抗癌药物丙卡巴肼的合成工艺再优化
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摘要
以对甲基苯甲酸为起始原料,与氯化亚砜反应得对甲基苯甲酰氯(2),酰氯直接与异丙胺反应得对甲苯甲酰异丙胺(3);化合物3经硝酸铈铵(CAN)氧化得4-甲酰基苯甲酰异丙胺(4);以氰基硼氢化钠为还原剂,化合物4与甲基肼硫酸盐在碱性条件下经经缩合还原反应生成目标化合物丙卡巴肼.该工艺路线共4步反应,总收率44.7%,每个单元反应收率71%~86%.所有化合物的结构均经1H-NMR、13C-NMR和MS确认.
Procarbazine has been prepared through a four-steps process. Firstly,4-methylbenzoyl chloride was synthesized by reaction of 4-methylbenzoic acid with dimethyl sulfoxide. The direct reaction of this chloride with isopropylamine form N-isopropyl-4-methylbenzamide. The amide was then oxidized to4-formyl-N-isopropylbenzamide by using ammonium ceric nitrate as oxidant. Afterwards,this intermediate condensed with methylhydrazine sulfate and then reduced by sodium cyanoborohydride under basic condition to offer the target compound. The overall yield was 44. 7%. The yield of each unit reaction was 71%to 86%. All the intermediates and target product were identified by1 H NMR,13 C NMR and mass spectroscopy( MS).
Procarbazine has been prepared through a four-steps process. Firstly,4-methylbenzoyl chloride was synthesized by reaction of 4-methylbenzoic acid with dimethyl sulfoxide. The direct reaction of this chloride with isopropylamine form N-isopropyl-4-methylbenzamide. The amide was then oxidized to4-formyl-N-isopropylbenzamide by using ammonium ceric nitrate as oxidant. Afterwards,this intermediate condensed with methylhydrazine sulfate and then reduced by sodium cyanoborohydride under basic condition to offer the target compound. The overall yield was 44. 7%. The yield of each unit reaction was 71%to 86%. All the intermediates and target product were identified by1 H NMR,13 C NMR and mass spectroscopy( MS).
引文
[1]SINLIA B K.Metabolic activation of procarbazine.Evidence for carbon-centered free-radical intermediates[J].Biochem Pharmacol,1984,33(17):2777-2781.
[2]HORSTMAN M G,MEADOWS G G,YOST G S.Separate mechanisms for procarbazine spermato toxicity and anticancer activity[J].Cancer Res,1987,47(6):1547-1550.
[3]谭卫宁,刘智凌.水合肼的衍生物及其应用[J].湖南化工,1996,26(4):5-8.
[4]刘志军,陈河如.抗癌药物丙卡巴肼的合成工艺优化研究[J].中国药物化学杂志,2012,22(6):499-502.
[5]宋磊,李静,陈勇强,等.对二甲苯液相空气氧化的研究[J].聚酯工业,2007,20(2):22-24.
[6]BABU V V S,VASANTHAKUMAR G R,TANTRY S J.N-Silylation of amines and amino acid esters under neutral conditions employing TMS-Cl in the presence of zinc dust[J].Tetrahedron Letters,2005,46(38):4099-4102.
[7]PRAJAPATI A K,MODI V P.Synthesis and biological activity of N-[5-(4-methylphenyl)diazenyl-4-phenyl-1,3-thiazol-2-yl]benzamide derivatives[J].Quimica Nova,2001,34(5):771-774.
[8]SUGIYAMA Y,KURATA Y,KUNDA Y,et al.A fluorous Mukaiyama coupling reagent for a concise condensation reaction:utility of medium-fluorous strategy[J].Tetrahedron,2012,68(20):3885-3892.
[9]MATSUGI M,HASEGAWA M,SADACHIKA D,et al.Preparation and condensation reactions of a new light-fluorous Mukaiyama reagent:reliable purification with fluorous solid phase extraction for esters and amides[J].Tetrahedron Letts,2007,48(38):4147-4150
[10]RAHMAN O,KIHLBERG T,LANGSTROM B.Aryl riflates and[11C]/[13C]carbon monoxide in the synthesis of 11C-13C-amides[J].J Org Chem,2003,68(9):3558-3562.
