CN106279083B - A kind of furocoumarin analog derivative and preparation method thereof - Google Patents

A kind of furocoumarin analog derivative and preparation method thereof Download PDF

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CN106279083B
CN106279083B CN201610629772.0A CN201610629772A CN106279083B CN 106279083 B CN106279083 B CN 106279083B CN 201610629772 A CN201610629772 A CN 201610629772A CN 106279083 B CN106279083 B CN 106279083B
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methyl
oxygen
furocoumarin
furans
formaldehyde
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CN106279083A (en
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吴军
何兴瑞
娄永根
商志才
顾海宁
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Zhejiang University ZJU
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Abstract

The present invention relates to field of medicaments, it is desirable to provide a kind of furocoumarin analog derivative and preparation method thereof.This kind of furocoumarin analog derivative is furan nucleus by methyl substituted furocoumarin analog derivative；The furocoumarin analog derivative the preparation method comprises the following steps: disubstituted-4-hydroxy -3- methyl benzofuran -5- formaldehyde,Weak base is dispersed in reaction dissolvent a, obtains raw mixture, then at 70 DEG C, is reacted 1~3 hour, filtering reacting liquid obtains sediment, and the sediment after washing is furocoumarin analog derivative.Furocoumarin analog derivative of the invention is a kind of Isopsoralen analog with new skeleton, with potential pharmaceutical activity, the preparation of such compound can be studied for the pharmaceutical activity of furocoumarin class and provide support, and preparation method step provided by the invention is simple, and loss late is low.

Description

A kind of furocoumarin analog derivative and preparation method thereof
Technical field
The present invention relates to field of medicaments, in particular to a kind of furocoumarin analog derivative and preparation method thereof.
Background technique
Furocoumarin is widespread in nature, China's traditional Chinese medicine root of Dahurain angelica, Radix Angelicae Pubescentis, the root of purple-flowered peucedanum, Radix Angelicae Sinensis, psoralea corylifolia Deng, and a variety of medicinal plants of external report contain furocoumarin compound.Furocoumarin has various medicines Reason activity, be mainly manifested in antitumor, AntiHIV1 RT activity, anti-oxidant, photochemical effect, resisting pathogenic microbes, anti-inflammatory and antalgic, antidepression, And influence to drug metabolic enzyme etc..Wherein, angular furocoumarin Isopsoralen (isopsoralen) has tool There is the effects of stronger optical sensibilization and calmness, spasmolysis, hemostasis, is treatment leucoderma, alopecia areata, psoriasis and tumor sample skin The active drug of disease.Isopsoralen has to be lost with proliferation as estrogens, the endocrine that body is adjusted Tune state is to achieve the effect that alleviate climacteric syndrome.
Methyl substituted furan ring structure is widely present in natural products, and has the bioactivity of multiplicity, such as red Ginseng ketone can treat cardiovascular disease, and furans Buddhist art alkane has Allelopathic Effect in Plants, and sesquiterpenoids cacalol has anti- The effect of hyperglycemia and antibacterial.
Therefore furan nucleus has potential pharmaceutical activity, and such by methyl substituted Isopsoralen and its derivative Compound is not reported yet so far.
Summary of the invention
It is a primary object of the present invention to overcome deficiency in the prior art, a kind of furan nucleus is provided by methyl substituted furan It mutters coumarin derivatives and preparation method thereof.In order to solve the above technical problems, solution of the invention is:
A kind of furocoumarin analog derivative is provided, shown in structural formula such as following formula (I):
Wherein, R is methyl, ethyl, ethyoxyl, propyl, isopropyl, phenyl, 3,4- Dimethoxyphenyl or 4- pyridyl group.
In the present invention, following compounds: 3- acetyl group -9- methyl -2H- furans [2,3-h] chromene-are specifically included 2- ketone, 9- methyl -2- oxygen -2H- furans [2,3-h] chromene -3- Ethyl formate, 9- methyl -3- propiono -2H- furans [2, 3-h] chromen-2-one, 3- isobutyryl -9- methyl -2H- furans [2,3-h] chromen-2-one, 3- bytyry -9- first Base -2H- furans [2,3-h] chromen-2-one, 3- benzoyl -9- methyl -2H- furans [2,3-h] chromen-2-one, 3- (3,4- Dimethoxybenzoyl) -9- methyl -2H- furans [2,3-h] chromen-2-one, the different nicotinoyl -9- methyl-of 3- 2H- furans [2,3-h] chromen-2-one.
