KR20060032502A - Method for preparing chloroformate compound using triphosgene - Google Patents

Abstract

The present invention relates to a method for preparing a chloroformate compound, comprising the steps of: (a) preparing a fatty acid monoester; And (b) reacting the prepared fatty acid monoester with triphosgene in the presence of a base to produce a chloroformate compound. The production method of the present invention is relatively safe and the reaction rate is fast and economical, it is possible to obtain a high yield of chloroformate compound.

Chloroformate Compounds, Triphosgene, Fatty Acid Monoester

Description

Process for preparing chloroformate compound using triphosgene

The present invention relates to a method for producing a chloroformate compound using triphosgene.

Chloroformate-based compounds are useful compounds mainly used as intermediates for medicines, cosmetics or foods, and especially chloroformate-based compounds may be useful for the synthesis of bleach activators, which are laundry detergent additives. For the synthesis of such chloroformate-based compounds, a manufacturing method using gaseous phosgene has been used for a long time in the past. However, the problem with this method is the decrease in yield due to the generation of hydrochloric acid and by-products that are toxic to the human body.

U.S. Patent No. 3,419,543 discloses a process for preparing menthyl chloroformate using liquid phosgene at -75 ° C, which has the disadvantage of maintaining the reaction temperature at -75 ° C. These very low temperatures are difficult to industrially use and require expensive equipment.

In addition, the Journal of Organic Chemistry 1998 (vol.63, pp.3225-3250), which discloses a method of synthesizing menthyl chloroformate using phosgene and menthol, addresses the problem of hydrochloric acid during reaction. To solve the above, a base such as tertiary amine, pyridine, and the like was added, and the salt thus produced was directly filtered or washed with water to prepare menthyl chloroformate, but the above problems were not completely solved. .

In addition, US Pat. No. 5,705,091 used phosgene gas and pyridine for the preparation of chloroformate-based compounds. When phosgene gas is added, the reaction temperature is reduced to about -78 ° C using argon gas. In addition, the yield is also very low as 65%.

In addition, a method for synthesizing chloroformate-based compounds without the addition of a base at relatively high temperatures has been published in Tetrahedron, 54 (1998), pp.10537-10534, using menthol and toluene at -10 ° C for phosgene gas. This method is a high yield of 82%, and can be prepared at normal pressure, but the reaction rate is very slow, making it difficult to use commercially.

On the other hand, when using gaseous phosgene, due to the severe toxicity of the phosgene gas, the complexity of the installation of the manufacturing equipment, and the instability at room temperature, in recent years, various types of compounds have been used by using solid triphosgene instead of gaseous or liquid phosgene. Attempts have been made to manufacture.

VK Gumaste et al. Introduced the synthesis of various acyl azides using safe triphosgene in terms of synthesis, and they disclosed that triphosgene can be converted to acyl azide in high yield in the presence of triethylamine. (Tetrahedron Letters, 43 (2002), pp. 1345-1346).

Nandkumar N. Bhongle et al. Have described a synthesis of 3'-H-phosphonate monoesters using triphosgene, which can be used in a variety of reactions because it is a commercially useful, safe and solid phase that allows accurate measurement. Yes, Tetrahedron Letters, 36 (1995), pp.6803-6806.

RR Cicchillo and P. Norris introduced a variety of glycosyl chloride synthesis methods, describing the advantages of the synthesis method using triphosgene and its commercial applicability (Carbohydrate Research, 328 (2000), pp.431-434 ).

US Pat. No. 5,639,875 discloses a method for preparing H-phosphate of oligonucleotides using triphosgene, which shows that triphosgen can maintain stability and safety at room temperature and has less hygroscopicity than other acid chlorides. Because of its advantages, it has been disclosed that it can also be used for mass production of oligonucleotides.

Therefore, the technical problem to be achieved by the present invention is to solve the above-mentioned problems, to provide a method of producing a chloroformate-based compound that can be obtained relatively high safety and fast reaction rate and economical, as well as high yield chloroformate-based compound It is.

