CN104788436A - Tetrahydrobenzofuran-4-ketoximetriazole medicine, and preparation method and application thereof - Google Patents
Tetrahydrobenzofuran-4-ketoximetriazole medicine, and preparation method and application thereof Download PDFInfo
- Publication number
- CN104788436A CN104788436A CN201510111498.3A CN201510111498A CN104788436A CN 104788436 A CN104788436 A CN 104788436A CN 201510111498 A CN201510111498 A CN 201510111498A CN 104788436 A CN104788436 A CN 104788436A
- Authority
- CN
- China
- Prior art keywords
- medicine
- tetrahydrochysene benzfuran
- ketoxime base
- mol ratio
- anhydrous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CC(C)(CC1C2C(C)=CC1)CC2=NCCc1c[n](*)cc1 Chemical compound CC(C)(CC1C2C(C)=CC1)CC2=NCCc1c[n](*)cc1 0.000 description 2
- ZWNZXJXLZPBQJR-ASPVSBEJSA-N CC(C)(CC1C2C(C)=CC1)C/C2=N/CC/C(/N=N\I)=C/C Chemical compound CC(C)(CC1C2C(C)=CC1)C/C2=N/CC/C(/N=N\I)=C/C ZWNZXJXLZPBQJR-ASPVSBEJSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a tetrahydrobenzofuran-4-ketoximetriazole medicine. The medicine is a cis-isomeride of tetrahydrobenzofuran-4-ketoximetriazole medicine, and also comprises pharmaceutically acceptable salts and derivatives of the tetrahydrobenzofuran-4-ketoximetriazole medicine. A preparation method of the tetrahydrobenzofuran-4-ketoximetriazole medicine comprises the following steps: preparing 3,6,6-trimethyl-6,7-dihydrobenzofuran-4(5H)-one (intermediate 1) and nitrine (intermediate 2), carrying out a condensation reaction to convert the intermediate 1 into cis-oxime (intermediate 3), separating, purifying, alkylating to obtain propargyl oxime ether (intermediate 4), and carrying out a copper catalyzed cycloaddition reaction on the intermediate 4 and the nitrine (intermediate 2) to synthesize 1,2,3-triazole substituted furocyclohexanone oxime and a derivative thereof. The above compounds have dual curative effects of antiulcer and stomach cancer resistance, and can be used in stomach cancer treatment as alternative medicines.
Description
Technical field
The present invention relates to the synthetic method of the anti-gastric cancer medicament of a class tetrahydrochysene benzfuran-4-ketoxime base triazole species, Structural Identification, anti-cancer of the stomach is active and acid suppression is active, this compounds has antiulcer agent and anti-cancer of the stomach dual activity, can be used as the alternative medicine of curing gastric cancer.
Background technology
Along with the change of the aggravation of aging population trend, environmental pollution and modern way of life, cancer has become one of principal disease of serious harm publilc health and social development.Since 20 century 70s, China's Cancer Mortality and mortality ratio present sustainable growth trend.According to the tumour registration data of national tumour Register and gathering and analyzing discovery of Third National coroner's inquest data, China's Cancer Mortality was obvious ascendant trend between nearly 20 years, annual tumour new cases about 3,090,000 at present, dead 1,960,000, lung cancer, women with breast cancer, cancer of the stomach, liver cancer and the esophageal carcinoma are modal malignant tumour (Chen Wanqing, Zheng Rongshou, Zhang Siwei. the dynamic change of Chinese malignant tumour. scientific and technological Leader the 32nd volume 26 phase in 2014,65-71 page).Therefore, rationally carry out health education, strengthen the Innovation Input of antitumor drug, from source, effectively could control the deterioration of cancer situation.
As a kind of common malignant gastrointestinal tumors, cancer of the stomach (Gastric Cancer) M & M is in the world always in occupation of the prostatitis of all kinds of tumour.Due to the reason such as lymphatic metastasis or abdominal metastas, cancer of the stomach is still one of the undesirable malignant tumour of surgical treatment (Rong Weiqi, Wu Jianxiong. the progress of early gastric caacer diagnosis. Chinese clinical tumor and rehabilitation volume the 5th phase October the 13rd in 2006,469-472 page), therefore complex therapy be must carry out to cancer of the stomach, operation and adjuvant chemotherapy, radiotherapy, immunotherapy etc. comprised.The common drug of chemotherapy of gastric cancer comprises taxol, 5 FU 5 fluorouracil, cis-platinum etc., because cancer of the stomach is mostly Wheat Protein to chemotherapeutics, therefore combine usually through the dosage or drug that strengthen chemotherapeutics clinically and increase susceptibility, but the toxicity that dosage increases normal tissue (as marrow, heart and liver etc.) also can increase, reduce the tolerance (Zhang Qi of body to chemotherapy on the contrary, Xu Zhi, Chen Jinfei. gastric cancer medicament therapeutic advance. cancer progression, 12nd volume the 1st phase in 2014,22-28 page).Cancer of the stomach middle and advanced stage lacks effective treatment means, still can not meet the clinical needs control effectively to cancer of the stomach, therefore must strengthen the research and development dynamics of the anti-chemotherapy of gastric cancer medicine of highly selective, improves the survival rate of patients with gastric cancer.
Benzofuran compounds is distributed widely in composite family (Asteraceae), Rutaceae (Rutaceae), a class biologically active substance in the higher plants such as Liliaceae (Liliaceae) and Cyperaceae (Cyperaceae), can be used as exciting estrogenic agents, pth receptor antagonist, H3 acceptor and NSC 630176 etc. are for preventing and treating alzheimer's disease, osteoporosis, irregular pulse, (king is precious in the aspect such as Parkinson's disease and tumour, Lai Yisheng, Zhang Yihua. the biological activity of benzofuran compounds and structure activity relationship. pharmacy is in progress, 32nd volume the 8th phase in 2008, 351-356 page).The synthetic method of this compounds and bioactivity research are the study hotspot (Pan Chongfeng in pharmaceutical chemistry and organic synthesis field always, (5R)-6-hydroxyl-3, the efficient new synthetic method research of 8-dioxy two ring [3.2.1] octane, coumaran and benzofuran derivative. China Science & Technology University Ph.D. Dissertation, 2007).Ou Yangyudi etc. are with 2,2,7,7-tetramethyl--2,3,6,7-tetrahydro benzo [1,2-b: 6,5-b '] two furans are raw material, through open loop, Fu Ke and nucleophilic reaction, have synthesized three 2,2,7,7-tetramethyl--2,3,6,7-tetrahydro benzo [1,2-b:6,5-b '] two furan derivatives (Ou Yangyudi, Wu Daoxin, Zang Yangling, Luo Xianfu, Zhou Yong, hair light of spring .2,2,7,7-tetramethyl--2,3,6,7-tetrahydro benzo [1,2-b:6,5-b '] synthesis of two furan derivatives. fine-chemical intermediate, the 42nd volume the 4th phase in 2012,29-31 page).Lv Zeliang etc. with methoxy substitution phenyl aldehyde and chloroform for initiator has synthesized 13 kinds of 3-arylben-zofuranone compounds; thiazole blue laws is adopted to carry out tumor cell proliferation inhibition activity research to wherein 11 kinds of compounds; find that compound 4a, 4b, 4i, 4j have stronger inhibitor against colon carcinoma cells activity (Lv Zeliang; soar; Li Jun; yellow paulownia Kun; He Shujie; the synthesis of Zou Yong .3-arylben-zofuranone compounds and anti-tumor activity. SCI; 34th volume 11 phase in 2013,2531-2539 page).Shen Fang etc. adopt acidylate, alpha-brominated, the Reactive Synthesis such as thiazole cyclisation and imidization 16 kinds of 4-(7-methoxyl groups-2, 2-dimethyl-2, 3-Dihydrobenzofuranes-5-base)-2-benzyl imino thiazole new compound, biological activity test finds that such material is to two-spotted spider mite, sclerotinia rot of colza all has kills activity, also to piemarker, thorn amaranth, lamb's-quarters has certain weeding activity (Shen Fang, Hu Aixi, Luo Xianfu, Ye Jiao, Ou Xiaoming .4-(7-methoxyl group-2, 2-dimethyl-2, 3-Dihydrobenzofuranes-5-base) synthesis of-2-benzyl imino thiazole and biological activity. organic chemistry, 32nd volume in 2012, 388-392 page).
