CN104788436B - Tetrahydrochysene benzfuran -4- ketoxime base triazole medicines, preparation method and applications - Google Patents

Tetrahydrochysene benzfuran -4- ketoxime base triazole medicines, preparation method and applications Download PDF

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CN104788436B
CN104788436B CN201510111498.3A CN201510111498A CN104788436B CN 104788436 B CN104788436 B CN 104788436B CN 201510111498 A CN201510111498 A CN 201510111498A CN 104788436 B CN104788436 B CN 104788436B
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phcoch
tetrahydrochysene benzfuran
ketoxime
ketoxime base
gastric cancer
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CN104788436A (en
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黄年玉
王文彬
金蕾
张凡
汪鋆植
邹坤
闫喜明
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China Three Gorges University CTGU
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    • 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

Abstract

The present invention relates to a kind of 4 ketoxime base triazole medicine of tetrahydrochysene benzfuran, which is the cis-isomer of 4 ketoxime base triazole of tetrahydrochysene benzfuran：The medicine further includes pharmaceutically acceptable salt and derivative.Specific preparation method is to be prepared for 3 first, 6,6 trimethyls 6,7 Dihydrobenzofuranes 4 (5H) ketone (intermediate 1) and nitrine (intermediate 2), intermediate 1 is converted into by cis ketoxime (intermediate 3) by condensation reaction again, it is alkylated to obtain propargyl oxime ether (intermediate 4) after separating-purifying, finally by the cycloaddition reaction synthesis 1 of intermediate 4 and azide intermediate 2 through copper catalysis, the furans and cyclohexanone oxime and its derivative of 2,3 triazol radicals substitution.Such compound has antiulcer and anti-gastric cancer dual activity, can be as the alternative medicine of curing gastric cancer.

Description

Tetrahydrochysene benzfuran -4- ketoxime base triazole medicines, preparation method and applications
Technical field
Synthetic method, structure mirror the present invention relates to a kind of tetrahydrochysene benzfuran -4- ketoximes base triazole type anti-gastric cancer medicament Fixed, anti-gastric cancer activity and acid suppression activity, such compound have antiulcer and anti-gastric cancer dual activity, can be as curing gastric cancer Alternative medicine.
Background technology
With the change of the aggravation of aging of population trend, environmental pollution and modern way of life, cancer has become serious Endanger one of principal disease of publilc health and social development.Since the 1970s, China's Cancer Mortality and The death rate shows sustainable growth trend.Tumour registration data and Third National coroner's inquest according to national tumour Register Data collect and analysis is found, China's Cancer Mortality was in obvious ascendant trend between nearly 20 years, current annual tumour New cases about 3,090,000, dead 1,960,000, lung cancer, women with breast cancer, stomach cancer, liver cancer and the cancer of the esophagus are most common malignant tumours (dynamic change science and technology Leader 26 phases of volume 32 in 2014 of Chen Wanqing, Zheng Rongshou, Zhang Siwei China malignant tumour, 65-71 Page).Therefore, rationally carry out health education, strengthen the Innovation Input of antitumor drug, cancer shape could be effectively controlled from source The deterioration of gesture.
As a kind of common malignant gastrointestinal tumors, the incidence of stomach cancer (Gastric Cancer) in the world and The death rate is always in occupation of the forefront of all kinds of tumours.Due to reasons such as Lymph Node Metastasis or abdominal metastas, stomach cancer is still surgical intervention One of undesirable malignant tumour of effect (Rong Weiqi, Wu Jian hero early gastric caacers diagnosis progress China's clinical tumors with Rehabilitation the 5th phase of volume 13 in October, 2006,469-472 pages), it is therefore necessary to carry out complex treatment to stomach cancer, including operation and auxiliary Help chemotherapy, radiotherapy, immunization therapy etc..The common drug of chemotherapy of gastric cancer includes taxol, 5 FU 5 fluorouracil, cis-platinum etc., due to stomach Cancer is mostly hyposensitivity to chemotherapeutics, therefore is clinically combined usually through the dosage or drug that increase chemotherapeutics to increase Add sensitiveness, but the toxicity of dosage increase normal tissue (such as marrow, heart and liver) can also increase, and reduce on the contrary Body to the tolerance of chemotherapy (Zhang Qi, Xu Zhi, Chen Jin fly gastric cancer medicament therapeutic advance cancer progressions, 2014 volume 12 the 1st Phase, 22-28 pages).Stomach cancer middle and advanced stage lacks effective treatment means, cannot still meet the clinical need controling effectively to stomach cancer Will, it is therefore necessary to strengthen the research and development dynamics of the anti-gastric cancer chemotherapeutics of high selectivity, improve the survival rate of patients with gastric cancer.
