CN106967076A - One kind has 6H dibenzopyrans structural compounds and preparation method thereof - Google Patents

Abstract

There are 6H dibenzopyrans structural compounds and preparation method thereof the invention discloses one kind, belong to the synthesis technical field of medicine.Technical scheme main points are：One kind has 6H dibenzopyrans structural compounds, and its structural formula is：

Description

A compound with 6H-dibenzopyran structure and its preparation method

technical field

The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and specifically relates to a compound with a 6H-dibenzopyran structure and a preparation method thereof.

Background technique

Gonadotropins exhibit important physiological functions in humans, such as metabolism, thermoregulation, and reproductive processes. It is synthesized and secreted by the hypothalamus, by inducing the secretion of follicle-stimulating hormone (FSH)/luteinizing hormone (LH) in the pituitary gland, and further inducing the growth and development of follicles at all levels in the ovary and ovulation. FSH is the core hormone in the reproductive process of mammals. It plays a role in fetal sexual differentiation, fetal oocyte peak generation and follicular atresia, development and maturation of sexually mature follicles, activation of granulosa cell aromatase and conversion of androgen to estrogen, reproductive It plays an irreplaceable key role in the regulation of the cycle. The effect of FSH on target organs is mainly mediated by the FSH receptor (FSHR). Studies have shown that FSHR is not only expressed in gonads, but also expressed in other tissues such as bone, prostate, and ovarian surface epithelium. Excessive levels of FSH in the body can lead to bone loss. Some hormone-dependent diseases, such as ovarian cancer, prostate cancer, endometriosis, ovarian hyperstimulation syndrome, etc., are greatly affected by FSH; Secretion, which can further inhibit the secretion of sex hormones by the gonads, resulting in a decrease in the level of disease-dependent hormones in the blood, inhibiting the growth of cancer cells or preventing, alleviating, and treating other diseases; for example, cetrorelix exerts anti-proliferative effects on ovarian cancer according to this mechanism. Based on the existing FSH receptor inhibitor drug molecules, we optimized the structure of one of the better drugs through computer drug-aided design, and obtained a compound with a 6H-dibenzopyran structure through a new synthesis method , and tested its activity.

Contents of the invention

The technical problem solved by the invention is to provide a compound with a 6H-dibenzopyran structure and a preparation method thereof, which has a simple synthesis method, a novel molecular structure and a good effect on FSH receptors.

The present invention adopts following technical scheme in order to solve the above-mentioned technical problem, a kind of compound with 6H-dibenzopyran structure is characterized in that the structural formula of this compound is:

.

A method for preparing a compound with a 6H-dibenzopyran structure, characterized in that the specific steps are:

A, 2-bromo-4-nitrobenzoic acid methyl ester and 2-aminophenylboronic acid have a substitution reaction under the effect of catalyst tetrakis (triphenylphosphine) palladium to obtain 2'-amino-5-nitrobiphenyl-2 - methyl formate;

B, 2'-amino-5-nitrobiphenyl-2-methyl carboxylate undergoes a nitro reduction reaction under the action of catalyst reducing iron powder to obtain 2'-amino-5-aminobiphenyl-2-methyl carboxylate;

C, 2'-amino-5-aminobiphenyl-2-formic acid methyl ester obtains 2'-amino-5-hydroxybiphenyl-2-formic acid methyl ester through amino reduction oxidation reaction under the effect of catalyst sodium nitrite;

D, 3-hydroxytoluene and 2-bromopropane undergo a substitution reaction to obtain 3-isopropoxytoluene;

E, 3-isopropoxytoluene is replaced with bromine under the effect of positioning catalyst iron powder to obtain 3-isopropoxy-6-bromobenzyl bromide;

F, 2'-amino-5-hydroxybiphenyl-2-formic acid methyl ester and 3-isopropoxy-6-bromobenzyl bromide undergo a substitution reaction under the effect of hydroxyl hydrogen activation catalyst palladium/hydroxyapatite to obtain 5 -(2-bromo-5-isopropoxybenzyl alcohol)-2'-aminobiphenyl-2-carboxylic acid methyl ester;

G, 5-(2-bromo-5-isopropoxybenzyl alcohol)-2'-aminobiphenyl-2-carboxylic acid methyl ester undergoes intramolecular synthesis under the action of benzene ring hydrogen activation catalyst palladium/hydroxyapatite Ring reaction to obtain 3-(2-aminophenyl)-8-isopropoxy-6H-dibenzopyran-2-carboxylic acid methyl ester;

H, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-carboxylic acid methyl ester is hydrolyzed in alkaline solution and then acidified to obtain 3-(2-aminobenzene )-8-isopropoxy-6H-dibenzopyran-2-carboxylic acid;

1, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-formic acid obtains 3-(2-aminobenzene) through carboxyl redox reaction under the effect of lithium aluminum hydride -8-isopropoxy-6H-dibenzopyran-2-methanol;

J, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methanol and p-methylsulfonyl chloride carry out hydroxyl activation protection reaction to obtain 3-(2-aminobenzene)- 8-isopropoxy-6H-dibenzopyran-2-methyl-p-methylsulfonate;

K, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methyl p-methylsulfonate undergoes a substitution reaction for intramolecular ring formation to obtain 8-isopropoxy Base-6H-dibenzopyranophenylpiperidobenzene;

L, 8-isopropoxy-6H-benzopyranophenylpiperidobenzene removes the isopropyl group under the action of lithium bromide to obtain 8-hydroxyl-6H-dibenzopyranophenylpiperido pyrocene;

M, 8-hydroxyl-6H-dibenzopyranophenylpiperidinocene reacts with trifluoromethanesulfonic anhydride to obtain 8-trifluoromethanesulfonate group-6H-dibenzopyranophenyl Piperidoacene;

N, 8-trifluoromethanesulfonate-6H-dibenzopyranophenylpiperidocene reacted with aniline under the catalyst of 1,3-bis(diphenylphosphino)propane and Raney nickel The reaction yields N-8-anilino-6H-dibenzopyrano-hexahydropyridocene.