The method for preparing the furocoumarin analog derivative is provided, specifically include the following steps:
(1) by 1, hydroresorcinol, potassium hydroxide are dispersed in water, and after stirring at normal temperature 5min, chloracetyl second is added Then the methanol solution of acetoacetic ester system is stirred at room temperature 5 days；Then the system hydrochloric acid of 4N is acidified, filtering acidification Reaction solution afterwards, obtained solid is product: 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formates；
Wherein, 1, hydroresorcinol, potassium hydroxide, chloroacetyl acetacetic ester molar ratio be 1:1:1；Every milliliter of water is corresponding Hydroresorcinol inventory be 0.1g；The inventory of the corresponding chloroacetyl acetacetic ester of every ml methanol is 0.2g；
(2) by the product 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formate and hydroxide of step (1) Potassium is dissolved with the mixed solvent of first alcohol and water, and reaction 5h is stirred at room temperature in system after dissolution；Then by reaction solution with 6N's Hydrochloric acid tune pH to 1, filtering reacting liquid filter resulting solid i.e. product: 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfurans - 2- formic acid；
Wherein, the volume ratio of the in the mixed solvent of the first alcohol and water, methanol and water is 2.5:1；Every ml methanol and water The corresponding 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formate of mixed solvent inventory be 0.2g；3- The molar ratio of methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formate and potassium hydroxide is 1:6；
(3) product 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- formic acid in step (2) is dispersed in two In glycol, copper powder and pyridine is added, system is then heated to 175 DEG C, is kept stirring 10h；System is cooled to room temperature, is added Ice water, and be acidified with the hydrochloric acid of 4N, the reaction solution after being acidified with petroleum ether extraction is washed with water one three times, by combined extract liquor It is secondary, it is then that extract liquor is dry with anhydrous sodium sulfate, it is spin-dried for, obtained solid is product: 3- methyl -6,7- dihydrobenzo furan It mutters -4- (5H) -one；
Wherein, the corresponding 3- methyl -4- oxygen -4,5 of every milliliter of diethylene glycol (DEG), 6,7- tetrahydrochysene benzfuran -2- formic acid feed intake Amount is 0.1g；3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- formic acid, copper powder, pyridine molar ratio be 1:1:2；
(4) under nitrogen protection, sodium hydride is dispersed in toluene solution, system is cooled to 0 DEG C, then to body The toluene solution of 3- methyl -6,7- Dihydrobenzofuranes -4 (5H) -one is added in system, keeping body ties up to 0 DEG C of stirring 30min；So The toluene solution that Ethyl formate is added (slow with 30min) in backward system, system is continued to stir 1h at 0 DEG C；Then will System is warmed to room temperature, and continues to stir 8h；End of reaction is slowly added to the aqueous ammonium chloride solution quenching reaction of saturation into system, Reaction solution is extracted with ethyl acetate 3 times, organic phase is dry with anhydrous sodium sulfate, and product can be obtained: 3- methyl -4- in concentration Oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde；
Wherein, 3- methyl -6,7- Dihydrobenzofuranes -4 (5H) -one, sodium hydride, Ethyl formate molar ratio be 1:5:3； Corresponding 3- methyl -6,7- Dihydrobenzofuranes -4 (5H) the -one inventory of every milliliter of toluene is 0.04g；
(5) the resulting product 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde of step (4) is evenly dispersed In toluene solution, chloro- 5, the 6- dicyanoquinone of 2,3- bis- is added into system, is heated to 130 DEG C of holding 6h；System is cooling To room temperature, filtering is concentrated filtrate, product can be obtained with silica gel chromatograph post separation in the filtrate after concentration: 4- hydroxy-3-methyl Benzofuran -5- formaldehyde；
Wherein, 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde, chloro- 5, the 6- dicyanoquinone of 2,3- bis- Molar ratio be 1:1.2；The corresponding 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde of every milliliter of toluene feeds intake Amount is 0.1g；
(6) by the resulting product 4- hydroxy-3-methyl benzofuran -5- formaldehyde of step (5),Weak base is uniform It is scattered in reaction dissolvent a, obtains raw mixture；
Wherein, 4- hydroxy-3-methyl benzofuran -5- formaldehyde,The molar ratio of weak base is 1:1:0.5；Often The inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of milliliter reaction dissolvent a is 0.1g；
It is describedIn, R is methyl, ethyl, ethyoxyl, propyl, isopropyl, 4- pyridyl group, 3,4- dimethoxy Phenyl or phenyl；
The weak base is piperidines or nafoxidine；
The reaction dissolvent a is ethyl alcohol or methanol；
(7) it by raw mixture made from step (6), at 70 DEG C, reacts 1~3 hour, filtering reacting liquid is precipitated Object, by precipitates washed with EtOH, the sediment after being washed is product, i.e. furocoumarin analog derivative.