Benzofuran compounds are to be distributed widely in composite family (Asteraceae), Rutaceae (Rutaceae), Liliaceae (Liliaceae) and a kind of bioactive substance in the higher plant such as Cyperaceae (Cyperaceae), it can be used as excitement is female to swash Plain receptor modulators, pth receptor antagonist, H3 acceptors and histon deacetylase (HDAC) inhibitor etc. are used to prevent A Er (king is precious, Lai Yisheng, Zhang Yihua benzo furans for Ci Haimo diseases, osteoporosis, arrhythmia cordis, Parkinson's and tumour etc. Bioactivity and structure-activity relationship the pharmacy progress of class of muttering compound, the 8th phase of volume 32 in 2008,351-356 pages).Such chemical combination The synthetic method and bioactivity research of thing be always pharmaceutical chemistry and organic synthesis field research hotspot (Pan Chongfeng, (5R)- 6- hydroxyl -3,8- dioxies two ring [3.2.1] octane, coumaran and benzofuran derivative efficiently synthesize new method Research China Science ＆ Technology University Ph.D. Dissertations, 2007).Ou Yangyudi etc. is with 2,2,7,7- tetramethyls -2,3,6,7- four Two furans of hydrogen benzo [1,2-b: 6,5-b '] is raw material, by open loop, Fu Ke and necleophilic reaction, has synthesized three 2,2,7,7- tetra- Methyl -2,3,6,7- tetrahydro benzos [1,2-b:6,5-b '] two furan derivatives (Ou Yangyudi, Wu Daoxin, Zang Yangling, Luo Xian Good fortune, Zhou Yong, hair light of spring .2,2,7,7- tetramethyl -2,3,6,7- tetrahydro benzos [1,2-b:6,5-b '] two furan derivatives conjunction Into fine-chemical intermediates, the 4th phase of volume 42 in 2012,29-31 pages).Lv Zeliang etc. is with methoxy substitution benzaldehyde and chloroform 13 kinds of 3- arylben-zofuranone class compounds have been synthesized for starting material, wherein 11 kinds of compounds have been carried out using thiazole blue laws Tumor cell proliferation inhibition activity is studied, find 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 class compounds and antitumor activity high etc. School's chemistry journal, 11 phases of volume 34 in 2013,2531-2539 pages).Shen Fang etc. is using acylated, alpha-brominated, thiazole cyclisation and Asia The reactions such as amination have synthesized 16 kinds of 4- (7- methoxyl group -2,2- dimethyl -2,3- Dihydrobenzofuranes -5- bases) -2- benzyl imino groups Thiazole noval chemical compound, biological activity test finds that such material is respectively provided with killing activity to two-spotted spider mite, sclerotinia sclerotiorum, also right Piemarker, thorn amaranth, lamb's-quarters have certain activity of weeding (the bright .4- of Shen Fang, Hu Aixi, Luo Xianfu, Ye Jiao, Ou Xiao (7- methoxyl group -2, 2- dimethyl -2,3- Dihydrobenzofuranes -5- bases) -2- benzyl imino thiazoles synthesis and bioactivity organic chemistry, 2012 Volume 32,388-392 pages of year).
In recent years pharmaceutical chemistry research shows that triazole derivatives can be as a kind of new chemical combination with antitumor potentiality Thing, existing multiple triazole type medicines are used for clinical treatment tumour.Such as commercial pharmaceutical Letrozole (Letrozole), Ah Nagqu Azoles (Anastrozole) and Vorozole, by suppressing the activity of aromatizing enzyme, reduce estrogen level, as a kind of new Estrogen antagonism medicine is used to treat postmenopausal women with advanced breast cancer.(meter Jia Li, Wu Jun, Zhou Chenghe triazole series antineoplastic medicaments are ground Study carefully progress West China pharmaceutical journal, the 1st phase of volume 23 in 2008,84-86 pages).Yang Ruisheng etc. is with 4- amino -5- (pyridine -3- Base) -1,2,4- Triazoles are raw material, have stronger external suppression people through thioetherification, the triazole class compounds being condensed to yield The activity of Liver cancer cell SMMC-7721 and Bel-7402 (Yang Ruisheng, Hu Guoqiang, Xie Songqiang, yellow text dragon .3- methyl mercapto -4- ammonia The synthesis of base -5- (pyridin-3-yl) -1,2,4- triazole schiff bases and antitumor activity applied chemistries, 2008 volume 25 the 7th Phase, 783-786 pages).Wang Meng alliances etc. obtain piperazinyl dithio formate pair for one pot using piperazine, carbon disulfide and propargyl bromide as raw material Alkine compounds, recycle " click chemistry " synthesized have no document report contain 1,2,3-triazoles and piperazine dithiocarbonic acid The Isosorbide-5-Nitrae of ester structure unit-dipiperazine dithiocarbonic acid [1- substitutes (1,2,3-triazoles) -4-] first ester type compound, it is external anti-swollen Tumor activity test finds that part of compounds is suitable with positive control fluorouracil to the antitumor activity of stomach cancer cell MGC -803, Positive control fluorouracil, half-inhibition concentration (IC are better than to the antitumor activity of Hepatocellular carcinoma cell line50) be respectively 11.15 and 14.75 μm of ol/L (double piperazines of the new 1,4- of Wang Mengmeng, Duan Yingchao, Ye Xianwei, Ren Jingli, Yu Bin, Zhang En, the Liu Hong people Piperazine dithiocarbonic acid [1- substitutes (1,2,3- triazoles) -4], design, synthesis and the antitumor activity of-first ester type compound had Chemical machine, 2013 volume 33,2384-2390 pages).
This patent using active subunits roll into a ball splicing principle for guidance, stereocpecificity prepare and separated tetrahydrochysene benzfuran- 4- ketoximes derivatives, using etherificate, click on synthesis by the way of be prepared for the drug molecule containing triazolyl, using NMR, ESI-MS, The Modern spectroscopy technical appraisement such as IR chemical constitution of product, passes through cytotoxic activity experiment and hydrogen potassium-ATP enzyme inhibitory activity is real The anti-gastric cancer activity and its mechanism of action for testing compound are tested, new reference drug is provided for the chemotherapy of stomach cancer.