In recent years pharmaceutical chemistry research shows, triazole derivatives can be used as the novel compound with antitumor potentiality of a class, and existing multiple triazole type medicine is used for clinical treatment tumour.Such as commercial pharmaceutical letrozole (Letrozole), Anastrozole (Anastrozole) and vorozole, by suppressing the activity of aromatizing enzyme, reduce estrogen level, be used for the treatment of postmenopausal women with advanced mammary cancer as a kind of novel estrogen antagonism medicine.(meter Jia Li, Wu Jun, Zhou Chenghe. the progress of triazole species antitumor drug. West China pharmaceutical journal, the 23rd volume the 1st phase in 2008,84-86 page).Yang Ruisheng etc. are with 4-amino-5-(pyridin-3-yl)-1,2,4-Triazole is raw material, and the triazole class compounds obtained through thioetherification, condensation has activity (Yang Ruisheng, the Hu Guoqiang of stronger vitro inhibition human hepatoma cell strain SMMC-7721 and Bel-7402, Xie Songqiang, the synthesis of yellow civilian imperial .3-methylthio group-4-amino-5-(pyridin-3-yl)-1,2,4-triazole Schiff's base and anti-tumor activity. applied chemistry, 25th volume the 7th phase in 2008,783-786 page).Wang Meng alliances etc. are with piperazine, dithiocarbonic anhydride and propargyl bromide are that raw material one pot obtains the two alkine compounds of piperazinyl dithio formate, recycling " click chemistry " synthesized have no bibliographical information containing 1, 2, 1 of 3-triazole and piperazine dithio formate structural unit, [1-replaces (1 to 4-BISPIP dithiocarbonic acid, 2, 3-triazole)-4-] methyl esters compounds, anti tumor activity in vitro test finds that part of compounds is suitable with positive control Fluracil to the anti-tumor activity of stomach cancer cell MGC-803, positive control Fluracil is better than to the anti-tumor activity of Hepatocellular carcinoma cell line, half-inhibition concentration (IC
50) be respectively 11.15 and 14.75 μm of ol/L (Wang Mengmeng, Duan Yingchao, Ye Xianwei, Ren Jingli, Yu Bin, Zhang En, Liu Hongmin. [1-replaces (1 to novel Isosorbide-5-Nitrae-BISPIP dithiocarbonic acid, 2,3-triazole)-4] design of-methyl esters compounds, synthesis and antitumor activity. organic chemistry, the 33rd volume in 2013,2384-2390 page).
This patent splices principle for instructing with active subunits group, stereospecificity is prepared and has been separated tetrahydrochysene benzfuran-4-ketoximes derivatives, the mode of employing etherificate, click synthesis has prepared the drug molecule containing triazolyl, utilize the Modern spectroscopy technical evaluation such as NMR, ESI-MS, IR chemical structure of product, by anti-cancer of the stomach activity and the mechanism of action thereof of cytotoxic activity experiment and hydrogen potassium-ATP enzyme inhibit activities experiment test compound, the chemotherapy for cancer of the stomach provides novel reference drug.
Summary of the invention
The object of the present invention is to provide a kind of tetrahydrochysene benzfuran-4-ketoxime base triazole medicine, the structural formula of this medicine is:
This structural formula is the cis-isomeride of tetrahydrochysene benzfuran-4-ketoxime base triazole;
This medicine also comprises pharmacy acceptable salt, such as hydrochloride, hydrobromate, phosphoric acid salt, vitriol or oxalate etc.
The invention provides a kind of tetrahydrochysene benzfuran-4-ketoxime base triazole derivative medicine further, the structural formula of this derivative class medicine is:
Wherein, wherein tetrahydrochysene benzfuran-4-ketoxime base triazole derivative is cis-isomeride, and R is alkyl or aryl;
This medicine also comprises pharmacy acceptable salt, such as hydrochloride, hydrobromate, phosphoric acid salt, vitriol or oxalate etc.
Described R is PhCH
2-, Ph-, PhCOCH
2-, (p)-MeO-PhCOCH
2-, (p)-F-PhCOCH
2-, (m)-HO-PhCOCH
2-, (p)-Ph-PhCOCH
2-in any one, R is (m)-HO-PhCOCH more preferably
2-.
The present invention also provides a kind of composition of the medicine containing tetrahydrochysene benzfuran-4-ketoxime base triazole, said composition comprises, tetrahydrochysene benzfuran-4-ketoxime base triazole, tetrahydrochysene benzfuran-4-ketoxime base triazolium salt, tetrahydrochysene benzfuran-4-ketoxime base triazole derivative or tetrahydrochysene benzfuran-4-ketoxime base triazole derivative salt, and pharmaceutically acceptable auxiliary material or carrier, wherein, tetrahydrochysene benzfuran-4-ketoxime base triazole derivative be above-mentioned in any derivative.
1. the preparation of tetrahydrochysene benzfuran-4-ketoxime base triazole compounds and derivative thereof
1.1 instruments and medicine
Laboratory apparatus comprises: the multiplex vacuum pump of SHB-IIIA circulating water type (Shanghai Yu Kang Science & Teaching Instrument equipment company limited), DZF-6020 type vacuum drying oven (Shanghai type new talent medicine equipment Manufacturing Co., Ltd), EYELA SB-1100 type Rotary Evaporators (Shanghai lover Instrument Ltd.), 2XZ-4 type rotary-vane vaccum pump (Linhai City Tan Shi vacuum apparatus company limited), FA2104B analytical balance (Shanghai Yue Ping tech equipment company limited), GZX-9240MBE type digital display air dry oven (Medical Equipment Plant of Shanghai Boxun Industrial Co., Ltd.), the dull and stereotyped magnetic stirring apparatus (Zhengzhou Greatwall Scientific Industrial & Trading Co., Ltd.) of CL-4 type, ZF-6 type ultraviolet analysis instrument for three purposed (Shanghai Jia Peng Science and Technology Ltd.), the micro-melting point detector of XRC-1 type (tech factory of Sichuan University), DF-101S type heat collecting type constant-temperature heating magnetic stirring apparatus (Ying Yu Yu Hua instrument plant of Gongyi City).
