CN106866692A - The preparation method of the FSHR antagonists with the Dioxin ketone structure of benzo 1,4 - Google Patents
The preparation method of the FSHR antagonists with the Dioxin ketone structure of benzo 1,4 Download PDFInfo
- Publication number
- CN106866692A CN106866692A CN201710204021.9A CN201710204021A CN106866692A CN 106866692 A CN106866692 A CN 106866692A CN 201710204021 A CN201710204021 A CN 201710204021A CN 106866692 A CN106866692 A CN 106866692A
- Authority
- CN
- China
- Prior art keywords
- reaction
- isopropoxy
- added
- methyl
- evaporated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
The invention discloses a kind of preparation method of the FSHR antagonists with benzo Isosorbide-5-Nitrae Dioxin ketone structure, 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 one kind has benzo Isosorbide-5-Nitrae-dioxa hexamethylene
The preparation method of the FSHR antagonists of dienone structure.
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 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.The current existing fsh receptor inhibitor medicaments molecule of present invention basis, to its structure
Optimize and obtained a kind of FSH antagonist pharmaceuticals molecules with benzo Isosorbide-5-Nitrae-Dioxin ketone structure, and to it
Related activity test is carried out.
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 preparation method of action effect preferably new FSHR antagonists.
The present invention adopts the following technical scheme that should there is benzo Isosorbide-5-Nitrae-Dioxin to solve above-mentioned technical problem
The structure of the FSHR antagonist pharmaceuticals molecules of ketone structure is
A kind of preparation method of the FSH antagonists with benzo Isosorbide-5-Nitrae-Dioxin ketone structure, 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 in methyl
There is intramolecular annulation in the presence of activated catalyst cuprous iodide and obtain 8- isopropoxy -9- methoxyl group -6H- benzo pyrroles
Mutter and phenyl and hexamethylene acene;
L, 8- isopropoxy -9- methoxyl group -6H- chromenes and phenyl and hexamethylene acene take off in the presence of lithium bromide
Demethyl and isopropyl obtain 8,9- dihydroxy -6H- chromenes and phenyl and hexamethylene acene;
M, 8,9- dihydroxy -6H- chromenes and phenyl and hexamethylene acene and chloracetyl chloride are in positioning catalyst acetic acid
Cyclization obtains target compound in the presence of calcium.
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:By 3- (2- methylbenzenes) -8- isopropyl oxygen in reaction vessel
Base -9- methoxyl group -6H- dibenzopyrans -2- methyl is added in acetonitrile to methanesulfonate ester, adds methyl activated catalyst
Cuprous iodide, nitrogen protection reaction system, stirring is warming up to 70 DEG C of reactions until TLC monitoring raw material reaction completely, is removed under reduced pressure
Solvent acetonitrile, adds methyl tertiary butyl ether(MTBE), is cooled to -5 DEG C, has a large amount of solids to separate out in whipping process, and filtering reacting liquid is obtained
To solid, and washed with cold toluene, 8- isopropoxy -9- methoxyl group -6H- chromenes are obtained and phenyl and ring after filter cake drying
Hexane acene.
Further preferably, the specific building-up process of step L is:In reaction vessel by 8- isopropoxy -9- methoxyl groups -
6H- chromenes and phenyl and hexamethylene acene is added in dichloromethane, add lithium bromide, in 0 DEG C of stirring reaction until
TLC monitoring raw material reaction completely, is then evaporated off reaction dissolvent and obtains 8,9- dihydroxy -6H- chromenes and phenyl and hexamethylene
Acene.
Further preferably, the specific building-up process of step M is:By 8,9- dihydroxy -6H- chromenes in reaction vessel
And phenyl and hexamethylene acene and chloracetyl chloride are added in dichloromethane, add potassium carbonate and positioning catalyst acetic acid calcium in
0 DEG C of reaction is until TLC monitoring raw material reaction completely, is evaporated off reaction dissolvent and obtains target compound.
