CN108295882A - 核壳纳米催化剂的制备及在替尼类药物制备中的应用 - Google Patents
核壳纳米催化剂的制备及在替尼类药物制备中的应用 Download PDFInfo
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- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/24—Nitrogen compounds
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- 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
- B01J23/8906—Iron and noble metals
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明涉及一种核壳纳米催化剂的制备及在替尼类药物制备中的应用,本发明制备了磁分离核‑壳负载型钯催化剂Pd/Fe3O4@C‑N,利用其催化替尼类化合物,并通过磁分离方式回收催化剂,且表面掺杂的N原子可以起到固定催化剂活性位的作用,提高催化性能。本发明与传统使用催化剂相比,环保,金属残留量少,工艺成本明显降低;同时,本发明提供了一种高效、催化剂可磁分离回收并循环利用的替尼类化合物中间体制备方法,本发明制备的催化剂能在替尼类化合物的制备中重复利用,催化剂仍保有原来活性没有失活现象,不仅大大提高了生产效率,而且减少了环境的污染。
Description
技术领域
本发明属于催化剂制备技术领域,具体地说是涉及一种核壳纳米催化剂的制备及在替尼类药物制备中的应用。
背景技术
替尼类是一类新型生物靶向治疗肿瘤药物,目前在我国市场上常见的替尼类抗肿瘤药物包括:吉非替尼、伊马替尼、尼罗替尼、舒尼替尼等。其中,尼罗替尼是一种靶向治疗肿瘤的新型药物,用于治疗甲磺酸伊马替尼无效的慢性粒细胞白血病。而埃罗替尼为小分子酪氨酸激酶抑制剂,它能选择性地遏制与EGFR相关的酪氨酸激酶的活性,使肿瘤细胞的黏附能力得以降低,并阻碍肿瘤细胞的侵袭、增殖和转移,阻止肿瘤细胞生长,从而诱导肿瘤细胞走向凋亡。
替尼类药物具有比较广阔的市场前景,其研究开发也受到了人们极大地重视,其中两个关键中间体的C-N偶联制备是技术关键所在,也是影响该产品工业化生产成本的最主要因素。式(Ⅰ)为替尼类药物中间体分子结构。
虽然,钯催化替尼类药物中间体的合成具有较高的反应收率,但是金属价格高昂且毒性较强,且目标产物中易残留钯,这大大阻碍了这类反应在药物合成中的应用。因此,寻找新的合成技术、探索新的催化剂制备方法,是目前研究工作的重点。
发明内容
针对现有替尼类药物的合成大多存在着成本较高、环境污染大、残留金属严重和三废量高等缺陷,本发明提供了一种磁分离核-壳结构负载型钯催化剂及其制备方法和应用,其制得的磁分离核-壳结构负载型钯催化剂用于合成替尼类化合物时,降低生产成本,减少三废,提高产品质量。
本发明采用的技术方案为:
一种核壳纳米催化剂的制备方法,包括下述步骤:
(1)在铁化合物乙二醇溶液中加入聚乙烯吡咯烷酮和乙酸钠,室温搅拌,转移至水热釜,在160~220℃下反应6~10小时,醇洗真空干燥得到Fe3O4颗粒;
(2)在适量的水中加入步骤(1)得到的Fe3O4颗粒、葡萄糖和胺类或者加入Fe3O4颗粒和含N的水溶性葡萄糖,超声搅拌5~20分钟,移至水热釜,在160~200℃下反应10~12小时,水洗、醇洗真空干燥得到Fe3O4@C-N复合纳米粒子;
