Method for producing ethyl 8-chlorooctanoate

Abstract

This invention discloses a method for preparing ethyl 8-chlorooctanoate for use in pharmaceutical or pesticide manufacturing. The alkylation reaction of the corresponding 1,6-dichlorohexane with diethyl malonate is carried out in the presence of potassium carbonate using a dual catalyst containing potassium bromide or sodium bromide and polyethylene glycol. After the reaction is complete, the crude product, 6-chlorohexyl diethyl malonate, is obtained by distillation. This is followed by hydrolysis and decarboxylation in a one-pot process under the catalysis of sulfonic acid, followed by vacuum distillation to remove water and esterify the ethanol. Finally, high-purity ethyl 8-chlorooctanoate is obtained by rectification, which satisfies customer needs. This method simplifies production operations, shortens unit operation times, reduces labor intensity, and improves product quality.

Description

[Technical Field]

[0001] The present invention relates to a method for producing an intermediate in the production of pharmaceuticals or agricultural chemicals, and in particular to a method for producing ethyl 8-chlorooctanoate. [Background technology]

[0002] The English name of ethyl 8-chlorooctanoate is 8-chlorooctanoic acid ethyl ester, ethyl 8-chlorooctanoate, its CAS Registry Number(s) is 105484-55-7, and its boiling point is 251.5±23.0°C (Predicted).

[0003] Its structural formula is as follows: [ka]

[0004] Ethyl 8-chlorooctanoate is an excellent solvent and an important pharmaceutical and agrochemical intermediate with high development value. For example, it is used to synthesize sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (SNAC), a chemically synthesized fatty acid derivative, which was initially selected by Emisphere from a number of penetration enhancers and is a highly efficient molecule.

[0005] The FDA approved the marketing of semaglutide injection (brand name: Ozempic) for blood sugar control in adults with type 2 diabetes in December 2017. Novo Nordisk submitted a marketing application to the FDA on December 4, 2020, for the use of semaglutide as a once-weekly subcutaneous injection of 2.4 mg for the treatment of obesity. The oral formulation of semaglutide cannot be achieved without a helpful tool: sodium N-(8-[2-hydroxybenzoyl]-amino)octanoate (salcaprozate sodium, SNAC).

[0006] For example, when SNAC is administered alone to an adult weighing approximately 70 kg, the recommended oral dose of ibandronate, an osteoporosis treatment, is 2.5 mg per day or 150 mg per month. When administered together with SNAC, the daily dose of ibandronate, an osteoporosis treatment, is reduced to approximately 1.25 mg to approximately 0.25 mg.

[0007] Currently, there are several main synthetic routes for ethyl 8-chlorooctanoate:

[0008] 1, EVONIK INDUSTRIES AG-EP1384706, 2004, A1, Shanghai Wanji Chemical Co., Ltd.

[0009] Patents such as CN101328120(A) disclose a method for preparing ethyl 8-halooctanoate, which uses 1,6-dihalohexane as a starting material, reacts with diethyl malonate, and then undergoes decarboxylation and hydrolysis, followed by esterification to obtain ethyl 8-halooctanoate.

[0010] The reaction formula is as follows: [ka]

[0011] This is currently a widely used process route, and the process has two main drawbacks:

[0012] (1) In the process of synthesizing 2-(6-chlorohexyl)diethylmalonate by reacting 1,6-dichlorohexane with diethyl malonate, disubstituted impurities (two cyclohexyls at the 2-position) are likely to be produced, and 2-(6-chlorohexyl)diethylmalonate itself undergoes ring closure to produce cycloheptyldiethylmalonate. One 1,6-dichlorohexane reacts with two diethyl malonates to produce large molecular impurities. The raw material 1,6-dichlorohexane and a base are likely to undergo elimination reactions at high temperatures, producing elimination impurities such as 1-chloro-6-hexene. These side reactions result in a low yield.

[0013] (2) The alkylation reaction of diethyl malonate requires the use of a phase transfer catalyst to promote the interaction between the liquid reactant and solid potassium carbonate. Conventional techniques use quaternary ammonium salts, such as tetrabutylammonium bromide and tetrabutylammonium chloride, as catalysts to promote the reaction. These catalysts undergo a C-alkylation reaction with diethyl malonate, producing impurities with boiling points very close to those of ethyl 8-chlorooctanoate, which are extremely difficult to separate (even by rectification). As a result, the purity of the products currently on the market is low, and they cannot meet customer needs.

