CN101928281A - Bicyclo-substituted pyrazolone azo derivative, preparation method thereof and application thereof in medicaments - Google Patents

Bicyclo-substituted pyrazolone azo derivative, preparation method thereof and application thereof in medicaments Download PDF

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CN101928281A
CN101928281A CN2009100536910A CN200910053691A CN101928281A CN 101928281 A CN101928281 A CN 101928281A CN 2009100536910 A CN2009100536910 A CN 2009100536910A CN 200910053691 A CN200910053691 A CN 200910053691A CN 101928281 A CN101928281 A CN 101928281A
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carboxylic acid
methyl
hydroxyl
compound
phenyl
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邓炳初
吕贺军
费洪博
陈一千
王�华
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Abstract

The invention discloses a bicyclo-substituted pyrazolone azo derivative or tautomer, a pharmaceutically acceptable salt, a hydrate or a solvent compound which is shown as a general formula (I), a preparation method thereof, a medicinal composition containing the derivative and application of the derivative serving as a therapeutic agent, particularly thrombopoietin (TPO) mimics and thrombopoietin receptor agonist. The definition of each substituent group in the general formula (I) is consistent with that in the specification.

Description

Dicyclo substituted pyrazolecarboxylic ketone azo analog derivative, its preparation method and in pharmaceutically application
Technical field
The present invention relates to dicyclo substituted pyrazolecarboxylic ketone azo analog derivative new shown in the general formula (I), its preparation method with and prodrug, contain this derivative pharmaceutical composition, with and as therapeutical agent particularly thrombopoietin (TPO) stand-in and they as the purposes of thrombopoietin receptor agonist.
Background technology
Thrombopoietin (Thrombopoietin, TPO), be called megakaryocyte growth development facor (megakaryocyte growth and development factor again, MGDF), thrombopoietic-stimulating factor (thrombocytopoiesis stimulating factor, TSF), c-Mpl part (c-myeloproliferativeleukemia ligand, c-Mpl), mpl part, megapoietin are a kind of and produce PA glycoprotein (Wendling, F., et.al., Biotherapy 10 (4): 269-77 (1998); Kuter is al. D.1.et, TheOncologist; 1:98-106 (1996); Metcalf, Nature 369:519-520 (1994)).
In some cases, the activated source of TPO combining from TPO and TPO acceptor (also claiming MPL).The TPO acceptor is successfully cloned, and has also carried out the order-checking (Vigon et al., Proc.Nat.Acad.Sci., 89:5640-5644 (1992)) of aminoacid sequence.
TPO is a kind of 332-amino acid glycosylated polypeptides, produces in the generation of adjusting megalokaryocyte with by bone marrow megakaryocyte to play a part crucial (Kuter et al., Proc.Nat.Acad.Sci.USA 91:11104-11108 (1994) in the hematoblastic process; Barley et al., Cell 77:1117-1124 (1994); Kaushansky et al., Nature 369:568-571 (1994); Wendling et al., Nature 369:571-574 (1994); AndSauvage et al., Nature 369:533-538 (1994)).TPO results from liver but mainly acts on marrow, stimulates differentiation of stem cells to become megalokaryocyte and Megakaryocytic propagation, and polyploidization the most important thing is to enter thrombocyte health circulation division.TPO is a kind of main conditioning agent (Metcalf Nature369:519-520 (1994)) in thrombocytopenia and a large amount of participating in the hematoblastic research about platelet increasing quantity, size, increase laboratory animal isotropic substance.TPO is considered to mainly to influence megalokaryocyte by several ways and generates: (1) causes the increase of megalokaryocyte size and quantity; (2) increase DNA inclusion, the form of polyploid, megalokaryocyte; (3) increase Megakaryocytic endomitosis; (4) increase sophisticated megalokaryocyte; (5) per-cent of increase precursor cell, the cell of little enzyme acetylcholine-positive form, medullary cell.
Thrombocyte is that blood coagulation is essential, and when its quantity was hanged down very much, patient just had the danger of hemorrhage death.Therefore, TPO has been used to diagnosis and has treated multiple hematologic disease, as the disease that is mainly caused by platelet defect.Simultaneously, TPO can be used for the treatment of thrombocytopenia, especially for treating chemotherapy, radiotherapy and the bone marrow transplantation that cancer and lymphoma are carried out.
The patient is a serious problem because of thrombocytopenia causes platelet levels to be recovered slowly, therefore wishes to find a kind of active TPO analogue for the treatment of thrombocytopenia.Several years ago, the development of polypeptide class TPO analogue is reported.(WO96/40750, WO98/25965) these polypeptide can in conjunction with and activate the TPO acceptor, but do not possess the sequence homology of natural TPO.Recent years, some micromolecular active TPO analogues are reported.Comprise 1,4-benzodiazepine-2-ketone (JP11001477), the metal complex (WO 99/11262) that obtains by the schiff bases part, ring polyamine derivative (WO00/28987), and thiazol-2-yl-benzamides (WO01/07423, WO01/53267), azo-aryl derivatives (WO00/35446, WO1/17349), (WO01/39773 is WO01/53267) with semicarbazone derivative (WO01/34585) for 2-aryl-naphthalene azole.In system based on cell, the signal transduction pathway of the TPO acceptor of all these molecules on can both the active cells film, some types can directly act on TPO acceptor itself.Some prepreerence compounds were found the propagation and the differentiation that can stimulate TPO-responsive human cell system during these were a series of.
GSK company reports thrombopoietin analogue eltrombopag in patent (WO2003098992/WO-01089457/WO-2002057300), and has shown suitable activity.
The invention discloses a series of compounds and more effectively be used as the TPO receptor stimulant, is effective TPO stand-in.
Summary of the invention
In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide the dicyclo substituted pyrazolecarboxylic ketone azo analog derivative shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmacy acceptable salt, hydrate or solvated compounds, and meta-bolites and metabolic precursor thereof or prodrug.
Figure B2009100536910D0000021
Wherein:
R is selected from hydrogen atom or alkyl;
R 1, R 2, R 3And R 4Be selected from hydrogen atom, alkyl, alkoxyl group, halogen, aryl or heteroaryl independently of one another, wherein aryl or heteroaryl are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, carboxylic acid or carboxylicesters;
R 5, R 6And R 7Be selected from hydrogen atom, alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, carboxylic acid or carboxylicesters independently of one another;
R 8, R 9, R 10And R 11Be selected from hydrogen atom, carbonyl, hydroxyl or alkyl independently of one another;
N is 0,1 or 2; And
Figure B2009100536910D0000031
Expression singly-bound or two key, condition is two in the general formula (I) Be not two keys simultaneously.
In the preferred embodiment of the invention,
General formula (I) carbon-to-nitrogen double bon is configured as (Z) type;
R is selected from hydrogen atom or alkyl;
R 1Be selected from aryl or heteroaryl, wherein aryl or heteroaryl are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, carboxylic acid or carboxylicesters;
R 2, R 3And R 4Be selected from hydrogen atom, alkyl, alkoxy or halogen independently of one another;
R 5, R 6And R 7Be selected from hydrogen atom, alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, carboxylic acid or carboxylicesters independently of one another;
R 8, R 9, R 10And R 11Be selected from hydrogen atom, carbonyl, hydroxyl or alkyl independently of one another;
N is 0,1 or 2; And
Figure B2009100536910D0000033
Expression singly-bound or two key, condition is two in the general formula (I) Be not two keys simultaneously.
The Equivalent of being considered---those skilled in the art will appreciate that into, also can there be the form of tautomer in compound (I).The change form of compound (I) can include but not limited to by following formula (II), (III) and (IV) structure of expression:
Figure B2009100536910D0000035
All these change forms are included in the scope of the present invention and are included in inherently in compound (I) definition.
The preferred compound of the compound shown in the general formula of the present invention (I) includes, but are not limited to:
Figure B2009100536910D0000036
Figure B2009100536910D0000041
Figure B2009100536910D0000051
Figure B2009100536910D0000061
Or its pharmaceutically acceptable salt, hydrate or solvated compounds.
Further, the present invention includes the compound shown in the general formula (IA) or its tautomer, the intermediate that it synthesizes as general formula (I) compound:
Figure B2009100536910D0000081
Wherein:
R 5, R 6And R 7Be selected from hydrogen atom, alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, carboxylic acid or carboxylicesters independently of one another;
R 8, R 9, R 10And R 11Be selected from hydrogen atom, carbonyl, hydroxyl or alkyl independently of one another;
N is 0,1 or 2; And
Figure B2009100536910D0000082
Expression singly-bound or two key, condition is two in the general formula (IA)
Figure B2009100536910D0000083
Be not two keys simultaneously.
The Equivalent of being considered---those skilled in the art will appreciate that into, also can there be the form of tautomer in compound (IA).The change form of compound (IA) can include but not limited to by following formula (IIA) and (IIIA) expression structure:
Figure B2009100536910D0000084
All these change forms are included in the scope of the present invention and are included in inherently in compound (IA) definition.
The preferred compound of the compound shown in the general formula of the present invention (IA) includes, but are not limited to:
Figure B2009100536910D0000085
Figure B2009100536910D0000091
Figure B2009100536910D0000101
In another aspect of the present invention is the method for preparing compound shown in the intermediate (IA), may further comprise the steps:
Figure B2009100536910D0000102
Diazotization reaction takes place in amino polynary ring of benzo and the Sodium Nitrite that replaces in acidic solution, obtain hydrazine by the tin protochloride reduction again, hydrazine is with close electric carbonyl compound such as methyl aceto acetate, condensation obtains general formula (IA) compound under (as acetate, ethanol etc.) heating in The suitable solvent;
Wherein n, R 5～R 11Definition consistent with the definition of general formula (IA) compound.
In another aspect of the present invention is the method for preparing compound shown in the intermediate (IA), may further comprise the steps:
Figure B2009100536910D0000103
Amino polynary ring of benzo that replaces and potassium halide, sodium nitrite solution reaction generate the polynary ring of benzo that halogen replaces, with the reaction of diazanyl carboxylic acid tert-butyl ester, the diazanyl substitution product of the carboxylic acid tert-butyl ester protection of generation is with the carbonyl compound of parent's electricity such as methyl aceto acetate, condensation obtains general formula (IA) compound under (as acetate, ethanol etc.) heating in The suitable solvent then;
Wherein X is selected from halogen, n, R 5～R 11Definition consistent with the definition of general formula (IA) compound.
In another aspect of the present invention is the method for preparing compound shown in the intermediate (IA), may further comprise the steps:
Figure B2009100536910D0000111
Polynary ring of benzo that halogen replaces and the reaction of azo-2-carboxylic acid's di tert butyl carbonate, the product that the diazanyl by two carboxylic acid tert-butyl ester protections of generation replaces is with the carbonyl compound of parent's electricity such as methyl aceto acetate, condensation obtains general formula (IA) compound under (as acetate, ethanol etc.) heating in The suitable solvent;
Wherein X is selected from halogen, group n, R 5～R 11Definition consistent with the definition of general formula (IA) compound.
Further, another aspect of the present invention provides the preparation method of general formula compound (I), and this method comprises:
Figure B2009100536910D0000112
The amino benzenes compounds and the Sodium Nitrite that replace carry out diazotization reaction in proper acidic solution (as nitric acid, sulfuric acid, hydrochloric acid), with general formula (IA) compound linked reaction takes place in basic solution (as sodium bicarbonate, saleratus) again and obtain general formula (I) compound;
Wherein n, R, R 1～R 11Definition consistent with the definition of general formula (I) compound.
The present invention relates to general formula (I) and (IA) compound or its tautomer, acceptable salt, hydrate or the solvated compounds purposes in preparation TPO receptor stimulant pharmaceutically.
The present invention relates to general formula (I) and (IA) compound or its tautomer, acceptable salt, hydrate or the solvated compounds purposes in preparation treatment thrombopenia disease drug pharmaceutically.Comprise and unite the following medicine that is selected from that uses the treatment significant quantity: G CFS, cytokine, chemokine, interleukin-or cytokine receptor agonist or antagonist, soluble acceptor, receptor stimulant or antagonist antibodies or have identical mechanism with one or more described medicines and the peptide or the small molecules compounds that work.
The present invention relates to a kind of medicinal compositions, it comprises the general formula (I) of medicine effective dose and (IA) compound or its tautomer, pharmaceutically acceptable salt, hydrate or solvated compounds.Said composition can further contain the associating use the treatment significant quantity be selected from following medicine: G CFS, cytokine, chemokine, interleukin-or cytokine receptor agonist.The purposes of this pharmaceutical composition in preparation treatment thrombopenia disease drug.
Described unite to use comprise and use or successively use successively compound of the present invention simultaneously.
The present invention relates to general formula (I) that a kind of preparation contains pharmaceutical carrier or thinner and significant quantity and (IA) compound or its tautomer, the method for the pharmaceutical composition of acceptable salt, hydrate or solvated compounds pharmaceutically, this method comprise with general formula (I) and (IA) compound combine with pharmaceutical carrier and thinner.
Detailed description of the invention
Unless the phase counter-statement is arranged, the following term that is used in specification sheets and claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl or amyl group etc.The low alkyl group that more preferably contains 1 to 4 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, is independently selected from alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, aryl, heteroaryl, carboxylic acid or carboxylicesters.
" aryl " refers to have the group of at least one aromatic ring structure, promptly has the aromatic ring of conjugated πDian Zi system, comprises isocyclic aryl, heteroaryl and dibenzyl.Alkynyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, is independently selected from alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, aryl, heteroaryl, carboxylic acid or carboxylicesters.
" heteroaryl " refers to have 1 to 4 heteroatoms as annular atoms, and remaining annular atoms is the aryl of carbon, and heteroatoms comprises oxygen, sulphur and nitrogen.Described ring can be 5 yuan or 6 yuan of rings.The example of heteroaryl groups comprises furyl, thienyl, pyridyl, pyrroles, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Heteroaryl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, is independently selected from alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, aryl, heteroaryl, carboxylic acid or carboxylicesters.
" hydroxyl " refers to-the OH group.
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl).Representative example includes but not limited to methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, is independently selected from alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, aryl, heteroaryl, carboxylic acid or carboxylicesters.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH 2
" cyano group " refers to-CN.
" nitro " refers to-NO 2
" alkoxyl group " refers to-O-(alkyl).
" carboxylic acid " refers to (alkyl) C (=O) OH.
" carboxylicesters " refers to (alkyl) C (=O) O (alkyl).
" dicyclo replacement " refers to that 4～8 yuan of rings of benzo replace, wherein 4～8 yuan of rings are non-aromatic carbocyclic, 4～8 yuan of rings of benzo can be that replace or unsubstituted, when being substituted, substituting group preferred alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, carbonyl, aryl, heteroaryl, carboxylic acid or carboxylicesters.
" pharmaceutical composition " represent on one or more compounds described herein or its physiology/mixture of pharmacy acceptable salt or prodrug and other chemical compositions, and other components are physiology/pharmaceutically acceptable carrier and vehicle for example.The purpose of pharmaceutical composition is to promote the administration of compound to organism.
The synthetic method of The compounds of this invention
In order to finish purpose of the present invention, the present invention adopts following technical scheme:
A kind of preparation general formula (IA) compound synthetic method, this method may further comprise the steps:
Figure B2009100536910D0000131
Diazotization reaction takes place in amino polynary ring of benzo and the Sodium Nitrite that replaces in acidic solution, obtain hydrazine by the tin protochloride reduction again, hydrazine is with close electric carbonyl compound such as methyl aceto acetate, condensation obtains general formula (IA) compound under (as acetate, ethanol etc.) heating in The suitable solvent;
Wherein n and R 5～R 11Definition consistent with the definition of general formula (IA) compound.
The synthetic method of a kind of preparation general formula (IA) compound, this method may further comprise the steps:
Amino polynary ring of benzo that replaces and potassium halide, sodium nitrite solution reaction generate the polynary ring of benzo that halogen replaces, with the tert-butyl carbazate reaction, the diazanyl substitution product of the carboxylic acid tert-butyl ester protection of generation is with the carbonyl compound of parent's electricity such as methyl aceto acetate, condensation obtains general formula (IA) compound under (as acetate, ethanol etc.) heating in The suitable solvent then;
Wherein X is selected from halogen, n and R 5～R 11Definition consistent with the definition of general formula (IA) compound.
The synthetic method of a kind of preparation general formula (IA) compound, this method may further comprise the steps:
Figure B2009100536910D0000141
Polynary ring of benzo that halogen replaces and tert-butyl azodicarboxylate reaction, the product that the diazanyl by two carboxylic acid tert-butyl ester protections of generation replaces is with the carbonyl compound of parent's electricity such as methyl aceto acetate, condensation obtains general formula (IA) compound under (as acetate, ethanol etc.) heating in The suitable solvent.
Wherein X is selected from halogen, n and R 5～R 11Definition consistent with the definition of general formula (IA) compound.
The synthetic method of a kind of preparation general formula (I) compound, this method may further comprise the steps:
Figure B2009100536910D0000142
The adjacent bromophenol that replaces is through the nitrated nitrophenols that obtains of SODIUMNITRATE, nitrophenols under suitable temperature with haloalkyl, obtain the protected nitrophenols of hydroxyl as methyl iodide generation alkylated reaction; The Suzuki coupling takes place in the aryl boric acid of protected nitrophenols of hydroxyl and replacement under palladium class catalyzer such as tetrakis triphenylphosphine palladium catalysis, perhaps with boric acid compound reaction, aryl boric acid compounds that obtains and halogenated compound R 1The Suzuki coupling takes place in X, obtains R 1The aryl compound that replaces; R 1The aryl compound that replaces under nitrogen atmosphere, palladium/carbon reduction or obtain aryl aniline with the ammonium formiate reduction.
Linked reaction takes place with general formula (IA) compound and obtains general formula (I) compound in diazotization in proper acidic solution (as nitric acid, sulfuric acid, hydrochloric acid) again with aryl aniline and Sodium Nitrite in basic solution (as sodium bicarbonate, saleratus);
Wherein X is selected from halogen, group n, R and R 1～R 11Definition consistent with general formula (I) compound.
Embodiment
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.
Embodiment
The structure of compound be by nucleus magnetic resonance ( 1HNMR) or mass spectrum (MS) come to determine. 1HNMR displacement (δ) provides with 1,000,000/(ppm) unit. 1The mensuration of HNMR is that measuring solvent is deuterated methanol (CD with Bruker AVANCE-400 nuclear magnetic resonance spectrometer 3OD), deuterochloroform (CDCl 3), be designated as tetramethylsilane (TMS) in the hexadeuterated dimethyl sulfoxide (DMSO-d6);
The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Therm, model: FinniganLCQ advantage MAX);
IC 50The mensuration of value is with NovoStar microplate reader (German BMG company);
Thin layer silica gel uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate;
Silica gel column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier;
Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 * 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 * 4.6mm chromatographic column) are used in the HPLC test;
Pau 3916EKX type hydrogenation instrument and clear blue QL type hydrogen generator are used in the pressure hydration reaction; Microwave reaction uses CEM Discover-S 908860 type microwave reactors;
Do not have specified otherwise among the embodiment, reaction is all carried out under nitrogen atmosphere;
Nitrogen atmosphere is meant that reaction flask connects an about 1L volumetrical nitrogen balloon;
Nitrogen atmosphere is meant that reaction flask connects an about 1L volumetrical hydrogen balloon;
Do not have specified otherwise among the embodiment, the solution in the reaction is meant the aqueous solution;
TLC is meant thin-layer chromatography.
Embodiment 1
(Z)-4-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-Asia Base]-diazanyl }-phenyl)-furans-2-carboxylate methyl ester
Figure B2009100536910D0000151
Figure B2009100536910D0000161
The first step
4-bromo-furans-2-carboxylic acid
Adopt known method Journal of Medicinal Chemistry, 2008,5 (3), 413, with 4, (5.5g 20.3mmol) is dissolved in the mixed solvent of 18mL ammoniacal liquor and 63mL water 5-two bromo-furans-2-carboxylic acid 1a, adds zinc powder (1.46g, 22.33mmol), stirring reaction is 6 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to the raw material disappearance, with the hydrochloric acid adjust pH to 3 of 1N, there are a large amount of solids to separate out, filter, filter cake is collected solid with normal hexane washing (15mL * 4), vacuum-drying, obtain 4-bromo-furans-2-carboxylic acid 1b (3.2g, white solid), productive rate: 83.1%.
