CN113233973B - Preparation method of symmetrical aromatic anhydride compound - Google Patents

Abstract

The invention discloses a preparation method of a symmetrical aromatic anhydride compound, which comprises the following steps: dissolving alpha-terpineol and pyridine in a solvent, adding an aromatic acyl chloride solution, and reacting for 8-16 h to obtain the symmetrical aromatic anhydride compound. The method has the advantages of easy operation, mild reaction conditions, high safety, simple process and post-treatment, low cost, high yield of partial products and the like by taking the alpha-terpineol and the aromatic acyl chloride as raw materials, and is very favorable for realizing industrialization.

Description

Preparation method of symmetrical aromatic anhydride compound

Technical Field

The invention relates to the field of organic synthesis, in particular to a preparation method of a symmetrical aromatic anhydride compound.

Background

The symmetric aromatic anhydride is an important organic intermediate and is widely applied to medicine preparation, dyes, preservatives, benzene acylating agents, softeners and the like. The partially symmetrical aromatic anhydride has good biological activity, such as good antiviral activity of the hydroxybenzoic acid anhydride with a symmetrical structure to human papilloma virus, can resist viruses which can be integrated into human cell chromosomes, can effectively inhibit the propagation of the viruses in vivo, and can prevent the recurrence of virus infection.

Chinese patent publication No. CN107501084a discloses that benzoic anhydride is distilled together at a higher temperature mainly by benzoic acid, acetic anhydride and syrupy phosphoric acid. When a certain amount of distillate was distilled off, acetic anhydride was additionally added to the reaction mixture, and this operation was repeated. The distillate was then distilled off until the temperature of the reaction mass reached 270 ℃. The distillation residue was subjected to fractional distillation under reduced pressure to obtain benzoic anhydride. Since the benzoic anhydride obtained by the above-mentioned reduced pressure distillation has a low purity, the crude product also needs to be recrystallized from benzene to obtain a pure product of benzoic anhydride. The method has the advantages of high reaction temperature, multiple distillations, complex operation, high benzene toxicity of a solvent used for separation and purification, difficult obtainment of a controlled and easily-toxic compound of raw material acetic anhydride, and less application of the reaction to preparation of other symmetrical aromatic anhydrides besides preparation of benzoic anhydride. In addition to the above methods, chinese patent publication No. CN101200426a discloses that some symmetric aromatic anhydrides can also be obtained by removing a molecule of water from aromatic carboxylic acids in concentrated sulfuric acid. However, this process is currently used mainly for the preparation of symmetrical or unsymmetrical hydroxybenzoic acid anhydrides, and rarely for the preparation of other symmetrical aromatic anhydrides, and requires the use of highly toxic solvents (e.g., benzene, etc.), and the crude product of the hydroxybenzoic acid anhydride obtained from the reaction needs to be purified by recrystallization from acetone, a managed, toxic compound.

In view of the defects of the existing preparation method of the symmetrical aromatic anhydride compound, the general method for preparing the series of symmetrical aromatic anhydrides is few. To this end, the invention providesαThe method for preparing the series of symmetrical aromatic acid anhydrides by using terpineol and aromatic acyl chloride as raw materials aims to lay a good foundation for developing the symmetrical aromatic acid anhydrides and downstream high-added-value products thereof with potential application values in the fields of pharmacy, dyes, preservatives, benzene acylating agents, softeners and the like.

Disclosure of Invention

Therefore, the technical problem to be solved by the invention is to overcome the defects of difficult obtainment of raw materials, high reaction temperature and high toxicity of the preparation of the symmetrical aromatic anhydride compounds in the prior art, thereby providing a preparation method of the symmetrical aromatic anhydride compounds, which comprises the following stepsαThe terpineol and the aromatic acyl chloride are used as raw materials, the method has the advantages of easiness in operation, mild reaction conditions, high safety, simplicity in technological process and post-treatment, low cost, high yield of partial products and the like, and is very favorable for realizing industrialization.

