CN111072606B - Octahydrobenzofuran derivative, preparation method and application thereof - Google Patents
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Abstract
The invention relates to an octahydrobenzofuran derivative, and preparation and application thereof, and belongs to the technical field of organic synthesis. The octahydrobenzofuran derivative is 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran, does not contain a sulfonamide structure, has a good inhibition effect on COX2 and human ovarian cancer cells, and does not cause anaphylactic reaction; in addition, the derivative has simple preparation process, cheap and easily obtained raw materials, does not need rare metals, and has good application prospect in the field of biological medicine.
Description
Technical Field
The invention relates to an octahydrobenzofuran derivative, and preparation and application thereof, and belongs to the technical field of organic synthesis.
Background
Non-steroidal anti-inflammatory drugs (NSAIDs) have anti-inflammatory, antipyretic, and analgesic effects, are widely used clinically for treating diseases such as rheumatoid arthritis and osteoarthritis, and are the second main class of drugs next to anti-infective drugs. The medicines mainly inhibit Cyclooxygenase (COX) to block the conversion of arachidonic acid into prostaglandin which is an inflammatory factor, thereby generating drug effect. COX includes 2 isoenzyme isomers, namely COX1 and COX 2.
The selective COX2 inhibitor is a novel class of NSAIDs, can selectively inhibit COX2 activity, has small influence on COX1 and has few adverse reactions. In addition, other clinical uses of COX2 inhibitors have anti-tumor and brain-protective effects (dermogan, et al, J.CHINA PAINT. 2006,12 (5): 297-. Therefore, the study of COX2 inhibitors is an important area in drug research. At present, some foreign pharmaceutical factories develop second-generation COX2 inhibitors, the main products of which include Valdecoxib (Valdecoxib) and parecoxib (Precoxib), and because both Valdecoxib and parecoxib contain sulfanilamide structures, severe anaphylactic reaction is easily caused. There is therefore a need to develop a new COX2 inhibitor to overcome the limitations of the prior art.
Disclosure of Invention
Aiming at the defects in the prior art, one of the purposes of the invention is to provide an octahydrobenzofuran derivative, namely 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran, which does not contain a sulfanilamide structure and avoids causing anaphylactic reaction;
the second purpose of the invention is to provide a preparation method of octahydrobenzofuran derivatives, which has simple process, cheap and easily available raw materials and no need of rare metals;
the invention also aims to provide the application of the octahydrobenzofuran derivative, and the substance has an inhibitory effect on COX2 and human ovarian cancer cells and has a good application prospect in the field of biological medicines.
The purpose of the invention is realized by the following technical scheme.
An octahydrobenzofuran derivative is 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran, and the specific structural formula is as follows:
the preparation method of the octahydrobenzofuran derivative comprises the following steps: reacting methyl diphenylacetate with 3-bromocyclohexene to obtain 2- (cyclohex-2-enyl) -2, 2-diphenylacetate, and reacting the 2- (cyclohex-2-enyl) -2, 2-diphenylacetate with lithium aluminum hydride to obtain 2- (cyclohex-2-enyl) -2, 2-diphenylethanol; reacting N-bromosuccinimide with sodium thiocyanate to obtain N-thiocyano succinimide (NTS); under the anhydrous and oxygen-free conditions and the action of a composite catalyst, 2- (cyclohex-2-enyl) -2, 2-diphenylethanol and N-thiocyano succinimide react in an organic solvent for not less than 8 hours, and the reaction product is purified by a silica gel column to obtain the 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran.
Wherein, the composite catalyst is prepared by mixing trifluoromethanesulfonate and phosphine ligand according to the weight ratio of 0.1: (0.1-0.2), and the trifluoromethanesulfonate is preferably copper trifluoromethanesulfonate (Cu (OTf)2) Or zinc trifluoromethanesulfonate (Zn (OTf)2) The phosphine ligand is preferably (+ -) -2,2' -bis- (diphenylphosphino) -1,1' -Binaphthyl (BINAP) or N, N ' -bis (diphenylphosphino) binaphthyl amine, and the molar ratio of the triflate to the phosphine ligand is preferably 0.1: 0.12; the organic solvent is preferably dichloromethane, acetonitrile, tetrahydrofuran or acetone; the molar ratio of 2- (cyclohex-2-enyl) -2, 2-diphenylethanol to N-thiocyanosuccinimide is preferably 1: 2.
