CN116554189A - Efficient preparation method of isopsoralen - Google Patents

Abstract

The invention discloses a high-efficiency preparation method of isopsoralen, which comprises the following steps: (1) resorcinol is used as a raw material, 3-allyloxyphenol is synthesized through etherification reaction with allyl bromide, (2) 2-allylresorcinol is synthesized through Claisen rearrangement reaction, (3) 4-hydroxybenzofuran is prepared through oxidation cyclization reaction, and (4) isopsoralen is synthesized through Pechmann condensation reaction. The high-efficiency preparation method of isopsoralen has the advantages of simple process, cheap and easily obtained raw materials, simple product separation and purification, high yield of 55%, and high isopsoralen purity of more than 99%, and can be used for large-scale production, thereby having wide application prospect.

Description

A kind of efficient preparation method of isopsoralen

technical field

The invention relates to the technical field of organic synthesis, in particular to a high-efficiency preparation method of isopsoralen.

Background technique

Isopsoralen (angelicin) is the main active ingredient in psoralen extract, which is isomer with psoralen, and the structure of pyrone ring, benzene ring and furan ring on a straight line is the complement Boralen, not in a straight line is V-type isopsoralen. Isopsoralen has anti-tumor, anti-inflammatory, anti-viral, osteogenic and cartilage-promoting effects, and has good research prospects in the treatment of cancer, osteoporosis, neurodegenerative diseases and other fields. In addition, isopsoralen is added to cigarettes, which reveals an elegant bean flavor when smoking, which can significantly improve the internal quality of cigarettes. It can be used as a substitute for coumarin and has important application value.

However, there are few reports on the synthesis methods of isopsoralen at present, and it is mainly obtained by extraction, separation and purification from natural plants. Due to the complicated extraction process and extremely low extraction rate, the price of isopsoralen is expensive, and the price of 10mg is more than 800 yuan, which limits the application range of isopsoralen.

Therefore, it is very important to develop new efficient preparation methods of isopsoralen.

Contents of the invention

The technical problem to be solved by the present invention is to provide a high-efficiency preparation method of isopsoralen. By analyzing the structure of isopsoralen, the present invention synthesizes isopsoralen by first constructing the furan ring and then constructing the pyrone ring. Lipogen. First, cheap resorcinol is used as raw material to produce 3-allyloxyphenol by etherification reaction with allyl bromide; then, 2-allyl resorcinol is synthesized by Claisen rearrangement reaction; after that, 4-Hydroxybenzofuran was obtained by oxidative cyclization; finally, the natural compound isopsoralen was synthesized by Pechmann condensation reaction. The preparation method has the advantages of simple operation, high yield and easy large-scale production.

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

An efficient preparation method of isopsoralen, the reaction formula of the preparation method is as follows:

The synthetic method of different psoralen comprises the following steps:

(1) Preparation of 3-allyloxyphenol (1): In a round bottom flask, add organic solvent, resorcinol and catalyst, under stirring condition, slowly add the organic solution containing allyl bromide in 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 3-allyloxy Phenol (1).

(2) Preparation of 2-allyl resorcinol (2): in a round bottom flask, add 3-allyloxyphenol (1) and an organic base, heat and reflux for 2-6 hours, after the reaction, reduce The solvent was evaporated under pressure, then ice water was added, stirred vigorously, the solid was collected by suction filtration, washed with water, and dried. The crude product was subjected to silica gel column chromatography to obtain 2-allyl resorcinol (2).

(3) Preparation of 4-hydroxybenzofuran (3): In a round bottom flask, add 2-allyl resorcinol (2), oxidizing agent and solvent, and react at room temperature for 12-24 hours. After the reaction, add The inorganic acid continued to stir for 0.5-2 hours, 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 4-hydroxybenzofuran (3).

(4) Preparation of isopsoralen (4): In a round bottom flask, add concentrated H ₂ SO ₄ , cool to 0～-25°C in a low-temperature reactor, and then, under stirring conditions, dissolve 4-hydroxy The mixed solids of benzofuran (3) and malic acid were slowly added to _{concentrated H2SO4} . After adding 4-hydroxybenzofuran and malic acid, continue to stir at low temperature for 0.5-2 hours, then rise to room temperature and react for 12-30 hours. Washed with water, dried, and recrystallized with 95% ethanol to obtain isopsoralen (4).

Preferably, in the technique scheme, in step (1), the organic solvent is one of acetone, dichloromethane or chloroform; the catalyst is one of potassium carbonate, sodium carbonate or potassium hydroxide; resorcinol , The molar ratio of catalyst and allyl bromide is 1: (1-1.2): (1-1.3).

