KR100892233B1 - Novel processes for the preparation of benzaldehyde derivatives - Google Patents

Novel processes for the preparation of benzaldehyde derivatives Download PDF

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KR100892233B1
KR100892233B1 KR1020070104326A KR20070104326A KR100892233B1 KR 100892233 B1 KR100892233 B1 KR 100892233B1 KR 1020070104326 A KR1020070104326 A KR 1020070104326A KR 20070104326 A KR20070104326 A KR 20070104326A KR 100892233 B1 KR100892233 B1 KR 100892233B1
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acid
derivative
hydroxybenzaldehyde
hydroxy
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윤성화
신영균
박호준
김현지
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(주)에스에이치제약
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C07C45/66—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D3/00—Distillation or related exchange processes in which liquids are contacted with gaseous media, e.g. stripping
    • B01D3/10—Vacuum distillation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D9/00—Crystallisation
    • B01D9/004—Fractional crystallisation; Fractionating or rectifying columns
    • B01D9/0045—Washing of crystals, e.g. in wash columns
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
    • C07C45/82—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/55—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
    • C07C47/565—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups all hydroxy groups bound to the ring

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Abstract

A method for preparing 4-hydroxybenzaldehyde derivatives is provided to improve safety by excluding the use of hydrochloride which is an essential material for performing formylation for mass production. A method for preparing 4-hydroxybenzaldehyde derivatives comprises a step of preparing 4-hydroxybenzaldehyde derivative represented by the formula I by reacting 4-hydroxyphenylglycine derivative represented by the formula III and inorganic acid or organic acid. In the formula I and III, R1, R2 and R3 are independently hydrogen, C1-C10 alkyl, nitro or halogen. The inorganic acid or organic acid is selected among hydrochloric acid, sulfuric acid, nitric acid and acetic acid.

Description

벤즈알데하이드 유도체의 신규한 제조방법{Novel processes for the preparation of benzaldehyde derivatives}Novel processes for the preparation of benzaldehyde derivatives

본 발명은 염료물질, 풍미제, 방향제, 제초제 화합물, 핵 형성제, 중합체 첨가제 등과 같은 여러 가지 화합물을 제조하는데 있어서 중간물질로 유용한 벤즈알데하이드 유도체의 신규한 제조방법에 관한 것으로, 더욱 상세하게는 4-하이드록시페닐글라이신 유도체로부터의 산의 농도를 변화시킨 포르밀화 반응을 통하여 4-하이드록시벤즈알데하이드 유도체 또는 4-하이드록시-3-나이트로벤즈알데하이드 유도체를 우수한 수율 및 안전한 공정으로 제조하는 것이다.The present invention relates to a novel process for preparing benzaldehyde derivatives useful as intermediates in the preparation of various compounds such as dyes, flavors, fragrances, herbicide compounds, nucleating agents, polymer additives, and the like. Formation of 4-hydroxybenzaldehyde derivatives or 4-hydroxy-3-nitrobenzaldehyde derivatives in an excellent yield and safe process is carried out through formylation reactions with varying concentrations of acid from -hydroxyphenylglycine derivatives.

기존의 방향족 알데하이드는 방향족 유도체상에 포르밀화를 통하여 부착시키는 공정으로 구성된 직접 방법과 방향족 유도체상에 이미 존재하는 작용기를 산화시키는 공정의 2가지 방법으로 제조된다. 본 발명은 위에서 설명한 직접, 간접 방법으로 방향족 알데하이드를 제조하는 방법이 아닌 4-하이드록시페닐글라이신으로부터의 포르밀화를 통해 제조하는 방법을 제공한다. Conventional aromatic aldehydes are prepared by two methods, a direct method consisting of attaching formylated on an aromatic derivative and a process of oxidizing functional groups already present on the aromatic derivative. The present invention provides a process for the preparation via formylation from 4-hydroxyphenylglycine, rather than the preparation of aromatic aldehydes by the direct and indirect methods described above.

