TW200305554A - Method for preparing p-aminobenzoic acid - Google Patents

Abstract

The method for preparing p-aminobenzoic acid using methyl-4-formylbenzoate as a starting material, which is a major by-product produced while synthesizing dimethylterphthalate is disclosed. The method comprises the steps of: chlorinating methyl-4-formylbenzoate to produce methyl-4-fchloromylbenzoate; amidating the methyl-4-chloroformylbenzoate to produce methyl-4-carbamoylbenzoate; and carrying out Hofmann reaction with the produced methyl-4-carbamoylbenzoate in aqueous solution. During the steps for preparing p-aminobenzoic acid, impurities in the methyl-4-formylbenzoate are removed.

Description

200305554 发明 Description of the invention [Technical field to which the invention belongs] The present invention relates to a method for preparing p-aminobenzoic acid (hereinafter referred to as "PAB A"). In particular, it relates to a method for preparing 4-formamylbenzoic acid methyl ester A method for preparing p-aminobenzoic acid with an ester as a starting material, wherein the 4-formamidinebenzoic acid methyl ester is a main by-product generated during the synthesis of dimethyl phthalate (hereinafter referred to as "DMT").

[Prior art]

Para-aminobenzoic acid (PABA) is a yellow crystalline compound that is soluble in water, ethanol, and ether. PABA is widely used in various chemical industries, and its application scope includes being used as a substance for absorbing UV in sunscreen emulsions, the starting material of aromatic polymer components, and manufacturing direct dyes or vat dyes. Intermediates, pharmaceutical intermediates, and vitamin B cofactors, vitamin B groups, and a benzocaine (ie, p-aminophenylacetate), procaine ) And other starting materials for local anesthetics. The conventional method for preparing PABA is shown below: [Reaction 1] 4 200305554

As shown in Reaction Formula 1, the toluene system is nitrated to produce o-nitrotoluene and p-nitrotoluene, and the resulting o-nitrotoluene and p-nitrotoluene are separated from each other. Thereafter, p-nitrotoluene is oxidized to form p-nitrophenylarsinic acid. In the last step, the nitro group in p-nitrobenzoic acid is reduced to the target compound, PABA, with a hydrogenation catalyst such as a mixture of chlorin-tin, platinum, and Raney Nickel. However, the method of reaction formula 1 has a disadvantage, that is, after the toluene is nitrated, ortho- and para-isomers are simultaneously formed, and the isomers need to be processed by a method such as fractionation. Separate them. In particular, the ortho-isomer is not used for any purpose, and it is generally directly discarded, which will increase the manufacturing cost of PABA. In addition, oxidants such as hydrogen peroxide and magnesium oxide used to oxidize p-nitrobenzone, and reducing agents such as platinum-catalyst and iron-catalyst to reduce p-nitrobenzoic acid are very expensive. Compounds will also increase manufacturing costs. 200305554 Another preparation method is disclosed in U.S. Patent No. 3,931,210, which uses a monomethyl compound of phthalic acid as a starting material to produce PABA. The monomethyl compound of the phthalic acid is the main by-product in the synthesis of dimethyl phthalate (DM T), and the dimethyl phthalate is the main raw material in the synthesis of the polyester resin. In this method, a monomethyl compound of phthalic acid is reacted with a monomethylamine compound, and the monomethylamine compound is converted into PABA by a Hofmann reaction. The monomethyl compound of phthalic acid or a lithium salt, calcium salt or magnesium salt thereof can be used. However, the monomethyl ester compound of phthalic acid can be obtained in large quantities from industrial or commercial processes of dimethyl phthalate. Therefore, from the perspective of manufacturing cost, the monomethyl ester compound of phthalic acid is the preferred starting compound for the production of PABA. However, this method also has disadvantages, that is, the The monomethyl vinegar compound of phthalic acid is a starting material, which cannot sufficiently reduce the production cost of PABA, and the ammonium reaction of the monomethyl phthalate compound of phthalic acid needs to be performed at high temperature and pressure. 【content】

P-Amine Therefore, the present invention is described as follows, and the method is beneficial to phenylbenzoic acid.

Another object of the present invention 200305554 Another object of the present invention is to provide a method for preparing p-aminobenzoic acid without using a protective group and without using a separate process.