Therefore, the invention provides a preparation method of a symmetrical aromatic anhydride compound, which comprises the following steps:

dissolving alpha-terpineol and pyridine in a solvent, adding an aromatic acyl chloride solution, and reacting for 8 to 169h to obtain a symmetrical aromatic anhydride compound;

the structural formula of the symmetrical aromatic anhydride compound is as follows:

，

r is-Cl, -F, -CH ₃ Or one of-H.

Preferably, the steps further comprise post-reaction treatment, wherein after the post-reaction treatment, the organic phase is subjected to rotary evaporation to remove the solvent after being extracted once by hydrochloric acid aqueous solution, sodium hydroxide aqueous solution and distilled water, and is further purified by silica gel column chromatography.

The reaction formula is as follows:

possible reaction mechanisms:

。

preferably, the solvent is dichloromethane.

Preferably, the reaction temperature is 40 ℃ to 45 ℃.

Preferably, the molar ratio of the alpha-terpineol to the aromatic acyl chloride is 1.2 to 1.

Preferably, the aromatic acid chloride is one of p-chlorobenzoyl chloride, p-fluorobenzoyl chloride, p-methylbenzoyl chloride or benzoyl chloride.

Preferably, the concentration of the hydrochloric acid aqueous solution is 1 to 1.5 mol/L, and the concentration of the sodium hydroxide aqueous solution is 1 to 1.5 mol/L.

The technical scheme of the invention has the following advantages:

1. according to the preparation method of the symmetric aromatic anhydride compound, the used raw materials alpha-terpineol and aromatic acyl chloride are common chemical raw materials, and are cheap and easy to obtain;

2. the preparation method of the symmetrical aromatic anhydride compound has the advantages of mild reaction conditions, high safety, proper reaction temperature and capability of reacting under normal pressure;

3. the preparation method of the symmetrical aromatic anhydride compound has the advantages of simple technical process and post-treatment, easy operation, low cost, high yield of partial products and good industrial application prospect.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.

FIG. 1 is an infrared (FT-IR) analysis spectrum of a substance of the present invention against chlorobenzoic anhydride;

FIG. 2 shows the preparation of p-chlorobenzoic anhydride of the present invention ¹ H nuclear magnetic resonance ( ¹ H NMR) analysis pattern;

FIG. 3 shows the preparation of p-chlorobenzoic anhydride of the present invention ¹³ C nuclear magnetic resonance ( ¹³ C NMR) analysis spectrum;

FIG. 4 is an infrared (FT-IR) analysis spectrum of p-toluic anhydride of the present invention;

FIG. 5 is a diagram showing the reaction of p-methylbenzoic anhydride of the present invention ¹ H nuclear magnetic resonance ( ¹ H NMR) analysis pattern;

FIG. 6 is a diagram showing the reaction of p-methylbenzoic anhydride of the present invention ¹³ C nuclear magnetic resonance ( ¹³ C NMR) analysis spectrum;

FIG. 7 is an infrared (FT-IR) analysis spectrum of p-fluorobenzoic anhydride according to the present invention;

FIG. 8 shows the preparation of p-fluorobenzoic anhydride according to the invention ¹ H nuclear magnetic resonance ( ¹ H NMR) analysis pattern;

FIG. 9 is a drawing of p-fluorobenzoic anhydride of the present invention ¹³ C nuclear magnetic resonance ( ¹³ C NMR) analysis spectrum;

FIG. 10 is an infrared (FT-IR) analysis spectrum of benzoic anhydride, a substance of the present invention;

FIG. 11 shows benzene as the substance of the present inventionProcess for preparing formic anhydride ¹ H nuclear magnetic resonance ( ¹ H NMR) analysis pattern;

FIG. 12 shows benzoic anhydride of the present invention ¹³ C nuclear magnetic resonance ( ¹³ C NMR) analysis pattern.

Detailed Description

The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.

