Dehydrogenating Aromatization of 1,4-Dihydropyridines Mediated by Nickel Element in Aqueous Media
ZHANG Shu-dong1, FU Hui2, YIN Guang3, JIA Bo-yang1, HU Qin1, ZHANG Zhe1*
1. NMPA Key Laboratory for Research and Evaluation of Generic Drugs, Beijing Key Laboratory of Analysis and Evaluation on Chinese Medicine, Beijing Institute for Drug Control, Beijing 102206, China;
2. Beijing Fresenius Kabi Pharmaceutical Co Ltd, Beijing 100004, China;
3. National Institutes for Food and Drug control, Beijing 100050, China
OBJECTIVE To study the principle of dehydroaromatization of such 1,4-dihydropyridines, determine the applicability of the reaction substrate, and optimize the reation conditions. METHODS HPLC method was used with amlodipine besylate as the main research compound. The amount of dehydroaromatic compounds was calculated according to the external standard method. The hydrogen ion concentration, the oxygen content of the medium, the organic solvent and surfactant, the acid species,the reaction time, and the amount of nickel on the effects of the reaction were observed. RESULTS The concentration of hydrogen ions in the acidic aqueous solution required for the reaction should be greater than 10-5 mol·L-1. Oxygen in the medium could increase the reaction rate, while nitrogen or other gases could inhibit the reaction. The reaction rate was proportional to the purity of the elemental nickel and the amount of the feed. The organic solvents and surfactants would inhibit the reaction rate, and the inorganic acids or organic acids could be used to prepare acidic aqueous solutions. The reaction could acquire the maximum conversion rate after 4 h. CONCLUSION 1,4-Dihydropyridine compounds can be dehydroaromatized in acidic aquous solution at normal temperature and pressure in the presence of nickel elemental and dissolved oxygen in the medium as the oxidant. The reaction is a new type of 1,4-dihydropyridine dehydroaromatization reaction, which is simple in operation, high in conversion rate, and environmentally friendly.
EISNER U, KUTHAN J. Chemistry of dihydropyridines[J]. Chem Rev, 1972, 72(1):1-42.
STOUT D M, MEYERS A I. Recent advances in the chemistry of dihydropyridines[J]. Chem Rev, 1982, 82(2):223-243.
BOSSERT F, VATER W. 1,4-Dihydropyridines-a basis for developing new drugs[J]. Med Res Rev, 2010, 9(3):291-324.
ZHANG L Y, WANG J, ZHOU L X, et al. Key influencing factors of stability of 1, 4-dihydropyridine drug solutions[J]. J Chin Pharm Sci(中国药学英文版), 2017, 52(11):978-980.
XU J H, LIY X, LUAN J J, et al. Chronopharmacokinetics of amlodipine in rats[J]. J Chin Pharm Sci(中国药学英文版), 2017, 52(21):1937-1943.
TIAN B, DU Z M. Pharmacokinetics interaction between valsartan and nifedipine in rats[J]. J Chin Pharm Sci(中国药学英文版), 2016, 51(9):732-736.
BELARDETTI F. Evolving therapeutic indications for N-type calcium channel blockers: from chronic pain to alcohol abuse[J]. Future Med Chem, 2010, 2(5):791-802.
HERAVI M M, BEHBAHANI F K, OSKOOIE H A, et al. Catalytic aromatization of Hantzsch 1,4-dihydropyridines by ferric perchlorate in acetic acid[J]. Tetrahedron Lett, 2005, 46(16):2775-2777.
MARIA B, IATVÁN H, ZOLTÁN M. Aromatization of 1, 4-dihydropyridines by clay-supported metal nitrates[J]. Helv Chim Acta, 2010, 67(8):2270-2272.
PFISTER J R. ChemInform abstract: rapid, high-yield oxidation of hantzsch-type 1, 4-dihydropyridines with ceric ammonium nitrate[J]. Synthesis, 1990,(8):689-690.
MAQUESTIAU A, MAYENCE A, EYNDE J J V. Ultrasound-promoted aromatization of Hantzsch 1,4-dihydropyridines by clay-supported cupric nitrate[J]. Cheminform, 2010, 23(17):3839-3840.
RONALD H, BOCKER, GUENGERICH F P. Oxidation of 4-aryl- and 4-alkyl-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4- dihydropy- ridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450[J]. J Med Chem, 1986, 29(9):1596-1603.
MASHRAQUI S H, KARNIK M A. Catalytic oxidation of Hantzsch 1,4-dihydropyridines by RuCl3 under oxygen atmosphere[J]. Tetrahedron Lett, 1998, 39(27):4895-4898.
VARMA R S, KUMAR D. Manganese triacetate mediated oxidation of Hantzsch 1,4-dihydropyridines to pyridines[J]. Cheminform, 2010, 30(14):21-24.
ARGUELLO J, NU&NTILDE, EZ-VERGARA L J, et al. Voltammetric oxidation of Hantzsch 1,4-dihydropyridines in protic media: substituent effect on positions 3, 4, 5 of the heterocyclic ring[J]. Electrochim Acta, 2004, 49(27):4849-4856.
JOAQUIN N, ARTURO S. Voltammetric oxidation of Hantzsch 1,4-dihydropyridines in protic and aprotic media: relevance of the substitution on N position[J]. Electrochim Acta, 2003, 48(17):2505-2516.
NAKAMICHI N, YUKA KAWASHITA A, HAYASHI M. Oxidative aromatization of 1,3,5-trisubstituted pyrazolines and Hantzsch 1,4-dihydropyridines by Pd/C in acetic acid[J]. Cheminform, 2003, 34(12):3955-3957.
NAKAMICHI N, KAWASHITA Y, HAYASHI M. Activated carbon-promoted oxidative aromatization of Hantzsch 1,4-dihydropyridines and 1, 3, 5-trisubstituted pyrazolines using molecular oxygen[J]. Cheminform, 2004, (7):1015-1020.
KIKUCHI D, SATOSHI SAKAGUCHI A, ISHII Y. An alternative method for the selective bromination of alkylbenzenes using NaBrO3/NaHSO3 reagent[J]. Cheminform, 1998, 63(17):6023-6026.
BAO M, LU W, ZHANG D, et al. An ideal dehydroaromatization reagent for Hantzsch 1,4-dihydropyridine-KBrO3/NaHSO3[J]. J Nanjing Normal Univ (Nat Sci Ed)(南京师大学报 自然科学版), 2000, 23 (3):66-69.
FU H. Method for dehydro-aromatization of dihydropyridine compound and application to drug detection: CN109020875A[P]. 2018-12-28.