CN116715675A - Synthetic method of isopsoralen - Google Patents
Synthetic method of isopsoralen Download PDFInfo
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- CN116715675A CN116715675A CN202310502034.XA CN202310502034A CN116715675A CN 116715675 A CN116715675 A CN 116715675A CN 202310502034 A CN202310502034 A CN 202310502034A CN 116715675 A CN116715675 A CN 116715675A
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- XDROKJSWHURZGO-UHFFFAOYSA-N angelicin Chemical compound C1=C2OC=CC2=C2OC(=O)C=CC2=C1 XDROKJSWHURZGO-UHFFFAOYSA-N 0.000 title claims abstract description 87
- MLMVLVJMKDPYBM-UHFFFAOYSA-N pseudoisopsoralene Natural products C1=C2C=COC2=C2OC(=O)C=CC2=C1 MLMVLVJMKDPYBM-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 claims abstract description 34
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 claims abstract description 29
- BVHRLXSFKYPLBR-UHFFFAOYSA-N 7-hydroxy-8-prop-2-enylchromen-2-one Chemical compound C1=CC(=O)OC2=C(CC=C)C(O)=CC=C21 BVHRLXSFKYPLBR-UHFFFAOYSA-N 0.000 claims abstract description 25
- KWNHWLBNDYLDEC-UHFFFAOYSA-N 7-prop-2-enoxychromen-2-one Chemical compound C1=CC(=O)OC2=CC(OCC=C)=CC=C21 KWNHWLBNDYLDEC-UHFFFAOYSA-N 0.000 claims abstract description 25
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 claims abstract description 22
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 22
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 17
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000001630 malic acid Substances 0.000 claims abstract description 17
- 235000011090 malic acid Nutrition 0.000 claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000001308 synthesis method Methods 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000005821 Claisen rearrangement reaction Methods 0.000 claims abstract description 5
- 238000006266 etherification reaction Methods 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- 238000005757 von Pechmann cycloaddition reaction Methods 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- 239000007787 solid Substances 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 20
- 239000005457 ice water Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 16
- 239000012043 crude product Substances 0.000 claims description 15
- 238000000967 suction filtration Methods 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 7
- 239000012153 distilled water Substances 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000012285 osmium tetroxide Substances 0.000 claims description 5
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 5
- MLIWQXBKMZNZNF-KUHOPJCQSA-N (2e)-2,6-bis[(4-azidophenyl)methylidene]-4-methylcyclohexan-1-one Chemical compound O=C1\C(=C\C=2C=CC(=CC=2)N=[N+]=[N-])CC(C)CC1=CC1=CC=C(N=[N+]=[N-])C=C1 MLIWQXBKMZNZNF-KUHOPJCQSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- AXZAYXJCENRGIM-UHFFFAOYSA-J dipotassium;tetrabromoplatinum(2-) Chemical compound [K+].[K+].[Br-].[Br-].[Br-].[Br-].[Pt+2] AXZAYXJCENRGIM-UHFFFAOYSA-J 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- FZPXKEPZZOEPGX-UHFFFAOYSA-N n,n-dibutylaniline Chemical compound CCCCN(CCCC)C1=CC=CC=C1 FZPXKEPZZOEPGX-UHFFFAOYSA-N 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910001487 potassium perchlorate Inorganic materials 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 239000013049 sediment Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims 1
- 229910052500 inorganic mineral Inorganic materials 0.000 claims 1
- 239000011707 mineral Substances 0.000 claims 1
- 238000010025 steaming Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- ZCCUUQDIBDJBTK-UHFFFAOYSA-N psoralen Chemical compound C1=C2OC(=O)C=CC2=CC2=C1OC=C2 ZCCUUQDIBDJBTK-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 10
- VXGRJERITKFWPL-UHFFFAOYSA-N 4',5'-Dihydropsoralen Natural products C1=C2OC(=O)C=CC2=CC2=C1OCC2 VXGRJERITKFWPL-UHFFFAOYSA-N 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 235000019504 cigarettes Nutrition 0.000 description 4
- 238000000605 extraction Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- CRMBVHJMQTYDMJ-QZTJIDSGSA-N furanocoumarin Natural products CC(C)OC(C)(C)[C@H](O)COc1c2C=CC(=O)Oc2c(OC[C@@H](O)C(=C)C)c3occc13 CRMBVHJMQTYDMJ-QZTJIDSGSA-N 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The application discloses a synthesis method of isopsoralen, which comprises the following steps: the method comprises the steps of (1) taking resorcinol and malic acid as raw materials, synthesizing 7-hydroxycoumarin through Pechmann condensation reaction, (2) synthesizing 7-allyloxy coumarin through etherification reaction, (3) preparing 7-hydroxy-8-allylcoumarin through Claisen rearrangement reaction, and (4) synthesizing isopsoralen through cyclization reaction. The synthesis method has simple process, cheap and easily obtained raw materials, simple separation and purification of the product, high yield of 45 percent and high final isopsoralen purity of more than 99 percent, can carry out large-scale production and has wide application prospect.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a synthesis method of isopsoralen.
