CN107952425A - 一种抗肿瘤药物nvp-bez235中间体的制备方法 - Google Patents
一种抗肿瘤药物nvp-bez235中间体的制备方法 Download PDFInfo
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- CN107952425A CN107952425A CN201711442658.8A CN201711442658A CN107952425A CN 107952425 A CN107952425 A CN 107952425A CN 201711442658 A CN201711442658 A CN 201711442658A CN 107952425 A CN107952425 A CN 107952425A
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- catalyst
- recessed
- propionitrile
- zro
- chloro
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- 238000002360 preparation method Methods 0.000 title claims abstract description 15
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- 229950006418 dactolisib Drugs 0.000 title abstract description 15
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 43
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims abstract description 38
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims abstract description 16
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims abstract description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 12
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- 238000001914 filtration Methods 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
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- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 13
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical group [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 abstract description 4
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract 1
- 229910052794 bromium Inorganic materials 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
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- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 12
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
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Classifications
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- 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
- B01J23/14—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of germanium, tin or lead
-
- 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
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/60—Catalysts, in general, characterised by their form or physical properties characterised by their surface properties or porosity
- B01J35/61—Surface area
- B01J35/615—100-500 m2/g
-
- 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
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/60—Catalysts, in general, characterised by their form or physical properties characterised by their surface properties or porosity
- B01J35/63—Pore volume
- B01J35/633—Pore volume less than 0.5 ml/g
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- 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
- B01J35/00—Catalysts, in general, characterised by their form or physical properties
- B01J35/60—Catalysts, in general, characterised by their form or physical properties characterised by their surface properties or porosity
- B01J35/64—Pore diameter
- B01J35/647—2-50 nm
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- 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
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/02—Impregnation, coating or precipitation
- B01J37/0201—Impregnation
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- 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
- B01J37/00—Processes, in general, for preparing catalysts; Processes, in general, for activation of catalysts
- B01J37/02—Impregnation, coating or precipitation
- B01J37/03—Precipitation; Co-precipitation
- B01J37/031—Precipitation
- B01J37/035—Precipitation on carriers
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- 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
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- B01J37/08—Heat treatment
- B01J37/082—Decomposition and pyrolysis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明属于药物合成技术领域,具体涉及一种抗肿瘤药物NVP‑BEZ235中间体的制备方法。本发明以凹土为负载载体,正丙醇锆为锆源,SnCl4·5H2O为锡源,依次在碱性条件下共沉积、煅烧,醋酸/浓硫酸组成的混酸中浸渍,最后煅烧得新型锡改性的ZrO2/凹土固体酸催化剂。本发明制备的新型固体酸催化剂可催化4‑氯‑6‑溴‑3‑硝基喹啉与2‑甲基‑2‑(4‑氨基苯基)丙腈反应制备抗肿瘤药物NVP‑BEZ235中间体2‑[4‑[(3‑硝基‑6‑溴喹啉‑4‑基)氨基]苯基]‑2‑甲基丙腈,该催化体系催化效率高,绿色无污染,适合生产放大;而且该催化剂可用于催化其它SNAr反应,通用性好。