The content of the invention
It is an object of the invention to provide a kind of tetrahydrochysene benzfuran -4- ketoximes base triazole medicine, the structural formula of the medicine For：
The structural formula is the cis-isomer of tetrahydrochysene benzfuran -4- ketoxime base triazoles；
The medicine further includes pharmaceutically acceptable salt, such as hydrochloride, hydrobromate, phosphate, sulfate or oxalic acid Salt etc..
Further the present invention provides a kind of tetrahydrochysene benzfuran -4- ketoximes base triazole derivative medicine, the derivative class medicine Structural formula be：
Wherein, wherein tetrahydrochysene benzfuran -4- ketoximes base triazole derivative is cis-isomer, and R is alkyl or aryl；
The medicine further includes pharmaceutically acceptable salt, such as hydrochloride, hydrobromate, phosphate, sulfate or oxalic acid Salt etc..
The R is PhCH2-、Ph-、PhCOCH2-、(p)-MeO-PhCOCH2-、(p)-F-PhCOCH2-、(m)-HO- PhCOCH2-、(p)-Ph-PhCOCH2- in any one, R be more preferably (m)-HO-PhCOCH2-。
The present invention also provides a kind of composition of the medicine of the ketoximes of -4- containing tetrahydrochysene benzfuran base triazole, said composition bag Include, tetrahydrochysene benzfuran -4- ketoxime bases triazole, tetrahydrochysene benzfuran -4- ketoxime bases triazolium salt, tetrahydrochysene benzfuran -4- ketoximes Base triazole derivative or tetrahydrochysene benzfuran -4- ketoxime base triazole derivative salt, and pharmaceutically acceptable auxiliary material or carrier, Wherein, tetrahydrochysene benzfuran -4- ketoximes base triazole derivative is any derivative in above-mentioned.
1. the preparation of tetrahydrochysene benzfuran -4- ketoxime base triazole compounds and its derivative
1.1 instruments and medicine
Laboratory apparatus includes：SHB-IIIA multiplex vavuum pump of circulating water type (the limited public affairs of Shanghai Yu Kang Science ＆ Teaching Instrument equipment Department), DZF-6020 types vacuum drying chamber (Shanghai type new talent medical instrument Manufacturing Co., Ltd), EYELA SB-1100 types rotation Evaporimeter (Shanghai lover Instrument Ltd.), 2XZ-4 types rotary-vane vaccum pump (Linhai City Tan Shi vacuum equipments Co., Ltd), FA2104B assay balances (Shanghai Yue Ping tech equipments Co., Ltd), GZX-9240MBE type digital display air dry ovens (are won in Shanghai Fast Medical Equipment Plant of Industrial Co., Ltd.), CL-4 type tablet magnetic stirring apparatus (Zhengzhou Greatwall Scientific Industrial ＆ Trading Co., Ltd.), ZF-6 types Ultraviolet analysis instrument for three purposed (Shanghai Jia Peng Science and Technology Ltd.s), the micro- melting point detector of XRC-1 types (tech factory of Sichuan University), DF- 101S type heat collecting types constant-temperature heating magnetic stirring apparatus (Ying Yu Yu Hua instrument plants of Gongyi City).
Chemical reagent includes：Absolute methanol (analyzing pure, Sinopharm Chemical Reagent Co., Ltd.), absolute ethyl alcohol (analysis Pure, Sinopharm Chemical Reagent Co., Ltd.), acetone (analyzing pure, Sinopharm Chemical Reagent Co., Ltd.), acetonitrile (analysis Pure, Tianjin Heng Xing chemical reagent Manufacturing Co., Ltd), petroleum ether (60-90 DEG C of boiling range, the permanent emerging chemical reagent manufacture in Tianjin Co., Ltd), ethyl acetate (analyze pure, Tianjin Kermel Chemical Reagent Co., Ltd.), the tert-butyl alcohol (analyze pure, traditional Chinese medicines collection Chemical reagent Co., Ltd of group), 5,5- dimethyl -1, hydroresorcinol (analyzing pure, Sinopharm Chemical Reagent Co., Ltd.), Pyruvic alcohol (analyzing pure, Sinopharm Chemical Reagent Co., Ltd.), (analysis is pure, and Chinese medicines group chemical reagent is limited for hydroxylamine hydrochloride Company), propargyl bromide (analyze pure, Sinopharm Chemical Reagent Co., Ltd.), ω-bromoacetophenone (analyze pure, Chinese medicines group Learn reagent Co., Ltd), sodium acetate (analyzing pure, Sinopharm Chemical Reagent Co., Ltd.), sodium hydride (analyze pure, traditional Chinese medicines collection Chemical reagent Co., Ltd of group), sodium azide (analyzing pure, Sinopharm Chemical Reagent Co., Ltd.), anhydrous sodium sulfate (analysis Pure, Sinopharm Chemical Reagent Co., Ltd.), copper bromide (analyzing pure, Sinopharm Chemical Reagent Co., Ltd.), ascorbic acid Sodium (analyzing pure, Sinopharm Chemical Reagent Co., Ltd.), anhydrous cupric sulfate (analyze pure, the limited public affairs of Chinese medicines group chemical reagent Department), thin layer prefabricated board (Qingdao is up to Chemical Co., Ltd.).
