WO2024077796A1 - Production method for ethyl 8-chlorooctanoate - Google Patents

Abstract

Disclosed is a production method for ethyl 8-chlorooctanoate in the field of medicine or pesticide manufacturing. A dual catalyst containing potassium bromide or sodium bromide and polyethylene glycol is used, and an alkylation reaction is carried out by corresponding 1,6-dichlorohexane and diethyl malonate in the presence of potassium carbonate. After the reaction ends, a crude product of diethyl 6-chlorohexyl malonate is obtained by distillation, and then under the catalysis of a sulfonic acid, a one-pot method is used to complete hydrolysis and decarboxylation, distillation under reduced pressure to remove water, and ethanol esterification, and finally rectification is performed to obtain high-purity ethyl 8-chlorooctanoate, which can meet the needs of customers. The present method simplifies production operations, shortens unit operation time, reduces labor intensity, and improves product quality.

Description

A kind of production method of 8-chlorooctanoic acid ethyl ester Technical Field

The invention relates to a production method of an intermediate in the manufacture of medicine or pesticide, and in particular to a production method of 8-chlorooctanoic acid ethyl ester.

Background technique

The English name of 8-chlorooctanoic acid ethyl ester is: 8-chlorooctanoic acid ethyl ester, ethyl 8-chlorooctanoate; CAS Registry Number(s): 105484-55-7; Boiling point: 251.5±23.0℃ (Predicted).

The structural formula is as follows:

Ethyl 8-chlorooctanoate is an excellent solvent and an important intermediate for medicine and pesticides, and has a high development value. For example, it is used to synthesize sodium N-(8-[2-hydroxybenzoyl]-amino) caprylate (SNAC), which is a chemically synthesized fatty acid derivative and was first selected by Emisphere as a high-efficiency molecule from a variety of penetration enhancers.

In December 2017, the FDA approved the marketing of semaglutide injection (trade name: Ozempic) for blood sugar control in adults with type 2 diabetes. On December 4, 2020, Novo Nordisk submitted a marketing application to the FDA for semaglutide 2.4 mg subcutaneously injected once a week for weight loss. When mentioning semaglutide as an oral preparation, we have to mention a booster weapon, N-(8-[2-hydroxybenzoyl]-amino) sodium caprylate (Salcaprozate Sodium, SNAC).

For another example, when SNAC is administered alone to an adult weighing about 70 kg, the recommended oral dose of ibandronate for treating osteoporosis is 2.5 mg per day or 150 mg per month. When administered with SNAC, the daily dose of ibandronate for treating osteoporosis is reduced to about 1.25 mg to about 0.25 mg.

At present, the synthetic routes of 8-chlorooctanoic acid ethyl ester mainly include the following:

1. EVONIK INDUSTRIES AG-EP1384706,2004,A1. Patents CN101328120 (A) of Shanghai Wansuo Chemical Co., Ltd. reported the preparation method of 8-halooctanoic acid ethyl ester. The above patents use 1,6-dihalohexane as the starting material, react with diethyl malonate, and then decarboxylate and hydrolyze to obtain 8-halooctanoic acid ethyl ester.

The reaction equation is as follows:

This route is currently the most commonly used process route. The above process has the following two major disadvantages:

(1) During the reaction of 1,6-dichlorohexane and diethyl malonate to synthesize diethyl 2-(6-chlorohexyl)malonate, disubstituted impurities (two chlorohexyl groups at the 2-position) are easily generated; diethyl 2-(6-chlorohexyl)malonate undergoes self-cyclization to generate diethyl cycloheptylmalonate; one 1,6-dichlorohexane reacts with two diethyl malonates to generate macromolecular impurities; the raw material 1,6-dichlorohexane and alkali are easily subjected to elimination reaction at high temperature to generate elimination impurities such as 1-chloro-6-hexene, etc. The above side reactions result in low yields.

(2) The alkylation reaction of diethyl malonate requires the use of a phase transfer catalyst to promote the interaction between the reactant in the liquid phase and the solid potassium carbonate. In the prior art, quaternary ammonium salts are used as catalysts to promote the reaction, such as tetrabutylammonium bromide, tetrabutylammonium chloride, etc., which react with diethyl malonate to generate an impurity with a boiling point very close to 8-chlorooctanoic acid ethyl ester, which is extremely difficult to separate (distillation cannot be separated). This makes the product purity on the market relatively poor and cannot meet the needs of customers.

