Page 219 - 《精细化工》2021年第5期

第 5 期 傅 鹏，等: 降压新药西尼地平杂质Ⅰ的制备 ·1073·

首先西尼地平在 MnO 2 表面发生吸附并与其形 application of the oxidizing properties of pyridinium chlorochromate:
Aromatization of Hantzsch 1,4-dihydrop-yridines[J]. Tetrahedron,
成配位化合物中间体（Ⅱ），然后二氢吡啶环中 1 位 1992, 48(3): 463-468.
[12] LU J (路军), BAI Y J (白银娟), YANG B Q (杨秉勤), et al. Study on
上的氢原子发生迁移得到含有锰酸酯的中间体 improvement of synthesis method and aromatization of 1,4-dihydropyridine
derivatives[J]. Chinese Journal of Organic Chemistry (有机化学),
（Ⅲ），后者二氢吡啶环 4 位上的氢原子发生进一步 2000, 20(4): 514-517.
[13] GARCÍA O, DELGADO F, CANO A C, et al. Oxydation d'esters de
迁移得到中间体（Ⅳ），最后产物在失去一分子水后 Hantzsch, par le nouveau système HNO 3/bentonite, et irradiation aux
micro-ondes[J]. Tetrahedron Letters, 1993, 34(4): 623-625.
4+
发生解吸，得到目标产物 [15,18,34-35] 。Mn 能促进西 [14] ITOH T, NAGATA K, MATSUYA Y, et al. Reaction of nitric oxide with
尼地平发生芳构化过程，因此，承接电子转移的氧 amines[J]. The Journal of Organic Chemistry, 1997, 62(11): 3582-3585.
[15] VARMA R S, KUMAR D. Manganese triacetate mediated oxidation
化剂 MnO 2 具体发生的反应机理为锰的不同价态间 of Hantzsch 1,4-dihydropyridines to pyridines[J]. Tetrahedron Letters,
1999, 40(1): 21-24.
2+
4+
的转化，即 Mn 还原为 Mn 。 [16] SADEGHI M M, MOHAMMADPOOR-BALTORK I, MEMARIAN
H R, et al. Efficient oxidation of Hantzsch 1,4-dihydropyridines with
nicotinium dichromate[J]. Synthetic Communications, 2000, 30(9):
3 结论 1661-1665.
[17] ABDOLI-SENEJANI M, FORUZAN N, BAHMANI M, et al.
Oxidative aromatization of some 1,4-dihydropyridine derivatives using
从二氢吡啶类钙离子拮抗剂易于在氧化剂中发 NaBrO 3[J]. Iranian Chemical Communication, 2016, 4(3): 309-317.
[18] HERAVI M M, BEHBAHANI F K, OSKOOIE H A, et al. Catalytic
生芳构化，生成吡啶化合物的反应机理入手，对比 aromatization of Hantzsch 1,4-dihydropyridines by ferric perchlorate
in acetic acid[J]. Tetrahedron Letters, 2005, 46(16): 2775-2777.
西尼地平 在 FeCl 3 •6H 2 O 、 KMnO 4 、浓 HNO 3 、 [19] FILIPAN-LITVIĆ M, LITVIĆ M, CEPANEC I, et al. Antimony(Ⅴ)
chloride-promoted room temperature aromatization of 1,4-dihydropyridines
Mn(OAc) 3 •2H 2 O、NaBrO 3 ，MnO 2 等氧化剂对制备 in non-acidic solvent[J]. Arkivoc, 2008, (11): 96-103.
西尼地平杂质Ⅰ的影响，选用西尼地平作为起始原 [20] VANDEN EYNDE J J, DELFOSSE F, MAYENCE A, et al. Old
reagents, new results: Aromatization of Hantzsch 1,4-dihydropyridines
料，MnO 2 作为氧化剂制备西尼地平杂质Ⅰ。 with manganese dioxide and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone[J].
Tetrahedron, 1995, 51(23): 6511-6516.
综合溶剂，温度和 MnO 2 是否活化等因素对反 [21] ZOLFIGOL M A, BAGHERZADEH M, NIKNAM K, et al.
Oxidation of 1,4-dihydropyridines under mild and heterogeneous
应的影响，对反应条件进行优化，得到制备西尼地 conditions using solid acids[J]. Journal of the Iranian Chemical
Society, 2006, 3(1): 73-80.
平杂质Ⅰ的最适宜条件为：在 105 ℃下，西尼地平 [22] NIKNAM K, RAZAVIAN S M, ZOLFIGOL M A, et al. Aromatization
与活化 MnO 2 质量比为 1.00∶1.24，甲苯为溶剂。 of 1,4-dihydropyridines in the presence of methanesulfonic acid/
NaNO 2/wet SiO 2 under both heterogeneous and solvent free conditions[J].
本方法具有原材料易得、反应条件温和、后处 Journal of Heterocyclic Chemistry, 2006, 43(1): 199-202.
[23] NAKAMICHI N, KAWASHITA Y, HAYASHI M. Oxidative
理操作简单、甲苯和 MnO 2 可回收再用、环保安全、 aromatization of 1,3,5-trisubstituted pyrazolines and Hantzsch
1,4-dihydropyridines by Pd/C in acetic acid[J]. Organic Letters,
产物纯度和收率高、制得的西尼地平杂质Ⅰ无需精 2002, 4(22): 3955-3957.
制的优点。按照面积归一化法计算，西尼地平杂质 [24] KARAMI B, MONTAZEROZOHORI M, NASR-ESFAHANI M.
