KR20020049492A - A process for preparing pyridone derivative - Google Patents
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/09—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to carbon atoms of an acyclic unsaturated carbon skeleton
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
본 발명은 노인성 치매 치료제로 유효한 다음 화학식 1로 표시되는 피리돈 유도체의 제조방법에 관한 것으로서, 더욱 상세하게는 다음 화학식 2로 표시되는 1,4-사이클로헥세인다이온 모노케탈을 2차아민과 산 촉매하에 반응시킨 후에, 프로피올아미드로 처리하는 비교적 간편한 제조방법에 의해 다음 화학식 1로 표시되는 피리돈 유도체를 고수율로 제조하는 방법에 관한 것이다.The present invention relates to a method for preparing a pyridone derivative represented by the following Chemical Formula 1, which is effective as a treatment for senile dementia, and more specifically, a 1,4-cyclohexanedione monoketal represented by the following Chemical Formula 2 with a secondary amine After reacting under an acid catalyst, the present invention relates to a method for producing a pyridone derivative represented by the following general formula (1) in a high yield by a relatively simple production process treated with propiolamide.
상기에서 : R1및 R2는 각각 C1∼C6알킬기이거나, 또는 R1및 R2가 서로 결합하여 5원자 내지 8원자 헤테로 고리를 형성할 수 있다.In the above: R 1 and R 2 are each a C 1 to C 6 alkyl group, or R 1 and R 2 may be bonded to each other to form a 5 to 8 membered hetero ring.
상기 화학식 1로 표시되는 피리돈 유도체는 치매 치료제로서 공지된후퍼진(Huperzine)의 합성을 위한 주요 중간체로 잘 알려져 있다.The pyridone derivative represented by Formula 1 is well known as a major intermediate for the synthesis of Huperzine, which is known as a treatment for dementia.
후퍼진(Huperzine)은 1986년에 중국의 이끼류에서 분리한 천연물로 중국에서는 종기, 해열, 정신분열증 등의 치료를 목적으로 사용하여 왔다. 또한, 후퍼진(Huperzine)은 현재 시판중인 타크린(tacrine), 도네페질(Donepezil; Aricept)과 비교하였을때 독성이 적고 치매환자의 기억력 증진에 좋은 효과를 보여 준다. 현재까지 알려진 바에 의하면, 후퍼진(Huperzine)보다 좋은 치매치료약은 없는 것으로 사료된다. 그러나, 후퍼진(Huperzine)은 천연물로서 천연에서의 함량이 <0.01%이고 자원도 제한되어 있어 대량생산에 많은 제약이 있다. 따라서, 후퍼진(Huperzine) 전합성에 많은 노력이 요구된다.Huperzine is a natural product isolated from Chinese moss in 1986 and has been used in China for the treatment of boils, fever and schizophrenia. In addition, Huperzine is less toxic compared to the currently available tacrine and Donepezil (Aricept), and shows a good effect on improving memory in dementia patients. As far as is known, no dementia medication is better than Huperzine. However, Huperzine is a natural product, which has a content of <0.01% in nature and limited resources, thereby limiting mass production. Therefore, much effort is required for the synthesis of Huperzine.
A. Kozikowski는 상기 화학식 2로 표시되는 1,4-사이클로헥세인다이온 모노에틸렌 케탈을 출발물질로 사용하고, 다음에 나타낸 각각의 제조방법에 의하여 상기 화학식 1로 표시되는 피리돈 유도체를 합성하는 방법을 보고한 바 있다[J. Chem. Soc. 1990, 195].A. Kozikowski uses a 1,4-cyclohexanedione monoethylene ketal represented by Formula 2 as a starting material, and synthesizes a pyridone derivative represented by Formula 1 according to the respective preparation methods shown below. I have reported how to do it [J. Chem. Soc. 1990, 195].
다음에 나타낸 바와 같이 만니히 염기, 피리디늄염 등을 사용하여 아주 낮은수율(9%)로 피리돈 유도체를 합성하는 방법을 보고한 바 있다.As described below, a method of synthesizing a pyridone derivative using a Mannich base, a pyridinium salt, and the like in a very low yield (9%) has been reported.
다음에 나타낸 바와 같이 피롤리딘, α-클로로아크릴아마이드 등을 사용하여 역시 낮은 수율(11%)로 피리돈 유도체를 합성하는 방법을 보고한 바 있다.As shown below, a method of synthesizing pyridone derivatives using pyrrolidin, α-chloroacrylamide and the like in low yield (11%) has also been reported.
