阿立哌唑的合成新方法
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摘要
阿立哌唑是一种新型高选择性非典型抗精神病药物，为突触后膜多巴胺受体拮抗剂和脑内DA能前膜自身受体激动剂。
本论文以廉价的肉桂酸和2，3-二氯苯胺为原料对一种合成阿立哌唑的新方法进行了研究。
论文重点研究了一种苯基哌嗪合成的新方法。2，3-二氯苯胺的硫酸盐与浓硫酸和NaNO_2反应生成芳基重氮盐，经碘化钾取代得芳基碘化物，收率81％；该化合物在CuI的催化，脯氨酸做配体，二甲基亚砜为溶剂，K_2CO_3为缚酸剂的条件下，与哌嗪反应生成2，3-二氯苯基哌嗪，收率20％。该方法简单，原料易得，条件温和，产物容易分离。
肉桂酸首先转化成肉桂酰氯，经胺解，Friedel-Crafts环合及氢化得到中间体7-羟基-3，4-二氢-2-(1H)-喹诺酮，收率37.36％。
7-羟基-3，4-二氢-2-(1H)-喹诺酮(喹啉酮化合物)转化成7-(4-氯丁氧基)-3，4-二氢-2-(1H)-喹诺酮，收率79％，然后再与苯基哌嗪化合物偶合生成最终产物，收率72.5％。
本文经7步反应合成了阿立哌唑，以肉桂酸计总收率为21.40％，产物经~1HNMR确认。
Aripiprazole is the latest atypical antipsychotic drug that possesses both,post-synaptic dopamine receptor antagonist and dopamine auto-receptoragonist. By having dual activity, it can treat schizophrenia with fewestside-effects.
The new pathway for the synthesis of aripiprazole from cheap raw materials,cinnamic acid and 2,3-dichloroaniline is presented.
Cinnamic acid was first converted to acid chloride, followed by aminolysis,Friedel-Crafts cyclization and hydrogenation to form the first key intermediate,carbostyril compound with overall yield of 37.36%.
The hydrogen sulphate salt of 2,3-dichloroaniline was converted to thecorresponding Aryl Iodide in good yield of 81% by reacting with conc. H_2SO_4and NaNO_2 to form intermediate diazonium salt, which was further displacedby KI. 2,3-dichlorophenylpiperazine(phenylpiperazine compound), the 2nd keyintermediate, was obtained by reacting Aryl Iodide and piperazine in thepresence of CuI as catalyst, proline as ligand, K_2CO_3 as base and dimethylsulfoxide as solvent with yield of 20%. The method is simple, utilizes cheapcatalyst and ligand, insensitive to moisture, and it is easy to separate theproduct. 7-hydroxy-3,4-dihydro-2-(1H)-quinolinone (carbostyril compound) wasconverted into 7-(4-chlorobutoxy)-3,4-dihydro-2-(1H)-quinolinone with theyield of 79% and then coupled with phenylpiperazine compound to form finalproduct with yield of 72.5%. The overall yield from cinnamic acid was21.40% and the analytical test and physical properties were correct. Most ofmaterial, reagents and condition applied are simple, easy and cheap; severalsteps can undergo large-scale production.
本论文以廉价的肉桂酸和2，3-二氯苯胺为原料对一种合成阿立哌唑的新方法进行了研究。
论文重点研究了一种苯基哌嗪合成的新方法。2，3-二氯苯胺的硫酸盐与浓硫酸和NaNO_2反应生成芳基重氮盐，经碘化钾取代得芳基碘化物，收率81％；该化合物在CuI的催化，脯氨酸做配体，二甲基亚砜为溶剂，K_2CO_3为缚酸剂的条件下，与哌嗪反应生成2，3-二氯苯基哌嗪，收率20％。该方法简单，原料易得，条件温和，产物容易分离。
肉桂酸首先转化成肉桂酰氯，经胺解，Friedel-Crafts环合及氢化得到中间体7-羟基-3，4-二氢-2-(1H)-喹诺酮，收率37.36％。
7-羟基-3，4-二氢-2-(1H)-喹诺酮(喹啉酮化合物)转化成7-(4-氯丁氧基)-3，4-二氢-2-(1H)-喹诺酮，收率79％，然后再与苯基哌嗪化合物偶合生成最终产物，收率72.5％。
本文经7步反应合成了阿立哌唑，以肉桂酸计总收率为21.40％，产物经~1HNMR确认。
Aripiprazole is the latest atypical antipsychotic drug that possesses both,post-synaptic dopamine receptor antagonist and dopamine auto-receptoragonist. By having dual activity, it can treat schizophrenia with fewestside-effects.