Further preferably, the specific process of step A is: adding 2-bromo-4-nitrobenzoic acid methyl ester, 2-aminophenylboron and potassium carbonate into a mixed solution of DME and water in a volume ratio of 10:1 in a reaction vessel , stirred at room temperature for 30 min under the protection of nitrogen, then added the catalyst tetrakis(triphenylphosphine) palladium, stirred evenly under the protection of nitrogen, raised the temperature to 100°C and reacted until the reaction of the raw materials monitored by TLC was complete, evaporated the solvent under vacuum conditions, and the residue Add dichloromethane, wash twice with pure water, dry the organic phase over anhydrous sodium sulfate, evaporate the solvent, and then separate and purify by silica gel column chromatography to obtain 2'-amino-5-nitrobiphenyl-2- Methyl formate.

More preferably, the specific process of step B is: add reduced iron powder to glacial acetic acid in a reaction vessel, heat up to 85°C and stir for 45 minutes to react, and add 2'-amino-5-nitrobisinated acid dissolved in nitrogen under the protection of nitrogen. The glacial acetic acid solution of methyl benzene-2-carboxylate, continue the reaction at 85°C after the dropwise addition until the raw materials are completely reacted by TLC, then filter the reaction solution through diatomaceous earth, the diatomite is washed with hot glacial acetic acid, and the filtrate is in The reaction solvent was evaporated under vacuum, saturated sodium bicarbonate was added, and the reaction solution was extracted three times with ethyl acetate, the organic phase was combined, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated, and concentrated to obtain 2'-amino-5- Aminobiphenyl-2-carboxylic acid methyl ester.

Further preferably, the specific process of step C is: add 2'-amino-5-aminobiphenyl-2-carboxylic acid methyl ester to dilute sulfuric acid with a mass concentration of 5% in a reaction vessel at 0°C, stir and drop The aqueous solution in which the catalyst sodium nitrite was dissolved was added dropwise, and the temperature was kept to continue the reaction for 1 hour, and then the temperature was raised to 60° C. to react until the reaction of the raw materials was monitored by TLC, and then cooled to room temperature, and the reaction solution was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, evaporated to remove the solvent, and separated and purified by silica gel column chromatography to obtain 2'-amino-5-hydroxybiphenyl-2-carboxylic acid methyl ester.

Further preferably, the specific process of step D is: in the reaction vessel, 3-hydroxytoluene and 2-bromopropane are added to anhydrous DMF, then potassium carbonate is added, and the temperature is raised to reflux reaction until TLC monitors that the reaction of raw materials is complete. The solvent was distilled off under vacuum, the residue was added to water, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined and the solvent was distilled off to obtain 3-isopropoxytoluene.

Further preferably, the specific process of step E is: add 3-isopropoxytoluene to glacial acetic acid in a reaction vessel, then add iron powder as a positioning catalyst, add bromine dropwise at room temperature, finish adding dropwise in 30 minutes, and heat up React at 40°C, then irradiate the reaction with a 300W tungsten lamp, evaporate the solvent glacial acetic acid under vacuum, add sodium hydroxide solution with a mass concentration of 20% to the concentrate, filter the reaction solution, extract the filtrate three times with dichloromethane, and combine the organic phase, and the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain 3-isopropoxy-6 bromobenzyl bromide.

Further preferably, the specific process of step F is: adding 2'-amino-5-hydroxybiphenyl-2-carboxylic acid methyl ester and 3-isopropoxy-6-bromobenzyl bromide to dry acetone in a reaction vessel , then add the hydroxyl hydrogen activation catalyst palladium/hydroxyapatite, heat to reflux reaction until TLC monitors the raw material reaction is complete, evaporate the reaction solvent under vacuum conditions, add the concentrate to dichloromethane, and wash the organic phase three times with pure water , separate the organic phase, evaporate the solvent under vacuum to obtain the crude product, then separate and purify by silica gel column chromatography to obtain 5-(2-bromo-5-isopropoxybenzyl alcohol)-2'-aminobiphenyl- 2-Methyl carboxylate.

Further preferably, the specific process of step G is: in a reaction vessel, 5-(2-bromo-5-isopropoxybenzyl alcohol)-2'-aminobiphenyl-2-formic acid methyl ester and potassium carbonate are added to di In methylacetamide, add benzene ring hydrogen activation catalyst palladium/hydroxyapatite under the protection of _N2 , continuously feed _N2 into the reaction system, and discharge _N2 at the same time to maintain a stable circulation environment, and stir at room temperature for 30 minutes Finally, seal the reaction vessel, then place the reaction vessel in a microwave reactor, heat it to 100°C and react until the raw materials are completely reacted as monitored by TLC, then take out the reaction vessel from the microwave reactor and add pure water to quench the reaction, then extract with ethyl acetate The reaction solution was three times, and the organic phase was combined, dried with anhydrous sodium sulfate, evaporated to remove the solvent, and finally separated and purified by silica gel column chromatography to obtain 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyridine Methyl pyran-2-carboxylate.

Further preferably, the specific process of step H is: adding 3-(2-aminophenyl)-8-isopropoxyl-6H-dibenzopyran-2-carboxylic acid methyl ester to ethanol in a reaction vessel, and then Add an aqueous solution dissolved in sodium hydroxide, raise the temperature to 70°C and react until the reaction of the raw materials is monitored by TLC, evaporate the solvent under vacuum, add the residue to water, wash the water phase with ethyl acetate three times, and wash the water phase with dilute hydrochloric acid Dissolve and adjust the pH to 3, then extract the aqueous phase three times with dichloromethane, combine the organic phases, and finally evaporate the solvent to obtain 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran- 2-Formic acid.