The examples do not show the specific experimental steps or conditions, and can be performed according to the conventional experimental steps described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.

Example 1

To a 150 ml three-necked flask equipped with a condenser and a thermometer was added 3.3.3 ml (20 mmol)αTerpineol, 2.4 ml pyridine, 35 ml dichloromethane, and the three-necked flask was placed in a thermostatically heated magnetic stirrer, the condensed water was turned on, magnetic stirring was started and heated. When the temperature of the solution increased to 30 ℃, a solution prepared from 3.1 mL (24 mmol) p-chlorobenzoyl chloride and 15 mL dry methylene chloride was added dropwise through a constant pressure funnel. After the dropwise addition is finished, heating and refluxing to react 16 h. After the reaction is finished, a large amount of white solid is separated out from the three-neck flask, 30 mL hydrochloric acid (1 mol/L) is added into the reaction liquid, the mixture is shaken and kept stand for 1 h, then is filtered by suction, and is washed for 1 time by 30 mL aqueous solution with the concentration of 1.5 mol/L NaOH and 30 mL distilled water in sequence, and is dried in vacuum at 75 ℃ to obtain 3.06 g p-chlorobenzoic anhydride, the yield is 92 percent, and the melting point is 191.5-192.8 ℃. ¹ H-NMR、 ¹³ C-NMR, FT-IR and organic element analysis were as follows:

¹ H NMR (CDCl ₃ , 600 MHz), δ _H 8.08 (4H, d, J=8.6, 2-H, 6-H, 2′-H, 6′-H), 7.51 (4H, d, J=8.6, 3-H, 5-H, 3′-H, 5′-H). ¹³ C NMR (CDCl ₃ , 150 MHz), δ _C 161.32 (C=O), 141.44 (4-C, 4′-C), 131.98 (2-C, 6-C, 2′-C, 6′-C), 129.23 (3-C, 5-C, 3′-C, 5′-C), 127.08 (1-C, 1′-C). FT-IR (cm ^-1 ): 3097 (w, ν _=C-H ); 1786, 1733 (s, ν _C=O ); 1588 (s, ν _C=C ); 1070 (m, ν _C-O-C ); 741 (m, ν _C-Cl ). Elem. Anal. calcd. for C ₁₄ H ₈ Cl ₂ O ₃ : C, 56.98; H, 2.73; O, 16.26. Found: C, 56.52; H, 2.87; O, 16.66.

FT-IR of p-chlorobenzoic anhydride, ¹ H-NMR、 ¹³ The spectra of C-NMR are respectively shown in 1~3, which can prove that the p-chlorobenzoic anhydride is successfully prepared.

Example 2

To a 150 ml three-necked flask equipped with a condenser and a thermometer was added 3.3.3 ml (20 mmol)αTerpineol, 2.4 ml pyridine, 35 ml dichloromethane, and the three-necked flask was placed in a thermostatically heated magnetic stirrer, the condensed water was turned on, magnetic stirring was started and heated. When the temperature of the solution increased to 30 ℃, a solution prepared from 3.2 mL (24 mmol) of p-methylbenzoyl chloride and 15 mL of dry dichloromethane was added dropwise through a constant pressure funnel. After the dropwise addition is finished, heating and refluxing to react 16 h. After the reaction is finished, the reaction liquid is respectively extracted for 1 time by 30 mL hydrochloric acid (1 mol/L), 30 mL aqueous solution with the concentration of 1.5 mol/L and 30 mL distilled water, the organic phase is subjected to vacuum rotary evaporation to obtain 6.15 g yellow oily concentrate, the yellow oily concentrate is subjected to silica gel column chromatography (the eluent is 5% ethyl acetate petroleum ether solution) and vacuum drying at 75 ℃ to obtain 2.82 g p-methyl benzoic anhydride, the yield is 93%, and the melting point is 86.1-89.1 ℃. ¹ H-NMR、 ¹³ C-NMR, FT-IR and organic element analysis were as follows:

¹ H NMR (CDCl ₃ , 600 MHz), δ _H 8.04 (4H, d, J=8.3, 2-H, 6-H, 2′-H, 6′-H), 7.31 (4H, d, J=8.0, 3-H, 5-H, 3′-H, 5′-H), 2.45 (6H, s, 4-CH ₃ , 4′- CH ₃ ). ¹³ C NMR (CDCl ₃ , 150 MHz), δ _C 161.51 (C=O), 144.55 (4-C, 4′-C), 129.59 (2-C, 6-C, 2′-C, 6′-C), 128.54 (3-C, 5-C, 3′-C, 5′-C), 125.14 (1-C, 1′-C). FT-IR (cm ^-1 ): 3045 (w, ν _=C-H ); 2956 (w, ν _C-H ); 1775, 1713 (s, ν _C=O ); 1608 (s, ν _C=C ); 1051 (m, ν _C-O-C ). Elem. Anal. calcd. for C ₁₆ H ₁₄ O ₃ : C, 75.57; H, 5.55; O, 18.88. Found: C, 75.13; H, 5.67; O, 19.20.

FT-IR of p-toluic anhydride, ¹ H-NMR、 ¹³ The spectra of C-NMR are respectively shown in 4~6, which can prove that the p-methyl benzoic anhydride is successfully prepared.

Example 3

To a 150 ml three-necked flask equipped with a condenser and a thermometer was added 3.3.3 ml (20 mmol)αTerpineol, 2.4 ml pyridine, 35 ml dichloromethane, and the three-necked flask was placed in a thermostatically heated magnetic stirrer, the condensed water was turned on, magnetic stirring was started and heated. When the temperature of the solution was raised to 30 ℃, a solution prepared from 2.84 mL (24 mmol) p-fluorobenzoyl chloride and 15 mL dry dichloromethane was added dropwise through a constant pressure funnel. After the addition was complete, 8 h was heated to reflux. After the reaction is finished, the reaction liquid is respectively extracted for 1 time by 30 mL hydrochloric acid (1 mol/L), 30 mL NaOH aqueous solution with the concentration of 1.5 mol/L and 30 mL distilled water, organic phase is subjected to vacuum rotary evaporation to obtain 5.35 g yellow oily concentrate, the yellow oily concentrate is subjected to silica gel column chromatography (eluent is 5% ethyl acetate petroleum ether solution) and vacuum drying at 75 ℃ to obtain 0.98 g p-fluorobenzoic anhydride, the yield is 16%, and the melting point is 106.8-108.1 ℃. ¹ H-NMR、 ¹³ C-NMR, FT-IR and organic element analysis were as follows: ¹ H-NMR ¹³ C-NMR, FT-IR and organic element analysis were as follows:

¹ H NMR (CDCl ₃ , 600 MHz), δ _H 8.20 (4H, d, J=14.2, 2-H, 6-H, 2′-H, 6′-H), 7.23 (4H, d, J=17.2, 3-H, 5-H, 3′-H, 5′-H). ¹³ C NMR (CDCl ₃ , 150 MHz), δ _C 165.90 (4-C, 4′-C), 161.22 (C=O), 133.36 (2-C, 6-C, 2′-C, 6′-C), 125.07 (1-C, 1′-C), 116.37 (3-C, 5-C, 3′-C, 5′-C). FT-IR (cm ^-1 ): 3083 (w, ν _=C-H ); 1786, 1722 (s, ν _C=O ); 1608, 1508 (s, ν _C=C ); 1154 (m, ν _C-F ); 1076 (m, ν _C-O-C ). Elem. Anal. calcd. for C ₁₄ H ₈ F ₂ O ₃ : C, 64.13; H, 3.08; O, 18.31. Found: C, 63.80; H, 3.19; O, 18.55.

