阅读说明：本技术 一种合成6,8-二氯辛酸酯的方法 (Method for synthesizing 6, 8-dichloro caprylic acid ester ) 是由 祁彦涛 于 2021-09-10 设计创作，主要内容包括：本发明涉及一种合成6,8-二氯辛酸酯的方法,包括下述步骤：使式(II)所示化合物7-(2-羟乙基)己-2-内酯在醇溶液中发生开环氯代,得到式(I)所示化合物6,8-二氯辛酸酯,其中R为C1-C4烷基,ROH选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇。本发明的方法副反应少、产品收率高、纯度高,有利于工业规模生产。(The invention relates to a method for synthesizing 6, 8-dichloro caprylic acid ester, which comprises the following steps: the compound 7- (2-hydroxyethyl) hex-2-lactone shown in the formula (II) is subjected to ring-opening chlorination in an alcohol solution to obtain the compound 6, 8-dichloro caprylic acid ester shown in the formula (I), wherein R is C1-C4 alkyl, and ROH is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol. According to the inventionThe method has less side reaction, high product yield and high purity, and is favorable for industrial scale production.)

1. A method for synthesizing 6, 8-dichloro caprylate, comprising the following steps:

A. subjecting 7- (2-hydroxyethyl) hex-2-lactone as a compound shown in formula (II) to ring-opening chlorination in an alcohol solution to obtain 6, 8-dichloro caprylate as a compound shown in formula (I):

wherein R is C1-C4 alkyl, and ROH is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol.

2. The method according to claim 1, wherein the reagent used in the ring-opening chlorination reaction in step a is thionyl chloride, phosgene or triphosgene.

3. The method according to claim 1, wherein the compound of formula (II), 7- (2-hydroxyethyl) hex-2-olide, is synthesized by:

B. carrying out oxidation reaction on a compound 2- (2-hydroxyethyl) cyclohex-1-one shown in a formula (III) to obtain a compound shown in a formula (II):

4. the method of claim 3, wherein the oxidation reaction is a Baeyer-Villiger oxidation reaction.

5. The method as claimed in claim 4, wherein the oxidation reaction in step B is carried out in a hydrogen peroxide/acetic acid system, a hydrogen peroxide/formic acid system, or an m-chloroperoxybenzoic acid system. The hydrogen peroxide/acetic acid system is preferred.

6. The method according to claim 3, wherein the compound 2- (2-hydroxyethyl) cyclohex-1-one of formula (III) is synthesized by:

C. adding ethylene oxide to a compound of formula (IV) 2-oxocyclohexane-1-carboxylate, and then decarboxylating to obtain a compound of formula (III):

wherein R1 is C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

7. The process of claim 6, wherein the base used in the addition reaction in step C is selected from sodium hydride, lithium bistrimethylsilylamide, lithium diisopropylamide, and the solvent used is selected from toluene, tetrahydrofuran, methanol, or a mixture of two or more thereof.

8. The process of claim 6, wherein the decarboxylation conditions in step C comprise heating in aqueous hydrochloric acid or aqueous sulfuric acid.

9. The method according to claim 6, wherein the compound 2-oxocyclohexane-1-carboxylate represented by the formula (IV) is synthesized by:

D. reacting cyclohexanone, a compound shown as a formula (V), with carbonic ester under the catalysis of alkali to obtain a compound shown as a formula (IV):

wherein R1 is C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

10. The process according to claim 9, wherein the base used in step D is sodium hydride and the reaction solvent used is toluene.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing 6, 8-dichloro caprylic acid ester.

Background

Lipoic acid (Lipoic acid) is chemically named as 1, 2-dithiolane-3-pentanoic acid, is a coenzyme existing in mitochondria, belongs to a class of compounds in B vitamins, catalyzes the oxidative decarboxylation of pyruvic acid into acetic acid and the oxidative decarboxylation of alpha-ketoglutaric acid into succinic acid in a multienzyme system, and is widely distributed in biological tissues of animals, plants and the like. The lipoic acid has strong oxidation resistance, is known as universal antioxidant, has better oxidation resistance than vitamins, and can eliminate free radicals which accelerate aging and cause diseases; can improve insulin function and heart rate variability of diabetic; the treatment of hepatitis c, the protection of the kidney and pancreas, the prevention of cataract and the like, and thus has received wide attention from researchers. Wherein, 6, 8-dichloro ethyl caprylate is one of key intermediates for synthesizing lipoic acid, and the lipoic acid product can be obtained by hydrolyzing ethyl ester after vulcanization:

at present, the preparation method of 6, 8-dichloro ethyl caprylate mainly comprises the following steps: zhejiang chemical engineering, 2010,41(5),10-11,14, reports a synthetic method using monoethyl adipate as a raw material. According to the method, firstly, adipic acid monoethyl ester reacts with triphosgene (BTC) to obtain acyl chloride, then Friedel-Crafts alkylation reaction is carried out on the acyl chloride and ethylene to obtain a chloroketone intermediate, the chloroketone intermediate is reduced by potassium borohydride to obtain a chlorohydrin intermediate, and finally the chlorohydrin intermediate is chlorinated by triphosgene to obtain a target product 6, 8-dichloro ethyl caprylate (I). In addition, patent documents CN101157614A and CN105693510A propose improvements for the chlorination reaction in the last step. In general, in the method, the raw material of the monoethyl adipate is very high in price, three wastes generated by using aluminum trichloride are more, and the reducing agent potassium borohydride is expensive and difficult to produce on a large scale.

Patent document CN107673972A reports that cyclohexanone and vinyl ethyl ether are used as raw materials, and an ethyl ether intermediate is obtained by a radical reaction, and is oxidized by Baeyer-Villiger and is subjected to ring opening to obtain an open-chain intermediate acid, then ether bonds are broken under the action of aluminum trichloride to obtain a dihydroxy acid, and finally the dihydroxy acid reacts with thionyl chloride in ethanol to obtain ethyl 6, 8-dichlorooctanoate (I). The method has the problems that the reaction condition for breaking ether bond of aluminum trichloride is harsh, the using amount of aluminum trichloride is large, the yield is low, and the application of the method is limited to a great extent.

Patent document CN112479878A uses 8-hydroxyoctanal as a raw material, and oxidizes and esterifies it to 8-hydroxyoctanoate ethyl ester, and then dehydrates it to generate an alkenyl ester intermediate, and the alkenyl ester intermediate undergoes Prins condensation reaction to obtain a methylal intermediate, and then undergoes hydrolysis hydrogenation to obtain a dihydroxy compound, and finally undergoes chlorination to obtain 6, 8-dichlorooctanoate ethyl ester (I). In the method, the raw material 8-hydroxyoctanal is expensive, a solid catalyst is used in multiple steps, the dehydration reaction temperature reaches 350 ℃, the condition requirement is high, and the method is not suitable for industrial production.

Disclosure of Invention

In order to overcome the defects of high raw material price, high production cost, more three wastes, complex operation and unsuitability for industrial production in the method for preparing 6, 8-dichloro caprylate in the prior art, the invention provides a novel method for synthesizing 6, 8-dichloro caprylate, which can prepare 6, 8-dichloro caprylate by using cheap reaction raw materials, mild reaction conditions and high yield and has industrial production feasibility and economical efficiency. Specifically, the present invention includes the following technical means.

A method for synthesizing a compound 6, 8-dichloro caprylic acid ester shown as a formula (I) comprises the following steps:

A. subjecting 7- (2-hydroxyethyl) hex-2-lactone as a compound shown in formula (II) to ring-opening chlorination in an alcohol solution to obtain 6, 8-dichloro caprylate as a compound shown in formula (I):

wherein R is C1-C4 alkyl, and ROH is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol. Preferably, ROH is ethanol or methanol, and ethanol is more preferable in view of environmental protection and raw material economy.

The reagent used in the ring-opening chlorination reaction in the step A can be thionyl chloride SOCl₂Phosgene or triphosgene BTC.

In one embodiment, the compound 7- (2-hydroxyethyl) hex-2-lactone of formula (II) in step A above can be synthesized by:

B. carrying out oxidation reaction on a compound 2- (2-hydroxyethyl) cyclohex-1-one shown in a formula (III) to obtain a compound shown in a formula (II):

wherein the oxidation reaction is a Baeyer-Villiger oxidation reaction.

The oxidation reaction in the step B can adopt a hydrogen peroxide/acetic acid system, a hydrogen peroxide/formic acid system or an m-chloroperoxybenzoic acid system. From the viewpoint of raw material economy, a hydrogen peroxide/acetic acid system is preferred.

