CN106967076A - One kind has 6H dibenzopyrans structural compounds and preparation method thereof - Google Patents
One kind has 6H dibenzopyrans structural compounds and preparation method thereof Download PDFInfo
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- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
There are 6H dibenzopyrans structural compounds and preparation method thereof the invention discloses one kind, belong to the synthesis technical field of medicine.Technical scheme main points are：One kind has 6H dibenzopyrans structural compounds, and its structural formula is：
Description
Technical field
The invention belongs to the synthesis technical field of medicine intermediate, and in particular to one kind has 6H- dibenzopyrans structures
Compound and preparation method thereof.
Background technology
Promoting sexual gland hormone shows important physiological function in human body, such as metabolism, body heat regulation and reproduction
Journey.It is synthesized and secreted by hypothalamus, by inducing follicle-stimulating hormone (FSH) in hypophysis（FSH）/ luteotropic hormone（LH）'s
Secretion, Follicles grows and ovulates in an one-step inducing ovary of going forward side by side.FSH is the core during Mammalian Reproduction
Hormone, it is fetal differentiation, foetal period ovum peak occur and follicle atresia, the genesis and development of sexual maturing period ovarian follicle and maturation,
Granulocyte aromatizing enzyme is activated and androgen plays conversion from irreplaceable crucial work to estrogen, the regulation of cyclostage
With.Effects of the FSH to target organ is main by fsh receptor（FSHR）Mediated.Research shows that FSHR is not expressed in sexual gland only,
Also in the expression of other tissues such as bone, prostate, Ovarian surface epithelium.Level is too high in vivo by FSH, can cause sclerotin stream
Lose, some hormone-dependent diseases, such as oophoroma, prostate cancer, mullerianosis, OHSS, all
Influenceed very big by FSH；By suppressing FSH secretion, can with so that inhibition glandular secretion sex hormone, cause disease dependence in blood
Hormonal readiness is reduced, and suppresses the growth or prevention, alleviation, treatment other illnesss of cancer cell；For example, Cetrorelix is exactly according to this
Mechanism plays anti-proliferative effect to oophoroma.We pass through computer according to current existing fsh receptor inhibitor medicaments molecule
Medicine Computer Aided Design, to one of them, relatively good medicines structure is optimized, and a kind of tool has been obtained by new synthetic method
There are 6H- dibenzopyrans structural compounds, and related activity test has been carried out to it.
The content of the invention
Present invention solves the technical problem that there is provided that a kind of synthetic method is simple, molecular structure is novel and to fsh receptor
Action effect is preferably a kind of to have 6H- dibenzopyrans structural compounds and preparation method thereof.
The present invention adopts the following technical scheme that one kind has 6H- dibenzopyrans structurings to solve above-mentioned technical problem
Compound, it is characterised in that the structural formula of the compound is：
。
A kind of preparation method with 6H- dibenzopyrans structural compounds, it is characterised in that concretely comprise the following steps：
The bromo- 4- nitrobenzene methyls of A, 2- and 2- amino phenyl boric acid take in the presence of catalyst tetrakis triphenylphosphine palladium
Generation reaction obtains 2 '-amino -5- nitrobiphenyl -2- methyl formates；
Nitro-reduction reaction occurs in the presence of catalyst reduction iron powder and obtains for B, 2 '-amino -5- nitrobiphenyl -2- methyl formates
To 2 '-amino -5- aminobphenyl -2- methyl formates；
C, 2 '-amino -5- aminobphenyl -2- methyl formates are anti-by amino reduction-oxidation in the presence of catalyst natrium nitrosum
2 '-amino -5- xenol -2- methyl formates should be obtained；
D, 3- hydroxy-methylbenzene and 2- N-Propyl Bromides occur substitution reaction and obtain 3- isopropoxy toluene；
E, 3- isopropoxy toluene positioning catalyst iron powder in the presence of with bromine occur substitution reaction obtain 3- isopropoxies-
6- bromobenzyl bromines；
F, 2 '-amino -5- xenol -2- methyl formates and 3- isopropoxies -6- bromobenzyls bromine hydroxyl hydrogen activation catalyst palladium/
Substitution reaction occurs in the presence of hydroxyapatite and obtains 5- (the bromo- 5- isopropoxies phenmethylols of 2-) -2 '-aminobphenyl -2- first
Sour methyl esters；
G, 5- (the bromo- 5- isopropoxies phenmethylols of 2-) -2 '-aminobphenyl -2- methyl formates are in phenyl ring hydrogen activation catalyst palladium/hydroxyl
In the presence of base apatite occur intramolecular annulation obtain 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -
2- methyl formates；
After H, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl formates are hydrolyzed in alkaline solution
Carry out being acidified again and obtain 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- formic acid；
I, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- formic acid is in the presence of lithium aluminium hydride reduction through carboxyl oxygen
Change reduction reaction and obtain 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methanol；
J, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methanol with to methylsufonyl chloride carry out it is hydroxy activated
Protection reaction obtains 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl to methanesulfonate ester；
K, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl occurs substitution reaction to methanesulfonate ester and entered
Row intramolecular cyclization obtains 8- isopropoxy -6H- dibenzopyrans and phenyl and piperidines acene；
L, 8- isopropoxy -6H- chromenes and phenyl and piperidines acene is sloughed isopropyl alkyl in the presence of lithium bromide and obtained
8- hydroxyl -6H- dibenzopyrans and phenyl and piperidines acene；
M, 8- hydroxyl -6H- dibenzopyrans and phenyl and piperidines acene and trifluoromethanesulfonic acid anhydride reactant obtain 8- trifluoromethanesulfonic acids
Ester group -6H- dibenzopyrans and phenyl and piperidines acene；
N, 8- trifluoromethanesulfonic acid ester group -6H- dibenzopyrans and phenyl and piperidines acene is double (diphenylphosphine) in catalyst 1,3-
N-8- anilino- -6H- dibenzopyrans and hexahydropyridine acene are obtained in the presence of propane and Raney's nickel with aniline reaction.
