CN106928243A - The preparation method of the benzo piperidines with bioactivity and anilino- class compound - Google Patents
The preparation method of the benzo piperidines with bioactivity and anilino- class compound 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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Abstract
The invention discloses a kind of benzo piperidines with bioactivity and the preparation method of anilino- class compound, belong to the synthesis technical field of medicine intermediate.Technical scheme main points are：
Description
Technical field
The invention belongs to the synthesis technical field of medicine intermediate, and in particular to a kind of benzo piperidines with bioactivity
And the preparation method of anilino- class compound.
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 is secreted by hypothalamus, by inducing follicle-stimulating hormone (FSH) (FSH)/luteotropic hormone (LH) in hypophysis
Secretion, Follicles grows and ovulates in an one-step inducing ovary of going forward side by side.FSH is glycoprotein hormones, there is α and β subunits
Each be released into blood after synthesis, be combined after can play its biological agent.Find that FSHR transcription products are in embryonic period, embryonic phase earliest
In the embryo's sexual gland of the male of 14.5 days and the women of 20.5 days.These transcription initial stage products are simultaneously imperfect, and only expression is in acceptor
Extracellular part, intact full length obtains mRNA to be occurred after a couple of days.Pregnant 10-13 weeks fetal pituitary starts secretion FSH and corpus luteum life
Into hormone, FSH levels slowly rise children after 4 years old and in puberty blood, rule in the menstrual cycle occur to sexual maturing period FSH
Property fluctuation, raised to the reduction of climacteric estradiol level, with FSH levels.FSH is the core during Mammalian Reproduction
Hormone, 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 is made to irreplaceable key is played in the conversion of estrogen, the regulation of cyclostage
With.Effects of the FSH to target organ is mainly mediated by fsh receptor (FSHR).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 for 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 the secretion of FSH, can with so that inhibition glandular secretion sex hormone, cause disease dependence in blood
Hormonal readiness reduction, suppresses growth or prevention, alleviation, the treatment other illnesss of cancer cell；For example, Cetrorelix is exactly according to this
Mechanism plays anti-proliferative effect to oophoroma.We enter according to current existing fsh receptor inhibitor medicaments molecule to its structure
Row optimization has obtained the fsh receptor inhibitor medicaments molecule of a series of new, and has carried out related activity test 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
The benzo piperidines and anilino- class compound of action effect preferably with bioactivity and preparation method thereof.
The present invention adopts the following technical scheme that to solve above-mentioned technical problem, the benzo piperidines with bioactivity and aniline
Base class compound, it is characterised in that structural formula isWherein R is o-hydroxy, o-methyl-benzene, adjacent iodobenzene
The present invention adopts the following technical scheme that to solve above-mentioned technical problem, the benzo piperidines with bioactivity and aniline
The preparation method of base class compound, it is characterised in that concretely comprise the following steps：
The bromo- 4- nitrobenzene methyls of A, 2- and 2- iodobenzenes boric acid pass through in the presence of catalyst tetrakis triphenylphosphine palladium
Substitution reaction obtains 2 '-iodo- 5- nitrobiphenyls -2- methyl formates；
B, 2 '-iodo- 5- nitrobiphenyls -2- methyl formates are in the presence of catalyst reduction iron powder by nitro-reduction reaction
Obtain 2 '-iodo- 5- aminobphenyls -2- methyl formates；
C, 2 '-iodo- 5- aminobphenyls -2- methyl formates are in the presence of catalyst natrium nitrosum by amino reduction-oxidation
Reaction obtains 2 '-iodo- 5- xenols -2- methyl formates；
3- isopropoxy -4- methoxy methyls obtained and substitution reaction in D, 3- hydroxyl -4- methoxy toluenes and 2- N-Propyl Bromides there is
Benzene；
E, 3- isopropoxy -4- methoxy toluenes occur 1 in the presence of catalyst iron powder and 6 bromo-reactions are obtained
3- isopropoxy -4- methoxyl group -6- bromobenzyl bromines；
F, 2 '-iodo- 5- xenols -2- methyl formates and 3- isopropoxies -4- methoxyl groups -6- bromobenzyls bromine are lived in hydroxyl hydrogen
Generation substitution reaction obtains 5- (the bromo- 5- isopropoxies -4- methoxybenzene first of 2- in the presence of changing palladium catalyst/hydroxyapatite
Alcohol) -2 '-iodine biphenyl -2- methyl formates；
G, 5- (the bromo- 5- isopropoxies -4- methoxy benzyl alcohols of 2-) -2 '-iodine biphenyl -2- methyl formates are activated in phenyl ring hydrogen
Intramolecular annulation is carried out in the presence of palladium catalyst/hydroxyapatite and obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxies
Base -6H- dibenzopyrans -2- methyl formates；
H, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl formates are in alkaline solution
Carry out being acidified again after hydrolysis and obtain 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- formic acid；
Effect of I, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- formic acid in lithium aluminium hydride reduction
It is lower to obtain 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl alcohol through carboxylic-oxidized reduction reaction；
J, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl alcohol enters with to methylsufonyl chloride
The hydroxy activated protection reaction of row obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl to first
Base sulphonic acid ester；
K, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- chromene -2- methyl is to methanesulfonate ester and amido
3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl-N- obtained and substitution reaction in compound there is
Amine compound；
L, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl-N- amine compounds exist
There is intramolecular annulation in the presence of the palladium of catalyst three (dibenzalacetone) two and cesium carbonate and obtain 8- isopropoxies -9-
Methoxyl group -6H- chromenes and phenyl and piperidines acene-N- amine compounds.
