CN116574108A - Synthesis method of psoralen - Google Patents

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

A kind of synthetic method of psoralen

technical field

The invention relates to the technical field of organic synthesis, in particular to a synthesis method of psoralen.

Background technique

Psoralen is a furanocoumarin compound derived from psoraleae, which is also widely found in traditional Chinese medicines such as Adenophora, Fangfeng and Duhuo. It has anti-tumor, anti-osteoporosis, neuroprotection, anti- Inflammation, anti-oxidation and other pharmacological activities can be used to treat rheumatoid arthritis, leukemia, Alzheimer's disease and other diseases. In addition, adding psoralen to cigarettes can reduce tar and free radicals in cigarette smoke, reduce tar and damage, and reveal an elegant bean fragrance when smoking, which can significantly enhance the inner quality of cigarettes Quality has important application value.

However, there are few reports on the synthesis methods of psoralen at present, and psoralen seeds are mainly used as raw materials, which are obtained through multi-step extraction, separation and purification. Due to the complicated extraction process and extremely low extraction rate, psoralen is expensive, which limits its application in cigarettes and medicines.

Therefore, it is particularly important to develop new efficient synthesis methods of psoralen.

Contents of the invention

The technical problem to be solved by this invention is to provide a kind of synthetic method of psoralen, the application uses cheap resorcinol and malic acid as raw materials, synthesizes 7-hydroxycoumarin through Pechmann condensation reaction; then, through etherification Reaction makes 7-allyloxy coumarin; Afterwards, adopts Claisen rearrangement reaction to generate 6-allyl-7-hydroxyl coumarin; Finally synthesize natural compound psoralen by cyclization reaction, this synthetic method The operation is simple, the yield is high, and large-scale production is easy.

The technical problem to be solved by the present invention is achieved through the following technical solutions:

A kind of synthetic method of psoralen, comprises the following steps: (1) take resorcinol and malic acid as raw material, synthesize 7-hydroxycoumarin by Pechmann condensation reaction, (2) synthesize 7-hydroxycoumarin through etherification reaction - Allyloxycoumarin, (3) adopt Claisen rearrangement reaction to obtain 6-allyl-7-hydroxycoumarin, (4) synthesize psoralen by cyclization reaction;

The reaction formula is as follows:

Preferably, it specifically includes the following steps:

(1) Preparation of 7-hydroxycoumarin: In a round bottom flask, add concentrated H ₂ SO ₄ , cool to 0～-25°C in a low-temperature reactor, and then mix resorcinol and The mixed solids of malic acid were slowly added to _{concentrated H2SO4} . After resorcinol and malic acid are added, continue to stir at low temperature for 0.5-2 hours, then rise to room temperature and react for 12-30 hours. After the reaction, slowly add the reaction mixture to ice water, collect the precipitate by suction filtration, and wash with ice water , dried, and recrystallized with 95% ethanol to obtain 7-hydroxycoumarin.

(2) Preparation of 7-allyloxycoumarin: In a round bottom flask, add organic solvent, 7-hydroxycoumarin and catalyst, and slowly drop the organic solution containing allyl bromide under stirring condition added to the reaction system. After the dropwise addition, heat to reflux for 5-12 hours. After the reaction, evaporate the solvent under reduced pressure, add distilled water to stir, collect the solid by suction filtration, wash with water, and dry. The crude product is recrystallized with 95% ethanol to obtain 7-allyloxy Coumarin.

(3) Preparation of 6-allyl-7-hydroxycoumarin: In a round bottom flask, add 7-allyloxycoumarin and an organic base, heat and reflux for 2-6 hours, after the reaction, depressurize The solvent was evaporated, then ice water was added, stirred vigorously, the solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized with 95% ethanol to obtain 6-allyl-7-hydroxycoumarin.

(4) Preparation of psoralen: in a round bottom flask, add 6-allyl-7-hydroxycoumarin, oxidizing agent and solvent, and react at room temperature for 12-24 hours. After the reaction, add mineral acid and continue to stir for 0.5 After ~2h, the reaction mixture was poured into ice water, the solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized with 95% ethanol to obtain psoralen.

Preferably, the mass fraction of concentrated H ₂ SO ₄ in step (1) is 70%-98%; the molar ratio of resorcinol to malic acid is 1:(1-1.3).

Preferably, in step (2), organic solvent is a kind of in acetone, dichloromethane or chloroform; Catalyst is a kind of in salt of wormwood, sodium carbonate or potassium hydroxide; 7-hydroxycoumarin, catalyzer and The molar ratio of allyl bromide is 1:(1~1.2):(1~1.3).

Preferably, the organic base in step (3) is one of triethylamine, N,N-dimethylaniline or N,N-diethylaniline; the organic base is both a solvent and a catalyst.