Description
技术领域
本发明属于药物合成技术领域,具体涉及一种抗肿瘤药物NVP-BEZ235中间体的制备方法。
背景技术
NVP-BEZ235,化学名为2-甲基-2-[4-[3-甲基-2-氧代-8-(喹啉-3-基)-2,3-二氢-1H-咪唑并[4,5-c]喹啉-1-基)苯基]丙腈,结构式为(1)式所示:
(1)
NVP-BEZ235是诺华公司开发的一种作用于PI3K/mTOR信号传导通路的ATP竞争性抑制剂,通过结合于酶的ATP结合槽,阻断PI3K和mTOR激酶活性。NVP-BEZ235对p110α/γ/δ/β和mTOR(p70S6K)的IC50分别为4、5、7、75和6nmol/L,同时在细胞中抑制丝氨酸蛋白激酶ATR的IC50为21nmol/L。临床结果表明,NVP-BEZ235对实体瘤和血液系统肿瘤具有良好的抑制增殖作用,单一口服给药时能够阻断疾病的发展,与其他抗肿瘤药联合使用时能够增强疗效。
NVP-BEZ235合成过程中有个关键中间体,其结构式如(2)式所示:
(2)
(2)式化合物(化学名为2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈)是由氯代喹啉化合物4-氯-6-溴-3-硝基喹啉与芳胺化合物2-甲基-2-(4-氨基苯基)丙腈进行SNAr反应制备所得,反应式如Scheme1所示:
目前合成(2)式化合物的方法是均是通过氯代喹啉化合物与芳胺化合物在醋酸催化的作用下进行SNAr(芳香族亲核取代)反应制备所得,例如文献1(中国医药工业杂志,2016,47(2):135-139,PI3K/mTOR双重抑制剂 NVP-BEZ235 的合成),文献2(Bioorganic &Medicinal Chemistry Letters 18 (2008) 1027–1030,Imidazo[4,5-c]quinolines asinhibitors of the PI3K/PKB-pathway),文献3(JAK PI3K/mTORcombination therapy:WO2013023119A1)。目前公开的现有技术均是采用大大过量的醋酸作为溶剂和酸促进剂来进行反应,后处理加入水作为反溶剂析出(2)式化合物,然后将析出的产品溶于乙酸乙酯/四氢呋喃的溶液中采用碳酸氢钠洗涤、硫酸镁干燥后浓缩得到浅黄色(2)式化合物。该反应环境污染较大、产生大量酸性废水,另外该反应收率较低,仅为50%左右。
凹土(Attapulgite Clay ,简写为ATP) 有“千用之土、万土之王”之美誉, 我国江苏省盱眙凹土矿资源量占世界储量的49% 和我国储量的74%。ATP 是一种天然链层状结构的含水镁铝硅酸盐黏土矿物, 其分子式为(Mg,Al)4(Si)8(O,OH,H2O)26·nH2O。 ATP具有一定酸性, 层结构中的结构羟基可形成Brönsted酸位点, 暴露的Al3+离子可形成Lewis 酸位点. ATP 经酸化或离子交换后作为催化剂直接应用较少。
将凹土进行改性制备固体酸催化剂用来催化反应制备抗肿瘤药物NVP-BEZ235中间体2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈未见文献报道。
发明内容
本发明的目的是克服现有技术中制备抗肿瘤药物NVP-BEZ235中间体2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈制备过程中产生大量废酸、且收率低的缺点,提供一种固体酸催化的方法制备该中间体。本发明以凹土为负载载体,正丙醇锆为锆源,SnCl4·5H2O为锡源,依次在碱性条件下共沉积、煅烧,醋酸/浓硫酸组成的混酸中浸渍,最后煅烧得新型锡改性的ZrO2/凹土固体酸催化剂。本发明制备的新型固体酸催化剂可催化4-氯-6-溴-3-硝基喹啉与2-甲基-2-(4-氨基苯基)丙腈反应制备抗肿瘤药物NVP-BEZ235中间体2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈,该催化体系催化效率高,绿色无污染,适合生产放大;而且该催化剂可用于催化其它SNAr反应,通用性好。
根据本发明的一个方面,本发明提供了一种新型锡改性的ZrO2/凹土固体酸催化剂的制备方法,包括以下步骤:
1)凹土前处理工序:将凹土气流粉碎至粒径为100目的颗粒物,然后置于盐酸的四氢呋喃溶液中超声处理24h后过滤,烘干、粉碎至粒径为200-300目得凹土粉;
2)共沉积工序:将凹土粉置于正丙醇中,然后加入70%wt正丙醇锆(IV)的正丙醇溶液和SnCl4·5H2O搅拌混合均匀,升温至60-70℃于1000rpm的转速下强烈搅拌30min;缓慢滴加0.5-2.0mol/L的氨水溶液调节溶液pH至9.5-10.5,然后保温搅拌陈化12-24h;降温至室温,抽滤、水洗至滤液成中性,收集滤饼在氮气氛围下,100-130℃煅烧1-2h后得共沉积沉淀物;