In order to achieve the above technical problem, the present invention comprises the steps of (a) preparing a fatty acid monoester; And (b) reacting the prepared fatty acid monoester with triphosgene in the presence of a base to produce a chloroformate compound, the method of producing a chloroformate compound represented by the following Chemical Formula 1.

In Formula 1, R ₁ is a linear or branched alkyl or alkenyl group having 1 to 19 carbon atoms, and n is an integer of 1 to 10.

Typically the excess chloroformate produced reacts again with fatty acid monoesters to form carbonate-based byproducts. In the case of using phosgene gas, degassing method is used to control the feed rate to suppress the formation of by-products, while in the case of using solid triphosphene, the dropping rate and reaction are reduced by dissolving triphosphogen in an organic solvent. Since it is easy to control the temperature and the like, it is much easier to suppress the reaction of by-products.

Hereinafter, the manufacturing method of the chloroformate compound of this invention is demonstrated in detail.

The preparation method of the present invention first includes preparing a fatty acid monoester compound represented by the following Chemical Formula 2.

In Formula 2, R ₁ is a linear or branched alkyl group or alkenyl group having 1 to 19 carbon atoms, and n is an integer of 1 to 10.

As the fatty acid monoester compound, not only a single type of fatty acid monoester but also various fatty acid monoesters can be used simultaneously to prepare a chloroformate-based compound. For example, fatty acid monoesters in which R ₁ is a linear alkyl group and fatty acid monoesters in which R ₁ is a linear alkenyl group may be used alone or in combination thereof.

The compound of Formula 2 may be obtained by esterifying a fatty acid with ethylene glycol or ethylene oxide. In more detail, an excess of ethylene glycol or ethylene oxide is added to the fatty acid and reacted under normal pressure, warming, and acid catalyst conditions, and then the resulting water is removed to proceed with the esterification reaction. The preferred amount of ethylene glycol or ethylene oxide is about 1 to 10 equivalents based on fatty acid, and the acid catalyst is preferably a method using 0 to 0.5% by weight of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, etc., based on the total weight of the reactants. Most preferred is the method by weight. The reaction temperature is preferably 60 to 150 ° C., and the reaction time is 2 to 10 hours.

As described above, in addition to preparing fatty acid monoesters using fatty acids, it is also possible to use alkanoyl chloride compounds instead of fatty acids. That is, the alkanoyl chloride compound may be obtained by reacting with ethylene glycol or ethylene oxide. In addition, various other methods for preparing fatty acid monoesters that are obvious to those skilled in the art can be used, as well as to purchase and use commercially available fatty acid monoesters.

In addition, the method for preparing a chloroformate-based compound of the present invention is prepared by the reaction of at least one fatty acid monoester prepared in the above-mentioned step with a triphosgene in an organic solvent in the presence of a base to prepare a chloroformate compound represented by the formula (1) It includes a step.

<Formula 1>

More specifically, while maintaining the reaction temperature of about -10 to 20 ℃ stirred for about 1-5 hours, after which water is added to separate the organic layer and then remove the moisture using a moisture remover such as magnesium sulfate anhydride, The organic solvent is distilled under reduced pressure to prepare a chloroformate compound. As for reaction temperature, 0-10 degreeC is more preferable, and 0-5 degreeC is the most preferable. This step is carried out at atmospheric pressure, and there is no need to apply special pressure.

In addition, it is even more preferable in terms of production efficiency to use 0.3 to 0.4 equivalents of triphosgene compared to fatty acid monoesters.

Meanwhile, as the base that can be used, both inorganic bases and organic bases can be used. Specifically, sodium hydroxide, potassium hydroxide, calcium hydroxide, triethylamine, N, N-diisopropylethylamine, pyridine, and the like can be used. Amine bases are more preferred, with triethylamine being most preferred.

Since the method for preparing the chloroformate compound of the present invention can be prepared at normal pressure, and the reaction temperature can be easily adjusted to -10 to 20 ° C., it is very advantageous especially in the case of mass production, and the formation reaction of the chloroformate compound This proceeds very quickly, and the yield is also very high, preferably about 97% or more.

