CN117304128A - 一种连续合成联苯型化合物的方法 - Google Patents
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- -1 biphenyl compound Chemical class 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 29
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- 235000010290 biphenyl Nutrition 0.000 title claims abstract description 6
- 239000004305 biphenyl Substances 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 239000003054 catalyst Substances 0.000 claims abstract description 24
- 239000003446 ligand Substances 0.000 claims abstract description 23
- FPIBKDDEZCKPGT-UHFFFAOYSA-N 4-propan-2-yl-4,5-dihydro-1,3-oxazole Chemical compound CC(C)C1COC=N1 FPIBKDDEZCKPGT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012043 crude product Substances 0.000 claims abstract description 5
- 238000010438 heat treatment Methods 0.000 claims description 22
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 12
- 239000005864 Sulphur Substances 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 8
- 230000000536 complexating effect Effects 0.000 claims description 5
- 239000006004 Quartz sand Substances 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
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- 239000000047 product Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000002699 waste material Substances 0.000 abstract 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 24
- 239000005751 Copper oxide Substances 0.000 description 13
- 229910000431 copper oxide Inorganic materials 0.000 description 13
- 230000000694 effects Effects 0.000 description 11
- 230000003197 catalytic effect Effects 0.000 description 7
- 238000005859 coupling reaction Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- 238000006555 catalytic reaction Methods 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920001968 ellagitannin Polymers 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- JMGCAHRKIVCLFW-UHFFFAOYSA-N 1-O-Galloylcastalagin Natural products Oc1cc(cc(O)c1O)C(=O)OC2C3OC(=O)c4c2c(O)c(O)c(O)c4c5c(O)c(O)c(O)c6c5C(=O)OC3C7OC(=O)c8cc(O)c(O)c(O)c8c9c(O)c(O)c(O)cc9C(=O)OCC7OC(=O)c%10cc(O)c(O)c(O)c6%10 JMGCAHRKIVCLFW-UHFFFAOYSA-N 0.000 description 2
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 229910001431 copper ion Inorganic materials 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- JMGCAHRKIVCLFW-CNWXVVPTSA-N ellagitannin Chemical compound OC1=C(O)C(O)=CC(C(=O)O[C@H]2C3=C4C(=O)O[C@@H]2[C@@H]2[C@@H]5OC(=O)C6=CC(O)=C(O)C(O)=C6C6=C(O)C(O)=C(O)C=C6C(=O)OC[C@H]5OC(=O)C5=CC(O)=C(O)C(O)=C5C=5C(O)=C(O)C(O)=C(C=5C(=O)O2)C4=C(O)C(O)=C3O)=C1 JMGCAHRKIVCLFW-CNWXVVPTSA-N 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
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- XHXXWWGGXFUMAJ-UHFFFAOYSA-N methanethiol;sodium Chemical compound [Na].SC XHXXWWGGXFUMAJ-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
