CN110092769B - Chromene derivative and synthesis method and application thereof - Google Patents
Chromene derivative and synthesis method and application thereof Download PDFInfo
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- CN110092769B CN110092769B CN201810091809.8A CN201810091809A CN110092769B CN 110092769 B CN110092769 B CN 110092769B CN 201810091809 A CN201810091809 A CN 201810091809A CN 110092769 B CN110092769 B CN 110092769B
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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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- C07—ORGANIC CHEMISTRY
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- 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
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- 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
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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Abstract
The invention discloses a chromene derivative and a chemical synthesis method and application thereof, wherein the chromene derivative comprises a structure shown as a formula (I). Firstly, diazo compound and o-hydroxy cinnamaldehyde compound are taken as raw materials, and
the molecular sieve is used as a water absorbent, and the chromene derivative is obtained by one-step reaction by using a metal compound as a catalyst and carbonate as an additive. The synthetic method has the advantages of high atom economy, high diastereoselectivity and high yield, and is mild in reaction conditions, simple and safe to operate. The chromene derivative obtained by the invention has biological activity and is suitable for preparation and application of antitumor drugs.
Description
Technical Field
The invention belongs to the field of synthetic medicine chemical industry, and mainly relates to a chromene derivative, a chemical synthesis method and application thereof.
Background
Chromene is an important core skeleton in natural products, pharmaceutically active molecules and photosensitive materials, and is also a hot spot skeleton in organic synthetic chemistry and material chemistry. For example, vitamin E is a lipid-soluble microorganism, the hydrolysis product of which, tocopherol, has important antioxidant activity in the human body, and the backbone of which is a dihydride of chromene, an important class of chromene derivatives. For another example, coumarin, also known as benzo- α -pyrone, also has a chromene skeleton, is widely present in plants, and is an active ingredient of some Chinese herbal medicines. Therefore, the synthesis of chromene derivatives is of great importance.
At present, the synthesis of chromene skeleton mainly comprises a ring closing reaction of phenyl propargyl phenol ether compounds (Synlett 2009,13, 2079; RSC adv.2016,6,40474) and a Petasis reaction of o-hydroxybenzaldehyde, or Lett.2000,2,4063; organomet. chem.2009,694, 1747. However, the introduction of a quaternary carbon at the 2-position carbon of the chromene skeleton cannot be achieved by the above method because the steric hindrance of the 2-position carbon is too great to facilitate the ring closure reaction. The invention provides a novel method for quickly and conveniently preparing a diazo compound and an o-hydroxycinnamaldehyde compound by taking a transition metal compound as a catalyst and reacting the diazo compound with the o-hydroxycinnamaldehyde compound under a mild condition.
Disclosure of Invention
The invention overcomes the defects of the prior art for synthesizing the chromene derivative and provides the chromene derivative and a preparation method and application thereof. In the preparation method, the diazo compound and the o-hydroxycinnamaldehyde compound are used for reaction, the obtained product is a chromene derivative with 2-position containing large steric hindrance quaternary carbon, which is difficult to prepare by other synthesis methods, and the raw materials are cheap and easy to obtain; the method has the advantages of mild reaction conditions, wide substrate application range, high atom economy, high diastereoselectivity, high yield and the like. Meanwhile, the chromene derivative prepared by the invention has an obvious inhibiting effect on HCT116 (human colon cancer cells), and is suitable for preparation and application of antitumor drugs.
The invention provides a chromene derivative, the structure of which is shown in formula (I),
wherein the content of the first and second substances,
R 1 hydrogen, halogen, nitro, C1-C10 alkyl, or C1-C10 alkoxy, etc.;
R 2 is C1-C10 alkyl;
ar is aryl, substituted aryl, or the like.
Preferably, R 1 Hydrogen, halogen, nitro, methyl, methoxy; r 2 Is methyl, ethyl, isopropyl; ar is phenyl, halogen substituted phenyl, alkyl substituted phenyl.
It is further preferred that the first and second liquid crystal compositions,R 1 hydrogen, chlorine, bromine, methoxy; r is 2 Is methyl; ar is phenyl, fluorine substituted phenyl, chlorine substituted phenyl, bromine substituted phenyl, methyl substituted phenyl.