3)酸浸渍工序:将共沉积沉淀物置于醋酸/浓硫酸组成的混酸中搅拌,氮气氛围下回流12h后降温至室温、过滤,水洗至滤液成中性,滤饼在氮气氛围下进行煅烧得新型锡改性的ZrO2/凹土固体酸催化剂。
优选的,步骤1)中所述盐酸的四氢呋喃溶液中盐酸的浓度可为1-3mol/L;盐酸的四氢呋喃溶液可通过盐酸气体通入四氢呋喃中制备所得或者购买市售产品;
步骤2)中可以调节正丙醇锆(IV)与SnCl4·5H2O的摩尔比来调节催化剂中锆、锡的负载量,从而调节催化剂的催化性能;优选的,步骤2)中正丙醇锆(IV)与SnCl4·5H2O的摩尔比为1:0.1-0.6,SnCl4·5H2O与凹土粉的重量比为0.5-10:100;更优选为,步骤2)中正丙醇锆(IV)与SnCl4·5H2O的摩尔比为1:0.3,SnCl4·5H2O与凹土粉的重量比为2:100;
优选的,步骤3)所述醋酸/浓硫酸组成的混酸是指醋酸与浓硫酸组成的混合物,其中醋酸与浓硫酸的重量比为1:2;
优选的,步骤3)所述滤饼在氮气氛围下进行煅烧是指在氮气的氛围下于200-400℃下煅烧6-12h,优选为260-300℃下煅烧6-12h;
根据本发明的另一个方面,本发明提供了一种新型锡改性的ZrO2/凹土固体酸催化剂的用途,在溶剂的存在下,用于催化4-氯-6-溴-3-硝基喹啉与2-甲基-2-(4-氨基苯基)丙腈反应制备2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈;其具体步骤为:
1)将4-氯-6-溴-3-硝基喹啉、2-甲基-2-(4-氨基苯基)丙腈和锡改性的ZrO2/凹土固体酸催化剂加入到溶剂中在10-80℃下搅拌反应;
2)HPLC检测待4-氯-6-溴-3-硝基喹啉反应完全后过滤去除锡改性的ZrO2/凹土固体酸催化剂得滤液;
3)对滤液浓缩或者加入反溶剂进行后处理得2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈。
优选的,步骤1)中4-氯-6-溴-3-硝基喹啉与2-甲基-2-(4-氨基苯基)丙腈的摩尔比为1:1-1.2,4-氯-6-溴-3-硝基喹啉与锡改性的ZrO2/凹土固体酸催化剂的重量比为1:0.01-0.20;更优选为,步骤1)中4-氯-6-溴-3-硝基喹啉与2-甲基-2-(4-氨基苯基)丙腈的摩尔比为1:1.1,4-氯-6-溴-3-硝基喹啉与锡改性的ZrO2/凹土固体酸催化剂的重量比为1:0.06;
优选的,步骤1)所述溶剂为醋酸、甲醇、乙醇、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、二氯甲烷或其复配溶剂,更优选为甲醇;
步骤3)所述反溶剂为正戊烷、正庚烷、甲苯或水,更优选为水;
多相催化剂通常会发生催化剂失活现象,固体酸催化剂往往会被一些碱性物质沉积在催化剂表面或者孔道内从而阻塞催化活性中心,或者由于小分子有机化合物在反应过程中沉积并掩盖催化活性中心使催化剂孔道口变窄或堵塞。本发明的锡改性的ZrO2/凹土固体酸催化剂在催化反应循环5次后,也发生了不同程度的催化剂失活现象。为解决催化剂失活问题,本发明提供了一种锡改性的ZrO2/凹土固体酸催化剂的活化方法,包括以下步骤:
1)将催化4-氯-6-溴-3-硝基喹啉与2-甲基-2-(4-氨基苯基)丙腈反应制备2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈的锡改性的ZrO2/凹土固体酸催化剂回收后,置于氮氮二甲基甲酰胺/四氢呋喃溶液中升温至60℃超声1-2h后过滤,丙酮洗涤后干燥得预处理催化剂;
2)将预处理催化剂放入浓硫酸中于60-80℃下浸渍24h,过滤,丙酮洗涤后100℃下真空干燥得酸处理催化剂;
3)将酸处理催化剂置于煅烧炉中,在氮气氛围下,于350-400℃下煅烧10-30min得活化后的锡改性的ZrO2/凹土固体酸催化剂。
催化剂活化通常采用煅烧的方法或者结合酸浸渍的方法,本发明中首先对回收后的催化剂在有机溶剂中高温超声处理,这样去除了大部分催化剂表面或者孔道内吸附的有机小分子,然后采用纯硫酸进行酸浸渍,最后采用高温短时间煅烧得活化后的催化剂;试验证明若是前期不进行有机溶剂超声处理,则后期需要的煅烧温度高且煅烧时间较长,但长时间的高温煅烧使催化剂会使催化剂孔结构容易坍塌导致锡源损失,从而影响催化效果。
为了验证本发明催化剂对SNAr(芳香族亲核取代反应)反应的通用性,本发明保持2-甲基-2-(4-氨基苯基)丙腈不变,分别与5-氯-8-羟基喹啉、6-氯喹啉、2-氯-8-氰基喹啉、6-氯-5-硝基喹啉、7-氯-2-甲基喹啉反应,均有较好的效果;其中喹啉环上含有吸电子集团的底物转化率高于供电子基团的底物,也验证了该类反应属于亲核取代反应。