Background
Psoralen (Psoralen) is furanocoumarin compound derived from fructus Psoraleae, and widely exists in radix Glehniae, radix Saposhnikoviae, radix Angelicae Pubescentis, etc., has pharmacological activities of resisting tumor, osteoporosis, neuroprotection, antiinflammatory, and antioxidant, etc., and can be used for treating diseases such as rheumatoid arthritis, leukemia, alzheimer disease, etc. In addition, the psoralen is added into the cigarettes, so that tar and free radicals in the cigarette smoke can be reduced, the effects of reducing tar and reducing harm are achieved, elegant bean fragrance is also revealed during smoking, the inherent quality of the cigarettes can be remarkably improved, and the method has important application value.
However, the current psoralen synthesis method has few reports, and mainly uses psoralen seeds as raw materials, and the psoralen is obtained through multi-step extraction, separation and purification. The psoralen has high price due to complex extraction process and extremely low extraction rate, so that the application of the psoralen in cigarettes and medicines is limited.
Therefore, the development of a novel efficient synthesis method of psoralen is particularly important.
Disclosure of Invention
The application aims to provide a method for synthesizing isopsoralen, which takes low-cost resorcinol and malic acid as raw materials to synthesize 7-hydroxycoumarin through Pechmann condensation reaction; then, 7-allyloxy coumarin is prepared through etherification reaction; then, a Claisen rearrangement reaction is adopted to generate 7-hydroxy-8-allyl coumarin; finally, synthesizing the natural compound isopsoralen through cyclization reaction. The synthetic route has simple operation, high yield and easy mass production.
The technical problems to be solved by the application are realized by the following technical scheme:
a synthesis method of isopsoralen comprises the following steps: the method comprises the steps of (1) taking resorcinol and malic acid as raw materials, synthesizing 7-hydroxycoumarin through Pechmann condensation reaction, (2) synthesizing 7-allyloxy coumarin through etherification reaction, (3) preparing 7-hydroxy-8-allylcoumarin through Claisen rearrangement reaction, and (4) synthesizing isopsoralen through cyclization reaction;
the reaction formula is as follows:
preferably, the method specifically comprises the following steps:
(1) Preparation of 7-hydroxycoumarin: in a round bottom flask, add concentrated H 2 SO 4 Cooling to 0-25 deg.c in a low temperature reactor, and adding mixed solid of resorcinol and malic acid into concentrated H slowly while stirring 2 SO 4 Is a kind of medium. After resorcinol and malic acid are added, stirring is continued for 0.5-2 h under the low temperature condition, then the reaction is carried out for 12-30 h at room temperature, after the reaction is finished, the reaction mixture is slowly added into ice water, sediment is collected by suction filtration, the ice water is washed and dried, and the 7-hydroxycoumarin is obtained by recrystallization with 95% ethanol.
(2) Preparation of 7-allyloxy coumarin: in a round bottom flask, adding an organic solvent, 7-hydroxy coumarin and a catalyst, and slowly dropwise adding an organic solution containing allyl bromide into a reaction system under stirring. After the dripping is finished, heating and refluxing for 5-12 h, after the reaction is finished, decompressing and distilling off the solvent, adding distilled water and stirring, filtering and collecting solid, washing with water, drying, and recrystallizing the crude product with 95% ethanol to obtain the 7-allyloxy coumarin.