Preferably, in the above technical scheme, the organic base in step (2) is one of N,N-dimethylaniline, N,N-diethylaniline or N,N-dibutylaniline; the organic base is either It is a solvent and a catalyst.

Preferably, in the above technical scheme, the oxidant in step (3) is one or more of osmium tetroxide, potassium periodate or potassium perchlorate; the solvent is one or more of methanol, ethanol or distilled water; inorganic The acid is one of 98% H ₂ SO ₄ , 37% HCl or 85% H ₃ PO ₄ .

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

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

The invention creatively synthesizes the natural compound isopsoralen by using cheap resorcinol as raw material. The first step is to synthesize 3-allyloxyphenol by etherification reaction, the second step is to synthesize 2-allyl resorcinol by Claisen rearrangement reaction, and the third step is to prepare 4-hydroxybenzo Furan, the fourth step is to synthesize isopsoralen by Pechmann condensation reaction.

The four-step reaction process of the technical scheme is simple, the raw materials used are cheap and easy to obtain, the product separation and purification are simple, the yield is higher than 55%, and the final purity of isopsoralen reaches more than 99%, which can be produced on a large scale and has a wide range of applications. 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 hydrogen nuclear magnetic resonance spectrogram of isopsoralen;

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

Figure 3 is the mass spectrum of isopsoralen.

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.

An efficient preparation method of isopsoralen, the reaction formula of the preparation method is as follows:

Wherein, formula (1) is 3-allyloxyphenol, formula (2) is 2-allyl resorcinol, formula (3) is 4-hydroxybenzofuran, and formula (4) is isotonic Lipogen.

The efficient preparation method of isopsoralen comprises the following steps:

(1) Preparation of 3-allyloxyphenol (1): In a round bottom flask, add organic solvent, resorcinol and catalyst, under stirring condition, slowly add the organic solution containing allyl bromide in 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 3-allyloxy Phenol (1).

Wherein, in the step (1), the organic solvent is one of acetone, dichloromethane or chloroform; the catalyst is one of potassium carbonate, sodium carbonate or potassium hydroxide; resorcinol, catalyst and allyl The molar ratio of bromine is 1:(1~1.2):(1~1.3).

(2) Preparation of 2-allyl resorcinol (2): in a round bottom flask, add 3-allyloxyphenol (1) and an organic base, heat and reflux for 2-6 hours, after the reaction, reduce The solvent was evaporated under pressure, then ice water was added, stirred vigorously, the solid was collected by suction filtration, washed with water, and dried. The crude product was subjected to silica gel column chromatography to obtain 2-allyl resorcinol (2).

Wherein, the organic base in step (2) is one of N,N-dimethylaniline, N,N-diethylaniline or N,N-dibutylaniline; the organic base is both a solvent and a catalyst .

(3) Preparation of 4-hydroxybenzofuran (3): In a round bottom flask, add 2-allyl resorcinol (2), oxidizing agent and solvent, and react at room temperature for 12-24 hours. After the reaction, add The inorganic acid continued to stir for 0.5-2 hours, 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 4-hydroxybenzofuran (3).

Wherein, in the step (3), 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% _H2 One of SO ₄ , 37% HCl or 85% H ₃ PO ₄ .

(4) Preparation of isopsoralen (4): In a round bottom flask, add concentrated H ₂ SO ₄ , cool to 0～-25°C in a low-temperature reactor, and then, under stirring conditions, dissolve 4-hydroxy The mixed solids of benzofuran (3) and malic acid were slowly added to _{concentrated H2SO4} . After adding 4-hydroxybenzofuran and malic acid, continue to stir at low temperature for 0.5-2 hours, then rise to room temperature and react for 12-30 hours. Washed with water, dried, and recrystallized with 95% ethanol to obtain isopsoralen (4).

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

The specific embodiment of this application is as follows:

Example 1

A high-efficiency preparation method of isopsoralen, comprising the following steps:

(1) Preparation of 3-allyloxyphenol (1): In a 250mL round bottom flask, add acetone (160mL), resorcinol (11.00g, 100mmol) and potassium carbonate (13.80g, 100mmol), Under the condition of stirring, the acetone solution of allyl bromide (12.10 g, 110 mmol) 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 13.77 g of white flaky solid 3-allyloxyphenol with a yield of 91.80%.

