2-oxo-pyrrolidine-1-yl) propoxy-] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[4-(2 ', 6 '-dimethyl-4 '-[(6-picoline-2-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[2-fluoro-4-(4 '-[(4-hydroxyl-1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) methoxyl group]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group) phenyl] propionic acid;
3-[4-(2 ', 6 '-dimethyl-4 '-[(methyl sulphonyl) oxygen base] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[4-(4 '-[(1,1-dioxo tetrahydrochysene-2H-thiapyran-4-yl) oxygen base]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[4-(2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-(4-{[2 ', 6 '-dimethyl-4 '-(tetrahydrochysene-2H-pyrans-4-base oxygen base) biphenyl-3-yl] methoxyl group }-the 2-fluorophenyl) propionic acid;
3-[4-(4 '-[3-(diethoxy phosphoryl) propoxy-]-2 ', 6 '-dimethyl diphenyl-3-yl } methoxyl group)-the 2-fluorophenyl] propionic acid;
3-[2-fluoro-4-(6-isopropoxy-2 ', 6 '-dimethyl-4 '-[(3-methyl trimethylene oxide-3-yl) methoxyl group] biphenyl-3-yl } methoxyl group) phenyl] propionic acid;
Or its salt.
12.GPR40 the function of receptors conditioning agent comprises compound or its salt or its prodrug of claim 1.
13. a medicament comprises compound or its salt or its prodrug of claim 1.
14. the medicament of claim 13, it is the medicament of prevention or treatment diabetes.
15. the compound or its salt of claim 1 or its prodrug purposes in preparation GPR40 function of receptors conditioning agent.
16. the compound or its salt of claim 1 or its prodrug purposes in the medicament of preparation prevention or treatment diabetes.
17. a method of regulating GPR40 function of receptors in the Mammals comprises the compound of the claim 1 that gives described Mammals significant quantity, or its salt, or its prodrug.
18. the method for diabetes in prevention or the treatment Mammals comprises compound or its salt or its prodrug of the claim 1 that gives described Mammals significant quantity.
19. the method for the compound or its salt of a preparation formula (Ib) representative:
R wherein 1, R 2, R 3, R 4, R 5, R 10, R 11, E and S 1Encircle as defined in claim 1,
This method comprises the compound or its salt that makes formula (X) representative:
Figure A2004800421390004C2
Wherein each symbol as defined above,
With the compound or its salt reaction of formula (II) representative,
R wherein 4, R 5, R 10And R 11As defined above, R ' is the optional C that replaces 1-6Alkoxyl group,
Obtain the compound or its salt of formula (Ib ') representative,
Wherein each symbol as defined above,
And to the reaction that is hydrolyzed of this compound or its salt.
20. the method for the compound or its salt of a preparation formula (Id) representative:
Figure A2004800421390005C1
R wherein 1, R 3, R 4, R 5, R 10, R 11, E and S 1Ring as defined in claim 1, Y is-O-or-S-, and R 2' be substituting group,
This method comprises the compound or its salt that makes formula (Ie ') representative,
Figure A2004800421390005C2
R wherein 1, R 3, R 4, R 5, R 10, R 11, E and S 1Ring is as top definition, R ' such as claim 19 definition,
With the compound or its salt reaction of following formula representative,
R 2′-OH
R wherein 2' as defined above,
Obtain the compound or its salt of formula (If ') representative,
Figure A2004800421390005C3
Wherein each symbol as defined above,
And to the reaction that is hydrolyzed of this compound or its salt.
