Synthetic method of o-hydroxybenzonitrile

Abstract

The invention discloses a synthetic method of o-hydroxybenzonitrile, and belongs to the technical field of organic synthesis. The method comprises the following steps: in a solvent, o-chlorobenzonitrile and organic alkali react under the action of a composite catalyst to obtain o-hydroxybenzonitrile, the reaction temperature is 90-100 DEG C, the reaction pH is 5.5-6.5, and the reaction time is 8-15 hours. The solvent is gamma-valerolactone; the composite catalyst is formed by compounding lithium chloride and an organic catalyst according to the mass ratio of (0.4-2.0): 1, and the organic catalyst is selected from one or more of a quaternary ammonium salt catalyst, a crown ether catalyst and tetrabutylammonium bromide; the molar ratio of o-chlorobenzonitrile to organic alkali to lithium chloride is 1: (2-3): (0.05-0.2); the organic base is selected from sodium methoxide, potassium ethoxide or potassium tert-butoxide. Compared with the prior art, the reaction is performed under normal pressure, the reaction temperature is low, the reaction time is short, and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a synthesis method of o-hydroxybenzonitrile. BACKGROUND

[0002] O-hydroxybenzonitrile, commonly known as salicylonitrile, also known as 2-hydroxybenzonitrile, o-hydroxybenzonitrile, 2-cyanophenol, etc., has a molecular formula of C7H5NO, a CAS registration number of 611-20-1, a certain water solubility, a Pka of 7.17, and is unstable to strong bases and oxidants. As a pharmaceutical intermediate, o-hydroxybenzonitrile can be used to synthesize the drug bunilol hydrochloride for treating hypertension and angina pectoris, and as a pesticide intermediate (such as fenitrothion, phencapton, bromophenyl cyanide, dichlofluanid, and white mycophenolic acid), o-hydroxybenzonitrile can be used to synthesize the fungicide azoxystrobin, and in addition, o-hydroxybenzonitrile can also be used to synthesize various flavors and liquid crystal materials.

[0003] The existing literature reports the following methods for preparing o-hydroxybenzonitrile: 1. Using o-hydroxybenzaldehyde as a raw material, the corresponding oxime is obtained by reacting with hydroxylamine hydrochloride, and then o-hydroxybenzonitrile is obtained by acidolysis. This method has a low yield and a low product content, and a large amount of wastewater is generated.

[0004] 2. Using o-methylphenol as a raw material, o-hydroxybenzonitrile is synthesized through etherification, methylation and cyanation. This method has a complicated process and a low yield, and is not suitable for industrial production.

[0005] 3. Using o-hydroxybenzoyl as a raw material, o-hydroxybenzoyl is obtained by dehydration with phosgene under the action of a catalyst.

[0006] 4. o-Chlorobenzonitrile and sodium methoxide are reacted in a microchannel.

[0007] For example, patent No. CN201910412231.6 discloses a method for synthesizing o-hydroxybenzonitrile by using a microchannel reactor, which comprises the following steps: S1: pretreatment of the reactants, sodium methoxide and o-chlorobenzonitrile are dissolved in anhydrous methanol to prepare sodium methoxide solution and o-chlorobenzonitrile solution with a certain concentration; S2: setting of the reaction conditions of the microchannel reactor, the heat exchange sheet integrated with the reaction sheet in the microchannel reactor is connected with the external heating and cooling circulator, the heat exchange medium in the heat exchange sheet is heat conducting oil, and the reaction temperature of the microchannel reactor is set by the heating and cooling circulator; S3: synthesis of o-hydroxybenzonitrile, using o-chlorobenzonitrile solution and sodium methoxide solution as raw materials, substitution reaction in a micro-channel reactor to synthesize o-hydroxybenzonitrile product: using different flow pumps to pass sodium methoxide solution and o-chlorobenzonitrile solution into the feed port of the micro-channel reactor at a certain feed flow rate, sodium methoxide and o-chlorobenzonitrile are preheated, mixed and reacted in the micro-channel reactor in sequence, and the reaction product mixture is obtained, wherein the molar ratio of o-chlorobenzonitrile to sodium methoxide is adjusted by the flow pump to be 1:1-4, the feed flow rate of o-chlorobenzonitrile solution is 1-5 mL / min, and the feed flow rate of sodium methoxide solution is 10-20 mL / min; the reaction process in the micro-channel reactor has a residence time of 60-120 s, a reaction temperature of 100-200℃, and a pressure of 0.5-2 Mpa; S4: post-treatment, the reaction product mixture synthesized in step S3 is sequentially cooled, distilled under reduced pressure to remove the solvent, and acidified with hydrochloric acid to obtain o-hydroxybenzonitrile solid, wherein the total conversion rate of o-chlorobenzonitrile is 100%, and the yield of o-hydroxybenzonitrile product is 90-95%.

[0008] This process requires the use of a micro-channel reactor, which has high equipment investment.

[0009] As disclosed in patent No. CN201110301805.6, a preparation method of o-hydroxybenzonitrile is provided, wherein 250g of sodium methoxide methanol solution with a concentration of 20.7% and 60g of o-chlorobenzonitrile are added into a 1000ml pressure tank, the tank is replaced with nitrogen gas, heated to 160℃, and the tank pressure is increased to 2.5Mpa, and the reaction is carried out for 6-9 hours, then the reaction is stopped, the temperature is reduced to below 50℃, and the methanol is recovered under reduced pressure, the residual product is dissolved in cold water, the insoluble matter is filtered, and the white product o-hydroxybenzonitrile is precipitated by acidification with 36% hydrochloric acid, and the content is >99.0% after drying, the mass is 50.5g, and the yield is 96.4%.

[0010] This process needs to be carried out at high temperature (160℃) and high pressure (2.5Mpa), which is not suitable for industrial production. SUMMARY

[0011] To solve the foregoing problems, the application discloses a synthesis method of o-hydroxybenzonitrile, which comprises the following steps: o-chlorobenzonitrile and an organic base are reacted in a solvent under the action of a composite catalyst to obtain o-hydroxybenzonitrile, the reaction temperature is 90-100 DEG C, the reaction pH is 5.5-6.5, and the reaction time is 8-15 h. The solvent is gamma-valerolactone. The composite catalyst is compounded by lithium chloride and an organic catalyst at a mass ratio of 0.4-2.0:1, and the organic catalyst is selected from one or more of quaternary ammonium salt catalysts, crown ether catalysts and tetrabutylammonium bromide. The crown ether catalyst is 18-crown-6, and the quaternary ammonium salt catalyst is selected from trimethylbenzylammonium chloride, triethylbenzylammonium chloride, tripropylbenzylammonium chloride or tributylbenzylammonium chloride. The molar ratio of o-chlorobenzonitrile, the organic base and lithium chloride is 1:2-3:0.05-0.2. The organic base is selected from sodium methoxide, potassium ethoxide or potassium tert-butoxide, and preferably, the organic base is sodium methoxide.

[0012] Further, after the reaction is completed, vacuum distillation is performed, ice water is added to crystallize, solid-liquid separation, water washing and recrystallization are performed to obtain o-hydroxybenzonitrile. The recrystallization solvent is selected from toluene, methanol or DMF, and preferably, the recrystallization solvent is methanol (more preferably, the recrystallization solvent is the methanol recovered by distillation).

[0013] Specifically, acetic acid is added to adjust the reaction pH to 6.

[0014] Preferably, the composite catalyst is compounded by lithium chloride and tetrabutylammonium bromide at a mass ratio of 0.4-1.5:1.

[0015] Preferably, the synthesis method of o-hydroxybenzonitrile comprises the following steps: (1) o-chlorobenzonitrile, sodium methoxide and a composite catalyst are added into gamma-valerolactone, wherein the composite catalyst is compounded by lithium chloride and tetrabutylammonium bromide at a mass ratio of 0.4-1.5:1, and the molar ratio of o-chlorobenzonitrile, sodium methoxide and lithium chloride is 1:2-3:0.05-0.2.

[0016] (2) under the protection of nitrogen, the reaction is performed at 90-100 DEG C for 6-15 h, and acetic acid is added to adjust the pH to 6 during the reaction; (3) after the reaction is completed, vacuum distillation is performed, ice water is added to crystallize, solid-liquid separation, water washing and recrystallization are performed to obtain o-hydroxybenzonitrile.

[0017] In the patent, the biphasic catalytic reaction system introduces a phase transfer catalyst (such as tetrabutylammonium bromide, TBAB), realizes homogeneous catalysis at normal temperature and pressure, and makes the rate of nucleophilic substitution reaction of organic base increase by 4-6 times, and the shortest reaction time is shortened to 8 hours. Through quantum chemical calculation to optimize the structure of the catalyst, it is found that the bromide ion of TBAB forms an ion pair intermediate with the CN group of o-chlorobenzonitrile, which significantly reduces the reaction activation energy (Ea decreases by about 35 kJ / mol). The biobased solvent gamma-valerolactone (GVL) is used to replace the traditional methanol / DMF, the matching degree of its polarity with the reactant is improved, and the selectivity is increased to 98.2%. A solvent recovery system is designed, and the boiling point difference (GVL bp=207°C, methanol bp=64.7°C) between GVL and methanol (as product) is used to realize solvent recycling (as recrystallization solvent) through vacuum distillation, and the economic efficiency reaches 92%. Under the conditions of the patent, the reaction can be carried out at normal pressure and low temperature (common kettle reactor can be used), and the reaction yield is greater than 96% and the purity is greater than 99.5%. DETAILED DESCRIPTION

[0018] In order to make the purpose, technical scheme and advantages of the present application clearer, the embodiments of the present application are described in further detail below.

[0019] Example 1: (1) Dissolve o-chlorobenzonitrile 13.8 g (0.1 mol) in an appropriate amount of gamma-valerolactone, and then mix with sodium methoxide 13.5 g (0.25 mol), lithium chloride 0.3 g (0.007 mol) and tetrabutylammonium bromide 0.5 g.

[0020] (2) React at 95°C for 8h under nitrogen protection, and add acetic acid to adjust the pH to 6 during the reaction.

[0021] (3) After the reaction is completed, vacuum distillation is carried out, ice water is added for crystallization, solid-liquid separation is carried out, and o-hydroxybenzonitrile crude product is obtained, with a yield of 97% and a crude product purity of 99.5%.

[0022] (4) After water washing 3 times and methanol recrystallization, o-hydroxybenzonitrile fine product is obtained, with a fine product purity of 99.9%.

[0023] Example 2: (1) Dissolve o-chlorobenzonitrile 13.8 g (0.1 mol) in an appropriate amount of gamma-valerolactone, and then mix with potassium ethoxide 18.5 (0.22 mol), lithium chloride 0.3 g (0.007 mol) and 18-crown-6 ether 0.4 g.

[0024] (2) React at 92°C for 12h under nitrogen protection, and add acetic acid to adjust the pH to 6 during the reaction.

[0025] (3) After the reaction is completed, vacuum distillation is performed, ice water is added to crystallize, solid-liquid separation is performed, and the crude o-hydroxybenzonitrile is obtained, with a yield of 97% and a crude product purity of 99.4%.

[0026] (4) The o-hydroxybenzonitrile is obtained by water washing three times and methanol recrystallization, with a product purity of 99.7%.

[0027] Example 3 (1) The o-chlorobenzonitrile 13.8 g (0.1 mol) is dissolved in an appropriate amount of γ-valerolactone, and then mixed with potassium tert-butoxide 26.9 (0.24 mol), lithium chloride 0.42 g (0.01 mol), and tetrabutylammonium bromide 0.4 g.

[0028] (2) The reaction is performed at 92°C for 12 h under nitrogen protection, and acetic acid is added to adjust the pH to 6.2 during the reaction.

[0029] (3) After the reaction is completed, vacuum distillation is performed, ice water is added to crystallize, solid-liquid separation is performed, and the crude o-hydroxybenzonitrile is obtained, with a yield of 97% and a crude product purity of 99.4%.

[0030] (4) The o-hydroxybenzonitrile is obtained by water washing three times and methanol recrystallization, with a product purity of 99.7%.

[0031] Example 4 (1) The o-chlorobenzonitrile 13.8 g (0.1 mol) is dissolved in an appropriate amount of γ-valerolactone, and then mixed with sodium methoxide 13.5 g (0.25 mol), lithium chloride 0.42 g (0.01 mol), and triethylbenzylammonium chloride 0.6 g.

[0032] (2) The reaction is performed at 92°C for 12 h under nitrogen protection, and acetic acid is added to adjust the pH to 6.3 during the reaction.

[0033] (3) After the reaction is completed, vacuum distillation is performed, ice water is added to crystallize, solid-liquid separation is performed, and the crude o-hydroxybenzonitrile is obtained, with a yield of 97% and a crude product purity of 99.4%.

[0034] (4) The o-hydroxybenzonitrile is obtained by water washing three times and methanol recrystallization, with a product purity of 99.7%.

