CN108218847A - Fragrant phenoxy acid derivative and its medical usage - Google Patents
Fragrant phenoxy acid derivative and its medical usage Download PDFInfo
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- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
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Abstract
The invention discloses fragrant phenoxy acid derivative and its medicinal activities, and chemical structural formula is shown in formula I：In formula, R1For hydrogen or C1~C3Alkyl or C1~C3Any one in halogenated alkyl；X is nitrogen or carbon；X1、X2For any one in hydrogen or fluorine or chlorine or bromine or iodine or trifluoromethyl or cyano or nitro.The invention further relates to the composition containing above compound and fragrant phenoxy acid derivative anti-tumor aspect application.
Description
Technical field
The present invention relates to a kind of compounds, and in particular to a kind of virtue phenoxy acid derivative and its medical usage.
Background technology
4- aryloxyphenoxies acid derivative is with extensive bioactivity, wherein fragrant phenoxy propanoic derivatives are made
For its Typical Representative, have more than 20 a commercial varieties in agricultural herbicide.4- aryloxyphenoxy acid derivatives simultaneously
Also have in the research of anticancer drug a large amount of reports [Investigational New Drugs, 1999,16:287–296；
Investigational New Drugs, 1998,16:129–139；Acta Pharmaceutica Sinica, 2005,40 (9):814-819], wherein
XK469 (2- (4- (7- chloroquinoxalin-2-yloxies base) phenoxy group) propionic acid) is that DuPont Corporation is carrying out the clinical research of I phase
A new type antineoplastic medicine, XK469 have very wide antitumor spectra, Small side effects are effective to a variety of solid tumor models, such as colon
[JMed Chem, 2001,44 (11) such as cancer Colon38 and breast cancer:1758-76].
Invention content
The present invention provides a kind of fragrant phenoxy acid derivative and its isomers, and chemical structural formula is shown in formula I：
In formula, R1For hydrogen or C1~C3Alkyl or C1~C3Any one in halogenated alkyl；X is nitrogen or carbon；X1、X2For hydrogen
Or any one in fluorine or chlorine or bromine or iodine or trifluoromethyl or cyano or nitro.
In the definition of compound I given above, no matter term used exclusive use is also used in compound word, represent such as
Lower substituent group:
Alkyl：Refer to linear or branched alkyl group；
Halogenated alkyl：Refer to linear or branched alkyl group, hydrogen moiety on these alkyl or all replaced by halogen atom；
The compound of the present invention can exist in the form of one or more isomers.Isomers includes enantiomter, non-
Enantiomter, geometric isomer.As the present invention Formulas I compound represented, due on a carbon atom connect four differences
Substituent group and form stereoisomer (respectively with R and S to represent different configurations), the present invention includes R types isomers and S types
The mixture of isomers and their any ratios.
In preferred scheme, the concrete structure formula of the fragrant phenoxy acid derivative is：
(1R, 2S, 5R) -2- isopropyl -5- methylcyclohexyls (2R, 5R) -5- [(R) -2- (4- (5- provided by the invention
Chloro-3-fluoropyridine -2- oxygroups) phenoxy group) propionyloxy] -1,3- oxathiolane -2- carboxylates are preparing anti-cervical cancer medicine
Application in object.
Specific embodiment
With reference to specific implementation, the present invention is furture elucidated.These embodiments are interpreted as being merely to illustrate the present invention
Rather than for limiting the scope of the invention.After the content of the invention recorded has been read, those skilled in the art can
To be made various changes or modifications to the present invention, these equivalence changes and modification equally fall into what claims of the present invention was limited
Range.