CN 200480042139 2003-12-25 2004-12-24 3-(4-benzyloxyphenyl)propanoic acid derivative Pending CN1922165A (en)

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CN103228622A (en) * 2010-07-23 2013-07-31 康内克斯生命科学私人有限公司 Agonists of gpr40
CN104109115A (en) * 2013-04-16 2014-10-22 中国科学院上海药物研究所 Phenylpropionic acid compounds chained by nitrogen-containing heterocyclic rings, pharmaceutical composition, preparation method, and application thereof
CN104250238A (en) * 2013-06-25 2014-12-31 南京圣和药业有限公司 G protein coupled receptor 40 (GPR40) agonist and use thereof
CN104326950A (en) * 2014-10-14 2015-02-04 中国药科大学 Phenoxyacetic acid derivative, preparation process thereof and use thereof as medicaments
CN104557512A (en) * 2015-01-06 2015-04-29 山西大学 Preparation method of 3-(bromophenyl)-2,2'-difluoropropanoic acid
CN104788405A (en) * 2014-01-22 2015-07-22 山东轩竹医药科技有限公司 Aromatic polycyclic carboxylic acid derivatives
CN106061943A (en) * 2014-03-07 2016-10-26 詹森药业有限公司 Bicyclic pyrrole derivatives useful as agonists of GPR120
CN107162913A (en) * 2017-06-29 2017-09-15 中国药科大学 The new deuterated phenylpropionic acid derivative of one class, its preparation method and its purposes as medicine
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CN108144612A (en) * 2016-12-02 2018-06-12 中国科学院大连化学物理研究所 It is a kind of for the cobalt-base catalyst of one pot process carboxylate and its preparation and application
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CN103228622A (en) * 2010-07-23 2013-07-31 康内克斯生命科学私人有限公司 Agonists of gpr40
CN104109115A (en) * 2013-04-16 2014-10-22 中国科学院上海药物研究所 Phenylpropionic acid compounds chained by nitrogen-containing heterocyclic rings, pharmaceutical composition, preparation method, and application thereof
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CN104250238A (en) * 2013-06-25 2014-12-31 南京圣和药业有限公司 G protein coupled receptor 40 (GPR40) agonist and use thereof
CN104250238B (en) * 2013-06-25 2017-12-26 南京圣和药业股份有限公司 GPR40 activators and its application
CN104788405A (en) * 2014-01-22 2015-07-22 山东轩竹医药科技有限公司 Aromatic polycyclic carboxylic acid derivatives
CN106061943A (en) * 2014-03-07 2016-10-26 詹森药业有限公司 Bicyclic pyrrole derivatives useful as agonists of GPR120
CN106061943B (en) * 2014-03-07 2019-11-05 詹森药业有限公司 It can be used as the bicyclic pyrrole derivatives of the agonist of GPR120
CN104326950A (en) * 2014-10-14 2015-02-04 中国药科大学 Phenoxyacetic acid derivative, preparation process thereof and use thereof as medicaments
CN104557512A (en) * 2015-01-06 2015-04-29 山西大学 Preparation method of 3-(bromophenyl)-2,2'-difluoropropanoic acid
CN108144612B (en) * 2016-12-02 2020-12-29 中国科学院大连化学物理研究所 Cobalt-based catalyst for synthesizing carboxylic ester by one-pot method and preparation and application thereof
CN108144612A (en) * 2016-12-02 2018-06-12 中国科学院大连化学物理研究所 It is a kind of for the cobalt-base catalyst of one pot process carboxylate and its preparation and application
CN107162913A (en) * 2017-06-29 2017-09-15 中国药科大学 The new deuterated phenylpropionic acid derivative of one class, its preparation method and its purposes as medicine
CN107162913B (en) * 2017-06-29 2021-04-30 中国药科大学 Novel deuterated phenylpropionic acid derivative, preparation method thereof and application thereof as medicine
CN108003074B (en) * 2017-12-21 2019-07-05 四川大学华西医院 Biphenyl carboxylic acid compound and preparation method and application thereof
CN108003074A (en) * 2017-12-21 2018-05-08 四川大学华西医院 Biphenyl carboxylic acid compound and preparation method and application thereof
CN110294744A (en) * 2018-03-21 2019-10-01 中国医学科学院药物研究所 GPR40 receptor stimulating agent, its preparation method and its pharmaceutical composition and purposes
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