In the present invention, the weak base uses piperidines.
In the present invention, the reaction dissolvent a uses ethyl alcohol.
Compared with prior art, the beneficial effects of the present invention are:
1, furocoumarin analog derivative provided by the invention is a kind of Isopsoralen analog with new skeleton, tool There is potential pharmaceutical activity, the preparation of such compound can be studied for the pharmaceutical activity of furocoumarin class provides support.
2, the preparation method of furocoumarin analog derivative provided by the invention, step of condensation is simple, and loss late is low. It is significant for industrialized production.
Detailed description of the invention
Fig. 1 is the synthesis schematic diagram of furocoumarin analog derivative.
Specific embodiment
Present invention is further described in detail with specific embodiment with reference to the accompanying drawing:
The following examples can make the professional technician of this profession that the present invention be more fully understood, but not with any side The formula limitation present invention.
Embodiment 1
By 1, hydroresorcinol and potassium hydroxide are uniformly dispersed in water, and after stirring at normal temperature 5min, chloracetyl second is added Then system is stirred at room temperature 5 days, is then acidified the system hydrochloric acid of 4N, filtering acidification by the methanol solution of acetoacetic ester Reaction solution afterwards, obtained solid is product: 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formates.It should 1 in step, the molar ratio of hydroresorcinol and potassium hydroxide and chloroacetyl acetacetic ester is 1:1:1, every milliliter of water corresponding 1, The inventory of hydroresorcinol is 0.1g, and the inventory of the corresponding chloroacetyl acetacetic ester of every ml methanol is 0.2g.The step Yield is 65%.The structure of products therefrom are as follows:
Molecular formula: C12H14O4
Chinese name: 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formate
English name: ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2- carboxylate
Molecular weight: 222.09
Appearance: white solid
Nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 4.38 (q, J=7.1Hz, 2H), 2.94 (t, J= 6.3Hz, 2H), 2.60-2.46 (m, 5H), 2.20 (p, J=6.4Hz, 2H), 1.40 (t, J=7.1Hz, 3H) ppm.
Embodiment 2
By the mixed of 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formate and potassium hydroxide first alcohol and water After dissolution reaction 5h is stirred at room temperature in system by bonding solvent dissolution.Then by the hydrochloric acid tune pH to 1 of reaction solution 6N, filtering Reaction solution, filtering resulting solid is product: 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- formic acid.The step Used in mixed solvent be that methanol and water are formulated with 2.5:1.Corresponding oxygen -4 3- methyl -4- of every milliliter of mixed solvent, The inventory of 5,6,7- tetrahydrochysene benzfuran -2- Ethyl formate is 0.2g.3- methyl -4- oxygen -4,5,6,7- tetrahydro in the step The molar ratio of coumarilic acid ethyl ester and potassium hydroxide is 1:6.The yield of the step is 90%.The structure of products therefrom are as follows:
Molecular formula: C10H10O4
Chinese name: 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- formic acid
English name: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid
Molecular weight: 194.06
Appearance: white solid
Nuclear magnetic resonance spectroscopy: (400MHz, DMSO-d6) δ 2.91 (t, J=6.2Hz, 2H), 2.44 (m, 5H),
2.08 (p, J=6.4Hz, 2H) ppm.
Embodiment 3
By 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- formic acid are uniformly scattered in diethylene glycol (DEG), and copper is added Then system is heated to 175 DEG C, is kept stirring 10h by powder and pyridine.System is cooled to room temperature, ice water is added, and with 4N's Three times, combined extract liquor is washed with water once for hydrochloric acid acidification, the reaction solution after being acidified with petroleum ether extraction, then will extraction Liquid is dry with anhydrous sodium sulfate, is spin-dried for.Resulting solid is product: 3- methyl -6,7- Dihydrobenzofuranes -4- (5H) -one. The inventory of the corresponding 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- formic acid of every milliliter of diethylene glycol (DEG) is in the step 0.1g.The molar ratio of 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- formic acid and copper powder and pyridine is 1 in the step: 1:2.The yield of the step is 85%.The structure of products therefrom are as follows:
Molecular formula: C9H10O2
Chinese name: 3- methyl -6,7- Dihydrobenzofuranes -4- (5H) -one
English name: 3-methyl-6,7-dihydrobenzofuran-4 (5H)-one
Molecular weight: 150.07
Appearance: yellow solid
Nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 7.11-6.98 (m, 1H), 2.83 (t, J=6.3Hz, 2H), 2.47 (dd, J=7.2,5.8Hz, 2H), 2.26-2.06 (m, 5H) ppm.