국제 공개번호 WO 2002/20447에 기존에 알려진 포르밀화 방법이 자세히 개시되어 있다. 직접 포르밀화 방법은 키셀라(Kysela) 등에게 부여된 미국 특허 제 4,588,844호에 개시되어 있는데, 이 특허문헌에는 불산 매질 중에서 방향족 화합물과 유로트로핀(헥사메틸렌테트라아민, HMT)을 반응시키는 공정이 기재되어 있다. 또다른 직접 포르밀화 방법은 크로케모어(Crochemore)등에게 부여된 미국 특허 제 5,068,450호에 개시되어 있는데, 이 특허문헌에는 삼불화붕소의 존재 하에 액체 불산 중에서 메틸 포르메이트를 방향족 유도체와 반응시키는 공정으로 구성된 방법이 기술되어 있다. 또 다른 방법으로는 랑(Lang)에게 부여된 미국 특허 제 5,138,099호에는 또한 불화 방향족 유도체를 염화철(Ⅱ)의 존재 하에서 메틸렌 클로라이드 중에서 디클로로메틸 메틸에테르와 반응시키는 직접 포르밀화 절차가 개시되어 있다. The previously known formylation process is described in detail in International Publication No. WO 2002/20447. A direct formylation method is disclosed in US Pat. No. 4,588,844 to Kysela et al., Which discloses a process of reacting an aromatic compound with eurotropin (hexamethylenetetraamine, HMT) in hydrofluoric acid medium. It is described. Another direct formylation method is disclosed in US Pat. No. 5,068,450 to Crochemore et al., Which discloses a process for reacting methyl formate with an aromatic derivative in liquid hydrofluoric acid in the presence of boron trifluoride. The constructed method is described. Alternatively, US Pat. No. 5,138,099 to Lang also discloses a direct formylation procedure in which a fluorinated aromatic derivative is reacted with dichloromethyl methylether in methylene chloride in the presence of iron (II) chloride.

또한 미국특허 제2003/0045725호에는 아미노기와 카복실산기가 결합되어 있는 방향족 화합물을 카보닐 화합물[R3C(=O)(CH=CH)nC(=O)(X)yR3]을 촉매로 하여 산소 존재시 5~200℃의 반응온도, 상압 또는 가압조건으로 물 등의 용매 내에서 방향족알데하이드로 전환되는 것이 기재되어 있고, 미국특허 제2003/0144558호에는 산성 매체내 -10~100℃에서 아미노기와 카복실산기가 결합되어 있는 방향족 화합물을 디아조화 시약으로 디아조화시킨 후 상응하는 히드록시카복실산으로 전환시켜 금속, 금속염, 금속옥사이드 또는 금속하이드록사이드의 촉매 하에서 산소와 반응시켜 방향족알데하이드를 생성하는 방법이 기재되어 있으나, 상기 특허는 다단계의 제조단계로 복잡하다.U.S. Patent No. 2003/0045725 also catalyzes an aromatic compound having an amino group and a carboxylic acid group bonded to a carbonyl compound [R 3 C (= 0) (CH = CH) n C (= 0) (X) y R 3 ]. In the presence of oxygen, it is described that the conversion to aromatic aldehyde in a solvent such as water at a reaction temperature, atmospheric pressure or pressurization condition of 5 to 200 ℃, US Patent No. 2003/0144558 -10 ~ 100 ℃ in acidic medium Aromatic compounds having an amino group and a carboxylic acid group bonded thereto are diazotized with a diazotization reagent, and then converted into a corresponding hydroxycarboxylic acid to react with oxygen under a catalyst of a metal, a metal salt, a metal oxide, or a metal hydroxide to generate an aromatic aldehyde. Although a method is described, the patent is complicated by a multi-step manufacturing step.

방향족 포르밀화 방법은 1800년대 후반에 개발된 이래로 방향족 유도체를 일 산화탄소, 염화수소 및 적절한 촉매 (통상 염화알루미늄)를 반응시킴을 포함하는 게터만(Gattermann)-코흐(Koch) 절차에 의해 전통적으로 수행되어 왔다. 이러한 표준 반응에서는 치환된 벤젠의 존재 하에서 동량의 염화알루미늄, 일산화탄소 및 염화수소 기체의 조합이 요구되었다. 온도는 25내지 50℃로 제어되었으며, 압력은 1,000psig에서 유지되었다. 상기 반응에서는 얻고자 하는 치환된 벤즈알데하이드가 약 70% 수득되나, 기체상 HCl을 이용하고 높은 반응 압력이 필요하기 때문에 안전성 측면에서 매우 바람직하지 않다. Aromatic formylation methods have been traditionally carried out by the Gettermann-Koch procedure, which involves reacting aromatic derivatives with carbon monoxide, hydrogen chloride, and a suitable catalyst (usually aluminum chloride) since its development in the late 1800s. Has been. This standard reaction required the same amount of combination of aluminum chloride, carbon monoxide and hydrogen chloride gas in the presence of substituted benzene. The temperature was controlled at 25-50 ° C. and the pressure was maintained at 1,000 psig. In this reaction, about 70% of the substituted benzaldehyde desired to be obtained is obtained, but it is very unfavorable in terms of safety because it uses gaseous HCl and requires a high reaction pressure.