When phosgene gas is used, phosgene itself may be synthesized without a solvent. In the case of triphosgene, it is preferable to dissolve it in an organic solvent because it is a solid phase. In this case, the solvent is more preferably using an inert organic solvent, such as methylene chloride; chloroform; Chlorinated or non-chlorinated aliphatic hydrocarbons such as heptane and pentane; Chlorinated or non-chlorinated aromatic hydrocarbons such as toluene and xylene; Esters such as ethyl acetate and isopropyl acetate; ethyl; Diisopropyl ether and the like can be used. More preferably, toluene is used as the solvent.

The purity of the prepared chloroformate-based compound is almost similar to that of the fatty acid monoester prepared in the previous step or may be higher by increasing the molecular weight. The purity of the fatty acid monoester prepared in the present invention is preferably 91% or more, the purity of the chloroformate compound prepared therefrom is preferably 95% or more, and the yield is preferably 97% or more.

In the method for producing the chloroformate compound of the present invention, almost no by-products are generated. The by-product that can occur in the preparation of chloroformate-based compounds is chloride which is freed from carbon dioxide in chloroformate, which is a highly reactive material, which acts as an interfering agent when the chloroformate-based compound is used as an intermediate. The small production rate is a big advantage in the manufacturing method.

Hereinafter, the present invention will be described with reference to Examples and Experimental Examples in more detail. However, the following examples are merely illustrative of the present invention, and the scope of the present invention should not be construed as being limited to the following examples.

Example 1

(a) Preparation of 2-hydroxyethyl decanoate

To prepare a fatty acid monoester represented by the formula (3).

Into a four-necked flask equipped with a stirrer, a thermometer, a condenser, and a distillation unit, 172 g (1 mol) of decanoic acid and 186 g (3 mol) of ethylene glycol in excess are added, and the catalyst is subjected to atmospheric pressure using 0.4 g of p-toluenesulfonic acid as a catalyst. Reacted at 90 ° C. for 2 hours. Thereafter, the pressure was 30 torr and esterified for 2 hours while removing the water produced during the reaction. After the reaction, the acid value was measured by the A.O.C.S. method (Official Method Te 2a-64, 1987) for analysis of the reactants, and the fatty acid content was less than 1%. In order to remove excess ethylene glycol from the reactant, 100 g of distilled water was added and stirred for 10 minutes, and the layered bottom layer was removed. Then, 150 g of distilled water was added thereto, followed by stirring for 20 minutes. Removed. After that, it contained 7% of water, and to remove it, water was removed for 20 minutes at a pressure of 30torr at 75 ° C to prepare a fatty acid monoester of compound 3.

The content of fatty acid monoester in the reactants was more than 93%, the fatty acid was less than 1%, the water content was less than 0.5%, and the content of diester was less than 5%. This was used as such for the reaction of the next step described later.

(b) Preparation of 2-chlorocarbonyl oxyethyl decanoate

To prepare a chloroformate compound represented by the formula (4).

11.85 g of triphosgene was dissolved in 50 mL of toluene, and then a mixture solution of 23.7 g of 2-hydroxyethyl decanoate prepared in step (a) and amine was slowly added at 0 to 4 ° C. for 2 hours to react. . The organic layer was then separated using water, and then water was removed using magnesium sulfate anhydride. Thereafter, the solvent was removed and dried to obtain 29 g of the compound represented by Chemical Formula 4.

Example 2-12

A chloroformate compound was prepared using the same conditions as in Example 1 except for the conditions described in Table 1 below. In other words, the effects of various manufacturing conditions were evaluated.