Chemical reagent comprises: anhydrous methanol (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), dehydrated alcohol (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), acetone (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), acetonitrile (analytical pure, Tianjin Heng Xing chemical reagent Manufacturing Co., Ltd), sherwood oil (boiling range 60-90 DEG C, Tianjin Heng Xing chemical reagent Manufacturing Co., Ltd), ethyl acetate (analytical pure, Tianjin Kermel Chemical Reagent Co., Ltd.), the trimethyl carbinol (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), 5,5-dimethyl-hydroresorcinol (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), hydroxyacetone (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), oxammonium hydrochloride (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), propargyl bromide (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), ω-bromoacetophenone (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), sodium-acetate (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), sodium hydride (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), sodiumazide (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), anhydrous sodium sulphate (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), cupric bromide (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), sodium ascorbate (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), anhydrous cupric sulfate (analytical pure, Chemical Reagent Co., Ltd., Sinopharm Group), thin layer precoated plate (Qingdao is up to Chemical Co., Ltd.).
The preparation method of tetrahydrochysene benzfuran-4-ketoxime base triazole medicine, comprises the steps:
1) adopt 55 ,-dimethyl-1,3 cyclohexanedione obtains 3,6,6-trimethylammonium-6,7-Dihydrobenzofuranes-4 (5H)-one (intermediate 1) after addition;
2) intermediate 1 and oxammonium hydrochloride anhydrous alcohol solution are obtained mixed solution, sodium acetate, anhydrous is added again in mixed solution, stir, backflow 2-5h, cooling, down to obtaining (Z)-3 in frozen water, after vacuum-drying, 6,6-trimethylammonium-6,7-Dihydrobenzofuranes-4 (5H)-one oxime (intermediate 3);
3) after intermediate 3 being dissolved in acetonitrile, add sodium hydride, under fully stirring, drip propargyl bromide, stirring at room temperature 1-3h, revolve steaming, extraction into ethyl acetate, separatory, drying, separation obtain intermediate 4;
4) parahydroxyacet-ophenone is dissolved in ethyl acetate, then in solution, cupric bromide is added, reflux, after being cooled to room temperature, filters, extraction into ethyl acetate, separatory, dry, suction filtration, separation obtains alpha-brominated-4-hydroxyacetophenone, by generate alpha-brominated-4-hydroxyacetophenone is dissolved in acetone, and adds sodiumazide, 35-50 DEG C is stirred 1-3 hour, be cooled to room temperature, add water, extraction into ethyl acetate, separatory, drying, suction filtration, separation obtain α-azido--4-hydroxyacetophenone (azide intermediate 2);
5) intermediate 4 and azide intermediate 2 are suspended in the mixed solution of water and the trimethyl carbinol, add sodium ascorbate, cupric sulfate pentahydrate successively, stirring in 70-90 DEG C of oil bath spends the night until react completely (TLC monitoring), cooling reaction solution, thin up in reaction mixture, obtain white depositions, filtration, vacuum-drying, obtain tetrahydrochysene benzfuran-4-ketoxime base triazole.
Technical process is as follows:
In preparation process, intermediate 3 can synthesize with methyl alcohol, ethanol, pyridine, toluene equal solvent, and the highest with methanol yield, cost is minimum, and particular methanol is solvent; Intermediate 4 can synthesize with ether, tetrahydrofuran (THF), toluene, benzene and acetonitrile, and fastest with acetonitrile reaction, productive rate is the highest, and preferred acetonitrile is solvent; Target product can be solvent with tertiary butanol and water, methylene dichloride-water or Virahol-chloroform, but the productive rate of tertiary butanol and water system is the highest, and shortest time, is preferably reaction solvent.
Wherein, step 2) in, the mol ratio of intermediate 1, oxammonium hydrochloride, sodium acetate, anhydrous is 8-12:10-15:10-15 (preferably the mol ratio of intermediate 1, oxammonium hydrochloride, sodium acetate, anhydrous is 5:6:6).
Step 3) in, the mol ratio of intermediate 3, sodium hydride, propargyl bromide is 8-12:8-12:10-15 (preferably the mol ratio of intermediate 3, sodium hydride, propargyl bromide is 5:5:6).
Step 4) in, the mol ratio of parahydroxyacet-ophenone, bromination ketone is 8-12:18-25, the mol ratio of alpha-brominated-4-hydroxyacetophenone, sodiumazide is 3-6:5-10 (preferably the mol ratio of parahydroxyacet-ophenone, bromination ketone is 1:2, and the mol ratio of alpha-brominated-4-hydroxyacetophenone, sodiumazide is 5:6).
Step 5) in, the mol ratio of intermediate 4, azide intermediate 2, xitix, anhydrous cupric sulfate is 5:5.05 ~ 5.5:0.8-1.5:0.05-0.2 (preferably the mol ratio of intermediate 4, intermediate 2, xitix, anhydrous cupric sulfate is 5:5:1:0.1).
Step 5) in, triazo-compound can also be any one in 2-nitrine aryl methyl ketone, nitrine aromatic hydrocarbons, aryl methylene base nitrine.
Prepare 2-nitrine aryl methyl ketone, aryl methylene base nitrine with the substitution reaction of sodium azide and haloalkane, prepare nitrine aromatic hydrocarbons with arylamine diazotization, azide substitution reaction.
2, the structural analysis of tetrahydrochysene benzfuran-4-ketoxime base triazole class compounds
2.1 instruments and reagent
Laboratory apparatus: Ultrashied 400MHz Plus nuclear magnetic resonance analyser (Bruker company of Switzerland), API 4000LC-MS/MS mass spectrograph (German Brooker dalton company), 360FT-IR type infrared spectrometer (Nicolet company of the U.S.).
Experiment reagent: deuterochloroform-d (D atom content 99.8%, TMS content 0.03%V/V, 10*0.5mL/ box, ARMAR company of Switzerland); Trifluoroacetic acid aqueous solution (content 99.99%, 4L is bottled, German MILAK company); Distilled water (4.5L/ bucket, Watson Watsons company); Nuclear magnetic tube (5mm 100/pk 2ST500-8, Norell company of the U.S.); Potassium Bromide (Chemical Reagent Co., Ltd., Sinopharm Group).
2.2 test process
Accurately take 10mg target compound, dissolve with 0.5mL deuterochloroform in nuclear magnetic tube, test its chemical structure by nuclear magnetic resonance analyser; Analytical balance is got 1.0mg sample, adds Potassium Bromide 200mg and grind evenly in agate mortar, after oven dry, in compression mold, pressurization prepares salt window, the infrared spectrogram of test compounds on infrared spectrometer; Testing sample chromatogram acetonitrile is dissolved, is mixed with the solution of 1.0ppm, after microsyringe sampling, electrospray mass spectrometer is tested its mass spectrum.
The structural analysis of 2.3 compounds
(Z)-3,6,6-Trimethy-6,7-dihydrobenzofuran-4(5H)-one O-(1-benzyl-1H-1,2,3-triazol-4-yl)methyl oxime(5a):Yellow solids,yield 88％,m.p:85-87 ℃；
1H NMR(400MHz,CDCl
3)δ(ppm):7.46(s,1H),7.36-7.33(m,3H),7.26-7.24(m,2H),7.02(brs,1H),5.52(s,2H),5.20(s,2H),2.47(s,2H),2.45(s,2H),2.04(d,J＝1.2Hz,3H),1.01(s,6H)；
13C NMR(100MHz,CDCl
3)δ(ppm):156.7,152.9,145.7,138.6,134.6,129.0,128.7,128.0,122.9,118.2,114.2,67.1,54.0,37.1,36.7,32.8,28.6,10.3；IR(KBr)ν(cm
-1):2959,2921,1633,1461,1435,1219,1034,1008,978,870,727,715,696.MS(ESI)m/z:365.02[M+H].