Embodiment 1:(1R, 2S, 5R) -2- isopropyl -5- methylcyclohexyls (2R, 5R) -5- [(R) -2- (4- (chloro- 3- of 5-
Fluorine pyridine -2- oxygroups) phenoxy group) propionyloxy] and -1,3- oxathiolane -2- carboxylates (1) preparation
N,N-Dimethylformamide (40mL), (R)-(+) -2- (4- hydroxy benzenes oxygen) propionic acid (0.02mol, 3.64g), carbonic acid
Potassium (0.02mol, 2.76g) at 75 DEG C after stirring 0.5h, adds the potassium carbonate of equivalent, continues to stir 0.5h.It is slowly added dropwise 2,
3- difluoro-5-chloropyridines (0.02mol, 3.00g), after being added dropwise, reaction temperature maintains 75 DEG C, overnight.Stop heating, cooling
To room temperature, reaction solution is poured into 200mL ice water, dilute hydrochloric acid adjusts pH 4-5, and filtering is washed three times, vacuum with a small amount of ice water
It is dry, obtain (R) -2- [4- (the fluoro- 5- chloropyridines -2- oxygroups of 3-) phenoxy group] propionic acid white solid 3.86g, yield 62.0%.
Toluene 40mL, (R) -2- [4- (the fluoro- 5- chloropyridines -2- oxygroups of 3-) phenoxy group] propionic acid (3.3mmol, 1.04g), adds
Enter into the single-necked flask of 100mL, after stirring and dissolving, add in thionyl chloride (20mmol, 2.24g), back flow reaction 4h, decompression is steamed
It evaporates, obtains (R) -2- [4- (the fluoro- 5- chloropyridines -2- oxygroups of 3-) phenoxy group] propionyl chloride yellow oily liquid, without isolating and purifying,
It is directly used in and reacts in next step.
Above-mentioned (R)-(+) -2- [4- (the fluoro- 5- chloropyridines -2- oxygroups of 3-) phenoxy group] propionyl chloride adds in dichloromethane
(40mL) then adds in (2R, 5R) -5- hydroxyls -1,3- oxygen thia ring -2- carboxylic acids (1R, 2S, 5R) -5- methyl -2- isopropyl basic rings
Own ester (0.31g, 3.3mmol), 4-dimethylaminopyridine (DMAP, 0.02g, 0.17mmol) stir 15min under ice bath, are added dropwise
Triethylamine (1.37mL, 10mmol) after being added dropwise, continues to stir 10min, removes ice bath, warm naturally to room temperature, stir
4h stops reaction, reaction solution is poured into 150mL ice water, and dichloromethane extraction (40mL*3), organic phase successively uses 50mL saturations
Sodium bicarbonate solution is washed twice, and 100mL is washed three times, and anhydrous sodium sulfate drying, filtering removes dichloromethane, silicagel column under reduced pressure
Chromatography purified product, eluant, eluent (VPetroleum ether：VEthyl acetate=3:1) yellow oily liquid (1R, 2S, 5R) -2- isopropyls -5-, is obtained
Methylcyclohexyl (2R, 5R) -5- [(R) -2- (4- (5- chloro-3-fluoropyridine -2- oxygroups) phenoxy group) propionyloxy] -1,3- oxygen sulphur
Heterocycle pentane -2- carboxylates (1) 0.27g, yield 14.1%；1H NMR(CDCl3,400MHz)δ:0.75 (d, 3H, J=6.8Hz,
CH3), 0.82~1.06 (m, 11H, cyclohexane-H+CH 3), 1.63~1.70 (m, 5H, CH3+cyclohexane-H),
1.93~2.02 (m, 2H, cyclohexane-H), 3.02~3.44 (m, 2H, CH 2), 4.69~4.79 (m, 2H, OCHCH2+
CHCH 2), S 5.61 (s, 1H, SCH), 6.81 (d, J=4.0Hz, 1H, CHCH2), S 6.92 (d, J=9.2Hz, 2H, PhH), 7.07
(d, J=9.2Hz, 2H, PhH), 7.49 (dd, J=8.8Hz, 2.0Hz, 1H, Py-H), 7.86 (d, J=2.0Hz, 1H, Py-H)
；13C NMR(CDCl3,100MHz)δ:16.13,18.37,20.71,21.94,23.25,26.06,31.36,34.09,40.59,
47.04,73.09,80.21,100.43,116.29,116.58,122.19,122.34,124.84,136.24,140.06,
140.17,147.21,154.77,168.44,170.81.
