KR100540888B1 - Method for preparing p-aminobenzoic acid - Google Patents
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- KR100540888B1 KR100540888B1 KR1020030010662A KR20030010662A KR100540888B1 KR 100540888 B1 KR100540888 B1 KR 100540888B1 KR 1020030010662 A KR1020030010662 A KR 1020030010662A KR 20030010662 A KR20030010662 A KR 20030010662A KR 100540888 B1 KR100540888 B1 KR 100540888B1
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- C07—ORGANIC CHEMISTRY
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
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- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
본 발명은 디메틸테레프탈레이트 제조 공정에서 발생하는 주요 부산물인 메틸-4-포밀벤조에이트를 출발물질로 이용하여 p-아미노벤조산을 제조하는 방법에 관한 것으로서, 불순물이 포함된 메틸-4-포밀벤조에이트를 클로리네이션시켜, 메틸-4-클로로포밀벤조에이트를 합성하는 공정, 얻어진 메틸-4-클로로포밀벤조에이트를 아미드화시켜 메틸-4-카바모일벤조에이트를 합성하는 공정, 및 얻어진 메틸-4-카바모일벤조에이트를 수용액 조건에서 호프만 반응을 진행하는 공정을 포함하며, 반응 공정 중 불순물이 제거되는 p-아미노벤조산의 제조방법을 제공한다.
The present invention relates to a method for preparing p-aminobenzoic acid using methyl-4-formylbenzoate, which is a major by-product of the dimethyl terephthalate manufacturing process, as a starting material, and methyl-4-formylbenzoate containing impurities. The step of chlorination to synthesize methyl-4-chloroformylbenzoate, the step of amidating the obtained methyl-4-chloroformylbenzoate to synthesize methyl-4-carbamoylbenzoate, and the obtained methyl-4 It provides a method for producing p-aminobenzoic acid comprising the step of proceeding the Hoffman reaction of the carbamoyl benzoate in an aqueous solution conditions, the impurities during the reaction process.
p-아미노벤조산, 디메틸테레프탈레이트, 호프만 반응, 클로리네이션, 아미드화반응, 메틸-4-포밀벤조에이트p-aminobenzoic acid, dimethyl terephthalate, Hoffman reaction, cloning, amidation reaction, methyl-4-formylbenzoate
Description
본 발명은 p-아미노벤조산(p-aminobenzoic acid: PABA)의 제조방법에 관한 것으로서, 더욱 상세하게는 디메틸테레프탈레이트(Dimethylterephthalate: 이하, DMT라 한다.) 제조 공정에서 발생하는 주요 부산물인 메틸-4-포밀벤조에이트를 출발물질로 이용하여 p-아미노벤조산을 제조하는 방법에 관한 것이다.
The present invention relates to a method for preparing p-aminobenzoic acid (PABA), and more particularly, methyl-4, which is a major by-product generated in the manufacturing process of dimethylterephthalate (hereinafter referred to as DMT). It relates to a method for preparing p-aminobenzoic acid using -formylbenzoate as a starting material.
p-아미노벤조산은 황색 결정으로서 물, 에탄올, 에테르에 용해되는 성질을 가지고 있으며, 선스크린(Sunscreen) 크림의 UV 흡수제, 방향제 원료, 고분자 첨가물(Ingredient), 직접염료 또는 배트염료의 중간체, 동물 사료용 비타민 B의 보조인자 또는 비타민 Bx, 벤조카인(Benzocaine), 프로카인(Procaine) 등의 국소마취제의 주원료, 제약학적 중간체 등 광범위한 용도로 사용되고 있다. 이와 같은 p-아미노벤조산을 제조하는 통상적인 방법을 하기 반응식 1에 나타내었다. p-Aminobenzoic acid is yellow crystal, soluble in water, ethanol and ether, UV absorber of sunscreen cream, fragrance raw material, polymer additive (Ingredient), intermediate of direct dye or bat dye, animal feed It is used in a wide range of applications such as co-factors of vitamin B or main ingredients of local anesthetics such as vitamin Bx, benzocaine, procaine, and pharmaceutical intermediates. A conventional method for preparing such p-aminobenzoic acid is shown in Scheme 1 below.