Further preferably, the specific building-up process of 2 ' described-iodo- 5- xenols -2- methyl formates is：(1) anti-
It is 10 to answer and the bromo- 4- nitrobenzene methyls of 2-, 2- iodobenzenes boric acid and potassium carbonate are added into volume ratio in container:1 DME and water
Mixed solution in, nitrogen protection under 30min is stirred at room temperature, add catalyst tetrakis triphenylphosphine palladium, nitrogen protection
Under stir, rise high-temperature to 100 DEG C reaction until TLC monitoring raw material reaction completely, solvent is evaporated off under vacuum, remain
Excess is added in dichloromethane, then is washed twice with pure water, and organic phase is evaporated off solvent after anhydrous sodium sulfate drying, then through silicon
Plastic column chromatography separating-purifying obtains 2 '-iodo- 5- nitrobiphenyls -2- methyl formates；(2) by catalyst reduction iron in reaction vessel
Powder is added in glacial acetic acid, stirring reaction 45min after being warming up to 85 DEG C, adds join dissolved with 2 '-iodo- 5- nitros under nitrogen protection
The glacial acetic acid solution of benzene -2- methyl formates, drips after 85 DEG C of reactions until TLC monitoring raw material reaction completely, then passes through
Diatomite filtering reacting liquid, diatomite is washed with the glacial acetic acid of heat, and reaction dissolvent is evaporated off under vacuum, adds saturation
Sodium acid carbonate, then it is extracted with ethyl acetate reaction solution three times, merging organic phase, organic phase is evaporated off molten after anhydrous sodium sulfate drying
Agent, is concentrated to give 2 '-iodo- 5- amidos biphenyl -2- methyl formates；(3) 2 '-iodo- 5- amidos are joined in 0 DEG C in reaction vessel
Benzene -2- methyl formates are added in the dilute sulfuric acid that mass concentration is 5%, are added dropwise again after stirring 10min sub- dissolved with oxidation catalyst
The aqueous solution of sodium nitrate, drips rear keeping temperature and continues to react 1h, then be warming up to 60 DEG C of reactions until TLC monitors raw material reaction
Completely, room temperature is subsequently cooled to, reaction solution is extracted with ethyl acetate three times, merges organic phase, organic phase is dry through anhydrous sodium sulfate
Solvent is evaporated off after dry, 2 '-iodo- 5- xenols -2- methyl formates are obtained through silica gel column chromatography separating-purifying.
Further preferably, the specific building-up process of described 3- isopropoxy -4- methoxyl group -6- bromobenzyl bromines is：(1) anti-
Answer and 3- hydroxyl -4- methoxy toluenes and 2- N-Propyl Bromides are added in the DMF of Non-aqueous processing in container, add potassium carbonate, rise
Temperature, up to TLC monitoring raw material reactions are complete, is evaporated off solvent under vacuum to back flow reaction, and residue is added to the water, then
With dichloromethane aqueous phase extracted three times, merge organic phase, 3- isopropoxy -4- methoxy toluenes are obtained after solvent is finally evaporated off；
(2) 3- isopropoxy -4- methoxy toluenes are added in glacial acetic acid in reaction vessel, add positioning catalyst iron powder,
Bromine is added dropwise at ambient temperature, 30min is dripped, 40 DEG C of reactions is warming up to up to TLC monitoring raw material reactions are complete, under vacuum
Solvent glacial acetic acid is evaporated off, the sodium hydroxide solution that mass concentration is 20%, filtering reacting liquid, filtrate dichloro are added in concentrate
Methane is extracted three times, merges organic phase, and organic phase is again by being concentrated to give 3- isopropoxy -4- methoxies after anhydrous sodium sulfate drying
The bromo- benzyl bromines of base -6-.
Further preferably, the specific building-up process of step F is：By 2 '-iodo- 5- xenols -2- first in reaction vessel
Sour methyl esters and 3- isopropoxy -4- methoxyl group -6- bromobenzyl bromines are added in dry acetone, add hydroxyl hydrogen activation catalyst
Palladium/hydroxyapatite, is heated to back flow reaction up to TLC monitoring raw material reactions are complete, and reaction dissolvent is evaporated off under vacuum,
Concentrate is added in dichloromethane, then with pure water washing organic phase three times, separates organic phase, is evaporated off under vacuum molten
Crude product is obtained after agent, then sterling 5- (the bromo- 5- isopropoxies -4- methoxybenzene first of 2- is obtained through silica gel column chromatography separating-purifying
Alcohol) -2 '-iodine biphenyl -2- methyl formates.