(Z)-3,6,6-Trimethy-6,7-dihydrobenzofuran-4(5H)-one O-(1-phenyl-1H-1,2,3-triazol-4-yl)methyl oxime(5b):Yellow oil,yield 83％；
1H NMR(400MHz,CDCl
3)δ(ppm):8.01(s,1H),7.74-7.71(m,2H),7.54-7.50(m,2H),7.45-7.41(m,1H),7.05(brs,1H),5.32(s,2H),2.52(s,2H),2.49(s,2H),2.17(d,J＝1.2Hz,3H),1.05(s,6H)；
13C NMR(100MHz,CDCl
3)δ(ppm):156.8,153.1,146.0,138.7,137.1,129.7,128.7,121.1,120.6,118.2,114.2,67.1,37.1,36.8,32.8,28.7,10.5；IR(KBr)ν(cm
-1):2958,2871,1805,1758,1598,1502,1466,1034,978,759,690.MS(ESI)m/z:351.08[M+H].
(Z)-3,6,6-trimethy-6,7-dihydrobenzofuran-4(5H)-one O-[1-(2-oxo-2-phenyl-ethyl)-1H-1,2,3-triazol-4- yl]methyl oxime(5c):Yellow solids,yield 89％,m.p.112-114 ℃；
1H NMR(400 MHz,CDCl
3)δ(ppm):8.01-7.98(m,2H),7.74(s,1H),7.67(t,J＝7.6 Hz,1H),7.53(t,J＝7.6 Hz,2H),7.03(brs,1H),5.84(s,2H),5.29(s,2H),2.50(s,2H),2.48(s,2H),2.15(d,J＝1.2 Hz,3H),1.04(s,6H)；
13C NMR(100 MHz,CDCl
3)δ(ppm):190.2,156.7,153.0,145.7,138.6,134.6,134.0,129.1,128.1,124.7,118.3,114.3,67.2,55.3,37.2,36.8,32.8,28.7,10.4；IR(KBr)ν(cm
-1):2957,2928,2871,1703,1632,1597,1450,1227,1052,1000,756,689.MS(ESI)m/z:393.11[M+H].
(Z)-3,6,6-Trimethy-6,7-dihydrobenzofuran-4(5H)-one O-{1-[2-(4-hydroxyphenyl)-2-oxo-2-ethyl]-1H-1,2,3-triazol-4-yl}methyl oxime(5d):Yellow solids,yield 84％,m.p.75-77 ℃；
1H NMR(400 MHz,CDCl
3)δ(ppm):7.82(d,J＝8.8 Hz,2H),7.77(s,1H),7.02(brs,1H),6.93(d,J＝8.8 Hz,2H),5.73(s,2H),5.25(s,2H),5.19(brs,1H),2.50(s,2H),2.48(s,2H),2.11(d,J＝1.2 Hz,3H),1.01(s,6H)；
13C NMR(100 MHz,CDCl
3)δ(ppm):188.4,163.6,156.8,153.2,145.3,138.6,130.9,125.5,125.2,118.3,116.3,114.2,66.7,55.1,37.1,36.8,32.8,28.6,10.4；IR(KBr)ν(cm
-1):3146,2958,2926,1687,1603,1582,1464,1235,1068,837.MS(ESI)m/z:409.06[M+H].
(Z)-3,6,6-Trimethy-6,7-dihydrobenzofuran-4(5H)-one O-{1-[2-(4-methoxyphenyl)-2-oxo-2-ethyl]-1H-1,2,3-triazol-4-yl}methyl oxime(5e):Yellow solids,yield 80％,m.p.129-131℃；
1H NMR(400 MHz,CDCl
3)δ(ppm):7.98-7.96(m,2H),7.74(s,1H),7.03(brs,1H),7.00-6.97(m,2H),5.79(s,2H),5.28(s,2H),3.89(s,3H),2.50(s,2H),2.48(s,2H),2.14(d,J＝1.2 Hz,3H),1.03(s,6H)；
13C NMR(100 MHz,CDCl
3)δ(ppm):188.6,164.6,156.7,152.9,145.5,138.6,130.9,126.9,124.8,118.3,114.3,114.2,67.2,55.6,55.0,37.1,36.8,32.8,28.6,10.4；IR(KBr)ν(cm
-1):2956,1757,1693,1601,1575,1265,1239,1172,990,834.MS(ESI)m/z:423.09[M+H].
(Z)-3,6,6-Trimethy-6,7-dihydrobenzofuran-4(5H)-one O-{1-[2-(4-fluolophenyl)-2-oxo-2-ethyl]-1H-1,2,3-triazol-4-yl}methyl oxime(5f):Yellow solids,yield 81％,m.p.60-62 ℃；
1H NMR(400 MHz,CDCl
3)δ(ppm):8.05-8.02(m,2H),7.74(s,1H),7.21(t,J＝8.4 Hz,2H),7.03(brs,1H),5.82(s,2H),5.29(s,2H),2.50(s,2H),2.48(s,2H),2.14(d,J＝1.2 Hz,3H),1.03(s,6H)；
13C NMR(100 MHz,CDCl
3)δ(ppm):188.8,166.5(d,J＝256.2 Hz),156.7,152.9,145.8,138.6,130.97(d,J＝9.4 Hz),130.40(d,J＝2.8 Hz),124.7,118.3,116.46(d,J＝22.0 Hz),114.2,67.1,55.3,37.1,36.8,32.8,28.6,10.4；IR(KBr)ν(cm
-1):2957,2926,1703,1599,1509,1231,1159,1052,995,836.MS(ESI)m/z:411.06[M+H].
(Z)-3,6,6-Trimethy-6,7-dihydrobenzofuran-4(5H)-one O-{1-[2-(3-hydroxyphenyl)-2-oxo-2-ethyl]-1H-1,2,3-triazol-4-yl}methyl oxime(5g):Yellow solid,yield 92％,m.p.86-88 ℃；
1H NMR(400 MHz,CDCl
3)δ(ppm):8.02(s,1H),7.99(s,1H),7.50(d,J＝8.0 Hz,1H),7.37(t,J＝8.0 Hz,1H),7.20-7.17(m,1H),7.02(brs,1H),6.01(s,2H),5.30(s,2H),5.05(brs,1H),2.50(s,2H),2.47(s,2H),2.14(d,J＝1.2 Hz,3H),1.03(s,6H)；
13C NMR(100MHz,CDCl
3)δ(ppm):190.3,157.7,156.9,153.3,145.5,138.6,134.7,130.4,125.7,122.3,119.1,118.3,115.8,114.2,66.6,55.7,37.1,36.8,32.8,28.6,10.4；IR(KBr)ν(cm
-1):3146,2958,1702,1585,1450,1281,1055,865.MS(ESI)m/z:409.02[M+H].