本发明所述的4-氯-6-溴-3-硝基喹啉反应完全是指HPLC检测结果显示反应液中按照面积百分比计算其含量小于0.5%或以下;本发明所述的反溶剂是指在室温下对2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈溶解度小的溶剂,例如小于1mg/ml或者溶解度更小的溶剂;所述的浓硫酸为市售的95.0~98.0%wt的浓硫酸。
与现有技术相比,本发明具有如下优点:
1)本发明提供了一种新型锡改性的ZrO2/凹土固体酸催化剂的制备方法,该制备方法简便、利于操作;
2)本发明制备的新型锡改性的ZrO2/凹土固体酸催化剂具有较高的酸性位点,可催化卤代芳烃与芳胺发生芳香族亲核取代反应用于制备抗肿瘤药物NVP-BEZ235中间体2-[4-[(3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈,避免了大量废酸的产生,而且提高了收率;
3)本发明制备的新型锡改性的ZrO2/凹土固体酸催化剂可回收套用,而且催化剂可活化;
4)本发明制备的新型锡改性的ZrO2/凹土固体酸催化剂通用性好,对反应对底物具有良好的官能团兼容性可催化其它SNAr反应,用来制备抗肿瘤药物中间体类似物。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明了,下面结合具体实施方式,对本发明进一步详细说明。应该理解,这些描述只是示例性的,而并非要限制本发明的范围。
4-氯-6-溴-3-硝基喹啉和2-甲基-2-(4-氨基苯基)丙腈来自于南京康满林化工实业有限公司,纯度为99.5%wt以上;正丙醇锆来自于西格玛奥德里奇(上海)贸易有限公司,为70%wt正丙醇锆的正丙醇溶液,货号为333972;SnCl4·5H2O来自(克拉玛尔)上海紫一试剂厂。
实施例1
制备新型锡改性的ZrO2/凹土固体酸催化剂,包括以下步骤:
1)凹土前处理工序:将100g凹土气流粉碎至粒径为100目的颗粒物,然后置于500ml盐酸的四氢呋喃溶液(盐酸浓度为2mol/L)中超声处理24h后过滤,100℃下烘干、研磨粉碎至粒径为200-300目得凹土粉;
2)共沉积工序:将10g凹土粉置于正丙醇中,然后加入0.89g 70%wt正丙醇锆(IV)的正丙醇溶液和0.20 g SnCl4·5H2O搅拌混合均匀,升温至60-70℃于1000rpm的转速下强烈搅拌30min;缓慢滴加1mol/L的氨水溶液调节溶液pH至10.0,然后保温搅拌陈化24h;降温至室温,抽滤、水洗至滤液成中性,收集滤饼在氮气氛围下,100-130℃煅烧1-2h后得共沉积沉淀物;
3)酸浸渍工序:将10.0g共沉积沉淀物置于30ml醋酸/浓硫酸组成的混酸中搅拌(混酸中醋酸与浓硫酸的重量比为1:2),氮气氛围下回流12h后降温至室温、过滤,水洗至滤液成中性,滤饼在氮气氛围下280±20℃下煅烧6-12h得新型锡改性的ZrO2/凹土固体酸催化剂。
实施例1-A
与实施例1相比,区别在于步骤2)中不添加SnCl4·5H2O,其余与实施例1完全一致。
实施例1-B
与实施例1相比,区别在于步骤3)中采用用30ml的醋酸替代30 ml醋酸/浓硫酸组成的混酸(混酸中醋酸与浓硫酸的重量比为1:2),其余与实施例1完全一致。
实施例1-C
与实施例相比,区别在于采用二氧化硅进行负载,即采用等质量的二氧化硅替代凹土。
采用Autosorb-1 MP/Kr仪器(气体吸附法)测试实施例1及其载体凹土的比表面积、孔径,结果如表1所示:
表1不同制备方法获得的催化剂比表面积
比表面积(m2/g) | 孔体积(cm3/g) | 平均孔径(nm) | |
原料凹土 | 180 | 0.32 | 5.1 |
凹土粉 | 242 | 0.52 | 7.8 |
实施例1 | 178 | 0.31 | 7.9 |
注:原料凹土为试验用最初原料;凹土粉为原料凹土经过盐酸的四氢呋喃溶液处理后所得的产品;实施例1代表实施例1制备出的最后产品,即锡改性的ZrO2/凹土固体酸催化剂。
试验结果表明,原料凹土经过盐酸的四氢呋喃溶液处理后比表面积、孔体积和平均孔径均不同程度增大,利于后续锆和锡的沉积;最后制备出的催化剂较载体凹土比表面积、孔体积没有发生明显变化,但孔径得到了部分增大,利于后期催化反应中小分子进出孔道。
实施例2
采用实施例1,实施例1-A、1-B、1-C制备的催化剂催化4-氯-6-溴-3-硝基喹啉与2-甲基-2-(4-氨基苯基)丙腈反应制备2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈:
100ml反应瓶中加入10mmol 4-氯-6-溴-3-硝基喹啉、11mmol 2-甲基-2-(4-氨基苯基)丙腈、0.17g催化剂、50ml甲醇于40℃下搅拌反应,HPLC检测反应液中原料不再转化后停止反应。
