CN106279307B - Fragrant ammonia is for glucosan derivative, preparation method and anticancer usage - Google Patents
Fragrant ammonia is for glucosan derivative, preparation method and anticancer usage Download PDFInfo
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Abstract
The invention belongs to field of medicinal chemistry, in particular to fragrant ammonia for glucosan derivative, preparation method and anticancer usage.Wherein fragrant ammonia is for glucosan derivative, and in particular to such as I compound represented of formula.The invention further relates to fragrant ammonia for the preparation method of glucosan derivative, and purposes of the fragrant ammonia for glucosan derivative in the drug of preparation treatment tumor disease, especially there is significant ground inhibiting effect to application on human skin epidermoid carcinoma cell, human lung carcinoma cell, human colon cancer cell.
Description
Technical field
The invention belongs to field of medicaments, and in particular to one kind 1,2-O- isopropylidene -5- virtue ammonia generation-α-furyl glucose spreads out
Biology, preparation method, and its purposes in the drug of preparation treatment tumor disease.
Background technique
The treatment of cancer is a global problem for a long time.The essence of cell carcinogenesis may be cell signalling
Cell infinite multiplication caused by access is lacked of proper care.Therefore with some intracellular signal transduction pathway relevant to tumor cell differentiation proliferation
Key enzyme as drug target, discovery efficiently, the new anticancer drug of low toxicity have become the weights of current anti-tumor drug research and development
Want direction.For example, using tyrosine kinase as medicine target antitumoral compounds Gefitinib [AstraZeneca, London, U.K.,
Http:// www.astrazeneca.com/], Erlotinib [Roche, Ltd, Basel, Switzerland, http: //
Www.roche.com/], Lapatinib [WO 99/35146] etc. be successfully used for the clinical treatment of kinds of tumors.But it is some
For a certain target drug after a period of use, apparent drug resistance [Bioorganic&Medicinal can be generated
Chemistry 2012,20,3756-3767], difficulty is brought to the anaphase of tumour.Thus, it is found that structure novel, low toxicity
Antitumoral compounds still urgently expected.
Based on the above reasons, the present inventor passes through long term test research, and synthesis has obtained a kind of fragrant ammonia for Derived from D-Glucose
Object.By testing to these fragrant ammonia for the growth of tumour cell inhibitory activity of glucosan derivative, it is found that this kind of compound has
Good anti-tumor activity is expected to be used for the treatment of tumour.
Summary of the invention
It is that 1,2-O- isopropylidene -5- virtue ammonia generation-α-furyl glucose shown in formula I spreads out the present invention provides a kind of structure
Biology and its salt:
Wherein, R1Selected from C1-C4Alkyl, hydrogen；R2Selected from halogen ,-CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6Independently
Selected from C1-C4Alkyl；R3Selected from halogen, C1-C4Alkyl ,-CH2-C4H2S-ph-F、-CH2-ph-O-R7,R7Independently selected from C1-C4
Alkyl；And work as R2When selected from halogen, R3Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R7,R7Independently selected from C1-C4Alkyl；
Work as R2Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R6,R6Independently selected from C1-C4When alkyl, R3Selected from halogen, C1-C4Alkane
Base；R4、R5It is independently selected from hydrogen, C1-C4Alkyl.
In some embodiments, R1Selected from methyl or hydrogen.
In some embodiments, work as R2When selected from halogen, wherein R3Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R7,
R7Selected from ethyl；In some embodiments, work as R2When selected from halogen, wherein R3Selected from-CH2-C4H2S-ph-F, 4- ethoxybenzene
Methyl, 2- ethoxybenzene methyl；In some embodiments, work as R2When selected from halogen, wherein R3Selected from 5- (4- fluorophenyl) thiophene
Pheno -2- ylmethyl, 4- ethoxybenzene methyl, 2- ethoxybenzene methyl；In some embodiments, work as R2When selected from chlorine, wherein R3
Selected from 5- (4- fluorophenyl) thiophene -2- ylmethyl, 4- ethoxybenzene methyl, 2- ethoxybenzene methyl.
In some embodiments, work as R2Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6Independently selected from C1-C4
When alkyl, R3Selected from halogen, methyl；In some embodiments, work as R2Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6
Independently selected from C1-C4When alkyl, R3Selected from chlorine, methyl；In some embodiments, R2Selected from-CH2-C4H2S-ph-F、-CH2-
ph-O-R6, R6Selected from ethyl, R3Selected from chlorine, methyl；In some embodiments, R2Selected from-CH2-C4H2S-ph-F, 4- ethoxy
Base benzyl, 2- ethoxybenzene methyl, R3Selected from chlorine, methyl；In some embodiments, R2Selected from 5- (4- fluorophenyl) thiophene-
2- ylmethyl, 4- ethoxybenzene methyl, 2- ethoxybenzene methyl, R3Selected from chlorine, methyl.
In some embodiments, wherein R4、R5It is independently selected from hydrogen, methyl；In some embodiments, wherein
R4、R5It is independently selected from hydrogen.
In some embodiments, type I compound is selected from following compounds, R1Selected from methyl or hydrogen, work as R2When selected from halogen,
Wherein R3Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R7,R7Selected from ethyl, R4、R5It is independently selected from hydrogen, methyl.
Preferred embodiment is R in the above-described embodiment3Selected from-CH2-C4H2S-ph-F, 4- ethoxybenzene methyl,
2- ethoxybenzene methyl.
Preferred embodiment is R in the above-described embodiment3Selected from 5- (4- fluorophenyl) thiophene -2- ylmethyl, 4- second
Oxygroup benzyl, 2- ethoxybenzene methyl.
Preferred embodiment is R in the above-described embodiment2Selected from chlorine.
Preferred embodiment is R in the above-described embodiment4、R5It is independently selected from hydrogen.
In other embodiments, type I compound is selected from following compounds, wherein R1Selected from methyl or hydrogen, R2Selected from-
CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6Independently selected from C1-C4When alkyl, R3Selected from halogen, methyl, R4、R5It is respectively independent
Be selected from hydrogen, methyl.
Preferred embodiment is R in the above-described embodiment3Selected from chlorine, methyl.
Preferred embodiment is R in the above-described embodiment2Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6
Selected from ethyl.
Preferred embodiment is R in the above-described embodiment2Selected from-CH2-C4H2S-ph-F, 4- ethoxybenzene methyl,
2- ethoxybenzene methyl.
Preferred embodiment is R in the above-described embodiment2Selected from selected from 5- (4- fluorophenyl) thiophene -2- ylmethyl,
4- ethoxybenzene methyl, 2- ethoxybenzene methyl.
Preferred embodiment is R in the above-described embodiment4、R5It is independently selected from hydrogen.
Preferred generalformulaⅰcompound or its salt, the acceptable compound of preferred agents is exemplified below, but is not limited to following
Compound:
Term " pharmaceutically acceptable salt " refers to when being administered to recipient, can (direct or indirect) offer herein
The salt of the compound.It keeps the biological effectiveness and property of free state alkali (acid), and will not be in terms of biology or other
It is undesirable.It will be appreciated, however, that acceptable salt is since it can be used for preparing pharmacy in the non-pharmaceutical of compound of Formula I
Upper acceptable salt thus also fall into the scope of the invention.
The pharmaceutically acceptable salt of type I compound includes inorganic acid or acylate.The inorganic acid includes but not
It is limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid etc.；The organic acid includes but is not limited to formic acid, acetic acid, and three
Fluoroacetic acid, citric acid, maleic acid, tartaric acid, fumaric acid, benzoic acid, lactic acid, methanesulfonic acid or 4- toluenesulfonic acid etc..
Term " halogen " refers to fluorine, chlorine, bromine or iodine, preferably chlorine.
Term " alkyl " refers to the aliphatic hydrocarbon group of the saturation for the linear chain or branched chain being made of carbon atom and hydrogen atom, leads to
The rest part for crossing singly-bound and molecule connects.The alkyl preferably has the C of 1-4 carbon atom1-4Alkyl.The alkyl is non-
Replace alkyl.The non-limiting example of unsubstituted alkyl includes but is not limited to such as methyl, ethyl, propyl, 2- propyl, positive fourth
Base, isobutyl group etc..
Another aspect of the present invention provides the preparation method of type I compound, including chemical compounds I -5 is dissolved in organic solvent
In, and under reducing agent existence condition, it reacts with 1,2-O- isopropylidene -5- oxo-α-furyl glucose, wherein R1、
R2、R3、R4、R5Definition is identical as general formula I,
Wherein, organic solvent is selected from methanol, and reducing agent is selected from sodium cyanoborohydride.
The compound that further aspect of the present invention provides a kind of formula I -5 is used to prepare the purposes of type I compound.
Further aspect of the present invention provides a kind of preparation method of I -5 compound of formula, including reaction a and reaction b, wherein R1、
R2、R3、R4、R5Define, R identical as general formula I2′、R3' separately it is selected from-C4H2S-Ph-F ,-Ph-O-R ', R ' is independently selected
From C1-C4Alkyl, in some embodiments, R2′、R3' it is selected from 5- (4- fluorophenyl) thiophene -2- base, 4- ethoxyl phenenyl, 2-
Ethoxyl phenenyl.
In a reaction, R2Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R6,R6Independently selected from C1-C4When alkyl, R3Choosing
From halogen, C1-C4Alkyl, specific reaction step are as follows:
In b reaction, R2Selected from halogen, R3Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R7,R7Independently selected from C1-C4
Alkyl, specific reaction step are as follows:
(a) in the presence of a catalyst, formula I -1 or I -1 ' react with chlorinating agent, obtain formula I -2 or I -2 '；
(b) in the presence of a catalyst, formula I -2 and R2' H or I -2 ' and R3Fridel-Crafts acylation reaction occurs for ' H,
Obtain formula I -3 or I -3 '；
I -3 or I -3 (c) in the presence of a catalyst, ' react with reducing agent, obtain formula I -4 or I -4 '；
(d) in the presence of a catalyst, formula I -4 or I -4 ' reacted with strong reductant, obtain formula I -5 or I -5 '；
Wherein, the catalyst in step (a) is selected from pyridine, and chlorinating agent is selected from thionyl chloride；Reaction temperature is 45-55 DEG C,
It is preferred that 50 DEG C.
Catalyst is selected from anhydrous AlCl in step (b)3；Reaction temperature is 0~5 DEG C, preferably 0 DEG C.
Catalyst is selected from boron trifluoride in step (c), and reducing agent is selected from triethylsilane.
Catalyst is selected from FeCl in step (d)3, reducing agent is selected from hydrazine hydrate；Reaction temperature is 75-85 DEG C, preferably 80 DEG C.
