CN114560867B - Oxygen bridge bicycloheptene sulfonate compound containing five-membered nitrogen heterocycle and application thereof in preparation of breast cancer resisting drugs - Google Patents
Oxygen bridge bicycloheptene sulfonate compound containing five-membered nitrogen heterocycle and application thereof in preparation of breast cancer resisting drugs Download PDFInfo
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Abstract
The invention discloses an oxygen bridge bicycloheptene sulfonate compound containing five-membered nitrogen heterocycle and application thereof in preparing breast cancer resistant medicaments, and belongs to the technical field of medicines. According to the invention, furan derivatives and ethylene sulfonate derivatives containing five-membered nitrogen heterocycle are used as raw materials, a catalyst is not needed, and the five-membered nitrogen heterocycle-containing oxo-bridged bicycloheptenes compound is prepared through one-step Diels-Alder reaction. The compound can well inhibit MCF-7 cells, has good inhibitory activity on drug-resistant breast cancer cells LCC2, can well inhibit aromatase, and has application prospects in breast cancer treatment.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a compound based on an oxygen bridge bicyclo- [2.2.1] -heptene sulfonate structure, and relates to an oxygen bridge bicyclo- [2.2.1] -heptene sulfonate compound containing five-membered nitrogen heterocycle, a preparation method thereof and application thereof in preparing anti-breast cancer medicines.
Background
In recent years, breast cancer has been one of the most common cancers in women. Over-expression of the Estrogen Receptor (ER) leads to the generation of breast cancer, and thus antiestrogenic drugs are continuously being developed and used. Studies have shown that long-term use of antiestrogens such as tamoxifen causes strong side effects and leads to the development of drug-resistant breast cancer. Therefore, there is a need to develop drugs with novel mechanisms of action against this target of estrogen receptors.
Disclosure of Invention
The primary purpose of the invention is to provide an oxygen bridge bicyclo- [2.2.1] -heptene sulfonate (OBHS) compound containing five-membered nitrogen heterocycle, wherein the compound combines the compound with the oxygen bridge bicyclo heptene sulfonate structure with the five-membered nitrogen heterocycle to obtain the compound which has a three-dimensional structure and has the function of inhibiting the activity of aromatizing enzyme, and the compound shows good activity of resisting breast cancer cells in the test of the biological activity.
The invention also aims to provide a preparation method of the oxygen bridge bicyclo- [2.2.1] -heptene sulfonate compound containing a five-membered nitrogen heterocyclic ring structure, wherein the target compound is prepared from two substrates: the furan derivative containing the five-membered nitrogen heterocycle and the ethylene sulfonate derivative are subjected to Diels-Alder reaction to prepare the oxygen bridge bicycloheptene compound containing the five-membered nitrogen heterocycle structure. The Diels-Alder reaction does not need a solvent, does not need catalysis of noble metal, and has mild reaction conditions.
The invention also aims to provide application of the oxygen bridged bicyclo- [2.2.1] -heptene sulfonate compounds containing different five-membered nitrogen heterocycles in preparation of breast cancer resisting medicines.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
in a first aspect, an oxygen bridged bicyclo- [2.2.1] -heptene sulfonate (OBHS) class of compounds is provided that contains a five-membered nitrogen heterocycle. The OBHS compound containing the five-membered nitrogen heterocycle has a structure shown in the following general formula I:
general formula I
In the general formula I, R 1 Selected from the group consisting of
OH, etc., R 2 Selected from-H, 4-CH 3 、4-OCH 3 、2-CF 3 、3-CF 3 、4-CF 3 2-Br, 3-Br, 4-Cl, 4-F, alpha-naphthol, beta-naphthol, < ->
Etc. />
Preferably, the five-membered nitrogen heterocycle-containing OBHS compound is selected from the following compounds:
phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 a),
4-methylphenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 b),
4-methoxyphenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 c),
2- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 d),
2- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 d),
3- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 e),
4- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 f),
2-bromophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 g),
3-bromophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22H 1-2),
4-bromophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 i),
4-fluorophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 j),
naphthalen-1-yl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 k),
naphthalen-2-yl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 l),
3- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 a),
4- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 b),
4-bromophenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 c),
4-methoxyphenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 d),
4-chlorophenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 e),
4-methylphenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 f),
4- (trifluoromethyl) phenyl (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 a),
4-bromophenyl (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 b),
4-methoxyphenyl (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 c),
4- (1H-1, 2, 4-triazol-1-yl) phenyl (1R, 4R) -5, 6-bis (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 d),
4- (1-methyl-1H-pyrazol-3-yl) phenyl (1R, 4R) -5, 6-bis (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 e).
In a second aspect, a preparation method of the oxygen bridge bicyclo- [2.2.1] -heptene sulfonate compound containing a five-membered nitrogen heterocyclic ring structure is provided, and the preparation method comprises the following steps: the furan derivative containing the five-membered nitrogen heterocycle and the ethylene sulfonate derivative are subjected to Diels-Alder reaction to prepare the oxygen bridge bicyclo- [2.2.1] -heptene sulfonate compound containing the five-membered nitrogen heterocycle structure.
The structural formula of the five-membered nitrogen heterocyclic furan derivative is
Wherein R is 1 Selected from the group consisting of
The structural formula of the ethylene sulfonate derivative is
R 2 Selected from-H, 4-CH 3 、4-OCH 3 、2-CF 3 、3-CF 3 、4-CF 3 2-Br, 3-Br, 4-Cl, 4-F, alpha-naphthol, beta-naphthol, < ->
Etc.
The Diels-Alder reaction conditions are preferably 90-100 ℃ for 12 hours.
In a third aspect, pharmaceutically acceptable salts of the aforementioned oxo bridged bicyclo- [2.2.1] -heptenesulfonates containing five membered nitrogen heterocyclic structures are provided.
In a fourth aspect, the application of the oxygen bridge bicyclo- [2.2.1] -heptene sulfonate compound containing five-membered nitrogen heterocyclic structure or pharmaceutically acceptable salt thereof in preparing medicaments is provided. The medicine comprises an estrogen receptor targeting medicine, an anti-breast cancer medicine, an aromatizing enzyme activity inhibiting medicine and a medicine for resisting the endocrine therapy of breast cancer.
An estrogen receptor targeting drug, an anti-breast cancer drug, an aromatizing enzyme activity inhibiting drug or a drug resistant to breast cancer endocrine therapy, comprising the five-membered nitrogen heterocyclic structure-containing oxo bridged bicyclo- [2.2.1] -heptenesulfonate compound or a pharmaceutically acceptable salt thereof, and further comprising one or more pharmaceutically acceptable carriers or excipients.
Preferably, in said application, the oxo-bridged bicyclo- [2.2.1] -heptene sulfonate compound containing a five-membered nitrogen heterocyclic structure is selected from:
phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 a),
4-methylphenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 b),
4-methoxyphenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 c),
4- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 f),
4-bromophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 g),
4-fluorophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 j),
4- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 b),
4-bromophenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 c),
4-methoxyphenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 d),
4-chlorophenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 e),
4-methylphenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 f),
4- (trifluoromethyl) phenyl (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 a),
4-bromophenyl (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 b),
4-methoxyphenyl (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 c).
4- (1H-1, 2, 4-triazol-1-yl) phenyl (1R, 4R) -5, 6-bis (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 d),
4- (1-methyl-1H-pyrazol-3-yl) phenyl (1R, 4R) -5, 6-bis (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 e).
Compared with the prior art, the invention has the advantages and beneficial effects that: the furan derivative containing five-membered nitrogen heterocycle and the ethylene sulfonate derivative are used as raw materials, a solvent and a catalyst are not needed, and the oxygen bridge bicyclo- [2.2.1] -heptene sulfonate compound containing the five-membered nitrogen heterocycle structure is prepared by reacting for 12 hours at 90 ℃ in one step. In vitro experiments show that most novel sulfonate oxygen bridge bicyclo- [2.2.1] -heptene compounds not only can well inhibit the activity of MCF-7 cells, but also have stronger inhibition activity on aromatizing enzyme than positive control medicine letrozole, and more importantly, the inhibition activity of the novel sulfonate oxygen bridge bicyclo- [2.2.1] -heptene compounds for drug-resistant breast cancer is 2-6 times of that of 4-hydroxy tamoxifen.