2. Anhui Haofan Biological Co., Ltd. Description of CN112409175 (A), using 1,8-octanediol as raw material, through chlorination reaction, oxidation reaction, and esterification reaction, 8-chlorooctanoic acid ethyl ester was obtained.

The reaction equation is as follows:

The disadvantages of this method are that the starting material 1,8-octanediol is difficult to obtain and is expensive, and the amount of three wastes oxidized by sodium hypochlorite is large, resulting in serious pollution.

In summary, finding a process route for producing ethyl 8-chlorooctanoate with the advantages of "low raw material cost, high product purity and yield, and less waste", has become a technical problem that needs to be solved urgently.

Summary of the invention

The purpose of the present invention is to improve the deficiencies of the existing synthesis technology and provide a production method of 8-chlorooctanoic acid ethyl ester, which has the advantages of low raw material cost, short reaction time, high product purity and yield, is very environmentally friendly, and meets the requirements of green chemical process.

To this end, the present invention provides a method for producing 8-chlorooctanoic acid ethyl ester, comprising the following steps:

S1, preparation of compound 4: 1,6-dichlorohexane 2 and diethyl malonate 3 are subjected to an alkylation reaction in the presence of potassium carbonate and a catalyst, wherein the molar ratio of diethyl malonate, 1,6-dichlorohexane and potassium carbonate is 1:(2-2.5):(1.2-2.0), washing is performed after the reaction is completed, and the raw material 1,6-dichlorohexane is recovered from the organic layer, and then vacuum distillation is performed to obtain compound 4; the catalyst is a mixture of PEG-600 and sodium bromide; the amount of the catalyst is 0.44%-0.8% of the sum of the weight amounts of diethyl malonate, 1,6-dichlorohexane and potassium carbonate, and the weight ratio of sodium bromide to PEG-600 in the catalyst is (4-7):(9-12);

S2, preparation of compound 1: Compound 4 is added with a hydrolysis catalyst to hydrolyze and decarboxylate at high temperature to obtain 8-chlorooctanoic acid; water is then removed by vacuum distillation, ethanol is added to carry out esterification reaction, and finally vacuum distillation is carried out to obtain compound 1, which is the target product 8-chlorooctanoic acid ethyl ester;

The reaction formula is as follows:

The present invention uses a dual catalyst comprising sodium bromide and polyethylene glycol, and the corresponding 1,6-dichlorohexane and diethyl malonate are subjected to an alkylation reaction in the presence of potassium carbonate, and the crude product of 6-chlorohexyl diethyl malonate is obtained by distillation after the reaction is completed; then, under the catalysis of sulfonic acid, hydrolysis and decarboxylation are completed in one pot, and water is removed by vacuum distillation and ethanol esterification is performed, and finally, high-purity 8-chlorooctanoic acid ethyl ester is obtained by rectification, which can meet the needs of customers. This method simplifies the production operation, shortens the unit operation time, reduces the labor intensity, and improves the product quality. From the basic theory of organic chemistry, the leaving ability of halogen atoms is: iodine> bromine> chlorine, so the introduction of bromine atoms in the reaction system will greatly enhance the ability of nucleophilic substitution, thereby accelerating the reaction speed or reducing the reaction temperature. The present invention selects p-toluenesulfonic acid after screening the hydrolysis catalyst, and solves the problem of production stratification.

Furthermore, in steps S1 and S2, the absolute pressure during the vacuum distillation and vacuum rectification is 0.005 MPa-0.01 MPa.

Furthermore, in step S1, the temperature of the alkylation reaction is 70-80°C, the reaction time is about 7-8h, and acetonitrile is the solvent.

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

Furthermore, in step S2, the hydrolysis reaction temperature is 100-160° C. The hydrolysis reaction temperature is preferably 130-150° C.

The present invention uses a dual catalyst comprising sodium bromide and polyethylene glycol PEG-600, and the corresponding 1,6-dichlorohexane and diethyl malonate are subjected to an alkylation reaction in the presence of potassium carbonate, and the reaction is terminated by distillation to obtain a crude product of 6-chlorohexyl diethyl malonate; then, under the catalysis of sulfonic acid, a one-pot method is used to complete hydrolysis and decarboxylation, dewatering by vacuum distillation, ethanol esterification, and finally distillation to obtain high-purity 8-chlorooctanoic acid ethyl ester. The use of the dual catalyst not only reduces the temperature of the alkylation reaction of 1,6-dichlorohexane and diethyl malonate, but also avoids the elimination side reaction of dechlorination; p-toluenesulfonic acid is used as a hydrolysis catalyst in the hydrolysis and decarboxylation process, which solves the problem of difficult emulsification and stratification in production; after hydrolysis and decarboxylation, a method of dewatering by vacuum distillation is adopted, which greatly simplifies the production operation, reduces the amount of ethanol solvent, improves the efficiency of the esterification reaction, and reduces the production cost. The present invention has the advantages of short reaction time, high product purity and yield, and the production process is economically beneficial, and is particularly suitable for large-scale commercial production.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a spectrum of purity detection of the industrially produced 8-chlorooctanoic acid ethyl ester product of Example 2.