表2为不同催化剂的原料转化率及其选择性
注:由于4-氯-6-溴-3-硝基喹啉中的6位可以发生反应的位点,生成副产物,故存在一定选择性。转化率是指底物4-氯-6-溴-3-硝基喹啉的转化率。
实施例3
不同煅烧温度对反应的影响:采用单因素变量法改变实施例1中步骤3)中的煅烧温度,以催化反应性能进行评估,考察不同煅烧温度对催化剂的影响:操作过程如下
100ml反应瓶中加入10mmol 4-氯-6-溴-3-硝基喹啉、11mmol 2-甲基-2-(4-氨基苯基)丙腈、0.17g催化剂(不同煅烧温度所得)、50ml甲醇于40℃下搅拌反应,2h后HPLC检测反应液中原料。
表3为不同溶剂对反应的影响
结果表明不同的煅烧温度直接影响催化剂的催化性能,低温无法起到活化作用,例如小于100℃时;在300℃左右获得了最优异的催化性能,使锡改性的ZrO2能够与凹土基体紧密结合;由于催化剂的热稳定性较差,温度过高(大于400℃)会使催化剂的酸性位点遭到破坏,从而催化活性降低。
实施例4
不同溶剂对反应的影响:100ml反应瓶中加入10mmol 4-氯-6-溴-3-硝基喹啉、11mmol2-甲基-2-(4-氨基苯基)丙腈、0.17g催化剂(实施例1制备所得的锡改性的ZrO2/凹土固体酸催化剂)、50ml溶剂于40℃下搅拌反应,HPLC检测反应液中原料不再转化后停止反应,结果如表4。
表4为不同溶剂对反应的影响
溶剂 | 反应时间/h | 转化率/% | 选择性/% |
醋酸 | 2h | 99.2 | 92.1 |
甲醇 | 3h | 99.4 | 97.2 |
乙醇 | 4h | 90.2 | 95.6 |
四氢呋喃 | 4h | 90.0 | 96.1 |
2-甲基四氢呋喃 | 8h | 83.1 | 96.2 |
乙酸乙酯 | 8h | 76.3 | 96.5 |
乙酸异丙酯 | 10h | 69.3 | 96.1 |
二氯甲烷 | 24h | 43.2 | 97.1 |
甲醇/H2O(体积比10/1) | 0.5h | 99.4 | 96.1 |
以上结果表明,不同溶剂对催化剂的影响较大,主要是影响底物的转化率,对选择性影响不大;其中含氢键的溶剂反应效果较好,以甲醇最为优异,其余溶剂反应时间较长;另外采取体积比为10:1的甲醇/ H2O的混合溶剂能加快反应速度,说明水的加入能加快反应速度,但是由于水过多会导致催化剂流失,所以反应中必须控制水的用量,甲醇与水的体积比保持在90-100:5之间为宜。
实施例5
采用优化后的条件,对反应进行后处理和放大研究
1)将4-氯-6-溴-3-硝基喹啉(1mol,287.5g)和锡改性的ZrO2/凹土固体酸催化剂(17.3g)加入到2.5L 95%V的甲醇中,然后滴加2-甲基-2-(4-氨基苯基)丙腈的甲醇溶液500ml(含2-甲基-2-(4-氨基苯基)丙腈1.1mol,176.2g),滴加结束后在45℃下搅拌反应1h;
2)HPLC检测反应液(转化率为99.7%),反应完全后过滤去除锡改性的ZrO2/凹土固体酸催化剂,催化剂用500ml甲醇洗涤,合并滤液;
3)对滤液进行减压蒸馏,蒸馏出0.8-1.2L甲醇,然后常压升温至55℃搅拌均匀;向体系中滴加纯化水,待体系变浑浊时停止滴加(此阶段滴入1.2L),55-60℃保温搅拌1-2h,然后继续滴加纯化水至固体全部析出(此阶段滴入2.0L,共计1.2+2.0L=3.2L)后降温至室温,抽滤、丙酮洗涤滤饼后干燥得378g(收率为92%)浅黄色固体,HPLC纯度为99.3%。
ESI-MS(m/z): 411[M+H]+;1H-NMR(400 MHz,DMSO-d6)δ: 9.08(s, 1H, NH),8.62(s, 1H, CH),7.91(s, 1H, CH), 7.94(d, J=8.7 Hz, 1H, CH), 7.82(d,J=8.3 Hz,1H, CH), 7.46(d, J=8.3 Hz, 2H, 2CH),7.17(d, J=8.2 Hz, 2H, 2CH), 1.66(s, 6H,2CH3)
实施例6
采用实施例5抽滤分离得到的锡改性的ZrO2/凹土固体酸催化剂60℃下干燥去除溶剂后进行回收套用:将4-氯-6-溴-3-硝基喹啉(10mmol,2.88g)和锡改性的ZrO2/凹土固体酸催化剂(0.17g)加入到25mL 95%V的甲醇中,然后滴加2-甲基-2-(4-氨基苯基)丙腈的甲醇溶液5ml(含2-甲基-2-(4-氨基苯基)丙腈11mol,1.76g),滴加结束后在45℃下搅拌反应1h,HPLC检测反应液;不同循环次数的反应情况如表5所示:
表5催化剂循环套用反应情况
循环套用次数 | 转化率/% |
R1 | 99.0 |
R2 | 94.3 |
R3 | 88.1 |
R4 | 75.4 |
R5 | 63.1 |
随着催化剂套用次数增加,原料转化率急剧下降,可能是由于过多的杂质阻塞了催化剂的酸性位点,导致套用五次后转化率仅为60%左右,不足以维持反应的进行。
