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公开(公告)号：KR101369207B1
公开(公告)日：2014-03-04
申请号：KR1020070035685
申请日：2007-04-11
IPC: C07D211/90
Abstract: 본 발명은 이하, "S-(-)-펠로디핀"로 표기되는 S-(-)-에틸메틸 4-(2,3-디클로로페닐)-1,4-디히드로-2,6-디메틸-3,5-피리딘-디카르복실레이트의 제조방법에 관한 것으로서, 키랄성 분리화합물을 포함하는 펠로디핀 유도체를 합성하여 (S)-이성질체를 분리한 후 베타히드록시에스테르의 선택적인 에스테르 교환반응을 통해 S-(-)-펠로디핀을 합성하는 효율적인 제조방법에 관한 것이다. 상기 키랄성 분리물질은 (R)-글리시돌(Glycidol) 또는 (S)-글리시돌로부터 다양한 친핵체와 에폭사이드와의 반응을 통해 합성한다.
(R)-글리시돌, (S)-글리시돌, (S)-(-)-펠로디핀-
Patent Agency Ranking
公开(公告)号：KR101059523B1
公开(公告)日：2011-08-26
申请号：KR1020070015680
申请日：2007-02-15
Applicant: 안국약품 주식회사
IPC: C07D473/10
Abstract: 본 발명은 3,7-디메틸크산틴의 개선된 제조방법에 관한 것이다. 구체적으로, 본 발명은 (a) 3-메틸크산틴을 설포레인으로 구성되는 용매 중에 현탁시키는 단계 및 (b) 상기 현탁물을 염기 존재 하에서 메틸화제와 반응시키는 단계를 포함하는 3,7-디메틸크산틴의 제조방법에 관한 것이다.
본 발명은 메틸화반응과 환원반응을 거치는 종래기술과 달리 매우 간단한 공정을 거쳐 진행되므로 시간과 비용의 측면에서 공업적으로 매우 유리하다. 보다 상세하게는, 2 내지 3시간에 걸쳐 진행되던 종래 반응을 30분 내지 1시간으로 단축할 수 있게 되었으며, 고가의 Pd/C 환원반응을 거치지 않고 목적화합물을 얻을 수 있게 되었고, 상전이촉매를 이용하여 2상에서 번거롭게 진행되던 반응을 유기 용매 상에서 진행할 수 있게 한다.
또한, 본 발명에 의하면 고수율, 고순도의 3,7-디메틸크산틴을 얻을 수 있다. 보다 상세하게는 90%이상, 바람직하게는 최대 95%의 수율을 갖고, 0.5% 이하의 불순물을 갖는 3,7-디메틸크산틴을 얻을 수 있다. 이러한 고수율, 고순도의 3,7-디메틸크산틴은 치료효능을 갖는 진해제로 사용하기에 유용하다.
3,7-디메틸크산틴, 테오브로민, 설포레인, 3-메틸크산틴, 진해제-
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公开(公告)号：KR1020080076149A
公开(公告)日：2008-08-20
申请号：KR1020070015680
申请日：2007-02-15
Applicant: 안국약품 주식회사
IPC: C07D473/10
Abstract: A method for preparation of 3,7-dimethylxanthine is provided to reduce the costs for preparation by removing a cost-consuming deprotection process, improve the convenience and reproducibility of reaction by performing methylation in organic phase, and enhance purity and yield of 3,7-dimethylxanthine. A method for preparation of 3,7-dimethylxanthine represented by the formula(1) comprises the steps of: (a) suspending 3-methylxanthine represented by the formula(2) in solvent of sulfolane represented by the formula(3); and (b) reacting the suspension with methylating agent selected from methyl p-toluenesulfonate, methyl methanesulfonate and a mixture thereof in the presence of base selected from potassium hydroxide, sodium hydroxide and sodium hydride at pH 9-10, wherein the reaction temperature is -10 to 100°C. Further, a volume ratio of the sulfolane and water is 3:1 to 1:3.
Abstract translation: 提供了制备3,7-二甲基黄嘌呤的方法，通过去除成本低的去保护方法来降低制备成本，通过在有机相中进行甲基化提高反应的方便性和再现性，提高了纯度和产率3,7 -dimethylxanthine。 由式（1）表示的制备3,7-二甲基黄嘌呤的方法包括以下步骤：（a）将由式（2）表示的3-甲基黄嘌呤悬浮在由式（3）表示的环丁砜的溶剂中; 和（b）使该悬浮液与选自甲基对甲苯磺酸甲酯，甲磺酸甲酯及其混合物的甲基化剂在选自氢氧化钾，氢氧化钠和氢化钠的碱的存在下，pH 9-10下反应，其中反应温度为 - 10〜100℃。 此外，环丁砜和水的体积比为3:1至1:3。
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公开(公告)号：KR1020080092163A
公开(公告)日：2008-10-15
申请号：KR1020070035685
申请日：2007-04-11
IPC: C07D211/90
Abstract: A method for preparing (S)-(-)-felodipine is provided to synthesize the (S)-(-)-felodipine conveniently from a cheap starting material of (R)- or (S)-glycidol and obtain various intermediates, thereby being applied to asymmetric synthesis of a dihydropyridine compound as well as felodipine. A method for preparing (S)-(-)-felodipine represented by a formula(1) comprises the steps of: (a) after reacting (R)- or (S)-glycidol represented by a formula(2) with dihydropyran(DHP), adding a nucleophile(Nu) thereto to obtain a compound represented by a formula(3); (b) reacting the compound of the formula(3) with di-chitin represented by a formula(4) to obtain a compound represented by a formula(5); (c) reacting the compound of the formula(5) with 2,3-dichlorobenzaldehyde represented by a formula(6) to obtain a compound represented by a formula(7); (d) reacting the compound of the formula(7) with 3-amino-2-butenoate represented by a formula(8) to obtain a felodipine intermediate represented by a formula(9); (e) isolating an (S)-isomer therefrom through recrystallization or silica gel chromatography after treating the felodipine intermediate of the formula(9) with an acid; and (f) subjecting the (S)-isomer to selective esterification to obtain the compound of the formula(1).
Abstract translation: 提供制备（S） - （ - ） - 非洛地平的方法，从（R） - 或（S） - 缩水甘油的廉价原料方便地合成（S） - （ - ） - 非洛地平，并获得各种中间体 适用于二氢吡啶化合物以及非洛地平的不对称合成。 由式（1）表示的（S） - （ - ） - 非洛地平的制备方法包括以下步骤：（a）使由式（2）表示的（R） - 或（S） - 缩水甘油与二氢吡喃 DHP），向其中加入亲核体（Nu），得到式（3）表示的化合物。 （b）使式（3）的化合物与由式（4）表示的二壳多糖反应得到式（5）表示的化合物; （c）使式（5）的化合物与式（6）表示的2,3-二氯苯甲醛反应，得到由式（7）表示的化合物; （d）使式（7）的化合物与由式（8）表示的3-氨基-2-丁烯酸酯反应，得到由式（9）表示的非洛地平中间体; （e）在用酸处理式（9）的非洛地平中间体后，通过重结晶或硅胶色谱分离（S） - 异构体; 和（f）使（S） - 异构体进行选择性酯化，得到式（1）的化合物。
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公开(公告)号：KR100780538B1
公开(公告)日：2007-11-30
申请号：KR1020060072945
申请日：2006-08-02
IPC: C07D319/20
CPC classification number: C07D319/20
Abstract: A method for preparing a methyl-1,4-benzodioxane compound is provided to obtain a chiral 1,4-benzodioxane compound with high optical purity of at least 99% by reducing side reactions. A method for preparing a methyl-1,4-benzodioxane compound comprises the steps of: (a) reacting an epoxide compound represented by the formula(2), in the presence of a tertiary organic amine or an ammonium salt thereof, with a catechol compound represented by the formula(3) to be subject to an epoxide ring opening reaction to obtain a ring opened product; and (b) treating the ring opened product with an inorganic base to be subject to a cyclization reaction to obtain a desired 2-hydroxymethyl-1,4,-benzodioxane compound represented by the formula(1), wherein * is a chiral center; each R1, R2, R3, and R4 is independently H, halogen, nitro, cyano, formyl, C1-4 alkyl, C1-4 alkoxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonyloxy, C1-4 haloalkyl, N,N-di-(C1-4)alkylamino, (C1-4)alkylcarbonyl, (C1-4)alkoxycarbonyloxy, C6-10 aromatic hydrocarbon, C6-10 aromatic hydrocarbon substituted with halogen, C6-10 aromatic hydrocarbon substituted with C1-4 alkyl or two of the R1, R2, R3, and R4 adjacent to each other forms methylene deoxy or benzene ring; and X is a leaving group such as halogen and sulfonate.
Abstract translation: 提供了制备甲基-1,4-苯并二恶烷化合物的方法，通过减少副反应来获得具有至少99％的高光学纯度的手性1,4-苯并二恶烷化合物。 一种制备甲基-1,4-苯并二恶烷化合物的方法包括以下步骤：（a）使式（2）表示的环氧化合物在叔有机胺或其铵盐存在下与邻苯二酚反应 由式（3）表示的化合物进行环氧化物开环反应得到开环产物; 和（b）用无机碱处理开环产物进行环化反应，得到式（1）所示的所需2-羟甲基-1,4 - 苯并二恶烷化合物，其中*是手性中心; 每个R 1，R 2，R 3和R 4独立地为H，卤素，硝基，氰基，甲酰基，C 1-4烷基，C 1-4烷氧基，C 1-4烷氧基羰基，C 1-4烷基羰氧基，C 1-4卤代烷基，N， 二（C 1-4）烷基氨基，（C 1-4）烷基羰基，（C 1-4）烷氧基羰氧基，C 6-10芳烃，被卤素取代的C 6-10芳烃，被C 1-4烷基取代的C 6-10芳烃或 相邻的R1，R2，R3和R4中的两个形成亚甲基脱氧或苯环; X是离去基团如卤素和磺酸根。
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