Further preferably, the specific building-up process of step G is：By 5- (the bromo- 5- isopropoxies -4- of 2- in reaction vessel
Methoxy benzyl alcohol) -2 '-iodine biphenyl -2- methyl formates and potassium carbonate is added in dimethylacetylamide, in N2Protection is lower to be added
Phenyl ring hydrogen activation catalyst palladium/hydroxyapatite, N is continually fed into toward reaction system2, while discharging N2, it is kept for one surely
Determine circulation environment, closed reaction vessel after 30min is stirred at room temperature, reaction vessel is placed in microwave reactor, be heated to 100
DEG C reaction until TLC monitoring raw material reaction completely, takes out from microwave reactor and reaction vessel and adds pure water that reaction is quenched,
Reaction solution is extracted with ethyl acetate again three times, merge organic phase, then with solvent is evaporated off after anhydrous sodium sulfate drying, most afterwards through silica gel
Column chromatography for separation purification obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl formates.
Further preferably, the specific building-up process of step H is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxies -
9- methoxyl group -6H- dibenzopyrans -2- methyl formates are added in ethanol, add the aqueous solution dissolved with NaOH, are heated up
To 70 DEG C of reactions until TLC monitoring raw material reaction completely, is evaporated off solvent under vacuum, residue is added to the water, then uses
Ethyl acetate washings phase three times, water diluted hydrochloric acid dissolution regulation pH is 3, then with dichloromethane aqueous phase extracted three times, is merged
Solvent is evaporated off after organic phase and obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- formic acid.
Further preferably, the specific building-up process of step I is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxies -
9- methoxyl group -6H- dibenzopyrans -2- formic acid is added in anhydrous THF, and reaction temperature is reduced to -60 DEG C, and lithium aluminium hydride reduction is added dropwise
Tetrahydrofuran solution, keeping temperature continues to react 2h, then is warming up to 0 DEG C of reaction 2h, adds frozen water to be quenched reaction, and suction filtration reacts
Liquid, filtrate is extracted with ethyl acetate repeatedly, merges after organic phase is evaporated off solvent and obtains 3- (2- iodobenzenes) -8- isopropoxy -9- first
Epoxide -6H- dibenzopyrans -2- methyl alcohol.
Further preferably, the specific building-up process of step J is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxies -
9- methoxyl group -6H- dibenzopyrans -2- methyl alcohol, methylsufonyl chloride and potassium carbonate are added in DMF, are warming up to 80 DEG C of reactions
Until TLC monitoring raw material reaction is completely, add pure water that reaction is quenched, then be extracted with ethyl acetate three times, merge organic phase, have
Machine is evaporated off solvent after anhydrous sodium sulfate drying, then obtains 3- (2- iodobenzenes) -8- isopropyl oxygen through silica gel column chromatography separating-purifying
Base -9- methoxyl group -6H- dibenzopyrans -2- methyl is to methanesulfonate ester.
Further preferably, the specific building-up process of step K is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxies -
9- methoxyl group -6H- dibenzopyrans -2- methyl is added in acetonitrile to methanesulfonate ester, adds amine compound, and machinery is stirred
Mix, be heated to 70 DEG C of reactions up to TLC monitoring raw material reactions are complete, decompression steams solvent acetonitrile, adds n-hexane, cools down
To -5 DEG C, there are a large amount of solids to separate out in whipping process, filtering reacting liquid obtains solid, and is washed with cold toluene, after filter cake drying
Obtain 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl-N- amine compounds.
Further preferably, the specific building-up process of step L is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxies -
9- methoxyl group -6H- dibenzopyrans -2- methyl-N- amine compounds are added in pyridine, add (two benzal of catalyst three
Benzylacetone) two palladiums and cesium carbonate, back flow reaction is warming up to, nitrogen protection reaction system, TLC monitoring raw material reaction completely, will be anti-
Answer liquid to stand a moment, pour out upper liquid, melt cinder is heated with ethanol and extracted, filtered while hot, filtrate and preceding liquid merge, and are separated out after cooling
Yellow flat crystal, filtering and drying to obtain to 8- isopropoxy -9- methoxyl group -6H- chromenes and phenyl and piperidines acene-N-
Amine compound.
Synthesis technique of the present invention is simple and with low cost, and obtained 8- isopropoxy -9- methoxies are understood by active testing
Base -6H- chromenes and phenyl and piperidines acene-N- amine compounds drug molecule preferably, have to the action effect of fsh receptor
Hope further genralrlization application.
Specific embodiment
The above of the invention is described in further details by the following examples, but this should not be interpreted as 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- iodobenzenes boric acid 4.0g and potassium carbonate 5g are added to
Volume ratio is 10:In the 1 DME and mixed solution 120mL of water, 30min is stirred at room temperature under nitrogen protection；, add catalyst
Tetrakis triphenylphosphine palladium 1g, stirs under nitrogen protection, and, to 100 DEG C, TLC monitoring is former after reaction 14h for the slow high-temperature that rises
Material reaction is complete, and solvent is evaporated off under vacuum, and residue is added in dichloromethane, then is washed twice with pure water 50mL,
After organic phase is through anhydrous sodium sulfate drying, solvent is evaporated off, then 2 ' pure-iodo- 5- nitre is obtained through silica gel column chromatography separating-purifying
Base biphenyl -2- methyl formates 4.9g；1H NMR(400MHz,CDCl3)δ:8.41 (s, 1H), 8.23 (d, J=2.4Hz, 1H),
8.16 (d, J=8.6Hz, 1H), 7.57-7.50 (m, 2H), 7.41-7.31 (m, 2H), 3.72 (s, 3H).
