CN117050016A - 一种卡马西平中间体的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 229960000623 carbamazepine Drugs 0.000 title claims abstract description 9
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- LCGTWRLJTMHIQZ-UHFFFAOYSA-N 5H-dibenzo[b,f]azepine Chemical compound C1=CC2=CC=CC=C2NC2=CC=CC=C21 LCGTWRLJTMHIQZ-UHFFFAOYSA-N 0.000 claims abstract description 18
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- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
- B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
- B01J23/89—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper combined with noble metals
- B01J23/8926—Copper and noble metals
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
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Abstract
本发明公开了一种卡马西平中间体的制备方法,以卤代甲苯、邻甲苯胺为原料,在Ir催化剂、磷配体和碱存在下一锅法反应生成亚氨基芪,反应路线短,操作简单,收率纯度高,安全性好,符合绿色化工趋势,具有良好的工业生产应用前景。
Description
技术领域
本发明涉及药物合成领域,具体涉及一种卡马西平中间体的制备方法。
背景技术
卡马西平(Carbamazepine),化学名为5H-二苯并[b,f]氮杂卓-5-甲酰胺,临床应用十分广泛,可用于抗癫痫、抗外周神经痛、抗躁狂抑郁和抗心律失常等疾病,具有安全、有效、不良反应少、价格低廉、疗效肯定等优点,结构式为:。
亚氨基芪,化学名5H-二苯并[b,f]氮杂,不仅是是合成卡马西平的重要中间体,同时也是基因工程、材料学等方面的重要合成原料,其结构式为:。
CN101654419A公开了一种亚氨基芪的化学合成方法,主要是以亚氨基二苄为主要原料来进行合成,反应式如下:;
该方法通过在固定催化床上填充大量催化剂,电加热使催化床温度提高至400-600℃,将预热至熔融的亚氨基二苄通过高压水蒸汽带入固定催化床内,控制整齐流速为0.2-20L/h,物料通过固定催化床后,进入装有冷却水的接收装置中,得到的混合液蒸干水分后重结晶,得到亚氨基芪。但是该方法催化脱氢工艺设备投资大、要求高,催化剂价格昂贵,消耗大量的水蒸气不能够重复利用,成本较高。
CN 1616433 A以邻硝基甲苯为起始原料在三种溶剂中缩合得到2,2-二硝基联苄,再经还原、高温环合得到亚氨基二苄,最后经氯甲酰化、溴代、脱溴化氢得到5-甲酰氯亚氨芪,不仅反应路线步骤繁琐,污染重,而且收率低,易爆炸,此外,上述反应引入了原料溴,产物中副产物较多,不可避免产生溴代副产物,具有一定的基因毒性,影响亚氨基芪的质量。
CN103483257A公开了一种亚氨基芪的合成方法,在催化量铜化合物和L-脯氨酸以及碱的存在下,邻甲苯胺与邻卤代甲苯在有机溶剂中加热反应,制得目的物亚氨基芪。反应路线如下:
然而,上述方法收率低、副产物多,不适合工业化生产。
针对现有技术存在的诸多问题,亟需开发一种适合工业化生产亚氨基芪的新方法。
发明内容
本发明提供一种制备卡马西平中间体亚氨基芪的新方法,其特征在于:以卤代甲苯、邻甲苯胺为原料,在Ir催化剂、磷配体和碱存在下一锅法反应生成亚氨基芪,反应式为:
其中,X为Cl、Br、I或F,优选Cl、Br、I。
在一些实施方案中,所述Ir催化剂选自Ir/CuO-Al2O3和[IrCl(C2H4)2]2,优选Ir/CuO-Al2O3;所述磷配体选自和配体PPh3。
在一些实施方案中,所述Ir催化剂优选负载型催化剂Ir/CuO-Al2O3。其中,负载型催化剂可以采用浸渍法制备得到。
