CN106957320B - The preparation method of biologically active benzo tetrahydropyrrole compounds - Google Patents
The preparation method of biologically active benzo tetrahydropyrrole compounds 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 preparation methods of biologically active benzo tetrahydropyrrole compounds, belong to the synthesis technical field of medicine intermediate.Technical scheme of the present invention main points are：
Description
Technical field
The invention belongs to the synthesis technical fields of medicine intermediate, and in particular to a kind of biologically active benzo tetrahydrochysene
The preparation method of azole compounds.
Background technology
Promoting sexual gland hormone shows important physiological function, such as metabolism, body heat regulation and reproduction in human body
Journey.It is synthesized and is secreted by hypothalamus, by inducing follicle-stimulating hormone (FSH) (FSH)/luteotropic hormone (LH) in hypophysis
It secretes, the growth and development and ovulation of Follicles in an one-step inducing ovary of going forward side by side.FSH is the core during Mammalian Reproduction
Hormone, it is fetal differentiation, foetal period ovum peak occur and follicle atresia, the genesis and development of sexual maturing period ovarian follicle and maturation,
Granulocyte aromatizing enzyme activates and androgen plays conversion from irreplaceable crucial work to estrogen, the adjusting of cyclostage
With.FSH is mainly mediated the effect of target organ by fsh receptor (FSHR).Studies have shown that FSHR is not expressed in sexual gland only,
Also in the expression of other tissues such as bone, prostate, Ovarian surface epithelium.FSH is horizontal excessively high in vivo, can lead to sclerotin stream
It loses, some hormone-dependent diseases, such as oophoroma, prostate cancer, mullerianosis, ovarian hyperstimulation syndrome, all
It is influenced by FSH very big；By inhibit FSH secretion, can so inhibition glandular secretion sex hormone, lead to disease dependence in blood
Hormonal readiness reduces, and inhibits 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 pass through computer according to current existing fsh receptor inhibitor medicaments molecule
Its structure is optimized in drug Computer Aided Design, and a kind of novel fsh receptor inhibitor has been obtained using new synthetic method
Drug molecule, and related activity test has been carried out to it.
Invention content
That the technical problem to be solved by the present invention is to provide a kind of synthetic methods is simple, molecular structure is novel and to fsh receptor
The preparation method of the preferably biologically active benzo tetrahydropyrrole compounds of function and effect.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, the biologically active benzo nafoxidine
The structure of compound is
The preparation method of biologically active benzo tetrahydropyrrole compounds, it is characterised in that the specific steps are：
A, the work of 2,4- dihydroxy-methyl phenylacetate and the bromo- 4,5- dimethoxybenzyl bromides of 2- in hydroxyl hydrogen activation catalyst
Substitution reaction is carried out under obtains 2- hydroxyls -4- (2- bromo-4,5-dimethoxies benzyloxy)-methyl phenylacetate, wherein hydroxyl hydrogen
Activated catalyst is palladium/calcium carbonate, platinum/calcium carbonate, palladium/activated carbon or platinum/activated carbon；
B, paratoluensulfonyl chloride under the action of catalyst stannous chloride to 2- hydroxyls -4- (the bromo- 4,5- dimethoxys benzyls of 2-
Oxygroup)-methyl phenylacetate 2 hydroxyls carry out activation protection 2- is obtained by the reaction to tosylate base -4- (the bromo- 4,5- diformazans of 2-
Oxygroup benzyloxy)-methyl phenylacetate；
C, 2- urges tosylate base -4- (the bromo- 4,5- dimethoxybenzyloxycarbonyls bases of 2-)-methyl phenylacetates in the activation of phenyl ring hydrogen
Intramolecular cyclization is carried out under the action of agent obtains 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid
Methyl esters, wherein phenyl ring hydrogen activation catalyst are palladium/calcium carbonate or platinum/calcium carbonate；
D, 3- hydrolyzes tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- methyl acetates in alkaline solution
3- is obtained to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid using acidification；
E, 3- obtains tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid and aniline progress acylation reaction
To 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetamido benzene；
F, 3- obtains tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetamido benzene progress carbonyl reduction
To 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- ethyl amido benzene；
G, 3- sloughs to tosylate tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- ethyl amido benzene
Intramolecular cyclization is carried out after base obtains 8,9- methoxyl group -6H- chromenes simultaneously phenyl and nafoxidine amido benzene.