Embodiment 2:(1R, 2S, 5R) -2- isopropyl -5- methylcyclohexyls (2R, 5R) -5- [(R) -2- (4- (chloro- 5- of 3-
Trifluoromethyl pyridine -2- oxygroups) phenoxy group) propionyloxy] and -1,3- oxathiolane -2- carboxylates (2) preparation
(R) -2- (4- hydroxyphenoxies) propionic acid (3g), DMF (35ml) are slowly added to K2CO3(4.55g), it is warming up to 70~
80 DEG C, 1h is stirred, 2,3-, bis- chloro-5-trifluoromethylpyridines (3.56g) are added dropwise, 70~80 DEG C of stirring 8h is kept, stops anti-
Should, cooled to room temperature is poured the mixture into ice water (200mL), is adjusted pH 4~5 using dilute hydrochloric acid, is used ethyl acetate
Extraction, organic phase washing is dry, and precipitation obtains (R) -2- [4- (5- trifluoromethyl -3- chloropyridine -2- oxygroups) phenoxy group] propionic acid palm fibre
Color liquid 5.03g, yield 84.4%.
(R) -2- [4- (5- trifluoromethyl -3- chloropyridine -2- oxygroups) phenoxy group] propionic acid (3.3mmol, 1.08g), is dissolved in
In toluene (35mL), SOCl is added dropwise2(20mmol, 2.24g), is heated to reflux, and reacts 4h, and precipitation obtains (R) -2- [4- (5- fluoroforms
Base -3- chloropyridine -2- oxygroups) phenoxy group] propionyl chloride be directly used in next step.
Gained acyl chlorides is dissolved in dichloromethane (35mL), adds in intermediate (2R, 5R) -5- hydroxyl -1,3- oxygen thia rings -2-
The DMAP of carboxylic acid (1R, 2S, 5R) -5- methyl -2- isopropyls cyclohexyls (0.80g) and catalytic amount, is slowly dropped into three with stirring
Ethamine (0.85g), is stirred to react 8h.Reaction is completed, by mixture to pouring into ice water (100mL), with dichloromethane (80mL*
2) it extracts, organic phase washing, dry, precipitation.(1R, 2S, 5R) -2- isopropyl -5- methylcyclohexyls are purified through column chromatography
(2R, 5R) -5- [(R) -2- (4- (3- chloro-5-trifluoromethylpyridine -2- oxygroups) phenoxy group) propionyloxy] -1,3- oxygen thia rings
Pentane -2- carboxylates (2) light brown viscous liquid 0.38g, yield 22.04%.1H NMR:δ 0.76 (d, J=7.2Hz, 3H,
CHCH3 ),0.90-1.10(m,11H,CH2,CH3),1.64-1.71(m,5H,CH,CH2),1.90-2.02(m,2H,CH2),
3.03-3.49(m,2H,CH2),4.69-4.80(m,2H,CH,CHCH3), 5.62 (d, J=10.0Hz, 1H, CH), 6.82 (d, J
=4.0Hz, 1H, CH), 6.93-6.98 (m, 2H, Ph-H), 7.06-7.09 (m, 2H, Ph-H), 7.96 (d, J=2.4Hz, 1H,
Py-H),8.25(s,1H,Py-H)；13C NMR:δ16.16,18.34,20.66,21.92,23.32,26.10,31.37,
34.12,40.61,47.08,73.11,80.26,100.47,116.33,116.62,119.17,122.53,122.67,
124.21,136.22,142.57,147.03,155.14,161.33,168.44,170.72.
