CN114478502B - Coumarin compound and synthesis method thereof - Google Patents
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Abstract
The invention relates to the field of organic compounds, and provides a coumarin compound and a synthetic method thereof. The synthesis method disclosed by the invention is simple to operate, high in yield and mild in reaction conditions, and according to the reaction, the 7-hydroxycoumarin, the 4-hydroxycoumarin and the 7-hydroxy-4-methylcoumarin are respectively obtained by utilizing aldol condensation reaction of aldehyde and ketone and an active methylene or active hydrogen compound. The whole reaction process is safe and environment-friendly, has low cost and high economic benefit, and belongs to a green chemical process. The method is applied to the field of coumarin synthesis.
Description
Technical Field
The invention relates to the field of organic matter synthesis, in particular to coumarin compounds and a synthesis method thereof.
Background
The natural product coumarin compound exists in secondary metabolites of plants and microorganisms in a large amount, has various pharmacological activities, and has prominent antitumor effect. The natural coumarin compound has good anti-tumor activity, and the cytotoxicity, the water solubility and the bioavailability of the natural coumarin compound are the main optimization directions for modifying the natural coumarin compound, and the modification is mainly carried out on 3,4,7 and 8 positions. The synthesized coumarin derivatives have the effects of anticoagulation, anti-tumor, antibiosis, antivirus, fluorescent probe monitoring and the like.
Lipoic acid is a new endogenous substance and is involved in important regulation in mitochondria of organisms, is 8-carbon saturated fatty acid containing cyclic disulfide bonds and is involved in oxidation and elimination reactions catalyzed by pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, and the lipoic acid can be involved in the regulation of active oxygen in two ways according to different contents of action parts. The lipoic acid can not only scavenge active oxygen, but also promote its release. The low concentration active oxygen can induce the proliferation, differentiation and metastasis of tumor cells, and the high concentration active oxygen destroys the molecular structure of the cells and induces the apoptosis. Coumarin has strong antitumor activity but high cytotoxicity, and can be used as prodrug. Lipoic acid inhibits the proliferation of tumor cells, has small effect on normal cells, but can be used for modifying active medicaments and participating in the design and synthesis of prodrugs due to the self limitations. The structural modification of the lipoic acid is mainly developed from two sites, wherein one site is the carboxyl of the lipoic acid and the other site is modified after a disulfide bond is opened to form a sulfhydryl group. Active ingredients with certain defects can be designed into prodrugs through reasonable modification, so that the defects of low drug effect, poor stability and the like are avoided.
At present, the coumarin derivatives mainly have the problems of high synthesis process cost, environmental harm, complex operation, low yield and the like which need to be solved urgently.
Disclosure of Invention
The invention aims to provide a coumarin compound and a synthesis method thereof.
The coumarin compound is a 7-hydroxycoumarin derivative, and the chemical structural formula of the 7-hydroxycoumarin derivative is as follows:
the synthesis method of the 7-hydroxycoumarin derivative is carried out according to the following steps:
step one, 7-hydroxycoumarin derivative intermediate
Placing 7-hydroxycoumarin and bromohydrin in a reaction bottle, sequentially adding potassium carbonate, sodium iodide and tetrabutylammonium fluoride, uniformly mixing, adding acetone, uniformly mixing, and reacting at 52-62 ℃ for 5.5-7.5 h; distilling under reduced pressure to obtain yellow oily substance; separating and purifying the yellow oily substance by a silica gel column by adopting a dry method, and removing the solvent by reducing pressure to obtain a white solid, namely the 7-hydroxycoumarin derivative intermediate; the 7-hydroxycoumarin derivative intermediate is 4;
step two, respectively putting the 7-hydroxycoumarin derivative intermediate and lipoic acid into a reaction bottle, sequentially adding EDCI and DMAP, uniformly mixing, then adding dichloromethane, and respectively stirring at room temperature for overnight reaction; filtering respectively after the reaction is finished, distilling under reduced pressure respectively to obtain viscous yellow oily substances, separating and purifying the obtained viscous yellow oily substances through silica gel columns respectively by a dry method, and removing solvents under reduced pressure respectively to obtain light yellow viscous liquid, namely the 7-hydroxycoumarin derivative;
wherein, the mol ratio of the 7-hydroxycoumarin to the bromohydrin, the potassium carbonate, the sodium iodide and the tetrabutyl ammonium fluoride is 1.5-2.5; the molar volume ratio of the 7-hydroxycoumarin to the acetone is 1mol; the molar ratio of the 7-hydroxycoumarin derivative intermediate to the lipoic acid, EDCI and DMAP is 1; the molar volume ratio of the 7-hydroxycoumarin derivative intermediate to dichloromethane is 1mol.
Further, the bromohydrin is 2-bromoethanol, 3-bromo-1-n-propanol, 6-bromo-1-n-hexanol and 10-bromo-1-n-decanol.
Further, TLC is adopted in both the first step and the second step to monitor the reaction, and the developing agent used in the monitoring reaction is formed by mixing petroleum ether and ethyl acetate according to the volume ratio of 10.
The coumarin compound is a 4-hydroxycoumarin derivative, and the chemical structural formula of the 4-hydroxycoumarin derivative is as follows:
the 4-hydroxycoumarin derivative is applied to the preparation of drugs for inhibiting tumor proliferation.
4-hydroxycoumarin derivatives, carried out according to the following steps:
step one, 4-hydroxy coumarin derivative intermediate
Putting 4-hydroxycoumarin and bromohydrin in a reaction bottle, sequentially adding potassium carbonate, sodium iodide and tetrabutylammonium fluoride, uniformly mixing, adding acetone, uniformly mixing, and reacting at 52-62 ℃ for 5.5-7.5 h; distilling under reduced pressure to obtain viscous yellow oil; separating and purifying the viscous yellow oily substance by a silica gel column by adopting a dry method, and removing the solvent under reduced pressure to obtain a white solid, namely the 4-hydroxycoumarin derivative intermediate; 4-hydroxycoumarin intermediates;
step two, respectively putting the 4-hydroxycoumarin derivative intermediate and lipoic acid into a reaction bottle, sequentially adding EDCI and DMAP, uniformly mixing, then adding dichloromethane, and respectively stirring at room temperature for overnight reaction; filtering respectively after the reaction is finished, distilling under reduced pressure respectively to obtain viscous yellow oily substances, separating and purifying the obtained viscous yellow oily substances through silica gel columns respectively by a dry method, and removing solvents under reduced pressure respectively to obtain light yellow viscous liquid, namely the 4-hydroxycoumarin derivative;
wherein, the mol ratio of the 4-hydroxycoumarin to the bromohydrin, the potassium carbonate, the sodium iodide and the tetrabutyl ammonium fluoride is 1.5-2.5; the molar volume ratio of the 4-hydroxycoumarin to the acetone is 1mol; the mol ratio of the 4-hydroxycoumarin derivative intermediate to the lipoic acid, EDCI and DMAP is 1; the molar volume ratio of the 4-hydroxycoumarin derivative intermediate to dichloromethane is 1mol.
Further, the bromohydrin is 2-bromoethanol, 3-bromo-1-n-propanol, 6-bromo-1-n-hexanol and 10-bromo-1-n-decanol.
Further, TLC is adopted in both the first step and the second step to monitor the reaction, and the developing agent used in the monitoring reaction is formed by mixing petroleum ether and ethyl acetate according to the volume ratio of 10.