(3) Preparation of 7-hydroxy-8-allyl coumarin: adding 7-allyloxy coumarin and organic base into a round-bottom flask, heating and refluxing for 2-6 h, decompressing and evaporating the solvent after the reaction is finished, adding ice water, vigorously stirring, filtering and collecting solid, washing with water, drying, and recrystallizing the crude product with 95% ethanol to obtain 7-hydroxy-8-allylcoumarin.
(4) Preparation of isopsoralen: adding 7-hydroxy-8-allyl coumarin, an oxidant and a solvent into a round bottom flask, reacting for 12-24 hours at room temperature, adding an inorganic acid, continuously stirring for 0.5-2 hours after the reaction is finished, pouring the reaction mixture into ice water, filtering to collect solid, washing with water, drying, and recrystallizing the crude product with 95% ethanol to obtain isopsoralen.
Preferably, in step (1) concentrated H 2 SO 4 The mass fraction is 70% -98%; the mol ratio of resorcinol to malic acid is 1: (1-1.3).
Preferably, the organic solvent in the step (2) is one of acetone, dichloromethane or chloroform; the catalyst is one of potassium carbonate, sodium carbonate or potassium hydroxide; the mole ratio of 7-hydroxycoumarin, catalyst and allyl bromide is 1: (1-1.2): (1-1.3).
Preferably, the organic base in the step (3) is one of N, N-dimethylaniline, N-diethylaniline or N, N-dibutylaniline; the organic base is both a solvent and a catalyst.
Preferably, the oxidant in the step (4) is one or more of osmium tetroxide, potassium periodate or potassium perchlorate; the solvent is one or more of methanol, ethanol or distilled water; the inorganic acid is 98% H 2 SO 4 37% HCl or 85% H 3 PO 4 One of them.
The technical scheme of the application has the following beneficial effects:
the synthesis method of isopsoralen has the advantages of simple process, cheap and easily obtained raw materials, simple product separation and purification, high yield of 45 percent, and high isopsoralen purity of more than 99 percent, and can be used for large-scale production, thereby having wide application prospect.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description, serve to explain the principles of the application.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of isopsoralen;
FIG. 2 is a nuclear magnetic resonance chromatogram of isopsoralen;
FIG. 3 is a mass spectrum of isopsoralen.
Detailed Description
Various exemplary embodiments of the present application will now be described in detail with reference to the accompanying drawings. It should be noted that: the relative arrangement of the components and steps, numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present application unless it is specifically stated otherwise.
A synthesis method of isopsoralen comprises the following steps: the method comprises the steps of (1) taking resorcinol and malic acid as raw materials, synthesizing 7-hydroxycoumarin through Pechmann condensation reaction, (2) synthesizing 7-allyloxy coumarin through etherification reaction, (3) preparing 7-hydroxy-8-allylcoumarin through Claisen rearrangement reaction, and (4) synthesizing isopsoralen through cyclization reaction;
the reaction formula is as follows:
wherein, formula (1) is 7-hydroxy coumarin, formula (2) is 7-allyloxy coumarin, formula (3) is 7-hydroxy-8-allylcoumarin, and formula (4) is isopsoralen. The following examples are described in detail:
example 1
A synthesis method of isopsoralen comprises the following steps:
(1) Preparation of 7-hydroxycoumarin (1): in a 250mL round bottom flask, 100mL H was added 2 SO 4 (98%) in a low temperature reactor to-25℃under stirring, resorcinol (11.00 g,100 mmol) and malic acid (14.74 g,110 mmol) were added slowly to the concentrated H 2 SO 4 In the above step, the reaction temperature was maintained at-25 ℃. After resorcinol and malic acid are added, stirring is continued for 1h at the temperature of minus 20 ℃, the reaction is carried out for 24h after the room temperature is reached, after the reaction is finished, the reaction mixture is slowly added into ice water, precipitate is separated out, the precipitate is collected by suction filtration, washed by ice water and dried, and recrystallized by 95 percent ethanol, 13.94g of white flocculent 7-hydroxycoumarin is obtained, and the yield is 86.05 percent.