The new pathway for the synthesis of aripiprazole from cheap raw materials,cinnamic acid and 2,3-dichloroaniline is presented.
Cinnamic acid was first converted to acid chloride, followed by aminolysis,Friedel-Crafts cyclization and hydrogenation to form the first key intermediate,carbostyril compound with overall yield of 37.36%.
The hydrogen sulphate salt of 2,3-dichloroaniline was converted to thecorresponding Aryl Iodide in good yield of 81% by reacting with conc. H_2SO_4and NaNO_2 to form intermediate diazonium salt, which was further displacedby KI. 2,3-dichlorophenylpiperazine(phenylpiperazine compound), the 2nd keyintermediate, was obtained by reacting Aryl Iodide and piperazine in thepresence of CuI as catalyst, proline as ligand, K_2CO_3 as base and dimethylsulfoxide as solvent with yield of 20%. The method is simple, utilizes cheapcatalyst and ligand, insensitive to moisture, and it is easy to separate theproduct. 7-hydroxy-3,4-dihydro-2-(1H)-quinolinone (carbostyril compound) wasconverted into 7-(4-chlorobutoxy)-3,4-dihydro-2-(1H)-quinolinone with theyield of 79% and then coupled with phenylpiperazine compound to form finalproduct with yield of 72.5%. The overall yield from cinnamic acid was21.40% and the analytical test and physical properties were correct. Most ofmaterial, reagents and condition applied are simple, easy and cheap; severalsteps can undergo large-scale production.
引文
[1] Aalten H L, Koten G V, Grove D M, Kuilmann T, Piekstra O G, Hulshof L A, Sheldon R A. The copper Catalysed Reaction of Sodium Methoxide with Aryl Bromides. A Mechanistic Study Leading to a Facile Synthesis of Anisole Derivatives [J]. Tetrahedron, 1989,45,17:5565-5578.
[2] Banno PC, Fujioka T, Kikuchi T, Oshiro Y, Hiyama T, Nakagawa K. Studies on 2(1H)-Quinolinone Derivatives as Neuroleptic Agents I Snthensis and Biological Activities of (4-Phenyl-1-piperaziny])-propoxy-2(lH)-quinolinone Derivatives [J]. Chemical Pharmacology Bulletin,1988,36,11:4377-4388.
[3] Bonacorsi S.J, Waller S. Rinehart J K. Synthesis of Multi-labeled [~(14)C] Aripiprazole [J]. Journal of Label Compounds and Radiopharmaceuticals, 2006,49:1-9.
[4] Burns D PC, Molski T F, Xu C, Ryan E, Tottori PC,Kikuchi T, Yocca D F, Molinoff P B. Aripiprazole, a Novel Antipsychotic, Is a High-Affinity Partial Agonist at Human Dopamine D_2 Receptors [J]. Pharmacology and Experimental Therepeutics, 2002, 32: 381-389.
[5] Claric W G, Brater D C, Johnson A R. Goth's Medical Pharmacology [B]. Twelfth Edition, the C.V Mosby Company, USA. 1998.
[6]Caprathe B W, Jaen C J, Wise L D, Heffner G H, Pugsley T A, Meltzer L T, Parvez M. Dopamine Autoreceptor Agonists as Pontential Antipsychotics. 3. 16-Propyl-4,5,5a,6,7,8-hexahydrothiazolo [4,5-f] quinolin-2-amine[J]. Journal of Medicinal chemistry, 1991, 34:2736-2746.
