CN108892645B - 一种制备四甲基吡嗪的方法 - Google Patents
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- FINHMKGKINIASC-UHFFFAOYSA-N Tetramethylpyrazine Chemical compound CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 title claims abstract description 104
- 238000000034 method Methods 0.000 title claims abstract description 12
- ROWKJAVDOGWPAT-UHFFFAOYSA-N Acetoin Chemical compound CC(O)C(C)=O ROWKJAVDOGWPAT-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000047 product Substances 0.000 claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 239000007858 starting material Substances 0.000 claims abstract description 5
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 8
- 229910001870 ammonium persulfate Inorganic materials 0.000 claims description 7
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 7
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 7
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical group [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 4
- 239000001099 ammonium carbonate Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000006356 dehydrogenation reaction Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000006317 isomerization reaction Methods 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 3
- MAAZDFZETNADTQ-UHFFFAOYSA-N 2,3,5,6-tetramethylpyrazine;trihydrate Chemical compound O.O.O.CC1=NC(C)=C(C)N=C1C MAAZDFZETNADTQ-UHFFFAOYSA-N 0.000 claims description 2
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical group NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 2
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical group [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 2
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 claims description 2
- 238000001256 steam distillation Methods 0.000 claims description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
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- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 241000208173 Apiaceae Species 0.000 description 1