[0014] 2. The specification of CN112409175(A) of Anhui Haofan Biological Co., Ltd. discloses a method for obtaining ethyl 8-chlorooctanoate from 1,8-octanediol as a raw material through chlorination, oxidation and esterification reactions.

[0015] The reaction formula is as follows: [ka]

[0016] The drawbacks are that the starting material, 1,8-octanediol, is difficult to obtain and expensive, and the amount of waste generated by oxidation using sodium hypochlorite is very large, causing serious pollution.

[0017] As described above, finding a process route for ethyl 8-chlorooctanoate that has the advantages of "low raw material costs, high product purity and yield, and little waste" has become a technical problem to be solved. Summary of the Invention [Problem to be solved by the invention]

[0018] The present invention aims to provide a method for producing ethyl 8-chlorooctanoate that overcomes the shortcomings of conventional synthesis techniques, has advantages such as low raw material costs, short reaction time, high product purity and yield, and is very environmentally friendly, meeting the requirements of green chemistry. [Means for solving the problem]

[0019] Here, the method for producing ethyl 8-chlorooctanoate according to the present invention comprises the steps of: a step S1 for producing compound 4, in which 1,6-dichlorohexane 2 and diethyl malonate 3 are alkylated in the presence of potassium carbonate and a catalyst, the molar ratio of diethyl malonate, 1,6-dichlorohexane, and potassium carbonate being 1:(2-2.5):(1.2-2.0); after the reaction is completed, washing is performed, and 1,6-dichlorohexane as a raw material is recovered from the organic layer, followed by vacuum distillation to obtain compound 4, the catalyst being a mixture of PEG-600 and sodium bromide, the amount of catalyst being 0.44%-0.8% of the sum of the amounts of diethyl malonate, 1,6-dichlorohexane, and potassium carbonate being used, and the weight ratio of sodium bromide to PEG-600 in the catalyst being (4-7):(9-12); and step S2 of preparing compound 1, in which a hydrolysis catalyst is added to compound 4 to carry out high-temperature hydrolysis and decarboxylation to obtain 8-chlorooctanoic acid, and then water is removed by distillation under reduced pressure, and ethanol is further added to carry out an esterification reaction, and finally, vacuum rectification is carried out to obtain compound 1, i.e., the target product, ethyl 8-chlorooctanoate. The reaction formula is as follows: [ka]

[0020] The present invention uses a dual catalyst containing sodium bromide and polyethylene glycol to alkylate the corresponding 1,6-dichlorohexane with diethyl malonate in the presence of potassium carbonate. After the reaction is complete, the crude product, 6-chlorohexyl diethyl malonate, is obtained by distillation. This product is then hydrolyzed and decarboxylated in a one-pot process under the catalysis of sulfonic acid, followed by vacuum distillation to remove water and esterify the ethanol. Finally, high-purity ethyl 8-chlorooctanoate is obtained by rectification, meeting customer needs. This method simplifies production operations, shortens unit operation time, reduces labor intensity, and improves product quality. According to the basic theory of organic chemistry, the order of elimination of halogen atoms is iodine > bromine > chlorine. Therefore, the introduction of bromine into the reaction system significantly enhances the nucleophilic substitution ability, accelerating the reaction rate and lowering the reaction temperature. The present invention solves the production separation problem by selecting a hydrolysis catalyst, preferably p-toluenesulfonic acid.

[0021] Furthermore, in steps S1 and S2, the absolute pressure during the vacuum distillation and vacuum rectification is 0.005 MPa to 0.01 MPa.

[0022] Furthermore, in step S1, the alkylation reaction temperature is 70 to 80° C., the reaction time is about 7 to 8 hours, and acetonitrile is used as the solvent.

[0023] Furthermore, the hydrolysis catalyst used in step S2 is p-toluenesulfonic acid.