본 발명의 목적은 벤즈알데하이드 유도체의 신규한 제조방법을 제공하는 것이다. It is an object of the present invention to provide a novel process for the preparation of benzaldehyde derivatives.

본 발명의 다른 목적은 지금까지 특히 대규모 절차로 수행할 때 안전성 측면에서 문제가 발생할 우려가 있는 기존의 방법을 대신하여, 벤즈알데하이드를 비용면에서 매우 효율적인 방식으로 제조하는 방법을 제공하는 것이다. Another object of the present invention is to provide a method for producing benzaldehyde in a very cost-effective manner, instead of the existing method which may cause problems in terms of safety, especially when performed in a large scale procedure.

본 발명의 또다른 목적은 벤즈알데하이드를 제조하는데 있어 필수적인 포르밀화 절차를 수행하기 위해 필요한 염화수소(수성, 무수 또는 기체)의 사용없이 4-하이드록시페닐글라이신 유도체로부터 4-하이드록시벤즈알데하이드 유도체 또는 4-하이드록시-3-나이트로벤즈알데하이드 유도체를 제공하는 것이다.Another object of the present invention is to provide 4-hydroxybenzaldehyde derivatives or 4-hydroxybenzaldehyde derivatives from 4-hydroxyphenylglycine derivatives without the use of hydrogen chloride (aqueous, anhydrous or gaseous), which is necessary for carrying out the formylation procedure necessary for preparing benzaldehyde. It is to provide a hydroxy-3-nitrobenzaldehyde derivative.

본 발명은 벤즈알데하이드 유도체의 신규한 제조방법에 관한 것으로, 더욱 상세하게는 4-하이드록시페닐글라이신 유도체로부터의 산 조건을 통한 포르밀화 반응을 통하여 4-하이드록시벤즈알데하이드 유도체 또는 4-하이드록시-3-나이트로벤즈알데하이드 유도체를 제조하는 것이다.The present invention relates to a novel process for the preparation of benzaldehyde derivatives, and more particularly to 4-hydroxybenzaldehyde derivatives or 4-hydroxy- via formylation reaction through acid conditions from 4-hydroxyphenylglycine derivatives. 3-nitrobenzaldehyde derivative is prepared.

이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명에 따른 4-하이드록시벤즈알데하이드 유도체의 제조방법은 하기 화학 식 III의 4-하이드록시페닐글라이신 유도체 및 무기산 또는 유기산을 환류반응시켜 하기 화학식 I의 4-하이드록시벤즈알데하이드 유도체를 제조하는 것을 특징으로 한다.Method for preparing a 4-hydroxybenzaldehyde derivative according to the present invention is to prepare a 4-hydroxybenzaldehyde derivative of the general formula (I) by refluxing the 4-hydroxyphenylglycine derivative of the formula It features.

[화학식 I][Formula I]

Figure 112007074169042-pat00003
Figure 112007074169042-pat00003

[화학식 III][Formula III]

Figure 112007074169042-pat00004
Figure 112007074169042-pat00004

[상기 식에서 R1, R2 및 R3는 서로 독립적으로 수소, (C1-C10)알킬, 나이트로 또는 할로겐이다.][Wherein R 1 , R 2 and R 3 are each independently hydrogen, (C 1 -C 10) alkyl, nitro or halogen.]

상기 무기산 또는 유기산은 산의 농도가 5 내지 50 %인 무기산 또는 유기산으로, 염산, 황산, 질산 및 아세트산으로부터 선택되는 1종을 사용한다. 목적하는 4-하이드록시벤즈알데하이드 유도체의 수율을 높이기 위해서는 염산, 황산 또는 아세트산을 사용하는 것이 바람직하다.The inorganic acid or organic acid is an inorganic acid or organic acid having an acid concentration of 5 to 50%, and one type selected from hydrochloric acid, sulfuric acid, nitric acid and acetic acid is used. In order to increase the yield of the desired 4-hydroxybenzaldehyde derivative, it is preferable to use hydrochloric acid, sulfuric acid or acetic acid.

또한, 본 발명에 따른 4-하이드록시-3-나이트로벤즈알데하이드 유도체의 제조방법은 하기 화학식 III의 4-하이드록시페닐글라이신 유도체 및 3 내지 5 %의 질산을 반응시켜 하기 화학식 II의 4-하이드록시-3-나이트로벤즈알데하이드 유도체를 제조하는 것을 특징으로 한다.In addition, the method for preparing 4-hydroxy-3-nitrobenzaldehyde derivatives according to the present invention is reacted with 4-hydroxyphenylglycine derivative of formula III and 3-5% nitric acid to 4-hydroxy of formula II It is characterized by producing a oxy-3-nitrobenzaldehyde derivative.

[화학식 II][Formula II]

Figure 112007074169042-pat00005
Figure 112007074169042-pat00005

[화학식 III][Formula III]

Figure 112007074169042-pat00006
Figure 112007074169042-pat00006

[상기 식에서 R1, R2 및 R3는 서로 독립적으로 수소, (C1-C10)알킬, 나이트로 또는 할로겐이다.][Wherein R 1 , R 2 and R 3 are each independently hydrogen, (C 1 -C 10) alkyl, nitro or halogen.]

상기 반응은 20 내지 80℃에서 수행되나, 상온에서 반응하는 경우 4-하이드록시벤즈알데하이드와 4-하이드록시-3-나이트로벤즈알데하이드의 혼합물이 얻어질 수 있어 반응온도를 적절하게 조절하여 각각의 화합물들을 수득할 수 있다. 또한, 4-하이드록시-3-나이트로벤즈알데하이드 유도체의 수율을 높이기 위해서는 반응을 50 내지 80℃에서 수행하는 것이 가장 바람직하다. 상기 반응온도가 20℃ 미만인 경우 온도가 낮아 반응이 잘 일어나지 않아 4-하이드록시-3-나이트로벤즈알데하이드 유도체의 수율이 낮아지는 문제가 있고, 80℃ 초과인 경우 다른 부반응이 생기는 문제가 있다.The reaction is carried out at 20 to 80 ℃, but when reacting at room temperature, a mixture of 4-hydroxybenzaldehyde and 4-hydroxy-3-nitrobenzaldehyde can be obtained so that the reaction temperature is appropriately adjusted for each Compounds can be obtained. In addition, in order to increase the yield of 4-hydroxy-3-nitrobenzaldehyde derivative, it is most preferable to carry out the reaction at 50 to 80 ℃. When the reaction temperature is less than 20 ℃ low temperature does not occur the reaction is a problem that the yield of 4-hydroxy-3-nitrobenzaldehyde derivative is lowered, if there is more than 80 ℃ there is a problem that other side reactions occur.

본 발명에 따른 4-하이드록시벤즈알데하이드 유도체 또는 4-하이드록시-3-나이트로벤즈알데하이드 유도체의 제조방법을 도식화하여 하기 반응식 1에 나타낸다.The method for preparing 4-hydroxybenzaldehyde derivative or 4-hydroxy-3-nitrobenzaldehyde derivative according to the present invention is shown in Scheme 1 below.

[반응식 1]Scheme 1

Figure 112007074245799-pat00018
Figure 112007074245799-pat00018

[상기 식에서 R1, R2 및 R3는 서로 독립적으로 수소, (C1-C10)알킬, 나이트로 또는 할로겐이고, H+는 염산, 황산, 질산 또는 아세트산이다.][Wherein R 1 , R 2 and R 3 are independently of each other hydrogen, (C 1 -C 10) alkyl, nitro or halogen and H + is hydrochloric acid, sulfuric acid, nitric acid or acetic acid.]

상기 반응식에서 4-하이드록시페닐글라이신 유도체(화합물 3)와 5 내지 50%의 진한 산을 환류반응시켜 4-하이드록시벤즈알데하이드 유도체(화합물 1)를 얻는다. 또한 4-하이드록시페닐글라이신 유도체(화합물 3)와 3 내지 5 %의 묽은 질산을 20 내지 80℃에서 반응시켜 4-하이드록시-3-나이트로벤즈알데하이드 유도체(화합물 2)를 얻을 수 있다. In the above scheme, 4-hydroxyphenylglycine derivative (Compound 3 ) is refluxed with 5 to 50% of concentrated acid to obtain 4-hydroxybenzaldehyde derivative (Compound 1 ). In addition, 4-hydroxyphenylglycine derivative (Compound 3 ) and 3 to 5% dilute nitric acid can be reacted at 20 to 80 ℃ to obtain 4-hydroxy-3-nitrobenzaldehyde derivative (Compound 2 ).

여기에 사용되는 출발물질인 4-하이드록시페닐글라이신 유도체(화합물 3)는 4-하이드록시페닐글라이신을 출발물질로 하여 통상적인 할로겐화 반응, 니트로화 반응을 통하여 얻어질 수 있다. 예를 들면, 아세트산과 설퍼닐 클로라이드를 사용하여 4-하이드록시페닐글라이신의 구조에서 3번 위치에 클로로가 치환된 화합물[화합물 3 : R1=Cl, R2=R3=H]을 얻었으며, 아세트산과 브롬산을 사용하여 4-하이드록시페닐글라이신의 구조에서 3번 위치에 브로모가 치환된 화합물[화합물 3 : R1=Br, R2=R3=H]을 얻을 수 있다.The 4-hydroxyphenylglycine derivative (compound 3 ), which is a starting material used herein, can be obtained through conventional halogenation reaction and nitration reaction using 4-hydroxyphenylglycine as a starting material. For example, acetic acid and sulfonyl chloride were used to obtain a compound having a chloro substitution at position 3 in the structure of 4-hydroxyphenylglycine [Compound 3 : R 1 = Cl, R 2 = R 3 = H]. By using acetic acid and bromic acid, a compound having a bromo substitution at position 3 in the structure of 4-hydroxyphenylglycine [Compound 3 : R 1 = Br, R 2 = R 3 = H] can be obtained.

본 발명에 따른 4-하이드록시벤즈알데하이드 유도체 또는 4-하이드록시-3-나이트로벤즈알데하이드 유도체의 제조방법으로 제조된 4-하이드록시벤즈알데하이드 유도체 또는 4-하이드록시-3-나이트로벤즈알데하이드 유도체는 하기의 화합물을 포함한다.4-hydroxybenzaldehyde derivative or 4-hydroxy-3-nitrobenzaldehyde derivative prepared by the method for preparing 4-hydroxybenzaldehyde derivative or 4-hydroxy-3-nitrobenzaldehyde derivative according to the present invention Includes the following compounds.

(1) 4-하이드록시벤즈알데하이드(1) 4-hydroxybenzaldehyde

(2) 4-하이드록시-3-나이트로벤즈알데하이드(2) 4-hydroxy-3-nitrobenzaldehyde

(3) 4-하이드록시-3,5-다이나이트로벤즈알데하이드(3) 4-hydroxy-3,5-dynatrobenzaldehyde

(4) 3-클로로-4-하이드록시-5-나이트로벤즈알데하이드(4) 3-chloro-4-hydroxy-5-nitrobenzaldehyde

(5) 3-브로모-4-하이드로시-5-나이트로벤즈알데하이드(5) 3-bromo-4-hydrocy-5-nitrobenzaldehyde

본 발명은 4-하이드록시페닐글라이신 유도체로부터의 산 조건에 따른 포르밀화 반응을 통한 4-하이드록시벤즈알데하이드 유도체 및 4-하이드록시-3-나이트로벤즈알데하이드 유도체의 신규한 제조방법에 관한 것으로, 염료물질, 풍미제, 방향제, 제초제 화합물, 핵 형성제, 중합체 첨가제 등과 같은 여러 가지 화합물을 제조하는데 있어 중간물질로 유용한 4-4-하이드록시-3-나이트로벤즈알데하이드 유도체를 우수한 수율로 제조할 수 있을 뿐만 아니라 포르밀화 반응을 수행하기 위해 필수적인 염화수소의 사용을 배제하여 대량생산시 안전성을 향상시키는 효과가 있다.The present invention relates to a novel process for preparing 4-hydroxybenzaldehyde derivatives and 4-hydroxy-3-nitrobenzaldehyde derivatives through formylation reactions according to acid conditions from 4-hydroxyphenylglycine derivatives. 4-4-hydroxy-3-nitrobenzaldehyde derivatives which are useful as intermediates for the preparation of various compounds such as dyes, flavors, fragrances, herbicide compounds, nucleating agents, polymer additives, etc. can be prepared in excellent yields. Not only can it eliminate the use of hydrogen chloride, which is essential for carrying out the formylation reaction, thereby improving safety in mass production.

이하, 본 발명을 다음 실시예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.

[[ 실시예Example 1] 4- 1] 4- 하이드록시벤즈알데하이드(화합물 A)의Of hydroxybenzaldehyde (Compound A) 제조 Produce

Figure 112007074169042-pat00008
Figure 112007074169042-pat00008

4-하이드록시페닐글라이신(200 mg, 1.196 mmole)을 물(10 mL)에 녹인 후 산(H+, 2 mL)을 가하고 환류시켰다. 12시간 후 반응을 종결하고 에틸아세테이트로 추출하였다. 감압증류하여 용매를 제거한 후 별도의 정제과정 없이 목적 화합물인 4-하이드록시벤즈알데하이드(화합물 A)를 얻었다.4-hydroxyphenylglycine (200 mg, 1.196 mmole) was dissolved in water (10 mL), acid (H + , 2 mL) was added, and the mixture was refluxed. After 12 hours, the reaction was terminated and extracted with ethyl acetate. After distillation under reduced pressure to remove the solvent, 4-hydroxybenzaldehyde (Compound A ) was obtained as a target compound without further purification.

Figure 112007074169042-pat00009
Figure 112007074169042-pat00009

융점 : 114℃Melting Point: 114 ℃

1H NMR(DMSO-d 6 ) : 9.81 (s, 1H), 7.65 (d, 2H), 6.89 (d, 2H); 1 H NMR (DMSO- d 6) : 9.81 (s, 1H), 7.65 (d, 2H), 6.89 (d, 2H);

13C NMR(DMSO-d 6 ) : 190.21, 163.44, 131.84, 128.50, 115.84 13 C NMR (DMSO- d 6 ): 190.21, 163.44, 131.84, 128.50, 115.84

[[ 실시예Example 2] 4- 2] 4- 하이드록시Hydroxy -3--3- 나이트로벤즈알데하이드(화합물 B)의Of nitrobenzaldehyde (Compound B) 제조 Produce

Figure 112007074169042-pat00010
Figure 112007074169042-pat00010

4-하이드록시페닐글라이신(1.00 g, 5.98 mmole)을 물(15 mL)에 녹인 후 질산(0.75 mL)을 적하하고 60 ℃에서 12시간 동안 교반시킨 후 반응물을 상온으로 냉각시켰다. 반응용액 내에서 생성된 고체를 여과하고, 여과된 고체를 에틸아세테이트에 녹여 물로 씻어 준 후 감압 하에서 용매를 제거하고 얻어진 오일을 에틸아세테이트/헥산(3 ml/30 ml)으로 결정화하여 목적 화합물인 4-하이드록시-3-나이트로벤즈알데하이드(화합물 B)를 0.71g(수율 70 %)얻었다.4-hydroxyphenylglycine (1.00 g, 5.98 mmole) was dissolved in water (15 mL), nitric acid (0.75 mL) was added dropwise, the mixture was stirred at 60 ° C. for 12 hours, and the reaction was cooled to room temperature. The solid produced in the reaction solution was filtered, the filtered solid was dissolved in ethyl acetate, washed with water, the solvent was removed under reduced pressure, and the obtained oil was crystallized with ethyl acetate / hexane (3 ml / 30 ml) to obtain the title compound (4). 0.71 g (yield 70%) of hydroxy-3-nitrobenzaldehyde (Compound B ) were obtained.

융점 : 142 ℃Melting Point: 142 ℃

1H NMR(DMSO-d 6 ) : 9.81 (s, 1H), 8.39 (s, 1H), 7.98 (d, 1H), 7.20 (d, 1H); 1 H NMR (DMSO- d 6) : 9.81 (s, 1H), 8.39 (s, 1H), 7.98 (d, 1H), 7.20 (d, 1H);

13C NMR(DMSO-d 6 ) : 189.91, 156.64, 136.94, 134.16, 128.07, 127.62, 119.61 13 C NMR (DMSO- d 6 ): 189.91, 156.64, 136.94, 134.16, 128.07, 127.62, 119.61

[[ 실시예Example 3] 4- 3] 4- 하이드록시Hydroxy -3,5--3,5- 다이나이트로벤즈알데하이드(화합물 C)의Of dynatrobenzaldehyde (Compound C) 제조 Produce

Figure 112007074169042-pat00011
Figure 112007074169042-pat00011

4-하이드록시-3-나이트로페닐글라이신(1.26 g, 5.98 mmole)을 물(15 mL)에 첨가 후 질산 (0.75 mL)을 사용하여 실시예 2와 동일한 방법으로 목적화합물인 4-하이드록시-3,5-다이나이트로벤즈알데하이드(화합물 C)를 0.82 g(수율 65 %)얻었다.4-hydroxy-3-nitrophenylglycine (1.26 g, 5.98 mmole) was added to water (15 mL), followed by nitric acid (0.75 mL). 0.82 g (yield 65%) of 3,5-dinitrobenzaldehyde (Compound C ) were obtained.

융점: 186 ℃Melting Point: 186 ℃

1H NMR(DMSO-d 6 ) : 9.88 (s, 1H), 9.12 (s, 2H); 1 H NMR (DMSO- d 6) : 9.88 (s, 1H), 9.12 (s, 2H);

13C NMR(DMSO-d 6 ) : 191.01, 155.92, 138.73, 132.92, 131.09 13 C NMR (DMSO- d 6 ): 191.01, 155.92, 138.73, 132.92, 131.09

[[ 실시예Example 4] 3- 4] 3- 클로로Chloro -4--4- 하이드록시Hydroxy -5--5- 나이트로벤즈알데하이드(화합물 D)의Of nitrobenzaldehyde (Compound D) 제조 Produce

Figure 112007074169042-pat00012
Figure 112007074169042-pat00012

3-클로로-4-하이드록시페닐글라이신(1.20 g, 5.98 mmole)을 물(15 mL)에 첨가 후 질산 (0.75 mL)을 사용하여 실시예 2와 동일한 방법으로 목적화합물인 3-클로로-4-하이드록시-5-나이트로벤즈알데하이드(화합물 D)를 0.72 g(수율 60%)얻었다.3-Chloro-4-hydroxyphenylglycine (1.20 g, 5.98 mmole) was added to water (15 mL), followed by nitric acid (0.75 mL). 0.72 g (yield 60%) of hydroxy-5-nitrobenzaldehyde (Compound D ) were obtained.

융점: 167 ℃Melting Point: 167 ℃

1H NMR(Acetone-d 6 ) : 9.92 (s, 1H), 8.59 (d, 1H), 8.20 (t, 1H); 1 H NMR (Acetone- d 6 ): 9.92 (s, 1H), 8.59 (d, 1H), 8.20 (t, 1H);

13C NMR(Acetone-d 6 ) : 188.80, 156.79, 135.13, 130.32, 127.64, 127.56, 126.89 13 C NMR (Acetone- d 6 ): 188.80, 156.79, 135.13, 130.32, 127.64, 127.56, 126.89

[[ 실시예Example 5] 3- 5] 3- 브로모Bromo -4--4- 하이드로시Hydro City -5--5- 나이트로벤즈알데하이드(화합물 E)의Of nitrobenzaldehyde (Compound E) 제조 Produce

Figure 112007074169042-pat00013
Figure 112007074169042-pat00013

3-브로모-4-하이드록시페닐글라이신(1.47 g, 5.98 mmole)을 물(15 mL)에 첨가 후 질산 (0.75 mL)을 사용하여 실시예 2와 동일한 방법으로 목적화합물인 3-브로모-4-하이드로시-5-나이트로벤즈알데하이드(화합물 E)를 0.95 g(수율 62%)얻었 다.3-bromo-4-hydroxyphenylglycine (1.47 g, 5.98 mmole) was added to water (15 mL), followed by nitric acid (0.75 mL). 0.95 g (yield 62%) of 4-hydrocy-5-nitrobenzaldehyde (Compound E ) were obtained.

융점: 151 ℃Melting Point: 151 ℃

1H NMR(DMSO-d 6 ) : 9.52 (s, 1H), 8.34 (d, 1H), 8.03 (d, 1H); 1 H NMR (DMSO- d 6) : 9.52 (s, 1H), 8.34 (d, 1H), 8.03 (d, 1H);

13C NMR(DMSO-d 6 ) :186.98, 165.34, 135.68, 133.96, 132.07, 123.09, 119.48 13 C NMR (DMSO- d 6 ): 186.98, 165.34, 135.68, 133.96, 132.07, 123.09, 119.48

Claims (7)