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241000244355 Ligusticum Species 0.000 description 1
- 241000244365 Ligusticum sinense Species 0.000 description 1
- 241000112528 Ligusticum striatum Species 0.000 description 1
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- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及化工技术领域,尤其是一种制备四甲基吡嗪的方法;以3‑羟基‑2‑丁酮为起始原料,铵盐为氮源,通过缩合、异构化、环化、脱氢获得四甲基吡嗪粗品,四甲基吡嗪粗品通过分离纯化获得成品四甲基吡嗪,使目标产物的产率达到85%以上,四甲基吡嗪纯度≥99.0%(液相色谱,外标);本发明所用原料是3‑羟基‑2‑丁酮(Acetoin),3‑羟基‑2‑丁酮,分子式C4H8O2,相对分子质量88.10,天然存在于谷物、酒、醋(从葡萄或其他原料制)、蜂蜜、可可,黄油以及烘烤过的咖啡中,我国GB2760‑86规定为允许使用的食用香料,主要用于配制奶油、乳品、酸奶和草莓等型香精,也用于有机合成,所以从源头上保证了产品的绿色环保安全,合成方法简单,使用一锅法生产,节省成本。
Description
技术领域
本发明涉及化工技术领域,尤其是一种制备四甲基吡嗪的方法。
背景技术
2,3,5,6-四甲基吡嗪是重要的精细化工产品,广泛应用于香料、食品添加剂、光敏剂、医药和农药的合成,主要用以配配制肉类和可可、花生、坚果、咖啡、巧克力等型香精,也用作调味剂、酒精饮料的甜味增强剂、卷烟的矫味剂和增补剂等。2,3,5,6-四甲基吡嗪在医学上被称为川芎嗪,具有扩张血管、轻度降压、抑制小血板反黏聚集和血栓形成、抑制平滑肌细胞和成纤维细胞增生等较为良好的药理作用,已引起国内外医学界的广泛关注;国产高档白酒因含有2,3,5,6-四甲基吡嗪等被赋予一定的保健功能。
2,3,5,6-四甲基吡嗪纯品是白色结晶或粉末,具有牛肉和猪脂加热时的香气和发酵的大豆味,稀释至20ppm时呈牛奶巧克力风味,熔点84~86℃,溶于乙醇、大多数非挥发性油和丙二醇,微溶于水。用作香料,主要用以配制肉类和巧克力等型香精,用于软饮料、糖果、焙烤食品、调味品、肉及肉类沙司、乳制品和汤类等的加香。
2,3,5,6-四甲基吡嗪的分子式:C8H12N2,相对分子质量:136.20,分子结构式:
目前有报道的2,3,5,6-四甲基吡嗪的制备方法主要有以下几种。
中药提取四甲基吡嗪多采用川芎系伞形科藁本属植物川芎(LigusticumChuanxiong Hort)的干燥根茎,味辛、微苦、性温,有行气活血,祛风止痛之功效,是活血化瘀常用中药(中国药典1985年版)。但因这种方法药物中四甲基吡嗪含量低(约占生药含量的0.1~0.2%),提过程取繁琐、耗时、收率低,且需耗费大量的有机溶剂,生产成本高。
CN200610026927公开了一株高产四甲基吡嗪的短小芽孢杆菌,名为Bacilluspumilus Rx3-17。这涉及到生物技术,存在收率太低的问题。
CN98124478.5公开了一种以VIII族金属化合物与有机配体形成的催化剂,通过催化氢气与2,3-丁二酮一肟反应而获得四甲基吡嗪,但是催化法因原料难得使成本较高,不适合工业化生产。
发明内容
针对现有技术的不足,本发明提供一种四甲基吡嗪的新型合成方法。以3-羟基-2-丁酮为起始原料,铵盐为氮源,通过对缩合、异构化、环化、脱氢等各步反应条件的优化,产物分离纯化过程的筛选,使四甲基吡嗪能实现一锅法生产,节省成本,反应溶剂和重结晶溶剂为水,实现了产品生产和纯化过程中绿色环保安全的理念。
本发明的技术方案为:
一种制备四甲基吡嗪的方法,以3-羟基-2-丁酮为起始原料,铵盐为氮源,通过缩合、异构化、环化、脱氢获得四甲基吡嗪粗品,四甲基吡嗪粗品通过分离纯化获得成品四甲基吡嗪,使目标产物的产率达到85%以上,四甲基吡嗪纯度≥99.0%(液相色谱,外标)。
反应式如下:
上述步骤中,所述的3-羟基-2-丁酮与铵盐、氧化脱氢剂的摩尔比为3-羟基-2-丁酮:铵盐:氧化脱氢剂=1:1.5:1.2。溶剂水的用量为3-羟基-2-丁酮质量的3~5倍,控制反应温度为80℃反应4小时,反应结束后。再滴加20%的NaOH调节pH值大约到10左右,有大量的固体物质生成,混合物冷至室温,为四甲基吡嗪粗品。
