CN106565733A - Synthetic method of polyhydroxy substituted coumestrol natural product - Google Patents
Synthetic method of polyhydroxy substituted coumestrol natural product Download PDFInfo
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Abstract
The invention discloses a synthetic method of a polyhydroxy substituted coumestrol natural product. 2-bromine-4-hydroxyphenylacetic acid serves as a raw material to make a condensation reaction with a hydroxy substituted salicylaldehyde compound, and a hydroxy substituted 3-(2-bromine-4-hydroxycyclohexyl phenyl)-7-hydroxy coumarin compound is obtained; and then a hydroxylation/oxidative coupling reaction is made under the condition of a catalyst and microwave heating, and the polyhydroxy substituted coumestrol natural product is obtained. The synthetic method is simple in route, easy and convenient to operate, high in yield, soft in reaction condition, free of needs of precious metal catalyzing, high in atom economy and low in cost, and multiple steps of cascade reactions are made simultaneously.
Description
Technical field
The present invention relates to organic synthesis field, more particularly to a kind of synthesis of polyhydroxy replacement coumestrol class natural product
Method.
Background technology
3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (Coumestrol) be Herba Medicaginiss, Herba Trifolii Pratentis and
A kind of polyhydroxy found in Semen sojae atricolor replaces coumestrol class phytoestrogen, with multiple biological activities, such as inhibitory activity sheath
Ammonia alcohol kinases (SPHK1), suppression alpha-glucosidase (α-glucosidase), the activation antibody of Sirtuin 1 (SIRT 1), people
The biological activity such as pregnane X receptor antagonists and neuroprotective, and can be used for the efficient of estrogen receptor as fluorescent probe
(the Steroids 2014,80,37 such as screening；Neurol.Res.2014,36,198；Mol.Endocrinol.2008,22,838；
J.Biomol.Screen.2014,19,253；J.Agric.Food Chem.2014,62,4298；Food Chem.2011,
126,1057；Bioorg.&Med.Chem.Lett.2014,24,2560；Appl.Environ.Microbiol.2012,78,
2896).Simultaneously [3,2-c] chromane -6- ketone (Aureol) is in Semen phaseoli radiati (Phaseolus to 1,3,9- trihydroxy -6H- benzofurans
Aureus Roxb.) in separate first discovery polyhydroxy replace coumestrol class natural product (Z.Naturforsch.1983,
38c, 698), with antifungal and neuroprotective activity (Physiol.Mol.Plant Pathology 1986,29,95；
Planta.Med.2005,71,835), its content in nature is more rare.Therefore, a kind of easy to operate, practicality is invented
Method come prepare polyhydroxy replace coumestrol class natural product it is significant.
The team such as Emers, Jurd, Sakamoto, Botting once completed 3,9- dihydroxy -6H- benzofurans simultaneously [3,
2-c] chromane -6- ketone (Coumestrol) synthetic work (J.Am.Chem.Soc.1958,80,4381-4383；
J.Org.Chem.1964,29,3036–3038；J.Chem.Soc.,Perkin Trans.1 2000,4339-4346；
Tetrahedron.2004,1637–1642).Use precious metal palladium as catalyst, reactions steps length more said method, receive
Rate is relatively low.In addition, 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (Aureol) synthesis at present also not
Appear in the newspapers.
The content of the invention
It is an object of the invention to overcome shortcoming present in prior art, there is provided a kind of simple and direct, efficient, low cost, work
The simple polyhydroxy of skill replaces coumestrol class natural product 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone
(Coumestrol, structural formula 4a) and 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (Aureol, structure
Formula 4b) synthetic method.
The purpose of the present invention is achieved through the following technical solutions：
A kind of polyhydroxy replace coumestrol class natural product 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -
The synthesis side of 6- ketone (Coumestrol) and 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (Aureol)
Method, comprises the steps：
(1) in solvent orange 2 A, in the presence of alkali A, the salicylide that the bromo- 4- hydroxyl phenylacetic acids (structural formula 1) of 2- replace with hydroxyl
There is condensation reaction in class compound (structural formula 2), obtain 3- (the bromo- 4- hydroxy phenyls of the 2-)-umbelliferone of hydroxyl replacement
Class compound (structural formula 3)；
(2) 3- (the bromo- 4- hydroxy phenyls of the 2-)-umbelliferone class compound that hydroxyl replaces is dissolved in solvent B,
In the presence of catalyst B, part B, alkali B, there is hydroxylating/oxidative coupling reaction under microwave heating condition, it is post-treated to obtain
Replace coumestrol class natural product (structural formula 4) to polyhydroxy.