In one embodiment, the compound 2- (2-hydroxyethyl) cyclohex-1-one of formula (III) in step B above can be synthesized by:

C. adding ethylene oxide to a compound of formula (IV) 2-oxocyclohexane-1-carboxylate, and then decarboxylating to obtain a compound of formula (III):

wherein R1 is C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

The base used in the addition reaction in the step C may be selected from sodium methoxide, sodium hydride, lithium bistrimethylsilyl amide, and lithium diisopropylamide, and from the viewpoint of catalytic efficiency and economy, sodium hydride is preferred; the solvent used is selected from toluene, tetrahydrofuran, methanol, or a mixture of two or more thereof, but is not limited thereto.

The decarboxylation conditions in the above step C may include heating in an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution.

In one embodiment, the compound 2-oxocyclohexane-1-carboxylate represented by the formula (IV) in the above step C may be synthesized by the following steps:

D. reacting cyclohexanone, a compound shown as a formula (V), with carbonic ester under the catalysis of alkali to obtain a compound shown as a formula (IV):

wherein R1 is C1-C4 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. Preferably, R1 is methyl or ethyl, i.e. the carbonate is dimethyl carbonate or diethyl carbonate.

The base used in the above step D may be sodium hydride, and the reaction solvent used may be toluene.

In a preferred embodiment, the product 2-oxocyclohexane-1-carboxylate (IV) in step D can be directly subjected to step C without separation and purification, and alkali is not added, so that the 2- (2-hydroxyethyl) cyclohex-1-one (III) is obtained, and the continuous reaction operation can reduce the production cost of the whole process and improve the economy.

The invention provides a new chemical synthesis way of 6, 8-dichloro caprylic acid ester, in the method, the raw material cyclohexanone is cheap and easy to obtain, the reaction condition is mild, the produced three wastes are less, the operation is simple, and the feasibility of industrial large-scale production is realized.

Detailed Description

The invention provides a new way for synthesizing the compound 6, 8-dichloro caprylic acid ester shown in the formula (I) from the economic concept of industrial production for reducing the production cost.

Herein, the term "compound of formula X" is sometimes expressed as "compound of formula X" or "compound X", as will be understood by those skilled in the art. The compound represented by the formula (I) and the compound (I) are both referred to as the same compound.

The preparation of the compound shown in the formula (I) from cheap chemical raw material cyclohexanone and using cheap and easily available bulk chemicals as a catalyst, a solvent and the like is an economic scheme.

R, R1 are as defined above.

For example, dimethyl carbonate (R1 is methyl) selected in step D and ethanol (ROH) selected in step a are the least expensive industrial raw materials of the same class of compounds. In this case, the method for synthesizing ethyl 6, 8-dichlorooctanoate (wherein R is ethyl in formula I) according to the present invention comprises the following steps:

1) cyclohexanone (V) is taken as a raw material and reacts with dimethyl carbonate under the action of alkali to obtain an intermediate 2-oxocyclohexane-1-carboxylic acid methyl ester (IV);

2) adding 2-oxocyclohexane-1-carboxylic acid methyl ester (IV) and ethylene oxide, and then decarboxylating to obtain an intermediate 2- (2-hydroxyethyl) cyclohex-1-one (III);

3) oxidizing the 2- (2-hydroxyethyl) cyclohex-1-one (III) by Baeyer-Villiger to obtain an intermediate 7- (2-hydroxyethyl) hex-2-lactone compound (II);

4) and (3) carrying out ring opening chlorination on the 7- (2-hydroxyethyl) hexyl-2-lactone compound (II) in ethanol to obtain the 6, 8-dichloro octanoic acid ethyl ester (I).

In a preferred embodiment, after the reaction in each step is completed, the post-treatment operations such as filtration, washing, decoloring purification, crystallization, drying, etc. may be performed according to the general knowledge in the art. On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

In a preferred embodiment, the product 2-oxocyclohexane-1-carboxylic acid methyl ester (IV) of step 1) can be directly subjected to step 2) without separation and purification, and alkali is not added, so that the 2- (2-hydroxyethyl) cyclohex-1-one (III) is obtained, and the continuous reaction operation can reduce the production cost and improve the economy of the invention.

The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Various changes or modifications thereof, which may occur to those skilled in the art based on the teachings of the present invention, are within the scope of the present invention.

The addition amount, content and concentration of various substances are referred to herein, wherein the percentage refers to the mass percentage unless otherwise specified.

In the examples herein, if no specific description is made about the reaction temperature or the operation temperature, the temperature is usually referred to as room temperature (15 to 30 ℃).

Examples

Reagent: the reactants and the catalyst used in the embodiment of the invention are chemically pure, and can be directly used or simply purified according to the requirement; the organic solvent and the like are analytically pure and are directly used. The reagents were purchased from Shanghai chemical reagent company, China medicine (group).

