KR20140013232A - Process for the preparation of n-(2-hydroxyethyl)nicotinamide and nicorandil - Google Patents
Process for the preparation of n-(2-hydroxyethyl)nicotinamide and nicorandil Download PDFInfo
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- KR20140013232A KR20140013232A KR1020120079722A KR20120079722A KR20140013232A KR 20140013232 A KR20140013232 A KR 20140013232A KR 1020120079722 A KR1020120079722 A KR 1020120079722A KR 20120079722 A KR20120079722 A KR 20120079722A KR 20140013232 A KR20140013232 A KR 20140013232A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/60—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 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/465—Nicotine; Derivatives thereof
Abstract
Description
본 발명은 니코란딜(Nicorandil) 제조에 있어 중간체인 N-(2-히드록시에틸)니코틴아미드(N-(2-hydroxyethyl)nicotinamide) 및 니코란딜의 제조방법에 관한 것이다. The present invention relates to a process for preparing N- (2-hydroxyethyl) nicotinamide and nicorandil, which are intermediates in the preparation of nicorandil.
본 발명의 최종생성물인 니코란딜은 2-[(피리딘-3일카르보닐)아미노]에틸니트레이트 또는 N-[2-(니트로옥시)에틸]-3-피리딘카르복사미드로 불리우며, 그 구조는 하기와 같다.Nicorandil, the final product of the present invention, is called 2-[(pyridin-3 ylcarbonyl) amino] ethylnitrate or N- [2- (nitrooxy) ethyl] -3-pyridinecarboxamide, and its structure Is as follows.
니코란딜은 혈관 확장 작용, 관동맥 연축 억제 작용을 갖고, 심혈행동태, 심기능에 미치는 영향이 적은 각종 병형의 협심증 치료제로서 유효한 약물이다. Nicorandil is an effective drug for treating various types of angina, having an effect of vasodilatation, coronary spasm, and less effect on cardiovascular behavior and cardiac function.
니코란딜은 영국, 호주 및 유럽의 대부분 지역에서 Ikorel, 스위스에서는 Dancor, 인도에서는 Nikoran, 필리핀에서는 Aprior, 일본에서는 Nitorubin 그리고 국내에서는 Sigmart라는 상품명으로 시판되고 있다.Nicolandil is marketed under the trade names Ikorel in most of the UK, Australia and Europe, Dancor in Switzerland, Nikoran in India, Aprior in the Philippines, Nitorubin in Japan and Sigmart in Korea.
니코란딜은 이를 제조하는 과정에 있어 하기 [화학식 1]의 N-(2-히드록시에틸)니코틴아미드를 그 중간체로 하며, 이는 미국등록특허 제 4,200,640호에 개시되어 있다. 또한 국제공개특허 제 WO 92/01668호에는 그 출발물질을 벤조산으로 하는 유사한 제조방법이 개시되어 있다.Nicorandil is an intermediate of N- (2-hydroxyethyl) nicotinamide of the following [Formula 1] in the process of preparing it, which is disclosed in US Patent No. 4,200,640. International Publication No. WO 92/01668 also discloses a similar process for the preparation of benzoic acid as its starting material.
[화학식 1][Formula 1]
한편, 미국등록특허 제4,200,640호 및 국제공개특허 제 WO 92/01668호에서는 상기 N-(2-히드록시에틸)니코틴아미드를 합성하는데 있어 메틸렌클로라이드 또는 클로로포름 용매 하에서 반응을 진행시키지만, 상당히 오랜 시간이 걸리고 반응의 수율이 떨어져 높은 순도를 가지는 니코란딜을 제조하는데 제한이 있었다.On the other hand, U.S. Patent No. 4,200,640 and WO 92/01668 disclose that the reaction proceeds under methylene chloride or chloroform solvent in synthesizing N- (2-hydroxyethyl) nicotinamide. There was a limit to the preparation of nicorandil with high purity due to the low yield of the reaction.
European Journal of Medicinal Chemistry 41(2006) 1167-1179에서는 160-165℃에서 에틸렌글리콜을 사용하여 상기 문헌과 유사한 반응을 수행하지만, 반응이 끝난 후 에틸렌글리콜을 제거하기가 쉽지 않고 반응의 수율이 62%로 낮게 나타난다는 단점이 있다. In the European Journal of Medicinal Chemistry 41 (2006) 1167-1179, reactions similar to those described above are carried out using ethylene glycol at 160-165 ° C., but after the reaction is not easy to remove ethylene glycol and the yield of the reaction is 62%. The disadvantage is that it appears as low.
따라서, 상기 N-(2-히드록시에틸)니코틴아미드를 합성하는데 있어 오랜 시간이 걸린다는 단점을 극복하고, 향상된 수율을 제공할 수 있는 니코란딜의 제조방법이 여전히 요구되고 있다.Therefore, there is still a need for a method for preparing nicorandil that can overcome the disadvantage of taking a long time to synthesize the N- (2-hydroxyethyl) nicotinamide and provide improved yield.
본 발명의 목적은 니코란딜 제조에 있어 중간체인 N-(2-히드록시에틸)니코틴아미드의 효율적인 제조방법을 제공하는 것이다.It is an object of the present invention to provide an efficient process for the preparation of N- (2-hydroxyethyl) nicotinamide, an intermediate in the preparation of nicolandyl.