Further preferably, the specific process of step I is: 3-(2-aminophenyl)-8-isopropoxyl-6H-dibenzopyran-2-carboxylic acid is added to anhydrous THF in a reaction vessel, and the reaction Lower the temperature to -60°C, add lithium aluminum hydride tetrahydrofuran solution dropwise, keep the temperature and continue the reaction for 2h, then raise the temperature to 0°C for 2h, add ice water to quench the reaction, filter the reaction solution with suction, and extract the filtrate with ethyl acetate. The second time, the organic phases were combined, and the solvent was distilled off to obtain 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methanol.

Further preferably, the specific process of step J is: in a reaction vessel, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methanol, p-methylsulfonyl chloride and carbonic acid Potassium was added to DMF, and the temperature was raised to 80°C to react until the reaction of raw materials monitored by TLC was complete. Then, pure water was added to quench the reaction, and then extracted three times with ethyl acetate, and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. After separation and purification by silica gel column chromatography, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methyl p-methylsulfonate was obtained.

Further preferably, the specific process of step K is: add 3-(2-aminobenzene)-8-isopropoxyl-6H-dibenzopyran-2-methyl p-methylsulfonate in the reaction vessel Add aniline to acetonitrile, stir mechanically and heat up to 70°C until TLC monitors that the reaction of raw materials is complete, distill off the solvent acetonitrile under reduced pressure, then add n-hexane, cool to -5°C, solids precipitate during stirring, filter the reaction The liquid was obtained as a solid, which was washed with cold toluene, and the filter cake was dried to obtain 8-isopropoxy-6H-dibenzopyranophenylpiperidoacene.

Further preferably, the specific process of step L is: add 8-isopropoxy-6H-dibenzopyranophenylpiperidocene into dichloromethane in a reaction vessel, then add lithium bromide, and The reaction was stirred at °C until the reaction of the raw materials was monitored by TLC, and the reaction solvent was distilled off to obtain 8-hydroxy-6H-dibenzopyrano-hexahydropyridocene.

Further preferably, the specific process of step M is: add 8-hydroxy-6H-dichromenhexahydropyridocene and triethylamine into anhydrous dichloromethane in a reaction vessel, and drop Add trifluoromethanesulfonic anhydride, after the dropwise addition, raise the temperature to room temperature until the reaction of the raw materials monitored by TLC is complete, evaporate the reaction solvent, add n-hexane to the residue, stir and crystallize at 0°C, a yellow solid appears, filter and dry 8-Trifluoromethanesulfonate-6H-dibenzopyranohexahydropyridocene is obtained.

Further preferably, the specific process of step N is: adding 8-trifluoromethanesulfonate group-6H-dibenzopyrano-hexahydropyridocene, aniline and triethylamine to anhydrous treatment in an autoclave In the final DMF, add the catalyst 1,3-bis(diphenylphosphine)propane, add Raney nickel after stirring at room temperature under the protection of nitrogen, then vacuumize the reaction system, discharge nitrogen, and introduce carbon monoxide to make the reaction The pressure reached 0.2MPa, and the temperature was raised to 60°C to react until the raw materials were completely reacted under TLC monitoring, then cooled to room temperature, and unreacted carbon monoxide was removed, the reaction liquid was filtered, the solvent DMF was evaporated under reduced pressure, toluene was added to the residue, and stirred at 0°C A light yellow solid was precipitated, and the solid was filtered with suction and dried to obtain N-8-anilino-6H-dibenzopyrano-hexahydropyrido-acene.

A synthetic route of a compound having a 6H-dibenzopyran structure described in the present invention is:

.

The synthesis process of the invention is simple and the cost is low, and the activity test shows that the prepared FSH antagonist drug molecule has a good effect on the FSH receptor, and it is expected to be further popularized and applied.

detailed description

The above-mentioned contents of the present invention are described in further detail below through the embodiments, but this should not be interpreted as the scope of the above-mentioned themes of the present invention being limited to the following embodiments, and all technologies realized based on the above-mentioned contents of the present invention all belong to the scope of the present invention.

Example 1

In the reaction flask, 5.0 g of methyl 2-bromo-4-nitrobenzoate, 4.0 g of 2-aminophenylboronic acid and 5 g of potassium carbonate were added into 120 mL of a mixed solution of DME and water at a volume ratio of 10:1, Stir at room temperature for 30 min under the protection of nitrogen, then add catalyst tetrakis (triphenylphosphine) palladium 1g, stir evenly under the protection of nitrogen, slowly heat up to 100 ° C, after 14 hours of reaction, TLC monitors the complete reaction of the raw materials, and evaporates the solvent under vacuum conditions. The residue was added to dichloromethane, washed twice with 50 mL of pure water, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated, and then separated and purified by silica gel column chromatography to obtain 2'-amino-5-nitrobi Benzene-2-carboxylic acid methyl ester 4.9g; ¹ H NMR (400 MHz, DMSO-d6) δ: 8.34 (s, 1 H), 8.17(d, J=2.4Hz, 1 H),7.97 (d, J= 8.6Hz, 1H), 7.62-7.57 (m, 2H), 7.33-7.30(m, 2H), 6.25(s, 2H), 3.79 (s, 3H).