하기 화학식 III의 4-하이드록시페닐글라이신 유도체 및 무기산 또는 유기산을 반응시켜 하기 화학식 I의 4-하이드록시벤즈알데하이드 유도체를 제조하는 것을 특징으로 하는 4-하이드록시벤즈알데하이드 유도체의 제조방법.The 4-hydroxybenzaldehyde derivative of formula (I) is prepared by reacting a 4-hydroxyphenylglycine derivative of formula (III) with an inorganic acid or an organic acid to prepare a 4-hydroxybenzaldehyde derivative. [화학식 I][Formula I]
Figure 112007074169042-pat00014
Figure 112007074169042-pat00014
 [화학식 III][Formula III]
Figure 112007074169042-pat00015
Figure 112007074169042-pat00015
 [상기 식에서 R1, R2 및 R3는 서로 독립적으로 수소, (C1-C10)알킬, 나이트로 또는 할로겐이다.][Wherein R 1 , R 2 and R 3 are each independently hydrogen, (C 1 -C 10) alkyl, nitro or halogen.] 제 1항에 있어서,The method of claim 1, 상기 무기산 또는 유기산은 염산, 황산, 질산 및 아세트산으로부터 선택되는 1종인 것을 특징으로 하는 4-하이드록시벤즈알데하이드 유도체의 제조방법.The inorganic or organic acid is a method for producing a 4-hydroxybenzaldehyde derivative, characterized in that one kind selected from hydrochloric acid, sulfuric acid, nitric acid and acetic acid. 제 1항에 있어서,The method of claim 1, 상기 무기산 또는 유기산의 농도가 5 내지 50 %인 것을 특징으로 하는 4-하이드록시벤즈알데하이드 유도체의 제조방법.Method for producing a 4-hydroxybenzaldehyde derivative, characterized in that the concentration of the inorganic acid or organic acid is 5 to 50%. 제 1항에 있어서,The method of claim 1, 상기 반응온도는 90 내지 100℃인 것을 특징으로 하는 4-하이드록시벤즈알데하이드 유도체의 제조방법.The reaction temperature is a method for producing 4-hydroxybenzaldehyde derivatives, characterized in that 90 to 100 ℃. 하기 화학식 III의 4-하이드록시페닐글라이신 유도체 및 질산을 반응시켜 하기 화학식 II의 4-하이드록시-3-나이트로벤즈알데하이드 유도체를 제조하는 것을 특징으로 하는 4-하이드록시-3-나이트로벤즈알데하이드 유도체의 제조방법.4-hydroxy-3-nitrobenzaldehyde characterized by preparing 4-hydroxy-3-nitrobenzaldehyde derivative of formula II by reacting 4-hydroxyphenylglycine derivative of formula III Method for preparing a derivative. [화학식 II][Formula II]
Figure 112007074169042-pat00016
Figure 112007074169042-pat00016
 [화학식 III][Formula III]
Figure 112007074169042-pat00017
Figure 112007074169042-pat00017
 [상기 식에서 R1, R2 및 R3는 서로 독립적으로 수소, (C1-C10)알킬, 나이트로 또는 할로겐이다.][Wherein R 1 , R 2 and R 3 are each independently hydrogen, (C 1 -C 10) alkyl, nitro or halogen.] 제 5항에 있어서,The method of claim 5, 상기 반응은 20 내지 80℃에서 수행되는 것을 특징으로 하는 4-하이드록시-3-나이트로벤즈알데하이드 유도체의 제조방법.The reaction is a method for producing 4-hydroxy-3-nitrobenzaldehyde derivative, characterized in that carried out at 20 to 80 ℃. 제 5항에 있어서,The method of claim 5, 상기 질산의 농도가 3 내지 5 %인 것을 특징으로 하는 4-하이드록시-3-나이 트로벤즈알데하이드 유도체의 제조방법.The method for producing 4-hydroxy-3-nitrobenzaldehyde derivative, characterized in that the concentration of nitric acid is 3 to 5%.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7395941B2 (en) 2002-07-26 2008-07-08 Suk-Chu Hong Artificial nipple with reinforcement

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07252180A (en) * 1994-02-11 1995-10-03 Rhone Poulenc Chim Preparation of hydroxybenzaldehyde
KR20000053360A (en) * 1996-11-22 2000-08-25 트롤리에 모리스, 다니엘 델로스 Method for preparing a 4-hydroxybenzaldehyde and derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07252180A (en) * 1994-02-11 1995-10-03 Rhone Poulenc Chim Preparation of hydroxybenzaldehyde
KR20000053360A (en) * 1996-11-22 2000-08-25 트롤리에 모리스, 다니엘 델로스 Method for preparing a 4-hydroxybenzaldehyde and derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7395941B2 (en) 2002-07-26 2008-07-08 Suk-Chu Hong Artificial nipple with reinforcement

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