The coumarin compound is a 4-methyl-7-hydroxycoumarin derivative, and the chemical structural formula of the 4-methyl-7-hydroxycoumarin derivative is as follows:
the 4-methyl-7-hydroxycoumarin derivative is applied to the preparation of medicines for inhibiting tumor proliferation.
The synthesis method of the 4-methyl-7-hydroxycoumarin derivative is carried out according to the following steps:
step one, 4-methyl-7-hydroxycoumarin derivative intermediate
Putting 4-methyl-7-hydroxycoumarin and bromohydrin in a reaction bottle, sequentially adding potassium carbonate, sodium iodide and tetrabutylammonium fluoride, uniformly mixing, adding acetone, uniformly mixing, and reacting at 52-62 ℃ for 5.5-7.5 h; distilling under reduced pressure to obtain viscous yellow oil; separating and purifying the viscous yellow oily substance by a silica gel column by adopting a dry method, and removing the solvent under reduced pressure to obtain a white solid, namely the 4-methyl-7-hydroxycoumarin derivative intermediate; 4-methyl-7-hydroxycoumarin intermediates;
step two, respectively putting the 4-methyl-7-hydroxycoumarin derivative intermediate and lipoic acid into a reaction bottle, sequentially adding EDCI and DMAP, uniformly mixing, adding dichloromethane, and respectively stirring at room temperature for overnight reaction; filtering respectively after the reaction is finished, distilling under reduced pressure respectively to obtain viscous yellow oily substances, separating and purifying the obtained viscous yellow oily substances through silica gel columns respectively by a dry method, and removing solvents under reduced pressure respectively to obtain light yellow viscous liquid, namely the 4-hydroxycoumarin derivative;
wherein the molar ratio of the 4-methyl-7-hydroxycoumarin to the bromohydrin, the potassium carbonate, the sodium iodide and the tetrabutylammonium fluoride is 1.5-2.5; the molar volume ratio of the 4-methyl-7-hydroxycoumarin to the acetone is 1mol; the mol ratio of the 4-methyl-7-hydroxycoumarin derivative intermediate to the lipoic acid, EDCI and DMAP is 1; the molar volume ratio of the 4-methyl-7-hydroxycoumarin derivative intermediate to dichloromethane is 1mol.
Further, the bromohydrin is 2-bromoethanol, 3-bromo-1-n-propanol, 6-bromo-1-n-hexanol and 10-bromo-1-n-decanol.
Further, TLC is adopted to monitor the reaction in the first step and the second step, and the developing solvent used in the monitoring reaction is formed by mixing petroleum ether and ethyl acetate according to the volume ratio of 10.
The synthetic route of the coumarin derivative comprises the following steps:
the invention has the following beneficial effects:
according to the invention, a Knoevenagel reaction is adopted, and an aldol condensation reaction of ketone and active methylene or active hydrogen compound is utilized to respectively obtain a 7-hydroxycoumarin derivative, a 4-hydroxycoumarin derivative and a 7-hydroxy-4-methylcoumarin derivative. The method takes the parent nucleus hydroxyl position of the synthesized three coumarins as an active site, takes the carboxyl group on the lipoic acid as another active site, and respectively introduces the lipoic acid through the coupling reaction of different bromoalcohols to obtain a series of novel coumarin derivatives.
The synthetic method disclosed by the invention is simple to operate, high in yield and mild in reaction conditions, and according to the reaction, the 7-hydroxycoumarin, the 4-hydroxycoumarin and the 7-hydroxy-4-methylcoumarin are respectively obtained by aldol condensation reaction of aldehyde and ketone with active methylene or active hydrogen compounds. According to the invention, hydroxyl hydrogen on coumarin is substituted by bromohydrin, and then carboxyl esterification reaction is carried out on hydroxyl on the obtained intermediate and lipoic acid to obtain 12 target new compounds A1, A2, A3, A4, B1, B2, B3, B4, C1, C2, C3 and C4. The whole reaction process is safe and environment-friendly, has low cost and high economic benefit, and belongs to a green chemical process.
Drawings
FIG. 1 is a schematic representation of 7-hydroxycoumarin 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 2 is a scheme of 7-hydroxycoumarin 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 3 is a 7-hydroxycoumarin derivative intermediate a1 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 4 is a 7-hydroxycoumarin derivative intermediate a1 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 5 is a drawing showing a scheme for 7-hydroxycoumarin derivative A1 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 6 shows 7-hydroxycoumarin derivative A1 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 7 shows 7-hydroxy cuminPreparation of intermediate a2 of a derivative of an alcohol 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 8 shows the preparation of 7-hydroxycoumarin derivative intermediate a2 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 9 shows 7-hydroxycoumarin derivative A2 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 10 shows 7-hydroxycoumarin derivative A2 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 11 is a scheme showing that 7-hydroxycoumarin derivative intermediate a3 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 12 is a scheme showing that 7-hydroxycoumarin derivative intermediate a3 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 13 is a drawing showing 7-hydroxycoumarin derivative A3 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 14 is a drawing showing 7-hydroxycoumarin derivative A3 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 15 shows the preparation of 7-hydroxycoumarin derivative intermediate a4 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 16 is a scheme showing the preparation of 7-hydroxycoumarin derivative intermediate a4 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 17 is a drawing showing 7-hydroxycoumarin derivative A4 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 18 is a schematic representation of 7-hydroxycoumarin derivative A4 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 19 is a scheme showing 4-hydroxycoumarin 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 20 is a scheme showing 4-hydroxycoumarin 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 21 is a scheme showing the preparation of 4-hydroxycoumarin derivative intermediate b1 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 22 is a scheme showing the preparation of 4-hydroxycoumarin derivative intermediate b1 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 23 is a drawing showing the preparation of 4-hydroxycoumarin derivative B1 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 24 is a drawing showing the preparation of 4-hydroxycoumarin derivative B1 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 25 is a scheme showing the preparation of 4-hydroxycoumarin derivative intermediate b2 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 26 is a scheme showing the preparation of 4-hydroxycoumarin derivative intermediate b2 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 27 is a drawing showing the preparation of 4-hydroxycoumarin derivative B2 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 28 is a drawing showing the preparation of 4-hydroxycoumarin derivative B2 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 29 is a drawing showing the preparation of 4-hydroxycoumarin derivative intermediate b3 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 30 is a drawing showing the preparation of 4-hydroxycoumarin derivative intermediate b3 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 31 is a scheme showing the derivatization of 4-hydroxycoumarinOf the object B3 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 32 is a drawing showing the preparation of 4-hydroxycoumarin derivative B3 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 33 is a drawing showing the preparation of 4-hydroxycoumarin derivative intermediate b4 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 34 is a drawing showing the preparation of 4-hydroxycoumarin derivative intermediate b4 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 35 is a drawing showing the preparation of 4-hydroxycoumarin derivative B4 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 36 is a drawing showing a scheme for preparing a 4-hydroxycoumarin derivative B4 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 37 is a schematic representation of 4-methyl-7 hydroxycoumarin 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 38 is a scheme showing that 4-methyl-7 hydroxycoumarin 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 39 is a scheme showing the preparation of 4-methyl-7-hydroxycoumarin derivative intermediate c1 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 40 is a scheme showing the preparation of 4-methyl-7-hydroxycoumarin derivative intermediate c1 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 41 is a diagram showing a scheme for preparing a 4-methyl-7 hydroxycoumarin derivative C1 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 42 is a drawing showing the synthesis of 4-methyl-7 hydroxycoumarin derivative C1 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 43 is a scheme showing that 4-methyl-7 hydroxycoumarin derivative intermediate c2 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 44 is a scheme showing the preparation of 4-methyl-7 hydroxycoumarin derivative intermediate c2 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 45 is a drawing showing the synthesis of 4-methyl-7 hydroxycoumarin derivative C2 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 46 is a drawing showing the synthesis of 4-methyl-7 hydroxycoumarin derivative C2 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 47 is a drawing showing the preparation of 4-methyl-7 hydroxycoumarin derivative intermediate c3 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 48 is a scheme showing that 4-methyl-7 hydroxycoumarin derivative intermediate c3 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 49 is a drawing showing the synthesis of 4-methyl-7 hydroxycoumarin derivative C3 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 50 is a drawing showing the synthesis of 4-methyl-7 hydroxycoumarin derivative C3 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 51 is a scheme showing the preparation of 4-methyl-7-hydroxycoumarin derivative intermediate c4 1 H-NMR (600MHz, DMSO-d 6) spectrum; FIG. 52 is a scheme showing the synthesis of 4-methyl-7-hydroxycoumarin derivative intermediate c4 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 53 is a drawing showing the synthesis of 4-methyl-7 hydroxycoumarin derivative C4 1 H-NMR (600MHz, DMSO-d 6) spectrum; drawing (A)54 is 4-methyl-7 hydroxycoumarin derivative C4 13 C-NMR (151MHz, DMSO-d 6) spectrum; FIG. 55 is a graph showing the inhibition rate of 4-hydroxycoumarin derivative B4 on HepG2 cell (human hepatoma cell) proliferation; FIG. 56 is a graph showing the inhibition rate of 4-methyl-7 hydroxycoumarin derivative C3 on the proliferation of A2780 cells (human ovarian cancer cells).