Detailed Description
The invention is described in further detail below in connection with the examples which are provided merely to illustrate the method of the invention and are not intended to limit the remainder of the disclosure in any way whatsoever.
3, 4-bis (4-hydroxyphenyl) furan 20, furan derivative 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan 8a containing five-membered nitrogen heterocycle, 3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan 8b, 3- (4-hydroxyphenyl) -4- ((1-methyl-1H-pyrazol-4-yl) phenyl) furan 8c, vinylsulfonate derivative were synthesized by the reaction shown below. The specific operation steps can be as follows:
1. synthesis of 3, 4-bis (4-hydroxyphenyl) -furan 20, five-membered nitrogen heterocycle-containing furan derivatives 8a-c
(1) Synthesis of 3, 4-bis (4-hydroxyphenyl) -furan 20
Reagents and conditions (a) NBS, p-TsOH, CHCl 3 ,rt,12h；(b)Et 3 N,CH 3 CN,rt,12h；(c)NaH,DMSO,rt,3h；(d)BBr 3 ,CH 2 Cl 2 ,-20℃,10h；(e)DIBAl-H,THF,-78℃,12h.
The methoxyacetophenone 1 is subjected to substitution, cyclization, demethylation, reduction hydrogenation and coupling reaction to obtain 3, 4-bis (4-hydroxyphenyl) -furan 20.
1) Synthesis of 2- (4-methoxyphenyl) -2-carbonylethyl-2- (4-methoxyphenyl) acetate (Compound 17)
Methoxyacetophenone 1 (1.50 g,1.0 mmol) was weighed, p-methoxybenzenesulfonic acid (1.72g,1.0mmol 172.2) was dissolved in a double-necked flask, N-bromosuccinimide (2.14 g,1.2 mmol) was slowly added to react overnight at room temperature after dissolution in methylene chloride, TLC was monitored to complete the reaction, and EA/H was used after the reaction was completed 2 O extraction to obtain off-white 2-bromo-1- (4-methoxyphenyl) ethane-1-one compound 2 with 89% yield. Compound 2 (1.5896 g,6.94 mmol) and p-methoxyphenylacetic acid 16 (1.1532 g,6.94 mmol) were weighed into a 50mL round bottom flask, 25mL of anhydrous acetonitrile was added, after a slow dropwise addition of anhydrous triethylamine (702.3 mg,6.94 mmol) and continued to react at room temperature for 12 hours, TLC was monitored to completion, after completion of the reaction, acetonitrile and triethylamine were removed by concentration under reduced pressure, ethyl acetate was added to dissolve, and washed successively with dilute hydrochloric acid (2M, 30 mL), saturated sodium bicarbonate (2X 30 mL) and saturated sodium chloride (30 mL), the organic layer was dried over anhydrous sodium sulfate, filtered and spun dry to give a crude product, which was purified by column chromatography (V) Dichloromethane (dichloromethane) :V Methanol After=500:1-400:1), compound 17 was obtained as a yellow solid in 88% yield.
2) Synthesis of 3, 4-bis (4-methoxy-phenyl) furan-2-one (Compound 18)
25mL of two-necked flask,The magnetons are baked at 105 ℃ for 15min, then the mixture is operated while hot, anhydrous and anaerobic, compound 17 (786.2 mg,2.5 mmol) is weighed and added under the condition of introducing Ar, 10mL of anhydrous DMSO is added, 80% NaH (150.1 mg,5.0 mmol) is slowly added dropwise, after the reaction is carried out for 3h at 25 ℃, TLC monitors that the reaction is complete, 5mL of 2N HCl is added for quenching reaction, ethyl acetate (3X 25 mL) is used for extraction, and the organic layer anhydrous NaSO is added 4 Drying, desolventizing under reduced pressure gave a crude product which was purified on a silica gel column (petroleum ether/ethyl acetate=9:1, v/v) to give 475.9mg (yield 64.3%) of compound 18.
3) Synthesis of 3, 4-bis (4-hydroxy-phenyl-furan) -2-one (Compound 19)
Baking 100mL single-necked flask and magneton at 105deg.C for 15min, heating, performing anhydrous and anaerobic operation, weighing compound 7 (1.345 g,4.56 mmol) under Ar, adding 25mL DCM, adding BBr at-20deg.C 3 (2.6 mL,27.33 mmol) for 12h, 10mL of water was added to quench the reaction, extracted with ethyl acetate (3X 20 mL), saturated NaHCO 3 Washing with solution (15 mL), the organic layer was anhydrous NaSO 4 Drying and desolventizing under reduced pressure gave a crude product which was purified on a silica gel column (petroleum ether/ethyl acetate=7:3) to give 1.06g (86.7% yield) of compound 19.
4) Synthesis of 3, 4-bis (4-hydroxy-phenyl) furan (Compound 20)
Baking 50mL single-necked flask and magneton at 105deg.C for 15min, heating, performing anhydrous and anaerobic operation, adding compound 19 (560 mg,1.98 mmol) under Ar, adding diisobutylaluminum hydride (DIBAl-H, 8mL,7.93 mmol) at-78deg.C, reacting for 12 hr, adding 4%H 2 SO 4 The reaction was quenched, extracted with ethyl acetate (3X 25 mL), washed with saturated NaCl solution (30 mL), and the organic layer was anhydrous NaSO 4 Drying, desolventizing under reduced pressure gave a crude product which was purified on a silica gel column (petroleum ether/ethyl acetate=6:4) to give 203.1mg (40.7% yield) of compound 20. 1 H NMR(400MHz,CDCl 3 ):δ7.41(s,2H),6.94(d,J＝8.4Hz,2H),6.87(d,J＝8.8Hz,2H).
(2) Synthesis of furan derivatives 8a-c containing five-membered nitrogen heterocycle
(a)NBS,p-TsOH,AlCl 3 ,CHCl 3 ,rt,12h；(b)2-(4-bromophenyl)acetic acid,Et 3 N,CH 3 CN,rt,12h；(c)NaH,DMSO,rt,3h；(d)BBr 3 ,CH 2 Cl 2 ,-20℃,12h；(e)DIBAL-H,THF,-78℃,8h；(f)For 8a:1H-imidazole,CuI,quinolin-8-ol,Cs 2 CO 3 ,DMF/H 2 O(10:1),110℃,24h；For 8b:1,2,4H-triazole,CuI,Cs 2 CO 3 ,DMF,120℃,24h.For 8c:1-methyl-1H-pyrazol-4-yl)boronic acid,Pd(dppf)Cl 2 ,K 3 PO 4 ,H 2 O,1,4-dioxane,80℃,16h.
The furan derivative 8a-c containing five-membered nitrogen heterocycle is similar to the synthesis of 3, 4-bis (4-hydroxyphenyl) -furan 20, with only the last reaction step being different.
Synthesis of Compound 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan 8a
Taking 25mL double-mouth bottle, baking the magneton at 105deg.C for 15min, heating, adding 7, 1H-imidazole, cuprous iodide, 8-quinolinol and cesium carbonate, performing anhydrous anaerobic operation, and using DMF/H 2 O (10:1) was dissolved, stirred at room temperature for 30min, and then reacted at 110℃for 24h to give 8a as a yellow solid in 65% yield.
Synthesis of Compound 3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan 8b
Taking a 25mL double-mouth bottle, baking the magnetons at 105 ℃ for 15min, adding the compounds 7,1,2,4H-triazole while the magnetons are hot, adding the cuprous iodide and the cesium carbonate, performing anhydrous and anaerobic operation, dissolving the mixture by using DMF, stirring the mixture for 30min at room temperature, and placing the mixture at 120 ℃ for reaction for 24h to obtain a yellow solid compound 8b with a yield of 70%.
