KR830000127B1 - Process for preparing cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid - Google Patents

Process for preparing cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid Download PDF

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KR830000127B1
KR830000127B1 KR1019780003126A KR780003126A KR830000127B1 KR 830000127 B1 KR830000127 B1 KR 830000127B1 KR 1019780003126 A KR1019780003126 A KR 1019780003126A KR 780003126 A KR780003126 A KR 780003126A KR 830000127 B1 KR830000127 B1 KR 830000127B1
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methyl
indene
fluoro
acetic acid
benzylidene
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KR830000127A (en
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에프.차자 로버트
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맬크 앤드 캄파니 인코포레이티드
제임스 에프. 너우톤
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    • C07C61/00Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
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Abstract

내용 없음.No content.

Description

시스-5-플루오로-2-메틸-1-[p-(메틸설피닐)벤질리덴]인덴-3-아세트산의 제조방법Process for preparing cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid

본 발명은 다음 일반식(I)의 시스-5-플루오로-2-메틸-1-[p-(메틸설피닐)벤질리덴]인덴-3-아세트산의 제조방법에 관한 것이다.The present invention relates to a process for preparing cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid of the following general formula (I).

Figure kpo00001
Figure kpo00001

본 화합물은 항-염증, 진통 및 해열작용을 가지고 있어서, 통증, 열 또는 염증을 나타내는 질병의 치료에 유용하다. 이와 같은 질병의 치료에 있어서, 본 발명의 시스-5-플루오로-2-메틸-1-[p-(메틸설피닐)벤질리덴]인덴-3-아세트산은 1일, 체중 kg당 0.1-50mg의 투약범위로(바람직하기로는 1일 체중 kg당 약 1-15mg범위로) 국부적으로, 경구적으로, 직장으로 또는 비경구적으로 투여할 수 있다.The compounds have anti-inflammatory, analgesic and antipyretic effects and are therefore useful for the treatment of diseases exhibiting pain, fever or inflammation. In the treatment of such diseases, the cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid of the present invention is 0.1-50 mg / kg body weight per day The dosage range (preferably in the range of about 1-15 mg / kg body weight per day) can be administered locally, orally, rectally or parenterally.

비록 5-플루오로-2-메틸-1-[p-(메틸설피닐)벤질리덴]인덴-3-아세트산이 시스 및 트란스 이성체의 양형태로 존재할 수 있긴 하지만, 벤질리덴기가 인덴핵의 페닐환아래 정렬되어 있는 시스이성체가 가장 바람직한 이성체 형태임을 본 기술분야에 숙련된 사람은 잘 알 수 있을 것이다.Although 5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid may be present in both cis and trans isomers, the benzylidene group is under the phenyl ring of the indene nucleus. Those skilled in the art will appreciate that the aligned cis isomers are the most preferred isomeric forms.

또한, 상술한 시스-5-플루오로-2-메틸-1-[p-(메틸설피닐)벤질리덴]인덴-3-아세트산중의 황원자는 비대칭 중심을 이루며, 이 하합물을 본 기술분야에 널리 알려진 방법에 의하여 (+) 및 (-)형태로 분리할 수 있음은 본 기술분야에 숙련된 사람은 잘 알 수 있을 것이다.In addition, the sulfur atoms in cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid form an asymmetric center, and this polymer is incorporated in the art. It will be appreciated by those skilled in the art that the separation into (+) and (-) forms by well known methods is possible.

또한 상기 화합물은 다형태이며, 하나이상의 결정구조를 가지고 있기 때문에 상이한 융점을 가진 고체상태로 분리시킬 수 있다.In addition, the compounds are polymorphic and have more than one crystal structure, so that they can be separated into solid states having different melting points.

본 발명의 목적은 시스-5-플루오로-2-메틸-1-[p-(메틸-설피닐) 벤질리덴]인덴-3-아세트산을 제조하는 신규한 방법을 제공함에 있다.It is an object of the present invention to provide a novel process for preparing cis-5-fluoro-2-methyl-1- [p- (methyl-sulfinyl) benzylidene] indene-3-acetic acid.