Detailed Description
It will be understood by those of ordinary skill in the art that the foregoing embodiments are specific examples of practicing the invention, and that various changes in form and detail may be made therein without departing from the spirit and scope of the invention in practice.
To make the objects, aspects and advantages of the embodiments of the present invention more apparent, the following detailed description clearly illustrates the spirit of the disclosure, and any person skilled in the art, after understanding the embodiments of the disclosure, may make changes and modifications to the technology taught by the disclosure without departing from the spirit and scope of the disclosure.
The exemplary embodiments of the present invention and the description thereof are provided to explain the present invention and not to limit the present invention.
Example 1
The synthesis of the 7-hydroxycoumarin derivative of this example was as follows:
step one, synthesis of 7-hydroxycoumarin derivative intermediates (a 1, a2, a3, a 4)
Putting 3.08mmol of 7-hydroxycoumarin, 2-bromoethanol, 3-bromo-1-n-propanol, 6-bromo-1-n-hexanol and 10-bromo-1-n-decanol into a reaction bottle, respectively and sequentially adding 15.4mmol of potassium carbonate, 3.08mmol of sodium iodide and 1.54mmol of tetrabutylammonium fluoride, respectively, then respectively adding 30mL of acetone, and respectively heating at 56 ℃ for 6 hours. The reaction was monitored by TLC, and the developing solvent used in the monitoring was V (petroleum ether) = V (ethyl acetate) = 5, (via R) f The value is judged between 1.2 and 1.5, and subsequent operation is carried out), filtering is respectively carried out after the reaction is finished, and yellow oily substances (38 to 45 ℃) are respectively obtained by reduced pressure distillation. And respectively separating and purifying by a silica gel column through dry method, eluting by an eluent V (petroleum ether) = V (ethyl acetate) =10Removing the solvent (38-45 ℃ C.) to obtain white solids, namely a1, a2, a3 and a4, wherein a1 corresponds to the raw material 2-bromoethanol, a2 corresponds to the raw material 3-bromo-1-n-propanol, a3 corresponds to the raw material 6-bromo-1-n-hexanol, and a4 corresponds to the raw material 10-bromo-1-n-decanol.
Step two, synthesis of 7-hydroxycoumarin derivative final products (A1, A2, A3 and A4)
0.45mmol and 0.45mmol of lipoic acid of each intermediate (a 1, a2, a3, a 4) are respectively placed in a reaction bottle, 0.23mmol of EDCI (1-ethyl-3 (3-dimethylpropylamine) carbodiimide, the same applies below) and 0.09mmol of DMAP (4-dimethylaminopyridine, the same applies below) are respectively and sequentially added, then 10mL of dichloromethane are respectively added, the mixture is stirred at room temperature overnight, TLC is respectively used for monitoring the reaction, and a developing agent is a solvent of V (petroleum ether) = V (ethyl acetate) =10 (through R f Judging the value between 1.2 and 1.5 for subsequent operation), filtering respectively after the reaction is finished, and distilling under reduced pressure respectively to obtain viscous yellow oily matters at 38-45 ℃. And (3) respectively separating and purifying by a silica gel column through a dry method, eluting by an eluent V (petroleum ether) = V (ethyl acetate) =10, and respectively removing the solvent (38-45 ℃) under reduced pressure to obtain light yellow viscous liquid.
The 7-hydroxycoumarin derivatives of this example were structurally characterized by thin-layer chromatography TLC, nuclear magnetic 1H-NMR and nuclear magnetic 13C-NMR.
The results are as follows:
1) Starting material 1 (7-hydroxycoumarin):
nuclear magnetism of raw material 1 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ10.58(s,1H),7.94(dd,J＝9.5,1.4Hz,1H),7.54(dd,J＝8.5,1.4Hz,1H),6.80(dd,J＝8.5,1.8Hz,1H),6.73(t,J＝1.7Hz,1H),6.22(dd,J＝9.4,1.4Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ161.65,160.79,155.86,144.86,130.05,113.47,111.70(d,J＝18.2Hz),102.53.
of starting material 1 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 1; 13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 2.
2) Nuclear magnetism of intermediate a1 of 7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 Results of C-NMRThe following were used:
1 H NMR(600MHz,DMSO-d 6 )δ7.99(d,J＝9.5Hz,1H),7.63(d,J＝8.6Hz,1H),7.01–6.93(m,2H),6.29(d,J＝9.5Hz,1H),4.93(t,J＝5.5Hz,1H),4.10(t,J＝4.9Hz,2H),3.74(q,J＝5.1Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ162.30,160.67,155.76,144.71,129.84,113.13,112.79,112.65,101.56,70.71,59.72.
process for preparation of product a1 from 7-hydroxycoumarin derivatives 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 3;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 4.
3) The final product A1 of the 7-hydroxycoumarin derivative of the example is light yellow solid nuclear magnetism 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,Chloroform-d)δ7.65(d,J＝9.5Hz,1H),7.39(d,J＝8.6Hz,1H),6.90–6.81(m,2H),6.27(d,J＝9.4Hz,1H),4.49–4.44(m,2H),4.26–4.21(m,2H),3.54(t,J＝8.7Hz,1H),3.21–3.06(m,2H),2.49–2.41(m,1H),2.38(t,J＝7.4Hz,1H),1.89(t,J＝12.7,7.0Hz,1H),1.75–1.61(m,4H),1.55–1.39(m,2H),1.26(d,J＝2.1Hz,1H). 13 C NMR(151MHz,Chloroform-d)δ173.20,161.51,160.96,155.70,143.21,128.80,113.37,112.82,112.75,101.53,66.37,62.13,56.23,40.13,38.39,34.48,33.80,28.61,24.52.
process for preparation of 7-hydroxycoumarin derivatives end product A1 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 5;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 6.