Detailed ways

The following examples will help researchers understand the key points of the preparation technology of the present invention, but they cannot limit the content of the present invention.

Example 1

A production method of 8-chlorooctanoic acid ethyl ester, its reaction formula is as follows:

The specific production steps are as follows:

S1: Synthesis of compound 4

In a 5L four-necked flask with mechanical stirring, add 830.0g potassium carbonate, 6.0g sodium bromide, 10.0g PEG-600, 1280g 1,6-dichlorohexane and 720g acetonitrile in sequence, heat to an internal temperature of 70°C under stirring, add 600g diethyl malonate dropwise, and control the temperature at 70-80°C. It takes about 3 hours to drip, and the temperature is controlled at 70-80°C for about 7-8 hours. When sampling, control: when diethyl malonate is less than 1.0%, the reaction is judged to be over.

The reaction solution was distilled under normal pressure, acetonitrile was recovered until no fraction flowed out, the temperature was lowered to 20-30°C, 2500g of water was added, and the mixture was stirred for 0.5h. The mixture was allowed to stand for 0.5h, the lower aqueous layer was separated, the upper organic layer was washed once with 500g of water, and the mixture was allowed to stand for stratification to obtain the lower organic layer. The organic layer was transferred to a distillation flask for vacuum distillation, 1,6-dichlorohexane was recovered by a water pump, and distilled by an oil pump. The absolute pressure during vacuum distillation was 0.005MPa-0.01MPa, and the weight of the S1 product was 810.5g, with a yield of 77.5%.

S2: Synthesis of compound 1

In a 500mL four-necked flask, add 300g of the first step product and 3.0g of p-toluenesulfonic acid, stir and heat; when the internal temperature reaches 130℃, slowly add 75g of water, control the internal temperature at 125-130℃, and add the water in about 3 hours. After the addition is complete, reflux for about 4 hours, monitor by GC, and judge the reaction is over when the raw material is less than 1.0%. Distill to remove water, and after there is no fraction, use the water pump to carry water under negative pressure until there is no fraction. Add 95.0g of anhydrous ethanol, reflux for about 3 hours, monitor by GC, and judge the reaction is over when the intermediate 8-chlorooctanoic acid is less than 1.0%.

The reaction solution was distilled under normal pressure to remove ethanol until no fraction flowed out. The temperature was lowered to 20-30°C, water (100g), 1.6g sodium bicarbonate and 20g sodium chloride were added, stirred for 0.5h, and the pH was controlled at 5-7. After standing for 0.5h, the lower aqueous phase was separated, and the upper organic phase was the crude target product. The crude target product was subjected to negative pressure distillation, and the absolute pressure during vacuum distillation was 0.005MPa-0.01MPa, to obtain a colorless transparent oily liquid (8-chlorooctanoic acid ethyl ester) weighing 178.0g, GC purity 99.52%, unknown impurities less than 0.1%, and a yield of 80.1%.

Screening of catalyst in step S1:

On the basis of keeping other substances unchanged, the catalyst is changed and only sodium bromide is used as the catalyst, and the data listed in Table 1 below are obtained:

Sodium bromide(g)	S1 product yield (%)	S2 step product purity (%)
2.0	40.5	98.5
3.0	41.6	98.2
4.0	42.5	97.9
5.0	47.6	98.9
6.0	49.6	99.2
8.0	47.6	99.1
9.0	47.2	99.3
10.0	46.8	98.8
12.0	47.3	99.1

On the basis of keeping other substances unchanged, the catalyst was changed and only PEG-600 was used as the catalyst, and the data listed in Table 2 below were obtained:

PEG-600(g)	S1 product yield (%)	S2 step product purity (%)
2.0	56.1	98.7
4.0	58.8	98.5
6.0	60.5	98.6
8.0	62.9	99.1
10.0	65.2	99.5
12.0	65.6	99.1
14.0	63.7	99.2
16.0	65.2	98.7
18.0	64.6	97.8
20.0	65.2	97.9

The optimal value of sodium bromide in Table 1 is 6.0g, and the optimal value in Table 2 is 10.0g. The weight ratio of the two is fixed, and the two are mixed as catalysts. At the same time, the dosage is increased or decreased in proportion, and steps S1 and S2 are performed again to obtain the data listed in Table 3:

From Table 3 we can see that:

1. The mixed catalyst is significantly better than the single use of sodium bromide or PEG-600 as a catalyst. Comparison of Tables 1-3 shows that when the dosage is 10.0g and 12.0g, the mixed catalyst has a better effect, and the product yield of step S1 is higher, which is better than the effect of the same dosage of a single substance as a catalyst.