本发明的有益效果为:本发明所用原料是3-羟基-2-丁酮(Acetoin),3-羟基-2-丁酮,分子式C4H8O2,相对分子质量88.10,天然存在于谷物、酒、醋(从葡萄或其他原料制)、蜂蜜、可可,黄油以及烘烤过的咖啡中,在红醋栗及草莓的芳香成份中也可检出。单体为无色或浅黄色液体,呈牛奶香气,具令人愉快的奶油似的香气和风味;熔点-72℃,沸点148℃(140/142℃),与水互溶,溶于乙醇、丙二醇,微溶于乙醚,几乎不溶于植物油。长期放置能形成二聚体,受热熔化仍可恢复为单体;二聚体为白色结晶性粉末(熔点15℃)。我国GB2760-86规定为允许使用的食用香料,主要用于配制奶油、乳品、酸奶和草莓等型香精,也用于有机合成,所以从源头上保证了产品的绿色环保安全。
适合工业化生产,合成方法简单,使用一锅法生产,节省成本。
具体实施方式
下面结合具体实施方式作进一步说明:
实施例1
步骤1、一锅法合成四甲基吡嗪,在装有冷凝管、温度计、搅拌器的500mL三口烧瓶中,加入3-羟基-2-丁酮44.0g、硫酸铵57.8g和200mL的水,搅拌下混匀;恒温水浴加热搅拌下40~45℃反应0.5h,至反应液变成棕红色。加入54.0g过硫酸铵,恒温水浴加热搅拌下80℃反应4h,反应结束后。搅拌下快速加入20%的NaOH溶液100g破坏过量的铵盐并使反应液pH值达到8~9(有氨气逸出);趁热将反应液倾入500mL烧杯中,静置过夜,自然降温、析晶,固体即为四甲基吡嗪粗品。
步骤2、四甲基吡嗪的水蒸气重结晶提纯,将步骤(1)得到的四甲基吡嗪粗品,加入水100g,接通水蒸气蒸馏装置中,控温至60℃,通入水蒸汽,四甲基吡嗪能通过水蒸气带入接收瓶中,自然冷却重结晶,得到颜色为白色的四甲基吡嗪三水化合物,干燥后,四甲基吡嗪纯度≥99.0%(液相色谱,外标),产率达到85%以上。
实施例2
与实施例1相同,只是在步骤(1)中将硫酸铵替换为碳酸铵,最终得到四甲基吡嗪。
实施例3
与实施例1相同,只是在步骤(1)中将硫酸铵替换为碳酸氢铵,最终得到四甲基吡嗪。
实施例4
与实施例1相同,只是在步骤(1)中将硫酸铵替换为磷酸胺和氨水的混合物,最终得到四甲基吡嗪。
实施例5
与实施例1相同,只是在步骤(1)中将过硫酸铵替换为过硫酸钠,最终得到四甲基吡嗪。
实施例6
与实施例1相同,只是在步骤(1)中将过硫酸铵替换为过硫酸钾,最终得到四甲基吡嗪。
实施例7
与实施例1相同,只是在步骤(1)中将过硫酸铵替换为双氧水,最终得到四甲基吡嗪。
上述实施例的各个步骤在不冲突的情况下可以自由组合。
上述实施例和说明书中描述的只是说明本发明的原理和最佳实施例,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。
Claims (5)
1.一种制备四甲基吡嗪的方法,以3-羟基-2-丁酮为起始原料,铵盐为氮源,通过缩合、异构化、环化、脱氢获得四甲基吡嗪粗品,四甲基吡嗪粗品通过分离纯化获得成品四甲基吡嗪;所述以3-羟基-2-丁酮为起始原料,铵盐为氮源,通过缩合、异构化、环化、脱氢获得产物的方式为:在装有冷凝管、温度计、搅拌器的500mL三口烧瓶中,加入3-羟基-2-丁酮44.0g、硫酸铵57.8g和200mL的水,搅拌下混匀;恒温水浴加热搅拌下40~45℃反应0.5h,至反应液变成棕红色,加入54.0g过硫酸铵,恒温水浴加热搅拌下80℃反应4h,反应结束后,搅拌下快速加入20%的NaOH溶液100g破坏过量的铵盐并使反应液pH值达到8~9;趁热将反应液倾入500mL烧杯中,静置过夜,自然降温、析晶,固体即为四甲基吡嗪粗品;
所述四甲基吡嗪粗品通过分离纯化获得成品四甲基吡嗪的方式为:加入水100g,接通水蒸气蒸馏装置中,控温至60℃,通入水蒸汽,四甲基吡嗪能通过水蒸气带入接收瓶中,自然冷却重结晶,得到颜色为白色的四甲基吡嗪三水化合物,干燥后,四甲基吡嗪纯度≥99.0%,产率达到85%以上。
2.根据权利要求1所述的一种制备四甲基吡嗪的方法,其特征在于:将硫酸铵替换为碳酸铵。
3.根据权利要求1所述的一种制备四甲基吡嗪的方法,其特征在于:将硫酸铵替换为碳酸氢铵。
4.根据权利要求1所述的一种制备四甲基吡嗪的方法,其特征在于:将过硫酸铵替换为过硫酸钠。
5.根据权利要求1所述的一种制备四甲基吡嗪的方法,其特征在于:将过硫酸铵替换为过硫酸钾。
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