(Z)-3,6,6-Trimethy-6,7-dihydrobenzofuran-4(5H)-one O-[1-(2-biphenyl-4-yl-2-oxo-2-ethyl)-1H-1,2,3-triazol-4-yl]methyloxime(5h):Yellow solid,yield 82％,m.p.66-68 ℃；
1HNMR(400MHz,CDCl
3)δ(ppm):8.07(d,J＝8.4Hz,2H),7.77-7.74(m,3H),7.66-7.63(m,2H),7.51-7.49(m,2H),7.47-7.43(m,1H),7.04(brs,1H),5.88(s,2H),5.30(s,2H),2.50(s,2H),2.48(s,2H),2.15(d,J＝1.2Hz,3H),1.04(s,6H)；
13C NMR(100MHz,CDCl
3)δ(ppm):189.8,156.7,152.9,147.3,145.7,139.3,138.6,132.6,129.1,128.7,128.6,127.7,127.3,124.8,118.3,114.3,67.2,55.4,37.1,36.8,32.8,28.7,27.8,10.4；IR(KBr)ν(cm
-1):2955,2869,1758,1697,1602,1404,1231,1059,996,764.MS(ESI)m/z:469.23[M+H].
Nuclear magnetic resonance spectrum interpretation of result: the three-dimensional arrangement of intermediate oxime (intermediate 3) and oxime ether (intermediate 4) is characterized by 1D and 2D NMR spectrum, can be observed the proton (δ: 8.93ppm) of hydroxyl and the relevant peaks of 3-methyl proton (δ: 2.15ppm) in NOE spectrum in intermediate 3, determine that intermediate oxime is (Z)-configuration thus.At oxime ether intermediate 4
1hNMR spectrum in, exist between the end alkynes proton of propargyl and methene proton long-range coupling (
4j=2.4Hz); Simultaneously at it
13also the carbon signal that can be observed propargyl in C nuclear magnetic resonance spectrum is respectively 80.2, and 73.8 and 61.3ppm.Target compound 5
1during H NMR composes, the proton of triazole occurs unimodal within the scope of 7.46 ~ 8.01ppm; Showing between 7.02 ~ 7.05ppm on furan nucleus is wide unimodal, and this proton and C (3)-methyl proton exist long-range coupling; N-CH
2and O-CH
2the proton of methylene radical show between 5.52 ~ 6.01ppm and 5.20 ~ 5.32ppm respectively two unimodal.
13resonance absorbing peak during C NMR composes within the scope of 114.2 ~ 190.3ppm is all consistent with the number of unsaturated carbon in compound, shows that tetrahydrochysene benzfuran ring is successfully connected with triazolyl.The strong stretching vibration absorption peak of C=N is can be observed at 1601 ~ 1646cm in the infrared spectra of target compound
- 1, the molecular weight of target compound is all corresponding with the ion adduction peak in ESI-MS.As the NOESY spectrogram that Fig. 1 is intermediate 3.
3. described tetrahydrochysene benzfuran-4-ketoxime base triazole and composition, tetrahydrochysene benzfuran-4-ketoxime base triazole derivative and composition thereof or its salt are applied in the anti-gastric cancer medicament of preparation treatment by the present invention.
3.1 reagent and instrument
Experiment reagent: 10.4g dry powder type (dissolves in 1000mL tri-distilled water without phenol red RPMI640 by RPMI1640 nutrient solution, add 2.0g sodium bicarbonate and be stirred to abundant dissolving, then filter with 0.22 μm of aseptic positive press filtration device, packing, then add 10% calf serum, 0.5% penicillin (100U/mL) and Streptomycin sulphate (100 μ g/mL).
Laboratory apparatus: Bechtop (Beijing Dong Lianhaer instrument manufacturing company limited), ultrasonic washing instrument (ride the waves Xin Zhi biotech inc), TDZ4-WS type low speed centrifuge (the ordinary instrument company limited in Changsha), DK-8A type electric heating constant temperature tank (the upper grand experimental installation company limited of Nereid), automatic distilled water distiller (Shanghai Ya Rong biochemical equipment Instrument Ltd.), HTC-100A type fixed temperature and humidity incubator (Instrument Ltd. is risen in Shanghai three), LDZX-30KBS type vertical pressure steam sterilizer (Shenan Medical Appliances Factory, Shanghai), CO2gas incubator (SANYO GS company), Stat Fax-2100 type enzyme-linked immunosorbent assay instrument (Awareness company of the U.S.).
3.2 experimental section
Utilize MTT method evaluation tetrahydrochysene benzfuran compounds to the inhibited proliferation of stomach cancer cell HGC-27: stomach cancer cell HGC-27 is provided by Chinese Academy of Sciences's Shanghai cell bank, adopt the RPMI1640 containing 100U/ml mycillin and 10% new fetal calf serum as cell culture fluid, cell is placed in 37 DEG C, 5%CO
2cell culture incubator cultivate.During passage, adjustment cell density is 5 × 10
4~ 1 × 10
5cells/well is inoculated into 96 orifice plates, is placed in 37 DEG C, 5%CO
2cultivate in incubator.Add the medicine of different concns after 24h, separately set blank group (nutrient solution), Normal group (cell+nutrient solution) and positive controls (taking antitumor drug paclitaxel as positive control), process 48h.Experiment adds 37 DEG C, MTT (5mg/mL) 20 μ L/ hole after stopping and continues to hatch 4h, sucking-off supernatant liquor, and every hole adds the DMSO of 150 μ L, shakes up, absorbancy (OD) during mensuration 492nm wavelength.Generate first a ceremonial jade-ladle, used in libation through Metabolism of Mitochondria after MTT is absorbed by viable cell, plastosome vigor more vigorous first a ceremonial jade-ladle, used in libation generates more, and absorbancy is also higher, reflection cell survival.Calculate cell inhibitory rate, judge whether medicine has restraining effect to the propagation of cell with cell inhibitory rate (the inhibiting rate T/C=1-dosing cell OD/ compared with control cells OD of cell).Half-inhibition concentration (IC
50), Chang Zuowei reflects the quantitative target of effect of drugs, widespread use in various drug screening, therefore utilizes statistic software SPSS 13.0 to calculate also comparative drug respectively and acts on the IC of different cell
50, reflection drug effectiveness.
3.3 activity rating analyses
With commercialization anti-cancer medicine paclitaxel for positive control, have rated the cytotoxic activity (see the following form) of triazolyl furo cyclohexanone-oxime compounds to HGC-27 by mtt assay.Result shows, majority of compounds has medium cytotoxic activity, and wherein 5c, 5g, 5h are to the antiproliferative IC of HGC-27
50value reaches less than 20 μMs, is conducive to the cytotoxic activity improving this compounds when inferring hydroxyl.Above result of study is that the anti-gastric cancer medicament purposes of benzofuran compounds provides reference.
4, described tetrahydrochysene benzfuran-4-ketoxime base triazole and composition, tetrahydrochysene benzfuran-4-ketoxime base triazole derivative and composition thereof or its salt are also applied on preparation treatment anti-ulcer medicament by the present invention.
Proton pump inhibitor is the medicine of the novel gastric acid secretion inhibiting of a class, specificity and noncompetitively act on H
+/ K
+-ATP enzyme, the acid that the secretion of basic hydrochloric acid in gastric juice and the multiple stimulation such as histamine, feed can be suppressed to cause is secreted.H
+/ K
+-ATP enzyme is positioned at the tubulovesicle of parietal cell and secretes on periosteum, the H completed by self phosphorylation (E1 → E2) and dephosphorylation (E2 → E1)
+/ K
+electric neutrality ion transport, constantly exercises the function of secreting acid outward, therefore suppresses H to film by the proton transport in parietal cell
+/ K
+-ATP enzyme, can play powerful suppression gastric secretion effect.Chemotherapy resistance is one of main bugbear of current oncotherapy, recent research confirms, it is the common trait of most of tumor drug resistance cell strain that internal pH increases, proton pump inhibitor is by inhibition tumor cell cavity atpase activity, improve the microenvironment of the outer acid of alkali in cell and block the acidifying of tumor microenvironment, improve tumour to the susceptibility of chemotherapeutic agent, also by increasing lysosomal permeability, by mechanism such as lysosome alkalization, induction stomach cancer cell generation autophagy or apoptosis.Given this, this patent adopts hydrogen potassium-ATP enzyme test kit assessing compound to the inhibit activities of hydrogen potassium-ATP, develops the drug effect of its acid suppression.