(2) Preparation of 7-allyloxy coumarin (2): in a 250mL round bottom flask, acetone (100 mL), 7-hydroxycoumarin (8.10 g,50 mmol) and potassium carbonate (6.90 g,50 mmol) were added and a solution of allyl bromide (6.66 g,55 mmol) in acetone was slowly added dropwise to the reaction system with stirring. After the completion of the dropwise addition, the mixture was heated and refluxed for 10 hours, and after the completion of the reaction, most of the solvent was distilled off under reduced pressure, and white solid was separated out by adding water. The solid was collected by suction filtration, washed with water and dried, and the crude product was recrystallized from 95% ethanol to give 8.79g of 7-allyloxy coumarin as a white flaky solid in 87.03% yield.
(3) Preparation of 7-hydroxy-8-allyl coumarin (3): to a 50mL round-bottomed flask were added 7-allyloxy coumarin (4.04 g,20 mmol) and N, N-dibutylaniline (20 mL), and the mixture was refluxed for 4 hours, after the reaction was completed, the solvent was distilled off under reduced pressure, ice water was added, and the mixture was vigorously stirred to precipitate a white solid. The solid was collected by suction filtration, washed with water and dried, and the crude product was chromatographed on a column of silica gel to give 1.82g of 7-hydroxy-8-allylcoumarin as a white solid in 45.05% yield.
(4) Preparation of isopsoralen (4): in a 100mL round bottom flask, 7-hydroxy-8-allylcoumarin (2.02 g,10 mmol), osmium tetroxide (0.26 g,1 mmol), potassium periodate (2.50 g), methanol (20 mL) and distilled water (10 mL) were added, the reaction was refluxed for 20 hours, and after the reaction was completed, 85% H was added 3 PO 4 (10 mL) stirring was continued for 1h, and the reaction mixture was poured into ice water, and a white solid precipitated. The solid was collected by suction filtration, washed with water and dried, and the crude product was recrystallized from 95% ethanol to give 1.34g of isopsoralen as a white solid in 72.04% yield.
Example 2
A synthesis method of isopsoralen comprises the following steps:
(1) Preparation of 7-hydroxycoumarin (1): in a 250mL round bottom flask, 100mL H was added 2 SO 4 (90%) in a low temperature reactor to-20deg.C, resorcinol (11.00 g,100 mmol) and malic acid (14.74 g,110 mmol) were added slowly to the concentrated H with stirring 2 SO 4 In the above step, the reaction temperature was maintained at-20 ℃. After resorcinol and malic acid are added, stirring is continued for 2 hours at the temperature of minus 20 ℃, then the reaction is carried out for 30 hours at room temperature, after the reaction is finished, the reaction mixture is slowly added into ice water, precipitate is separated out, the precipitate is collected by suction filtration, and the ice waterWashing, drying and recrystallisation from 95% ethanol gave 13.29g of 7-hydroxycoumarin as a white flocculent product in 82.04% yield.
(2) Preparation of 7-allyloxy coumarin (2): in a 250mL round bottom flask, dichloromethane (100 mL), 7-hydroxycoumarin (8.10 g,50 mmol) and sodium carbonate (5.83 g,55 mmol) were added and a solution of allyl bromide (6.66 g,55 mmol) in dichloromethane was slowly added dropwise to the reaction system with stirring. After the completion of the dropwise addition, the mixture was heated and refluxed for 12 hours, and after the completion of the reaction, most of the solvent was distilled off under reduced pressure, and white solid was separated out by adding water. The solid was collected by suction filtration, washed with water and dried, and the crude product was chromatographed on a silica gel column to give 7.37g of 7-allyloxy coumarin as a white flaky solid in 72.97% yield.
(3) Preparation of 7-hydroxy-8-allyl coumarin (3): to a 50mL round-bottomed flask were added 7-allyloxy coumarin (4.04 g,20 mmol) and N, N-diethylaniline (20 mL), and the mixture was refluxed for 6 hours, and after the reaction was completed, the solvent was distilled off under reduced pressure, ice water was added thereto, and the mixture was vigorously stirred to precipitate a white solid. The solid was collected by suction filtration, washed with water and dried, and the crude product was recrystallized from 95% ethanol to give 0.72g of 7-hydroxy-8-allylcoumarin as a white solid in 17.82% yield.