The preparation method of tetrahydrochysene benzfuran -4- ketoxime base triazole medicines, includes the following steps：
1) 55 are used,-dimethyl -1,3 cyclohexanedione obtains 3,6,6- trimethyl -6,7- dihydrobenzo furans after addition Mutter -4 (5H) -one (intermediate 1)；
2) intermediate 1 and hydroxylamine hydrochloride are dissolved with absolute ethyl alcohol to obtain mixed liquor, then anhydrous vinegar is added into mixed liquor Sour sodium, stirring, reflux 2-5h, cooling, down in frozen water, be dried in vacuo after obtain (Z) -3,6,6- trimethyl -6,7- dihydrobenzenes And (5H) the -one oxime of furans -4 (intermediate 3)；
3) after intermediate 3 being dissolved in acetonitrile, sodium hydride is added, in the case where being sufficiently stirred, propargyl bromide is added dropwise, 1- is stirred at room temperature 3h, revolving, ethyl acetate extraction, liquid separation, drying, isolated intermediate 4；
4) parahydroxyacet-ophenone is dissolved in ethyl acetate, copper bromide is then added into solution, be heated to reflux, is cooled to After room temperature, filtering, ethyl acetate extraction, liquid separation is dry, filters, isolated alpha-brominated -4-hydroxyacetophenone, by generation Alpha-brominated -4-hydroxyacetophenone is dissolved in acetone, and adds sodium azide, when 35-50 DEG C of stirring 1-3 is small, is cooled to room temperature, is added Water, ethyl acetate extraction, liquid separation is dry, filters, isolated α-azido -4-hydroxyacetophenone (azide intermediate 2)；
5) intermediate 4 and azide intermediate 2 are suspended in the mixed liquor of water and the tert-butyl alcohol, sequentially add ascorbic acid Sodium, cupric sulfate pentahydrate, are stirred overnight (TLC monitorings) until the reaction is complete in 70-90 DEG C of oil bath, reaction solution are cooled down, to reaction It is diluted with water in mixture, obtains white depositions, filtering, vacuum drying, obtain tetrahydrochysene benzfuran -4- ketoxime base triazoles.
Technological process is as follows：
In preparation process, intermediate 3 can be synthesized with methanol, ethanol, pyridine, toluene equal solvent, with methanol yield most Height, cost is minimum, and preferably methanol is solvent；Intermediate 4 can be synthesized with ether, tetrahydrofuran, toluene, benzene and acetonitrile, with Acetonitrile reaction is fastest, and yield highest, preferably acetonitrile are solvent；Target product can use tertiary butanol and water, dichloromethane-water or Isopropanol-chloroform is solvent, but the yield highest of tertiary butanol and water system, and the time is most short, is preferably reaction dissolvent.
Wherein, in step 2), intermediate 1, hydroxylamine hydrochloride, the molar ratio of anhydrous sodium acetate are 8-12：10-15：10-15 (preferably intermediate 1, hydroxylamine hydrochloride, the molar ratio of anhydrous sodium acetate are 5：6：6).
In step 3), intermediate 3, sodium hydride, the molar ratio of propargyl bromide are 8-12：8-12：10-15 is (among being preferably Body 3, sodium hydride, the molar ratio of propargyl bromide are 5：5：6).
In step 4), parahydroxyacet-ophenone, the molar ratio of bromination ketone are 8-12：18-25, alpha-brominated -4-hydroxyacetophenone, The molar ratio of sodium azide is 3-6：(preferably parahydroxyacet-ophenone, the molar ratio of bromination ketone are 1 to 5-10：2, alpha-brominated -4- hydroxyls Benzoylformaldoxime, the molar ratio of sodium azide are 5：6).
In step 5), intermediate 4, azide intermediate 2, ascorbic acid, the molar ratio of anhydrous cupric sulfate are 5：5.05~ 5.5：0.8-1.5：(preferably intermediate 4, intermediate 2, ascorbic acid, the molar ratio of anhydrous cupric sulfate are 5 to 0.05-0.2：5： 1：0.1).
In step 5), azido compound can also be in 2- nitrine aryl methyl ketone, nitrine aromatic hydrocarbons, aryl methylene base nitrine Any one.
2- nitrine aryl methyl ketone, aryl methylene base nitrine are prepared with the substitution reaction of Sodium azide and alkyl halide, with arylamine weight Nitridation, azide substitution reaction prepare nitrine aromatic hydrocarbons.
2nd, the structural analysis of tetrahydrochysene benzfuran -4- ketoximes base triazole class compounds
2.1 instruments and reagent
Laboratory apparatus：Ultrashied 400MHz Plus Nuclear Magnetic Resonance (Bruker companies of Switzerland), API 4000LC- MS/MS mass spectrographs (German Brooker dalton company), 360FT-IR types infrared spectrometer (Nicolet companies of the U.S.).
Experiment reagent：(D-atom content 99.8%, TMS contents 0.03%V/V, 10*0.5mL/ box are auspicious by deuterochloroform-d Scholar ARMAR companies)；Trifluoroacetic acid aqueous solution (content 99.99%, 4L is bottled, German MILAK companies)；Distilled water (4.5L/ barrels, Qu Chen Family name Watsons companies)；Nuclear magnetic tube (5mm 100/pk 2ST500-8, Norell companies of the U.S.)；Potassium bromide (Chinese medicines group chemistry Reagent Co., Ltd).
2.2 test process
10mg target compounds accurately are weighed, is dissolved with 0.5mL deuterochloroforms in nuclear magnetic tube, is surveyed by Nuclear Magnetic Resonance Try its chemical constitution；1.0mg samples are taken on assay balance, add potassium bromide 200mg to be ground in agate mortar uniformly, after drying Pressurization prepares salt window in compression mold, and the infrared spectrogram of compound is tested on infrared spectrometer；By sample to be tested color Acetonitrile dissolving is composed, the solution of 1.0ppm is configured to, after being sampled with micro syringe, its mass spectrum is tested on electrospray mass spectrometer.