External H
+/ K
+-ATP enzyme inhibit activities test philosophy
4.1 external H
+/ K
+-ATP enzyme inhibit activities experimental program
Get the Mouse Gastric Mucous Membrane of stomach ulcer, add physiological saline and make stomach mucous membrane homogenate, obtain after differential centrifugation containing H
+, K
+the MC supernatant liquor of-ATP enzyme.Proceed to Tissue Culture Plate, add medicine to be measured and after hatching certain hour, with commercially available H
+/ K
+-atpase activity measures kit measurement enzymic activity.
The foundation of 4.2 gastric ulcer models
Get body 18 ~ 22g Kunming mouse, put to death under waking state, sterilizing 3 ~ 5min in 75% alcohol, cuts open inspection under aseptic condition.Get Mouse Stomach, by cold PBS buffer solution for cleaning, after washing away food debris and bloodstain, with flat mouth tweezers, stratum mucosum inside stomach is scraped, put into aseptic centrifuge tube, shred, with liquid-transfering gun, 0.5% pancreatin is injected centrifuge tube (every stomach is about 5ml), 37 DEG C of water-baths digestion, 8 ~ 10min, and in digestive process suitable vibration centrifugal pipe.After having digested, add rapidly cold PBS solution, reduce the digestion ability of pancreatin, simultaneously with liquid-transfering gun piping and druming, make cell detachment, cross 200 mesh sieves, repeated collection 2 times, the centrifugal 7min of 1200r/min, centrifuge tube bottom settlings is parietal cell.Reject supernatant liquid, cell precipitation DMEM substratum suspends, and is parietal cell suspension.
4.3 parietal cell qualifications
Parietal cell: 1. form: parietal cell form is comparatively large, core centre how placed in the middle, rich in mitochondria.HE dyes, and under light microscopic, Visible Core dyes blueness, kytoplasm pink.2. motility rate: 1.0g/L Trypan blue dyes, and dead cell dyes blueness, and viable cell is not painted.3. cell counting: instilled carefully by cell suspension in cytometry dish, by automatic counting of red blood, several four block plaid inner cell number sums are N, then often liter of cell count is: cells/L=N × 4 × 10
4.
The cultivation of 4.4 parietal cells and H
+/ K
+-atpase activity measures
Parietal cell suspension after purifying proceeds to 96 porocyte culture plates, adds after medicine 37 DEG C hatches 2h, uses H
+, K
+-atpase activity measures kit measurement enzymic activity, and operation by specification carries out, and specifying that the ATP enzyme of every milligram of albumen per hour decomposes the amount that ATP produces 1 μm of ol inorganic phosphorus is 1 H
+/ K
+-atpase activity unit, with mmolmg
-1h
-1represent.Positive control medicine: commercially available proton pump inhibitor omeprazole, Revaprazan.
The enzyme inhibition activity result of 4.5 active compounds
Conclusion: compound 5c, 5g and 5h (IC with stronger anti-cancer of the stomach activity
50<20 μM) all there is stronger H
+/ K
+-ATP enzyme inhibit activities, is better than commercially available irreversible proton pump inhibitor omeprazole (IC
5080.03 μMs), be slightly better than commercially available reversible proton pump inhibitor Revaprazan (IC
5038.77 μM).Structure-activity relation research shows, triazole group is introduced xenyl or 3-hydroxy phenyl, is expected to the Acidinhibitor improving compound.
Accompanying drawing explanation
Fig. 1 is the NOESY spectrogram of intermediate 3.
Embodiment
Embodiment 1
First 3 have been prepared, 6,6-trimethylammonium-6,7-Dihydrobenzofuranes-4 (5H)-one (intermediate 1) and nitrine (intermediate 2), by condensation reaction, intermediate 1 is converted into cis ketoxime (intermediate 3) again, after separating-purifying, its alkylation is obtained propargyl oxime ether (intermediate 4), finally intermediate 4 and azide intermediate 2 are synthesized 1 through the cycloaddition reaction of copper catalysis, 2, the furo cyclohexanone-oxime analog derivative that 3-triazol radical replaces, synthetic route is as follows:
The synthesis (intermediate 2) of nitrine: by parahydroxyacet-ophenone (1.36g, 10.0mmol) be dissolved in ethyl acetate (20ml), then in solution, cupric bromide (4.48g, 20.0mmol) is added, reflux 5 hours.After being cooled to room temperature, filter, 100mL water is poured in filtrate, be extracted with ethyl acetate (3 × 100mL), separatory, organic phase anhydrous sodium sulfate drying, suction filtration, lower resistates column chromatography separation (eluent: ethyl acetate/petroleum ether=1:25, v/v) except obtaining after desolventizing of decompression, obtains alpha-brominated-4-hydroxyacetophenone.
By generate alpha-brominated-4-hydroxyacetophenone (1.075g, 5.0mmol) is dissolved in acetone (20ml), then in solution, adds sodiumazide (0.39g, 6.0mmol), 40 DEG C are stirred 2 hours.After being cooled to room temperature, 50mL water is poured in solution, be extracted with ethyl acetate (3 × 50mL), separatory, organic phase anhydrous sodium sulfate drying, suction filtration, the lower resistates column chromatography separation (eluent: ethyl acetate/petroleum ether=1:15 except obtaining after desolventizing of decompression, v/v), α-azido--4-hydroxyacetophenone is obtained.
The synthesis of oxime (intermediate 3): (Z)-3,6,6-trimethylammonium-6, the synthesis of 7-Dihydrobenzofuranes-4 (5H)-one oxime (intermediate 3): by 3,6,6-trimethylammonium-6,7-Dihydrobenzofuranes-4 (5H)-one (intermediate 1,1.78g, 10.0mmol) with oxammonium hydrochloride (0.834g, 12.0mmol) dissolve with 30mL anhydrous methanol, then in solution, add sodium acetate, anhydrous (0.984g, 12.0mmol).Stirring, reflux 4h, but, by it down in 150ml frozen water, filter and obtain white solid, namely dried in vacuo overnight obtains compound 3 in question response liquid cooling.
The synthesis of oxime ether (intermediate 4): (Z)-3,6,6-trimethylammonium-6, the synthesis of the synthesis (intermediate 4) of 7-Dihydrobenzofuranes-4 (5H)-one oximido alkynes propyl ether: by intermediate 3 (1.92g, 10.0mmol) be dissolved in acetonitrile (25ml), then in solution, sodium hydride (0.24g is slowly added, 10.0mmol), propargyl bromide (1.428g is dripped under abundant stirring, 12.0mmol), stirring at room temperature 2 hours.Revolve and steam except after desolventizing, pour 50mL water wherein into, be extracted with ethyl acetate (3 × 50mL), separatory, organic phase anhydrous sodium sulfate drying, suction filtration, the lower resistates column chromatography separation (eluent: ethyl acetate/petroleum ether=1:20 except obtaining after desolventizing of decompression, v/v), intermediate 4 is obtained.