The chemical structural formula is as follows:
4) Nuclear magnetism of intermediate a2 of 7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.99(d,J＝9.5Hz,1H),7.62(d,J＝8.6Hz,1H),6.99–6.92(m,2H),6.28(d,J＝9.4Hz,1H),4.59(t,J＝5.1Hz,1H),4.15(t,J＝6.3Hz,2H),3.57(q,J＝5.9Hz,2H),1.89(m,2H). 13 CNMR(151MHz,DMSO-d 6 )δ162.27,160.67,155.77,144.70,129.84,113.05,112.75,112.61,101.49,65.78,57.47,32.22.
process for preparation of 7-hydroxycoumarin derivative intermediate a2 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 7;
13 a C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 8.
5) The final product A2 of the 7-hydroxycoumarin derivative in the example is light yellow solid nuclear magnetism 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.99(d,J＝9.5Hz,1H),7.63(d,J＝8.6Hz,1H),6.99(d,J＝2.4Hz,1H),6.95(dd,J＝8.6,2.4Hz,1H),6.29(d,J＝9.5Hz,1H),4.17(t,J＝18.3Hz,4H),3.55(t,J＝8.8Hz,1H),3.16(ddd,J＝11.1,6.8,5.5Hz,1H),3.09(t,J＝11.0Hz,1H),2.38(t,J＝12.4Hz,1H),2.31(t,J＝7.3Hz,2H),2.06(m，2H),1.83(q,J＝13.4Hz,1H),1.68–1.59(m,1H),1.59–1.47(m,3H),1.41–1.29(m,2H). 13 C NMR(151MHz,DMSO-d 6 )δ173.16,161.97,160.63,155.76,144.68,129.87,113.07,112.89,112.78,101.54,65.46,60.94,56.39,40.18,38.44,34.39,33.68,28.47,28.22,24.59.
process for preparation of 7-hydroxycoumarin derivative end product A2 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 9;
13 a C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 10.
6) Nuclear magnetism of intermediate a3 of 7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.99(d,J＝9.5Hz,1H),7.62(d,J＝8.6Hz,1H),6.99–6.91(m,2H),6.28(dd,J＝9.5,1.0Hz,1H),4.38–4.30(m,1H),4.07(t,J＝6.5Hz,2H),3.40(q,J＝6.2Hz,2H),1.73(m，2H),1.47–1.34(m,6H). 13 C NMR(151MHz,DMSO-d 6 )δ162.26,160.67,155.79,144.70,129.82,113.07,112.72,112.59,101.47,68.64,61.00,32.83,28.87,25.72,25.61.
process for preparation of 7-hydroxycoumarin derivative intermediate a3 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 11;
13 a C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 12.
7) The final product A3 of the 7-hydroxycoumarin derivative in the example is light yellow solid nuclear magnetism 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.99(d,J＝9.4Hz,1H),7.62(d,J＝8.5Hz,1H),6.99–6.91(m,2H),6.28(d,J＝9.4Hz,1H),4.07(t,J＝6.5Hz,2H),4.02(t,J＝6.5Hz,2H),3.59(q,J＝8.5Hz,1H),3.17(ddd,J＝10.8,6.9,5.5Hz,1H),3.10(t,J＝10.8Hz,1H),2.40(q,J＝12.6Hz,1H),2.29(t,J＝7.3Hz,2H),1.85(q,J＝13.4Hz,1H),1.74(m,2H),1.70–1.62(m,1H),1.62–1.57(m,2H),1.57–1.47(m,3H),1.47–1.41(m,2H),1.36(ddd,J＝17.1,12.3,8.4Hz,4H),1.06(t,J＝7.0Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ173.17,162.24,160.66,155.79,144.70,129.83,113.07,112.75,112.62,101.48,68.56,64.00,56.42,40.19，38.47,34.39,33.74,28.69,28.48,28.45,25.50,25.45,24.64.
process for preparation of 7-hydroxycoumarin derivatives end product A3 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 13;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 14.
The chemical structural formula is as follows:
8) Nuclear magnetism of intermediate a4 of 7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.99(d,J＝9.5Hz,1H),7.61(d,J＝8.6Hz,1H),6.99–6.91(m,2H),6.28(d,J＝9.4Hz,1H),4.31(t,J＝5.2Hz,1H),4.06(t,J＝6.5Hz,2H),3.37(q,J＝6.3Hz,2H),1.73(m,2H),1.40(m,4H),1.32(t,J＝7.9Hz,2H),1.27(d,J＝10.8Hz,9H). 13 C NMR(151MHz,DMSO-d 6 )δ161.86,160.27,155.39,144.31,129.43,112.68,112.33,112.19,101.08,68.25,60.68,32.51,29.01,28.92,28.91,28.69,28.40,25.48,25.39.
preparation of 7-hydroxycoumarin derivative intermediate a4 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 15;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 16.
9) The final product A4 of the 7-hydroxycoumarin derivative of the example is light yellow solid nuclear magnetism 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,Chloroform-d)δ7.63(d,J＝9.4Hz,1H),7.36(d,J＝8.6Hz,1H),6.86–6.78(m,2H),6.24(d,J＝9.4Hz,1H),4.06(t,J＝6.7Hz,2H),4.01(t,J＝6.5Hz,2H),3.57(q,J＝8.6Hz,1H),3.22–3.08(m,2H),2.46(q,J＝12.4,1H),2.31(t,J＝7.4Hz,2H),1.91(q,J＝13.6Hz,1H),1.82(q,J＝7.6Hz,2H),1.76–1.58(m,7H),1.47(m,J＝22.4Hz,4H),1.39–1.29(m,9H). 13 C NMR(151MHz,Chloroform-d)δ173.50,162.33，161.18,155.83,143.35,128.60,112.90,112.83,112.27,101.23,68.56,64.41,56.27,40.14,38.40,34.53,34.04,29.36,29.34,29.21,29.13,28.88,28.69,28.55,25.86,25.83,24.65.
process for the preparation of 7-hydroxycoumarin derivatives end product A4 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 17;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 18.