(3)在步骤(2)得到的Fe3O4@C-N的乙醇溶液中加入钯化合物的乙醇溶液,并加入还原剂,搅拌1~3小时,磁分离、醇洗后,真空干燥得到磁分离核-壳结构负载型钯催化剂Pd/Fe3O4@C-N。
作为优选,所述铁化合物:葡萄糖:胺类:钯化合物的摩尔数比为1:0.1~2:0~1:0.01~0.1。
作为优选,所述的铁化合物为FeCl3、FeCl3·6H2O或FeCl2·4H2O;所述的胺类为乙二胺或乙醇胺;所述的含N的水溶性葡萄糖为水溶性壳聚糖或N-乙酰-D-氨基葡萄糖;所述的钯化合物为氯化钯、醋酸钯或氯钯酸钠;所述的还原剂为抗坏血酸、水合肼或硼氢化钠。
作为优选,所述的铁化合物为FeCl3·6H2O,所述的胺类为乙二胺,所述的含N的水溶性葡萄糖为N-乙酰-D-氨基葡萄糖,所述的钯化合物为氯化钯,所述的还原剂为抗坏血酸。
作为优选,步骤(1)加入作为还原剂的乙二醇,持续搅拌至铁化合物的胶体全溶,水热反应之后用外部磁铁分离并用乙醇洗涤,最后真空干燥得到Fe3O4颗粒;步骤(2)中,加入水后,持续超声至葡萄糖全溶,水热反应之后先用水洗涤除碳,再用乙醇洗涤;步骤(3)中,所述的Fe3O4@C-N和钯的乙醇溶液均要在超声搅拌中分散均匀,再互溶。
上述制备方法制备的新型核壳纳米催化剂为磁分离核-壳结构负载型钯催化剂Pd/Fe3O4@C-N。
上述核壳纳米催化剂在替尼类药物制备中的应用。
作为优选,所述新型核壳纳米催化剂在替尼类药物制备中的应用,包括下述反应步骤:
(i)搅拌3-溴-5-(三氟甲基)-苯胺、4-甲基-1H-咪唑、溶剂和Pd/Fe3O4@C-N催化剂,并加入碱,在100~130℃下反应8~15小时;
(ii)用外部磁铁分离催化剂,反应液加入饱和食盐水后,用乙酸乙酯分出有机相,无机相用乙酸乙酯萃取数次,合并有机相;
(iii)有机相用硫酸镁干燥,抽滤,减压蒸馏,得到粗品;
(iv)粗品用甲苯重结晶得到替尼类中间体。
本发明替尼类药物关键中间体的合成方法,以3-溴-5-(三氟甲基)-苯胺和4-甲基-1H-咪唑为主要起始原料,在新型磁分离核-壳负载型钯催化剂Pd/Fe3O4@C-N催化下,制备得替尼类药物中间体5-(4-甲基-1咪唑-1基)-3-三氟甲基苯胺。
替尼类药物关键中间体化合物的制备流程如下:
作为优选,所述的溶剂为二甲基亚砜、二甲基亚砜和水或甲苯和叔丁醇两者的混合物,所述的碱为氢氧化钾、氢氧化钠、碳酸钾、碳酸钠或碳酸铯。
作为优选,所述的溶剂为二甲基亚砜和水的混合物,所述的碱为氢氧化钾。
本发明的有益效果在于:
本发明制备了磁分离核-壳负载型钯催化剂Pd/Fe3O4@C-N,利用其催化替尼类化合物,并通过磁分离方式回收催化剂,且表面掺杂的N原子可以起到固定催化剂活性位的作用,提高催化性能。与传统使用催化剂相比,环保,金属残留量少,工艺成本明显降低。同时,本发明提供了一种高效、催化剂可磁分离回收并循环利用的替尼类化合物中间体制备方法,本发明制备的催化剂能在替尼类化合物的制备中重复利用,催化剂仍保有原来活性没有失活现象,不仅大大提高了生产效率,而且减少了环境的污染。
附图说明
图1为本发明磁分离核-壳负载型钯催化剂Pd/Fe3O4@C-N的结构示意图;
图2为本发明实施例3的核-壳负载型钯催化剂的投射电镜图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明,但本发明所要保护的范围并不限于此。
参照图1,本发明磁分离核-壳负载型钯催化剂Pd/Fe3O4@C-N的制备流程如下:
首先运用水热法制备Fe3O4纳米粒子,然后通过水热法碳化法制备得到Fe3O4@C-N复合纳米粒子,最后通过浸渍焙烧法制备得到磁分离核-壳负载型钯催化剂Pd/Fe3O4@C-N。