Synthesis of Compound 3- (4-hydroxyphenyl) -4- ((1-methyl-1H-pyrazol-4-yl) phenyl) furan 8c
Taking 25mL double-mouth bottle, baking the magneton at 105deg.C for 15min, heating, adding compound 7, (1-methyl-1H-pyrazol-4-yl) boric acid and Pd (dppf) Cl 2 Potassium phosphate, anaerobic operation, adding 1,4Dioxane and water (1:1), dissolved, reacted at 80 ℃ for 16h to give compound 8c as a yellow solid in 73% yield.
2. Synthesis of ethylene sulfonate derivatives
(1) Synthesis of ethylene sulfonate derivatives 15a-m
Reaction reagents and conditions: (g) TEA, DCM, 0deg.C, 12h
Wherein R is-H, 4-CH 3 、4-OCH 3 、2-CF 3 、3-CF 3 、4-CF 3 2-Br, 3-Br, 4-Cl, 4-F, α -workbench, β -workbench, respectively 15a-m.
Synthesis of Compounds 15a-m
Taking a 100mL single-mouth bottle, baking the magnetons at 105 ℃ for 15min, performing anhydrous and anaerobic operation while the magnetons are hot, weighing the corresponding compound 11 under the condition of introducing Ar, dissolving in anhydrous DCM, slowly adding 2-chloroethanesulfonyl chloride (1.2 equiv.) at 0 ℃, reacting for 10min, and slowly dropwise adding anhydrous triethylamine. After reacting at room temperature for 12 hours, the solvent is removed under reduced pressure to obtain a crude product, and the crude product is purified by a silica gel column (petroleum ether/ethyl acetate=12:1-3:2) to obtain vinylsulfonate dienophile compounds 15a-m (yield 61-95%).
(2) Synthesis of ethylene sulfonate derivative 22, 24
After taking a 100mL single-necked flask and baking the magneton at 105℃for 15 minutes, 11i (1.0 equiv.) and 1H-1,2, 4-triazole (1.1 equiv.) or (1-methyl-1H-pyrazol-4-yl) boronic acid (1.1 equiv.), cuI (5% mmol), cs were weighed 2 CO 3 (1.2 equiv.) Anhydrous anaerobic operation, dissolution with DMF, reaction at 120deg.C for 24H, and removal of solvent under reduced pressure to give crude product, purification by silica gel column (petroleum ether/ethyl acetate=4:1-1:1) to give 4- (1H-1, 2, 4-triazol-1-yl) phenol 21 or 4- (1-methyl-1H-pyrazol-4-yl) benzenePhenol 23 (70-90% yield).
A100 mL single-necked flask was taken, compound 21 or 23 (1.0 equiv.) was weighed, anhydrous and anaerobic operation was performed, dissolved in anhydrous DCM, 2-chloroethanesulfonyl chloride (1.2 equiv.) was slowly added at 0deg.C, and after 10min of reaction, anhydrous triethylamine (1.2 equiv.) was slowly added dropwise. After reaction at room temperature for 12 hours, the solvent was removed under reduced pressure to give a crude product, which was purified by silica gel column (dichloromethane/methanol=100:1 to 10:1) to give vinylsulfonate dienophile compound 22 or 24 (yield 61 to 90%).
3. Synthesis of target Compounds 22a-n, 23a-f and 24a-e
Taking a 25mL double-mouth bottle, baking a magneton at 105 ℃ for 15min, carrying out anhydrous and anaerobic operation while the magneton is hot, dissolving the synthesized 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a, 3- (4-hydroxyphenyl) -4- ((1H-1, 2, 4-triazol-1-yl) phenyl) furan compound 8b, 3- (4-hydroxyphenyl) -4- ((1-methyl-1H-pyrazol-4-yl) phenyl) furan compound 8c or 3, 4-di (4-hydroxy-phenyl) furan compound 20 and vinylsulfonate derivative 15a-m, 22 or 24 in tetrahydrofuran under the condition of passing Ar, and reacting at 90 ℃ for 8H to prepare the five-membered nitrogen heterocycle-containing oxygen bridge bicycloheptene compound, wherein the reaction formula is as follows:
preparation of phenyl (1 r,4 r) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 a):
3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a (100 mg,0.33 mmol) and vinylbenzenesulfonate 15a (121.86 mg,0.66 mmol) were weighed into a 25mL two port round bottom bottle, 2mL anhydrous THF was added to assist dissolution, then slowly warmed to 90 ℃, reacted for 8H, TLC detection reaction completed, quenched with water, extracted with ethyl acetate, and the organic layer dried over anhydrous sodium sulfate. Desolventizing under reduced pressure, separating and purifying by column chromatography, wherein the eluent ratio is dichloromethane: methanol=200:1-20:1 (V/V), 108.8mg of yellow solid is obtained, the yield is 68%, and the temperature is m.p.137-138 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.80(s,1H),8.31(s,1H),7.80(s,1H),7.67(dd,J＝14.1,8.6Hz,2H),7.44(dd,J＝16.4,8.2Hz,4H),7.34(dd,J＝15.0,7.3Hz,2H),7.28(d,J＝7.7Hz,1H),7.22(dd,J＝12.9,8.6Hz,2H),7.13(s,1H),6.77(dd,J＝10.7,8.7Hz,2H),5.79(d,J＝14.2Hz,1H),5.54(d,J＝12.2Hz,1H),3.92(ddd,J＝19.5,10.6,5.6Hz,1H),2.27(dd,J＝12.0,4.6Hz,1H),2.19(dd,J＝12.1,8.3Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ158.27,149.33,144.33,140.18,136.63,135.83,131.66,131.00,130.57,129.88,129.20,128.77,122.75,120.79,116.25,84.00,82.69,60.78,30.54.HRMS(ESI)calcd for C 27 H 22 N 2 O 5 S[M+H] + ,487.1322；found 487.1323.
Preparation of 4-methylphenyl (1 r,4 r) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 b):
with reference to the preparation of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15c, 125mg of a yellow solid was obtained in 76% yield, m.p.145-146 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ9.80(s,1H),8.33(s,1H),7.79(d,J＝7.4Hz,1H),7.67(dd,J＝14.8,8.6Hz,2H),7.45(dd,J＝11.2,8.7Hz,2H),7.25–7.17(m,5H),7.14(d,J＝8.9Hz,2H),6.77(dd,J＝11.2,8.6Hz,2H),5.77(d,J＝16.5Hz,1H),5.54(d,J＝8.6Hz,1H),3.99–3.76(m,1H),2.29(d,J＝5.6Hz,4H),2.18(dd,J＝12.0,8.3Hz,1H). 13 C NMR(101MHz,DMSO-d 6 )δ158.30,147.28,140.29,137.23,135.95,130.87,130.52,129.89,129.42,128.81,122.43,120.87,118.29,116.20,110.00,84.11,82.74,60.68,30.59,20.86.HRMS(ESI)calcd for C 28 H 24 N 2 O 5 S[M+H] + ,501.1479；found 501.1475.
Preparation of 4-methoxyphenyl (1 r,4 r) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 c):
according to the preparation method of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15b, 113.2mg of a yellow solid was obtained in 67% yield, m.p.143-144 ℃. 1 H NMR(400MHz,DMSO-d 6 )δ8.33(s,1H),7.80(s,1H),7.68(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),7.22(dd,J＝18.2,8.7Hz,4H),7.13(s,1H),6.92(d,J＝9.0Hz,2H),6.75(d,J＝8.5Hz,2H),5.79(s,1H),5.52(s,1H),3.94(d,J＝8.0Hz,1H),3.72(s,3H),2.29–2.22(m,1H),2.21–2.12(m,1H). 13 C NMR(101MHz,DMSO-d 6 )δ158.37,144.30,142.66,136.69,135.83,131.01,129.92,129.47,129.17,123.78,123.01,120.79,116.25,116.10,115.31,84.02,82.67,60.40,55.94,30.55.HRMS(ESI)calcd for C 28 H 24 N 2 O 6 S[M+H] + ,517.1428；found 517.1427.