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,CDCl3)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,CDCl3)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,CDCl3)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,CDCl3)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 DEG C；1H NMR(400 MHz,CDCl3)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,CDCl3)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 DEG C；1H NMR(400 MHz,CDCl3)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,CDCl3)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 DEG C；1H NMR(400 MHz,CDCl3)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,CDCl3)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 DEG C；1H NMR(400 MHz,CDCl3)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,CDCl3)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 DEG C；1H NMR(400 MHz,CDCl3)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,CDCl3)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 DEG C；1HNMR(400MHz,CDCl3)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,CDCl3)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 resoance spectrum interpretation of result：The stereochemical structure of intermediate oxime (intermediate 3) and oxime ether (intermediate 4) by 1D and 2D H NMR spectroscopies are characterized, and the proton (δ of hydroxyl can be observed in the NOE spectrum in intermediate 3：8.93ppm) and 3- methyl Proton (δ：Relevant peaks 2.15ppm), it is (Z)-configuration to thereby determine that intermediate oxime.In oxime ether intermediate 41In HNMR spectrums, Between the end alkynes proton and methene proton of propargyl there are long-range coupling (4J=2.4Hz)；At the same time at it13C nuclear magnetic resonance The carbon signal that propargyl is also observed that in spectrum is respectively 80.2,73.8 and 61.3ppm.Target compound 51In H H NMR spectroscopies, The proton of triazole occurs unimodal in the range of 7.46~8.01ppm；Width is shown between 7.02~7.05ppm on furan nucleus It is unimodal, the proton and C (3)-there are long-range coupling for methyl proton；N-CH2And O-CH2Methylene proton respectively 5.52~ Shown between 6.01ppm and 5.20~5.32ppm two it is unimodal.13In C H NMR spectroscopies in the range of 114.2~190.3ppm Resonance absorbing peak is consistent with the number of unsaturated carbon in compound, shows that tetrahydrochysene benzfuran ring successfully connects with triazolyl Connect.The strong stretching vibration absworption peaks of C=N can be observed in the infrared spectrum of target compound in 1601~1646cm- 1, targeted The molecular weight of compound is corresponding with the ion adduction peak in ESI-MS.Such as the NOESY spectrograms that Fig. 1 is intermediate 3.
It is 3. of the invention by described tetrahydrochysene benzfuran -4- ketoxime base triazoles and combinations thereof, tetrahydrochysene benzfuran -4- ketone Oximido triazole derivative and combinations thereof or its salt are applied to prepare in treatment anti-gastric cancer medicament.
3.1 reagents and instrument
Experiment reagent：RPMI1640 nutrient solutions (10.4g dry-types are dissolved in 1000mL tri-distilled waters without phenol red RPMI640, Add 2.0g sodium acid carbonates to stir to abundant dissolving, then filtered with 0.22 μm of sterile positive press filtration device, packing, adds 10% Calf serum, 0.5% penicillin (100U/mL) and streptomysin (100 μ g/mL).
Laboratory apparatus：Superclean bench (Beijing Dong Lianhaer instrument manufacturings Co., Ltd), ultrasonic washing instrument (are ridden the waves new Sesame biotech inc), TDZ4-WS types low speed centrifuge (the ordinary instrument and meter Co., Ltd in Changsha), DK-8A types Electric heating constant temperature sink (the upper grand experimental facilities Co., Ltd of Nereid), automatic distilled water distiller (the sub- flourish biochemical equipment instrument in Shanghai Co., Ltd), HTC-100A type constant temperature and humidities incubator (rising Instrument Ltd. in Shanghai three), LDZX-30KBS type vertical pressures Steam sterilizer (Shenan Medical Appliances Factory, Shanghai), CO2gas incubator (SANYO GS company), Stat Fax-2100 type enzymes Join immune detector (Awareness companies of the U.S.).
3.2 experimental section
Inhibited proliferation of the tetrahydrochysene benzfuran class compound to stomach cancer cell HGC-27 is evaluated using MTT methods：Stomach Cancer cell HGC-27 is provided by Chinese Academy of Sciences Shanghai cell bank, using mycillin containing 100U/ml and 10% new fetal calf serum For RPMI1640 as cell culture fluid, cell is placed in 37 DEG C, 5%CO2Cell incubator culture.When cell passes on, adjustment is thin Born of the same parents' density is 5 × 104~1 × 105Cells/well is inoculated into 96 orifice plates, is placed in 37 DEG C, 5%CO2Cultivated in incubator.Add after 24h Enter the medicine of various concentrations, separately set blank control group (nutrient solution), Normal group (cell+nutrient solution) and positive controls (using antitumor drug paclitaxel as positive control), handles 48h.The continuation of 37 DEG C of after experiment terminates plus 20 μ L/ holes of MTT (5mg/mL) 4h is incubated, suctions out supernatant, the DMSO of 150 μ L is added per hole, is shaken up, absorbance (OD) when measuring 492nm wavelength.MTT is lived First a ceremonial jade-ladle, used in libation is generated through Metabolism of Mitochondria after cellular uptake, mitochondria vigor is more vigorous, and the generation of first a ceremonial jade-ladle, used in libation is more, and absorbance is also higher, reflection Cell survival.Cell inhibitory rate is calculated, (the inhibiting rate T/C=1- dosing cells OD/ controls of cell are thin with cell inhibitory rate Born of the same parents OD) judge whether medicine has inhibitory action to the propagation of cell.Half-inhibition concentration (IC50), frequently as reflection effect of drugs Quantitative target, the extensive use in various drug screenings, therefore calculated respectively using statistic software SPSS 13.0 and compare medicine Thing acts on the IC of different cells50, reflect drug effectiveness.