实施例1
一种核壳纳米催化剂(磁分离核-壳负载型钯催化剂Pd/Fe3O4@C-N)的制备方法,依次按以下步骤进行:
(1)制备Fe3O4纳米粒子
运用水热法制备Fe3O4纳米粒子:在室温下将3g FeCl3·6H2O,2g PVP和4g NaOAc加入到100mL烧瓶中,并用60ml乙二醇溶解;完全溶解后,转移至水热反应釜,在200℃下反应8h;反应结束后,用外部磁体分离颗粒,并用乙醇洗涤;在60℃下,真空干燥12h,得到稳定的Fe3O4颗粒;
(2)制备Fe3O4@C-N复合纳米粒子
在常温下,往100mL烧杯中依次加0.4g Fe3O4颗粒,1.6g葡萄糖,0.2ml乙二胺和10ml水或者0.4g Fe3O4颗粒,1.9g N-乙酰D-氨基葡萄糖和10ml水,超声搅拌15分钟,然后转移至水热反应釜,在180℃下反应8h;反应结束后,用外部磁铁分离,先用水洗除去碳,再醇洗,最后真空干燥得到Fe3O4@C-N复合纳米粒子;
(3)制备磁分离核-壳(Core-Shell)负载型钯催化剂Pd/Fe3O4@C-N
在常温下,往100mL烧杯中依次加入0.4g Fe3O4@C-N颗粒和40ml乙醇,搅拌30min,往50ml烧杯中依次加入35mg PdCl2,60mg抗坏血酸和10ml乙醇,搅拌30分钟;混合两者溶液,在60℃条件下搅拌2h;反应结束后,用外部磁铁分离,用乙醇洗涤数次后,于60℃真空干燥,得到磁分离Core-Shell负载型钯催化剂Pd/Fe3O4@C-N。
实施例2
除了使用的N源为乙醇胺,不同于实施例1中的N源N-乙酰-D氨基葡萄糖,其他实施步骤和实施条件均与实施例1相同。
实施例3
除了使用的N源为乙二胺,不同于实施例1中的N源N-乙酰-D氨基葡萄糖,其他实施步骤和实施条件均与实施例1相同。
核-壳负载型钯催化剂Pd/Fe3O4@C-N的投射电镜(TEM)图见图2,从图2中可以看出制备的催化剂具有包裹均匀、粒径小、团聚少等特点,有助于高效催化环合反应。
实施例1-3使用的N源如表1所示:
表1
序号 | N源 |
实施例1 | N-乙酰-D氨基葡萄糖 |
实施例2 | 乙醇胺 |
实施例3 | 乙二胺 |
实施例4
替尼类药物中间体的合成
向反应瓶内投入2.40g 3-溴-5-(三氟甲基)-苯胺,1.64g 4-甲基-1H-咪唑,0.84g氢氧化钾,0.1g Pd/Fe3O4@C-N催化剂(来源于实施例1)和30ml二甲基亚砜和水(v:v=1:1)的溶剂,在120℃反应12h;反应结束后冷却至室温,加入20ml乙酸乙酯,萃取分出有机相;无机相用乙酸乙酯萃取3次,合并有机相用硫酸镁干燥;抽滤,旋干得到粗品,用甲苯重结晶得到替尼类药物中间体5-(4-甲基-1咪唑-1基)-3-三氟甲基苯胺。
实施例5
催化剂Pd/Fe3O4@C-N来源于实施例2,其他实施步骤和实施条件均与实施例4相同。
实施例6
催化剂Pd/Fe3O4@C-N来源于实施例3,其他实施步骤和实施条件均与实施例4相同。
实施例4-5各实施例条件及收率如表2所示:
表2
实施例7
磁分离核-壳负载型钯催化剂Pd/Fe3O4@C-N的循环套用实验
在实施例6催化条件下,磁分离核-壳负载型钯催化剂Pd/Fe3O4@C-N回收、循环使用第八次,仍保持有优异的替尼类药物中间体收率,催化效果没有明显下降,具体见下表3:
表3
以上列举的仅是本发明的若干个具体实施例。显然,本发明不限于以上实施例,还可以有许多变形。本领域的普通技术人员能从本发明公开的内容直接导出或联想到的所有变形,均应认为是本发明的保护范围。