Further preferably, the chromene derivative represented by the formula (I) of the present invention includes:
2- (2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester (formula (1));
2- (5-chloro-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester (formula (2));
2- (5-bromo-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester (formula (3));
2- (6-methoxy-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester (formula (4));
2- (7-methoxy-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester (formula (5));
2- (7-bromo-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester (formula (6));
2- (8-methoxy-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester (formula (7));
methyl 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-phenylacetate (formula (8));
2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-fluorophenylacetic acid methyl ester (formula (9));
methyl 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-chlorophenylacetate (formula (10));
methyl 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-bromophenylacetate (formula (11));
methyl 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-methylphenylacetate (formula (12));
methyl 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-m-bromophenylacetate (formula (13));
methyl 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-o-bromobenzoate (formula (14)).
The invention also provides a synthesis method of the chromene derivative shown in the formula (I), which takes the diazo compound and the o-hydroxy cinnamaldehyde compound as raw materials and takes
Molecular sieve as water absorbent, metal compound as catalyst and carbonate as additiveAdding an agent, and carrying out one-step reaction in an organic solvent to obtain the chromene derivative.
Specifically, the synthesis method comprises the following steps:
firstly, catalyst, stirrer, additive,
Putting a molecular sieve and an o-hydroxy cinnamaldehyde compound shown in a formula (2) into a reaction bottle, sealing the reaction bottle, changing into a nitrogen environment, and adding an organic solvent to prepare a mixed solution A;
dissolving a diazo compound shown in the formula (1) in an organic solvent to prepare a mixed solution B; adding the mixed solution B into the mixed solution A in the step (I) at a certain speed for reaction; after diazo decomposition is completed and purification is carried out, the chromene derivative shown in the formula (I) is obtained.
The formula of the synthesis reaction is shown as formula (II):
wherein R is 1 Hydrogen, halogen, nitro, C1-C10 alkyl, or C1-C10 alkoxy, etc.;
R 2 is C1-C10 alkyl;
ar is aryl, substituted aryl, or the like.
Preferably, R 1 Hydrogen, halogen, nitro, methyl, methoxy; r 2 Is methyl, ethyl, isopropyl; ar is phenyl, halogen substituted phenyl, alkyl substituted phenyl.
Further preferably, R 1 Hydrogen, chlorine, bromine, methoxy; r 2 Is methyl; ar is phenyl, fluorine substituted phenyl, chlorine substituted phenyl, bromine substituted phenyl, methyl substituted phenyl.
In the method, the reaction temperature is 0-40 ℃; preferably, it is 20 ℃.
In the method, the reaction time is 1-20 hours; preferably, 3 hours.
In the method, the diazo compound comprises one or more of phenyl diazo acetate, substituted phenyl diazo acetate and the like; preferably, it is phenyl diazoacetate.
In the method, the o-hydroxycinnamaldehyde compound comprises one or more of o-hydroxycinnamaldehyde, o-hydroxycinnamaldehyde with a substituted benzene ring and the like; wherein the o-hydroxycinnamic aldehyde with substituted benzene ring comprises one or more of 3-chloro-o-hydroxycinnamic aldehyde, 3-bromo-o-hydroxycinnamic aldehyde, 4-methoxy-o-hydroxycinnamic aldehyde, 5-bromo-o-hydroxycinnamic aldehyde, 6-methoxy-o-hydroxycinnamic aldehyde, 6-chloro-o-hydroxycinnamic aldehyde and the like; preferably, it is 3-bromo-o-hydroxycinnamaldehyde.
In the method, the additive is carbonate selected from one or more of lithium carbonate, cesium carbonate, sodium carbonate or potassium carbonate; preferably, sodium carbonate.
In the method, the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, chloroform, ethyl acetate, ethanol and the like; preferably, it is dichloromethane.
In the method, the catalyst is a metal compound and is selected from one or more of a metal iridium compound, a metal rhodium compound or a metal ruthenium compound, a metal palladium compound, a metal copper compound and the like; preferably, a metal rhodium complex; further preferably, the metal rhodium complex is bis [ (Α, Α, Α ', Α' -tetramethyl-1, 3-benzenedipropionic acid) rhodium]I.e. Rh 2 (esp) 2 Or rhodium acetate.
In the method of the present invention
The molecular sieve is a water absorbent.
In the process of the present invention, a diazo compound represented by the formula (1): an o-hydroxycinnamaldehyde compound represented by the formula (2): catalyst: the molar ratio of the additives is 1.0: (0.5-1.5): (0.008-0.05): (0.1 to 0.5); preferably, the diazo compound represented by formula (1): an o-hydroxycinnamic aldehyde compound represented by the formula (2): catalyst: the molar ratio of the additives is 1.0: 0.5: 0.1: 0.25.
in the method of the present invention, the
The feeding amount of the molecular sieve is 30-50 mg/mmol based on the dosage of the diazo compound; preferably, it is 40 mg/mmol.