Further preferably, the detailed process of step A is：In the reaction vessel by 2,4- dihydroxy-methyl phenylacetate and 2-
Bromo-4,5-dimethoxy benzyl bromine is added in dry acetone, adds hydroxyl hydrogen activation catalyst palladium/activated carbon, wherein 2,
The mass ratio of 4- dihydroxy-methyl phenylacetate and hydroxyl hydrogen activation catalyst palladium/activated carbon is 5:1, be heated to 80 DEG C into
Row back flow reaction, the reaction was complete for TLC monitoring raw material after reacting 4h, solvent is evaporated off under vacuum, dichloromethane is added in residue
In alkane, then three times with pure water washing, after organic phase is dried over anhydrous sodium sulfate, solvent is evaporated off, then detach through silica gel column chromatography
Purification obtains pure 2- hydroxyls -4- (the bromo- 4,5- dimethoxybenzyloxycarbonyls bases of 2-)-methyl phenylacetate.
Further preferably, the detailed process of step B is：In the reaction vessel by 2- hydroxyls -4- (the bromo- 4,5- dimethoxies of 2-
Base benzyloxy)-methyl phenylacetate, triethylamine and catalyst stannous chloride be added in dichloromethane, under nitrogen protection in 0 DEG C
The dichloromethane solution dissolved with paratoluensulfonyl chloride is added, reacts at room temperature 3h, TLC monitors raw material, and the reaction was complete, and addition mole is dense
Reaction is quenched in the hydrochloric acid solution that degree is 0.5mol/L, and water phase pH is 6-7, separates organic phase, and water phase dichloromethane extracts three times,
Merge organic phase, anhydrous sodium sulfate is added and removes residual moisture in organic phase, 2- is obtained to tosylate base -4- after solvent is evaporated off
(the bromo- 4,5- dimethoxybenzyloxycarbonyls bases of 2-)-methyl phenylacetate.
Further preferably, the detailed process of step C is：In the reaction vessel by 2- to tosylate base -4- (2- bromo- 4,
5- dimethoxybenzyloxycarbonyls base)-methyl phenylacetate and phenyl ring hydrogen activation catalyst palladium/calcium carbonate is added in dimethylacetylamide,
Wherein 2- is to tosylate base -4- (the bromo- 4,5- dimethoxybenzyloxycarbonyls bases of 2-)-methyl phenylacetates and phenyl ring hydrogen activation catalyst
The mass ratio of palladium/calcium carbonate is 10:1, then N is constantly passed through into reaction system2, while N is discharged2, it is made to keep a stationary flow
Logical environment, is stirred at room temperature closed reaction vessel after 30min, then reaction vessel is positioned in microwave reactor, is heated to 130 DEG C
2h is reacted, TLC monitors raw material, and the reaction was complete, takes out reaction vessel addition pure water and reaction is quenched, then be extracted with ethyl acetate three
It is secondary, merge organic phase, then solvent is evaporated off after being dried with anhydrous sodium sulfate, most obtains 3- to first through silica gel column chromatography separating-purifying afterwards
Benzene sulphur ester group -8,9- methoxyl group -6H- dibenzopyrans -2- methyl acetates.
Further preferably, the detailed process of step D is：In the reaction vessel by 3- to tosylate base -8,9- methoxyl groups -
6H- dibenzopyrans -2- methyl acetates are added in ethyl alcohol, are added the aqueous solution dissolved with sodium hydroxide, are heated to 80
DEG C reaction 1h, TLC monitors raw material, and the reaction was complete, and solvent is evaporated off under vacuum, and residue is added to the water, then with acetic acid second
Ester washs water phase three times, and it is 4 that water phase dilute hydrochloric acid, which adjusts pH, then three times with dichloromethane aqueous phase extracted, merges organic phase, finally
3- is obtained to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid after solvent is evaporated off.