Carbon-13 nmr spectra (101MHz, Chloroform-d) δ 195.70,167.40,138.90,120.41,119.07, 38.29,23.63,22.75,9.07ppm。
Embodiment 4
(1) under nitrogen protection, uniformly disperse sodium hydride in toluene solution, system be cooled to 0 DEG C, then to The toluene solution of 3- methyl -6,7- Dihydrobenzofuranes -4 (5H) -one is added in system, keeping body ties up to 0 DEG C of stirring 30min. Then the toluene solution of Ethyl formate is added with 30min into system, system is continued to stir 1h at 0 DEG C.Then by system It is warmed to room temperature, continues to stir 8h.End of reaction is slowly added to the aqueous ammonium chloride solution quenching reaction of saturation into system, will be anti- Liquid is answered to be extracted with ethyl acetate 3 times, organic phase is dry with anhydrous sodium sulfate, and the product of the step: 3- methyl-can be obtained in concentration 4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde.- 4 (5H) -one of 3- methyl -6,7- Dihydrobenzofuranes and hydrogen in the step The molar ratio for changing sodium and Ethyl formate is 1:5:3, corresponding 3- methyl -6, the 7- Dihydrobenzofuranes -4 (5H)-of every milliliter of toluene Ketone inventory is 0.04g.
(2) resulting product 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde is dispersed in toluene In solution, chloro- 5, the 6- dicyanoquinone of 2,3- bis- is added into system, is heated to 130 DEG C of holding 6h.System is cooled to room Temperature, filtering are concentrated filtrate, crude product can be obtained to the product of the step: 4- hydroxy-3-methyl benzo with silica gel chromatograph post separation Furans -5- formaldehyde.3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde and the chloro- 5,6- bis- of 2,3- bis- in the step The molar ratio of cyanogen 1,4-benzoquinone is 1:1.2, the corresponding 3- methyl -4- oxygen -4,5 of every milliliter of toluene, 6,7- tetrahydrochysene benzfuran -5- first The inventory of aldehyde is 0.1g.The yield of two steps is 70%.The structure of products therefrom are as follows:
Molecular formula: C10H8O3
Chinese name: 4- hydroxy-3-methyl benzofuran -5- formaldehyde
English name: 4-hydroxy-3-methylbenzofuran-5-carbaldehyde
Molecular weight: 176.05
Appearance: yellow solid
Nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 11.97 (s, 1H), 9.87 (s, 1H), 7.37 (d, J= 8.6Hz, 1H), 7.31 (q, J=1.4Hz, 1H), 7.04 (d, J=8.6Hz, 1H), 2.41 (d, J=1.4Hz, 3H) ppm.
Carbon-13 nmr spectra (101MHz, Chloroform-d) δ 195.98,161.03,159.49,141.21,129.73, 117.71,117.00,115.28,104.85,9.46ppm。
Embodiment 5
By 4- hydroxy-3-methyl benzofuran -5- formaldehyde, ethyl acetoacetate and piperidines are dispersed in ethyl alcohol, make 4- hydroxy-3-methyl benzofuran -5- formaldehyde, the molar ratio of ethyl acetoacetate and piperidines are 1:1:0.5, every milliliter of reaction The inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of solvent is 0.1g, obtains raw mixture.Raw material is mixed Object is closed, at 70 DEG C, is reacted 3 hours, cooled and filtered, with ethanol washing, obtaining filter cake is product.Gained furocoumarin Analog derivative are as follows: 3- acetyl group -9- methyl -2H- furans [2,3-h] chromen-2-one, yield 90%, the knot of the derivative Structure are as follows:
Molecular formula: C14H10O4
Chinese name: 3- acetyl group -9- methyl -2H- furans [2,3-h] chromen-2-one
English name: 3-acetyl-9-methyl-2H-furo [2,3-h] chromen-2-one
Molecular weight: 242.06
Appearance: bright yellow solid
Nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 8.55 (s, 1H), 7.47-7.36 (m, 2H), 7.33 (d, J=8.6Hz, 1H), 2.67 (s, 3H), 2.46 (d, J=1.3Hz, 3H) ppm.