In order to achieve these objectives, the present invention provides a method for preparing p-aminobenzoic acid, which comprises the following steps: chlorinating methyl 4-formamylbenzoate to form 4-methylformylbenzoate; -Amine methyl chloroformate benzoate is aminated to form methyl 4-amine benzoate; and a Huffman reaction is performed with the resulting 4-amine benzoate benzoate in solution. In this method, the gasification step is preferably performed by melting methyl 4-formamidinebenzoate into a liquid phase and adding 1 to 3 mole equivalents of chlorine gas (Cl2). The amidation step is preferably performed by adding methyl 4-chloroformamidinebenzoate dissolved in an organic solvent to ammonia water, or by supplying ammonia gas to 4-chloroformamidine dissolved in an organic solvent. Acetyl phenylacetate was performed. The Huffman reaction is preferably performed by adding an alkali compound to 4-aminophosphonium benzoate dissolved in an alkaline solution.

[Embodiment] With reference to the following description, the advantages and applications of the present invention will be better understood. According to the present invention, the starting material for the preparation of p-aminophenylarsine, methyl 4-arsylbenzoate (MFB), is a major by-product in the process of synthesizing DMT. DMT is a raw material for preparing polyester resin, and it is conventionally prepared according to the following reaction formula 2, where Me represents a methyl group. [Reaction formula 2] 7 200305554

COOH

COOH COOMe

The composition of the by-products generated in the DMT synthesis process described above will change as the conditions of the synthesis process change. When the synthesis rate is increased, the by-products produced include 80% (wt%) of methyl 4-benzophenylate (MFB), 9% (wt%) of DMT, and 4% (wt%) of p- Toluyl methyl ester (MPT), so methyl 4-formamylbenzoate is the main by-product. Eastman Kodak, DuPont, and SK Chemicals, which are known to use DMT synthesis processes worldwide, generally discard or incinerate by-products from their processes. In the present invention, p-aminobenzoic acid is prepared according to the following reaction formula 3 using methyl 4-formamylbenzoate as a starting material. [Reaction formula 3]

COOCH3 COOCH3 COOCH3 COOH 200305554

As shown in Reaction Formula 3, in the first step, the 4-formamylbenzoate methyl alcohol system is gasified to produce 4-methylammonium benzoate. This chlorination step is preferably performed by dissolving methyl 4-fluorenebenzoate into a liquid phase 'at atmospheric pressure and adding 1 to 3 molar equivalents of gas (C12). The melting temperature of the reactant 4-methylbenzyl benzate is preferably between 40 cc and 200 C, more preferably between 40 ° C and 100 ° C, and most preferably between 50 C and 70 C. between. When the melting temperature is lower than 40 ° C, the reactant 4-formamidinebenzoate 曱 8 cannot be fully melted, and the reaction rate will be slowed down, which will prevent the reaction from proceeding effectively. When the melting temperature is higher than 2000, it will increase energy consumption ' and cause side reactions, and the yield will decrease significantly. If the amount of gas used is less than 1 mole equivalent, the reaction will not be complete; but if the amount of gas used is greater than 3 mole equivalents, the yield cannot be increased further. The product of the chlorination process stays in the liquid phase at the reaction temperature, and the reaction time is generally 10 hours, and the reaction yield is about 90/0.