本发明对循环使用3次后的催化剂(即R3批次使用后的催化剂)进行活化,活化方法如下:
1)将1.0g锡改性的ZrO2/凹土固体酸催化剂回收后(循环套用三次的催化剂,即R3批次,多次累积所得),置于5ml氮氮二甲基甲酰胺/四氢呋喃溶液(体积比计DMF/THF=1:1)中升温至60℃超声1-2h后过滤,丙酮洗涤后干燥得预处理催化剂;
2)将预处理催化剂放入5ml浓硫酸中于70℃下浸渍24h,过滤,丙酮洗涤后100℃下真空干燥得酸处理催化剂;
3)将酸处理催化剂置于煅烧炉中,在氮气氛围下,于360℃下煅烧10-30min得活化后的锡改性的ZrO2/凹土固体酸催化剂。
将活化后的催化剂进行反应检测(摩尔比4-氯-6-溴-3-硝基喹啉/2-甲基-2-(4-氨基苯基)丙腈=1:1.1,活化后催化剂重量为4-氯-6-溴-3-硝基喹啉的6%wt,溶剂95%V甲醇水溶液),反应1h后HPLC检测原料转化率为97.2%,催化活性得到恢复;然而试验中发现若不对回收后的催化剂进行氮氮二甲基甲酰胺/四氢呋喃溶液中60℃超声处理则活化后的催化剂原料转化率仅为80.2%,活化作用不明显,所以硫酸浸渍前必须采用DMF/THF的混合溶液进行超声处理去除催化剂表面和内部孔道的小分子化合物,释放出更多酸性结合位点。
实施例7
为了验证本发明制备的催化剂对该官能团反应的其它底物的催化效果,本发明固定底物2-甲基-2-(4-氨基苯基)丙腈不变,分别与5-氯-8-羟基喹啉、6-氯喹啉、2-氯-8-氰基喹啉、6-氯-5-硝基喹啉、7-氯-2-甲基喹啉反应,反应条件为:11mmol 2-甲基-2-(4-氨基苯基)丙腈与喹啉衍生物10mmol、实施例1制备的锡改性的ZrO2/凹土固体酸催化剂0.15g在50ml甲醇中反应,每隔0.5h采用LC-MS检测反应液中喹啉衍生物的剩余量并检测是否有目标产物的分子离子峰生成,当前后两次检测原料不再转化后,计算转化率结果如表6所示:
表6不同底物的反应情况
注:“—”表明未对反应液进行分子离子峰进行分析
试验结果表明本发明制备的催化剂对该类反应均均有较好的催化效果;其中喹啉环上含有吸电子集团的底物转化率高于供电子基团的底物,也验证了该类反应属于亲核取代反应。
尽管已经详细描述了本发明的实施方式,但是应该理解的是,在不偏离本发明的精神和范围的情况下,可以对本发明的实施方式做出各种改变、替换和变更。
Claims (9)
1.一种新型锡改性的ZrO2/凹土固体酸催化剂的制备方法,包括以下步骤:
1)凹土前处理工序:将凹土气流粉碎至粒径为100目的颗粒物,然后置于盐酸的四氢呋喃溶液中超声处理24h后过滤,烘干、粉碎至粒径为200-300目得凹土粉;
2)共沉积工序:将凹土粉置于正丙醇中,然后加入70%wt正丙醇锆(IV)的正丙醇溶液和SnCl4·5H2O搅拌混合均匀,升温至60-70℃于1000rpm的转速下强烈搅拌30min;缓慢滴加0.5-2.0mol/L的氨水溶液调节溶液pH至9.5-10.5,然后保温搅拌陈化12-24h;降温至室温,抽滤、水洗至滤液成中性,收集滤饼在氮气氛围下,100-130℃煅烧1-2h后得共沉积沉淀物;
3)酸浸渍工序:将共沉积沉淀物置于醋酸/浓硫酸组成的混酸中搅拌,氮气氛围下回流12h后降温至室温、过滤,水洗至滤液成中性,滤饼在氮气氛围下进行煅烧得新型锡改性的ZrO2/凹土固体酸催化剂。
2.根据权利要求1所述的制备方法,其特征在于:步骤2)中正丙醇锆(IV)与SnCl4·5H2O的摩尔比为1:0.1-0.6,SnCl4·5H2O与凹土粉的重量比为0.5-10:100。
3.根据权利要求2所述的制备方法,其特征在于:步骤2)中正丙醇锆(IV)与SnCl4·5H2O的摩尔比为1:0.3,SnCl4·5H2O与凹土粉的重量比为2:100。
4.根据权利要求1所述的制备方法,其特征在于:步骤3)所述滤饼在氮气氛围下进行煅烧是指在氮气的氛围下于200-400℃下煅烧6-12h。
5.根据权利要求4所述的制备方法,其特征在于:步骤3)所述滤饼在氮气氛围下进行煅烧是指在氮气的氛围下于260-300℃下煅烧6-12h。
6.一种权利要求1所述新型锡改性的ZrO2/凹土固体酸催化剂的用途,其特征在于:在溶剂的存在下,用于催化4-氯-6-溴-3-硝基喹啉与2-甲基-2-(4-氨基苯基)丙腈反应制备2-[4-[ (3-硝基-6-溴喹啉-4-基)氨基]苯基]-2-甲基丙腈。
7.根据权利要求6所述的用途,其特征在于:步骤1)中4-氯-6-溴-3-硝基喹啉与2-甲基-2-(4-氨基苯基)丙腈的摩尔比为1:1-1.2,4-氯-6-溴-3-硝基喹啉与锡改性的ZrO2/凹土固体酸催化剂的重量比为1:0.01-0.20。
8.根据权利要求7所述的用途,其特征在于:步骤1)中4-氯-6-溴-3-硝基喹啉与2-甲基-2-(4-氨基苯基)丙腈的摩尔比为1:1.1,4-氯-6-溴-3-硝基喹啉与锡改性的ZrO2/凹土固体酸催化剂的重量比为1:0.06。