(2) Preparation of 2-allyl resorcinol (2): In a 100mL round bottom flask, add 3-allyloxyphenol (7.50g, 50mmol) and N,N-dibutylaniline ( 50 mL), and heated to reflux for 4 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 subjected to silica gel column chromatography to obtain 4.77 g of white solid 2-allyl resorcinol with a yield of 63.60%.

(3) Preparation of 4-hydroxybenzofuran (3): In a 100mL round bottom flask, add 2-allyl resorcinol (3.00g, 20mmol), osmium tetroxide (0.52g, 2mmol), Potassium periodate (2.50g), methanol (20mL) and distilled water (10mL) were refluxed for 20h. After the reaction, 85% H ₃ PO ₄ (10mL) was added and stirred for 1h. The reaction mixture was poured into ice water to precipitate white solid. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized with 95% ethanol to obtain 2.01 g of white solid isopsoralen with a yield of 75.00%.

(4) Preparation of isopsoralen (4): In a 50mL round bottom flask, add 20mL H ₂ SO ₄ (98%), cool to -5°C in a low-temperature reactor, and stir the 4-Hydroxybenzofuran (1.34g, 10mmol) and malic acid (1.47g, 11mmol) mixed solids were slowly added to concentrated _H2SO4 , keeping the reaction temperature at -5°C _. After adding 4-hydroxybenzofuran and malic acid, continue to stir at -5°C for 1 hour, then raise to room temperature and react for 24 hours. Washed with water, dried, and recrystallized with 95% ethanol to obtain 1.16 g of white flocculent product isopsoralen, with a yield of 62.37%.

Example 2

A high-efficiency preparation method of isopsoralen, comprising the following steps:

(1) Preparation of 3-allyloxyphenol (1): In a 250mL round bottom flask, add dichloromethane (160mL), resorcinol (11.00g, 100mmol) and sodium carbonate (11.66g, 110mmol ), under stirring conditions, a solution of allyl bromide (12.10 g, 110 mmol) in dichloromethane 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 11.36 g of white flaky solid 3-allyloxyphenol with a yield of 75.73%.

(2) Preparation of 2-allyl resorcinol (2): In a 100mL round bottom flask, add 3-allyloxyphenol (7.50g, 50mmol) and N,N-diethylaniline ( 50 mL), and heated to reflux for 5 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 subjected to silica gel column chromatography to obtain 3.45 g of white solid 2-allyl resorcinol with a yield of 46.00%.

(3) Preparation of 4-hydroxybenzofuran (3): In a 100mL round bottom flask, add 2-allyl resorcinol (3.00g, 20mmol), osmium tetroxide (0.52g, 2mmol), Potassium perchlorate (2.00g), methanol (20mL) and distilled water (10mL), reflux for 20h, after the reaction, add 98% H ₂ SO ₄ (10mL) and continue stirring for 1h, pour the reaction mixture into ice water, and a white solid precipitates . The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized with 95% ethanol to obtain 1.73 g of white solid isopsoralen, with a yield of 64.55%.

(4) Preparation of isopsoralen (4): In a 50mL round bottom flask, add 20mL H ₂ SO ₄ (98%), cool to -10°C in a low-temperature reactor, and stir the 4-Hydroxybenzofuran (1.34g, 10mmol) and malic acid (1.47g, 11mmol) mixed solids were slowly added to concentrated _H2SO4 , keeping the reaction temperature at -10°C _. After adding 4-hydroxybenzofuran and malic acid, continue to stir at -10°C for 2 hours, then raise to room temperature and react for 30 hours. After the reaction, slowly add the reaction mixture into ice water to precipitate precipitates, and collect the precipitates by suction filtration. Washed with ice water, dried, and recrystallized with 95% ethanol to obtain 1.09 g of white flocculent product isopsoralen, with a yield of 58.60%.

Example 3

A high-efficiency preparation method of isopsoralen, comprising the following steps:

(1) Preparation of 3-allyloxyphenol (1): In a 250mL round bottom flask, add chloroform (160mL), resorcinol (11.00g, 100mmol) and potassium hydroxide (5.60g, 100mmol), under the condition of stirring, the chloroform solution of allyl bromide (12.10g, 110mmol) was slowly added dropwise into the reaction system. After the dropwise addition, it was heated to reflux for 9 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 10.56 g of white flaky solid 3-allyloxyphenol with a yield of 70.40%.

(2) Preparation of 2-allyl resorcinol (2): In a 100mL round bottom flask, add 3-allyloxyphenol (7.50g, 50mmol) and N,N-dimethylaniline ( 50 mL), and 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 subjected to silica gel column chromatography to obtain 2.91 g of white solid 2-allyl resorcinol with a yield of 38.80%.