In the method of the present invention, the ratio of the amount of the organic solvent to the amount of the diazo compound represented by formula (1) is (1mL to 5 mL): 1mmol of the active component; preferably, 5 mL: 1 mmol.
In the method of the present invention, the reaction further comprises separating and purifying the chromene derivative obtained by the reaction, wherein the separation and purification are performed by using an ethyl acetate: petroleum ether is 1:30-1:10 eluent to carry out column chromatography; preferably, the volume ratio of ethyl acetate for separation and purification is: petroleum ether is 1: column chromatography is carried out with 20 eluents.
In one embodiment, the present invention provides a method for synthesizing chromene derivatives, comprising the steps of: based on the dosage of the diazo compound, according to the diazo compound: o-hydroxycinnamic aldehyde compounds: catalyst metal complex: the molar ratio of the carbonate is 1.0: 0.5: 0.1: 0.25, weighing the raw materials. Metal rhodium complex Rh 2 (esp) 2 A stirrer, sodium carbonate,
Putting a molecular sieve and an o-hydroxy cinnamaldehyde compound into a reaction bottle according to a certain amount, sealing the reaction bottle, changing the reaction bottle into a nitrogen environment, and adding a certain amount of organic solvent dichloromethane to prepare a mixed solution A; dissolving diazo compounds in an organic solvent dichloromethane to prepare a mixed solution B; adding the mixed solution B into the mixed solution A at a certain speed by using an injection pump, and reacting; when the diazo decomposition is complete, the reaction is carried out by using ethyl acetate: petroleum ether is 1: and (3) carrying out column chromatography purification by using an eluent of 20 to obtain the chromene derivative shown in the formula (I).
The invention also provides the chromene derivative shown in the formula (I) prepared by the synthesis method.
The invention also provides the application of the chromene derivative shown as the formula (I) in the preparation of important chemical and medical intermediates; the important chemical and medical intermediates comprise vitamin E, coumarin and the like.
The invention also provides application of the chromene derivative shown as the formula (I) in preparation of antitumor drugs. Wherein, the tumor comprises one or 2 of colon cancer and lymph cancer; preferably, inhibition of HCT116 (human colon cancer cells).
The invention has the beneficial effects that: the chromene derivative shown as the formula (I) is an important chemical and pharmaceutical intermediate, is widely applied to the field of pharmaceutical chemicals, and has a great application prospect. The preparation method of the chromene derivative shown in the formula (I) takes the cheap and easily-obtained compound as the raw material, and has the beneficial effects of mild reaction conditions, few reaction steps, quick reaction, low cost, less generated waste, simple and safe operation, high atom economy, high selectivity, high yield and the like.
Drawings
FIG. 1 shows the product (1) obtained in example 1 1 H NMR scheme.
FIG. 2 shows the product (1) obtained in example 1 13 Schematic C NMR.
FIG. 3 shows the product (2) obtained in example 2 1 H NMR scheme.
FIG. 4 shows the product (2) obtained in example 2 13 Schematic C NMR.
FIG. 5 shows the product (3) obtained in example 3 1 H NMR scheme.
FIG. 6 shows the product (3) obtained in example 3 13 Schematic C NMR.
FIG. 7 shows the product (4) obtained in example 4 1 H NMR scheme.
FIG. 8 shows the product (4) obtained in example 4 13 C NMR is a schematic drawing.
FIG. 9 shows the product (5) obtained in example 5 1 H NMR scheme.
FIG. 10 shows the product (5) obtained in example 5 13 C NMR is a schematic drawing.
FIG. 11 shows example 6Of the resulting product (6) 1 H NMR scheme.
FIG. 12 shows a schematic view of a product (6) obtained in example 6 13 C NMR is a schematic drawing.
FIG. 13 shows a sample of the product (7) obtained in example 7 1 H NMR scheme.
FIG. 14 shows the product (7) obtained in example 7 13 Schematic C NMR.
FIG. 15 shows the product (8) obtained in example 8 1 H NMR scheme.
FIG. 16 shows the product (8) obtained in example 8 13 Schematic C NMR.
FIG. 17 shows production of (9) in example 9 1 H NMR scheme.
FIG. 18 shows production of (9) in example 9 13 Schematic C NMR.
FIG. 19 shows production of (9) by example 9 19 F NMR scheme.
FIG. 20 shows a photograph of the product (10) obtained in example 10 1 H NMR scheme.
FIG. 21 shows the product (10) obtained in example 10 13 C NMR is a schematic drawing.
FIG. 22 shows a sample of the product (11) obtained in example 11 1 H NMR scheme.
