CN105566156A - Method for synthesizing clotrimazole pharmaceutical intermediate o-chlorobenzonitrile - Google Patents

Method for synthesizing clotrimazole pharmaceutical intermediate o-chlorobenzonitrile Download PDF

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CN105566156A
CN105566156A CN 201511002595 CN201511002595A CN105566156A CN 105566156 A CN105566156 A CN 105566156A CN 201511002595 CN201511002595 CN 201511002595 CN 201511002595 A CN201511002595 A CN 201511002595A CN 105566156 A CN105566156 A CN 105566156A
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reaction
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clotrimazole
chlorobenzonitrile
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CN 201511002595
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关艮安
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成都千叶龙华石油工程技术咨询有限公司
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    • C07C253/00Preparation of carboxylic acid nitriles

Abstract

A method for synthesizing a clotrimazole pharmaceutical intermediate o-chlorobenzonitrile comprises the following steps: adding 3.1 mol of 2-chloro-benzenemethanol, 3.6-3.9 mol of aniline, 310 ml of nitromethane and 1.56 mol of cuprous chloride into a reaction vessel provided with a stirrer, a thermometer and a distillation device, mixing the raw materials evenly, and controlling the stirring speed to be 110-160 rpm; increasing the solution temperature to 110-115 DEG C, and carrying out a reaction for 3-5 h; increasing the solution temperature to 130-135 DEG C, and carrying out a reaction for 2-3 h; increasing the solution temperature to 190-195 DEG C, and carrying out a reaction for 90-120 min; decreasing the solution temperature to 15-20 DEG C, adding 700 ml of a salt solution and 130 ml of a sodium bisulfite solution into the reaction liquid, carrying out reduced pressure distillation, collecting a 130-135 DEG C fraction, washing the fraction with triethylamine, recrystallizing in toluene, and thus obtaining the crystal o-chlorobenzonitrile.

Description

一种克霉唑药物中间体邻氯苯甲腈的合成方法 One method of synthesis of Intermediate o-chlorobenzonitrile pharmaceutical clotrimazole

技术领域 FIELD

[0001 ]本发明涉及一种克霉唑药物中间体邻氯苯甲腈的合成方法。 [0001] The present invention relates to a pharmaceutical Clotrimazole synthesis of intermediate o-chlorophenyl-carbonitrile.

背景技术 Background technique

[0002] 克霉唑属吡咯类抗真菌药,对白念珠菌则可抑制其自芽孢转变为侵袭性菌丝的过程。 [0002] The azole-based antifungal clotrimazole genus, Candida albicans suppressed during its transition from Bacillus invasive hyphae. 克霉唑具广谱抗真菌活性,对表皮癣菌、毛发癣菌、曲菌、着色真菌、隐球菌属和念珠菌属均有较好抗菌作用,对申克氏孢子丝菌、皮炎芽生菌、粗球孢子菌属、组织浆胞菌属等也有一定抗菌活性。 Clotrimazole with broad-spectrum antifungal activity, to Epidermophyton, Trichophyton, aspergillosis, coloring fungi, Cryptococcus and Candida have good antibacterial activity, Sporothrix schenckii, Blastomyces dermatitidis The crude Coccidioides, Histoplasma spp cells also have some antibacterial activity. 克霉唑曲霉、某些暗色孢科、毛霉菌属等作用差。 Clotrimazole Aspergillus, some action Dematiaceae, Mucor and so poor. 该品通过干扰细胞色素P-450的活性,从而抑制真菌麦角固醇等固醇的生物合成,损伤真菌细胞膜并改变其通透性,以致重要的细胞内物质外漏;可抑制真菌的甘油三脂和磷脂的生物合成;也可抑制氧化酶和过氧化酶的活性,引起细胞内过氧化氢积聚导致细胞亚微结构变性和细胞坏死。 The product by interfering activity of cytochrome P-450, thus inhibiting fungal ergosterol biosynthesis like sterol, fungal cell membrane damage and change its permeability so important intracellular material leakage; inhibit fungal triglyceride lipid and phospholipid biosynthesis; also inhibit oxidase and peroxidase activity, causing accumulation of hydrogen peroxide causes cell submicroscopic structures intracellular degeneration and necrosis. 白色念珠菌所致的皮肤念珠菌病,浓度高时也可具杀菌作用。 Candida albicans-induced cutaneous candidiasis, also has a bactericidal effect at high concentrations. 可抑制真菌麦角留醇等固醇的生物合成;损伤真菌细胞膜和改变其通透性,致细胞内重要物质漏失;也可抑制真菌的甘油三酸和磷脂的生物合成;该品尚可抑制氧化和过氧化酶的活性,引起过氧化物在细胞内过度积聚,致真菌亚细胞结构变性和坏死。 Sterols inhibit fungal ergosterol biosynthesis remain alcohol; fungal cell membrane damage and changes its permeability, causing leakage of intracellular important material; also inhibit the biosynthesis of triglycerides and phospholipids fungi; the product can still inhibit oxidation and peroxidase activity, causing an excessive accumulation of peroxides in the cell, fungal induced degeneration subcellular structures and necrosis. 对白色念珠菌则可抑制其芽孢转变为具侵袭性的菌丝。 Candida albicans mycelial which suppressed with spores into invasive. 邻氯苯甲腈作为克霉唑药物中间体,其合成方法优劣对于提高药物合成产品质量,减少副产物含量具有重要经济意义。 O-chlorobenzonitrile as clotrimazole drug intermediates, synthetic method has advantages and disadvantages of economic importance to improve the synthesis of a pharmaceutical product quality, reduce the content of byproducts.