MS?m/z(ESI)：188.7[M-1]
1HNMR(400MHz，CDCl 3)：δ8.16(s，1H)，7.38(d，1H)
Second step
2-bromo-6-nitro-phenol
With joining in the 1.6L water under the stirring of the 537mL vitriol oil, be chilled to room temperature, add SODIUMNITRATE (648g, 7.63mol), stirring makes its dissolving, and slow dropping 2-bromo-phenol 1c under 50 ℃ (800g, 4.62mol), drip and finish, reacted 2.5 hours down in 10 ℃, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, filters, filter cake washes (500mL * 4) with water, obtain thick solid, add the 1L acetic acid ethyl dissolution, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate with silica gel column chromatography purifying gained resistates, obtains 2-bromo-6-nitro-phenol 1d (428g, yellow solid), productive rate: 42.9%.
MS?m/z(ESI)：218.7[M+1]
1HNMR(400MHz，CDCl 3)：δ11.17(br，1H)，8.14(d，1H)，7.91(d，1H)，6.95(t，1H)
The 3rd step
1-bromo-2-methoxyl group-3-nitro-benzene
(100g 0.459mol) is dissolved in the 600mL acetone, adds p-methyl benzenesulfonic acid methyl esters (70mL with 2-bromo-6-nitro-phenol 1d, 0.459mol) and salt of wormwood (75.963g, 0.55mol), in 55 ℃ of following back flow reaction 42 hours, thin-layer chromatography was followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, concentrating under reduced pressure filtrate with silica gel column chromatography purifying gained resistates, obtains 1-bromo-2-methoxyl group-3-nitro-benzene 1e (93g, white solid), productive rate: 87.4%.
MS?m/z(ESI)：230.8[M-1]
The 4th step
2-(2-methoxyl group-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] two assorted oxygen pentaboranes
(76g 0.328mol) is dissolved in the 600mL dme, adds 4 with 1-bromo-2-methoxyl group-3-nitro-benzene 1e, 4,5,5,4 ', 4 ', 5 ', 5 '-prestox-[2,2 '] two rings [[1,3,2] two assorted oxygen pentaboranes (124.77g, 0.491mol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (II) (13.38g, 0.016mol) and sodium acetate (80.37g, 0.819mol), heating reflux reaction 17 hours, thin-layer chromatography are followed the tracks of to react to raw material and are disappeared, the concentrating under reduced pressure reaction solution, with silica gel column chromatography purifying gained resistates, obtain 2-(2-methoxyl group-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] two assorted oxygen pentaborane 1f (90g, yellow thick solid), productive rate: 98.4%.
The 5th step
4-(2-methoxyl group-3-nitro-phenyl)-furans-2-carboxylic acid
With 2-(2-methoxyl group-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] (4.0g 14.34mmol) is dissolved in 80mL1 to two assorted oxygen pentaborane 1f, in the mixed solvent of 4-dioxane and 30mL water, add 4-bromo-furans-2-carboxylic acid 1b (2.18g, 11.47mmol), salt of wormwood (3.96g, 28.68mmol) and tetrakis triphenylphosphine palladium (829mg, 0.717mmol), heating reflux reaction 5 hours, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, transfers reacting liquid pH value to 3 with the hydrochloric acid soln of 1N, with ethyl acetate extraction (80mL * 3), merge organic phase, anhydrous magnesium sulfate drying filters concentrating under reduced pressure, with silica gel column chromatography purifying gained resistates, obtain 4-(2-methoxyl group-3-nitro-phenyl)-furans-2-carboxylic acid 1g (3.42g, brown oil), productive rate: 90.7%.
MS?m/z(ESI)：261.8[M-1]
The 6th step
4-(3-amino-2-methoxyl group-phenyl)-furans-2-carboxylic acid
With 4-(2-methoxyl group-3-nitro-phenyl)-furans-2-carboxylic acid 1g (500mg, 1.9mmol) be dissolved in the 15mL ethyl acetate, the adding ammonium formiate (479mg, 7.6mmol) with 100mg palladium/carbon (10%), heating reflux reaction 3 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, concentrating under reduced pressure filtrate obtains 4-(3-amino-2-methoxyl group-phenyl)-furans-2-carboxylic acid 1h (325mg, yellow oil), productive rate: 73.4%.
MS?m/z(ESI)：231.8[M-1]
The 7th step
4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylate methyl ester
With 4-(3-amino-2-methoxyl group-phenyl)-furans-2-carboxylic acid 1h (325mg, 1.4mmol) be dissolved in the 5mL methylene dichloride, the dichloromethane solution that adds 2.8mL 2M boron tribromide, stirring reaction is 4.5 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, react with the small amount of methanol cancellation, the concentrating under reduced pressure reaction solution, add the 5mL ethyl acetate, stirred 0.5 hour, filter, collect solid, obtain 4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylate methyl ester 1i (38.6mg, gray solid), productive rate: 12.7%.
MS?m/z(ESI)：217.7[M-1]
The 8th step
2-diazanyl-5,6,7, the 8-naphthane
Under the ice bath with 2-amino-5,6,7,8-naphthane 1j (3.68g 25.0mmol) is dissolved in the 20mL concentrated hydrochloric acid, stirs 10 minutes, drip the 10mL sodium nitrite solution (1.72g, 25.0mmol), ice bath continue down to stir 15 minutes standby.
(22.6g 100mmol) was dissolved in the 10mL concentrated hydrochloric acid, and standby midbody solution is added wherein with two hydrated stannous chlorides under cryosel was bathed, stirring reaction is 1.5 hours under the room temperature, and ice bath descends the sodium hydroxide solution adjust pH to 9 with 40%, adds the 400mL ethyl acetate extraction, collect organic phase, anhydrous magnesium sulfate drying filters, concentrating under reduced pressure filtrate, vacuum-drying obtains 2-diazanyl-5,6,7,8-naphthane 1k (2.19g, yellow oily liquid), productive rate: 53.7%.
MS?m/z(ESI)：163[M+1]
The 9th step
5-methyl-2-(5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone
With 2-diazanyl-5,6,7, (2.0g 12.3mmol) is dissolved in the 50mL acetate 8-naphthane 1k, adds methyl aceto acetate (1.57mL, 12.3mmol), in 100 ℃ of down reactions 16 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, the concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains 5-methyl-2-(5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone 1m (1.58g, colourless oil liquid), productive rate: 56.2%.
MS?m/z(ESI)：457[2M+1]
1HNMR(400MHz，CDCl 3)：δ7.54-7.58(m，2H)，7.08-7.10(d，J＝8Hz，1H)，3.43(s，2H)，δ2.77-2.81(m，4H)，2.21(s，3H)，1.80-1.83(m，4H)
The tenth step
(Z)-4-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylate methyl ester
Adopt known method WO0189457, under the ice bath with 4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylate methyl ester 1i (38.6mg, 0.13mmol) be dissolved in the hydrochloric acid soln of 0.4mL 1N, drip the aqueous solution (9.5mg of 0.16mL Sodium Nitrite, 0.14mmol), drip and finish, continued stirring reaction 20 minutes down in ice bath, add 5-methyl-2-(5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone 1m (25.7mg, 0.11mmol), (ethanol cancellation bubble is used in 159mg, 1.9mmol) adjust pH to 8～9 with sodium bicarbonate, stirring reaction 16 hours, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, filters filter cake 5mL water dissolution, with concentrated hydrochloric acid adjust pH to 2～3, filter, filter cake 4mL acetic acid ethyl dissolution filters, filter cake HPLC separation and purification, obtain title product (Z)-4-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylate methyl ester 1 (8mg, red solid), productive rate: 10.2%.
MS?m/z(ESI)：470.8[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.73(br，1H)，9.68(br，1H)，8.43(s，1H)，7.78(s，1H)，7.63(m，3H)，7.43(d，1H)，7.13(m，2H)，3.91(s，3H)，2.76(m，4H)，2.31(s，3H)，1.68(m，4H)
Embodiment 2
(Z)-5-(2-methoxyl group-3-{N '-[3-methyl-5-oxo-1-(5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-Asia Base]-diazanyl }-phenyl)-furans-2-carboxylic acid
The first step
5-(2-methoxyl group-3-nitro-phenyl)-furans-2-carboxylic acid
With 2-(2-methoxyl group-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] two assorted oxygen pentaborane 1f (54g, 0.193mol) be dissolved in 450mL 1, in the mixed solvent of 4-dioxane and 120mL water, and adding 5-bromo-furans-2-carboxylic acid (18.48g, 0.097mol), tetrakis triphenylphosphine palladium (11.16g, 9.67mmol) and yellow soda ash (41.02g, 0.387mol), heating reflux reaction 2.5 hours, thin-layer chromatography are followed the tracks of to react to raw material and are disappeared, filtering reacting liquid, concentrating under reduced pressure filtrate adds 100mL water in resistates, regulate pH=3 with hydrochloric acid, filter, filter cake with normal hexane washing (50mL), is collected solid with ethyl acetate washing (200mL), vacuum-drying, obtain 5-(2-methoxyl group-3-nitro-phenyl)-furans-2-carboxylic acid 2a (14.08g, yellow solid), productive rate: 55.3%.
MS?m/z(ESI)：262.1[M-1]
1HNMR(400MHz，DMSO-d 6)：δ8.10(m，1H)，7.95(m，1H)，7.42(m，3H)，3.84(s，3H)
Second step
5-(3-amino-2-methoxyl group-phenyl)-furans-2-carboxylic acid
With 5-(2-methoxyl group-3-nitro-phenyl)-furans-2-carboxylic acid 2a (5g, 18.99mmol) be dissolved in the 300mL ethyl acetate, add ammonium formiate (4.79g, 75.99mmol) and 500mg palladium/carbon (10%), heating reflux reaction 25 hours, filtering reacting liquid, concentrating under reduced pressure filtrate, obtain 5-(3-amino-2-methoxyl group-phenyl)-furans-2-carboxylic acid 2b (3.96g, yellow solid), productive rate: 89.6%.
MS?m/z(ESI)：232.1[M-1]
The 3rd step
(Z)-5-(2-methoxyl group-3-{N '-[3-methyl-5-oxo-1-(5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
With 5-(3-amino-2-methoxyl group-phenyl)-furans-2-carboxylic acid 2b (500mg, 2.15mmol) be dissolved in the hydrochloric acid soln of 5mL1N, (163mg 2.37mmol), drips and finishes the aqueous solution of dropping 2mL Sodium Nitrite, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 5-methyl-2-(5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone 1m (440mg, 1.93mmol), (2.71g is 32.25mmol) with 2mL ethanol for sodium bicarbonate, stirring reaction is 10 hours under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, filters the filter cake hydrochloric acid adjust pH to 3 of 1N, filter, collect solid, vacuum-drying obtains title product (Z)-5-(2-methoxyl group-3-{N '-[3-methyl-5-oxo-1-(5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid 2 (380mg, yellow solid), productive rate: 41.7%.
MS?m/z(ESI)：473.1[M+I]
1HNMR(400MHz，DMSO-d 6)：δ13.73(br，1H)，13.23(br，1H)，7.78(d，1H)，7.63(m，3H)，7.41(dd，2H)，7.16(m，2H)，3.85(s，3H)，2.77(m，4H)，2.32(s，3H)，1.75(m，4H)
Embodiment 3
(Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-Asia Base]-diazanyl }-phenyl)-3-methyl-furans-2-carboxylic acid
Figure B2009100536910D0000201
The first step
5-bromo-3-methyl-furans-2-carboxylate methyl ester
Adopt known method Tetrahedron Letters, 2001,42,2643-2644, (7g 0.05mol) melts under 50 ℃ and is liquid, slowly dripping bromine (11.97g with 3-methyl-furans-2-carboxylate methyl ester 3a, 0.075mol), drip to finish, in 50 ℃ of reactions 15 minutes down, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, in reaction solution, add the 20mL ethyl acetate, concentrating under reduced pressure with silica gel column chromatography purifying gained resistates, obtains 5-bromo-3-methyl-furans-2-carboxylate methyl ester 3b (8.5g, white solid), productive rate: 78.0%.
MS?m/z(ESI)：221.0[M+1]
Second step
5-(2-methoxyl group-3-nitro-phenyl)-3-methyl-furans-2-carboxylate methyl ester
With 2-(2-methoxyl group-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] two assorted oxygen pentaborane 1f (15.29g, 55mmol) be dissolved in 100mL 1, in the mixed solvent of 4-dioxane and 25mL water, add 5-bromo-3-methyl-furans-2-carboxylate methyl ester 3b (6g, 27mmol), tetrakis triphenylphosphine palladium (1.58g, 1.37mmol) and yellow soda ash (6.39g, 60.2mmol), in 100 ℃ of following stirring reactions 2.5 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, the concentrating under reduced pressure reaction solution adds 100mL ethyl acetate and 100mL water, removes by filter insolubles, separatory, water merges organic phase, anhydrous sodium sulfate drying with ethyl acetate extraction (100mL * 4), filter, concentrating under reduced pressure filtrate with silica gel column chromatography purifying gained resistates, obtains 5-(2-methoxyl group-3-nitro-phenyl)-3-methyl-furans-2-carboxylate methyl ester 3c (5.8g, yellow solid), productive rate: 72.8%.
MS?m/z(ESI)：292.1[M+1]
The 3rd step
5-(3-amino-2-methoxyl group-phenyl)-3-methyl-furans-2-carboxylate methyl ester
With 5-(2-methoxyl group-3-nitro-phenyl)-3-methyl-furans-2-carboxylate methyl ester 3c (2.8g, 9.6mmol) be dissolved in the 120mL ethyl acetate, add ammonium formiate (6.06g, 96mmol) with 300mg palladium/carbon (10%), in 70 ℃ of following stirring reactions 24 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 5-(3-amino-2-methoxyl group-phenyl)-3-methyl-furans-2-carboxylate methyl ester 3d (2.3g, white solid), productive rate: 92.0%.
1HNMR(400MHz，CDCl 3)：δ7.30(t，1H)，6.99(t，1H)，6.87(s，1H)，6.74(d，1H)，3.91(s，3H)，3.75(s，3H)，2.42(s，3H)
The 4th step
5-(3-amino-2-methoxyl group-phenyl)-3-methyl-furans-2-carboxylic acid
With 5-(3-amino-2-methoxyl group-phenyl)-3-methyl-furans-2-carboxylate methyl ester 3d (3.7g, 14mmol) be dissolved in the 50mL methyl alcohol, with sodium hydroxide (2.27g, 57mmol) be dissolved in the 20mL water, join in the reaction solution, in 50 ℃ of following stirring reactions 1.5 hours, thin-layer chromatography was followed the tracks of to react to raw material and is disappeared the concentrating under reduced pressure reaction solution, hydrochloric acid adjust pH to 6 with 1N, filter, filter cake washs with less water, collects solid, vacuum-drying, obtain 5-(3-amino-2-methoxyl group-phenyl)-3-methyl-furans-2-carboxylic acid 3e (3.4g, white solid), productive rate: 97.1%.
MS?m/z(ESI)：246.1[M-1]
The 5th step
5-(3-amino-2-hydroxyl-phenyl)-3-methyl-furans-2-carboxylic acid hydrobromate
With 5-(3-amino-2-methoxyl group-phenyl)-3-methyl-furans-2-carboxylic acid 3e (3.3g, 13.4mmol) be dissolved in the methylene dichloride that 100mL heavily steams, dichloromethane solution (the 40mL that adds boron tribromide, 40mmol), stirring reaction 6 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, add 5mL methyl alcohol cancellation reaction in the ice bath downhill reaction liquid, the concentrating under reduced pressure reaction solution, in resistates, add 50mL ethyl acetate and 5mL methyl alcohol, stir 10 minutes after-filtration, filter cake is collected solid with the mixed solvent washing of ethyl acetate (200mL) and methyl alcohol (20mL), obtains 5-(3-amino-2-hydroxyl-phenyl)-3-methyl-furans-2-carboxylic acid hydrobromate 3f (4g, pale solid), productive rate: 95.4%.
MS?m/z(ESI)：232.1[M-1]
The 6th step
(Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-3-methyl-furans-2-carboxylic acid
Under the ice bath, (400mg 1.27mmol) is dissolved in the hydrochloric acid of 4.3mL 1N with 5-(3-amino-2-hydroxyl-phenyl)-3-methyl-furans-2-carboxylic acid hydrobromate 3f, (96mg 1.40mmol), adds 5-methyl-2-(5 to drip the 1.7mL sodium nitrite in aqueous solution, 6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone 1m (261mg, 1.15mmol) and sodium bicarbonate (96mg, 1.40mmol), with ethanol cancellation bubble, stirring reaction 16 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filter, filter cake 20mL water dissolution is with concentrated hydrochloric acid adjust pH to 3～4, filter, filter cake washs (5mL * 4) with ethyl acetate, and concentrating under reduced pressure filtrate is used the HPLC separation and purification, merge with filter cake, obtain title product (Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-3-methyl-furans-2-carboxylic acid 3 (93mg, red solid), productive rate: 17.2%.
MS?m/z(ESI)：471.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.73(br，1H)，13.05(br，1H)，9.91(br，1H)，7.70(dd，1H)，7.62(m，2H)，7.52(dd，1H)，7.19(t，1H)，7.12(d，1H)，7.04(s，1H)，2.71(m，4H)，2.35(s，3H)，2.31(s，3H)，1.75(m，4H)
Embodiment 4
(Z)-2 '-hydroxyl-3 '-N '-[3-methyl-5-oxo-1-(3-oxo-indenes-5-yl)-1,5-dihydro-pyrazoles-4-subunit]-hydrazine Base }-xenyl-3-carboxylic acid
The first step
2 '-methoxyl group-3 '-nitrobiphenyl base-3-carboxylic acid
With 1-bromo-2-methoxyl group-3-nitro-benzene 1e (23.25g, 0.10mol) be dissolved in sodium carbonate solution and the 500mL 1 of 100mL 2N, in the mixed solvent of 4-dioxane, add 3-carboxyl phenyl boric acid (19.5g, 0.117mol) and tetrakis triphenylphosphine palladium (8.86g, 7.7mol), in 105 ℃ of following heating reflux reactions 43 hours, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, concentrating under reduced pressure reaction solution, hydrochloric acid soln and the 400mL ethyl acetate of adding 300mL 6N, separatory, water merges organic phase, anhydrous magnesium sulfate drying with ethyl acetate extraction (200mL * 2), filter, concentrating under reduced pressure filtrate, obtain 2 '-methoxyl group-3 '-nitrobiphenyl base-3-carboxylic acid 4a (53.93g, light yellow solid).
MS?m/z(ESI)：272[M-1]
1HNMR(400MHz，CDCl 3)：δ8.11(s，1H)，8.01-8.03(d，J＝8Hz，1H)，7.90-7.92(m，1H)，7.82-7.84(m，1H)，7.21-7.75(m，1H)，7.63-7.67(m，1H)，7.42-7.46(m，1H)，3.44-3.46(d，J＝8Hz，3H)
Second step
2 '-methoxyl group-3 '-phenylaniline base-3-carboxylic acid
With 2 '-methoxyl group-3 '-nitrobiphenyl base-3-carboxylic acid 4a (0.48g, 1.74mmol) be dissolved in the 60mL ethanol, adding 0.5g palladium/carbon (10%) and ammonium formiate (1.1g, 17.4mmol), in 80 ℃ of following heating reflux reactions 20 minutes, thin-layer chromatography is followed the tracks of and is reacted to raw material disappearance, filtering reacting liquid, concentrating under reduced pressure filtrate, vacuum-drying, obtain 2 '-methoxyl group-3 '-phenylaniline base-3-carboxylic acid 4b (0.42g, white solid), productive rate: 93.3%.