Example 4 preparation of 2- (trifluoromethyl) phenyl (1 r,4 r) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 d):
with reference to the preparation of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15f, 90mg of a brown solid was obtained in 49% yield, m.p.158.9-162.3 ℃. 1 H NMR(400MHz,MeOD)δ8.17(s,1H),7.79(d,J＝7.7Hz,1H),7.73(s,1H),7.70(d,J＝3.9Hz,1H),7.60(s,1H),7.56(s,1H),7.54(s,1H),7.52(s,1H),7.50(s,1H),7.47(s,1H),7.24(d,J＝8.6Hz,1H),7.21(d,J＝8.7Hz,1H),7.16(s,1H),6.77(d,J＝8.5Hz,2H),5.76(s,1H),5.52(t,J＝4.6Hz,1H),3.97(ddd,J＝51.5,8.3,4.3Hz,1H),2.64-2.54(m,1H),2.38-2.19(m,1H).HRMS(ESI)calcd for C 34 H 29 BrO 7 S[M+Na] + ,544.1123；found.
Example 5 preparation of 3- (trifluoromethyl) phenyl (1 r,4 r) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 e):
with reference to the preparation of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15e, 85mg of a pale yellow solid was obtained in a yield of 46%, m.p.164.3-166.7 ℃. 1 H NMR(400MHz,Acetone)δ8.19,7.77,7.74,7.71,7.69,7.65,7.64,7.63,7.61,7.56,7.55,7.53,7.32,7.30,7.28,7.17,6.89,6.86,5.84,5.82,5.57,5.56,2.53,2.52,2.51,2.50,2.48,2.46,2.38,2.36,2.35,2.33. 13 C NMR(101MHz,Acetone)δ154.13(s),149.73(s),132.92(s),132.21(s),131.47(s),131.37(s),131.29(s),131.22(s),129.41(s),129.13(s),129.09(s),129.02(s),128.67(s),126.60(s),126.43(s),123.95(s),122.20(s),120.84(s),120.73(s),119.50(s),119.43(s),115.90(s),115.75(s),114.98(s),84.16(s),82.82(s),61.13(s),31.74(s).HRMS(ESI)calcd for C 34 H 30 O 7 S[M+Na] + ,544.1123；found
Example 6 preparation of 4- (trifluoromethyl) phenyl (1 r,4 r) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 f):
according to the preparation method of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15d, 96.3mg of a yellow solid was obtained in a yield of 60%, m.p.130-132 ℃. 1 H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.31(s,2H),7.84(d,J＝8.6Hz,2H),7.79(s,1H),7.68(d,J＝8.6Hz,2H),7.61–7.56(m,2H),7.45(d,J＝8.4Hz,2H),7.20(d,J＝8.5Hz,2H),7.12(s,1H),6.75(d,J＝8.3Hz,2H),5.85(s,1H),5.54(d,J＝3.9Hz,1H),4.14(dd,J＝8.0,4.3Hz,1H),2.27(dd,J＝10.5,5.8Hz,1H),2.19(dd,J＝12.1,8.3Hz,1H).13C NMR(101MHz,DMSO-d6)δ158.29,157.17,152.03,144.36,136.68,135.75,130.93,129.40,129.25,128.06,123.76,120.73,116.10,83.92,82.71,61.28,30.57.HRMS(ESI)calcd for C28H21F3N2O5S[M+H]+,555.1196；found555.1199.
Preparation of 2-bromophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 g):
with reference to the preparation of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15i, 137mg of a yellow solid was obtained in 73% yield, m.p.100.8-101.7 ℃. 1 H NMR(400MHz,Acetone)δ8.14(s,1H),7.78(d,J＝8.1Hz,1H),7.74(s,1H),7.65(d,J＝8.6Hz,2H),7.60(s,1H),7.57(s,1H),7.55(s,1H),7.54(s,1H),7.52(s,1H),7.49(s,1H),7.47(s,1H),7.45(s,1H),7.43(s,1H),7.41(s,1H),7.34(s,1H),7.32(s,1H),7.30(s,1H),5.90–5.84(m,1H),5.63–5.58(m,1H),5.52(dd,J＝10.3,3.9Hz,1H),5.38–5.29(m,1H),4.69(s,2H),4.54(t,J＝8.5Hz,1H),2.79(d,J＝4.6Hz,1H),2.60(dt,J＝16.4,6.1Hz,1H),2.53–2.37(m,1H),2.15(dd,J＝15.2,7.6Hz,1H).13C NMR(101MHz,Acetone)δ158.29(s),146.68(s),144.24(s),136.96(s),135.31(s),134.08(s),130.92(s),130.32(s),129.23(s),129.09(s),128.70(s),128.54(s),125.49(s),124.78(s),123.99(s),123.86(s),120.81(s),120.72(s),120.13(s),117.60(s),115.95(s),115.06(s),114.39(s),84.30(s),82.91(s),62.03(s),30.38(s).HRMS(ESI)calcd for C 32 H 25 ClO 7 S[M+Na] + ,564.0355；found.
Preparation of 3-bromophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22H 1-2):
with reference to the preparation of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15H, two isomers were obtained in total 130mg of a yellow solid in a yield of 70%, m.p.117.3-120.1 ℃. Nuclear magnetic hydrogen profile at point 1: 1 H NMR(400MHz,Acetone)δ8.13(d,J＝6.0Hz,1H),7.62(s,3H),7.60(d,J＝1.7Hz,1H),7.58(d,J＝1.8Hz,1H),7.56(d,J＝4.1Hz,1H),7.54(d,J＝2.1Hz,1H),7.49(d,J＝5.3Hz,1H),7.46(d,J＝1.7Hz,1H),7.44(d,J＝2.4Hz,1H),7.42(d,J＝1.6Hz,1H),7.39(d,J＝2.2Hz,1H),7.12(d,J＝15.6Hz,1H),7.07(d,J＝10.4Hz,1H),7.03(d,J＝2.0Hz,1H),4.20–4.09(m,1H),3.95(dd,J＝8.1,4.7Hz,1H),2.50(dd,J＝10.0,6.4Hz,1H),2.46–2.32(m,1H).HRMS(ESI)calcd for C 32 H 25 BrO 7 S[M+Na] + ,564.0355；found.
preparation of 4-bromophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 g):
with reference to the preparation method of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and 15g of the vinylsulfonate derivative, 101.6mg of a yellow solid was obtained in a yield of 65%, m.p.134-136 ℃.1H NMR (400 MHz, DMSO-d 6) δ9.79 (S, 1H), 8.30 (d, J=13.5 Hz, 1H), 7.80 (S, 1H), 7.66 (dd, J=19.6, 8.6Hz, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.12 (S, 1H), 6.75 (d, J=8.5 Hz, 2H), 5.81 (S, 1H), 5.53 (d, J=3.7 Hz, 1H), 4.06 (dd, j=8.0, 4.3hz, 1H), 2.29-2.23 (M, 1H), 2.17 (dd, j=12.0, 8.3hz, 1H). 13C NMR (101 mhz, dmso-d 6) δ 158.29,148.53,144.33,135.77,133.45,130.96,129.40,129.22,125.02,122.94,120.77,120.37,116.10,83.96,82.69,55.39,30.59.hrms (ESI) calcd for C27H21BrN2O5S [ m+h ] +,565.0427; found565.0428.