Further preferably, the detailed process of step E is：In the reaction vessel by 1- ethyls -3- (3- dimethylamino-propyls)
Carbodiimide hydrochloride is added to dissolved with 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid, diisopropyl
It in the DMF of base ethamine, I-hydroxybenzotriazole and aniline, reacts at ambient temperature for 24 hours, TLC monitors raw material, and the reaction was complete, will
Reaction solution is poured into water, then reaction solution is extracted with ethyl acetate three times, merges organic phase, then through silicon after being dried with anhydrous sodium sulfate
Plastic column chromatography separating-purifying obtains 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetamido benzene.
Further preferably, the detailed process of step F is：In the reaction vessel by 3- to tosylate base -8,9- methoxyl groups -
6H- dibenzopyrans -2- acetamidos benzene, potassium hydroxide and hydrazine are added in diethylene glycol (DEG), are heated to 180 DEG C, are reacted
It isolates excessive water and unreacted hydrazine in journey, 200 DEG C is continuously heating to after reacting 5h, reaction solution is fallen after the reaction was continued 2h
Enter in ice water, extracts reaction solution with chloroform, merge organic phase, 3- is obtained to tosylate base -8,9- first after solvent is finally evaporated off
Oxygroup -6H- dibenzopyrans -2- ethyl amido benzene；Or in the reaction vessel by 3- to tosylate base -8,9- methoxyl groups -
6H- dibenzopyrans -2- acetamido benzene is added in THF, adds NaBH4-AlCl3Complex reducing agent is protected in inert gas
It is heated to flowing back under shield, TLC monitoring raw materials pour into ice water reaction solution after the reaction was complete, extract reaction solution with chloroform, merge
Organic phase obtains 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- ethyl amidos after solvent is finally evaporated off
Benzene；Or under nitrogen protection, make solvent with anhydrous THF, the borine tetrahydrofuran that molar concentration is 1mol/L is added dropwise thereto
Solution is again heated to 90 DEG C of back flow reaction 15h, adds water destruct residue borine, THF is steamed, and enriching hydrochloric acid reflux 3h uses NaOH
It is 12 to adjust pH, and 3- is obtained by extraction to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- ethyl amido benzene with chloroform.
Further preferably, the detailed process of step G is：In the reaction vessel by 3- to tosylate base -8,9- methoxyl groups -
6H- dibenzopyrans -2- ethyl amido benzene is added in acetonitrile, mechanical agitation, is heated to 70 DEG C of reaction 10h, is monitored through TLC former
The reaction was complete for material, and decompression steams solvent acetonitrile, adds n-hexane, is cooled to -5 DEG C, there is solid precipitation in whipping process, filters
Reaction solution obtains solid, and cold toluene is used in combination to wash, and 8,9- methoxyl group -6H- chromenes are obtained and phenyl and four after filter cake drying
Hydrogen pyrroles's amido benzene.
Specific synthesis road in the preparation method of biologically active benzo tetrahydropyrrole compounds of the present invention
Line is：
Synthesis technology of the present invention is simple and of low cost, by fsh receptor antagonist pharmaceuticals obtained known to active testing
Molecule is preferable to the function and effect of fsh receptor, is expected to further genralrlization application.
Specific implementation mode
The above of the present invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on the above of the present invention belong to this hair
Bright range.
Embodiment 1
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, is 4.5 with the pH of sodium carbonate regulation system, activated carbon 50g is added, is put after 2h is stirred at room temperature
Enter in autoclave, hydrogenation reduction 2h stirred under the conditions of 100KPa, 100 DEG C, decompression filters, deionized water be washed till it is neutral and
Through silver nitrate solution detection without chlorion, dry 3h obtains palladium/activated carbon 43g under the conditions of 60 DEG C of normal pressure.
Embodiment 2
Platinous 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, is 4.5 with the pH of sodium carbonate regulation system, activated carbon 50g is added, is put after 2h is stirred at room temperature
Enter in autoclave, hydrogenation reduction 2h stirred under the conditions of 100KPa, 100 DEG C, decompression filters, deionized water be washed till it is neutral and
Through silver nitrate solution detection without chlorion, dry 3h obtains platinum/activated carbon 45g under the conditions of 60 DEG C of normal pressure.
Embodiment 3
Palladium chloride 5g is added in reaction bulb, adds methanol 100mL, adds sodium carboxymethylcellulose 1g, use carbon
The pH of sour sodium regulation system is 4.5, and calcium carbonate 50g is added, is put into autoclave after 2h is stirred at room temperature, in 100KPa, 100
Under the conditions of DEG C stir hydrogenation reduction 2h, decompression filter, deionized water be washed till neutrality and through silver nitrate solution detection without chlorine from
Son, dry 3h obtains palladium/calcium carbonate 46g under the conditions of 60 DEG C of normal pressure.
Embodiment 4
Platinous chloride 5g is added in reaction bulb, adds methanol 100mL, adds sodium carboxymethylcellulose 1g, use carbon
The pH of sour sodium regulation system is 4.5, and calcium carbonate 50g is added, is put into autoclave after 2h is stirred at room temperature, in 100KPa, 100
Under the conditions of DEG C stir hydrogenation reduction 2h, decompression filter, deionized water be washed till neutrality and through silver nitrate solution detection without chlorine from
Son, dry 3h obtains platinum/calcium carbonate 43g under the conditions of 60 DEG C of normal pressure.
Embodiment 5
In reaction bulb, 2,4- dihydroxy-methyl phenylacetate 1g and 2- bromo-4,5-dimethoxy benzyl bromine 2g is added to dry
In dry acetone 160mL, palladium/calcium carbonate 0.2g is added, slowly increases temperature to 80 DEG C of progress back flow reactions, after reacting 4h
TLC monitors raw material, and the reaction was complete, solvent is evaporated off under vacuum, residue is added in dichloromethane 100mL, then uses pure water
40mL is washed three times, and after organic phase is dried over anhydrous sodium sulfate, solvent is evaporated off, then is obtained through silica gel column chromatography separating-purifying pure
2- hydroxyls -4- (2- bromo-4,5-dimethoxies benzyloxy)-methyl phenylacetate 1.20g, yield 91%；1H NMR(400MHz,
CDCl3)δ:10.97 (s, 1H), 7.76 (d, J=8.8Hz, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.56-6.50 (m,
2H),5.08(s,2H),3.92(s,3H),3.89(s,3H),3.86(s,3H)。
Embodiment 6
In reaction bulb, 2,4- dihydroxy-methyl phenylacetate 1g and 2- bromo-4,5-dimethoxy benzyl bromine 2g is added to dry
In dry acetone 160mL, palladium/activated carbon 0.2g is added, slowly increases temperature to 80 DEG C of progress back flow reactions, after reacting 4h
TLC monitors raw material, and the reaction was complete, solvent is evaporated off under vacuum, residue is added in dichloromethane 100mL, then uses pure water
40mL is washed three times, and after organic phase is dried over anhydrous sodium sulfate, solvent is evaporated off, then is obtained through silica gel column chromatography separating-purifying pure
2- hydroxyls -4- (2- bromo-4,5-dimethoxies benzyloxy)-methyl phenylacetate 1.26g, yield 95%；1H NMR(400MHz,
CDCl3)δ:10.97 (s, 1H), 7.76 (d, J=8.8Hz, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.56-6.50 (m,
2H),5.08(s,2H),3.92(s,3H),3.89(s,3H),3.86(s,3H)。
Embodiment 7
In reaction bulb, 2,4- dihydroxy-methyl phenylacetate 1g and 2- bromo-4,5-dimethoxy benzyl bromine 2g is added to dry
In dry acetone 160mL, platinum/activated carbon 0.2g is added, slowly increases temperature to 80 DEG C of progress back flow reactions, after reacting 4h
TLC monitors raw material, and the reaction was complete, solvent is evaporated off under vacuum, residue is added in dichloromethane 100mL, then uses pure water
40mL is washed three times, and after organic phase is dried over anhydrous sodium sulfate, solvent is evaporated off, then is obtained through silica gel column chromatography separating-purifying pure
2- hydroxyls -4- (2- bromo-4,5-dimethoxies benzyloxy)-methyl phenylacetate 1.15g, yield 87%；1H NMR(400MHz,
CDCl3)δ:10.97 (s, 1H), 7.76 (d, J=8.8Hz, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.56-6.50 (m,
2H),5.08(s,2H),3.92(s,3H),3.89(s,3H),3.86(s,3H)。
Embodiment 8
In reaction bulb, by 2- hydroxyls -4- (2- bromo-4,5-dimethoxies benzyloxy)-methyl phenylacetate 2g, triethylamine
1.5g and stannous chloride 0.75g are added in dichloromethane 20mL, under the conditions of 0 DEG C, in nitrogen protection, are slowly added dropwise dissolved with right
The dichloromethane 30mL solution of toluene sulfochloride 2.0g is warmed to room temperature reaction 3h, TLC and monitors [ after dripping;Solvent:PE:EA
