CN116574108A - Synthesis method of psoralen - Google Patents

Synthesis method of psoralen Download PDF

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Publication number
CN116574108A
CN116574108A CN202310502030.1A CN202310502030A CN116574108A CN 116574108 A CN116574108 A CN 116574108A CN 202310502030 A CN202310502030 A CN 202310502030A CN 116574108 A CN116574108 A CN 116574108A
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reaction
psoralen
synthesizing
hydroxycoumarin
allyl
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王清福
陈芝飞
席高磊
于建春
杜佳
刘强
王根发
孙志涛
杨琦
赵学斌
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China Tobacco Henan Industrial Co Ltd
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China Tobacco Henan Industrial Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D493/00Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The application discloses a method for synthesizing psoralen, 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 6-allyl-7-hydroxycoumarin through Claisen rearrangement reaction, and (4) synthesizing psoralen 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 70%, and high final psoralen purity of more than 99%, and can be used for large-scale production, thereby having wide application prospect.

Description

Synthesis method of psoralen
Technical Field
The application relates to the technical field of organic synthesis, in particular to a method for synthesizing psoralen.
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 psoralen, 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 6-allyl-7-hydroxycoumarin; finally, the natural compound psoralen is synthesized through cyclization reaction, and the synthesis method is simple to operate, high in yield and easy for large-scale production.
The technical problems to be solved by the application are realized by the following technical scheme:
a method for synthesizing psoralen 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 6-allyl-7-hydroxycoumarin through Claisen rearrangement reaction, and (4) synthesizing psoralen 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 6-allyl-7-hydroxycoumarin: 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 6-allyl-7-hydroxy coumarin.
(4) Preparation of psoralen: adding 6-allyl-7-hydroxycoumarin, 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 the psoralen.
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 triethylamine, N-dimethylaniline or N, N-diethylaniline; 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 the psoralen has the advantages of simple process, cheap and easily obtained raw materials, simple product separation and purification, high yield of 70 percent, and high psoralen 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 psoralen;
FIG. 2 is a nuclear magnetic resonance chromatogram of psoralen;
FIG. 3 is a mass spectrum of psoralen.
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 method for synthesizing psoralen 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 6-allyl-7-hydroxycoumarin through Claisen rearrangement reaction, and (4) synthesizing psoralen through cyclization reaction;
the reaction formula is as follows:
wherein, formula (1) is 7-hydroxycoumarin, formula (2) is 7-allyloxy coumarin, formula (3) is 6-allyl-7-hydroxycoumarin, and formula (4) is psoralen. The following examples are described in detail:
example 1
A method for synthesizing psoralen 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 6-allyl-7-hydroxycoumarin (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 4 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 3.13g of 6-allyl-7-hydroxycoumarin as a white solid in 77.48% yield.
(4) Preparation of psoralen (4): in a 100mL round bottom flask, 6-allyl-7-hydroxycoumarin (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 20H, 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 psoralen as a white solid in 72.04% yield.
Example 2
A method for synthesizing psoralen 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 ℃. Adding resorcinol and malic acid, stirring at-20deg.C for 2 hr, cooling to room temperature for 30 hr, slowly adding the reaction mixture into ice water after the reaction is completed, precipitating, vacuum filtering to collect precipitate, washing with ice water, drying, recrystallizing with 95% ethanol to obtain 13.29g white battingThe product 7-hydroxycoumarin was obtained 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 recrystallized from 95% ethanol to give 7.37g of 7-allyloxy coumarin as a white flaky solid in 72.97% yield.
(3) Preparation of 6-allyl-7-hydroxycoumarin (3): 7-allyloxy coumarin (4.04 g,20 mmol) and triethylamine (20 mL) were added to a 50mL round-bottomed flask, and the mixture was heated under reflux for 6 hours, after the reaction was completed, the solvent was distilled off under reduced pressure, ice water was further added thereto, and stirring was vigorously performed 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 2.58g of 6-allyl-7-hydroxycoumarin as a white solid in 63.86% yield.
(4) Preparation of psoralen (4): in a 100mL round bottom flask, 6-allyl-7-hydroxycoumarin (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 psoralen as a white solid in 68.82% yield.
Example 3
A method for synthesizing psoralen comprises the following steps:
(1) Preparation of 7-hydroxycoumarin (1): in a 250mL round bottom flask, 100mL H was added 2 SO 4 (80%) in a low temperature reactor to-15℃and 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 which the reaction temperature was maintained at-15DEG C. 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 6-allyl-7-hydroxycoumarin (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 2.97g of 6-allyl-7-hydroxycoumarin as a white solid in 73.51% yield.
(4) Preparation of psoralen (4): in a 100mL round bottom flask, 6-allyl-7-hydroxycoumarin (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, after the reaction was completed, 37% HCl (10 mL) was added and 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 psoralen as a white solid in 52.15% yield.
Structural characterization data for compounds:
psoralen: 1 H NMR(600MHz),δ:8.18(d,J=9.6Hz,1H),8.12(d,J=2.4Hz,1H),8.01(s,1H),7.73(s,1H),7.10(dd,J=2.4,1.2Hz,1H),6.44(d,J=9.0Hz,1H). 13 C NMR(150MHz,),δ:160.66,156.17,151.99,148.41,145.50,125.04,121.16,115.85,114.58,107.23,99.81.HRMS m/z calcd for C 11 H 6 O 3 [M+H] + 187.0390,found 187.0402。
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. A method for synthesizing psoralen, which 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 6-allyl-7-hydroxycoumarin through Claisen rearrangement reaction, and (4) synthesizing psoralen through cyclization reaction;
the reaction formula is as follows:
2. the method for synthesizing psoralen 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 0.5-2 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: 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 6-allyl-7-hydroxycoumarin: 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 6-allyl-7-hydroxy coumarin;
(4) Preparation of psoralen: adding 6-allyl-7-hydroxycoumarin (3), an oxidant and a solvent into a round bottom flask, reacting for 12-24 hours at room temperature, adding 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 the psoralen.
3. The method for synthesizing psoralen 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 psoralen according to claim 2, wherein in step (2), the organic solvent is one of acetone, dichloromethane or chloroform.
5. The method for synthesizing psoralen according to claim 4, 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 psoralen according to claim 2, wherein in step (3), the organic base is one of triethylamine, N-dimethylaniline or N, N-diethylaniline; the organic base is both a solvent and a catalyst.
7. The method for synthesizing psoralen 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 psoralen according to claim 7, wherein in step (4), the solvent is one or more of methanol, ethanol and distilled water.
9. The method for synthesizing psoralen according to claim 8, wherein in step (4), the inorganic acid is 98% h 2 SO 4 37% HCl or 85% H 3 PO 4 One of them.
CN202310502030.1A 2023-05-06 2023-05-06 Synthesis method of psoralen Pending CN116574108A (en)

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