A detection instrument:

nuclear magnetic resonance apparatus type: bruker affinity III 400 MHz;

mass spectrometer (liquid mass spectrometry (LCMS)), type: agilent 6120B.

Example 1: preparation of methyl 2-oxocyclohexane-1-carboxylate (IV)

A1000 mL four-necked flask was charged with 400mL of toluene and 50.0g of dimethyl carbonate, nitrogen-substituted three times, 31.0g of sodium hydride was added in portions, after completion of the addition, the temperature was slowly raised to reflux, the reaction was carried out for 30 minutes, and 27.2g of cyclohexanone (V) was added dropwise over about 2 hours. The reaction was maintained at reflux for 8 hours. After the control reaction is finished, the reaction system is cooled to room temperature, and 140mL of methanol is added dropwise to quench the excessive sodium hydride, so as to obtain a solution of the compound 2-oxocyclohexane-1-carboxylic acid methyl ester (IV). Washing the solution once with dilute hydrochloric acid, washing once with a small amount of water, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, performing reduced pressure rectification (2mmHg), collecting fractions at 75-80 ℃ to obtain 36.8g of 2-oxocyclohexane-1-carboxylic acid methyl ester (IV), wherein the yield is as follows: 85 percent.

¹H NMR(400MHz,CDCl₃)δ3.75(s,3H),2.27(t,2H),2.22(t,2H),1.65(m,5H)。

MS(ESI)m/z＝157.1(M⁺+1)。

Example 2: preparation of 2- (2-hydroxyethyl) cyclohex-1-one (III)

In a 1000mL autoclave, 36.8g of methyl 2-oxocyclohexane-1-carboxylate (IV) was dissolved in 500mL of toluene, and 17.7g of sodium methoxide and 24.4g of ethylene oxide were added thereto, followed by slowly raising the temperature to 50 ℃ and reacting for 6 hours. And after the reaction is finished, adding 100mL of water and 100mL of concentrated hydrochloric acid into the system, heating to 50 ℃ for reaction for 3 hours, cooling to room temperature, standing for layering, washing a toluene phase with a small amount of water once, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, performing reduced pressure rectification (2mmHg), collecting a fraction at 120-125 ℃, and obtaining 24.4g of 2- (2-hydroxyethyl) cyclohex-1-one (III) with the yield of 73%.

¹H NMR(400MHz,CDCl₃)δ4.65(s,1H),3.83(t,2H),2.28(m,2H),2.12(m,1H),1.65(m,8H)。

MS(ESI)m/z＝143.1(M⁺+1)。

The above reduction reaction operation was repeated, different solvents and bases were used, the yield was calculated by separation, and the experimental results are shown in the following table:

serial number	Solvent(s)	Alkali	Yield of
				1	Toluene	Sodium methoxide	73％
2	Toluene	Sodium hydride	77％
				3	Tetrahydrofuran (THF)	Bis-trimethylsilyl amido lithium	70％
4	Tetrahydrofuran (THF)	Lithium diisopropylamide	67％
				5	Methanol	Sodium methoxide	52％

As can be seen from the table, sodium hydride has the highest catalytic efficiency.

Example 3: continuous preparation of 2- (2-hydroxyethyl) cyclohex-1-one (III)

200mL of toluene and 25.0g of dimethyl carbonate were charged into a 500mL four-necked flask, nitrogen gas was substituted three times, 15.5g of sodium hydride was added in portions, after completion of the addition, the temperature was slowly raised to reflux, the reaction was carried out for 30 minutes, and 13.6g of cyclohexanone (V) was added dropwise over about 2 hours. The reaction was maintained at reflux for 8 hours. The reaction was monitored for completion, the reaction system was cooled to room temperature, and excess sodium hydride was quenched by dropwise addition of 70mL of methanol to give a solution of the compound methyl 2-oxocyclohexane-1-carboxylate (IV). The solution was directly charged to the next reaction.

The solution of methyl 2-oxocyclohexane-1-carboxylate (IV) was transferred to an autoclave, 12.2g of ethylene oxide was added, and the temperature was slowly raised to 50 ℃ for reaction for 6 hours. After the reaction is finished, adding 50mL of water and 25mL of concentrated sulfuric acid (98%) into the system, heating to 50 ℃ for reaction for 3 hours, cooling to room temperature, standing for layering, washing a toluene phase with a small amount of water once, drying with anhydrous sodium sulfate, concentrating under reduced pressure to obtain a crude product, rectifying under reduced pressure, collecting fractions at 120-125 ℃ to obtain 12.2g of 2- (2-hydroxyethyl) cyclohex-1-one (III), wherein the total yield is 62%.