Embodiment 2
In reaction bulb, reduced iron powder 5g is added in glacial acetic acid 70mL, stirring reaction 45min after being warming up to 85 DEG C,
The glacial acetic acid solution 70mL dissolved with 2 '-iodo- 5- nitrobiphenyls -2- methyl formates 6g is slowly added under nitrogen protection, is dripped
Continue to react 2h under the conditions of 85 DEG C afterwards, TLC carries out filtering reacting liquid, diatomite after monitoring raw material reaction completely by diatomite
Washed with the glacial acetic acid of a certain amount of heat again, reaction dissolvent is evaporated off under vacuum, added a certain amount of unsaturated carbonate
Hydrogen sodium, then it is extracted with ethyl acetate reaction solution three times, merging organic phase, organic phase is evaporated off solvent after anhydrous sodium sulfate drying,
It is concentrated to give 2 ' pure-iodo- 5- amidos biphenyl -2- methyl formates 5.1g；1H NMR(400MHz,CDCl3)δ:7.72 (d, J=
8.6Hz, 1H), 7.41-7.35 (m, 1H), 7.24 (d, J=8.6Hz, 2H), 7.18 (s, 1H), 6.63 (s, 1H), 6.45 (s,
1H),6.02(s,2H),3.54(s,3H)。
Embodiment 3
In reaction bulb, under the conditions of being 0 DEG C in temperature, 2 '-iodo- 5- amidos biphenyl -2- methyl formates 5.0g is added to
During mass concentration is 5% dilute sulfuric acid 100mL, after stirring 10min, then the aqueous solution dissolved with natrium nitrosum 2.0g is slowly added dropwise
20mL, drips rear keeping temperature and continues to react 1h, then be to slowly warm up to 60 DEG C and react 8h, after TLC monitoring raw material reactions are complete
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 ' pure-iodo- 5- xenols -2- methyl formates 3.9g is obtained through silica gel column chromatography separating-purifying；1H NMR
(400MHz,CDCl3)δ:10.45 (s, 1H), 7.84 (d, J=8.6Hz, 1H), 7.45-7.38 (m, 1H), 7.37-7.20 (m,
3H), 6.92 (d, J=8.0Hz, 1H), 6.72 (s, 1H), 3.59 (s, 3H).
Embodiment 4
In reaction bulb, 3- hydroxyl -4- methoxy toluene 10g and 2- N-Propyl Bromides 10g is added to Non-aqueous processing
In DMF100mL, potassium carbonate 15g is added, back flow reaction 24h, TLC monitoring raw material reaction is to slowly warm up to completely, in vacuum bar
Solvent is evaporated off under part, residue is added to the water, then with dichloromethane aqueous phase extracted three times, merges organic phase, be finally evaporated off molten
Product 3- isopropoxy -4- methoxy toluenes 13g is obtained after agent；1H NMR(400MHz,CDCl3)δ:7.31-7.28(m,1H),
7.17-7.12 (m, 2H), 5.08-5.01 (m, 1H), 4.57-4.47 (m, 2H), 4.34 (d, J=8.0Hz, 2H), 3.75 (s,
3H), 1.28 (d, J=8.0Hz, 6H).
Embodiment 5
In reaction bulb, 3- isopropoxy -4- methoxy toluenes 15g is added in glacial acetic acid 100mL, adds positioning
Catalyst iron powder 3g, is slowly added dropwise bromine 8mL at ambient temperature, and about 30min is dripped, and 10h is reacted after being warming up to 40 DEG C,
TLC monitoring raw material reaction completely, is evaporated off solvent glacial acetic acid under vacuum, it is 20% that a certain amount of mass concentration is added in concentrate
Sodium hydroxide solution, filtering reacting liquid, filtrate is extracted three times with dichloromethane, merges organic phase, and organic phase is again by anhydrous sulphur
Sour sodium is concentrated to give the bromo- benzyl bromine 23g of 3- isopropoxy -4- methoxyl groups -6- after drying；1H NMR(400MHz,CDCl3)δ:7.29
(s, 1H), 7.20 (s, 1H), 4.72 (s, 2H), 4.61-4.53 (m, 1H), 3.81 (s, 3H), 1.28 (d, J=8.0Hz, 6H).