(4) Preparation of isopsoralen (4): in a 100mL round bottom flask, 7-hydroxy-8-allylcoumarin (2.02 g,10 mmol), osmium tetroxide (0.51 g,2 mmol), potassium perchlorate (2.00 g), ethanol (20 mL) and distilled water (10 mL) were added, and after the reaction was completed, the mixture was refluxed for 24 hours, and 98% H was added 2 SO 4 (10 mL) stirring was continued for 1h, and the reaction mixture was poured into ice water, and a white solid precipitated. The solid was collected by suction filtration, washed with water and dried, and the crude product was recrystallized from 95% ethanol to give 1.28g of isopsoralen as a white solid in 68.82% yield.
Example 3
A synthesis method of isopsoralen comprises the following steps:
(1) Preparation of 7-hydroxycoumarin (1): in a 250mL round bottom flask, 100mL H was added 2 SO 4 (80%) resorcinol (11.00 g,100 mmol) and malic acid (14.74 g,110 mmol) were mixed with stirring, cooled to-15℃in a low temperature reactorSlowly adding solid into concentrated H 2 SO 4 In the above step, the reaction temperature was maintained at-15 ℃. After resorcinol and malic acid are added, stirring is continued for 1h at the temperature of minus 15 ℃, the reaction is carried out for 30h after the room temperature is reached, after the reaction is finished, the reaction mixture is slowly added into ice water, precipitate is separated out, the precipitate is collected by suction filtration, washed by ice water and dried, and recrystallized by 95 percent ethanol, 13.10g of white flocculent 7-hydroxycoumarin is obtained, and the yield is 80.86 percent.
(2) Preparation of 7-allyloxy coumarin (2): in a 250mL round bottom flask, chloroform (100 mL), 7-hydroxycoumarin (8.10 g,50 mmol) and potassium hydroxide (2.80 g,50 mmol) were added and a solution of allyl bromide (6.66 g,55 mmol) in chloroform was slowly added dropwise to the reaction system with stirring. After the completion of the dropwise addition, the mixture was heated and refluxed for 10 hours, and after the completion of the reaction, most of the solvent was distilled off under reduced pressure, and white solid was separated out by adding water. The solid was collected by suction filtration, washed with water, dried, and the crude product was recrystallized from 95% ethanol to give 8.52g of 7-allyloxy coumarin as a white flaky solid in 84.36% yield.
(3) Preparation of 7-hydroxy-8-allyl coumarin (3): to a 50mL round-bottomed flask were added 7-allyloxy coumarin (4.04 g,20 mmol) and N, N-dimethylaniline (20 mL), and the mixture was refluxed for 6 hours, after the reaction was completed, the solvent was distilled off under reduced pressure, ice water was added thereto, and the mixture was vigorously stirred to precipitate a white solid. The solid was collected by suction filtration, washed with water and dried, and the crude product was recrystallized from 95% ethanol to give 0.65g of 7-hydroxy-8-allylcoumarin as a white solid in 16.09% yield.
(4) Preparation of isopsoralen (4): in a 100mL round bottom flask, 7-hydroxy-8-allylcoumarin (2.02 g,10 mmol), osmium tetroxide (0.51 g,2 mmol), potassium periodate (3.00 g), methanol (20 mL) and distilled water (10 mL) were added, the reaction was refluxed for 20h, 37% HCl (10 mL) was added after the reaction was completed, stirring was continued for 2h, and the reaction mixture was poured into ice water to precipitate a white solid. The solid was collected by suction filtration, washed with water and dried, and the crude product was recrystallized from 95% ethanol to give 0.97g of isopsoralen as a white solid in 52.15% yield.
Structural characterization data for compounds:
isopsoralen: 1 H NMR(600MHz),δ:8.21(d,J＝9.0Hz,1H),8.08(d,J＝8.4Hz,1H),7.84(d,J＝9.6Hz,1H),7.66(d,J＝9.6Hz,1H),7.02(dd,J＝8.4,1.8Hz,1H),6.59(d,J＝9.0Hz,1H). 13 C NMR(150MHz,),δ:163.77,154.25,153.97,145.24,145.11,135.50,129.61,118.16,115.34,110.72,102.43.HRMS m/z calcd for C 11 H 6 O 3 [M+H] + 187.0390,found 187.0397。
although the present application has been described with reference to the above embodiments, it should be understood that the present application is not limited thereto, and that various changes and modifications may be made by those skilled in the art without departing from the spirit and scope of the present application, and the scope of the present application is defined by the appended claims and their equivalents.