3.3 activity ratings are analyzed
Using commercialization anti-cancer medicine paclitaxel as positive control, triazolyl furans and cyclohexanone oxime have rated by mtt assay Cytotoxic activity (see the table below) of the class compound to HGC-27.The result shows that there is majority of compounds medium cell toxicant to live Property, the wherein antiproliferative IC of 5c, 5g, 5h to HGC-2750Value reaches less than 20 μM, thus it is speculated that is conducive to improve such change during hydroxyl The cytotoxic activity of compound.Result of study above provides reference for the anti-gastric cancer medicament purposes of benzofuran compounds.
4th, the present invention is also by described tetrahydrochysene benzfuran -4- ketoxime base triazoles and combinations thereof, tetrahydrochysene benzfuran -4- Ketoxime base triazole derivative and combinations thereof or its salt are applied to prepare on treatment anti-ulcer medicament.
Proton pump inhibitor is the medicine of a kind of new gastric acid secretion inhibiting, and specific and noncompetitive acts on H+/K+- ATP enzyme, can suppress acid secretion caused by a variety of stimulations such as secretion and histamine, the feed of basic hydrochloric acid in gastric juice.H+/K+- ATP enzyme position In on the tubulovesicle and secretion periosteum of parietal cell, completed by the phosphorylation (E1 → E2) of itself and dephosphorylation (E2 → E1) H+/K+Electroneutral ion transport, will constantly exercise the function of secreting acid outside the proton transport in parietal cell to film, therefore press down H processed+/K+- ATP enzyme, can play powerful suppression gastric secretion effect.Chemotherapy resistance be current oncotherapy main bugbear it One, recently research it has proven convenient that internal pH increase be most of tumor drug resistance cell lines common trait, proton pump inhibitor can By suppressing tumour cell vacuole atpase activity, improve the microenvironment of the outer acid of intracellular alkali and block the acidifying of tumor microenvironment, Tumour is improved to the sensitiveness of chemotherapeutic agent, can also by increasing the permeability of lysosome, alkalize lysosome etc. mechanism, Induce stomach cancer cell that autophagy or apoptosis occurs.In consideration of it, this patent using hydrogen potassium-ATP enzyme kit evaluation compound to hydrogen potassium- The inhibitory activity of ATP, develops the drug effect of its acid suppression.
External H+/K+- ATP enzyme inhibitory activity test philosophy
4.1 external H+/K+- ATP enzyme inhibitory activity experimental program
The Mouse Gastric Mucous Membrane of gastric ulcer is taken, adds physiological saline that gastric mucosa homogenate is made, obtains containing H after differential centrifugation+, K+- The supernatant of ATP enzyme microsome.Tissue Culture Plate is transferred to, medicine to be measured is added and is incubated after a certain period of time, with commercially available H+/K+- Atpase activity assay kit measures enzymatic activity.
The foundation of 4.2 gastric ulcer models
Body 18~22g Kunming mouses are taken, are put to death under waking state, sterilize 3~5min in 75% alcohol, sterile bar Dissect under part.Mouse Stomach is taken, is cleaned with cold PBS buffer, after washing away food debris and bloodstain, with flat mouth tweezers by the inside of stomach Mucous layer scrapes, and is put into sterile centrifuge tube, shreds, and is injected 0.5% pancreatin in centrifuge tube with liquid-transfering gun (per stomach about 5ml), 37 DEG C of water-baths digest 8~10min, and the appropriate vibration centrifugal pipe in digestion process.After the completion of digestion, it is rapidly added cold PBS solution, reduce the digestion power of pancreatin, while blown and beaten with liquid-transfering gun, make cell detachment, cross 200 mesh sieves, repeated collection 2 Secondary, 1200r/min centrifugation 7min, centrifuge tube bottom precipitation is parietal cell.Reject supernatant liquid, cell precipitation are trained with DMEM Support base to suspend, be parietal cell suspension.
4.3 parietal cells are identified
Parietal cell：1. form：Parietal cell form is larger, core centre more placed in the middle, rich in mitochondria.HE is dyed, can under light microscopic See that core dyes blueness, kytoplasm pink.2. motility rate:1.0g/L Trypan blue are dyed, and dead cell dyes blueness, and living cells is not Coloring.3. cell count：Cell suspension is carefully instilled in blood count disk, by automatic counting of red blood, number four is generous The sum of lattice inner cell number is N, then every liter of cell number is：Cells/L=N × 4 × 104。
The culture of 4.4 parietal cells and H+/K+- atpase activity measures
Parietal cell suspension after purification is transferred to 96 porocyte culture plates, adds after 37 DEG C of incubation 2h of medicine, uses H+, K+- Atpase activity assay kit measures enzymatic activity, and operation by specification carries out, it is specified that the ATP enzyme of every milligram of albumen is divided per hour The amount for solving ATP 1 μm of ol Phos of generation is 1 H+/K+- atpase activity unit, with mmolmg-1·h-1Represent.Positive control Medicine：Commercially available proton pump inhibitor Omeprazole, Revaprazan.