FIG. 23 shows a sample of the product (11) obtained in example 11 13 Schematic C NMR.
FIG. 24 shows a schematic view of a product (12) obtained in example 12 1 H NMR scheme.
FIG. 25 shows a schematic view of a product (12) obtained in example 12 13 Schematic C NMR.
FIG. 26 is a photograph of the product (13) obtained in example 13 1 H NMR scheme.
FIG. 27 shows a schematic view of a product (13) obtained in example 13 13 C NMR is a schematic drawing.
FIG. 28 shows a sample of the product (14) obtained in example 14 1 H NMR scheme.
FIG. 29 shows a schematic view of a product (14) obtained in example 14 13 Schematic C NMR.
FIG. 30 is a graph of concentration-survival for HCT116 (human colon cancer cells) for different concentrations of two compounds of the invention (10).
FIG. 31 is a graph of concentration-survival for HCT116 (human colon cancer cells) for different concentrations of two compounds of the invention (11).
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and drawings, and the present invention is not limited to the following examples. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected. The procedures, conditions, reagents, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art, except for the contents specifically mentioned below, and the present invention is not particularly limited.
Example 1
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (1), the formula (1) is 2- (2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester, the total yield of the formula (1) is 70%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 1, which 13 The C NMR chart is shown in FIG. 2.
1 H NMR(400MHz,CDCl 3 )δ7.71(d,J＝7.4Hz,2H),7.48–7.30(m,3H),7.09(t,J＝7.5Hz,1H),6.93(d,J＝7.1Hz,1H),6.83(t,J＝7.3Hz,1H),6.73(d,J＝8.0Hz,1H),6.43(d,J＝10.0Hz,1H),5.74(s,1H),5.23(dd,J＝10.0,2.6Hz,1H),3.89(s,3H),3.85(s,1H).
13 C NMR(100MHz,CDCl 3 )δ173.42,153.50,136.24,129.35,128.52,128.36,126.73,126.56,126.08,121.27,121.02,119.18,115.22,81.58,80.02,53.60.
Example 2
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting the molecular sieve into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen for protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (2), the (2) is 2- (5-chloro-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester, the total yield of the (2) is 59%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 3, which 13 The C NMR chart is shown in FIG. 4.
1 H NMR(400MHz,CDCl 3 )δ7.70(d,J＝7.2Hz,2H),7.48–7.29(m,3H),7.00(t,J＝7.9Hz,1H),6.92–6.72(m,2H),6.65(d,J＝8.2Hz,1H),5.72(s,1H),5.33(d,J＝8.2Hz,1H),3.89(s,3H),3.87(s,1H).
13 C NMR(100MHz,CDCl 3 )δ173.28,154.49,135.98,131.34,129.32,128.62,128.53,126.04,122.91,122.10,120.51,119.34,114.03,81.35,79.85,53.76.
Example 3
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (3), the formula (3) is 2- (5-bromo-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester, the total yield of the formula (3) is 45%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 5, which 13 The C NMR chart is shown in FIG. 6.
1 H NMR(400MHz,CDCl 3 )δ7.69(d,J＝7.3Hz,2H),7.49–7.27(m,3H),7.05(d,J＝7.9Hz,1H),6.93(t,J＝8.0Hz,1H),6.75(d,J＝10.2Hz,1H),6.69(d,J＝8.0Hz,1H),5.70(s,1H),5.32(d,J＝10.2Hz,1H),3.88(s,4H).
13 C NMR(100MHz,CDCl 3 )δ173.27,154.60,135.98,129.78,128.63,128.54,126.05,125.37,125.35,121.66,120.96,120.91,114.74,81.29,79.96,53.76.
Example 4
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting the molecular sieve into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen for protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (4), the formula (4) is 2- (6-methoxy-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester, the total yield of the formula (4) is 52%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 7, which 13 The C NMR chart is shown in FIG. 8.
1 H NMR(400MHz,CDCl 3 )δ7.71(d,J＝5.8Hz,2H),7.49–7.29(m,3H),6.67(s,2H),6.53(s,1H),6.41(d,J＝10.0Hz,1H),5.69(s,1H),5.27(d,J＝10.0Hz,1H),3.90(d,J＝2.3Hz,3H),3.85(s,1H),3.74(d,J＝2.3Hz,3H).
13 C NMR(100MHz,CDCl 3 )δ173.46,154.04,147.38,136.22,128.53,128.37,126.62,126.06,121.63,120.23,115.73,114.38,111.96,81.46,79.92,55.74,53.65.