본 발명의 또 다른 목적은 본 발법의 최종단계로서 p-메틸설피닐 페닐치환기가 형성되는 본 발명의 화합물을 제조하는 방법을 제공함에 있다.Another object of the present invention is to provide a method for preparing a compound of the present invention in which a p-methylsulfinyl phenyl substituent is formed as a final step of the present method.

본 발명의 한 특징은 p-플루오로아닐린을 디아조화한 다음 에틸-4-메틸- 3-옥소(OXO)-4-헥세노에이트와 반응시켜 최초 중간물질로서 에틸-5-(p-플루오로페닐)-4-메틸-3-옥소-4-헥세노에이트 화합물을 제조하는 것이다. 디아조화 반응은 0-10℃에서 p-플루오로아닐린을 산성화시킨 다음 아질산 나트륨 수용액으로 처리하여 수행한다. 얻어진 p-플루오로아닐린의 디아조늄염의 용액을 20-25℃까지 가온한 다음 에틸-4-메틸-3-옥소-4-헥세노에이트, 초산나트륨 3수화물 및 염화 제2동 2수화물의 혼합물에 가하고, 20-30℃에서 1-3시간 동안 교반하여 에틸-5-(p-플루오로페닐)-4-메틸-3-옥소-4-헥세노에이트를 제조한다.One feature of the present invention is that diazotized p-fluoroaniline and then reacted with ethyl-4-methyl-3-oxo (OXO) -4-hexenoate to yield ethyl-5- (p-fluoro as the first intermediate. Phenyl) -4-methyl-3-oxo-4-hexenoate compound is prepared. The diazotization reaction is carried out by acidifying p-fluoroaniline at 0-10 ° C. and then treating with aqueous sodium nitrite solution. The resulting solution of the diazonium salt of p-fluoroaniline was warmed up to 20-25 ° C and then added to a mixture of ethyl-4-methyl-3-oxo-4-hexenoate, sodium acetate trihydrate and cupric chloride dihydrate. Was added and stirred at 20-30 ° C. for 1-3 hours to prepare ethyl-5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate.

얻어진 생성물을 황산으로 처리하므로써 환화시켜 치환인덴을 제조한다. 이 단계에서, 에틸-5-(p-플루오로페닐)-4-메틸-3-옥소-4-헥세노에이트를 100-150℃에서 1-4시간 동안 농황산과 함께 가열하여 5-플루오로-2-메틸-1-메틸리덴-3-인덴아세트산을 제조한다.The obtained product is cyclized by treating with sulfuric acid to produce substituted indene. In this step, ethyl-5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate is heated with concentrated sulfuric acid at 100-150 ° C. for 1-4 hours to give 5-fluoro- 2-Methyl-1-methylidene-3-indeneacetic acid is prepared.

본 방법의 최종단계에서, 디아조화된 p-메틸설피닐아닐린을 중간물질인 5-플루오로-2-메틸-1-메틸리덴-인덴-3-아세트산과 커플링시켜 목적생성물인 시스-5-플루오로-2-메틸-1-[p-(메틸설피닐)벤질리덴]인덴-3-아세트산을 제조한다. 이 단계를 좀더 구체적으로 설명하면 p-메틸설피닐아닐린을 0-10℃에서 산에 용해시킨 다음 아질산나트륨 수용액으로 처리하여 디아조늄염을 제조하고, 얻어진 디아조늄염을 20-30℃까지 가온한 다음 5-플루오로-2-메틸-1-메틸리덴-인덴 -3-아세트산, 초산나트륨 3수화물 및 염화 제2동 2수화물의 혼합물에 가하여 목적생성물인 시스-5-플루오로 -2-메틸-1-[p-(메틸설피닐)벤질리덴]인덴-3-아세트산을 제조한다.In the final step of the process, the diazotized p-methylsulfinylaniline is coupled with the intermediate 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid to yield the desired product cis-5- Fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid is prepared. To explain this step more specifically, p-methylsulfinylaniline is dissolved in an acid at 0-10 ° C. and treated with an aqueous sodium nitrite solution to prepare a diazonium salt, and the diazonium salt obtained is warmed to 20-30 ° C. Next, to a mixture of 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid, sodium acetate trihydrate and cupric chloride dihydrate, the desired product, cis-5-fluoro-2-methyl- Prepare 1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid.