9.根据权利要求6所述的用途,其特征在于:步骤1)所述溶剂为醋酸、甲醇、乙醇、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、二氯甲烷或其复配溶剂;步骤3)所述反溶剂为正戊烷、正庚烷、甲苯或水。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101437808A (zh) * | 2006-03-21 | 2009-05-20 | 耶鲁大学 | 由芳香化合物与氨或金属酰胺反应合成芳基胺的方法 |
CN102898329A (zh) * | 2012-09-29 | 2013-01-30 | 西安近代化学研究所 | 一种酸性催化脱水合成n-芳基酮亚胺的方法 |
CN105085439A (zh) * | 2015-08-31 | 2015-11-25 | 江苏七洲绿色化工股份有限公司 | 一种氟环唑中间体的制备方法 |
CN105693536A (zh) * | 2016-03-08 | 2016-06-22 | 温州永宏科技孵化有限公司 | 一种合成喹吖啶酮颜料中间体dxta的制备方法 |
CN106748801A (zh) * | 2016-12-28 | 2017-05-31 | 华东师范大学 | 一种3,5‑二氯苯胺的合成方法 |
US20170321281A1 (en) * | 2016-04-25 | 2017-11-09 | The Trustees Of Columbia University In The City Of New York | Methods and compositions for treatment of glioblastoma |
-
2017
- 2017-12-27 CN CN201711442658.8A patent/CN107952425B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101437808A (zh) * | 2006-03-21 | 2009-05-20 | 耶鲁大学 | 由芳香化合物与氨或金属酰胺反应合成芳基胺的方法 |
CN102898329A (zh) * | 2012-09-29 | 2013-01-30 | 西安近代化学研究所 | 一种酸性催化脱水合成n-芳基酮亚胺的方法 |
CN105085439A (zh) * | 2015-08-31 | 2015-11-25 | 江苏七洲绿色化工股份有限公司 | 一种氟环唑中间体的制备方法 |
CN105693536A (zh) * | 2016-03-08 | 2016-06-22 | 温州永宏科技孵化有限公司 | 一种合成喹吖啶酮颜料中间体dxta的制备方法 |
US20170321281A1 (en) * | 2016-04-25 | 2017-11-09 | The Trustees Of Columbia University In The City Of New York | Methods and compositions for treatment of glioblastoma |
CN106748801A (zh) * | 2016-12-28 | 2017-05-31 | 华东师范大学 | 一种3,5‑二氯苯胺的合成方法 |
Non-Patent Citations (2)
Title |
---|
刘珊珊: ""高岭土基固体酸催化剂的研制及应用"", 《中国优秀硕士学位论文全文数据库工程科技I辑》 * |
雷飞等: ""PI13K/mTOR双重抑制剂NVP-BEZ235的合成"", 《中国医药工业杂志》 * |
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Effective date of registration: 20200408 Address after: 611930 Middle Section 588 Peony Avenue, Tianpeng Town, Pengzhou City, Chengdu City, Sichuan Province Applicant after: SICHUAN XIELI PHARMACEUTICAL Co.,Ltd. Address before: 721000 Baoji City, Shaanxi province Jintai District of Yongxing dongin Xiang Town Applicant before: Gao Jun |
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