The bigcatkin willow aldehyde compound that the hydroxyl replaces include but is not limited to 2,4- 4-dihydroxy benzaldehydes (structural formula 2a) with
2,4,6- tri hydroxybenzaldehydes (structural formula 2b).
3- (the bromo- 4- hydroxy phenyls of the 2-)-umbelliferone class compound that the hydroxyl replaces includes but is not limited to 3-
(the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a) and 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxy tonkabeans
Plain (structural formula 3b).
In step (1), after condensation reaction is finished, crude product is poured in frozen water, stirred, sucking filtration, wash filter cake, filter cake is used
Sodium hydrate aqueous solution dissolves, and is washed with ethyl acetate, and with hydrochloric acid pH=3～4 are acidified to, and separates out solid, and sucking filtration, washing is received
Collection filter cake, obtains 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound (structural formula 3) of hydroxyl replacement after being dried.
In step (2), after hydroxylating/oxidative coupling reaction, reactant liquor is cooled to into room temperature, is filtered, filtrate Jing acetic acid second
PH=4～5 are acidified to hydrochloric acid after ester washing, sucking filtration, washing is dried, and uses ethyl acetate-light petrol recrystallization, obtains polyhydroxy
Base replaces coumestrol class natural product (structural formula 4).
In step (1), described solvent orange 2 A can be, but not limited to be acetic anhydride, propionic andydride, butyryl oxide. that preferred solvent A is second
Anhydride；Described alkali A can be, but not limited to be sodium acetate, Sodium ethylate, triethylamine that preferred alkali A is triethylamine.
In step (1), the temperature of the condensation reaction is 100～140 DEG C, and preferable temperature is 110 DEG C；Response time is 5
～9 hours, preferred reaction time was 7 hours.
In step (1), the bromo- 4- hydroxyl phenylacetic acids of 2-, the bigcatkin willow aldehyde compound of hydroxyl replacement, the mol ratio of alkali A are 1：
(1.0～1.2)：(1～4), bigcatkin willow aldehyde compound, the mol ratio of alkali A that the bromo- 4- hydroxyl phenylacetic acids of preferred 2-, hydroxyl replace
For 1：1：2.
In step (2), described catalyst B can be, but not limited to be copper sulfate, basic copper carbonate, copper oxide, Schweinfurt green,
Hydro-Giene (Water Science)., preferred catalyst B is Schweinfurt green；Described part B can be, but not limited to be glycolic, glycine, the adjacent phenanthrene of 1,10-
Sieve quinoline, 8-hydroxyquinoline, tetramethylethylenediamine, preferred part B is 1,10- Phens.
In step (2), described alkali B can be, but not limited to be sodium hydroxide, potassium hydroxide, cesium carbonate, tripotassium phosphate, three
Ethamine, preferred alkali B is potassium hydroxide；Described solvent B be distilled water, dimethyl sulfoxide, PEG-4000 (PEG-400), two
(volume ratio is 1 to first sulfoxide-water：1), DMF, preferred solvent B is dimethyl sulfoxide.
In step (2), the temperature of microwave heating is 100～180 DEG C, and preferable temperature is 120 DEG C；Response time is 2～4 little
When, preferred reaction time is 3 hours.
In step (2), hydroxyl replace 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound, catalyst B,
Part B, the mol ratio of alkali B are 1：(0.1～0.4)：(0.1～0.4)：(5～15), 3- (the bromo- 4- hydroxyls of 2- that preferred hydroxyl replaces
Base phenyl)-umbelliferone class compound, catalyst B, part B, alkali B mol ratio be 1：0.2：0.2：10.
Chemical equation according to the present invention is as follows：
It is pointed out that the synthetic method of coumestrol class natural product of the present invention can be not limited to 3,9- bis-
Hydroxyl -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4a) and 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-
C] chromane -6- ketone (structural formula 4b) preparation.In fact, can synthesize numerous containing hydroxyl using method of the present invention
Substituted coumestrol class natural product and derivant.