Example 5
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; phenyl is heavyMethyl azoacetate (0.5mmol) is dissolved in 0.3mL of dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (5), the pure product is 2- (7-methoxy-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester (5), the total yield of the product is 48%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 9, which 13 The C NMR chart is shown in FIG. 10.
1 H NMR(400MHz,CDCl 3 )δ7.70(d,J＝7.5Hz,2H),7.45–7.30(m,3H),6.85(d,J＝8.2Hz,1H),6.40(d,J＝10.0Hz,2H),6.33(s,1H),5.73(s,1H),5.08(d,J＝10.0Hz,1H),3.90(s,3H),3.84(s,1H),3.77(s,3H).
13 C NMR(100MHz,CDCl 3 )δ173.45,160.82,154.68,136.29,128.51,128.34,127.39,126.18,126.07,116.10,114.29,106.79,101.38,81.59,80.07,55.38,53.64.
Example 6
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed and the reaction is finished, column chromatography is carried out on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as eluent) to obtain a pure product, the structure of which is shown as formula (6), and the formula (6) is 2- (7-bromo-2H-Total yield of chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester (6) 47%, dr value greater than 20: 1. it is composed of 1 H NMR is shown in FIG. 11, which 13 The C NMR chart is shown in FIG. 12.
1 H NMR(400MHz,CDCl 3 )δ7.62(d,J＝5.3Hz,2H),7.29–7.32(m,3H),7.00–6.76(m,2H),6.71(d,J＝6.8Hz,1H),6.32(d,J＝9.3Hz,1H),5.66(s,1H),5.16(d,J＝9.3Hz,1H),3.83(s,4H).
13 C NMR(100MHz,CDCl 3 )δ172.19,153.12,134.93,127.56,127.44,126.62,124.97,124.72,123.23,120.94,118.89,118.37,117.47,80.57,79.07,52.77.
Example 7
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (7), the formula (7) is 2- (8-methoxy-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester, the total yield of the formula (7) is 58%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 13 13 The C NMR chart is shown in FIG. 14.
1 H NMR(400MHz,CDCl 3 )δ7.65(d,J＝7.4Hz,2H),7.40–7.21(m,3H),6.71(d,J＝4.1Hz,2H),6.59–6.49(m,1H),6.37(d,J＝10.0Hz,1H),5.69(s,1H),5.20(d,J＝10.0Hz,1H),3.83–3.84(m,4H),3.75(s,3H).
13 C NMR(100MHz,CDCl 3 )δ172.42,146.32,141.79,135.14,127.47,127.33,125.58,125.07,120.83,119.82,118.32,118.27,112.82,80.58,79.10,55.61,52.68.
Example 8
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen protection; then 0.3ml of dichloromethane is added into the reaction bottle to prepare a mixed solution A, and the mixed solution A is stirred for 5 minutes at the temperature of 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (8), the formula (8) is 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester, the total yield of the formula (8) is 54%, and the dr value is more than 20: 1. it is provided with 1 H NMR is shown in FIG. 15, which 13 The C NMR chart is shown in FIG. 16.
1 H NMR(400MHz,CDCl 3 )δ7.80–7.65(m,2H),7.46–7.30(m,3H),7.16(dd,J＝8.0,1.5Hz,1H),6.88–6.72(m,2H),6.45(dd,J＝10.1,1.9Hz,1H),5.83(dd,J＝3.3,1.9Hz,1H),5.30(dd,J＝10.1,3.3Hz,1H),3.95(s,3H).
13 C NMR(100MHz,CDCl 3 )δ173.19,149.16,135.83,129.86,128.59,128.50,126.10,126.04,125.05,122.46,121.45,120.28,119.86,81.68,80.74,53.94.
Example 9
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting the molecular sieve into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen for protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ by a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (9), the formula (9) is 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-fluorophenylacetic acid methyl ester, the total yield of the formula (9) is 68%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 17, which 13 The C NMR is shown in FIG. 18, which 19 The F NMR chart is shown in FIG. 19.
1 H NMR(400MHz,CDCl 3 )δ7.71(dd,J＝8.8,5.3Hz,2H),7.20–7.02(m,3H),6.85(d,J＝6.4Hz,1H),6.77(t,J＝7.7Hz,1H),6.46(dd,J＝10.1,1.6Hz,1H),5.81–5.72(m,1H),5.28(dd,J＝10.1,3.3Hz,1H),3.95(s,3H).
13 C NMR(100MHz,CDCl 3 )δ173.00,149.06,129.93,128.06,127.98,126.28,125.08,122.39,121.53,120.29,119.52,115.58,115.37,81.32,80.70,54.00.
