CN106866608B - A kind of preparation method of fluoro -3,4- dihydrocoumarin derivative - Google Patents
A kind of preparation method of fluoro -3,4- dihydrocoumarin derivative Download PDFInfo
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a kind of preparation methods of fluoro -3,4- Dihydroiso-coumarin derivative (I), belong to organic chemistry filed.This method, to replace adjacent styryl benzoic acid and Selectfluor fluorine reagent as raw material, reacts synthesizing fluoro -3,4- Dihydroiso-coumarin derivative under microwave-assisted in a solvent.
Description
Technical field
The present invention relates to a kind of preparation methods of fluoro -3,4- dihydrocoumarin derivative, belong to organic synthesis field.
Background technique
Isocoumarin is the basic structure of some natural products, is widely present in nature, and derivative has extensive
Physiological activity and bioactivity, such as antibacterial, anti-inflammatory, anticancer, protease inhibition and anticancer isoreactivity.3,4- Dihydroiso-coumarin is
The secondary metabolites of fungi, mould, bacterium, higher plant and animal.3,4- Dihydroiso-coumarin containing halogen has anti-thin
Bacterium, antimycotic effect, and can be used as the inhibitor of serpin and human body Q31 grain dissolution enzyme A.Contain
3, the 4- Dihydroiso-coumarin of chlorine and bromine is it has been reported that still, the synthesis of fluorine-containing 3,4- Dihydroiso-coumarin derivative is reported
It is less.Due to the unique physical property of fluoro -3,4- Dihydroiso-coumarin and bioactivity, it is in organic synthesis and pharmacology
Valuable molecule construction module, all containing this important structure in many drug molecules.Therefore, synthetic method is long-term
Since be constantly valued by people.
Fluoro -3,4- Dihydroiso-coumarin derivative is as one kind important in coumarin derivatives, in recent years, synthesis
Method is taken seriously with bioactivity research.Currently, using adjacent styryl benzoic acid as halogenated 3, the 4- dihydro an unusually sweet smell of Material synthesis
Legumin derivative mainly passes through two kinds of methods: (1) using adjacent styryl benzoic acid and NBS as reaction raw materials, by trifluoroacetic acid,
Or chiral molecules is catalyst, synthetic bromide generation -3,4- Dihydroiso-coumarin derivative (Chen J, Zhou L, Tan CK, Yeung
YY,J.Org.Chem.,2012,77,999‐1009；Chen T,Yeung YY,Org.Biomol.Chem.,2016,14,
4571‐4575.)；This synthetic method needs chiral catalyst or strong acid trifluoroacetic acid is catalyst.(2) with adjacent vinyl benzene
The hydrofluoride of methyl formate and pyridine is raw material, and metachloroperbenzoic acid is oxidant, under chiral catalyst catalysis ,-
It is reacted at 50 DEG C and obtains within 24 hours fluoro -3,4- Dihydroiso-coumarin derivative (Woerly EM, Banik SM, Jacobsen
EN,J.Am.Chem.Soc.,2016,138,13858‐13861)；This method needs reaction condition harsher, the reaction time
Long, catalyst is more expensive, and the scope of application of substrate is also limited.
From the above, it can be seen that traditional synthetic method be generally needed to be added strong acid or catalyst be catalyzed reaction, substrate or
Costly, reaction condition is harsher for catalyst price, and the reaction time is long, substrate restricted application etc..This is for advising greatly
For the industrial production of mould, equipment anti-corrosion capability with higher is generally required, and from the point of view of environmental protection, is not
It is very ideal.Therefore, find that a reaction condition is mild, high income, it is at low cost and meet Green Chemistry and require to be effectively synthesized fluorine
The generation approach of -3,4- Dihydroiso-coumarin derivative just becomes the target that researcher pursues all the time.
Summary of the invention
Based on the studies above background, cheap, mild condition that the purpose of the present invention is to provide a kind of raw materials, selectivity be high,
High income and environmentally protective, obtains the new synthetic method of fluoro -3,4- Dihydroiso-coumarin derivative by single step reaction.
The purpose of the invention is achieved by the following technical solution:
One kind fluoro -3,4- Dihydroiso-coumarin derivative, structure are indicated with following formula (I)s:
In formula, R1Represent following group: hydrogen-based, C1-5 alkyl, C1-5 alkoxy or halogen；R2Represent following group: hydrogen
Base, C1-5 alkyl, C1-5 alkoxy, nitro, amino, hydroxyl, acetoxyl group or halogen.