The synthetic route of the FSH antagonists with benzo 1,4- Dioxin ketone structures of the present invention is:
Synthesis technique of the present invention is simple and with low cost, is understood by active testing obtained with benzo Isosorbide-5-Nitrae-dioxa
The FSH antagonist pharmaceuticals molecule of cyclohexadienone structure is preferable to the action effect of FSHR acceptors, is expected to 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- methylbenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl pair
Methanesulfonate ester 10g is added in acetonitrile 150mL, adds catalyst cuprous iodide 5g, and nitrogen protection reaction system, machinery is stirred
Mix and be heated to 70 DEG C, decompression steams solvent acetonitrile, adds a certain amount of after reaction 10h through TLC monitoring raw material reaction completely
Methyl tertiary butyl ether(MTBE) 700mL, be cooled to -5 DEG C, gradually there are a large amount of solids to separate out in whipping process, filtering reacting liquid is consolidated
Body, and washed with a certain amount of cold toluene 200mL, obtain 8- isopropoxy -9- methoxyl group -6H- chromenes after filter cake drying
And phenyl and hexamethylene acene 9.3g;1H NMR(400MHz,CDCl3)δ:7.95 (d, J=12.0Hz, 2H), 7.72 (d, J=
12.0Hz,1H),7.55-7.48(m,4H),7.22-7.21(m,1H),5.17(s,2H),4.73(s,1H),3.84(s,3H),
3.01-2.97(m,4H),1.27-1.22(m,6H)。
Embodiment 13
In reaction bulb, 8- isopropoxy -9- methoxyl group -6H- chromenes and phenyl and hexamethylene acene 15g additions
To in dichloromethane 300mL, lithium bromide 10g is added, 2h is stirred under the conditions of 0 DEG C, after TLC monitoring raw material reactions are complete, steamed
Except reaction dissolvent obtains 8,9- dihydroxy -6H- chromenes and phenyl and hexamethylene acene;1H NMR(400MHz,CDCl3)δ:
7.82-7.77(m,3H),7.55-7.48(m,4H),7.22-7.21(m,1H),5.37-5.35(m,2H),5.17(s,2H),
3.06-3.02(m,4H)。
Embodiment 14 (lacks the addition of raw material chloracetyl chloride, supplemented)
In reaction bulb, 8,9- dihydroxy -6H- chromenes and phenyl and hexamethylene acene 15g is added to dichloromethane
In alkane 300mL, potassium carbonate 10g and positioning catalyst acetic acid calcium are added, chloracetyl chloride 30mL is slowly added dropwise under the conditions of 0 DEG C and is stirred
2h is mixed, after TLC monitoring raw material reactions are complete, reaction dissolvent are evaporated off and obtained target compound 13g.1H NMR(400MHz,CDCl3)
δ:7.89-7.85 (m, 2H), 7.68 (d, J=12.0Hz, 1H), 7.52-7.47 (m, 4H), 7.21-7.20 (m, 1H), 5.37-
5.35(m,2H),5.17(s,2H),4.78(s,2H),3.06-3.02(m,4H)。
Embodiment 15
Antitumor activity is tested
Collect growth period ovarian cancer cell OVCAR-3, 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 surveyed
It is fixed, FSHR antagonist pharmaceuticals moleculesInhibiting rate IC50 to the cell is 201 μm of olL-1。
Preliminary biological activity test shows that the compound has suppression to make in ovarian cancer cell OVCAR-3 to cancer cell
With.
In sum, the invention provides a kind of FSHR antagonists with benzo Isosorbide-5-Nitrae-Dioxin ketone structure
And preparation method thereof, this is the discovery first of such compound purposes, 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 preparation method of the FSHR antagonists of benzo Isosorbide-5-Nitrae-Dioxin ketone structure, it is characterised in that specific step
Suddenly it is:
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 activated to methanesulfonate ester in methyl
There is intramolecular annulation in the presence of catalyst cuprous iodide and obtain 8- isopropoxy -9- methoxyl group -6H- chromenes simultaneously
Phenyl and hexamethylene acene;
L, 8- isopropoxy -9- methoxyl group -6H- chromenes and phenyl and hexamethylene acene slough first in the presence of lithium bromide
Base and isopropyl obtain 8,9- dihydroxy -6H- chromenes and phenyl and hexamethylene acene;
M, 8,9- dihydroxy -6H- chromenes and phenyl and hexamethylene acene and chloracetyl chloride are in positioning catalyst acetic acid calcium
The lower cyclization of effect obtains target compound.