The specific conditions for the preparation of 2- (cyclohex-2-enyl) -2, 2-diphenylethanol are as follows: reacting methyl diphenylacetate and 3-bromocyclohexene under anhydrous and oxygen-free conditions for not less than 20 hours by taking tetrahydrofuran as a solvent and lithium diisopropylamide as a catalyst according to a molar ratio of 1 (1-1.5), then quenching the reaction, and washing, drying and purifying to obtain 2- (cyclohex-2-enyl) -2, 2-methyl diphenylacetate; tetrahydrofuran is used as a solvent, 2- (cyclohex-2-enyl) -2, 2-diphenyl methyl acetate and lithium aluminum hydride react for not less than 20 hours under the anhydrous and oxygen-free conditions according to the molar ratio of 1 (1-1.5), and then the reaction is carried out according to H2O、NaOH、H2O in sequence for quenching reaction, and H2O:NaOH:H2The volume ratio of O is 1:2:3, and then the 2- (cyclohex-2-enyl) -2, 2-diphenylethanol is obtained after washing, drying and purification.
The specific conditions for the preparation of N-thiocyanosuccinimide were as follows: using dichloromethane as a solvent, reacting N-bromosuccinimide with sodium thiocyanate according to the molar ratio of 1:1.5 for 1-3 h under the conditions of no water, no oxygen and light protection, filtering by using kieselguhr, and then concentrating under reduced pressure in the light protection to obtain the N-thiocyanosuccinimide.
The application of the octahydrobenzofuran derivative in preparing COX2 inhibitor is disclosed.
The octahydrobenzofuran derivative disclosed by the invention is applied to preparation of a medicine for inhibiting human ovarian cancer cells.
Has the advantages that:
the octahydrobenzofuran derivative does not contain a sulfanilamide structure, has a good inhibition effect on COX2 and human ovarian cancer cells, and does not cause anaphylactic reaction; in addition, the derivative has simple preparation process, cheap and easily obtained raw materials, does not need rare metals, and has good application prospect in the field of biological medicine.
Drawings
FIG. 1 is a schematic diagram of the synthetic route of 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran of the present invention.
FIG. 2 is a graph comparing the results of culturing cells with and without the addition of 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran in example 5.
Detailed Description
The invention is further illustrated by the following figures and detailed description, wherein the process is conventional unless otherwise specified, and the starting materials are commercially available from a public disclosure without further specification.
Example 1
The specific preparation steps of the 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran are as follows:
(1) placing a 250mL double-mouth round-bottom flask and a magneton on a magnetic stirrer, and ensuring that the flask is anhydrous and oxygen-free through argon replacement; anhydrous oxygen-free Tetrahydrofuran (THF) (4mL), diisopropylamine solution (0.40mL, 2.87mmol, 1.3equiv), n-BuLi (n-butyllithium, 1.65mL, 1.6mol/L, 2.65mmol, 1.2equiv) at-78 deg.C to generate Lithium Diisopropylamide (LDA) in situ, stirring for 30min, and addingSlowly dripping a solution of methyl diphenylacetate (500mg, 2.21mmol) in anhydrous oxygen-free THF (5mL) at the temperature of minus 78 ℃ for 1h into the flask, stirring for 1h, adding 3-bromocyclohexene (0.28mL, 2.43mmol, 1.1equiv), heating the reaction system of the flask to room temperature under natural conditions, stirring for 24h, and detecting the completion of the reaction through thin-layer chromatography (TLC); quenching the reaction with 5mL hydrochloric acid (1mol/L) and 10mL distilled water under stirring, separating the solution to obtain the upper organic phase, washing with dichloromethane, removing water from saturated saline solution, and adding Na2SO4Drying, concentrating under reduced pressure, and purifying with silica gel column chromatography (eluent is ethyl acetate and petroleum ether at volume ratio of 1: 49) to obtain transparent colorless oily 2- (cyclohex-2-enyl) -2, 2-diphenyl methyl acetate with yield of 92%;