본 발명은 [화학식 1]의 니코란딜 제조에 있어 중간체인 N-(2-히드록시에틸)니코틴아미드의 제조방법을 제공한다.The present invention provides a method for preparing N- (2-hydroxyethyl) nicotinamide, which is an intermediate in the preparation of nicolandyl of [Formula 1].
[화학식 1][Formula 1]
본 발명은 하기 [화학식 2]의 화합물 및 하기 [화학식 3]의 화합물을 용매없이 반응시키는 단계를 포함하는 [화학식 1]의 N-(2-히드록시에틸)니코틴아미드를 제조하는 방법을 제공한다.The present invention provides a method for preparing N- (2-hydroxyethyl) nicotinamide of [Formula 1] comprising the step of reacting a compound of Formula 2 and a compound of Formula 3 without solvent. .
[화학식 1][Formula 1]
[화학식 2](2)
[화학식 3](3)
또한 본 발명은 하기 [반응식 1]의 새로운 제조 방법을 제공한다.The present invention also provides a novel production method of the following [scheme 1].
[반응식 1][Reaction Scheme 1]
백색의 고체인 메틸 니코티네이트(Methyl nicotinate)에 용매를 사용함이 없이 액체의 모노에탄올아민을 투입하여 교반을 하면서 60℃로 가열을 하면 4시간 후에 반응이 종료되며 다른 불순물이 없어 크로마토그래피와 같은 복잡한 분리공정 없이 [화학식 1]의 N-(2-히드록시에틸)니코틴아미드를 높은 수율 및 순도로 획득할 수 있다.The reaction is terminated after 4 hours when the liquid is heated to 60 ° C while stirring by adding liquid monoethanolamine without using a solvent to methyl nicotinate as a white solid. N- (2-hydroxyethyl) nicotinamide of [Formula 1] can be obtained in high yield and purity without a complicated separation process.
메틸 니코티네이트(Methyl nicotinate)와 모노에탄올아민의 반응 종결 후 반응물에 이소프로필알콜을 가하고 온도를 낮춘 후 이소프로필에테르를 이소프로필알콜의 4배를 가하여 95% 이상의 고순도의 깨끗한 N-(2-히드록시에틸)니코틴아미드의 백색 결정을 얻을 수 있다.After completion of the reaction of methyl nicotinate and monoethanolamine, isopropyl alcohol was added to the reaction product and the temperature was lowered. Then, isopropyl ether was added 4 times of isopropyl alcohol to clean 95% of pure N- (2- White crystals of hydroxyethyl) nicotinamide can be obtained.
본 발명은 하기 [반응식 1]에 따라 용매없이 N-(2-히드록시에틸)니코틴아미드를 제조함으로써 N-(2-히드록시에틸)니코틴아미드를 합성하는데 있어 오랜 시간이 걸린다는 단점을 극복하고, 향상된 수율 및 순도를 제공할 수 있는 N-(2-히드록시에틸)니코틴아미드 및 니코란딜의 새로운 제조 방법을 제공한다.The present invention overcomes the disadvantage that it takes a long time to synthesize N- (2-hydroxyethyl) nicotinamide by preparing N- (2-hydroxyethyl) nicotinamide without solvent according to [Scheme 1] It provides a new process for preparing N- (2-hydroxyethyl) nicotinamide and nicorandil, which can provide improved yields and purity.
[반응식 1][Reaction Scheme 1]
도 1은 N-(2-히드록시에틸)니코틴아미드의 NMR 그래프이다.
도 2는 N-(2-히드록시에틸)니코틴아미드의 XRD 그래프이다.
도 3은 고순도 니코란딜 결정의 NMR 그래프이다.1 is an NMR graph of N- (2-hydroxyethyl) nicotinamide.
2 is an XRD graph of N- (2-hydroxyethyl) nicotinamide.
3 is an NMR graph of high purity nicolandil crystals.
[N-(2-[N- (2- 히드록시에틸Hydroxyethyl )) 니코틴아미드의Nicotinamide 제조 방법] Manufacturing method]
본 발명은 하기 [화학식 2]의 화합물 및 하기 [화학식 3]의 화합물을 용매 없이 반응시키는 단계를 포함하는 [화학식 1]의 N-(2-히드록시에틸)니코틴아미드를 제조하는 방법을 제공한다.The present invention provides a method for preparing N- (2-hydroxyethyl) nicotinamide of [Formula 1] comprising the step of reacting a compound of Formula 2 and a compound of Formula 3 without solvent. .
[화학식 1][Formula 1]
[화학식 2](2)
[화학식 3](3)
상기 제조방법은, 고체인 상기 [화학식 2]의 화합물을 액체인 상기 [화학식 3]의 화합물과 혼합하여 혼합물을 제조하는 단계; 및 상기 혼합물을 가열하여 상기 [화학식 2]의 화합물을 상기 [화학식 3]의 화합물에 반응시키는 단계를 포함할 수 있다.The preparation method may include preparing a mixture by mixing the compound of Chemical Formula 2, which is a solid, with the compound of Chemical Formula 3, which is a liquid; And heating the mixture to react the compound of [Formula 2] with the compound of [Formula 3].