Claims (10)
1.一种核壳纳米催化剂的制备方法,其特征在于包括下述步骤:
(1)在铁化合物乙二醇溶液中加入聚乙烯吡咯烷酮和乙酸钠,室温搅拌,转移至水热釜,在160~220℃下反应6~10小时,醇洗真空干燥得到Fe3O4颗粒;
(2)在水中加入步骤(1)得到的Fe3O4颗粒、葡萄糖和胺类或者加入Fe3O4颗粒和含N的水溶性葡萄糖,超声搅拌5~20分钟,移至水热釜,在160~200℃下反应10~12小时,水洗、醇洗真空干燥得到Fe3O4@C-N复合纳米粒子;
(3)在步骤(2)得到的Fe3O4@C-N的乙醇溶液中加入钯化合物的乙醇溶液,并加入还原剂,搅拌1~3小时,磁分离、醇洗后,真空干燥得到磁分离核-壳结构负载型钯催化剂Pd/Fe3O4@C-N。
2.根据权利要求1所述的核壳纳米催化剂的制备方法,其特征在于:所述铁化合物:葡萄糖:胺类:钯化合物的摩尔数比为1:0.1~2:0~1:0.01~0.1。
3.根据权利要求2所述的核壳纳米催化剂的制备方法,其特征在于:所述的铁化合物为FeCl3、FeCl3·6H2O或FeCl2·4H2O;所述的胺类为乙二胺或乙醇胺;所述的含N的水溶性葡萄糖为水溶性壳聚糖或N-乙酰-D-氨基葡萄糖;所述的钯化合物为氯化钯、醋酸钯或氯钯酸钠;所述的还原剂为抗坏血酸、水合肼或硼氢化钠。
4.根据权利要求3所述的核壳纳米催化剂的制备方法,其特征在于:所述的铁化合物为FeCl3·6H2O,所述的胺类为乙二胺,所述的含N的水溶性葡萄糖为N-乙酰-D-氨基葡萄糖,所述的钯化合物为氯化钯,所述的还原剂为抗坏血酸。
5.根据权利要求2所述的核壳纳米催化剂的制备方法,其特征在于:步骤(1)加入作为还原剂的乙二醇,持续搅拌至铁化合物的胶体全溶,水热反应之后用外部磁铁分离并用乙醇洗涤,最后真空干燥得到Fe3O4颗粒;步骤(2)中,加入水后,持续超声至葡萄糖全溶,水热反应之后先用水洗涤除碳,再用乙醇洗涤;步骤(3)中,所述的Fe3O4@C-N和钯的乙醇溶液均要在超声搅拌中分散均匀,再互溶。
6.由权利要求1-5任一项制备方法制备的核壳纳米催化剂为磁分离核-壳结构负载型钯催化剂Pd/Fe3O4@C-N。
7.由权利要求1-6任一项所述的核壳纳米催化剂在替尼类药物制备中的应用。
8.根据权利要求7所述核壳纳米催化剂在替尼类药物制备中的应用,其特征在于包括下述反应步骤:
(i)搅拌3-溴-5-(三氟甲基)-苯胺、4-甲基-1H-咪唑、溶剂和Pd/Fe3O4@C-N催化剂,并加入碱,在100~130℃下反应8~15小时;
(ii)用外部磁铁分离催化剂,反应液加入饱和食盐水后用乙酸乙酯分出有机相,无机相用乙酸乙酯萃取数次,合并有机相;
(iii)有机相用硫酸镁干燥,抽滤,减压蒸馏,得到粗品;
(iv)粗品用甲苯重结晶得到替尼类中间体。
9.根据权利要求8所述核壳纳米催化剂在替尼类药物制备中的应用,其特征在于:所述的溶剂为二甲基亚砜、二甲基亚砜和水或甲苯和叔丁醇两者的混合物,所述的碱为氢氧化钾、氢氧化钠、碳酸钾、碳酸钠或碳酸铯。
10.根据权利要求9所述核壳纳米催化剂在替尼类药物制备中的应用,其特征在于:所述的溶剂为二甲基亚砜和水的混合物,所述的碱为氢氧化钾。
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CN114768766B (zh) * | 2022-05-24 | 2024-01-19 | 浙江树人学院 | 一种氮掺杂碳纳米管包覆钴铁锰纳米颗粒改性生物炭的制备方法和应用 |
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