新型含氮稠杂环类心血管药物及中间体合成的研究
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摘要
四氮唑及2(1H)-喹啉酮类含氮稠杂环化合物及其衍生物是重要的医药中间体，其药物广泛应用于心血管类疾病的治疗。
论文在查阅国内外文献的基础上，对四唑类及2(1H)-喹啉酮类化合物在医药及医药中间体上的应用及其合成路线和方法作了综合评述。
论文研究了药物Pilozol(1-1)及其中间体N-环己基-5-(4-氯丁基)-1H-四唑(3-1)与6-羟基-3，4-二氢-2(1H)-喹啉酮(4-1)的合成；以分子内Friedel-Crafts烷基化反应合成了7-羟基-3，4-二氢-2(1H)-喹啉酮(4-2)、8-羟基-3，4-二氢-2(1H)-喹啉酮(4-3)；同时合成了β肾上腺素受体拮抗剂卡替洛尔(Carteollol，2-48)的中间体5-羟基-3，4-二氢-2(1H)-喹啉酮(5-1)。
论文第三章以δ-戊内酯和环己胺为原料，先缩合得到N-环己基-5-羟基戊酰胺(3-2)，再经PCl_5氯化、NaN_3关环得到N-环己基-5-(4-氯丁基)-1H-四唑(3-1)，两步总收率为71％。同时对四唑环的合成机理、合成工艺进行了研究和实验探索并初步研究了相转移催化合成方法。
论文第四章研究了6-羟基-3，4-二氢-2(1H)-喹啉酮(4-1)的合成反应机理及过程。以对氨基酚为原料，与3-氯丙酰氯反应后在催化剂AlCl_3存在下关环得到6-羟基-3，4-二氢-2(1H)-喹啉酮(4-1)，两步收率为87％。同时对分子内Friedel-Crafts烷基化反应进行研究，类似合成了7-羟基-3，4-二氢-2(1H)-喹啉酮(4-2)及8-羟基-3，4-二氢-2(1H)-喹啉酮(4-3)等化合物。
论文第五章以1，3-环己二酮为原料，经醋酸铵胺解、丙烯酸关环、NBS脱氢三步得到5-羟基-3，4-二氢-2(1H)-喹啉酮(5-1)，总收率达到73.4％。实验研究了新的胺化反应试剂，使反应条件由加压变为常压；并选择了新的脱氢反应溶剂，使脱氢反应收率由68％提高到84％。
论文第六章以N-环己基-5-(4-氯丁基)-1H-四唑(3-1)及6-羟基-3,4-二氢-2(1H)-喹啉酮(4-1)为原料在相转移催化条件下合成了药物Pilozol(1-1)，收率为84.7％。
浙江工业大学2003硕士学位论文
论文用红外、质谱、核磁共振等有机光波谱手段对合成化合物的结构进行了鉴
定和表征，研究了产品和中间体的色谱含量测定方法。
论文通过优化实验确定了Pilozol(1一1)及中间体N一环己基一5一(4一氯丁基关IH-
四哇(3一1)、6一轻基一3，4一二氢一2(1H>哇琳酮(4一l)的合成工艺参数组合，确定了适
合工业化生产的合成新工艺路线，为该类产品的工业化开发提供了理论依据。
Tetrazole and carbostyril and their derivatives are widely applied as cardiovascular drugs.
Based on the analysis and evaluation of bibliographer, the applications of tetrazole and carbostyril in cardiovascular drugs and its intermediates were reviewed. The processes for synthesis of them were summarized. Pilozol (1-1) and its intermediates N-cyclohexyl-5-(4-chlorobutyl)-lH-tetrazole (3-1) and 6-hydroxy-3,4-dihydrocarbostyril (4-1) were synthesized in the dissertation, 7-hydroxy-3,4- dihydrocarbostyril (4-2) and 8-hydroxyl-3,4-dihydrocarbostyril (4-3) were similarly prepared by the intramolecular Friedel-Crafts reaction. 5-hydroxy -3,4-dihydrocarbostyril (5-1) was synthesized starting from 1,3-cyclohexanedione as the important intermediates of Carteollol (2-48).
In chapter 3, starting from 5 -valerolactone and cyclohexylamine, N-cyclohexyl -5-hydroxyl-valeroamide (3-2) was prepared. And N-cyclohexyl-5-(4-chlorobutyl) -IH-tetrazole (3-1) was prepared by the chlorination reaction of compound (3-2) with phosphorous pentachloride and the cyclic-reaction with NaNa. The total yield of compound (3-1) was 71%. The mechanism of the reaction of preparation for tetrazole was studied and phase transfer catalyst was probed primarily. The optimal reaction conditions were evaluated.