The chemical structural formula is as follows:
example 2
The synthesis method of the 4-hydroxycoumarin derivative of the present example is as follows:
step one, synthesis of 4-hydroxycoumarin derivative intermediates (b 1, b2, b3, b 4)
Putting 3.08mmol of 4-hydroxycoumarin, 2-bromoethanol, 3-bromo-1-n-propanol, 6-bromo-1-n-hexanol and 10-bromo-1-n-decanol into a reaction bottle, respectively and sequentially adding 15.4mmol of potassium carbonate, 3.08mmol of sodium iodide and 1.54mmol of tetrabutylammonium fluoride, respectively, then respectively adding 30mL of acetone, and respectively heating at 56 ℃ for 6 hours. Follow-up by TLC, and the developing solvent is V (petroleum ether) = V (ethyl acetate) = 5 (by R) f The value is judged to be between 1.2 and 1.5 for subsequent operation), after the reaction is finished, the mixture is respectively filtered and respectively distilled under reduced pressure to obtain viscous yellow oily matters (38 to 45 ℃). Separating and purifying by a silica gel column respectively in a dry method, eluting V (petroleum ether) = V (ethyl acetate) =10, 10;
step two, synthesis of 4-hydroxycoumarin derivative final products (B1, B2, B3, B4)
0.45mmol and 0.45mmol of lipoic acid of each intermediate (b 1, b2, b3 and b 4) are respectively placed in a reaction bottle, 0.23mmol of EDCI and 0.09mmol of DMAP are respectively and sequentially added, then 10mL of dichloromethane are respectively added, and the mixture is stirred at room temperature overnight. The reaction was monitored by TLC, and the developing solvent was V (petroleum ether) = V (ethyl acetate) = 5 (via R) f The value is determined to be between 1.2 and 1.5 for subsequent operation), filtering respectively after the reaction is finished, and distilling under reduced pressure respectively to obtain viscous yellow oily matters (38 to 45 ℃). And (3) respectively separating and purifying by a silica gel column through a dry method, eluting by an eluent V (petroleum ether) = V (ethyl acetate) =10, and respectively removing the solvent (38-45 ℃) under reduced pressure to obtain light yellow viscous liquid.
Adopting Thin Layer Chromatography (TLC) and nuclear magnetism 1 The 4-hydroxycoumarin derivative of this example was structurally identified by H-NMR and nuclear magnetic 13C-NMR methods.
The results are as follows:
1) Raw material 2 (4-hydroxycoumarin):
nuclear magnetism of raw material 2 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ12.52(s,1H),7.84(dd,J＝7.9,1.3Hz,1H),7.65(dd,J＝7.8,7.2,1.4Hz,1H),7.40–7.33(m,2H),5.62(d,J＝1.0Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ165.98,162.23,153.88,133.04,124.26,123.55,116.72,116.16,91.37,39.89.
of starting materials 2 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 19; 13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 20.
2) Nuclear magnetism of intermediate b1 of 4-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.92(dd,J＝7.9,1.6Hz,1H),7.67(ddd,J＝8.7,7.2,1.6Hz,1H),7.43–7.35(m,2H),5.90(s,1H),5.08(t,J＝5.8Hz,1H),4.23(t,J＝4.6Hz,2H),3.85–3.79(m,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.13,161.64,152.73,132.70,124.03,123.13,116.36,115.25,90.47,71.46,58.91.
process for preparing 4-hydroxycoumarin derivative intermediate b1 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 21;
13 a C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 22.
3) Nuclear magnetism of final product B1 of 4-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,Chloroform-d)δ7.82(dd,J＝7.9,1.6Hz,1H),7.57(ddd,J＝8.6,7.3,1.6Hz,1H),7.35–7.28(m,2H),5.69(s,1H),4.59–4.55(m,2H),4.36–4.31(m,2H),3.52(q,J＝8.6Hz,1H),3.20–3.14(m,1H),3.14–3.05(m,1H),2.46–2.37(m,3H),1.87(q,J＝12.6Hz,1H),1.72–1.63(m,4H),1.54–1.41(m,2H). 13 C NMR(151MHz,Chloroform-d)δ173.09,165.17,162.50,153.25,132.52,123.94,122.99,116.72,115.33,90.71,67.11,61.31,56.19,40.13,38.39,34.46,33.78,28.60,24.53.
process for preparing 4-hydroxycoumarin derivatives as end products B1 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 23;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 24.
The chemical structural formula of the final product B1 of the 4-hydroxycoumarin derivative is as follows:
4) Nuclear magnetism of intermediate b2 of 4-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.82(dd,J＝7.8,1.6Hz,1H),7.69–7.63(m,1H),7.42–7.34(m,2H),5.90(s,1H),4.64(t,J＝5.2Hz,1H),4.29(t,J＝6.2Hz,2H),3.62(q,J＝5.9Hz,2H),1.97(m,2H). 13 C NMR(151MHz,DMSO-d 6 )δ165.39,162.03,153.12,133.09,124.54,123.22,116.81,115.65,90.81,66.94,57.33,31.74.
process for preparing 4-hydroxycoumarin derivative intermediate b2 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 25;
13 a C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 26.
5) Nuclear magnetism of final product B2 of 4-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,Chloroform-d)δ7.81(dd,J＝7.9,1.6Hz,1H),7.56(ddd,J＝8.7,7.3,1.6Hz,1H),7.34–7.27(m,2H),5.70(s,1H),4.32(t,J＝6.2Hz,2H),4.23(t,J＝6.1Hz,2H),3.55(q,J＝8.7Hz,1H),3.21–3.07(m,2H),2.45(m,1H),2.34(t,J＝7.5Hz,2H),2.26(m,2H),1.90(q,J＝12.7Hz,1H),1.73–1.61(m,4H),1.54–1.38(m,2H). 13 C NMR(151MHz,Chloroform-d)δ173.25,165.31,162.71,153.25,132.42,123.86,122.84,116.75,115.48,90.60,65.72,60.42,56.24,40.16,38.40,34.48,33.88,28.66,27.92,24.55.
process for preparing 4-hydroxycoumarin derivatives as end products B2 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 27;
13 a C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 28.
The chemical structural formula of the final product B2 of the 4-hydroxycoumarin derivative is as follows:
6) Nuclear magnetism of intermediate b3 of 4-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13
The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.81(dd,J＝7.9,1.6Hz,1H),7.66(dd,J＝15.6,1.6Hz,1H),7.42–7.34(m,2H),5.89(s,1H),4.36(t,J＝5.1Hz,1H),4.21(t,J＝6.4Hz,2H),3.44–3.29(m,1H),1.83(m,2H),1.46(m,4H),1.39(q,J＝8.1Hz,2H),1.29–1.21(m,1H). 13 C NMR(151MHz,DMSO-d 6 )δ164.94,161.63,152.73,132.67,124.16,122.75,116.42,115.25,90.42,69.43,60.59,32.38,27.97,25.28,25.14.
process for preparing 4-hydroxycoumarin derivative intermediate b3 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 29;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 30.
7) Nuclear magnetism of final product B3 of 4-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,Chloroform-d)δ7.82(dd,J＝7.9,1.6Hz,1H),7.55(ddd,J＝8.7,7.3,1.7Hz,1H),7.34–7.26(m,2H),5.67(s,1H),4.12(t,J＝22.6Hz,3H),3.57(q,J＝8.7Hz,1H),3.22–3.08(m,2H),2.46(m,1H),2.32(t,J＝7.4Hz,2H),1.97–1.86(m,3H),1.76–1.40(m,12H),1.26(s,1H). 13 C NMR(151MHz,Chloroform-d)δ173.48,165.58,162.93,132.28,123.78,122.89,116.73,115.70,90.35,69.13,64.09,56.29,40.16,38.41,34.53,34.01,28.70,28.48,28.34,25.61,25.60,24.63,24.36.
process for preparing 4-hydroxycoumarin derivative end product B3 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 31;
13 a C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 32.