Further preferably, step A detailed process is：By the bromo- 4- nitrobenzene methyls of 2-, 2- ammonia in reaction vessel
It is 10 that base benzene boron and potassium carbonate, which add volume ratio,:In 1 DME and the mixed solution of water, 30min is stirred at room temperature under nitrogen protection,
Catalyst tetrakis triphenylphosphine palladium is added, is stirred under nitrogen protection, 100 DEG C of reactions are warming up to until TLC monitors former
Material reaction is complete, solvent is evaporated off under vacuum, residue is added in dichloromethane, then washed twice with pure water, organic
Solvent is evaporated off after anhydrous sodium sulfate drying, then 2 '-amino -5- nitrobiphenyls -2- is obtained through silica gel column chromatography separating-purifying
Methyl formate.
Further preferably, step B detailed process is：Reduced iron powder is added in glacial acetic acid in reaction vessel, risen
Temperature adds the ice dissolved with 2 '-amino -5- nitrobiphenyl -2- methyl formates under nitrogen protection to stirring reaction 45min after 85 DEG C
Acetic acid solution, drips and continues to react up to TLC monitoring raw material reactions are complete after 85 DEG C, then filter reaction by diatomite
Liquid, diatomite is washed with the glacial acetic acid of heat, and reaction dissolvent is evaporated off in filtrate under vacuum, adds saturated sodium bicarbonate,
Reaction solution is extracted with ethyl acetate again three times, merges organic phase, solvent is evaporated off after anhydrous sodium sulfate drying, is concentrated to give for organic phase
To 2 '-amino -5- amido biphenyl -2- methyl formates.
Further preferably, step C detailed process is：In 0 DEG C by 2 '-amino -5- amido biphenyl -2- in reaction vessel
Methyl formate is added in the dilute sulfuric acid that mass concentration is 5%, and agitation and dropping is added dropwise dissolved with the aqueous solution of catalyst natrium nitrosum
Complete rear keeping temperature continues to react 1h, then is warming up to 60 DEG C of reactions up to TLC monitoring raw material reactions are complete, is subsequently cooled to room
Temperature, is extracted with ethyl acetate reaction solution three times, merges organic phase, solvent is evaporated off in organic phase after anhydrous sodium sulfate drying, through silicon
Plastic column chromatography separating-purifying obtains 2 '-amino -5- xenol -2- methyl formates.
Further preferably, step D detailed process is：3- hydroxy-methylbenzenes are added to 2- N-Propyl Bromides in reaction vessel
In the DMF of Non-aqueous processing, potassium carbonate is added, back flow reaction is warming up to until TLC monitoring raw material reactions are complete, in vacuum condition
Under solvent is evaporated off, residue is added to the water, then with dichloromethane aqueous phase extracted three times, merges and solvent is evaporated off after organic phase obtains
3- isopropoxy toluene.
Further preferably, step E detailed process is：3- isopropoxy toluene is added to glacial acetic acid in reaction vessel
In, positioning catalyst iron powder is added, bromine is added dropwise at ambient temperature, 30min is dripped, is warming up to 40 DEG C of reactions, then use
Addition mass concentration in solvent glacial acetic acid, concentrate is evaporated off under the irradiation reaction of 300W tungsten lamps, vacuum molten for 20% sodium hydroxide
Liquid, filtering reacting liquid, filtrate is extracted three times with dichloromethane, merges organic phase, organic phase is again after anhydrous sodium sulfate drying
It is concentrated to give the bromobenzyl bromine of 3- isopropoxies -6.
Further preferably, step F detailed process is：By 2 '-amino -5- xenol -2- formic acid in reaction vessel
Methyl esters is added in dry acetone with 3- isopropoxy -6- bromobenzyl bromines, adds hydroxyl hydrogen activation catalyst palladium/hydroxy-apatite
Stone, is heated to back flow reaction until completely, reaction dissolvent is evaporated off, concentrate is added in the reaction of TLC monitoring raw materials under vacuum
Into dichloromethane, with pure water washing organic phase three times, organic phase is separated, is evaporated off obtaining thick after solvent under vacuum
Product, then obtain 5- (the bromo- 5- isopropoxies phenmethylols of 2-) -2 '-aminobphenyl -2- formic acid first through silica gel column chromatography separating-purifying
Ester.
Further preferably, step G detailed process is：In reaction vessel by 5- (the bromo- 5- isopropoxies phenmethylols of 2-)-
2 '-aminobphenyl -2- methyl formates are added in dimethyl acetamide with potassium carbonate, in N2The lower addition phenyl ring hydrogen activation of protection is urged
Agent palladium/hydroxyapatite, N is continually fed into reaction system2, while discharging N2, it is kept a stable circulation environment,
Closed reaction vessel after 30min is stirred at room temperature, then reaction vessel is placed in microwave reactor, 100 DEG C of reactions are heated to straight
It is complete to TLC monitoring raw material reactions, reaction vessel addition pure water is then taken out from microwave reactor reaction is quenched, then use second
Acetoacetic ester extractive reaction liquid three times, merges organic phase, with solvent is evaporated off after anhydrous sodium sulfate drying, most afterwards through silica gel column chromatography point
3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl formates are obtained from purification.
Further preferably, step H detailed process is：In reaction vessel by 3- (2- aminobenzenes) -8- isopropoxies -
6H- dibenzopyrans -2- methyl formates are added in ethanol, add the aqueous solution dissolved with sodium hydroxide, are warming up to 70 DEG C instead
Should be complete up to TLC monitoring raw material reactions, solvent is evaporated off under vacuum, residue is added to the water, then uses ethyl acetate
Aqueous phase three times is washed, aqueous phase diluted hydrochloric acid dissolution regulation pH is 3, then with dichloromethane aqueous phase extracted three times, merge organic phase, most
After be evaporated off obtaining 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- formic acid after solvent.