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- 239000007787 solid Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QADXKWUCCGPQNR-UHFFFAOYSA-N 3-bromo-4-chloropyridine Chemical compound ClC1=CC=NC=C1Br QADXKWUCCGPQNR-UHFFFAOYSA-N 0.000 description 1
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 108090000323 DNA Topoisomerases Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
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- 150000005347 biaryls Chemical group 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
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- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
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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
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
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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
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/226—Sulfur, e.g. thiocarbamates
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- B01J8/00—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes
- B01J8/02—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with stationary particles, e.g. in fixed beds
- B01J8/04—Chemical or physical processes in general, conducted in the presence of fluids and solid particles; Apparatus for such processes with stationary particles, e.g. in fixed beds the fluid passing successively through two or more beds
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Abstract
本发明属于化工合成技术领域,特别涉及一种连续合成联苯型化合物的方法,将纳米CuO催化剂加装到固定床反应器中,再将2‑(2‑溴‑3,4,5‑三甲氧基苯基)噁唑啉、配体3‑溴‑4‑硫甲基吡啶的DMF溶液通入固定床反应器进行反应,并对反应后的混合体系冷却后,收集粗产物并通过重结晶得到纯化后的(4S,4'S)‑2,2'‑(S)‑4,4',5,5',6,6'‑六甲氧基‑[1,1'‑联苯]‑2,2'‑二基)双(4‑异丙基‑4,5‑二氢噁唑)。本发明方法具有成本低廉、操作简便、装备效率高、产品收率高、三废污染较少等特点,具有较高的工业化价值。
Description
技术领域
本发明属于化工合成技术领域,特别涉及一种连续合成联苯型化合物的方法。
背景技术
联苯型化合物(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑)的水解产物(S)-4,5,6,4',5',6'-六甲氧基联苯二甲酸是重要的精细化工中间体,如(S)-4,5,6,4',5',6'-六甲氧基联苯二甲酸是合成单宁异构体的关键中间体,鞣花单宁是葡萄糖的没食子酸酯,其含有至少一个手性联芳基结构单元。鞣花单宁已显示出抑制HIV逆转逆转录酶和DNA拓扑异构酶介导的活性。这些化合物具有抗氧化活性,在食品、饮料、草药、皮革制革等领域具有重要的应用。
目前公开的(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑)的合成路线,以2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉为原料,铜为催化剂,回流48h(Nelson T D,Meyers AI.ARapid Total Synthesis of anEllagitannin[J].The Journal of Organic Chemistry,1994,59(9):879.):
该路线原料转化率低,收率仅为60%,后处理复杂。
发明内容
为解决上述技术问题,本发明提供了一种连续合成联苯型化合物的方法,以2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉为原料,在以纳米CuO为活性中心、以3-溴-4-硫甲基吡啶为配体的络合型催化剂的作用下,反应合成(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑),反应式如下:
作为优选:将纳米CuO为催化剂活性中心加装到固定床反应器中,再将2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、配体3-溴-4-硫甲基吡啶的DMF溶液通入固定床反应器进行反应,并对反应后的混合体系冷却后,收集粗产物并通过重结晶得到纯化后的(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑)。
作为优选:2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、配体3-溴-4-硫甲基吡啶的DMF溶液中,2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉浓度为0.8~1.5mol/L。