The chemical structural formula of the final product B3 of the 4-hydroxycoumarin derivative is as follows:
8) Nuclear magnetism of intermediate b4 of 4-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.80(dd,J＝7.9,1.6Hz,1H),7.69–7.62(m,1H),7.42–7.33(m,2H),5.89(s,1H),4.31(t,J＝5.1Hz,1H),4.21(t,J＝6.4Hz,2H),3.37(q,J＝6.3Hz,1H),1.82(m,2H),1.46(m,2H),1.37(t,J＝26.3Hz,4H),1.27(q,J＝4.4Hz,9H). 13 C NMR(151MHz,DMSO-d 6 )δ165.34,162.03,153.14,133.08,124.56,123.12,116.84,115.65,90.84,69.86,61.08,32.92,29.40,29.31,29.28,29.00,28.29,25.89,25.77.
process for preparation of 4-hydroxycoumarin derivative intermediate b4 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 33;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 34.
9) Nuclear magnetism of final product B4 of 4-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.79(dd,J＝7.9,1.5Hz,1H),7.69–7.62(m,1H),7.42–7.33(m,2H),5.88(s,1H),4.20(t,J＝6.3Hz,2H),3.99(t,J＝6.6Hz,2H),3.58(q,J＝8.7Hz,1H),3.17(t,J＝12.0Hz,1H),3.10(t,J＝11.0Hz,1H),2.40(q,J＝12.4Hz,1H),2.28(t,J＝7.3Hz,2H),1.84(t,J＝23.8Hz,3H),1.65(ddd,J＝14.0,11.2,6.0Hz,1H),1.54(m,5H),1.45(q,J＝7.9Hz,2H),1.41–1.35(m,2H),1.35–1.29(m,4H),1.27(s,6H). 13 C NMR(151MHz,DMSO-d 6 )δ173.10,165.30,161.98,153.14,133.03,124.48,123.08,116.81,115.64,90.81,69.83,64.03,64.03,56.41,38.46,38.46,34.41,33.75,29.23,28.99,28.99,28.52,28.48,28.31,25.77,25.77,24.66.
process for preparing 4-hydroxycoumarin derivatives as end products B4 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 35;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 36.
The chemical structural formula of the final product B4 of the 4-hydroxycoumarin derivative is as follows:
example 3
The synthesis method of the 4-methyl-7-hydroxycoumarin derivative of the present example comprises:
step one, synthesis of 4-methyl-7-hydroxycoumarin derivative intermediates (c 1, c2, c3, c 4)
Putting 2.84mmol of 4-methyl-7-hydroxycoumarin and 2-bromoethanol, 3-bromo-1-n-propanol, 6-bromo-1-n-hexanol and 10-bromo-1-n-decanol respectively into a reaction bottle, sequentially adding 14.20mmol of potassium carbonate, 2.84mmol of sodium iodide and 1.42mmol of tetrabutylammonium fluoride respectively, adding 30ml of acetone respectively, and heating at 56 ℃ for 6 hours respectively. The reaction was monitored by TLC, V (petroleum ether) = 5 (via R) f The value is determined to be between 1.2 and 1.5 for subsequent operation), filtering respectively after the reaction is finished, and distilling under reduced pressure respectively to obtain viscous yellow oily matters (38 to 45 ℃). Separating and purifying by a silica gel column respectively in a dry method, eluting V (petroleum ether) =10, 2 and 10;
step two, synthesis of 4-methyl-7-hydroxycoumarin derivative final products (C1, C2, C3 and C4)
0.30mmol of each intermediate (c 1, c2, c3 and c 4) and 0.30mmol of lipoic acid are respectively placed in a reaction bottle, 0.15mmol of EDCI and 0.06mmol of DMAP are respectively and sequentially added, then 10ml of dichloromethane are respectively added, and the mixture is stirred at room temperature overnight. The reaction was monitored by TLC, V (petroleum ether) = 5 (via R) f The value is determined to be between 1.2 and 1.5 for subsequent operation), filtering respectively after the reaction is finished, and distilling under reduced pressure respectively to obtain viscous yellow oily matters (38 to 45 ℃). And respectively performing separation and purification on the mixture by a silica gel column through a dry method, eluting an eluent V (petroleum ether) = V (ethyl acetate) =10, and respectively removing the solvent under reduced pressure (38-45 ℃) to obtain light yellow viscous liquid.
Adopting Thin Layer Chromatography (TLC) and nuclear magnetism 1 H-NMR and nuclear magnetism 13 C-NMR method for 4-methyl-7-hydroxy group of this example
And carrying out structural identification on the coumarin derivative.
The results are as follows:
1) Starting material 3 (4-methyl-7 hydroxycoumarin):
nuclear magnetic of raw material 3 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ10.53(s,1H),7.62–7.54(m,1H),6.82(dd,J＝8.8,2.2Hz,1H),6.72(t,J＝2.2Hz,1H),6.12(s,1H),2.37(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ161.48,160.61,155.16,153.74,126.82,113.16,112.33,110.59,102.51,18.42.
of starting materials 3 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 37; 13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 38.
2) Nuclear magnetism of intermediate c1 of 4-methyl-7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.71–7.66(m,1H),6.97(d,J＝7.4Hz,2H),6.21(s,1H),4.93(t,J＝5.5Hz,1H),4.10(t,J＝4.9Hz,2H),3.74(q,J＝5.1Hz,2H),2.40(s,3H). 13 C NMR(151MHz,DMSO-d 6 )δ161.80,160.13,154.70,153.40,126.41,113.01,112.42,111.05,101.17,70.28,59.33,18.10.
process for preparing 4-methyl-7-hydroxycoumarin derivative intermediate c1 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 39;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 40.
3) Nuclear magnetic 1H-NMR and nuclear magnetic 13C-NMR of final product C1 of 4-methyl-7-hydroxycoumarin derivative in this example
The results are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.68(d,J＝8.7Hz,1H),7.03–6.96(m,2H),6.22(s,1H),4.41–4.36(m,2H),4.36–4.29(m,2H),3.59–3.51(m,1H),3.12(d,J＝32.7Hz,2H),2.44(s,1H),2.40(s,3H),2.34(t,J＝7.4Hz,2H),1.83(dd,J＝12.9,6.6Hz,1H),1.65–1.61(m,1H),1.53(m,4H),1.36(d,J＝7.6Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ173.09,161.60,160.46,155.05,153.71,126.87,113.71,112.78,111.67,101.71,66.91,62.50,56.40,40.23,38.44,34.38,33.60,28.41,24.58,18.51.
process for preparing 4-methyl-7-hydroxycoumarin derivative end product C1 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 41;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 42.
The chemical structural formula of the final product C1 of the 4-methyl-7-hydroxycoumarin derivative is as follows:
4) Nuclear magnetism of final product c2 of 4-methyl-7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 C-NMR
The results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.67(d,J＝9.5Hz,1H),6.96(dq,J＝4.4,2.4Hz,2H),6.20(d,J＝1.7Hz,1H),4.59(t,J＝5.2Hz,1H),4.15(t,J＝6.4Hz,2H),3.57(q,J＝5.9Hz,2H),2.41–2.38(m,3H),1.89(p,J＝6.3Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ161.75,160.13,154.71,153.37,126.39,112.96,112.33,111.02,101.10,65.35,57.08,31.83,18.09.
process for preparing 4-methyl-7-hydroxycoumarin derivative intermediate c2 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 43;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 44.
