KR100278967B1 - A preparing method of ortho-difluorobenzoic acid derivatives - Google Patents
A preparing method of ortho-difluorobenzoic acid derivatives Download PDFInfo
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- KR100278967B1 KR100278967B1 KR1019990006502A KR19990006502A KR100278967B1 KR 100278967 B1 KR100278967 B1 KR 100278967B1 KR 1019990006502 A KR1019990006502 A KR 1019990006502A KR 19990006502 A KR19990006502 A KR 19990006502A KR 100278967 B1 KR100278967 B1 KR 100278967B1
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- ortho
- derivative
- difluorobenzene
- added
- difluorobenzoic acid
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Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- ZNEHIDGAPGVZSA-UHFFFAOYSA-N 1,2-difluoro-3-methylbenzene Chemical class CC1=CC=CC(F)=C1F ZNEHIDGAPGVZSA-UHFFFAOYSA-N 0.000 claims abstract description 21
- OVUKQQRPTLPXTD-UHFFFAOYSA-N 1-(chloromethyl)-2,3-difluorobenzene Chemical class FC1=CC=CC(CCl)=C1F OVUKQQRPTLPXTD-UHFFFAOYSA-N 0.000 claims abstract description 10
- KETSQFAGKHMSRV-UHFFFAOYSA-N 1-(dichloromethyl)-2,3-difluorobenzene Chemical class FC=1C(=C(C=CC1)C(Cl)Cl)F KETSQFAGKHMSRV-UHFFFAOYSA-N 0.000 claims abstract description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 11
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000007800 oxidant agent Substances 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 8
- 239000004342 Benzoyl peroxide Substances 0.000 claims description 7
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 7
- 235000019400 benzoyl peroxide Nutrition 0.000 claims description 7
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 6
- 229910052753 mercury Inorganic materials 0.000 claims description 6
- 238000010306 acid treatment Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000012286 potassium permanganate Substances 0.000 claims description 4
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 4
- 229960002218 sodium chlorite Drugs 0.000 claims description 4
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 238000005580 one pot reaction Methods 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 9
- 239000002253 acid Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- FPENCTDAQQQKNY-UHFFFAOYSA-N 3,4-difluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C(F)=C1 FPENCTDAQQQKNY-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CGFMLBSNHNWJAW-UHFFFAOYSA-N 2-chloro-4,5-difluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=C(F)C=C1Cl CGFMLBSNHNWJAW-UHFFFAOYSA-N 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- FZMPLKVGINKUJZ-UHFFFAOYSA-N 1,2-difluoro-4-methylbenzene Chemical compound CC1=CC=C(F)C(F)=C1 FZMPLKVGINKUJZ-UHFFFAOYSA-N 0.000 description 3
- GWUMAKZIHXGJKC-UHFFFAOYSA-N 2-chloro-4,5-difluorobenzaldehyde Chemical compound FC1=CC(Cl)=C(C=O)C=C1F GWUMAKZIHXGJKC-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- PKZMDIAFGCOUAX-UHFFFAOYSA-N 1-chloro-4,5-difluoro-2-methylbenzene Chemical compound CC1=CC(F)=C(F)C=C1Cl PKZMDIAFGCOUAX-UHFFFAOYSA-N 0.000 description 2
- JPHKMYXKNKLNDF-UHFFFAOYSA-N 3,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1F JPHKMYXKNKLNDF-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 1
- LLVWLCAZSOLOTF-UHFFFAOYSA-N 1-methyl-4-[1,4,4-tris(4-methylphenyl)buta-1,3-dienyl]benzene Chemical class C1=CC(C)=CC=C1C(C=1C=CC(C)=CC=1)=CC=C(C=1C=CC(C)=CC=1)C1=CC=C(C)C=C1 LLVWLCAZSOLOTF-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- -1 aromatic fluorine compound Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- XUCNUKMRBVNAPB-UHFFFAOYSA-N fluoroethene Chemical group FC=C XUCNUKMRBVNAPB-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/093—Preparation of carboxylic acids or their salts, halides or anhydrides by hydrolysis of —CX3 groups, X being halogen
Abstract
본 발명은 오르쏘-디플루오로벤조산 유도체(Ⅰ)의 제조방법에 관한 것으로, 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ)로부터 클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-1)를 제조한 후 이것을 산화시켜 오르쏘-디플루오로벤조산 유도체를 제조하거나(하기 반응식 1), 또는 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ)로부터 디클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-2)를 제조한 후 이것을 산처리하여 오르쏘-디플루오로벤즈알데하이드 유도체(Ⅳ)를 제조하고 이것을 산화시켜 오르쏘-디플루오로벤조산 유도체(Ⅰ)를 제조한다(하기 반응식 2):The present invention relates to a method for preparing ortho-difluorobenzoic acid derivative (I), wherein the chloromethyl ortho-difluorobenzene derivative (III-1) is prepared from methyl ortho-difluorobenzene derivative (II). After the preparation, it is oxidized to prepare an ortho-difluorobenzoic acid derivative (Scheme 1), or dichloromethyl ortho-difluorobenzene derivative (III-) from methyl ortho-difluorobenzene derivative (II). 2) was prepared and then acid treated to prepare ortho-difluorobenzaldehyde derivative (IV), which was then oxidized to prepare ortho-difluorobenzoic acid derivative (I) (Scheme 2):
상기식에서 n은 1∼2의 정수이고 m은 0∼2의 정수이다.N is an integer of 1-2 and m is an integer of 0-2.
Description
발명의 분야Field of invention
본 발명은 오르쏘-디플루오로벤조산 유도체의 제조방법에 관한 것이다. 보다 구체적으로 메틸 오르쏘-디플루오로벤젠 유도체를 출발물질로 하여 오르쏘-디플루오로벤조산 유도체를 저렴한 비용으로 제조하는 효과적인 합성방법에 관한 것이다.The present invention relates to a process for the preparation of ortho-difluorobenzoic acid derivatives. More specifically, the present invention relates to an effective synthesis method for producing an ortho-difluorobenzoic acid derivative at low cost using a methyl ortho-difluorobenzene derivative as a starting material.
발명의 배경Background of the Invention
오르쏘-디플루오로벤조산 유도체는 여러 정밀화학제품에 원료로 사용될 수 있는 유용한 물질이다. 종래의 오르쏘-디플루오로벤조산 유도체의 제조방법으로 오르쏘-디플루오로벤젠 디카르복실산의 탈모노카르복실화 방법이 미국특허 제4,937,377호에 기재되어 있으나, 이 방법은 고온을 필요로 하는 단점이 있다. 오르쏘-디플루오로톨루엔을 질산을 사용하여 고온, 고압에서 제조하는 방법이 J. of Organic Chemistry 27, 2923(1962)에 기재되어 있으나, 이 방법은 반응온도가 높을 뿐만 아니라 매우 높은 압력을 요구하므로 산업적으로는 이용이 불가능한 단점이 있다. 오르쏘-디클로로벤조트리플루오라이드로부터 오르쏘-디플루오로벤조산을 제조하는 방법이 J. of Fluorine Chemistry 50, 365(1990)에 기술되어 있으나 생성되는 여러 유사 화합물들의 분리가 필요하고 반응온도 또한 매우 높은 문제점이 있다.Ortho-difluorobenzoic acid derivatives are useful materials that can be used as raw materials in many fine chemicals. Demonocarboxylation of ortho-difluorobenzene dicarboxylic acid as a method for preparing a conventional ortho-difluorobenzoic acid derivative is described in US Pat. No. 4,937,377, but this method requires high temperature. There is a disadvantage. Process for preparing ortho-difluorotoluene at high temperature and high pressure using nitric acid J. of Organic Chemistry 27, 2923 (1962), but this method is not only industrially available because the reaction temperature is not only high but also requires a very high pressure. The process for preparing ortho-difluorobenzoic acid from ortho-dichlorobenzotrifluoride J. of Fluorine Chemistry 50, 365 (1990), but there is a problem that requires the separation of a number of similar compounds produced and the reaction temperature is also very high.
따라서 본 발명자들은 상기와 같은 문제점을 해결하기 위한 방법으로 메틸 오르쏘-디플루오로벤젠 유도체를 출발물질로 하여 오르쏘-디플루오로벤조산 유도체를 저렴한 비용으로 효과적으로 합성하는 방법을 개발하기에 이르렀다.Accordingly, the present inventors have developed a method for effectively and inexpensively synthesizing an ortho-difluorobenzoic acid derivative using a methyl ortho-difluorobenzene derivative as a starting material as a method for solving the above problems.
본 발명의 목적은 메틸 오르쏘-디플루오로벤젠 유도체로부터 오르쏘-디플루오로벤조산 유도체를 제조하는 방법을 제공하기 위한 것이다.It is an object of the present invention to provide a method for preparing an ortho-difluorobenzoic acid derivative from a methyl ortho-difluorobenzene derivative.
본 발명의 다른 목적은 제조비용이 저렴하고 효과적으로 오르쏘-디플루오로벤조산 유도체를 제조하는 방법을 제공하기 위한 것이다.Another object of the present invention is to provide a method for preparing an ortho-difluorobenzoic acid derivative at low cost and effectively.
상기 목적 및 기타 목적들은 모두 하기 설명되는 본 발명에 의하여 모두 달성될 수 있다.The above and other objects can all be achieved by the present invention described below.
본 발명은 메틸 오르쏘-디플루오로벤젠 유도체를 출발물질로 하여 오르쏘-디플루오로벤조산 유도체를 효율적으로 합성하는 방법에 관한 것이다. 본 발명의 오르쏘-디플루오로벤조산 유도체의 제조방법은 하기 반응식 1로 나타내어진다:The present invention relates to a method for efficiently synthesizing an ortho-difluorobenzoic acid derivative using a methyl ortho-difluorobenzene derivative as a starting material. The process for preparing the ortho-difluorobenzoic acid derivatives of the present invention is represented by the following Scheme 1:
반응식 1Scheme 1
상기식에서 n은 1∼2의 정수이고 m은 0∼2의 정수이다.N is an integer of 1-2 and m is an integer of 0-2.
상기 반응식 1에서 오르쏘-디플루오로벤조산 유도체(Ⅰ)는 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ)로부터 얻어진 클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-1)를 산화시켜 제조된다.In Scheme 1, ortho-difluorobenzoic acid derivative (I) is prepared by oxidizing chloromethyl ortho-difluorobenzene derivative (III-1) obtained from methyl ortho-difluorobenzene derivative (II). .
클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-1)는 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ)에 설퓨릴 클로라이드를 첨가시키고 촉매를 부가하여 60∼70℃의 온도에서 반응시키거나, 또는 반응온도 80∼100℃에서 유기용매없이 머큐리 램프하에서 염소가스와 반응시켜 합성된다. 상기에서 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ) : 설퓨릴 클로라이드의 몰비는 1 : 1∼2.5가 바람직하고 상기 촉매로는 벤조일 퍼옥사이드 또는 t-부틸 퍼옥사이드가 사용될 수 있다.The chloromethyl ortho-difluorobenzene derivative (III-1) may be reacted at a temperature of 60 to 70 ° C. by adding sulfuryl chloride to the methyl ortho-difluorobenzene derivative (II) and adding a catalyst. Or synthesized by reacting with chlorine gas under a Mercury lamp at an reaction temperature of 80 to 100 ° C. without an organic solvent. The molar ratio of methyl ortho-difluorobenzene derivative (II) to sulfuryl chloride is preferably 1: 1 to 2.5, and benzoyl peroxide or t-butyl peroxide may be used as the catalyst.
상기 클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-1)에 1∼4의 몰비로 무기염기 및 2∼4의 몰비로 산화제를 첨가하고 상전이 촉매의 존재하에서 물에서 반응시켜 오르쏘-디플루오로벤조산 유도체(Ⅰ)를 제조한다. 상기 무기염기로는 수산화나트륨, 수산화칼륨, 탄산나트륨 또는 탄산칼륨이 사용될 수 있으며, 상기 산화제로는 과망간산칼륨이 사용될 수 있고, 상기 상전이 촉매로는 테트라부틸암모늄 브로마이드가 바람직하게 사용될 수 있다.To the chloromethyl ortho-difluorobenzene derivative (III-1), an inorganic base is added at a molar ratio of 1 to 4 and an oxidizing agent at a molar ratio of 2 to 4, and reacted in water in the presence of a phase transfer catalyst to react with ortho-difluoro. Robenzoic acid derivative (I) is prepared. Sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate may be used as the inorganic base, potassium permanganate may be used as the oxidizing agent, and tetrabutylammonium bromide may be preferably used as the phase transfer catalyst.
또한 하기 반응식 2로 나타내어지는 방법에 의해서도 본 발명의 오르쏘 디플루오로벤조산 유도체를 합성할 수 있다:The ortho-difluorobenzoic acid derivatives of the present invention can also be synthesized by the method shown in Scheme 2:
반응식 2Scheme 2
상기식에서 n은 1∼2의 정수이고 m은 0∼2의 정수이다.N is an integer of 1-2 and m is an integer of 0-2.
상기 반응식 2에서 오르쏘-디플루오로벤조산 유도체(Ⅰ)는 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ)로부터 얻어진 디클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-2)를 산처리하여 오르쏘-디플루오로벤즈알데하이드 유도체(Ⅳ)를 생성시키고, 이것을 산화시켜 합성한다.In Scheme 2, ortho-difluorobenzoic acid derivative (I) is obtained by acid treatment of dichloromethyl ortho-difluorobenzene derivative (III-2) obtained from methyl ortho-difluorobenzene derivative (II). So-difluorobenzaldehyde derivative (IV) is produced and synthesized by oxidizing it.
디클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-2)는 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ)에 과량의 설퓨릴 클로라이드를 첨가시키고 촉매를 부가하여 60∼70℃에서 반응시키거나, 또는 80∼120℃의 반응온도에서 유기용매없이 머큐리 램프하에서 염소가스와 광반응시켜 합성한다. 상기에서 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ) : 설퓨릴 클로라이드의 몰비는 1 : 5∼8의 범위인 것이 바람직하고, 촉매로는 벤조일 퍼옥사이드 또는 t-부틸 퍼옥사이드를 사용한다.Dichloromethyl ortho-difluorobenzene derivative (III-2) is added to the methyl ortho-difluorobenzene derivative (II) in excess of sulfuryl chloride and reacted at 60 ~ 70 ℃ by adding a catalyst, Or synthesized by photoreaction with chlorine gas under a Mercury lamp without an organic solvent at a reaction temperature of 80 ~ 120 ℃. In the above, the molar ratio of methyl ortho-difluorobenzene derivative (II): sulfuryl chloride is preferably in the range of 1: 5 to 8, and benzoyl peroxide or t-butyl peroxide is used as the catalyst.
상기 합성된 디클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-2)를 산처리하여 오르쏘-디플루오로벤즈알데하이드 유도체(Ⅳ)를 원포트(one pot) 반응으로 얻는다. 상기 오르쏘-디플루오로벤즈알데하이드 유도체(Ⅳ)를 산화제와 산화반응시켜 오르쏘-디플루오로벤조산 유도체(Ⅰ)를 제조한다. 상기 산화반응은 유기용매하에서 물에 녹인 인산이수소나트륨, 과산화수소 및 상전이 촉매의 존재하에서 진행될 수도 있다. 상기 디클로로메틸 오르쏘-디플루오로벤젠 유도체의 산처리에는 황산이 사용될 수 있으며, 상기 상전이 촉매로는 테트라부틸암모늄 브로마이드를 사용하고, 상기 산화제로는 아염소산나트륨을 사용하는 것이 바람직하며, 상기 산화반응에 선택적으로 사용될 수 있는 유기용매로는 톨루엔, 메탄올, 에탄올 또는 아세토니트릴이 사용될 수 있다.The synthesized dichloromethyl ortho-difluorobenzene derivative (III-2) is subjected to acid treatment to obtain an ortho-difluorobenzaldehyde derivative (IV) by one pot reaction. The ortho-difluorobenzaldehyde derivative (IV) is oxidized with an oxidizing agent to prepare an ortho-difluorobenzoic acid derivative (I). The oxidation reaction may be carried out in the presence of sodium dihydrogen phosphate, hydrogen peroxide and a phase transfer catalyst dissolved in water in an organic solvent. Sulfuric acid may be used for acid treatment of the dichloromethyl ortho-difluorobenzene derivative, tetrabutylammonium bromide is used as the phase transfer catalyst, and sodium chlorite is used as the oxidizing agent. Toluene, methanol, ethanol or acetonitrile can be used as the organic solvent that can be optionally used in the reaction.
상기 반응식 1 및 2에서 출발물질로 사용되는 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ)는 본 출원인의 발명인 한국 특허출원 제98-38405호(방향족 불소 화합물의 제조방법)에 기재된 방법으로 클로로트리플루오로에틸렌과 1,3-디엔 유도체를 반응시켜 제조할 수 있다.Methyl ortho-difluorobenzene derivative (II) used as starting materials in Schemes 1 and 2 is a chlorotree by the method described in Korean Patent Application No. 98-38405 (Method for producing aromatic fluorine compound) of the present applicant. It can be prepared by reacting fluoroethylene with 1,3-diene derivatives.
본 발명은 하기의 실시예에 의하여, 보다 명확히 이해될 수 있으며, 하기의 실시예는 본 발명의 예시 목적에 불과하며 발명의 영역을 제한하고자 하는 것은 아니다.The present invention can be more clearly understood by the following examples, which are only intended to illustrate the present invention and are not intended to limit the scope of the invention.
실시예Example
실시예 1: 3,4-디플루오로벤조산의 제조Example 1: Preparation of 3,4-difluorobenzoic acid
2.57g의 3,4-디플루오로톨루엔에 0.2g의 70% 벤조일 퍼옥사이드 및 3.3ml의 설퓨릴 클로라이드를 첨가하고 65℃에서 1시간 동안 가열하였다. 실온에서 물과 20% 수산화나트륨 수용액으로 각각 세척하고 유기층에 0.64g의 테트라부틸암모늄 브로마이드, 6.32g의 과망간산칼륨, 12ml 20% 수산화나트륨 수용액 및 20ml의 물을 첨가하고 70℃에서 3시간 동안 가열하였다. 생성된 고체를 실온에서 여과하고 물과 디클로로에탄으로 세척하였다. 층분리 후 물층을 산성화시키고 생성된 고체를 여과하고 찬물로 세척하여 건조시켜 1.95g의 목적 생성물인 3,4-디플루오로벤조산을 얻었다.To 2.57 g of 3,4-difluorotoluene was added 0.2 g of 70% benzoyl peroxide and 3.3 ml of sulfuryl chloride and heated at 65 ° C. for 1 hour. Washed with water and 20% aqueous sodium hydroxide solution at room temperature, respectively, and added 0.64 g of tetrabutylammonium bromide, 6.32 g of potassium permanganate, 12 ml of 20% aqueous sodium hydroxide solution and 20 ml of water to the organic layer, and heated at 70 ° C. for 3 hours. . The resulting solid was filtered at room temperature and washed with water and dichloroethane. After layer separation, the water layer was acidified and the resulting solid was filtered, washed with cold water and dried to obtain 1.95 g of the desired product, 3,4-difluorobenzoic acid.
1H-NMR(CDCl3)δ(ppm): 7.2∼7.3(1H, m), 7.9∼7.95(2H, m), 12.8(1H) 1 H-NMR (CDCl 3 ) δ (ppm): 7.2 to 7.3 (1H, m), 7.9 to 7.95 (2H, m), 12.8 (1H)
실시예 2: 3,4-디플루오로벤조산의 제조Example 2: Preparation of 3,4-difluorobenzoic acid
23.6g의 3,4-디플루오로톨루엔에 머큐리램프로 광을 주사하며, 내부온도 100℃에서 염소가스를 시간당 0.5L씩 10시간 동안 주입 후 질소가스를 주입하여 과량의 염소가스를 방출시키고 5.9g의 테트라부틸암모늄 브로마이드, 58.0g의 과망간산칼륨, 110ml 20% 수산화나트륨 수용액, 및 200ml의 물을 첨가하고 70℃에서 3시간 동안 가열하였다. 생성된 고체를 실온에서 여과하고 물과 디클로로에탄으로 세척하였다. 층분리후 물층을 산성화시키고 생성된 고체를 여과하고 찬물로 세척하여 건조시켜 18g의 목적 생성물인 3,4-디플루오로벤조산을 얻었다.Mercury lamp is injected into 23.6 g of 3,4-difluorotoluene with mercury lamp.Injection of chlorine gas at 0.5 ° C per hour for 10 hours at 100 ° C and nitrogen gas is injected to release excess chlorine gas. g tetrabutylammonium bromide, 58.0 g potassium permanganate, 110 ml 20% sodium hydroxide aqueous solution, and 200 ml water were added and heated at 70 ° C. for 3 hours. The resulting solid was filtered at room temperature and washed with water and dichloroethane. After layer separation, the water layer was acidified and the resulting solid was filtered, washed with cold water and dried to obtain 18 g of the desired product, 3,4-difluorobenzoic acid.
1H-NMR(CDCl3)δ(ppm): 7.2∼7.3(1H, m), 7.9∼7.95(2H, m), 12.8(1H) 1 H-NMR (CDCl 3 ) δ (ppm): 7.2 to 7.3 (1H, m), 7.9 to 7.95 (2H, m), 12.8 (1H)
실시예 3: 2-클로로-4,5-디플루오로벤조산의 제조Example 3: Preparation of 2-chloro-4,5-difluorobenzoic acid
65℃에서 6.50g의 2-클로로-4,5-디플루오로톨루엔에 2.42g의 70% 벤조일 퍼옥사이드와 25.7ml의 설퓨릴 클로라이드를 세번에 나누어 첨가하며 24시간 동안 교반하였다. 과량의 설퓨릴 클로라이드를 증류제거하고 실온에서 4ml의 90%(v/v) 황산을 적가하고 65℃에서 1.5시간 동안 교반하였다. 얼음물에 반응물을 첨가한 후 톨루엔으로 추출하고 5% 수산화나트륨 수용액과 소금물로 세척하였다. 톨루엔층에 8ml의 물에 녹인 1.50g의 인산이수소나트륨·2H2O와 0.13g의 테트라부틸암모늄 브로마이드를 실온에서 첨가하였다. 10℃에서 4.2ml의 30% 과산화수소를 첨가하고 22ml의 물에 녹인 5.76g의 아염소산나트륨을 2시간 동안 적가하였다. 10℃에서 1시간 교반 후 실온에서 30분 동안 더 교반하였다. 0.36g의 아황산나트륨을 첨가하고 톨루엔층을 분리하였다. 5% 수산화나트륨 수용액으로 추출, 분리하고 10.3g의 소금을 첨가하였다. 진한 염산으로 산성화시켜 생성된 고체를 여과하고 찬물로 세척하여 건조시켜 4.79g의 목적 생성물인 2-클로로-4,5-디플루오로벤조산을 얻었다.To 6.50 g of 2-chloro-4,5-difluorotoluene at 65 ° C., 2.42 g of 70% benzoyl peroxide and 25.7 ml of sulfuryl chloride were added in three portions and stirred for 24 hours. Excess sulfuryl chloride was distilled off and 4 ml of 90% (v / v) sulfuric acid was added dropwise at room temperature and stirred at 65 ° C. for 1.5 hours. The reaction was added to ice water, extracted with toluene, and washed with 5% aqueous sodium hydroxide solution and brine. 1.50 g of sodium dihydrogen phosphate 2H 2 O and 0.13 g of tetrabutylammonium bromide dissolved in 8 ml of water were added to the toluene layer at room temperature. At 10 ° C., 4.2 ml of 30% hydrogen peroxide was added and 5.76 g of sodium chlorite dissolved in 22 ml of water was added dropwise for 2 hours. After stirring for 1 hour at 10 ° C., the mixture was further stirred at room temperature for 30 minutes. 0.36 g of sodium sulfite was added and the toluene layer was separated. Extracted with 5% aqueous sodium hydroxide solution, separated and added 10.3 g of salt. The resulting solid, acidified with concentrated hydrochloric acid, was filtered, washed with cold water and dried to afford 4.79 g of the desired product, 2-chloro-4,5-difluorobenzoic acid.
1H-NMR(CDCl3)δ(ppm): 7.35(1H, d+d), 7.95(1H, d+d), 11.50(1H) 1 H-NMR (CDCl 3 ) δ (ppm): 7.35 (1H, d + d), 7.95 (1H, d + d), 11.50 (1H)
실시예 4: 2-클로로-4,5-디플루오로벤즈알데하이드의 제조Example 4: Preparation of 2-chloro-4,5-difluorobenzaldehyde
실시예 3과 유사한 방법으로 65℃에서 3.25g의 2-클로로-4,5-디플루오로톨루엔에 1.04g의 70% 벤조일 퍼옥사이드와 11.01ml의 설퓨릴 클로라이드를 세번에 나누어 첨가하며 20시간 동안 교반하였다. 과량의 설퓨릴 클로라이드를 증류 제거하고 실온에서 2ml의 90%(v/v) 황산을 적가하고 65℃에서 1.5시간 동안 교반하였다. 얼음물에 반응물을 첨가한 후 메틸렌클로라이드로 추출하고 5% 수산화나트륨 수용액과 소금물로 세척하였다. 메틸렌클로라이드층을 MgSO4로 건조, 여과 후 메틸렌클로라이드를 증류, 제거하여 2.50g의 목적 생성물인 2-클로로-4,5-디플루오로벤즈알데하이드를 고체상으로 얻었다.In a similar manner to Example 3, 1.04 g of 70% benzoyl peroxide and 11.01 ml of sulfuryl chloride were added to 3.25 g of 2-chloro-4,5-difluorotoluene at 65 ° C. in three portions for 20 hours. Stirred. Excess sulfuryl chloride was distilled off and 2 ml of 90% (v / v) sulfuric acid was added dropwise at room temperature and stirred at 65 ° C. for 1.5 hours. The reactant was added to ice water, extracted with methylene chloride, and washed with 5% aqueous sodium hydroxide solution and brine. The methylene chloride layer was dried over MgSO 4 , filtered, and the methylene chloride was distilled off to remove 2.50 g of the desired product, 2-chloro-4,5-difluorobenzaldehyde, as a solid.
1H-NMR(CDCl3)δ(ppm): 7.34(1H, d+d), 7.77(1H, d+d), 10.37(1H) 1 H-NMR (CDCl 3 ) δ (ppm): 7.34 (1H, d + d), 7.77 (1H, d + d), 10.37 (1H)
실시예 5: 2-클로로-4,5-디플루오로벤조산의 제조Example 5: Preparation of 2-chloro-4,5-difluorobenzoic acid
4ml의 메탄올에 녹인 883mg의 2-클로로-4,5-디플루오로벤즈알데하이드에 1ml의 물에 녹인 208mg의 인산이소나트륨·2H2O을 실온에서 첨가하였다. 10℃에서 0.58ml의 30% 과산화수소를 첨가하고 4ml의 물에 녹인 800mg의 아염소산나트륨을 1시간동안 적가하였다. 10℃에서 1시간동안 교반후 실온에서 30분동안 교반하였다. 그런 다음 50mg의 아황산나트륨을 첨가하였다. 메탄올을 감압증류 제거 후 생성된 여과하고 물과 헥산으로 세척하여 790mg의 목적 생성물인 2-클로로-4,5-디플루오로벤조산을 얻었다.In 883 mg of 2-chloro-4,5-difluorobenzaldehyde dissolved in 4 ml of methanol, 208 mg of sodium isophosphate 2H 2 O dissolved in 1 ml of water was added at room temperature. 0.58 ml of 30% hydrogen peroxide was added at 10 DEG C, and 800 mg of sodium chlorite dissolved in 4 ml of water was added dropwise for 1 hour. Stirred at 10 ° C. for 1 hour and then stirred at room temperature for 30 minutes. Then 50 mg sodium sulfite was added. Methanol was distilled off under reduced pressure, and the resulting filtrate was washed with water and hexane to obtain 790 mg of the desired product, 2-chloro-4,5-difluorobenzoic acid.
1H-NMR(CDCl3)δ(ppm): 7.35(1H, d+d), 7.95(1H, d+d), 11.50(1H) 1 H-NMR (CDCl 3 ) δ (ppm): 7.35 (1H, d + d), 7.95 (1H, d + d), 11.50 (1H)
실시예 6: 3,4-디플루오로벤즈알데하이드의 제조Example 6: Preparation of 3,4-difluorobenzaldehyde
2.56g의 3,4-디플루오로톨루엔을 실시예 4와 같은 방법으로 실시하여 2.1g의 목적 생성물을 얻었다.2.56 g of 3,4-difluorotoluene was carried out in the same manner as in Example 4 to obtain 2.1 g of the desired product.
1H-NMR(CDCl3)δ(ppm): 7.3∼7.4(1H, m), 7.7∼7.75(2H, m), 9.94(1H) 1 H-NMR (CDCl 3 ) δ (ppm): 7.3 to 7.4 (1H, m), 7.7 to 7.75 (2H, m), 9.94 (1H)
실시예 7: 3,4-디플루오로벤조산의 제조Example 7: Preparation of 3,4-difluorobenzoic acid
상기 실시예 6에서 제조된 711mg의 3,4-디플루오로벤즈알데하이드를 상기 실시예 5와 같은 방법으로 실시하여 633mg의 목적 생성물을 얻었다.711 mg of 3,4-difluorobenzaldehyde prepared in Example 6 was carried out in the same manner as in Example 5 to obtain 633 mg of the desired product.
1H-NMR(CDCl3)δ(ppm): 7.2∼7.3(1H, m), 7.9∼7.95(2H, m), 12.8(1H) 1 H-NMR (CDCl 3 ) δ (ppm): 7.2 to 7.3 (1H, m), 7.9 to 7.95 (2H, m), 12.8 (1H)
본 발명은 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ)로부터 얻어진 클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-1)를 산화시키거나, 또는 메틸 오르쏘-디플루오로벤젠 유도체(Ⅱ)로부터 얻어진 디클로로메틸 오르쏘-디플루오로벤젠 유도체(Ⅲ-2)를 산처리하여 오르쏘-디플루오로벤즈알데하이드 유도체(Ⅳ)를 생성시키고, 이것을 산화시킴으로써 오르쏘-디플루오로벤조산 유도체(Ⅰ)를 저렴한 비용으로 효과적으로 합성하는 발명의 효과를 가진다.The present invention oxidizes chloromethyl ortho-difluorobenzene derivative (III-1) obtained from methyl ortho-difluorobenzene derivative (II), or methyl ortho-difluorobenzene derivative (II). The dichloromethyl ortho-difluorobenzene derivative (III-2) obtained from the above was subjected to acid treatment to produce an ortho-difluorobenzaldehyde derivative (IV), which was then oxidized to obtain an ortho-difluorobenzoic acid derivative (I). ) And the effect of the invention to effectively synthesize at low cost.
본 발명의 단순한 변형 내지 변경은 이 분야의 통상의 지식을 가진 자에 의하여 용이하게 이용될 수 있으며, 이러한 변형이나 변경은 모두 본 발명의 영역에 포함되는 것으로 볼 수 있다.Simple modifications and variations of the present invention can be readily used by those skilled in the art, and all such variations or modifications can be considered to be included within the scope of the present invention.
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