在一些实施方案中,所述Ir/CuO-Al2O3中活性成分Ir的质量比为0.5%-5.0%,优选0.5%、1.0%、2.0%、2.5%、3.0%。
在一些实施方案中,所述碱选自NaOH、KOH、Na2CO3、K2CO3、CS2CO3、甲醇钠、乙醇钠。
在一些实施方案中,所述卤代甲苯与邻甲苯胺的摩尔比为1: (1~1.2);卤代甲苯与磷配体的摩尔比为1: (0.05~0.2);卤代甲苯与碱的摩尔比为1: (2~5)。
在一些实施方案中,反应温度为90~120℃,反应时间为24~48h。
在一些实施方案中,反应溶剂选自DMSO、DMF、THF、甲苯、乙酸乙酯,优选DMSO、DMF。
在一些实施方案中,反应结束后经过滤、萃取、减压浓缩、柱层析纯化得到亚氨基芪,上述处理操作可以使用本领域常规的方法及条件。
本发明取得了以下有益效果:
1)本发明以卤代甲苯、邻甲苯胺为原料,在Ir催化剂、磷配体和碱存在下一锅法反应生成亚氨基芪,反应路线短,操作简单,成本低,安全性好,符合绿色化工趋势,具有良好的工业生产应用前景。
2)本发明负载催化剂Ir/CuO-Al2O3中的CuO能吸收反应产生的氢气,进而协同活性成分Ir高效催化反应,收率可达80%、纯度可达99.5%,效果远远优于于普通Ir催化剂,大大提升了工业化生产效率。
具体实施方式
本发明所述的范围的端点和任何值都不限于该精确的范围或值,这些范围或值应当理解为包含接近这些范围或值的值。对于数值范围来说,各个范围的端点值之间、各个范围的端点值和单独的点值之间,以及单独的点值之间可以彼此组合而得到一个或多个新的数值范围,这些数值范围应被视为在本文中具体公开。
实施例1 Ir/CuO-Al2O3催化剂的制备
将Cu(NO3)2·6H2O(8.87 g)与Al(NO3)3·9H2O(3.74 g)分别溶解于100mL水中,将所得两溶液混合,随后用氨水溶液(氨水与水的体积比为1:1)调节pH=11,室温下搅拌6h,将所得沉淀过滤分离,去离子水洗涤三次,将滤饼于110℃烘箱中干燥过夜,在550℃下焙烧5h,即得到复合金属氧化物CuO-Al2O3。称取CuO-Al2O3(5.0 g)与一定含量的H2IrCl6水溶液中进行浸渍,使Ir的负载量分别为0.5%、1.0%、2.0%、2.5%、3.0%(质量比),室温下搅拌10h,120℃下蒸发干燥,再置于箱式马弗炉中以2℃/min的升温速率升到450℃焙烧4h,冷却后,转移至卧式石英管式炉,先通入N2排除空气,再连续通入H2,以5℃/min升温至 500℃保持6h,冷却至室温,即得0.5%、1.0%、2.0%、2.5%、3.0%的Ir/CuO-Al2O3催化剂。
实施例2 亚氨基芪的制备
在氮气保护下,将邻氯甲苯(126.50 mg, 1.0 mmol)加入到DMSO(50 mL)中,随后加入KOH(112.0 mg, 2.0 mmol)、邻甲苯胺(107.0 mg, 1.0 mmol)、磷配体(52.20 mg, 0.1 mmol)和3 wt % Ir/CuO-Al2O3催化剂(6 g),加热至110℃反应24h。反应毕,过滤,滤饼用DMSO洗涤,然后加入水(100 mL),用乙酸乙酯(200 mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,经硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)=1:3)得到黄色固体157.10 mg,产率81.4%,纯度为99.5%。
LC-MS (ESI): [M+H]+ =194.2
1HNMR (500 MHz, DMSO-d 6):δ= 6.94-6.88 (m,2H), 6.77-6.71 (m,2H), 6.67-6.62 (m,2H), 6.51-6.40 (m,2H), 6.06 (d,2H)。
实施例3亚氨基芪的制备
在氮气保护下,将邻溴甲苯(171. 0 mg, 1.0 mmol)加入到DMF(50 mL)中,随后加入Na2CO3(318.0 mg, 3.0 mmol)、邻甲苯胺(117.7 mg, 1.1 mmol)、磷配体PPh3(26.23 mg,0.1 mmol)和2.5 wt % Ir/CuO-Al2O3催化剂(6.5 g),加热至100℃反应28h。反应毕,过滤,滤饼用DMF洗涤,然后加入水(100 mL),用乙酸乙酯(200 mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,经硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)=1:3)得到黄色固体153.45 mg,产率79.5%,纯度为99.3%。