[7] Cohen T, Wood J, Diertz A G. Organocopper Intermediates in the Exchange Reaction of Aryl Halides with Salts of Copp'er(I). The Possible Role of Copper(III) [J]. Tetrahedron letters, 19974, 40:3555-3558.
[8]Hacksell U, Arvidsson L E, Svensson U, Lars J, Nilson G. 3-Phenylpiperidines. Central Dopamine_Autoreceptor Stimulating Activity [J]. Journal of Medicinal Chemistry, 1981, 24:1475-1482.
[9] Helferich B, Chaefer W. N-Butyl Chloride [J]. Organic Syntheses, 1963, 1:147.
[10]Jaen J C, Wise L D, Heffer T G, Pugsley T A, Meltzer L T. Dopamine Autoreceptor Agonists as Potential Antipsychotics. 1. (Aminoalkoxy)amlines [J]. Journal of Medicinal Chemistry, 1988, 31:1621-1625.
[11] Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar C A. The antipsychotic aripiprazole is a potent, partial agonist at human 5-HT1A receptor [J]. European Journal of Pharmacology, 2002, 441:137-140.
[12] Kyong F Y, Buchwald L S. Mild and Effient Copper-Catalyzed Amination of Aryl Bromides with Primary Alkylamines [J]. Organic Letters,2003,5(6):793
[13] Leclerc G, Marciniak G, Decker N, Schartz J. Cardiotonic Agents. 2. Synthesis and Structure-Activity Relationships in a New Class of 6-, 7- and 8-Pyridly-2(1H)-quinolone Derivative [J]. J.Med.Chem, 1986, 29:2433-2438.
[14] Leon D A, Patel C.N, Crismon M L. Aripiprazole: A comprehensive Review off it pharmacology, Clinical Efficacy and Tolerability. Clinical Therapeutics, 2004, 26, 5: 649.
[15] Li M D, Cai J, Ji M. Synthesis of Atypical Antipsychotic Aripiprazole [J]. Progress in pharmaceutical sciences (China), 2004, 28, 6:275-277.
[16] Li Z, Ichikawa J, Dai J, Meliza Y. Aripiprazole, a Novel Antipsychotic Drug, Preferentially Increases Dopamine Release in the Prefrontal Cortex and Hippocampus in the Rat Brain [J]. European Journal of Pharmacology, 2004, 493: 74-83.
[17] Lindley J. Copper Assisted Nucleophillic Substitution of Aryl Halogen [J]. Tetrahedron, 1984,40,9:1433-1456.
[18] Manimaran T, Thiruvengadam T K, Ramakrishnan V T. Synthesis of Coumarins (2-oxo-2H-1-benzopyrans), Thio Coumarins (2-oxo-2H-1-benzothiopyrans) and Carbostyrils (2-oxo-1,2-dihydroquinolines) [J]. Synthesis, 1975,739-741.
[19] Morita S, Kitano K, Matsubara J, Ohtani T, Kawano Y, Otsubo K, Uchila M. Practical Application of the Palladium-Catalyzed Amination in Phenylpiperazine: An Efficient Synthesis of a Metabolite of the Antipsychotic Agent Aripiprazole [J]. Tetrahedron Letters, 1998, 54:4811-4818.
[20] NAMI (National Association of Mental illness). Accessed on August, 2005 at http://www.nami.org/helpline/schizophrenia.html
[21] Oshiro Y, Sato S, Kurahashi N, Tanaka T, Kikuchi T, Tottori K, Uwahodo Y, Nishi K Novel Antipsychotic Agents with Dopamine Auto receptor Agonist Properties: Synthesis and Pharmacology of 7-{4-(4-Phenyl-1-piperazinyl) butoxy}-3, 4-dihydro-2(1H)-quinolinone Derivatives[J]. Journal of Medicinal Chemistry, 1998, 41:658-667.
[22]Paine A J. Mechanisms and Models for Copper Mediated Nucleophillic Aromatic Substitution. 2. A single Catalytic Species from Three Different Oxidation States of Copper in an Ullmann Synthesis of Triarylamines [J]. Journal of America Chemical Society, 1987,109:1496-1502.