The synthesis of target compound 5: by propargyl ether (intermediate 4,0.5mmol) with α-azido--4-hydroxyacetophenone (azide intermediate 2,0.5mmol) be suspended in the mixed solution of water (3mL) and the trimethyl carbinol (3mL), add sodium ascorbate (19.8mg again, 0.1mmol), then cupric sulfate pentahydrate (2.5mg is added, 0.01mL), stir in 80 DEG C of oil baths and spend the night until react completely (TLC monitoring).Cooling reaction solution, add water (20mL) dilution in reaction mixture, obtains white depositions.Filter and vacuum-drying, obtain tetrahydrochysene benzfuran-4-ketoxime base triazole.
Embodiment 2
Other step is with embodiment 1, in the synthesis step of target compound 5a ~ 5h, by propargyl ether (intermediate 4,0.5mmol) react in tertiary butanol and water mixed system with 2-nitrine aryl methyl ketone, reaction controlling and separation and purification mode, with embodiment 1, only need change dissimilar azide intermediate 2.Triazo-compound is 2-nitrine aryl methyl ketone, nitrine aromatic hydrocarbons, aryl methylene base nitrine
Embodiment 3
The preparation method of tetrahydrochysene benzfuran-4-ketoxime base triazolium salt, for hydrochloride.1.0mmol target product 5a ~ 5h one is wherein taken in 50mL three-necked bottle; be dissolved in 5mL anhydrous methanol; under nitrogen protection reaction flask is cooled to 0 DEG C; hydrogenchloride/the methanol solution of 1mol/L is dripped with constant pressure funnel; be stirred to the complete salify of product (the salinization process of thin-layer chromatography monitoring neutral molecule); solvent evaporated, and obtain tetrahydrochysene benzfuran-4-ketoxime base triazolium salt hydrochlorate.
The preparation method of hydrobromate, vitriol, oxalate etc. is the same.
Claims (12)
1. a tetrahydrochysene benzfuran-4-ketoxime base triazole medicine, is characterized in that, the structural formula of this medicine is:
This structural formula is the cis-isomeride of tetrahydrochysene benzfuran-4-ketoxime base triazole;
This medicine also comprises pharmacy acceptable salt, tetrahydrochysene benzfuran-4-ketoxime base triazole pharmacologically acceptable salts comprise in hydrochloride, hydrobromate, phosphoric acid salt, vitriol or oxalate any one, its structural formula is
2. tetrahydrochysene benzfuran-4-ketoxime base triazole medicine according to claim 1 can also be tetrahydrochysene benzfuran-4-ketoxime base triazole derivative medicine, and it is characterized in that, the structural formula of this derivative class medicine is:
Wherein, tetrahydrochysene benzfuran-4-ketoxime base triazole derivative is cis-isomeride, and R is alkyl or aryl;
This medicine also comprises pharmacy acceptable salt, tetrahydrochysene benzfuran-4-ketoxime base triazole derivative pharmacologically acceptable salts comprise in hydrochloride, hydrobromate, phosphoric acid salt, vitriol or oxalate any one, its structural formula is
3. derivative medicine according to claim 2, is characterized in that, described R is PhCH
2-, Ph-, PhCOCH
2-, (p)-MeO-PhCOCH
2-, (p)-F-PhCOCH
2-, (m)-HO-PhCOCH
2-, (p)-Ph-PhCOCH
2-in any one.
4. derivative medicine according to claim 2, is characterized in that, described R is (m)-HO-PhCOCH
2-.
5. the composition of medicine containing tetrahydrochysene benzfuran-4-ketoxime base triazole described in any one of claim 1-4, it is characterized in that, said composition comprises the medicine described in any one of Claims 1 to 4, and pharmaceutically acceptable auxiliary material or carrier.
6. a preparation method for the medicine of tetrahydrochysene benzfuran-4-ketoxime base triazole or derivatives thereof, is characterized in that, comprise the steps:
1) adopt 55 ,-dimethyl-1,3 cyclohexanedione obtains 3,6,6-trimethylammonium-6,7-Dihydrobenzofuranes-4 (5H)-one (intermediate 1) after addition;
2) intermediate 1 and oxammonium hydrochloride solvent anhydrous alcohol solution are obtained mixed solution, sodium acetate, anhydrous is added again in mixed solution, stir, backflow 2-5h, cooling, down to obtaining (Z)-3 in frozen water, after vacuum-drying, 6,6-trimethylammonium-6,7-Dihydrobenzofuranes-4 (5H)-one oxime (intermediate 3);
3) after intermediate 3 being dissolved in acetonitrile solvent, add sodium hydride, under fully stirring, drip propargyl bromide, stirring at room temperature 1-3h, revolves steaming, extraction into ethyl acetate, separatory, drying, separation obtains (Z)-3,6,6-trimethylammonium-6,7-Dihydrobenzofuranes-4 (5H)-one oximido alkynes propyl ether (intermediate 4);
4) parahydroxyacet-ophenone is dissolved in ethyl acetate, then in solution, cupric bromide is added, reflux, after being cooled to room temperature, filters, extraction into ethyl acetate, separatory, dry, suction filtration, separation obtains alpha-brominated-4-hydroxyacetophenone, by generate alpha-brominated-4-hydroxyacetophenone is dissolved in acetone, and adds sodiumazide, 35-50 DEG C is stirred 1-3 hour, be cooled to room temperature, add water, extraction into ethyl acetate, separatory, drying, suction filtration, separation obtain α-azido--4-hydroxyacetophenone (azide intermediate 2);
5) intermediate 4, azide intermediate 2 or triazo-compound are suspended in the mixed solvent of water and the trimethyl carbinol, add sodium ascorbate, cupric sulfate pentahydrate successively, stirring in 70-90 DEG C of oil bath spends the night until react completely (TLC monitoring), cooling reaction solution, thin up in reaction mixture, obtain white depositions, filtration, vacuum-drying, obtain tetrahydrochysene benzfuran-4-ketoxime base triazole or tetrahydrochysene benzfuran-4-ketoxime base triazole derivative.
7. preparation method according to claim 6, is characterized in that,
Step 2) in, the mol ratio of intermediate 1, oxammonium hydrochloride, sodium acetate, anhydrous is 8-12:10-15:10-15;
Step 3) in, the mol ratio of intermediate 3, sodium hydride, propargyl bromide is 8-12:8-12:10-15;
Step 4) in, the mol ratio of parahydroxyacet-ophenone, bromination ketone is 8-12:18-25, and the mol ratio of alpha-brominated-4-hydroxyacetophenone, sodiumazide is 3-6:5-10;
Step 5) in, the mol ratio of intermediate 4, azide intermediate 2, xitix, anhydrous cupric sulfate is 5:5.05 ~ 5.5:0.8-1.5:0.05-0.2.
8. preparation method according to claim 6, is characterized in that,
Step 2) in, the mol ratio of intermediate 1, oxammonium hydrochloride, sodium acetate, anhydrous is 5:6:6;
Step 3) in, the mol ratio of intermediate 3, sodium hydride, propargyl bromide is 5:5:6;
Step 4) in, the mol ratio of parahydroxyacet-ophenone, bromination ketone is 1:2, and the mol ratio of alpha-brominated-4-hydroxyacetophenone, sodiumazide is 5:6;
Step 5) in, the mol ratio of intermediate 4, azide intermediate 2, xitix, anhydrous cupric sulfate is 5:5:1:0.1.