=10:1]The reaction was complete for raw material, and reaction solution is quenched in the dilute hydrochloric acid 10mL for being 0.5mol/L with molar concentration, and water phase pH is 6-7, point
Go out organic phase, water phase uses dichloromethane 10mL extractions three times, merge organic phase, anhydrous sodium sulfate 10g is added and removes organic phase again
Residual moisture obtains 2- to tosylate base -4- (2- bromo-4,5-dimethoxies benzyloxy)-methyl phenylacetate after solvent is evaporated off
(2.3g)。1H NMR(400MHz,CDCl3)δ:10.62 (s, 1H), 7.59 (d, J=8.8Hz, 1H), 7.42 (s, 2H), 7.16
(s,1H),7.08(s,2H),7.03(s,1H),6.59-6.55(m,2H),5.18(s,2H),3.97(s,3H),3.81(s,
3H),3.36(s,3H),2.31(s,3H)。
Embodiment 9
In reaction bulb, 2- to tosylate base -4- (2- bromo-4,5-dimethoxies benzyloxy)-methyl phenylacetate 2g
It is added in dimethylacetylamide 30mL with palladium/calcium carbonate 0.2g, does not stop to be passed through N into reaction system2, while N is discharged2, make it
A stable circulation environment is kept, confined reaction bottle after 30min is stirred at room temperature, it is placed in microwave reactor, is heated to
130 DEG C of reaction 2h, TLC monitors raw material, and the reaction was complete, and reaction bulb is taken out from microwave reactor, and a certain amount of pure water quenching is added
It goes out reaction, then reaction solution is extracted with ethyl acetate three times, merge organic phase, then solvent is evaporated off after being dried with anhydrous sodium sulfate, most
3- is obtained to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- methyl acetates by silica gel column chromatography separating-purifying
1.66g, yield 97%；1H NMR(400MHz,CDCl3):8.16(s,1H),7.74-7.59(m,4H),7.09-7.06(m,
2H),7.19(s,1H),6.63(s,1H),5.21(s,2H),4.61-4.50(m,5H),3.81(s,3H),3.64(s,3H),
2.48 (d, J=6.0Hz, 3H).
Embodiment 10
In reaction bulb, tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- methyl acetates 2g is added in 3-
Into ethyl alcohol 20mL, the aqueous solution 15mL dissolved with sodium hydroxide 2g is added, it is former to be heated to 80 DEG C of reaction 1h, TLC monitoring
The reaction was complete for material, solvent is evaporated off under vacuum, residue is added to the water, then washs water phase three times with ethyl acetate, water
It is 4 mutually to adjust pH with dilute hydrochloric acid again, then three times with dichloromethane aqueous phase extracted, merges organic phase, obtained after solvent is finally evaporated off
Product 3- is to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid 1.6g；1H NMR(400MHz,CDCl3):
8.15(s,1H),7.74-7.62(m,4H),7.11-7.08(m,2H),7.11(s,1H),6.75(s,1H),5.22(s,2H),
4.64-4.56(m,5H),3.87(s,3H),2.41(s,3H)。
Embodiment 11
In reaction bulb, 1- ethyls -3- (3- dimethylamino-propyls) carbodiimide hydrochloride 0.092g be added to dissolved with
3- is to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid 2.0g, diisopropylethylamine 0.167mL, 1- hydroxyl
In the DMF 20mL of benzotriazole 0.065g and aniline 1g, reacting at ambient temperature for 24 hours, TLC monitors raw material after the reaction was complete,
A certain amount of pure water is added, then reaction solution is extracted with ethyl acetate three times, merges organic phase, then after being dried with anhydrous sodium sulfate
3- is obtained to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetamido benzene through silica gel column chromatography separating-purifying
2.2g；1H NMR(400MHz,CDCl3):8.07-8.01(m,3H),7.87-7.82(m,3H),7.15-7.07(m,5H),
6.75-6.71(m,2H),5.25(s,1H),5.07(s,2H),4.71-4.66(m,4H),4.23(s,1H),3.96-3.92(m,
6H),2.45(s,3H)。
Embodiment 12
In reaction bulb, 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetamido benzene 2g,
Potassium hydroxide 1g and hydrazine 10mL are added in diethylene glycol (DEG) 20mL, are to slowly warm up to 180 DEG C, pay attention to isolating excess in reaction process
Water and unreacted hydrazine, be continuously heating to 200 DEG C after reacting 5h, reaction solution poured into ice water after the reaction was continued 2h, uses chlorine
Imitative extraction reaction solution, merges organic phase, 3- is obtained to tosylate base -8,9- methoxyl group -6H- dibenzo after solvent is finally evaporated off
Pyrans -2- ethyl amido benzene 1.7g.
Embodiment 13
In reaction bulb, 3- adds tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetamido benzene 2g
Enter into THF 20mL, adds NaBH4-AlCl3Complex reducing agent 0.5g is heated to flowing back under inert gas protection, TLC
Monitoring raw material pours into reaction solution in ice water after the reaction was complete, extracts reaction solution with chloroform, merges organic phase, solvent is finally evaporated off
After obtain 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- ethyl amido benzene 1.6g.
Embodiment 14
In reaction bulb, tosylate base -8,9- methoxyl group -6H- chromene -2- ethyl amido benzene 2g is added in 3-
Into acetonitrile 20mL, mechanical agitation is heated to 70 DEG C of reaction 10h, [ is monitored through TLC;Solvent:PE:EA=7:1]Raw material reacts
Completely, decompression steams solvent acetonitrile, adds n-hexane 50mL, is cooled to -5 DEG C, gradually has a large amount of solids to analyse in whipping process
Going out, filtering reacting liquid obtains solid, and a certain amount of cold toluene (200ml) is used in combination to wash, and target product 8 is obtained after filter cake drying,
9- methoxyl group -6H- chromenes and phenyl and nafoxidine amido benzene 1.1g.1H NMR(400MHz,CDCl3):7.87-7.86
(m,2H),7.71-7.65(m,3H),7.24-7.23(m,3H),7.11(s,1H),5.39(s,2H),4.14(s,2H),4.23
(s,1H),3.81-3.79(m,6H),3.09-3.08(m,1H)。
Embodiment 15
Antitumor activity is tested
Collect growth period ovarian cancer cell OVCAR-3, the active anticancer of compound is measured with MTS methods, by cell with
(every milliliter 4 × 10 of debita spissitudo4A cell) it is added in 96 porocyte culture plates and (obtains culture solution containing 10% tire calf serum to be made into
Individual cells suspension), after cultivating 24 hours, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of compound with various concentration
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, continues to set incubator incubation 4h.After acting on 4h, liquid is discarded supernatant, 150 μ LDMSO are added per hole,
Oscillation, cell survival rate survey absorptivity of the metabolin of MTS effects under enzyme linked immunological monitor 490nm wavelength by it
It is fixed, fsh receptor antagonist pharmaceuticals moleculeInhibiting rate IC50 to the cell is 197 μm of olL-1。
Embodiment above describes the basic principles and main features and advantage of the present invention, and the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe the originals of the present invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (9)
1. the preparation method of biologically active benzo tetrahydropyrrole compounds, the structural formula of the benzo tetrahydropyrrole compounds
ForIt is characterized in that the specific steps are：
A, 2,4- dihydroxy-methyl phenylacetate and the bromo- 4,5- dimethoxybenzyl bromides of 2- are under the action of hydroxyl hydrogen activation catalyst
It carries out substitution reaction and obtains 2- hydroxyls -4- (2- bromo-4,5-dimethoxies benzyloxy)-methyl phenylacetate, wherein hydroxyl hydrogen activates
Catalyst is palladium/calcium carbonate, platinum/calcium carbonate, palladium/activated carbon or platinum/activated carbon；
B, paratoluensulfonyl chloride under the action of catalyst stannous chloride to 2- hydroxyls -4- (the bromo- 4,5- dimethoxybenzyloxycarbonyls of 2-
Base)-methyl phenylacetate 2 hydroxyls carry out activation protection 2- is obtained by the reaction to tosylate base -4- (the bromo- 4,5- dimethoxies of 2-
Base benzyloxy)-methyl phenylacetate；
C, 2- to tosylate base -4- (the bromo- 4,5- dimethoxybenzyloxycarbonyls bases of 2-)-methyl phenylacetate in phenyl ring hydrogen activation catalyst
Under the action of carry out intramolecular cyclization and obtain 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- methyl acetates,
Wherein phenyl ring hydrogen activation catalyst is palladium/calcium carbonate or platinum/calcium carbonate；
D, 3- hydrolyzes tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- methyl acetates in alkaline solution and passes through again
The peracid 3- that obtains is to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid；
E, 3- carries out acylation reaction to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid and aniline and obtains 3-
To tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetamido benzene；
F, 3- carries out carbonyl reduction to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetamido benzene and obtains 3-
To tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- ethyl amido benzene；
G, 3- sloughs to after tosylate base tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- ethyl amido benzene
It carries out intramolecular cyclization and obtains 8,9- methoxyl group -6H- chromenes simultaneously phenyl and nafoxidine amido benzene.
2. the preparation method of biologically active benzo tetrahydropyrrole compounds according to claim 1, feature exist
It is in the detailed process of step A：In the reaction vessel by 2,4- dihydroxy-methyl phenylacetate and the bromo- 4,5- dimethoxys benzyls of 2-
Bromine is added in dry acetone, adds hydroxyl hydrogen activation catalyst palladium/activated carbon, wherein 2,4- dihydroxy-phenylacetic acid first
The mass ratio of ester and hydroxyl hydrogen activation catalyst palladium/activated carbon is 5:1,80 DEG C of progress back flow reactions are heated to, 4h is reacted
TLC monitors raw material the reaction was complete afterwards, is evaporated off solvent under vacuum, and residue is added in dichloromethane, then with pure washing
It washs three times, after organic phase is dried over anhydrous sodium sulfate, solvent is evaporated off, then pure 2- hydroxyls are obtained through silica gel column chromatography separating-purifying
Base -4- (the bromo- 4,5- dimethoxybenzyloxycarbonyls bases of 2-)-methyl phenylacetate.
3. the preparation method of biologically active benzo tetrahydropyrrole compounds according to claim 1, feature exist
It is in the detailed process of step B：In the reaction vessel by 2- hydroxyls -4- (the bromo- 4,5- dimethoxybenzyloxycarbonyls bases of 2-)-phenylacetic acid first
Ester, triethylamine and catalyst stannous chloride are added in dichloromethane, are added under nitrogen protection dissolved with tolysulfonyl in 0 DEG C
The dichloromethane solution of chlorine reacts at room temperature 3h, and TLC monitors raw material, and the reaction was complete, and the hydrochloric acid that molar concentration is 0.5mol/L is added
Reaction is quenched in solution, and water phase pH is 6-7, separates organic phase, and water phase dichloromethane extracts three times, merges organic phase, nothing is added
Aqueous sodium persulfate removes residual moisture in organic phase, and 2- is obtained to tosylate base -4- (bromo- 4, the 5- dimethoxies of 2- after solvent is evaporated off
Base benzyloxy)-methyl phenylacetate.
4. the preparation method of biologically active benzo tetrahydropyrrole compounds according to claim 1, feature exist
It is in the detailed process of step C：In the reaction vessel by 2- to tosylate base -4- (the bromo- 4,5- dimethoxybenzyloxycarbonyls bases of 2-) -
Methyl phenylacetate and phenyl ring hydrogen activation catalyst palladium/calcium carbonate are added in dimethylacetylamide, and wherein 2- is to tosylate base-
The mass ratio of 4- (the bromo- 4,5- dimethoxybenzyloxycarbonyls bases of 2-)-methyl phenylacetate and phenyl ring hydrogen activation catalyst palladium/calcium carbonate is
10:1, then N is constantly passed through into reaction system2, while N is discharged2, so that it is kept a stable circulation environment, be stirred at room temperature
Closed reaction vessel after 30min, then reaction vessel is positioned in microwave reactor, it is heated to 130 DEG C of reaction 2h, TLC monitoring
The reaction was complete for raw material, takes out reaction vessel addition pure water and reaction is quenched, then be extracted with ethyl acetate three times, merge organic phase,
Solvent is evaporated off after being dried again with anhydrous sodium sulfate, most obtains 3- to tosylate base -8,9- through silica gel column chromatography separating-purifying afterwards
Methoxyl group -6H- dibenzopyrans -2- methyl acetates.