The present invention has the advantage that compared with prior art and effect：
(1) route of the present invention is simple and direct, easy to operate, multistep cascade reaction occurs simultaneously, yield is higher；Gained in the first step
The product for arriving does not need complicated purification to process, and next step reaction can be direct plungeed into after sucking filtration, drying.
(2), without the need for the harsh reaction condition such as anhydrous and oxygen-free, without the need for precious metal catalyst, Atom economy is high, symbol for the present invention
Close the theory of Modern Green Chemistry and there is cost advantage, be conducive to prepare with scale and industrialized implementation.
Description of the drawings
Fig. 1 is the proton nmr spectra of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4a)
(400MHz,DMSO-d6)。
Fig. 2 is the carbon-13 nmr spectra of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4a)
(100MHz,DMSO-d6)。
Fig. 3 is the hydrogen nuclear magnetic resonance of 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4b)
Spectrum (400MHz, DMSO-d6)。
Fig. 4 is the nuclear magnetic resonance, NMR carbon of 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4b)
Spectrum (100MHz, DMSO-d6)。
Specific embodiment
Further detailed description, but embodiments of the present invention not limited to this are done to the present invention with reference to embodiment.
Embodiment 1
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes are added
(25mmol, 3.45g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, and reaction 7 is little
When.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects filter
Cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.83g, yield
94%.1H NMR(DMSO-d6, 400MHz, ppm) and δ 10.38 (s, OH), 9.94 (s, OH), 7.89 (s, 1H), 7.57 (d, J=
8.8Hz, 1H), 7.26 (d, J=8.4Hz, 1H), 7.11 (d, J=2.0Hz, 1H), 6.86 (dd, J=2.0,8.8Hz, 1H),
6.83 (dd, J=2.0,8.4Hz, 1H), 6.78 (d, J=2.0Hz, 1H)；13C NMR(DMSO-d6,100MHz,ppm)δ
161.3,159.6,158.2,155.2,143.0,132.5,129.9,126.9,123.6,123.4,118.9,114.8,
113.4,111.4,102.0
(2) preparation of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), Schweinfurt green (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol, 2.81g),
Dimethyl sulfoxide (20mL), stirring, microwave heating reacts 3 hours to 120 DEG C.After the completion of reaction, room temperature is cooled to, uses acetic acid second
Ester washs (10mL × 3), and water dilute hydrochloric acid is acidified to pH=4～5, has solid to separate out, sucking filtration, washes filter cake, is dried, and uses second
Acetoacetic ester-petroleum ether recrystallization, obtains white solid, is natural product 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -
6- ketone, weight 0.99g, yield 74%.1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),10.04(s,1H),7.85(d,
J=8.8Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 7.16 (d, J=2.0Hz, 1H), 6.90-6.96 (m, 3H) is (such as Fig. 1 institutes
Show)；13C NMR(100MHz,DMSO-d6)δ161.2,159.5,157.6,157.0,155.9,154.6,122.7,120.6,
(114.6,114.0,113.7,104.2,103.0,102.0,98.7 as shown in Figure 2).
Embodiment 2
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes are added
(25mmol, 3.45g), triethylamine (25mmol, 2.53g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, and reaction 7 is little
When.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects filter
Cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 6.91g, yield
83%.
(2) preparation of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), basic copper carbonate (1mmol, 0.24g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating reacts 3 hours to 120 DEG C.After the completion of reaction, room temperature is cooled to,
In entering 50mL distilled water, pH=4～5 are acidified to dilute hydrochloric acid, have solid to separate out, sucking filtration washes filter cake, is dried, and uses acetic acid second
Ester-petroleum ether recrystallization, obtains white solid, is natural product 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6-
Ketone, weight 0.87g, yield 65%.
Embodiment 3
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes are added
(25mmol, 3.45g), triethylamine (75mmol, 7.59g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, and reaction 7 is little
When.After completion of the reaction, reacting liquor while hot is poured in 80mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects filter
Cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.16g, yield
86%.