19 F NMR(376MHz,CDCl 3 )δ-113.69,-113.70,-113.70,-113.71,-113.72,-113.72,-113.73.
Example 10
Cortex CinnamomiAldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (10), the formula (10) is 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-chlorophenylacetic acid methyl ester, the total yield of the formula (10) is 48%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 20, which 13 A schematic C NMR chart is shown in FIG. 21.
1 H NMR(400MHz,CDCl 3 )δ7.67(d,J＝8.7Hz,1H),7.37(d,J＝8.7Hz,1H),7.15(dd,J＝8.0,1.4Hz,1H),6.90–6.65(m,1H),6.45(dd,J＝10.1,1.9Hz,1H),5.75(dd,J＝3.3,1.9Hz,1H),5.27(dd,J＝10.1,3.3Hz,1H),3.99(s,1H),3.95(s,1H).
13 C NMR(100MHz,CDCl 3 )δ172.78,149.03,134.65,134.39,129.94,128.74,127.62,126.33,125.08,122.36,121.54,120.29,119.43,81.35,80.66,54.02,21.04.
Example 11
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen protection; re-directional reaction bottleAdding 0.3ml of dichloromethane to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (11), the formula (11) is 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-bromophenylacetic acid methyl ester, the total yield of the formula (11) is 66%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 22 13 A C NMR chart is shown in FIG. 23.
1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝8.6Hz,2H),7.53(d,J＝8.6Hz,2H),7.20–7.11(m,1H),6.85(d,J＝6.4Hz,1H),6.77(t,J＝7.7Hz,1H),6.46(dd,J＝10.1,1.5Hz,1H),5.75–5.73(m,1H),5.28(dd,J＝10.1,3.3Hz,1H),3.95(s,3H).
13 C NMR(100MHz,CDCl 3 )δ172.71,149.02,134.91,131.72,129.96,127.94,126.36,125.09,122.91,122.34,121.56,120.30,119.39,81.40,80.60,54.06.
Example 12
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen protection; adding 0.3ml of dichloromethane into the reaction bottle to prepare a mixed solution A, and stirring for 5 minutes at 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After the diazo decomposition is completed and the reaction is finished, column chromatography is carried out to the crude product (A)Mixing the following raw materials in percentage by weight of ethyl acetate: petroleum ether 1:30-1:10 as eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (12), the formula (12) is 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-methyl phenylacetate, the total yield of the formula (12) is 54%, and the dr value is more than 20: 1. it is provided with 1 H NMR is shown in FIG. 24, which 13 A C NMR chart is shown in FIG. 25.
1 H NMR(400MHz,CDCl 3 )δ7.52(d,J＝8.2Hz,2H),7.24–6.98(m,4H),6.76(d,J＝6.7Hz,1H),6.68(t,J＝7.7Hz,1H),6.36(dd,J＝10.1,1.4Hz,1H),5.73–5.72(m,1H),5.24(dd,J＝10.1,3.2Hz,1H),3.85(s,4H),2.28(s,3H).
13 C NMR(100MHz,CDCl 3 )δ173.34,149.21,138.32,132.94,129.82,129.29,126.01,125.95,125.02,122.54,121.41,120.30,120.04,81.57,80.72,77.37,77.26,77.06,76.74,53.82,21.06.
Example 13
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting the molecular sieve into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen for protection; then 0.3ml of dichloromethane is added into the reaction bottle to prepare a mixed solution A, and the mixed solution A is stirred for 5 minutes at the temperature of 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (13), (13) is 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-m-bromophenylacetic acid methyl ester, (13) the total yield is 54%, and the dr value is more than 20: 1. it is composed of 1 H NMR is shown in FIG. 26 13 A C NMR chart is shown in FIG. 27.
1 H NMR(400MHz,CDCl 3 )δ7.91(s,1H),7.66(d,J＝7.7Hz,1H),7.49(d,J＝7.7Hz,1H),7.28–7.25(m,1H),7.16(d,J＝7.8Hz,1H),6.85(d,J＝7.1Hz,1H),6.78–6.75(m,1H),6.47(d,J＝10.0Hz,1H),5.75(s,1H),5.29(d,J＝10.0Hz,1H),3.99(s,1H),3.96(s,1H).
13 C NMR(100MHz,CDCl 3 )δ172.61,149.03,138.14,131.69,130.10,129.97,129.34,126.40,125.09,124.79,122.96,122.34,121.56,120.29,119.37,81.25,80.68,54.14.