Preparation of 4-fluorophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 j 1-2):
with reference to the preparation of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15j, two chiral isomers were obtained, point 1 as a 75mg pale yellow solid, point 2 as a 105mg pale yellow solid, yield 90%, m.p.110-113 ℃. 1 H NMR(400MHz,Acetone)δ8.14(d,J＝6.6Hz,1H),7.63(dd,J＝6.7,4.6Hz,3H),7.55–7.52(m,2H),7.49–7.46(m,2H),7.41(d,J＝4.1Hz,1H),7.36–7.31(m,2H),7.28(d,J＝6.9Hz,1H),7.22–7.18(m,2H),7.14(s,1H),7.10–7.03(m,2H),5.78(d,J＝5.6Hz,1H),5.58(t,J＝5.1Hz,1H),3.91(dd,J＝8.1,4.7Hz,1H),2.49(ddd,J＝12.3,8.3,3.9Hz,1H),2.44–2.13(m,1H). 13 C NMR(101MHz,Acetone)δ159.75(s),158.40(s),145.51(s),141.44(s),139.83(s),131.61(s),130.31(s),129.58(s),129.19(s),129.03(s),128.68(s),124.74(s),124.33(s),124.24(s),124.15(s),120.83(s),120.70(s),116.71(s),116.59(s),116.47(s),116.35(s),115.14(s),114.99(s),84.41(s),82.77(s),62.17(s),30.54(s).HRMS(ESI)calcd for C 33 H 25 F 3 O 7 S[M+Na] + ,645.1165；found 645.1162.
Preparation of naphthalen-1-yl (1 r,4 r) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 k):
with reference to the preparation of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15k, 125.3mg of a yellow solid was obtained in 71% yield, m.p.125.8-125.7deg.C; 1 H NMR(400MHz,Acetone-d 6 )δ8.27(d,J＝9.0Hz,1H),8.22–8.18(m,1H),8.00(d,J＝9.0Hz,2H),7.91(dd,J＝15.1,8.1Hz,2H),7.66(d,J＝7.7Hz,2H),7.60(d,J＝3.9Hz,3H),7.58(s,4H),7.51(d,J＝8.4Hz,2H),7.39(d,J＝8.7Hz,2H),7.24(s,1H),7.01(d,J＝8.6Hz,2H),5.89(s,1H),5.66–5.59(m,1H),4.15(dd,J＝8.2,4.6Hz,1H),2.71–2.61(m,1H),2.47(m,J＝29.2,12.2,8.4Hz,1H). 13 C NMR(101MHz,Acetone)δ158.31(s),145.37(s),141.53(s),139.88(s),134.99(s),131.61(s),129.89(s),129.27(d,J＝37.1Hz),128.75(s),127.94(s),127.15(ddd,J＝11.0,8.5,5.5Hz),125.53(d,J＝5.8Hz),124.70(s),121.79(d,J＝16.3Hz),120.72(s),118.28(d,J＝13.4Hz),115.16(s),84.55(s),82.84(s),62.24(s),30.79(s). 13 C NMR(100MHz,Acetone)δ158.31(s),145.37(s),141.53(s),139.88(s),134.99(s),131.61(s),129.89(s),129.46(s),129.09(s),128.75(s),127.94(s),127.37(s),127.28(s),127.19(s),127.15(s),127.10(s),127.05(s),127.03(s),127.02(s),125.56(s),125.50(s),124.70(s),121.87(s),121.71(s),120.72(s),118.34(s),118.21(s),115.16(s),114.39(s),84.55(s),82.84(s),62.24(s),30.79(s).HRMS(ESI)calcd for C 36 H 34 O 7 S[M+Na] + ,536.1406；found.
preparation of naphthalen-2-yl (1 r,4 r) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (22 l):
according to the preparation method of example 1, starting with 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8a and vinylsulfonate derivative 15l, 116.8mg of a yellow solid was obtained in 66% yield, m.p.102.4-104.2 ℃. 1 H NMR(400MHz,DMSO)δ9.78(s,1H),8.31(s,1H),7.99(d,J＝8.9Hz,1H),7.95(d,J＝7.7Hz,1H),7.86(d,J＝7.8Hz,1H),7.83(s,1H),7.79(s,1H),7.67(s,1H),7.65(s,1H),7.58–7.52(m,2H),7.51–7.49(m,1H),7.48(s,1H),7.46(s,1H),7.20(s,1H),7.18(s,1H),7.13(s,1H),6.75(s,1H),6.73(s,1H),5.86(s,1H),5.54(t,J＝5.6Hz,1H),4.06(dd,J＝8.0,4.3Hz,1H),2.35–2.29(m,1H),2.27–2.19(m,1H). 13 C NMR(100MHz,DMSO)δ158.26(s),146.96(s),144.40(s),136.68(s),135.89(s),135.78(s),133.57(s),131.96(s),131.01(s),130.60(s),130.45(s),129.92(s),129.49(s),129.16(s),128.74(s),128.19(s),127.58(s),127.51(s),127.03(s),122.99(s),121.73(s),120.77(s),120.71(s),119.92(s),118.21(s),116.29(s),116.10(s),84.09(s),82.70(s),60.75(s),31.13(s).HRMS(ESI)calcd for C 35 H 32 O 8 S[M+Na] + ,536.1406；found.
Example 13 preparation of 3- (trifluoromethyl) phenyl (1 r,4 r) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 a):
referring to the preparation of example 1, starting with 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8b and vinylsulfonate derivative 15e, 146.6mg of a pale yellow solid was obtained in 67% yield, m.p.98.7-103.6 ℃. 1 H NMR(400MHz,Acetone)δ9.05(dd,J＝20.3,10.8Hz,2H),8.12(t,J＝7.2Hz,1H),7.86(dd,J＝13.5,8.2Hz,2H),7.76–7.64(m,4H),7.56(dd,J＝11.4,7.6Hz,2H),7.29(dd,J＝19.0,10.1Hz,2H),6.86(dd,J＝16.5,7.6Hz,2H),5.84(d,J＝7.8Hz,1H),5.56(dd,J＝11.0,4.5Hz,1H),4.18–3.93(m,1H),2.55–2.47(m,1H),2.46–2.26(m,1H). 13 C NMR(101MHz,Acetone)δ158.09(s),152.42(s),149.58(s),144.93(s),141.65(s),140.52(s),136.62(s),135.88(s),132.78(s),132.08(s),131.24(s),129.49(s),129.10(s),128.84(s),128.46(s),126.41(s),126.41(s),123.95(s),123.20(s),119.82(s),119.68(s),119.45(s),115.91(s),115.77(s),84.19(s),82.97(s),61.50(s),30.24(s).HRMS(ESI)calcd for C 32 H 25 BrO 7 S[M+Na] + ,655.0397；found 655.0368.
Example 14 preparation of 4- (trifluoromethyl) phenyl (1 r,4 r) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 b):
according to the preparation method of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8b and vinylsulfonate derivative 15d, 167.5mg of a tan solid was obtained in 92% yield, m.p.95.4-97.8 ℃. 1 H NMR(400MHz,DMSO)δ9.54(s,1H),9.30(s,1H),8.59(s,1H),8.34(d,J＝8.8Hz,2H),8.27(d,J＝8.7Hz,2H),8.03(dd,J＝13.9,5.1Hz,4H),7.74(d,J＝8.8Hz,2H),7.30(d,J＝8.8Hz,2H),6.26(dd,J＝4.7,1.1Hz,1H),6.03(d,J＝5.4Hz,1H),4.58–4.37(m,1H),2.99–2.89(m,1H),2.84–2.70(m,1H). 13 C NMR(101MHz,Acetone)δ158.18(s),152.45(s),152.22(s),144.88(s),141.66(s),140.52(s),136.57(s),135.87(s),132.75(s),132.07(s),129.58(s),129.07(s),128.90(s),128.42(s),127.37(s),127.34(s),127.30(s),123.11(s),123.08(s),119.81(s),119.66(s),115.89(s),115.73(s),84.37(s),82.93(s),61.48(s),30.69(s).HRMS(ESI)calcd for C 32 H 26 O 8 S[M+Na] + ,593.1241；found 593.1239.