It is that structure is formula 1 in one's power in compound synthesis described in formula I the present invention also provides structure, formula 2, formula 3, formula 4, formula 5,
Formula 6, formula 7, formula 8, formula 9, formula 10, formula 11, formula 12, formula 13, formula 14, formula 15, formula 16, formula 17, formula 18, formula 19, formula 20,21 He of formula
The midbody compound of formula 22:
It is that 1,2-O- isopropylidene -5- virtue ammonia generation-α-furyl glucose shown in formula I spreads out that further aspect of the present invention, which provides structure,
Purposes of the biology in oncotherapy.The tumour is selected from people's epidermal carcinoma, cervical carcinoma, kidney, cancer of pancreas, liver cancer, gastric cancer, mammary gland
Cancer, colorectal cancer, bladder cancer, lung cancer, head and neck cancer, oophoroma, prostate cancer, genitourinary tract cancer, melanoma, squamous cell
Cancer, astrocyte cancer, Kaposi sarcoma, spongioblast cancer.Wherein, preferably application on human skin epidermoid carcinoma cell, human lung cancer are thin
Born of the same parents, human colon cancer cell.
Specific embodiment
With specific embodiment, invention is further described in detail below, but the content of present invention is not limited to these implementations
Example.
1,2-O- isopropylidene -5- oxo-α-furyl glucose used in the embodiment of the present invention presses document
The method synthesis of [Chem.Pharm.Bull., 1989,37 (9), 2344-2350] report；4- methyl -3- ((5- fluorophenyl)-thiophene
Pheno -2- ylmethyl) aniline and the synthesis of other analog reference literature [CN102115468A] method；Other agents useful for same are
It analyzes pure.Compound structure identifies that Nuclear Magnetic Resonance used is 300,400,600 superconduction nuclear magnetic resonance of Bruker Avance
Instrument, TMS is as internal standard；Infrared spectroscopy uses Nicolet170SX FT-IR determination of infrared spectroscopy；Fusing point is micro- molten using X-6
Point analyzer measurement (temperature is not corrected)；Mass spectrum is measured with Bruker Esquire 3000plus mass spectrograph.
Embodiment 1: the synthesis of compound ii -1
(1) preparation of chloro- -4 '-ethoxy diphenyl ketone of 5- nitro of 2-
It weighs 2- chloro-5-nitrobenzoic acid 2.06g (10mmol) to be dissolved in 5mL thionyl chloride, 3 drop pyridines is added dropwise, so
It is stirred to react at 50 DEG C afterwards 3 hours, TLC tracking, raw material fully reacting stops reaction.Vacuum rotary steam removes thionyl chloride, no
It direct plunges into through processing and reacts in next step.
By 2.12g (15mmol) anhydrous AlCl3It is added to 18mLCH2Cl2In, it is cooled to 0 DEG C, is slowly added to phenetole
1.35g (11mmol), while 0~5 DEG C is maintained the temperature at, it completes after being added, is stirred 15-20 minutes at 0 DEG C.Then by upper one
The chloro- 5- nitrobenzoyl chloride of 2- of step preparation is dissolved in 6mLCH2Cl2In, it is added in phenetole system, the speed of addition will make
Temperature is maintained at 0~5 DEG C, reacts 12 hours, obtains blackish green solution.TLC tracking, raw material have largely reacted, and stop reaction.
By being added into the case where being vigorously stirred and cooling down into 70mL2NHCl, reaction mixture is quenched, stirs 20 at 20~25 DEG C
Minute, then separate each phase.Organic phase is washed with 2NHCl, combined water phase CH2Cl2Extraction.The organic phase of collection is saturated
NaHCO3Solution washes twice, and at least stirs 30 minutes every time, then use CH2Cl2Extraction, is finally washed with brine the organic of merging
Layer.Pass through the isolated chloro- 5- nitre of white solid 2- of silica gel column chromatography (eluant ethyl acetate: petroleum ether=1:40, V/V)
Base -4 '-ethoxy diphenyl ketone 1.7g, yield 54%.1H NMR(600MHz,CDCl3) δ: 8.28 (dd, J=8.8,2.7Hz,
1H), 8.24 (d, J=2.7Hz, 1H), 7.79~7.73 (m, 2H), 7.65 (d, J=8.8Hz, 1H), 6.97~6.93 (m,
2H), 4.13 (q, J=7.0Hz, 2H), 1.46 (t, J=7.0Hz, 3H)13C NMR(151MHz,CDCl3)δ:191.0,
164.2,146.3,140.3,138.1,132.6,131.2,128.1,125.3,124.0,114.7,64.1,14.6。
(2) preparation of compound 1
It weighs chloro- -4 '-ethoxy diphenyl ketone 0.61g (2mmol) of 5- nitro of 2- to be dissolved in 6mL acetonitrile, triethyl group silicon is added
Alkane 1.0mL is slowly added to boron trifluoride ether solution 0.5mL, 40 DEG C of reaction 12h, adds triethylsilane 1mL every 6h, and three
Boron fluoride diethyl ether solution 0.5mL, TLC tracking, fully reacting stop reaction.Saturated sodium bicarbonate solution is added dropwise to stir 30 minutes,
Twice, ethyl acetate extraction, organic phase is washed with brine stir process, collects organic phase, decompression obtains solid 0.55g, i.e. mesh
Mark compound 1, yield 94%.M.p.:84~84.8 DEG C；1H NMR(600MHz,CDCl3) δ: 8.00 (dt, J=6.5,2.6Hz,
2H), 7.52 (d, J=8.6Hz, 1H), 7.10 (d, J=8.7Hz, 2H), 6.85 (d, J=8.7Hz, 2H), 4.09 (s, 2H),
4.02 (q, J=7.0Hz, 2H), 1.41 (t, J=7.0Hz, 3H)13C NMR(151MHz,CDCl3)δ:158.0,146.7,
141.3,141.0,130.4,123.0,129.5,125.5,122.5,114.9,63.5,38.4,14.9.IR vmax(KBr)cm-1: 2979,1609,1528,1348,1249,1113,1057,902,840,734.
(3) preparation of compound 2
Weigh chloro- -4 '-ethoxy diphenyl methylmethane of 5- nitro of 0.29g (1mmol) 2-, 0.19g active carbon,
0.10gFeCl3·6H2O is dissolved in 4mL dehydrated alcohol, and 0.5mL hydrazine hydrate is slowly dropped to instead by heating stirring to 80 DEG C of reflux
Ying Zhong, after forty minutes, TLC tracking, raw material fully reacting.Stop reaction, filtrate is concentrated in heat filtering, analyses after cold water stirring is added
White solid out filters, dry, obtains white solid 0.25g, i.e. target compound 2, yield 95%.M.p.:101.5~102.3
℃；1H NMR(600MHz,CDCl3) δ: 7.10 (t, J=7.8Hz, 3H), 6.82 (d, J=8.5Hz, 2H), 6.45 (dd, J=
8.4,2.8Hz, 1H), 6.39 (d, J=2.8Hz, 1H), 3.99 (q, J=7.0Hz, 2H), 3.92 (s, 2H), 3.52 (s, 2H),
1.39 (t, J=7.0Hz, 3H)13C NMR(151MHz,CDCl3) δ: 157.4,145.2,139.8,131.6,130.0,
129.9,123.2,117.3,114.5,114.3,63.4,38.3,14.9.IR vmax(KBr)cm-1: 3475,3364,2929,
1609,1516,1243,1175,1119,1044,877,821,772。
(3) preparation of compound ii -1
Weigh 2- chloro- -4 '-ethoxy diphenyl methylmethane 1.17g (4.5mmol) of 5- amino, sodium cyanoborohydride 1.15g
(18mmol), 5- oxidation list acetone glucose 6.3g (28mmol), are added in 10mL methanol, are heated to by 10,4A molecular sieve
70 DEG C of back flow reaction 4h, TLC tracking, fully reacting.Stop reaction, vacuum distillation removes solvent, and distilled water stirring, acetic acid is added
Ethyl ester extraction, organic phase are washed with brine, and collect organic phase.Silica gel column chromatography separates (ethyl acetate: petroleum ether=1:2, V/V)
Obtain white solid 1.40g, i.e. compound ii -1, yield 67%.M.p.:159.4~160.5 DEG C；HRMS m/z (ESI):
464.1843[M+H]+, calculated value: 464.1839；1H NMR(600MHz,DMSO-d6) δ: 7.09 (d, J=8.6Hz, 2H),
7.02 (d, J=8.7Hz, 1H), 6.86~6.78 (m, 2H), 6.53 (d, J=2.7Hz, 1H), 6.50 (dd, J=8.7,
2.8Hz, 1H), 5.81 (d, J=3.7Hz, 1H), 5.53 (d, J=9.4Hz, 1H), 5.25 (d, J=5.0Hz, 1H), 4.55 (t,
J=5.2Hz, 1H), 4.36 (d, J=3.7Hz, 1H), 4.08 (dd, J=9.0,2.4Hz, 1H), 3.98 (d, J=2.0Hz,
1H), 3.98~3.94 (m, 2H), 3.81 (s, 2H), 3.65 (ddd, J=12.9,9.1,3.6Hz, 1H), 3.62~3.54 (m,
1H), 3.48~3.40 (m, 1H), 1.38 (s, 3H), 1.30 (t, J=7.0Hz, 3H), 1.23 (s, 3H)13C NMR(151MHz,
DMSO-d6) δ: 156.8,147.4,138.5,131.5,129.6,129.1,118.5,115.3,114.2,11 2.1,110.4,
104.3,84.8,79.1,72.9,62.8,60.1,51.8,37.8,26.7,26.1,14.7.IR vmax(KBr)cm-1: 3432,
3357,2967,2936,1590,1516,1385,1243,1162,1038,852,796。
Embodiment 2: the synthesis of compound II-2
(1) preparation of compound 3
It weighs 2- chloro-5-nitrobenzoic acid 2.06g (10mmol) to be dissolved in 5mL thionyl chloride, 3 drop pyridines is added dropwise, so
It is stirred to react at 50 DEG C afterwards 3 hours, TLC tracking, raw material fully reacting stops reaction.Vacuum rotary steam removes thionyl chloride, no
It direct plunges into through processing and reacts in next step.