상기 N-(2-히드록시에틸)니코틴아미드를 제조하는 방법은 하기의 반응식 1에 따라 진행될 수 있다.The method for preparing the N- (2-hydroxyethyl) nicotinamide may be performed according to Scheme 1 below.
[반응식 1][Reaction Scheme 1]
본 발명의 N-(2-히드록시에틸)니코틴아미드 제조방법은 상기 [화학식 2]의 화합물 및 상기 [화학식 3]의 화합물을 포함하는 혼합물을 50-70℃로 가열하면서 교반하여 제조하는 것일 수 있다. 상기 혼합물은 바람직하게는 60℃로 가열되어 교반될 수 있다. N- (2-hydroxyethyl) nicotinamide production method of the present invention may be prepared by stirring the mixture containing the compound of [Formula 2] and the compound of [Formula 3] while heating to 50-70 ℃ have. The mixture may preferably be heated to 60 ° C. and stirred.
본 발명의 N-(2-히드록시에틸)니코틴아미드 제조방법에 있어 상기 혼합물의 가열 및 교반공정은 30분 내지 10시간 동안 수행될 수 있으며, 바람직하게는 4시간 동안 수행될 수 있다.In the method for preparing N- (2-hydroxyethyl) nicotinamide of the present invention, the heating and stirring of the mixture may be performed for 30 minutes to 10 hours, and preferably for 4 hours.
본 발명의 N-(2-히드록시에틸)니코틴아미드 제조방법은 상기 혼합물을 제조하는 단계 후, 상기 [화학식 2]의 화합물과 상기 [화학식 3]의 화합물을 포함하는 혼합물을 교반하는 단계를 더 포함할 수 있다.In the method for preparing N- (2-hydroxyethyl) nicotinamide of the present invention, after the step of preparing the mixture, the step of stirring the mixture comprising the compound of Formula 2 and the compound of Formula 3 further It may include.
본 발명의 N-(2-히드록시에틸)니코틴아미드 제조방법은 상기 [화학식 2]의 화합물과 상기 [화학식 3]의 화합물을 반응시킨 후, 이소프로필알콜을 첨가하여 용액을 제조하는 단계; 및 상기 용액을 50-70℃로, 바람직하게는 60℃로 가열하면서 교반하는 단계를 더 포함할 수 있다.N- (2-hydroxyethyl) nicotinamide production method of the present invention comprises the steps of preparing a solution by reacting the compound of [Formula 2] and the compound of [Formula 3], isopropyl alcohol; And it may further comprise the step of stirring while heating the solution to 50-70 ℃, preferably 60 ℃.
본 발명의 N-(2-히드록시에틸)니코틴아미드 제조방법은 상기 용액을 교반하는 단계 후, 상기 용액을 30-45℃, 바람직하게는 40℃로 냉각하는 단계; 상기 용액에 이소프로필에테르를 투입하는 단계; 및 이소프로필에테르가 투입된 용액을 냉각시키는 단계를 더 포함할 수 있다.The method for preparing N- (2-hydroxyethyl) nicotinamide of the present invention comprises, after stirring the solution, cooling the solution to 30-45 ° C., preferably 40 ° C .; Injecting isopropyl ether into the solution; And cooling the solution in which isopropyl ether is added.
본 발명의 방법에 따라 수득된 N-(2-히드록시에틸)니코틴아미드는 결정일 수 있다. 상기 결정은 상기 N-(2-히드록시에틸)니코틴아미드의 결정형은 Cu-Kα 방사선을 사용하는 X-선 분말 회절 스펙트럼 2θ(±0.2)값이 11.980, 13.441, 13.959, 20.420, 21.060, 23.238, 24.097, 24.760, 28.521, 32.438에서 상대세기가 10% 이상인 피크를 가지는 것일 수 있다.The N- (2-hydroxyethyl) nicotinamide obtained according to the process of the invention may be a crystal. The crystals of the N- (2-hydroxyethyl) nicotinamide crystal form X-ray powder diffraction spectrum 2θ (± 0.2) value using Cu-Kα radiation is 11.980, 13.441, 13.959, 20.420, 21.060, 23.238, 24.097, 24.760, 28.521, 32.438 may have a peak with a relative intensity of 10% or more.
본 발명은 상기 제조방법으로 제조된 N-(2-히드록시에틸)니코틴아미드로부터 제조된 니코란딜을 제공한다.The present invention provides nicorandil prepared from N- (2-hydroxyethyl) nicotinamide prepared by the above method.
본 발명은 하기 [화학식 2]의 화합물 및 하기 [화학식 3]의 화합물을 용매없이 반응시켜 [화학식 1]의 화합물을 생성하는 단계 및; [화학식 1]의 화합물을 발연질산과 반응시키는 단계를 포함하는 니코란딜을 제조하는 방법을 제공한다.The present invention comprises the steps of producing a compound of [Formula 1] by reacting the compound of the formula [2] and the compound of the following [Formula 3] without a solvent; It provides a method for producing nicorandil comprising the step of reacting the compound of Formula 1 with fuming nitric acid.