Further preferably, step I detailed process is：In reaction vessel by 3- (2- aminobenzenes) -8- isopropoxies -
6H- dibenzopyrans -2- formic acid is added in anhydrous THF, and reaction temperature is reduced to -60 DEG C, and the tetrahydrochysene furan of lithium aluminium hydride reduction is added dropwise
Mutter solution, keeping temperature continues to react 2h, then is warming up to 0 DEG C of reaction 2h, adds frozen water and reaction, suction filtration reaction solution, filtrate is quenched
It is extracted with ethyl acetate repeatedly, merges organic phase, be evaporated off obtaining 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzo after solvent
Pyrans -2- methanol.
Further preferably, step J detailed process is：In reaction vessel by 3- (2- aminobenzenes) -8- isopropoxies -
6H- dibenzopyrans -2- methanol, methylsufonyl chloride and potassium carbonate are added in DMF, are warming up to 80 DEG C of reactions until TLC prisons
Control raw material reaction complete, add pure water and reaction is quenched, then be extracted with ethyl acetate three times, merge organic phase, organic phase is through nothing
Solvent is evaporated off after drying in aqueous sodium persulfate, then obtains 3- (2- aminobenzenes) -8- isopropoxies -6H- through silica gel column chromatography separating-purifying
Dibenzopyrans -2- methyl is to methanesulfonate ester.
Further preferably, step K detailed process is：In reaction vessel by 3- (2- aminobenzenes) -8- isopropoxies -
6H- dibenzopyrans -2- methyl is added in acetonitrile to methanesulfonate ester, adds aniline, and mechanical agitation is simultaneously warming up to 70 DEG C
Reaction is until TLC monitoring raw material reactions are complete, and decompression steams solvent acetonitrile, adds n-hexane, is cooled to -5 DEG C, whipping process
In have solid precipitation, filtering reacting liquid obtains solid, and is washed with cold toluene, filter cake drying after obtain 8- isopropoxies -6H- two
Chromene and phenyl and piperidines acene.
Further preferably, step L detailed process is：In reaction vessel by 8- isopropoxy -6H- dibenzopyrans simultaneously
Simultaneously piperidines acene is added in dichloromethane phenyl, adds lithium bromide, in 0 DEG C of stirring reaction until TLC monitoring raw material reactions
Completely, reaction dissolvent is evaporated off and obtains 8- hydroxyl -6H- dibenzopyrans and hexahydropyridine acene.
Further preferably, step M detailed process is：By 8- hydroxyl -6H- dibenzopyrans and hexahydro in reaction vessel
Pyridine acene is added with triethylamine in the dichloromethane of Non-aqueous processing, and trifluoromethanesulfanhydride anhydride is added dropwise in 0 DEG C, is warming up to after dripping
Room temperature is until the reaction of TLC monitoring raw materials completely, is evaporated off adding n-hexane in reaction dissolvent, residue, in 0 DEG C of stirring and crystallizing, had
Yellow solid occurs, filtering and drying to obtain to 8- trifluoromethanesulfonic acids ester group -6H- dibenzopyrans and hexahydropyridine acene.
Further preferably, step N detailed process is：By 8- trifluoromethanesulfonic acid ester group -6H- hexichol in autoclave
And simultaneously hexahydropyridine acene, aniline and triethylamine are added in the DMF after Non-aqueous processing pyrans, add catalyst 1,3- is double
(diphenylphosphine) propane, adds Raney's nickel after being stirred at room temperature under nitrogen protection, then reaction system is vacuumized, and discharges nitrogen
Gas, is passed through carbon monoxide, reaction pressure is reached 0.2MPa, is warming up to 60 DEG C of reactions and reacts complete up to TLC monitors raw material, drop
To room temperature, the complete carbon monoxide of unreacted is excluded, filtering reacting liquid removes solvent DMF under reduced pressure, toluene is added into residue,
There is faint yellow solid precipitation in 0 DEG C of stirring, suction filtration solid obtains N-8- anilino- -6H- dibenzopyrans and hexahydro pyrrole after drying
Pyridine acene.
A kind of synthetic route with 6H- dibenzopyrans structural compounds of the present invention is：
。
Synthesis technique of the present invention is simple and with low cost, and obtained FSH antagonist pharmaceuticals molecules are understood by active testing
It is preferable to the action effect of fsh receptor, it is expected to further genralrlization application.
Embodiment
The above to the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
In reaction bulb, 2- bromo- 4- nitrobenzene methyls 5.0g, 2- amino phenyl boric acid 4.0g and potassium carbonate 5g are added to body
Product is than being 10:In 1 DME and the mixed solution 120mL of water, 30min is stirred at room temperature under nitrogen protection, catalyst four is added
(triphenylphosphine) palladium 1g, stirs under nitrogen protection, is to slowly warm up to TLC monitoring raw material reaction after 100 DEG C, reaction 14h
Completely, solvent is evaporated off under vacuum, residue is added in dichloromethane, then washed twice with pure water 50mL, organic phase
Solvent is evaporated off after anhydrous sodium sulfate drying, then 2 '-amido -5- nitrobiphenyl -2- first is obtained through silica gel column chromatography separating-purifying
Sour methyl esters 4.9g；1H NMR (400 MHz, DMSO-d6) δ: 8.34 (s, 1 H), 8.17(d, J=2.4Hz, 1 H),
7.97 (d, J=8.6Hz,1 H), 7.62-7.57 (m, 2 H), 7.33-7.30(m, 2 H), 6.25(s, 2H),
3.79 (s, 3 H)。
Embodiment 2
In reaction bulb, reduced iron powder 5g is added in glacial acetic acid 70mL, stirring reaction 45min after 85 DEG C is warming up to, in nitrogen
The glacial acetic acid solution 70mL dissolved with 2 '-amino -5- nitrobiphenyl -2- methyl formates 6g is slowly added under gas shielded, after dripping