By 2.12g (15mmol) anhydrous AlCl3It is added to 18mLCH2Cl2In, it is cooled to 0 DEG C, is slowly added to phenetole
1.35g (11mmol), while 0~5 DEG C is maintained the temperature at, it completes after being added, is stirred 15~20 minutes at 0 DEG C.It then will be upper
The chloro- 5- nitrobenzoyl chloride of 2- of one step preparation is dissolved in 6mLCH2Cl2In, it is added in phenetole system, the speed of addition is wanted
0~5 DEG C is kept the temperature at, reacts 12 hours, obtains blackish green solution.TLC tracking, raw material have largely reacted, and stop anti-
It answers.By being added into the case where being vigorously stirred and cooling down into 70mL2NHCl, reaction mixture is quenched, is stirred at 20~25 DEG C
It mixes 20 minutes, then separates each phase.Organic phase is washed with 2NHCl, combined water phase CH2Cl2Extraction.The organic phase of collection is used
It is saturated NaHCO3Solution washes twice, and at least stirs 30 minutes every time, then use CH2Cl2Extraction, is finally washed with brine merging
Organic layer.Pass through column layer chromatography (eluant ethyl acetate: petroleum ether=1:40, V/V) isolated white solid 0.6g, i.e. mesh
Mark compound 3, yield 19%.M.p.:86.5~88 DEG C；1H NMR(600MHz,CDCl3) δ: 8.21 (dd, J=7.7,2.3Hz,
2H), 7.90 (dd, J=7.8,1.8Hz, 1H), 7.61~7.50 (m, 2H), 7.14~7.04 (m, 1H), 6.88 (d, J=
8.4Hz, 1H), 3.84 (q, J=7.0Hz, 2H), 0.85 (t, J=7.0Hz, 3H)13C NMR(151MHz,CDCl3) δ:
192.1,158.8,146.4,143.2,137.8,135.6,131.3,130.6,125.9,124.7,123.6,121.0,
112.3,63.7,13.9.IR vmax(KBr)cm-1: 2868,2589,1981,1609,1479,1249,1125,1051,815,
741。
(2) preparation of compound 4
It weighs chloro- -2 '-ethoxy diphenyl ketone 0.60g (2mmol) of 5- nitro of 2- to be dissolved in 6mL acetonitrile, triethyl group silicon is added
Alkane 1.0mL is slowly added to boron trifluoride ether solution 0.5mL, 40 DEG C of reaction 48h, every adding triethylsilane 1mL for 24 hours, three
Boron fluoride diethyl ether solution 0.5mL, TLC tracking, raw material react endless always, stop reaction.Saturated sodium bicarbonate solution is added dropwise to stir
It mixes 30 minutes, twice, ethyl acetate extraction, organic phase is washed with brine stir process, collects organic phase, silica gel column chromatography separation
(eluant ethyl acetate: petroleum ether=1:20, V/V), obtains faint yellow solid 0.24g, i.e. target compound 4, yield 41%.
M.p.:90.8~92.5 DEG C；1H NMR(300MHz,CDCl3) δ: 8.10 (d, J=2.4Hz, 1H), 7.97 (dd, J=8.7,
2.5Hz, 1H), 7.49 (d, J=8.7Hz, 1H), 7.20 (dd, J=12.8,8.1Hz, 2H), 6.89 (dd, J=13.8,
7.6Hz, 2H), 4.14 (s, 2H), 4.02 (dd, J=13.9,6.9Hz, 2H), 1.38 (t, J=6.9Hz, 3H)13C NMR
(75MHz,CDCl3) δ: 156.8,146.5,141.1,140.7,130.8,130.0,128.5,126.1,126.0,12 2.1,
120.4,111.4,63.5,34.1,14.8.IR vmax(KBr)cm-1: 2990,1612,1521,1471,1350,1260,1124,
1049,933,903,843,747,647,531。
(3) preparation of compound 5
Weigh chloro- -2 '-ethoxy diphenyl methylmethane of 5- nitro of 2.6g (9mmol) 2-, 1.35g active carbon, 0.92g
FeCl3·6H2O is dissolved in 30mL dehydrated alcohol, and 3.6mL hydrazine hydrate is slowly dropped to reaction to 80 DEG C of reflux by heating stirring
In, after forty minutes, TLC tracking, raw material fully reacting.Stop reaction, ethyl alcohol is removed under reduced pressure, adds water and stirs, is extracted with ethyl acetate
It takes, organic phase is washed with brine, and collects organic phase, faint yellow solid 2.0g, i.e. target compound 5, yield is concentrated under reduced pressure to obtain
85%.M.p.:119~120 DEG C；1H NMR(600MHz,CDCl3) δ: 7.18 (t, J=7.8Hz, 1H), 7.11 (d, J=
8.4Hz, 1H), 7.01 (d, J=7.7Hz, 1H), 6.85 (t, J=7.3Hz, 2H), 6.44 (dd, J=8.4,2.8Hz, 1H),
6.41 (d, J=2.7Hz, 1H), 4.02 (dd, J=13.9,7.0Hz, 2H), 3.99 (s, 2H), 3.37 (s, 2H), 1.37 (td, J
=6.9,1.3Hz, 3H)13C NMR(151MHz,CDCl3) δ: 156.88,145.01,139.24,130.34,129.73,
128.34,127.47,123.65,120.33,117.58,114.25,111.38,63.65,33.32,14.95.IR vmax
(KBr)cm-1: 3457,2868,2594,1987,1479,1231,1125,1051,815,747.
(4) preparation of compound ii -2
Weigh 2- chloro- -2 '-ethoxy diphenyl methylmethane 0.92g (3.5mmol) of 5- amino, sodium cyanoborohydride 0.88g
(14mmol), 5- oxidation list acetone glucose 5.9g (23mmol), are added in 10mL methanol, are heated to by 10,4A molecular sieve
70 DEG C of back flow reaction 4h, TLC tracking, fully reacting.Stop reaction, vacuum distillation removes solvent, and distilled water stirring, acetic acid is added
Ethyl ester extraction, organic phase are washed with brine, and collect organic phase.Silica gel column chromatography separation (ethyl acetate: petroleum ether=1:2) obtains
White solid product 1.10g, i.e. target compound II -2, yield 68%.M.p.:105.6~106.8 DEG C；HRMS m/z
(ESI): 464.1843 [M+H]+, calculated value: 464.1839；1H NMR(600MHz,DMSO-d6) δ: 7.21~7.13 (m, 1H),
7.04 (d, J=8.7Hz, 1H), 6.95 (t, J=8.3Hz, 2H), 6.83 (t, J=7.5Hz, 1H), 6.51 (dd, J=8.8,
2.4Hz, 1H), 6.46 (d, J=2.3Hz, 1H), 5.80 (d, J=3.6Hz, 1H), 5.50 (d, J=9.3Hz, 1H), 5.23 (d,
J=4.9Hz, 1H), 4.53 (s, 1H), 4.36 (d, J=3.6Hz, 1H), 4.08 (d, J=8.9Hz, 1H), 4.03 (q, J=
6.9Hz, 2H), 3.97 (s, 1H), 3.84 (s, 2H), 3.67~3.54 (m, 2H), 3.43 (d, J=10.2Hz, 1H), 1.38 (s,
3H), 1.33 (t, J=6.9Hz, 3H), 1.22 (s, 3H)13C NMR(151MHz,DMSO-d6) δ: 156.2,147.3,137.5,
129.5,129.0,127.7,127.4,120.1,118.9,115.4,112.0,111.5,110.4,104.2,84.8,79.0,
72.8,63.2,59.9,51.8,32.7,26.7,26.1,14.7.IR vmax(KBr)cm-1: 3475,3382,2991,2929,
1801,1609,1485,1374,1236,1169,1032,865,753。
Embodiment 3: the synthesis of compound ii -3
(1) preparation of compound 6
It weighs 2- methyl-5-nitro benzoic acid 4.52g (25mmol) to be dissolved in 8mL thionyl chloride, 3 drop pyridines is added dropwise,
Then 3h, TLC tracking are stirred to react at 50 DEG C, raw material fully reacting stops reaction.Vacuum rotary steam removes thionyl chloride, no
It direct plunges into through processing and reacts in next step.
By anhydrous AlCl35.00g (37.5mmol) is added to 45mLCH2Cl2In, it is cooled to 0 DEG C, is slowly added to phenetole
3.36g (27.5mmol), while 0~5 DEG C is maintained the temperature at, it completes after being added, is stirred 15~20 minutes at 0 DEG C.Then will
The 2- methyl-5-nitro chlorobenzoyl chloride of previous step preparation is dissolved in 14mLCH2Cl2In, it is added in phenetole system, addition
Speed will keep the temperature at 0~5 DEG C, react 1h, obtain blackish green solution.TLC tracking, raw material have largely reacted, and stop
Reaction.By being added into the case where being vigorously stirred and cooling down into 80mL2NHCl, reaction mixture is quenched, at 20~25 DEG C
Stirring 20 minutes, then separates each phase.Organic phase is washed with 2NHCl, combined water phase CH2Cl2Extraction.The organic phase of collection
With saturation NaHCO3Solution washes twice, and at least stirs 30 minutes every time, then use CH2Cl2Extraction, is finally washed with brine merging
Organic layer.By column layer chromatography (eluant ethyl acetate: petroleum ether=1:20, V/V) isolated white solid 6.3g, i.e.,
Target compound 6, yield 88%.M.p.:81.2~83 DEG C；1H NMR(300MHz,CDCl3) δ: 8.33~8.00 (m, 2H),
7.76 (d, J=8.8Hz, 2H), 7.46 (d, J=8.3Hz, 1H), 6.95 (d, J=8.8Hz, 2H), 4.13 (dd, J=13.9,
6.9Hz, 2H), 2.41 (s, 3H), 1.46 (t, J=7.0Hz, 3H)13C NMR(75MHz,CDCl3) δ: 194.5,163.9,
145.7,144.1,140.3,132.5,131.9,129.0,124.3,122.7,114.6,64.0,20.0,14.6.IR vmax
(KBr)cm-1: 2967,1659,1602,1528,1348,1256,1150,1038,914,834,728.
(2) preparation of compound 7
It weighs 2- methyl-5-nitro -4 '-ethoxy diphenyl ketone 1.75g (6mmol) to be dissolved in 6mL acetonitrile, triethyl group is added
Silane 6.0mL, is slowly added to boron trifluoride ether solution 3.0mL, 40 DEG C of reaction 2h, TLC tracking, and fully reacting stops reaction.