MS?m/z(ESI)：242[M-1]
The 3rd step
3 '-amino-2 '-Hydroxybiphenyl-3-carboxylic acid hydrobromate
With 2 '-methoxyl group-3 '-phenylaniline base-3-carboxylic acid 4b (2.5g, 10.3mmol) be dissolved in the hydrobromic acid solution of 100mL 40%, in 120 ℃ of following heating reflux reactions 16 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, the concentrating under reduced pressure reaction solution, with silica gel column chromatography purifying gained resistates, obtain 3 '-amino-2 '-Hydroxybiphenyl-3-carboxylic acid hydrobromate 4c (2.4g, the khaki color solid), productive rate: 88.8%.
MS?m/z(ESI)：230[M+1]
The 4th step
6-nitro-1-Indanone
Under the ice bath, (20.18g 152.9mmol) is dissolved in the 100mL vitriol oil with 1-Indanone 4d, add in batches saltpetre (16.76g, 165.9mmol), stirring reaction is 48 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, reaction solution is poured in the ice, stirred 30 minutes, filter, the ethyl acetate extraction of filtrate usefulness equivalent once, the filter cake acetic acid ethyl dissolution, the organic phase that obtains with extraction merges, and washes (300mL) with water, with saturated common salt washing (300mL), anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 6-nitro-1-Indanone 4e (12.03g, light yellow solid), productive rate: 44.5%.
1HNMR(400MHz，CDCl 3)：δ8.62(d，1H)，8.50(dd，1H)，7.71(d，1H)，3.32(t，2H)，2.88(m，2H)
The 5th step
6-amino-1-Indanone
With 6-nitro-1-Indanone 4e (5.45g, 30.8mmol) be dissolved in the mixed solvent of 60mL ethanol and 20mL water, add the 5mL ethyl acetate, iron (5.30g, 94.6mmol) and ammonium chloride (0.69g, 12.9mmol), heating reflux reaction 0.5 hour, thin-layer chromatography are followed the tracks of and are reacted to the raw material disappearance, add 200mL methyl alcohol dilute reaction solution, filter, filter cake methanol wash (100mL), concentrating under reduced pressure filtrate adds 200mL ethyl acetate and 200mL water in resistates, separatory, merge organic phase, anhydrous sodium sulfate drying filters, concentrating under reduced pressure filtrate, obtain 6-amino-1-Indanone 4f (3.76g, yellow solid), productive rate: 83.0%.
MS?m/z(ESI)：148.1[M+1]
1HNMR(400MHz，DMSO-d 6)：δ7.22(d，1H)，6.92(dd，1H)，6.75(d，1H)，5.27(s，2H)，2.90(t，2H)，2.54(m，2H)
The 6th step
6-diazanyl-1-Indanone hydrochloride
(1.20g 8.16mmol) is dissolved in the mixed solvent of 15mL concentrated hydrochloric acid and 15mL water, and (656mg, 9.51mmol), the ice bath cooling is standby to add Sodium Nitrite with 6-amino-1-Indanone 4f.
Tin protochloride is dissolved in the 20mL concentrated hydrochloric acid, adds standby midbody solution, stirring reaction is 3 hours under the ice bath, obtains crude product 6-diazanyl-1-Indanone hydrochloride 4g, is directly used in next step reaction without separation.
The 7th step
5-methyl-2-(3-oxo-indenes-5-yl)-2,4-dihydro-pyrazoles-3-ketone
With crude product 6-diazanyl-1-Indanone hydrochloride 4g (1.62g, 8.16mmol) be dissolved in the 20mL ethanol, add the 1.2mL methyl acetoacetate, reacted 1 hour down in 80 ℃, the concentrating under reduced pressure reaction solution adds 30mL water, transfer reacting liquid pH value to＞7 with sodium hydroxide, with ethyl acetate extraction reaction solution (50mL * 3), merge organic phase, with saturated common salt washing (100mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate is with silica gel column chromatography purifying gained resistates, obtain 5-methyl-2-(3-oxo-indenes-5-yl)-2,4-dihydro-pyrazoles-3-ketone 4h (478mg, yellow solid), productive rate: 25.7%.
MS?m/z(ESI)：229.1[M+1]
1HNMR(400MHz，CDCl 3)：δ8.27(dd，1H)，8.23(d，1H)，7.53(dd，1H)，3.50(s，2H)，3.18(t，2H)，2.77(m，2H)，2.25(s，3H)
The 8th step
(Z)-2 '-hydroxyl-3 '-N '-[3-methyl-5-oxo-1-(3-oxo-indenes-5-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-xenyl-3-carboxylic acid
With 3 '-amino-2 '-Hydroxybiphenyl-3-carboxylic acid hydrobromate 4c (259mg, 0.86mmol) be dissolved in the hydrochloric acid of 6mL1N, under the ice bath, add Sodium Nitrite (64mg, 0.93mmol) and 5-methyl-2-(3-oxo-indenes-5-yl)-2, and 4-dihydro-pyrazoles-3-ketone 4h (160mg, 0.70mmol), add sodium bicarbonate (1.07g in batches, 12.7mmol), with small amount of ethanol cancellation bubble, stirring reaction is 16 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, filter cake washs with less water, collects solid, hydrochloric acid adjust pH to 3～4 with 1N, filter, filter cake washs with less water, collects solid, dissolve with tetrahydrofuran (THF), concentrating under reduced pressure, obtain title product (Z)-2 '-hydroxyl-3 '-{ N '-[3-methyl-5-oxo-1-(3-oxo-indenes-5-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-xenyl-3-carboxylic acid 4 (230mg, tangerine look solid), productive rate: 56.9%.
MS?m/z(ESI)：467.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.69(s，1H)，13.07(br，1H)，9.72(s，1H)，8.23(d，1H)，8.14(d，2H)，7.97(d，1H)，7.80(d，1H)，7.64(m，3H)，7.15(m，2H)，3.10(m，2H)，2.69(m，2H)，2.40(s，3H)
Embodiment 5
(Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(3-oxo-indenes-5-yl)-1,5-dihydro-pyrazoles-4-subunit]-hydrazine Base }-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000251
The first step
5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate
With 5-(3-amino-2-methoxyl group-phenyl)-furans-2-carboxylic acid 2b (4.25g, 18.24mmol) be dissolved in the 50mL methylene dichloride, dichloromethane solution (the 34mL that adds the boron tribromide of 1.06N, 36.48mmol), stirring reaction is 24 hours under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, adds 50mL methyl alcohol cancellation reaction, the concentrating under reduced pressure reaction solution, with ethyl acetate debris (50mL), filter, filter cake is collected solid with the mixed solvent washing of ethyl acetate (40mL) and methyl alcohol (10mL), vacuum-drying, obtain 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a (2.09g, gray solid), productive rate: 52.3%.
MS?m/z(ESI)：217.7[M-1]
Second step
(Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(3-oxo-indenes-5-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
With 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a (250mg, 0.80mmol) be dissolved in the hydrochloric acid of 6mL 1N, the ice bath cooling, add Sodium Nitrite (74mg, 1.07mmol) and 5-methyl-2-(3-oxo-indenes-5-yl)-2,4-dihydro-pyrazoles-3-ketone 4h (158mg, 0.69mmol), add in batches sodium bicarbonate (1.0g, 11.9mmol), with small amount of ethanol cancellation bubble, stirring reaction 1.5 hours, thin-layer chromatography are followed the tracks of and are reacted to raw material disappearance, filtering reacting liquid, filter cake is used hydrochloric acid adjust pH to 3～4 of 1N, filter, filter cake is collected solid with ethyl acetate washing (10mL), dissolve with tetrahydrofuran (THF), concentrating under reduced pressure obtains title product (Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(3-oxo-indenes-5-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid 5 (110mg, brown solid), productive rate: 30.1%.
MS?m/z(ESI)：457.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.66(s，1H)，10.01(s，1H)，8.22(d，1H)，8.15(s，1H)，7.69(m，2H)，7.54(m，1H)，7.36(d，1H)，7.20(t，1H)，3.02(m，2H)，2.61(t，2H)，2.33(s，3H)
Embodiment 6
(Z)-3 '-N '-[1-(8,8-dimethyl-5,6,7-8-naphthane-2-yl)-3-methyl-5-hydrogen generation-1,5-dihydro-pyrrole Base]-diazanyl }-2 '-hydroxyl-xenyl-3-carboxylic acid
Figure B2009100536910D0000261
The first step
7-nitro-3,4-dihydro-2H-naphthalene-1-ketone
Under the ice bath, with 3,4-dihydro-2H-naphthalene-1-ketone 6a (20g, 0.14mol) be dissolved in the 125mL vitriol oil, add in batches saltpetre (15.2g, 0.15mol), in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, and reaction solution is poured in the frozen water, filters, filter cake washes (20mL * 3) with water, collect solid, add acetic acid ethyl dissolution, use the silica gel column chromatography purifying, obtain 7-nitro-3,4-dihydro-2H-naphthalene-1-ketone 6b (16.8g, yellow solid), productive rate: 64.6%.
1HNMR(400MHz，CDCl 3)：δ8.84(d，1H)，8.30(dd，1H)，7.47(d，1H)，3.09(t，2H)，2.74(t，2H)，2.21(m，2H)
Second step
7-amino-3,4-dihydro-2H-naphthalene-1-ketone
With 7-nitro-3,4-dihydro-2H-naphthalene-1-ketone 6b (7.5g, 0.04mol) be dissolved in the mixed solvent of 100mL ethanol and 25mL water, add iron (8.3g, 0.148mol) and ammonium chloride (856mg, 0.016mol), heating reflux reaction 1 hour, thin-layer chromatography are followed the tracks of and are reacted to raw material disappearance, concentrating under reduced pressure reaction solution, with dichloromethane extraction (50mL * 3), merge organic phase, wash (50mL) with water, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate obtains 7-amino-3,4-dihydro-2H-naphthalene-1-ketone 6c (6.2g, the khaki color solid), productive rate: 98.1%.
MS?m/z(ESI)：162.4[M+1]
1HNMR(400MHz，CDCl 3)：δ7.32(d，1H)，7.04(d，1H)，6.83(dd，1H)，3.71(br，2H)，2.84(t，2H)，2.62(m，2H)，2.07(m，2H)
The 3rd step
7-iodo-3,4-dihydro-2H-naphthalene-1-ketone
With 7-amino-3,4-dihydro-2H-naphthalene-1-ketone 6c (4.0g, 25mmol) be dissolved in the 20mL acetonitrile, add the mixed solvent of 20mL concentrated hydrochloric acid and 60mL water, ice bath drips the aqueous solution (1.9g of 8mL Sodium Nitrite down, 27.5mmol), drip to finish,, add potassiumiodide (8.7g in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, 52.5mmol), stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to the raw material disappearance, with ethyl acetate extraction reaction solution (50mL * 3), merge organic phase, with saturated sodium bisulfite solution washing (50mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 7-iodo-3,4-dihydro-2H-naphthalene-1-ketone 6d (5.2g, red solid), productive rate: 76.5%.
1HNMR(400MHz，CDCl 3)：δ8.34(d，1H)，7.76(dd，1H)，7.02(d，1H)，2.96(m，2H)，2.64(m，2H)，2.13(m，2H)
The 4th step
7-iodo-1,1-dimethyl-1,2,3,4-naphthane
(3.71mL 33.8mmol) is dissolved in the 100mL methylene dichloride, is chilled to-40 ℃ with titanium tetrachloride, drip zinc methide (42.3mL, 50.7mmol), with 7-iodo-3,4-dihydro-2H-naphthalene-1-ketone 6d (4.6g, 16.9mmol) be dissolved in the 50mL methylene dichloride, splash in the reaction solution under-40 ℃, stirring reaction 16 hours, thin-layer chromatography are followed the tracks of to react to raw material and are disappeared, add small amount of methanol cancellation reaction, the concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains 7-iodo-1,1-dimethyl-1,2,3,4-naphthane 6e (3.98g, colorless oil), productive rate: 82.4%.
1HNMR(400MHz，CDCl 3)：δ7.61(s，1H)，7.36(dd，1H)，6.77(d，1H)，2.71-2.65(m，2H)，1.81-1.75(m，2H)，1.64-1.61(m，2H)，1.26(s，6H)
The 5th step
N-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-diazanyl carboxylic acid tert-butyl ester
With 2-oxo-cyclohexane carboxylic acid ethyl ester (0.41mL, 2.58mmol), cuprous iodide (0.70g, 3.67mmol) and cesium carbonate (7.1g, 21.76mmol) be dissolved in the 50mL dimethyl sulfoxide (DMSO), with 7-iodo-1,1-dimethyl-1,2,3, and 4-naphthane 6e (3.9g, 13.6mmol) and tert-butyl carbazate (1.80g, 17.7mmol) be dissolved in the 50mL dimethyl sulfoxide (DMSO), splash into reaction solution, in 80 ℃ of following stirring reactions 2 hours, thin-layer chromatography was followed the tracks of to react to raw material and is disappeared, in reaction solution, add 300mL water, filter,, merge organic phase with ethyl acetate extraction filtrate (150mL * 2), with saturated common salt water washing (200mL), anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain N-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-and diazanyl carboxylic acid tert-butyl ester 6f (3.52g, yellow oil), productive rate: 89.3%.
1HNMR(400MHz，CDCl 3)：δ7.37(s，1H)，7.16(dd，1H)，7.02(d，1H)，4.74(s，1H)，2.78-2.75(m，2H)，1.86-1.80(m，2H)，1.71-1.68(m，2H)，1.51(s，4H)，1.32(s，6H)
The 6th step
2-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-dihydro-pyrazoles-3-ketone
With N '-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-(3.5g 12.1mmol) is dissolved in the 20mL acetate diazanyl carboxylic acid tert-butyl ester 6f, add the 20mL trifluoroacetic acid, stirring reaction is 30 minutes under the room temperature, adds methyl acetoacetate (1.38mL, 12.7mmol), in 90 ℃ of following stirring reactions 2 hours, thin-layer chromatography was followed the tracks of to react to raw material and is disappeared, the concentrating under reduced pressure reaction solution to neutral, is used ethyl acetate extraction (100mL * 3) with the saturated sodium bicarbonate solution adjust pH, merge organic phase, with saturated common salt water washing (200mL), anhydrous magnesium sulfate drying filters, concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 2-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-dihydro-pyrazoles-3-ketone 6g (0.88g, yellow solid), productive rate: 28.4%.
1HNMR(400MHz，CDCl 3)：δ7.78(s，1H)，7.54(dd，1H)，7.07(d，1H)，3.44(s，2H)，2.79-2.71(m，2H)，2.20(s，3H)，1.86-1.79(m，2H)，1.70-1.64(m，2H)，1.33(s，6H)
The 7th step
(Z)-3 '-N '-[1-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-2 '-hydroxyl-xenyl-3-carboxylic acid
Under the ice bath, with 3 '-amino-2 '-(404mg 1.30mmol) is dissolved in the hydrochloric acid of 4.6mL 1N Hydroxybiphenyl-3-carboxylic acid hydrobromate 4c, the aqueous solution of dropping 1.6mL Sodium Nitrite (99mg, 1.43mmol), stirring reaction 20 minutes, adding 2-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-dihydro-pyrazoles-3-ketone 6g (300mg, 1.17mmol) and sodium bicarbonate (1.64g, 19.53mmol), with small amount of ethanol cancellation bubble, stirring reaction 48 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, filter cake 30mL water dissolution is with concentrated hydrochloric acid adjust pH to 3～4, filter, filter cake is collected solid, vacuum-drying with ethyl acetate washing (4mL * 3), obtain title product (Z)-3 '-N '-[1-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-2 '-hydroxyl-xenyl-3-carboxylic acid 6 (220mg, red solid), productive rate: 37.9%.
MS?m/z(ESI)：495.3[M-1]
1HNMR(400MHz，DMSO-d 6)：δ8.13(s，1H)，7.95(d，1H)，7.90(s，1H)，7.80(d，1H)，7.72(m，1H)，7.59(m，2H)，7.12(m，3H)，2.72(m，2H)，2.34(s，3H)，1.75(m，2H)，1.65(m，2H)，1.27(s，6H)
Embodiment 7
(Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(8-oxo-5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles -4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000291
The first step
7-diazanyl-3,4-dihydro-2H-naphthalene-1-keto hydrochloride
With 7-amino-3,4-dihydro-2H-naphthalene-1-ketone 6c (4.0g, 25mmol) be dissolved in the mixed solvent of 20mL concentrated hydrochloric acid and 20mL water, in 0 ℃-5 ℃ aqueous solution (1.89g that drip Sodium Nitrite down, 27.5mmol), drip and finish, stirring reaction 30 minutes is with a hydration zinc chloride (16.95g, 75mmol) be dissolved in the 30mL concentrated hydrochloric acid, splash into reaction solution under 0 ℃-5 ℃, stirring reaction is 3 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and disappeared, filtering reacting liquid, filter cake is collected solid, vacuum-drying with the salt acid elution (3mL * 4) of 1N, obtain 7-diazanyl-3,4-dihydro-2H-naphthalene-1-keto hydrochloride 7a (6.8g, light yellow solid) is directly used in next step reaction without separation.
Second step
5-methyl-2-(8-oxo-5,6,7,8-naphthane-2-yl)-2,4-dihydro-pyrazoles-3-ketone
With 7-diazanyl-3, (5.36g 25mmol) is dissolved in the 20mL acetate 4-dihydro-2H-naphthalene-1-keto hydrochloride 7a, add methyl acetoacetate (14.5g, 125mmol), in 80 ℃ of following stirring reactions 2 hours, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, and the concentrating under reduced pressure reaction solution adds 50mL methylene dichloride and 50mL water, separatory, water merges organic phase, anhydrous magnesium sulfate drying with dichloromethane extraction (50mL * 2), filter, concentrating under reduced pressure filtrate with silica gel column chromatography purifying gained resistates, obtains 5-methyl-2-(8-oxo-5,6,7,8-naphthane-2-yl)-2,4-dihydro-pyrazoles-3-ketone 7b (2.5g, yellow solid), productive rate: 41.7%.
The 3rd step
(Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(8-oxo-5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
With 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a (300mg, 1mmol) be dissolved in the hydrochloric acid soln of 5mL 1N, in 0 ℃-5 ℃ aqueous solution (76mg that drip the 1mL Sodium Nitrite down, 1.1mmol), stirring reaction 0.5 hour adds 5-methyl-2-(8-oxo-5,6,7,8-naphthane-2-yl)-2,4-dihydro-pyrazoles-3-ketone 7b (218mg, 0.9mmol), sodium bicarbonate (1.26g, 15mmol) and 2mL ethanol, stirring reaction is 10 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and disappeared, filtering reacting liquid, filter cake filters with the hydrochloric acid adjust pH to 3 of 1N, collects solid, vacuum-drying, obtain title product (Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(8-oxo-5,6,7,8-naphthane-2-yl)-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid 7 (312mg, yellow solid), productive rate: 66.1%.
MS?m/z(ESI)：471.1[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.71(br，1H)，10.04(br，1H)，8.19(s，1H)，7.90(d，1H)，7.69(d，1H)，7.54(d，1H)，7.39(m，2H)，7.23(m，2H)，2.95(s，3H)，2.62(m，2H)，2.12(m，4H)
Embodiment 8
(Z)-5-(2-hydroxyl-3-{N '-[1-(8-hydroxyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazoles -4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000301
The first step
2-(8-hydroxyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-dihydro-pyrazoles-3-ketone
With 5-methyl-2-(8-oxo-5,6,7,8-naphthane-2-yl)-2,4-dihydro-pyrazoles-3-ketone 7b (1.0g, 4.13mmol) be dissolved in the 20mL tetrahydrofuran (THF), slow adding lithium borohydrides under 10 ℃ (135mg, 6.2mmol), stirring reaction is 0.5 hour under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, adds small amount of methanol cancellation reaction, the concentrating under reduced pressure reaction solution, with silica gel column chromatography purifying gained resistates, obtain 2-(8-hydroxyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-dihydro-pyrazoles-3-ketone 8a (850mg, yellow solid), productive rate: 85.0%.