The enzyme inhibition activity result of 4.5 reactive compounds
Conclusion：Compound 5c, 5g and 5h (IC with stronger anti-gastric cancer activity50<20 μM) it is respectively provided with stronger H+/K+- ATP enzyme inhibitory activity, is better than commercially available irreversible proton pump inhibitor Omeprazole (IC5080.03 μM), slightly better than commercially available Reversible proton pump inhibitor Revaprazan (IC5038.77μM).Structure-activity relation research shows, is introduced on triazole group Xenyl or 3- hydroxy phenyls, are expected to improve the Acidinhibitor of compound.
Brief description of the drawings
Fig. 1 is the NOESY spectrograms of intermediate 3.
Embodiment
Embodiment 1
- 4 (5H) -one (intermediate 1) of 3,6,6- trimethyl -6,7- Dihydrobenzofuranes is prepared for first and nitrine is (middle Body 2), then intermediate 1 is converted into by cis ketoxime (intermediate 3) by condensation reaction, it is alkylated after separating-purifying To propargyl oxime ether (intermediate 4), the cycloaddition reaction of intermediate 4 and azide intermediate 2 through copper catalysis is finally synthesized 1,2, The furans and cyclohexanone oxime analog derivative of 3- triazol radicals substitution, synthetic route are as follows：
The synthesis (intermediate 2) of nitrine：Parahydroxyacet-ophenone (1.36g, 10.0mmol) is dissolved in ethyl acetate (20ml) In, then into solution add copper bromide (4.48g, 20.0mmol), be heated to reflux 5 it is small when.After being cooled to room temperature, filtering, to 100mL water to be poured into filtrate, (3 × 100mL) is extracted with ethyl acetate, liquid separation, organic phase is dried with anhydrous sodium sulfate, is filtered, The residue obtained after the lower removing solvent of decompression separates (eluant, eluent with column chromatography：Ethyl acetate/petroleum ether=1:25, v/v), Obtain alpha-brominated -4-hydroxyacetophenone.
Alpha-brominated -4-hydroxyacetophenone (1.075g, 5.0mmol) of generation is dissolved in acetone (20ml), then to molten Sodium azide (0.39g, 6.0mmol) is added in liquid, when 40 DEG C of stirrings 2 are small.After being cooled to room temperature, 50mL is poured into solution Water, is extracted with ethyl acetate (3 × 50mL), and liquid separation, organic phase is dried with anhydrous sodium sulfate, filters, after depressurizing lower removing solvent Obtained residue separates (eluant, eluent with column chromatography：Ethyl acetate/petroleum ether=1:15, v/v) α-azido -4-, is obtained Hydroxy acetophenone.
The synthesis of oxime (intermediate 3)：(Z) -3,6,6- trimethyls -6,7- Dihydrobenzofuranes -4 (5H) -one oxime (intermediate 3) synthesis：By 3,6,6- trimethyl -6,7- Dihydrobenzofuranes -4 (5H) -one (intermediate 1,1.78g, 10.0mmol) and salt Sour azanol (0.834g, 12.0mmol) with 30mL absolute methanols dissolve, then into solution add anhydrous sodium acetate (0.984g, 12.0mmol).To stir, be heated to reflux 4h, the cooling of question response liquid, by it down in 150ml frozen water, is obtained by filtration white solid, It is dried in vacuum overnight up to compound 3.
The synthesis of oxime ether (intermediate 4)：(Z) -3,6,6- trimethyls -6,7- Dihydrobenzofuranes -4 (5H) -one oximido alkynes The synthesis of the synthesis (intermediate 4) of propyl ether：Intermediate 3 (1.92g, 10.0mmol) is dissolved in acetonitrile (25ml), then to molten Sodium hydride (0.24g, 10.0mmol) is slowly added in liquid, is sufficiently stirred lower dropwise addition propargyl bromide (1.428g, 12.0mmol), room When temperature stirring 2 is small.After revolving removes solvent, 50mL water is poured into thereto, is extracted with ethyl acetate (3 × 50mL), liquid separation is organic Mutually dried, filtered with anhydrous sodium sulfate, depressurized the residue obtained after lower removing solvent and separate (eluant, eluent with column chromatography：Second Acetoacetic ester/petroleum ether=1:20, v/v) intermediate 4, is obtained.
The synthesis of target compound 5：By propargyl ether (intermediate 4,0.5mmol) and α-azido -4-hydroxyacetophenone (azide intermediate 2,0.5mmol) is suspended in the mixed liquor of water (3mL) and the tert-butyl alcohol (3mL), adds sodium ascorbate (19.8mg, 0.1mmol), then adds cupric sulfate pentahydrate (2.5mg, 0.01mL), is stirred overnight in 80 DEG C of oil baths until anti- Should completely (TLC monitorings).Reaction solution is cooled down, into reaction mixture plus water (20mL) dilutes, and obtains white depositions.Filtering is simultaneously Vacuum drying, obtains tetrahydrochysene benzfuran -4- ketoxime base triazoles.
Embodiment 2
Other steps are with embodiment 1, in the synthesis step of target compound 5a~5h, by propargyl ether (intermediate 4, 0.5mmol) reacted with 2- nitrine aryl methyl ketone in tertiary butanol and water mixed system, reaction controlling and isolate and purify mode with real Example 1 is applied, only needs to change different types of azide intermediate 2.Azido compound for 2- nitrine aryl methyl ketone, nitrine aromatic hydrocarbons, Aryl methylene base nitrine
Embodiment 3
The preparation method of tetrahydrochysene benzfuran -4- ketoxime base triazolium salts, by taking hydrochloride as an example.Weighed in 50mL three-necked bottles 1.0mmol target products 5a~5h one kind therein, is dissolved in 5mL absolute methanols, under nitrogen protection cools down reaction bulb To 0 DEG C, hydrogen chloride/methanol solution of 1mol/L is added dropwise with constant pressure funnel, stirs to product completely into salt (thin-layer chromatography prison Survey the salinization process of neutral molecule), solvent evaporated, and obtain tetrahydrochysene benzfuran -4- ketoxime base triazole hydrochlorides.