(2) placing a 250mL double-mouth round-bottom flask and a magneton on a magnetic stirrer, and ensuring that the flask is anhydrous and oxygen-free through argon replacement; firstly adding LiAlH4(96mg,2.52mmol,1.4equiv) in THF (2.6mL), then slowly adding a solution of methyl 2- (cyclohex-2-enyl) -2, 2-diphenylacetate (552mg,1.80mmol) in THF (2mL) dropwise at 0 deg.C, allowing the reaction system in the flask to warm to room temperature under natural conditions and stirring for 24h, and detecting the completion of the reaction by Thin Layer Chromatography (TLC); under stirring, with H2O(2.5mL)、NaOH(5.0mL，1.0mol/L)、H2Quenching with O (7.5mL), filtering with diatomaceous earth, collecting solid product, washing with ethyl acetate, dehydrating with saturated saline, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and purifying with silica gel column chromatography (eluent is ethyl acetate and petroleum ether at volume ratio of 1: 20) to obtain white solid particle 2- (cyclohex-2-enyl) -2, 2-diphenylethanol with yield of 73%;
(3) placing a 250mL double-mouth round-bottom flask and an additive magneton on a magnetic stirrer in a dark place, and ensuring that the flask is anhydrous and oxygen-free through argon replacement; n-bromosuccinimide (NBS) (6mmol), NaSCN (9mmol) and anhydrous oxygen-free CH2Cl2(45mL) of the mixed system, stirring in a flask for reaction for 2h, filtering with diatomite to remove NaBr, evaporating the solvent at 30 ℃, dropwise adding n-hexane into a rotary evaporation bottle when the solvent is evaporated to two thirds, and dropwise adding a small amount of n-hexane when white solid appearsHexane, and the concentration under reduced pressure is continued to obtain pure white solid NTS with the yield of 83 percent;
(4) a25 mL reaction tube was taken and added with magnetons, Zn (OTf)2(0.1equiv) and BINAP (0.12equiv) were placed on a magnetic stirrer, and the anhydrous and oxygen-free reaction tube was maintained by argon displacement, after which 0.5mL of anhydrous and oxygen-free CH was added3CN, stirring for 0.5h, adding 2- (cyclohex-2-enyl) -2, 2-diphenylethanol (0.05mmol) and N-thiocyanosuccinimide (1.6equiv) under the protection of argon to react for 29h, and purifying by silica gel column chromatography (eluent is ethyl acetate and petroleum ether in a volume ratio of 1: 20) to obtain transparent colorless oily 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran with a yield of 66%, wherein the synthetic route is shown in figure 1.
Performing nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, infrared spectrum and high-resolution mass spectrum characterization on the prepared 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran, wherein the characterization results are as follows:
1H-NMR(400MHz,CDCl3):δ(ppm)＝7.38–7.10(m,10H),4.78(d,J＝9.0Hz,1H),4.28(m,2H),3.41–3.33(m,1H),3.29(m,1H),2.02–1.39(m,6H)；
13C-NMR(100MHz,d6-DMSO)δ(ppm)＝146.2,143.8,129.0,128.7,128.6,127.2,126.8,126.6,112.3,79.9,75.5,58.7,48.7,42.4,26.4,23.7,19.9；
IR(KBr):ν(cm-1)＝2150,1597,1493,1447,1067；
HRMS(ESI)m/z:[M+NH4]+calculated for C21H21NOSNH4 353.1682；Found 353.1679。
example 2
Steps (1) to (3) are the same as in example 1;
(4) a25 mL reaction tube was taken and added with magnetons, Zn (OTf)2(0.1equiv) and BINAP (0.12equiv) were placed on a magnetic stirrer, and the anhydrous and oxygen-free reaction tube was maintained by argon displacement, after which 0.5mL of anhydrous and oxygen-free CH was added2Cl2After stirring for 0.5h, 2- (cyclohex-2-enyl) -2, 2-diphenylethanol (0.05mmol) and N-thiocyanosuccinimidyl were added under argonThe amine (1.6equiv) was reacted for 29h and purified by silica gel column chromatography (eluent was ethyl acetate and petroleum ether at a volume ratio of 1: 20) to give 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran as a clear colorless oil in 79% yield.
Example 3
Steps (1) to (3) are the same as in example 1;
(4) a25 mL reaction tube was taken and added with magnetons, Zn (OTf)2(0.1equiv) and BINAP (0.12equiv) were placed on a magnetic stirrer, and the anhydrous and oxygen-free reaction tube was maintained by argon displacement, after which 0.5mL of anhydrous and oxygen-free CH was added2Cl2After stirring for 0.5h, 2- (cyclohex-2-enyl) -2, 2-diphenylethanol (0.05mmol) and N-thiocyanosuccinimide (2.0equiv) were added under argon protection to react for 29h and purified by silica gel column chromatography (eluent was ethyl acetate and petroleum ether at a volume ratio of 1: 20) to give 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran as a clear colorless oil in 84% yield.