Saturated sodium bicarbonate solution is added dropwise to stir 30 minutes, twice, ethyl acetate extraction, organic phase is washed with brine stir process, is received
Collect organic phase, decompression obtains solid 1.15g, i.e. target compound 7, yield 69%.M.p.:50.9~52.3 DEG C；1H NMR
(600MHz,CDCl3) δ: 7.99 (dd, J=8.3,2.4Hz, 1H), 7.95 (d, J=2.2Hz, 1H), 7.29 (d, J=8.3Hz,
1H), 7.01 (d, J=8.5Hz, 2H), 6.83 (d, J=8.6Hz, 2H), 4.00 (q, J=7.0Hz, 2H), 3.97 (s, 2H),
2.34 (s, 3H), 1.40 (t, J=7.0Hz, 3H)13C NMR(151MHz,CDCl3) δ: 157.7,146.5,144.7,141.2,
130.9,130.3,129.6,124.4,121.4,114.7,63.4,38.5,19.9,14.8.IR vmax(KBr)cm-1: 2985,
1609,1516,1348,1243,1187,1113,1038,840,741。
(3) preparation of compound 8
Weigh 2- methyl-5-nitro -4 '-ethoxy diphenyl methylmethane 1.15g (4mmol), active carbon 0.63g, FeCl3·
6H2O 0.40g is dissolved in 10mL dehydrated alcohol, and 1.7mL hydrazine hydrate is slowly dropped to reaction to 80 DEG C of reflux by heating stirring
In, after forty minutes, TLC tracking, raw material fully reacting.Stop reaction, filtrate is concentrated in heat filtering, is precipitated after cold water stirring is added
White solid filters, dry, obtains white solid 0.75g, i.e. target compound 8, yield 74%.M.p.:66.5~66.2 DEG C；1H NMR(400MHz,CDCl3) δ: 7.06 (d, J=8.7Hz, 2H), 6.97 (d, J=7.9Hz, 1H), 6.87~6.79 (m,
2H), 6.52 (dd, J=7.9,2.5Hz, 1H), 6.45 (d, J=2.4Hz, 1H), 4.03 (q, J=7.0Hz, 2H), 3.85 (s,
2H), 3.40 (s, 2H), 2.16 (s, 3H), 1.43 (t, J=7.0Hz, 3H)13C NMR(101MHz,CDCl3) δ: 157.3,
144.4,140.4,132.4,131.0,129.8,126.7,117.1,114.5,113.3,63.5,38.6,18.7,15.0.IR
vmax(KBr)cm-1: 3457,3364,2985,1609,1510,1243,1181,1106,1044,914,815,772.
(4) preparation of compound ii -3
Weigh 2- methyl -5- amino -4 '-ethoxy diphenyl methylmethane 724mg (3mmol), sodium cyanoborohydride 754mg
(12mmol), 5- oxidation list acetone glucose 5.0g (23mmol), are added in 10mL methanol, are heated to by 10,4A molecular sieve
70 DEG C of back flow reaction 1h, TLC tracking, fully reacting.Stop reaction, vacuum distillation removes solvent, and distilled water stirring, acetic acid is added
Ethyl ester extraction, organic phase are washed with brine, and collect organic phase.Silica gel column chromatography separates (ethyl acetate: petroleum ether=1:2, V/V)
Obtain white solid product 0.94g, i.e. target compound II -3, yield 70%.M.p.:175.4~175.9 DEG C；HRMS m/z
(ESI):466.2190[M+Na]+, calculated value: 466.22061H NMR(600MHz,DMSO-d6) δ: 7.02 (d, J=8.5Hz,
2H), 6.81 (dd, J=8.0,5.6Hz, 3H), 6.50~6.35 (m, 2H), 5.82 (d, J=3.7Hz, 1H), 5.24 (d, J=
4.9Hz, 1H), 5.05 (d, J=9.5Hz, 1H), 4.50 (t, J=5.2Hz, 1H), 4.37 (d, J=3.7Hz, 1H), 4.10
(dd, J=8.8,2.2Hz, 1H), 4.01 (dd, J=4.7,2.7Hz, 1H), 3.96 (q, J=7.0Hz, 2H), 3.71 (s, 2H),
3.70~3.63 (m, 1H), 3.58 (dt, J=10.0,4.1Hz, 1H), 3.50~3.44 (m, 1H), 2.02 (s, 3H), 1.38
(s, 3H), 1.30 (t, J=7.0Hz, 3H), 1.23 (s, 3H)13C NMR(151MHz,DMSO-d6) δ: 156.6,146.4,
139.3,132.3,130.3,129.4,122.5,115.2,114.1,110.7,110.3,104.2,84.8,79.2,73.0,
62.8,59.9,52.1,38.2,26.7,26.1,18.2,14.7.IR vmax(KBr)cm-1: 3432,3345,2985,2924,
1621,1510,1385,1243,1169,1044,957,865,803。
Embodiment 4: the synthesis of compound ii -4
Weigh 2- (4- fluorophenyl) -5- (2- methyl -5- aminophenyl)-methylthiophene 0.30g (1mmol), cyano boron hydrogen
Change sodium 0.25g (4mmol), 5- oxidation list acetone glucose 1.09g (5mmol), 10,4A molecular sieve, 10mL methanol is added
In, it is heated to 70 DEG C of back flow reaction 4h, TLC tracking, fully reacting.Stop reaction, vacuum distillation removes solvent, and distilled water is added
Stirring, ethyl acetate extraction, organic phase are washed with brine, and collect organic phase.Silica gel column chromatography separates (ethyl acetate: petroleum ether
=1:1, V/V) obtain the faint yellow target compound II -4 of 0.34g, yield 68%.M.p.:140.8~141.3 DEG C.HRMS m/z
(ESI):500.1902[M+H]+, calculated value: 500.1901；1H NMR(600MHz,CDCl3) δ: 7.46 (dd, 2H), 7.07~
6.95 (m, 4H), 6.67 (d, J=3.5Hz, 1H), 6.61 (d, J=2.4Hz, 1H), 6.57 (dd, 1H), 5.91 (d, J=
3.7Hz, 1H), 4.48 (d, J=3.7Hz, 1H), 4.24 (d, J=2.6Hz, 1H), 4.20 (dd, 1H), 4.01 (s, 2H), 3.80
(dt,3H),2.20(s,3H),1.47(s,3H),1.29(s,3H).13C NMR(151MHz,CDCl3) δ: 157.7,156.0,
139.7,138.1,136.3,134.1,126.2,125.6,125.6,121.9,121.9,121.5,120.8,117.5,
111.2,110.5,110.4,108.0,106.5,99.5,79.8,75.4,70.0,56.3,49.0,29.0,21.5,20.9,
13.2.IR vmax(KBr)cm-1: 3427,3306,2927,1616,1514,1380,1232,1163,1074,833,808.
Embodiment 5: the synthesis of compound ii -5
(1) preparation of compound 9
It weighs 2- chloro-5-nitrobenzoic acid 5.04g (25mmol) to be dissolved in 8mL thionyl chloride, 4 drop pyridines is added dropwise, so
3h, TLC tracking are stirred to react at 50 DEG C afterwards, raw material fully reacting stops reaction.Vacuum rotary steam removes thionyl chloride, without
Processing direct plunges into reacts in next step.
By anhydrous AlCl34.55g (25mmol) is added to 15mLCH2Cl2In, it is cooled to 0 DEG C, is slowly added to 2- (4- fluorine
Phenyl) thiophene 4.45g (25mmol), while 0~5 DEG C is maintained the temperature at, it completes after being added, is stirred 15~20 minutes at 0 DEG C.
Then the chloro- 5- nitrobenzoyl chloride of 2- prepared by previous step is dissolved in 45mLCH2Cl2In, it is added to 2- (4- fluorophenyl) thiophene
In system, the speed of addition will keep the temperature at 0~5 DEG C, react 1h, obtain blackish green solution, stop reaction.By in play
Strong stirring and it is cooling under be added into 80mL2NHCl, quench reaction mixture, stir 20 minutes at 20~25 DEG C, so
After separate each phase.Organic phase is washed with 2NHCl, combined water phase CH2Cl2Extraction.The organic phase of collection saturation NaHCO3It is molten
Liquid washes twice, and is finally washed with brine the organic layer of merging.By column layer chromatography (eluant ethyl acetate: petroleum ether=1:
20, V/V) the faint yellow target compound 9 of isolated 7.0g, yield 78%.M.p.:155.4~156.1 DEG C；1HNMR
(600MHz,CDCl3) δ: 8.32 (s, 1H), 8.28 (d, 1H), 7.70~7.60 (m, 3H), 7.34 (s, 1H), 7.27 (s, 1H),
7.11(t,2H).13C NMR(151MHz,CDCl3)δ:184.9,165.3,163.6,155.7,147.1,141.8,140.1,
139.2,138.3,132.4,129.3,128.5,127.5,126.7,125.4,124.9,117.4,117.3.IR vmax(KBr)
cm-1: 3070,1645,1523,1442,1342,1301,1230,1045,815,728.
(2) preparation of compound 10
It weighs 2- (the chloro- 5- nitro benzoyl of 2-) -5- (4- fluorophenyl)-thiophene 2.17g (6mmol) and is dissolved in 6mL acetonitrile
In 6mL methylene chloride, triethylsilane 6.0mL is added, is slowly added to boron trifluoride ether solution 3.0mL, 40 DEG C of reaction 2h,
TLC tracking, fully reacting stop reaction.Be added dropwise saturated sodium bicarbonate solution stir 30 minutes, stir process twice, acetic acid second
Ester extraction, organic phase are washed with brine, and collect organic phase, and decompression obtains 2.0g target compound 10, yield 96%.m.p.:
81.6~82.3 DEG C；1HNMR(600MHz,CDCl3) δ: 7.28 (d, J=2.6Hz, 1H), 7.17 (dd, J=8.7,2.6Hz,
1H), 6.66 (d, J=8.7Hz, 1H), 6.60 (dd, J=8.6Hz, 2H), 6.19 (d, J=3.5Hz, 1H), 6.15 (t, J=
8.6Hz, 2H), 5.94 (d, J=3.5Hz, 1H), 3.44 (s, 2H)13C NMR(151MHz,CDCl3) δ: 163.9,162.2,
147.5,143.5,141.5,140.5,140.1,131.3,131.2,131.2,128.1,128.1,128.0,126.1,
123.8,123.7,116.7,116.5,34.6.IR vmax(KBr)cm-1: 3103,2929,1521,1346,1240,1045,
810,742。
(3) preparation of compound 11
Weigh 2- (4- fluorophenyl) -5- (the chloro- 5- nitrobenzophenone of 2-)-methylthiophene 1.39g (4mmol), active carbon
0.63g, FeCl3·6H2O 0.40g is dissolved in 10mL dehydrated alcohol, and heating stirring is slow by 1.7mL hydrazine hydrate to 80 DEG C of reflux
It is added drop-wise in reaction, after forty minutes, TLC tracking, raw material fully reacting.Stop reaction, filtrate is concentrated in heat filtering, and cold water is added
White solid is precipitated after stirring, filters, it is dry, obtain 1.22g white object chemical combination 11, yield 92%.M.p.:145.7~146.2
℃；1HNMR(600MHz,DMSO-d6) δ: 7.62 (dd, J=8.8Hz, 2H), 7.30 (d, J=3.6Hz, 1H), 7.22 (t, J=
8.8Hz, 2H), 7.11 (d, 1H), 6.89 (d, J=3.6Hz, 1H), 6.66 (d, 1H), 6.58~6.54 (m, 1H), 5.73 (s,
2H),4.12(s,2H).13C NMR(151MHz,DMSO-d6)δ162.2,160.6,147.0,142.3,140.6,137.6,
130.5,130.5,129.6,127.0,126.9,126.8,123.4,119.4,116.3,115.9,115.8,114.6,
33.2.IR vmax(KBr)cm-1: 3405,3388,3060,1615,1510,1224,834,803.