MS?m/z(ESI)：245.2[M+1]
1HNMR(400MHz，CDCl 3)：δ7.87(d，1H)，7.67(dd，1H)，7.13(dd，1H)，4.79(m，1H)，3.48(s，2H)，2.71(m，2H)，2.19(s，3H)，1.92(m，4H)
Second step
(Z)-5-(2-hydroxyl-3-{N '-[1-(8-hydroxyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
With 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a (285mg, 0.95mmol) be dissolved in the hydrochloric acid soln of 4mL 1N, in 0 ℃-5 ℃ aqueous solution (72mg that drip the 1mL Sodium Nitrite down, 1.05mmol), drip and finish, stirring reaction 0.5 hour, add 2-(8-hydroxyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-dihydro-pyrazoles-3-ketone 8a (210mg, 0.86mmol), sodium bicarbonate (1.2g, 14.25mmol) with 2mL ethanol, stirring reaction is 16 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, filter cake wash (2mL * 3) with water, the filter cake hydrochloric acid adjust pH to 3 of 1N, filter, filter cake washes (3mL * 3) with water, with the mixed solvent washing of 8mL methylene dichloride and 2mL methyl alcohol, collects solid, vacuum-drying, obtain title product (Z)-5-(2-hydroxyl-3-{N '-[1-(8-hydroxyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid 8 (280mg, red solid), productive rate: 62.2%.
MS?m/z(ESI)：473.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.77(br，1H)，13.12(br，1H)，9.96(br，1H)，7.98(s，1H)，7.84(m，2H)，7.54(d，1H)，7.36(d，1H)，7.19(m，3H)，4.58(m，1H)，2.71(m，2H)，2.32(s，3H)，1.97(m，4H)
Embodiment 9
(Z)-2 '-hydroxyl-3 '-N '-[3-methyl-5-oxo-1-(1-oxo-indenes-5-yl)-1,5-pyrazoline-4-subunit]-hydrazine Base }-xenyl-3-carboxylic acid
Figure B2009100536910D0000311
The first step
N-indenes-5-base-ethanamide
With indenes-5-base amine 9a (40g, 300mmol) be dissolved in the 500mL methylene dichloride, and the adding trolamine (28.2g, 360mmol), in 0 ℃ of dichloromethane solution (28.2g that adds the 100mL Acetyl Chloride 98Min. down, 360mmol), stirring reaction is 2 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and disappeared, filtering reacting liquid, concentrating under reduced pressure filtrate adds 200mL water, the hydrochloric acid soln of 100mL 1N and 200mL ethyl acetate, separatory, water ethyl acetate extraction (200mL * 3), merge organic phase, with saturated sodium bicarbonate solution washing (50mL), with saturated common salt water washing (50mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate is with the mixed solvent washing of 20mL normal hexane and 10mL ethyl acetate, vacuum-drying, obtain N-indenes-5-base-ethanamide 9b (45g, white solid), productive rate: 85.7%.
Second step
N-(1-oxo-indenes-5-yl)-ethanamide
With N-indenes-5-base-ethanamide 9b (45g, 0.257mmol) be dissolved in the 450mL acetate, under 80 ℃, add in batches chromium trioxide (51.3g, 0.513mol), stirring reaction 2 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, the concentrating under reduced pressure reaction solution adds 300mL water and 300mL ethyl acetate, separatory in resistates, water ethyl acetate extraction (200mL * 3), merge organic phase, with saturated common salt water washing (200mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate with 50mL normal hexane and 50mL re-crystallizing in ethyl acetate, obtains N-(1-oxo-indenes-5-yl)-ethanamide 9c (25g, yellow solid), productive rate: 81.7%.
1HNMR(400MHz，CDCl 3)：δ7.97(s，1H)，7.71(d，1H)，7.58(s，1H)，7.25(d，1H)，3.12(t，2H)，3.69(t，2H)，2.23(s，3H)
The 3rd step
5-amino-1-Indanone hydrochloride
With N-(1-oxo-indenes-5-yl)-ethanamide 9c (10.0g, 52.9mmol) and the hydrochloric acid soln of 10mL 6N put into reaction flask, in 60 ℃ of following stirring reactions 2 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, obtain crude product 5-amino-1-Indanone hydrochloride 9d, be directly used in next step reaction without separation.
The 4th step
5-methyl-2-(1-oxo-indenes-5-yl)-2,4-pyrazoline-3-ketone
Under 0 ℃ to crude product 5-amino-1-Indanone hydrochloride 9d (10.5g, add in 52.9mmol) the 10mL Sodium Nitrite the aqueous solution (3.65g, 52.9mmol), drip to finish and stirred 30 minutes, (23.8g 105.78mmol) is dissolved in the 100mL concentrated hydrochloric acid, splashes in the reaction solution under 0 ℃ with tin protochloride, drip and finish, stirring reaction 1 hour, add again 50mL ethanol and methyl acetoacetate (6.14g, 52.9mmol), in 70 ℃ of following stirring reactions 1 hour, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, and the concentrating under reduced pressure reaction solution is extremely neutral with the saturated sodium bicarbonate solution adjust pH, filter, remove insolubles, with ethyl acetate extraction filtrate (200mL), water ethyl acetate extraction (50mL * 3), merge organic phase, with saturated common salt water washing (50mL), anhydrous sodium sulfate drying filters, concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 5-methyl-2-(1-oxo-indenes-5-yl)-2,4-pyrazoline-3-ketone 9e (2.0g, light yellow solid), productive rate: 16.6%.
The 5th step
(Z)-2 '-hydroxyl-3 '-N '-[3-methyl-5-oxo-1-(1-oxo-indenes-5-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-phenylbenzene-3-carboxylic acid
With 3 '-amino-2 '-Hydroxybiphenyl-3-carboxylic acid hydrobromate 4c (341mg, 1.1mmol) be dissolved in the hydrochloric acid soln of 4mL1N, the ice bath cooling, drip the aqueous solution (83mg of 1mL Sodium Nitrite, 1.2mmol), in 0 ℃ of following stirring reaction 0.5 hour, add 5-methyl-2-(1-oxo-indenes-5-yl)-2,4-pyrazoline-3-ketone 9e (250mg, 1.1mmol), with sodium bicarbonate adjust pH to 9, stirring reaction is 4 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and disappeared, hydrochloric acid adjust pH with 1N is extremely acid, filter, collect solid, vacuum-drying, obtain title product (Z)-2 '-hydroxyl-3 '-N '-[3-methyl-5-oxo-1-(1-oxo-indenes-5-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-phenylbenzene-3-carboxylic acid 9 (120mg, yellow solid), productive rate: 23.3%.
1HNMR(400MHz，DMSO-d 6)：δ13.72(s，1H)，13.04(s，1H)，9.73(s，1H)，8.13(s，1H)，8.11(s，1H)，8.05(d，1H)，7.93(d，1H)，7.80(d，1H)，7.69(m，2H)，7.62(t，1H)，7.14(m，2H)，3.13(t，2H)，2.64(t，2H)，2.36(s，3H)
Embodiment 10
(Z)-2 '-hydroxyl-3 '-N '-[1-(3-hydroxyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-hydrazine Base }-xenyl-3-carboxylic acid
Figure B2009100536910D0000331
The first step
2-(3-hydroxyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone
With 5-methyl-2-(3-oxo-indenes-5-yl)-2,4-dihydro-pyrazoles-3-ketone 4h (610mg, 2.68mmol) be dissolved in the 40mL anhydrous tetrahydro furan, the ice bath cooling, add lithium borohydride (96mg, 4.40mmol), stirring reaction is 10 minutes under the ice bath, and thin-layer chromatography is followed the tracks of and reacted to the raw material disappearance, adds 10mL methyl alcohol cancellation reaction, the concentrating under reduced pressure reaction solution, with silica gel column chromatography purifying gained resistates, obtain 2-(3-hydroxyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 10a (497mg, light yellow solid), productive rate: 80.8%.
1HNMR(400MHz，CDCl 3)：δ7.88(s，1H)，7.45(dd，1H)，7.26(d，1H)，5.26(t，1H)，3.43(s，2H)，3.08(m，1H)，2.81(m，1H)，2.51(m，1H)，2.20(s，3H)，1.98(m，1H)
Second step
(Z)-2 '-hydroxyl-3 '-N '-[1-(3-hydroxyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-xenyl-3-carboxylic acid
With 3 '-amino-2 '-Hydroxybiphenyl-3-carboxylic acid hydrobromate 4c (380mg, 1.27mmol) be dissolved in the hydrochloric acid soln of 10mL 1N, the adding Sodium Nitrite (110mg, 1.59mmol), stirring reaction is 20 minutes under the ice bath, add 2-(3-hydroxyl-indenes-5-yl)-5-methyl-2, (170mg 0.74mmol), adds sodium bicarbonate (1.56g to 4-pyrazoline-3-ketone 10a in batches, 18.57mmol), with small amount of ethanol cancellation bubble, stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and disappeared, filtering reacting liquid, filter cake washs with less water, with hydrochloric acid adjust pH to 3～4 of 1N, filters, filter cake washs with less water, collect solid, with tetrahydrofuran (THF) dissolving, concentrating under reduced pressure, use the 3-4mL washed with dichloromethane, vacuum-drying, obtain title product (Z)-2 '-hydroxyl-3 '-{ N '-[1-(3-hydroxyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-xenyl-3-carboxylic acid 10 (221mg, pale brown look solid), productive rate: 63.6%.
MS?m/z(ESI)：469.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.76(s，1H)，13.09(br，1H)，9.65(s，1H)，8.17(s，1H)，7.98(d，1H)，7.95(d，1H)，7.79(dd，1H)，7.78(dd，1H)，7.72(dd，1H)，7.62(t，1H)，7.27(d，1H)，7.16(dd，1H)，5.07(t，1H)，2.89(m，1H)，2.73(m，1H)，2.37(s，3H)，2.35(m，4H)，1.79(m，1H)
Embodiment 11
(Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5-oxo-5,6,7,8-naphthane-2-yl)-1,5-pyrazoline -4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000341
The first step
5-methyl-2-(5-oxo-5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone
With 6-amino-3, (6g 37.22mmol) is dissolved in the mixed solvent of 50mL concentrated hydrochloric acid and 50mL water 4-dihydro-2H-naphthalene-1-ketone 11a, and under the ice bath, (3.775g, 54.72mmol), ice bath reaction 30 minutes down is standby to add the aqueous solution of 25mL Sodium Nitrite.
With tin protochloride (26.115g, 115,76mmol) be dissolved in the 50mL concentrated hydrochloric acid, splash into standby midbody solution under the ice bath, drip and finish, stirring reaction is 3 hours under the ice bath, and adding 200mL ethanol and methyl acetoacetate in reaction solution (4.5mL, 40.94mmol), in 80 ℃ of following stirring reactions 1.5 hours, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, the concentrating under reduced pressure reaction solution, and resistates is used sodium hydroxide and sodium bicarbonate adjust pH to 8～9, filter, filtrate merges organic phase with dichloromethane extraction (200mL * 4), with saturated common salt water washing (100mL), with silica gel column chromatography purifying gained resistates, obtain 5-methyl-2-(5-oxo-5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone 11b (2.5g, yellow solid), productive rate: 27.7%.
MS?m/z(ESI)：243.1[M+1]
1HNMR(400MHz，CDCl 3)：δ8.10(d，1H)，7.89(m，2H)，3.50(s，2H)，3.02(t，2H)，2.68(t，2H)，2.26(s，3H)，2.18(m，2H)
Second step
(Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5-oxo-5,6,7,8-naphthane-2-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
(200mg 0.67mmol) is dissolved in the hydrochloric acid soln of 4mL 1N, adds Sodium Nitrite (51mg down in 0 ℃-5 ℃ with 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a, 0.73mmol), stirring reaction 30 minutes adds 5-methyl-2-(5-oxo-5,6 down in 0 ℃-5 ℃, 7,8-naphthane-2-yl)-2, and 4-pyrazoline-3-ketone 11b (146mg, 0.6mmol) and sodium bicarbonate (840mg, 10mmol), add 2mL ethanol, stirring reaction is 6 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and disappeared, filter, filter cake washes (3mL * 3) with water, with the hydrochloric acid adjust pH to 3 of 1N, filters, filter cake washs with amount of ethyl acetate, collect solid, vacuum-drying obtains title product (Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5-oxo-5,6,7,8-naphthane-2-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid 11 (107mg, brown solid), productive rate: 37.5%.
MS?m/z(ESI)：471.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.63(br，1H)，10.00(br，1H)，7.99(m，4H)，7.93(d，1H)，7.81(d，1H)，7.55(d，1H)，7.19(m，1H)，3.02(m，2H)，2.67(m，2H)，2.39(s，3H)，2.31(m，2H)
Embodiment 12
(Z)-5-(3-{N '-[1-(7,8-dihydronaphthalene-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-the 2-hydroxyl Base-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000351
The first step
2-(5-hydroxyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-pyrazoline-3-ketone
With 5-methyl-2-(5-oxo-5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone 11b (1g, 4.13mmol) be dissolved in the 20mL tetrahydrofuran (THF), the adding sodium borohydride (312mg, 8.26mmol), in 60 ℃ of following stirring reactions 1 hour, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, with 20mL methyl alcohol cancellation reaction solution, concentrating under reduced pressure reaction solution, with silica gel column chromatography purifying gained resistates, obtain 2-(5-hydroxyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-pyrazoline-3-ketone 12a (835mg, yellow solid), productive rate: 82.8%.
MS?m/z(ESI)：245.2[M+1]
Second step
2-(7,8-dihydronaphthalene-2-yl)-5-methyl-2,4-pyrazoline-3-ketone
With 2-(5-hydroxyl-5,6,7,8-naphthane-2-yl)-5-methyl-2, (200mg 0.82mmol) is dissolved in the 15mL methylene dichloride 4-pyrazoline-3-ketone 12a, adds the 8mL concentrated hydrochloric acid, heating reflux reaction 2.5 hours, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, transfers reacting liquid pH value to 7～8 with saturated sodium bicarbonate solution, with dichloromethane extraction reaction solution (200mL * 2), merge organic phase, with saturated common salt water washing (200mL * 2), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate, obtain 2-(7,8-dihydronaphthalene-2-yl)-5-methyl-2,4-pyrazoline-3-ketone 12b (158mg, yellow solid), productive rate: 85.4%.
MS?m/z(ESI)：227.1[M+1]
1HNMR(400MHz，CDCl 3)：δ7.62(m，2H)，7.03(d，1H)，6.45(d，1H)，6.00(m，1H)，3.42(s，2H)，2.82(t，2H)，2.31(m，2H)，2.20(s，3H)
The 3rd step
(Z)-5-(3-{N '-[1-(7,8-dihydronaphthalene-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
With 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a (136mg, 0.60mmol) be dissolved in the hydrochloric acid of 4mL 1N, add Sodium Nitrite (51mg down in 0 ℃-5 ℃, 0.73mmol), stirring reaction 30 minutes adds 2-(7,8-dihydronaphthalene-2-yl)-5-methyl-2 down in 0 ℃-5 ℃, 4-pyrazoline-3-ketone 12b (136mg, 0.6mmol) and sodium bicarbonate (840mg, 10mmol), adding 2mL ethanol, stirring reaction is 6 hours under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, filters, and filter cake washes (3mL * 3) with water, hydrochloric acid adjust pH to 3 with 1N, filter, filter cake washs with amount of ethyl acetate, collects solid, vacuum-drying, obtain title product (Z)-5-(3-{N '-[1-(7,8-dihydronaphthalene-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl-2-hydroxyl-phenyl)-furans-2-carboxylic acid 12 (119mg, yellow solid), productive rate: 43.3%.
MS?m/z(ESI)：455.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.77(br，1H)，10.06(br，1H)，7.95(s，1H)，7.61(m，4H)，7.22(m，3H)，6.53(d，1H)，6.05(t，1H)，2.85(m，2H)，2.41(s，3H)，2.28(m，4H)
Embodiment 13
(Z)-3 '-N '-[1-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo- Base]-diazanyl }-2 '-hydroxyl-xenyl-3-carboxylic acid
Figure B2009100536910D0000361
Figure B2009100536910D0000371
The first step
6-iodo-3,4-dihydro-2H-naphthalene-1-ketone
With 6-amino-3, (4.0g 25mmol) is dissolved in the 20mL acetonitrile 4-dihydro-2H-naphthalene-1-ketone 13a, adds the mixed solvent of 20mL concentrated hydrochloric acid and 60mL water, the aqueous solution (the 1.9g of Dropwise 5 mL Sodium Nitrite under the ice bath, 27.5mmol), drip to finish, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add potassiumiodide (8.7g, 52.5mmol), stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, reaction solution saturated sodium thiosulfate solution washing (50mL), water merges organic phase with ethyl acetate extraction (150mL * 2), with saturated common salt water washing (200mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate is with silica gel column chromatography purifying gained resistates, obtain 6-iodo-3,4-dihydro-2H-naphthalene-1-ketone 13b (5.54g, yellow solid), productive rate: 81.5%.
MS?m/z(ESI)：271.9[M-1]
1HNMR(400MHz，CDCl 3)：δ7.68-7.76(m，3H)，2.95(t，2H)，2.67(t，2H)，2.16(q，2H)
Second step
6-iodo-1,1-dimethyl-1,2,3,4-naphthane
(2.42mL 22.1mmol) is dissolved in the 50mL methylene dichloride, is chilled to-40 ℃ with titanium tetrachloride, drip zinc methide (27.5mL, 33.0mmol), with 6-iodo-3,4-dihydro-2H-naphthalene-1-ketone 13b (3.0g, 11.0mmol) be dissolved in the 50mL methylene dichloride, splash in the reaction solution under-40 ℃, stirring reaction 4 hours, thin-layer chromatography are followed the tracks of to react to raw material and are disappeared, add small amount of methanol cancellation reaction, the concentrating under reduced pressure reaction solution with silica gel column chromatography purifying gained resistates, obtains 6-iodo-1,1-dimethyl-1,2,3,4-naphthane 13c (2.9g, light yellow oil), productive rate: 92.1%.
1HNMR(400MHz，CDCl 3)：δ7.44-7.39(m，2H)，7.05(d，1H)，2.71(t，2H)，1.80-1.74(m，2H)，1.65-1.62(m，2H)，1.25(s，6H)
The 3rd step
N-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-diazanyl carboxylic acid tert-butyl ester
With 2-oxo-cyclohexyl ethyl formate (0.3mL, 1.9mmol), cuprous iodide (0.52g, 2.7mmol) and cesium carbonate (5.2g, 16mmol) be dissolved in the 40mL dimethyl sulfoxide (DMSO), with 6-iodo-1,1-dimethyl-1,2,3, and 4-naphthane 13c (2.86g, 10mmol) and tert-butyl carbazate (1.72g, 13mmol) be dissolved in the 40mL dimethyl sulfoxide (DMSO), splash into reaction solution, in 80 ℃ of following stirring reactions 3 hours, thin-layer chromatography was followed the tracks of to react to raw material and is disappeared, in reaction solution, add 300mL water, filter,, merge organic phase with ethyl acetate extraction filtrate (100mL * 3), with saturated common salt water washing (200mL), anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain N-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-and diazanyl carboxylic acid tert-butyl ester 13d (2.45g, yellow oil), productive rate: 84.3%.
1HNMR(400MHz，CDCl 3)：δ7.19-7.12(m，2H)，7.06(s，1H)，4.34(s，2H)，2.68(t，2H)，1.74-1.69(m，2H)，1.59-1.56(m，2H)，1.44(s，9H)，1.19(s，6H)
The 4th step
2-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-pyrazoline-3-ketone
With N '-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-(2.4g 8.27mmol) is dissolved in the 20mL acetate diazanyl carboxylic acid tert-butyl ester 13d, add the 20mL trifluoroacetic acid, stirring reaction is 40 minutes under the room temperature, adds methyl acetoacetate (0.95mL, 8.69mmol), in 90 ℃ of following stirring reactions 2 hours, thin-layer chromatography was followed the tracks of to react to raw material and is disappeared, the concentrating under reduced pressure reaction solution to neutral, is used ethyl acetate extraction (100mL * 2) with the saturated sodium bicarbonate solution adjust pH, merge organic phase, with saturated common salt water washing (100mL), anhydrous sodium sulfate drying filters, concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 2-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-pyrazoline-3-ketone 13e (1.37g, white solid), productive rate: 64.6%.