5) Nuclear magnetic 1H-NMR and nuclear magnetic 13C-NMR of the final product C2 of the 4-methyl-7-hydroxycoumarin derivative of this example
The results are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.68(d,J＝8.6Hz,1H),7.00–6.94(m,2H),6.21(s,1H),4.17(t,J＝17.8Hz,4H),3.55(q,J＝8.7Hz,1H),3.21–3.14(m,1H),3.09(t,J＝11.0Hz,1H),2.40(s,3H),2.31(t,J＝7.3Hz,2H),2.10–1.98(m,2H),1.84(q,J＝13.4Hz,1H),1.67–1.60(m,1H),1.52(m,4H),1.35(q,J＝7.4Hz,2H). 13 C NMR(151MHz,DMSO-d 6 )δ173.16,161.88,160.49,155.11,153.76,126.85,113.55,112.79,111.55,101.56,65.43,60.94,40.29,56.39,38.44,34.39,33.69,28.47,28.22,24.59,18.51.
process for preparing 4-methyl-7-hydroxycoumarin derivative end product C2 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 45; 13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 46
The chemical structural formula of the final product C2 of the 4-methyl-7-hydroxycoumarin derivative is as follows:
6) Nuclear magnetism of final product c3 of 4-methyl-7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.69–7.64(m,1H),6.97–6.92(m,2H),6.20(d,J＝1.5Hz,1H),4.34(t,J＝19.5Hz,1H),4.08(t,J＝20.9Hz,2H),3.40(d,J＝6.5,5.2Hz,2H),3.18(d,J＝5.2Hz,1H),2.39(d,J＝1.3Hz,2H),1.73(m,2H),1.43(m,4H),1.38–1.31(m,2H),1.27(m,J＝3.5Hz,1H). 13 C NMR(151MHz,DMSO-d 6 )δ161.74,160.12,154.72,153.37,126.37,112.94,112.37,110.99,101.07,68.20,60.60,32.42,28.47,25.31,25.22,18.08.
process for preparing 4-methyl-7-hydroxycoumarin derivative intermediate c3 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 47;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 48.
7) Nuclear magnetism of final product C3 of 4-methyl-7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.66(s,1H),6.95(d,J＝9.9Hz,2H),6.20(d,J＝7.3Hz,1H),4.02(t,J＝6.2Hz,2H),3.58(q,J＝11.9Hz,1H),3.33(s,1H),3.18(q,J＝12.0Hz,1H),3.15–3.06(m,1H),2.58–2.48(m,1H),2.29(q,J＝6.8Hz,2H),1.85(t,J＝12.9Hz,1H),1.74(m,2H),1.68–1.63(m,1H),1.63–1.48(m,7H),1.44(q,J＝7.5Hz,3H),1.41–1.34(m,5H). 13 C NMR(151MHz,DMSO-d 6 )δ173.15,162.12,160.50,155.13,153.72,126.75,113.36,112.77,112.75,111.42,101.47,68.52,64.00,56.42,38.47,34.40,33.74,28.70,28.48,28.45,25.52,25.46,24.64,18.49.
process for preparing 4-methyl-7-hydroxycoumarin derivative end product C3 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 49;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 50.
The chemical structural formula of the final product C3 of the 4-methyl-7-hydroxycoumarin derivative is as follows:
8) Nuclear magnetism of final product c4 of 4-methyl-7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 C-NMR
The results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.67(d,J＝8.5Hz,1H),6.96(s,2H),6.20(d,J＝1.5Hz,1H),4.31(t,J＝5.2Hz,1H),4.07(t,J＝6.5Hz,2H),3.37(d,J＝6.5,5.1Hz,2H),2.39(d,J＝1.2Hz,3H),1.74–1.71(m,1H),1.45–1.21(m,15H). 13 C NMR(151MHz,DMSO-d 6 )δ162.16,160.53,155.14,153.76,126.79,112.79,111.41,101.50,68.62,61.08,61.08,32.92,29.41,29.33,29.32,29.10,28.81,25.88,25.79,18.50.
process for preparing 4-methyl-7-hydroxycoumarin derivative intermediate c4 1 An H-NMR (600MHz, DMSO-d 6) spectrum was as shown in FIG. 51;
13 the C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 52.
9) Nuclear magnetism of the final product C4 of the 4-methyl-7-hydroxycoumarin derivative of this example 1 H-NMR and nuclear magnetism 13 The C-NMR results were as follows:
1 H NMR(600MHz,DMSO-d 6 )δ7.67(d,J＝8.5Hz,1H),6.97–6.92(m,2H),6.20(s,1H),4.06(t,J＝6.5Hz,2H),3.99(t,J＝6.6Hz,2H),3.59(q,J＝8.5Hz,1H),3.21–3.07(m,2H),2.44–2.36(m,4H),2.29(t,J＝7.3Hz,2H),1.85(q,J＝13.5Hz,1H),1.77–1.61(m,3H),1.60–1.47(m,5H),1.44–1.25(m,14H). 13 C NMR(151MHz,DMSO-d 6 )δ173.15,162.15,160.52,155.14,153.76,126.78,113.36,112.78,111.41,101.49,68.62,64.05,56.43,40.27,38.47,34.41,33.75,29.26,29.23,29.06,28.98,28.81,28.51,28.48,25.78,25.76,24.66,18.50.
4-methyl-7-hydroxycoumarin derivative end product C4 1 The H-NMR (600MHz, DMSO-d 6) spectrum is shown in FIG. 53;
13 a C-NMR (151MHz, DMSO-d 6) spectrum is shown in FIG. 54.
The chemical structural formula of the final product C4 of the 4-methyl-7-hydroxycoumarin derivative is as follows:
example 4
In vitro antitumor Activity assay (MTT) was performed on the 4-hydroxycoumarin derivative final product B4 of example 2, and the 4-methyl-7-hydroxycoumarin derivative final product C3 of example 3
1) Cell culture
HepG2 cells (human hepatoma cells) and A2780 cells (human ovarian carcinoma cells) were removed from liquid nitrogen, placed in a 37 ℃ water bath and thawed by gentle shaking. The mixture was transferred to a 15mL centrifuge tube, 4mL of the prepared 10% culture medium was added thereto, and the mixture was centrifuged at 2000 rpm for 3 minutes, and the supernatant was discarded. After adding the culture medium containing the double antibody, the cells were suspended and transferred to a cell culture flask. Gently left and right to distribute the cells evenly, at 37 ℃ C. And 5% CO 2 And incubating in an incubator with saturated humidity.
2) CCK8 method for detecting cell viability
Digesting and counting cultured adherent cells HepG2 and adjusting the cell density to 3000/mL, wherein the total amount of culture solution in each hole200. Mu.l were inoculated into 96-well plates. Culturing until the cell monolayer is paved on the bottom layer of a 96-well plate, and taking the cell monolayer as an administration group; adding target compound B4 dissolved in dimethyl sulfoxide (DMSO) (content of 0.1%) to HepG2 cell administration group at concentrations of 3.125, 6.25, 12.5, 25, 50, 100 (μ M), and DMSO should not exceed 0.10% of the total volume; the concentration of target compound C3 dissolved in dimethyl sulfoxide (DMSO) was 3.125, 6.25, 12.5, 25, 50, 100 (μ M), and DMSO could not exceed 0.10% of the total volume, added to the a2780 cell administration group. 8 parallel wells were set for each concentration of target compounds B4 and C3. Setting a blank group: only 10.00% of the culture medium was added, and the control group: and (4) culturing normal group cells. Positive control group: 5-Fluorouracil was added to each administration group. The 96-well plate was incubated in an incubator for 24 hours. Mu.l of CCK8 solution (5 mg/mL) was added to each of the auxiliary wells, and the incubation was continued in an incubator for 2 hours, to terminate the incubation. The absorbance (OD) of each well at 490nm was measured using an enzyme linked immunosorbent assay. Then, the inhibition rate of the target compound on HepG2 cells and A2780 cells is calculated respectively. The absorbance (OD) of each well at 490nm was measured using an enzyme linked immunosorbent assay. Then respectively calculating the proliferation inhibition rate and IC of the target compound on HepG2 and A2780 cells 50 The value is obtained.
