KR910003636B1 - Process for the preparation of benzophenon oxime compounds - Google Patents
Process for the preparation of benzophenon oxime compounds Download PDFInfo
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- KR910003636B1 KR910003636B1 KR1019880014679A KR880014679A KR910003636B1 KR 910003636 B1 KR910003636 B1 KR 910003636B1 KR 1019880014679 A KR1019880014679 A KR 1019880014679A KR 880014679 A KR880014679 A KR 880014679A KR 910003636 B1 KR910003636 B1 KR 910003636B1
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- C07C251/50—Oximes having oxygen atoms of oxyimino groups bound to carbon atoms of substituted hydrocarbon radicals
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Abstract
Description
본 발명은 2-위치에 아미노기를 갖는 다음 일반식(Ⅰ)로 표시되는 벤조페논 옥심화합물의 새로운 제조방법에 관한 것이다.The present invention relates to a novel process for preparing a benzophenone oxime compound represented by the following general formula (I) having an amino group in the 2-position.
윗식중에서, R1,R2,R3,R4,R5,R6,는 각가 수소, 할로겐, 1내지 6개의 탄소원자를 갖는 알킬기 또는 1내지 6개의 탄소원자를 갖는 알콕시기를 나타낸다.Wherein R 1, R 2, R 3, R 4, R 5, R 6, each represents hydrogen, halogen, an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms.
상기 일반식(Ⅰ)로 표시되는 벤조페논 옥심화합물 즉, 2-위치에 아미노기를 갖는 벤조페논 옥심화합물은 신경안정제로 쓰이는 벤조디아제핀 계열의 화합물을 합성하는데 있어서의 중요한 중간체로서, 일반적으로 다음 일반식(Ⅱ)로 표시되는 벤조페논화합물로부터 제조된다.The benzophenone oxime compound represented by the general formula (I), that is, the benzophenone oxime compound having an amino group at the 2-position is an important intermediate in synthesizing the benzodiazepine-based compound which is used as a neurostable agent. It is prepared from the benzophenone compound represented by II).
윗식에서, R1,R2,R3,R4,R5,R6는각각 상기와 같다.In the above formula, R 1, R 2, R 3, R 4, R 5, and R 6 are the same as above.
종래, 상기 일반식(Ⅱ)로 표시되는 벤조페논화합물로부터 상기 일반식(Ⅰ)로 표시되는 벤조페논 옥심화합물을 합성하는 일반적인 방법은 유기화학회지(J.Org. Chem), 26,4488(1961)에 발표되어 있는바, 이 방법에 따르면 상기 일반식(Ⅱ)의 화합물에서 R4에 치환기가 없는 경우에는 상기 일반식(Ⅱ)의 화합물과 염산 히드록실아민을 에탄올 용매에서만 반응시키거나 피리딘 염기를 사용하여 수율 25-70%로 상기 일반식(Ⅰ)의 화합물을 제조하며, 또 R4에 치환기가 있는 경우에는 피리딘에 1%의 피페리딘을 사용하여 16%의 수율로 상기 일반식(Ⅰ)의 화합물을 제조하는 것으로 기술되어 있다.Conventionally, a general method for synthesizing the benzophenone oxime compound represented by the general formula (I) from the benzophenone compound represented by the general formula (II) is J. Org. Chem, 26,4488 (1961). According to this method, according to this method, when R 4 in the compound of formula (II) has no substituent, the compound of formula (II) and hydroxylamine hydrochloride are reacted only in an ethanol solvent or pyridine base is reacted. To prepare the compound of formula (I) in 25-70% yield, and when R 4 has a substituent, 1% piperidine in pyridine to yield 16% of the formula (I). It is described to prepare a compound of.
또한, 그후 발간된 유기화학회지(J.Org.Chem), 49,296(1984)에 발표된 바에 따르면, 피리딘에 10%의 피페리딘 염기를 사용하여 R4에 치환기가 붙어있는 상기 일반식(Ⅰ)의 화합물을 최대수율 27.4%까지 제조하는 방법이 기술되어 있다.In addition, according to the published organic chemical journal (J.Org.Chem), 49,296 (1984), the general formula (I) having a substituent attached to R 4 using 10% piperidine base in pyridine A process for the preparation of compounds of up to 27.4% is described.