In the second step, methyl 4-chloroformamidinebenzoate produced by the gasification process is amidated to form methyl 4-amineformamate benzoate. This ammonium amination step is preferably performed by reacting methyl 4-gasformamidinebenzoate with ammonia (NHWH) or ammonia (NH3) dissolved in water and / or an organic solvent. In detail, the amidation reaction is preferably performed by adding the 4-gas mesylate sulfonate to ammonia water dropwise, or by adding 4- It is performed by adding trimethylammonium benzoate to ammonia water dropwise, or by supplying ammonia gas to 4-methylformamidine benzoate methyl ester which has been dissolved in an organic solvent. Organic solvents that can be used in this amidation process include various types of organic solvents that can dissolve 4-chloromethyl benzoate methyl vinegar, and preferred examples of such organic solvents include, for example, toluene, ethyl acetate, and A hydrophobic organic solvent such as a mixture thereof. The amount of the organic solvent used is preferably between 0 and 10 times the weight of 4-chloroformamidine benzoate, and more preferably between 0.5 and 8 times the weight of 4-chloroformamidine benzoate. In this ammonium amination step, the 4-gasobenzoic acid methyl ester is formed in the solid phase, so it can be easily separated from various by-product solutions. By-products such as p-galacene and diacetic acid in the reaction vessel are dissolved in an organic solvent, and thus can be separated from 4-pyridenebenzoate. This ammonium amination step can be performed under atmospheric pressure, and the reaction temperature is preferably between i ° C and 50 ° C, and more preferably between 3 ° C and 30 ° C. If the source of nitrogen is ammonia, this amination step is preferably performed at a relatively high temperature ', e.g., at 250 ° C to increase gas activity. If the reaction temperature is lower than 1 C ', the reaction rate will be slower; if the reaction temperature is lower than 50 ° C, side reactions will occur. The amount of organic solvent depends on the amount of impurities. If the amount of the organic solvent used is more than 10 times the weight of 4-g-methanetoluenebenzoate g, the reaction rate will decrease and the manufacturing cost will increase. In this ammonium amination step, when the source of nitrogen is ammonia water (NH4jj), the amount of ammonia water is between 5 and 20 mole equivalents, and preferably between 7 and 15 mole equivalents. When the source of nitrogen is ammonia (nh3), the amount of elephant gas is between 1.5 and 5 mole equivalents, preferably between 2 and 3 mole equivalents. If the amount of ammonia (nioh) and ammonia (NH3) is less than 5 to 1.5 mole equivalents, respectively, the reaction rate will be slowed down. If the amount of ammonia water (NK ^ OH) and ammonia gas (Ν) 3) is higher than 20 to 5 moles 10 200305554 miles or more ’, then there will be no additional desire effect. The product of this amidation step is a white crystalline compound with a reaction time of about 1 hour and a reaction yield of about 98%. In the final step, Huffman reaction is performed with the 4-aminomethyl acetobenzoate produced to form p-aminobenzoic acid. For example, the ‘Huffman reaction’ is based on the combination of methyl 4-aminoformamidine benzoate with 1 to 1.5 JB1 fields, prepared halogenation tests (eg, NaOCl and NaOBr), and 3 to 15

A molar amount of NaOH solution was used to perform the reaction, or the Huff reaction was performed by adding a halogenated base to the 4-aminobenzoic acid methyl ester test solution. The reaction temperature of the Huffman reaction is between 0 ° C and 80 ° C, preferably between 3 ° C and 6 ° C, and the reaction pressure is atmospheric pressure, and the reaction time is about 2 hours. If the amount of reactants is lower than The yield rate will be reduced, and even if the amount of reactants exceeds the above, the two yields cannot be improved. If the reaction temperature of the Huffman reaction is lower than 0 ° C, the reaction rate will decrease, and if When the reaction temperature of Huffman reaction exceeds 2 80 ° c, side reactions will occur.

After the Huffman reaction is completed, the p-amine can be extracted with an acidic solution. It is preferably a 5% to 0% hydrogenated hydrogen solution.

The acid value of the reaction product is neutralized to about 4.0, and it is preferable to use NaOH 57L / 1¾ Γχι to obtain pure, ~ p-amino stearic acid. After that, the reaction was filtered to make p-aminobenzoic acid. The Huffman reaction yields about 90%. w. The preferred embodiments of the present invention are mentioned, but the scope of the present invention is not limited to the following embodiments. 11 200305554 Example 1

75% of ethyl 4-benzylbenzoate (16.4 g) was added to 60%. (: Melt down, and add 1.5 molar equivalents of gas and aeration for 10 hours to obtain ethyl 4-chloroformamidine benzoate, the yield is 90%. 19.8 g of 4-chloroformamidine benzoate The ester was dissolved in 80 g of toluene at 60 ° C, and the resulting solution was added dropwise to 100/0 ammonia water within 2 hours. The weight of I contained in the ammonia water was 4-gastoluene Ten times the weight of ethyl formate. In this reaction, the reaction temperature was maintained at 5. (: to 2 (TC). After that, the temperature of the reactant was stopped to cool and the temperature was raised to room temperature. The reaction was filtered to obtain Crystallization of methyl 4-aminoformamylbenzoate with a yield of 98% and a purity of 95%.