Embodiment 6
Palladium chloride 5g is added in reaction bulb, it is 1 to add mass ratio:1 methanol-water mixed solution 250mL, then add
Enter sodium carboxymethylcellulose 1g, be 4.5 with the pH of sodium carbonate regulation system, add hydroxyapatite 50g, 2h is stirred at room temperature
After be put into autoclave, in 100KPa, under the conditions of 100 DEG C stir hydrogenation reduction 2h, depressurize suction filtration, during deionized water is washed till
Property 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 '-iodo- 5- xenols -2- methyl formates 10g and 3- isopropoxy -4- methoxyl group -6- bromines
Benzyl bromine 15g is added in dry acetone 5000mL, adds hydroxyl hydrogen activation catalyst palladium/hydroxyapatite 1g, is heated to
Back flow reaction 4h, TLC monitoring raw material reaction completely, is evaporated off reaction dissolvent under vacuum, and concentrate is added to dichloromethane
In 150mL, then organic phase is washed three times with pure water 100mL, separate organic phase, produced after solvent is evaporated off under vacuum
Product crude product, then through silica gel column chromatography separating-purifying obtain pure 5- (the bromo- 5- isopropoxies -4- methoxy benzyl alcohols of 2-) -2 ' -
Iodine biphenyl -2- methyl formates 15g；1H NMR(400MHz,CDCl3)δ:7.94 (d, J=8.0Hz, 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,
3H), 3.62 (s, 3H), 1.28 (d, J=8.0Hz, 6H).
Embodiment 8
In reaction bulb, 5- (the bromo- 5- isopropoxies -4- methoxy benzyl alcohols of 2-) -2 '-iodine biphenyl -2- methyl formates
10g and potassium carbonate 5g is added in dimethylacetylamide 100mL, in N2Protection is lower to add phenyl ring hydrogen activation catalyst palladium/hydroxyl phosphorus
Lime stone 1g, does not stop to be passed through N toward reaction system2, while discharging N2, it is kept a stabilization circulation environment, it is stirred at room temperature
Confined reaction bottle, it is placed in microwave reactor after 30min, is heated to 100 DEG C of reaction 24h, TLC monitoring raw material reactions complete
Entirely；Reaction bulb is taken out from microwave reactor, adds a certain amount of pure water that reaction is quenched, then be extracted with ethyl acetate reaction solution
Three times, merge organic phase, then with solvent is evaporated off after anhydrous sodium sulfate drying, most obtain 3- through silica gel column chromatography separating-purifying afterwards
(2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl formates 7.5g；1H NMR(400MHz,CDCl3)
δ:8.57 (d, J=8.0Hz, 1H), 7.68-7.51 (m, 4H), 7.43 (s, 1H), 7.11-7.05 (m, 3H), 5.20 (s, 2H),
4.70 (d, J=12.0Hz, 1H), 3.89 (s, 3H), 3.83 (s, 3H), 1.25 (d, J=8.0Hz, 6H).
Embodiment 9
In reaction bulb, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl formates
5g is added in ethanol 30mL, adds the aqueous solution 10mL dissolved with NaOH 2.5g, is warming up to 70 DEG C of reaction 1h, TLC prisons
Control raw material reaction completely, is evaporated off solvent under vacuum, and residue is added to the water, then with ethyl acetate 30mL washings phases
Three times, it is 3 that water mutually adjusts pH with diluted hydrochloric acid dissolution again, then with dichloromethane aqueous phase extracted three times, merges organic phase, is finally evaporated off
3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- formic acid 4.1g is obtained after solvent；1H NMR
(400MHz,CDCl3)δ:8.56 (d, J=8.0Hz, 1H), 7.68-7.51 (m, 4H), 7.43 (s, 1H), 7.11-7.05 (m,
3H), 5.22 (s, 2H), 4.70 (d, J=12.0Hz, 1H), 3.81 (s, 3H), 1.27 (d, J=8.0Hz, 6H).
Embodiment 10
In reaction bulb, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- formic acid 10g is added
Enter in anhydrous THF 200mL, reaction temperature is reduced to -60 DEG C, be slowly added dropwise the tetrahydrofuran solution 30mL of lithium aluminium hydride reduction, protect
Hold temperature to continue to react 2h, then be to slowly warm up to 0 DEG C, react 2h, add a certain amount of frozen water to be quenched reaction, suction filtration reaction solution,
Filtrate is extracted with ethyl acetate repeatedly, merges after organic phase is evaporated off solvent and obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxies
Base -6H- dibenzopyrans -2- methyl alcohol 7.7g；1H NMR(400MHz,CDCl3)δ:8.61 (d, J=8.0Hz, 1H), 7.71-
7.57(m,4H),7.43-7.39(m,2H),7.11-7.15(m,2H),5.22(s,2H),4.70(s,1H),4.53(s,2H),
3.81 (s, 3H), 1.21 (d, J=8.0Hz, 6H).