9. preparation method according to claim 6, is characterized in that, step 5) in, azide intermediate 2 can also be any one in 2-nitrine aryl methyl ketone, nitrine aromatic hydrocarbons, aryl methylene base nitrine for triazo-compound.
10. preparation method according to claim 6, is characterized in that, step 2) in, described anhydrous ethanol solvent can also be any one in methyl alcohol, pyridine or toluene; Step 3) in, acetonitrile solvent can also be any one in ether, tetrahydrofuran (THF), toluene or benzene; Step 5) in, the mixed solvent of tertiary butanol and water can also be the mixed solvent of methylene dichloride-water or Virahol-chloroform.
11. tetrahydrochysene benzfuran-4-ketoxime base triazoles according to any one of claim 1 ~ 10 and composition, tetrahydrochysene benzfuran-4-ketoxime base triazole derivative and composition thereof or the application of its salt in the anti-gastric cancer medicament of preparation treatment.
12. tetrahydrochysene benzfuran-4-ketoxime base triazoles according to any one of claim 1 ~ 10 and composition, tetrahydrochysene benzfuran-4-ketoxime base triazole derivative and composition thereof or the application of its salt on preparation treatment anti-ulcer medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510111498.3A CN104788436B (en) | 2015-03-13 | 2015-03-13 | Tetrahydrochysene benzfuran -4- ketoxime base triazole medicines, preparation method and applications |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510111498.3A CN104788436B (en) | 2015-03-13 | 2015-03-13 | Tetrahydrochysene benzfuran -4- ketoxime base triazole medicines, preparation method and applications |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104788436A true CN104788436A (en) | 2015-07-22 |
| CN104788436B CN104788436B (en) | 2018-05-01 |
Family
ID=53553673
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510111498.3A Active CN104788436B (en) | 2015-03-13 | 2015-03-13 | Tetrahydrochysene benzfuran -4- ketoxime base triazole medicines, preparation method and applications |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104788436B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110804035A (en) * | 2019-11-11 | 2020-02-18 | 三峡大学 | Tetrahydrobenzofuran Mannich alkali compounds, and preparation method and application thereof |
| CN110840896A (en) * | 2019-11-11 | 2020-02-28 | 三峡大学 | Preparation method and application of dihydro quinazolinone medicine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100497323C (en) * | 2003-07-28 | 2009-06-10 | 瑟维尔实验室 | New heterocyclic oxime compounds, preparing process and medical composition thereof |
-
2015
- 2015-03-13 CN CN201510111498.3A patent/CN104788436B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100497323C (en) * | 2003-07-28 | 2009-06-10 | 瑟维尔实验室 | New heterocyclic oxime compounds, preparing process and medical composition thereof |
Non-Patent Citations (4)
| Title |
|---|
| CAO CHENG-QIAO, ET AL.,: "Synthesis and Crystal Structure of (Z)-2-Methyl-5,6-dihydrobenzo[d]thiazol-7(4H)-one O-Prop-2-yn-1-yl Oxime Derivatives.", 《CHINESE J. STRUCT. CHEM.》 * |
| HUBIAO FANG, ET AL.,: "Synthesis and in vitro anti-ulcer effect of triazolo-methyl tetrahydrobenzofuran oxime ether derivatives.", 《ADVANCED MATERIALS RESEARCH》 * |
| JIN LEI, ET AL.,: "Synthesis and Crystal Structure of (E)-2-phenyl-6,7-dihydrobenzofuran-4(5H)-one O-cyanomethyl Oxime.", 《CHINESE J. STRUCT. CHEM.》 * |
| LEI JIN, ET AL.,: "Synthesis and structure elucidation of novel oxime ether type H+/K+-ATPase inhibitors.", 《ADVANCED MATERIALS RESEARCH》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110804035A (en) * | 2019-11-11 | 2020-02-18 | 三峡大学 | Tetrahydrobenzofuran Mannich alkali compounds, and preparation method and application thereof |
| CN110840896A (en) * | 2019-11-11 | 2020-02-28 | 三峡大学 | Preparation method and application of dihydro quinazolinone medicine |
| CN110840896B (en) * | 2019-11-11 | 2022-05-03 | 三峡大学 | Preparation method and application of dihydro quinazolinone medicine |
| CN110804035B (en) * | 2019-11-11 | 2022-11-18 | 三峡大学 | Tetrahydrobenzofuran Mannich alkali compounds, and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104788436B (en) | 2018-05-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Pingaew et al. | Design, synthesis and molecular docking studies of novel N-benzenesulfonyl-1, 2, 3, 4-tetrahydroisoquinoline-based triazoles with potential anticancer activity | |
| Firoozpour et al. | Cytotoxic activity evaluation and QSAR study of chromene-based chalcones | |
| Dziewulska-Kułaczkowska et al. | Structural studies and characterization of 3-formylchromone and products of its reactions with chosen primary aromatic amines | |
| CN110551145A (en) | furocoumarin-Tr gers' Base derivatives, and synthetic method and application thereof | |
| Murali et al. | Regio-and stereoselective synthesis of dispirooxindole-pyrrolocarbazole hybrids via 1, 3-dipolar cycloaddition reactions: Cytotoxic activity and SAR studies | |
| CN104072493A (en) | Naphthalimide compound containing 2-mercaptobenzothiazole and triazole heterocycle, preparation method and application thereof | |
| CN104788436A (en) | Tetrahydrobenzofuran-4-ketoximetriazole medicine, and preparation method and application thereof | |
| CN112939868B (en) | Indazole hydrazide compound and application thereof | |
| CN103102331B (en) | Pharmaceutical application of chalcone compound containing piperazine ring | |
| CN113149942A (en) | Rockmilanol phenolic hydroxyl derivative, preparation method and application thereof | |
| CN110128343A (en) | A kind of hydrazide kind compound | |
| CN106632374B (en) | Different mannitol-bisbenzimidazole salt compound and preparation method thereof | |
| CN111269253B (en) | Chalcone Sanjunolide derivative and application thereof in preparation of castration-resistant prostate cancer drugs | |
| CN104804047A (en) | Preparation method and application of novel ferrocene derivative containing free radicals of nitroxide | |
| CN112062799B (en) | Methoxy-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative and preparation method and application thereof | |
| CN110183467B (en) | P-methoxyphenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| Mikiciuk‐Olasik et al. | New derivatives of quinazoline and 1, 2‐dihydroquinazoline n3‐oxide with expected antitumor activity | |
| CN104817544B (en) | Tetrahydroindole-4-ketoxime drug, preparation method and application thereof | |
| Han et al. | Pyran Derivatives: Anti-Breast Cancer Activity and Docking Study | |
| CN112028955B (en) | Trimethoxylated arabinose triazole structure spiroisoxazole-pyrrolizine derivative and preparation method and application thereof | |
| CN108997149A (en) | A kind of dehydroabietylamine derivatives and its preparation method and application that aryl replaces | |
| CN111961100B (en) | Fluorine-substituted arabinose triazole structure spiroisoxazole-pyrrolizine derivative and preparation method and application thereof | |
| CN111961101B (en) | Spiroisoxazole-pyrrolizine derivative with arabinose triazole structure as well as preparation method and application thereof | |
| CN110143971B (en) | Methylthiophenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN111909230B (en) | Chlorine-substituted arabinose triazole structure spiro isoxazole-pyrrolizine derivative and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |