WO2019161705A1

WO2019161705A1 - New method for synthesizing 1,6-(p-amidinophenyl)hexyl diether

Info

Publication number: WO2019161705A1
Application number: PCT/CN2018/123346
Authority: WO
Inventors: 郑庆泉
Original assignee: 广州同隽医药科技有限公司
Priority date: 2018-02-23
Filing date: 2018-12-25
Publication date: 2019-08-29
Also published as: CN108299239B; CN108299239A

Abstract

Disclosed is a new method for synthesizing 1,6-(p-amidinophenyl)hexyl diether, comprising the steps of: (1) preparing 1,6-(p-cyanophenyl)hexyl diether by reacting p-cyanophenol with 1,6-dibromohexane; (2) reacting the 1,6-(p-cyanophenyl)hexyl diether obtained in step (1) with hydroxylamine, or with hydroxylamine hydrochloride under a condition of the presence of a base, so as to prepare 1,6-(p-amidoximephenyl)hexyl diether; and (3) reducing the 1,6-(p-amidoximephenyl)hexyl diether obtained in step (2), to obtain the 1,6-(p-amidinophenyl)hexyl diether; or first reacting the 1,6-(p-amidoximephenyl)hexyl diether obtained in step (2) with an esterification reagent or etherification reagent to obtain an ester or ether, and then subjecting same to a reduction reaction, to obtain the 1,6-(p-amidinophenyl)hexyl diether. The new synthesis method of the present invention is more green and environmentally friendly than traditional processes, has a greatly improved yield, and is suitable for large-scale industrial production.

Description

A new synthesis method of 1,6-(p-nonylphenyl) hexanedicarboxylate

Technical field

The invention belongs to the technical field of organic synthesis, and in particular relates to a novel synthesis method of 1,6-(p-nonylphenyl)hexanediether.

Background technique

1,6-(p-nonylphenyl) hexanedicarboxylate is a new type of water-soluble cationic antidandruff anti-itching agent with broad-spectrum antibacterial and bactericidal properties against various Gram Positive bacteria, negative bacteria and various molds and yeasts have high killing and inhibition effects, and are very safe and mild, have little skin irritation, and are excellent in compatibility with raw materials commonly used in daily chemical products. Has a very important and unique position.

The synthesis of 1,6-(p-nonylphenyl) hexanedicarboxylate is generally carried out in the following three parts: (1) by reacting p-cyanophenol with 1,6-dibromohexane to synthesize 1, 6-(p-cyanophenyl) hexanedicarboxylate (intermediate A), (2) alcoholysis of intermediate 1 to 1,6-(p-iminophenylphenyl) hexanedicarboxylate (intermediate B), (3) A new method for the aminolysis of intermediate 2 to 1,6-(p-nonylphenyl)hexanedicarboxylate, (4) 1,6-(p-nonylphenyl)hexanedicarboxylate and hydroxyethyl The base sulfonic acid is salted to give 1,6-(p-nonylphenyl)hexanedicarboxylate.

J Med Chem, 1990, 33: p1252-1257 reports that intermediate A is cooled to 0-5 ° C in absolute ethanol, anhydrous benzene and hydrogen chloride gas is passed until the system is saturated, sealed and stirred, room temperature reaction, after 3 days Intermediate 2, then ammonia-decomposed in an ammonia-ethanol solution system to obtain 1,6-(p-nonylphenyl)hexanedicarboxylate; CN105884652 also reported a method of hydrolyzing alcohol and then ammonia ammoxidation; Synthetic Chemistry, 2009 P. 642-644, No. 17巻, No. 5, reported that intermediate A was catalyzed by sodium methoxide in methanol and toluene solution to obtain intermediate B; Guangdong Chemical Industry, Vol. 41, No. 4 (2014) p39-40 reported Intermediate A is catalyzed by acetic acid to give intermediate B in ethanol and 1,4-dioxane.

In the second step of synthesis, the sodium methoxide and acetic acid reported in the literature catalyzed the reaction, the intermediate B yield was very low, and even the product was not obtained, the industrial value was small; the current method for obtaining the expected result is still the anhydrous hydrogen chloride catalytic reaction. Then ammonia hydrolysis, but this method has obvious defects: hydrogen chloride gas is a strong corrosive gas and the amount is large, the pollution is serious during use, the safety is poor, the equipment anti-corrosion requirements are high, and the amount of waste acid is difficult to handle, the alcoholysis reaction time Long; the use of volatile gas ammonia in ammonia solution, serious pollution, poor safety; in short, this method is not suitable for large-scale industrial production.

Summary of the invention

Based on this, the object of the present invention is to overcome the above-mentioned deficiencies of the prior art and to provide a novel synthesis method of 1,6-(p-nonylphenyl)hexanedicarboxylate, which is more green and environmentally friendly than conventional processes. The rate is greatly improved and is suitable for large-scale industrial production.

In order to achieve the above object, the technical scheme adopted by the present invention is: a novel synthesis method of 1,6-(p-nonylphenyl) hexanedicarboxylate, comprising the following steps:

(1) reacting sodium ethoxide, p-cyanophenol and 1,6-dibromohexane in an ethanol solution to obtain 1,6-(p-cyanophenyl)hexanediether;

(2) reacting 1,6-(p-cyanophenyl)hexanedicarboxylate obtained in the step (1) with hydroxylamine or reacting with hydroxylamine hydrochloride in the presence of a base in a solvent A to obtain 1,6-(pair Amidoxime phenyl) hexanedicarboxylate;

(3a) The 1,6-(p-amidinophenyl)hexanedicarboxylate obtained in the step (2), a catalyst and a hydrogen donor reagent are subjected to a reduction reaction in a solvent B to obtain the 1,6-( P-nonylphenyl) hexanedicarboxylate; or the reduction reaction of 1,6-(p-ammonium decylphenyl)hexanedicarboxylate obtained in step (2) and a chemical reduction reagent in solvent B, 1,6-(p-nonylphenyl) hexanedicarboxylate;

Or (3b) first reacting the 1,6-(p-aminodecylphenyl) hexanedicarboxylate obtained in the step (2), the acid binding agent and the derivatizing reagent in the solvent C to obtain the intermediate of the formula (I) After the body, the reduction reaction as described in the step (3a) is further carried out to obtain the 1,6-(p-nonylphenyl) hexanedicarboxylate;

Where R1 and R2 are

Wherein R1 and R2 are the same or different groups; X1, X2, X3 are any group; preferably, X1 is methyl, ethyl, phenyl, p-methylphenyl or trifluoromethyl; preferably X2 is a methyl group, a phenyl group or a p-methylphenyl group; and X3 is preferably a methyl group, an ethyl group, a phenyl group or a benzyl group.

Preferably, the molar ratio of sodium ethoxide, p-cyanophenol and 1,6-dibromohexane in the step (1) is (1.5 to 5): (1.5 to 5): 1; preferably, sodium ethoxide, The molar ratio of p-cyanophenol to 1,6-dibromohexane is (2 to 2.5): (2 to 2.5): 1.

Preferably, the reaction temperature of the step (1) is 60 to 80 ° C, and the reaction time is 1 to 10 h.

Preferably, the molar ratio of 1,6-(p-cyanophenyl)hexanedicarboxylate to hydroxylamine in the step (2) is 1: (2-10); the 1,6-(p-cyanophenyl) The molar ratio of hexamethylene ether, base and hydroxylamine hydrochloride is 1: (1 to 10): (2-10).

Preferably, the reaction temperature in the step (2) is 20 to 100 ° C, and the reaction time is 5 to 20 h; more preferably, the reaction temperature is 60 to 80 ° C.

Preferably, in the step (3a), the molar ratio of 1,6-(p-aminodecylphenyl) hexanediene to the hydrogen donor reagent is 1: (2-20), and the catalyst usage is 1,6. 2 to 20%, preferably 5 to 10% by mass of (for amidoxime phenyl) hexanedicarboxylate; 1 molar ratio of 1,6-(p-amidinophenyl) hexanedicarboxylate to reducing agent is 1 :(2~20).

Preferably, the reaction temperature in the step (3a) is 40 to 120 ° C, and the reaction time is 2 to 20 h; more preferably, the reaction temperature is 60 to 80 ° C.

Preferably, the molar ratio of 1,6-(p-amidinophenyl)hexanedicarboxylate, acid binding agent and derivatizing reagent in the step (3b) is 1: (0-10): (2-10) The reaction temperature is below 0 ° C and the reaction time is 1 h.

Preferably, the solvent A in the step (2) is at least one selected from the group consisting of methanol, ethanol, dichloromethane, ethyl acetate, THF, DMF, DMSO, and NMP; more preferably, the solvent A is selected from the group consisting of methanol , ethanol or DMF.

Preferably, the weight-to-volume ratio of 1,6-(p-cyanophenyl)hexanedicarboxylate and solvent A in the step (2) is 1 g: (3 to 10) mL.

Preferably, the base in the step (2) is selected from the group consisting of potassium carbonate, sodium carbonate, sodium ethoxide, sodium hydroxide, triethylamine or pyridine; more preferably, the base is selected from potassium carbonate or sodium carbonate.

Preferably, the solvent B in the step (3a) is at least one selected from the group consisting of water, methanol, ethanol, dichloromethane, ethyl acetate, THF, DMF, DMSO, NMP, formic acid, acetic acid, and dimethyl carbonate; More preferably, the solvent B is selected from the group consisting of methanol or ethanol.

Preferably, the weight-to-volume ratio of 1,6-(p-amidinophenyl)hexanedicarboxylate and solvent B in the step (3a) is 1 g: (3 to 10) mL.

Preferably, the catalyst in the step (3a) is selected from the group consisting of palladium, rhodium, platinum or Raney nickel; more preferably, the catalyst is selected from palladium or Raney nickel.

Preferably, the hydrogen donor reagent in the step (3a) is selected from the group consisting of hydrogen, formic acid, sodium formate, potassium formate or ammonium formate.

Preferably, the hydrogen pressure in the step (3a) is 0 to 1 MPa.

Preferably, the chemical reduction agent in the step (3a) is selected from the group consisting of magnesium powder, aluminum powder, zinc powder, iron powder, nickel powder, aluminum nickel alloy, sodium borohydride or potassium borohydride; more preferably, the chemical reduction The reagent is selected from magnesium powder or sodium borohydride.

Preferably, the solvent C in the step (3b) is at least one selected from the group consisting of water, methanol, ethanol, dichloromethane, ethyl acetate, THF, DMF, DMSO, NMP, formic acid, acetic acid and dimethyl carbonate; More preferably, the solvent C is selected from the group consisting of methanol or ethanol.

Preferably, the weight-to-volume ratio of 1,6-(p-amidinophenyl)hexanedicarboxylate and solvent C in the step (3b) is 1 g: (3 to 10) mL.

Preferably, the acid binding agent in the step (3b) is at least one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, sodium hydroxide and sodium ethoxide; more preferably The acid binding agent is selected from the group consisting of sodium carbonate or potassium carbonate.

Preferably, the derivatizing agent in the step (3b) is selected from a carboxylate derivatizing reagent, a sulfonate derivatizing reagent or an etherifying reagent, wherein the carboxylate derivatizing reagent is selected from the group consisting of acetyl chloride, acetic anhydride, and propionyl chloride. , propionic anhydride, benzoyl chloride or trifluoroacetyl chloride; the sulfonate derivatization reagent is selected from methanesulfonyl chloride, benzoyl chloride or p-toluenesulfonyl chloride; the etherification reagent is preferably dimethyl carbonate, diethyl carbonate, methyl iodide , ethyl bromide, bromobenzene or benzyl bromide.

Preferably, the specific method of the step (1) is: adding p-cyanophenol and sodium ethoxide to the ethanol solution, adding the temperature to reflux reaction for 1 hour, and then slowly adding 1,6-dibromohexane. After the completion of the dropwise addition, the reaction is continued for 1 to 10 hours, and the liquid phase detection reaction is complete, and the temperature is lowered to 20 to 25 ° C. After stirring for 1 hour, it is filtered to obtain a solid wet product, which is then beaten with water, filtered, and dried to obtain 1,6-(cyanide). Phenyl phenyl) hexamethylene ether.

Preferably, the specific method of the step (2) is: adding 1,6-(p-cyanophenyl)hexanedicarboxylate obtained from the step (1) and hydroxylamine hydrochloride to the solvent A, then adding a base, and heating up to After refluxing for 5-20 hours, the liquid phase monitoring reaction is complete, the temperature is lowered to 20-25 ° C, stirred for 1 h, and the wet product is filtered, and after water beating, it is filtered and dried to obtain 1,6-(p-amidinobenzobenzene). Ethylene hexane.

Preferably, the specific method of the step (3a) is: adding 1,6-(p-aminodecylphenyl) hexanedicarboxylate obtained in the step (2) to a certain amount of the solvent B and then adding the catalyst, and then adding the catalyst. The hydrogen donor reagent is added, and the temperature is raised for 2-20 hours; after the liquid phase monitoring reaction is completed, the catalyst is filtered while hot to obtain a 1,6-(p-nonylphenyl)hexanediether solution, and the temperature is lowered to 20-25 ° C, and stirred for 1 hour. It was filtered and washed with water to give a white solid, which was 1,6-(p-nonylphenyl)hexanedicarboxylate.

Or the specific method of the step (3a) is: adding 1,6-(p-amidinophenyl) hexanedicarboxylate obtained in the step (2) to a certain amount of the solvent B, adding a chemical reducing reagent, and heating the reaction. 2~20h; after the liquid phase monitoring reaction, the solution of 1,6-(p-nonylphenyl)hexanedicarboxylate is obtained, the temperature is lowered to 20-25 ° C, stirred for 1 h, and the mixture is filtered and washed with water to obtain a white solid. 1,6-(p-nonylphenyl) hexanedicarboxylate.

Preferably, the specific method of the step (3b) is: adding 1,6-(p-aminodecylphenyl) hexanedicarboxylate obtained in the step (2) to a certain amount of the solvent C, and then adding the acid The agent is cooled to below 0 ° C, and the derivatization reagent is added dropwise, and the mixture is stirred at room temperature for 1 hour, and then the intermediate represented by the formula (I) is obtained, and then the reduction reaction is carried out according to the reduction method described in the step (3a) to obtain 1, 6-(p-nonylphenyl) hexanedicarboxylate.

Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The present invention adopts a new synthetic route, and compared with the conventional anhydrous hydrogen chloride catalytic alcoholysis re-aminolysis effect, firstly, the total yield is greatly improved and reduced. Production cost; secondly, avoid the use of strong corrosive hydrogen chloride gas, there will be no serious pollution during the use of hydrogen chloride, poor safety, strict anti-corrosion requirements for equipment, large amount of waste acid and difficult to handle, etc., more environmentally friendly; again, avoid The use of volatile gas ammonia gas, the whole operation is more simple and safe, and can be applied to large-scale industrial production; (2) The raw material of the invention is safe and easy to obtain, the number of steps is small, and the operation is simple, and the solvent used can be recycled and applied.

Detailed ways

The present invention will be further described with reference to specific embodiments in order to better illustrate the objects, aspects and advantages of the invention.

Example 1

An embodiment of the novel synthesis method of 1,6-(p-nonylphenyl)hexanediether of the present invention comprises the following steps:

(1) Synthesis of 1,6-(p-cyanophenyl)hexanediether:

In a 1 L four-necked flask equipped with a stirring, a thermometer, a dropping funnel and a reflux condenser, 500 ml of ethanol and 57.16 g (0.840 mol; 1.5 eq) of sodium ethoxide were successively added, and the mixture was stirred and dissolved, and then 100 g (0.840) was added in portions. Mol; 1.5 eq) p-cyanophenol, then heated to 60 ° C reflux reaction for 1 h, controlled to slowly add 136.6 g (0.560 mol; 1 eq) 1,6-dibromohexane at this temperature, after the completion of the temperature The reaction was carried out for 4 hours, and the reaction was monitored in the liquid phase. The temperature was lowered to 20 ° C. After stirring for 1 h, it was filtered to obtain a solid wet product. After beating with 300 ml of water, it was filtered and dried to obtain 121.0 g of a white solid, which was 1,6-(pair Cyanophenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-cyanophenyl)hexanediether was 94.5%, and the purity by HPLC was 99.6%; 1H NMR: (d6-DMSO, 500 MHz) δ=1.43 (s, 4H), 1.76 (t , 4H), 4.06 (t, 4H), 7.17 (d, 4H), 7.77 (d, 4H).

(2) Synthesis of 1,6-(p-aminodecylphenyl) hexanedicarboxylate:

In a 2L four-necked flask equipped with a stirring, thermometer, dropping funnel and reflux condenser, 1 L of methanol, 121.0 g (0.378 mol, 1 eq) of 1,6-(p-cyanophenyl)hexanedicarboxylate, 78.8 were added in sequence. g (1.134mol, 3eq) hydroxylamine hydrochloride and 60.1g (0.567mol, 1.5eq) sodium carbonate, after the temperature was dropped to 20 ° C reflux for 20h sampling, liquid phase detection reaction was complete, cooled to 25 ° C, stirred for 1h, then filtered The solid wet product was beaten with 300 ml of water and filtered to dryness to obtain 144.7 g of a white solid, which was 1,6-(p-aminodecylphenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-amidinophenyl)hexanedicarboxylate is 99.1%, and the purity by HPLC is 99.3%; 1H NMR: (d6-DMSO, 500 MHz) δ=1.48 (s, 4H), 1.74 (t, 4H), 3.99 (t, 4H), 5.67 (s, 4H), 6.90 (d, 4H), 7.58 (d, 4H), 9.40 (s, 2H).

(3) Synthesis of 1,6-(p-nonylphenyl) hexanedicarboxylate: To a 2 L autoclave, 1 L of methanol, 144.7 g (0.375 mol, 1 eq) of 1,6-(p-aminodecylbenzene) were sequentially added. Base hexane diether, add 7.2g palladium carbon, pass 0.2MPa hydrogen, then heat up to 60 ° C reaction for 20h, release pressure, sample, liquid phase detection reaction is complete, hot filtered palladium carbon, filtrate, steamed After 700ml of methanol, the mixture was cooled to 20 ° C and stirred for 1 h, and filtered to obtain a white solid, which was the final product 1,6-(p-nonylphenyl) hexanedicarboxylate, and dried to 125.34 g;

In this step 1, the yield of 6-(p-nonylphenyl)hexanedicarboxylate was 94.3%, and the purity by HPLC was 99.5%; 1H NMR: (d6-DMSO, 500 MHz) δ=1.48 (s, 4H), 1.75 ( t, 4H), 2.0 (s, 2H) 2.68 (t, 4H) 4.0 (t, 4H), 4.10 (t, 4H), 4.52 (s, 2H), 6.95 - 7.01 (m, 10H), 7.74 (d , 4H).

The total yield of the above three-step synthesis was 88.3%.

Example 2

(1) Synthesis of 1,6-(p-cyanophenyl)hexanediether:

In a 1 L four-necked flask equipped with a stirring, a thermometer, a dropping funnel and a reflux condenser, 500 ml of ethanol and 57.16 g (0.840 mol; 2.2 eq) of sodium ethoxide were sequentially added, stirred to completely dissolve, and then cooled to room temperature. 100 g (0.840 mol; 2.2 eq) of p-cyanophenol was added in batches, and then the temperature was raised to 80 ° C for 1 h. Then, 93.2 g (0.382 mol; 1 eq) of 1,6-dibromohexane was added dropwise at this temperature, and the dropwise addition was maintained. The reaction was sampled at this temperature for 1 h, and the reaction was monitored in the liquid phase. The temperature was lowered to 25 ° C. After stirring for 1 h, it was filtered to obtain a solid wet product. After beating with 300 ml of water, it was filtered and dried to obtain a white solid 116.8 g, which was 1,6- (p-cyanophenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-cyanophenyl)hexanediether was 95.5%, and the purity by HPLC was 99.8%.

(2) Synthesis of 1,6-(p-aminodecylphenyl) hexanedicarboxylate:

In a 2L four-necked flask equipped with a stirring, thermometer, dropping funnel and reflux condenser, 1 L of ethanol, 116.8 g (0.365 mol, 1 eq) of 1,6-(p-cyanophenyl)hexanedicarboxylate were added sequentially at room temperature. 101.5g (1.460mol, 4eq) hydroxylamine hydrochloride, 100.9g (0.730mol; 2eq) potassium carbonate, after heating and refluxing to 100 ° C reflux for 5h sampling, liquid phase detection reaction is complete, cooling to 20 ° C, stirring for 1h, then filtering The solid wet product was beaten with 300 ml of water and filtered to dryness to obtain 139.0 g of a white solid, which was 1,6-(p-aminodecylphenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-amidinophenyl)hexanedicarboxylate was 98.6%, and the purity by HPLC was 99.4%.

(3) Synthesis of 1,6-(p-nonylphenyl) hexanedicarboxylate (final product):

In a 2L three-necked flask equipped with a stirring, thermometer, and reflux condenser, 1 L of formic acid, 139.0 g (0.360 mol, 1 eq) of 1,6-(p-aminodecylphenyl) hexanedicarboxylate was added in sequence, and then the temperature was raised to 80. °C, then add 87.5g (3.600mol, 10eq) of magnesium powder in batches. After adding the reaction for 3h, the magnesium powder is completely consumed, sampled, and the liquid phase detection reaction is complete. After evaporation of formic acid, 300ml of water is added dropwise at 80 °C to cool down. Filtration to room temperature gave solid wet product, adding 300 ml of water, adding 49.8 g (0.360 mol, 1 eq) of potassium carbonate in portions, stirring at room temperature for 1 h, and then filtering and drying to obtain 117.78 g of white solid, which is the final product 1,6- (p-nonylphenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-nonylphenyl)hexanedicarboxylate was 92.3%, and the purity by HPLC was 99.7%.

The total yield of the above three steps was 86.9%.

Example 3

(1) Synthesis of 1,6-(p-cyanophenyl)hexanedicarboxylate: In a 1 L four-necked flask equipped with a stirring, thermometer, dropping funnel and reflux condenser, 500 ml of ethanol and 57.2 g (0.840) were sequentially added. Mol; 2 eq) sodium ethoxide, after stirring to completely dissolve, 100 g (0.840 mol; 2 eq) of p-cyanophenol was added in portions, and then the temperature was raised to 65 ° C for 1 h, and then 102.5 g (0.42 mol; 1 eq) was added dropwise under reflux. 1,6-dibromohexane, the reaction was continued at this temperature for 10 h, the liquid phase monitoring reaction was completed, the temperature was lowered to 22 ° C, and after stirring for 1 h, it was filtered to obtain a solid wet product, which was beaten with 300 ml of water, and then filtered and dried. Obtained 125.2 g of white solid, which is 1,6-(p-cyanophenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-cyanophenyl)hexanedicarboxylate was 93.1%, and the purity by HPLC was 99.8%.

(2) Synthesis of 1,6-(p-aminodecylphenyl) hexanedicarboxylate:

In a 2L four-necked flask equipped with a stirring, thermometer, dropping funnel and reflux condenser, 1 L of dichloromethane, 125.2 g (0.391 mol, 1 eq) of 1,6-(p-cyanophenyl) Diether, 54.3g (0.782mol, 2eq) hydroxylamine hydrochloride, 31.3g (0.782mol; 2eq) NaOH, after heating to 60 ° C reflux for 10h sampling, liquid phase detection reaction is complete, cooling to 22 ° C, stirring for 1h The solid wet product was filtered, and the mixture was beaten with 300 ml of water, and then filtered and dried to obtain 144.4 g of a white solid, which was 1,6-(p-aminodecylphenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-amidinophenyl)hexanedicarboxylate was 95.6%, and the purity by HPLC was 99.2%.

(3) Synthesis of 1,6-(p-nonylphenyl) hexanedicarboxylate (final product):

Into a 2 L autoclave, 1 L of ethanol, 144.4 g (0.374 mol, 1 eq) of 1,6-(p-aminodecylphenyl) hexanedicarboxylate, and then 14.4 g of Raney nickel were added, and 0.5 MPa of hydrogen was introduced. Then, the temperature was raised to 40 ° C for 20 h, the pressure was released, the sample was taken, and the liquid phase detection reaction was completed. The Raney nickel was filtered while hot, the filtrate was obtained, and 700 ml of ethanol was distilled off, and the mixture was cooled to 25 ° C for 1 hour, and filtered to obtain a white solid. Is the final product 1,6-(p-nonylphenyl) hexanedicarboxylate, drying 126.60g;

In this step 1, the yield of 6-(p-nonylphenyl)hexanedicarboxylate was 95.5%, and the purity by HPLC was 99.6%.

The total yield of the above three steps was 85.0%.

Example 4

(1) Synthesis of 1,6-(p-cyanophenyl)hexanedicarboxylate: 500 ml of ethanol and 57.16 g (0.840) were sequentially added to a 1 L four-necked flask equipped with a stirring, a thermometer, a dropping funnel and a reflux condenser. Mol; 2.1 eq) sodium ethoxide, after stirring to dissolve, 100 g (0.840 mol; 2.1 eq) of p-cyanophenol was added in portions, and then the temperature was raised to 70 ° C for 1 h, and then 97.61 g of the mixture was added dropwise. 0.400mol; 1eq) 1,6-dibromohexane, the reaction was continued at this temperature for 4h sampling, the liquid phase monitoring reaction was completed, the temperature was lowered to 21 ° C, and after stirring for 1 h, it was filtered to obtain a solid wet product, which was beaten with 300 ml of water. After filtration, it was dried to give 121.3 g of a white solid, which was 1,6-(p-cyanophenyl)hexanedicarboxylate;

In this step 1, the yield of 6-(p-cyanophenyl)hexanedicarboxylate was 94.7%, and the purity by HPLC was 99.4%.

(2) Synthesis of 1,6-(p-aminodecylphenyl) hexanedicarboxylate:

In a 2L four-necked flask equipped with a stirring, thermometer, dropping funnel and reflux condenser, 1 L of DMSO, 116.8 g (0.365 mol, 1 eq) of 1,6-(p-cyanophenyl) hexanedicarboxylate, were added sequentially at room temperature. 50.7g (0.730mol, 2eq) hydroxylamine hydrochloride, 50.4g (0.365mol; 1eq) potassium carbonate, after heating to 80 ° C reflux for 15h sampling, liquid phase detection reaction is complete, cooling to 25 ° C, stirring for 1h, then filtered The solid wet product was beaten with 300 ml of water and filtered to dryness to obtain 144.5 g of a white solid, which was 1,6-(p-aminodecylphenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-amidinophenyl)hexanedicarboxylate was 98.7%, and the purity by HPLC was 99.1%.

(3) Synthesis of 1,6-(p-nonylphenyl) hexanedicarboxylate (final product):

In a 2L three-necked flask equipped with a stirring, thermometer, and reflux condenser, 580 ml of formic acid and 144.5 g (0.374 mol; 1 eq) of 1,6-(p-aminodecylphenyl) hexanedicarboxylate were sequentially added, and the temperature was lowered to -5. °C, temperature control 0 ° C below the addition of 152.8g (1.497mol; 4eq) acetic anhydride, after stirring and stirring at room temperature for 1h, add 7.2g palladium carbon, warmed to 80 ° C reaction 5h sampling, liquid phase detection reaction is complete, hot The palladium carbon was filtered off, the filtrate was obtained, and the formic acid was evaporated under reduced pressure. Then, 300 ml of water and 49.8 g (0.360 mol, 1 eq) of potassium carbonate were added, and the mixture was stirred at 80 ° C for 1 h, then cooled to room temperature, and dried by filtration to obtain a white solid to cool to 25 ° C. After stirring for 1 h, it was filtered to give a white solid, which was the final product 1,6-(p-nonylphenyl)hexanedicarboxylate, and dried 122.0 g;

In this step 1, the yield of 6-(p-nonylphenyl)hexanedicarboxylate is 92.0%, and the purity by HPLC detection is 99.6%;

The total yield of the above three-step synthesis was 86.0%.

Example 5

(1) Synthesis of 1,6-(p-cyanophenyl)hexanediether:

In a 1 L four-necked flask equipped with a stirring, a thermometer, a dropping funnel and a reflux condenser, 500 ml of ethanol and 57.16 g (0.840 mol; 2.2 eq) of sodium ethoxide were sequentially added, stirred to completely dissolve, and then cooled to room temperature. 100 g (0.840 mol; 2.2 eq) of p-cyanophenol was added in batches, and then the temperature was raised to about 75 ° C for 1 h. Then, 93.2 g (0.382 mol; 1 eq) of 1,6-dibromohexane was added dropwise at this temperature. Maintain the reaction at this temperature for 8h sampling, the liquid phase monitoring reaction is complete, reduce the temperature to 20 ~ 25 ° C, stir for 1h, then filter it to obtain a solid wet product, beat with 300ml water, filter and dry, to obtain a white solid 116.3g, which is 1 , 6-(p-cyanophenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-cyanophenyl)hexanedicarboxylate was 95.2%, and the purity by HPLC was 99.7%.

(2) Synthesis of 1,6-(p-aminodecylphenyl) hexanedicarboxylate:

In a 2L four-necked flask equipped with a stirring, thermometer, dropping funnel and reflux condenser, 1 L of ethyl acetate, 116.3 g (0.363 mol, 1 eq) of 1,6-(p-cyanophenyl) Diether, 100.9g (1.452mol, 4eq) hydroxylamine hydrochloride, 100.3g (0.726mol; 2eq) potassium carbonate, after heating and refluxing to 85 ° C reflux for 10h sampling, liquid phase detection reaction is complete, cooling to 24 ° C, stirring 1h will The solid wet product was filtered, and after being beaten with 300 ml of water, it was filtered and dried to obtain 138.8 g of a white solid, which was 1,6-(p-aminodecylphenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-amidinophenyl)hexanedicarboxylate was 99.0%, and the purity by HPLC was 99.3%.

(3) Synthesis of 1,6-(p-nonylphenyl) hexanedicarboxylate (final product):

In a 2 L three-necked flask equipped with a stirring, thermometer, and reflux condenser, 700 ml of ethyl acetate, 138.8 g (0.359 mol; 1 eq) of 1,6-(p-aminodecylphenyl) hexanedicarboxylate, 124.2 g were sequentially added. (0.898 mol; 2.5 eq) potassium carbonate, the temperature was lowered to -5 ° C, and 205.6 g (1.795 mol; 5 eq) of methanesulfonyl chloride was added dropwise under the temperature control of 0 ° C. After stirring for 1 hour at room temperature, 13.9 g of Raney nickel was added. The hydrogen balloon was heated to 80 ° C and refluxed for 5 h. The liquid phase detection reaction was completed. The Raney nickel was filtered off while hot, and the filtrate was obtained. 420 ml of ethyl acetate was evaporated, and the mixture was cooled to 20 ° C for 1 hour, and filtered to give a white solid. Is the final product 1,6-(p-nonylphenyl) hexanedicarboxylate, dried 119.7g;

In this step 1, the yield of 6-(p-nonylphenyl)hexanedicarboxylate was 94.0%, and the purity by HPLC was 99.0%.

The total yield of the above three-step synthesis was 88.6%.

Example 6

(1) Synthesis of 1,6-(p-cyanophenyl)hexanedicarboxylate: In a 1 L four-necked flask equipped with a stirring, thermometer, dropping funnel and reflux condenser, 500 ml of ethanol and 57.2 g (0.840) were sequentially added. Mol; 5 eq) sodium ethoxide, stirred to completely dissolve, 100 g (0.840 mol; 5 eq) of p-cyanophenol was added in portions, then heated to 78 ° C for 1 h, then 41.0 g (0.168 mol; 1 eq) was added dropwise under reflux. 1,6-dibromohexane, the reaction was continued at this temperature for 3 h sampling, the liquid phase monitoring reaction was complete, the temperature was lowered to 24 ° C, and after stirring for 1 h, it was filtered to obtain a solid wet product, which was beaten with 300 ml of water, filtered and dried. 53.5 g of white solid, ie 1,6-(p-cyanophenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-cyanophenyl)hexanedicarboxylate was 99.5%, and the purity by HPLC was 99.8%.

(2) Synthesis of 1,6-(p-amidinophenyl)hexanedicarboxylate: In a 1 L four-necked flask equipped with a stirring, thermometer, dropping funnel and reflux condenser, 500 ml of DMF was added at room temperature, 53.5 g (0.167 mol, 1 eq) 1,6-(p-cyanophenyl)hexanedicarboxylate, 116.0 g (1.67 mol, 10 eq) hydroxylamine hydrochloride, 66.8 g (1.67 mol; 10 eq) NaOH, and the temperature was raised to 90 ° C The sample was refluxed for 10 hours, and the reaction was completed in liquid phase. The temperature was lowered to 20 ° C. After stirring for 1 h, it was filtered to obtain a solid wet product. After beating with 300 ml of water, it was filtered and dried to obtain 61.5 g of a white solid, which was 1,6-(p. Aminomethylphenyl) hexanedicarboxylate;

In this step 1, the yield of 6-(p-amidinophenyl)hexanedicarboxylate was 95.3%, and the purity by HPLC was 99.0%.

(3) Synthesis of 1,6-(p-nonylphenyl) hexanedicarboxylate (final product):

Into a 2 L autoclave, 300 ml of THF, 61.5 g (0.159 mol; 1 eq) of 1,6-(p-amidinophenyl)hexanedicarboxylate, 48.3 g (0.478 mol; 3 eq) of triethylamine, 32.4 g (32.4 g ( 0.478mol, 3eq) methyl iodide, after heating to 60 ° C for 24h, add 14g palladium carbon, then pass 0.5MPa hydrogen, heat to 80 ° C reflux for 20h sampling, liquid phase detection reaction is complete, hot filtered off palladium carbon, obtained The filtrate was distilled off 400 ml of THF, and the mixture was cooled to 25 ° C for 1 h, filtered, and dried to give a white solid, that is, the final product 1,6-(p-nonylphenyl)hexanedicarboxylate, dried 38.3 g;

In this step 1, the yield of 6-(p-nonylphenyl)hexanedicarboxylate was 68.0%, and the purity by HPLC was 99.0%.

The total yield of the above three-step synthesis was 64.5%.

It should be noted that the above embodiments are only intended to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention, although the present invention will be described in detail with reference to the preferred embodiments, The technical solutions of the present invention may be modified or equivalently substituted without departing from the spirit and scope of the technical solutions of the present invention.

Claims

A novel synthesis method of 1,6-(p-nonylphenyl) hexanedicarboxylate, which comprises the following steps:

(1) reacting sodium ethoxide, p-cyanophenol and 1,6-dibromohexane in an ethanol solution to obtain 1,6-(p-cyanophenyl)hexanediether;

(2) reacting 1,6-(p-cyanophenyl)hexanedicarboxylate obtained in the step (1) with hydroxylamine or reacting with hydroxylamine hydrochloride in the presence of a base in a solvent A to obtain 1,6-(pair Amidoxime phenyl) hexanedicarboxylate;

(3a) The 1,6-(p-amidinophenyl)hexanedicarboxylate obtained in the step (2), a catalyst and a hydrogen donor reagent are subjected to a reduction reaction in a solvent B to obtain the 1,6-( P-nonylphenyl) hexanedicarboxylate; or the reduction reaction of 1,6-(p-ammonium decylphenyl)hexanedicarboxylate obtained in step (2) and a chemical reduction reagent in solvent B, 1,6-(p-nonylphenyl) hexanedicarboxylate;

Or (3b) first reacting 1,6-(p-aminodecylphenyl) hexanedicarboxylate obtained in the step (2), an acid binding agent and a derivatizing reagent in a solvent C to obtain an intermediate of the formula (I) After the body, the reduction reaction as described in the step (3a) is further carried out to obtain the 1,6-(p-nonylphenyl) hexanedicarboxylate;