Carbon-13 nmr spectra (101MHz, Chloroform-d) δ 194.55,158.46,158.24,150.55,147.86, 141.68,124.99,120.29,116.14,115.13,111.87,108.82,29.59,8.47ppm。
Embodiment 6
By 4- hydroxy-3-methyl benzofuran -5- formaldehyde, diethyl malonate and nafoxidine are dispersed in ethyl alcohol In, so that the molar ratio of 4- hydroxy-3-methyl benzofuran -5- formaldehyde, diethyl malonate and nafoxidine is 1:1:0.5, The inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of every milliliter of reaction dissolvent is 0.1g, obtains raw material mixing Object.By raw mixture, at 70 DEG C, react 3 hours, cooled and filtered, with ethanol washing, obtaining filter cake is product.Institute Obtain furocoumarin analog derivative are as follows: 9- methyl -2- oxygen -2H- furans [2,3-h] chromene -3- Ethyl formate, yield 92%, the structure of the derivative are as follows:
Molecular formula: C15H12O5
Chinese name: 9- methyl -2- oxygen -2H- furans [2,3-h] chromene -3- Ethyl formate
English name: ethyl 9-methyl-2-oxo-2H-furo [2,3-h] chromene-3-carboxylate
Molecular weight: 272.07
Appearance: Off-white solid
Nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 8.63 (s, 1H), 7.51-7.33 (m, 3H), 4.42 (q, J=7.1Hz, 2H), 2.51 (d, J=1.4Hz, 3H), 1.43 (t, J=7.1Hz, 3H) ppm.
Carbon-13 nmr spectra (101MHz, Chloroform-d) δ 163.37,159.37,156.53,151.35,149.89, 142.64,125.27,117.18,116.16,114.93,112.43,109.58,61.76,14.27,9.51ppm。
Embodiment 7
By 4- hydroxy-3-methyl benzofuran -5- formaldehyde, Propionylacetic acid ethyl ester and piperidines are dispersed in ethyl alcohol, make 4- hydroxy-3-methyl benzofuran -5- formaldehyde, the molar ratio of Propionylacetic acid ethyl ester and piperidines are 1:1:0.5, every milliliter of reaction The inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of solvent is 0.1g, obtains raw mixture.Raw material is mixed Object is closed, at 70 DEG C, is reacted 3 hours, cooled and filtered, with ethanol washing, obtaining filter cake is product.Gained furocoumarin Analog derivative are as follows: 9- methyl -3- propiono -2H- furans [2,3-h] chromen-2-one, yield 92%, the knot of the derivative Structure are as follows:
Molecular formula: C15H12O4
Chinese name: 9- methyl -3- propiono -2H- furans [2,3-h] chromen-2-one
English name: 9-methyl-3-propionyl-2H-furo [2,3-h] chromen-2-one
Molecular weight: 256.07
Appearance: faint yellow solid
Nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 8.64 (s, 1H), 7.52-7.45 (m, 2H), 7.41 (d, J=8.6Hz, 1H), 3.19 (q, J=7.2Hz, 2H), 2.54 (d, J=1.4Hz, 3H), 1.20 (t, J=7.2Hz, 3H) ppm.
Carbon-13 nmr spectra (101MHz, Chloroform-d) δ 198.63,159.40,159.14,151.45,148.82, 142.66,125.94,121.30,117.15,116.15,112.97,109.79,36.00,9.53,8.00ppm。
Embodiment 8
By 4- hydroxy-3-methyl benzofuran -5- formaldehyde, ethyl isobutyryl and piperidines are dispersed in methanol, So that the molar ratio of 4- hydroxy-3-methyl benzofuran -5- formaldehyde, ethyl isobutyryl and piperidines be 1:1:0.5, every milliliter The inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of reaction dissolvent is 0.1g, obtains raw mixture.It will be former Expect mixture, at 70 DEG C, reacts 1 hour, cooled and filtered, with ethanol washing, obtaining filter cake is product.Gained furans is fragrant Legumin analog derivative are as follows: 3- isobutyryl -9- methyl -2H- furans [2,3-h] chromen-2-one, yield 84%, the derivative The structure of object are as follows:
Molecular formula: C16H14O4
Chinese name: 3- isobutyryl -9- methyl -2H- furans [2,3-h] chromen-2-one
English name: 3-isobutyryl-9-methyl-2H-furo [2,3-h] chromen-2-one
Molecular weight: 270.09
Appearance: faint yellow solid
Nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 8.59 (s, 1H), 7.52-7.44 (m, 2H), 7.40 (d, J=8.6Hz, 1H), 3.90 (hept, J=6.8Hz, 1H), 2.54 (d, J=1.4Hz, 3H), 1.21 (d, J=6.8Hz, 6H) ppm。