In chapter 4, 6-hydroxy-3,4-dihydrocarbostyril (4-1) was synthesized from N-(4-hydroxyphenyl)-3-chloropropionamide with the yield of 92% in the presence of Lewis acid catalyst. N-(4-hydroxyphenyl)-3-chloropropionamide was synthesized by the condensation of p-aminophenol with 3-chloropropionyl chloride. 7-hydroxy-3,4-dihydrocarbostyril (4-2) and 8-hydroxy-3,4-dihydrocarbostyril (4-3) were similarly prepared by the intramolecular Friedel-Crafts reaction.
In chapter 5, starting from 1,3-cyclohexanedione, 5-hydroxy-3,4-dihydro -carbostyril (5-1) was prepared in three steps with the yield of 73.4%. In the
process the novel agent of ammonolysis reaction was evaluated and the solvent of dehydrogenation reaction was replaced by toluene. The yield of the dehydrogenation reaction was improved from 68% to 84%.
In chapter 6, Pilozol (1-1) was prepared by the dehalohydrogen reaction of 6-hydroxy-3,4-dihydrocarbostyril (4-1) with N-cyclohexyl-5-(4-chlorobutyl)-lH -tetrazole (3-1) with the yield of 87% in the presence of TEBA as the phase transfer catalyst.
The chemical structures of the product and intermediates were identified and confirmed by IR, NMR, MS. Furthermore the methods of analysis were studied.
It provided the theoretical basis and the feasible process parameters for the industrialization of Pilozol (1-1) and its intermediates N-cyclohexyl-5-(4-chlorobutyl) -IH-tetrazole (3-1) and 6-hydroxy-3,4-dihydrocarbostyril (4-1) in the dissertation.
论文在查阅国内外文献的基础上，对四唑类及2(1H)-喹啉酮类化合物在医药及医药中间体上的应用及其合成路线和方法作了综合评述。
论文研究了药物Pilozol(1-1)及其中间体N-环己基-5-(4-氯丁基)-1H-四唑(3-1)与6-羟基-3，4-二氢-2(1H)-喹啉酮(4-1)的合成；以分子内Friedel-Crafts烷基化反应合成了7-羟基-3，4-二氢-2(1H)-喹啉酮(4-2)、8-羟基-3，4-二氢-2(1H)-喹啉酮(4-3)；同时合成了β肾上腺素受体拮抗剂卡替洛尔(Carteollol，2-48)的中间体5-羟基-3，4-二氢-2(1H)-喹啉酮(5-1)。
论文第三章以δ-戊内酯和环己胺为原料，先缩合得到N-环己基-5-羟基戊酰胺(3-2)，再经PCl_5氯化、NaN_3关环得到N-环己基-5-(4-氯丁基)-1H-四唑(3-1)，两步总收率为71％。同时对四唑环的合成机理、合成工艺进行了研究和实验探索并初步研究了相转移催化合成方法。
论文第四章研究了6-羟基-3，4-二氢-2(1H)-喹啉酮(4-1)的合成反应机理及过程。以对氨基酚为原料，与3-氯丙酰氯反应后在催化剂AlCl_3存在下关环得到6-羟基-3，4-二氢-2(1H)-喹啉酮(4-1)，两步收率为87％。同时对分子内Friedel-Crafts烷基化反应进行研究，类似合成了7-羟基-3，4-二氢-2(1H)-喹啉酮(4-2)及8-羟基-3，4-二氢-2(1H)-喹啉酮(4-3)等化合物。
论文第五章以1，3-环己二酮为原料，经醋酸铵胺解、丙烯酸关环、NBS脱氢三步得到5-羟基-3，4-二氢-2(1H)-喹啉酮(5-1)，总收率达到73.4％。实验研究了新的胺化反应试剂，使反应条件由加压变为常压；并选择了新的脱氢反应溶剂，使脱氢反应收率由68％提高到84％。
论文第六章以N-环己基-5-(4-氯丁基)-1H-四唑(3-1)及6-羟基-3,4-二氢-2(1H)-喹啉酮(4-1)为原料在相转移催化条件下合成了药物Pilozol(1-1)，收率为84.7％。
浙江工业大学2003硕士学位论文
论文用红外、质谱、核磁共振等有机光波谱手段对合成化合物的结构进行了鉴
定和表征，研究了产品和中间体的色谱含量测定方法。
论文通过优化实验确定了Pilozol(1一1)及中间体N一环己基一5一(4一氯丁基关IH-
四哇(3一1)、6一轻基一3，4一二氢一2(1H>哇琳酮(4一l)的合成工艺参数组合，确定了适
合工业化生产的合成新工艺路线，为该类产品的工业化开发提供了理论依据。
Tetrazole and carbostyril and their derivatives are widely applied as cardiovascular drugs.