1HNMR(400MHz，CDCl 3)：δ7.66(dd，1H)，7.51(s，1H)，7.36(d，1H)，3.43(s，2H)，2.73(m，2H)，2.21(s，3H)，1.85-1.70(m，4H)，1.31(s，6H)
The 5th step
(Z)-3 '-N '-[1-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2 '-hydroxyl-xenyl-3-carboxylic acid
Under the ice bath, with 3 '-amino-2 '-(400mg 1.29mmol) is dissolved in the hydrochloric acid of 4.3mL 1N Hydroxybiphenyl-3-carboxylic acid hydrobromate 4c, the aqueous solution of dropping 1.7mL Sodium Nitrite (98mg, 1.42mmol), stirring reaction 20 minutes, adding 2-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-pyrazoline-3-ketone 13e (297mg, 1.16mmol) and sodium bicarbonate (1.63g, 19.35mmol), with small amount of ethanol cancellation bubble, stirring reaction 48 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, filter cake 30mL water dissolution is with concentrated hydrochloric acid adjust pH to 3～4, filter, filter cake is collected solid, vacuum-drying with ethyl acetate washing (5mL * 3), obtain title product (Z)-3 '-N '-[1-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2 '-hydroxyl-xenyl-3-carboxylic acid 13 (252mg, red solid), productive rate: 43.8%.
MS?m/z(ESI)：495.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.75(br，1H)，13.00(br，1H)，9.66(br，1H)，8.13(s，1H)，7.96(d，1H)，7.79(d，1H)，7.70(m，5H)，7.36(d，1H)，7.14(m，2H)，2.74(m，2H)，2.32(s，3H)，1.76(m，2H)，1.64(m，2H)，1.25(s，6H)
Embodiment 14
(Z)-2 '-hydroxyl-3 '-N '-[3-methyl-5-oxo-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-1,5-dihydro Pyrazoles-4-subunit]-diazanyl }-xenyl-3-carboxylic acid
Figure B2009100536910D0000391
The first step
2,5-two chloro-2,5-dimethyl-hexane
With 2,5-dimethyl-hexane-2,5-glycol 14a (14.6g, 0.1mol) be dissolved in the 100mL concentrated hydrochloric acid, stirring reaction is 2 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filter, collect solid, vacuum-drying obtains 2,5-two chloro-2,5-dimethyl-hexane 14b (16.1g, white solid), productive rate: 88.0%.
1HNMR(400MHz，CDCl 3)：δ1.95(s，4H)，1.60(s，12H)
Second step
6-bromo-1,1,4,4-tetramethyl--1,2,3,4-naphthane
Adopt known method Journal of Medicinal Chemistry, 1994,37,2930-2941, with 2,5-two chloro-2, (18g 98.36mmol) is dissolved in the methylene dichloride that 75mL heavily steams 5-dimethyl-hexane 14b, adds bromobenzene (30.88g, 196.7mmol), the adding aluminum chloride (2.62g, 19.67mmol), stirring reaction 30 minutes, thin-layer chromatography are followed the tracks of and are reacted to the raw material disappearance, add the hydrochloric acid soln of 30mL water and 30mL 6N, with dichloromethane extraction (200mL * 3), merge organic phase, with saturated common salt water washing (100mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate obtains crude product 6-bromo-1,1,4,4-tetramethyl--1,2,3,4-naphthane 14c (30.5g, light yellow oil) is directly used in next step reaction without separation.
1HNMR(400MHz，CDCl 3)：δ7.39(d，1H)，7.21(d，1H)，7.15(d，1H)，1.69(s，4H)，1.26(s，12H)
The 3rd step
1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) diazanyl-1, the 2-di-tert-butyl dicarboxylate
With crude product 6-bromo-1,1,4,4-tetramethyl--1,2,3, (10g 37.45mmol) is dissolved in the 60mL tetrahydrofuran (THF) 4-naphthane 14c, is chilled to-78 ℃ and stirs 1 hour, drip the 60mL tert-butyl azodicarboxylate (17.23g, tetrahydrofuran solution 74.90mmol) was in-78 ℃ of following stirring reactions 0.5 hour, slowly rose to room temperature reaction 16 hours, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, adds 50mL saturated ammonium chloride solution cancellation reaction, add 50mL water, with ethyl acetate extraction (200mL * 3), merge organic phase, with saturated common salt water washing (100mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate is with silica gel column chromatography purifying gained resistates, obtain 1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) diazanyl-1,2-di-tert-butyl dicarboxylate 14d (2.9g, white solid), productive rate: 18.6%.
The 4th step
5-methyl-2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone
With 1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl) diazanyl-1, (5.5g 13.16mmol) is dissolved in the 20mL acetate 2-di-tert-butyl dicarboxylate 14d, (1.83g 15.79mmol), adds the 4mL trifluoroacetic acid to add methyl acetoacetate, stirring reaction is 30 minutes under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to raw material disappearance, concentrating under reduced pressure reaction solution, with ethyl acetate extraction (50mL * 3), merge organic phase, with saturated common salt water washing (50mL), anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 5-methyl-2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone 14e (1.51g, faint yellow solid), productive rate: 40.5%.
The 5th step
(Z)-2 '-hydroxyl-3 '-N '-[3-methyl-5-oxo-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-xenyl-3-carboxylic acid
Under the ice bath, with 3 '-amino-2 '-(420mg 1.29mmol) is dissolved in the hydrochloric acid soln of 4.3mL 1N Hydroxybiphenyl-3-carboxylic acid hydrobromate 4c, (98mg 1.42mmol), adds 5-methyl-2-(5 to the aqueous solution of dropping 1.7mL Sodium Nitrite, 5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone 14e (329mg, 1.16mmol), with sodium bicarbonate adjust pH to 8～9, with small amount of ethanol cancellation bubble, stirring reaction is 16 hours under the room temperature, filters, filter cake is dissolved in the 20mL water, with concentrated hydrochloric acid adjust pH to 3～4, filter, filter cake washs with 4mL ethyl acetate and 2mL normal hexane, collect solid, vacuum-drying, obtain title product (Z)-2 '-hydroxyl-3 '-N '-[3-methyl-5-oxo-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-xenyl-3-carboxylic acid 14 (147mg, red solid), productive rate: 24.2%.
MS?m/z(ESI)：523.4[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.75(br，1H)，13.05(br，1H)，9.70(br，1H)，8.13(s，1H)，7.95(d，1H)，7.86(s，1H)，7.80(d，1H)，7.71(d，1H)，7.51(m，2H)，7.39(m，1H)，7.14(m，2H)，2.38(s，3H)，1.27(s，12H)
Embodiment 15
(Z)-2 '-hydroxyl-3 '-N '-[1-(1-hydroxyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-hydrazine Base }-xenyl-3-carboxylic acid
Figure B2009100536910D0000411
The first step
2-(1-hydroxyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone
With 5-methyl-2-(1-oxo-indenes-5-yl)-2,4-pyrazoline-3-ketone 9e (500mg, 2.19mmol) be dissolved in the 5mL tetrahydrofuran (THF), under 0 ℃, add lithium borohydride (71.6mg in batches, 3.29mmol), stirring reaction is 2 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to the raw material disappearance, adds small amount of methanol cancellation reaction, filtering reacting liquid, filter cake methanol wash (0.5mL * 3), concentrating under reduced pressure filtrate is with silica gel column chromatography purifying gained resistates, obtain 2-(1-hydroxyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 15a (450mg, white thick solid), productive rate: 89.5%.
Second step
(Z)-2 '-hydroxyl-3 '-N '-[1-(1-hydroxyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-xenyl-3-carboxylic acid
With 3 '-amino-2 '-Hydroxybiphenyl-3-carboxylic acid hydrobromate 4c (270mg, 0.87mmol) be dissolved in the hydrochloric acid soln of 4mL1N ice bath cooling, the aqueous solution (65mg of dropping 1mL Sodium Nitrite, 0.95mmol), standby in 0 ℃ of following stirring reaction 0.5 hour.
With 5-methyl-2-(1-oxo-indenes-5-yl)-2,4-pyrazoline-3-ketone 9e (200mg, 0.87mmol) and sodium bicarbonate (1.09g, 13mmol) be dissolved in the 1mL water, drip standby midbody solution down in 0 ℃, drip to finish, stirring reaction is 4 hours under room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and disappeared, filter, filter cake is collected solid, vacuum-drying with the salt acid elution (5mL) of 0.5N, obtain title product (Z)-2 '-hydroxyl-3 '-N '-[1-(1-hydroxyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-xenyl-3-carboxylic acid 15 (180mg, red solid), productive rate: 44.0%.
MS?m/z(ESI)：469.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ8.16(s，1H)，7.97(s，1H)，7.94(s，1H)，7.80(m，3H)，7.71(s，1H)，7.59(d，1H)，7.37(d，1H)，7.13(m，2H)，5.23(s，1H)，5.05(s，1H)，2.95(t，1H)，2.75(t，1H)，2.37(d，1H)，2.33(s，3H)，1.80(t，1H)
Embodiment 16
(Z)-5-(3-{N '-[1-(1,1-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-hydrazine Base }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000421
The first step
5-iodo-1-Indanone
(6.80g 37mmol) is dissolved in the hydrochloric acid of 6N, in the aqueous solution (3.06g of 0 ℃ of following Dropwise 5 mL Sodium Nitrite with 5-amino-1-Indanone hydrochloride 9d, 44mmol), stirring reaction 0.5 hour, and the aqueous solution of adding 5mL potassiumiodide (7.3g, 44mmol), stirring reaction is 16 hours under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, filters, and adds 20mL water and 100mL ethyl acetate in filtrate, separatory, merge organic phase, with saturated common salt water washing (50mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate with silica gel column chromatography purifying gained resistates, obtains 5-iodo-1-Indanone 16a (1.4g, colorless oil), productive rate: 14.7%.
1HNMR(400MHz，CDCl 3)：δ7.91(s，1H)，7.30(d，1H)，7.49(d，1H)，3.12(t，2H)，2.68(t，2H)
Second step
5-iodo-1,1-dimethyl indenes
(1.2mL 10.8mmol) joins in the 15mL methylene dichloride, in-40 ℃ of toluene solution (13.5mL that drip the 1.2M zinc methide down with titanium tetrachloride, 16.2mmol), stirring reaction 1 hour, (1.4g 5.4mmol) is dissolved in the 15mL methylene dichloride with 5-iodo-1-Indanone 16a, stirring reaction is 16 hours under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, with small amount of methanol cancellation reaction, adds 20mL ethyl acetate and 20mL water, separatory, merge organic phase, anhydrous magnesium sulfate drying filters, concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 5-iodo-1,1-dimethyl indenes 16b (1.1g, colorless oil), productive rate: 74.8%.
1HNMR(400MHz，CDCl 3)：δ7.53(s，1H)，7.49(d，1H)，6.88(d，1H)，2.86(t，2H)，1.89(t，2H)，1.23(s，3H)
The 3rd step
N-(1,1-dimethyl-indenes-5-yl)-diazanyl carboxylic acid tert-butyl ester
2-oxo-cyclohexyl ethyl formate (156mg, 0.92mmol), inferior ketone (the 176mg of iodate, 0.92mmol) and cesium carbonate (1.8g, 5.52mmol) be dissolved in the 10mL dimethyl sulfoxide (DMSO), stirred 0.5 hour under the room temperature, with 5-iodo-1,1-dimethyl indenes 16b (1.0g, 3.68mmol) and tert-butyl carbazate (0.58g, 4.41mmol) be dissolved in the 20mL dimethyl sulfoxide (DMSO), join in the reaction solution, in 80 ℃ of following stirring reactions 4 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid adds 50mL water and 100mL ethyl acetate, separatory in filtrate, water ethyl acetate extraction (20mL * 2), merge organic phase, anhydrous magnesium sulfate drying filters, concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain N-(1,1-dimethyl-indenes-5-yl)-diazanyl carboxylic acid tert-butyl ester 16c (700mg, colorless oil), productive rate: 69.3%.
The 4th step
2-(1,1-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone
With N-(1,1-dimethyl-indenes-5-yl)-(650mg 2.3mmol) is dissolved in the 6mL acetate diazanyl carboxylic acid tert-butyl ester 16c, add the 2mL trifluoroacetic acid, stirring reaction 0.5 hour, and the adding methyl acetoacetate (273mg, 2.3mmol), in 80 ℃ of following stirring reactions 1 hour, the concentrating under reduced pressure reaction solution adds 3mL saturated sodium bicarbonate solution and 20mL ethyl acetate, separatory, merge organic phase, anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 2-(1,1-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 16d (200mg, white solid), productive rate: 36.0%.
MS?m/z(ESI)：243.2[M+1]
1HNMR(400MHz，CDCl 3)：δ7.60(s，1H)，7.58(d，1H)，7.13(d，1H)，3.40(s，2H)，2.90(t，2H)，2.19(s，3H)，1.93(t，2H)，1.25(s，6H)
The 5th step
(Z)-5-(3-{N '-[1-(1,1-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
Under the ice bath, with 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a (344mg, 1.15mmol) be dissolved in the hydrochloric acid soln of 4.1mL 1N, drip the aqueous solution (87mg of 1.3mL Sodium Nitrite, 1.27mmol), add 2-(1,1-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 16d (250mg, 1.03mmol), with sodium bicarbonate adjust pH to 8～9, with small amount of ethanol cancellation bubble, stirring reaction is 16 hours under the room temperature, filter, filter cake is dissolved in the 15mL water,, filters with concentrated hydrochloric acid adjust pH to 3～4, filter cake washs with the mixed solvent of 10mL methylene dichloride and 1mL methyl alcohol, collect solid, vacuum-drying, obtain title product (Z)-5-(3-{N '-[1-(1,1-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid 16 (160mg, yellow solid), productive rate: 32.8%.
MS?m/z(ESI)：471.8[M-1]
1HNMR(400MHz，DMSO-d 6)：δ7.71-7.63(m，2H)，7.52(d，1H)，7.32(d，1H)，7.21(m，2H)，7.08(m，1H)，2.90(t，2H)，2.29(s，3H)，1.91(t，2H)，1.24(t，6H)
Embodiment 17
(Z)-5-(3-{N '-[1-(3,3-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-hydrazine Base }-2-hydroxy-5-methyl base-phenyl)-furans-2-carboxylic acid
The first step
2-bromo-4-methyl-6-nitro-phenol
With the 150mL diluting concentrated sulfuric acid in 450mL water, add SODIUMNITRATE (45.5g, 0.54mol), under-5 ℃, slowly drip 2-bromo-4-methyl-phenol 17a (50g, 0.27mol), stirring reaction 2 hours, rise to stirring at room reaction 1 hour, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, with ethyl acetate extraction reaction solution (600mL * 2), washes (200mL * 5) with water, merge organic phase, anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 2-bromo-4-methyl-6-nitro-phenol 17b (33.1g, yellow solid), productive rate: 53.5%.
1HNMR(400MHz，DMSO-d 6)：δ2.30(s，3H)，7.81-7.83(m，2H)，10.77(s，1H)
Second step
1-bromo-2-methoxyl group-5-methyl-3-nitro-benzene
(30.9g 0.13mol) is dissolved in the 300mL acetone, adds salt of wormwood (22.1g with 2-bromo-4-methyl-6-nitro-phenol 17b, 0.16mol) and p-methyl benzenesulfonic acid (40.3mL, 0.27mol), heating reflux reaction 16 hours, thin-layer chromatography are followed the tracks of to react to raw material and are disappeared, filtering reacting liquid, concentrating under reduced pressure filtrate with silica gel column chromatography purifying gained resistates, obtains 1-bromo-2-methoxyl group-5-methyl-3-nitro-benzene 17c (31.1g, white solid), productive rate: 95.1%.
The 3rd step
2-(2-methoxyl group-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] two assorted oxygen pentaboranes
With 1-bromo-2-methoxyl group-5-methyl-3-nitro-benzene 17c (5.3g, 0.02mol) be dissolved in the 100mL dme, add 4,4,5,5,4 ', 4 ', 5 ', 5 '-prestox-[2,2 '] two rings [[1,3,2] two assorted oxygen pentaborane (7.86g, 0.03mol), 1,1 '-two (diphenyl phosphine) ferrocene palladium chloride (II) (842mg, 1mmol) and potassium acetate (5.06g, 0.05mol), heating reflux reaction 2 hours, thin-layer chromatography are followed the tracks of to react to raw material and are disappeared, filtering reacting liquid, filter cake washs with the 30mL ether, and concentrating under reduced pressure filtrate adds 100mL ethyl acetate and 100mL water, separatory, water merges organic phase with extracted with diethyl ether (40mL * 3), with saturated common salt water washing (50mL * 2), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate is with silica gel column chromatography purifying gained resistates, obtain crude product 2-(2-methoxyl group-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] two assorted oxygen pentaborane 17d (5.76g, yellow oil) are directly used in next step reaction without separation.
The 4th step
5-(2-methoxyl group-5-methyl-3-nitro-phenyl)-furans-2-carboxylic acid
With crude product 2-(2-methoxyl group-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] (5.76g 14.45mmol) is dissolved in 100mL 1 to two assorted oxygen pentaborane 17d, in the mixed solvent of 4-dioxane and 20mL water, add 5-bromo-furans-2-carboxylic acid (2.48g, 13.0mmol), tetrakis triphenylphosphine palladium (833.8mg, 0.72mmol) and yellow soda ash (3.06g, 28.90mmol), heating reflux reaction 3 hours, thin-layer chromatography are followed the tracks of and are reacted to raw material disappearance, filtering reacting liquid, concentrating under reduced pressure filtrate, add 100mL water, with ethyl acetate extraction (30mL * 3), the water hydrochloric acid adjust pH to 3 of 1N, filter, filter cake washes (20mL) with water, with ether washing (20mL), collects solid, vacuum-drying, obtain 5-(2-methoxyl group-5-methyl-3-nitro-phenyl)-furans-2-carboxylic acid 17e (1.57g, yellow solid), productive rate: 27.5%.
MS?m/z(ESI)：276.6[M-1]
The 5th step
5-(3-amino-2-methoxyl group-5-methyl-phenyl)-furans-2-carboxylic acid
With 5-(2-methoxyl group-5-methyl-3-nitro-phenyl)-furans-2-carboxylic acid 17e (1.5g, 5.4mmol) be dissolved in the 120mL ethyl acetate, add 230mg palladium/carbon (10%) and ammonium formiate (3.4g, 54mmol), heating reflux reaction 4 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtered while hot, concentrating under reduced pressure filtrate, filter cake is collected solid with the mixed solvent washing of 400mL ethyl acetate and 40mL methyl alcohol, vacuum-drying, obtain crude product 5-(3-amino-2-methoxyl group-5-methyl-phenyl)-furans-2-carboxylic acid 17f (1.35g, foaming solid), be directly used in next step reaction without separation.
MS?m/z(ESI)：248.2[M+1]
The 6th step
5-(3-amino-2-hydroxy-5-methyl base-phenyl)-furans-2-carboxylic acid hydrobromate
With crude product 5-(3-amino-2-methoxyl group-5-methyl-phenyl)-furans-2-carboxylic acid 17f (1.35g, 5.4mmol) be dissolved in the methylene dichloride that 45mL heavily steams, drip boron tribromide (16.4mL, 16.4mmol), stirring reaction is 2.5 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, ice bath adds 5mL methyl alcohol cancellation reaction down, the concentrating under reduced pressure reaction solution, mixed solvent dissolving resistates with 24mL ether and 1mL methyl alcohol, filter, filter cake is collected solid with the mixed solvent washing of 143mL ethyl acetate and 7mL methyl alcohol, obtains 5-(3-amino-2-hydroxy-5-methyl base-phenyl)-furan food in one's mouth-2-carboxylic acid hydrobromate 17g (1.19g, light yellow solid), productive rate: 71.3%.