2. the preparation side of the FSH antagonists with benzo 1,4- Dioxin ketone structures according to claim 1
Method, it is characterised in that the specific building-up process of described 2 '-iodo- 5- xenols -2- methyl formates is:(1)In reaction vessel
It is middle that the bromo- 4- nitrobenzene methyls of 2-, 2- iodobenzenes boric acid and potassium carbonate are added to volume ratio for 10:1 DME and the mixing of water
In solution, 30min is stirred at room temperature under nitrogen protection, adds catalyst tetrakis triphenylphosphine palladium, stir under nitrogen protection
Uniformly, high-temperature being risen to 100 DEG C of reactions up to TLC monitoring raw material reactions are complete, solvent being evaporated off under vacuum, residue adds
In entering dichloromethane, then washed twice with pure water, organic phase is evaporated off solvent after anhydrous sodium sulfate drying, then through silica gel column layer
Analysis separating-purifying obtains 2 '-iodo- 5- nitrobiphenyls -2- methyl formates;(2)Catalyst reduction iron powder is added in reaction vessel
To in glacial acetic acid, stirring reaction 45min after being warming up to 85 DEG C is added dissolved with 2 '-iodo- 5- nitrobiphenyls -2- under nitrogen protection
The glacial acetic acid solution of methyl formate, drips after 85 DEG C of reactions up to TLC monitoring raw material reactions are complete, then by diatomite
Filtering reacting liquid, diatomite is washed with the glacial acetic acid of heat, and reaction dissolvent is evaporated off under vacuum, adds 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, dense
Contracting obtains 2 '-iodo- 5- amidos biphenyl -2- methyl formates;(3)In 0 DEG C by 2 '-iodo- 5- amidos biphenyl -2- first in reaction vessel
Sour methyl esters is added in the dilute sulfuric acid that mass concentration is 5%, is added dropwise again dissolved with oxidation catalyst natrium nitrosum after stirring 10min
The aqueous solution, 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, so
After be cooled to room temperature, be extracted with ethyl acetate reaction solution three times, merge organic phase, organic phase is evaporated off after anhydrous sodium sulfate drying
Solvent, 2 '-iodo- 5- xenols -2- methyl formates are obtained through silica gel column chromatography separating-purifying.
3. the preparation side of the FSHR antagonists with benzo 1,4- Dioxin ketone structures according to claim 1
Method, it is characterised in that the specific building-up process of described 3- isopropoxy -4- methoxyl group -6- bromobenzyl bromines is:(1)In reaction vessel
It is middle that 3- hydroxyl -4- methoxy toluenes and 2- N-Propyl Bromides are added in the DMF of Non-aqueous processing, potassium carbonate is added, it is warming up to back
Stream reaction is complete up to TLC monitoring raw material reactions, and solvent is evaporated off under vacuum, and residue is added to the water, then uses dichloro
Methane aqueous phase extracted three times, merges organic phase, and 3- isopropoxy -4- methoxy toluenes are obtained after solvent is finally evaporated off;(2)Anti-
Answer and 3- isopropoxy -4- methoxy toluenes are added in glacial acetic acid in container, positioning catalyst iron powder is added, in room temperature bar
Bromine is added dropwise under part, 30min is dripped, is warming up to 40 DEG C of reactions until TLC monitoring raw material reaction completely, solvent is evaporated off under vacuum
Glacial acetic acid, adds the sodium hydroxide solution that mass concentration is 20% in concentrate, filtering reacting liquid, filtrate is extracted with dichloromethane
Three times, merge organic phase, organic phase is bromo- by being concentrated to give 3- isopropoxy -4- methoxyl groups -6- after anhydrous sodium sulfate drying again
Benzyl bromine.
4. the preparation side of the FSHR antagonists with benzo 1,4- Dioxin ketone structures according to claim 1
Method, it is characterised in that the specific building-up process of step F is:By 2 '-iodo- 5- xenols -2- methyl formates in reaction vessel
It is added in dry acetone with 3- isopropoxy -4- methoxyl group -6- bromobenzyl bromines, adds hydroxyl hydrogen activation catalyst palladium/hydroxyl
Base apatite, is heated to back flow reaction until TLC monitoring raw material reaction completely, is evaporated off reaction dissolvent, concentration under vacuum
Thing is added in dichloromethane, then with pure water washing organic phase three times, organic phase is separated, after solvent is evaporated off under vacuum
Obtain crude product, then through silica gel column chromatography separating-purifying obtain sterling 5- (the bromo- 5- isopropoxies -4- methoxy benzyl alcohols of 2-) -2 ' -
Iodine biphenyl -2- methyl formates.
5. the preparation side of the FSHR antagonists with benzo 1,4- Dioxin ketone structures according to claim 1
Method, it is characterised in that the specific building-up process of step G is:By 5- (the bromo- 5- isopropoxies -4- methoxyl groups of 2- in reaction vessel
Phenmethylol) -2 '-iodine biphenyl -2- methyl formates and potassium carbonate is added in dimethylacetylamide, in N2Protection is lower to add phenyl ring hydrogen
Activated catalyst palladium/hydroxyapatite, N is continually fed into toward reaction system2, while discharging N2, it is kept a stabilization circulation
Environment, 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
Until TLC monitoring raw material reaction is completely, reaction vessel is taken out from microwave reactor and adds pure water that reaction is quenched, then use second
Acetoacetic 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
Separating-purifying obtains 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- methyl formates.