3) Experimental results of antitumor activity of coumarin derivatives
The absorbance value (OD value) at 490nm was measured by an enzyme-linked immunosorbent assay and the inhibition was calculated.
The results are as follows:
1) The inhibition results of the final product B4 of the 4-hydroxycoumarin derivative on HepG2 cells are shown in FIG. 55. From the data in the figure, the inhibitory effect of compound B4 on HepG2 cells at concentrations of 3.125, 6.25, 12.5, 25, 50, and 100 (μ M) increased with increasing concentration, and the inhibitory effect increased in a gradient. The inhibition rates are respectively 22.27 +/-3.32, 24.36 +/-4.05, 27.00 +/-4.52, 33.11 +/-3.04, 50.24 +/-4.55 and 52.90 +/-4.49 percent, and p<0.05. IC of Compound B4 50 76.53 μ M, positive control drug5-Fluorouracil IC 50 108.50μM。
2) The inhibition result of the final product C3 of the 4-methyl-7-hydroxycoumarin derivative on A2780 cells is shown in FIG. 56. As can be seen from the data in the figure, the inhibitory effect of compound C3 on a2780 cells at concentrations of 3.125, 6.25, 12.5, 25, 50, and 100 (μ M) increased with increasing concentration, and the inhibitory effect increased in a gradient manner. The inhibition rates are respectively 0.83 + -12.31%, 20.19 + -11.92%, 40.75 + -4.26%, 52.84 + -6.59%, 57.92 + -7.87%, 54.93 + -6.17%, p<0.05. IC of Compound C3 50 32.92. Mu.M, positive control 5-Fluorouracil IC 50 35.42μM。
According to the results, the coumarin has strong antitumor activity but has high cytotoxicity, the lipoic acid inhibits the proliferation of tumor cells and has small influence on normal cells, the coumarin and the hydrogen sulfide are coupled to obtain a series of novel coumarin derivatives, the hydroxyl position of the coumarin parent nucleus is taken as an active site, the carboxyl group on the lipoic acid is taken as another active site, and the coupling reaction is carried out through different bromoalcohols, so that the limitations of two prodrugs are overcome, the antitumor effect is enhanced, and the toxicity on the normal cells is reduced.
The 12 new compounds synthesized for the first time show the effect of inhibiting the growth of tumor cells HepG2 and A2780. The IC50 values of the compounds C3 and B4 on A2780 and HepG2 cells are respectively better than that of a positive control drug 5-fluorouracil.
Claims (6)
1. The coumarin compound is characterized in that the coumarin compound is a 4-hydroxycoumarin derivative, and the chemical structural formula of the 4-hydroxycoumarin derivative is as follows:
2. the use of a coumarin according to claim 1 in the manufacture of a medicament for the inhibition of tumour proliferation.
3. The method for synthesizing coumarin compounds according to claim 1, which comprises the following steps:
step one, 4-hydroxycoumarin derivative intermediate
Putting 4-hydroxycoumarin and bromohydrin in a reaction bottle, sequentially adding potassium carbonate, sodium iodide and tetrabutylammonium fluoride, uniformly mixing, adding acetone, uniformly mixing, and reacting for 5.5-7.5 h at the reaction temperature of 52-62 ℃; distilling under reduced pressure to obtain viscous yellow oil; separating and purifying the viscous yellow oily substance by a silica gel column by adopting a dry method, and removing the solvent under reduced pressure to obtain a white solid, namely the 4-hydroxycoumarin derivative intermediate;
placing the 4-hydroxycoumarin derivative intermediate and lipoic acid in a reaction bottle, sequentially adding EDCI and DMAP, uniformly mixing, adding dichloromethane, and stirring at room temperature for overnight reaction; filtering after the reaction is finished, distilling under reduced pressure to obtain viscous yellow oily matter, separating and purifying the obtained viscous yellow oily matter through a silica gel column by a dry method, and removing the solvent under reduced pressure to obtain light yellow viscous liquid, namely the 4-hydroxycoumarin derivative;
wherein, the molar ratio of the 4-hydroxycoumarin to the bromohydrin, the potassium carbonate, the sodium iodide and the tetrabutylammonium fluoride is 1.5-2.5; the molar volume ratio of the 4-hydroxycoumarin to the acetone is 1mol; the molar ratio of the 4-hydroxycoumarin derivative intermediate to the lipoic acid, EDCI and DMAP is 1; the molar volume ratio of the 4-hydroxycoumarin derivative intermediate to dichloromethane is 1mol; the bromohydrin is 10-bromo-1-n-decanol.
4. The coumarin compound is characterized in that the coumarin compound is a 4-methyl-7-hydroxycoumarin derivative, and the chemical structural formula of the 4-methyl-7-hydroxycoumarin derivative is as follows:
5. use of a coumarin as claimed in claim 4 in the manufacture of a medicament for the inhibition of tumour proliferation.
6. The method for synthesizing coumarin compounds according to claim 4, characterized by comprising the following steps:
step one, 4-methyl-7-hydroxycoumarin derivative intermediate
Putting 4-methyl-7-hydroxycoumarin and bromohydrin in a reaction bottle, sequentially adding potassium carbonate, sodium iodide and tetrabutylammonium fluoride, uniformly mixing, adding acetone, uniformly mixing, and reacting at 52-62 ℃ for 5.5-7.5 h; distilling under reduced pressure to obtain viscous yellow oil; separating and purifying the viscous yellow oily substance by a silica gel column by adopting a dry method, and removing the solvent under reduced pressure to obtain a white solid, namely the 4-methyl-7-hydroxycoumarin derivative intermediate;
step two, putting the 4-methyl-7-hydroxycoumarin derivative intermediate and lipoic acid into a reaction bottle, sequentially adding EDCI and DMAP, uniformly mixing, adding dichloromethane, and stirring at room temperature for overnight reaction; filtering after the reaction is finished, distilling under reduced pressure to obtain viscous yellow oily matter, separating and purifying the obtained viscous yellow oily matter through a silica gel column by a dry method, and removing the solvent under reduced pressure to obtain light yellow viscous liquid, namely the 4-methyl-7-hydroxycoumarin derivative;
wherein the molar ratio of the 4-methyl-7-hydroxycoumarin to the bromohydrin, the potassium carbonate, the sodium iodide and the tetrabutylammonium fluoride is 1.5-2.5; the molar volume ratio of the 4-methyl-7-hydroxycoumarin to the acetone is 1mol; the mol ratio of the 4-methyl-7-hydroxycoumarin derivative intermediate to the lipoic acid, EDCI and DMAP is 1; the molar volume ratio of the 4-methyl-7-hydroxycoumarin derivative intermediate to dichloromethane is 1mol; the bromohydrin is 6-bromo-1-n-hexanol.
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