Continue to react 2h under the conditions of 85 DEG C, filtering reacting liquid is carried out by diatomite after TLC monitoring raw material reactions completely, diatomite is used
A certain amount of hot glacial acetic acid is washed, and reaction dissolvent is evaporated off in filtrate under vacuum, adds a certain amount of unsaturated carbonate
Hydrogen sodium, then reaction solution is extracted with ethyl acetate three times, merge organic phase, solvent is evaporated off in organic phase after anhydrous sodium sulfate drying,
It is concentrated to give 2 '-amino -5- aminobphenyl -2- methyl formates 5.1g；1H NMR (400 MHz, CDCl3) δ: 7.97 (s,
1 H), 7.71-7.69 (m, 1 H), 7.35 (s, 2 H), 7.23-7.21 (m, 1 H), 6.67-6.61(m,
4H), 6.44-6.39 (m, 3 H), 6.21 (s, 1 H), 6.07(s, 1H), 5.93-5.90 (m, 2 H), 3.27
(s, 3 H)。
Embodiment 3
In reaction bulb, under the conditions of temperature is 0 DEG C, 2 '-amino -5- amido biphenyl -2- methyl formates 5.0g is added to matter
Concentration is measured in 5% dilute sulfuric acid 100mL, after stirring 10min, then the aqueous solution dissolved with natrium nitrosum 2.0g to be slowly added dropwise
20mL, drips rear keeping temperature and continues to react 1h, then be to slowly warm up to after 60 DEG C of reaction 8h, TLC monitoring raw material reactions completely
Room temperature is cooled to, reaction solution is extracted with ethyl acetate three times, merges organic phase, organic phase is evaporated off molten after anhydrous sodium sulfate drying
Agent, 2 '-amino -5- xenol -2- methyl formates 3.9g is obtained through silica gel column chromatography separating-purifying；1H NMR (400 MHz,
CDCl3) δ: 7.94 (d, J=12.0Hz, 1 H), 7.54-7.49 (m, 2H), 7.16 (d, J=12.0Hz, 1
H), 6.92-6.91 (m, 3 H), 6.27 (s, 2 H), 5.35(s, 1H), 3.25 (s, 3 H)。
Embodiment 4
In reaction bulb, 3- hydroxy-methylbenzene 10g and 2- N-Propyl Bromides 10g is added in the DMF 100mL of Non-aqueous processing, added
Potassium carbonate 15g, is to slowly warm up to the reaction of back flow reaction 24h, TLC monitoring raw material completely, solvent is evaporated off under vacuum, remaining
Thing is added to the water, then with dichloromethane aqueous phase extracted three times, merges organic phase, be finally evaporated off obtaining product 3- isopropyls after solvent
Epoxide toluene 13g；1H NMR (400 MHz, CDCl3) δ: 7.33 (s, 1H), 7.17-7.12(m, 3H), 4.73-
4.71 (m, 1H), 2.61 (s, 3 H), 1.34 (d, J=8.0Hz, 6 H)。
Embodiment 5
In reaction bulb, 3- isopropoxy toluene 15g is added in glacial acetic acid 100mL, positioning catalyst iron powder 3g is added,
Bromine 8mL is slowly added dropwise at ambient temperature, about 30min is dripped, and is warming up to after 40 DEG C and is reacted 10h, then is shone with 300W tungsten lamps
Reaction 5h is penetrated, is evaporated off under vacuum adding the sodium hydroxide that a certain amount of mass concentration is 20% in solvent glacial acetic acid, concentrate molten
Liquid, filtering reacting liquid, filtrate is extracted three times with dichloromethane, merges organic phase, organic phase is again after anhydrous sodium sulfate drying
It is concentrated to give 3- isopropoxy -6- bromobenzyl bromines 23g；1H NMR (400 MHz, CDCl3) δ: 7.50-7.49 (m, 1H),
7.06-7.04 (m, 2H), 4.69 (s, 2H), 4.29-4.27(m, 1H), 1.37 (d, J=8.0Hz, 6 H)。
Embodiment 6
Palladium chloride 5g is added in reaction bulb, it is 1 to add mass ratio:1 methanol-water mixed solution 250mL, adds carboxylic
Sodium carboxymethylcellulose pyce 1g, is 4.5 with the pH of sodium carbonate regulation system, adds hydroxyapatite 50g, be stirred at room temperature after 2h and put
Enter in autoclave, hydrogenation reduction 2h stirred under the conditions of 100KPa, 100 DEG C, depressurize suction filtration, deionized water be washed till it is neutral and
Through silver nitrate solution detection without chlorion, under the conditions of 60 DEG C of normal pressure drying 3h obtains palladium/hydroxyapatite 40g.
Embodiment 7
In reaction bulb, 2 '-amino -5- xenol -2- methyl formate 5g and 3- isopropoxy -6- bromobenzyl bromines 8g is added to
In dry acetone 250mL, hydroxyl hydrogen activation catalyst palladium/hydroxyapatite 0.5g is added, back flow reaction 4h is heated to,
TLC monitoring raw material reactions are complete, reaction dissolvent are evaporated off under vacuum, concentrate is added in dichloromethane, then with pure
Water washing organic phase three times, separates organic phase, is evaporated off obtaining product crude product after solvent under vacuum, then through silica gel column chromatography
Separating-purifying obtains 5- (the bromo- 5- isopropoxies phenmethylols of 2-) -2 '-aminobphenyl -2- methyl formates 7.1g；1H NMR (400
MHz, CDCl3) δ: 7.94 (d, J=8.0 Hz, 1H), 7.47-7.41(m, 1H), 7.40 (s, 1H), 7.34-
7.18 (m, 5H), 7.03 (s, 1H), 5.18 (s, 2H), 4.61-4.53(m, 1H), 3.81 (s, 3 H),
3.62 (s, 3H), 1.28 (d, J=8.0Hz, 6 H)。
Embodiment 8
In reaction bulb, 5- (the bromo- 5- isopropoxies phenmethylols of 2-) -2 '-aminobphenyl -2- methyl formates 10g and potassium carbonate
5g is added in dimethyl acetamide 100mL, in N2Protection is lower to add phenyl ring hydrogen activation catalyst palladium/hydroxyapatite 1g, toward instead
Answer and do not stop to be passed through N in system2, while discharging N2, it is kept a stable circulation environment, confined reaction after 30min be stirred at room temperature
Bottle, it is placed in microwave reactor, 100 DEG C of reaction 24h, TLC monitoring raw material reactions is heated to completely, from microwave reactor
In take out reaction bulb, add a certain amount of pure water and reaction be quenched, then reaction solution is extracted with ethyl acetate three times, merging is organic