6. the preparation side of the FSHR antagonists with benzo 1,4- Dioxin ketone structures according to claim 1
Method, it is characterised in that the specific building-up process of step H is:By 3- (2- iodobenzenes) -8- isopropoxy -9- methoxies in reaction vessel
Base -6H- dibenzopyrans -2- methyl formates are added in ethanol, add the aqueous solution dissolved with NaOH, are warming up to 70 DEG C
Reaction is complete up to TLC monitoring raw material reactions, and solvent is evaporated off under vacuum, and residue is added to the water, then uses acetic acid second
Ester washings phase three times, water diluted hydrochloric acid dissolution regulation pH is 3, then with dichloromethane aqueous phase extracted three times, merges organic phase
After solvent be evaporated off obtain 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl group -6H- dibenzopyrans -2- formic acid.
7. the preparation side of the FSHR antagonists with benzo 1,4- Dioxin ketone structures according to claim 1
Method, it is characterised in that the specific building-up process of step I is:By 3- (2- iodobenzenes) -8- isopropoxy -9- methoxies in reaction vessel
Base -6H- dibenzopyrans -2- formic acid is added in anhydrous THF, and reaction temperature is reduced to -60 DEG C, and the tetrahydrochysene of 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 that reaction, suction filtration reaction solution, filter is quenched
Liquid is extracted with ethyl acetate repeatedly, merge organic phase be evaporated off obtaining after solvent 3- (2- iodobenzenes) -8- isopropoxy -9- methoxyl groups -
6H- dibenzopyrans -2- methyl alcohol.
8. the preparation side of the FSHR antagonists with benzo 1,4- Dioxin ketone structures according to claim 1
Method, it is characterised in that the specific building-up process of step J is:By 3- (2- iodobenzenes) -8- isopropoxy -9- methoxies in reaction vessel
Base -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 completely, adds pure water that reaction is quenched, then is extracted with ethyl acetate three times, merges organic phase, organic phase warp
Solvent is evaporated off after anhydrous sodium sulfate drying, then 3- (2- iodobenzenes) -8- isopropoxy -9- first is obtained through silica gel column chromatography separating-purifying
Epoxide -6H- dibenzopyrans -2- methyl is to methanesulfonate ester.
9. the preparation side of the FSHR antagonists with benzo 1,4- Dioxin ketone structures according to claim 1
Method, it is characterised in that the specific building-up process of step K is:By 3- (2- methylbenzenes) -8- isopropoxy -9- first in reaction vessel
Epoxide -6H- dibenzopyrans -2- methyl is added in acetonitrile to methanesulfonate ester, adds the iodate of methyl activated catalyst sub-
Copper, nitrogen protection reaction system, stirring is warming up to 70 DEG C of reactions until TLC monitoring raw material reaction completely, removes solvent second under reduced pressure
Nitrile, adds methyl tertiary butyl ether(MTBE), is cooled to -5 DEG C, has a large amount of solids to separate out in whipping process, and filtering reacting liquid obtains solid,
And washed with cold toluene, obtain 8- isopropoxy -9- methoxyl group -6H- chromenes and phenyl after filter cake drying and hexamethylene simultaneously
Benzene.