Embodiment 3:(1R, 2S, 5R) -2- isopropyl -5- methylcyclohexyls (2R, 5R) -5- [(R) -2- (4- (4- cyano -
2- fluorophenoxies) phenoxy group) propionyloxy] and -1,3- oxathiolane -2- carboxylates (3) preparation
In n,N-Dimethylformamide (DMF, 40mL), addition (R) -2- (4- hydroxy benzenes oxygen) propionic acid (3.03g,
0.02mol), potassium carbonate (5.52g, 0.04mol) is added portionwise, is warming up at 70 DEG C~80 DEG C, persistently stirs 1h, is added in by amount
(2.38g, the 0.02mol) of 3,4- difluorobenzonilyiles, continues to be stirred to react 6~7h.It is cooled to room temperature, pours into ice water (250mL),
Be slowly added to dilute hydrochloric acid, adjust to pH 4~5, filter, washing, vacuum dried case it is dry (R) -2- [4- (4- cyano -2-
Fluorophenoxy) phenoxy group] propionic acid gray solid (R) -2- [4- (4- cyano -2- fluorophenoxies) phenoxy group] propionic acid 3.26g, yield
65.7%.
(R) -2- [4- (4- cyano -2- fluorophenoxies) phenoxy group] propionic acid (1g, 3.3mmol) is dissolved in toluene (40ml)
In, it is slowly added to SOCl2(1.18g, 10mmol), back flow reaction 5h after sloughing solvent with Rotary Evaporators, obtain (R) -2- [4-
(4- cyano -2- fluorophenoxies) phenoxy group] propionyl chloride, directly carry out next step reaction.
Gained acyl chlorides is dissolved in dichloromethane (40ml), adds in (2R, 5R) -5- hydroxyl -1,3- oxygen thia ring -2- carboxylic acids
The 4-dimethylaminopyridine of (1R, 2S, 5R) -5- methyl -2- isopropyls cyclohexyls (0.95g, 3.3mmol) and catalytic amount
(DMAP), 10min is stirred under ice bath, triethylamine (1g, 10mmol) is added dropwise dropwise.Continue stirring 3 hours to 10 hours.It has reacted
Cheng Hou is poured into 100ml ice water, is extracted with dichloromethane, collects organic phase, and (100ml × 2) are washed with water, gained crude product
Dried with anhydrous sodium sulfate, after precipitation through silica gel chromatographic column purify faint yellow mucus shape (1R, 2S, 5R) -2- isopropyls -5-
Methylcyclohexyl (2R, 5R) -5- [(R) -2- (4- (4- cyano -2- fluorophenoxies) phenoxy group) propionyloxy] -1,3- oxygen thias
Pentamethylene -2- carboxylates (3) 1.067g, yield 56.7%.1H NMR:δ 0.74 (d, J=6.8Hz, 3H, CH3), 0.80~1.01
(m,11H,CH+CH2+CH3), 1.62~1.69 (m, 5H, CH, CH 2), 1.88~1.99 (m, 2H, CH, CH 2), 3.21~3.47
(m,2H,CH 2), 4.67~4.76 (m, 2H, CH), 5.59 (s, 1H, S-CH- O), 6.80~6.99 (m, 6H, PhH, CH),7.30
~7.34 (m, 1H, PhH), 7.42~7.45 (m, 1H, PhH)；13C NMR:δ16.14,18.34,20.70,21.93,23.26,
26.08,31.35,34.07,40.59,47.06,72.91,80.24,100.02,100.51,116.77,117.09,118.60,
120.67,120.97,121.06,129.36,148.77,149.54,152.31,154.80,168.36,170.64.
Embodiment 4:Antitumor activity is tested
1. Cell culture invitro
By Caski cell culture in containing 10% newborn calf serum, 105The RPMI- of U/L penicillin, 100mg/L streptomysins
In 1640 culture mediums, it is placed in 37 DEG C, CO2Volume fraction is treated cell adherent growth, is taken to be cultivated under the conditions of 5% saturated humidity
Exponential phase cell is used to test.