[0024] Furthermore, in step S2, the temperature of the hydrolysis reaction is 100 to 160°C. The temperature of the hydrolysis reaction is preferably 130 to 150°C. [Effects of the Invention]

[0025] This invention uses a dual catalyst containing sodium bromide and polyethylene glycol PEG-600 to alkylate the corresponding 1,6-dichlorohexane with diethyl malonate in the presence of potassium carbonate, followed by distillation to obtain crude 6-chlorohexyl diethyl malonate. This is followed by hydrolysis and decarboxylation in a one-pot process under the catalysis of sulfonic acid, followed by vacuum distillation to remove water, esterification with ethanol, and finally rectification to obtain high-purity ethyl 8-chlorooctanoate. The use of dual catalysts reduces the temperature of the alkylation reaction between 1,6-dichlorohexane and diethyl malonate and avoids side reactions caused by dechlorination. The use of p-toluenesulfonic acid as a hydrolysis catalyst in the hydrolysis and decarboxylation steps solves the problem of difficult separation due to emulsification during production. The use of vacuum distillation to remove water after hydrolysis and decarboxylation significantly simplifies the production process, reduces the amount of ethanol used as solvent, improves esterification efficiency, and lowers production costs. The present invention has advantages such as a short reaction time, high purity of the product and high yield, and the production by this process is economically profitable and particularly suitable for commercialized large-scale production. [Brief explanation of the drawings]

[0026] [Figure 1] 1 shows the purity detection spectrum of the industrially produced ethyl 8-chlorooctanoate product in Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0027] The following examples are provided to assist the researcher in understanding the gist of the manufacturing techniques of the present invention, but are not intended to limit the scope of the present invention.

[0028] Example 1 A method for producing ethyl 8-chlorooctanoate is provided, the reaction scheme of which is as follows: [ka]

[0029] The specific manufacturing steps are as follows:

[0030] Step S1, synthesis of compound 4 In a 5 L four-neck flask equipped with a mechanical stirrer, 830.0 g of potassium carbonate, 6.0 g of sodium bromide, 10.0 g of PEG-600, 1280 g of 1,6-dichlorohexane, and 720 g of acetonitrile were sequentially added, and the mixture was heated with stirring until the internal temperature reached 70°C, and 600 g of diethyl malonate was added dropwise, controlling the temperature at 70-80°C. The dropwise addition took approximately 3 hours, and the reaction was carried out for approximately 7-8 hours while controlling the temperature at 70-80°C. Sampling was performed and in-process control was performed; the reaction was deemed to have ended when the diethyl malonate concentration was less than 1.0%.

[0031] The reaction mixture was distilled under atmospheric pressure, and acetonitrile was collected until no more distillates were produced. The temperature was lowered to 20-30°C, 2500 g of water was added, and the mixture was stirred for 0.5 hours. After standing for 0.5 hours, the lower aqueous layer was separated, and the upper organic layer was washed once with 500 g of water. After standing, the mixture was separated to obtain the lower organic layer. The organic layer was transferred to a distillation flask and subjected to vacuum distillation. 1,6-dichlorohexane was collected using a pump and distilled using an oil pump. The absolute pressure during vacuum distillation was 0.005 MPa to 0.01 MPa, and the product of Step S1 was obtained, weighing 810.5 g and yielding 77.5%.

[0032] Step S2, synthesis of compound 1 A 500 mL four-neck flask was charged with 300 g of the product from step S1 and 3.0 g of p-toluenesulfonic acid, and the mixture was heated with stirring. When the internal temperature reached 130 °C, 75 g of water was slowly added dropwise over approximately 3 hours, controlling the internal temperature at 125-130 °C. After the addition was complete, the reaction was refluxed for approximately 4 hours and monitored by GC. The reaction was deemed complete when the raw material concentration was less than 1.0%. Water was removed by distillation, and after the distillate disappeared, water was removed by pumping under negative pressure until the distillate disappeared. 95.0 g of absolute ethanol was added, refluxed for approximately 3 hours, and monitored by GC. The reaction was deemed complete when the intermediate 8-chlorooctanoic acid concentration was less than 1.0%.

[0033] The reaction mixture was distilled under atmospheric pressure to remove ethanol until no further distillates were produced. The temperature was lowered to 20-30°C, and water (100 g), 1.6 g of sodium bicarbonate, and 20 g of sodium chloride were added. The mixture was stirred for 0.5 hours and the pH was adjusted to 5-7. After standing for 0.5 hours, the lower aqueous phase was separated, and the upper organic phase was the crude target product. The crude target product was subjected to vacuum rectification under an absolute pressure of 0.005-0.01 MPa. A colorless, transparent oily liquid (ethyl 8-chlorooctanoate) weighing 178.0 g was obtained with a GC purity of 99.52%, a content of unknown impurities of less than 0.1%, and a yield of 80.1%.