Example 2

In the reaction flask, add 5g of reduced iron powder into 70mL of glacial acetic acid, raise the temperature to 85°C and stir for 45min, then slowly add the solution of 2'-amino-5-nitrobiphenyl-2-formic acid under the protection of nitrogen. 70mL of glacial acetic acid solution of 6g of ester, after the dropwise addition, continue to react at 85°C for 2h, monitor the raw material reaction by TLC, filter the reaction solution through diatomaceous earth, wash the diatomite with a certain amount of hot glacial acetic acid, The filtrate was evaporated to remove the reaction solvent under vacuum conditions, a certain amount of saturated sodium bicarbonate was added, and the reaction solution was extracted three times with ethyl acetate, the organic phases were combined, the organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated, and concentrated to obtain 2' -Amino-5-aminobiphenyl-2-methyl carboxylate 5.1g; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.97 (s,1 H), 7.71-7.69 (m, 1 H), 7.35 (s , 2 H), 7.23-7.21 (m, 1 H), 6.67-6.61(m,4H), 6.44-6.39 (m, 3 H), 6.21 (s, 1 H), 6.07(s, 1H), 5.93 -5.90 (m, 2H), 3.27(s, 3H).

Example 3

In the reaction flask, at a temperature of 0°C, add 5.0 g of 2'-amino-5-aminobiphenyl-2-carboxylic acid methyl ester into 100 mL of dilute sulfuric acid with a mass concentration of 5%, and stir for 10 min. Slowly add 20 mL of an aqueous solution dissolved with 2.0 g of sodium nitrite dropwise. After the dropwise addition, keep the temperature and continue the reaction for 1 hour, then slowly raise the temperature to 60°C and react for 8 hours. After TLC monitors the complete reaction of the raw materials, cool to room temperature and extract the reaction with ethyl acetate. liquid three times, combined the organic phase, the organic phase was dried over anhydrous sodium sulfate, evaporated to remove the solvent, separated and purified by silica gel column chromatography to obtain 3.9 g of 2'-amino-5-hydroxybiphenyl-2-carboxylic acid methyl ester; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.94 (d, J=12.0Hz, 1 H), 7.54-7.49 (m, 2H), 7.16 (d, J=12.0Hz, 1H), 6.92-6.91 (m, 3 H), 6.27(s, 2H), 5.35(s, 1H), 3.25(s, 3H).

Example 4

In a reaction flask, add 10 g of 3-hydroxytoluene and 10 g of 2-bromopropane to 100 mL of anhydrous DMF, then add 15 g of potassium carbonate, and slowly raise the temperature to reflux for 24 hours. TLC monitors that the reaction of the raw materials is complete. The solvent was evaporated, the residue was added to water, and the aqueous phase was extracted three times with dichloromethane, the organic phases were combined, and the solvent was finally evaporated to obtain 13 g of the product 3-isopropoxytoluene; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.33 (s, 1H), 7.17-7.12(m, 3H), 4.73-4.71 (m, 1H), 2.61 (s, 3H), 1.34 (d, J=8.0Hz, 6H).

Example 5

In the reaction flask, add 15g of 3-isopropoxytoluene to 100mL of glacial acetic acid, then add 3g of iron powder as a positioning catalyst, slowly add 8mL of bromine dropwise at room temperature, the dropwise addition is completed in about 30 minutes, and the temperature is raised to 40°C After reacting for 10 hours, irradiate the reaction with 300W tungsten lamp for 5 hours, evaporate the solvent glacial acetic acid under vacuum, add a certain amount of sodium hydroxide solution with a mass concentration of 20% in the concentrate, filter the reaction solution, and extract the filtrate three times with dichloromethane , the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain 23 g of 3-isopropoxy-6-bromobenzyl bromide; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.50-7.49 (m, 1H ), 7.06-7.04 (m, 2H), 4.69 (s, 2H), 4.29-4.27(m, 1H), 1.37 (d, J=8.0Hz, 6H).

Example 6

Add 5g of palladium dichloride to the reaction flask, then add 250mL of methanol-water mixed solution with a mass ratio of 1:1, then add 1g of sodium carboxymethylcellulose, adjust the pH of the system to 4.5 with sodium carbonate, add hydroxyphosphorus Limestone 50g, stirred at room temperature for 2h, put into autoclave, stirred at 100KPa, 100°C for hydrogenation reduction reaction for 2h, filtered under reduced pressure, washed with deionized water until neutral and detected by silver nitrate solution to be free of chloride ions , and dried under normal pressure at 60° C. for 3 hours to obtain 40 g of palladium/hydroxyapatite.

Example 7

In a reaction flask, add 5 g of 2'-amino-5-hydroxybiphenyl-2-methyl carboxylate and 8 g of 3-isopropoxy-6-bromobenzyl bromide into 250 mL of dry acetone, and then add hydroxyl hydrogen to activate Catalyst palladium/hydroxyapatite 0.5g, heated to reflux reaction for 4h, TLC monitors raw material reaction is complete, evaporates the reaction solvent under vacuum condition, joins in dichloromethane concentrate, washes organic phase three times with pure water again, separates The organic phase was taken out, and the crude product was obtained after distilling off the solvent under vacuum conditions, and then separated and purified by silica gel column chromatography to obtain 5-(2-bromo-5-isopropoxybenzyl alcohol)-2'-aminobiphenyl-2 -Methyl formate 7.1g; ¹ H NMR (400MHz, CDCl ₃ ) δ: 7.94 (d, J=8.0 Hz, 1H), 7.47-7.41(m, 1H), 7.40 (s, 1H), 7.34-7.18 ( m, 5H), 7.03 (s, 1H), 5.18 (s, 2H), 4.61-4.53(m, 1H), 3.81 (s, 3H), 3.62 (s, 3H), 1.28 (d, J=8.0 Hz, 6H).