(3) Preparation of 4-hydroxybenzofuran (3): In a 100mL round bottom flask, add 2-allyl resorcinol (3.00g, 20mmol), osmium tetroxide (0.52g, 2mmol), Potassium periodate (3.00g), methanol (20mL) and distilled water (10mL) were refluxed for 24h. After the reaction, 37% HCl (10mL) was added to continue stirring for 1h. 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. The crude product was recrystallized with 95% ethanol to obtain 1.55 g of white solid isopsoralen, with a yield of 57.84%.

(4) Preparation of isopsoralen (4): In a 50mL round bottom flask, add 20mL H ₂ SO ₄ (98%), cool to -15°C in a low-temperature reactor, under stirring conditions, 4-Hydroxybenzofuran (1.34 g, 10 _mmol ) and malic acid (1.47 g, 11 mmol) were added as solid mixture slowly to concentrated _H2SO4 , keeping the reaction temperature at -15°C. After adding 4-hydroxybenzofuran and malic acid, continue to stir at -15°C for 1 hour, then rise to room temperature and react for 30 hours. Washed with water, dried, and recrystallized with 95% ethanol to obtain 1.01 g of white floc product isopsoralen with a yield of 54.30%.

The structural characterization data of the compound:

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 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 (8)

1. The efficient preparation method of the isopsoralen is characterized by comprising the steps of (1) taking resorcinol as a raw material, synthesizing 3-allyloxyphenol through etherification reaction with allyl bromide, (2) synthesizing 2-allylresorcinol through Claisen rearrangement reaction, (3) preparing 4-hydroxybenzofuran through oxidation cyclization reaction, and (4) synthesizing the isopsoralen through Pechmann condensation reaction;

the reaction formula is as follows:

2. the efficient preparation method of isopsoralen according to claim 1, which is characterized by comprising the following steps:

(1) Preparation of 3-allyloxyphenol: adding an organic solvent, resorcinol 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 for stirring, filtering and collecting solids, washing with water, drying, and recrystallizing a crude product with 95% ethanol to obtain 3-allyloxyphenol;

(2) Preparation of 2-allyl resorcinol: adding 3-allyloxyphenol 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, suction-filtering and collecting solid, washing with water, drying, and carrying out silica gel column chromatography on the crude product to obtain 2-allylresorcinol;

(3) Preparation of 4-hydroxybenzofuran: adding 2-allyl resorcinol, 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, suction-filtering to collect solid, washing with water, drying, and recrystallizing a crude product with 95% ethanol to obtain 4-hydroxy benzofuran;

(4) Preparation of isopsoralen: in a round bottom flask, add concentrated H ₂ SO ₄ Cooling to 0 to minus 25 ℃ in a low-temperature reactor, and then slowly adding the mixed solid of 4-hydroxy benzofuran and malic acid into concentrated H under stirring condition ₂ SO ₄ After adding 4-hydroxy benzofuran and malic acid, stirring continuously for 0.5-2 h at low temperature, then heating to room temperature for reaction for 12-30 h, after the reaction is finished, slowly adding the reaction mixture into ice water, suction filtering, collecting precipitate, washing with ice water, drying, and obtaining 95% ethyl acetateRecrystallizing with alcohol to obtain isopsoralen.

3. The efficient preparation method of isopsoralen according to claim 2, wherein in step (1), the organic solvent is one of acetone, dichloromethane or chloroform; the catalyst is one of potassium carbonate, sodium carbonate or potassium hydroxide; the molar ratio of resorcinol, catalyst and allyl bromide is 1: (1-1.2): (1-1.3).

4. The efficient preparation method of isopsoralen according to claim 2, wherein the organic base in step (2) is one of N, N-dimethylaniline, N-diethylaniline or N, N-dibutylaniline; the organic base is a solvent and a catalyst.

5. The efficient isopsoralen production method according to claim 2, wherein in step (3), the oxidizing agent is one or more of osmium tetroxide, potassium periodate, and potassium perchlorate.

6. The efficient isopsoralen production method according to claim 2, wherein in step (3), the solvent is one or more of methanol, ethanol, and distilled water.

7. The efficient isopsoralen production method according to claim 2, wherein in step (3), the mineral acid is 98% h ₂ SO ₄ 37% HCl or 85% H ₃ PO ₄ One of them.

8. The efficient isopsoralen production method according to claim 1, wherein concentrated H in step (4) ₂ SO ₄ The mass fraction is 70% -98%; the molar ratio of 4-hydroxy benzofuran to malic acid is 1: (1-1.3).