[화학식 1][Formula 1]
[화학식 2](2)
[화학식 3](3)
본 발명의 제조 목적물이 되는 니코란딜은 하기 [반응식 2]의 반응으로 제조할 수 있다. Nicorandil, which is the production target of the present invention, can be produced by the reaction of the following [Scheme 2].
[반응식 2][Reaction Scheme 2]
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예, 실험예 및 비교예를 제시한다. 그러나 하기의 실시예, 실험예 및 비교예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예, 실험예 및 비교예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples, experimental examples, and comparative examples are presented to help understand the present invention. However, the following Examples, Experimental Examples and Comparative Examples are provided only to more easily understand the present invention, but are not limited to the contents of the present invention by Examples, Experimental Examples and Comparative Examples.
니코틴산(Nantong acetic acid chemical, 중국), 메탄올아민(삼전시약), 발연질산(Matsunoen chemicals, 일본) 및 염산(삼전시약)을 준비하였다. 상기 실험 방법 중 특별한 언급이 없는 시약은 모두 Sigma, Aldrich 제품을 사용하였다.Nicotinic acid (Nantong acetic acid chemical, China), methanol amine (Samjeon reagent), fuming nitric acid (Matsunoen chemicals, Japan) and hydrochloric acid (Samjeon reagent) were prepared. Reagents not particularly mentioned in the above experimental methods were all used by Sigma, Aldrich.
물질의 녹는점(M.P)은 BUCHI Melting Point B-540를 이용하여, 온도를 5℃/ Min의 속도로 40℃까지 상승시키며 측정하고 기록하였다.The melting point (M.P) of the material was measured and recorded using a BUCHI Melting Point B-540 while raising the temperature to 40 ° C. at a rate of 5 ° C./Min.
생성된 결정의 1H-NMR(500 MHz, DMSO-d6)은 Varian 500MHz Superconducting FT-NMR Spectrometer console 1 set를 이용하여 측정하였다.1H-NMR (500 MHz, DMSO-d6) of the resulting crystals was measured using a Varian 500 MHz Superconducting FT-NMR Spectrometer console 1 set.
결정의 X-선 분말회절(XRD) 스펙트럼은 Rigaku사 D/MAX 2500 model을 이용하여 하기의 조건으로 측정하였다.X-ray powder diffraction (XRD) spectra of the crystals were measured under the following conditions using a Rigaku D / MAX 2500 model.
- 18kW rotating anode type의 high power 사용, Multi Purpose attachment, JADE Software- High power use of 18kW rotating anode type, Multi Purpose attachment, JADE Software
- oniometer: RINT2000 wide angle goniometeroniometer: RINT2000 wide angle goniometer
- Attachment: Standard sample holderAttachment: Standard sample holder
- Monochromater: Fixed MonochromatorMonochromater: Fixed Monochromator
- ScanningMode: 2Theta/Theta-ScanningMode: 2Theta / Theta
- ScanningType: Continuos Scanning-ScanningType: Continuos Scanning
- X-Ray: 40kV/100mAX-Ray: 40kV / 100mA
- DivSlit: 1 deg.DivSlit: 1 deg.
- DivH.L.Slit: 10mmDivH.L.Slit: 10mm
- SctSlit: 1 deg.SctSlit: 1 deg.
- RecSlit: 0.15mmRecSlit: 0.15mm
- Monochro RS: 0.8mmMonochro RS: 0.8mm
- Start: 2.2-Start: 2.2
- Stop: 50
Stop: 50
<< 제조예Manufacturing example 1> 1> 메틸니코티네이트의Methylnicotinate 제조 Produce
(1) 26℃에서 니코틴산 100g(0.812 mol)에 메탄올 0.8kg을 가하고 교반하였다.(1) 0.8 kg of methanol was added to 100 g (0.812 mol) of nicotinic acid at 26 ° C and stirred.
(2) 염산 216g(36%, 2.13 mol, 1.2eq)을 가한 다음 반응물을 70℃로 가열하여 reflux 하에 24시간 교반하였다.(2) 216 g (36%, 2.13 mol, 1.2eq) of hydrochloric acid were added, and then the reaction was heated to 70 DEG C and stirred under reflux for 24 hours.
(3) 상온 냉각 후 40℃ bath에서 감압 농축하여 메탄올을 증류하였다. (3) After cooling to room temperature, the mixture was concentrated under reduced pressure in a 40 ° C bath to distill methanol.
(4) 반응물에 얼음물 600g을 천천히 투입하고, 정제수 1.76kg에 NaHCO3 160g을 녹인 용액을 반응물에 천천히 교반하면서 가하여 pH 7로 중화하였다.(4) 600 g of ice water was slowly added to the reaction mixture, and a solution of 160 g of NaHCO 3 dissolved in 1.76 kg of purified water was slowly added to the reaction mixture while being neutralized to pH 7.
(5) Methylene Chloride 800g으로 수층을 2회 추출하였다.(5) The aqueous layer was extracted twice with 800 g of Methylene Chloride.
(6) 유기층을 황산나트륨(Na2SO4) 20g으로 건조한 후, 유기층을 bath 온도 30℃ 에서 감압 농축하였다.(6) The organic layer was dried over 20 g of sodium sulfate (Na 2 SO 4 ), and the organic layer was concentrated under reduced pressure at a bath temperature of 30 ° C.