The 7th step
6-bromo-1,1-dimethyl-indenes
(5.79mL 52.5mmol) is dissolved in the 100mL methylene dichloride, and-50 ℃ add zinc methide (63mL down with titanium tetrachloride, 75mmol), stirring reaction 1 hour adds 60mL 6-bromo-1-Indanone 17h (5.28g, dichloromethane solution 25mmol), reacted 3 hours down in-50 ℃, stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to the raw material disappearance, adds 40mL methyl alcohol cancellation reaction, filtering reacting liquid, in filtrate, add 100mL water, separatory, water dichloromethane extraction (100mL * 2), merge organic phase, with saturated common salt water washing (100mL), anhydrous sodium sulfate drying filters, concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 6-bromo-1,1-dimethyl-indenes 17i (3.61g, faint yellow oily thing), productive rate: 64.5%.
The 8th step
1-(3,3-dimethyl-2,3-dihydro-1H-indenes-5-yl) diazanyl-1, the 2-di-tert-butyl dicarboxylate
With 6-bromo-1,1-dimethyl-indenes 17i (3.61g, 16.1mmol) be dissolved in the 70mL tetrahydrofuran (THF), drip n-Butyl Lithium (9.7mL down in-78 ℃, 24.2mmol), dripped complete stirring reaction 1 hour, drip 70mL azo-2-carboxylic acid di tert butyl carbonate (4.82g, 20.9mmol) tetrahydrofuran solution, in-78 ℃ of following stirring reactions 3 hours, thin-layer chromatography was followed the tracks of to react to raw material and is disappeared, and adds 20mL methyl alcohol, stirring reaction is 0.5 hour under the room temperature, the pad filtered through silica gel, concentrating under reduced pressure filtrate is with silica gel column chromatography purifying gained resistates, obtain 1-(3,3-dimethyl-2,3-dihydro-1H-indenes-5-yl) diazanyl-1,2-di-tert-butyl dicarboxylate 17j (2.85g, yellow oil), productive rate: 47.1%.
The 9th step
2-(3,3-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone
With 1-(3,3-dimethyl-2,3-dihydro-1H-indenes-5-yl) diazanyl-1,2-di-tert-butyl dicarboxylate 17j (2.85g, 7.59mmol) be dissolved in the 200mL acetate, adding the 40mL trifluoroacetic acid, stirring reaction is 2 hours under the room temperature, in 100 ℃ of acetic acid solution (0.9g that drip the 10mL methyl acetoacetate down, 7.96mmol), stirring reaction 1.5 hours, thin-layer chromatography are followed the tracks of to react to raw material and are disappeared, the concentrating under reduced pressure reaction solution, with saturated sodium bicarbonate solution neutralization reaction liquid,, merge organic phase with ethyl acetate extraction reaction solution (100mL * 3), with saturated common salt water washing (100mL), anhydrous sodium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 2-(3,3-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 17k (1.6g, white solid), productive rate: 87.0%.
MS?m/z(ESI)：243.2[M+1]
The tenth step
(Z)-5-(3-{N '-[1-(3,3-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxy-5-methyl base-phenyl)-furans-2-carboxylic acid
With 5-(3-amino-2-hydroxy-5-methyl base-phenyl)-furans-2-carboxylic acid hydrobromate 17g (380mg, 1.21mmol) be dissolved in the hydrochloric acid soln of 5mL 1N, the ice bath cooling, drip the aqueous solution (92mg of 1mL Sodium Nitrite, 1.33mmol), dripped complete stirring reaction 20 minutes, add 2-(3,3-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 17k (264mg, 1.09mmol), (1.52g is 18.15mmol) with 3mL ethanol for sodium bicarbonate, stirring reaction is 16 hours under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, and filtering reacting liquid, filter cake wash (3mL * 3) with water, hydrochloric acid adjust pH to 3 with 1N, filter, filter cake washes (3mL * 4) with water, collects solid, use the n-hexane/ethyl acetate recrystallization, obtain title product (Z)-5-(3-{N '-[1-(3,3-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl-2-hydroxy-5-methyl base-phenyl)-furans-2-carboxylic acid 17 (320mg, yellow solid), productive rate: 60.4%.
MS?m/z(ESI)：487.2[M+1]
1HNMR(400MHz，DMSO-d 6)：δ9.71(br，1H)，7.69(s，2H)，7.52(s，1H)，7.24(m，4H)，2.86(m，2H)，2.38(s，3H)，2.32(s，3H)，1.92(m，2H)，1.20(s，6H)
Embodiment 18
(Z)-5-(2-hydroxy-5-methyl base-3-{N '-[and 3-methyl-5-oxo-1-(1,1,3, the 3-tetramethyl Base-indenes-5-yl)-1,5-dihydro pyrrole Azoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
The first step
5-bromo-3,3-dimethyl-1-Indanone
With 6-bromo-1, (13.33g 59.24mmol) is dissolved in the 120mL methylene dichloride 1-dimethyl-indenes 17i, adds chromium sesquioxide (1.18g, 11.85mmol), the dropping tertbutanol peroxide (26.69g, 296.2mmol), stirring reaction is 16 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, the concentrating under reduced pressure reaction solution with dichloromethane extraction reaction solution (100mL * 3), merges organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate is with silica gel column chromatography purifying gained resistates, obtain 5-bromo-3,3-dimethyl-1-Indanone 18a (9.82g, pale pink solid), productive rate: 69.4%.
MS?m/z(ESI)：240.9[M+1]
1HNMR(400MHz，CDCl 3)：δ7.65(s，1H)，7.55(d，1H)，7.50(d，1H)，2.58(s，2H)，1.42(s，6H)
Second step
5-bromo-1,1,3,3-tetramethyl--indenes
Under-40 ℃, (8mL 82.16mmol) is dissolved in the 100mL methylene dichloride with titanium tetrachloride, the adding zinc methide (103.2mL, 123.54mmol), with 5-bromo-3,3-dimethyl-1-Indanone 18a (9.82g, 41.08mmol) be dissolved in the 60mL methylene dichloride, splash in the reaction solution, rise to stirring at room reaction 16 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, add small amount of methanol cancellation reaction, the concentrating under reduced pressure reaction solution adds 200mL ethyl acetate and 200mL water, separatory, merge organic phase, anhydrous magnesium sulfate drying filters, concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 5-bromo-1,1,3,3-tetramethyl--indenes 18b (9.94g, faint yellow oily thing), productive rate: 95.7%.
1HNMR(400MHz，CDCl 3)：δ7.29(d，1H)，7.22(d，1H)，6.97(d，1H)，1.91(s，2H)，1.28(m，12H)
The 3rd step
1-(1,1,3,3-tetramethyl--2,3-dihydro-1H-indenes-5-yl) diazanyl-1, the 2-di-tert-butyl dicarboxylate
Under the low temperature, with 5-bromo-1,1,3, (9.94g 39.3mmol) is dissolved in the 50mL tetrahydrofuran (THF) 3-tetramethyl--indenes 18b, the adding n-Butyl Lithium (39.2mL, 98.25mmol), Dropwise 5 0mL tert-butyl azodicarboxylate (11.30g, 49.1mmol) tetrahydrofuran solution, slowly rose to stirring at room reaction 3 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, add small amount of methanol cancellation reaction, the concentrating under reduced pressure reaction solution adds 200mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, with saturated common salt water washing (100mL), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate obtains crude product 1-(1,1,3,3-tetramethyl--2,3-dihydro-1H-indenes-5-yl) diazanyl-1,2-di-tert-butyl dicarboxylate 18c (22g, yellow oil), be directly used in next step reaction without separation.
MS?m/z(ESI)：403.0[M-1]
The 4th step
5-methyl-2-(1,1,3,3-tetramethyl--indenes-5-yl)-2,4-pyrazoline-3-ketone
With crude product 1-(1,1,3,3-tetramethyl--2,3-dihydro-1H-indenes-5-yl) diazanyl-1,2-di-tert-butyl dicarboxylate 18c (22g, 54.5mmol) be dissolved in the 167mL acetate, add the 220mL trifluoroacetic acid, stirring reaction 0.5 hour, add methyl acetoacetate (8.5g, 65.3mmol), in 100 ℃ of following stirring reactions 1 hour, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, and the concentrating under reduced pressure reaction solution adds 250mL water, with ethyl acetate extraction (150mL * 3), merge organic phase, with saturated sodium bicarbonate solution washing (100mL), with saturated common salt water washing (100mL), anhydrous magnesium sulfate drying filters concentrating under reduced pressure filtrate, with silica gel column chromatography purifying gained resistates, obtain 5-methyl-2-(1,1,3,3-tetramethyl--indenes-5-yl)-2,4-pyrazoline-3-ketone 18d (994mg, yellow solid), productive rate: 6.8%.
MS?m/z(ESI)：271.4[M+1]
1HNMR(400MHz，CDCl 3)：δ7.65(d，1H)，7.51(s，1H)，7.12(d，1H)，3.41(s，2H)，2.20(s，3H)，1.92(s，2H)，1.32(m，12H)
The 5th step
(Z)-5-(2-hydroxy-5-methyl base-3-{N '-[3-methyl-5-oxo-1-(1,1,3,3-tetramethyl--indenes-5-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
Under the ice-water bath, with 5-(3-amino-2-hydroxy-5-methyl base-phenyl)-furans-2-carboxylic acid hydrobromate 17g (314mg, 1.0mmol) be dissolved in the hydrochloric acid of 3.4mL 1N, the aqueous solution of dropping 1.2mL Sodium Nitrite (76mg, 1.1mmol), stirring reaction 20 minutes, add 5-methyl-2-(1,1,3,3-tetramethyl--indenes-5-yl)-2,4-pyrazoline-3-ketone 18d (243mg, 0.9mmol), with saturated sodium bicarbonate adjust pH to 8～9, add small amount of ethanol cancellation bubble, filter, filter cake 15mL water dissolution is with concentrated hydrochloric acid adjust pH to 3～4, filter, collect solid, vacuum-drying obtains title product (Z)-5-(2-hydroxy-5-methyl base-3-{N '-[3-methyl-5-oxo-1-(1,1,3,3-tetramethyl--indenes-5-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid 18 (187mg, red solid), productive rate: 40.4%.
MS?m/z(ESI)：513.3[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.76(br，1H)，13.13(br，1H)，9.73(br，1H)，7.74(d，1H)，7.66(s，1H)，7.54(s，1H)，7.36(m，2H)，7.23(d，1H)，7.13(d，1H)，2.38(s，3H)，2.34(s，3H)，1.92(s，2H)，1.29(d，12H)
Embodiment 19
(Z)-5-(3-{N '-[1-(5,6-dihydronaphthalene-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-the 2-hydroxyl Base-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000491
The first step
7-nitro-1,2,3,4-naphthane-1-alcohol
With 7-nitro-3, (4.7g 24.6mmol) is dissolved in the 100mL methyl alcohol 4-dihydro-2H-naphthalene-1-ketone 6b, under 0 ℃-5 ℃, add in batches sodium borohydride (1.1g, 29.5mmol), stirring reaction is 1.5 hours under the room temperature, the concentrating under reduced pressure reaction solution, with silica gel column chromatography purifying gained resistates, obtain 7-nitro-1,2,3,4-naphthane-1-alcohol 19a (3.5g, faint yellow solid), productive rate: 73.7%.
Second step
7-amino-1,2,3,4-naphthane-1-alcohol
With 7-nitro-1,2,3, the 4-naphthane-(3.0g 15.53mmol) is dissolved in the 60mL ethyl acetate 1-alcohol 19a, adds ammonium formiate (3.92g, 62.12mmol) and 350mg palladium/carbon (10%), heating reflux reaction 2 hours, thin-layer chromatography are followed the tracks of to react to raw material and are disappeared, filter, concentrating under reduced pressure filtrate is used the n-hexane/ethyl acetate recrystallization, obtain 7-amino-1,2,3,4-naphthane-1-alcohol 19b (2.2g, gray solid), productive rate: 87.0%.
1HNMR(400MHz，CDCl 3)：δ6.88(d，1H)，6.75(d，1H)，6.55(dd，1H)，4.66(m，1H)，2.75(m，2H)，1.91(m，4H)
The 3rd step
7-diazanyl-1,2,3,4-naphthane-1-alcohol hydrochloride
With 7-amino-1,2,3, (1.66g 10.2mmol) is dissolved in the mixed solvent of 10mL concentrated hydrochloric acid and 10mL water 4-naphthane-1-alcohol 19b, in 0 ℃-5 ℃ aqueous solution (772mg that drip the 2mL Sodium Nitrite down, 11mmol), drip to finish, stirring reaction 0.5 hour is standby.
(3.9g 31mmol) is dissolved in the 15mL concentrated hydrochloric acid, adds standby midbody solution down in-5 ℃ with tin protochloride, stirring reaction 0.5 hour, stirring reaction is 2 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, filter cake is collected solid with concentrated hydrochloric acid washing (5mL * 4), vacuum-drying, obtain crude product 7-diazanyl-1,2,3,4-naphthane-1-alcohol hydrochloride 19c is directly used in next step reaction without separation.
The 4th step
2-(5,6-dihydronaphthalene-2-yl)-5-methyl-2,4-pyrazoline-3-ketone
With 7-diazanyl-1,2,3, (2.14g 0.01mol) is dissolved in the 50mL methylene dichloride 4-naphthane-1-alcohol hydrochloride 19c, adds methyl acetoacetate (2.33g, 0.02mol), stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to raw material disappearance, concentrating under reduced pressure reaction solution, add 50mL water, with dichloromethane extraction (25mL * 4), merge organic phase, anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure filtrate with silica gel column chromatography purifying gained resistates, obtains 2-(5,6-dihydronaphthalene-2-yl)-5-methyl-2,4-pyrazoline-3-ketone 19d (780mg, yellow solid), productive rate: 32.5%.
1HNMR(400MHz，CDCl 3)：δ7.59(d，1H)，7.51(s，1H)，7.26(d，1H)，6.48(t，1H)，6.06(m，1H)，3.41(s，2H)，2.31(m，4H)，2.27(s，3H)
The 5th step
(Z)-5-(3-{N '-[1-(5,6-dihydronaphthalene-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
With 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a (620mg, 2.07mmol) be dissolved in the hydrochloric acid soln of 10mL 1N, in 0 ℃-5 ℃ aqueous solution (157mg that drip the 2mL Sodium Nitrite down, 2.28mmol), stirring reaction 0.5 hour, add 2-(5,6-dihydronaphthalene-2-yl)-5-methyl-2,4-pyrazoline-3-ketone 19d (455mg, 1.86mmol), (2.61g is 31.05mmol) with 3mL ethanol for sodium bicarbonate, stirring reaction is 10 hours under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, filtering reacting liquid, the filter cake hydrochloric acid adjust pH to 3 of 1N, filter, collect solid, vacuum-drying, obtain title product (Z)-5-(3-{N '-[1-(5,6-dihydronaphthalene-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid 19 (620mg, yellow solid), productive rate: 70.3%.
MS?m/z(ESI)：473.5[M-1]
1HNMR(400MHz，DMSO-d 6)：δ9.99(br，1H)，7.77(m，1H)，7.67(1H，s)δ7.37(d，1H)，7.26(m，2H)，7.14(m，3H)，6.55(d，1H)，6.10(d，1H)，5.03(s，2H)，2.75(s，2H)，2.23(s，3H)
Embodiment 20
(Z)-4-(3-{N '-[1-(3,3-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-hydrazine Base }-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid
Figure B2009100536910D0000511
The first step
4-bromo-thiophene-2-carboxylic acid
Adopt known method WO2005040161, with 4-bromo-thiophene-2-formaldehyde 20a (1.5g, 7.85mmol) be dissolved in the 50mL water, add potassium permanganate (1.35g, 8.54mmol) and sodium hydroxide (0.5g, 12.5mmol), stirring reaction is 6 hours under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, and reaction solution is poured in the mixture of ice and water, filters, transfer filtrate pH value to 3 with the hydrochloric acid of 6N, filter,, collect solid with ethyl acetate washing (20mL * 3), vacuum-drying, obtain 4-bromo-thiophene-2-carboxylic acid 20b (1.43g, white solid), productive rate: 88.9%.
1HNMR(400MHz，DMSO-d 6)：δ7.89(d，1H)，7.54(d，1H)
Second step
4-(2-methoxyl group-3-nitro-phenyl)-thiophene-2-carboxylic acid
With 2-(2-methoxyl group-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] two assorted oxygen pentaborane 1f (8.1g, 29.0mmol) be dissolved in 60mL 1, in the mixed solvent of 4-dioxane and 20mL water, add 4-bromo-thiophene-2-carboxylic acid 20b (3.0g, 14.5mmol), tetrakis triphenylphosphine palladium (0.84g, 0.73mmol) and yellow soda ash (3.1g, 29.0mmol), heating reflux reaction 3 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, the concentrating under reduced pressure reaction solution, sodium hydroxide solution and the 200mL water of adding 10mL 1N are with ethyl acetate extraction (100mL * 3), water concentrated hydrochloric acid adjust pH to 1～2, with ethyl acetate extraction (100mL * 3), merge organic phase, with saturated common salt water washing (150mL), anhydrous sodium sulfate drying, filter, concentrating under reduced pressure filtrate obtains crude product 4-(2-methoxyl group-3-nitro-phenyl)-thiophene-2-carboxylic acid 20c (6.9g, the dark oil thing), be directly used in next step reaction without separation.
MS?m/z(ESI)：277.6[M-1]
The 3rd step
4-(3-amino-2-methoxyl group-phenyl)-thiophene-2-carboxylic acid hydrochloride
With crude product 4-(2-methoxyl group-3-nitro-phenyl)-thiophene-2-carboxylic acid 20c (4.05g, 14.5mmol) be dissolved in the 130mL ethyl acetate, adding 1.0g palladium/carbon (10%) and ammonium formiate (3.65g, 58mmol), heating reflux reaction 1.5 hours, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, the diethyl ether solution of the hydrogenchloride of adding 50mL 2N obtains 4-(3-amino-2-methoxyl group-phenyl)-thiophene-2-carboxylic acid hydrochloride 20d (1.84g, white solid), productive rate: 44.9%.
The 4th step
4-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate
With 4-(3-amino-2-methoxyl group-phenyl)-thiophene-2-carboxylic acid hydrochloride 20d (1.84g, 6.44mmol) be dissolved in the dichloromethane solution of 30mL 1.06M boron tribromide, stirring reaction is 1 hour under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, add small amount of methanol cancellation reaction, the concentrating under reduced pressure reaction solution, with ethyl acetate extraction (50mL * 3), merge organic phase, anhydrous magnesium sulfate drying filters, concentrating under reduced pressure filtrate, obtain 4-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate 20e (1.2g, white solid), productive rate: 59.1%.
1HNMR(400MHz，DMSO-d 6)：δ8.08(s，1H)，7.98(s，1H)，7.41(d，1H)，7.27(d，1H)，7.02(t，1H)
The 5th step
(Z)-4-(3-{N '-[1-(3,3-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid
With 4-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate 20e (297mg, 0.94mmol) be dissolved in the hydrochloric acid soln of 3.4mL 1N, the aqueous solution (the 71mg that adds the 1.1mL Sodium Nitrite, 1.04mmol), stirring reaction 20 minutes, add 2-(3,3-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 17k (205mg, 0.85mmol), with saturated sodium bicarbonate adjust pH to 8～9, with small amount of ethanol cancellation bubble, stirring reaction 16 hours, filter, filter cake is dissolved in the 15mL water, with concentrated hydrochloric acid adjust pH to 3～4, filter, collect solid, vacuum-drying, obtain title product (Z)-4-(3-{N '-[1-(3,3-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid 20 (345mg, red solid), productive rate: 83.5%.
MS?m/z(ESI)：487.8[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.76(br，1H)，13.18(br，1H)，9.70(br，1H)，8.14(s，1H)，8.05(s，1H)，7.69(m，3H)，7.34(d，1H)，7.26(d，1H)，7.13(t，1H)，2.86(t，2H)，2.33(s，3H)，1.91(t，2H)，1.23(s，6H)
Embodiment 21
(Z)-4-(3-{N '-[1-(3,3-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-hydrazine Base }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000531
The first step
4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate
With 4-(3-amino-2-methoxyl group-phenyl)-furans-2-carboxylic acid 1h (4.3g, 0.018mol) be dissolved in the 100mL methylene dichloride, the dichloromethane solution that adds 55mL 1M boron tribromide, stirring reaction is 5 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, add 10mL methyl alcohol cancellation reaction, the concentrating under reduced pressure reaction solution adds 50mL ethyl acetate and 4mL methyl alcohol, stirred 20 minutes, filter, filter cake washs with amount of ethyl acetate, collects solid, vacuum-drying, obtain 4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 21a (3.2g, pale solid), productive rate: 58.2%.
1HNMR(400MHz，CD 3OD)：δ8.11(s，1H)，7.54(s，1H)，7.52(d，1H)，7.33(d，1H)，7.11(t，1H)
Second step
(Z)-4-(3-{N '-[1-(3,3-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
With 4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 21a (360mg, 1.2mmol) be dissolved in the hydrochloric acid soln of 4.4mL 1N, the aqueous solution (the 91mg that adds the 1.5mL Sodium Nitrite, 1.32mmol), stirring reaction 20 minutes, add 2-(3,3-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 17k (261mg, 1.08mmol), with saturated sodium bicarbonate adjust pH to 8～9, with small amount of ethanol cancellation bubble, stirring reaction 2 hours, filter, filter cake is dissolved in the 15mL water,, filters with concentrated hydrochloric acid adjust pH to 3～4, filter cake washs (5mL) with ethyl acetate, collect solid, vacuum-drying, obtain title product (Z)-4-(3-{N '-[1-(3,3-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid 21 (300mg, red solid), productive rate: 63.6%.
MS?m/z(ESI)：471.2[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.75(br，1H)，13.15(br，1H)，9.78(br，1H)，8.37(s，1H)，7.68(m，4H)，7.42(dd，1H)，7.25(d，1H)，7.13(t，1H)，2.86(t，2H)，2.32(s，3H)，1.91(t，2H)，1.25(s，6H)
Embodiment 22
(Z)-5-(3-{N '-[1-(1,1-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-hydrazine Base }-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid
Figure B2009100536910D0000541
The first step
5-(2-methoxyl group-3-nitro-phenyl)-thiophene-2-carboxylic acid
With 2-(2-methoxyl group-3-nitro-phenyl)-4,4,5,5-tetramethyl--[1,3,2] (30.18g 0.11mol) is dissolved in 400mL 1 to two assorted oxygen pentaborane 1f, in the mixed solvent of 4-dioxane and 100mL water, adding 5-bromo-thiophene-2-carboxylic acid 22a (15g, 0.07mol), tetrakis triphenylphosphine palladium (6.24g, 5.41mmol) and yellow soda ash (22.92g, 0.22mol), heating reflux reaction 3.5 hours, thin-layer chromatography are followed the tracks of and are reacted to raw material disappearance, filtering reacting liquid, add 150mL ethyl acetate and 60mL methyl alcohol, stirred 20 minutes, and filtered concentrating under reduced pressure filtrate, in resistates, add 200mL ethyl acetate and 20mL methyl alcohol, filter, collect twice and filter the gained solid, obtain 5-(2-methoxyl group-3-nitro-phenyl)-thiophene-2-carboxylic acid 22b (12.2g, yellow solid), productive rate: 60.4%.
MS?m/z(ESI)：277.8[M-1]
Second step
5-(3-amino-2-methoxyl group-phenyl)-thiophene-2-carboxylic acid hydrochloride
With 5-(2-methoxyl group-3-nitro-phenyl)-thiophene-2-carboxylic acid 22b (10.5g, 0.038mol) be dissolved in the 500mL ethyl acetate, add 1.0g palladium/carbon (10%) and ammonium formiate (9.48g, 0.15mol), heating reflux reaction 26.5 hours, thin-layer chromatography are followed the tracks of to react to raw material and are disappeared, filtering reacting liquid, concentrating under reduced pressure filtrate obtains 5-(3-amino-2-methoxyl group-phenyl)-thiophene-2-carboxylic acid hydrochloride 22c (7.16g, brownish black oily matter), productive rate: 76.4%.
MS?m/z(ESI)：248.0[M-1]
The 3rd step
5-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate
With 5-(3-amino-2-methoxyl group-phenyl)-thiophene-2-carboxylic acid hydrochloride 22c (1.84g, 6.44mmol) be dissolved in the dichloromethane solution of 54mL 1.06M boron tribromide, stirring reaction is 16 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, add 50mL methyl alcohol cancellation reaction, filtering reacting liquid, concentrating under reduced pressure filtrate adds 200mL ethyl acetate and 20mL methyl alcohol in resistates, stirred 20 minutes, filter, collect solid, vacuum-drying obtains 5-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate 22d (4.9g, yellow solid), productive rate: 53.9%.
MS?m/z(ESI)：233.8[M-1]
1HNMR(400MHz，DMSO-d 6)：δ7.73(m，1H)，7.60(m，2H)，7.28(m，2H)，7.16(s，1H)，7.05(t，2H)
The 4th step
(Z)-5-(3-{N '-[1-(1,1-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid
With 5-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate 22d (297mg, 0.94mmol) be dissolved in the hydrochloric acid soln of 3.4mL 1N, the aqueous solution (the 71mg that adds the 1.1mL Sodium Nitrite, 1.04mmol), stirring reaction 20 minutes, add 2-(1,1-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 16d (205mg, 0.85mmol), with saturated sodium bicarbonate adjust pH to 8～9, with small amount of ethanol cancellation bubble, stirring reaction 4 hours, filter, filter cake is dissolved in the 15mL water, with concentrated hydrochloric acid adjust pH to 3～4, filter, collect solid, vacuum-drying, obtain title product (Z)-5-(3-{N '-[1-(1,1-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid 22 (55mg, red solid), productive rate: 13.3%.
MS?m/z(ESI)：486.7[M-1]
1HNMR(400MHz，DMSO-d 6)：δ13.71(br，1H)，13.10(br，1H)，10.07(br，1H)，7.74(m，4H)，7.63(d，1H)，7.54(d，1H)，7.23(d，1H)，7.17(t，1H)，2.90(t，2H)，2.31(s，3H)，1.90(t，2H)，1.24(s，6H)
Embodiment 23
(Z)-5-(2-hydroxyl-3-{N '-[1-(5-hydroxyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline -4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
(200mg 0.67mmol) is dissolved in the hydrochloric acid of 3mL 1N, stirs 0.5 hour down in 0 ℃-5 ℃ with 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a, (51mg 0.73mmol), drips and finishes the aqueous solution of dropping 1mL Sodium Nitrite, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 2-(5-hydroxyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-pyrazoline-3-ketone 12a (146mg, 0.6mmol), sodium bicarbonate (840mg, 10mmol) with 2mL ethanol, stirring reaction is 3 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to raw material disappearance, filtering reacting liquid, the filter cake hydrochloric acid adjust pH to 3 of 1N, filter, filter cake washs with amount of ethyl acetate, collects solid, vacuum-drying, obtain title product (Z)-5-(2-hydroxyl-3-{N '-[1-(5-hydroxyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid 23 (90mg, yellow solid), productive rate: 28.5%.
1HNMR(400MHz，DMSO-d 6)：δ13.73(br，1H)，10.05(br，1H)，7.81(m，3H)，7.56(d，1H)，7.34(d，1H)，7.14(m，2H)，6.51(d，1H)，5.68(m，1H)，2.78(m，2H)，2.32(s，3H)，2.22(m，4H)
Embodiment 24
(Z)-5-(3-{N '-[1-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4- Subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000562
(380mg 1.27mmol) is dissolved in the hydrochloric acid of 4mL 1N, stirs 0.5 hour down in 0 ℃-5 ℃ with 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a, (96mg 1.4mmol), drips and finishes the aqueous solution of dropping 2mL Sodium Nitrite, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 2-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-dihydro-pyrazoles-3-ketone 6g (292mg, 1.14mmol), (1.6g is 19.05mmol) with 3mL ethanol for sodium bicarbonate, stirring reaction is 10 hours under the room temperature, thin-layer chromatography is followed the tracks of and is reacted to the raw material disappearance, filtering reacting liquid, the filter cake hydrochloric acid adjust pH to 3 of 1N, filter, filter cake washs with amount of ethyl acetate, collects solid, vacuum-drying, obtain title product (Z)-5-(3-{N '-[1-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid 24 (298mg, sorrel solid), productive rate: 57.3%.
1HNMR(400MHz，DMSO-d 6)：δ7.71(m，2H)，7.56(t，1H)，7.45(m，2H)，7.34(m，3H)，2.67(m，2H)，2.23(s，3H)，1.74(m，4H)，1.25(s，6H)
Embodiment 25
(Z)-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-1,5-two for 5- Hydrogen pyrazoles-4-subunit]-subunit }-phenyl)-furans-2-carboxylic acid
With 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a (351mg, 1.17mmol) be dissolved in the hydrochloric acid of 4mL 1N, stirred 0.5 hour down in 0 ℃-5 ℃, drip the aqueous solution (89mg of 2mL Sodium Nitrite, 1.29mmol), drip to finish,, add 5-methyl-2-(5 in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, 5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-2, and 4-pyrazoline-3-ketone 14e (300mg, 1.05mmol), sodium bicarbonate (1.47g, 17.55mmol) and 2mL ethanol, stirring reaction is 10 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, filter cake filters with the hydrochloric acid adjust pH to 3 of 1N, and filter cake washs with amount of ethyl acetate, collect solid, vacuum-drying obtains title product (Z)-5-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-1,5-pyrazoline-4-subunit]-subunit }-phenyl)-furans-2-carboxylic acid 25 (312mg, sorrel solid), productive rate: 57.9%.
MS?m/z(ESI)：513.3[M-1]
1HNMR(400MHz，DMSO-d 6)：δ7.89(s，1H)，7.72(d，1H)，7.63(d，1H)，7.55(d，1H)，7.37(m，2H)，7.17(m，2H)
Embodiment 26
(Z)-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-1,5-two for 4- Hydrogen pyrazoles-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000581
With 4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 21a (300mg, 1mmol) be dissolved in the hydrochloric acid of 4mL 1N, stirred 0.5 hour down in 0 ℃-5 ℃, drip the aqueous solution (76mg of 2mL Sodium Nitrite, 1.1mmol), drip to finish, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 5-methyl-2-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-2,4-pyrazoline-3-ketone 14e (285mg, 1mmol), sodium bicarbonate (1.26g, 15mmol) with 2mL ethanol, stirring reaction is 18 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, filter cake wash (2mL) with water, with the hydrochloric acid adjust pH to 3 of 1N, filter, filter cake is collected solid, vacuum-drying with the mixed solvent washing of 2.5mL methylene dichloride and 0.5mL methyl alcohol, obtain title product (Z)-4-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-phenyl)-furans-2-carboxylic acid 26 (80mg, red solid), productive rate: 15.6%.
1HNMR(400MHz，DMSO-d 6)：δ13.79(br，1H)，13.19(br，1H)，9.72(br，1H)，8.38(s，1H)，7.88(d，1H)，7.62(m，2H)，7.47(m，3H)，7.11(t，1H)，2.33(s，4H)，1.67(s，6H)，1.43(s，9H)
Embodiment 27
(Z)-4-(3-{N '-[1-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4- Subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000591
With 4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 21a (170mg, 0.57mmol) be dissolved in the hydrochloric acid of 2mL 1N, stirred 0.5 hour down in 0 ℃-5 ℃, drip the aqueous solution (43mg of 0.5mL Sodium Nitrite, 0.62mmol), drip and finish, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 2-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-pyrazoline-3-ketone 13e (145mg, 0.57mmol), sodium bicarbonate (714mg, 8.49mmol) and 1mL ethanol, stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to raw material disappearance, filtering reacting liquid, filter cake washes (2mL * 3) with water, with the hydrochloric acid adjust pH to 3 of 1N, filter, filter cake washs with amount of ethyl acetate, collect solid, vacuum-drying, obtain title product (Z)-4-(3-{N '-[1-(and 5,5-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid 27 (38mg, red solid), productive rate: 13.8%.
1HNMR(400MHz，DMSO-d 6)：δ8.39(d，1H)，7.69(m，4H)，7.43(m，2H)，7.15(d，1H)，2.90(m，2H)，2.02(m，4H)，1.14(s，9H)
Embodiment 28
(Z)-4-(2-hydroxyl-3-{N '-[and 3-methyl-5-oxo-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-base Hydrogen pyrazoles-4-subunit]-diazanyl }-phenyl)-thiophene-2-carboxylic acid
With 4-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate 20e (316mg, 1.0mmol) be dissolved in the hydrochloric acid of 3mL 1N, stirred 0.5 hour down in 0 ℃-5 ℃, drip the aqueous solution (76mg of 1mL Sodium Nitrite, 1.1mmol), drip to finish,, add 5-methyl-2-(5 in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, 5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-2, and 4-pyrazoline-3-ketone 14e (285mg, 1.0mmol), sodium bicarbonate (1.26g, 15mmol) and 2mL ethanol, stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of to react to raw material and disappeared, filtering reacting liquid, filter cake filters with the hydrochloric acid adjust pH to 3 of 1N, and filter cake washs with the mixed solvent of 4mL methylene dichloride and 1mL methyl alcohol, collect solid, vacuum-drying obtains title product (Z)-4-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-2-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-phenyl)-thiophene-2-carboxylic acid 28 (218mg, red solid), productive rate: 41.1%.
1HNMR(400MHz，DMSO-d 6)：δ15.27(br，1H)，8.14(d，2H)，7.68(t，2H)，7.30(m，2H)，6.99(d，1H)，2.31(s，3H)，1.31(m，4H)，1.25(s，12H)
Embodiment 29
(Z)-4-(3-{N '-[1-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4- Subunit]-diazanyl }-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid
Figure B2009100536910D0000601
With 4-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate 20e (316mg, 1.0mmol) be dissolved in the hydrochloric acid of 4mL 1N, stirred 0.5 hour down in 0 ℃-5 ℃, drip the aqueous solution (76mg of 1mL Sodium Nitrite, 1.1mmol), drip and finish, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 2-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-dihydro-pyrazoles-3-ketone 6g (256mg, 1mmol), sodium bicarbonate (1.26g, 15mmol) with 4mL ethanol, stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to raw material disappearance, filtering reacting liquid, filter cake washes (2mL * 3) with water, with the hydrochloric acid adjust pH to 3 of 1N, filter, filter cake washs with the mixed solvent of 4mL methylene dichloride and 1mL methyl alcohol, collect solid, vacuum-drying, obtain title product (Z)-4-(3-{N '-[1-(and 8,8-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid 29 (256mg, yellow solid), productive rate: 51.0%.
1HNMR(400MHz，DMSO-d 6)：δ13.75(br，1H)，13.17(br，1H)，9.70(br，1H)，8.14(s，1H)，8.06(s，1H)，7.91(d，1H)，7.61(m，2H)，7.34(d，1H)，7.15(m，2H)，2.74(m，2H)，2.33(s，3H)，1.77(m，4H)，1.27(s，6H)
Embodiment 30
(Z)-4-(3-{N '-[1-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-hydrogen generation-1,5-pyrazoline-4- Subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000602
Figure B2009100536910D0000611
With 4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 21a (300mg, 1.0mmol) be dissolved in the hydrochloric acid of 4mL 1N, stirred 0.5 hour down in 0 ℃-5 ℃, drip the aqueous solution (76mg of 1mL Sodium Nitrite, 1.1mmol), drip and finish, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 2-(8,8-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-dihydro-pyrazoles-3-ketone 6g (256mg, 1.0mmol), sodium bicarbonate (1.26g, 15mmol) with 2mL ethanol, stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to raw material disappearance, filtering reacting liquid, filter cake washes (2mL * 3) with water, with the hydrochloric acid adjust pH to 3 of 1N, filter, filter cake washs with the mixed solvent of 4mL methylene dichloride and 1mL methyl alcohol, collect solid, vacuum-drying, obtain title product (Z)-4-(3-{N '-[1-(and 8,8-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid 30 (216mg, red solid), productive rate: 44.4%.
1HNMR(400MHz，DMSO-d 6)：δ13.75(br，1H)，13.20(br，1H)，9.70(br，1H)，8.43(s，1H)，7.92(s，1H)，7.59(m，3H)，7.41(d，1H)，7.14(m，2H)，2.71(m，2H)，2.31(s，3H)，1.74(m，4H)，1.27(s，6H)
Embodiment 31
(Z)-4-(3-{N '-[1-(1,1-dimethyl-indenes-5-yl)-3-methyl-5-hydrogen generation-1,5-pyrazoline-4-subunit]-hydrazine Base }-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid
Figure B2009100536910D0000612
With 4-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate 20e (310mg, 0.98mmol) be dissolved in the hydrochloric acid of 3.4mL 1N, stirred 0.5 hour down in 0 ℃-5 ℃, (75mg 1.08mmol), drips and finishes the aqueous solution of dropping 1.1mL Sodium Nitrite, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 2-(1,1-dimethyl-indenes-5-yl)-5-methyl-2,4-pyrazoline-3-ketone 16d (214mg, 0.88mmol), sodium bicarbonate (1.24g, 14.7mmol) with 2mL ethanol, stirring reaction is 16 hours under the room temperature, thin-layer chromatography is followed the tracks of to react to raw material and is disappeared, filtering reacting liquid, filter cake filters with the hydrochloric acid adjust pH to 3 of 1N, filter cake washs with amount of ethyl acetate, collect solid, vacuum-drying, obtain title product (Z)-4-(3-{N '-[1-(1,1-dimethyl-indenes-5-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid 31 (302mg, red solid), productive rate: 69.9%.
1HNMR(400MHz，DMSO-d 6)：δ2.88(m，2H)，2.31(s，3H)，1.91(m，2H)，1.24(s，6H)
Embodiment 32
(Z)-4-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(1,1,3,3-tetramethyl--indenes-5-yl)-1,5-dihydro azoles azoles-4-Asia Base]-subunit }-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000621
With 4-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 21a (350mg, 1.17mmol) be dissolved in the hydrochloric acid of 4.2mL 1N, stirred 0.5 hour down in 0 ℃-5 ℃, drip the aqueous solution (89mg of 1.3mL Sodium Nitrite, 1.29mmol), drip and finish, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 5-methyl-2-(1,1,3,3-tetramethyl--indenes-5-yl)-2,4-pyrazoline-3-ketone 18d (283mg, 1.05mmol), sodium bicarbonate (1.47g, 17.55mmol) and 2mL ethanol, stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to raw material disappearance, filtering reacting liquid, the filter cake hydrochloric acid adjust pH to 3 of 1N, filter, filter cake is collected solid with the mixed solvent washing of 13mL methylene dichloride and 2mL methyl alcohol, vacuum-drying, obtain title product (Z)-4-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(1,1,3,3-tetramethyl--indenes-5-yl)-1,5-pyrazoline-4-subunit]-subunit }-phenyl)-furans-2-carboxylic acid 32 (155mg, yellow solid), productive rate: 29.6%.
1HNMR(400MHz，DMSO-d 6)：δ8.39(s，1H)，7.69(m，4H)，7.41(d，1H)，7.22(d，1H)，7.09(m，1H)，2.33(s，3H)，1.91(s，2H)，1.29(m，12H)
Embodiment 33
(Z)-4-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(1,1,3,3-tetramethyl--indenes-5-yl)-1,5-pyrazoline-4-Asia Base]-diazanyl }-phenyl)-thiophene-2-carboxylic acid
Figure B2009100536910D0000622
(316mg 1.0mmol) is dissolved in the hydrochloric acid of 3.6mL 1N, stirs 0.5 hour down in 0 ℃-5 ℃ with 4-(3-amino-2-hydroxyl-phenyl)-thiophene-2-carboxylic acid hydrobromate 20e, (76mg 1.1mmol), drips and finishes the aqueous solution of dropping 1.2mL Sodium Nitrite, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 5-methyl-2-(1,1,3,3-tetramethyl--indenes-5-yl)-2,4-pyrazoline-3-ketone 18d (243mg, 0.9mmol), sodium bicarbonate (1.26g, 15mmol) with 2mL ethanol, stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to raw material disappearance, filtering reacting liquid, filter cake 15mL water dissolution, with concentrated hydrochloric acid adjust pH to 3, filter, collect solid, vacuum-drying, obtain title product (Z)-4-(2-hydroxyl-3-{N '-[3-methyl-5-oxo-1-(1,1,3,3-tetramethyl--indenes-5-yl)-1,5-pyrazoline-4-subunit]-diazanyl }-phenyl)-thiophene-2-carboxylic acid 33 (435mg, yellow solid), productive rate: 93.8%.
1HNMR(400MHz，DMSO-d 6)：δ13.75(br，1H)，13.18(br，1H)，9.70(br，1H)，8.14(s，1H)，8.05(s，1H)，7.75(d，1H)，7.68(m，2H)，7.33(d，1H)，7.23(d，1H)，7.13(t，1H)，2.33(s，3H)，1.91(s，2H)，1.29(s，12H)
Embodiment 34
(Z)-5-(3-{N '-[1-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4- Subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid
Figure B2009100536910D0000632
With 5-(3-amino-2-hydroxyl-phenyl)-furans-2-carboxylic acid hydrobromate 5a (500mg, 1.67mmol) be dissolved in the hydrochloric acid of 5.6mL 1N, stirred 0.5 hour down in 0 ℃-5 ℃, drip the aqueous solution (127mg of 2.2mL Sodium Nitrite, 1.84mmol), drip and finish, in 0 ℃ of-5 ℃ of following stirring reaction 0.5 hour, add 2-(5,5-dimethyl-5,6,7,8-naphthane-2-yl)-5-methyl-2,4-pyrazoline-3-ketone 13e (384mg, 1.50mmol), sodium bicarbonate (2.1g, 25.05mmol) and 3.7mL ethanol, stirring reaction is 16 hours under the room temperature, and thin-layer chromatography is followed the tracks of and reacted to raw material disappearance, filtering reacting liquid, filter cake 20mL water dissolution, with concentrated hydrochloric acid adjust pH to 3, filter, filter cake washs with amount of ethyl acetate, collect solid, vacuum-drying, obtain title product (Z)-5-(3-{N '-[1-(and 5,5-dimethyl-5,6,7,8-naphthane-2-yl)-3-methyl-5-oxo-1,5-pyrazoline-4-subunit]-diazanyl }-2-hydroxyl-phenyl)-furans-2-carboxylic acid 34 (256mg, red solid), productive rate: 52.7%.
1HNMR(400MHz，DMSO-d 6)：δ7.71(m，2H)，7.55(m，2H)，7.41(d，1H)，7.36(d，1H)，7.20(t，1H)，7.14(d，1H)，2.76(t，2H)，2.31(s，3H)，1.76(m，2H)，1.63(m，2H)，1.25(s，6H)
Test case:
Biological assessment
Test case 1 series compound of the present invention is to the proliferation function of BAF3-TPOR cell
1. material and method:
A.RPM1 Medium 1640, Powder, 10*1L contains HEPES (Gibco Catalog no.23400021)
B.FBS foetal calf serum (Gibco Catalog no.10099-141)
c.PENICILLIN?STREPTOMYCIN?SOL(Gibco?Catalog?no.15140-122)
d.Geneticin(G418)(Gibco?Catalog?no.11811-098)
e.recombinant?mouse?IL-3(chemicon?Catalog?no.IL015)
f.Human?Thrombopoietin?R?Mab(TPO)(R&D?Catalog?no.MAB1016)
g.DMSO(AppliChem?Catalog?no.A3672)
h.
Figure B2009100536910D0000641
Multi?Site?Directed?Mutagenesis?Kit，10Runs(StratageneST200515)
I, Cell Counting Kit-8 (colleague's chemistry institute Catalog no.CK04-13)
J, Ba/F3 cell (consonance cell bank Catalog no.0095)
k.EX-EGFP-M02(FulenGen?Catalog?no.EX-EGFP-M02?Control)
l.EX-B0010-M02(FulenGen?Catalog?no.EX-B0010-M02)
2. operation steps:
(1) plasmid construction: according to Entrez Gene ID:4325, the TPOR gene order that Refseq:NM_005373 provides is utilized the EX-B0010-M02 plasmid of buying (FulenGen) Multi SiteDirected Mutagenesis Kit (Stratagene) test kit carries out 2 point mutation.The multipoint mutation primer sequence is respectively: g491a:5 '-gggaacttcagatcagctgggaggagccg-3 ', g491a_antisense:5 '-cggctcctcccagctgatctgaagttccc-3 '; C965t:5 '-caggaccatgctagctcccaaggcttcttct-3 ', c965t_antisense:5 '-agaagaagccttgggagctagcatggtcctg-3 '.Sudden change back plasmid transformation escherichia coli DH5 α filters out positive colony through Amp, and order-checking identifies that the sudden change result is correct.
(2) the BAF3-TPOR cell strain makes up: make up the BaF3 cell strain of stablizing the functional TPO acceptor of high expression level.Will be through the EX-B0010-M02 plasmid 25 μ g transfection wild-type BaF3 cell (1X10 of expressing human TPO acceptor after 2 point mutation and screening-gene neomycin 7) the used instrument of transfection is that (BTX Division of Genetronic, Inc.US), transfection conditions is Electro Square PoratorECM830: 250V, 18ms.(Gibco, US) screening obtains the BAF3-TPOR stable cell line by G418.BAF3-TPOR is RPMI1640 (Gibco, US) substratum, 10%FB (Gibco, US) S, 800ng/ml G418,5ng/mL, rmIL-3 (Chemicon, US) the middle cultivation.
3. screening compound:
(1) eccentric cleaning cell: get an amount of cell suspension 1000rpm, centrifugal 5 minutes, supernatant discarded was hanged cell 1000rpm, centrifugal 5 minutes, supernatant discarded again with the cell culture fluid that 10mL does not contain IL3 again;
(2) add cell culture fluid that 1ml do not contain IL3 evenly, get an amount of cell suspension dilution back counting cell piping and druming;
(3) prepare the cell suspension that density is 100000/mL according to the cell counting result;
(4) every hole adds 100 μ L cell suspensions in the 96-well flat board, 3 multiple holes is set, and blank group (B) is set, negative control group (N), TPO positive controls (P) and testing compound group (S);
(5) with DMSO the testing compound powder is made into the storage liquid of 10mM, is diluted to different concns with RPM11640 again: 30 μ M, 10 μ M, 3 μ M, 1 μ M, 0.3 μ M, 0.1 μ M, 0.03 μ M, 0.01 μ M, 0.003 μ M and 0.001 μ M;
(6) every hole adds the soup of 10 μ L respective concentration, adds 1 μ L rhTPO (10 μ g/mL) in the positive control hole;
(7) place 5%CO 2, cultivated 24 hours in 37 ℃ of cell culture incubators;
(8) every hole adds 10 μ LCCK-8, cultivates 4 hours in cell culture incubator;
(9) utilize VICTOR3 (Perkin Elmer 1420-120) instrument to detect the OD value at 450nm.
4. interpretation of result is calculated:
(1) appreciation rate definition: [(S-B)/(P-B)] * 100%
S: sample; B: blank; P: positive control
(2) calculate EC by Origin 7.0 50
5. result:
The active EC of compound TPO 50Value
Embodiment EC 50Value (nM)
Eltrombopag 299
1 65
3 68
5 156
7 152
8 31
12 126
16 45
17 137
18 128
19 183
20 52
21 70
23 120
24 30
25 84
26 244
27 78
28 142
29 103
30 190
31 55
32 130
33 148
34 44
Experimental result shows that The compounds of this invention is compared with positive control Eltrombopag, its EC 50Value is lower than positive control Eltrombopag, and wherein compound 8,24,31 and 34 activity are stronger.
The pharmacokinetics test
The pharmacokinetics test of test case 1 The compounds of this invention
1, test objective
With the rat is animal subject, uses the HPLC-UV method and has measured rat and irritate stomach respectively and give the drug level in the different moment blood plasma behind embodiment 21,31 and the positive control Eltrombopag.Study compound of the present invention in the pharmacokinetics in rats behavior, estimate its characteristics of pharmacokinetics.
2, testing program
2.1, test drug
Embodiment 21, embodiment 31 compounds and positive control Eltrombopag
2.2, experimental animal
24 of healthy adult SD rats, male and female half and half are available from west, Shanghai pul-Bi Kai laboratory animal company limited, animal production licence number: SCXK (Shanghai) 2003-0002.
2.3, plant and instrument
TSQ Quantum Ultra AM triple quadrupole bar mass spectrograph, U.S. Thermo Finnigan company;
Agilent 1200 highly effective liquid phase chromatographic systems, U.S. Agilent company.
2.4, medicine preparation
Take by weighing an amount of sample and add 1% Xylo-Mucine and make 5.0mg/mL (in original shape) suspension, face the time spent preparation.
2.5, administration
24 of healthy adult SD rats, male and female half and half are divided into 5 groups, difference gastric infusion behind the overnight fasting, dosage is 50.0mg/kg (in original shape), administration volume 10mL/kg.
2.6, sample collecting
24 of SD rats, male and female half and half, gastric infusion after one night of fasting, dosage is 5.0mg/kg.Before administration and after the administration 0.5,1.0,2.0,3.0,4.0,5.0,6.0,8.0,11.0,14.0,24.0,36.0,48.0 hour by eye socket blood sampling 0.2mL, place the heparinization test tube, centrifugal 10 minutes separated plasmas of 3500rpm, feed in 2 hours after-20 ℃ of preservation administrations.
2.7, analytical procedure
Draw each rat plasma 50 μ L constantly behind the medicine, add inner mark solution 50 μ L, methyl alcohol: water (80: 20, v/v) 20 μ L, methyl alcohol 100 μ L, vortex mixed 3 minutes, centrifugal 10 minutes (13500r/min) gets supernatant liquor 40 μ L and carries out HPLC-UV and analyze.
2.8, typical curve preparation
Get rat blank plasma 50 μ L, add standard serial solution respectively, making Plasma Concentration is 1.0ng/mL, 5.0ng/mL, 25.0ng/mL, 50.0ng/mL, 100.0ng/mL, 250.0ng/mL and 500.0ng/mL, add inner mark solution 20 μ L, by operating under " plasma sample pre-treatment " item.With the Plasma Concentration is X-coordinate, and sample is ordinate zou with interior mark chromatographic peak area ratio, with weighted least-squares method (w=1/x 2) carry out linear regression, obtain the representative standard curve equation.
2.9, pharmacokinetic parameter calculates
The compartment model match is carried out in pharmacokinetics behavior to test-compound, and calculates main pharmacokinetic parameter, wherein C Max, t MaxAdopt measured value.
3, pharmacokinetic parameter result
The pharmacokinetic parameter of compound of the present invention is as follows:
Figure B2009100536910D0000681
Test-results shows, rat is irritated respectively after stomach gives above-claimed cpd, and the salt of embodiment 21 and 31 compounds is compared with positive compound Eltrombopag, and pharmacokinetic property and bioavailability are obviously improved, the medicine codes or data is better, and pharmacokinetic curve is preferably arranged.

Claims (17)

1. the compound shown in the general formula (I) or its tautomer, pharmaceutically acceptable salt, hydrate or solvated compounds:
Figure F2009100536910C0000011
Wherein:
R is selected from hydrogen atom or alkyl;
R 1, R 2, R 3And R 4Be selected from hydrogen atom, alkyl, alkoxyl group, halogen, aryl or heteroaryl independently of one another, wherein aryl or heteroaryl are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, carboxylic acid or carboxylicesters;
R 5, R 6And R 7Be selected from hydrogen atom, alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, carboxylic acid or carboxylicesters independently of one another;
R 8, R 9, R 10And R 11Be selected from hydrogen atom, carbonyl, hydroxyl or alkyl independently of one another;
N is 0,1 or 2; And
Figure F2009100536910C0000012
Expression singly-bound or two key, condition is two
Figure F2009100536910C0000013
Be not two keys simultaneously.
2. compound according to claim 1 or its tautomer, pharmacy acceptable salt, hydrate or solvated compounds,
Wherein:
General formula (I) carbon-to-nitrogen double bon is configured as (Z) type;
R is selected from hydrogen atom or alkyl;
R 1Be selected from aryl or heteroaryl, wherein aryl or heteroaryl are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, hydroxyl, carboxylic acid or carboxylicesters;
R 2, R 3And R 4Be selected from hydrogen atom, alkyl, alkoxy or halogen independently of one another;
R 5, R 6And R 7Be selected from hydrogen atom, alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, carboxylic acid or carboxylicesters independently of one another;
R 8, R 9, R 10And R 11Be selected from hydrogen atom, carbonyl, hydroxyl or alkyl independently of one another;
N is 0,1 or 2; And
Figure F2009100536910C0000014
Expression singly-bound or two key, condition is two
Figure F2009100536910C0000015
Be not two keys simultaneously.
3. compound according to claim 1 and 2 or its tautomer, pharmacy acceptable salt, hydrate or solvated compounds, wherein said tautomer comprises:
Figure F2009100536910C0000021
Wherein n, R and R 1～R 11Definition according to claim 1.
4. compound according to claim 1 and 2 or its tautomer, pharmacy acceptable salt, hydrate or solvated compounds, wherein said compound comprises:
Figure F2009100536910C0000022
Figure F2009100536910C0000031
5. the compound shown in the general formula (IA) or its tautomer, described compound is the intermediate of synthetic general formula as claimed in claim 1 (I) compound:
Figure F2009100536910C0000032
Wherein:
R 5, R 6And R 7Be selected from hydrogen atom, alkyl, alkoxyl group, halogen, hydroxyl, amino, nitro, cyano group, carboxylic acid or carboxylicesters independently of one another;
R 8, R 9, R 10And R 11Be selected from hydrogen atom, carbonyl, hydroxyl or alkyl independently of one another;
N is 0,1 or 2; And
Figure F2009100536910C0000033
Expression singly-bound or two key, condition is two
Figure F2009100536910C0000034
Be not two keys simultaneously.
6. compound according to claim 5 or its tautomer, wherein said tautomer comprises:
Figure F2009100536910C0000041
Wherein n and R 5～R 11Definition as described in the claim 5.
7. compound according to claim 5 or its tautomer, wherein said compound comprises:
Figure F2009100536910C0000042
8. preparation is as the method for claim 5 or 6 described general formula (IA) compounds, and this method comprises:
Figure F2009100536910C0000043
Diazotization reaction takes place in amino polynary ring of benzo and the Sodium Nitrite that replaces in acidic solution, obtain hydrazine by the tin protochloride reduction again, and condensation obtained general formula (IA) compound under the carbonyl compound of hydrazine and parent's electricity heated in solvent;
Wherein n and R 5～R 11Definition as described in the claim 5.
9. preparation is as the method for claim 5 or 6 described general formula (IA) compounds, and this method comprises:
Figure F2009100536910C0000051
Amino polynary ring of benzo that replaces and potassium halide, sodium nitrite solution reaction generate the polynary ring of benzo that halogen replaces, with the reaction of diazanyl carboxylic acid tert-butyl ester, condensation obtained general formula (IA) compound under the diazanyl substitution product of the carboxylic acid tert-butyl ester protection of generation heated in solvent with the carbonyl compound of parent's electricity then;
Wherein X is selected from halogen, n and R 5～R 11Definition as described in the claim 5.
10. preparation is as the method for claim 5 or 6 described general formula (IA) compounds, and this method comprises:
Figure F2009100536910C0000052
Condensation obtained general formula (IA) compound under polynary ring of benzo that halogen replaces and the reaction of azo-2-carboxylic acid's di tert butyl carbonate, the product that the diazanyl by two carboxylic acid tert-butyl ester protections of generation replaces were heated in solvent with the carbonyl compound of parent's electricity;
Wherein X is selected from halogen, n, R 5～R 11Definition as described in the claim 5.
11. prepare the method for general formula as claimed in claim 1 (I) compound, this method comprises:
Figure F2009100536910C0000053
The amino benzenes compounds and the Sodium Nitrite that replace are carried out diazotization reaction in acidic solution, again with general formula (IA) thus linked reaction takes place in basic solution compound obtains general formula (I) compound;
Wherein n, R and R 1～R 11Definition according to claim 1.
12. the purposes in the preparation thrombopoietin receptor agonist according to each described compound of claim 1～7 or its tautomer, pharmacy acceptable salt, hydrate or solvated compounds.
13. the purposes in preparation treatment thrombopenia disease drug according to each described compound of claim 1～7 or its tautomer, pharmacy acceptable salt, hydrate or solvated compounds.
14. purposes according to claim 12, wherein said medicine further be selected from following medication combined use: G CFS, cytokine, chemokine, interleukin-or cytokine receptor agonist or antagonist, soluble acceptor, receptor stimulant or antagonist antibodies or the peptide or the small molecules class material that have the identical mechanism of action with one or more and described medicine.
15. a pharmaceutical composition, described composition comprise effective dose as each described compound of claim 1～7 or its tautomer, pharmaceutically acceptable salt, hydrate or solvated compounds, and acceptable carrier pharmaceutically.
16. pharmaceutical composition according to claim 15, wherein said composition further contain the associating use the treatment significant quantity be selected from following medicine: G CFS, cytokine, chemokine, interleukin-or cytokine receptor agonist.
17. pharmaceutical composition according to claim 15 is in the purposes of preparation treatment thrombopenia disease drug.
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EP2566854A2 (en) * 2010-05-04 2013-03-13 Shire LLC Desazadesferrothiocin and desazadesferrothiocin polyether analogues as metal chelation agents
WO2013152683A1 (en) * 2012-04-11 2013-10-17 齐鲁制药有限公司 Bicycle substituted pyrazoloneazo derivatives and preparation method and use thereof
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* Cited by examiner, † Cited by third party
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EP2566854A2 (en) * 2010-05-04 2013-03-13 Shire LLC Desazadesferrothiocin and desazadesferrothiocin polyether analogues as metal chelation agents
EP2566854A4 (en) * 2010-05-04 2013-11-06 Shire Llc Desazadesferrothiocin and desazadesferrothiocin polyether analogues as metal chelation agents
US9045440B2 (en) 2010-05-04 2015-06-02 Ferrokin Biosciences, Inc. Desazadesferrothiocin and desazadesferrothiocin polyether analogues as metal chelation agents
WO2013152683A1 (en) * 2012-04-11 2013-10-17 齐鲁制药有限公司 Bicycle substituted pyrazoloneazo derivatives and preparation method and use thereof
CN103360317A (en) * 2012-04-11 2013-10-23 齐鲁制药有限公司 Dicyclo-substituted pyrazolone azo derivatives, as well as preparation method and use thereof
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CN103910718B (en) * 2013-01-08 2018-08-14 齐鲁制药有限公司 Double cyclosubstituted pyrazolone azo compounds, preparation method and use
CN105412930A (en) * 2015-08-07 2016-03-23 军事医学科学院华南干细胞与再生医学研究中心 Application of TPO (thrombopoietin) receptor agonist in promoting homing of HSCs (hematopoietic stem cells)
CN110407702A (en) * 2019-07-03 2019-11-05 武汉工程大学 A kind of preparation method of eltrombopag olamine key intermediate 3 '-amino -2 '-xenol -3- carboxylic acid
WO2024088302A1 (en) * 2022-10-25 2024-05-02 江苏恒瑞医药股份有限公司 Use of herombopag or pharmaceutically acceptable salt thereof in treatment of tumor chemotherapy-induced thrombocytopenia

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Application publication date: 20101229