Example 14
Cinnamic aldehyde (0.2mmol), rhodium acetate (0.05mmol), sodium carbonate (0.06mmol) and
weighing a molecular sieve (30mg), putting the molecular sieve into a reaction bottle, sealing the reaction bottle by using a sealing film, and pumping air out of the reaction bottle to be replaced by nitrogen for protection; then 0.3ml of dichloromethane is added into the reaction bottle to prepare a mixed solution A, and the mixed solution A is stirred for 5 minutes at the temperature of 20 ℃; dissolving methyl phenyl diazoacetate (0.5mmol) in 0.3mL dichloromethane to prepare a mixed solution B; the mixed solution B was added to the mixed solution A at 20 ℃ with a syringe pump, and the mixture was stirred to effect a reaction. After diazo decomposition is completed and the reaction is finished, carrying out column chromatography on the crude product (ethyl acetate: petroleum ether: 1:30-1:10 is used as an eluent) to obtain a pure product, wherein the structure of the pure product is shown as a formula (14), the formula (14) is 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-o-bromophenylacetic acid methyl ester, the total yield of the formula (14) is 74%, and the dr value is more than 20: 1. it is provided with 1 H NMR is shown in FIG. 28 13 A C NMR chart is shown in FIG. 29.
1 H NMR(400MHz,CDCl 3 )δ7.70(dd,J＝8.0,1.5Hz,1H),7.54(dd,J＝8.0,1.5Hz,1H),7.31–7.29(m,1H),7.17–7.03(m,2H),6.79(dd,J＝7.5,1.4Hz,1H),6.70(t,J＝7.7Hz,1H),6.48(dd,J＝10.1,1.7Hz,1H),6.02(dd,J＝3.5,1.7Hz,1H),5.83(dd,J＝10.1,3.5Hz,1H),4.15(s,1H),3.57(s,3H).
13 C NMR(100MHz,CDCl 3 )δ172.71,149.02,134.91,131.72,129.96,127.94,126.36,125.09,122.91,122.34,121.56,120.30,119.39,81.40,80.60,54.06.
Example 15
In this example, the biological activity of the compound of the present invention was tested by the CCK8 method, and the compound of the present invention (10) prepared in example 10, methyl 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-chlorophenyl acetate and the compound of the present invention (11) prepared in example 11, methyl 2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-bromophenyl acetate, were used to study their tumor cell inhibitory effects. The cell lines specifically used in this example are: HCT116 (human colon cancer cells).
1. Inoculating cells: single cell suspensions were prepared in McCoy'5A medium containing 10% fetal bovine serum, 1% penicillin and streptomycin, and seeded into 96 well cell culture plates in 3000 cells per well, 100. mu.l per well.
2. The compound of the present invention was prepared as a powdery drug by a milling treatment step, and the powdery drug was prepared as a mother liquor at a final concentration of 10mM, followed by gradient dilution to 0.01mM, 0.03mM, 0.1mM, 0.3mM, 1mM, 3mM, 10mM, 30mM in this order. Three duplicate wells were set for each concentration group.
3. Administration: the gradient stock solution was diluted with complete medium to a final concentration of 0.01. mu.M, 0.03. mu.M, 0.1. mu.M, 0.3. mu.M, 1. mu.M, 3. mu.M, 10. mu.M, 30. mu.M, 200. mu.l per well acted on the cells, three duplicate wells were set for each group concentration, and the DMSO content in the culture solution was 1 ‰.
4. Culturing: 5% CO 2 And culturing in an incubator with saturated humidity at 37 ℃ for 72 hours.
5. Color generation: the culture was aspirated for 72 hours, 100. mu.l of complete 1640 medium and 10. mu.l of CCK8 were added to each well, and incubated at 37 ℃ for 4 hours.
6. Color comparison: the wavelengths of 620nm and 450nm were selected, and the Optical Density (OD) value of each well was measured on a microplate reader, and the results were recorded.
7. The absorbance value at 450nm to 620nm (background absorbance value) of the same well was used as the final absorbance, and the final absorbance was substituted into the following formula.
8. Cell proliferation activity (%) ([ a (dosed) -a (blank) ]/[ a (0 dosed) -a (blank) ] × 100
A (dosing): absorbance of wells with cells, CCK solution and drug solution
A (blank): absorbance of wells with medium and CCK solution without cells
A (0 dosing): absorbance of wells with cells, CCK solution and no drug solution
9. The experimental results show that: the proliferation activity of HCT116 cells was significantly inhibited by the compound of the present invention at a concentration of 10. mu.M and 30. mu.M.