[0034] Catalyst selection in step S1: The catalyst was changed with the other materials unchanged, using only sodium bromide as the catalyst, to obtain the data shown in Table 1 below. [Table 1]

[0035] The catalyst was changed without changing any other materials, using only PEG-600 as the catalyst, to obtain the data shown in Table 2 below. [Table 2]

[0036] In Table 1, the optimum amount of sodium bromide is 6.0 g, and in Table 2, the optimum amount is 10.0 g. The weight ratio of the two is fixed, and the two are mixed to form the catalyst. At the same time, the amount used is proportionally increased or decreased. Steps S1 and S2 are then repeated, and the data shown in Table 3 is obtained. [Table 3]

[0037] Table 3 reveals the following: 1. The effect of the mixed catalyst is significantly better than that of sodium bromide or PEG-600 used alone. Comparing Tables 1 to 3, when the amounts used are 10.0 g and 12.0 g, the effect of the mixed catalyst is better, and the product yield in step S1 is higher, which is better than the effect of using a single substance as a catalyst in the same amount.

[0038] 2. When the amount of the mixed catalyst used is 12.0g-22.0g, the yield in step S1 and the purity in step S2 are both high. When it is less than 12.0g, the yield in step S1 is significantly reduced. When it is more than 22.0g, the impact on the yield is not significant, and the purity of the product in step S2 is slightly reduced. Therefore, the amount of the mixed catalyst used is preferably 12.0g-22.0g, and in this case, the amount of the catalyst used is 0.44%-0.8% of the sum of the weights of the raw materials diethyl malonate + 1,6-dichlorohexane + potassium carbonate.

[0039] Selection of proportional relationship between sodium bromide and PEG-600 in step S1: The total amount of catalyst used is fixed at 16 g, and only the weight ratio of sodium bromide to PEG-600 is varied to obtain the data shown in Table 4 below. [Table 4]

[0040] As can be seen from Table 4, the effect is best when the weight ratio of sodium bromide to PEG-600 in the mixed catalyst is (4-7):(9-12), so we determined that the weight ratio of sodium bromide to PEG-600 in the catalyst is (4-7):(9-12).

[0041] In Example 1 of the present invention, the molar ratio of diethyl malonate, 1,6-dichlorohexane, and potassium carbonate used was 1:2.2:1.6. Based on Example 1, only the amount of potassium carbonate used was changed to obtain the data shown in Table 5 below. [Table 5]

[0042] As can be seen from the above table, the preferred molar range of diethyl malonate:potassium carbonate is 1:(1.2 to 2.0).

[0043] Based on Example 1, 1,6-dichlorohexane is used in excess to recover, and only the amount of 1,6-dichlorohexane used is changed to obtain the data shown in Table 6 below. [Table 6]

[0044] As can be seen from Table 6 above, the preferred molar range of diethyl malonate:1,6-dichlorohexane is 1:(2.0-2.5).

[0045] As can be seen from Tables 5 and 6, the molar ratio of the amounts of diethyl malonate, 1,6-dichlorohexane, and potassium carbonate used is preferably 1:(2 to 2.5):(1.2 to 2.0).

[0046] The temperature selection for the hydrolysis reaction in step S2 is shown in Table 7 below. [Table 7]

[0047] As can be seen from the above table, the reaction temperature range is 100 to 160°C, preferably 130 to 150°C, and within this temperature range, the purity of the product in step S2 is high and the yield is also high.

[0048] Example 2 Based on Example 1, the optimum data was obtained, and then verified in an industrial production scale example, and the steps were as follows:

[0049] Step S1, synthesis of compound 4 In a 5000 L reactor equipped with a mechanical stirrer, 830.0 kg of potassium carbonate, 6.0 kg of sodium bromide, 10.0 kg of PEG-600, 1280 kg of 1,6-dichlorohexane, and 900 kg of acetonitrile were added in that order, and the mixture was heated with stirring until the internal temperature reached 70-75°C, and 600 kg of diethyl malonate was added dropwise, controlling the temperature to 70-80°C. The dropwise addition took approximately 3 hours, and the reaction was carried out for approximately 7-8 hours while controlling the temperature at 70-80°C. Sampling was performed and in-process control was performed; the reaction was deemed to have ended when the diethyl malonate concentration was less than 1.0%.