(4) preparation of compound ii -5
Weigh 2- (4- fluorophenyl) -5- (the chloro- 5- aminophenyl of 2-)-methylthiophene 0.30g (1mmol), cyano hydroboration
Sodium 0.25g (4mmol), 5- oxidation list acetone glucose 1.09g (5mmol), are added in 10mL methanol by 10,4A molecular sieve,
It is heated to 70 DEG C of back flow reaction 4h, TLC tracking, fully reacting.Stop reaction, vacuum distillation removes solvent, and distilled water is added and stirs
It mixes, ethyl acetate extraction, organic phase is washed with brine, and collects organic phase.Silica gel column chromatography separation (ethyl acetate: petroleum ether=
1:1, V/V) obtain the faint yellow target compound II -5 of 0.34g, yield 68%.M.p.:140.8~141.3 DEG C, HRMS m/z
(ESI):542.1159[M+Na]+, calculated value: 542.1175；1HNMR(600MHz,DMSO-d6) δ: 7.60 (dd, J=8.8,
2H), 7.28 (d, J=3.6Hz, 1H), 7.21 (t, J=8.8Hz, 2H), 7.06 (d, J=8.8Hz, 1H), 6.87 (d, J=
3.6Hz, 1H), 6.67 (d, J=2.8Hz, 1H), 6.56 (dd, J=8.8,2.8Hz, 1H), 5.82 (d, J=3.7Hz, 1H),
5.61 (d, 1H), 5.25 (d, 1H), 4.55 (s, 1H), 4.37 (d, J=3.7Hz, 1H), 4.08 (s, 3H), 4.00 (s, 1H),
3.69 (s, 1H), 3.62 (d, J=7.5Hz, 1H), 3.47 (d, J=7.5Hz, 1H), 1.38 (s, 3H), 1.23 (s, 3H)13C
NMR(151MHz,DMSO-d6) δ: 162.2,160.6,147.6,142.5,140.4,137.2,130.5,130.5,129.3,
127.0,127.0,126.7,123.4,118.2,115.9,115.8,114.9,112.7,110.4,104.3,84.9,79.1,
72.9,60.1,51.9,33.4,26.7,26.1.IR vmax(KBr)cm-1: 3450,3355,2925,1604,1514,1232,
1159,1076,837,804。
Embodiment 6: the synthesis of compound ii -6
(1) preparation of compound 12
It weighs 2- methyl-3-nitro benzoic acid 4.55g (25mmol) to be dissolved in 8mL thionyl chloride, 4 drop pyridines is added dropwise,
Then 3h, TLC tracking are stirred to react at 50 DEG C, raw material fully reacting stops reaction.Vacuum rotary steam removes thionyl chloride, no
It direct plunges into through processing and reacts in next step.
By anhydrous AlCl34.55g (25mmol) is added to 15mLCH2Cl2In, it is cooled to 0 DEG C, is slowly added to 2- (4- fluorobenzene
Base) thiophene 4.45g (25mmol), while 0~5 DEG C is maintained the temperature at, it completes after being added, is stirred 15~20 minutes at 0 DEG C.So
2- methyl-3-nitro chlorobenzoyl chloride prepared by previous step is dissolved in 45mLCH afterwards2Cl2In, it is added to 2- (4- fluorophenyl) thiophene
In system, the speed of addition will keep the temperature at 0~5 DEG C, react 1h, obtain blackish green solution, stop reaction.By in play
Strong stirring and it is cooling under be added into 80mL2NHCl, quench reaction mixture, stir 20 minutes at 20~25 DEG C, so
After separate each phase.Organic phase is washed with 2NHCl, combined water phase CH2Cl2Extraction.The organic phase of collection saturation NaHCO3It is molten
Liquid washes twice, and is finally washed with brine, combined organic layer.By silica gel column chromatography (eluant ethyl acetate: petroleum ether=
1:20, V/V) isolated 12 yield 73% of 6.23g target compound.M.p.:126.8~127.4 DEG C；1HNMR(600MHz,
CDCl3) δ: 7.87 (d, J=8.0Hz, 1H), 7.59~7.53 (m, 3H), 7.37 (t, J=8.0Hz, 1H), 7.24 (d, J=
4.0Hz, 1H), 7.18 (d, J=4.0Hz, 1H), 7.04 (t, 2H), 2.40 (s, 3H)13C NMR(151MHz,CDCl3)δ:
188.0,164.3,162.7,154.2,150.9,142.3,141.6,137.1,131.3,130.8,129.3,129.3,
128.3,128.3,126.5,125.7,124.3,116.5,116.3,16.3.IR vmax(KBr)cm-1: 3091,1631,1531,
1438,1244,1074,825,682。
(2) preparation of compound 13
It weighs 2- (2- methyl-3-nitro benzoyl) -5- (4- fluorophenyl)-thiophene 2.05g (6mmol) and is dissolved in 6mL second
In nitrile and 6mL methylene chloride, triethylsilane 6.0mL is added, is slowly added to boron trifluoride ether solution 3.0mL, 40 DEG C of reactions
2h, TLC tracking, fully reacting stop reaction.Be added dropwise saturated sodium bicarbonate solution stir 30 minutes, stir process twice, acetic acid
Ethyl ester extraction, organic phase are washed with brine, and collect organic phase, and decompression obtains 1.91g target compound 13, yield 97%.m.p.:
97.4~98.2 DEG C；1HNMR(600MHz,CDCl3) δ: 6.42 (d, J=8.0Hz, 1H), 6.24~6.17 (m, 3H), 6.03 (t,
J=8.0Hz, 1H), 5.77 (dd, 3H), 5.40 (d, 1H), 2.95 (s, 2H), 1.17 (s, 3H)13C NMR(151MHz,
CDCl3) δ: 157.8,156.2,146.3,137.0,136.2,135.8,128.4,125.5,125.3,12 5.3,122.0,
121.9,121.3,121.3,117.6,117.5,110.7,110.5,29.1,9.7.IR vmax(KBr)cm-1: 3095,1533,
1363,1234,811,777,732。
(3) preparation of compound 14
Weigh 2- (4- fluorophenyl) -5- (2- methyl-3-nitro phenyl)-methylthiophene 1.31g (4mmol), active carbon
0.63g, FeCl3·6H2O 0.40g is dissolved in 10mL dehydrated alcohol, and heating stirring is slow by 1.7mL hydrazine hydrate to 80 DEG C of reflux
It is added drop-wise in reaction, after forty minutes, TLC tracking, raw material fully reacting.Stop reaction, filtrate is concentrated in heat filtering, and cold water is added
White solid is precipitated after stirring, filters, it is dry, obtain 1.16g target compound 14, yield 98%.M.p.:116.8~117.3
℃；1H NMR(600MHz,DMSO-d6) δ: 7.57 (dd, J=8.9Hz, 2H), 7.24 (d, J=3.6Hz, 1H), 7.18 (t, J=
8.9Hz, 2H), 6.87 (t, J=7.7Hz, 1H), 6.78 (d, J=3.6Hz, 1H), 6.59 (d, J=7.7Hz, 1H), 6.51 (d,
1H),4.84(s,2H),4.05(d,2H),2.01(s,3H).13C NMR(151MHz,DMSO-d6) δ: 162.1,160.5,
146.9,144.6,115.9,115.7,113.3,34.1,12.8.IR vmax(KBr)cm-1: 3280,3260,3070,1583,
1467,1228,1097,825,800,757。
(4) synthesis of compound ii -6
Weigh 2- (4- fluorophenyl) -5- (2- methyl -3- aminophenyl)-methylthiophene 0.30g (1mmol), cyano boron hydrogen
Change sodium 0.25g (4mmol), 5- oxidation list acetone glucose 1.09g (5mmol), 10,4A molecular sieve, 10mL methanol is added
In, it is heated to 70 DEG C of back flow reaction 4h, TLC tracking, fully reacting.Stop reaction, vacuum distillation removes solvent, and distilled water is added
Stirring, ethyl acetate extraction, organic phase are washed with brine, and collect organic phase.Silica gel column chromatography separates (ethyl acetate: petroleum ether
=1:1, V/V) obtain the faint yellow target compound II -6 of 3.60g, yield 72%.m.p.:161.3-161.8℃.HRMS m/z
(ESI):522.1709[M+Na]+, calculated value: 522.1721；1H NMR(300MHz,CDCl3)δ:7.49–7.27(m,2H),
6.96(dt,4H),6.65(t,2H),6.57(d,1H),5.86(s,1H),4.43(d,1H),4.21(s,2H),4.03(s,
2H),3.84(s,1H),3.74(d,2H),2.03(s,3H),1.41(s,3H),1.22(s,3H).13C NMR(151MHz,
CDCl3)δ:157.6,156.0,139.9,138.7,136.1,133.7,125.7,125.6,121.9,121.8,121.6,
120.5,117.4,116.7,115.3,110.5,110.4,106.5,105.9,99.6,79.7,75.5,70.2,56.1,
48.7,29.8,21.5,20.9,7.6.IR vmax(KBr)cm-1: 3456,3207,2920,1591,1514,1226,1060,
1014,827,790。
Embodiment 7: the synthesis of compound ii -7
(1) preparation of chloro- -4 '-ethoxy diphenyl ketone of 4- nitro of 2-
It weighs the chloro- 4- nitrobenzoic acid 3.12g (15mmol) of 2- to be dissolved in 8mL thionyl chloride, 4 drop pyridines is added dropwise, so
It is stirred to react at 50 DEG C afterwards 3 hours, TLC tracking, raw material fully reacting stops reaction.Vacuum rotary steam removes thionyl chloride, no
It direct plunges into through processing and reacts in next step.