(7) 농축물에 헥산(Hexane) 200g을 가하고 60℃로 가열하여 reflux 하에 1시간동안 교반하였다.(7) 200 g of hexane was added to the concentrate, and the mixture was heated to 60 ° C. and stirred for 1 hour under reflux.
(8) reflux 후 반응물의 온도를 상온으로 내린 후 1시간동안 교반하였고 다시 5℃로 냉각시킨 후 4시간 동안 교반하여 86g(77%, M/M)의 메틸니코티네이트(methyl nicotinate, Mp: 38-41℃)를 얻었다. (8) After reflux, the reaction temperature was lowered to room temperature, stirred for 1 hour, cooled to 5 ° C., and stirred for 4 hours, followed by 86 g (77%, M / M) of methyl nicotinate (MP: 38-41 ° C.).
<< 실시예Example 1> N-(2- 1> N- (2- 히드록시에틸Hydroxyethyl )) 니코틴아미드의Nicotinamide 제조 Produce
(1) 메틸니코티네이트 86g(0.627 mol)을 반응기에 투입한 후 모노에탄올아민 46g(0.752 mol, 1.2eq)을 넣고 10분간 25℃에서 교반하였다. (1) 86 g (0.627 mol) of methyl nicotinate was added to the reactor, and 46 g (0.752 mol, 1.2 eq) of monoethanolamine was added thereto, followed by stirring at 25 ° C. for 10 minutes.
(2) 반응물을 60℃로 가열하면서 4시간 동안 교반하였다.(2) The reaction was stirred for 4 hours while heating to 60 ° C.
(3) 반응물에 이소프로필알콜 31g을 가하고 60℃에서 1시간 동안 교반하였다. (3) 31 g of isopropyl alcohol was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 1 hour.
(4) 반응물을 40℃로 냉각시킨 후 이소프로필에테르 125g을 천천히 30분간 투입하였다. (4) After the reaction was cooled to 40 ° C, 125 g of isopropyl ether was slowly added for 30 minutes.
(5) 반응물을 상온으로 냉각 한 다음 1시간 동안 교반하였고, 다시 반응물을 5℃로 냉각한 다음 4시간 동안 교반하였다.(5) The reaction was cooled to room temperature and stirred for 1 hour, and the reaction was cooled to 5 ° C. and then stirred for 4 hours.
(6) 생성된 결정을 여과하고 이소프로필에테르 125g으로 세척한 다음 N-(2-히드록시에틸)니코틴아미드(Mp: 78-80℃) 101g(97%, M/M)의 깨끗한 백색 결정을 얻었다.(6) The resulting crystals were filtered, washed with 125 g of isopropyl ether, and then 101 g (97%, M / M) of clear white crystals of N- (2-hydroxyethyl) nicotinamide (Mp: 78-80 ° C.) were obtained. Got it.
도 1은 N-(2-히드록시에틸)니코틴아미드의 NMR을 나타내는 그래프이며, 그 측정치는 δ 3.35(dd, 2H), 3.54(t, 2H), 4.67(m, 1H), 7.52(m, 1H), 8.22(m, 1H), 8.68(s, 1H), 8.70(s, 1H), 9.02 (s, 1H)과 같다.1 is a graph showing NMR of N- (2-hydroxyethyl) nicotinamide, the measurement of which is δ 3.35 (dd, 2H), 3.54 (t, 2H), 4.67 (m, 1H), 7.52 (m, 1H), 8.22 (m, 1H), 8.68 (s, 1H), 8.70 (s, 1H), 9.02 (s, 1H).
도 2는 N-(2-히드록시에틸)니코틴아미드의 XRD를 나타내는 그래프이며, Cu-Kα 1.540562Å 방사선을 사용할 때, 2θ(±0.2)의 값이 11.980, 13.441, 13.959, 20.420, 21.060, 23.238, 24.097, 24.760, 28.521, 32.438에서 상대세기가 10% 이상인 피크를 가지는 것으로 측정된다.Fig. 2 is a graph showing XRD of N- (2-hydroxyethyl) nicotinamide, and when the Cu-Kα 1.540562Å radiation is used, the values of 2θ (± 0.2) are 11.980, 13.441, 13.959, 20.420, 21.060, and 23.238. , 24.097, 24.760, 28.521, and 32.438 have been determined to have peaks with a relative intensity of at least 10%.
<< 실시예Example 2> 2>
(1) 발연질산(Fuming nitric acid) 4.74g(75.3mmol)을 반응기에 넣고 0℃로 냉각하였다.(1) 4.74 g (75.3 mmol) of fuming nitric acid was placed in a reactor and cooled to 0 ° C.
(2) 상기 발연질산에 N-(2-히드록시에틸)니코틴아미드 1.31g(7.89mmol)을 5℃에서 천천히 가한 후 5℃를 유지하도록 냉각하면서 1시간 동안 교반하였다. (2) 1.31 g (7.89 mmol) of N- (2-hydroxyethyl) nicotinamide was slowly added to the fuming nitric acid at 5 ° C, followed by stirring for 1 hour while cooling to maintain 5 ° C.