Phase, then with solvent is evaporated off after anhydrous sodium sulfate drying, most through silica gel column chromatography separating-purifying obtains 3- (2- aminobenzenes) -8- different afterwards
Propoxyl group -6H- dibenzopyrans -2- methyl formates 7.5g；1H NMR (400 MHz, CDCl3) δ: 8.12 (d, J=8.0
Hz, 1H), 7.71-7.65(m, 4H), 7.43-7.41 (m, 2H), 7.16-7.12 (m, 2H), 6.27(s, 2H),
5.16 (s, 2H), 4.72(d, J=8.0Hz, 1H), 3.47 (s, 3H), 1.25-1.23 (m, 6 H)。
Embodiment 9
In reaction bulb, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl formates 5g is added to ethanol
In 20mL, the aqueous solution 10mL dissolved with sodium hydroxide 2.5g is added, 70 DEG C of reaction 1h, TLC monitoring raw materials is warming up to and has reacted
Entirely, solvent is evaporated off under vacuum, residue is added to the water, then washs with ethyl acetate aqueous phase three times, aqueous phase is again with dilute
Dissolving with hydrochloric acid regulation pH is 3, then with dichloromethane aqueous phase extracted three times, merges organic phase, be finally evaporated off after solvent obtaining product
3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- formic acid 4.1g；1H NMR (400 MHz, CDCl3) δ:
7.96-7.95 (m, 1H), 7.69-7.65(m, 4H), 7.39-7.37 (m, 2H), 7.12-7.10 (m, 2H),
6.26(s, 2H), 5.16 (s, 2H), 4.72(d, J=8.0Hz, 1H), 1.21-1.19 (m, 6 H)。
Embodiment 10
In reaction bulb, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- formic acid 10g is added to anhydrous THF
In 200mL, reaction temperature is reduced to -60 DEG C, and the tetrahydrofuran solution 30mL of lithium aluminium hydride reduction is slowly added dropwise, and keeping temperature continues anti-
Answer 2h, then be to slowly warm up to 0 DEG C, react 2h, add a certain amount of frozen water and reaction is quenched, suction filtration reaction solution, filtrate uses acetic acid second
Ester extraction is multiple, merges organic phase, is evaporated off obtaining 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- after solvent
Methanol 7.7g；1H NMR (400 MHz, CDCl3) δ: 7.87-7.69 (m, 4H), 7.61-7.55(m, 2H), 7.12-
7.10 (m, 3H), 6.27(s, 2H), 4.70 (s, 2H), 4.39(s, 2H), 3.65(s, 1H), 1.23 (s, 6
H)。
Embodiment 11
In reaction bulb, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methanol 10g, to methylsufonyl chloride
5g and potassium carbonate 20g are added in DMF, are to slowly warm up to TLC monitoring raw materials reaction after 80 DEG C, reaction 8h and completely, are added certain
Reaction is quenched in the pure water of amount, then is extracted three times with ethyl acetate 50mL, merges organic phase, organic phase is through anhydrous sodium sulfate 30g
Solvent is evaporated off after drying and obtains 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl to methanesulfonate ester
8.4g；1H NMR (400 MHz, CDCl3) δ: 7.87-7.69 (m, 4H), 7.61-7.55(m, 2H), 7.12-7.10
(m, 3H), 6.27(s, 2H), 4.70 (s, 2H), 4.39(s, 2H), 3.16(s, 3H), 1.23 (s, 6 H)。
Embodiment 12
In reaction bulb, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl is added to methanesulfonate ester 10g
Enter into acetonitrile 150mL, add aniline 10g, mechanical agitation simultaneously monitors [solvent after being heated to 70 DEG C, reaction 10h through TLC:
PE:EA=7:1] raw material reaction is complete, and decompression steams solvent acetonitrile, adds a certain amount of n-hexane 700mL, is cooled to -5 DEG C,
Gradually there are a large amount of solids to separate out in whipping process, filtering reacting liquid obtains solid, and is washed with a certain amount of cold toluene 200mL,
8- isopropoxy -6H- dibenzopyrans is obtained after filter cake drying and phenyl and piperidines acene 9.3g；1H NMR (400 MHz,
CDCl3) δ: 7.75(d, J=8.0Hz, 1H), 7.62(s, 1H), 7.57(s, 1H), 7.21-7.19(m, 2H),
7.03-7.02 (m, 1H), 5.27 (s, 1H), 5.15-5.13(m, 2H), 4.69(s, 1H), 4.27(s, 2H),
1.21 (d, J=8.0Hz, 6 H)。
Embodiment 13
In reaction bulb, 8- isopropoxy -6H- dibenzopyrans and phenyl and piperidines acene 15g is added to dichloromethane
In 300mL, lithium bromide 10g is added, 2h is stirred under the conditions of 0 DEG C, after TLC monitoring raw material reactions completely, reaction dissolvent is evaporated off
Obtain 8- hydroxyl -6H- dibenzopyrans and hexahydropyridine acene；1H NMR (400 MHz, CDCl3) δ: 7.75(d, J=
8.0Hz, 1H), 7.62(s, 1H), 7.57(s, 1H), 7.21-7.19(m, 2H), 7.03-7.02 (m, 1H),
5.36(s, 1H), 5.27 (s, 1H), 5.15-5.13(m, 2H), 4.69(s, 1H), 4.27(s, 2H)。
Embodiment 14
In reaction bulb, 8- hydroxyl -6H- dibenzopyrans and hexahydropyridine acene 10g and triethylamine 15g addition Non-aqueous processing
Dichloromethane 300mL in, reaction system temperature is set as 0 DEG C, and trifluoromethanesulfanhydride anhydride 30g is slowly added dropwise, and is risen to after dripping
2h is reacted at room temperature, TLC monitoring raw material reactions are complete, are evaporated off adding n-hexane in reaction dissolvent, residue, in 0 DEG C of stirring and crystallizing,
There are a large amount of yellow solids to occur, filtering and drying to obtain to 8-TfO base -6H- dibenzopyrans and hexahydropyridine acene；1H NMR
(400 MHz, CDCl3) δ: 7.75-7.72(m, 2H), 7.57(s, 1H), 7.21-7.19(m, 2H), 7.03-
7.02 (m, 1H), 5.27 (s, 1H), 5.15-5.13(m, 2H), 4.69(s, 1H), 4.27(s, 2H)。
Embodiment 15
In autoclave, 8-TfO base -6H- dibenzopyrans and hexahydropyridine acene 10g, aniline 5g and triethylamine 5g
Add in the DMF after Non-aqueous processing, add catalyst 1, double (diphenylphosphine) the propane 1g of 3-, under nitrogen protection, room temperature is stirred
Addition Raney's nickel 1g after 2h is mixed, reaction system is vacuumized, nitrogen is discharged, is passed through carbon monoxide, reaches reaction pressure