By anhydrous AlCl33.06g (15mmol) is added to 25mLCH2Cl2In, it is cooled to 0 DEG C, is slowly added to phenetole
2.08g (16.5mmol), while 0~5 DEG C is maintained the temperature at, it completes after being added, is stirred 15~20 minutes at 0 DEG C.Then will
The chloro- 4- nitrobenzoyl chloride of 2- of previous step preparation is dissolved in 8mLCH2Cl2In, it is added in phenetole system, the speed of addition
0~5 DEG C is kept the temperature at, reacts 12 hours, obtains blackish green solution.TLC tracking, raw material have largely reacted, and stop
Reaction.By being added into the case where being vigorously stirred and cooling down into 80mL2NHCl, reaction mixture is quenched, at 20~25 DEG C
Stirring 20 minutes, then separates each phase.Organic phase is washed with 2NHCl, combined water phase CH2Cl2Extraction.The organic phase of collection
With saturation NaHCO3Solution washes twice, and at least stirs 30 minutes every time, then use CH2Cl2Extraction, is finally washed with brine merging
Organic layer.By silica gel column chromatography (eluant ethyl acetate: petroleum ether=1:40, V/V) isolated white solid 2.6g,
That is chloro- -4 '-ethoxy diphenyl ketone of 4- nitro of 2-, yield 55%.1H NMR(600MHz,CDCl3) δ: 8.34 (d, J=2.1Hz,
1H), 8.23 (dd, J=8.3,2.1Hz, 1H), 7.74 (d, J=8.9Hz, 2H), 7.54 (d, J=8.3Hz, 1H), 6.95 (d, J
=9.0Hz, 2H), 4.13 (q, J=7.0Hz, 2H), 1.46 (t, J=7.0Hz, 3H)13C NMR(151MHz,CDCl3) δ:
191.7,164.3,148.7,145.0,132.51,132.4,129.5,128.1,125.2,121.9,114.7,64.1,14.6。
(2) preparation of compound 15
It weighs chloro- -4 '-ethoxy diphenyl ketone 0.63g (2mmol) of 4- nitro of 2- to be dissolved in 6mL acetonitrile, triethyl group silicon is added
Alkane 1.0mL, is slowly added to boron trifluoride ether solution 0.5mL, 40 DEG C, reacts 12h, adds triethylsilane 1mL every 6h, and three
Boron fluoride diethyl ether solution 0.5mL, TLC tracking, fully reacting stop reaction.Saturated sodium bicarbonate solution is added dropwise to stir 30 minutes,
Twice, ethyl acetate extraction, organic phase is washed with brine stir process, collects organic phase, decompression obtains solid 0.50g, i.e. mesh
Mark compound 15, yield 92%.M.p.:51.4~52.7 DEG C；1H NMR(600MHz,CDCl3) δ: 8.23 (d, J=2.1Hz,
1H), 8.00 (dd, J=8.5,2.3Hz, 1H), 7.26 (d, J=8.5Hz, 1H), 7.08 (d, J=8.6Hz, 2H), 6.84 (d, J
=8.6Hz, 2H), 4.09 (s, 2H), 4.01 (q, J=7.0Hz, 2H), 1.40 (t, J=7.0Hz, 3H)13C NMR(151MHz,
CDCl3) δ: 157.9,146.9,146.8,134.9,131.2,130.1,129.4,124.7,121.8,11 4.8,63.5,
38.5,14.9.IR vmax(KBr)cm-1: 2979,1615,1534,1354,1243,1038,908,796,728.
(3) preparation of compound 16
Weigh 2- chloro- -4 '-ethoxy diphenyl methylmethane 2.92g (10mmol) of 4- nitro, active carbon 1.5g, FeCl3·
6H2O 0.20g is dissolved in 30mL dehydrated alcohol, and 4mL hydrazine hydrate is slowly dropped in reaction by heating stirring to 80 DEG C of reflux,
After forty minutes, TLC is tracked, raw material fully reacting.Stop reaction, filtrate is concentrated in heat filtering, and white is precipitated after cold water stirring is added
Solid filters, dry, obtains white solid 2.35g, i.e. target compound 16, yield 90%.M.p.:87.1~88.6 DEG C；1H
NMR(600MHz,CDCl3) δ: 7.09 (d, J=8.4Hz, 2H), 6.92 (d, J=8.2Hz, 1H), 6.87~6.78 (m, 2H),
6.72 (d, J=2.4Hz, 1H), 6.51 (dd, J=8.2,2.4Hz, 1H), 4.01 (q, J=7.0Hz, 2H), 3.93 (s, 2H),
3.57 (s, 2H), 1.41 (t, J=7.0Hz, 3H)13C NMR(151MHz,CDCl3) δ: 157.3,145.7,134.5,132.4,
131.5,129.7,128.8,115.8,114.4,113.9,63.4,37.5,14.9.IR vmax(KBr)cm-1: 3469,3370,
2960,1882,1621,1510,1218,1169,1113,1044,908,772.
(4) preparation of compound ii -7
Weigh 2- chloro- -4 '-ethoxy diphenyl methylmethane 786mg (3mmol) of 4- amino, sodium cyanoborohydride 754mg
(12mmol), 5- oxidation list acetone glucose 6.0g (27mmol), are added in 10mL methanol, are heated to by 10,4A molecular sieve
70 DEG C of back flow reaction 3h, TLC tracking, fully reacting.Stop reaction, vacuum distillation removes solvent, and distilled water stirring, acetic acid is added
Ethyl ester extraction, organic phase are washed with brine, and collect organic phase.Silica gel column chromatography separates (ethyl acetate: petroleum ether=1:2, V/V)
Obtain white solid product 0.97g, i.e. target compound II -7, yield 70%.M.p.:114.5~115.2 DEG C；HRMS m/z
(ESI):486.1644[M+Na]+, calculated value: 486.1659；1H NMR(600MHz,DMSO-d6) δ: 7.05 (d, J=8.6Hz,
2H), 6.93 (d, J=8.4Hz, 1H), 6.81 (d, J=8.6Hz, 2H), 6.68 (d, J=2.3Hz, 1H), 6.55 (dd, J=
8.4,2.3Hz, 1H), 5.82 (d, J=3.7Hz, 1H), 5.57 (d, J=9.4Hz, 1H), 5.27 (d, J=5.0Hz, 1H),
4.58 (t, J=5.3Hz, 1H), 4.37 (d, J=3.7Hz, 1H), 4.07 (dd, J=9.2,2.4Hz, 1H), 3.98 (dd, J=
4.9,2.7Hz, 1H), 3.95 (q, J=7.0Hz, 2H), 3.78 (s, 2H), 3.66 (ddd, J=13.1,9.2,3.7Hz, 1H),
3.63~3.57 (m, 1H), 3.50~3.42 (m, 1H), 1.39 (s, 3H), 1.29 (t, J=7.0Hz, 3H), 1.23 (s, 3H)
.13C NMR(151MHz,DMSO-d6) δ: 156.7,148.1,133.1,132.5,131.1,129.3,124.7,114.1,
112.7,112.0,110.4,104.3,84.8,79.2,72.9,62.8,60.5,51.9,36.6,26.7,26.1,14.7.IR
vmax(KBr)cm-1:3426,3345,2967,2929,1770,1609,1503,1379,1249,1162,1069,1038,883,
796。
Embodiment 8: the synthesis of compound ii -8
(1) preparation of compound 17
It weighs the chloro- 4- nitrobenzoic acid 3.12g (15mmol) of 2- to be dissolved in 8mL thionyl chloride, 4 drop pyridines is added dropwise, so
3h, TLC tracking are stirred to react at 50 DEG C afterwards, raw material fully reacting stops reaction.Vacuum rotary steam removes thionyl chloride, without
Processing direct plunges into reacts in next step.
By anhydrous AlCl33.06g (15mmol) is added to 25mLCH2Cl2In, it is cooled to 0 DEG C, is slowly added to phenetole
2.08g (16.5mmol), while 0~5 DEG C is maintained the temperature at, it completes after being added, is stirred 15~20 minutes at 0 DEG C.Then will
The chloro- 4- nitrobenzoyl chloride of 2- of previous step preparation is dissolved in 8mLCH2Cl2In, it is added in phenetole system, the speed of addition
0~5 DEG C is kept the temperature at, 12h is reacted, obtains blackish green solution.TLC tracking, raw material have largely reacted, and stop anti-
It answers.By being added into the case where being vigorously stirred and cooling down into 80mL2NHCl, reaction mixture is quenched, is stirred at 20~25 DEG C
It mixes 20 minutes, then separates each phase.Organic phase is washed with 2NHCl, combined water phase CH2Cl2Extraction.The organic phase of collection is used
It is saturated NaHCO3Solution washes twice, and at least stirs 30 minutes every time, then use CH2Cl2Extraction, is finally washed with brine merging
Organic layer.By silica gel column chromatography (eluant ethyl acetate: petroleum ether=1:40, V/V) isolated white solid 0.94g,
That is target compound 17, yield 20%.M.p.:86.7~88.7 DEG C；1H NMR(600MHz,CDCl3) δ: 8.27 (d, J=
2.1Hz, 1H), 8.17 (dd, J=8.4,2.1Hz, 1H), 7.91 (dd, J=7.8,1.8Hz, 1H), 7.59~7.53 (m, 1H),
7.51 (d, J=8.4Hz, 1H), 7.09 (t, J=7.8Hz, 1H), 6.89 (d, J=8.4Hz, 1H), 3.84 (q, J=7.0Hz,
2H), 0.85 (t, J=7.0Hz, 3H)13C NMR(151MHz,CDCl3) δ: 192.6,158.9,148.2,147.9,135.7,
131.9,131.2,128.9,125.8,124.7,121.7,121.0,112.3,63.8,13.8.IR vmax(KBr)cm-1:
3091,2991,1659,1584,1528,1447,1391,1298,1161,1124,1036,949,887,838,763,694。
(2) preparation of compound 18
It weighs chloro- -2 '-ethoxy diphenyl ketone 0.61g (2mmol) of 4- nitro of 2- to be dissolved in 6mL acetonitrile, triethyl group silicon is added
Alkane 1.0mL is slowly added to boron trifluoride ether solution 0.5mL, 40 DEG C of reaction 48h, every adding triethylsilane 1mL for 24 hours, three
Boron fluoride diethyl ether solution 0.5mL, TLC tracking, raw material react endless always, stop reaction.Saturated sodium bicarbonate solution is added dropwise to stir
It mixes 30 minutes, twice, ethyl acetate extraction, organic phase is washed with brine stir process, collects organic phase, silica gel column chromatography separation
(eluant ethyl acetate: petroleum ether=1:20, V/V) obtains faint yellow solid 0.26g, i.e. target compound 18, yield
45%,.M.p.:23~24.5 DEG C；1H NMR(600MHz,CDCl3) δ 8.24 (s, 1H), 7.97 (d, J=8.5Hz, 1H), 7.25
(d, J=8.0Hz, 2H), 7.11 (d, J=7.4Hz, 1H), 6.90 (t, J=7.4Hz, 1H), 6.87 (d, J=8.2Hz, 1H),
4.14 (s, 2H), 4.00 (m, J=6.9,3.5Hz, 2H), 1.33 (td, J=6.9,1.2Hz, 3H)13C NMR(151MHz,
CDCl3) δ: 156.8,146.6,146.6,134.9,131.1,130.7,128.4,126.21,124.4,1 21.4,120.5,
111.4,63.5,34.1,14.8.IR vmax(KBr)cm-1: 2984,1600,1522,1457,1396,1348,1239,1113,
1039,922,891,817,743。
(3) preparation of compound 19
Weigh 2- chloro- -2 '-ethoxy diphenyl methylmethane 1.1g (4mmol) of 5- nitro, active carbon 0.57g, FeCl3·6H2O
0.38g is dissolved in 10mL dehydrated alcohol, and 1.5mL hydrazine hydrate is slowly dropped in reaction, 40 points by heating stirring to 80 DEG C of reflux
Zhong Hou, TLC tracking, raw material fully reacting.Stop reaction, ethyl alcohol is removed under reduced pressure, adds water and stirs, is extracted with ethyl acetate, it is organic
It is mutually washed with brine, collects organic phase, faint yellow solid 0.76g, i.e. target compound 19, yield 77% is concentrated under reduced pressure to obtain.