It is preferred that: R1Represent following group: hydrogen-based, methyl, ethyl, methoxyl group, halogen etc.；R2Represent following group: hydrogen-based,
Methyl, methoxyl group, halogen, nitro, hydroxyl etc..
The preparation method of above-mentioned fluoro -3,4- Dihydroiso-coumarin derivative, includes the following steps:
Adjacent styryl benzoic acid and Selectfluor fluorine reagent will be replaced to be dissolved in solvent, under microwave-assisted, heating
Reaction after reaction by pillar layer separation, or carries out recrystallizing isolated fluoro -3,4- Dihydroiso-coumarin derivative
(I)。
The molar ratio of the adjacent styryl benzoic acid of the substitution and Selectfluor fluorine reagent selects 1:1-3, preferably 1:2.
The reaction dissolvent is acetonitrile, dioxane, tetrahydrofuran, dimethyl sulfoxide, 1,2- dichloroethanes, methanol, second
One of alcohol, water are a variety of, and preferably acetonitrile and water mixed solvent are reaction dissolvent.
The reaction temperature is 60-100 DEG C, and preferably 100 DEG C, the reaction time is 0.5-1.0 hours.
Synthetic route of the invention is as follows:
R in formula1And R2Statement is same as above.
The separation, purification process: (1) by reaction solution depressurize it is lower remove solvent, suitable quantity of water is added into raffinate, uses second
Acetoacetic ester extracts three times, and the brine It of extract liquor saturation is primary.Extract liquor passes through column chromatography point after drying, concentration
From purification, yield 90-95%；Or be added in ice water and stir in the raffinate after (2) Xiang Shangshu evaporating solvent under reduced pressure, then to water
Middle addition ether or petroleum ether extraction are three times；It dries to obtain crude product after extract liquor solvent evaporated, crude product is tied again using methanol
It is brilliant.
Agents useful for same of the present invention is commercially available.
The principle of the invention is the electrophilic addition reaction that alkene and F cation occur: adjacent styryl benzoic acid A first with F
Reagent reacts the fluorine ion B to form three-membered ring；In the fluorine ion of carboxylate radical anion attack three-membered ring in fluorine ion B
β carbon atom, generate product C.
The beneficial effects of the invention are that: the synthetic method raw material of fluoro -3,4- Dihydroiso-coumarin derivative of the present invention is honest and clean
Valence is easy to get, and obtains object by single step reaction, reaction condition is mild, easy to operate, yield is high, up to 90% or more.Green ring
Possess and be conducive to industrialized production, to prepare there is fluoro -3,4- Dihydroiso-coumarin derivative of function affect to provide one
The new approach of item.
Specific embodiment
Below by embodiment, the present invention will be further elaborated, but is not meant to that the contents of the present invention are confined to
Embodiment.
Embodiment 1.R1=-H, R2=-m-CH3When, the fluoro- 3- of 4- (3- tolyl) -3,4- Dihydroiso-coumarin derivative
Preparation
2- (3- Tolyl-vinyl) benzoic acid (0.2mmol, 47.6mg) is added in 25mL microwave reaction pipe,
Selectfluor fluorine reagent (0.4mmol, 141.6mg) and 2mL acetonitrile and 2mL water are mixed solvent, are reacted at 100 DEG C
0.5h；After reaction, solvent is removed under reduced pressure, 10mL water is added into raffinate, extracts secondary, extract liquor with 20mL ethyl acetate
It is primary with the brine It of saturation；Extract liquor anhydrous Na2SO4It is dry, pass through column chromatography (eluant, eluent: acetic acid after reduced pressure
Ethyl ester/petroleum ether=1/3) separating-purifying, obtain colorless solid 0.047g, yield 92.0%.
1H NMR(400MHz,CDCl3)δ:8.16(d,JH‐H=7.6Hz, 1H), 7.67 (t, JH‐H=7.4Hz, 1H),
7.57‐7.51(m,2H),7.23(t,JH‐H=7.6Hz, 1H), 7.18-7.12 (m, 3H), 5.80-5.66 (m, 2H), 2.32 (s,
3H).13C NMR(100MHz,CDCl3)δ:163.2,138.6,135.8(d,JF‐C=18.8Hz), 134.7 (d, JF‐C=
2.8Hz),134.6(CH),130.4(d,JF‐C=2.5Hz) (CH), 130.3 (CH), 129.3 (d, JF‐C=121.5Hz) (CH),
127.3(CH),126.4(d,JF‐C=5.9Hz) (CH), 123.9 (d, JF‐C=3.6Hz), 123.7 (CH), 87.1 (d, JF‐C=
179.4Hz)(CH),81.5(d,JF‐C=24.1Hz) (CH), 21.4 (CH3).19F NMR(376MHz,CDCl3)δ:‐
179.0.HR MS(ESI)m/z:257.0974[M+H]+(calcd for C16H14FO2 +257.0972).
Embodiment 2.R1=-H, R2=-p-NO2When, the fluoro- 3- of 4- (4- nitrobenzophenone) -3,4- Dihydroiso-coumarin derivative
Preparation
2- (4- nitrostyrolene base) benzoic acid (0.2mmol, 53.8mg) is added in 25mL microwave reaction pipe,
Selectfluor fluorine reagent (0.3mmol, 106.2mg) and 4mL acetonitrile are solvent, react 1.0h at 80 DEG C；Reaction terminates
Afterwards, solvent is removed under reduced pressure, 10mL water is added into raffinate, secondary, the salt of extract liquor saturation is extracted with 20mL ethyl acetate
Water washing is primary；Extract liquor anhydrous Na2SO4It is dry, pass through column chromatography (eluant, eluent: ethyl acetate/petroleum ether after reduced pressure
=1/2) separating-purifying obtains colorless solid 0.051g, yield 90.0%.
1H NMR(400MHz,CDCl3)δ:8.28(d,JH‐H=8.7Hz, 2H), 8.19 (d, JH‐H=7.8Hz, 1H), 7.75
(t,JH‐H=7.5Hz, 1H), 7.68-7.58 (m, 4H), 5.81-5.66 (m, 2H)13C NMR(100MHz,CDCl3)δ:
162.5,148.3,141.7,136.1(d,JF‐C=19.4Hz), 134.9 (CH), 130.5 (d, JF‐C=16.4Hz) (CH),
127.7(CH),125.5(d,JF‐C=6.5Hz) (CH), 124.0 (CH), 123.0,86.9 (d, JF‐C=182.2Hz) (CH),
79.9(d,JF‐C=23.8Hz) (CH)19F NMR(376MHz,CDCl3)δ:‐186.3.HR MS(ESI)m/z:288.0670[M
+H]+(calcd for C15H11FNO4 +288.0667).
Embodiment 3.R1=-Br, R2When=- H, the preparation of fluoro- 3- phenyl -3, the 4- Dihydroiso-coumarin derivative of the bromo- 4- of 7-
The bromo- 2- of 5- (styryl) benzoic acid (0.2mmol, 60.4mg) is added in 25mL microwave reaction pipe,
Selectfluor fluorine reagent (0.6mmol, 212.4mg) and 4mL DMSO are solvent, react 1.0h at 90 DEG C；Reaction terminates
Afterwards, solvent is removed under reduced pressure, 10mL water is added into raffinate, secondary, the salt of extract liquor saturation is extracted with 20mL ethyl acetate
Water washing is primary；Extract liquor anhydrous Na2SO4It is dry, pass through column chromatography (eluant, eluent: ethyl acetate/petroleum ether after reduced pressure
=1/3) separating-purifying obtains colorless solid 0.058g, yield 91.0%.
1H NMR(400MHz,DMSO)δ:8.16(s,1H),8.00(d,JH‐H=8.1Hz, 1H), 7.63 (d, JH‐H=
8.0Hz,1H),7.40‐7.34(m,5H),6.26(dd,JF‐H=47.6Hz, JH‐H=5.6Hz, 1H), 6.14-6.10 (m, 1H)
.13C NMR(100MHz,DMSO)δ:162.0,138.1(CH),135.1(d,JF‐C=5.3Hz), 134.9,134.7,132.3
(CH),130.0(d,JF‐C=5.1Hz) (CH), 129.3 (d, JF‐C=17.1Hz) (CH), 127.1 (CH), 126.3 (d, JF‐C=
3.4Hz),124.2(d,JF‐C=3.4Hz), 86.3 (d, JF‐C=174.7Hz) (CH), 81.1 (d, JF‐C=24.7Hz) (CH)
.19F NMR(376MHz,DMSO)δ:‐175.5.HR MS(ESI)m/z:320.9924[M+H]+(calcd for C15H11BrFO2 +320.9921).