[23]Reddy N P, Tanaka M. Palladium-Catalyzed Amination of Aryl Chlorides[J]. Tetrahedron Letters, 1997,38:4807-4810.
[24] Robarge M,Husbands S,Kieltyka A, Brodbeck R, Thurkauf A. Design and Synthesis of [(2,3-Dichlorophenyl) piperazin-l-yl]alkylfluorenylcarboxamides as Novel Ligands Selective for the Dopamine D_3 Receptor Subtype[J]. Journal of Medicinal Chemistry, 2001, 44:3175-3186.
[25]Shao Jiangyong, Wu Fanhong. Synthesis of Aripiprazole [J]. Chinese Journal of New Drugs. 2006, 15(15):1274-1276.
[26] Tadori Y, Miwa K, Totorri K, Burns K D, Stark A, Mori T, Kikuchi T. Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic [J]. European Journal of Pharmacology, 2005, 515:10-19.
[27]Tsujomori H, Yamaguchi T. Process for Preparing Aripiprazole [P]. USA Patent, US2004/0192915A1.
[28]Villani F J, King M S. 3-benzoylpyridine [J], Organic Syntheses, 1963, 88-90.
[29]Wang Junling, JIA Xiangman, BAO Chunhe, et al. Synthesis of Aripiprazole[J]. Chinese Journal of Pharmaceuticals, 2004,35( 12):707-709
[30] Wang J L, Jia X M, Bao C H, Chen Z M, Jiang Y. Synthesis of Aripiprazole [J]. Chinese Journal of Pharmaceuticals, 2004,35,12:707-708.
[31] Wang T C, Chen Y L, Lee K H, Tzeng C C. An Intermolecular Michael Addition of Benzene [J] Tetrahedron Letter, 1996, 37, 5: 6369-6370.
[32]Wang T C, Chen Y L, Lee K H, Tzeng C C. Lewis Acid Catalyzed Reaction of Cinnamanilides: Competition of Intramolecular and Intermolecular Friedel-Craft Reaction [J]. Snthesis, 1997,87-90.
[33]Wolfe J P, Buchwald L S. Improved Functional Group Compatibility in the Palladium-Catalyzed Amination of Aryl Bromides[J]. Tetrahedron Letter, 1997, 38: 6359-6362.
[34] Yuan J, Chen X, Brodbeck R, Prismus R, Braun J, Wasley J, Thurkauf A... NGB 2904 and NGB 2849: Two Highly Selective Dopamine D_3 Receptor Antagonists[J]. Bioorganic & Medicinal Chemistry Letters, 1998, 8: 2715-2718.
[35]Zhang H, Cai Q, Ma D W. Amino Acid Promoted-Catalyzed C-N Bond Formation between Aryl Halides and Amines or N-Containing Heterocycles [J]. Journal of Organic Chemistry, 2005,70:5164-5173.
[36]Zhang G S, Zhu Y C, Ma Y Q. Synthesis of Aripiprazole [J]. Chinese Journal of Pharmaceuticals, 2006, 37,10:655-656.
[37] Zhu L, Ichikawa J, Dai J, Meltzer H Y. Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in the rat brain [J]. European Journal of Pharmacology, 2004, 493: 75-83.
[2] Banno PC, Fujioka T, Kikuchi T, Oshiro Y, Hiyama T, Nakagawa K. Studies on 2(1H)-Quinolinone Derivatives as Neuroleptic Agents I Snthensis and Biological Activities of (4-Phenyl-1-piperaziny])-propoxy-2(lH)-quinolinone Derivatives [J]. Chemical Pharmacology Bulletin,1988,36,11:4377-4388.
[3] Bonacorsi S.J, Waller S. Rinehart J K. Synthesis of Multi-labeled [~(14)C] Aripiprazole [J]. Journal of Label Compounds and Radiopharmaceuticals, 2006,49:1-9.
[4] Burns D PC, Molski T F, Xu C, Ryan E, Tottori PC,Kikuchi T, Yocca D F, Molinoff P B. Aripiprazole, a Novel Antipsychotic, Is a High-Affinity Partial Agonist at Human Dopamine D_2 Receptors [J]. Pharmacology and Experimental Therepeutics, 2002, 32: 381-389.