FT-IR of p-fluorobenzoic anhydride, ¹ H-NMR、 ¹³ The spectra of C-NMR are respectively shown in 7~9, which can prove that the p-fluorobenzoic anhydride is successfully prepared.

Example 4

To a 150 ml three-necked flask equipped with a condenser and a thermometer was added 3.3.3 ml (20 mmol)αTerpineol, 2.4 ml pyridine, 35 ml dichloromethane, and the three-necked flask was placed in a thermostatically heated magnetic stirrer, the condensed water was turned on, magnetic stirring was started and heated. When the temperature of the solution increased to 30 ℃, a solution prepared from 2.77 mL (24 mmol) benzoyl chloride and 15 mL dry dichloromethane was added dropwise through a constant pressure funnel. After the addition was complete, 8 h was heated to reflux. After the reaction is finished, the reaction liquid is respectively extracted for 1 time by 30 mL hydrochloric acid (1 mol/L), 30 mL NaOH aqueous solution with the concentration of 1.5 mol/L and 30 mL distilled water, 5.25 g yellow oily concentrate is obtained by vacuum rotary evaporation of an organic phase, the yellow oily concentrate is subjected to silica gel column chromatography (eluent is 5% ethyl acetate petroleum ether solution) and vacuum drying at 75 ℃ to obtain 0.84 g benzoic anhydride, the yield is 15%, and the melting point is 41.8-43.1 ℃. ¹ H-NMR ¹³ C-NMR, FT-IR and organic element analysis were as follows: ¹ H-NMR、 ¹³ C-NMR, FT-IR and organic element analysis were as follows:

¹ H NMR (CDCl ₃ , 600 MHz), δ _H 8.16 (4H, d, J=7.1, 2-H, 6-H, 2′-H, 6′-H), 7.65 (4H, t, J=7.4, 4-H, 4′-H), 7.50-7.53 (4H, m, 3-H, 5-H, 3′-H, 5′-H). ¹³ C NMR (CDCl ₃ , 150 MHz), δ _C 172.39 (C=O), 133.85 (4-C, 4′-C), 130.24 (2-C, 6-C, 2′-C, 6′-C), 129.33 (1-C, 1′-C), 128.51 (3-C, 5-C, 3′-C, 5′-C). FT-IR (cm ^-1 ): 3069 (w, ν _=C-H ); 1787, 1722 (s, ν _C=O ); 1599 (s, ν _C=C ); 1044 (m, ν _C-O-C )). Elem. Anal. calcd. for C ₁₄ H ₁₀ O ₃ : C, 74.33; H, 4.46; O, 21.22. Found: C, 73.99; H, 4.57; O, 21.44.

FT-IR of benzoic anhydride, ¹ H-NMR、 ¹³ The spectra of C-NMR are respectively shown in FIGS. 10 to 12, which can prove that benzoic anhydride is successfully prepared.

Example 5

Into a 150 ml three-necked flask equipped with a condenser and a thermometer was charged 1.7 ml (12 mmol)αTerpineol, 2.4 ml pyridine, 35 ml dichloromethane, and the three-necked flask was placed in a thermostatically heated magnetic stirrer, the condensed water was turned on, magnetic stirring was started and heated. When the temperature of the solution increased to 30 ℃, a solution prepared from 3.2 mL (24 mmol) of p-methylbenzoyl chloride and 15 mL of dry dichloromethane was added dropwise through a constant pressure funnel. After the dropwise addition is finished, heating and refluxing to react 16 h. After the reaction, the reaction solution was extracted 1 time with 30 mL hydrochloric acid (1.5 mol/L), 1.5 mol/L NaOH aqueous solution for 30 mL concentration, and mL distilled water, the organic phase was vacuum rotary evaporated to obtain 4.35 g yellow oily concentrate, the yellow oily concentrate was subjected to silica gel column chromatography (eluent is 5% ethyl acetate petroleum ether solution), vacuum drying at 75 deg.C to obtain 2.32 g p-methyl benzoic anhydride, the yield was 77%.