Embodiment 4.R1=-H, R2When=- m-F, the fluoro- 3- of 4- (3- fluorophenyl) -3,4- Dihydroiso-coumarin derivative system
It is standby
2- (3- fluorostyryl) benzoic acid (0.2mmol, 48.4mg) is added in 25mL microwave reaction pipe,
Selectfluor fluorine reagent (0.2mmol, 70.8mg) and 4mL dioxane are solvent, react 1.0h at 60 DEG C；Reaction knot
Solvent is removed under reduced pressure in Shu Hou, and 10mL water is added into raffinate, and secondary, the food of extract liquor saturation is extracted with 20mL ethyl acetate
Salt water washed once；Extract liquor anhydrous Na2SO4It is dry, pass through column chromatography (eluant, eluent: ethyl acetate/petroleum after reduced pressure
Ether=1/3) separating-purifying, obtain colorless solid 0.047g, yield 90.0%.
1H NMR(400MHz,CDCl3)δ:8.17(d,JH‐H=7.7Hz, 1H), 7.71 (t, JH‐H=7.5Hz, 1H),
7.60‐7.54(m,2H),7.38‐7.33(m,1H),7.18(d,JH‐H=7.6Hz, 1H), 7.12 (d, JH‐H=9.4Hz, 1H),
7.07‐7.03(m,1H),5.79‐5.65(m,2H).13C NMR(100MHz,CDCl3)δ:164.0,162.2(d,JF‐C=
127.5Hz),137.3(dd,JF‐C=7.2Hz, JF‐C=3.2Hz), 135.9 (d, JF‐C=18.9Hz), 134.7 (CH), 130.5
(d,JF‐C=8.2Hz) (CH), 130.4 (CH), 130.3 (d, JF‐C=2.3Hz) (CH), 126.0 (d, JF‐C=6.1Hz) (CH),
123.5(d,JF‐C=3.7Hz), 122.4 (d, JF‐C=2.8Hz) (CH), 116.1 (d, JF‐C=20.9Hz) (CH), 113.8 (d,
JF‐C=22.7Hz) (CH), 86.9 (d, JF‐C=180.4Hz) (CH), 80.5 (dd, JF‐C=24.2Hz, JF‐C=1.6Hz)
(CH).19F NMR(376MHz,CDCl3)δ:‐111.5,‐181.8.HR MS(ESI)m/z:261.0726[M+H]+(calcd
for C15H11F2O2 +261.0722).。
Claims (5)
1. a kind of method for preparing fluoro -3,4- Dihydroiso-coumarin derivative, which is characterized in that be achieved by the steps of:
Under microwave-assisted, compound 1 and compound 2 are added in reactor, heating reaction, passes through column after reaction in a solvent
Chromatographic isolation, or carry out recrystallizing isolated fluoro -3,4- Dihydroiso-coumarin derivative (I)；
In formula, R1Represent following group: hydrogen-based, C1-5 alkyl, C1-5 alkoxy or halogen；R2Represent following group: hydrogen-based, C1-
5 alkyl, C1-5 alkoxy, nitro, amino, hydroxyl, acetoxyl group or halogen.
2. the preparation method of fluoro -3,4- Dihydroiso-coumarin derivative according to claim 1, which is characterized in that R1
Represent following group: hydrogen-based, methyl, ethyl, methoxyl group or halogen；R2Represent following group: hydrogen-based, methyl, methoxyl group, halogen
Base, nitro or hydroxyl.
3. the preparation method of fluoro -3,4- Dihydroiso-coumarin derivative according to claim 1 or 2, feature exist
In the solvent is acetonitrile, in dioxane, tetrahydrofuran, dimethyl sulfoxide, 1,2- dichloroethanes, methanol, ethyl alcohol, water
It is one or more.
4. the preparation method of fluoro -3,4- Dihydroiso-coumarin derivative according to claim 1 or 2, feature exist
In the molar ratio of the compound 1 and compound 2 is 1: 1-3.
5. the preparation method of fluoro -3,4- Dihydroiso-coumarin derivative according to claim 1 or 2, feature exist
In reaction temperature is 60-100 DEG C, and the reaction time is 0.5-1.0 hours.
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