[0035] Comparative Example 1 The same as Example 1, except that tetrabutylammonium bromide is not added. The reaction time is 8 h, the crude product yield is 75%, and the crude product purity is 91.3%.

[0036] Comparative Example 2 The same as Example 1, except that tetrabutylammonium bromide is not added. The reaction time is 18 h, the crude product yield is 93.8%, and the crude product purity is 99.2%.

[0037] Comparative Example 3 The same as Example 1, except that no tetrabutylammonium bromide was added. The reaction time was 24 hours, the crude product yield was 96.4%, and the crude product purity was 99.3%.

[0038] Comparative Example 4 The same as Example 1, except that no tetrabutylammonium bromide was added. The reaction time was 48 hours, the crude product yield was 96.9%, and the crude product purity was 99.3%.

[0039] Comparative Example 5 The same as Example 1, except that an equal volume of a mixed solvent of DMSO and methanol was used instead of γ-valerolactone, and the volume ratio of methanol to DMSO was 3:1. The crude product yield was 84%, and the crude product purity was 95.7%.

[0040] Comparative Example 6 The same as Example 1, except that methanol was used as the solvent. The crude product yield was 79.3%, and the crude product purity was 95.8%.

[0041] Comparative Example 7 The same as Example 1, except that an equal mass of tetrabutylammonium chloride was used instead of tetrabutylammonium bromide. The crude product yield was 79%, and the crude product purity was 92.8%.

[0042] Comparative Example 8 The same as Example 1, except that zinc chloride was used instead of lithium chloride. The crude product yield was 84.3%, and the crude product purity was 94.1%.

[0043] Comparative Example 9 The method of CN201110301805.6 was used, the reaction temperature was 160°C, the reaction pressure was 2.5 Mpa, and the reaction time was 8 hours. The yield was 95.4%, and the crude product purity was 98.3%.

[0044] Comparative Example 10 The method of CN201110301805.6 was used, 0.5 g of tetrabutylammonium bromide was added, the reaction temperature was 160°C, the reaction pressure was 2.5 Mpa, and the reaction time was 8 hours. The yield was 95.5%, and the crude product purity was 98.7%.

[0045] The above description is merely preferred embodiments of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for synthesizing o-hydroxybenzonitrile, characterized in that: The method comprises: reacting o-chlorobenzonitrile and an organic base in a solvent under the action of a composite catalyst to obtain o-hydroxybenzonitrile, the reaction temperature being 90-100° C., the reaction pH being 5.5-6.5, and the reaction time being 8-15 hours; the solvent being γ-valerolactone; the composite catalyst being prepared by compounding lithium chloride and an organic catalyst in a mass ratio of 0.4-2.0:1, the organic catalyst being selected from one or more of a quaternary ammonium salt catalyst, a crown ether catalyst, and tetrabutylammonium bromide; the molar ratio of o-chlorobenzonitrile:organic base:lithium chloride being 1:2-3:0.05-0.2; and the organic base being selected from sodium methoxide, potassium ethoxide, or potassium tert-butoxide.

2. The method according to claim 1, characterized in that After the reaction is completed, the product is distilled under reduced pressure, ice water is added for crystallization, solid-liquid separation, water washing and recrystallization are performed to obtain o-hydroxybenzonitrile.

3. The method according to claim 2, characterized in that The recrystallization solvent is selected from toluene, methanol or DMF.

4. The method according to claim 1, wherein Acetic acid was added to adjust the reaction pH to 6.

5. The method according to claim 1, wherein The organic base is sodium methoxide.

6. The method according to claim 1, characterized in that The crown ether catalyst is 18-crown-6, and the quaternary ammonium salt catalyst is selected from trimethylbenzylammonium chloride, triethylbenzylammonium chloride, tripropylbenzylammonium chloride or tributylbenzylammonium chloride.

7. The method according to claim 1, characterized in that The composite catalyst is prepared by compounding lithium chloride and tetrabutylammonium bromide in a mass ratio of 0.4-1.5:

1.

8. The method according to claim 1, characterized in that The method comprises the following steps: (1) adding o-chlorobenzonitrile, sodium methoxide and a composite catalyst to γ-valerolactone; (2) Under nitrogen protection, react at 90-100°C for 6-15 hours. During the reaction, add acetic acid to adjust the pH to 6; (3) After the reaction is completed, distill under reduced pressure, add ice water for crystallization, separate the solid and liquid, wash with water and recrystallize to obtain o-hydroxybenzonitrile.