Example 8

In a reaction flask, add 10 g of 5-(2-bromo-5-isopropoxybenzyl alcohol)-2'-aminobiphenyl-2-formic acid methyl ester and 5 g of potassium carbonate into 100 mL of dimethylacetamide. Add 1 g of benzene ring hydrogen activation catalyst palladium/hydroxyapatite under the protection of N ₂ , continuously feed N ₂ into the reaction system, and discharge N ₂ at the same time to maintain a stable circulation environment, and seal the reaction bottle after stirring at room temperature for 30 minutes. Place it in a microwave reactor, heat it to 100°C and react for 24 hours. TLC monitors the complete reaction of the raw materials. Take out the reaction bottle from the microwave reactor, add a certain amount of pure water to quench the reaction, and then extract the reaction solution with ethyl acetate. Three times, the organic phases were combined, dried with anhydrous sodium sulfate, evaporated to remove the solvent, and finally separated and purified by silica gel column chromatography to obtain 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran -Methyl 2-carboxylate 7.5g; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.12 (d, J=8.0Hz, 1H), 7.71-7.65(m, 4H), 7.43-7.41 (m, 2H) , 7.16-7.12 (m, 2H), 6.27(s, 2H),5.16 (s, 2H), 4.72(d, J=8.0Hz, 1H), 3.47 (s, 3H), 1.25-1.23 (m, 6 h).

Example 9

In the reaction flask, add 5 g of 3-(2-aminophenyl)-8-isopropoxy-6H-dibenzopyran-2-carboxylic acid methyl ester into 20 mL of ethanol, and then add 2.5 mL of dissolved sodium hydroxide 10 mL of aqueous solution of g, heated to 70°C and reacted for 1 h, TLC monitored the complete reaction of the raw materials, evaporated the solvent under vacuum, added the residue into water, washed the water phase with ethyl acetate three times, and dissolved the water phase with dilute hydrochloric acid to adjust The pH is 3, and the aqueous phase is extracted three times with dichloromethane, the organic phases are combined, and the solvent is finally evaporated to obtain the product 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2 -Formic acid 4.1g; ¹ H NMR (400 MHz, CDCl ₃ ) δ:7.96-7.95 (m, 1H), 7.69-7.65(m, 4H), 7.39-7.37 (m, 2H), 7.12-7.10 (m, 2H), 6.26(s, 2H), 5.16 (s, 2H), 4.72(d, J=8.0Hz, 1H), 1.21-1.19 (m, 6H).

Example 10

In the reaction flask, add 10 g of 3-(2-aminophenyl)-8-isopropoxy-6H-dibenzopyran-2-carboxylic acid into 200 mL of anhydrous THF, lower the reaction temperature to -60°C, and slowly drop Add 30 mL of tetrahydrofuran solution of lithium aluminum hydride, keep the temperature and continue to react for 2 hours, then slowly raise the temperature to 0°C, react for 2 hours, add a certain amount of ice water to quench the reaction, filter the reaction solution with suction, and extract the filtrate with ethyl acetate several times, The organic phases were combined, and the solvent was evaporated to obtain 7.7 g of 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methanol; ¹ H NMR (400 MHz, CDCl ₃ ) δ : 7.87-7.69 (m, 4H), 7.61-7.55(m, 2H), 7.12-7.10 (m, 3H), 6.27(s, 2H), 4.70 (s, 2H), 4.39(s, 2H), 3.65 (s, 1H), 1.23 (s, 6H).

Example 11

In a reaction flask, 10 g of 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methanol, 5 g of p-methylsulfonyl chloride and 20 g of potassium carbonate were added to DMF, Slowly raise the temperature to 80°C. After reacting for 8 hours, TLC monitors the complete reaction of the raw materials. Add a certain amount of pure water to quench the reaction, then extract three times with 50 mL of ethyl acetate, combine the organic phase, dry the organic phase with 30 g of anhydrous sodium sulfate, and evaporate The solvent was used to obtain 8.4 g of 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methyl p-methylsulfonate; ¹ H NMR (400 MHz, CDCl ₃ ) δ : 7.87-7.69 (m, 4H), 7.61-7.55(m, 2H), 7.12-7.10(m, 3H), 6.27(s, 2H), 4.70 (s, 2H), 4.39(s, 2H), 3.16 (s, 3H), 1.23 (s, 6H).

Example 12

In the reaction flask, add 10 g of 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methyl p-methylsulfonate into 150 mL of acetonitrile, then add 10 g of aniline , stirred mechanically and heated to 70°C, and monitored by TLC after 10 hours of reaction [developing agent: PE:EA=7:1] The raw materials were completely reacted, the solvent acetonitrile was distilled off under reduced pressure, and then a certain amount of n-hexane 700mL was added, cooled to - 5°C, a large amount of solids gradually precipitated during the stirring process, the reaction solution was filtered to obtain solids, and washed with a certain amount of cold toluene 200mL, and the filter cake was dried to obtain 8-isopropoxy-6H-dibenzopyranophenyl Piperidoacene 9.3g; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.75(d, J=8.0Hz, 1H), 7.62(s, 1H), 7.57(s, 1H), 7.21-7.19( m, 2H), 7.03-7.02 (m, 1H), 5.27 (s, 1H), 5.15-5.13(m, 2H), 4.69(s, 1H), 4.27(s, 2H), 1.21 (d, J= 8.0Hz, 6H).

Example 13

In a reaction flask, add 15 g of 8-isopropoxy-6H-dibenzopyranophenylpiperidocene into 300 mL of dichloromethane, then add 10 g of lithium bromide, and stir at 0°C for 2 h. After TLC monitors the complete reaction of the raw materials, the reaction solvent is evaporated to obtain 8-hydroxy-6H-dibenzopyrano-hexahydropyridocene; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.75(d, J=8.0Hz , 1H), 7.62(s, 1H), 7.57(s, 1H), 7.21-7.19(m, 2H), 7.03-7.02 (m, 1H), 5.36(s, 1H), 5.27 (s, 1H), 5.15-5.13(m, 2H), 4.69(s, 1H), 4.27(s, 2H).