作为优选:纳米CuO占2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉摩尔量的2%~5%,3-溴-4-硫甲基吡啶占2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉摩尔量的5%~15%。
作为优选:2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、配体3-溴-4-硫甲基吡啶于固定床反应器中的反应温度为200~220℃。
作为优选:2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、配体3-溴-4-硫甲基吡啶的DMF溶液于固定床反应器中经过纳米CuO时的质量空速为2~6h-1。
作为优选:固定床反应器为绝热式固定床反应器,包括进样器、加热管、热电偶、催化剂床层、冷凝器、收集器,其中,热电偶安装于加热管中,可以监测反应温度,加热管外覆盖有一层保温层,有利于保持加热管中的恒温状态,加热管管腔的上部和下部分别装填了40目的石英砂充当支撑物,管腔中间段填充有催化剂作为催化剂床层,
2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、配体3-溴-4-硫甲基吡啶的DMF溶液通过双柱塞泵由固定床反应器上的进样器定量进入加热管,原料的预热及双分子偶联反应在加热管中进行,溶液的预热主要发生在加热管管腔的上部,偶联反应则主要发生在加热管管腔中间段的纳米CuO床层中。
本方案采用以纳米CuO为活性中心、以3-溴-4-硫甲基吡啶为配体的络合型催化剂进行非均相催化反应,并且充分利用了纳米CuO与3-溴-4-硫甲基吡啶之间络合活性高、络合速度快这一特点,将作为配体的3-溴-4-硫甲基吡啶直接与原料2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉混合后作为液相,一起于固体床反应器中流经催化活性中心纳米CuO,纳米CuO与液相中的3-溴-4-硫甲基吡啶接触并快速络合成催化剂配合物,同步催化2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉发生双分子偶联反应。从而避免了事先专门络合制备纳米CuO与3-溴-4-硫甲基吡啶的配合物,节省了工序,也更加便于工业生产操作。
并且流动催化过程中,催化剂床层中的Cu2+流失有限,可长时间连续使用,使用寿命长。
在上述催化反应的基础上,本方案通过反应条件的优化,使原料单程转化率≥80%(以起始原料2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉计,下同),选择性≥95%(目的产物质量相对于发生转化的2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉质量的百分比,下同),重结晶后产品(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑)纯度达到99.0%(以质量分数计,下同)以上。
本方案催化工艺反应速度快、操作简便,催化剂活性高,偶联反应在固定床反应器中实现,过程连续,显著提高反应效率,缩短了操作时间,且具有较好的反应稳定性。
附图说明
图1为本发明合成方法的工艺流程图;
图2为本发明合成方法中所使用的固定床反应器的结构组成示意图,其中,1—进样器,2—石英砂床层,3—催化剂床层,4—保温层,5—加热管,6—冷凝器,7—热电偶,8—收集器。
具体实施方式
需要说明的是,本申请描述中使用的方向限定词“上部”、“下部”、“上端”、“下端”、“从上而下”指的是附图2中的方向,仅是为了便于描述本申请和简化描述,而不是指示或暗示必须具有特定的方向、操作,因此不能理解为对本申请的限制。
实施例1
3-溴-4-硫甲基吡啶的制备:
向配备有温度计、冷凝管的四口烧瓶中加入1.2mol的3-溴-4-氯吡啶和0.055mol的四正丁基溴化铵相转移剂,然后向其中加入1.3mol甲硫醇钠(甲硫醇钠按15%的重量浓度分散于水中加入),升温至80℃后搅拌反应3h,冷却至室温后,将析出的结晶滤出后,加入甲醇中进行重结晶,从而得到纯的3-溴-4-硫甲基吡啶;
将0.6g纳米CuO(粒径30nm,下同)作为催化剂活性中心填充至绝热式固定床反应器的加热管管腔中部区域作为催化剂活性中心床层,并在该管腔的上部和下部分别填充40目的石英砂作为对该催化剂活性中心床层的支撑;
将摩尔浓度为1mol/L 2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、0.125mol/L本实施例制备的3-溴-4-硫甲基吡啶的DMF溶液共150mL,持续通过双柱塞泵由固定床反应器上的进样器定量进入加热管(从加热管上端从上而下进入加热管),控制该溶液通过加热管内的催化剂活性中心床层时质量空速为4h-1,并通过加热管控制该溶液通过催化剂活性中心床层时的温度达到210℃发生双分子偶联反应,经双分子偶联反应后的混合体系从加热管下端流出加热管后,进入冷凝器被冷却,再进入收集器。
反应结束后,取出收集器中的混合体系,浓缩后得到黄色油状液体粗品,将粗品进行重结晶得到纯化后的(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑)。1H NMR(400MHz,CDCl3),δ7.24(s,2H),4.04(dd,J=9.3,7.9Hz,2H),3.91(s,6H),3.88(s,6H),3.66-3.80(m,4H),3.64(s,6H),1.54-1.63(m,2H),0.82(d,J=6.7Hz,6H),0.74(d,J=6.7Hz,6H);ESI-MS:[M+H+]:557.2829;[M+Na+]:579.2658。通液相色谱分析,产物(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑)纯度达到99.0%,进一步计算得到原料单程转化率为80%、选择性为95%,因此单程收率为76%。
将本实施例得到的产物(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑)经质量浓度10%的稀盐酸回流水解得到(S)-4,4',5,5',6,6',-六甲氧基-2,2'-联苯二甲酸,所得二甲酸在HPLC上保留时间与市售标准品一致,二者混合熔点不下降,说明是同一化合物。
对收集器中的混合体系进行浓缩过程中,将气化了的母液冷凝回收,将回收到的母液重新按实施例1的操作进入固体床反应器进行回用反应,多次回用后的总收率超过92%。
实施例2至4
参照实施例1的方法,其他实验条件保持不变,仅改变催化剂配体的种类,考察对反应结果的影响并与实施例1进行比较,如表1所示:
表1
配体 | 转化率 | 选择性 | |
实施例1 | 3-溴-4-硫甲基吡啶 | 80% | 95% |