[5] Claric W G, Brater D C, Johnson A R. Goth's Medical Pharmacology [B]. Twelfth Edition, the C.V Mosby Company, USA. 1998.
[6]Caprathe B W, Jaen C J, Wise L D, Heffner G H, Pugsley T A, Meltzer L T, Parvez M. Dopamine Autoreceptor Agonists as Pontential Antipsychotics. 3. 16-Propyl-4,5,5a,6,7,8-hexahydrothiazolo [4,5-f] quinolin-2-amine[J]. Journal of Medicinal chemistry, 1991, 34:2736-2746.
[7] Cohen T, Wood J, Diertz A G. Organocopper Intermediates in the Exchange Reaction of Aryl Halides with Salts of Copp'er(I). The Possible Role of Copper(III) [J]. Tetrahedron letters, 19974, 40:3555-3558.
[8]Hacksell U, Arvidsson L E, Svensson U, Lars J, Nilson G. 3-Phenylpiperidines. Central Dopamine_Autoreceptor Stimulating Activity [J]. Journal of Medicinal Chemistry, 1981, 24:1475-1482.
[9] Helferich B, Chaefer W. N-Butyl Chloride [J]. Organic Syntheses, 1963, 1:147.
[10]Jaen J C, Wise L D, Heffer T G, Pugsley T A, Meltzer L T. Dopamine Autoreceptor Agonists as Potential Antipsychotics. 1. (Aminoalkoxy)amlines [J]. Journal of Medicinal Chemistry, 1988, 31:1621-1625.
[11] Jordan S, Koprivica V, Chen R, Tottori K, Kikuchi T, Altar C A. The antipsychotic aripiprazole is a potent, partial agonist at human 5-HT1A receptor [J]. European Journal of Pharmacology, 2002, 441:137-140.
[12] Kyong F Y, Buchwald L S. Mild and Effient Copper-Catalyzed Amination of Aryl Bromides with Primary Alkylamines [J]. Organic Letters,2003,5(6):793
[13] Leclerc G, Marciniak G, Decker N, Schartz J. Cardiotonic Agents. 2. Synthesis and Structure-Activity Relationships in a New Class of 6-, 7- and 8-Pyridly-2(1H)-quinolone Derivative [J]. J.Med.Chem, 1986, 29:2433-2438.
[14] Leon D A, Patel C.N, Crismon M L. Aripiprazole: A comprehensive Review off it pharmacology, Clinical Efficacy and Tolerability. Clinical Therapeutics, 2004, 26, 5: 649.
[15] Li M D, Cai J, Ji M. Synthesis of Atypical Antipsychotic Aripiprazole [J]. Progress in pharmaceutical sciences (China), 2004, 28, 6:275-277.
[16] Li Z, Ichikawa J, Dai J, Meliza Y. Aripiprazole, a Novel Antipsychotic Drug, Preferentially Increases Dopamine Release in the Prefrontal Cortex and Hippocampus in the Rat Brain [J]. European Journal of Pharmacology, 2004, 493: 74-83.
[17] Lindley J. Copper Assisted Nucleophillic Substitution of Aryl Halogen [J]. Tetrahedron, 1984,40,9:1433-1456.
[18] Manimaran T, Thiruvengadam T K, Ramakrishnan V T. Synthesis of Coumarins (2-oxo-2H-1-benzopyrans), Thio Coumarins (2-oxo-2H-1-benzothiopyrans) and Carbostyrils (2-oxo-1,2-dihydroquinolines) [J]. Synthesis, 1975,739-741.
[19] Morita S, Kitano K, Matsubara J, Ohtani T, Kawano Y, Otsubo K, Uchila M. Practical Application of the Palladium-Catalyzed Amination in Phenylpiperazine: An Efficient Synthesis of a Metabolite of the Antipsychotic Agent Aripiprazole [J]. Tetrahedron Letters, 1998, 54:4811-4818.