본원의 반응기구를 간단히 기재하면 다음과 같다.Briefly describing the reactor of the present application is as follows.

Figure kpo00002
Figure kpo00002

Figure kpo00003
Figure kpo00003

시스-이성체와 소량이면서 불확정량의 트란스-이성체.Cis-isomers and small but indeterminate trans-isomers.

본 발명의 화합물에 대한 시스 및 트랜스 이성체의 존재여부는 분광법에 의해 확인되며, 용액(0.1NHCl/메탄올) 100ml중의 1g농도인 용액의 UV흡광데이터는 표 1과 같다.The presence of cis and trans isomers for the compounds of the present invention was confirmed by spectroscopy, and the UV absorption data of the solution at a concentration of 1 g in 100 ml of solution (0.1NHCl / methanol) are shown in Table 1.

[표 1]TABLE 1

Figure kpo00004
Figure kpo00004

본 발명은 실시예에 의거 상세히 설명하면 다음과 같다.The present invention is described in detail based on the following examples.

[실시예 1]Example 1

에틸 5-(p-플루오로페닐)-4-메틸-3-옥소-4-헥세노에이트Ethyl 5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate

p-플루오로아닐린(27.8g, 0.25몰)을 300ml의 5N염산에 용해시켜 5-10℃까지 냉각시킨 다음 70ml의 30% 아질산나트륨 수용액으로 처리하여 상응하는 디아조늄 클로라이드로 전환시켰다. 이 용액을 200ml의 아세톤중의 42.3g(0.25몰)의 에틸 4- 메틸-3-옥소-4-헥세노에이트, 30g의 초산나트륨 트리하이드레이트 및 5g의 염화 제2동 2수화물의 혼합물에 20-25℃에서 적가하였다. 25-30℃에서 2시간 경과후, 질소가스발생이 중지되었다. 침전물을 여과하고 200ml의 물로 세척한 결과 에틸 5-(p-플루오로페닐)-4-메틸-3-옥소-4-헥세노에이트가 얻어졌다.p-fluoroaniline (27.8 g, 0.25 mol) was dissolved in 300 ml of 5N hydrochloric acid, cooled to 5-10 ° C. and then treated with 70 ml of 30% aqueous sodium nitrite solution to convert to the corresponding diazonium chloride. The solution was added to a mixture of 42.3 g (0.25 mol) of ethyl 4-methyl-3-oxo-4-hexenoate, 30 g of sodium acetate trihydrate and 5 g of cupric chloride dihydrate in 200 ml of acetone. Dropwise at 25 ° C. After 2 hours at 25-30 ° C., nitrogen gas evolution ceased. The precipitate was filtered off and washed with 200 ml of water to afford ethyl 5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate.

[실시예 2]Example 2

5-플루오로-2-메틸-1-메틸리덴-인덴-3-아세트산5-Fluoro-2-methyl-1-methylidene-indene-3-acetic acid

에틸 5-(p-플루오로페닐)-4-메틸-3-옥소-4-헥세노에이트와 250ml의 농황산의 혼합물(132g, 0.5몰)을 125℃에서 3시간동안 교반하였다. 반응물을 25℃까지 냉각시킨 다음 750ml의 물에서 급냉시켰다. 침전물을 여과하고, 물로 세척한 다음 공기로 건조시킨 결과 5-플루오로-2-메틸-1-메틸리덴-인덴-3-아세트산이 얻어졌다.A mixture of ethyl 5- (p-fluorophenyl) -4-methyl-3-oxo-4-hexenoate and 250 ml of concentrated sulfuric acid (132 g, 0.5 mole) was stirred at 125 ° C. for 3 hours. The reaction was cooled to 25 ° C. and then quenched in 750 ml of water. The precipitate was filtered off, washed with water and dried with air to afford 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid.