(2) preparation of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), copper oxide (1mmol, 0.08g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol, 2.81g),
Dimethyl sulfoxide (20mL), stirring, microwave heating reacts 3 hours to 120 DEG C.After the completion of reaction, room temperature is cooled to, uses acetic acid second
Ester washs (10mL × 3), and water dilute hydrochloric acid is acidified to pH=4～5, has solid to separate out, sucking filtration, washes filter cake, is dried, and uses second
Acetoacetic ester-petroleum ether recrystallization, obtains white solid, is natural product 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -
6- ketone, weight 0.78g, yield 58%.
Embodiment 4
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes are added
(27.5mmol, 3.80g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating reacts 7 to 110 DEG C
Hour.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects
Filter cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.08g, yield
85%.
(2) preparation of 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), Schweinfurt green (1mmol, 0.18g), 1,10- o-phenanthrolins (1mmol, 0.19g), sodium hydroxide (50mmol, 20g), two
First sulfoxide (20mL), stirring, microwave heating reacts 3 hours to 120 DEG C.After the completion of reaction, room temperature is cooled to, pours 50mL water into
In, pH=4～5 are acidified to dilute hydrochloric acid, ethyl acetate extraction (20mL × 3), washing is dried, concentration, with ethyl acetate-stone
Oily ether recrystallization, obtains white solid, is natural product 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone, weight
0.91g, yield 68%.
Embodiment 5
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes are added
(25mmol, 3.45g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, and reaction 9 is little
When.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects filter
Cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.49g, yield
90%.
(2) preparation of natural product 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), Schweinfurt green (1mmol, 0.18g), tetramethylethylenediamine (1mmol, 0.12g), potassium hydroxide (50mmol, 2.81g),
Dimethyl sulfoxide (20mL), stirring, microwave heating reacts 3 hours to 120 DEG C.After the completion of reaction, room temperature is cooled to, pours 50mL into
In water, pH=4～5 are acidified to dilute hydrochloric acid, are extracted with ethyl acetate (20mL × 3), washed, be dried, acetic acid second is used in concentration
Ester-petroleum ether recrystallization, obtains white solid, is natural product 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6-
Ketone, weight 0.72g, yield 54%.
Embodiment 6
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (structural formula 3a)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4- 4-dihydroxy benzaldehydes are added
(25mmol, 3.45g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, and reaction 5 is little
When.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects filter
Cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone, weight 7.66g, yield
92%.
(2) preparation of natural product 3,9- dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4a)
In 50mL microwave reaction bottles, sequentially add 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone (5mmol,
1.67g), Schweinfurt green (1mmol, 0.18g), 1,10- o-phenanthrolins (1mmol, 0.19g), potassium hydroxide (50mmol, 2.81g),
(volume ratio is 1 to dimethyl sulfoxide-water：1,20mL), stir, microwave heating reacts 3 hours to 120 DEG C.After the completion of reaction, cooling
To room temperature, washed with ethyl acetate (10mL × 3), water dilute hydrochloric acid is acidified to pH=4～5, have solid to separate out, sucking filtration, water
Filter wash cake, is dried, and uses ethyl acetate-light petrol recrystallization, obtains white solid, is natural product 3,9- dihydroxy -6H- benzo furans
Mutter simultaneously [3,2-c] chromane -6- ketone, weight 0.97g, yield 72%.
Embodiment 7
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- trihydroxy benzene first are added
Aldehyde (25mmol, 3.85g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating reacts 7 to 110 DEG C
Hour.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects
Filter cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, and weight 7.68g is received
Rate 88%.1H NMR(DMSO-d6,400MHz,ppm)δ10.75(s,OH),10.46(s,OH),10.05(s,OH),7.78(s,
1H), 7.24 (d, J=8.4Hz, 1H), 7.08 (d, J=2.4Hz, 1H), 6.83 (dd, J=2.4,8.4Hz, 1H), 6.29 (d, J
=2.0Hz, 1H), 6.24 (d, J=2.0Hz, 1H)；13C NMR(DMSO-d6,100MHz,ppm)δ162.1,159.8,158.1,
156.1,156.1,137.9,132.5,127.2,123.6,120.7,118.9,114.8,101.6,98.4,93.9
(2) preparation of natural product 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), Schweinfurt green (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating to 120 DEG C, react 3 hours.After the completion of reaction, room temperature is cooled to, is used
Ethyl acetate washs (10mL × 3), and water dilute hydrochloric acid is acidified to pH=4～5, has solid to separate out, sucking filtration, washes filter cake, does
It is dry, use ethyl acetate-light petrol recrystallization, obtain white solid, be the trihydroxy -6H- benzofurans of natural product 1,3,9- simultaneously [3,
2-c] chromane -6- ketone (Aureol), weight 0.91g, yield 64%.1H NMR(DMSO-d6,400MHz,ppm)δ10.92(s,
), OH 10.50 (s, OH), 9.96 (s, OH), 7.67 (d, J=8.4Hz, 1H), 7.14 (d, J=1.6Hz, 1H), 6.93 (dd, J
=2.0,8.4Hz, 1H), 6.41 (d, J=2.0Hz, 1H), 6.38 (d, J=2.0Hz, 1H) (as shown in Figure 3)；13C NMR
(DMSO-d6,100MHz,ppm)δ161.4,159.8,157.7,156.6,155.8,155.6,155.2,120.2,114.4,
(113.8,100.7,99.1,98.6,95.2,94.9 as shown in Figure 4).