Example 6

To a 150 ml three-necked flask equipped with a condenser and a thermometer was added 3.3 ml (20 mmol)αTerpineol, 2.4 ml pyridine, 35 ml dichloromethane, and the three-necked flask was placed in a thermostatically heated magnetic stirrer, the condensed water was turned on, magnetic stirring was started and heated. When the temperature of the solution was raised to 30 ℃, a solution prepared from 2.84 mL (24 mmol) p-fluorobenzoyl chloride and 15 mL dry dichloromethane was added dropwise through a constant pressure funnel. After the dropwise addition is finished, heating and refluxing to react 16 h. After the reaction, the reaction solution was extracted 1 time with 30 mL hydrochloric acid (1 mol/L), 50 mL NaOH aqueous solution with concentration of 1 mol/L, and 30 mL distilled water, respectively, and the organic phase was subjected to vacuumRotary evaporation to obtain 5.35 g yellow oily concentrate, which is subjected to silica gel column chromatography (eluent is 5% ethyl acetate petroleum ether solution) and vacuum drying at 75 deg.C to obtain 1.62 g p-fluorobenzoic anhydride with yield of 26%.

Example 7

To a 150 ml three-necked flask equipped with a condenser and a thermometer was added 3.3.3 ml (20 mmol)αTerpineol, 2.4 ml pyridine, 35 ml dichloromethane, and the three-necked flask was placed in a thermostatically heated magnetic stirrer, the condensate was turned on, magnetic stirring was started and heated. When the temperature of the solution increased to 30 ℃, a solution prepared from 2.77 mL (24 mmol) benzoyl chloride and 15 mL dry dichloromethane was added dropwise through a constant pressure funnel. After the dropwise addition is finished, heating and refluxing to react 16 h. After the reaction, the reaction solution was extracted 1 time with 30 mL hydrochloric acid (1 mol/L), 30 mL NaOH aqueous solution with concentration of 1.5 mol/L, and 30 mL distilled water, the organic phase was vacuum rotary evaporated to obtain 5.25 g yellow oily concentrate, the yellow oily concentrate was subjected to silica gel column chromatography (eluent is 5% ethyl acetate petroleum ether solution), vacuum drying at 75 deg.C to obtain 1.08 g benzoic anhydride, the yield was 19%.

The method uses the raw materials of the alpha-terpineol and the aromatic acyl chloride, adopts mild reaction conditions, has high safety and proper reaction temperature, obtains the symmetrical aromatic anhydride compound by normal pressure reaction, and has the advantages of simple process and post-treatment, easy operation, low cost, high yield of partial products and good industrial application prospect.

It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims (3)

1. The preparation method of the symmetrical aromatic anhydride compound is characterized by comprising the following steps:

dissolving alpha-terpineol and pyridine in a solvent, adding an aromatic acyl chloride solution, and reacting for 8 to 169h to obtain a symmetrical aromatic anhydride compound;

the structural formula of the symmetrical aromatic anhydride compound is as follows:

，

r is-Cl or-CH ₃ One of (1);

the solvent is dichloromethane;

the reaction temperature is 40-45 ℃;

the molar ratio of the alpha-terpineol to the aromatic acyl chloride is 1.2 to 1;

the aromatic acyl chloride is one of p-chlorobenzoyl chloride or p-methylbenzoyl chloride.

2. The method of claim 1, wherein the step further comprises a post-reaction treatment, wherein the post-reaction treatment comprises extracting the organic phase with aqueous hydrochloric acid, aqueous sodium hydroxide and distilled water once, removing the solvent by rotary evaporation, and further purifying by silica gel column chromatography.

3. The method for preparing the symmetric aromatic anhydride compound according to claim 2, wherein the concentration of the hydrochloric acid aqueous solution is 1 to 1.5 mol/L, and the concentration of the sodium hydroxide aqueous solution is 1 to 1.5 mol/L.

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