Preferably, in the step (4), the oxidant 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 One of ₂ SO ₄ , 37% HCl or 85% H ₃ PO ₄ .

The technical scheme of the present invention has the following beneficial effects:

The synthesis method of psoralen of the present application has simple process, cheap and easy-to-obtain raw materials, simple separation and purification of products, and the yield is higher than 70%. Finally, the psoralen has a purity of more than 99%, and can be mass-produced , has broad application prospects.

Description of drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention.

Fig. 1 is the proton nuclear magnetic resonance spectrum figure of psoralen;

Fig. 2 is the carbon nuclear magnetic resonance spectrogram of psoralen;

Figure 3 is the mass spectrum of psoralen.

Detailed ways

Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be noted that the relative arrangements of components and steps, numerical expressions and numerical values set forth in these embodiments do not limit the scope of the present invention unless specifically stated otherwise.

A kind of synthetic method of psoralen, comprises the following steps: (1) take resorcinol and malic acid as raw material, synthesize 7-hydroxycoumarin by Pechmann condensation reaction, (2) synthesize 7-hydroxycoumarin through etherification reaction - Allyloxycoumarin, (3) adopt Claisen rearrangement reaction to obtain 6-allyl-7-hydroxycoumarin, (4) synthesize psoralen by cyclization reaction;

The reaction formula is as follows:

Wherein, formula (1) is 7-hydroxy coumarin, formula (2) is 7-allyloxy coumarin, formula (3) is 6-allyl-7-hydroxy coumarin, formula (4 ) is psoralen. Describe in detail with embodiment below:

Example 1

A synthetic method for psoralen, comprising the following steps:

(1) Preparation of 7-hydroxycoumarin (1): In a 250mL round bottom flask, add 100mL H ₂ SO ₄ (98%), cool to -25°C in a low-temperature reactor, and A mixed solid of resorcinol (11.00 g, 100 mmol) and malic acid (14.74 g, 110 mmol) was slowly added to concentrated _H2SO4 , keeping the reaction temperature at -25°C _. After resorcinol and malic acid were added, continue to stir at -20°C for 1 hour, then raise to room temperature and react for 24 hours. After the reaction, slowly add the reaction mixture into ice water to precipitate a precipitate, collect the precipitate by suction filtration, and wash with ice water , dried, and recrystallized with 95% ethanol to obtain 13.94 g of white flocculent product 7-hydroxycoumarin, with a yield of 86.05%.

(2) Preparation of 7-allyloxycoumarin (2): In a 250mL round bottom flask, add acetone (100mL), 7-hydroxycoumarin (8.10g, 50mmol) and potassium carbonate (6.90g , 50mmol), under stirring condition, the acetone solution of allyl bromide (6.66g, 55mmol) was slowly added dropwise into the reaction system. After the dropwise addition, it was heated to reflux for 10 h. After the reaction, most of the solvent was evaporated under reduced pressure, and a white solid was precipitated by adding water. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized from 95% ethanol to obtain 8.79 g of white flaky solid 7-allyloxycoumarin with a yield of 87.03%.

(3) Preparation of 6-allyl-7-hydroxycoumarin (3): In a 50mL round bottom flask, add 7-allyloxycoumarin (4.04g, 20mmol) and N,N- Diethylaniline (20 mL) was heated to reflux for 4 h. After the reaction, the solvent was evaporated under reduced pressure, and then ice water was added and stirred vigorously to precipitate a white solid. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized from 95% ethanol to obtain 3.13 g of white solid 6-allyl-7-hydroxycoumarin with a yield of 77.48%.

(4) Preparation of psoralen (4): In a 100mL round bottom flask, add 6-allyl-7-hydroxycoumarin (2.02g, 10mmol), osmium tetroxide (0.26g, 1mmol) , potassium periodate (2.50g), methanol (20mL) and distilled water (10mL), reflux for 20h, after the reaction, add 85% H ₃ PO ₄ (10mL) and continue stirring for 1h, pour the reaction mixture into ice water, A white solid precipitated out. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized with 95% ethanol to obtain 1.34 g of white solid psoralen, with a yield of 72.04%.

Example 2

A synthetic method for psoralen, comprising the following steps:

(1) Preparation of 7-hydroxycoumarin (1): In a 250mL round-bottomed flask, add 100mL H ₂ SO ₄ (90%), cool to -20°C in a low-temperature reactor, and, under stirring, A mixed solid of resorcinol (11.00 g, 100 mmol) and malic acid (14.74 g, 110 mmol) _was slowly added to concentrated _H2SO4 , keeping the reaction temperature at -20°C. After adding resorcinol and malic acid, continue to stir at -20°C for 2 hours, then rise to room temperature and react for 30 hours. After the reaction is completed, slowly add the reaction mixture to ice water to precipitate precipitates, collect the precipitates by suction filtration, and wash with ice water , dried, and recrystallized with 95% ethanol to obtain 13.29 g of white flocculent product 7-hydroxycoumarin, with a yield of 82.04%.