实施例2 | 无配体 | 65% | 78% |
实施例3 | DPPB | 65% | 78% |
实施例4 | 甘氨酸 | 68% | 80% |
从表1可以看出:相比于实施例2中无任何配体的催化操作,本申请的方案(实施例1)在催化效果上有了明显提升,可见3-溴-4-硫甲基吡啶配体在流经纳米氧化铜床层时,与氧化铜之间存在相互配合促进催化的效果,从而认为此过程中,3-溴-4-硫甲基吡啶与纳米氧化铜之间至少形成了暂时的络合状态。而实施例3和实施例4中采用其他配体时,对催化效果几乎无任何帮助,说明其他几种配体在类似的流动状态下,并无法与纳米氧化铜之间形成有效络合。
实施例5至9
参照实施例1的方法,其他实验条件保持不变,仅改变催化剂活性中心的相对用量,考察对反应结果的影响并与实施例1进行比较,如表3所示:
表2
从表2可以看出:摩尔比n(反应物):n(纳米CuO)为1:0.05为最佳条件。
实施例10至13
参照实施例1的方法,其他实验条件保持不变,仅改变催化剂配体的相对用量,考察对反应结果的影响并与实施例1进行比较,如表2所示:
表3
从表3可以看出:摩尔比n(反应物):n(纳米CuO):n(3-溴-4-硫甲基吡啶)为1:0.05:0.1为最佳条件。
实施例14至17
参照实施例1的方法,其他实验条件保持不变,仅改变反应温度,考察对反应结果的影响并与实施例1进行比较,如表4所示:
表4
反应温度 | 转化率 | 选择性 | |
实施例1 | 210℃ | 80% | 95% |
实施例14 | 190℃ | 70.4% | 96% |
实施例15 | 200℃ | 75.2% | 95.6% |
实施例16 | 220℃ | 85.1% | 90.6% |
实施例17 | 230℃ | 89.2% | 88.8% |
从表4可以看出,温度210℃为最佳条件。
实施例18至21
参照实施例1的方法,其他实验条件保持不变,仅改变质量空速,考察对反应结果的影响并与实施例1进行比较,如表5所示:
表5
质量空速 | 转化率 | 选择性 | |
实施例1 | 4h-1 | 80% | 95% |
实施例18 | 2h-1 | 82.2% | 93% |
实施例19 | 3h-1 | 81.3% | 93.5% |
实施例20 | 5h-1 | 76.6% | 95.6% |
实施例21 | 6h-1 | 73.4% | 95.9% |
从表5可以看出,床层质量空速4h-1为最佳条件。
实施例22
参照实施例1的方法,其他实验条件保持不变,仅使用等质量的粒径400目的氧化铜代替实施例1中粒径30nm的氧化铜,考察对反应结果的影响并与实施例1进行比较,如表6所示:
表6
(表6中,“流出液中铜离子浓度”指的是:实施例中通过双柱塞泵从固定床反应器上的进样器定量进入加热管的总共150mL的DMF溶液,反应结束后全部进入到固定床反应器的收集器中后,被测到的铜离子浓度;
“连续反应100h后氧化铜活性保留百分比”指的是:在操作参数不变的情况下,持续不断地向固定床反应器中单程通实施例中的“摩尔浓度为1mol/L 2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、0.125mol/L实施例1制备的3-溴-4-硫甲基吡啶的DMF溶液”持续100小时,检测此时原料的催化转化率,并计算与起初的原料转化率(表6中的转化率数据)的比值。)
配体属于有机物,并且与催化活性中心氧化铜之间能形成配合结合,因此在DMF溶液持续从氧化铜床层上流过时,会不可避免地通过配体与氧化铜之间的配合作用携带出一些氧化铜粒子。而从表6来看,纳米级氧化铜在本方案的动态络合及催化操作下,Cu2+的流失却十分有限,仅相当于普通催化剂粒子的6%,取得了意想不到的效果,这有可能是基于纳米氧化铜的热稳定性所致。长时间连续使用后活性更耐久,因而使用寿命长、节省成本,更有利于用于工业化生产。
Claims (7)
1.一种连续合成联苯型化合物的方法,其特征在于:所述方法为,以2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉为原料,在以纳米CuO为活性中心、以3-溴-4-硫甲基吡啶为配体的络合型催化剂的作用下,反应合成(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑)。
2.如权利要求1所述的连续合成联苯型化合物的方法,其特征在于:所述方法为,将所述纳米CuO加装到固定床反应器中,再将2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、配体3-溴-4-硫甲基吡啶的DMF溶液通入所述固定床反应器进行反应,并对反应后的混合体系冷却后,收集粗产物并通过重结晶得到纯化后的(4S,4'S)-2,2'-(S)-4,4',5,5',6,6'-六甲氧基-[1,1'-联苯]-2,2'-二基)双(4-异丙基-4,5-二氢噁唑)。
3.如权利要求2所述的连续合成联苯型化合物的方法,其特征在于:所述2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、配体3-溴-4-硫甲基吡啶的DMF溶液中,2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉浓度为0.8~1.5mol/L。
4.如权利要求2所述的连续合成联苯型化合物的方法,其特征在于:所述纳米CuO占所述2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉摩尔量的2%~5%,所述3-溴-4-硫甲基吡啶占所述2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉摩尔量的5%~15%。
5.如权利要求2所述的连续合成联苯型化合物的方法,其特征在于:所述2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、配体3-溴-4-硫甲基吡啶的DMF溶液通入所述固定床反应器进行反应的温度为200~220℃。
6.如权利要求2所述的连续合成联苯型化合物的方法,其特征在于:所述2-(2-溴-3,4,5-三甲氧基苯基)噁唑啉、配体3-溴-4-硫甲基吡啶的DMF溶液于所述固定床反应器中经过所述纳米CuO时的质量空速为2~6h-1。
7.如权利要求2所述的连续合成联苯型化合物的方法,其特征在于:所述固定床反应器为绝热式固定床反应器,包括进样器、加热管、热电偶、冷凝器、收集器,其中,所述热电偶安装于所述加热管中,所述加热管外覆盖有一层保温层,所述加热管管腔的上部和下部分别装填石英砂充当支撑物,所述管腔中间段填充有所述络合型催化剂作为催化剂床层。
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