Where R1 and R2 are

Wherein R1 and R2 are the same or different groups; X1, X2, X3 are any group; preferably, X1 is methyl, ethyl, phenyl, p-methylphenyl or trifluoromethyl; preferably X2 is a methyl group, a phenyl group or a p-methylphenyl group; and X3 is preferably a methyl group, an ethyl group, a phenyl group or a benzyl group.
The novel synthesis method of 1,6-(p-nonylphenyl)hexanedicarboxylate according to claim 1, wherein in the step (1), sodium ethoxide, p-cyanophenol and 1,6-di are used. The molar ratio of bromohexane is (1.5 to 5): (1.5 to 5): 1; preferably, the molar ratio of sodium ethoxide, p-cyanophenol and 1,6-dibromohexane is (2 to 2.5): (2~2.5): 1.
The novel synthesis method of 1,6-(p-nonylphenyl)hexanedicarboxylate according to claim 1, wherein the reaction temperature of the step (1) is 60 to 80 ° C, and the reaction time is 1 to 10h.
The novel synthesis method of 1,6-(p-nonylphenyl)hexanedicarboxylate according to claim 1, wherein in the step (2), 1,6-(p-cyanophenyl)hexan The molar ratio of ether to hydroxylamine is 1: (2-10); the molar ratio of the 1,6-(p-cyanophenyl)hexanedicarboxylate, base and hydroxylamine hydrochloride is 1: (1~10): (2 ~10).
The novel synthesis method of 1,6-(p-nonylphenyl) hexanedicarboxylate according to claim 1, wherein the reaction temperature in the step (2) is 20 to 100 ° C, and the reaction time is 5 ～. 20h; preferably, the reaction temperature is 60 to 80 °C.
The novel synthesis method of 1,6-(p-nonylphenyl)hexanedicarboxylate according to claim 1, wherein in the step (3a), 1,6-(p-aminodecylphenyl) The molar ratio of hexamethylene ether to hydrogen donor reagent is 1: (2-20), and the amount of catalyst used is 2-20%, preferably 5~, of the mass of 1,6-(p-aminodecylphenyl) hexanedicarboxylate. 10%; the molar ratio of 1,6-(p-aminodecylphenyl) hexanediene to the reducing agent is 1: (2-20).
The novel synthesis method of 1,6-(p-nonylphenyl)hexanedicarboxylate according to claim 1, wherein the reaction temperature in the step (3a) is 40 to 120 ° C, and the reaction time is 2 to 20h; preferably, the reaction temperature is 60 to 80 °C.
The novel synthesis method of 1,6-(p-nonylphenyl)hexanedicarboxylate according to claim 1, wherein in the step (3b), 1,6-(p-amidinophenyl) The molar ratio of the hexamethylene ether, the acid binding agent and the derivatizing agent is 1: (0 to 10): (2 to 10); the reaction temperature is 0 ° C or lower, and the reaction time is 1 h.
The novel synthesis method of 1,6-(p-nonylphenyl) hexanedicarboxylate according to claim 1, wherein the solvent A in the step (2) is selected from the group consisting of methanol, ethanol, dichloromethane, and acetic acid. At least one of ethyl ester, THF, DMF, DMSO, and NMP; the base is selected from the group consisting of potassium carbonate, sodium carbonate, sodium ethoxide, sodium hydroxide, triethylamine or pyridine; and solvent B is selected in the step (3a) At least one of water, methanol, ethanol, dichloromethane, ethyl acetate, THF, DMF, DMSO, NMP, formic acid, acetic acid, and dimethyl carbonate; the catalyst is selected from the group consisting of palladium, rhodium, platinum, or lenni Nickel; the hydrogen donor reagent is selected from the group consisting of hydrogen, formic acid, sodium formate, potassium formate or ammonium formate; the chemical reduction reagent is selected from the group consisting of magnesium powder, aluminum powder, zinc powder, iron powder, nickel powder, aluminum nickel alloy, and hydroboration Sodium or potassium borohydride.
The novel synthesis method of 1,6-(p-nonylphenyl)hexanedicarboxylate according to claim 1, wherein the solvent C in the step (3b) is selected from the group consisting of water, methanol, ethanol, and dichloromethane. At least one of ethyl acetate, THF, DMF, DMSO, NMP, formic acid, acetic acid and dimethyl carbonate; the acid binding agent is selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and triethyl ethane At least one of an amine, pyridine, sodium hydroxide and sodium ethoxide; the derivatizing agent is selected from the group consisting of a carboxylic acid ester derivatizing agent, a sulfonate derivatizing agent or an etherifying agent, wherein the carboxylic acid ester derivatizing agent is selected from the group consisting of Acetyl chloride, acetic anhydride, propionyl chloride, propionic anhydride, benzoyl chloride or trifluoroacetyl chloride; the sulfonate derivatization reagent is selected from methanesulfonyl chloride, benzoyl chloride or p-toluenesulfonyl chloride; the etherification reagent is preferably dimethyl carbonate , diethyl carbonate, methyl iodide, ethyl bromide, bromobenzene or benzyl bromide.