Fig. 30 and 31 show the survival rate of HCT116 (human colon cancer cells) at different concentrations of the compounds (10) and (11) of the present invention, and concentration-survival rate curves plotted on the abscissa and the ordinate. From the curves, it can be seen that the half-lethal concentrations IC of the compounds (10) and (11) of the present invention on HCT116 (human colon cancer cells) 50 79.48 μ M and 31.31 μ M, respectively.
Therefore, the compounds (10) and (11) have an inhibiting effect on the activity of HCT116 (human colon cancer cells), and are suitable for preparation and application of antitumor drugs.
The protection content of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (8)
1. A chromene derivative is characterized in that the structure is shown as formula (I),
wherein, the first and the second end of the pipe are connected with each other,
R 1 is hydrogen, halogen or C1-C10 alkoxy;
R 2 is C1-C10 alkyl;
ar is phenyl, halogen substituted phenyl, methyl substituted phenyl.
2. The chromene derivative of claim 1, wherein R is 1 Is hydrogen, halogen, methoxy; r 2 Is methyl, ethyl, isopropyl; ar is phenyl, halogen substituted phenyl, methyl substituted phenyl.
3. The chromene derivative of any one of claims 1-2, wherein the chromene derivative is:
2- (2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester;
2- (5-chloro-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester;
2- (5-bromo-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester;
2- (6-methoxy-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester;
2- (7-methoxy-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester;
2- (7-bromo-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester;
2- (8-methoxy-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester;
2- (8-chloro-2H-chromenyl) -2-hydroxy-2-phenylacetic acid methyl ester;
2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-fluorophenylacetic acid methyl ester;
2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-chlorophenylacetic acid methyl ester;
2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-bromophenylacetic acid methyl ester;
2- (8-chloro-2H-chromenyl) -2-hydroxy-2-p-methylphenylacetic acid methyl ester;
2- (8-chloro-2H-chromenyl) -2-hydroxy-2-m-bromophenylacetic acid methyl ester;
2- (8-chloro-2H-chromenyl) -2-hydroxy-2-o-bromophenylacetic acid methyl ester.
4. A method for synthesizing chromene derivative is characterized in that diazo compound shown in formula 1 and o-hydroxy cinnamaldehyde compound shown in formula 2 are used as raw materials, and
the molecular sieve is used as a water absorbent, the metal compound is used as a catalyst, and carbonate is used as an additive, and the chromene derivative shown in the formula (I) is obtained through one-step reaction in an organic solvent; the synthesis reaction is shown as a formula (II):
wherein, the first and the second end of the pipe are connected with each other,
R 1 is hydrogen, halogen or C1-C10 alkoxy;
R 2 is C1-C10 alkyl;
ar is phenyl, halogen substituted phenyl, methyl substituted phenyl;
the catalyst is a metal compound and is selected from one or more of a metal iridium compound, a metal rhodium compound or a metal ruthenium compound, a metal palladium compound and a metal copper compound; the organic solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, chloroform, ethyl acetate and ethanol; the additive is carbonate selected from one or more of lithium carbonate, cesium carbonate, sodium carbonate or potassium carbonate.
5. The synthesis method according to claim 4, wherein the reaction temperature is 0-40 ℃.
6. The synthetic method of claim 4 wherein the diazo compound of formula 1: an o-hydroxycinnamaldehyde compound represented by formula 2: catalyst: the molar ratio of the additives is 1.0: (0.5-1.5): (0.008-0.05): (0.1 to 0.5); the above-mentioned
The feeding amount of the molecular sieve is 30-50 mg/mmol based on the diazo compound shown in the formula 1; the ratio of the dosage of the organic solvent to the dosage of the diazo compound shown in the formula 1 is (1)mL～5mL)：1mmol。
7. The synthetic method of claim 4 wherein the diazo compound comprises a phenyl diazoacetate, a halogen substituted phenyl diazoacetate, or a methyl substituted phenyl diazoacetate; the o-hydroxycinnamaldehyde comprises o-hydroxycinnamaldehyde and o-hydroxycinnamaldehyde with a substituted benzene ring; wherein the o-hydroxycinnamaldehyde substituted on the benzene ring comprises 3-chloro-o-hydroxycinnamaldehyde, 3-bromo-o-hydroxycinnamaldehyde, 4-methoxy-o-hydroxycinnamaldehyde, 5-bromo-o-hydroxycinnamaldehyde, 6-methoxy-o-hydroxycinnamaldehyde or 6-chloro-o-hydroxycinnamaldehyde.
8. Use of the chromene derivative of formula (I) according to any one of claims 1 to 3, in the preparation of a medicament against tumors, characterized in that said tumors are colon cancers.
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