M.p.:58.4~59.5 DEG C；1H NMR(300MHz,CDCl3) δ: 7.16 (t, J=7.0Hz, 1H), 6.99 (d, J=6.8Hz,
1H), 6.92 (d, J=8.2Hz, 1H), 6.84 (dd, J=7.1,4.2Hz, 2H), 6.70 (d, J=2.1Hz, 1H), 6.46 (dd,
J=8.1,2.1Hz, 1H), 4.01 (dd, J=15.9,9.0Hz, 4H), 3.44 (s, 2H), 1.38 (t, J=6.9Hz, 3H)13C
NMR(75MHz,CDCl3) δ: 156.8,145.5,134.8,131.8,130.1,129.0,128.1,127.3,120.3,
115.7,113.8,111.2,63.6,32.5,14.9.IR vmax(KBr)cm-1: 3432,3348,2983,1619,1505,
1451,1248,1116,1044,925,865,799,745。
(4) preparation of compound ii -8
Weigh 2- chloro- -2 '-ethoxy diphenyl methylmethane 0.69g (2.6mmol) of 4- amino, sodium cyanoborohydride 655mg
(10.4mmol), 5- oxidation list acetone glucose 6.0g (27mmol) 10,4A molecular sieve, are added in 10mL methanol, heating
To 70 DEG C of back flow reaction 4h, TLC tracking, fully reacting.Stop reaction, vacuum distillation removes solvent, and distilled water stirring, second is added
Acetoacetic ester extraction, organic phase are washed with brine, and collect organic phase.Silica gel column chromatography separates (ethyl acetate: petroleum ether=1:2, V/
V white solid 0.88g, i.e. target compound II -8, yield 73%) are obtained.M.p.:54.5~55.2 DEG C；HRMS m/z
(ESI):486.1638[M+Na]+, calculated value: 486.1659；1H NMR(600MHz,DMSO-d6) δ: 7.17~7.11 (m,
1H), 6.93 (d, J=8.1Hz, 1H), 6.88 (dd, J=10.4,8.9Hz, 2H), 6.81 (t, J=7.4Hz, 1H), 6.70 (d,
J=2.3Hz, 1H), 6.53 (dd, J=8.4,2.3Hz, 1H), 5.82 (d, J=3.6Hz, 1H), 5.56 (d, J=9.4Hz,
1H), 5.28 (d, J=4.8Hz, 1H), 4.59 (t, J=5.2Hz, 1H), 4.37 (d, J=3.6Hz, 1H), 4.08 (dd, J=
9.0,2.4Hz, 1H), 4.05~3.97 (m, 3H), 3.81 (s, 2H), 3.71~3.57 (m, 2H), 3.51~3.42 (m, 1H),
1.39 (s, 3H), 1.34 (t, J=7.0Hz, 3H), 1.23 (s, 3H)13C NMR(151MHz,DMSO-d6) δ: 156.2,
148.1,133.4,131.3,129.4,128.5,127.2,123.4,119.9,112.6,111.9,111.4,110.4,
104.3,84.8,79.2,72.9,63.1,60.4,51.9,31.7,26.7,26.1,14.7.IR vmax(KBr)cm-1: 3395,
2991,2929,1801,1615,1503,1379,1243,1044,846,753。
Embodiment 9: the synthesis of compound ii -9
(1) preparation of compound 20
It weighs the chloro- 4- nitrobenzoic acid 5.04g (25mmol) of 2- to be dissolved in 8mL thionyl chloride, 4 drop pyridines is added dropwise, so
3h, TLC tracking are stirred to react at 50 DEG C afterwards, raw material fully reacting stops reaction.Vacuum rotary steam removes thionyl chloride, without
Processing direct plunges into reacts in next step.
By anhydrous AlCl34.55g (25mmol) is added to 15mLCH2Cl2In, it is cooled to 0 DEG C, is slowly added to 2- (4- fluorine
Phenyl) thiophene 4.45g (25mmol), while 0~5 DEG C is maintained the temperature at, it completes after being added, is stirred 15~20 minutes at 0 DEG C.
Then the chloro- 4- nitrobenzoyl chloride of 2- prepared by previous step is dissolved in 45mLCH2Cl2In, it is added to 2- (4- fluorophenyl) thiophene
In system, the speed of addition will keep the temperature at 0~5 DEG C, react 1h, obtain blackish green solution, stop reaction.By in play
Strong stirring and it is cooling under be added into 80mL2NHCl, quench reaction mixture, stir 20 minutes at 20~25 DEG C, so
After separate each phase.Organic phase is washed with 2NHCl, combined water phase CH2Cl2Extraction.The organic phase of collection saturation NaHCO3It is molten
Liquid washes twice, and is finally washed with brine the organic layer of merging.By silica gel column chromatography (eluant ethyl acetate: petroleum ether=
1:20, V/V) isolated white solid 6.73g, i.e. target compound 20, yield 75%.m.p:62.8-63.4℃；1HNMR
(600MHz,CDCl3) δ: 8.36 (d, J=2.1Hz, 1H), 8.25 (dd, J=8.3,2.1Hz, 1H), 7.68~7.63 (m,
3H), 7.34 (d, J=4.0Hz, 1H), 7.28 (d, J=4.0Hz, 1H), 7.14 (t, 2H)13CNMR(151MHz,CDCl3) δ:
184.6,164.4,162.8,154.8,149.0,143.9,140.9,137.3,132.7,129.5,129.2,129.1,
128.4,128.4,125.5,124.4,121.8,116.5,116.7.IR vmax(KBr)cm-1: 3105,2925,1744,1517,
1346,1234,913,790,728。
(2) preparation of compound 21
It weighs 2- (the chloro- 4- nitro benzoyl of 2-) -5- (4- fluorophenyl)-thiophene 2.17g (6mmol) and is dissolved in 6mL acetonitrile
In 6mL methylene chloride, triethylsilane 6.0mL is added, is slowly added to boron trifluoride ether solution 3.0mL, 40 DEG C of reaction 2h,
TLC tracking, fully reacting stop reaction.Be added dropwise saturated sodium bicarbonate solution stir 30 minutes, stir process twice, acetic acid second
Ester extraction, organic phase are washed with brine, and collect organic phase, and decompression obtains solid 2.02g, i.e. target compound 21, yield 97%.
M.p.:131.6~132.2 DEG C；1H NMR(600MHz,CDCl3) δ: 8.27 (d, J=2.3Hz, 1H), 8.07 (dd, J=8.5,
2.3Hz, 1H), 7.48 (dd, J=8.7Hz, 2H), 7.44 (d, J=8.5Hz, 1H), 7.07 (d, J=3.6Hz, 1H), 7.03
(t, J=8.7Hz, 2H), 6.81 (d, J=3.6Hz, 1H), 4.33 (s, 2H)13C NMR(151MHz,CDCl3)δ:163.1,
161.5,147.2,145.2,142.8,139.2,134.7,131.0,130.5,130.4,127.5,127.3,127.3,
124.8,123.0,122.0,115.9,115.8,33.82.IR vmax(KBr)cm-1: 3068,2920,1521,1350,1230,
1043,827,740。
(3) preparation of compound 22
Weigh 2- (4- fluorophenyl) -5- (2- chloro-4 nitrophenyl)-methylthiophene 1.39g (4mmol), active carbon
0.63g, FeCl3·6H2O 0.40g is dissolved in 10mL dehydrated alcohol, and heating stirring is slow by 1.7mL hydrazine hydrate to 80 DEG C of reflux
It is added drop-wise in reaction, after forty minutes, TLC tracking, raw material fully reacting.Stop reaction, filtrate is concentrated in heat filtering, and cold water is added
White solid is precipitated after stirring, filters, it is dry, obtain white solid 1.28g, i.e. target chemical combination 22, yield 97%.m.p.:163.4
~164.1 DEG C；1H NMR(600MHz,DMSO-d6) δ: 7.56 (dd, J=8.3,5.5Hz, 2H), 7.23 (d, J=3.5Hz,
1H), 7.17 (t, J=8.2Hz, 2H), 7.04 (d, J=8.3Hz, 1H), 6.79 (d, J=3.5Hz, 1H), 6.64 (d, J=
1.8Hz, 1H), 6.51 (dd, J=8.2,1.8Hz, 1H), 5.31 (s, 2H), 4.03 (s, 2H)13C NMR(151MHz,DMSO-
d6) δ: 162.2,160.6,149.0,144.0,140.2,133.0,131.3,130.6,130.6,12 6.9,126.1,123.8,
123.4,123.3,115.9,115.8,113.8,113.8,113.1,39.5,32.3.IR vmax(KBr)cm-1: 3360,3274,
3075,1611,1508,1313,1026,831,667。
(4) preparation of compound ii -9
Weigh 2- (4- fluorophenyl) -5- (the chloro- 4- aminophenyl of 2-)-methylthiophene 0.30g (1mmol), cyano hydroboration
Sodium 0.25g (4mmol), 5- oxidation list acetone glucose 1.09g (5mmol), are added in 10mL methanol by 10,4A molecular sieve,
It is heated to 70 DEG C of back flow reaction 4h, TLC tracking, fully reacting.Stop reaction, vacuum distillation removes solvent, and distilled water is added and stirs
It mixes, ethyl acetate extraction, organic phase is washed with brine, and collects organic phase.Silica gel column chromatography separation (ethyl acetate: petroleum ether=
1:1, V/V) obtain faint yellow solid product 0.37g, i.e. target compound II-9, yield 74%.M.p.:110.8~111.3
℃；HRMS m/z(ESI):542.1162[M+Na]+, calculated value: 542.1175；1HNMR(600MHz,CDCl3) δ: 7.45 (s,
2H),7.02(dd,4H),6.73(d,2H),6.54(d,J 1H),5.90(s,1H),4.48(s,1H),4.24(s,1H),4.19
(s,1H),4.09(s,2H),3.78(d,3H),1.46(s,3H),1.28(s,3H).13CNMR(151MHz,CDCl3) δ:
162.9,161.3,146.8,143.2,141.6,134.6,131.4,130.9,130.9,127.3,127.2,127.1,
126.1,122.7,115.8,115.6,114.7,113.2,111.8,104.7,85.1,80.2,75.0,61.3,53.3,
33.0,26.7,26.8.IR vmax(KBr)cm-1: 3427,3328,2927,1616,1514,1380,1232,1163,1074,
833,808。
Embodiment 10: to the Cell suppression test of tumour cell
1, test-compound is prepared according to the method for above embodiments
2, by mtt assay detection compound to the cytotoxicity of tumour cell, and the IC of each compound is obtained50
3, material and method
(1) cell strain:
Application on human skin epidermoid carcinoma cell strain A431 (is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences)
Human lung carcinoma cell line A549 (is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences)
Human colon cancer cell strain SW480 (is purchased from Shanghai Cell Bank of the Chinese Academy of Sciences)
(2) reagent and consumptive material:
MTT(MPBIO)
96 porocyte culture plates (Corning Costar)
Fetal calf serum (Hyclone)
Culture medium (Invitrogen)
Microplate reader (Thermo MULTISKAN MK3)
4, experimental procedure
(1) cell culture
A431 and A549 cell, which uses, contains 20% fetal calf serum, 100U/mL penicillin, 100U/mL streptomysin, 2mM L-
The DMEM high glucose medium of Glu, SW480 cell, which uses, contains 10% fetal calf serum, 100U/mL penicillin, 100U/mL strepto-
The DMEM high glucose medium of element, 2mML-Glu, in saturated humidity, 37 DEG C and 5%CO2Under the conditions of routine culture.When cell is grown
When converging to about 80%~90%, cell is passed on by proper proportion, about 2~3d is passed on 1 time.
