KR920004782B1 - Process for producing of dialkyl 5-fluoro-2,4-dichlorobenzoyl malonate derivatives - Google Patents
Process for producing of dialkyl 5-fluoro-2,4-dichlorobenzoyl malonate derivatives Download PDFInfo
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- KR920004782B1 KR920004782B1 KR1019890020269A KR890020269A KR920004782B1 KR 920004782 B1 KR920004782 B1 KR 920004782B1 KR 1019890020269 A KR1019890020269 A KR 1019890020269A KR 890020269 A KR890020269 A KR 890020269A KR 920004782 B1 KR920004782 B1 KR 920004782B1
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- dichlorobenzoyl
- malonate
- fluoro
- dialkyl
- acetonitrile
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- 0 CCIc(cc(c(C(C(*)CC*)=N)c1)I)c1I Chemical compound CCIc(cc(c(C(C(*)CC*)=N)c1)I)c1I 0.000 description 2
- OVVRLLQNXVUVHC-UHFFFAOYSA-N CC([Cl]=C1)=CC(C([IH+])=[ClH])=C1[I]1CC1 Chemical compound CC([Cl]=C1)=CC(C([IH+])=[ClH])=C1[I]1CC1 OVVRLLQNXVUVHC-UHFFFAOYSA-N 0.000 description 1
- SIUAZJWRRKULOW-UHFFFAOYSA-N O=C(C(C=C(F)[Cl]=C1)=C1Cl)Cl Chemical compound O=C(C(C=C(F)[Cl]=C1)=C1Cl)Cl SIUAZJWRRKULOW-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/26—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms containing rings other than aromatic rings
- C07C55/28—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms containing rings other than aromatic rings monocyclic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
- C07C63/70—Monocarboxylic acids
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
본 발명은 유기용매 존재하에 반응온도 -15-60℃에서 마그네슘 클로라이드와 3차 아민을 사용하여 벤도일 클로라이드 유도체(Ⅰ)과 디에틸말로네이트(또는 디메틸말로네이트)를 반응시켜 디알킬 5-플루오르-2, 4-디클로로벤조일 말로네이트(dialkyl 5-fluoro-2, 4-dichlorobenzoyl malonate) 화합물(Ⅱ)를 제조하는 방법에 관한 것이다.The present invention relates to dialkyl 5- by reacting bendoyl chloride derivative (I) with diethylmalonate (or dimethylmalonate) using magnesium chloride and a tertiary amine at a reaction temperature of -15-60 ° C in the presence of an organic solvent. Fluorine-2, 4-dichlorobenzoyl malonate (dialkyl 5-fluoro-2, 4-dichlorobenzoyl malonate) relates to a process for preparing compound (II).
(상기식에서 R은 C1-C2의 저급알킬이다.)(Wherein R is C1-C2 lower alkyl)
본 발명의 일반식(Ⅱ)화합물로 나타내어지는 디알킬 5-플루오르-2, 4-디클로로벤조일 말로네이트는 우수한 항균 효과를 나타내는 1-사이클로프로필-6-플루오르-1, 4-디하이드로-4-옥소-7-피페라지노-퀴놀린-카르복실산(시프로프록사신) 합성의 중간체이다.Dialkyl 5-fluor-2, 4-dichlorobenzoyl malonate represented by the general formula (II) compound of the present invention is 1-cyclopropyl-6-fluor-1, 4-dihydro-4- showing excellent antibacterial effect. It is the intermediate of oxo-7-piperazino-quinoline-carboxylic acid (ciproproxacin) synthesis.
일반적으로 일반식(Ⅱ)로 표현되는 디알킬 5-플루오르-2, 4-디클로로벤조일 말로네이트를 제조하는 공지의 방법으로는, 금속마그네슘과 디에틸말로네이트(또는 디메틸말로네이트)를 반응시켜 얻은 방법(독일 특허 제 3,142,854호)에 알려져 있으나, 반응중 부산물로 수소가 발생하므로 공업적으로 다루기가 불편하고 반응조건이 격렬하여 위험을 야기시키는 경향이 있으므로, 이러한 단점을 개선하고자 공업적으로 유용한 제법에 대해 여러 가지 검토한 결과 본 발명에 이르렀다.As a well-known method for producing dialkyl 5-fluor-2, 4-dichlorobenzoyl malonate represented by general formula (II), it is obtained by reacting metal magnesium with diethyl malonate (or dimethyl malonate). Although known in the process (German Patent No. 3,142,854), since hydrogen is generated as a by-product during the reaction, it is inconvenient to handle industrially and the reaction conditions are violent, which tends to pose a danger. As a result of various studies on the present invention, the present invention was reached.
본 발명을 반응도식으로 표시하면 다음과 같다.When the present invention is represented by the reaction scheme as follows.