LC-MS (ESI): [M+H]+ =194.2
1HNMR (500 MHz, DMSO-d 6):δ= 6.94-6.88 (m,2H), 6.77-6.71 (m,2H), 6.67-6.62 (m,2H), 6.51-6.40 (m,2H), 6.06 (d,2H)。
实施例4亚氨基芪的制备
在氮气保护下,将邻碘甲苯(218. 0 mg, 1.0 mmol)加入到DMSO(50 mL)中,随后加入NaOH(100.0 mg, 2.5 mmol)、邻甲苯胺(112.35 mg, 1.05 mmol)、磷配体PPh3(39.35mg, 0.15 mmol)和1.0 wt % Ir/CuO-Al2O3催化剂(7 g),加热至120℃反应30h。反应毕,过滤,滤饼用DMSO洗涤,然后加入水(100 mL),用乙酸乙酯(200 mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,经硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)=1:3)得到黄色固体159.84 mg,产率82.8%,纯度为99.1%。
LC-MS (ESI): [M+H]+ =194.2
1HNMR (500 MHz, DMSO-d 6):δ= 6.94-6.88 (m,2H), 6.77-6.71 (m,2H), 6.67-6.62 (m,2H), 6.51-6.40 (m,2H), 6.06 (d,2H)。
对比例1
在氮气保护下,将邻氯甲苯(126.50 mg, 1.0 mmol)加入到DMSO(50 mL)中,随后加入KOH(112.0 mg, 2.0 mmol)、邻甲苯胺(107.0 mg, 1.0 mmol)、磷配体(52.20 mg, 0.1 mmol)和催化剂[IrCl(C2H4)2]2 (113.4 mg, 0.2 mmol),加热至120℃反应36h。反应毕,过滤,滤饼用DMSO洗涤,然后加入水(100 mL),用乙酸乙酯(200 mL×3)萃取,合并有机相,用无水硫酸钠干燥,减压浓缩,经硅胶柱层析分离纯化(洗脱剂EtOAc:PE(v/v)=1:3)得到黄色固体24.1 mg,产率12.5%,纯度为98.9%。
LC-MS (ESI): [M+H]+ =194.2
1HNMR (500 MHz, DMSO-d 6):δ= 6.94-6.88 (m,2H), 6.77-6.71 (m,2H), 6.67-6.62 (m,2H), 6.51-6.40 (m,2H), 6.06 (d,2H)。
上述实施例仅仅是为清楚地说明所作的实例,而并非对实施方式的限制。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而因此所引申的显而易见的变化或变动仍处于本发明创造的保护范围之内。
Claims (8)
1.一种卡马西平中间体亚氨基芪的制备方法,其特征在于:以卤代甲苯、邻甲苯胺为原料,在Ir催化剂、磷配体和碱存在下一锅法反应生成亚氨基芪,反应式为:
其中,X为Cl、Br、I或F。
2.根据权利要求1所述的制备方法,其特征在于:所述Ir催化剂选自Ir/CuO-Al2O3和[IrCl(C2H4)2]2;所述磷配体选自和配体PPh3。
3.根据权利要求2所述的制备方法,其特征在于:所述Ir/CuO-Al2O3中活性成分Ir的质量比为0.5%-5.0%。
4.根据权利要求1所述的制备方法,其特征在于:所述碱选自NaOH、KOH、Na2CO3、K2CO3、CS2CO3、甲醇钠、乙醇钠。
5.根据权利要求1所述的制备方法,其特征在于:所述卤代甲苯与邻甲苯胺的摩尔比为1: (1~1.2);卤代甲苯与磷配体的摩尔比为1: (0.05~0.2);卤代甲苯与碱的摩尔比为1:(2~5)。
6.根据权利要求1所述的制备方法,其特征在于:反应温度为90~120℃,反应时间为24~48h。
7.根据权利要求1所述的制备方法,其特征在于:反应溶剂选自DMSO、DMF、THF、甲苯、乙酸乙酯。
8.根据权利要求1所述的制备方法,其特征在于:反应结束后经过滤、萃取、减压浓缩、柱层析纯化得到亚氨基芪。
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