KR100792004B1 - Process for preparing 4-bromo-3,5-difluorophenyl acetate - Google Patents

Process for preparing 4-bromo-3,5-difluorophenyl acetate Download PDF

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KR100792004B1
KR100792004B1 KR1020060068001A KR20060068001A KR100792004B1 KR 100792004 B1 KR100792004 B1 KR 100792004B1 KR 1020060068001 A KR1020060068001 A KR 1020060068001A KR 20060068001 A KR20060068001 A KR 20060068001A KR 100792004 B1 KR100792004 B1 KR 100792004B1
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bromo
acetate
bicarbonate
difluorophenyl
difluorophenyl acetate
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Korean (ko)
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장석구
박상수
하병조
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을지대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/48—Separation; Purification; Stabilisation; Use of additives
    • C07C67/62—Use of additives, e.g. for stabilisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/65—Halogen-containing esters of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers

Abstract

A method for preparing 4-bromo-3,5-difluorophenyl acetate is provided to inhibit production of phenolic compounds during bromination of phenyl acetate, thereby providing a target product, para-isomer, with high selectivity. A method for preparing 4-bromo-3,5-difluorophenyl acetate comprises a step of carrying out 3,5-difluorophenyl acetate by adding bromine to 3,5-difluorophenyl acetate as a starting material in a conventional manner, and further adding a bicarbonate salt thereto in a molar ratio of 0.5-1.5 based on the starting material. The bicarbonate salt includes sodium bicarbonate or potassium bicarbonate.

Description

4-브로모-3,5-디플루오로 페닐아세테이트의 합성방법{Process for preparing 4-bromo-3,5-difluorophenyl acetate}Process for preparing 4-bromo-3,5-difluorophenyl acetate

본 발명은 4-브로모-3,5-디플루오로 페닐아세테이트의 합성방법에 관한 것이다. 더욱 상세하게는, 파라브로모디플루오로 페닐아세테이트를 높은 수율로 얻을 수 있는 4-브로모-3,5-디플루오로 페닐아세테이트의 합성방법에 관한 것이다.The present invention relates to a process for the synthesis of 4-bromo-3,5-difluoro phenylacetate. More specifically, the present invention relates to a method for synthesizing 4-bromo-3,5-difluoro phenylacetate, which can obtain a high yield of parabromodifluoro phenylacetate.

이하에서 파라브로모디플루오로 페닐아세테이트는 "파라이성체"로, 오르쏘브로모디플루오로아세테이트, 예를 들면 2-브로모-3,5-디플로오로페닐 아세테이트는 "오르쏘이성체"로 명명하기로 한다. In the following parabromodifluoro phenylacetates are referred to as "paraisomers" and orthobromodifluoroacetates such as 2-bromo-3,5-difluorophenyl acetate as "ortho isomers" Shall be.

일반적으로 상기 파라이성체는 의약, 농약, 액정화합물 등의 중요한 중간체로 이용되고 있다.In general, the paraisomers are used as important intermediates of medicines, pesticides, liquid crystal compounds and the like.

종래의 파라이성체의 합성방법으로는 일본공개특허공보 제2000-309555호에 개시되어 있는 바와 같이, 디플루오로페놀의 브롬화 반응용매로서 1,2-디메톡시에탄을 사용하여 상온에서 브롬화 반응을 진행하여 합성하였다. 이렇게 진행된 브롬화 반응의 결과 반응액에서 목적 물질인 파라이성체가 65.8% 생성되었으며, 디플루오로페놀은 8.1%가 미반응되어 검출되었다.As a conventional method for synthesizing paraisomers, the bromination reaction is performed at room temperature using 1,2-dimethoxyethane as a bromination reaction solvent of difluorophenol, as disclosed in Japanese Patent Application Laid-Open No. 2000-309555. Synthesized. As a result of the bromination reaction, 65.8% of the target substance was produced as paraisomer, and 8.1% of the difluorophenol was unreacted and detected.

또한, 반응액에서 부생성물질인 오르쏘이성체와 비스이성체는 각각 20.5%와 5.1%로 검출되었다. 그러나, 상기 특허에서는 목적 물질인 파라이성체 이외에도 다량의 부생성물질과 출발물질이 혼재되어 있어 파라이성체의 수율이 극히 낮은 문제점이 있었다. In addition, ortho and bis isomers were detected as 20.5% and 5.1%, respectively. However, the patent has a problem that the yield of the paraisomer is extremely low because a large amount of by-products and starting materials are mixed in addition to the paraisomer as the target substance.

본 발명자들은 상기한 문제점을 해결하고 파라이성체를 높은 수율로 얻기 위하여 예의연구를 거듭한 결과, 페닐아세테이트의 브롬화 과정에서 염기성물질을 첨가할 경우 강산인 브롬산(HBr)을 중화시켜 부산물로 생성되는 페놀류의 생성을 억제하여 목적물인 파라이성체를 높은 선택성으로 합성할 수 있음을 알게 되어 본 발명에 이르게 되었다.In order to solve the above problems and to obtain paraisomers in high yields, the present inventors have conducted extensive research, and when a basic substance is added in the bromination process of phenylacetate, a strong acid bromic acid (HBr) is neutralized to be produced as a byproduct. The present invention has been found that the production of phenols can be suppressed to synthesize the desired paraisomer with high selectivity.

이에 본 발명은 파라이성체를 높은 수율로 얻을 수 있는 파라브로모디플루오로 페닐아세테이트, 예를 들면 4-브로모-3,5-디플루오로 페닐아세테이트의 합성방법을 제공하는데 그 목적이 있는 것이다.Accordingly, an object of the present invention is to provide a method for synthesizing parabromodifluoro phenylacetate, for example 4-bromo-3,5-difluoro phenylacetate, in which paraisomers can be obtained in high yield.

상기 목적을 달성하기 위한 본 발명의 파라브로모디플루오로 페닐아세테이트즉, 4-브로모-3,5-디플루오로 페닐아세테이트의 합성방법은 출발물질로서 3,5-디플루오로 페닐아세테이트에 브롬을 첨가하고, 중탄산염을 상기 출발물질에 대해 0.5 내지 1.5의 몰비율로 첨가하여서 이루어지는 것을 특징으로 한다.The method for the synthesis of parabromodifluoro phenylacetate, namely 4-bromo-3,5-difluorophenylacetate, of the present invention for achieving the above object is bromine to 3,5-difluorophenylacetate as a starting material. And adding bicarbonate at a molar ratio of 0.5 to 1.5 with respect to the starting material.

이와 같은 본 발명을 더욱 상세히 설명하기로 한다. This invention will be described in more detail.

본 발명은 페닐아세테이트류의 파라선택성이 있는 브롬체인 파라브로모디플 루오로 페닐아세테이트, 구체적으로 예를 들면 4-브로모-3,5-디플루오로 페닐아세테이트를 합성하기 위한 것으로 페닐아세테이트의 브롬화 과정에서 염기성물질을 첨가하여 생성되는 강산인 브롬산(HBr)을 중화시켜 부산물로 생성되는 페놀류의 생성을 억제하여 목적물인 파라이성체를 높은 선택성으로 합성할 수 있다는 것이 특징이다.The present invention is for the preparation of parabromodifluoro phenylacetate, which is a paraselective bromine chain of phenylacetates, specifically, for example, 4-bromo-3,5-difluoro phenylacetate, for bromination of phenylacetate. It is characterized in that the paraisomer as a target can be synthesized with high selectivity by neutralizing strong acid bromic acid (HBr) generated by adding a basic substance in the process to suppress the production of phenols produced as a by-product.

즉, 본 발명에 의하면, 3,5-디플루오로 페닐아세테이트의 브롬화 반응에 있어서 일반적인 방법에 의한 브롬화 반응의 경우 다음 반응식 1에서와 같이 출발물질[식(1)], 파라이성체[식(2)], 오르쏘이성체[식(3)]와 함께 생성되는 브롬산(HBr)에 의해 분해되는 페놀[식(4)]의 생성 등의 양상을 보이게 된다.That is, according to the present invention, in the bromination reaction of the 3,5-difluoro phenyl acetate by the general method, starting materials [formula (1)], paraisomers [formula (2) ), And the production of phenol [formula (4)] decomposed by bromic acid (HBr) produced together with the ortho isomer [formula (3)].

[반응식][Scheme]

Figure 112006051726191-pat00001
Figure 112006051726191-pat00001

(1) (2) (3) (4)        (1) (2) (3) (4)

본 발명에 의하면, 출발물질로서 3,5-디플루오로 페닐아세테이트에 브롬을 첨가하는 통상적인 브롬화 반응에서, 상기 출발물질에 대해 0.5 내지 1.5의 몰비율로 염기성 물질로서 중탄산염을 첨가하는 것을 특징으로 한다. 이와 같이 할 경우 염기성물질에 의해 반응과정에서 생성되는 강산인 브롬산(HBr)이 중화되어 페놀류 의 생성을 억제하여 목적물인 파라이성체가 높은 선택성으로 합성되게 된다.According to the present invention, in the conventional bromination reaction in which bromine is added to 3,5-difluoro phenylacetate as a starting material, bicarbonate is added as a basic material in a molar ratio of 0.5 to 1.5 with respect to the starting material. do. In this case, the strong acid bromic acid (HBr), which is generated in the reaction process by the basic material, is neutralized to inhibit the production of phenols, thereby synthesizing the desired paraisomer with high selectivity.

상기에서 중탄산염을 만일 0.5몰 미만으로 첨가할 경우에는 강산을 충분히 중화시키지 못하게 되고, 반대로 1.5몰이 넘는 경우에는 반응용액의 점도가 증가하게 되어 부작용이 생기게 된다. 따라서 상기 범위로 중탄산염을 첨가하는 것이 바람직하다. If the bicarbonate is added in less than 0.5 mole does not sufficiently neutralize the strong acid, on the contrary, if more than 1.5 mole, the viscosity of the reaction solution is increased to cause side effects. Therefore, it is preferable to add bicarbonate in the above range.

본 발명에서 상기 염기성물질인 중탄산염으로는 중탄산나트륨(NaHCO3) 또는 중탄산포타슘(KHCO3)이 바람직하다.In the present invention, the basic bicarbonate is preferably sodium bicarbonate (NaHCO 3 ) or potassium bicarbonate (KHCO 3 ).

이와 같은 본 발명을 실시예에 의거하여 더욱 상세히 설명하면 다음과 같다.The present invention will be described in more detail based on the following examples.

실시예Example 1 One

3구 플라스크에 3,5-디플루오로 아세테이트(MW 172, 8.6g, 50mmol), 중탄산나트륨 50 mmol, 디클로로메탄(10ml)에 넣고, 상온에서 15분간 저어주었다. 그 후에 브롬(50mmol)을 투입하였다. 10시간 뒤에 반응액을 여과하고, 여액에 황산수소나트륨 용액(10%, 100mmol)을 투입하여 브롬을 제거하였다. 유기층을 증류수로 세척을 한 뒤 황산마그네슘으로 처리하여 물을 제거한 후 여과하였다. 가스크로마토그래피를 이용하여 반응물을 분석하였다.In a three-necked flask, 3,5-difluoro acetate (MW 172, 8.6 g, 50 mmol), 50 mmol of sodium bicarbonate, and dichloromethane (10 ml) were added and stirred at room temperature for 15 minutes. Then bromine (50 mmol) was added. After 10 hours, the reaction solution was filtered and bromine was removed by adding sodium hydrogen sulfate solution (10%, 100 mmol) to the filtrate. The organic layer was washed with distilled water and treated with magnesium sulfate to remove water and filtered. The reaction was analyzed using gas chromatography.

분석결과, 3,5-디플루오로페닐 아세테이트 19%, 2-브로모-3,5-디플루오로페닐 아세테이트 1%, 목적물인 4-브로모-3,5-디플루오로페닐 아세테이트 80%의 전환율을 보였다.As a result of analysis, 3,5-difluorophenyl acetate 19%, 2-bromo-3,5-difluorophenyl acetate 1%, the target 4-bromo-3,5-difluorophenyl acetate 80% Showed a conversion rate of.

비교예Comparative example 1 One

3구 플라스크에 3,5-디플루오로 아세테이트(MW 172, 8.6g, 50mmol), 디클로로메탄(10ml)에 넣고, 상온에서 15분간 저어주었다. 그 후에 브롬(50mmol)을 투입하였다. 10시간 뒤에 반응액을 여과하고, 여액에 황산수소나트륨 용액(10%, 100mmol)을 투입하여 브롬을 제거하였다. 유기층을 증류수로 세척을 한 뒤 황산마그네슘으로 처리하여 물을 제거한 후 여과하였다. 가스크로마토그래피를 이용하여 반응물을 분석하였다.In a three-necked flask, 3,5-difluoro acetate (MW 172, 8.6 g, 50 mmol) and dichloromethane (10 ml) were added and stirred at room temperature for 15 minutes. Then bromine (50 mmol) was added. After 10 hours, the reaction solution was filtered and bromine was removed by adding sodium hydrogen sulfate solution (10%, 100 mmol) to the filtrate. The organic layer was washed with distilled water and treated with magnesium sulfate to remove water and filtered. The reaction was analyzed using gas chromatography.

분석결과, 3,5-디플루오로페닐 아세테이트 12%, 2-브로모-3,5-디플로오페닐 아세테이트 5%, 4-브로모-3,5-디플루오로페닐 아세테이트 70%, 기타 3,5-디플루오로페닐 13%의 전환율을 보였다. As a result, 3,5-difluorophenyl acetate 12%, 2-bromo-3,5-difluorophenyl acetate 5%, 4-bromo-3,5-difluorophenyl acetate 70%, other 3,5-difluorophenyl showed a conversion of 13%.

본 발명의 파라브로모디플루오로 페닐아세테이트, 즉 4-브로모-3,5-디플루오로 페닐아세테이트의 합성방법은 페닐아세테이트의 브롬화 과정에서 염기성물질을 첨가함으로써 강산인 브롬산(HBr)을 중화시켜 부산물로 생성되는 페놀류의 생성을 억제하여 목적물인 파라이성체를 높은 선택성으로 합성할 수 있는 효과가 있다. The method for synthesizing parabromodifluoro phenylacetate, namely 4-bromo-3,5-difluoro phenylacetate, neutralizes the strong acid bromic acid (HBr) by adding a basic substance in the bromination process of phenylacetate. By suppressing the production of phenols generated as by-products, paraisomers can be synthesized with high selectivity.

Claims (2)

3,5-디플루오로페닐아세테이트의 브롬화반응에 있어서, 출발물질로서 3,5-디플루오로페닐 아세테이트에 브롬을 통상의 방법으로 첨가하고, 상기 출발물질에 대해 중탄산염을 0.5 내지 1.5의 몰비율로 첨가하는 것으로 이루어지는 것을 특징으로 하는 4-브로모-3,5-디플루오로 페닐아세테이트의 합성방법. In bromination of 3,5-difluorophenylacetate, bromine is added to 3,5-difluorophenyl acetate as a starting material in a conventional manner, and a bicarbonate ratio of 0.5 to 1.5 is used for the starting material. Synthesis method of 4-bromo-3,5-difluoro phenylacetate, characterized in that the addition to. 제 1항에 있어서, 상기 중탄산염은 중탄산나트륨 또는 중탄산포타슘인 것을 특징으로 하는 4-브로모-3,5-디플루오로 페닐아세테이트의 합성방법.The method of claim 1, wherein the bicarbonate is sodium bicarbonate or potassium bicarbonate.
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JP2000309555A (en) * 1999-04-28 2000-11-07 Kanto Denka Kogyo Co Ltd PRODUCTION OF p-BROMOPHENOL COMPOUND

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000309555A (en) * 1999-04-28 2000-11-07 Kanto Denka Kogyo Co Ltd PRODUCTION OF p-BROMOPHENOL COMPOUND

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