KR900001173B1 - Process for preparing 2-alkoxy carbonyl-4-(4-pyridyl) cyclohexanone - Google Patents
Process for preparing 2-alkoxy carbonyl-4-(4-pyridyl) cyclohexanone Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
Description
본 발명은 2-알콕시카르보닐-4-(4-피리딜)시클로헥사논의 제조방법에 관한 것이다. 2-알콕시카르보닐-4-(4-피리딜)시클로헥사논은 농약 및 의약의 중간체, 특히 의약으로서 유용한 이소퀴놀린 유도체의 제조용 중간체로서 중요한 물질이다.The present invention relates to a process for the preparation of 2-alkoxycarbonyl-4- (4-pyridyl) cyclohexanone. 2-alkoxycarbonyl-4- (4-pyridyl) cyclohexanone is an important substance as an intermediate for the preparation of isoquinoline derivatives useful as pesticides and intermediates of medicaments, in particular medicaments.
제4위치에 치환기를 갖고 있는 시클로헥사논의 2-카르복실산 유도체가 알려져왔으며(참조 : D.Y.Curtin·J·A·C·S··1960, 82, 2357), 제4위치에 페닐치환기를 갖는 전술한 카르복실산류를 에스테르화하면 2-알콕시카르보닐-4-페닐시클로헥사논류를 제조할 수 있으나, 본 발명의 목적인 2-알콕시카르보닐-4-(4-피리딜)시클로헥사논에 대해서는 지금까지 전연 알려져 있지 않았다.2-carboxylic acid derivatives of cyclohexanone having a substituent at the fourth position have been known (see DYCurtinJJ AC S1960, 82, 2357) and a phenyl substituent at the fourth position. By esterifying the aforementioned carboxylic acids, 2-alkoxycarbonyl-4-phenylcyclohexanones can be prepared, but for the 2-alkoxycarbonyl-4- (4-pyridyl) cyclohexanone which is an object of the present invention, So far not known.
종래, 전술한 2-알콕시카르보닐-4-페닐시클로헥사논은 먼저 4-페닐시클로헥사논을 제조한 다음 제2위치에 카르복실기를 도입시킴으로써 제조되었다.Conventionally, the aforementioned 2-alkoxycarbonyl-4-phenylcyclohexanone was prepared by first preparing 4-phenylcyclohexanone and then introducing a carboxyl group in a second position.
즉, 본 발명에 따른 2-알콕시카르보닐-4-(4-피리딜)시클로헥사논을 종래의 방법에 의해 제조하고자 할 경우에는 먼저 4-(4-피리딜)시클로헥사논을 제조하여야만 되는바, 4-(4-피리딜)시클로헥사논 그 자체는 미지의 화합물이기 때문에 신규물질인 2-알콕시카르보닐-4-(4-피리딜)시클로헥사논을 제조하는 과제는 종래의 방법에 의해서는 해결할 수가 없는 것이다.That is, when preparing the 2-alkoxycarbonyl-4- (4-pyridyl) cyclohexanone according to the present invention by the conventional method must first prepare 4- (4-pyridyl) cyclohexanone Since 4- (4-pyridyl) cyclohexanone itself is an unknown compound, the problem of preparing 2-alkoxycarbonyl-4- (4-pyridyl) cyclohexanone, which is a novel substance, has been solved in conventional methods. It cannot be solved by
본 발명자들은 농약 및 의약의 중간체로서 유용한, 특히 의약 그 자체로서 유용한 이소퀴놀린유도체의 제조용 중간체로서 중요한 2-알콕시카르보닐-4-(4-피리딜)시클로헥사논의 제조방법에 대해 광범위한 연구를 수행한 결과, 4-(4-피리딜)피멜산 에스테르류를 디크만 축합시키면 2-알콕시카르보닐-4-(4-피리딜)시클로헥사논을 용이하게 제조할 수 있다는 사실을 발견해내고 본 발명을 완성하기에 이르렀다.The inventors have carried out extensive research on the preparation of 2-alkoxycarbonyl-4- (4-pyridyl) cyclohexanone, which is useful as an intermediate for the preparation of isoquinoline derivatives, which is useful as an intermediate of pesticides and medicaments, and particularly useful as a medicament itself. As a result, the inventors have found that, if Dikman condensed 4- (4-pyridyl) pimelic acid esters can easily prepare 2-alkoxycarbonyl-4- (4-pyridyl) cyclohexanone and the present invention. Came to complete.
이하, 본 발명의 방법을 상세히 설명한다.Hereinafter, the method of the present invention will be described in detail.
본 발명의 방법 반응하기의 반응 공정식에 의해 실행된다.The process of the present invention is carried out by the reaction process formula below.
(식중, R은 메틸기 또는 에틸기를 나타낸다.)(Wherein R represents a methyl group or an ethyl group)
일반식(Ⅲ)의 화합물은 제조하기 위한 일반식(Ⅱ)의 화합물과 아크릴산에스테르의 반응은 촉매로서 1,8-디아자비시클로-[5.4.0]-7-운데센과 같은염기를 사용하면서 실온 내지 50℃의 온도 범위하의 유기 용매중에서 또는 어떠한 용매도 사용하지 않고 수행할 수 있다.The reaction of the compound of the formula (II) and the acrylate ester for preparing the compound of the formula (III) is carried out at room temperature using a base such as 1,8-diazabicyclo- [5.4.0] -7-undecene as a catalyst. It may be carried out in an organic solvent at a temperature in the range of 50 ° C. or without using any solvent.
다음, 일반식(Ⅲ)의 화합물을 염산중에서 가열시키면, 에스테르 잔기중 R기를 가수분해함과 동시에 시아노기의 가수분해 및 얻어지는 카르복실기의 탈카르복실화가 실행된다.Next, when the compound of the general formula (III) is heated in hydrochloric acid, hydrolysis of the R group in the ester moiety and hydrolysis of the cyano group and decarboxylation of the resulting carboxyl group are performed.
이렇게 얻어진 생성물을 분리시키지 않고 직접 에스테르화시키면 일반식(Ⅰ)의 4-(4-피리딜)-피멜산 에스테르가 생성된다.Direct esterification without separation of the product thus obtained yields the 4- (4-pyridyl) -pimelic acid ester of general formula (I).
다음에 일반식(Ⅰ) 화합물을 디크만 축합시키면 본 발명에 따른 2-알콕시카르보닐-4-(4-피리딜)시클로헥사논이 제조된다.Next, Dikman condensation of the compound of formula (I) yields 2-alkoxycarbonyl-4- (4-pyridyl) cyclohexanone according to the present invention.
디크만 축합의 반응용매로서는 각종의 유기용매를 사용하여도 좋으며, 알콜류, 벤젠, 톨루엔 또는 테트라히드로푸란 용매가 바림직하다. 온도는 실온 내지 사용된 용매의 비점 범위내에서 어떤 온도도 가능하나, 반드시 고온일 필요는 없다.Various organic solvents may be used as the reaction solvent for Dichman condensation, and alcohols, benzene, toluene or tetrahydrofuran solvents are preferred. The temperature may be any temperature within room temperature to the boiling point of the solvent used, but need not necessarily be high temperature.
디크만 축합의 염기로서는 각종의 염기를 사용하여도 좋으나, 나트륨알콕시드 또는 칼륨 t-부톡시드 염기가 바람직하다.Various bases may be used as the base of Dikman condensation, but sodium alkoxide or potassium t-butoxide base is preferable.
본 발명에 의하면 농약 및 의약의 중간체, 특히 의약으로서 유용한 이소퀴놀린 유도체의 제조용 중간체로서 중요한 신규의 2-알콕시카르보닐-4-(4-피리딜)시클로헥사논을 제공할 수 있다.According to the present invention it is possible to provide novel 2-alkoxycarbonyl-4- (4-pyridyl) cyclohexanone which is important as an intermediate for the preparation of isoquinoline derivatives useful as agrochemicals and pharmaceutical intermediates, especially medicaments.
하기에 본 발명에 한정되지 않는 실시예를 열거하여 본 발명을 보다 상세하게 설명한다.The present invention will be described in more detail below with examples which are not limited to the present invention.
실시예에 있어서는 아크릴산의 메틸에스테르에 대해서만 기재하였으나, 아크릴산 에틸에스테르의 경우에도 아주 동일한 방법으로 본 발명의 방법을 실행할 수 있다.In the examples, only the methyl ester of acrylic acid is described, but in the case of acrylic acid ethyl ester, the method of the present invention can be carried out by the very same method.
[실시예]EXAMPLE
(1) 4-시아노-4-(4-피리딜)피멜산 메틸에스테르 아크릴산메틸 10.4g에 1,8-디아자비시클로 [5.4.0]-7-운데센 0.2g을 첨가한다. 혼합물을 빙냉하에 교반하면서 20 내지 40℃로 유지한다. 아크릴메틸 20.8g중에 4-피리딜아세토니트릴 14.2g을 용해시킨 용액을 첨가한다. 30분후 수욕을 제거하고 반응 혼합물을 실온에서 또 1시간 동안 교반한다. 과잉의 아크릴산메틸을 감압하에 증류한다. 실리카겔 컬럼에 의해 정제하면 4-시아노-4-(4-피리딜)피멜산 메틸에스테르 35g이 유상물질로서 얻어진다.(1) To 10.4 g of 4-cyano-4- (4-pyridyl) pimelic acid methyl ester methyl 0.2 g of 1,8-diazabicyclo [5.4.0] -7-undecene is added. The mixture is kept at 20-40 ° C. while stirring under ice cooling. A solution of 14.2 g of 4-pyridylacetonitrile dissolved in 20.8 g of acrylmethyl is added. After 30 minutes the water bath is removed and the reaction mixture is stirred for another hour at room temperature. Excess methyl acrylate is distilled off under reduced pressure. Purification by silica gel column yields 35 g of 4-cyano-4- (4-pyridyl) pimelic acid methyl ester as an oily substance.
IR(Neat) : 2950, 2230, 1740, 1590, 1430, 1200cm-1 IR (Neat): 2950, 2230, 1740, 1590, 1430, 1200cm -1
NMR(100 MHz, CCl4, δ) : 8.6(2H, m) : 7.4(2H, m) : 3.58(6H,s) : 1.9-2.7(8H, m)NMR (100 MHz, CCl 4 , δ): 8.6 (2H, m): 7.4 (2H, m): 3.58 (6H, s): 1.9-2.7 (8H, m)
(2) 4-(4-피리딜)피멜산 메틸에스테르(2) 4- (4-pyridyl) pimelic acid methyl ester
진함 염산 250ml 중에 4-시아노-4-(4-피리 딜)피멜산 메틸에스테르 13g을 용해시키고, 이 용액을 14시간동안 환류시킨다.13 g of 4-cyano-4- (4-pyridyl) pimelic acid methyl ester is dissolved in 250 ml of concentrated hydrochloric acid, and the solution is refluxed for 14 hours.
감압하에 염산을 증류시키고 잔사를 메탄올 200ml중에 용해 시킨다. 이 용액에 진한황산 1ml를 첨가시키고 혼합물을 4시간 동안 환류시킨다. 중탄산나트륨 3g을 첨가하고 메탄올을 증류시킨 후, 물 150ml 와 아세트산 에틸 150ml를 첨가하고, 또 중탄산나트륨 25g을 서서히 첨가한다. 유기층을 제거하고, 염화나트륨의 포화수 용액 50ml로 세척한 다음, 무수 황산나트륨으로 건조시킨다.Hydrochloric acid is distilled off under reduced pressure and the residue is dissolved in 200 ml of methanol. 1 ml of concentrated sulfuric acid is added to the solution and the mixture is refluxed for 4 hours. After adding 3 g of sodium bicarbonate and distilling methanol, 150 ml of water and 150 ml of ethyl acetate are added, and 25 g of sodium bicarbonate is gradually added. The organic layer is removed, washed with 50 ml of saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate.
다음에 용매를 증류시키면 4-(4-프리딜)피멜산 메틸에스테르 26g의 유상물질로서 얻어진다.The solvent is then distilled off to obtain an oily substance of 26 g of 4- (4-pridyl) pimelic acid methyl ester.
IR(Neat) : 2950, 1740, 1600, 1435, 1250, 1200, 1170cm-1 IR (Neat): 2950, 1740, 1600, 1435, 1250, 1200, 1170cm -1
NMR(100 MHz, CCl4, δ) : 8.6(2H, m) : 7.4(2H, m) : 3.58(6H,s) : 2.55(1H, m) : 1.7-2.28(8H, m)NMR (100 MHz, CCl 4 , δ): 8.6 (2H, m): 7.4 (2H, m): 3.58 (6H, s): 2.55 (1H, m): 1.7-2.28 (8H, m)
(3) 2-메톡시카르보닐-4-(4-피리딜)시클로헥사논(3) 2-methoxycarbonyl-4- (4-pyridyl) cyclohexanone
테트라히드로푸란 100ml중에 칼륨 t-부톡시드 13g을 첨가한다. 테트라히드로푸란 50ml의 중에 4-(4-피리딜)피멜산 메틸에스테르 26g를 용해시킨 용액을 20 내지 40℃에서 첨가시키고 혼합물을 2시간동안 교반한다. 반응을 종료시킨 후, 혼합물을 염화암모늄의 포화수용액으로 처리한 다음 에테르로 추출한다.13 g of potassium t-butoxide is added to 100 ml of tetrahydrofuran. A solution of 26 g of 4- (4-pyridyl) pimelic acid methyl ester in 50 ml of tetrahydrofuran is added at 20 to 40 DEG C and the mixture is stirred for 2 hours. After the reaction was completed, the mixture was treated with a saturated aqueous solution of ammonium chloride and then extracted with ether.
에테르용액을 물로 세척한 다음 건조시킨다. 에테르를 증류시키고, 잔사를 에테르로 재결정하면 융점 82 내지 84℃인 2-메톡시카르보닐-4-(4-피리딜)시클로헥사논 9.6g이 얻어진다.The ether solution is washed with water and dried. The ether was distilled off and the residue was recrystallized from ether to give 9.6 g of 2-methoxycarbonyl-4- (4-pyridyl) cyclohexanone having a melting point of 82 to 84 캜.
IR(KBr) : 2940, 1730, 1650, 1620, 1610, 1440, 1230cm-1 IR (KBr): 2940, 1730, 1650, 1620, 1610, 1440, 1230 cm -1
NMR(100 MHz, CCl3, δ) : 12.18(1H, s) : 8.5-8.64(2H, m) : 7.12-7.28(2H, m) : 3.76(3H,s) : 1.6-2.5(7H, m).NMR (100 MHz, CCl 3 , δ): 12.18 (1H, s): 8.5-8.64 (2H, m): 7.12-7.28 (2H, m): 3.76 (3H, s): 1.6-2.5 (7H, m ).
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| KR1019870002109A KR900001173B1 (en) | 1987-03-10 | 1987-03-10 | Process for preparing 2-alkoxy carbonyl-4-(4-pyridyl) cyclohexanone |
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