Example 4
Steps (1) to (3) are the same as in example 1;
(4) a25 mL reaction tube was taken and magnetons were added, Cu (OTf) was added2(0.1equiv) and N, N' -bis (diphenylphosphino) binaphthylamine (0.12equiv) were placed on a magnetic stirrer, anhydrous and anaerobic reaction in the reaction tube was ensured by argon gas replacement, then 0.5mL of anhydrous and anaerobic acetonitrile was added, stirring was carried out for 0.5h, then 2- (cyclohex-2-enyl) -2, 2-diphenylethanol (0.05mmol) and N-thiocyanosuccinimide (2.0equiv) were added under argon gas protection to carry out reaction for 29h, and purification was carried out by silica gel column chromatography (eluent was ethyl acetate and petroleum ether in a volume ratio of 1: 20) to obtain a transparent colorless oil, 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran, in 58% yield.
Example 5
Spreading mouse mononuclear macrophage RAW264.7 on 6-well culture plate, adding culture solution, and culturing at 37 deg.C under CO2Culturing in 5% volume incubator for 24 hr, adding Lipopolysaccharide (LPS) to give final concentration of 5 μ g/mL for stimulating macrophage for 4 hr, adding 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran (P0105) to give final concentration of 10 μmol/L, and culturing in a culture medium at room temperature37℃、5％CO2Continuously incubating in the incubator for 24h, discarding the supernatant, adding a radioimmunoprecipitation buffer solution (RIPA) lysate containing a protease inhibitor, performing cell scraping after the lysis on ice, centrifuging at 12000r/min and 4 ℃ for 5min, taking the supernatant, and determining the protein content according to a BCA (bicinchoninic acid) protein concentration determination method; then detecting the protein content of COX2 in the cells according to a Western blot method; the experiment was repeated three times and statistically analyzed, and the results are shown in FIG. 2. Wherein CON is a normal control group (compared with a P0105 experimental group, 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran is not added and is not stimulated by lipopolysaccharide, and RAW264.7 cells cultured in an incubator for 48h are cultured conventionally), and MOD is a model control group (compared with the P0105 experimental group, only 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran is replaced by a solvent dimethyl sulfoxide with the same volume, and other conditions are not changed).
The characterization results of fig. 2 show that: 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran with a final concentration of 10. mu. mol/L had a very significant inhibitory effect on COX 2.
Example 6
Tumor cells A2780, SK-OV-3, KUROMOCHI and OVCAR8 in logarithmic growth phase are digested with pancreatin to obtain 2.5 × 104Inoculating 2500 cells/mL of cell sap into a 96-well plate, and adding 100 mu L of cell sap per well; changing fresh culture medium the next day, setting 6 experimental groups with 3 parallel holes, adding 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran into 6 experimental groups respectively to make final concentration of 0.001, 0.01, 0.1, 1, 10 and 100 μmol/L, setting 1 blank control group with 3 parallel holes, adding 100 μ L solvent dimethyl sulfoxide (DMSO final concentration) into the blank control group<0.5 percent), 6 groups of positive control groups are arranged, each group is provided with 3 parallel holes, the dimethyl sulfoxide solution of the paclitaxel is respectively added into the 6 positive control groups to ensure that the final concentration of the paclitaxel is 0.001, 0.01, 0.1, 1, 10 and 100 mu mol/L in sequence, after all the test groups are continuously cultured for 72 hours at 37 ℃, 20 mu L of freshly prepared phosphate buffer solution containing 5mg/mL of 3- (4, 5-dimethylthiazole-2) -2, 5-diphenylazoterazoterabromate (MTT) is added into each hole, the culture is continuously carried out for 4 hours, after supernatant is discarded, 150 mu L of DMSO is added into each hole to ensure that MTT formazan precipitates are dissolved, and micro vibration is carried outAfter shaking and mixing uniformly by using an oscillator, measuring an Optical Density (OD) value under the conditions of a reference wavelength of 450nm and a detection wavelength of 570nm, calculating the growth inhibition rate of the tested compound on the tumor cells by using the tumor cells treated by the solvent as a control group by using the following formula, and calculating the half inhibition rate (IC) according to a middle efficiency equation50) The value is obtained. The results show that: IC of 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran on human ovarian cancer cells A2780, SK-OV-3, KUROMOCHI, OVCAR850(mu mol/L) are 42.38, 72.71, 89.21 and 97.55 in sequence.