Carbon-13 nmr spectra: δ 202.41,159.33,158.82,151.40,149.21,142.66,125.77, 121.37,117.14,116.13,113.06,109.73,38.42,18.33,9.50ppm。
Embodiment 9
By 4- hydroxy-3-methyl benzofuran -5- formaldehyde, ethyl butyrylacetate and piperidines are dispersed in ethyl alcohol, make 4- hydroxy-3-methyl benzofuran -5- formaldehyde, the molar ratio of ethyl butyrylacetate and piperidines are 1:1:0.5, every milliliter of reaction The inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of solvent is 0.1g, obtains raw mixture.Raw material is mixed Object is closed, at 70 DEG C, is reacted 2 hours, cooled and filtered, with ethanol washing, obtaining filter cake is product.Gained furocoumarin Analog derivative are as follows: 3- bytyry -9- methyl -2H- furans [2,3-h] chromen-2-one, yield 86%, the knot of the derivative Structure are as follows:
Molecular formula: C16H14O4
Chinese name: 3- bytyry -9- methyl -2H- furans [2,3-h] chromen-2-one
English name: 3-butyryl-9-methyl-2H-furo [2,3-h] chromen-2-one
Molecular weight: 270.09
Appearance: faint yellow solid
Nuclear magnetic resonance spectroscopy: δ 8.62 (s, 1H), 7.52-7.44 (m, 2H), 7.41 (d, J=8.5Hz, 1H), 3.13 (t, J =7.2Hz, 2H), 2.54 (d, J=1.4Hz, 3H), 1.74 (h, J=7.4Hz, 2H), 1.01 (t, J=7.4Hz, 3H) ppm.
Carbon-13 nmr spectra: 198.14,159.39,159.11,151.46,148.80,142.66,125.92,121.53, 117.16,116.16,112.99,109.78,44.40,17.44,13.81,9.52ppm。
Embodiment 10
By 4- hydroxy-3-methyl benzofuran -5- formaldehyde, ethyl benzoylacetate and piperidines are dispersed in ethyl alcohol, So that the molar ratio of 4- hydroxy-3-methyl benzofuran -5- formaldehyde, ethyl benzoylacetate and piperidines be 1:1:0.5, every milliliter The inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of reaction dissolvent is 0.1g, obtains raw mixture.It will be former Expect mixture, at 70 DEG C, reacts 3 hours, cooled and filtered, with ethanol washing, obtaining filter cake is product.Gained furans is fragrant Legumin analog derivative are as follows: 3- benzoyl -9- methyl -2H- furans [2,3-h] chromen-2-one, yield 85%, the derivative The structure of object are as follows:
Molecular formula: C19H12O4
Chinese name: 3- benzoyl -9- methyl -2H- furans [2,3-h] chromen-2-one
English name: 3-benzoyl-9-methyl-2H-furo [2,3-h] chromen-2-one
Molecular weight: 304.07
Appearance: faint yellow solid
Nuclear magnetic resonance spectroscopy: (400MHz, DMSO-d6)δ8.55(s,1H),8.03–7.87(m,3H),7.81–7.65(m, 2H), 7.67-7.50 (m, 3H), 2.45 (d, J=1.3Hz, 3H) ppm.
Carbon-13 nmr spectra: (101MHz, DMSO-d6)δ191.78,158.10,157.80,149.96,147.11, 143.50,136.32,133.63,129.46,128.62,125.84,123.31,116.28,114.93,112.91,109.24, 9.15ppm。
Embodiment 11
By 4- hydroxy-3-methyl benzofuran -5- formaldehyde, 3,4- dimethoxybenzoyl ethyl acetate and piperidines uniformly divide It dissipates in ethyl alcohol, so that 4- hydroxy-3-methyl benzofuran -5- formaldehyde, 3,4- dimethoxybenzoyl ethyl acetate and piperidines Molar ratio be 1:1:0.5, the inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of every milliliter of reaction dissolvent is 0.1g obtains raw mixture.By raw mixture, at 70 DEG C, react 3 hours, cooled and filtered is obtained with ethanol washing It is product to filter cake.Gained furocoumarin analog derivative are as follows: 3- (3,4- Dimethoxybenzoyl) -9- methyl -2H- furan It mutters [2,3-h] chromen-2-one, yield 85%, the structure of the derivative are as follows:
Molecular formula: C19H12O4
Chinese name: 3- (3,4- Dimethoxybenzoyl) -9- methyl -2H- furans [2,3-h] chromen-2-one
English name: 3- (3,4-dimethoxybenzoyl) -9-methyl-2H-furo [2,3-h] chromen-2- one
Molecular weight: 364.09
Appearance: white solid
Nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 8.15 (s, 1H), 7.57 (d, J=2.0Hz, 1H), 7.51-7.38 (m, 4H), 6.89 (d, J=8.4Hz, 1H), 3.96 (d, J=1.6Hz, 6H), 2.58-2.53 (m, 3H) ppm.