Fatty Acid Monoester Input (g) Triphosgene Input (g) Solvent (60ml) base Reaction temperature (℃) Hour (hr) Example 2 23.2 12 toluene Triethanolamine 0-5 3hr Example 3 23.2 12 toluene - 13 24hr Example 4 23.2 12 - - 28 24hr Example 5 23.2 12 - - 15 24hr Example 6 23.2 12 - Pyridine 26 6hr Example 7 23.2 12 toluene Pyridine 26 19hr Example 8 23.2 12 - Pyridine 26 20hr Example 9 23.2 12 Methylene chloride Pyridine 26 20hr Example 10 23.2 12 toluene 25% sodium hydroxide solution 20 4hr Example 11 23.2 12 Ethyl acetate Triethanolamine 8-13 10hr Example 12 23.2 12 Dichloroethane Triethanolamine 8-13 10hr

Experimental Example : Purity Measurement of Chloroformate Compound

The purity of chloroformate was measured by the following method. First, 25 ml of a mixture of alcohol (ethanol or methanol) and 1N-sodium hydroxide (1: 1 (v / v)) was added to a 100 ml beaker. Approximately 1 g of sample was accurately weighed and placed in the solution and stirred at room temperature for 30 minutes. 30 ml of alcohol was further added and stirred again. To the solution, 2-3 drops of phenolphthalein indicator were added and then neutralized with 50% HNO ₃ aqueous solution until the color disappeared. Thereafter, the mixture was titrated with 0.1 N-AgNO ₃ using a potentiometric titrator (automatic potential titrator APB-510). Then, the purity of the chloroformate compound was calculated by substituting Equation 1 below. The results are shown in Table 2.

Purity (%) = A x N x F x M _W x 100 / (wx 1000)

In Equation 1, A is 0.1N-AgNO ₃ Consumption and, N is the normality of the AgNO ₃ solution, F is the factor (factor) value of the AgNO ₃ solution, M _W is the chloroformate molecular weight of formate-based compound to be measured, w is the weight of the measurement sample.

Sample amount (g) AgNO ₃ dosage (ml) Chloroformate Purity (%) Example 2 0.1328 4.522 94.84 Example 3 0.1253 3.566 79.04 Example 4 0.1217 3.256 74.51 Example 5 0.1158 3.011 72.41 Example 6 0.1165 3.133 74.89 Example 7 0.1435 4.214 81.78 Example 8 0.1223 3.445 78.45 Example 9 0.1333 3.865 80.75 Example 10 0.1021 3.302 90.07 Example 11 0.1125 3.520 87.14 Example 12 0.1021 3.115 84.97

As can be seen from the results of Table 2, in preparing the chloroformate-based compound using triphosgene according to the present invention, triethanolamine was used as a base, toluene was used as a solvent, and the reaction temperature was 0-. The chloroforme compound of Example 2 prepared at 5 ° C. in a short time does not use solvents and / or bases, other solvents, or bases other than amine bases. B, or higher purity than the reaction temperature was found to be higher.

As described above, the method for preparing a chloroformate compound according to the present invention is not only safe by using a solid triphosgene in place of gaseous phosgene, but also stable at room temperature, and can be measured in mg, and easy to control the reaction rate. It is economical because there is no installation cost for the manufacture. In addition, the production method according to the present invention can produce a chloroformate compound with high purity and high yield.

Claims (6)

(a) preparing a fatty acid monoester represented by Formula 2 below; And (b) reacting the prepared fatty acid monoester with triphosgene in the presence of a base to produce a chloroformate compound represented by the following formula (1). <Formula 1>

<Formula 2>

In Chemical Formulas 1 and 2, R ₁ is a linear or branched alkyl or alkenyl group having 1 to 19 carbon atoms, and n is an integer of 1 to 10. The method of claim 1, wherein step (a) uses 1 to 10 equivalents of ethylene glycol or ethylene oxide relative to fatty acids and fatty acids, and at least one acid catalyst selected from the group consisting of p-toluenesulfonic acid, sulfuric acid, and hydrochloric acid, relative to the total weight of the reactants. A method for producing a chloroformate-based compound, wherein 0 to 0.5% by weight is used and the reaction temperature is maintained at 60 to 150 ° C. The method of claim 1, wherein the base of step (b) is triethylamine or N, N-diisopropylethylamine. The method for producing a chloroformate compound according to any one of claims 1 to 3, wherein the reaction temperature of step (b) is maintained at -10 to 20 ° C. The method of claim 4, wherein the step (b) comprises the use of triphosgene 0.3 to 0.4 equivalents to the fatty acid monoester. The method of claim 4, wherein the reaction of step (b) uses toluene as a reaction solvent.