The preparation method of hydrobromate, sulfate, oxalates etc. is same as above.

Claims (5)

  1. A kind of 1. tetrahydrochysene benzfuran -4- ketoxime base triazole derivative medicines of anti-gastric cancer, it is characterised in that the derivative class medicine Structural formula be：
    Tetrahydrochysene benzfuran -4- ketoxime bases triazole derivative is cis-isomer, and the R is PhCH2-、Ph-、PhCOCH2-、 (p)-HO-PhCOCH2-、(p)-MeO-PhCOCH2-、(p)-F-PhCOCH2-、(m)-HO-PhCOCH2-、(p)-Ph-PhCOCH2- In any one.
  2. 2. tetrahydrochysene benzfuran -4- ketoxime base triazole derivative the medicines of the anti-gastric cancer described in claim 1, it is characterised in that The R is (m)-HO-PhCOCH2-。
  3. 3. the preparation method of the tetrahydrochysene benzfuran -4- ketoxime base triazole derivative medicines of the anti-gastric cancer described in claim 1, its It is characterized in that, includes the following steps,
    1) 3,6,6- trimethyl -6,7- Dihydrobenzofuranes -4 are obtained after addition using -1,3 cyclohexanedione of 5,5- dimethyl (5H) -one, i.e. intermediate 1；
    2) intermediate 1 and hydroxylamine hydrochloride are dissolved with solvent absolute ethyl alcohol to obtain mixed liquor, then anhydrous vinegar is added into mixed liquor Sour sodium, stirring, reflux 2-5h, cooling, down in frozen water, be dried in vacuo after obtain (Z) -3,6,6- trimethyl -6,7- dihydrobenzenes And furans -4 (5H) -one oxime, i.e. intermediate 3；
    3) after intermediate 3 being dissolved in acetonitrile solvent, sodium hydride is added, in the case where being sufficiently stirred, propargyl bromide is added dropwise, 1- is stirred at room temperature 3h, revolving, ethyl acetate extraction, liquid separation, drying, isolated (Z) -3,6,6- trimethyl -6,7- Dihydrobenzofuranes -4 (5H) -one oximido alkynes propyl ether, i.e. intermediate 4；
    4) parahydroxyacet-ophenone is dissolved in ethyl acetate, copper bromide is then added into solution, be heated to reflux, is cooled to room temperature Afterwards, filter, ethyl acetate extraction, liquid separation is dry, filters, isolated alpha-brominated -4-hydroxyacetophenone, by α-bromine of generation Generation -4-hydroxyacetophenone is dissolved in acetone, and adds sodium azide, when 35-50 DEG C of stirring 1-3 is small, is cooled to room temperature, is added water, Ethyl acetate extracts, liquid separation, dry, filters, isolated α-azido -4-hydroxyacetophenone, i.e. azide intermediate 2；
    5) intermediate 4, azide intermediate 2 or azido compound are suspended in the in the mixed solvent of water and the tert-butyl alcohol, sequentially added Sodium ascorbate, cupric sulfate pentahydrate, are stirred overnight until the reaction is complete in 70-90 DEG C of oil bath, cool down reaction solution, mixed to reaction It is diluted with water in compound, obtains white depositions, filtering, vacuum drying, obtain tetrahydrochysene benzfuran -4- ketoxime base triazoles or four Hydrogen benzofuran -4- ketoxime base triazole derivatives, the structural formula of compound of the derivative are as follows：
    Tetrahydrochysene benzfuran -4- ketoxime base triazoles or tetrahydrochysene benzfuran -4- ketoxime bases triazole derivative are cis-isomer, institute The R stated is PhCH2-、Ph-、PhCOCH2-、(p)-HO-PhCOCH2-、(p)-MeO-PhCOCH2-、(p)-F-PhCOCH2-、(m)- HO-PhCOCH2-、(p)-Ph-PhCOCH2- in any one.
  4. 4. the preparation method of the tetrahydrochysene benzfuran -4- ketoxime base triazole derivative medicines of the anti-gastric cancer described in claim 3, its It is characterized in that, in step 2), intermediate 1, hydroxylamine hydrochloride, the molar ratio of anhydrous sodium acetate are 5：6：6；
    In step 3), intermediate 3, sodium hydride, the molar ratio of propargyl bromide are 5：5：6；
    In step 4), parahydroxyacet-ophenone, the molar ratio of bromination ketone are 1：2, alpha-brominated -4-hydroxyacetophenone, sodium azide Molar ratio is 5：6；
    In step 5), intermediate 4, azide intermediate 2, ascorbic acid, the molar ratio of anhydrous cupric sulfate are 5：5：1：0.1.
  5. 5. the preparation method of the tetrahydrochysene benzfuran -4- ketoxime base triazole derivative medicines of the anti-gastric cancer described in claim 3, its It is characterized in that, in step 2), the anhydrous ethanol solvent can also be replaced by any one in methanol, pyridine or toluene； In step 3), acetonitrile solvent can also be replaced by any one in ether, tetrahydrofuran, toluene or benzene；In step 5), tertiary fourth The mixed solvent of alcohol-water can also be replaced by the mixed solvent of dichloromethane-water or isopropanol-chloroform.
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