Example 14

In a reaction flask, add 10 g of 8-hydroxy-6H-dibenzohexahydropyridocene and 15 g of triethylamine into 300 mL of anhydrous dichloromethane, set the temperature of the reaction system to 0°C, and slowly Add 30 g of trifluoromethanesulfonic anhydride dropwise, and after the dropwise addition, rise to room temperature and react for 2 hours. TLC monitors the complete reaction of the raw materials, evaporates the reaction solvent, adds n-hexane to the residue, stirs and crystallizes at 0°C, and a large amount of yellow solid appears. After suction filtration and drying, 8-TfO-6H-dibenzopyrano-hexahydropyridobenzene was obtained; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 7.75-7.72(m, 2H), 7.57(s, 1H), 7.21-7.19(m, 2H), 7.03-7.02 (m, 1H), 5.27 (s, 1H), 5.15-5.13(m, 2H), 4.69(s, 1H), 4.27(s, 2H) .

Example 15

In a high-pressure reactor, add 10 g of 8-TfO-6H-dibenzopyrano-hexahydropyridocene, 5 g of aniline and 5 g of triethylamine into DMF after anhydrous treatment, and then add the catalyst 1,3- Add 1 g of bis(diphenylphosphine) propane, under the protection of nitrogen, stir at room temperature for 2 hours, then add 1 g of Raney nickel, vacuumize the reaction system, discharge nitrogen, feed carbon monoxide, make the reaction pressure reach 0.2 MPa, and slowly raise the temperature to 60°C , TLC monitors the complete reaction of the raw material, slowly lowers to room temperature, removes unreacted carbon monoxide, filters the reaction solution, evaporates the solvent DMF under reduced pressure, adds toluene to the residue, stirs at 0°C, a large amount of light yellow solid precipitates, and suction filters Solid, N-8-anilino-6H-dibenzopyrano-hexahydropyridocene was obtained after drying; ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.17(s, 1H), 8.06-7.97( m, 4H), 7.59-7.54(m, 4H), 7.21-7.19(m, 2H),7.03-7.00 (m, 3H), 5.33 (s, 1H), 5.15-5.13(m, 2H), 4.26( s, 2H).

Example 15

Antitumor activity test

Collect growth phase prostate cancer cells DU145, and use the MTS method to measure the anticancer activity of the compound, and add the cells at an appropriate concentration (4×10 ⁴ cells per milliliter) to a 96-well cell culture plate (containing 10% fetal calf serum After 24 hours of culture, they were treated with different concentrations of compounds for 72 hours at 37°C under the condition of 5% CO ₂ , and then MTS (final mass concentration 2mg/mL) Add the mixture of DMS and DMS (final molar concentration 30μM) directly into the medium containing the cells, and continue to incubate in the incubator for 4h. After acting for 4 hours, discard the supernatant, add 150 μ L DMSO to each well, shake, and the cell survival rate is measured by the absorption rate of the metabolites that act on MTS at the wavelength of 490 nm of the enzyme-linked immunosorbent monitor, FSHR antagonist drug molecule The inhibitory rate IC50 of this cell is 3.7μmol·L ^-1 , and the preliminary biological activity test shows that this compound has a certain inhibitory effect on prostate cancer cell DU145.

In summary, the present invention provides a FSHR antagonist with a 6H-dibenzopyran structure and a preparation method thereof. This is the first discovery of this type of compound for this purpose, and has certain potential for research and development.

The above embodiments have described the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What are described in the above embodiments and description are only to illustrate the principles of the present invention. Without departing from the scope of the principle of the present invention, there will be various changes and improvements in the present invention, and these changes and improvements all fall within the protection scope of the present invention.

Claims (10)

1. A compound with a 6H-dibenzopyran structure, characterized in that the structural formula is: . 2. a preparation method with 6H-dibenzopyran structure compound as claimed in claim 1, characterized in that the specific steps are: A, 2-bromo-4-nitrobenzoic acid methyl ester and 2-aminophenylboronic acid have a substitution reaction under the effect of catalyst tetrakis (triphenylphosphine) palladium to obtain 2'-amino-5-nitrobiphenyl-2 - methyl formate; B, 2'-amino-5-nitrobiphenyl-2-methyl carboxylate undergoes a nitro reduction reaction under the action of catalyst reducing iron powder to obtain 2'-amino-5-aminobiphenyl-2-methyl carboxylate; C, 2'-amino-5-aminobiphenyl-2-formic acid methyl ester obtains 2'-amino-5-hydroxybiphenyl-2-formic acid methyl ester through amino reduction oxidation reaction under the effect of catalyst sodium nitrite; D, 3-hydroxytoluene and 2-bromopropane undergo a substitution reaction to obtain 3-isopropoxytoluene; E, 3-isopropoxytoluene is replaced with bromine under the effect of positioning catalyst iron powder to obtain 3-isopropoxy-6-bromobenzyl bromide; F, 2'-amino-5-hydroxybiphenyl-2-formic acid methyl ester and 3-isopropoxy-6-bromobenzyl bromide undergo a substitution reaction under the effect of hydroxyl hydrogen activation catalyst palladium/hydroxyapatite to obtain 5 -(2-bromo-5-isopropoxybenzyl alcohol)-2'-aminobiphenyl-2-carboxylic acid methyl ester; G, 5-(2-bromo-5-isopropoxybenzyl alcohol)-2'-aminobiphenyl-2-carboxylic acid methyl ester undergoes intramolecular synthesis under the action of benzene ring hydrogen activation catalyst palladium/hydroxyapatite Ring reaction to obtain 3-(2-aminophenyl)-8-isopropoxy-6H-dibenzopyran-2-carboxylic acid methyl ester; H, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-carboxylic acid methyl ester is hydrolyzed in alkaline solution and then acidified to obtain 3-(2-aminobenzene )-8-isopropoxy-6H-dibenzopyran-2-carboxylic acid; 1, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-formic acid obtains 3-(2-aminobenzene) through carboxyl redox reaction under the effect of lithium aluminum hydride -8-isopropoxy-6H-dibenzopyran-2-methanol; J, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methanol and p-methylsulfonyl chloride carry out hydroxyl activation protection reaction to obtain 3-(2-aminobenzene)- 8-isopropoxy-6H-dibenzopyran-2-methyl-p-methylsulfonate; K, 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-methyl p-methylsulfonate undergoes a substitution reaction for intramolecular ring formation to obtain 8-isopropoxy Base-6H-dibenzopyranophenylpiperidobenzene; L, 8-isopropoxy-6H-benzopyranophenylpiperidobenzene removes the isopropyl group under the action of lithium bromide to obtain 8-hydroxyl-6H-dibenzopyranophenylpiperido pyrocene; M, 8-hydroxyl-6H-dibenzopyranophenylpiperidinocene reacts with trifluoromethanesulfonic anhydride to obtain 8-trifluoromethanesulfonate group-6H-dibenzopyranophenyl Piperidoacene; N, 8-trifluoromethanesulfonate-6H-dibenzopyranophenylpiperidocene reacted with aniline under the catalyst of 1,3-bis(diphenylphosphino)propane and Raney nickel The reaction yields N-8-anilino-6H-dibenzopyrano-hexahydropyridocene. 3. have the preparation method of 6H-dibenzopyran structure compound according to claim 2, it is characterized in that the concrete synthesis process of 2'-amino-5-hydroxybiphenyl-2-formic acid methyl ester is: (1 ) Add methyl 2-bromo-4-nitrobenzoate, 2-aminophenylboron and potassium carbonate into a mixed solution of DME and water at a volume ratio of 10:1 in a reaction vessel, stir at room temperature for 30 minutes under nitrogen protection, Then add the catalyst tetrakis (triphenylphosphine) palladium, stir evenly under the protection of nitrogen, heat up to 100 ° C until the reaction of the raw materials monitored by TLC is complete, evaporate the solvent under vacuum conditions, add the residue in dichloromethane, and then use pure Wash twice with water, dry the organic phase over anhydrous sodium sulfate, evaporate the solvent, and then separate and purify by silica gel column chromatography to obtain methyl 2'-amino-5-nitrobiphenyl-2-carboxylate; (2) in the reaction Add the reduced iron powder into the glacial acetic acid in the container, heat up to 85°C, stir and react for 45 minutes, and add the glacial acetic acid solution dissolved in 2'-amino-5-nitrobiphenyl-2-carboxylic acid methyl ester under the protection of nitrogen. After the dropwise addition, continue the reaction at 85°C until the reaction of the raw materials monitored by TLC is complete, then filter the reaction solution through diatomaceous earth, wash the diatomaceous earth with hot glacial acetic acid, distill the filtrate to remove the reaction solvent under vacuum conditions, and add saturated bicarbonate sodium, then extracted the reaction solution three times with ethyl acetate, combined the organic phases, dried the organic phases over anhydrous sodium sulfate, evaporated the solvent, concentrated to obtain 2'-amino-5-aminobiphenyl-2-formic acid methyl ester; Add methyl 2'-amino-5-aminobiphenyl-2-carboxylate into dilute sulfuric acid with a mass concentration of 5% in the reaction vessel at 0°C, stir and add the aqueous solution containing the catalyst sodium nitrite dropwise, add dropwise After completion, keep the temperature and continue the reaction for 1 h, then raise the temperature to 60°C until the reaction of the raw materials is monitored by TLC, then cool to room temperature, extract the reaction solution with ethyl acetate three times, combine the organic phases, dry the organic phases over anhydrous sodium sulfate, and evaporate The solvent was separated and purified by silica gel column chromatography to obtain 2'-amino-5-hydroxybiphenyl-2-carboxylic acid methyl ester. 4. The preparation method of the compound with 6H-dibenzopyran structure according to claim 2, characterized in that the specific synthesis process of 3-isopropoxy-6 bromobenzyl bromide is: (1) in the reaction vessel Add 3-hydroxytoluene and 2-bromopropane to anhydrous DMF, then add potassium carbonate, heat up to reflux reaction until TLC monitors that the reaction of raw materials is complete, evaporate the solvent under vacuum conditions, add the residue to water, and then Extract the aqueous phase with dichloromethane three times, combine the organic phases and evaporate the solvent to obtain 3-isopropoxytoluene; (2) add 3-isopropoxytoluene to glacial acetic acid in the reaction vessel, and then add the positioning catalyst Iron powder, add bromine dropwise at room temperature, finish adding dropwise in 30 minutes, heat up to 40°C to react, then irradiate the reaction with a 300W tungsten lamp, evaporate the solvent glacial acetic acid under vacuum, add hydrogen with a mass concentration of 20% to the concentrate Sodium oxide solution, the reaction solution was filtered, the filtrate was extracted three times with dichloromethane, the organic phase was combined, and the organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain 3-isopropoxy-6 bromobenzyl bromide. 