Claims (9)
1. The synthesis method of isopsoralen is characterized by comprising the following steps: the method comprises the steps of (1) taking resorcinol and malic acid as raw materials, synthesizing 7-hydroxycoumarin through Pechmann condensation reaction, (2) synthesizing 7-allyloxy coumarin through etherification reaction, (3) preparing 7-hydroxy-8-allylcoumarin through Claisen rearrangement reaction, and (4) synthesizing isopsoralen through cyclization reaction;
the reaction formula is as follows:
2. the method for synthesizing isopsoralen according to claim 1, comprising the following steps:
(1) Preparation of 7-hydroxycoumarin: in a round bottom flask, add concentrated H 2 SO 4 Cooling to 0-25 deg.c in a low temperature reactor, and adding mixed solid of resorcinol and malic acid into concentrated H slowly while stirring 2 SO 4 After resorcinol and malic acid are added, stirring is continued for 0.5 to 2 hours under the low temperature condition, then the reaction is carried out for 12 to 30 hours at room temperature, after the reaction is finished, the reaction mixture is slowly added into ice water, the sediment is collected by suction filtration, the ice water is washed and dried, and the ethanol with the concentration of 95 percent is used for recrystallization, thus obtaining7-hydroxycoumarin;
(2) Preparation of 7-allyloxy coumarin: adding an organic solvent, 7-hydroxycoumarin and a catalyst into a round bottom flask, slowly dropwise adding an organic solution containing allyl bromide into a reaction system under the condition of stirring, heating and refluxing for 5-12 h after the dropwise adding is finished, evaporating the solvent under reduced pressure after the reaction is finished, adding distilled water and stirring, filtering and collecting solids, washing with water, drying, and recrystallizing a crude product with 95% ethanol to obtain 7-allyloxy coumarin;
(3) Preparation of 7-hydroxy-8-allyl coumarin: adding 7-allyloxy coumarin and organic base into a round-bottom flask, heating and refluxing for 2-6 h, after the reaction is finished, decompressing and steaming to remove the solvent, adding ice water, vigorously stirring, filtering and collecting solid, washing with water, drying, and recrystallizing the crude product with 95% ethanol to obtain 7-hydroxy-8-allylcoumarin;
(4) Preparation of isopsoralen: adding 7-hydroxy-8-allyl coumarin, an oxidant and a solvent into a round bottom flask, reacting for 12-24 hours at room temperature, adding an inorganic acid, continuously stirring for 0.5-2 hours after the reaction is finished, pouring the reaction mixture into ice water, filtering to collect solid, washing with water, drying, and recrystallizing the crude product with 95% ethanol to obtain isopsoralen.
3. The method for synthesizing isopsoralen according to claim 2, wherein in step (1), concentrated H 2 SO 4 The mass fraction is 70% -98%; the mol ratio of resorcinol to malic acid is 1: (1-1.3).
4. The method for synthesizing isopsoralen according to claim 2, wherein in step (2), the organic solvent is one of acetone, dichloromethane or chloroform.
5. The method for synthesizing isopsoralen according to claim 2, wherein in step (2), the catalyst is one of potassium carbonate, sodium carbonate or potassium hydroxide; the mole ratio of 7-hydroxycoumarin, catalyst and allyl bromide is 1: (1-1.2): (1-1.3).
6. The method for synthesizing isopsoralen according to claim 2, wherein in step (3), the organic base is one of N, N-dimethylaniline, N-diethylaniline or N, N-dibutylaniline; the organic base is both a solvent and a catalyst.
7. The method for synthesizing isopsoralen according to claim 2, wherein in step (4), the oxidizing agent is one or more of osmium tetroxide, potassium periodate, and potassium perchlorate.
8. The method for synthesizing isopsoralen according to claim 2, wherein in step (4), the solvent is one or more of methanol, ethanol, and distilled water.
9. The method for synthesizing isopsoralen according to claim 1, wherein in step (4), the mineral acid is 98% h 2 SO 4 37% HCl or 85% H 3 PO 4 One of them.
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