发明内容 SUMMARY

[0003] 本发明的目的在于提供一种克霉唑药物中间体邻氯苯甲腈的合成方法,包括如下步骤: [0003] The object of the present invention is to provide a method for synthesizing a pharmaceutical Clotrimazole intermediate o-chlorobenzonitrile, comprising the steps of:

[0004] (i)在安装有搅拌器、温度计、蒸馏装置的反应容器中,加入邻氯苯甲醇(2) 3. lmol,苯胺(3)3.6-3 · 9mol,硝基甲烧310ml,氯化亚铜1 · 56mol,混合均勾,控制搅拌速度110-160rpm,升高溶液温度至110-115°C,反应3-5h,升高溶液温度至130-135°C,反应2-3h,升高溶液温度至190-195°C,反应90-120min,降低溶液温度至15-20°C,加入盐溶液700ml,亚硫酸氢钠溶液130ml,减压蒸馏,收集130-135°C的馏分,三乙胺洗涤,在甲苯中重结晶,得晶体邻氯苯甲腈(1)。 [0004] (i) in a reaction container equipped with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. lmol, aniline (3) 3.6-3 · 9mol, nitromethane burning 310ml, chloro cuprous 1 · 56mol, hook are mixed, controlling the stirring speed 110-160rpm, the solution temperature increased to 110-115 ° C, 3-5h the reaction, the solution temperature increased to 130-135 ° C, the reaction 2-3h, solution temperature increased to 190-195 ° C, the reaction 90-120min, reducing the solution temperature to 15-20 ° C, was added 700 ml of saline solution, sodium bisulfite solution, 130ml, distilled under reduced pressure to collect 130-135 ° C fraction , washed with triethylamine in toluene and recrystallized to give crystals of o-chlorobenzonitrile (1).

[0005] 其中,步骤(i)所述的硝基甲烷质量分数为60-65%,步骤(i)所述的盐溶液为硝酸铵、碘化钾中的任意一种,步骤(i)所述的亚硫酸氢钠溶液质量分数为40-45%,步骤(i) 所述的减压蒸馏所处压力为1.6-1.7kPa,步骤(i)所述的三乙胺质量分数为70-75%,步骤(i)所述的甲苯质量分数为90-95%。 [0005] wherein the mass fraction of nitromethane according to step (i) is 60-65%, of the salt solution in step (i) is ammonium nitrate, potassium iodide to any one of the steps of (i) mass fraction of sodium hydrogen sulfite solution was 40-45%, which pressure in the vacuum distillation of step (i) is 1.6-1.7kPa, triethylamine mass fraction of said step (i) is 70-75%, step (i) in toluene of the mass fraction of 90-95%. 整个反应过程可用如下反应式表示: Throughout the reaction using the following reaction formula:

[0006 [0006

[0007」 不及明1 兀点仕卞:赪少J [0007 "not as good as Wu Ming 1 point Shi Bian: J Cheng less

Figure CN105566156AD00041

反奴的甲I日」*1、节,阵低J反应温度及反应时间,提高了反应收率。 A slave I anti Day "* 1, section A, J array low reaction temperature and reaction time, the reaction yield improved.