(2) Preparation of 7-allyloxycoumarin (2): In a 250mL round bottom flask, add dichloromethane (100mL), 7-hydroxycoumarin (8.10g, 50mmol) and sodium carbonate ( 5.83g, 55mmol), under the condition of stirring, a solution of allyl bromide (6.66g, 55mmol) in dichloromethane was slowly added dropwise into the reaction system. After the dropwise addition, it was heated to reflux for 12 hours. After the reaction, most of the solvent was evaporated under reduced pressure, and a white solid was precipitated by adding water. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized from 95% ethanol to obtain 7.37 g of white flaky solid 7-allyloxycoumarin with a yield of 72.97%.

(3) Preparation of 6-allyl-7-hydroxycoumarin (3): In a 50mL round bottom flask, add 7-allyloxycoumarin (4.04g, 20mmol) and triethylamine ( 20 mL), heated to reflux for 6 h, after the reaction, the solvent was evaporated under reduced pressure, then ice water was added, stirred vigorously, and a white solid was precipitated. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized from 95% ethanol to obtain 2.58 g of white solid 6-allyl-7-hydroxycoumarin with a yield of 63.86%.

(4) Preparation of psoralen (4): In a 100mL round bottom flask, add 6-allyl-7-hydroxycoumarin (2.02g, 10mmol), osmium tetroxide (0.51g, 2mmol) , potassium perchlorate (2.00g), ethanol (20mL) and distilled water (10mL), reflux for 24h, after the reaction, add 98% H ₂ SO ₄ (10mL) and continue to stir for 1h, pour the reaction mixture into ice water, and white solid. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized with 95% ethanol to obtain 1.28 g of white solid psoralen with a yield of 68.82%.

Example 3

A synthetic method for psoralen, comprising the following steps:

(1) Preparation of 7-hydroxycoumarin (1): In a 250mL round-bottomed flask, add 100mL H ₂ SO ₄ (80%), cool to -15°C in a low-temperature reactor, and, under stirring, A mixed solid of resorcinol (11.00 g, 100 mmol) and malic acid (14.74 g, 110 mmol) was slowly added to concentrated _H2SO4 , keeping the reaction temperature at -15°C _. After adding resorcinol and malic acid, continue to stir at -15°C for 1 hour, then rise to room temperature and react for 30 hours. After the reaction is completed, slowly add the reaction mixture to ice water to precipitate a precipitate, collect the precipitate by suction filtration, and wash with ice water , dried, and recrystallized with 95% ethanol to obtain 13.10 g of white flocculent product 7-hydroxycoumarin, with a yield of 80.86%.

(2) Preparation of 7-allyloxycoumarin (2): In a 250mL round bottom flask, add chloroform (100mL), 7-hydroxycoumarin (8.10g, 50mmol) and potassium hydroxide (2.80g, 50mmol), and under stirring conditions, a solution of allyl bromide (6.66g, 55mmol) in chloroform was slowly added dropwise to the reaction system. After the dropwise addition, it was heated to reflux for 10 h. After the reaction, most of the solvent was evaporated under reduced pressure, and a white solid was precipitated by adding water. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized from 95% ethanol to obtain 8.52 g of white flaky solid 7-allyloxycoumarin with a yield of 84.36%.

(3) Preparation of 6-allyl-7-hydroxycoumarin (3): In a 50mL round bottom flask, add 7-allyloxycoumarin (4.04g, 20mmol) and N,N- Dimethylaniline (20mL) was heated to reflux for 6h. After the reaction, the solvent was evaporated under reduced pressure, and then ice water was added and stirred vigorously to precipitate a white solid. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized from 95% ethanol to obtain 2.97 g of white solid 6-allyl-7-hydroxycoumarin with a yield of 73.51%.

(4) Preparation of psoralen (4): In a 100mL round bottom flask, add 6-allyl-7-hydroxycoumarin (2.02g, 10mmol), osmium tetroxide (0.51g, 2mmol) , potassium periodate (3.00g), methanol (20mL) and distilled water (10mL), reflux for 20h, after the reaction, add 37% HCl (10mL) and continue to stir for 2h, pour the reaction mixture into ice water, and precipitate a white solid . The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized with 95% ethanol to obtain 0.97 g of white solid psoralen, with a yield of 52.15%.

The structural characterization data of the compound:

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 invention has been disclosed as above with the embodiments, it is not intended to limit the present invention, and any person skilled in the art can make various choices and modifications without departing from the spirit and scope of the present invention. Therefore, the present invention The scope of protection is defined by the 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.