상기 반응식 1에 나타낸 바와 같이, p-아미노벤조산을 제조하기 위해서는 먼저, 톨루엔을 니트로화시켜, 오르토(ortho)-니트로톨루엔 및 파라(para)-니트로톨루엔을 합성하고, 이들을 분리한 다음, p-니트로톨루엔을 산화시켜 p-니트로벤조산을 제조하고, p-니트로벤조산의 니트로기를 염산 및 주석 혼합물, 백금, 라니(Raney) 니켈 등의 적절한 수소화 촉매를 이용하여 환원시켜 합성한다. 그러나 이와 같은 방법은 톨루엔의 니트로화 반응에서 오르토(ortho) 및 파라(para) 이성질체가 동시에 생기므로, 이들을 분별 결정 등의 방법으로 분리한 후, 두 가지 용도로 전개해야 하는 단점이 있다. 특히 오르토 이성질체는 상대적으로 쓰임이 적어 부산물로 폐기되는 경우가 많으므로 p-아미노벤조산의 제조비를 상승시키는 원인이 된다. 또한 과산화수소 또는 이산화망간 등 고가의 화합물을 사용하여 p-니트로톨루엔을 산화시켜야 하며, 얻어진 p-니트로벤조산을 백금 촉매, 철 촉매 등 화학적으로 매우 고가의 촉매를 사용하여 환원시켜야 하므로, 전체적으로 목적화합물의 제조비용이 상승하는 단점이 있다.
As shown in Scheme 1, in order to prepare p-aminobenzoic acid, toluene is first nitrated to synthesize ortho-nitrotoluene and para-nitrotoluene, which are separated, and then p- Nitrotoluene is oxidized to prepare p-nitrobenzoic acid, and the nitro group of p-nitrobenzoic acid is synthesized by reduction using an appropriate hydrogenation catalyst such as hydrochloric acid and tin mixture, platinum, Raney nickel and the like. However, since the ortho and para isomers are generated at the same time in the nitration reaction of toluene, these methods have a disadvantage in that they are separated by a method such as fractional crystallization and then developed for two purposes. In particular, ortho isomers are used relatively little and are often discarded as by-products, which increases the production cost of p-aminobenzoic acid. In addition, p-nitrotoluene should be oxidized using an expensive compound such as hydrogen peroxide or manganese dioxide, and the resulting p-nitrobenzoic acid should be reduced using a chemically very expensive catalyst such as a platinum catalyst or an iron catalyst. There is a disadvantage that the cost increases.
또한 미국 특허 제3,931,210호에서는 폴리에스테르 섬유의 제조에 대량으로 사용되는 디메틸테레프탈레이트(DMT)를 합성할 경우, 부산물로 생성되는 테레프탈산의 모노메틸에스테르를 출발물질로 하여 p-아미노벤조산을 제조하는 방법을 개시하고 있다. 상기 미국 특허는 테레프탈산의 모노메틸에스테르를 암모니아와 반응시켜, 모노아미드 생성물을 합성하고, 합성된 모노아미드 생성물을 호프만 반응시킴으로서 p-아미노벤조산을 제조한다. 상기 반응의 출발물질로 사용되는 테레프탈산의 모노메틸에스테르로는 테레프탈산의 모노메틸에스테르의 리튬, 칼슘, 마그네슘염 등 다양한 유도체가 사용될 수 있으나, 테레프탈산의 모노메틸에스테르 자체를 산업부산물로서 대량으로 얻을 수 있으므로, 이를 직접 사용하는 것이 제조비용의 측면에서 가장 바람직한 것으로 개시되어 있다. 그러나, 상기 방법에 사용되는 출발물질인 모노에틸에스테르는 제조비용을 충분히 저하시킬 정도로 다량으로 얻기 어려울 뿐만 아니라, 아미드화 반응에 고온고압이 필요하다는 단점이 있다.
In addition, U.S. Patent No. 3,931,210 discloses a method for preparing p-aminobenzoic acid using monomethyl ester of terephthalic acid, which is produced as a by-product, when synthesizing dimethyl terephthalate (DMT), which is used in large quantities in the production of polyester fibers. Is starting. This US patent produces p-aminobenzoic acid by reacting a monomethyl ester of terephthalic acid with ammonia to synthesize a monoamide product and by reacting the synthesized monoamide product with a Hoffman reaction. As the monomethyl ester of terephthalic acid used as a starting material of the reaction, various derivatives such as lithium, calcium and magnesium salts of the monomethyl ester of terephthalic acid may be used, but the monomethyl ester of terephthalic acid itself may be obtained in large quantities as an industrial by-product. It is disclosed that the direct use thereof is most preferable in terms of manufacturing cost. However, monoethyl ester, which is a starting material used in the above method, is difficult to obtain in a large amount to sufficiently reduce the production cost, and has a disadvantage of requiring high temperature and high pressure for the amidation reaction.
본 발명의 목적은 종래에 사용된 바 없는 DMT 제조 공정 부산물을 이용하여 p-아미노벤조산을 경제적으로 제조하는 신규한 방법을 제공하는 것이다.It is an object of the present invention to provide a novel process for the economic production of p-aminobenzoic acids using by-products of DMT preparation which have not been used conventionally.