Embodiment 11
In reaction bulb, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl alcohol 10g,
DMF is added to methylsufonyl chloride 5g and potassium carbonate 20g, 80 DEG C are to slowly warm up to, TLC monitoring raw material reaction is complete after reaction 8h
Entirely, add a certain amount of pure water that reaction is quenched, then extracted three times with ethyl acetate 50mL, merge organic phase, organic phase is through nothing
Aqueous sodium persulfate 30g is evaporated off solvent and obtains pure 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzo pyrroles after drying
- 2- methyl mutter to methanesulfonate ester 8.4g；1H NMR(400MHz,CDCl3)δ:7.87-7.55(m,5H),7.39-7.09(m,
3H),5.09(s,2H),4.56(s,1H),4.31(s,2H),3.79(s,3H),3.13(s,3H),1.25-1.20(m,6H)。
Embodiment 12
In reaction bulb, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl to methyl
Sulphonic acid ester 10g is added in acetonitrile 150mL, adds ortho-aminophenol 12g, and mechanical agitation is heated to 70 DEG C, after reaction 10h
[solvent is monitored through TLC:PE:EA=7:1], raw material reaction completely, decompression steam solvent acetonitrile, add it is a certain amount of just oneself
Alkane (700ml), is cooled to -5 DEG C, gradually has a large amount of solids to separate out in whipping process, and filtering reacting liquid obtains solid, and with necessarily
Cold toluene (200ml) washing of amount, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzo is obtained after filter cake drying
Pyrans -2- methyl-N- amido o-hydroxies 9.3g；1H NMR(400MHz,CDCl3)δ:8.04 (d, J=8.0Hz, 2H), 7.91-
7.82(m,4H),7.72-7.65(m,2H),7.35-7.21(m,5H),5.16(s,2H),4.34(s,1H),4.17(s,2H),
3.92(s,3H),3.22(s,3H),1.27-1.22(m,6H)。
Embodiment 13
In reaction bulb, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl-N- amine
Base benzene 10g is added in pyridine 200mL, adds three (dibenzalacetone) two palladium 1g and cesium carbonate 30g, is warming up to backflow,
Nitrogen protects reaction system, and reaction solution completely, is stood a moment, slowly pours out upper liquid, melt cinder second by TLC monitoring raw material reaction
Alcohol heating extraction, filters while hot, and filtrate and preceding liquid merge, and yellow flat crystal are separated out after cooling, filtering and drying to obtain different to 8-
Propoxyl group -9- methoxyl group -6H- chromenes and phenyl and piperidines acene-N- amido o-hydroxies 7.7g；1H NMR(400MHz,
CDCl3)δ:8.16-8.13(m,2H),7.93-7.85(m,4H),7.79-7.71(m,3H),7.31-7.22(m,4H),5.16
(s, 2H), 4.39 (s, 1H), 4.13 (s, 2H), 3.92 (s, 3H), 3.25 (s, 3H), 1.21 (d, J=8.0Hz, 6H).
Embodiment 14
Antitumor activity is tested
Collect growth period prostate gland cancer cell DU145, the active anticancer of compound is determined with MTS methods, by cell with
(every milliliter 4 × 10 of debita spissitudo4Individual cell) it is added in 96 porocyte culture plates and (obtains nutrient solution containing 10% tire calf serum to be made into
Individual cells suspension), after cultivating 24 hours, in the CO that 37 DEG C, volumetric concentration are 5%2Under the conditions of compound with various concentrations
Effect 72 hours, then directly adds the mixture of MTS (final mass concentration 2mg/mL) and DMS (30 μM of final molar concentration)
Enter in celliferous culture medium, continue to put incubator incubation 4h.After effect 4h, abandoning supernatant adds 150 μ LDMSO per hole,
Vibration, absorptivity of the cell survival rate by its metabolin to MTS effects under enzyme linked immunological monitor 490nm wavelength is determined
Preliminary biological activity test shows that such compound has suppression to make in prostate gland cancer cell DU145 to cancer cell
With.
In sum, the invention provides a kind of new FSH antagonists and preparation method thereof, this is such compound use
The discovery first on way, with great research and development potentiality.
Embodiment above describes general principle of the invention, principal character and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, simply original of the invention is illustrated 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 each fall within
In the scope of protection of the invention.
Claims (10)
1. there is the benzo piperidines of bioactivity and the preparation method of anilino- class compound, it is characterised in that concretely comprise the following steps：
The bromo- 4- nitrobenzene methyls of A, 2- and 2- iodobenzenes boric acid are in the presence of catalyst tetrakis triphenylphosphine palladium by substitution
Reaction obtains 2 '-iodo- 5- nitrobiphenyls -2- methyl formates；
B, 2 '-iodo- 5- nitrobiphenyls -2- methyl formates are obtained in the presence of catalyst reduction iron powder by nitro-reduction reaction
2 '-iodo- 5- aminobphenyls -2- methyl formates；
C, 2 '-iodo- 5- aminobphenyls -2- methyl formates are in the presence of catalyst natrium nitrosum by amino redox reaction
Obtain 2 '-iodo- 5- xenols -2- methyl formates；
3- isopropoxy -4- methoxy toluenes obtained and substitution reaction in D, 3- hydroxyl -4- methoxy toluenes and 2- N-Propyl Bromides there is；
E, 3- isopropoxy -4- methoxy toluenes occur 1 in the presence of catalyst iron powder and 6 bromo-reactions to obtain 3- different
Propoxyl group -4- methoxyl group -6- bromobenzyl bromines；
F, 2 '-iodo- 5- xenols -2- methyl formates and 3- isopropoxies -4- methoxyl groups -6- bromobenzyls bromine are urged in hydroxyl hydrogen activation
In the presence of agent palladium/hydroxyapatite occur substitution reaction obtain 5- (the bromo- 5- isopropoxies -4- methoxy benzyl alcohols of 2-) -
2 '-iodine biphenyl -2- methyl formates；
G, 5- (the bromo- 5- isopropoxies -4- methoxy benzyl alcohols of 2-) -2 '-iodine biphenyl -2- methyl formates are in phenyl ring hydrogen activating catalytic
Carried out in the presence of agent palladium/hydroxyapatite intramolecular annulation obtain 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl groups -
6H- dibenzopyrans -2- methyl formates；
H, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl formates are hydrolyzed in alkaline solution
Carry out being acidified again afterwards and obtain 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- formic acid；
I, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- formic acid is passed through in the presence of lithium aluminium hydride reduction
Carboxylic-oxidized reduction reaction obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl alcohol；
J, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl alcohol carries out hydroxyl with to methylsufonyl chloride
Base activation protection reaction obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl to methyl sulphur
Acid esters；
K, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- chromene -2- methyl is to methanesulfonate ester and amido benzene class
3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl-N- obtained and substitution reaction in compound there is
Amido benzene compound；
L, 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl-N- amidos benzene compounds are being urged
There is intramolecular annulation in the presence of the palladium of agent three (dibenzalacetone) two and cesium carbonate and obtain 8- isopropoxy -9- first
Epoxide -6H- chromenes and phenyl and piperidines acene-N- amido benzene compounds.