Preparation of 4-bromophenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 c):
according to the preparation method of example 1, starting with 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8b and 15g of an ethylene sulfonate derivative, 71.5mg of a brown solid was obtained in a yield% m.p.97.9-105.2 ℃. 1 H NMR(400MHz,Acetone)δ9.10(s,1H),8.89(s,1H),8.15(s,1H),7.89(d,J＝8.8Hz,2H),7.58(dd,J＝17.7,8.2Hz,4H),7.28(dd,J＝20.8,12.1Hz,4H),6.87(d,J＝21.7Hz,2H),5.78(d,J＝2.9Hz,1H),5.56(d,J＝5.5Hz,1H),3.96(ddd,J＝64.9,8.3,4.6Hz,1H),2.46(dd,J＝9.9,5.5Hz,1H),2.37–2.26(m,1H).HRMS(ESI)calcd for C 33 H 28 O 7 S[M+Na] + ,591.1448；found 591.1447.
Preparation of 4-methoxyphenyl (1 r,4 r) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 d):
with reference to the preparation of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8b and vinylsulfonate derivative 15b, 131mg of a pale yellow solid was obtained in a yield of 64%, m.p.98-101 ℃. 1 H NMR(400MHz,DMSO)δ9.82(d,J＝17.4Hz,1H),9.31(d,J＝6.3Hz,1H),8.24(d,J＝5.0Hz,1H),7.85(dd,J＝15.0,8.6Hz,2H),7.52(d,J＝4.3Hz,1H),7.47(d,J＝8.6Hz,1H),7.24(s,1H),7.22(d,J＝2.3Hz,1H),7.20(d,J＝4.6Hz,1H),7.18(d,J＝5.1Hz,1H),6.90(dd,J＝8.9,7.0Hz,2H),6.79(d,J＝8.6Hz,1H),6.76(d,J＝8.7Hz,1H),5.78(s,1H),5.54(d,J＝2.7Hz,1H),4.46–3.94(m,1H),3.72(d,J＝11.0Hz,4H),2.33–2.28(m,1H),2.27–2.14(m,1H). 13 C NMR(101MHz,DMSO)δ158.36(s),152.94(s),144.68(s),142.77(s),142.64(s),140.62(s),140.11(s),136.48(s),136.32(s),135.70(s),132.13(s),130.00(s),129.42(s),129.22(s),128.61(s),123.75(s),122.86(s),120.13(s),119.95(s),116.28(s),116.13(s),115.28(s),84.11(s),82.58(s),60.40(s),55.90(s),30.52(s).HRMS(ESI)calcd for C 38 H 30 O 7 S[M+Na] + ,653.1604；found 653.1605.
Preparation of 4-chlorophenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 e):
according to the preparation method of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8b and vinylsulfonate derivative 15H, 155.8mg of a yellow solid was obtained in 7 yield6％,m.p.122.5-124.6℃。 1 H NMR(400MHz,Acetone)δ9.07(dd,J＝9.6,4.1Hz,1H),8.97(d,J＝20.2Hz,1H),8.14(t,J＝5.2Hz,1H),7.91–7.82(m,2H),7.59–7.51(m,2H),7.43(t,J＝9.6Hz,2H),7.36(d,J＝8.8Hz,1H),7.29(t,J＝8.5Hz,3H),6.87(dd,J＝12.3,8.7Hz,2H),5.81–5.75(m,1H),5.56(d,J＝3.9Hz,1H),4.09–3.85(m,1H),2.56–2.46(m,1H),2.45–2.28(m,1H). 13 C NMR(101MHz,Acetone)δ158.17(s),152.41(s),148.22(s),140.56(s),136.52(s),135.89(s),132.77(s),132.16(s),129.92(s),129.89(s),129.62(s),129.06(s),128.91(s),128.39(s),124.01(s),123.98(s),123.23(s),122.41(s),119.84(s),119.67(s),115.93(s),115.76(s),84.40(s),82.78(s),60.59(s),30.69(s).HRMS(ESI)calcd for C 36 H 28 O 7 S[M+Na] + ,627.1448；found 627.1450.
Preparation of 4-methylphenyl (1 r,4 r) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (23 f):
according to the preparation method of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8b and vinylsulfonate derivative 15c, 120.7mg of a pale yellow solid was obtained in 78% yield, m.p.112-114 ℃. 1 H NMR(400MHz,DMSO)δ9.81(d,J＝15.8Hz,1H),9.32(d,J＝5.4Hz,1H),8.25(d,J＝5.1Hz,1H),7.85(dd,J＝11.7,8.7Hz,3H),7.49(t,J＝9.1Hz,3H),7.25–7.21(m,3H),7.19(s,3H),7.15(t,J＝8.2Hz,3H),6.77(dd,J＝12.0,8.6Hz,3H),5.77(s,1H),5.55(s,1H),4.03–3.78(m,2H),2.30(s,1H),2.28(d,J＝7.1Hz,4H),2.25–2.13(m,1H).13C NMR(101MHz,DMSO)δ158.34(s),152.95(s),147.23(d,J＝1.9Hz),144.69(s),142.78(s),140.60(s),140.11(s),137.23(s),136.32(s),135.70(s),132.77(s),132.12(s),130.82(s),129.96(s),129.39(s),128.63(s),122.85(s),122.38(s),120.11(s),116.11(s),84.09(s),82.63(s),60.60(s),30.51(s),20.83(s).HRMS(ESI)calcd for C 33 H 25 F 3 O 7 S[M+Na] + ,645.1165；found 645.1159.
Example 19 preparation of 4- (trifluoromethyl) phenyl (1 r,4 r) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 a):
according to the preparation method of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8c and vinylsulfonate derivative 15d, 147.1mg of a yellow solid was obtained in a yield of 91%, m.p.103.8-106.1 ℃. 1 H NMR(400MHz,Acetone)δ8.84(dd,J＝16.5,5.4Hz,1H),7.99(d,J＝4.3Hz,1H),7.83(d,J＝4.8Hz,1H),7.79(d,J＝2.8Hz,1H),7.77(d,J＝2.9Hz,1H),7.56(d,J＝3.6Hz,1H),7.54(d,J＝3.2Hz,2H),7.46(d,J＝6.1Hz,1H),7.35(dd,J＝8.3,4.6Hz,2H),7.28(dd,J＝8.5,5.6Hz,2H),6.87–6.81(m,2H),5.76(d,J＝2.5Hz,1H),5.51(d,J＝4.3Hz,1H),4.09–3.98(m,1H),2.53–2.42(m,1H),2.34(ddd,J＝28.6,12.2,8.4Hz,1H). 13 C NMR(101MHz,Acetone)δ163.03(s),157.44(s),148.46(s),146.45(s),144.06(s),141.95(s),141.28(s),138.16(s),138.05(s),135.79(s),135.11(s),134.92(s),134.67(s),134.17(s),133.22(s),132.78(s),130.55(s),130.40(s),128.86(s),128.33(s),127.32(s),89.44(s),88.11(s),66.70(s),43.48(s),35.59(s).HRMS(ESI)calcd for C 33 H 28 O 8 S[M+Na] + ,607.1397；found 607.1392.