具体实施方式 Detailed ways

[0008] 下面结合具体实施实例对本发明作进一步说明: [0008] The following examples with reference to specific embodiments of the present invention is further described:

[0009] -种克霉唑药物中间体邻氯苯甲腈的合成方法 Clotrimazole synthesis kinds drug intermediates of o-chlorobenzonitrile - [0009]

[0010] 实例1: [0010] Example 1:

[0011] 在安装有搅拌器、温度计、蒸馏装置的反应容器中,加入邻氯苯甲醇(2)3. lmol,苯胺(3)3.6111〇1,质量分数为60%硝基甲烷3101111,氯化亚铜1.56111 〇1,混合均匀,控制搅拌速度1 lOrpm,升高溶液温度至110°C,反应3h,升高溶液温度至130°C,反应2h,升高溶液温度至190°(:,反应9011^11,降低溶液温度至15°(:,加入硝酸铵溶液7001111,质量分数为40%亚硫酸氢钠溶液130ml,1.6kPa减压蒸馏,收集130-135°C的馏分,质量分数为70%三乙胺洗涤,在质量分数为90%甲苯中重结晶,得晶体邻氯苯甲腈308.02g,收率72%。 [0011] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.6111〇1, mass fraction of 60% nitromethane 3,101,111 chloride cuprous 1.56111 〇1, mixing, stirring speed control lOrpm 1, the solution temperature increased to 110 ° C, the reaction 3h, the solution temperature increased to 130 ° C, the reaction 2h, the solution temperature is raised to 190 ° (:, reaction 9011 ^ 11, reducing the solution temperature to 15 ° (:, 7,001,111 ammonium nitrate solution was added, the mass fraction of 40% sodium bisulfite solution was 130ml, 1.6kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 70 washed% triethylamine, 90% toluene to a mass fraction of recrystallized to give crystals of o-chlorobenzonitrile 308.02g, yield 72%.

[0012] 实例2: [0012] Example 2:

[0013]在安装有搅拌器、温度计、蒸馏装置的反应容器中,加入邻氯苯甲醇(2)3. lmol,苯胺(3)3.7111〇1,质量分数为62%硝基甲烷31〇1111,氯化亚铜1.56111〇1,混合均匀,控制搅拌速度130rpm,升高溶液温度至112°C,反应4h,升高溶液温度至132°C,反应2h,升高溶液温度至192°C,反应llOmin,降低溶液温度至17°C,加入碘化钾溶液700ml,质量分数为42%亚硫酸氢钠溶液130ml,1.65kPa减压蒸馏,收集130-135°C的馏分,质量分数为72%三乙胺洗涤, 在质量分数为92%甲苯中重结晶,得晶体邻氯苯甲腈337.96g,收率79%。 [0013] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.7111〇1, mass fraction of 62% nitromethane 31〇1111, 1.56111〇1 cuprous chloride, mixed, controlling the stirring speed of 130 rpm, the temperature was raised to 112 ° C, the reaction 4h, the solution temperature increased to 132 ° C, the reaction 2h, the solution temperature increased to 192 ° C, the reaction llOmin, reducing the solution temperature to 17 ° C, 700 ml of a solution of potassium iodide was added, the mass fraction of 42% sodium bisulfite solution 130ml, 1.65kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 72% triethylamine washed, recrystallized from toluene to 92% mass fraction, to obtain crystals of o-chlorobenzonitrile 337.96g, yield 79%.

[0014] 实例3: [0014] Example 3:

[0015] 在安装有搅拌器、温度计、蒸馏装置的反应容器中,加入邻氯苯甲醇(2)3. lmol,苯胺(3)3.9111〇1,质量分数为65%硝基甲烷31〇1111,氯化亚铜1.56111 〇1,混合均匀,控制搅拌速度160rpm,升高溶液温度至115°C,反应5h,升高溶液温度至135°C,反应3h,升高溶液温度至195°C,反应120min,降低溶液温度至20°C,加入硝酸铵溶液700ml,质量分数为45%亚硫酸氢钠溶液130ml,1.7kPa减压蒸馏,收集130-135°C的馏分,质量分数为75%三乙胺洗涤,在质量分数为95%甲苯中重结晶,得晶体邻氯苯甲腈350.80g,收率82%。 [0015] In a reaction vessel fitted with a stirrer, a thermometer, a distillation apparatus, was added o-chlorobenzyl alcohol (2) 3. Lmol, aniline (3) 3.9111〇1, mass fraction of 65% nitromethane 31〇1111, 1.56111 〇1 cuprous chloride, mixed, controlling stirring speed 160 rpm, temperature was raised to 115 ° C, the reaction 5h, the solution temperature increased to 135 ° C, the reaction 3h, the solution temperature increased to 195 ° C, the reaction 120min, reducing the solution temperature to 20 ° C, was added 700 ml of a solution of ammonium nitrate, 45% mass fraction of sodium bisulfite solution was 130ml, 1.7kPa vacuum distillation, collecting the fraction 130-135 ° C, mass fraction of 75% triacetyl amine scrubbing, 95%, recrystallized from toluene to a mass fraction to obtain crystals of o-chlorobenzonitrile 350.80g, yield 82%.