본 발명의 다른 목적은 DMT 제조공정에서 발생하는 부산물을 별도의 정제과정 없이 그대로 이용하여 p-아미노벤조산을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing p-aminobenzoic acid by using the by-products generated in the DMT manufacturing process as it is without further purification.
본 발명의 또 다른 목적은 별도의 보호기를 형성하는 공정 및 이성질체가 형 성되지 않으므로 별도의 분리 공정이 불필요한 p-아미노벤조산을 제조하는 방법을 제공하는 것이다.
Still another object of the present invention is to provide a process for forming a separate protecting group and a method for preparing p-aminobenzoic acid, which does not require a separate separation process because no isomer is formed.
상기 목적을 달성하기 위하여, 본 발명은 메틸-4-포밀벤조에이트를 클로리네이션시켜, 메틸-4-클로로포밀벤조에이트를 합성하는 공정, 얻어진 메틸-4-클로로포밀벤조에이트를 아미드화시켜 메틸-4-카바모일벤조에이트를 합성하는 공정, 및 얻어진 메틸-4-카바모일벤조에이트를 수용액 조건에서 호프만 반응을 진행하는 공정을 포함하는 p-아미노벤조산의 제조방법을 제공한다.In order to achieve the above object, the present invention is a step of cloning methyl-4-formylbenzoate, synthesizing methyl-4-chloroformylbenzoate, amidating methyl-4-chloroformylbenzoate obtained, and methylation. It provides a method for producing p-aminobenzoic acid comprising the step of synthesizing 4-carbamoylbenzoate, and the step of Hoffman reaction of the obtained methyl-4-carbamoylbenzoate in aqueous solution conditions.
여기서, 상기 클로리네이션 공정은 메틸-4-포밀벤조에이트를 용융시켜 액상으로 만든 다음, 1 내지 3 당량(eq)의 염소 가스(Cl2)를 투입하여 수행하는 것이 바람직하고, 상기 아미드화 공정은 암모니아 수용액에 유기 용매로 용해시킨 메틸-4-클로로포밀벤조에이트를 적가하거나, 유기 용매에 용해시킨 메틸-4-클로로포밀벤조에이트에 암모니아 가스를 투입하여 이루어지는 것이 바람직하다. 또한, 상기 호프만 반응은 염기성 수용액에 용해된 상기 메틸-4-카바모일벤조에이트에 할로겐화 염기를 첨가하여 수행되는 것이 바람직하다.
Herein, the cloning process may be performed by melting methyl-4-formylbenzoate into a liquid phase and then adding 1 to 3 equivalents (eq) of chlorine gas (Cl 2 ) to the amidation process. It is preferable to add the methyl-4-chloroformyl benzoate dissolved in the silver ammonia aqueous solution in the organic solvent dropwise, or to add the ammonia gas to the methyl-4-chloroformyl benzoate dissolved in the organic solvent. In addition, the Hoffman reaction is preferably performed by adding a halogenated base to the methyl-4-carbamoylbenzoate dissolved in a basic aqueous solution.
이하, 본 발명을 더욱 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in more detail.
본 발명에 따른 p-아미노벤조산의 제조에서 출발물질로 사용되는 메틸-4-포 밀벤조에이트(Methyl 4-formylbenzoate: MFB)는 폴리에스테르 제조의 원료로서 대량 사용되는 DMT 제조공정의 주요 부산물이다. 통상적인 DMT 합성과정은 다음 반응식 2 (여기서, Me는 메틸기를 의미한다.)와 같다.Methyl-4-formylbenzoate (MFB), which is used as a starting material in the preparation of p-aminobenzoic acid according to the present invention, is a major by-product of the DMT manufacturing process used in large quantities as a raw material for polyester production. A typical DMT synthesis process is shown in the following Scheme 2, where Me represents a methyl group.
이와 같은 DMT의 제조과정에서 생성되는 부산물의 성분은 DMT의 제조 공정 조건에 따라 달라질 수 있으나, DMT 제조 반응 속도를 충분히 증가시키는 경우 얻어진 부산물을 분석하면 메틸-4-포밀벤조에이트(MFB) 80중량%, DMT 9중량%, 메틸-p-톨루에이트(Methyl p-toluate: MPT) 4중량%를 포함하고 있어, 메틸-4-포밀벤조에이트(MFB)가 주요 부산물로 생성되고 있다. 세계적으로는 이스트만 코닥(Eastman Kodak), 듀퐁(Dupont), SK케미칼 등이 이와 같은 DMT 제조 공정을 채택하고 있는 것으로 알려져 있으며, 발생되는 부산물은 일반적으로 폐기되거나 소각되고 있다.