(상기식에서 R은 C1-C2의 저급 알킬이다.)(Wherein R is C1-C2 lower alkyl)
본 발명을 상세히 설명하면, 일반식(Ⅰ)인 5-플루오르-2, 4-디클로로벤조일 클로라이드 화합물과 디에틸말로네이트(또는 디메틸말로네이트)를 마그네슘 클로라이드와 3차 아민 등의 존재하에 반응시켜 일반식(Ⅱ)로 나타내는 디알킬 5-플루오르-2, 4-디클로로벤조일 말로네이트화합물을 제조하는 방법이며, 본 발명에서 마그네슘 클로라이드의 사용량은 1.0-1.2몰을 사용하는 것이 바람직하고, 3차 아민으로는 트리에틸아민, 피리딘 등이 사용되고, 용매로는 아세토니트릴, 이소프로필에테르 등이 있으나, 공업적으로는 아세토니트릴이 가장 바람직하다. 통상적으로 반응온도는 -15-60℃ 사이에서 실시하는 것이 좋다.DETAILED DESCRIPTION OF THE INVENTION The present invention is described in detail by reacting 5-fluoro-2, 4-dichlorobenzoyl chloride compound of general formula (I) with diethylmalonate (or dimethylmalonate) in the presence of magnesium chloride and tertiary amine, and the like. A method for producing a dialkyl 5-fluor-2, 4-dichlorobenzoyl malonate compound represented by formula (II), wherein the amount of magnesium chloride used in the present invention is preferably 1.0-1.2 mol, and is used as tertiary amine. Triethylamine, pyridine and the like are used, and solvents include acetonitrile and isopropyl ether, but acetonitrile is most preferred industrially. In general, the reaction temperature is preferably carried out between -15-60 ℃.
위에서 설명한 본 발명의 방법을 다음의 실시예에서 보다 상세히 설명하고자 한다.The method of the present invention described above will be described in more detail in the following examples.
[실시예 1]Example 1
[제 1 공정][Step 1]
4구-플라스크에 마그네슘 클로라이드 1.52gm과 아세토니트릴 13㎖를 넣고 충분히 교반하여 냉각한다. 여기에 디에틸말로네이트 2.55gm을 서서히 적가하고 약 1시간 동안 교반한 다음, 트리에틸아민 3.2gm을 5℃에서 적가하고 약 1시간 동안 교반한다.1.52gm of magnesium chloride and 13ml of acetonitrile were added to the four-neck flask and cooled by stirring sufficiently. 2.55 gm of diethylmalonate was slowly added dropwise and stirred for about 1 hour, and then 3.2 gm of triethylamine was added dropwise at 5 ° C and stirred for about 1 hour.
[제 2 공정]Second Process
5-플루오르-2, 4-디클로로벤조일 클로라이드 3.62gm과 아세토니트릴 7㎖의 혼합액을 제 1 공정에서 제조한 화합물에 반응온도 5℃를 유지하면서 서서히 적가하고 실온에서 일야 교반한다. 여기에 얼믈물로 냉각시켜 5몰-염산 수용액으로 산성화하고, 약 1시간 동안 교반한다. 아세토니트릴층과 물층을 분리하고, 물층을 다시 아세토니트릴 7㎖로 추출, 분리한 다음, 물 10㎖로 아세토니트릴층을 세척하고 망초로 처리하여 농축하면 액상의 디에틸 5-플루오르-2, 4-디클로로벤조일 말로네이트 화합물을 얻는다.A mixture of 3.62 gm of 5-fluoro-2, 4-dichlorobenzoyl chloride and 7 ml of acetonitrile was slowly added dropwise to the compound prepared in the first step while maintaining a reaction temperature of 5 ° C. and stirred at room temperature overnight. It was cooled with ice water, acidified with 5 molar hydrochloric acid, and stirred for about 1 hour. The acetonitrile layer and the water layer were separated, the water layer was extracted and separated again with 7 ml of acetonitrile, and the acetonitrile layer was washed with 10 ml of water, treated with forget-me-not and concentrated to give a liquid diethyl 5-fluor-2, 4. Obtain a dichlorobenzoyl malonate compound.
수율 : 85.0%Yield: 85.0%
IR(cm-1) : 3010, 2950, 1770, 1750, 1727, 1660, 1630, 1600, 1050, 900, 883.IR (cm -1 ): 3010, 2950, 1770, 1750, 1727, 1660, 1630, 1600, 1050, 900, 883.
[실시예 2]Example 2
[제 1 공정][Step 1]
4구-플라스크에 마그네슘 클로라이드 1.75gm과 아세토니트릴 13㎖를 넣고 충분히 교반하여 냉각한다. 디에틸말로네이트 2.67gm을 서서히 적가하고 약 1시간 동안 교반한 다음, 여기에 피리딘 2.9gm을 5℃에서 적가하고 약 1시간 동안 교반한다.Into a four-flask, 1.75 gm of magnesium chloride and 13 ml of acetonitrile were added, followed by cooling with sufficient stirring. 2.67 gm of diethylmalonate is slowly added dropwise and stirred for about 1 hour, after which 2.9 gm of pyridine is added dropwise at 5 ° C and stirred for about 1 hour.