그러나, 이와 같은 기존의 방법들은 피리딘이나 피레리딘과 같은 유기염기를 사용하기 때문에 수율이 비교적 낮고 반응시간이 길뿐만 아니라 반응후의 공정이 매우 복잡한 단점이 있었다. 그리고, 특히 R4의 위치에 치환체가 존재하는 경우에는 상기 일반식(Ⅰ)의 목적화합물의 수율이 더욱 낮아지는 문제가 있었다.However, these conventional methods use organic bases such as pyridine or pyridine, and thus have a relatively low yield, a long reaction time, and a complicated post-reaction process. In particular, when a substituent is present at the position of R 4 , there is a problem that the yield of the target compound of the general formula (I) is further lowered.
따라서, 본 발명자는 상기와 같은 종래방법에서의 제문제점을 해결하여 간단한 공정으로 고수율로 목적화합물을 제조하고자 오랜 기간동안 연구를 거듭해온 결과, 상기와 같은 방법에서 종래 사용되었던 피리딘이나 피페리딘 대신에 알칼리금속염기를 사용하게 되면 기준의 방법보다 정제과정이 매우 간단하고 빠른 시간내에 반응을 진행시킬 수 있으며, 상기 일반식(Ⅰ)의 목적화합물을 고수율로 제조할 수 있음을 알게되어 본 발명을 완성하게 되었다.Therefore, the present inventors have been studying for a long time to solve the problems in the conventional method as described above to produce the target compound in a high yield in a simple process, pyridine or piperidine that has been conventionally used in the above method Instead of using an alkali metal base, the purification process is much simpler than the standard method, and the reaction can proceed in a short time, and it can be seen that the target compound of the general formula (I) can be prepared in high yield. The invention was completed.
즉, 본 발명은 종래의 방법에 비해 간단하고 신속한 공정을 거쳐 고수율로 상기 일반식(Ⅰ)의 화합물을 제조할 수 있는 새로운 방법을 제공하는데 그 목적이 있다.That is, an object of the present invention is to provide a new method for producing the compound of formula (I) in a high yield through a simple and rapid process compared to the conventional method.
이하, 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명은 상기 일반식(Ⅱ)의 화합물로부터 상기 일반식(Ⅰ)의 화합물을 제조함에 있어서, 상기 일반식(Ⅱ)의 화합물을 알칼리금속염기 존재하에서 알코올용매중에서 염산히드록실아민과 반응시키는 것을 그 특징으로 한다.In the present invention, in preparing the compound of the general formula (I) from the compound of the general formula (II), reacting the compound of the general formula (II) with hydroxylamine hydrochloride in an alcohol solvent in the presence of an alkali metal base It is characterized by.
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 상기 일반식(Ⅱ)의 화합물로부터 상기 일반식(Ⅰ)의 화합물을 제조함에 있어서, 상기 일반식(Ⅱ)의 화합물과 과량의 염산히드록실아민을 가성소오다 또는 수산화칼륨 등과 같은 알칼리금속염기의 존재하에 95-99.5%의 메탄올, 에탄올 또는 프로판올 등의 저급 알코올에 현탁시킨 후 반응시키되 40-80℃의 온도에서 3-6시간 동안 교반시킨다.The present invention relates to the preparation of the compound of the general formula (I) from the compound of the general formula (II), wherein the compound of the general formula (II) and an excess of hydroxylamine hydrochloride are alkalis such as caustic soda or potassium hydroxide. In the presence of a metal base, suspended in a lower alcohol, such as 95-99.5% methanol, ethanol or propanol and then reacted and stirred for 3-6 hours at a temperature of 40-80 ℃.
이와 같이 교반시킨 후에는 혼합물을 여과하여 알칼리금속염을 제거해 낸다음, 감압하에서 알코올을 날려보내고 잔사를 염화메틸렌, 벤젠, 클로로포름 또는 에테르와 같은 유기용매로 수회 추출시킨 후 추출유기상을 물로 수회 세척한다.After stirring in this way, the mixture is filtered to remove the alkali metal salt, the alcohol is blown off under reduced pressure, the residue is extracted several times with an organic solvent such as methylene chloride, benzene, chloroform or ether, and the extracted organic phase is washed several times with water.