2. the preparation method of the benzo piperidines with bioactivity according to claim 1 and anilino- class compound, its
The specific building-up process for being characterised by 2 ' described-iodo- 5- xenols -2- methyl formates is：（1）By 2- in reaction vessel
It is 10 that bromo- 4- nitrobenzene methyls, 2- iodobenzenes boric acid and potassium carbonate are added to volume ratio:1 DME and the mixed solution of water
In, 30min is stirred at room temperature under nitrogen protection, catalyst tetrakis triphenylphosphine palladium is added, stir under nitrogen protection,
High-temperature is risen to 100 DEG C of reactions up to TLC monitoring raw material reactions are complete, solvent is evaporated off under vacuum, residue adds two
In chloromethanes, then washed twice with pure water, organic phase is evaporated off solvent after anhydrous sodium sulfate drying, then through silica gel column chromatography point
2 '-iodo- 5- nitrobiphenyls -2- methyl formates are obtained from purification；（2）Catalyst reduction iron powder is added to ice in reaction vessel
In acetic acid, stirring reaction 45min after being warming up to 85 DEG C is added dissolved with 2 '-iodo- 5- nitrobiphenyls -2- formic acid under nitrogen protection
The glacial acetic acid solution of methyl esters, drips after 85 DEG C of reactions until TLC monitoring raw material reaction completely, is then filtered by diatomite
Reaction solution, diatomite is washed with the glacial acetic acid of heat, and reaction dissolvent is evaporated off under vacuum, adds saturated sodium bicarbonate,
Reaction solution being extracted with ethyl acetate again three times, merging organic phase, organic phase solvent is evaporated off after anhydrous sodium sulfate drying, is concentrated to give
To 2 '-iodo- 5- amidos biphenyl -2- methyl formates；（3）In 0 DEG C by 2 '-iodo- 5- amidos biphenyl -2- formic acid first in reaction vessel
Ester is added in the dilute sulfuric acid that mass concentration is 5%, is added dropwise again dissolved with the water-soluble of oxidation catalyst natrium nitrosum after stirring 10min
Liquid, drips rear keeping temperature and continues to react 1h, then is warming up to 60 DEG C of reactions up to TLC monitors raw material reaction completely, Ran Houleng
But to room temperature, it is extracted with ethyl acetate reaction solution three times, merges organic phase, organic phase is evaporated off molten after anhydrous sodium sulfate drying
Agent, 2 '-iodo- 5- xenols -2- methyl formates are obtained through silica gel column chromatography separating-purifying.
3. the preparation method of the benzo piperidines with bioactivity according to claim 1 and anilino- class compound, its
The specific building-up process for being characterised by described 3- isopropoxy -4- methoxyl group -6- bromobenzyl bromines is：（1）Will in reaction vessel
3- hydroxyl -4- methoxy toluenes and 2- N-Propyl Bromides are added in the DMF of Non-aqueous processing, add potassium carbonate, are warming up to backflow anti-
Should be complete up to TLC monitoring raw material reactions, solvent is evaporated off under vacuum, residue is added to the water, then uses dichloromethane
Aqueous phase extracted three times, merges organic phase, and 3- isopropoxy -4- methoxy toluenes are obtained after solvent is finally evaporated off；（2）Hold in reaction
3- isopropoxy -4- methoxy toluenes are added in glacial acetic acid in device, add positioning catalyst iron powder, at ambient temperature
Bromine is added dropwise, 30min is dripped, is warming up to 40 DEG C of reactions until TLC monitoring raw material reaction completely, is evaporated off solvent ice second under vacuum
Acid, adds the sodium hydroxide solution that mass concentration is 20% in concentrate, filtering reacting liquid, filtrate is extracted three times with dichloromethane,
Merge organic phase, organic phase is again by being concentrated to give the 3- isopropoxy -4- methoxyl groups bromo- benzyl bromines of -6- after anhydrous sodium sulfate drying.