다음에 나타낸 바와 같이 음이온화 반응 및 메틸 시스-3-클로로아크릴레이트와 반응시킨 후 암모니아수로 처리하여 22% 수율로 피리돈 유도체를 합성하는 방법을 보고한 바 있다.As shown below, a method of synthesizing a pyridone derivative in 22% yield by treating with anionization reaction and methyl cis-3-chloroacrylate followed by treatment with ammonia water has been reported.
또한, A. Kozikowski는 상기한 제조방법 이외에도 피롤리딘 등과 반응시킨 후에 아크릴아마이드와 반응시켜 이중결합이 없는 피리돈을 얻은 다음, 피리돈의 NH를 보호하고 이중결합 도입 그리고 보호기를 제거하는 여러 단계를 거쳐 최고 45% 수율로 피리돈 유도체를 합성하는 방법을 보고한 바도 있다[J. Org. Chem.4636].In addition to A. Kozikowski, in addition to the above-described preparation method, after reacting with pyrrolidin and the like, acrylamide is obtained to obtain pyridone without a double bond, and then various steps of protecting NH from pyridone, introducing a double bond and removing a protecting group. We have also reported a method for synthesizing pyridone derivatives up to 45% yield [ J. Org. Chem. 4636].
이 방법은 상기한 방법들에 비교하여 수율이 많이 개선된 효과는 있지만, 대량 합성이 어렵고 수율의 변동이 심하며 5 단계 전체수율은 대략 45% 정도이다.This method has the effect of much improved yield compared to the above methods, but the mass synthesis is difficult, the fluctuation of the yield is high, and the overall five-step yield is about 45%.
또다른 방법으로서, 100 ℃ 정도 및 200 기압 정도를 유지하는 고압반응용기에서 메탄올에 용해한 암모니아 가스를 사용하여 피리돈 유도체를 70% 수율로 얻었다. 이 방법의 경우 수율은 비교적 합리적이지만 고압반응으로 인한 위험성을 내포하고 있다.As another method, pyridone derivatives were obtained in 70% yield using ammonia gas dissolved in methanol in a high pressure reaction vessel maintained at about 100 ° C. and about 200 atm. The yield is relatively reasonable for this method, but it poses the risk of high pressure reaction.
이에, 본 발명자들은 보다 공업적으로 유리하고 제조수율도 우수한 상기 화학식 1로 표시되는 피리돈 유도체를 제조하고자 노력하였다. 그 결과, 상기 화학식 2로 표시되는 화합물을 출발물질로 사용하고, 이를 2차아민과 산촉매하에서 반응시킨 후에 프로피올아미드로 처리하는 간편한 제조방법으로 고수율의 피리돈 유도체를 합성함으로써 본 발명을 완성하게 되었다.Thus, the present inventors have tried to produce a pyridone derivative represented by the formula (1) more industrially advantageous and excellent production yield. As a result, the present invention is completed by synthesizing a high yield pyridone derivative using a compound represented by Chemical Formula 2 as a starting material, and reacting it with a secondary amine under an acid catalyst and then treating with propiolamide. Was done.
따라서, 본 발명은 상기 화학식 1로 표시되는 피리돈 유도체를 공업적으로 유리하게 제조하는 방법을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide a method for industrially advantageously preparing a pyridone derivative represented by Chemical Formula 1.
본 발명은 다음 화학식 2로 표시되는 1,4-사이클로헥세인다이온 모노케탈을 2차아민과 산 촉매하에 반응시킨 후에, 다음 화학식 3으로 프로피올아미드로 처리하여 다음 화학식 1로 표시되는 피리돈 유도체를 제조하는 방법을 그 특징으로 한다.The present invention is the reaction of 1,4-cyclohexanedione monoketal represented by the following formula (2) with a secondary amine and an acid catalyst, and then treated with propiolamide by the following formula (3) to the pyridone represented by the following formula (1) It is characterized by a method for producing a derivative.
상기 화학식에서 : R1및 R2는 각각 C1∼C6알킬기이거나, 또는 R1및 R2가 서로 결합하여 5원자 내지 8원자 헤테로 고리를 형성할 수 있다.In the above formula: R 1 and R 2 are each a C 1 ~ C 6 alkyl group, or R 1 and R 2 may be bonded to each other to form a 5 to 8 membered hetero ring.
이와 같은 본 발명을 더욱 상세히 설명하면 다음과 같다.Referring to the present invention in more detail as follows.
본 발명은 상기 화학식 2로 표시되는 1,4-사이클로헥세인다이온 모노케탈으로부터 상기 화학식 1로 표시되는 피리돈 유도체 합성을 위하여, 피롤리딘과 산 촉매 하에서 반응한 후에 프로피올아미드에 의한 반응을 수행하는 2단계 공정으로 구성된다. 상기한 본 발명의 2단계 공정은 중간체의 분리공정 없이 일용기반응(one-pot reaction)으로 수행할 수도 있다.The present invention for the synthesis of pyridone derivatives represented by the formula (1) from the 1,4-cyclohexanedione monoketal represented by the formula (2), the reaction with pyrrolidin and an acid catalyst and then reaction with propiolamide It consists of a two-step process to carry out. The two-step process of the present invention described above may be carried out in a one-pot reaction without an intermediate separation process.
상기에서 : R1및 R2는 각각 C1∼C6알킬기이거나, 또는 R1및 R2가 서로 결합하여 5원자 내지 8원자 헤테로 고리를 형성할 수 있다.In the above: R 1 and R 2 are each a C 1 to C 6 alkyl group, or R 1 and R 2 may be bonded to each other to form a 5 to 8 membered hetero ring.
상기 화학식 2로 표시되는 1,4-사이클로헥세인다이온 모노케탈을 2차아민 및 산촉매 하에서의 반응은 용매환류 조건하에서의 가열반응에 의해 수행되며, 반응도중에 계속적으로 물이 생성되므로 딘-스탁(Dean-Stark) 물 분리기를 설치하여 더 이상의 물이 생성되지 않을 때까지 반응을 수행한다. 상기 반응에 사용되는 2차아민으로는 피롤리딘, 모르폴린, 피페리딘 등의 이나민류가 사용될 수 있고, 산촉매로는p-톨루엔술폰산, 캄파술폰산, 피리디니움 파라톨루엔술폰산, 황산 등이 사용될 수 있다. 그리고, 반응용매로는 벤젠, 톨루엔, 자일렌 등의 방향족탄화수소류를 사용한다.The reaction of the 1,4-cyclohexanedione monoketal represented by Chemical Formula 2 under the secondary amine and the acid catalyst is carried out by heating under solvent reflux conditions, and water is continuously produced during the reaction, so Dean-Stark (Dean Stark) Install a water separator and carry out the reaction until no more water is produced. Inamines such as pyrrolidine, morpholine, and piperidine may be used as secondary amines used in the reaction, and acid catalysts include p -toluenesulfonic acid, campasulfonic acid, pyridinium paratoluenesulfonic acid, sulfuric acid, and the like. Can be used. As the reaction solvent, aromatic hydrocarbons such as benzene, toluene and xylene are used.
다음으로는 상기 반응액을 진공 증류시켜 용매를 제거한 다음, 프로피올 아마이드를 가하고 용매환류 조건하에서의 다시 가열반응을 수행한다. 이때, 반응용매로는 다이옥산, 테트라하이드로퓨란 등의 고리형 에테르 계열의 용매를 사용한다.Next, the reaction solution is vacuum distilled to remove the solvent, and then propionol amide is added and heating is performed again under solvent reflux conditions. In this case, a cyclic ether solvent such as dioxane or tetrahydrofuran is used as the reaction solvent.
상기 반응이 완결되면 용매를 감압하에 증류시키고 크로마토그래피 등의 통상의 분리 정제 방법을 수행하여 본 발명이 목적하는 상기 화학식 1로 표시되는 피리돈 유도체를 수득한다.When the reaction is completed, the solvent is distilled under reduced pressure and a conventional separation and purification method such as chromatography is performed to obtain a pyridone derivative represented by Chemical Formula 1, which is the object of the present invention.
이상에서 설명한 바와 같은 제조방법에 따르면, 상기 화학식 1로 표시되는 피리돈 유도체는 75% 이상의 높은 수율로 용이하게 합성할 수 있다.According to the manufacturing method as described above, the pyridone derivative represented by the formula (1) can be easily synthesized in a high yield of 75% or more.
이와 같은 본 발명을 다음의 실시예에 의거하여 더욱 상세히 설명하면 다음과 같은 바, 본 발명이 이에 한정되는 것은 아니다.When the present invention is described in more detail based on the following examples, the present invention is not limited thereto.
실시예 1: 1',5',7',8'-테트라하이드로-스파이로[1,3-다이옥소레인-2,6'(2'H)-퀴놀린]-2'온의 제조Example 1: Preparation of 1 ', 5', 7 ', 8'-tetrahydro-spiro [1,3-dioxolane-2,6' (2'H) -quinolin] -2'one
1,4-사이클로헥세인다이온 모노에틸렌 케탈(5.0 g, 32 mmol)을 벤젠(100 mL)에 녹이고 피롤리딘(5.4 g, 64 mmol)과p-톨루엔 술폰산(200 mg, 1.1 mmol)을 가하고 딘-스탁(Dean-Stark) 물 분리기에서 더 이상 물이 나오지 않을 때까지 가열하였다. 벤젠을 진공하에서 제거하고 잔류물을 다이옥산(80 mL)에서 녹인 다음 프로피올 아마이드(6.62 g, 96 mmol) 가하고 다시 10 시간동안 환류하였다. 이나민의 완전한 가수분해를 위해 물(20 mL)를 가하고 10 시간 환류한 후 실온으로 냉각 후 다이옥산을 제거하고 얻은 불순한 잔류물에 물을 가하고 연속추출기를 사용하여 다이클로로메탄으로 추출 후 감압 농축하여 얻은 불순물을 후레쉬 칼럼 크로마토그래피(실리카젤, 10% 메탄올/디클로로메탄)로 분리하여 상기 화학식 1로 표시되는 순수한 피리돈 유도체(4.97 g, 75% 수율)를 얻었다.Dissolve 1,4-cyclohexanedione monoethylene ketal (5.0 g, 32 mmol) in benzene (100 mL), and pyrrolidine (5.4 g, 64 mmol) and p -toluene sulfonic acid (200 mg, 1.1 mmol). It was added and heated until no more water emerged from the Dean-Stark water separator. Benzene was removed in vacuo and the residue was taken up in dioxane (80 mL), then propionol amide (6.62 g, 96 mmol) was added and refluxed again for 10 h. For complete hydrolysis of inamin, water (20 mL) was added, refluxed for 10 hours, cooled to room temperature, dioxane was removed, water was added to the resulting impure residue, extracted with dichloromethane using a continuous extractor, and concentrated under reduced pressure. Impurities were separated by flash column chromatography (silica gel, 10% methanol / dichloromethane) to obtain pure pyridone derivatives represented by Formula 1 (4.97 g, 75% yield).
1H NMR(CDCl3, 200 MHz) δ 12.6(s, brs, 1H), 7.14(d,J=9.3Hz, 1H), 6,40(d,J=9.2Hz, 1H), 4.02(s, 4H), 2.89(t,J=6.5Hz, 2H), 2.71(s, 2H), 1.93(t,J=6.5Hz, 2H). 1 H NMR (CDCl 3 , 200 MHz) δ 12.6 (s, brs, 1H), 7.14 (d, J = 9.3 Hz, 1H), 6,40 (d, J = 9.2 Hz, 1H), 4.02 (s, 4H), 2.89 (t, J = 6.5 Hz, 2H), 2.71 (s, 2H), 1.93 (t, J = 6.5 Hz, 2H).
실시예 2:1',5',7',8'-테트라하이드로-스파이로[5,5-다이메틸1,3-다이옥소레인-2,6'(2'H)-퀴놀린]-2'온의 제조 Example 2 1 ', 5', 7 ', 8'-tetrahydro-spiro [5,5-dimethyl1,3-dioxolane-2,6'(2'H) -quinoline] -2 'Manufacture of the came
1,4-사이클로헥세인다이온 모노-2,2-다이메틸트라이메틸렌 케탈(500 mg, 2.52 mmol)을 벤젠(15 mL)에 녹이고 피롤리딘(358 mg, 5.04 mmol)과p-톨루엔 술폰산(15 mg, 0.08 mmol)을 가하고 딘-스탁(Dean-Stark) 물 분리기에서 더 이상 물이 나오지 않을 때까지 가열하였다. 벤젠을 진공하에서 제거하고 잔류물을 다이옥산(15 mL)에서 녹인 다음 프로피올 아마이드(522 g, 7.56 mmol) 가하고 다시 10 시간동안 환류하였다. 이나민의 완전한 가수분해를 위해 물(2 mL)를 가하고 10 시간 환류한 후 실온으로 냉각 후 다이옥산을 제거하고 얻은 불순한 잔류물에 물을 가하고 다이클로로메탄으로 추출 후 감압 농축하여 얻은 불순물을 후레쉬 칼럼 크로마토그래피(실리카젤, 에틸아세테이트)로 분리하여 상기 화학식 1로 표시되는 순수한 피리돈 유도체(326 mg, 52% 수율)를 얻었다.Dissolve 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal (500 mg, 2.52 mmol) in benzene (15 mL), pyrrolidine (358 mg, 5.04 mmol) and p -toluene sulfonic acid (15 mg, 0.08 mmol) was added and heated until no more water came out of the Dean-Stark water separator. Benzene was removed in vacuo and the residue was taken up in dioxane (15 mL), then propionol amide (522 g, 7.56 mmol) was added and refluxed again for 10 h. For complete hydrolysis of inamin, water (2 mL) was added, refluxed for 10 hours, cooled to room temperature, dioxane was removed, water was added to the resulting impure residue, extracted with dichloromethane, and concentrated under reduced pressure. Separation was performed by chromatography (silica gel, ethyl acetate) to obtain a pure pyridone derivative (326 mg, 52% yield) represented by Chemical Formula 1.
1H NMR(CDCl3, 200 MHz) δ 12.9(brs, 1H), 7.18(d,J=11.8Hz, 1H), 6.39(d,J=11.8Hz, 1H), 3.53(d,J=11.2Hz, 2H), 3.47(d,J=11.3Hz, 2H), 2.79(s, 4H), 2.13(t,J=6.6 Hz, 2H), 1.07, 0.92(2s, 6H). 1 H NMR (CDCl 3 , 200 MHz) δ 12.9 (brs, 1H), 7.18 (d, J = 11.8 Hz, 1H), 6.39 (d, J = 11.8 Hz, 1H), 3.53 (d, J = 11.2 Hz , 2H), 3.47 (d, J = 11.3 Hz, 2H), 2.79 (s, 4H), 2.13 (t, J = 6.6 Hz, 2H), 1.07, 0.92 (2s, 6H).
실시예 3:1',5',7',8'-테트라하이드로-스파이로[5,5-다이메틸1,3-다이옥소레인-2,6'(2'H)-퀴놀린]-2'온의 제조Example 3: 1 ', 5', 7 ', 8'-tetrahydro-spiro [5,5-dimethyl1,3-dioxolane-2,6' (2'H) -quinoline] -2 'Manufacture of the came
1,4-사이클로헥세인 모노-2,2-다이메틸트라이메틸렌 케탈(500 mg, 2.52 mmol)을 벤젠(15 mL)에 녹이고 모르폴린(439 mg, 5.04 mmol)과p-톨루엔 술폰산(15 mg, 0.08 mmol)을 가하고 딘-스탁(Dean-Stark) 물 분리기에서 더 이상 물이 나오지 않을 때까지 가열하였다. 벤젠을 진공하에서 제거하고 잔류물을 다이옥산(15 mL)에서 녹인 다음 프로피올 아마이드(522 g, 7.56 mmol) 가하고 다시 10 시간동안 환류하였다. 이나민의 완전한 가수분해를 위해 물(2 mL)를 가하고 10 시간 환류한 후 실온으로 냉각 후 다이옥산을 제거하고 얻은 불순한 잔류물에 물을 가하고 다이클로로메탄으로 추출 후 감압 농축하여 얻은 불순물을 후레쉬 칼럼 크로마토그래피(실리카젤, 에틸아세테이트)로 분리하여 상기 화학식 1로 표시되는 순수한 피리돈 유도체(270 mg, 43% 수율)를 얻었다.1,4-cyclohexane mono-2,2-dimethyltrimethylene ketal (500 mg, 2.52 mmol) was dissolved in benzene (15 mL), morpholine (439 mg, 5.04 mmol) and p -toluene sulfonic acid (15 mg). , 0.08 mmol) was added and heated until no more water emerged in a Dean-Stark water separator. Benzene was removed in vacuo and the residue was taken up in dioxane (15 mL), then propionol amide (522 g, 7.56 mmol) was added and refluxed again for 10 h. For complete hydrolysis of inamin, water (2 mL) was added, refluxed for 10 hours, cooled to room temperature, dioxane was removed, water was added to the resulting impure residue, extracted with dichloromethane, and concentrated under reduced pressure. Separation by chromatography (silica gel, ethyl acetate) to obtain a pure pyridone derivative (270 mg, 43% yield) represented by the formula (1).
이상에서 설명한 바와 같이, 본 발명에 따른 제조방법은 고압반응기를 사용하거나 또는 복잡한 반응 공정을 수행하지 않고서도 목적하는 피리돈 유도체를 고수율로 수득할 수 있으므로 공업적으로 매우 유용하다.As described above, the production method according to the present invention is very industrially useful because the desired pyridone derivative can be obtained in high yield without using a high pressure reactor or performing a complicated reaction process.
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