(3) 준비해둔 얼음물 600ml에 반응물을 15℃를 유지하면서 천천히 투입하였다. (3) The reactant was slowly added to 600 ml of prepared iced water while maintaining 15 ° C.
(4) 정제수 1.05L에 탄산나트륨 256g을 넣은 용액을 반응물에 천천히 가하면서 pH 8로 맞춘다. (4) A solution containing 256 g of sodium carbonate in 1.05 L of purified water is slowly added to the reaction to pH 8.
(5) 반응물을 5℃에서 3시간 동안 교반한 후 생성된 결정을 여과하였다. (5) The reaction was stirred at 5 ° C. for 3 hours and the resulting crystals were filtered off.
(6) 정제수 612g을 55℃로 가열하면서 여과한 결정을 투입하여 완전 용해시킨 후 55℃에서 1시간 동안 교반하였다.(6) 612 g of purified water was heated to 55 ° C, and the filtered crystals were added to dissolve completely, followed by stirring at 55 ° C for 1 hour.
(7) 반응물을 상온으로 천천히 냉각하며 1시간 동안 교반한 후 다시 반응물을 5℃ 냉각하면서 3시간 동안 교반하였다. (7) The reaction was slowly cooled to room temperature and stirred for 1 hour, followed by stirring for 3 hours while cooling the reaction at 5 ° C.
(8) 생성된 결정을 여과하고 이소프로필에테르로 세척하고 감압 건조하여 79g(66%, M/M)의 고순도 니코란딜 결정(Mp: 88.5-93.5℃)을 얻었다.(8) The resulting crystals were filtered, washed with isopropyl ether, and dried under reduced pressure to obtain 79 g (66%, M / M) of high purity nicorandil crystals (Mp: 88.5-93.5 ° C).
도 3은 고순도 니코란딜 결정의 NMR을 나타내는 그래프이며, 그 측정치는 NMR Data : IH NMR(500 MHz, CDCl3): δ 3.81(dd, 2H), 4.66(t, 2H), 7.12(m, 1H), 7.42(m, 1H), 8.15(m, 1H), 8.72(d, 1H), 9.01(d, 1H)과 같다.3 is a graph showing NMR of high-purity nicorandil crystals, and the measured values are NMR Data: IH NMR (500 MHz, CDCl 3): δ 3.81 (dd, 2H), 4.66 (t, 2H), 7.12 (m, 1H). ), 7.42 (m, 1H), 8.15 (m, 1H), 8.72 (d, 1H), 9.01 (d, 1H).
<< 비교예Comparative Example 1> 1>
(1) 에탄올(EtOH) 50ml를 용매로 하여 메틸니코티네이트 1g(7.29 mmol)을 반응기에 투입한 후 모노에탄올아민 2.67g(43.74 mmol, 6eq)을 넣고 10분간 상온 교반하였다. (1) 50 ml of ethanol (EtOH) was used as a solvent, and 1 g (7.29 mmol) of methyl nicotinate was added to the reactor, followed by adding 2.67 g (43.74 mmol, 6eq) of monoethanolamine and stirring at room temperature for 10 minutes.
(2) 반응물을 21시간동안 70℃에서 reflux 하였다.(2) The reaction was refluxed at 70 ° C. for 21 hours.
(3) 반응물을 감압증류 후 컬럼에 전개하여(전개용매 MeOH:MC=1:1) N-(2-히드록시에틸)니코틴아미드 1g(83%)을 얻었다.(3) The reaction was evaporated under reduced pressure and developed on a column (developing solvent MeOH: MC = 1: 1) to obtain 1 g (83%) of N- (2-hydroxyethyl) nicotinamide.
<< 비교예Comparative Example 2> 2>
(1) Dimethyl Formamide 10ml를 용매로 하여 모노에탄올아민 0.89g(14.58 mmol, 2eq)을 반응기에 넣고 K2CO3 2g(14.58 mmol, 2eq) 을 넣고 10분간 25℃에서 교반하였다. (1) 10 ml of dimethyl formamide was used as a solvent, and 0.89 g (14.58 mmol, 2eq) of monoethanolamine was added to the reactor, followed by 2 g (14.58 mmol, 2eq) of K 2 CO 3 , followed by stirring at 25 ° C. for 10 minutes.
(2) 반응물에 메틸니코티네이트 1g(7.29 mmol)을 넣고 25℃에서 4일 동안 교반한다. (2) 1g (7.29 mmol) of methyl nicotinate was added to the reaction and stirred at 25 ° C. for 4 days.
(3) 반응물을 여과하여 K2CO3를 제거하고 메틸렌클로라이드로 세척한 후 여액을 감압 하에 농축하여 오일형태의 N-(2-히드록시에틸)니코틴아미드 1.1g(85%)을 얻었다.(3) The reaction was filtered to remove K 2 CO 3 , washed with methylene chloride, and the filtrate was concentrated under reduced pressure to obtain 1.1 g (85%) of N- (2-hydroxyethyl) nicotinamide in the form of an oil.