10. the preparation of the FSHR antagonists with benzo 1,4- Dioxin ketone structures according to claim 1
Method, it is characterised in that the specific building-up process of step L is:By 8- isopropoxy -9- methoxyl group -6H- benzene in reaction vessel
And pyrans and phenyl and hexamethylene acene are added in dichloromethane, lithium bromide is added, in 0 DEG C of stirring reaction until TLC is supervised
Control raw material reaction completely, is then evaporated off reaction dissolvent and obtains 8,9- dihydroxy -6H- chromenes and phenyl and hexamethylene acene;
The specific building-up process of step M is:By 8,9- dihydroxy -6H- chromenes and phenyl and hexamethylene acene in reaction vessel
It is added in dichloromethane with chloracetyl chloride, adds potassium carbonate and positioning catalyst acetic acid calcium in 0 DEG C of reaction until TLC monitoring
Raw material reaction completely, is evaporated off reaction dissolvent and obtains target compound.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710204021.9A CN106866692A (en) | 2017-03-30 | 2017-03-30 | The preparation method of the FSHR antagonists with the Dioxin ketone structure of benzo 1,4 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710204021.9A CN106866692A (en) | 2017-03-30 | 2017-03-30 | The preparation method of the FSHR antagonists with the Dioxin ketone structure of benzo 1,4 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN106866692A true CN106866692A (en) | 2017-06-20 |
Family
ID=59160517
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710204021.9A Withdrawn CN106866692A (en) | 2017-03-30 | 2017-03-30 | The preparation method of the FSHR antagonists with the Dioxin ketone structure of benzo 1,4 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106866692A (en) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101238126A (en) * | 2005-05-12 | 2008-08-06 | 惠氏公司 | Pyrrolobenzodiazepines and heteroaryl, aryl and cycloalkylamino ketone derivatives as follicle stimulating hormone receptor -(FSH-R) antagonists |
CN102448961A (en) * | 2009-05-27 | 2012-05-09 | 奥根农股份公司 | Dihydro) imidazoiso (5, 1-A) quinolines as fsh receptor agonists for the treatment of fertility disorders |
CN103415513A (en) * | 2011-03-14 | 2013-11-27 | 勃林格殷格翰国际有限公司 | Benzodioxane inhibitors of leukotriene production |
WO2015196335A1 (en) * | 2014-06-23 | 2015-12-30 | Tocopherx, Inc. | Pyrazole compounds as modulators of fshr and uses thereof |
-
2017
- 2017-03-30 CN CN201710204021.9A patent/CN106866692A/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101238126A (en) * | 2005-05-12 | 2008-08-06 | 惠氏公司 | Pyrrolobenzodiazepines and heteroaryl, aryl and cycloalkylamino ketone derivatives as follicle stimulating hormone receptor -(FSH-R) antagonists |
CN102448961A (en) * | 2009-05-27 | 2012-05-09 | 奥根农股份公司 | Dihydro) imidazoiso (5, 1-A) quinolines as fsh receptor agonists for the treatment of fertility disorders |
CN103415513A (en) * | 2011-03-14 | 2013-11-27 | 勃林格殷格翰国际有限公司 | Benzodioxane inhibitors of leukotriene production |
WO2015196335A1 (en) * | 2014-06-23 | 2015-12-30 | Tocopherx, Inc. | Pyrazole compounds as modulators of fshr and uses thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101279997B (en) | Novel preparation of budesonide | |
CN105111205B (en) | A kind of preparation method of Pa Boxini | |
CN104478877B (en) | The method preparing Lei Dipawei intermediate | |
CN107311875A (en) | The synthetic method of aramine | |
CN102471302A (en) | Preparation process of dronedarone and its salts | |
CN110372608A (en) | A kind of preparation method of antagonists of gonadotropin-releasing hormone | |
CN102731605B (en) | A kind of purification process of Abiraterone acetate | |
CN107245072A (en) | A kind of preparation method of the triazole compound of Tarceva 1,2,3 | |
CN106928243A (en) | The preparation method of the benzo piperidines with bioactivity and anilino- class compound | |
CN106866692A (en) | The preparation method of the FSHR antagonists with the Dioxin ketone structure of benzo 1,4 | |
CN104844593A (en) | Synthetic method for Apixaban drug intermediate | |
CN107216298A (en) | A kind of preparation method of butylphenyl phthaleine | |
CN106986880B (en) | A kind of preparation method of the FSH antagonists with benzopyran structure | |
CN106967076A (en) | One kind has 6H dibenzopyrans structural compounds and preparation method thereof | |
CN105601537B (en) | A kind of preparation method of 2- (7- methoxy-1-naphthyls) acetonitrile | |
CN113754619B (en) | Method for preparing polysubstituted benzofuran-4-formic acid compound under catalysis of ruthenium | |
CN106957320B (en) | The preparation method of biologically active benzo tetrahydropyrrole compounds | |
CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
CN107573395A (en) | A kind of preparation method of medroxyproges-terone acetate | |
CN102617376A (en) | Synthesis method of calcium ion selective chelating agents | |
CN107382730B (en) | A kind of derivative of lourerin B and its preparation and application | |
CN101792446A (en) | Preparation method of L-erythro biopterin | |
CN106977523A (en) | FSHR antagonists with phenyl and nafoxidine structure and preparation method thereof | |
CN102093381A (en) | 6H-benzofuran[3,2-c][1]benzopryan-6-ketone compound as well as preparation method and application of 6H-benzofuran[3,2-c][1] benzopryan-6-ketone compound | |
CN104387221A (en) | Synthesis method of peretinoin decarboxylative body impurities |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WW01 | Invention patent application withdrawn after publication | ||
WW01 | Invention patent application withdrawn after publication |
Application publication date: 20170620 |