Carbon-13 nmr spectra: δ 190.43,158.86,158.49,153.98,150.68,149.22,146.26, 142.66,129.40,125.41,124.83,124.32,117.43,116.10,112.78,111.14,109.90,109.57, 56.15,56.09,9.58ppm。
Embodiment 12
By 4- hydroxy-3-methyl benzofuran -5- formaldehyde, different nicotinoyl ethyl acetate and piperidines are dispersed in ethyl alcohol, So that the molar ratio of 4- hydroxy-3-methyl benzofuran -5- formaldehyde, different nicotinoyl ethyl acetate and piperidines be 1:1:0.5, every milliliter The inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of reaction dissolvent is 0.1g, obtains raw mixture.It will be former Expect mixture, at 70 DEG C, reacts 3 hours, cooled and filtered, with ethanol washing, obtaining filter cake is product.Gained furans is fragrant Legumin analog derivative are as follows: different nicotinoyl -9- methyl -2H- furans [2, the 3-h] chromen-2-one of 3-, yield 85%, the derivative Structure are as follows:
Molecular formula: C18H11NO4
Chinese name: different nicotinoyl -9- methyl -2H- furans [2,3-h] chromen-2-one of 3-
English name: 3-isonicotinoyl-9-methyl-2H-furo [2,3-h] chromen-2-one
Molecular weight: 305.07
Appearance: yellow solid
Nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 8.85-8.79 (m, 2H), 8.44 (s, 1H), 7.69- 7.62 (m, 2H), 7.55-7.43 (m, 3H), 2.55 (d, J=1.4Hz, 3H) ppm.
Carbon-13 nmr spectra: (101MHz, Chloroform-d) δ 191.35,159.61,158.28,151.54, 150.24,149.62,143.75,142.97,125.58,122.09,121.79,117.55,116.20,112.74,110.11, 9.51ppm。
Finally it should be noted that the above enumerated are only specific embodiments of the present invention.It is clear that the invention is not restricted to Above embodiments can also have many variations.Those skilled in the art can directly lead from present disclosure Out or all deformations for associating, it is considered as protection scope of the present invention.

Claims (4)

1. a kind of method for preparing furocoumarin analog derivative, which is characterized in that specifically include the following steps:
(1) by 1, hydroresorcinol, potassium hydroxide are dispersed in water, and after stirring at normal temperature 5min, chloroethene ethyl acetoacetic acid second is added Then the methanol solution of ester system is stirred at room temperature 5 days；Then the system hydrochloric acid of 4N is acidified, after filtering acidification Reaction solution, obtained solid is product: 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formates；
Wherein, 1, hydroresorcinol, potassium hydroxide, chloroacetyl acetacetic ester molar ratio be 1:1:1；Every milliliter of water corresponding 1, The inventory of hydroresorcinol is 0.1g；The inventory of the corresponding chloroacetyl acetacetic ester of every ml methanol is 0.2g；
(2) by product 3- methyl -4- oxygen -4,5 of step (1), 6,7- tetrahydrochysene benzfuran -2- Ethyl formates and potassium hydroxide, It is dissolved with the mixed solvent of first alcohol and water, reaction 5h is stirred at room temperature in system after dissolution；Then by the salt of reaction solution 6N Acid adjusts pH to 1, and filtering reacting liquid filters resulting solid i.e. product: 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Formic acid；
Wherein, the volume ratio of the in the mixed solvent of the first alcohol and water, methanol and water is 2.5:1；Every ml methanol and water it is mixed The inventory of the corresponding 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formate of bonding solvent is 0.2g；3- methyl- The molar ratio of 4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- Ethyl formate and potassium hydroxide is 1:6；
(3) product 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- formic acid in step (2) is dispersed in diethylene glycol (DEG) In, copper powder and pyridine is added, system is then heated to 175 DEG C, is kept stirring 10h；System is cooled to room temperature, ice is added Water, and be acidified with the hydrochloric acid of 4N, the reaction solution after being acidified with petroleum ether extraction is washed with water one three times, by combined extract liquor It is secondary, it is then that extract liquor is dry with anhydrous sodium sulfate, it is spin-dried for, obtained solid is product: 3- methyl -6,7- dihydrobenzo furan It mutters -4- (5H) -one；