Embodiment 8
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- trihydroxy benzene first are added
Aldehyde (25mmol, 3.85g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating reacts 7 to 100 DEG C
Hour.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects
Filter cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, and weight 6.81g is received
Rate 78%.
(2) preparation of natural product 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), Schweinfurt green (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), DMF (20mL), stirring, microwave heating reacts 3 hours to 120 DEG C.After the completion of reaction, cooling
To room temperature, in pouring 50mL distilled water into, pH=4～5 are acidified to dilute hydrochloric acid, have solid to separate out, sucking filtration washes filter cake, is dried,
Ethyl acetate-light petrol recrystallization is used, white solid is obtained, is the trihydroxy -6H- benzofurans of natural product 1,3,9- simultaneously [3,2-
C] chromane -6- ketone, weight 0.88g, yield 62%.
Embodiment 9
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- trihydroxy benzene first are added
Aldehyde (25mmol, 3.85g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating reacts 7 to 140 DEG C
Hour.After completion of the reaction, reacting liquor while hot is poured in 80mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects
Filter cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, and weight 6.89g is received
Rate 79%.
(2) preparation of natural product 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), Schweinfurt green (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating reacts 3 hours to 100 DEG C.After the completion of reaction, room temperature is cooled to, is used
Ethyl acetate washs (10mL × 3), and water dilute hydrochloric acid is acidified to pH=4～5, has solid to separate out, sucking filtration, washes filter cake, does
It is dry, use ethyl acetate-light petrol recrystallization, obtain white solid, be the trihydroxy -6H- benzofurans of natural product 1,3,9- simultaneously [3,
2-c] chromane -6- ketone, weight 0.71g, yield 50%.
Embodiment 10
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- trihydroxy benzene first are added
Aldehyde (25mmol, 3.85g), sodium acetate (50mmol, 4.10g), acetic anhydride (10mL), stirring, oil bath heating reacts 7 to 110 DEG C
Hour.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects
Filter cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, and weight 7.33g is received
Rate 84%.
(2) preparation of natural product 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), Schweinfurt green (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating reacts 3 hours to 160 DEG C.After the completion of reaction, room temperature is cooled to,
In entering 50mL water, pH=4～5 are acidified to dilute hydrochloric acid, ethyl acetate extraction (20mL × 3), washing is dried, and acetic acid is used in concentration
Ethyl ester-petroleum ether recrystallization, obtains white solid, be the trihydroxy -6H- benzofurans of natural product 1,3,9- simultaneously [3,2-c] chromane -
6- ketone, weight 0.74g, yield 52%.
Embodiment 11
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- tri- oxybenzene formaldehyde are added
(25mmol, 3.85g), Sodium ethylate (50mmol, 3.40g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, and reaction 7 is little
When.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects filter
Cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, weight 7.24g, yield
83%.
(2) preparation of natural product 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), Schweinfurt green (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating to 120 DEG C, react 2 hours.After the completion of reaction, room temperature is cooled to,
In entering 50mL water, pH=4～5 are acidified to dilute hydrochloric acid, are extracted with ethyl acetate (20mL × 3), washed, be dried, second is used in concentration
Acetoacetic ester-petroleum ether recrystallization, obtains white solid, is the trihydroxy -6H- benzofurans of natural product 1,3,9- simultaneously [3,2-c] color
Full -6- ketone, weight 0.80g, yield 56%.