The 1N sodium hydroxide solution contained 5 mol equivalents of sodium hydroxide relative to the weight of the 4-amine benzoate benzoate, cooled to 0 ° C and added 17.9 grams of amine amine Benzyl benzoate. The temperature of the reactant was maintained at (TC to 10 ° C), and a 10% NaOCl solution (containing 1.05 Molar equivalent of NaOCl) was added for 30 minutes to allow the reaction to continue for 2 hours. After that, the temperature of the reactant was increased To 50 ° C, and maintained for 1 hour. By adding NaOH, the pH value of the reactant can be adjusted to 4.0, while the target compound can be precipitated out. The reactant can be filtered to obtain the target compound, p-aminophenylhydrazone Acid with a yield of 95%. 2 In this example, 4-chloroformamidine benzoate methyl ester dissolved in ethyl acetate was used in place of 60 ° C methyl 4-methaneformylbenzoate. The volume of ethyl acetate used is 4 times the volume of 4-gasoylbenzoic acid ethyl ester. 12 200305554 In addition, the p-aminobenzoic acid was prepared according to the method of Example 1 above. The rate was 95%, and the purity of the obtained amidine compound was 96%. Example 3

2 molar equivalents of anhydrous ammonia were added to a toluene solution of methyl 4-chloroacetobenzoate for about 2 hours. The volume of toluene is four times the volume of 4-gastoluene methyl methyl acetate. After that, the toluene was distilled off, and the reaction product was washed with pure water. After filtration, white crystals of methyl 4-aminoformamidinebenzoate were obtained with a yield of 96%. Except this, p-aminophenylarsinic acid was prepared according to the method of Example 1 above.

As described above, the present invention provides a novel method for preparing p-aminophenylarsine. The 4-methylammonium benzoate ethyl ester used in this method is the main by-product when synthesizing DMT, and it can be used as a raw material for the synthesis of p-aminobenzoic acid without purification. The impurities in ethyl 4-formamylbenzoate can be removed during the preparation of p-aminobenzoic acid. The novel preparation method of the present invention utilizes the asymmetry of acenaphthyl 4-phenylbenzoate and does not require the use of a protecting group. Therefore, the method of the present invention for preparing p-aminobenzoic acid is very simple and can reduce the manufacturing cost. In the present invention, other purification methods can also be used between the steps, or the target compound can be purified by other purification methods after obtaining the target compound. The present invention has been described in detail through the examples above. The skilled artisan will be able to understand other improvements or replacements of the method of the present invention, and without departing from the spirit of the present invention 13 200305554, it still belongs to the scope of the appended patent application.

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Claims (1)

200305554 Scope of application and patent application 1. A method for preparing p-aminophenylbenzoic acid, comprising the steps of: chlorinating ethyl 4-benzoate benzoate to form methyl 4-chloroacetobenzoate; Amidation of methyl 4-chloroformamidinebenzoate to form methyl 4-amineformamidinebenzoate; Huffman reaction was performed with the generated 4-aminoformamidine benzoate methyl ester in solution. 2. The method as described in item 1 of the scope of the patent application, wherein the chlorination step is performed by melting 4-methylpyrenebenzoate into a liquid phase, and adding 1 to 3 molar equivalents of gas (Cl2 ). 3. The method according to item 1 of the scope of patent application, wherein the amidation step is carried out by adding 4-methylformamidine benzoate methyl ester dissolved in an organic solvent to ammonia water. 4. The method as described in item 1 of the scope of the patent application, wherein the ammonium amination step is performed by supplying ammonia gas into 4-gas ammonium phenylacetate dissolved in an organic solvent. 5. The method as described in item 1 of the scope of patent application, wherein the Huffman reaction is performed by adding a halogenated base to 4-amine benzophenone 15 200305554 acid ester dissolved in an alkaline solution. . 6. The method according to item 3 of the scope of patent application, wherein the organic solvent is selected from the group consisting of toluene, ethyl acetate, and mixtures thereof. 7. The method according to item 4 of the scope of patent application, wherein the organic solvent is selected from the group consisting of toluene, ethyl acetate, and mixtures thereof. 16 200305554 Lu, (1), the designated representative of the case is: Figure _ (2), the representative symbols of the representative diagram are briefly explained: 柒, if there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention ·