●.6●中國醫(yī)藥工業(yè)雜志Chinese Jourmal of Pharmaceuticals 2008, 39(1)阿雷地平的合成李.玲，羅振福，丁一(天津藥物研究院，天津300193)摘要:丙炔醇和乙二醇經(jīng)加成后與雙乙烯酮反應(yīng)得乙酰乙酸2,2-亞乙二氧基丙酯，再經(jīng)胺化、與2-<(2-硝基 亞芐基)-3-氧代丁酸甲酯縮合、水解得抗高血壓藥阿雷地平，總收率約為34%。關(guān)鍵詞:阿雷地平:抗高血壓藥;鈣拮抗劑;合成中團(tuán)分類號(hào): R972*.4文獻(xiàn)標(biāo)識(shí)碼: A文章編號(hào): 1001-8255 (00801-000603Synthesis of AranidipineLI Ling, LUO Zhen-fu, DING Yi(Tianjin Institute of Pharmaceutical Research, Tianjin 300193)ABSTRACT: Aranidipine was synthesized by the addition of propynol and ethylene glycol followed by reactionwith ketene dimer to give 2,2-ethylenedioxypropyl acetoacetate, which was subjected to amination, condensation with2- (2-nitrobenzylidene) -3-oxobutyric acid methyl ester and then hydrolysis with an overall yield of about 34%.Key Words: aranidipine; antihypertensive; calcium antagonist; synthesis阿雷地平(aranidipine, 1)， 化學(xué)名為1,4-二炎以及惡性腎硬化的發(fā)生率D。氫-2,6-二甲基-4- (2-硝基苯基) -3,5-吡啶二羧酸甲基本研究參考文獻(xiàn)B.4，用丙炔醇和乙二醇加成得2-氧代丙基酯，是日本Maruko Seiyaku公司研發(fā)的2,2-亞乙二氧基丙醇(2)，2和雙乙烯酮加成開環(huán)得強(qiáng)效、長效鈣拮抗劑，1996年首 次在日本上市”。乙酰乙酸2,2-亞乙二氧基丙酯(3)，3經(jīng)氨氣胺化得3-本品兼有L型和T型鈣通道阻滯作用，還有開放鉀氨基-2-丁烯酸2,2-亞乙二氧基丙酯(4)，4與2-(2-硝通道的作用。臨床對(duì)原發(fā)性高血壓有較好的療效，基亞芐基) -3~氧代丁酸甲酯經(jīng)縮合、水解得1 (圖1),能降低外周血管阻力，增強(qiáng)射血功能。此外，1還并進(jìn)行了工藝改進(jìn)。2的制備文獻(xiàn)未有詳細(xì)報(bào)道，能降低腦卒中、心臟纖維化、增生性纖維樣小動(dòng)脈參考類似反應(yīng)f)采用三氟化硼催化的收率為60%,本研究改用對(duì)甲苯磺酸，收率提高至84%60,7]。制收稿日期: 207-07-11作者簡介:李玲(1974), 女，助理研究員，從事藥物合成的研備3時(shí)，參照文獻(xiàn))采用氫化鈉催化收率為70%，改用三乙胺催化，50~60C無溶劑反應(yīng)，產(chǎn)物無Tel; 02-2300604E-mail: syilig@sina .com需純化立即可直接進(jìn)行下步反應(yīng)8]。制備4時(shí)，按Chem Soc Jpn, 1972, 45(8): 2603-2607.43(5): 797-917.8] 楊貫羽，宋延林,嵇耀武,等. 1,4-二氫吡啶類化合物的合[10]鮑春和, 陳子明,杜玉民尼莫地平合成工藝的改進(jìn)[J].中成[J].鄭州大學(xué)學(xué)報(bào)(自然科學(xué)版), 1996, 28(2): 86-89.國醫(yī)藥工業(yè)雜志, 1996, 7(7): 295-296.9] Kobayashi T, Inoue T, Kita z. Novel 2-amino-1,4-[11] 李坤,杜玉民，王海榮.1,4二氫-2,6-二甲基4(3-硝基苯dibydropyridine calcium antagonists. II. Synthesis and基)-3,5~吡啶二羧酸單甲酯的制備[J].中國醫(yī)藥工業(yè)雜antihypertensive effects of 2-amino- ,4-dihydropyridine中國煤化工derivatives having N,N-dialkylaminoalkloxycarbonyl groupsMHCNMHG成鹽酸尼卡地平[J].中at 3- and/or 5-position[]. Chem Pharm Bull(Tokyo), 1995,四達(dá)到工業(yè)宋心，199L, 6J(1/: 0-火中國醫(yī)藥工業(yè)雜志Chinese Journal of Pharmaceuticals 2008, 39(1)OHH2C- -0- OH0、, oo。HOCH2C=CHH2CCH2OHHzCX CH2OCOCH2COCH,O2NCOCHgNHz0。CH=CCOOCH3HzCX CH20COCH=CCH,NH2021HCICHz0OC,COOCH2CHg0OC,COOCH2COCH3CH3CH;H;C NH51圖1 1的合成路線文獻(xiàn)')通氨后即停止反應(yīng)，發(fā)現(xiàn)有部分原料未被胺烷(300ml)，依次用飽和碳酸鈉溶液(100m1)和水化，繼續(xù)密閉24h后反應(yīng)完全;發(fā)現(xiàn)4在甲醇中可結(jié)(100m1)洗滌，無水硫酸鈉千燥，過濾，濾液蒸除晶，革除了文獻(xiàn)”的蒸餾操作。4與2-(2-硝基亞芐溶劑，得淡黃色液體3,直接用于下步反應(yīng)?；?-3-氧代丁酸甲酯縮合得到的5無需分離，加鹽3-氨基-2-丁烯酸2,2-亞乙二氧基丙酯(4)酸水解即得1，簡化了操作。改進(jìn)后的工藝總收率如.上所得3中加入甲醇(500ml)，冷卻至0C,為33.5% (以丙炔醇計(jì)) (文獻(xiàn)34: 16.9%)。攪拌下通氨3h。停止通氣，密閉反應(yīng)瓶，同溫繼續(xù)實(shí)驗(yàn)部分?jǐn)嚢?4h，反應(yīng)畢減壓蒸出甲醇(約400ml),剩余物冷凍析晶，過濾，濾餅室溫減壓干燥，得白色結(jié)晶2,2-亞乙二氧基丙醇(2)乙二醇(310g, 5.0mol)、 氧化汞(7.0g,4(189.5g, 62.9%， 以2計(jì)), mp 62~64C (文獻(xiàn)[5]:0.03mol)和對(duì)甲苯磺酸(1.8g, 0.01mol) 混勻，升溫收率58.8%，bp 120C/5mmHg)阿雷地平(1)至30C攪拌滴加丙炔醇(280g, 5.0mol), 滴畢同溫2- (2-硝基亞芐基)-3-氧代丁酸甲酯(按文獻(xiàn)[4]反應(yīng)3h,過濾，濾液減壓蒸餾收集77~80'C/0.8kPa餾分，得無色液體2(496.8g, 84.2%)， 直接用于下自制，74.7g, 0.3mol) 和4(60.3g, 0.3mol)溶于乙醇(120ml)，避光回流5h。加入10%鹽酸(20ml)步反應(yīng)。后繼續(xù)回流2h，減壓蒸去溶劑，剩余物中加入乙乙酰乙酸2,2-亞乙二氧基丙酯(3)2(177.0g，1.5mol) 和三乙胺(10ml, 0.07mol)醇(60ml)，攪拌析晶，過濾，濾餅用乙醇(25ml的混合液加熱至50C，攪拌下滴加雙乙烯酮x2)中國煤化工結(jié)晶，得淺黃色固(159.6g, 1.9mol)， 滴畢同溫反應(yīng)2h.加入二氯甲體1|YHC N M H G150"C(文獻(xiàn)[4):收中國醫(yī)藥工業(yè)雜志Chinese Jourmal of Pharmaceuticals 2008, 39(1)率41.0%，mp 155C)，含量≥99.0% (滴定法測of asymmetric 4-aryl-1,4-dihydro 2,6-dimethyl-定)。元素分析(Ci,H2oN2O,)實(shí)測值(計(jì)算值, %):3,5-pyridinedicarboxylates with vasodilating andantihypertensive activities[J]. Chem Pharm Bull(Tokyo),C 58.61(58.76), H 5.18(5.19), N 7.28(7.21)。1986, 34(4): 1589-1606.IR(KBr)v(cm~): 1679(C=0), 1645(C=C),[4] Ohno s, Mizukoshi K, Komatsu 0, et al.1,4Dibydropyridine1620(C=C), 1526(NO), 1350(NO2), 1206(C-0)。compound: us, 446325[P]. 1984-05-01. (CA 1983, 99:MS-EI (m/z): 388(M*)。'HNMR (CDC])8: 2.03(s,88063)3H), 2.29~2.34(s, 6H), 3.56(s, 3H), 4.59(d, AB型,[5] Gall M, Kamdar BV. Synthesis of aminoalkyl-substituted2H, J=16.4Hz), 5.74(s, 1H), 6.61 (brs, 1H), 7.25~imidazo[1,2-a]benzodiazepines and imidazo[1 ,5-7.67 (m, 4H)。'CNMR(CDCl,)8: 18.7, 25.6,a]benzodiazcpines[J]. J Org Chem, 1981, 46(8): .1575-1585.34.3, 50.7, 67.5, 101.1, 103.3, 123.5, 126.8, 131.1,6] Karaev SF, Dzhafarov DS, Askerov ME. Propargyl ether of132.8, 142.1, 145.1, 147.5, 166.1, 167.4, 203.3. .a-phenylethlyl alcohol and its deriatives[J]. Zh Org Khim,1980, 16(5): 928-933.參考文獻(xiàn):[7] Fujisawa T, Kooriyama Y, Shimizu M. Switchover of[1] Anonymous. Aranidipine[J]. Drugs Future, 1997, 22(1):diastereofacial selectivity in the condensation reaction63-64.of optically active N-sulfinimine with ester enolate[].[2]汪嘯洋. 世界上市新藥[M].北京:化學(xué)工業(yè)出版社, 2006:Tetrahedron Lett, 1996, 37 (22): 3881-3884.134-136.[8]伍小云, 胡艾希,譚英.鈣拮抗劑普拉地平合成的改進(jìn)[3] Ohno s, Komatsu O, Mizukoshi K, et al. Synthesis[J]. 應(yīng)用化學(xué), 2003, 20(10): 1015-1017.(上接第2頁)of resveratrol synthesis by Perkins reaction. Application to[1] Jang M, Cai L, Udeani GO, et al. Cancer chemopreventivethe synthesis of aryl cnamic acids[J]. Tetrahedron, 2003,activity of resveratrol, a natural product derived from59(18): 3315-3321.grapes[J]. Science, 1997, 275: 218-220.[8] Andrus MB, Liu J, Meredith EL, et al. Synthesis of[2] Aggarwal BB, Bhardwaj A, Aggarwal RS, e1 al. Role ofresveratrol using a direct decarbonylative Heck approachresveratrol in prevention and therapy of cancer: preclinicalfrom resorcylic acid[J]. Tetrahedron Lett, 2003, 44 (26):and clinical studies[J]. Anticancer Res, 2004, 24:4819-4822.2783-2840.[9]王世盛, 趙偉杰,劉志廣,等.白冀蘆醇的化學(xué)合成研究[3] Signorelli P, Ghidoni R. Resveratrol as an anticancer[J].中國藥物化學(xué)雜志, 2004, 14(2): 91-93.nutrient: molecular basis, open questions and promises[J].J[10] 王尊元,馬臻,李強(qiáng),等白藜蘆酶的合成[J].中國醫(yī)藥Nutr Biochem, 2005, 16(8): 449-466.工業(yè)雜志, 2003, 34 (9): 428-429.[4陳毅平,雷同康.白藜蘆醇合成路線圖解[J].中國醫(yī)藥工[11] 白冬花，諸葛尚琦,楊潤升,等.天然產(chǎn)物白藜蘆醇的合成業(yè)雜志, 20000 31(7): 34-336.[].天津師范大學(xué)學(xué)報(bào)(自然科學(xué)版), 2006, 26(1): 17-19.[5]楊琨,曹映玉,趙妍,等.白藝蘆醇的有機(jī)合成方法[D].[12] 晏日安，丁劉剛，李愛軍,等.功能性食品配料白藜蘆醇的天津化工, 2004, 18(3): 14-16.合成研究[].生產(chǎn)與科研經(jīng)驗(yàn), 2006, 32(11): 95-97.[6Morenno-Manas M, Pleixats R. Dehydroacetic acid[13] Durrani AA, Tyman JHP. Long-chain phenols. Part 16. Achemistry: a new synthesis of resveratrol[J]. An Quim Sernovel synthesis of homologous orsellinic acids and theirC, 1985, 81 (2): 157-161. (CA 1986, 105: 133624)中國煤化工rkin TransI, 1980, 8:[7] Slladie G, Pastural-jacope Y, Maignan J. A re-investigationYHCNMHG