그후에 수세한 상기의 유기상을 무수황산마그네슘 또는 무수망초 등으로 건조한 후, 감압하에서 농축시킨다음 적당한 유기용매, 즉 벤젠, 석유에테르 또는 에테르 등에서 결정화시켜 목적하는 상기 일반식(Ⅰ)의 화합물을 얻는다.The organic phase washed with water is then dried over anhydrous magnesium sulfate, anhydrous manganese, or the like, and then concentrated under reduced pressure, and then crystallized with a suitable organic solvent, i.e., benzene, petroleum ether or ether, to obtain the desired compound of formula (I).
이와 같은 본 발명의 방법에 따라 상기 일반식(Ⅰ)의 화합물을 제조하게 되면 목적화합물이 75-85%의 높은 수율로 제조되게 된다.When the compound of Formula (I) is prepared according to the method of the present invention, the target compound is prepared in a high yield of 75-85%.
이와 같은 본 발명에 따르면, 상기 일반식(Ⅱ)의 화합물을 알칼리금속염기 존재하에 염산히드록실아민과 반응시키는 것을 그 특징으로 하고 있는바, 이와 같이 알칼리금속염기를 사용하여 상기 일반식(Ⅰ)의 화합물을 제조하는 경우 공정이 간단할 뿐아니라 반응이 신속하게 이루어지고, 또 R4에 치환체가 있는 때에도 높은 수율로 목적하는 상기 일반식(Ⅰ)의 화합물을 제조할 수가 있다.According to the present invention, it is characterized in that the compound of the general formula (II) is reacted with hydroxylamine hydrochloride in the presence of an alkali metal base. Thus, using the alkali metal base, the general formula (I) In the case of preparing the compound of, the process is simple, the reaction is carried out quickly, and even when there is a substituent in R 4 , the desired compound of formula (I) can be produced in high yield.
이와 같은 본 발명을 실시예에 의거 더욱 상세히 설명하겠는바, 본 발명이 다음의 실시예에 의해 한정되는 것은 아니다.The present invention will be described in more detail with reference to Examples, but the present invention is not limited by the following Examples.
[실시예 1]Example 1
2-아미노-4,5-디메틸-4'-클로로벤조페논옥심의 제조Preparation of 2-amino-4,5-dimethyl-4'-chlorobenzophenone oxime
2-아미노-4,5-디메틸-4'-클로로벤조페논 15.0g과 염산히드록실아민 15.6g 및 수산화칼륨 11.6g을 95%에탄올에 현탁시킨 후, 40℃의 온도에서 6시간 동안 교반시켰다.15.0 g of 2-amino-4,5-dimethyl-4'-chlorobenzophenone, 15.6 g of hydroxylamine hydrochloride, and 11.6 g of potassium hydroxide were suspended in 95% ethanol and then stirred at a temperature of 40 ° C. for 6 hours.
이 혼합물을 여과하여 염화칼륨을 제거해낸 다음 에탄올을 감압하에서 날려보내고 잔사를 250ml에테르로 2회에 걸쳐 추출하고나서, 물로 세척한 후 무수 황산마그네슘으로 건조시키고 에테르/석유에테르에서 재결정하여 백색결정의 2-아미노-4,5-디메틸-4'-클로로벤조페논 옥심 13.49g을 얻었다.(수율 : 85%)The mixture was filtered to remove potassium chloride, ethanol was blown off under reduced pressure, the residue was extracted twice with 250 ml ether, washed with water, dried over anhydrous magnesium sulfate and recrystallized from ether / petroleum ether to give white crystals. 13.49 g of -amino-4,5-dimethyl-4'-chlorobenzophenone oxime was obtained. (Yield: 85%)
융점 : 156-157℃Melting Point: 156-157 ℃
C15H15N2O Cl에 대한 원소분석치 :Elemental Analysis for C 15 H 15 N 2 O Cl:
계산치 : C ; 65.67, H ; 5.50, N ; 10.20Calculated Value: C; 65.67, H; 5.50, N; 10.20
실슥치 : C ; 65.82, H ; 5.65, N ; 9.92Squelch: C; 65.82, H; 5.65, N; 9.92
적외선 스팩트럼(KBr)은 1617㎝(C=N)에서 다른 것중에서도 뚜렷한 밴드를 나타내었다.Infrared spectrum (KBr) showed a clear band among others at 1617 cm (C = N).
[실시예 2]Example 2
2-아미노-4',5-디클로로 벤조페논 옥심의 제조Preparation of 2-amino-4 ', 5-dichloro benzophenone oxime
2-아미노-4',5-디클로로 벤조페논 10.0g과 염산히드록실아민 10.4g 및 가성소오다 5.3g을 95%의 에탄올에 현탁시킨 후 50℃의 온도에서 6시간 동안 교반시켰다.10.0 g of 2-amino-4 ', 5-dichloro benzophenone, 10.4 g of hydroxylamine hydrochloride and 5.3 g of sodium hydroxide were suspended in 95% ethanol and stirred at a temperature of 50 ° C. for 6 hours.
이 혼합물을 여과하여 염화나트륨을 제거시킨 다음, 에탄올을 감압하에서 날려보내고 잔사를 250㎖벤젠으로 추출하고 나서, 물로 2회에 걸쳐 세척한 후 무수 황산마그네슘으로 건조시키고 벤젠/석유에테르에서 재결정하여 무색 결정의 2-아미노-4',5-디클로로 벤조페논 옥심 7.92g을 얻었다.(수율 : 75%)The mixture was filtered to remove sodium chloride, then ethanol was blown off under reduced pressure, the residue was extracted with 250 ml benzene, washed twice with water, dried over anhydrous magnesium sulfate and recrystallized from benzene / petroleum ether to give colorless crystals. 7.92 g of 2-amino-4 ', 5-dichlorobenzophenone oxime was obtained. (Yield: 75%)
융점 : 151-154℃Melting Point: 151-154 ℃
C13H10N2O Cl2에 대한 원소분석치 :Elemental Analysis for C 13 H 10 N 2 O Cl 2 :
계산치 : C ; 55.53, H ; 3.59, N ; 9.96Calculated Value: C; 55.53, H; 3.59, N; 9.96
실측치 : C ; 55.70, H ; 3.62, N ; 9.84Found: C; 55.70, H; 3.62, N; 9.84
[실시예3]Example 3
2-아미노-2',5-디클로로 벤조페논 옥심의 제조Preparation of 2-amino-2 ', 5-dichloro benzophenone oxime
2-아미노-2',5-디클로로 벤조페논 10.0g과 염산히드록실아민 10.4g 및 수산화칼륨 8.1g을 95%의 에탄올에 현탁시킨 후 50℃의 온도에서 5시간 동안 교반시켰다.10.0 g of 2-amino-2 ', 5-dichloro benzophenone, 10.4 g of hydroxylamine hydrochloride and 8.1 g of potassium hydroxide were suspended in 95% ethanol and stirred at a temperature of 50 ° C. for 5 hours.
이 혼합물을 여과하여 염화칼륨을 제거한 다음 에탄올을 감압하에서 날려보내고 잔사를 200㎖벤젠으로 추출하고 물로 2회에 걸쳐 세척한 후 무수망초로 건조시키고 벤젠/석유에테르에서 재결정하여 여린노란색결정의 2-아미노-2',5-디클로로 벤조페논 옥심 8.1g을 얻었다.(수율 : 76%)The mixture was filtered to remove potassium chloride, then ethanol was blown off under reduced pressure, the residue was extracted with 200 ml benzene, washed twice with water, dried over anhydrous forget-me-not and recrystallized from benzene / petroleum ether to give 2-amino of pale yellow crystals. 8.1 g of -2 ', 5-dichloro benzophenone oxime was obtained. (Yield: 76%)
융점 : 134-137℃Melting Point: 134-137 ℃
C13H10N2O Cl2에 대한 원소분석치 :Elemental Analysis for C 13 H 10 N 2 O Cl 2 :
계산치 : C ; 55.53, H ; 3.59, N ; 9.96Calculated Value: C; 55.53, H; 3.59, N; 9.96
실슥치 : C ; 55.80, H ; 3.55, N ; 9.88Squelch: C; 55.80, H; 3.55, N; 9.88
[실시예 4]Example 4
2-아미노-3',4'-메톡시 벤조페논 옥심의 제조Preparation of 2-amino-3 ', 4'-methoxy benzophenone oxime
2-아미노-3',4'-메톡시 벤조페논 15.0g과 염산히드록실아민 14.2g 및 가성소오다 7.9g을 95% 에탄올에 현탁시킨 후 70℃의 온도에서 6시간 동안 교반시켰다.15.0 g of 2-amino-3 ', 4'-methoxy benzophenone, 14.2 g of hydroxylamine hydrochloride and 7.9 g of sodium hydroxide were suspended in 95% ethanol and stirred at a temperature of 70 ° C. for 6 hours.
이 혼합물을 여과시켜서 염화나트륨을 제거시킨 다음 에탄올을 감압하에서 날려보내고 잔사를 250㎖에테르로 2회에 걸쳐 추출하고나서 물로 세척한 후 무수망초로 건조시키고 에테르에서 재결정하여 백색결정의 2-아미노-3',4'-메톡시 벤조페논 옥심 12.9g을 얻었다.(수율 : 81%)The mixture was filtered to remove sodium chloride, then ethanol was blown off under reduced pressure, the residue was extracted twice with 250 ml ether, washed with water, dried over anhydrous forget-me-not and recrystallized from ether to give 2-amino-3 as white crystals. 12.9 g of ', 4'-methoxy benzophenone oxime was obtained. (Yield: 81%)
융점 : 162-163℃Melting Point: 162-163 ℃
C15H16N2O3에 대한 원소분석치 :Elemental Analysis for C 15 H 16 N 2 O 3 :
계산치 : C ; 66.16, H ; 5.92, N ; 10.3Calculated Value: C; 66.16, H; 5.92, N; 10.3
실슥치 : C ; 66.01, H ; 5.95, N ; 9.70Squelch: C; 66.01, H; 5.95, N; 9.70
[비교예][Comparative Example]
2-아미노-2',5-디클로로 벤존페논 옥심의 제조Preparation of 2-amino-2 ', 5-dichloro benzonphenone oxime
2-아미노-2',5-디클로로 벤조페논 34.2g과 염산히드록실아민 26.8g을 피리딘 100㎖와 피페리딘 10㎖의 혼합용액에 현탁시킨 후 150-170℃의 온도에서 20시간동안 교반시켰다.34.2 g of 2-amino-2 ', 5-dichloro benzophenone and 26.8 g of hydroxylamine hydrochloride were suspended in a mixed solution of 100 ml of pyridine and 10 ml of piperidine and stirred at a temperature of 150-170 ° C. for 20 hours. .
이 혼합물중에서 사용된 용매를 감압하에 날려보내고 잔사를 에테르로 추출한 후 물로 세척하여 노란 옥일상의 물질을 얻었다. 이를 헥산 : 에틸아세테이트의 비 1:1에서 실리카겔크로마토그래피로 분리하여 백색결정의 2-아미노-2',5-디클로로 벤조페논옥심 9.8g을 얻었다.(수율 : 27%)The solvent used in this mixture was blown off under reduced pressure, the residue was extracted with ether and washed with water to give a yellow jade-like substance. This was separated by silica gel chromatography at a ratio of hexane: ethyl acetate 1: 1 to obtain 9.8 g of 2-amino-2 ', 5-dichloro benzophenone oxime as white crystals (yield: 27%).
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019880014679A KR910003636B1 (en) | 1988-11-09 | 1988-11-09 | Process for the preparation of benzophenon oxime compounds |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019880014679A KR910003636B1 (en) | 1988-11-09 | 1988-11-09 | Process for the preparation of benzophenon oxime compounds |
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| Publication Number | Publication Date |
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| KR900007792A KR900007792A (en) | 1990-06-02 |
| KR910003636B1 true KR910003636B1 (en) | 1991-06-07 |
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| KR1019880014679A KR910003636B1 (en) | 1988-11-09 | 1988-11-09 | Process for the preparation of benzophenon oxime compounds |
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1988
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| KR900007792A (en) | 1990-06-02 |
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