[20] NAMI (National Association of Mental illness). Accessed on August, 2005 at http://www.nami.org/helpline/schizophrenia.html
[21] Oshiro Y, Sato S, Kurahashi N, Tanaka T, Kikuchi T, Tottori K, Uwahodo Y, Nishi K Novel Antipsychotic Agents with Dopamine Auto receptor Agonist Properties: Synthesis and Pharmacology of 7-{4-(4-Phenyl-1-piperazinyl) butoxy}-3, 4-dihydro-2(1H)-quinolinone Derivatives[J]. Journal of Medicinal Chemistry, 1998, 41:658-667.
[22]Paine A J. Mechanisms and Models for Copper Mediated Nucleophillic Aromatic Substitution. 2. A single Catalytic Species from Three Different Oxidation States of Copper in an Ullmann Synthesis of Triarylamines [J]. Journal of America Chemical Society, 1987,109:1496-1502.
[23]Reddy N P, Tanaka M. Palladium-Catalyzed Amination of Aryl Chlorides[J]. Tetrahedron Letters, 1997,38:4807-4810.
[24] Robarge M,Husbands S,Kieltyka A, Brodbeck R, Thurkauf A. Design and Synthesis of [(2,3-Dichlorophenyl) piperazin-l-yl]alkylfluorenylcarboxamides as Novel Ligands Selective for the Dopamine D_3 Receptor Subtype[J]. Journal of Medicinal Chemistry, 2001, 44:3175-3186.
[25]Shao Jiangyong, Wu Fanhong. Synthesis of Aripiprazole [J]. Chinese Journal of New Drugs. 2006, 15(15):1274-1276.
[26] Tadori Y, Miwa K, Totorri K, Burns K D, Stark A, Mori T, Kikuchi T. Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic [J]. European Journal of Pharmacology, 2005, 515:10-19.
[27]Tsujomori H, Yamaguchi T. Process for Preparing Aripiprazole [P]. USA Patent, US2004/0192915A1.
[28]Villani F J, King M S. 3-benzoylpyridine [J], Organic Syntheses, 1963, 88-90.
[29]Wang Junling, JIA Xiangman, BAO Chunhe, et al. Synthesis of Aripiprazole[J]. Chinese Journal of Pharmaceuticals, 2004,35( 12):707-709
[30] Wang J L, Jia X M, Bao C H, Chen Z M, Jiang Y. Synthesis of Aripiprazole [J]. Chinese Journal of Pharmaceuticals, 2004,35,12:707-708.
[31] Wang T C, Chen Y L, Lee K H, Tzeng C C. An Intermolecular Michael Addition of Benzene [J] Tetrahedron Letter, 1996, 37, 5: 6369-6370.
[32]Wang T C, Chen Y L, Lee K H, Tzeng C C. Lewis Acid Catalyzed Reaction of Cinnamanilides: Competition of Intramolecular and Intermolecular Friedel-Craft Reaction [J]. Snthesis, 1997,87-90.
[33]Wolfe J P, Buchwald L S. Improved Functional Group Compatibility in the Palladium-Catalyzed Amination of Aryl Bromides[J]. Tetrahedron Letter, 1997, 38: 6359-6362.
[34] Yuan J, Chen X, Brodbeck R, Prismus R, Braun J, Wasley J, Thurkauf A... NGB 2904 and NGB 2849: Two Highly Selective Dopamine D_3 Receptor Antagonists[J]. Bioorganic & Medicinal Chemistry Letters, 1998, 8: 2715-2718.
[35]Zhang H, Cai Q, Ma D W. Amino Acid Promoted-Catalyzed C-N Bond Formation between Aryl Halides and Amines or N-Containing Heterocycles [J]. Journal of Organic Chemistry, 2005,70:5164-5173.
[36]Zhang G S, Zhu Y C, Ma Y Q. Synthesis of Aripiprazole [J]. Chinese Journal of Pharmaceuticals, 2006, 37,10:655-656.
[37] Zhu L, Ichikawa J, Dai J, Meltzer H Y. Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in the rat brain [J]. European Journal of Pharmacology, 2004, 493: 75-83.