Catalytic aromatization of Hantzsch 1,4-dihydropyridines by
Ⅰ纯度可达 99.0%以上。 bis(salicylaldehyde-1,2-phenylenediimine) Mn( Ⅲ ) chloride using
urea hydrogen peroxide as mild and efficient oxidant[J].
Heterocycles, 2005, 65(9): 2181-2188.
参考文献： [25] TUROVSKA B, GOBA I, TUROVSKIS I, et al. Electrochemical
oxidation of 4-monoalkyl-substituted 1,4-dihydropyridines[J]. Chemistry
[1] KISHOR S. A complete guide on the pharmacologic and of Heterocyclic Compounds, 2008, 44(12): 1483-1490.
pharmacotherapeutic aspects of calcium channel blockers: An extensive [26] KORMOS C, HULL R. Microwave heating in conjunction with UV
review[J]. International Journal of Pharmaceutical Sciences and irradiation: A tool for the oxidation of 1,4-dihydropyridines to
Research, 2019, 10(11): 4830-4843. pyridines[J]. Australian Journal of Chemistry, 2009, 62(1): 51-57.
[2] TAJIRI K, GUICHARD J B, QI X Y, et al. An N-/L-type calcium [27] POESCHL A, MOUNTFORD D M. A facile manganese dioxide
channel blocker, cilnidipine, suppresses autonomic, electrical, and mediated oxidation of primary benzylamines to benzamides[J].
structural remodelling associated with atrial fibrillation[J]. Cardiovascular Organic & Biomolecular Chemistry, 2014,12(36): 7150-7158.
Research, 2019, 115(14): 1975-1985. [28] JING H Q (荆华青), LI H L (李红亮). One-pot three-steps method
[3] GU S X (顾司勋). Medicinal chemistry—Review and development[M]. for the synthesis of phenyl-2-pyridyl-methanol[J]. Fine Chemicals
Beijing: People's Medical Publishing House Co., Ltd. (人民卫生出 (精细化工), 2020, 37(10): 2150-2153.
版社有限公司), 2002: 199-211. [29] ZHANG J H (张家海), DU D Z (杜定准), WU J H (吴季辉).
[4] CH K R, JV S K, PALUSA S K G. Isolation and characterization of Attribution of the peaks of the NMR carbon spectrum hydrogen
novel degradation products in cilnidipine by LC-QTOF-MS/MS, spectrum of cilnidipine[J]. Chinese Journal of Analytical Chemistry
LCMS, 2D-NMR and FTIR[J]. New Journal of Chemistry, 2018, (分析化学), 2003, 31(9): 1044-1047.
42(1): 634-646. [30] WANG Y D (王永东), ZHANG M (张敏), XU F P (徐福培). One
[5] FANG X Q, LIU Y C, LI C Z. 9-Phenyl-10-methylacridinium: A oxygen of 1,4-dihydropyridine compounds participates in aromatization
highly efficient and reusable organocatalyst for mild aromatization of reaction[J]. Journal of Shanghai University (Natural Science Edition)
1,4-dihydropyridines by molecular oxygen[J]. Journal of Organic (上海大学学报: 自然科学版), 1998, 4(4): 373-376.
Chemistry, 2007, 72(22): 8608-8610. [31] FULMER G R, MILLER A J M, SHERDEN N H, et al. NMR
[6] HU C C (胡楚楚), GU X (顾霄). Structural analysis of cindipine chemical shifts of trace impurities: Common laboratory solvents,
photodegradation impurities[J]. Chinese Journal of Pharmaceutical organics, and gases in deuterated solvents relevant to the organometallic
Analysis (药物分析杂志), 2016, 36(8): 1446-1450. chemist[J]. Organometallics, 2010, 29(9): 2176-2179.
[7] ZENG H X, WANG J, ZHU B Q, et al. Rationality evaluation of [32] ALBERTI A, ASTOLFI P, CARLONI P, et al. The reactivity of
packaging materials and study on impurity profiling of cilnidipine manganese dioxide towards different substrates in organic
preparations by HPLC-Q-TOF/MS[J]. Current Pharmaceutical solvents[J]. New Journal of Chemistry, 2015, 39(11): 8964-8970.
Analysis, 2020, 16(2): 220-230. [33] MA C J, WEN Y Y, RONG C L, et al. δ-MnO 2 with an ultrahigh
4+
[8] ZHENG A (郑爱), XU X (徐新), LI L B (李立标), et al. Kind of Mn fraction is highly active and stable for catalytic wet air
method for preparing cilnidipine impurity or its oxide impurity: CN oxidation of phenol under mild conditions[J]. Catalysis Science &
108101836A[P]. 2017-12-29. Technology, 2017, 7(15): 3200-3204.
[9] KO K Y, KIM J Y. Aromatization of Hantzsch 1,4-dihydropyridines [34] GOLDMEN I M. Observation of a large isotope effect in the
with Magtrieve™[J]. Tetrahedron Letters, 1999, 40(16): 3207-3208. manganese dioxide oxidation of benzyl alcohol[J]. Journal of Organic
[10] EYNDE J J V, D'ORAZIO R, VAN HAVERBEKE Y. Potassium Chemistry, 1969, 34(11): 3289-3295.
permanganate, a versatile reagent for the aromatization of Hantzsch [35] THOMAS K H, PAUL R S. Novel oxidative rearrangement with
1,4-dihydropyridines[J]. Tetrahedron, 1994, 50(8): 2479-2484. manganese dioxide[J]. Journal of the American Chemical Society,
[11] VANDEN EYNDE J J, MAYENCE, A, MAQUESTIAU A. A novel 1967, 89(25): 6759-6761.