[0050] The reaction mixture was distilled under atmospheric pressure, and acetonitrile was recovered until no more distillates were produced. 820 kg of acetonitrile solvent was obtained by distillation. The temperature inside the reactor was lowered to 20-30°C, and 2000 kg of water was added and stirred for 0.5 hours. After standing for 0.5 hours, the lower aqueous layer was separated. The upper organic layer was washed once with 500 kg of water, and the mixture was allowed to stand for layer separation to obtain the lower organic layer. The organic layer was transferred to a still and 1,6-dichlorohexane was recovered using a pump. It was then distilled using an oil pump (pay attention to the GC tracking). 825.5 kg of the product from Step S1 was obtained in 78.9% yield.

[0051] Step S2, synthesis of compound 1 A 1000 L enamel reactor was charged with 600 kg of the product from step S1 and 5.0 kg of p-toluenesulfonic acid, and the temperature was raised while stirring. When the internal temperature reached 130-140°C, 160 kg of water was slowly added dropwise over approximately 3 hours, controlling the internal temperature at 135-140°C. After the addition was complete, the reaction was refluxed for approximately 4 hours and monitored by GC. The reaction was considered complete when the raw material concentration was less than 1.0%. Water was removed by distillation, and after the distillate disappeared, water was removed by pumping under negative pressure until the distillate disappeared. 200 kg of absolute ethanol was added, refluxed for approximately 3 hours, and monitored by GC. The reaction was considered complete when the intermediate 8-chlorooctanoic acid concentration was less than 1.0%.

[0052] The reaction mixture was distilled under atmospheric pressure to remove ethanol until no more distillates were produced. The temperature was lowered to 20-30°C, and 200 kg of water, 5 kg of sodium bicarbonate, and 50 kg of sodium chloride were added. The mixture was stirred for 0.5 hours and the pH was adjusted to 5-7. After standing for 0.5 hours, the lower aqueous phase was separated, and the upper organic phase was the crude target product. The crude target product was subjected to vacuum rectification to obtain 336.6 kg of a colorless, transparent, oily liquid (ethyl 8-chlorooctanoate) with a GC purity of 99.42%, an unknown impurity content of less than 0.1%, and a yield of 75.5%.

[0053] The present invention is not limited to the above embodiments, and based on the technical means disclosed in the present invention, a person skilled in the art can make some substitutions and modifications to some technical features based on the disclosed technical content without any creative efforts, and all of these substitutions and modifications fall within the protection scope of the present invention.

Claims

1. a step S1 for producing compound 4, in which 1,6-dichlorohexane 2 and diethyl malonate 3 are alkylated in the presence of potassium carbonate and a catalyst, the molar ratio of diethyl malonate, 1,6-dichlorohexane, and potassium carbonate being 1:(2-2.5):(1.2-2.0); after the reaction is completed, washing is performed, and the raw material 1,6-dichlorohexane is recovered from the organic layer, followed by vacuum distillation to obtain compound 4, the catalyst being a mixture of PEG-600 and sodium bromide, the amount of catalyst being 0.44%-0.8% of the sum of the amounts of diethyl malonate, 1,6-dichlorohexane, and potassium carbonate being used, and the weight ratio of sodium bromide to PEG-600 in the catalyst being (4-7):(9-12); and a step S2 for preparing compound 1, in which a hydrolysis catalyst is added to compound 4 to carry out high-temperature hydrolysis and decarboxylation to obtain 8-chlorooctanoic acid, water is removed by distillation under reduced pressure, ethanol is further added to carry out an esterification reaction, and finally, vacuum rectification is carried out to obtain compound 1, i.e., the target product, ethyl 8-chlorooctanoate. A method for producing ethyl 8-chlorooctanoate, characterized in that the reaction formula is as follows: 【Chemical 1】

2. 2. The method for producing ethyl 8-chlorooctanoate according to claim 1, wherein the absolute pressure during the vacuum distillation and vacuum rectification in steps S1 and S2 is 0.005 MPa to 0.01 MPa.

3. 2. The method for producing ethyl 8-chlorooctanoate according to claim 1, wherein in step S1, the alkylation reaction temperature is 70 to 80°C, the reaction time is about 7 to 8 hours, and acetonitrile is used as a solvent.

4. The method for producing ethyl 8-chlorooctanoate according to any one of claims 1 to 3, wherein the hydrolysis catalyst used in step S2 is p-toluenesulfonic acid.

5. The method for producing ethyl 8-chlorooctanoate according to any one of claims 1 to 3, wherein in step S2, the temperature of the hydrolysis reaction is 100 to 160°C.

6. 6. The method for producing ethyl 8-chlorooctanoate according to claim 5, wherein the temperature of the hydrolysis reaction in step S2 is 130 to 150°C.

Images