Claims (4)

  1. 1. 一种克霉唑药物中间体邻氯苯甲腈的合成方法,其特征在于,包括如下步骤:(i)在安装有搅拌器、温度计、蒸馏装置的反应容器中,加入邻氯苯甲醇(2) 3. lmo 1,苯胺(3) 3.6- 3.9111〇1,硝基甲烷3101111,氯化亚铜1.56111〇1,混合均匀,控制搅拌速度110-160印111,升高溶液温度至11〇-115°(:,反应3-511,升高溶液温度至130-135°(:,反应2-311,升高溶液温度至190-195°C,反应90-120min,降低溶液温度至15-20°C,加入盐溶液700ml,亚硫酸氢钠溶液130ml,减压蒸馏,收集130--135Γ的馏分,三乙胺洗涤,在甲苯中重结晶,得晶体邻氯苯甲腈(1);其中,步骤(i)所述的硝基甲烷质量分数为60-65%,步骤(i)所述的盐溶液为硝酸铵、碘化钾中的任意一种,步骤(i)所述的亚硫酸氢钠溶液质量分数为40-45%。 A pharmaceutical Clotrimazole synthesis intermediate o-chlorophenyl-carbonitrile, characterized by comprising the steps of: (i) in a reaction container equipped with a stirrer, a thermometer, a distillation apparatus, o-chlorobenzyl alcohol (2) 3. lmo 1, aniline (3) 3.6 3.9111〇1, nitromethane 3101111, cuprous chloride 1.56111〇1, mixing, stirring speed 110-160 print control 111, the temperature of the solution raised to 11〇 -115 ° (:, 3-511 reaction, the solution temperature increased to 130-135 ° (:, 2-311 reaction, the solution temperature increased to 190-195 ° C, the reaction 90-120min, reducing the solution temperature to 15 20 ° C, was added 700 ml of saline solution, sodium bisulfite solution, 130ml, vacuum distillation, collecting the fraction washed 130--135Γ, triethylamine, and recrystallized from toluene to give crystals of o-chlorobenzonitrile (1); wherein the mass fraction of nitromethane according to step (i) is 60-65%, step (i) said salt solution is a nitrate, any potassium iodide in step (i) said hydrogen sulfite sodium mass fraction of 40-45%.
  2. 2. 根据权利要求1所述一种克霉唑药物中间体邻氯苯甲腈的合成方法,其特征在于,步骤(i)所述的减压蒸馏所处压力为1 · 6-1 · 7kPa。 The synthesis method of Intermediate Clotrimazole o-chlorobenzonitrile medicament of claim 1, wherein, in step (i) said vacuum distillation in which a pressure 1 · 6-1 · 7kPa .
  3. 3. 根据权利要求1所述一种克霉唑药物中间体邻氯苯甲腈的合成方法,其特征在于,步骤(i)所述的三乙胺质量分数为70-75%。 3. The pharmaceutical Clotrimazole A synthesis method of Intermediate o-chlorophenyl-carbonitrile claim, wherein said step (i) of triethylamine mass fraction of 70-75%.
  4. 4. 根据权利要求1所述一种克霉唑药物中间体邻氯苯甲腈的合成方法,其特征在于,步骤(i)所述的甲苯质量分数为90-95 %。 According to claim 1. A method for the synthesis of o-chlorobenzonitrile drug intermediates clotrimazole, wherein step (i) in toluene of the mass fraction of 90-95%.
CN 201511002595 2015-12-25 2015-12-25 Method for synthesizing clotrimazole pharmaceutical intermediate o-chlorobenzonitrile CN105566156A (en)

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