5. the preparation method of biologically active benzo tetrahydropyrrole compounds according to claim 1, feature exist
It is in the detailed process of step D：In the reaction vessel by 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2-
Methyl acetate is added in ethyl alcohol, adds the aqueous solution dissolved with sodium hydroxide, is heated to 80 DEG C of reaction 1h, TLC monitoring
The reaction was complete for raw material, and solvent is evaporated off under vacuum, and residue is added to the water, then washs water phase three times with ethyl acetate,
It is 4 that water phase dilute hydrochloric acid, which adjusts pH, then three times with dichloromethane aqueous phase extracted, merges organic phase, is obtained after solvent is finally evaporated off
3- is to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid.
6. the preparation method of biologically active benzo tetrahydropyrrole compounds according to claim 1, feature exist
It is in the detailed process of step E：1- ethyls -3- (3- dimethylamino-propyls) carbodiimide hydrochloride is added in the reaction vessel
To dissolved with 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetic acid, diisopropylethylamine, 1- hydroxy benzos
In the DMF of triazole and aniline, reacting at ambient temperature for 24 hours, TLC monitors raw material, and the reaction was complete, and reaction solution is poured into water, then
Reaction solution is extracted with ethyl acetate three times, merges organic phase, then through silica gel column chromatography separating-purifying after being dried with anhydrous sodium sulfate
3- is obtained to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- acetamido benzene.
7. the preparation method of biologically active benzo tetrahydropyrrole compounds according to claim 1, feature exist
It is in the detailed process of step F：In the reaction vessel by 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2-
Acetamido benzene, potassium hydroxide and hydrazine are added in diethylene glycol (DEG), are heated to 180 DEG C, are isolated in reaction process excessive
Water and unreacted hydrazine are continuously heating to 200 DEG C after reacting 5h, and reaction solution is poured into ice water after the reaction was continued 2h, uses chloroform
Reaction solution is extracted, merges organic phase, 3- is obtained to tosylate base -8,9- methoxyl group -6H- dibenzo pyrroles after solvent is finally evaporated off
It mutters -2- ethyl amido benzene；Or in the reaction vessel by 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2-
Acetamido benzene is added in THF, adds NaBH4-AlCl3Complex reducing agent is heated to flowing back under inert gas protection,
TLC monitoring raw material pours into reaction solution in ice water after the reaction was complete, extracts reaction solution with chloroform, merges organic phase, be finally evaporated off
3- is obtained after solvent to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- ethyl amido benzene；Or in nitrogen protection
Under, make solvent with anhydrous THF, the borine tetrahydrofuran solution that molar concentration is 1mol/L is added dropwise thereto, is again heated to 90 DEG C
Back flow reaction 15h adds water destruct residue borine, THF is steamed, enriching hydrochloric acid reflux 3h, is 12 with NaOH tune pH, is extracted with chloroform
3- is obtained to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2- ethyl amido benzene.
8. the preparation method of biologically active benzo tetrahydropyrrole compounds according to claim 1, feature exist
It is in the detailed process of step G：In the reaction vessel by 3- to tosylate base -8,9- methoxyl group -6H- dibenzopyrans -2-
Ethyl amido benzene is added in acetonitrile, mechanical agitation, is heated to 70 DEG C of reaction 10h, and through TLC monitoring raw material, the reaction was complete, decompression
Solvent acetonitrile is steamed, n-hexane is added, -5 DEG C is cooled to, has solid precipitation, filtering reacting liquid to obtain solid in whipping process,
It is used in combination cold toluene to wash, 8,9- methoxyl group -6H- chromenes simultaneously phenyl and nafoxidine amido benzene is obtained after filter cake drying.
9. the preparation method of biologically active benzo tetrahydropyrrole compounds according to claim 1, feature exist
Specific synthetic route in preparation method is：
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