Wherein, the inventory of the corresponding 3- methyl -4- oxygen -4,5 of every milliliter of diethylene glycol (DEG), 6,7- tetrahydrochysene benzfuran -2- formic acid is 0.1g；3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -2- formic acid, copper powder, pyridine molar ratio be 1:1:2；
(4) under nitrogen protection, sodium hydride is dispersed in toluene solution, system is cooled to 0 DEG C, then into system The toluene solution of 3- methyl -6,7- Dihydrobenzofuranes -4 (5H) -one is added, keeping body ties up to 0 DEG C of stirring 30min；Then to The toluene solution of Ethyl formate is added in system, system is continued to stir 1h at 0 DEG C；Then system is warmed to room temperature, is continued Stir 8h；End of reaction is slowly added to the aqueous ammonium chloride solution quenching reaction of saturation into system, by reaction solution ethyl acetate Extraction 3 times, organic phase is dry with anhydrous sodium sulfate, and product can be obtained: 3- methyl -4- oxygen -4,5,6,7- tetrahydro benzos in concentration Furans -5- formaldehyde；
Wherein, 3- methyl -6,7- Dihydrobenzofuranes -4 (5H) -one, sodium hydride, Ethyl formate molar ratio be 1:5:3；Every milli Rising corresponding 3- methyl -6,7- Dihydrobenzofuranes -4 (5H) the -one inventory of toluene is 0.04g；
(5) the resulting product 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde of step (4) is dispersed in first In benzole soln, chloro- 5, the 6- dicyanoquinone of 2,3- bis- is added into system, is heated to 130 DEG C of holding 6h；System is cooled to room Temperature, filtering are concentrated filtrate, product can be obtained with silica gel chromatograph post separation in the filtrate after concentration: 4- hydroxy-3-methyl benzo Furans -5- formaldehyde；
Wherein, 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde, chloro- 5, the 6- dicyanoquinone of 2,3- bis- are rubbed You are than being 1:1.2；The inventory of the corresponding 3- methyl -4- oxygen -4,5,6,7- tetrahydrochysene benzfuran -5- formaldehyde of every milliliter of toluene is 0.1g；
(6) by the resulting product 4- hydroxy-3-methyl benzofuran -5- formaldehyde of step (5),Weak base is evenly dispersed In reaction dissolvent a, raw mixture is obtained；
Wherein, 4- hydroxy-3-methyl benzofuran -5- formaldehyde,The molar ratio of weak base is 1:1:0.5；Every milliliter The inventory of the corresponding 4- hydroxy-3-methyl benzofuran -5- formaldehyde of reaction dissolvent a is 0.1g；
It is describedIn, R is methyl, ethyl, ethyoxyl, propyl, isopropyl, 4- pyridyl group, 3,4- Dimethoxyphenyl Or phenyl；
The weak base is piperidines or nafoxidine；
The reaction dissolvent a is ethyl alcohol or methanol；
(7) it by raw mixture made from step (6), at 70 DEG C, reacting 1~3 hour, filtering reacting liquid obtains sediment, By precipitates washed with EtOH, the sediment after being washed is product, i.e. furocoumarin analog derivative；
Shown in the structural formula for the furocoumarin analog derivative being prepared such as following formula (I):
Wherein, R is methyl, ethyl, ethyoxyl, propyl, isopropyl, phenyl, 3,4- Dimethoxyphenyl or 4- pyridyl group.
2. a kind of method for preparing furocoumarin analog derivative according to claim 1, which is characterized in that the weak base Using piperidines.
3. a kind of method for preparing furocoumarin analog derivative according to claim 1, which is characterized in that the reaction Solvent a uses ethyl alcohol.
4. a kind of method for preparing furocoumarin analog derivative according to claim 1, which is characterized in that the furans Coumarin derivatives specifically include following compounds: 3- acetyl group -9- methyl -2H- furans [2,3-h] chromene -2- Ketone, 9- methyl -2- oxygen -2H- furans [2,3-h] chromene -3- Ethyl formate, 9- methyl -3- propiono -2H- furans [2,3- H] chromen-2-one, 3- isobutyryl -9- methyl -2H- furans [2,3-h] chromen-2-one, 3- bytyry -9- first Base -2H- furans [2,3-h] chromen-2-one, 3- benzoyl -9- methyl -2H- furans [2,3-h] chromen-2-one, 3- (3,4- Dimethoxybenzoyl) -9- methyl -2H- furans [2,3-h] chromen-2-one, the different nicotinoyl -9- methyl-of 3- 2H- furans [2,3-h] chromen-2-one.
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