Example 4: preparation of 7- (2-hydroxyethyl) hex-2-olide compound (II)

10g of 2- (2-hydroxyethyl) cyclohex-1-one (III) was added to a mixture of 20mL of acetic acid and 20mL of hydrogen peroxide (30%) and reacted at room temperature for 24 hours. After the reaction, 50mL of dichloromethane is added, the system is washed to be neutral by using 5% sodium carbonate solution, an organic layer is obtained by separation, the washing is carried out, the drying is carried out by using anhydrous sodium sulfate, and the solvent is concentrated under reduced pressure. The residual liquid is rectified under reduced pressure, and 130-134 ℃ fractions are collected to obtain 6.8g of 7- (2-hydroxyethyl) hex-2-lactone (II), and the yield is as follows: and 63 percent.

¹H NMR(400MHz,CDCl₃)δ4.52(m,1H),3.81(m,2H),3.60(s,1H),2.67(m,2H),1.95(m,4H),1.82(m,1H),1.64(m,3H)。

MS(ESI)m/z＝159.2(M⁺+1)。

The above reduction reaction operation was repeated, different solvents and oxidation conditions were used, and the yield was calculated by separation, and the experimental results are shown in the following table:

serial number	Solvent(s)	Alkali	Yield of
				1	Acetic acid	Hydrogen peroxide solution	63％
2	Formic acid	Hydrogen peroxide solution	70％
				3	Methylene dichloride	Meta-chloroperoxybenzoic acid	77％
4	Acetonitrile	Meta-chloroperoxybenzoic acid	75％

From the table, it can be seen that the oxidation efficiency of the m-chloroperoxybenzoic acid/dichloromethane system is the highest, and although the oxidation efficiency of the hydrogen peroxide/acetic acid system is relatively low, the reaction requirement can be met, and the hydrogen peroxide/acetic acid system can be accepted from the viewpoint of raw material economy.

Example 5: preparation of ethyl 6, 8-dichlorooctanoate (I)

Adding 5g of 7- (2-hydroxyethyl) hexane-2-lactone (II) into 30mL of ethanol, cooling to 10 ℃, dropwise adding 11.2g of thionyl chloride, heating to 50 ℃ for reaction for 3 hours, concentrating the system to dryness, adding 50mL of dichloromethane, washing with 5% sodium bicarbonate aqueous solution once, drying with anhydrous sodium sulfate, concentrating the solvent under reduced pressure to obtain a crude product, and purifying by column chromatography to obtain 5.9g of 6, 8-dichloro ethyl caprylate (I), wherein the yield is 78%.

¹H NMR(400MHz,CDCl₃)δ4.01(q,2H),3.70(t,2H),3.21(m,1H),2.37(t,2H),1.79(q,2H),1.60(m,2H),1.45(q,2H),1.25(m,2H),1.03(t,3H)。

MS(ESI)m/z＝242.1(M⁺+1)。

The reduction reaction operation is repeated, different chlorination reagents are adopted, after the reaction is finished, the yield is calculated through separation, and the experimental results are shown in the following table:

serial number	Chlorination reagent	Yield of
			1	Thionyl chloride	78％
2	Triphosgene	63％
			3	triphosgene/DMF	82％

As can be seen from the above table, the ring-opening chlorination efficiency catalyzed by the triphosgene/DMF system is the highest, the thionyl chloride/ethanol catalytic efficiency can also meet the reaction requirement, and the thionyl chloride/ethanol can be accepted from the viewpoints of production safety and raw material economy.

Experiments show that the method opens up a new 6, 8-dichloro caprylate synthesis route, the purity of the prepared product is high, the post-treatment of each step is simple, and the production cost of the 6, 8-dichloro caprylate can be obviously reduced, so that the method is more suitable for industrial large-scale production.

Although the technical scheme of the invention is verified by taking ethyl 6, 8-dichlorooctoate (i.e. R in formula I is ethyl) as an example, the process route concept designed by the invention can also be applied to the synthesis of other 6, 8-dichlorooctoates according to the disclosure of the invention. As will be apparent to those skilled in the art. Without departing from the spirit of the invention, it is intended that all such changes, modifications, and applications be considered as within the scope of the invention by those skilled in the art.