Embodiment 12
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- tri- oxybenzene formaldehyde are added
(25mmol, 3.85g), triethylamine (50mmol, 5.06g), butyryl oxide. (10mL), stirring, oil bath heating is to 110 DEG C, and reaction 7 is little
When.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects filter
Cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, weight 6.55g, yield
75%.
(2) preparation of natural product 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), Schweinfurt green (1mmol, 0.18g), 1,10- Phens (1mmol, 0.19g), potassium hydroxide (50mmol,
2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating reacts 4 hours to 120 DEG C.After the completion of reaction, room temperature is cooled to, is used
Ethyl acetate washs (10mL × 3), and water dilute hydrochloric acid is acidified to pH=4～5, has solid to separate out, sucking filtration, washes filter cake, does
It is dry, use ethyl acetate-light petrol recrystallization, obtain white solid, be the trihydroxy -6H- benzofurans of natural product 1,3,9- simultaneously [3,
2-c] chromane -6- ketone, weight 0.82g, yield 58%.
Embodiment 13
(1) preparation of 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins (structural formula 3b)
In 50mL round-bottomed flasks, the bromo- 4- hydroxyl phenylacetic acids (25mmol, 5.78g) of 2-, 2,4,6- tri- oxybenzene formaldehyde are added
(25mmol, 3.85g), triethylamine (50mmol, 5.06g), acetic anhydride (10mL), stirring, oil bath heating is to 110 DEG C, and reaction 7 is little
When.After completion of the reaction, reacting liquor while hot is poured in 50mL frozen water, is stirred, have solid to separate out, sucking filtration washes filter cake, collects filter
Cake, after being dried hazel-color solid is obtained, and is 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins, weight 7.68g, yield
88%..
(2) preparation of natural product 1,3,9- trihydroxies -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone (structural formula 4b)
In 50mL microwave reaction bottles, 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins are sequentially added
(5mmol, 1.75g), Schweinfurt green (0.5mmol, 0.09g), 1,10- Phens (0.5mmol, 0.095g), potassium hydroxide
(50mmol, 2.81g), dimethyl sulfoxide (20mL), stirring, microwave heating reacts 3 hours to 120 DEG C.After the completion of reaction, cooling
To room temperature, washed with ethyl acetate (10mL × 3), water dilute hydrochloric acid is acidified to pH=4～5, have solid to separate out, sucking filtration, water
Filter wash cake, is dried, and uses ethyl acetate-light petrol recrystallization, obtains white solid, is the trihydroxy -6H- benzos of natural product 1,3,9-
Furo [3,2-c] chromane -6- ketone, weight 0.68g, yield 48%.
Claims (10)
1. a kind of polyhydroxy replaces the synthetic method of coumestrol class natural product, it is characterised in that comprise the steps：
(1) in solvent orange 2 A, in the presence of alkali A, the bromo- 4- hydroxyl phenylacetic acids of 2- occur with the bigcatkin willow aldehyde compound that hydroxyl replaces
Condensation reaction, obtains 3- (the bromo- 4- hydroxy phenyls of the 2-)-umbelliferone class compound of hydroxyl replacement；
(2) 3- (the bromo- 4- hydroxy phenyls of the 2-)-umbelliferone class compound that hydroxyl replaces is dissolved in solvent B, in catalysis
In the presence of agent B, part B, alkali B, there is hydroxylating/oxidative coupling reaction under microwave heating condition, it is post-treated to obtain many
Hydroxyl replaces coumestrol class natural product.
2. polyhydroxy according to claim 1 replaces the synthetic method of coumestrol class natural product, it is characterised in that：Institute
The bigcatkin willow aldehyde compound for stating hydroxyl replacement is 2,4- 4-dihydroxy benzaldehydes or 2,4,6- tri hydroxybenzaldehydes；The hydroxyl replaces
3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound be 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone
Or 3- (the bromo- 4- hydroxy phenyls of 2-) -5,7- dihydroxycoumarins；It is 3,9- that the polyhydroxy replaces coumestrol class natural product
Dihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -6- ketone or 1,3,9- trihydroxy -6H- benzofurans simultaneously [3,2-c] chromane -
6- ketone.