4. the preparation method of the benzo piperidines with bioactivity according to claim 1 and anilino- class compound, its
The specific building-up process for being characterised by step F is：It is in reaction vessel that 2 '-iodo- 5- xenols -2- methyl formates and 3- is different
Propoxyl group -4- methoxyl group -6- bromobenzyl bromines are added in dry acetone, add hydroxyl hydrogen activation catalyst palladium/hydroxy-apatite
Stone, is heated to back flow reaction until TLC monitoring raw material reaction completely, is evaporated off reaction dissolvent, concentrate addition under vacuum
To in dichloromethane, then with pure water washing organic phase three times, organic phase is separated, obtain thick after solvent is evaporated off under vacuum
Product, then obtain sterling 5- (the bromo- 5- isopropoxies -4- methoxy benzyl alcohols of 2-) -2 '-iodine connection through silica gel column chromatography separating-purifying
Benzene -2- methyl formates.
5. the preparation method of the benzo piperidines with bioactivity according to claim 1 and anilino- class compound, its
The specific building-up process for being characterised by step G is：By 5- (the bromo- 5- isopropoxies -4- methoxybenzene first of 2- in reaction vessel
Alcohol) -2 '-iodine biphenyl -2- methyl formates and potassium carbonate is added in dimethylacetylamide, in N2Protection is lower to add the activation of phenyl ring hydrogen
Palladium catalyst/hydroxyapatite, N is continually fed into toward reaction system2, while discharging N2, it is kept a stabilization circulation ring
Border, is stirred at room temperature closed reaction vessel after 30min, and reaction vessel is placed in microwave reactor, is heated to 100 DEG C of reactions straight
To TLC monitoring raw material reaction completely, reaction vessel is taken out from microwave reactor and adds pure water that reaction is quenched, then use acetic acid
Ethyl ester extractive reaction liquid three times, merges organic phase, then with solvent is evaporated off after anhydrous sodium sulfate drying, most afterwards through silica gel column chromatography point
3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl formates are obtained from purification.
6. the preparation method of the benzo piperidines with bioactivity according to claim 1 and anilino- class compound, its
The specific building-up process for being characterised by step H is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl groups -
6H- dibenzopyrans -2- methyl formates are added in ethanol, add the aqueous solution dissolved with NaOH, 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
Washings phase three times, water diluted hydrochloric acid dissolution regulation pH is 3, then with dichloromethane aqueous phase extracted three times, after merging organic phase
Solvent is evaporated off and obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- formic acid.
7. the preparation method of the benzo piperidines with bioactivity according to claim 1 and anilino- class compound, its
The specific building-up process for being characterised by step I is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl groups -
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 that reaction, suction filtration reaction solution, filtrate is quenched
It is extracted with ethyl acetate repeatedly, merges after organic phase is evaporated off solvent and obtain 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl groups -6H-
Dibenzopyrans -2- methyl alcohol.
8. the preparation method of the benzo piperidines with bioactivity according to claim 1 and anilino- class compound, its
The specific building-up process for being characterised by step J is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl groups -
6H- dibenzopyrans -2- methyl alcohol, 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 completely, adds pure water that reaction is quenched, then is extracted with ethyl acetate three times, merges organic phase, and organic phase is through nothing
Aqueous sodium persulfate is evaporated off solvent after drying, then obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxies through silica gel column chromatography separating-purifying
Base -6H- dibenzopyrans -2- methyl is to methanesulfonate ester.
9. the preparation method of the benzo piperidines with bioactivity according to claim 1 and anilino- class compound, its
The specific building-up process for being characterised by step K is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl groups -
6H- dibenzopyrans -2- methyl is added in acetonitrile to methanesulfonate ester, adds amine compound, and mechanical agitation is heated to
70 DEG C of reactions are complete up to TLC monitoring raw material reactions, and decompression steams solvent acetonitrile, adds n-hexane, are cooled to -5 DEG C, stirring
During there are a large amount of solids to separate out, filtering reacting liquid obtains solid, and wash with cold toluene, and filter cake obtains 3- (2- iodine after drying
Benzene) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl-N- amine compounds.
10. the preparation method of the benzo piperidines with bioactivity according to claim 1 and anilino- class compound, its
The specific building-up process for being characterised by step L is：In reaction vessel by 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl groups -
6H- dibenzopyrans -2- methyl-N- amido benzene compounds are added in pyridine, add catalyst three (dibenzalacetone)
Two palladiums and cesium carbonate, are warming up to back flow reaction, and nitrogen protection reaction system, TLC monitoring raw material reaction completely, reaction solution is stood
For a moment, upper liquid is poured out, melt cinder is heated with ethanol and extracted, filtered while hot, filtrate and preceding liquid merge, and yellow sheet is separated out after cooling
Crystal, filtering and drying to obtain to 8- isopropoxy -9- methoxyl group -6H- chromenes and phenyl and piperidines acene-N- amido chemical combination
Thing.
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