Preparation of 4-bromophenyl (1 r,4 r) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 b):
with reference to the preparation method of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8c and 15g of the vinylsulfonate derivative, 124mg of a yellow solid was obtained in a yield of 75%, m.p.102.8-105.2℃。 1 H NMR(400MHz,Acetone)δ8.84(d,J＝20.1Hz,1H),8.03(d,J＝6.9Hz,1H),7.84(d,J＝7.8Hz,1H),7.60–7.54(m,4H),7.36(d,J＝8.3Hz,2H),7.30(s,1H),7.29(d,J＝2.7Hz,1H),7.27(s,1H),7.24(s,1H),6.87(d,J＝8.6Hz,1H),6.85–6.82(m,1H),5.72(s,1H),5.51(t,J＝3.5Hz,1H),3.92(d,J＝2.7Hz,3H),3.87–3.82(m,1H),2.45(ddd,J＝16.8,8.9,4.4Hz,1H),2.33(ddd,J＝28.4,12.2,8.3Hz,1H). 13 C NMR(101MHz,CDCl3)δ163.12(s),148.39(s),146.41(s),144.10(s),141.98(s),141.25(s),138.13(s),135.80(s),135.12(s),134.90(s),134.68(s),134.12(s),133.90(s),133.24(s),132.74(s),132.56(s),130.55(s),130.38(s),129.59(s),128.89(s),125.09(s),120.97(s),120.80(s),89.61(s),87.94(s),65.95(s),43.46(s),35.88(s).HRMS(ESI)calcd for C 33 H 28 O 7 S[M+Na] + ,591.1448；found 591.1450.
Preparation of 4-methoxyphenyl (1 r,4 r) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 c):
according to the preparation method of example 1, starting from 3- (4-hydroxyphenyl) -4- ((1H-imidazol-1-yl) phenyl) furan compound 8c and vinylsulfonate derivative 15b, 146.3mg of a yellow solid was obtained in 97% yield, m.p.106.2-107.5 ℃. 1 H NMR(400MHz,Acetone)δ8.82(d,J＝23.7Hz,1H),8.02(d,J＝10.3Hz,1H),7.84(d,J＝10.1Hz,1H),7.58(d,J＝8.4Hz,1H),7.54(d,J＝8.4Hz,1H),7.36(dd,J＝8.3,6.9Hz,2H),7.29(dd,J＝8.7,7.0Hz,2H),7.21(d,J＝9.1Hz,1H),7.18(d,J＝9.1Hz,1H),6.91(s,1H),6.86(dd,J＝14.5,8.6Hz,3H),5.71(d,J＝5.6Hz,1H),5.50(s,1H),3.92(d,J＝3.1Hz,3H),3.85–3.82(m,1H),3.78(d,J＝10.5Hz,3H),3.74(dd,J＝8.3,4.5Hz,1H),2.45(ddd,J＝18.3,9.2,4.5Hz,1H),2.31(ddd,J＝27.3,12.1,8.4Hz,1H). 13 C NMR(101MHz,CDCl3)δ163.60(s),162.95(s),148.12(s),146.36(s),144.21(s),142.07(s),141.30(s),138.15(s),135.88(s),135.18(s),134.76(s),134.08(s),133.35(s),132.70(s),132.61(s),130.58(s),130.39(s),128.99(s),128.46(s),127.38(s),121.00(s),120.80(s),119.87(s),89.65(s),87.89(s),65.55(s),65.22(s),60.27(s),43.48(s).HRMS(ESI)calcd for C 32 H 26 O 8 S[M+Na] + ,593.1241；found 593.1235.
Preparation of 4- (1H-1, 2, 4-triazol-1-yl) phenyl (1 r,4 r) -5, 6-bis (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 d):
3, 4-Dihydroxyphenyl furan compound 20 (100 mg,0.40 mmol) and 4- (1H-1, 2, 4-triazol-1-yl) styryl sulfonate 22 (110 mg,0.44 mmol) were weighed into a 25mL two-port round bottom bottle, 2.5mL anhydrous THF was added to aid dissolution, then slowly warmed to 90 ℃, reacted for 8H, TLC detection reaction completed, quenched with water, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. Decompression desolventizing, column chromatography separation and purification, wherein the eluent proportion is methylene dichloride: methanol=120: 1-50:1 (V/V) to give 121.3mg of a milky powdery solid in 61% yield, m.p.138-139 ℃. 1 H NMR(400MHz,Acetone)δ9.08(s,1H),8.77(s,1H),8.72(s,1H),8.15(s,1H),7.94(s,1H),7.91(s,1H),7.51(d,J＝2.2Hz,1H),7.49(d,J＝2.1Hz,1H),7.27(d,J＝1.9Hz,1H),7.25(s,2H),7.24(d,J＝1.9Hz,1H),6.85(d,J＝1.9Hz,1H),6.83(d,J＝2.4Hz,2H),6.81(d,J＝1.9Hz,1H),5.70(d,J＝0.9Hz,1H),5.47(d,J＝3.6Hz,1H),3.88(dd,J＝8.3,4.5Hz,1H),2.46(dt,J＝12.1,4.4Hz,1H),2.33(dd,J＝12.1,8.4Hz,1H). 13 C NMR(101MHz,Acetone)δ157.57(s),157.47(s),152.57(s),148.53(s),141.94(s),141.41(s),136.97(s),135.94(s),129.21(s),129.21(s),128.63(s),128.63(s),124.08(s),123.67(s),123.67(s),123.33(s),121.05(s),121.05(s),115.70(s),115.52(s),115.70(s),115.52(s),84.38(s),82.80(s),61.03(s),30.64(s).HRMS(ESI)calcd for C 34 H 30 O 8 S[M+Na] + ,621.1554；found 621.1545.
Example 23 preparation of 4- (1-methyl-1H-pyrazol-3-yl) phenyl (1 r,4 r) -5, 6-bis (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate (24 e):
3, 4-Dihydroxyphenyl furan compound 20 (108 mg,0.428 mmol) and 4- (1-methyl-1H-pyrazol-3-yl) styrenesulfonate 24 (97.6 mg,0.428 mmol) were weighed into a 25mL two-port round bottom bottle, 2mL anhydrous THF was added to aid dissolution, then the temperature was slowly raised to 90 ℃, the reaction was allowed to proceed for 8H, TLC detection was complete, water quenching was performed, ethyl acetate extraction was performed, and the organic layer was dried over anhydrous sodium sulfate. Decompression desolventizing, column chromatography separation and purification, wherein the eluent proportion is methylene dichloride: methanol=120: 1-50:1 (V/V) to give 118.4mg of white powdery solid in 53% yield, m.p.139-141 ℃. 1 H NMR(400MHz,Acetone)δ8.75(s,1H),8.68(s,1H),8.00(s,1H),7.80(s,1H),7.57(d,J＝8.7Hz,2H),7.27–7.23(m,5H),6.83(dd,J＝14.7,8.6Hz,4H),5.66(d,J＝0.8Hz,1H),5.45(d,J＝4.2Hz,1H),3.92(s,3H),3.78(dd,J＝8.3,4.5Hz,1H),2.43(dt,J＝12.1,4.4Hz,1H),2.29(dd,J＝12.1,8.4Hz,1H).HRMS(ESI)calcd for C 32 H 26 O 8 S[M+Na] + ,593.1241；found 593.1234.
Example 24 antitumor Activity experiments of oxygen bridged bicyclo- [2.2.1] -heptenesulfonates with different five-membered nitrogen heterocyclic structures
The MCF-7 human breast cancer cell line and MCF-10A normal breast cells were obtained from ATCC. Cells were cultured in phenol red-containing DMEM with 10% fbs and 1% diabody. Test compounds were dissolved in DMSO at a drug concentration of 100mol/L. Cells were seeded in 96-well plates (Nest Biotech Co, china) and incubated for 24h in an incubator. Test compounds at different concentrations were added to 96-well plates, 3 wells in parallel, with vehicle DMSO as negative control and 4-hydroxy tamoxifen as positive control. After 72H, 10. Mu.L of 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfonic acid benzene) -2H-tetrazole monosodium salt (CCK-8) solution was added to each well and incubated for an additional 2H. Absorbance (OD) was read at 490nm on a WellscanMK-2 microplate reader. Determination of IC by Logit method 50 (induction 50%)Concentration of apoptosis). All compounds were tested at least 3 times in duplicate and the results are shown in table 1. The activity of the compound on MCF-7 is generally better than that of 4-hydroxy tamoxifen, wherein the activity of the compounds 22i and 23b is 2-6 times that of the 4-hydroxy tamoxifen. In addition, compounds 23a,23c and 23e-f have better inhibitory activity on LCC2 cells than 4-hydroxy tamoxifen against drug resistant breast cancer cells LCC 2.