0.2MPa, is to slowly warm up to 60 DEG C, TLC monitoring raw material reactions are complete, are slowly dropped to room temperature, exclude the complete oxidation of unreacted
Carbon, filtering reacting liquid removes solvent DMF under reduced pressure, and toluene is added into residue, has a large amount of faint yellow solids to analyse in 0 DEG C of stirring
Go out, suction filtration solid, N-8- anilino- -6H- dibenzopyrans and hexahydropyridine acene are obtained after drying；1H NMR (400 MHz,
CDCl3) δ: 9.17(s, 1H), 8.06-7.97(m, 4H), 7.59-7.54(m, 4H), 7.21-7.19(m, 2H),
7.03-7.00 (m, 3H), 5.33 (s, 1H), 5.15-5.13(m, 2H), 4.26(s, 2H)。
Embodiment 15
Antitumor activity is tested
Growth period prostate gland cancer cell DU145 is collected, the active anticancer of compound is determined with MTS methods, by cell with appropriate
Concentration（Every milliliter 4 × 104Individual cell）It is added in 96 porocyte culture plates（Containing 10% tire calf serum obtain nutrient solution be made into it is single
Cell suspension）, after cultivating 24 hours, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of compound effects 72 with various concentrations
Hour, then by MTS（Final mass concentration 2mg/mL）And DMS（Final 30 μM of molar concentration）Mixture be directly added into containing thin
In the culture medium of born of the same parents, continue to put incubator incubation 4h.Act on after 4h, abandoning supernatant, 150 μ LDMSO are added per hole, vibrate, carefully
Absorptivity of the metabolin that born of the same parents' survival rate is acted on MTS by it under enzyme linked immunological monitor 490nm wavelength is determined, and FSHR is short of money
Anti-agent drug moleculeInhibiting rate IC50 to the cell is 3.7 μm of olL-1, preliminary bioactivity
Test shows that the compound has certain inhibitory action in prostate gland cancer cell DU145 to cancer cell.
In summary, the invention provides a kind of FSHR antagonists with 6H- dibenzopyrans structures and its preparation side
Method, this is the discovery first of such compound purposes, with certain research and development potentiality.
Embodiment above describes general principle, principal character and the advantage of the present invention, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. one kind has 6H- dibenzopyrans structural compounds, it is characterised in that structural formula is：
。
2. the preparation method with 6H- dibenzopyrans structural compounds described in a kind of claim 1, it is characterised in that specific
Step is：
The bromo- 4- nitrobenzene methyls of A, 2- and 2- amino phenyl boric acid take in the presence of catalyst tetrakis triphenylphosphine palladium
Generation reaction obtains 2 '-amino -5- nitrobiphenyl -2- methyl formates；
Nitro-reduction reaction occurs in the presence of catalyst reduction iron powder and obtains for B, 2 '-amino -5- nitrobiphenyl -2- methyl formates
To 2 '-amino -5- aminobphenyl -2- methyl formates；
C, 2 '-amino -5- aminobphenyl -2- methyl formates are anti-by amino reduction-oxidation in the presence of catalyst natrium nitrosum
2 '-amino -5- xenol -2- methyl formates should be obtained；
D, 3- hydroxy-methylbenzene and 2- N-Propyl Bromides occur substitution reaction and obtain 3- isopropoxy toluene；
E, 3- isopropoxy toluene positioning catalyst iron powder in the presence of with bromine occur substitution reaction obtain 3- isopropoxies-
6- bromobenzyl bromines；
F, 2 '-amino -5- xenol -2- methyl formates and 3- isopropoxies -6- bromobenzyls bromine hydroxyl hydrogen activation catalyst palladium/
Substitution reaction occurs in the presence of hydroxyapatite and obtains 5- (the bromo- 5- isopropoxies phenmethylols of 2-) -2 '-aminobphenyl -2- first
Sour methyl esters；
G, 5- (the bromo- 5- isopropoxies phenmethylols of 2-) -2 '-aminobphenyl -2- methyl formates are in phenyl ring hydrogen activation catalyst palladium/hydroxyl
In the presence of base apatite occur intramolecular annulation obtain 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -
2- methyl formates；
After H, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl formates are hydrolyzed in alkaline solution
Carry out being acidified again and obtain 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- formic acid；
I, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- formic acid is in the presence of lithium aluminium hydride reduction through carboxyl oxygen
Change reduction reaction and obtain 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methanol；
J, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methanol with to methylsufonyl chloride carry out it is hydroxy activated
Protection reaction obtains 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl to methanesulfonate ester；
K, 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl occurs substitution reaction to methanesulfonate ester and entered
Row intramolecular cyclization obtains 8- isopropoxy -6H- dibenzopyrans and phenyl and piperidines acene；
L, 8- isopropoxy -6H- chromenes and phenyl and piperidines acene is sloughed isopropyl alkyl in the presence of lithium bromide and obtained
8- hydroxyl -6H- dibenzopyrans and phenyl and piperidines acene；
M, 8- hydroxyl -6H- dibenzopyrans and phenyl and piperidines acene and trifluoromethanesulfonic acid anhydride reactant obtain 8- trifluoromethanesulfonic acids
Ester group -6H- dibenzopyrans and phenyl and piperidines acene；
N, 8- trifluoromethanesulfonic acid ester group -6H- dibenzopyrans and phenyl and piperidines acene is double (diphenylphosphine) in catalyst 1,3-
N-8- anilino- -6H- dibenzopyrans and hexahydropyridine acene are obtained in the presence of propane and Raney's nickel with aniline reaction.