The components of the by-products generated in the manufacturing process of the DMT may vary depending on the manufacturing process conditions of the DMT, but when the reaction rate of the obtained by-products is sufficiently increased, the methyl-4-formylbenzoate (MFB) 80 wt. %, 9% by weight of DMT, 4% by weight of methyl p-toluate (MPT), methyl-4-formylbenzoate (MFB) is produced as a major by-product. Globally, Eastman Kodak, Dupont and SK Chemicals are known to adopt this DMT manufacturing process, and the by-products that are generated are generally disposed of or incinerated.
본 발명은 하기 반응식 3에 나타낸 바와 같이 p-아미노벤조산을 제조하기 위하여 상기 DMT 제조 공정의 주요 부산물인 메틸-4-포밀벤조에이트를 출발물질로 사용한다.The present invention uses methyl-4-formylbenzoate as a starting material, which is a major byproduct of the DMT preparation process, to prepare p-aminobenzoic acid as shown in Scheme 3 below.
상기 반응식 3에 나타낸 바와 같이, 본 발명에 따라 p-아미노벤조산을 제조하기 위해서는, 먼저 메틸-4-포밀벤조에이트를 클로리네이션(chlorination)시켜, 메틸-4-클로로포밀벤조에이트를 합성한다. 이와 같은 클로리네이션(chlorination) 반응은 반응물인 메틸-4-포밀벤조에이트를 상압에서 용융시켜 액상으로 만든 다음, 1 내지 3 당량(eq)의 염소 가스(Cl2)를 투입하여 수행할 수 있다. As shown in Scheme 3, to prepare p-aminobenzoic acid according to the present invention, methyl-4-formylbenzoate is first chlorated to synthesize methyl-4-chloroformylbenzoate. This chlorination reaction can be carried out by melting the reactant methyl-4-formylbenzoate at normal pressure to make it liquid, and then adding 1 to 3 equivalents (eq) of chlorine gas (Cl 2 ). .
반응물인 메틸-4-포밀벤조에이트를 용융시키는 온도는 40 내지 200℃, 바람직하게는 40 내지 100℃이고, 더욱 바람직하게는 50 내지 70℃이다. 이때 용융 온도가 40℃ 미만인 경우에는 반응물인 메틸-4-포밀벤조에이트가 충분히 용융되지 않고, 반응속도가 느려 반응을 효율적으로 진행하지 못하는 문제가 있으며, 용융 온도가 200℃를 초과하는 경우에는 불필요한 에너지가 낭비될 뿐만 아니라, 반응시 부반응이 심각하게 발생하여 반응수율이 현저하게 떨어지는 단점이 있다. 또한 염소 가스(Cl2)의 사용 당량이 1당량 미만인 경우에는 반응이 완전히 수행되지 않으며, 3당량을 초과하여도 반응 수율이 더 이상 향상되지 않는다. 상기 클로리네이션 반응의 생성물은 반응 온도에서 액상으로 존재하며, 반응시간은 약 10시간이며, 반응 수율은 약 90% 정도이다.
The temperature for melting the methyl-4-formylbenzoate as the reactant is 40 to 200 ° C, preferably 40 to 100 ° C, more preferably 50 to 70 ° C. At this time, when the melting temperature is less than 40 ℃, methyl-4-formylbenzoate as a reactant is not sufficiently melted, there is a problem that the reaction rate is slow to progress the reaction efficiently, if the melting temperature exceeds 200 ℃ unnecessary Not only is energy wasted, but side reactions occur seriously during the reaction, and the yield of the reaction is significantly reduced. In addition, when the use equivalent of chlorine gas (Cl 2 ) is less than 1 equivalent, the reaction is not carried out completely, and the reaction yield is no longer improved even when exceeding 3 equivalents. The product of the chloride reaction is present in the liquid phase at the reaction temperature, the reaction time is about 10 hours, the reaction yield is about 90%.
다음으로, 이와 같이 클로리네이션 반응에 의하여 생성된 메틸-4-클로로포밀벤조에이트를 아미드화시켜 메틸-4-카바모일벤조에이트(methyl-4- carbamoylbenzoate)를 합성한다. 이와 같은 아미드화 반응은 물 및/또는 유기 용매 중에서, 메틸-4-클로로포밀벤조에이트와 수산화암모늄(NH4OH) 또는 암모니아 가스(NH3)를 반응시켜 수행할 수 있다. 구체적으로 상기 아미드화 반응은 암모니아 수용액에 용융상태의 메틸-4-클로로포밀벤조에이트를 적가하거나, 유기 용매로 용해시킨 메틸-4-클로로포밀벤조에이트를 적가하거나, 유기 용매로 용해시킨 메틸-4-클로로포밀벤조에이트에 암모니아 가스를 투입하여 수행할 수 있다.Next, a methylated methyl-4-chloroformylbenzoate produced by the cloning reaction in this way to synthesize methyl-4-carbamoylbenzoate (methyl-4-carbamoylbenzoate). This amidation reaction can be carried out by reacting methyl-4-chloroformylbenzoate with ammonium hydroxide (NH 4 OH) or ammonia gas (NH 3 ) in water and / or an organic solvent. Specifically, in the amidation reaction, methyl-4-chloroformylbenzoate in a molten state is added dropwise to an aqueous ammonia solution, methyl-4-chloroformylbenzoate dissolved in an organic solvent is added dropwise, or methyl-4 dissolved in an organic solvent is added. Ammonia gas may be added to chloroformylbenzoate.
상기 아미드화 반응의 유기 용매로는 메틸-4-클로로포밀벤조에이트를 용해시킬 수 있는 다양한 유기 용매를 사용할 수 있으며, 바람직하게는 톨루엔, 에틸아세테이트 등 혐수성 유기 용매를 단독으로 또는 혼합하여 메틸-4-클로로포밀벤조에이트에 대하여 질량비로 0 내지 10 배, 바람직하게는 0.5 내지 8배 사용한다. 이때 반응에 의하여 생성된 메틸-4-카바모일벤조에이트는 고체로 형성되어 용매 및 암모니아 수용액과 분리되며 반응물에 포함되어 있던 디메틸테레프탈산, 메틸파라톨루일산 등과 같은 불순물은 유기용매에 용해되어 제거된다. 상기 아미드화 반응은 상압에서 수행할 수 있으며, 반응 온도는 1 내지 50℃, 바람직하게는 3 내지 30℃이며, 상기 질소원이 암모니아 가스인 경우 가스의 활성을 고려하여 비교적 높은 온도, 예를 들면 25℃에서 반응을 수행하는 것이 바람직하다. 여기서 상기 반응 온도가 1℃ 미만인 경우에는 반응 속도가 느려지는 단점이 있으며, 50℃를 초과하 는 경우에는 부반응의 우려가 있다. 또한 사용하는 유기용매의 양은 불순물의 양에 따라 달라질 수 있는데 10배 이상의 질량을 투여할 경우 생산효율의 감소 및 재료비의 상승으로 공정의 적용이 어려워진다.As the organic solvent of the amidation reaction, various organic solvents capable of dissolving methyl-4-chloroformylbenzoate may be used. Preferably, methyl-chloro-hydrophilic organic solvents such as toluene and ethyl acetate may be used alone or mixed. 0 to 10 times, preferably 0.5 to 8 times, by mass ratio relative to 4-chloroformylbenzoate is used. At this time, the methyl-4-carbamoylbenzoate produced by the reaction is formed as a solid and separated from the solvent and the aqueous ammonia solution, and impurities such as dimethyl terephthalic acid and methyl paratoluic acid contained in the reactant are dissolved and removed in the organic solvent. The amidation reaction can be carried out at atmospheric pressure, the reaction temperature is 1 to 50 ℃, preferably 3 to 30 ℃, when the nitrogen source is ammonia gas, considering the activity of the gas relatively high temperature, for example 25 Preference is given to carrying out the reaction at < RTI ID = 0.0 > Here, when the reaction temperature is less than 1 ℃ there is a disadvantage that the reaction rate is slow, if it exceeds 50 ℃ there is a fear of side reactions. In addition, the amount of the organic solvent used may vary depending on the amount of impurities. If a mass of 10 times or more is administered, it is difficult to apply the process due to a decrease in production efficiency and an increase in material cost.
상기 아미드화 반응에 있어서, 질소원이 수산화암모늄(NH4OH)인 경우에 그 사용량은 5 내지 20당량, 바람직하게는 7 내지 15당량이고, 상기 질소원이 암모니아 가스(NH3)인 경우에 그 사용량은 1.5 내지 5당량, 바람직하게는 2 내지 3 당량이다. 여기서 상기 수산화암모늄 및 암모니아 가스의 사용량이 각각 5당량 및 1.5당량 미만인 경우에는 반응속도가 느려지며, 수산화암모늄 및 암모니아 가스의 사용량이 각각 20당량 및 5당량을 초과하여도 반응에 특별한 이익이 없다. 이와 같은 아미드화반응의 생성물은 백색 고체이며, 반응시간은 약 1시간, 반응 수율은 대략 98%이다.
In the amidation reaction, when the nitrogen source is ammonium hydroxide (NH 4 OH), its amount is 5 to 20 equivalents, preferably 7 to 15 equivalents, and when the nitrogen source is ammonia gas (NH 3 ), the amount is used. Is 1.5 to 5 equivalents, preferably 2 to 3 equivalents. In this case, when the amount of ammonium hydroxide and ammonia gas used is less than 5 equivalents and 1.5 equivalents, respectively, the reaction rate is slowed, and even when the amount of ammonium hydroxide and ammonia gas exceeds 20 equivalents and 5 equivalents, respectively, there is no particular benefit in the reaction. The product of this amidation reaction is a white solid, the reaction time is about 1 hour, the reaction yield is approximately 98%.
다음으로, 상기 아미드화 반응에서 수득한 메틸-4-카바모일벤조에이트에 대하여 호프만(Hofmann) 반응을 수행함으로서 최종 목적물인 p-아미노벤조산을 얻을 수 있다. 상기 호프만 반응은 예를 들면, 수용액상에서 메틸-4-카바모일벤조에이트와 1 내지 1.5 당량의 NaOCl, NaOBr 등의 할로겐화 염기 및 3 내지 15당량의 NaOH를 반응시켜 수행할 수 있으며, 염기성 수용액에 용해된 메틸-4-카바모일벤조에이트에 할로겐화 염기를 첨가하여 수행할 수도 있다. 상기 호프만 반응의 온도는 0 내지 80℃, 바람직하게는 3 내지 60℃이며, 반응 압력은 상압이며, 반응시간 은 약 2시간이다. 이때 상기 반응물의 사용량이 상기 범위 미만일 경우에는 반응 수율이 감소되며, 상기 범위를 초과하여도 반응 수율이 더 이상 향상되지 않는다. 또한 상기 호프만 반응의 온도가 0℃ 미만인 경우에는 반응 속도가 저하되며, 80℃를 초과하면 부반응의 우려가 있다. Next, p-aminobenzoic acid which is the final target can be obtained by performing a Hofmann reaction on the methyl-4-carbamoylbenzoate obtained in the amidation reaction. The Hoffmann reaction can be carried out, for example, by reacting methyl-4-carbamoylbenzoate with 1 to 1.5 equivalents of NaOCl, a halogenated base such as NaOBr, and 3 to 15 equivalents of NaOH in an aqueous solution, and dissolved in a basic aqueous solution. It can also be carried out by the addition of a halogenated base to the methyl-4-carbamoylbenzoate. The temperature of the Hoffman reaction is 0 to 80 ° C, preferably 3 to 60 ° C, the reaction pressure is atmospheric pressure, and the reaction time is about 2 hours. In this case, when the amount of the reactants used is less than the above range, the reaction yield is reduced, and the reaction yield is no longer improved even if the amount exceeds the above range. Moreover, when the temperature of the said Hoffman reaction is less than 0 degreeC, reaction rate falls and when it exceeds 80 degreeC, there exists a possibility of side reaction.
상기 호프만 반응이 완료되면, 필요에 따라 산 수용액, 바람직하게는 5 내지 10%의 염산 수용액으로 p-아미노벤조산을 추출한 후, 염기, 바람직하게는 NaOH를 이용하여 반응액의 pH를 약 4로 중화하여 p-아미노벤조산을 고체로 침전시킨 후, 이를 여과함으로서 최종적으로 순수한 p-아미노벤조산을 수득한다. 이와 같은 호프만 반응의 수율은 대략 90%이다.
When the Hoffmann reaction is completed, p-aminobenzoic acid is extracted with an aqueous acid solution, preferably 5-10% aqueous hydrochloric acid, if necessary, and the pH of the reaction solution is neutralized to about 4 using a base, preferably NaOH. P-aminobenzoic acid is precipitated as a solid, which is then filtered to give finally pure p-aminobenzoic acid. The yield of this Hoffman reaction is approximately 90%.
이하, 실시예를 들어 본 발명을 더욱 상세하게 설명하나, 하기 실시예는 본 발명을 예시하기 위한 것으로서, 본 발명이 하기 실시예에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to Examples, but the following Examples are for illustrating the present invention, and the present invention is not limited to the following Examples.
[실시예 1]Example 1
75%의 메틸-4-포밀벤조에이트(메틸-4-포밀벤조에이트 16.4g)를 60℃로 가열하여 용융시킨 다음, 1.5당량의 염소가스를 10시간 동안 버블링하여 투입하여 메틸-4-클로로포밀벤조에이트를 90%의 수율로 수득하였다. 메틸-4-클로로포밀벤조에이트에 대하여 10당량의 암모니아를 포함하는 10% 암모니아 수용액에, 60℃의 메틸-4-클로로포밀벤조에이트 19.8g을 80g의 톨루엔에 녹여 2시간 동안 적가하였으며, 이때 반응액의 온도는 5 내지 20℃가 되도록 유지하였다. 반응기의 냉각을 중 지하고, 반응액을 상온까지 승온한 다음, 여과하여 백색 고체 상태의 메틸-4-카바모일벤조에이트를 98%의 수율로 수득하였으며 순도는 95%였다.75% of methyl-4-formylbenzoate (16.4 g of methyl-4-formylbenzoate) was heated to 60 DEG C and melted, followed by bubbling 1.5 equivalents of chlorine gas for 10 hours to prepare methyl-4-chloro Formylbenzoate was obtained in 90% yield. To a 10% aqueous ammonia solution containing 10 equivalents of ammonia relative to methyl-4-chloroformylbenzoate, 19.8 g of methyl-4-chloroformylbenzoate at 60 ° C. was dissolved in 80 g of toluene, and added dropwise for 2 hours. The temperature of the liquid was kept to be 5-20 degreeC. Cooling of the reactor was stopped, the reaction solution was allowed to warm up to room temperature, and filtered to give methyl-4-carbamoylbenzoate as a white solid in a yield of 98%, with a purity of 95%.
메틸-4-카바모일벤조에이트에 대하여 5당량의 수산화나트륨을 포함하는 1N 수산화나트륨 수용액을 0℃로 냉각한 후, 메틸-4-카바모일벤조에이트 17.9g를 투입하고, 반응액의 온도를 0 내지 10℃로 유지하면서 1.05당량의 NaOCl을 포함하는 10% NaOCl 수용액을 30분 동안 적가하고, 2시간동안 반응을 진행한 다음, 반응기의 온도를 50℃로 승온하고, 1시간동안 방치하였다. NaOH 수용액을 첨가하여 반응액의 pH를 4로 조절하여 고체를 침전시킨 후, 여과하여 최종 생성물인 p-아미노벤조산을 95%의 수율로 수득하였다.
After cooling 1N sodium hydroxide aqueous solution containing 5 equivalents of sodium hydroxide with respect to methyl-4-carbamoyl benzoate at 0 degreeC, 17.9 g of methyl-4- carbamoyl benzoate is thrown in, and the temperature of the reaction liquid is 0. 10% aqueous NaOCl solution containing 1.05 equivalents of NaOCl was added dropwise for 30 minutes while maintaining at 10 ° C, the reaction proceeded for 2 hours, and the temperature of the reactor was increased to 50 ° C and left for 1 hour. NaOH aqueous solution was added to adjust the pH of the reaction solution to 4 to precipitate a solid, and then filtered to obtain p-aminobenzoic acid as a final product in a yield of 95%.
[실시예 2]Example 2
60℃의 메틸-4-클로로포밀벤조에이트 대신 부피비로 4배의 초산에틸에 용해시킨 메틸-4-클로로포밀벤조에이트를 사용한 것을 제외하고는 실시예 1과 동일한 방법으로 실시하여 p-아미노벤조산을 수득하였다. 이때 아미드화반응의 수율은 95%였으며 아미드의 순도는 96%였다.
P-aminobenzoic acid was prepared in the same manner as in Example 1, except that methyl-4-chloroformylbenzoate dissolved in 4-fold ethyl acetate in a volume ratio instead of methyl-4-chloroformylbenzoate at 60 ° C was used. Obtained. The yield of the amidation reaction was 95% and the purity of the amide was 96%.
[실시예 3]Example 3
부피비로 4배의 톨루엔에 용해시킨 메틸-4-클로로포밀벤조에이트에 무수 암모니아 가스 2당량을 2시간 동안 버블링하여 투입한 후, 톨루엔을 증류하고, 순수로 세정한 다음, 여과하여 백색 고체 상태의 메틸-4-카바모일벤조에이트를 96%의 수율로 얻은 것을 제외하고는 실시예 1과 동일한 방법으로 실시하여 p-아미노벤조산을 수득하였다.
After adding 2 equivalents of anhydrous ammonia gas to methyl-4-chloroformylbenzoate dissolved in 4 times of toluene by volume ratio for 2 hours, toluene was distilled off, washed with pure water, and filtered to obtain a white solid state. P-aminobenzoic acid was obtained in the same manner as in Example 1 except that methyl-4-carbamoylbenzoate of was obtained in a yield of 96%.
이상 상술한 바와 같이, 본 발명에 따른 p-아미노벤조산의 제조방법은 기존에 알려진 바 없는 새로운 공정으로서, DMT 제조공정에서 발생하며 종래에 사용된 바 없는 부산물인 메틸-4-포밀벤조에이트를 별도의 정제과정 없이 그대로 이용하여 p-아미노벤조산을 합성할 수 있다. 또한 메틸-4-포밀벤조에이트의 비대칭성(Asymmetry)을 최대한 이용하고, 별도의 보호기 사용하지 않음으로서, 공정 단계를 감소시켜 목적화합물의 제조비용을 절감할 수 있으며, 목적화합물이 합성된 후 또는 합성 과정 중에 필요에 따라 정제과정을 수행할 수 있는 장점이 있다.
As described above, the method for preparing p-aminobenzoic acid according to the present invention is a novel process that has not been known in the past, and is a separate by-product of methyl-4-formylbenzoate, which is a by-product which has not been used in the past and is used in the DMT manufacturing process. P-aminobenzoic acid can be synthesized as it is without purification. In addition, by utilizing the asymmetry of methyl-4-formylbenzoate as much as possible and not using a separate protecting group, it is possible to reduce the process step and reduce the manufacturing cost of the target compound, or after the target compound is synthesized or There is an advantage that the purification process can be carried out as needed during the synthesis process.
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| AU (1) | AU2003208633A1 (en) |
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| CN102191231B (en) * | 2010-08-11 | 2013-01-09 | 中国农业科学院生物技术研究所 | Soybean folic acid synthesis key enzyme ADCS and gene and application thereof |
| KR101329242B1 (en) * | 2012-02-15 | 2013-11-28 | 한국화학연구원 | Method for preparing p-aminobenzoic acid |
| CN105646180A (en) * | 2016-03-01 | 2016-06-08 | 苏州艾缇克药物化学有限公司 | Pharmaceutical intermediate 2,4-difluorobenzoic acid synthesis method |
| CN105777565B (en) * | 2016-03-31 | 2017-09-22 | 盖领 | A kind of synthetic method of the aminobenzoic acid of 2 aldehyde radical 4 |
| WO2018048882A1 (en) | 2016-09-06 | 2018-03-15 | The Research Foundation For The State University Of New York | Positron imaging tomography imaging agent composition and method for bacterial infection |
| CN116082181B (en) * | 2022-12-12 | 2025-03-04 | 爱斯特（成都）生物制药股份有限公司 | A method for preparing 3-amino-5-ethoxy-benzoic acid |
| CN116693843A (en) * | 2023-06-27 | 2023-09-05 | 中国科学院微生物研究所 | Preparation method of nylon 11 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3931210A (en) * | 1973-03-19 | 1976-01-06 | Akzo N.V. | Production of p-aminobenzoic acid |
| US4551549A (en) * | 1981-08-17 | 1985-11-05 | E. I. Du Pont De Nemours And Company | Preparation and use of nitroterephthalamic acids |
| JP2006116451A (en) * | 2004-10-22 | 2006-05-11 | Asahi Breweries Ltd | Box foreign matter dropping device |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3371232D1 (en) * | 1983-02-22 | 1987-06-04 | Electricite De France | Process for the production of aminobenzoic acids from corresponding nitrotoluenes |
| JPS6112653A (en) * | 1984-06-28 | 1986-01-21 | Nippon Kayaku Co Ltd | Production of aminobenzoic acids |
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2003
- 2003-02-20 KR KR1020030010662A patent/KR100540888B1/en not_active Expired - Fee Related
- 2003-02-26 CN CNB038029553A patent/CN100427457C/en not_active Expired - Fee Related
- 2003-02-26 TW TW092104107A patent/TWI250971B/en not_active IP Right Cessation
- 2003-02-26 WO PCT/KR2003/000380 patent/WO2003072534A1/en not_active Ceased
- 2003-02-26 AU AU2003208633A patent/AU2003208633A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3931210A (en) * | 1973-03-19 | 1976-01-06 | Akzo N.V. | Production of p-aminobenzoic acid |
| US4551549A (en) * | 1981-08-17 | 1985-11-05 | E. I. Du Pont De Nemours And Company | Preparation and use of nitroterephthalamic acids |
| JP2006116451A (en) * | 2004-10-22 | 2006-05-11 | Asahi Breweries Ltd | Box foreign matter dropping device |
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| CN100427457C (en) | 2008-10-22 |
| WO2003072534A1 (en) | 2003-09-04 |
| CN1625545A (en) | 2005-06-08 |
| AU2003208633A1 (en) | 2003-09-09 |
| TWI250971B (en) | 2006-03-11 |
| TW200305554A (en) | 2003-11-01 |
| KR20030070824A (en) | 2003-09-02 |
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