<< 비교예Comparative Example 3> 3>
(1) Ethylene Glycol 4.98g(80.19 mmol, 11eq)을 용매로 하여 메틸니코티네이트 1g(7.29 mmol)을 반응기에 투입한 후 모노에탄올아민 0.89g(14.58 mmol, 2eq)을 넣고 10분간 상온 교반하였다. (1) Methyl nicotinate 1g (7.29 mmol) was added to a reactor using 4.98 g (80.19 mmol, 11eq) of ethylene glycol, and 0.89 g (14.58 mmol, 2eq) of monoethanolamine was added thereto, followed by stirring at room temperature for 10 minutes. .
(2) 반응물을 160℃로 가열하면서 1시간 동안 교반하였다.(2) The reaction was stirred for 1 hour while heating to 160 ° C.
(3) 상기 반응물에 대해 감압농축 공정을 수행하였으나 Ethylene Glycol이 제거되지 아니하여 N-(2-히드록시에틸)니코틴아미드를 수득하는데 실패하였다.(3) The reaction was concentrated under reduced pressure, but Ethylene Glycol was not removed, resulting in failure to obtain N- (2-hydroxyethyl) nicotinamide.
<< 비교예Comparative Example 4> 4>
(1) 아세토니트릴(Acetonitrile) 50ml를 용매로 하여 메틸니코티네이트 1g(7.29 mmol)을 반응기에 투입한 후 모노에탄올아민 0.54g(8.75 mmol, 1.2eq)을 넣고 10분간 상온 교반하였다. (1) 1 g (7.29 mmol) of methyl nicotinate was added to a reactor using 50 ml of acetonitrile as a solvent, and 0.54 g (8.75 mmol, 1.2eq) of monoethanolamine was added thereto, followed by stirring at room temperature for 10 minutes.
(2) 반응물을 6시간 동안 70℃에서 reflux 하였다.(2) The reaction was refluxed at 70 ° C. for 6 hours.
(3) 반응물을 TLC (톨루엔:에탄올 = 5:2)로 확인하였지만 반응이 진행되지 아니하여 N-(2-히드록시에틸)니코틴아미드를 수득하는데 실패하였다.(3) The reaction was confirmed by TLC (toluene: ethanol = 5: 2) but the reaction did not proceed and failed to obtain N- (2-hydroxyethyl) nicotinamide.
<비교예 5>≪ Comparative Example 5 &
(1) Dioxane을 50ml를 용매로 하여 메틸니코티네이트 1g(7.29 mmol)을 반응기에 투입한 후 모노에탄올아민 0.54g(8.75 mmol, 1.2eq)을 넣고 10분간 상온 교반하였다. (1) 50 g of Dioxane was used as a solvent, and 1 g (7.29 mmol) of methyl nicotinate was added to a reactor, and 0.54 g (8.75 mmol, 1.2 eq) of monoethanolamine was added thereto, followed by stirring at room temperature for 10 minutes.
(2) 반응물을 8시간 동안 70℃에서 reflux 하였다.(2) The reaction was refluxed at 70 ° C. for 8 hours.
(3) 반응물을 TLC (톨루엔:에탄올 = 5:2)로 확인하였지만 반응이 진행이 되지 아니하여 N-(2-히드록시에틸)니코틴아미드를 수득하는데 실패하였다.(3) The reaction was confirmed by TLC (toluene: ethanol = 5: 2), but the reaction did not proceed and failed to obtain N- (2-hydroxyethyl) nicotinamide.
상기 비교예 1 내지 5의 반응 조건 및 그 결과를 하기 표 1에 나타내었다.The reaction conditions of the Comparative Examples 1 to 5 and the results are shown in Table 1 below.
[표 1][Table 1]
상기 표 1의 결과로부터 알 수 있듯이, 화합물을 반응물이 아닌 용매에 용해시켜서 사용하는 경우에는 오히려 반응속도가 저하되거나 아예 반응이 진행되지 않았으며 수율의 저하가 나타났다. 또한 상기 용매가 추후 수득된 생성물로부터 쉽게 증발되지 않는 등 불순물로 작용함을 알 수 있었다. 특히 에틸렌글리콜 같은 경우는 반응은 1시간 만에 완료되었지만 에틸렌글리콜을 제거하지 못하여 분리하는데 실패하였으며, 아세토나이트릴, 디메틸포름아미드 등의 용매를 사용하는 경우 전혀 반응이 진행되지 않았다.As can be seen from the results of Table 1, when the compound is dissolved in a solvent rather than a reactant, the reaction rate is lowered or the reaction does not proceed at all, and the yield is lowered. It was also found that the solvent acts as an impurity, such as not being easily evaporated from the product obtained later. In particular, in the case of ethylene glycol, the reaction was completed in 1 hour but failed to separate due to the failure to remove ethylene glycol, and when using a solvent such as acetonitrile or dimethylformamide, the reaction did not proceed at all.
Claims (7)
[화학식 1]
[화학식 2]
[화학식 3]
[Chemical Formula 1]
(2)
(3)
고체인 상기 [화학식 2]의 화합물을 액체인 상기 [화학식 3]의 화합물과 혼합하여 혼합물을 제조하는 단계; 및
상기 혼합물을 가열하여 상기 [화학식 2]의 화합물과 상기 [화학식 3]의 화합물을 반응시키는 단계를 포함하는 것인 [화학식 1]의 N-(2-히드록시에틸)니코틴아미드를 제조하는 방법.The method of claim 1, wherein the reaction of the compound of [Formula 2] and the compound of [Formula 3] without solvent,
Preparing a mixture by mixing the compound of Formula 2 as a solid with the compound of Formula 3 as a liquid; And
Heating the mixture to prepare the N- (2-hydroxyethyl) nicotinamide of [Formula 1] comprising reacting the compound of [Formula 2] with the compound of [Formula 3].
상기 [화학식 2]의 화합물을 상기 [화학식 3]의 화합물과 반응시키는 단계는 상기 혼합물은 50-70℃로 가열하면서 교반하는 것인 [화학식 1]의 N-(2-히드록시에틸)니코틴아미드를 제조하는 방법.3. The method of claim 2,
Reacting the compound of Formula 2 with the compound of Formula 3 is N- (2-hydroxyethyl) nicotinamide of Formula 1, wherein the mixture is stirred while heating to 50-70 ° C. How to prepare.
상기 [화학식 2]의 화합물과 [화학식 3]의 화합물을 포함하는 혼합물을 교반하는 단계를 더 포함하는 것인 [화학식 1]의 N-(2-히드록시에틸)니코틴아미드를 제조하는 방법.The method of claim 2, wherein after preparing the mixture,
A method of preparing N- (2-hydroxyethyl) nicotinamide of [Formula 1] further comprising the step of stirring the mixture comprising the compound of [Formula 2] and the compound of [Formula 3].
이소프로필알콜을 첨가하여 용액을 제조하는 단계; 및
상기 용액을 50-70℃로 교반하는 단계를 더 포함하는 것인 [화학식 1]의 N-(2-히드록시에틸)니코틴아미드를 제조하는 방법.According to claim 2, After reacting the compound of [Formula 2] and the compound of [Formula 3],
Preparing a solution by adding isopropyl alcohol; And
A method of preparing N- (2-hydroxyethyl) nicotinamide of [Formula 1] further comprising the step of stirring the solution to 50-70 ℃.
상기 용액을 30-50℃로 냉각하는 단계;
상기 용액에 이소프로필에테르를 투입하는 단계; 및
이소프로필에테르가 투입된 용액을 냉각시키는 단계를 더 포함하는 것인 [화학식 1]의 N-(2-히드록시에틸)니코틴아미드를 제조하는 방법.The method of claim 5, wherein after stirring the solution,
Cooling the solution to 30-50 ° C .;
Injecting isopropyl ether into the solution; And
A method of preparing N- (2-hydroxyethyl) nicotinamide of [Formula 1] further comprising the step of cooling the solution in which isopropyl ether is added.
[화학식 1]
[화학식 2]
[화학식 3]
[Chemical Formula 1]
(2)
(3)
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| KR1020120079722A KR20140013232A (en) | 2012-07-22 | 2012-07-22 | Process for the preparation of n-(2-hydroxyethyl)nicotinamide and nicorandil |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105218441A (en) * | 2014-07-01 | 2016-01-06 | 江苏天士力帝益药业有限公司 | A kind of N-(2-hydroxyethyl)-niacinamide preparation method |
| CN110845403A (en) * | 2019-10-30 | 2020-02-28 | 北京沃邦医药科技有限公司 | Preparation method of nicorandil |
| CN111269175A (en) * | 2020-02-13 | 2020-06-12 | 张家港九力新材料科技有限公司 | Nicorandil preparation method |
| CN114920691A (en) * | 2021-06-22 | 2022-08-19 | 海口天行健药物研究有限公司 | Preparation method of N- (2-hydroxyethyl) nicotinamide and preparation method of nicorandil |
| CN116253679A (en) * | 2023-01-12 | 2023-06-13 | 北京沃邦医药科技有限公司 | Refining method of nicorandil refined mother liquor recovery product |
-
2012
- 2012-07-22 KR KR1020120079722A patent/KR20140013232A/en not_active Application Discontinuation
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105218441A (en) * | 2014-07-01 | 2016-01-06 | 江苏天士力帝益药业有限公司 | A kind of N-(2-hydroxyethyl)-niacinamide preparation method |
| CN110845403A (en) * | 2019-10-30 | 2020-02-28 | 北京沃邦医药科技有限公司 | Preparation method of nicorandil |
| CN111269175A (en) * | 2020-02-13 | 2020-06-12 | 张家港九力新材料科技有限公司 | Nicorandil preparation method |
| CN114920691A (en) * | 2021-06-22 | 2022-08-19 | 海口天行健药物研究有限公司 | Preparation method of N- (2-hydroxyethyl) nicotinamide and preparation method of nicorandil |
| CN114920691B (en) * | 2021-06-22 | 2024-03-08 | 海口天行健药物研究有限公司 | Preparation method of N- (2-hydroxyethyl) nicotinamide and preparation method of nicorandil |
| CN116253679A (en) * | 2023-01-12 | 2023-06-13 | 北京沃邦医药科技有限公司 | Refining method of nicorandil refined mother liquor recovery product |
| CN116253679B (en) * | 2023-01-12 | 2023-09-15 | 北京沃邦医药科技有限公司 | Refining method of nicorandil refined mother liquor recovery product |
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