3. polyhydroxy according to claim 1 replaces the synthetic method of coumestrol class natural product, it is characterised in that：Step
Suddenly in (1), after condensation reaction is finished, crude product is poured in frozen water, is stirred, sucking filtration, wash filter cake, filter cake sodium hydroxide water
Solution dissolves, and is washed with ethyl acetate, and with hydrochloric acid pH=3～4 are acidified to, and separates out solid, and sucking filtration, washing is collected filter cake, is dried
3- (the bromo- 4- hydroxy phenyls of the 2-)-umbelliferone class compound of hydroxyl replacement is obtained afterwards.
4. polyhydroxy according to claim 1 replaces the synthetic method of coumestrol class natural product, it is characterised in that：Step
Suddenly in (2), after hydroxylating/oxidative coupling reaction, reactant liquor is cooled to into room temperature, is filtered, filtrate is used Jing after ethyl acetate washing
Hydrochloric acid is acidified to pH=4～5, and sucking filtration, washing is dried, and uses ethyl acetate-light petrol recrystallization, obtains polyhydroxy and replaces tonkabean
Female phenols natural product.
5. polyhydroxy according to claim 1 replaces the synthetic method of coumestrol class natural product, it is characterised in that：Step
Suddenly in (1), described solvent orange 2 A is acetic anhydride, propionic andydride or butyryl oxide.；Described alkali A is sodium acetate, Sodium ethylate or triethylamine.
6. polyhydroxy according to claim 1 replaces the synthetic method of coumestrol class natural product, it is characterised in that：Step
Suddenly in (1), the bromo- 4- hydroxyl phenylacetic acids of 2-, the bigcatkin willow aldehyde compound of hydroxyl replacement, the mol ratio of alkali A are 1：(1.0～1.2)：
(1～4).
7. polyhydroxy according to claim 1 replaces the synthetic method of coumestrol class natural product, it is characterised in that：Step
Suddenly in (2), described catalyst B is copper sulfate, basic copper carbonate, copper oxide, Schweinfurt green or Hydro-Giene (Water Science).；Described part B
It is glycolic, glycine, 1,10- Phens, 8-hydroxyquinoline or tetramethylethylenediamine.
8. polyhydroxy according to claim 1 replaces the synthetic method of coumestrol class natural product, it is characterised in that：Step
Suddenly in (2), described alkali B is sodium hydroxide, potassium hydroxide, cesium carbonate, tripotassium phosphate or triethylamine；Described solvent B is to steam
Distilled water, dimethyl sulfoxide, PEG-4000, dimethyl sulfoxide-water or N,N-dimethylformamide.
9. polyhydroxy according to claim 1 replaces the synthetic method of coumestrol class natural product, it is characterised in that：Step
Suddenly in (1), the temperature of the condensation reaction is 100～140 DEG C, and the response time is 5～9 hours；In step (2), microwave heating
Temperature be 100～180 DEG C, the response time be 2～4 hours.
10. polyhydroxy according to claim 1 replaces the synthetic method of coumestrol class natural product, it is characterised in that：
In step (2), 3- (the bromo- 4- hydroxy phenyls of 2-)-umbelliferone class compound, catalyst B, part B, alkali that hydroxyl replaces
The mol ratio of B is 1：(0.1～0.4)：(0.1～0.4)：(5～15).
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| CN1388756A (en) * | 2000-06-23 | 2003-01-01 | 株式会社韩佛化粧品 | Ferulic ester derivative, 3,9-diferulylcoumestrol and cosmetic product containing same |
| WO2014106848A1 (en) * | 2013-01-07 | 2014-07-10 | B.G. Negev Technologies And Applications Ltd. | Coumestan, coumestrol, coumestan derivatives and processes of making the same and uses of same |
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| CN1388756A (en) * | 2000-06-23 | 2003-01-01 | 株式会社韩佛化粧品 | Ferulic ester derivative, 3,9-diferulylcoumestrol and cosmetic product containing same |
| WO2014106848A1 (en) * | 2013-01-07 | 2014-07-10 | B.G. Negev Technologies And Applications Ltd. | Coumestan, coumestrol, coumestan derivatives and processes of making the same and uses of same |
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| CN113121485A (en) * | 2021-03-01 | 2021-07-16 | 中山大学 | 3-aryl coumarin derivative and preparation method and application thereof |
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