[제 2 공정]Second Process
5-플루오르-2, 4-디클로로벤조일 클로라이드 3.62gm과 아세토니트릴 10㎖의 혼합액을 제 1 공정에서 제조한 화합물에 반응온도 5℃를 유지하면서 서서히 적가하고 실온에서 일야 교반한다. 여기에 실시예 1과 동일한 방법으로 실시하면 액상의 디에틸 5-플루오르-2,4-디클로로벤조일 말로네이트 화합물을 얻는다.A mixture of 3.62 gm of 5-fluor-2, 4-dichlorobenzoyl chloride and 10 ml of acetonitrile was slowly added dropwise to the compound prepared in the first step while maintaining a reaction temperature of 5 ° C. and stirred at room temperature overnight. When this is carried out in the same manner as in Example 1, a liquid diethyl 5-fluor-2,4-dichlorobenzoyl malonate compound is obtained.
수율 : 89.0%Yield: 89.0%
[실시예 3]Example 3
[제 1 공정][Step 1]
4구-플라스크에 마그네슘 클로라이드 1.52gm과 이소프로필에테르 15㎖를 넣고 충분히 교반하여 냉각한다. 디에틸말로네이트 2.55gm을 서서히 적가하고 약 1시간 동안 교반한 다음, 트리에틸아민 3.2gm을 5℃에서 적가하고 약 1시간 동안 교반한다.1.52 gm of magnesium chloride and 15 ml of isopropyl ether are added to a four-necked flask, and the mixture is sufficiently stirred and cooled. 2.55 gm of diethylmalonate is slowly added dropwise and stirred for about 1 hour, then 3.2 gm of triethylamine is added dropwise at 5 ° C. and stirred for about 1 hour.
[제 2 공정]Second Process
5-플루오르-2, 4-디클로로벤조일 클로라이드 3.62gm과 이소프로필에테르 10㎖의 혼합액을 제 1 공정에서 제조한 화합물에 반응온도 5℃를 유지하면서 서서히 적가하고 실온에서 일야 교반한다. 여기에 얼음물로 냉각시켜 5몰-염산 수용액으로 산성화하고, 약 1시간동안 교반한다. 이소프로필에테르층과 물층을 분리하고, 물층을 다시 이소프로필에테르 10㎖로 추출, 분리한 다음물 10㎖로 이소프로필에테르층을 세척하고 망초를 처리하여 농축하면 액상의 디에틸 5-플루오르-2, 4-디클로로벤조일 말로네이트 화합물을 얻는다.A mixture of 3.62 gm of 5-fluoro-2, 4-dichlorobenzoyl chloride and 10 ml of isopropyl ether is slowly added dropwise to the compound prepared in the first step while maintaining a reaction temperature of 5 ° C. and stirred at room temperature overnight. It is cooled with ice water, acidified with 5 molar hydrochloric acid, and stirred for about 1 hour. The isopropyl ether layer and the water layer were separated, and the water layer was extracted with 10 ml of isopropyl ether again. , 4-dichlorobenzoyl malonate compound is obtained.
수율 : 79%Yield: 79%
[실시예 4]Example 4
실시예 1과 동일한 방법으로 실시하나 반응온도를 실온으로 하여 행하면 목적물질인 디에틸 5-플루오르-2, 4-디클로로벤조일 말로네이트 화합물을 얻는다.The procedure was carried out in the same manner as in Example 1, but the reaction temperature was adjusted to room temperature to obtain diethyl 5-fluor-2 and 4-dichlorobenzoyl malonate compounds as target substances.
수율 : 75%Yield: 75%
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019890020269A KR920004782B1 (en) | 1989-12-29 | 1989-12-29 | Process for producing of dialkyl 5-fluoro-2,4-dichlorobenzoyl malonate derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019890020269A KR920004782B1 (en) | 1989-12-29 | 1989-12-29 | Process for producing of dialkyl 5-fluoro-2,4-dichlorobenzoyl malonate derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR910011737A KR910011737A (en) | 1991-08-07 |
| KR920004782B1 true KR920004782B1 (en) | 1992-06-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019890020269A KR920004782B1 (en) | 1989-12-29 | 1989-12-29 | Process for producing of dialkyl 5-fluoro-2,4-dichlorobenzoyl malonate derivatives |
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| Country | Link |
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| KR (1) | KR920004782B1 (en) |
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1989
- 1989-12-29 KR KR1019890020269A patent/KR920004782B1/en not_active IP Right Cessation
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| Publication number | Publication date |
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| KR910011737A (en) | 1991-08-07 |
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