3. the preparation method according to claim 2 with 6H- dibenzopyrans structural compounds, it is characterised in that 2 '-
The specific building-up process of amino -5- xenol -2- methyl formates is：（1）By the bromo- 4- nitrobenzoic acids of 2- in reaction vessel
It is 10 that methyl esters, 2- aminobenzenes boron and potassium carbonate, which add volume ratio,:In 1 DME and the mixed solution of water, the lower room temperature of nitrogen protection is stirred
Mix 30min, add catalyst tetrakis triphenylphosphine palladium, stir under nitrogen protection, be warming up to 100 DEG C reaction until
TLC monitoring raw material reactions are complete, solvent are evaporated off under vacuum, residue is added in dichloromethane, then uses pure water washing
Twice, solvent is evaporated off in organic phase after anhydrous sodium sulfate drying, then obtains 2 '-amino -5- nitre through silica gel column chromatography separating-purifying
Base biphenyl -2- methyl formates；（2）Reduced iron powder is added in glacial acetic acid in reaction vessel, is warming up to after 85 DEG C and stirs anti-
45min is answered, the glacial acetic acid solution dissolved with 2 '-amino -5- nitrobiphenyl -2- methyl formates is added under nitrogen protection, is dripped
Continue to react after 85 DEG C up to TLC monitoring raw material reactions are complete, then by diatomite filtering reacting liquid, diatomite heat
Glacial acetic acid is washed, and reaction dissolvent is evaporated off in filtrate under vacuum, adds saturated sodium bicarbonate, then be extracted with ethyl acetate
Reaction solution three times, merges organic phase, and solvent is evaporated off after anhydrous sodium sulfate drying, 2 '-amino -5- amidos are concentrated to give for organic phase
Biphenyl -2- methyl formates；In 0 DEG C 2 '-amino -5- amido biphenyl -2- methyl formates are added to quality in reaction vessel dense
Spend in the dilute sulfuric acid for 5%, agitation and dropping drips rear keeping temperature and continue to react dissolved with the aqueous solution of catalyst natrium nitrosum
1h, then 60 DEG C of reactions are warming up to until the reaction of TLC monitoring raw materials completely, is subsequently cooled to room temperature, reaction is extracted with ethyl acetate
Liquid three times, merges organic phase, and solvent is evaporated off after anhydrous sodium sulfate drying, is obtained through silica gel column chromatography separating-purifying for organic phase
2 '-amino -5- xenol -2- methyl formates.
4. the preparation method according to claim 2 with 6H- dibenzopyrans structural compounds, it is characterised in that 3- is different
The specific building-up process of the bromobenzyl bromine of propoxyl group -6 is：（1）3- hydroxy-methylbenzenes and 2- N-Propyl Bromides are added to nothing in reaction vessel
In the DMF of water process, potassium carbonate is added, back flow reaction is warming up to until TLC monitoring raw material reactions are complete, under vacuum
Solvent is evaporated off, residue is added to the water, then with dichloromethane aqueous phase extracted three times, merges and solvent is evaporated off after organic phase obtains 3-
Isopropoxy toluene；（2）3- isopropoxy toluene is added in glacial acetic acid in reaction vessel, positioning catalyst iron is added
Powder, is added dropwise bromine at ambient temperature, and 30min is dripped, and is warming up to 40 DEG C of reactions, then irradiate reaction, vacuum with 300W tungsten lamps
Under be evaporated off adding the sodium hydroxide solution that mass concentration is 20% in solvent glacial acetic acid, concentrate, filtering reacting liquid, filtrate uses two
Chloromethanes is extracted three times, merges organic phase, and organic phase is concentrated to give the bromine of 3- isopropoxies -6 after anhydrous sodium sulfate drying again
Benzyl bromine.
5. the preparation method according to claim 2 with 6H- dibenzopyrans structural compounds, it is characterised in that step
F detailed process is：By 2 '-amino -5- xenol -2- methyl formates and 3- isopropoxy -6- bromobenzyls in reaction vessel
Bromine is added in dry acetone, adds hydroxyl hydrogen activation catalyst palladium/hydroxyapatite, be heated to back flow reaction until
TLC monitoring raw material reactions are complete, reaction dissolvent are evaporated off under vacuum, concentrate is added in dichloromethane, uses pure water
Wash organic phase three times, separate organic phase, be evaporated off after solvent obtaining crude product under vacuum, then carry through silica gel column chromatography separation
It is pure to obtain 5- (the bromo- 5- isopropoxies phenmethylols of 2-) -2 '-aminobphenyl -2- methyl formates；Step G detailed process is：Anti-
Answer in container and 5- (the bromo- 5- isopropoxies phenmethylols of 2-) -2 '-aminobphenyl -2- methyl formates and potassium carbonate are added to diformazan
In yl acetamide, in N2Protection is lower to add phenyl ring hydrogen activation catalyst palladium/hydroxyapatite, and N is continually fed into reaction system2,
N is discharged simultaneously2, it is kept a stable circulation environment, be stirred at room temperature closed reaction vessel after 30min, then by reaction vessel
It is placed in microwave reactor, is heated to 100 DEG C of reactions until TLC monitoring raw material reactions are complete, then from microwave reactor
Take out reaction vessel addition pure water and reaction is quenched, then reaction solution is extracted with ethyl acetate three times, merge organic phase, use anhydrous sulphur
Solvent is evaporated off after drying in sour sodium, most obtains 3- (2- aminobenzenes) -8- isopropoxies -6H- two through silica gel column chromatography separating-purifying afterwards
Chromene -2- methyl formates.