TABLE 1 oxygen bridged bicyclo- [2.2.1] s of different five membered nitrogen heterocyclic structures]Inhibition Activity test (IC) of heptenesulfonates on MCF-7 and LCC2 50 ,μM)
a IC 50 Is the mean ± standard deviation of at least three independent experiments.
Test of the aromatizing enzyme inhibitory Activity of Compounds [ example 25 ]
Aromatase (CYP 19A) inhibitor screening kit (fluorescence) kit A recombinant human aromatase stock solution (2X) was prepared by reconstitution with 1mL of aromatase assay buffer, selected from Biovision Inc. The contents were thoroughly mixed by vortexing to obtain a homogeneous solution (the solution would have a slightly opaque milky appearance) and the solution was transferred to a 15mL conical tube. The volume was increased to 2450. Mu.L using Aromatase Assay Buffer, 50. Mu.L of NADPH generating system (10X) was added and the final total volume was 2.5mL.
Solutions containing test compound and corresponding inhibitor-free control, background control solution (without fluorogenic aromatase substrate) and 5. Mu.M letrozole solution (5X positive inhibition control solution, final concentration 1. Mu.M) were prepared. A small aliquot of aromatase assay buffer was prepared containing an organic solvent for dissolving the test compound at a final concentration of 5X.
Table 2 solution formulation for each test well in the aromatizing enzyme test
| No inhibitor (mu L) | Test compound (μL) | Negative control (μL) | Positive control (μL) | |
| Aromatization zymogen liquid (2×) | 50 | 50 | 50 | 50 |
| Test compound solution (5×) | -- | 20 | -- | -- |
| 5 mu M letrozole solution (5×) | -- | -- | -- | 20 |
| Aromatizing enzyme buffer (5×) | 20 | -- | 50 | -- |
Corning 384 well plates were incubated at 37 ℃ for at least 10 minutes to allow the test ligand to interact with the aromatase. Depending on the mechanism of action, the pre-incubation time can be optimized for other test ligands.
During incubation, the aromatase substrate/NADP was prepared by adding 6. Mu.L of reconstituted 1mM aromatase + Mixture (3×) substrate stock solution and 50 μl of reconstituted 10mM β -NADP + Stock (100×) to 1444 μl aromatase assay buffer, total volume 1.5mL.
Add 30. Mu.l of aromatase substrate/NADP to each well by using a multichannel pipette + The reaction was started (3×) with the mixture (except background control) yielding a final reaction volume of 100 μl/well.
Fluorescence at Ex/em=488/527 nm was measured immediately (within 1 min) in kinetic mode for 60 min. Δf= (RFU) 2 –RFU 1 )，ΔT＝(T 2 –T 1 )。R＝(ΔF-ΔF BC )/ΔT。％Relative Inhibition＝(R SC –R TC )/R SC ×100％。
TABLE 3 oxygen bridged bicyclo- [2.2.1] s of different five membered nitrogen heterocyclic structures]Test of the inhibitory Activity of heptenesulfonates on aromatizing enzymes (IC 50 ,nM)
The data in the table show that compounds 22a-l and compounds 23a-c are very active, with an inhibition of the aromatizing enzyme exceeding 80%, whereas compounds 24b and compounds 22d-e are essentially incapable of inhibiting the enzyme activity at 1. Mu.M. With letrozole (IC) 50 A value of 1.8 nM), compounds 22f, 22i and 23b-c were activeBetter, IC 50 The values reached 0.9nM and 1.3nM,2.9nM and 3.48nM, where the activity of compounds 22f and 22i was superior to that of the control drug letrozole, which also provides a basis and foundation for the excellent anti-cell proliferation activity of the compounds.
Claims (8)
1. An oxygen bridged bicyclo- [2.2.1] -heptenesulfonate compound containing five-membered nitrogen heterocycle, which is characterized in that: has a structure shown in the following general formula I:
general formula I
In the general formula I, R 1 Selected from the group consisting of
、/>
、/>
，R 2 Selected from-H, 4-CH 3 、4-OCH 3 、2-CF 3 、3-CF 3 、4-CF 3 2-Br, 3-Br, 4-Cl, 4-F, alpha-naphthol, beta-naphthol, < ->
And->
The method comprises the steps of carrying out a first treatment on the surface of the Or R is 1 Selected from OH, R 2 Selected from->
And->
。
2. The five-membered nitrogen heterocycle-containing oxo-bridged bicyclo- [2.2.1] -heptenesulfonate compound according to claim 1, wherein: a compound selected from the group consisting of:
phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-methylphenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-methoxyphenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
2- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
3- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
2-bromophenyl (1R, 4R) -6- (4- (1)H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1]Hept-5-ene-2-sulfonate,
3-bromophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-bromophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-fluorophenyl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
naphthalen-1-yl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
naphthalen-2-yl (1R, 4R) -6- (4- (1H-imidazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
3- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4- (trifluoromethyl) phenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-bromophenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-methoxyphenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-chlorophenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-methylphenyl (1R, 4R) -6- (4- (1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4- (trifluoromethyl) phenyl (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-bromophenyl (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4-methoxyphenyl (1R, 4R) -5- (4-hydroxyphenyl) -6- (4- (1-methyl-1H-pyrazol-4-yl) phenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4- (1H-1, 2, 4-triazol-1-yl) phenyl (1R, 4R) -5, 6-bis (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate,
4- (1-methyl-1H-pyrazol-3-yl) phenyl (1R, 4R) -5, 6-bis (4-hydroxyphenyl) -7-oxabicyclo [2.2.1] hept-5-ene-2-sulfonate.
3. The process for producing an oxygen bridged bicyclo- [2.2.1] -heptenesulfonate compound containing a five-membered nitrogen heterocycle according to claim 1 or 2, which is characterized in that: the method comprises the following steps: preparing an oxygen bridge bicyclo- [2.2.1] -heptenesulfonate compound containing a five-membered nitrogen heterocycle structure by a Diels-Alder reaction of a furan derivative containing the five-membered nitrogen heterocycle and an ethylene sulfonate derivative;
the structural formula of the five-membered nitrogen heterocyclic furan derivative is
Wherein R is 1 Selected from->
、
、/>
、OH；
The structural formula of the ethylene sulfonate derivative is
，R 2 Selected from-H, 4-CH 3 、4-OCH 3 、2-CF 3 、3-CF 3 、4-CF 3 2-Br, 3-Br, 4-Cl, 4-F, alpha-naphthol, beta-naphthol, < ->
、/>
。/>
4. A method of preparation according to claim 3, characterized in that: the Diels-Alder reaction condition is that the reaction is carried out for 12 hours at the temperature of 90-100 ℃.
5. The pharmaceutically acceptable salt of an oxo-bridged bicyclo- [2.2.1] -heptenesulfonate containing five-membered nitrogen heterocycle of claim 1 or 2.
6. The use of an oxo-bridged bicyclo- [2.2.1] -heptenesulfonate compound containing a five-membered nitrogen heterocycle as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament, characterized in that: the medicine is selected from estrogen receptor targeting medicine, breast cancer resisting medicine, aromatizing enzyme activity inhibiting medicine and medicine for resisting breast cancer endocrine therapy.
7. A medicament, characterized in that: an oxo-bridged bicyclo- [2.2.1] -heptene sulfonate compound containing a five-membered nitrogen heterocyclic ring structure as described in claim 1 or 2, or a pharmaceutically acceptable salt thereof; the medicine is selected from estrogen receptor targeting medicine, breast cancer resisting medicine, aromatizing enzyme activity inhibiting medicine and medicine for resisting breast cancer endocrine therapy.
8. A medicament according to claim 7, characterized in that: comprising one or more pharmaceutically acceptable carriers or excipients.
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