2. When the dosage of the mixed catalyst is 12.0g-22.0g, the yield of step S1 and the purity of step S2 are relatively high. When it is lower than 12.0g, the yield of step S1 is significantly reduced. When it is higher than 22.0g, the effect on the yield does not change much, and the purity of the product in step S2 is slightly reduced. Therefore, the preferred dosage of the mixed catalyst is 12.0g-22.0g. At this time, the dosage of the catalyst is 0.44%-0.8% of the sum of the weight of the raw materials diethyl malonate + 1,6-dichlorohexane + potassium carbonate.

Selection of the ratio of sodium bromide to PEG-600 in step S1:

The total amount of catalyst used was fixed at 16 g, and only the weight ratio of sodium bromide to PEG-600 was changed to obtain the data listed in Table 4 below:

Weight ratio of sodium bromide to PEG-600	S1 product yield (%)	S2 step product purity (%)
2∶14	65.6	99.10
3:13	67.5	99.23
4:12	72.8	99.12
5:11	72.9	99.48
6:10	77.5	99.52
7∶9	73.1	99.32
8∶8	69.9	99.12
9∶7	69.5	99.09
10:6	68.8	98.78
11:5	67.6	98.65
12:4	65.3	99.02
13:3	61.7	98.90
14:2	53.9	98.56

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

In Example 1 of the present invention, the molar ratio of diethyl malonate, 1,6-dichlorohexane and potassium carbonate is 1:2.2:1.6; on the basis of Example 1, only the amount of potassium carbonate is changed to obtain the data listed in Table 5 below:

Potassium carbonate dosage (g)	The molar ratio of diethyl malonate	S1 product yield (%)
415	0.8∶1	53.3
519	1.0∶1	66.1
623	1.2∶1	74.5
726	1.4∶1	76.3
830	1.6∶1	77.5
934	1.8∶1	77.2
1037.5	2.0∶1	76.9
1141	2.2∶1	72.1

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

On the basis of Example 1, 1,6-dichlorohexane was used in excess and recovered, and only the amount of 1,6-dichlorohexane was changed to obtain the data listed in Table 6 below:

From Table 6 above, it can be seen that the preferred molar ratio range of diethyl malonate:1,6-dichlorohexane is 1:(2.0-2.5).

It can be seen from Tables 5 and 6 that the molar ratio of diethyl malonate, 1,6-dichlorohexane and potassium carbonate is preferably 1:(2-2.5):(1.2-2.0).

The screening of the hydrolysis reaction temperature in step S2 is shown in Table 7 below:

Hydrolysis temperature(℃)	S2 step product yield (%)	S2 less sudden production purity (%)
80	54.3	98.5
90	65.9	98.3
100	71.2	99.1
110	78.2	99.4
120	78.9	99.5
130	80.1	99.4
140	79.5	99.3
150	79.3	98.7
160	73.8	97.9
170	65.2	98.1
180	56.1	97.6

As can be seen from the above table, the reaction temperature range can be selected from 100-160°C, preferably 130-150°C. Within this temperature range, the product of step S2 has a higher purity and a higher yield.

Example 2

After obtaining the preferred data based on Example 1, verification was performed using an industrial production scale example, and the steps are as follows:

S1: Synthesis of compound 4

In a 5000L reactor with mechanical stirring, add 830.0Kg potassium carbonate, 6.0Kg sodium bromide, 10.0Kg PEG-600, 1280Kg 1,6-dichlorohexane and 900Kg acetonitrile in sequence, heat to an internal temperature of 70-75℃ under stirring, add 600Kg diethyl malonate dropwise, and control the temperature at 70-80℃. It takes about 3 hours to drip, control the temperature at 70-80℃ and react for about 7-8 hours. When sampling, control: when diethyl malonate is less than 1.0%, the reaction is judged to be over.