5. The preparation method with 6H-dibenzopyran structure compound according to claim 2, characterized in that the specific process of step F is: in the reaction vessel, 2'-amino-5-hydroxybiphenyl-2 -Methyl formate and 3-isopropoxy-6-bromobenzyl bromide are added to dry acetone, then the hydroxyl hydrogen activation catalyst palladium/hydroxyapatite is added, heated to reflux until TLC monitors that the reaction of raw materials is complete, The reaction solvent was evaporated under the conditions, the concentrate was added in dichloromethane, the organic phase was washed three times with pure water, and the organic phase was separated. After the solvent was evaporated under vacuum conditions, the crude product was obtained, and then separated and purified by silica gel column chromatography to obtain 5 -(2-bromo-5-isopropoxybenzyl alcohol)-2'-aminobiphenyl-2-methyl carboxylate; the specific process of step G is: 5-(2-bromo-5- Isopropoxybenzyl alcohol)-2'-aminobiphenyl-2-methyl carboxylate and potassium carbonate are added to dimethylacetamide, and the benzene ring hydrogen activation catalyst palladium/hydroxyapatite is added under the protection of _N2 , Continuously feed N ₂ into the reaction system, and exhaust N ₂ at the same time to maintain a stable circulation environment. After stirring at room temperature for 30 minutes, seal the reaction vessel, then place the reaction vessel in a microwave reactor, and heat it to 100°C to react until TLC monitoring The raw materials were completely reacted, then the reaction vessel was taken out from the microwave reactor and added with purified water to quench the reaction, and the reaction solution was extracted three times with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated, and finally passed through a silica gel column layer Analysis, separation and purification gave 3-(2-aminophenyl)-8-isopropoxy-6H-dibenzopyran-2-carboxylic acid methyl ester. 6. the preparation method with 6H-dibenzopyran structure compound according to claim 2, is characterized in that the specific process of step H is: 3-(2-aminobenzene)-8-iso Propoxy-6H-dibenzopyran-2-carboxylic acid methyl ester was added to ethanol, then an aqueous solution dissolved in sodium hydroxide was added, and the temperature was raised to 70°C to react until the reaction of the raw materials monitored by TLC was complete, and evaporated under vacuum conditions Solvent, the residue was added to water, and the aqueous phase was washed three times with ethyl acetate, the aqueous phase was dissolved with dilute hydrochloric acid to adjust the pH to 3, and the aqueous phase was extracted three times with dichloromethane, the organic phase was combined, and finally the solvent was evaporated to obtain 3 -(2-aminobenzene)-8-isopropoxy-6H-dibenzopyran-2-formic acid; the specific process of step I is: 3-(2-aminobenzene)-8- Isopropoxy-6H-dibenzopyran-2-carboxylic acid was added to anhydrous THF, the reaction temperature was lowered to -60°C, a tetrahydrofuran solution of lithium aluminum hydride was added dropwise, and the temperature was kept to continue the reaction for 2 hours, and then the temperature was raised to React at 0°C for 2 hours, add ice water to quench the reaction, filter the reaction solution with suction, extract the filtrate several times with ethyl acetate, combine the organic phases, and evaporate the solvent to obtain 3-(2-aminobenzene)-8-isopropoxy -6H-Dibenzopyran-2-methanol. 7. the preparation method with 6H-dibenzopyran structure compound according to claim 2, is characterized in that the specific process of step J is: 3-(2-aminobenzene)-8-iso Propoxy-6H-dibenzopyran-2-methanol, p-methylsulfonyl chloride and potassium carbonate were added to DMF, and the temperature was raised to 80°C to react until the reaction of the raw materials was monitored by TLC. Then, pure water was added to quench the reaction, and then Extracted three times with ethyl acetate, combined the organic phases, dried the organic phases over anhydrous sodium sulfate, evaporated the solvent, and separated and purified by silica gel column chromatography to obtain 3-(2-aminobenzene)-8-isopropoxy-6H- Dibenzopyran-2-methyl p-methylsulfonate; the specific process of step K is: 3-(2-aminobenzene)-8-isopropoxy-6H-dibenzo Add pyran-2-methyl p-methylsulfonate to acetonitrile, then add aniline, stir mechanically and raise the temperature to 70°C to react until TLC monitors that the reaction of raw materials is complete, evaporate the solvent acetonitrile under reduced pressure, then add n-hexane, cool To -5 ° C, solids precipitated during the stirring process, filtered the reaction solution to obtain solids, and washed with cold toluene, dried the filter cake to obtain 8-isopropoxy-6H-dibenzopyranophenylpiperido benzene. 8. The preparation method with 6H-dibenzopyran structure compound according to claim 2, characterized in that the specific process of step L is: in the reaction vessel, 8-isopropoxy-6H-dibenzopyran Pyranophenylpiperidocene was added to dichloromethane, then lithium bromide was added, and the reaction was stirred at 0°C until the reaction of raw materials monitored by TLC was complete, and the reaction solvent was evaporated to obtain 8-hydroxy-6H-dibenzopyrano Hexahydropyridocene; the specific process of step M is: 8-hydroxyl-6H-dibenzopyrano-hexahydropyridocene and triethylamine are added in anhydrous dichloromethane in a reaction vessel, and Add trifluoromethanesulfonic anhydride dropwise at 0°C. After the dropwise addition, warm up to room temperature until the reaction of the raw materials is monitored by TLC. Remove the reaction solvent, add n-hexane to the residue, stir and crystallize at 0°C, a yellow solid appears, and filter with suction After drying, 8-trifluoromethanesulfonate-6H-dibenzopyrano-hexahydropyrido-acene was obtained. 9. The preparation method with 6H-dibenzopyran structure compound according to claim 2, characterized in that the specific process of step N is: in an autoclave, 8-trifluoromethanesulfonate group-6H -Dibenzopyrano-hexahydropyridocene, aniline and triethylamine were added to DMF after anhydrous treatment, and then the catalyst 1,3-bis(diphenylphosphine)propane was added, under nitrogen protection at room temperature After stirring, add Raney nickel, then evacuate the reaction system, discharge nitrogen, and introduce carbon monoxide to make the reaction pressure reach 0.2MPa, raise the temperature to 60°C and react until the raw materials are completely reacted by TLC, then cool down to room temperature, and remove unreacted carbon monoxide , filter the reaction solution, distill off the solvent DMF under reduced pressure, add toluene to the residue, stir at 0°C, a light yellow solid precipitates, filter the solid with suction, and dry to obtain N-8-anilino-6H-dibenzopyridine Hexahydropyridocene. 10. The preparation method with 6H-dibenzopyran structure compound according to claim 2, characterized in that the specific synthetic route in the preparation method is: .