In summary, the above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. An octahydrobenzofuran derivative, characterized in that: the derivative is 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran, and the specific structural formula is shown as follows:
2. a process for the preparation of octahydrobenzofuran derivatives according to claim 1, wherein: the method comprises the following steps: reacting methyl diphenylacetate with 3-bromocyclohexene to obtain 2- (cyclohex-2-enyl) -2, 2-diphenylacetate, and reacting the 2- (cyclohex-2-enyl) -2, 2-diphenylacetate with lithium aluminum hydride to obtain 2- (cyclohex-2-enyl) -2, 2-diphenylethanol; reacting N-bromosuccinimide with sodium thiocyanate to obtain N-thiocyano succinimide; under the anhydrous and oxygen-free conditions and the action of a composite catalyst, reacting 2- (cyclohex-2-enyl) -2, 2-diphenylethanol with N-thiocyano succinimide in an organic solvent for not less than 8 hours, and purifying by a silica gel column to obtain 7-thiocyano-3, 3-diphenyl-octahydrobenzofuran;
wherein, the composite catalyst is prepared by mixing trifluoromethanesulfonate and phosphine ligand according to the weight ratio of 0.1: (0.1-0.2) in a molar ratio.
3. The process for producing an octahydrobenzofuran derivative according to claim 2, wherein: the trifluoromethanesulfonate is copper trifluoromethanesulfonate or zinc trifluoromethanesulfonate.
4. The process for producing an octahydrobenzofuran derivative according to claim 2, wherein: the phosphine ligand is (+/-) -2,2' -bis- (diphenylphosphino) -1,1' -binaphthyl or N, N ' -bis (diphenylphosphino) binaphthyl amine.
5. The process for producing an octahydrobenzofuran derivative according to claim 2, wherein: the organic solvent is dichloromethane, acetonitrile, tetrahydrofuran or acetone.
6. The process for producing an octahydrobenzofuran derivative according to claim 2, wherein: the molar ratio of the triflate to the phosphine ligand is 0.1:0.12 and the molar ratio of 2- (cyclohex-2-enyl) -2, 2-diphenylethanol to N-thiocyanosuccinimide is 1: 2.
7. The process for producing an octahydrobenzofuran derivative according to claim 2, wherein: the specific conditions for the preparation of 2- (cyclohex-2-enyl) -2, 2-diphenylethanol are as follows,
reacting methyl diphenylacetate and 3-bromocyclohexene under anhydrous and oxygen-free conditions for not less than 20 hours by taking tetrahydrofuran as a solvent and lithium diisopropylamide as a catalyst according to a molar ratio of 1 (1-1.5), then quenching the reaction, and washing, drying and purifying to obtain 2- (cyclohex-2-enyl) -2, 2-methyl diphenylacetate; tetrahydrofuran is used as a solvent, and the 2- (cyclohex-2-enyl) -2, 2-diphenyl methyl acetate and lithium aluminum hydride react under the anhydrous and oxygen-free conditions according to the molar ratio of 1 (1-1.5)20H, then according to H2O、NaOH、H2O in sequence for quenching reaction, and H2O:NaOH:H2The volume ratio of O is 1:2:3, and then the 2- (cyclohex-2-enyl) -2, 2-diphenylethanol is obtained after washing, drying and purification.
8. The process for producing an octahydrobenzofuran derivative according to claim 2, wherein: the specific conditions for the preparation of N-thiocyanosuccinimide are as follows,
using dichloromethane as a solvent, reacting N-bromosuccinimide with sodium thiocyanate according to a molar ratio of 1:1.5 under the conditions of no water, no oxygen and light protection for 1-3 h, filtering with diatomite, and concentrating under reduced pressure in the light protection to obtain the N-thiocyanosuccinimide.
9. Use of an octahydrobenzofuran derivative according to claim 1 in the preparation of a COX2 inhibitor.
10. Use of the octahydrobenzofuran derivative of claim 1 in the preparation of a medicament for inhibiting ovarian cancer cells in a human.
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