The reaction solution was distilled at normal pressure, and acetonitrile was recovered until no fraction flowed out. 820 kg of acetonitrile solvent was recovered by distillation. The temperature in the reactor was lowered to 20-30°C, 2000 kg of water was added, and stirred for 0.5 h. After standing for 0.5 h, the lower aqueous layer was separated, and the upper organic layer was washed once with 500 kg of water, and the lower organic layer was obtained by standing. The organic layer was transferred to a distillation kettle, 1,6-dichlorohexane was recovered by a water pump, and distilled by an oil pump (pay attention to GC tracking), and the weight of the S1 product was 825.5 kg, and the yield was 78.9%.

S2: Synthesis of compound 1

In a 1000L enamel reactor, add 600Kg S1 product and 5.0Kg p-toluenesulfonic acid, stir and heat; when the internal temperature reaches 130-140℃, slowly add 160Kg water, control the internal temperature at 135-140℃, and add the water in about 3 hours. After the addition is completed, reflux for about 4 hours, and monitor by GC. The reaction is over when the raw material is less than 1.0%. Distill to remove water, and after there is no fraction, use the water pump to carry water under negative pressure until there is no fraction. Add 200Kg anhydrous ethanol, reflux for about 3 hours, and monitor by GC. The reaction is over when the intermediate 8-chlorooctanoic acid is less than 1.0%.

The reaction solution was distilled under normal pressure to remove ethanol until no fraction flowed out. The temperature was lowered to 20-30°C, 200 kg of water, 5 kg of sodium bicarbonate and 50 kg of sodium chloride were added, stirred for 0.5 h, and the pH was controlled at 5-7. After standing for 0.5 h, the lower aqueous phase was separated, and the upper organic phase was the crude target product. The crude target product was distilled under negative pressure to obtain 336.6 kg of colorless transparent oily liquid (8-chlorooctanoic acid ethyl ester), with a GC purity of 99.42%, less than 0.1% of unknown impurities, and a yield of 75.5%.

The present invention is not limited to the above-mentioned embodiments. On the basis of the technical solution disclosed in the present invention, technicians in this field can make some substitutions and deformations to some technical features therein according to the disclosed technical content without creative labor, and these substitutions and deformations are all within the protection scope of the present invention.

Claims (6)

1. A method for producing ethyl 8-chlorooctanoate, characterized in that it comprises the following steps:

   S1, preparation of compound 4: 1,6-dichlorohexane 2 and diethyl malonate 3 are subjected to an alkylation reaction in the presence of potassium carbonate and a catalyst, wherein the molar ratio of diethyl malonate, 1,6-dichlorohexane and potassium carbonate is 1:(2-2.5):(1.2-2.0), washing is performed after the reaction is completed, and the raw material 1,6-dichlorohexane is recovered from the organic layer, and then vacuum distillation is performed to obtain compound 4; the catalyst is a mixture of PEG-600 and sodium bromide; the amount of the catalyst is 0.44%-0.8% of the sum of the weight amounts of diethyl malonate, 1,6-dichlorohexane and potassium carbonate, and the weight ratio of sodium bromide to PEG-600 in the catalyst is (4-7):(9-12);

   S2, preparation of compound 1: Compound 4 is added with a hydrolysis catalyst and decarboxylated at high temperature to obtain 8-chlorooctanoic acid; water is then removed by vacuum distillation, ethanol is added for esterification, and finally vacuum distillation is performed to obtain compound 1, which is the target product 8-chlorooctanoic acid ethyl ester;

   The reaction formula is as follows:

   
2. The method for producing 8-chlorooctanoic acid ethyl ester according to claim 1, characterized in that, in steps S1 and S2, the absolute pressure during the vacuum distillation and vacuum rectification is 0.005MPa-0.01MPa.
3. The method for producing 8-chlorooctanoic acid ethyl ester according to claim 1, characterized in that in step S1, the temperature of the alkylation reaction is 70-80° C., the reaction time is 7-8h, and acetonitrile is the solvent.
4. The method for producing 8-chlorooctanoic acid ethyl ester according to any one of claims 1 to 3, characterized in that the hydrolysis catalyst used in step S2 is p-toluenesulfonic acid.
5. The method for producing 8-chlorooctanoic acid ethyl ester according to any one of claims 1 to 3, characterized in that in step S2, the hydrolysis reaction temperature is 100-160° C.
6. The method for producing 8-chlorooctanoic acid ethyl ester according to claim 5, characterized in that in the step S2, the hydrolysis reaction temperature is 130-150°C.

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