2.MTT methods detect inhibitory rate of cell growth
The cervical carcinoma CAKSI cells of phase growth of taking the logarithm are configured to cell density as 1 × 105The cell suspending liquid of a/mL,
It is inoculated in 96 orifice plates, per hole 100 μ L, 5%CO2, 37 DEG C be incubated, after cell is adherent, replace culture solution, experimental group is divided into not
With the red Bo alcohol extract group in south of concentration, sequentially add from low to high different quality concentration fragrant phenoxy acid derivative (6.25,
12.5th, 25.0,50.0,100 μ g/mL) 100 μ L, every group sets 4 multiple holes.Culture plate is moved into CO2Continue to cultivate in incubator, point
Not in taking out culture plate afterwards for 24 hours, the 20 μ L of 5mg/mL MTT liquid newly prepared are added in every time, 37 DEG C are protected from light incubation 4h, terminate culture.
Supernatant is sucked, 150 μ L of DMSO are added in per hole, are put on shaking table after low-speed oscillation 10min, is measured respectively at 490nm with microplate reader
Absorbance value (the OD in hole490Nm) according to formula：Cell inhibitory rate=(1- administration groups OD values/blank control group OD values) ×
100%.IC50Value calculates：Sample solution concentration logarithm and cell inhibitory rate linear regression calculate sample to the half of cell using software
Number inhibition concentration IC50Value.
Active testing is the results show that (1R, 2S, 5R) -2- isopropyl -5- methylcyclohexyls (2R, 5R) -5- [(R) -2- (4-
(5- chloro-3-fluoropyridine -2- oxygroups) phenoxy group) propionyloxy] a concentration of 25.0 μ g/ of -1,3- oxathiolane -2- carboxylates
To the IC of cervical cancer cell CAKSI during mL50It is worth for 55.98 μm of ol/L.Other numerical value are as follows, other numerical value are a concentration of 25.0
The data that μ g/mL are detected.
Claims (5)
1. a kind of virtue phenoxy acid derivative, which is characterized in that its chemical structural formula is shown in formula I：
In formula, R1For hydrogen or C1~C3Alkyl or C1~C3Any one in halogenated alkyl；X is nitrogen or carbon；X1、X2For hydrogen or fluorine
Or any one in chlorine or bromine or iodine or trifluoromethyl or cyano or nitro.
2. virtue phenoxy acid derivative according to claim 1, it is characterised in that：The fragrant phenoxy alkanoic acid derives
The concrete structure formula of object is：
3. the fragrant phenoxy acid derivative described in claims 1 or 2 includes R types isomers or S types isomers and R types are different
Structure body and S types isomers are with the mixture of arbitrary proportion.
Claim 1-3 any one of them 4. (1R, 2S, 5R) -2- isopropyl -5- methylcyclohexyls (2R, 5R) -5- [(R) -
2- (4- (5- chloro-3-fluoropyridine -2- oxygroups) phenoxy group) propionyloxy] -1,3- oxathiolane -2- carboxylates are antitumor
Application on drug.
5. the application described in claim 4, which is characterized in that (1R, 2S, 5R) -2- isopropyl -5- methylcyclohexyls
(2R, 5R) -5- [(R) -2- (4- (5- chloro-3-fluoropyridine -2- oxygroups) phenoxy group) propionyloxy] -1,3- oxathiolanes -
Application of the 2- carboxylates on the drug of cervical carcinoma.
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| CN115490617A (en) * | 2022-10-14 | 2022-12-20 | 江苏丰山集团股份有限公司 | Preparation process of low-cost high-light pure content cyhalofop-butyl |
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| CN115490617A (en) * | 2022-10-14 | 2022-12-20 | 江苏丰山集团股份有限公司 | Preparation process of low-cost high-light pure content cyhalofop-butyl |
| CN115490617B (en) * | 2022-10-14 | 2024-03-26 | 江苏丰山生化科技有限公司 | Preparation process of cyhalofop-butyl with low cost and high optical purity content |
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Effective date of registration: 20210330 Address after: 443000 No.25 Xihu Road, Xiling District, Yichang City, Hubei Province (building C4) Patentee after: Hubei Zilan Biomedical Technology Co.,Ltd. Address before: 443002 No. 8, University Road, Yichang, Hubei Patentee before: CHINA THREE GORGES University |