[실시예 3]Example 3

시스-5-플루오로-2-메틸-1-[p-(메틸설피닐)벤질리덴]-인덴-3-아세트산Cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] -indene-3-acetic acid

p-메틸설피닐아닐린(77.6g, 0.5몰)을 600ml의 5N염산에 용해시킨 다음 5-10℃까지 냉각시킨 후 140ml의 30% 아질산나트륨 수용액으로 처리하여 상응하는 디아조늄 클로라이드로 전환시켰다. 이 용액을 400ml의 아세톤중의 13213g(0.5몰)의 5-플루오로-2-메틸-1-메틸리덴-인덴-3-아세트산, 60g의 초산나트륨 3수화물 및 10g의 염화 제2동 2수화물의 혼합물에 20-25℃에서 적가하였다. 25-30℃에서 2시간 경과후, 질소가스 발생이 중지되었다. 침전물을 여과하고, 물로 세척시킨 다음 공기로 건조시킨 결과 시스-5-플루오로-2-메틸-1-[p-(메틸설피닐)벤질리덴]인덴-3-아세트산이 얻어졌다.p-methylsulfinanianiline (77.6 g, 0.5 mole) was dissolved in 600 ml of 5N hydrochloric acid and then cooled to 5-10 ° C. and then treated with 140 ml of 30% aqueous sodium nitrite solution to convert to the corresponding diazonium chloride. This solution was prepared from 13213 g (0.5 mole) of 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid, 60 g of sodium acetate trihydrate and 10 g of cupric chloride dihydrate in 400 ml of acetone. To the mixture was added dropwise at 20-25 ° C. After 2 hours at 25-30 ° C., nitrogen gas evolution ceased. The precipitate was filtered off, washed with water and dried with air to afford cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid.

Claims (1)

p-플루오로아닐린을 디아조화시켜 상응하는 디아조늄염을 제조한 다음, 얻어진 디아조늄염을 에틸 4-메틸-3-옥소헥세노에이트와 반응시켜 에틸-5-(p-플루오로페닐 )-4-메틸-3-옥소-4-헥세노에이트를 제조하고 이것을 황산으로 환화시켜 5-플루오로-2-메틸-1-메틸리덴-인덴-3-아세트산을 얻은 다음 상술한 인덴-3-아세트산을 디아조화된 p-메틸설피닐아닐린과 반응시킴을 특징으로 하는, 일반식(I)의 시스-5-플루오로-2-메틸-1-[p-(메틸설피닐)벤질리덴]인덴-3-아세트산을 제조하는 방법.
Figure kpo00005
Diazolation of p-fluoroaniline to produce the corresponding diazonium salt, followed by reaction of the obtained diazonium salt with ethyl 4-methyl-3-oxohexanoate to give ethyl-5- (p-fluorophenyl)- 4-Methyl-3-oxo-4-hexenoate is prepared and cyclized to sulfuric acid to give 5-fluoro-2-methyl-1-methylidene-indene-3-acetic acid followed by indene-3-acetic acid Cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene- of general formula (I), characterized by reacting with diazotized p-methylsulfinylaniline Process for preparing 3-acetic acid.
Figure kpo00005
KR1019780003126A 1978-10-16 1978-10-16 Process for preparing cis-5-fluoro-2-methyl-1- [p- (methylsulfinyl) benzylidene] indene-3-acetic acid KR830000127B1 (en)

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