(2) configuration and storage of compound
Compound is stored in -20 DEG C after being dissolved with DMSO.It is diluted to debita spissitudo with culture medium before use, and keeps DMSO whole
Concentration is 0.5%.
(3) cell inoculation and drug-treated
Logarithmic growth phase cell is collected, is counted, with corresponding culture medium suspension cell, adjusts cell to suitable concentration, by one
Determine cell number (hole A431 3000cell/, the hole A549 2500cell/, the hole SW480 5000cell/) and is inoculated in the training of 96 hole cells
Plate is supported, every hole is inoculated with 100 μ L cell suspensions, in saturated humidity, 37 DEG C and 5%CO2It is cultivated for 24 hours in incubator.
Untested compound is diluted to debita spissitudo with culture medium, each compound does 8 gradients, 2 multiple holes, by 100 μ
Cell is added in the hole L/.It is put into saturated humidity, 37 DEG C and 5%CO272h is incubated in incubator.
MTT (storage concentration: 5mg/mL) 20 holes μ L/ are added, are placed in saturated humidity, 37 DEG C and 5%CO2It is incubated in incubator
4h。
It inhales and abandons liquid in hole, the hole DMSO150 μ L/ is added, shake 10 minutes, after formazan is completely dissolved, in microplate reader
The absorbance at 570nm wavelength is measured, absorbance calculates inhibiting rate as reference using at 630nm.
(4) drug is as follows to the calculation of growth of tumour cell inhibiting rate:
Growth of tumour cell inhibiting rate %=[1- (ODs-ODNC)/(ODPC-ODNC)] × 100%
Wherein:
ODS: the light absorption value (cell+untested compound+MTT) of sample well
ODPC: the light absorption value (cell+DMSO+MTT) of control wells
ODNC: the light absorption value (culture medium+DMSO+MTT) of zeroing hole
ODs=OD570s-OD630s
ODPC=OD570 controls-OD630 controls
ODNC=OD570 zeroings-OD630 zeroings
(5) fitting and IC of the drug to growth of tumour cell suppression curve50Calculating
Drug is fitted to the suppression curve of growth of tumour cell using Graphpad Prism 5, and obtains IC50Value.
(6) every group of this experiment setting 2 multiple holes, experiment are at least repeated 3 times.
5, experimental result
Using the anti-tumor drug Gefitinib of clinical use as positive control, experimental result is as shown in table 1 for this experiment.Experiment
Statistics indicate that test-compound all has different degrees of inhibiting effect to the proliferation of 3 kinds of tumor cell lines.All compounds pair
It is relatively aobvious for the growth inhibition effect of A431 cell that apparent inhibiting effect, especially compound ii -9 are all had in A431 cell
It writes.Compound ii -9 shows activity more better than Gefitinib on A549 tumour cell simultaneously, shows that these compounds have
There is the purposes in anti-tumor aspect.
The IC50 (μM) of 1 test-compound of table inhibition tumor cell proliferation
| Compound | SW480 | A549 | A431 |
| Gefitinib | 12.54±0.31 | 18.48±1.34 | 4.12±0.29 |
| Ⅱ-1 | 46.12±3.25 | 43.33±9.30 | 34.62±0.96 |
| Ⅱ-2 | 35.27±0.16 | 48.43±0.27 | 18.84±3.27 |
| Ⅱ-3 | 14.58±0.34 | 19.49±1.32 | 11.25±1.76 |
| Ⅱ-4 | 67.06±14.17 | >100 | >100 |
| Ⅱ-5 | 22.37±4.26 | 155.3 | 20.08±0.92 |
| Ⅱ-6 | 46.44±2.78 | >100 | 102.70±3.39 |
| Ⅱ-7 | 79.46±8.46 | >100 | 78.71±25.30 |
| Ⅱ-8 | 52.28±8.78 | 70.88±8.14 | 34.99±2.18 |
| Ⅱ-9 | 8.57±2.79 | 15.24±6.64 | 5.15±0.40 |
Claims (19)
1. a kind of compound or its salt of formula I:
Wherein, R1Selected from C1-C4Alkyl, hydrogen；
R2Selected from halogen ,-CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6Independently selected from C1-C4Alkyl；
R3Selected from halogen, C1-C4Alkyl ,-CH2-C4H2S-ph-F、-CH2-ph-O-R7, R7Independently selected from C1-C4Alkyl；
Work as R2When selected from halogen, R3Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R7, R7Independently selected from C1-C4Alkyl；
Work as R2Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6Independently selected from C1-C4When alkyl, R3Selected from halogen, C1-C4
Alkyl；
R4、R5It is independently selected from hydrogen, C1-C4Alkyl.
2. compound described in claim 1, wherein R1Selected from methyl or hydrogen.
3. compound described in claim 1, R2When selected from halogen, wherein R3Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R7,
R7Selected from ethyl.
4. compound as claimed in claim 3, R2When selected from halogen, wherein R3Selected from-CH2-C4H2S-ph-F, 4- ethoxy benzonitrile
Base, 2- ethoxybenzene methyl.
5. compound as claimed in claim 4, R2When selected from halogen, wherein R3Selected from 5- (4- fluorophenyl) thiophene -2- ylmethyl,
4- ethoxybenzene methyl, 2- ethoxybenzene methyl.
6. compound described in claim 5, R2Selected from chlorine.
7. compound described in claim 1, R2Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6Independently selected from C1-C4
When alkyl, wherein R3Selected from halogen, methyl.
8. compound as claimed in claim 7, R2Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6Independently selected from C1-C4
Alkyl, R3Selected from chlorine, methyl.
9. compound according to any one of claims 8, R2Selected from-CH2-C4H2S-ph-F、-CH2-ph-O-R6, R6Selected from ethyl.
10. compound as claimed in claim 9, R2Selected from-CH2-C4H2S-ph-F, 4- ethoxybenzene methyl, 2- ethoxy benzonitrile
Base.
11. compound described in any one of claim 10, R2Selected from 5- (4- fluorophenyl) thiophene -2- ylmethyl, 4- ethoxybenzene methyl,
2- ethoxybenzene methyl.
12. compound described in claim 1, wherein R4、R5It is independently selected from hydrogen, methyl.
13. compound described in claim 12, wherein R4、R5It is independently selected from hydrogen.
14. compound of formula I or its salt are selected from following compounds:
15. a kind of preparation method of the type I compound of claim 1, including in the presence of a reducing agent by chemical compounds I -5, and 1,
2-O- isopropylidene -5- oxo-α-furyl glucose reacts, wherein R1、R2、R3、R4、R5Definition with formula I:
16. the preparation method of claim 15, wherein reducing agent is selected from sodium cyanoborohydride.
17. purposes of I compound or its salt of claim 1 Chinese style in the drug of preparation treatment tumour.
18. purposes according to claim 17, wherein the tumour is selected from people's epidermal carcinoma, cervical carcinoma, kidney, pancreas
Cancer, liver cancer, gastric cancer, breast cancer, colorectal cancer, bladder cancer, lung cancer, head and neck cancer, oophoroma, prostate cancer, genitourinary tract cancer,
Melanoma, squamous cell carcinoma, astrocyte cancer, Kaposi sarcoma, spongioblast cancer.
19. purposes according to claim 18, wherein the tumour is selected from application on human skin epidermoid carcinoma cell, human lung cancer
Cell, human colon cancer cell.
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| CN1292788A (en) * | 1998-01-12 | 2001-04-25 | 葛兰素集团有限公司 | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1292788A (en) * | 1998-01-12 | 2001-04-25 | 葛兰素集团有限公司 | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
Non-Patent Citations (2)
| Title |
|---|
| First Diastereoselective Passerini-Smiles and Ugi-Smiles Reactions Using Chiral Aldehydes;Palakodety Radha Krishna，等;《Helvetica Chimica Acta》;20141231;第97卷;1076-1087 |
| Identification of novel drug-resistant EGFR mutant inhibitors by in silico screening using comprehensive assessments of protein structures;Tomohiro Sato，等;《Bioorganic & Medicinal Chemistry》;20120427;第20卷;3756-3767 |
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