Based on the analysis and evaluation of bibliographer, the applications of tetrazole and carbostyril in cardiovascular drugs and its intermediates were reviewed. The processes for synthesis of them were summarized. Pilozol (1-1) and its intermediates N-cyclohexyl-5-(4-chlorobutyl)-lH-tetrazole (3-1) and 6-hydroxy-3,4-dihydrocarbostyril (4-1) were synthesized in the dissertation, 7-hydroxy-3,4- dihydrocarbostyril (4-2) and 8-hydroxyl-3,4-dihydrocarbostyril (4-3) were similarly prepared by the intramolecular Friedel-Crafts reaction. 5-hydroxy -3,4-dihydrocarbostyril (5-1) was synthesized starting from 1,3-cyclohexanedione as the important intermediates of Carteollol (2-48).
In chapter 3, starting from 5 -valerolactone and cyclohexylamine, N-cyclohexyl -5-hydroxyl-valeroamide (3-2) was prepared. And N-cyclohexyl-5-(4-chlorobutyl) -IH-tetrazole (3-1) was prepared by the chlorination reaction of compound (3-2) with phosphorous pentachloride and the cyclic-reaction with NaNa. The total yield of compound (3-1) was 71%. The mechanism of the reaction of preparation for tetrazole was studied and phase transfer catalyst was probed primarily. The optimal reaction conditions were evaluated.
In chapter 4, 6-hydroxy-3,4-dihydrocarbostyril (4-1) was synthesized from N-(4-hydroxyphenyl)-3-chloropropionamide with the yield of 92% in the presence of Lewis acid catalyst. N-(4-hydroxyphenyl)-3-chloropropionamide was synthesized by the condensation of p-aminophenol with 3-chloropropionyl chloride. 7-hydroxy-3,4-dihydrocarbostyril (4-2) and 8-hydroxy-3,4-dihydrocarbostyril (4-3) were similarly prepared by the intramolecular Friedel-Crafts reaction.
In chapter 5, starting from 1,3-cyclohexanedione, 5-hydroxy-3,4-dihydro -carbostyril (5-1) was prepared in three steps with the yield of 73.4%. In the
process the novel agent of ammonolysis reaction was evaluated and the solvent of dehydrogenation reaction was replaced by toluene. The yield of the dehydrogenation reaction was improved from 68% to 84%.
In chapter 6, Pilozol (1-1) was prepared by the dehalohydrogen reaction of 6-hydroxy-3,4-dihydrocarbostyril (4-1) with N-cyclohexyl-5-(4-chlorobutyl)-lH -tetrazole (3-1) with the yield of 87% in the presence of TEBA as the phase transfer catalyst.
The chemical structures of the product and intermediates were identified and confirmed by IR, NMR, MS. Furthermore the methods of analysis were studied.
It provided the theoretical basis and the feasible process parameters for the industrialization of Pilozol (1-1) and its intermediates N-cyclohexyl-5-(4-chlorobutyl) -IH-tetrazole (3-1) and 6-hydroxy-3,4-dihydrocarbostyril (4-1) in the dissertation.
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148 M Tominaga, E Yo, et al., Chem Pham Bull, 1984,32:2100
149 M Tominaga, E Yo, et al., Chem Pham Bull, 1986,34:682
150 Feldman A M et al., J Med,1993, 3:149
151 H Hideyuki, O Chieko, et al., JP 03120283
152 T Fujioka, S Teramoto, et al., J. Med. Chem. 1992,35:3607
153 T Fujiloka, S Teramoto, et al., Chem Pham Bull 1996,44(8) : 1596
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155 J Deruiter, Abram N Brubaker, et al., J Med Chem, 1986,29:2024
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159 Merck Index 12th: 7939
160 L Gattermaun,Ber, 1894,27:1936
161 Y Sahashi, Biochem Z, 189-208(1927) ; 168,69(1926)
162 J M Gulland, R A Peters, Biochem J, 1929,23:1124
163 Richard R Holmes, J Conrady, et al., Biochem, 1954,76:2400
164 Kobayashi Y, Kumadaki I, Chem Pham Bull, 1969,17:510
165 Manabe Yoshiaki, et al., Jpn Kokai Tokkyo Koho79 19,985(1980)
166 Tai-Chi Wang, et al., Synthesis. 1:87(1997)
167 F Mayer, L Van Zutphen and H Philipps.Ber. 60B, 858-864(1927)
168 N Shigematsu Chem Pharm Bull, 9:970-975(1961)
169 Yokota Keiichi JP11269148
170 Lee Byo Suku JP 2000229944
171 Yokota Keiichi JP 9124605
172 Mendelovici, Marioarai, et al., WO 0170697
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174 Hidenosuke Proc. Imp. Acad. (Tokyo) 15,148-155(1939)
175 C Marc and L Xarier Tetrahedron Lett. 1989,30(6) ,715-718
176 F W Wassmundt and S J Padegimas J Am Chem Soc,1967,26:7131-7132
177 Leon Denivelle, et al., Bull Soc Chim France, 1957,630-632
178 Gurbachan Singh Sidhu,Ann,627,218-224(1959)
179 J D Loudon and J Ogg, J Chem Soc,1955,739-744
180 E Lellman, Ber., 20:2172(1887)
181 T Shono, Y Matsumura and S Kashimura, J Org Chem. 1981,46:3719-3721
182 S Kashimura, JP 57146759
183 Bohme E W, Valenta Z, et al., Tetrahedron Lett., 1965,2441
184 Yanhe Huang and R W Hartmann, Syn Comm., 28(7) : 1197-120(1998)
185 O Kazunar and T Takamistu, JP 7138789
186 T Takamistu and Terashima, Chem Ind. (London), 1970(45) : 1435
187 M Mitsuhiko and T Takamistu, JP 7139694
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189 Chen Ling-Ching, et al.,J Chin Chem Soc(Taipei),1984,31(4) :413-415
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160 L Gattermaun,Ber, 1894,27:1936
161 Y Sahashi, Biochem Z, 189-208(1927) ; 168,69(1926)
162 J M Gulland, R A Peters, Biochem J, 1929,23:1124
163 Richard R Holmes, J Conrady, et al., Biochem, 1954,76:2400
164 Kobayashi Y, Kumadaki I, Chem Pham Bull, 1969,17:510
165 Manabe Yoshiaki, et al., Jpn Kokai Tokkyo Koho79 19,985(1980)
166 Tai-Chi Wang, et al., Synthesis. 1:87(1997)
167 F Mayer, L Van Zutphen and H Philipps.Ber. 60B, 858-864(1927)
168 N Shigematsu Chem Pharm Bull, 9:970-975(1961)
169 Yokota Keiichi JP11269148
170 Lee Byo Suku JP 2000229944
171 Yokota Keiichi JP 9124605
172 Mendelovici, Marioarai, et al., WO 0170697
173 M Kiyoshi, T Kenji, et al., JP 0413681
174 Hidenosuke Proc. Imp. Acad. (Tokyo) 15,148-155(1939)
175 C Marc and L Xarier Tetrahedron Lett. 1989,30(6) ,715-718
176 F W Wassmundt and S J Padegimas J Am Chem Soc,1967,26:7131-7132
177 Leon Denivelle, et al., Bull Soc Chim France, 1957,630-632
178 Gurbachan Singh Sidhu,Ann,627,218-224(1959)
179 J D Loudon and J Ogg, J Chem Soc,1955,739-744
180 E Lellman, Ber., 20:2172(1887)
181 T Shono, Y Matsumura and S Kashimura, J Org Chem. 1981,46:3719-3721
182 S Kashimura, JP 57146759
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184 Yanhe Huang and R W Hartmann, Syn Comm., 28(7) : 1197-120(1998)
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187 M Mitsuhiko and T Takamistu, JP 7139694
188 Y Tamura, L C Chen, M Fujita, et al., Chem Pharm Bull,1982,30(4) ,1257-1262
189 Chen Ling-Ching, et al.,J Chin Chem Soc(Taipei),1984,31(4) :413-415
190 Bull. Soc. Chim. Fr. 1984,11,285