6. the preparation method according to claim 2 with 6H- dibenzopyrans structural compounds, it is characterised in that step
H detailed process is：By 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl formates in reaction vessel
It is added in ethanol, adds the aqueous solution dissolved with sodium hydroxide, is warming up to 70 DEG C of reactions until TLC monitoring raw materials have reacted
Entirely, solvent is evaporated off under vacuum, residue is added to the water, then washs with ethyl acetate aqueous phase three times, the dilute salt of aqueous phase
Acid dissolving regulation pH is 3, then with dichloromethane aqueous phase extracted three times, merges organic phase, be finally evaporated off obtaining 3- (2- ammonia after solvent
Base benzene) -8- isopropoxy -6H- dibenzopyrans -2- formic acid；Step I detailed process is：By 3- (2- ammonia in reaction vessel
Base benzene) -8- isopropoxy -6H- dibenzopyrans -2- formic acid is added in anhydrous THF, and reaction temperature is reduced to -60 DEG C, dropwise addition
The tetrahydrofuran solution of lithium aluminium hydride reduction, keeping temperature continues to react 2h, then is warming up to 0 DEG C of reaction 2h, adds frozen water and reaction is quenched,
Suction filtration reaction solution, filtrate is extracted with ethyl acetate repeatedly, merges organic phase, is evaporated off obtaining 3- (2- aminobenzenes) -8- after solvent different
Propoxyl group -6H- dibenzopyrans -2- methanol.
7. the preparation method according to claim 2 with 6H- dibenzopyrans structural compounds, it is characterised in that step
J detailed process is：By 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methanol, to first in reaction vessel
Base sulfonic acid chloride and potassium carbonate are added in DMF, are warming up to 80 DEG C of reactions until the reaction of TLC monitoring raw materials completely, adds pure water
Reaction is quenched, then is extracted with ethyl acetate three times, merges organic phase, solvent is evaporated off in organic phase after anhydrous sodium sulfate drying, then
3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- methyl is obtained to methyl sulphur through silica gel column chromatography separating-purifying
Acid esters；Step K detailed process is：By 3- (2- aminobenzenes) -8- isopropoxy -6H- dibenzopyrans -2- in reaction vessel
Methyl is added in acetonitrile to methanesulfonate ester, adds aniline, and mechanical agitation is simultaneously warming up to 70 DEG C of reactions until TLC monitors former
Material reaction is complete, and decompression steams solvent acetonitrile, adds n-hexane, being cooled in -5 DEG C, whipping process has solid precipitation, filters
Reaction solution obtains solid, and is washed with cold toluene, and 8- isopropoxy -6H- dibenzopyrans and phenyl are obtained simultaneously after filter cake drying
Piperidines acene.
8. the preparation method according to claim 2 with 6H- dibenzopyrans structural compounds, it is characterised in that step
L detailed process is：By 8- isopropoxy -6H- dibenzopyrans and phenyl and piperidines acene is added to two in reaction vessel
In chloromethanes, lithium bromide is added, in 0 DEG C of stirring reaction until TLC monitoring raw material reactions are complete, reaction dissolvent is evaporated off and obtains 8-
Hydroxyl -6H- dibenzopyrans and hexahydropyridine acene；Step M detailed process is：By 8- hydroxyls -6H- two in reaction vessel
In the dichloromethane of chromene and hexahydropyridine acene and triethylamine addition Non-aqueous processing, trifluoromethanesulfanhydride anhydride is added dropwise in 0 DEG C,
Room temperature is warming up to after dripping until the reaction of TLC monitoring raw materials completely, is evaporated off adding n-hexane in reaction dissolvent, residue, in 0
DEG C stirring and crystallizing, there is yellow solid appearance, filtering and drying to obtain to 8- trifluoromethanesulfonic acids ester group -6H- dibenzopyrans and hexahydro
Pyridine acene.
9. the preparation method according to claim 2 with 6H- dibenzopyrans structural compounds, it is characterised in that step
N detailed process is：By 8- trifluoromethanesulfonic acids ester group -6H- dibenzopyrans and hexahydropyridine acene, benzene in autoclave
Amine and triethylamine are added in the DMF after Non-aqueous processing, add catalyst 1, double (diphenylphosphine) propane of 3-, in nitrogen protection
Under be stirred at room temperature after add Raney's nickel, then reaction system is vacuumized, discharges nitrogen, be passed through carbon monoxide, make reaction pressure
0.2MPa is reached, 60 DEG C of reactions are warming up to until the reaction of TLC monitoring raw materials completely, is down to room temperature, excludes the complete oxygen of unreacted
Change carbon, filtering reacting liquid removes solvent DMF under reduced pressure, toluene is added into residue, has faint yellow solid precipitation in 0 DEG C of stirring,
N-8- anilino- -6H- dibenzopyrans and hexahydropyridine acene are obtained after suction filtration solid, drying.
10. the preparation method according to claim 2 with 6H- dibenzopyrans structural compounds, it is characterised in that system
Specific synthetic route in Preparation Method is：
。
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| CN101052641A (en) * | 2004-09-07 | 2007-10-10 | 惠氏公司 | 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents |
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| EP2459560B1 (en) * | 2009-07-29 | 2015-08-19 | Merck Sharp & Dohme B.V. | Ring-annulated dihydropyrrolo[2,l-a]isoquinolines |
| WO2015196335A1 (en) * | 2014-06-23 | 2015-12-30 | Tocopherx, Inc. | Pyrazole compounds as modulators of fshr and uses thereof |
| CN105473596A (en) * | 2013-06-24 | 2016-04-06 | 默克专利有限公司 | Pyrazole compounds as modulators of FSHR and uses thereof |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101052641A (en) * | 2004-09-07 | 2007-10-10 | 惠氏公司 | 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents |
| EP2459560B1 (en) * | 2009-07-29 | 2015-08-19 | Merck Sharp & Dohme B.V. | Ring-annulated dihydropyrrolo[2,l-a]isoquinolines |
| WO2013041461A1 (en) * | 2011-09-22 | 2013-03-28 | Msd Oss B.V. | Fsh receptor antagonists |
| CN105473596A (en) * | 2013-06-24 | 2016-04-06 | 默克专利有限公司 | Pyrazole compounds as modulators of FSHR and uses thereof |
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