[11]Al TALIB M,JOCHIMS J C.The reaction of acylium salts with carbodiimides[J].Chemische Berichte,1985,118(4):1304-1314.
[12]LEI M,MA L,HU LI.A convenient one-pot synthesis of formamide derivatives using thiamine hydrochloride as a novel catalyst[J].Tetrahedron Letters,2010,51(32):4186-4188.
[13]DUST L A,GILL E W.Nitrate Esters as Intermediates in the Oxidation of Toluenes by Ammonium Cerium(Ⅳ)Nitrate[J].J Chem Soc(C),1970,1630-1670.
[14]ZHAO H.The synthesis and structures of deuterium-labeled 5-substituted 1H-tetrazoles[J].J Label Compd Radiopharm,2008,51:293-296.
[15]HOSSEINZADEH R,TAJBAKHSH M,VAHEDI H.Selective oxidation of methylarenes with pyridinium chlorochromate[J].Synlett,2005,18:2769-2770.
[16]姜华,陈蓉蓉,蒲含林.长春西汀的半合成工艺[J].暨南大学学报:自然科学版,2012,33(1):65-68.
[2]HORSTMAN M G,MEADOWS G G,YOST G S.Separate mechanisms for procarbazine spermato toxicity and anticancer activity[J].Cancer Res,1987,47(6):1547-1550.
[3]谭卫宁,刘智凌.水合肼的衍生物及其应用[J].湖南化工,1996,26(4):5-8.
[4]刘志军,陈河如.抗癌药物丙卡巴肼的合成工艺优化研究[J].中国药物化学杂志,2012,22(6):499-502.
[5]宋磊,李静,陈勇强,等.对二甲苯液相空气氧化的研究[J].聚酯工业,2007,20(2):22-24.
[6]BABU V V S,VASANTHAKUMAR G R,TANTRY S J.N-Silylation of amines and amino acid esters under neutral conditions employing TMS-Cl in the presence of zinc dust[J].Tetrahedron Letters,2005,46(38):4099-4102.
[7]PRAJAPATI A K,MODI V P.Synthesis and biological activity of N-[5-(4-methylphenyl)diazenyl-4-phenyl-1,3-thiazol-2-yl]benzamide derivatives[J].Quimica Nova,2001,34(5):771-774.
[8]SUGIYAMA Y,KURATA Y,KUNDA Y,et al.A fluorous Mukaiyama coupling reagent for a concise condensation reaction:utility of medium-fluorous strategy[J].Tetrahedron,2012,68(20):3885-3892.
[9]MATSUGI M,HASEGAWA M,SADACHIKA D,et al.Preparation and condensation reactions of a new light-fluorous Mukaiyama reagent:reliable purification with fluorous solid phase extraction for esters and amides[J].Tetrahedron Letts,2007,48(38):4147-4150
[10]RAHMAN O,KIHLBERG T,LANGSTROM B.Aryl riflates and[11C]/[13C]carbon monoxide in the synthesis of 11C-13C-amides[J].J Org Chem,2003,68(9):3558-3562.
[11]Al TALIB M,JOCHIMS J C.The reaction of acylium salts with carbodiimides[J].Chemische Berichte,1985,118(4):1304-1314.
[12]LEI M,MA L,HU LI.A convenient one-pot synthesis of formamide derivatives using thiamine hydrochloride as a novel catalyst[J].Tetrahedron Letters,2010,51(32):4186-4188.
[13]DUST L A,GILL E W.Nitrate Esters as Intermediates in the Oxidation of Toluenes by Ammonium Cerium(Ⅳ)Nitrate[J].J Chem Soc(C),1970,1630-1670.
[14]ZHAO H.The synthesis and structures of deuterium-labeled 5-substituted 1H-tetrazoles[J].J Label Compd Radiopharm,2008,51:293-296.
[15]HOSSEINZADEH R,TAJBAKHSH M,VAHEDI H.Selective oxidation of methylarenes with pyridinium chlorochromate[J].Synlett,2005,18:2769-2770.
[16]姜华,陈蓉蓉,蒲含林.长春西汀的半合成工艺[J].暨南大学学报:自然科学版,2012,33(1):65-68.