CN114436931A - 一种n-取代烷基化吡咯衍生物的制备方法及其在卷烟加香中的应用 - Google Patents
一种n-取代烷基化吡咯衍生物的制备方法及其在卷烟加香中的应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B15/00—Chemical features or treatment of tobacco; Tobacco substitutes, e.g. in liquid form
- A24B15/18—Treatment of tobacco products or tobacco substitutes
- A24B15/28—Treatment of tobacco products or tobacco substitutes by chemical substances
- A24B15/30—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances
- A24B15/36—Treatment of tobacco products or tobacco substitutes by chemical substances by organic substances containing a heterocyclic ring
-
- A—HUMAN NECESSITIES
- A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
- A24B—MANUFACTURE OR PREPARATION OF TOBACCO FOR SMOKING OR CHEWING; TOBACCO; SNUFF
- A24B3/00—Preparing tobacco in the factory
- A24B3/12—Steaming, curing, or flavouring tobacco
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明提供一种N‑取代烷基化吡咯衍生物的制备方法及其在卷烟加香中的应用,采用四丁基溴化铵为相转移催化剂,无水碳酸钾为催化剂的作用下,化合物2‑甲基‑3‑乙酰基‑5‑1′2′3′4′‑四羟基丁基吡咯先进行氧化反应,再分别与溴乙烷、正溴丁烷和苄基氯进行N取代烷基化反应,得到的N‑取代烷基化吡咯衍生物应用于卷烟加香,香味不易挥发,高温下能够裂解释放出多种小分子吡咯类挥发性香气成分,使烟气香质、量提高,提高卷烟抽吸品质。
Description
技术领域
本发明属于香烟添加剂技术领域,具体涉及一种N-取代烷基化吡咯衍生物的制备方法及其在卷烟加香中的应用。
背景技术
近年来,随着人们健康意识的不断提升,卷烟消费者对卷烟的安全性关注日益增强,这对烟草行业的发展无疑是一个严峻的考验,低焦油卷烟产品的研发、生产与销售已是我国烟草行业发展的大势所趋。我国卷烟产品95%以上为烤烟型卷烟,其糖碱比较高,所以烟气酸性较为明显,游离烟碱所占比例较少,烟气生理强度较低,烟气较柔和,所以劲头比相同焦油含量的混合型卷烟小,其降焦难度更大。由上可知,对低焦油烤烟型卷烟的香味补偿研究更为迫切,因此被称为核心技术的香精香料技术广泛受到行业的高度重视。近年来,国内的烟用香精香料技术研究虽然有一定的进展,但主要还是以仿制为主,缺乏拥有自主知识产权的产品,与国际先进水平相比,还有较大差距,主要表现在基础性研究比较薄弱,缺乏对香料的系统性研究,不具备稳固的核心竞争力。
吡咯类化合物一直以其突出的香气特征和极低的阈值而被广泛关注和应用。它是一种重要的五元含氮杂环化合物,许多天然或非天然的吡咯衍生物都具有较为显著的生物学活性,被广泛应用于医药、食品、香料、日用化妆品、农药等其他领域。目前在食品挥发性成分中已经发现的吡咯衍生物有50多种,主要包括吡咯和它的烷基、酰基取代物、加氢产物和吲哚类化合物,他们大都具有焦香,坚果香、壤善香韵特性。此香类物质可很好地应用于卷烟调香研究,对卷烟加香应用具有很重要的意义。
虽然吡咯类香料香气特征突出,但是由于其阈值低(用量一般在百万分之一),挥发性强,香味容易散失等缺点,使得吡咯香料化合物在食品加香中的应用受到相应的限制,人们一直试图寻找新型的吡咯类潜香化合物,在高温下能裂解释放小分子吡咯类挥发性香气成分,来代替挥发性的吡咯香料。
关于吡咯及其衍生物其合成方法很多,比较传统同时也比较经典的吡咯合成途径,就是克诺尔(Knorr)合成法与Paal.Knorr合成法,此外还有Hantzsch(汉栖)合成法。就合成途径来看大致可分为缩合法、环转换法、缩环法、和扩环法几类,其中缩合法研究的最为广泛和深入。随着人们对吡咯认识的不断加深,亟需开发更多增香效果更好的吡咯衍生物种类。
发明内容
本发明的目的在于针对现有技术的不足之处,提供一种新型的N-取代烷基化吡咯衍生物及其制备方法,能够作为潜香化合物应用于卷烟中,并且具有较好的加香效果。
为解决上述技术问题,本发明采用如下技术方案:
一种N-取代烷基化吡咯衍生物,具有如下结构:
其中R选自乙基、丁基、苯甲基中的任一种。
本发明的另一目的是提供上述的N-取代烷基化吡咯衍生物的制备方法,包括如下步骤:
(1)碱性条件下,以氨基葡萄糖盐酸盐与乙酰丙酮为原料,在水溶液中加热回流,TLC跟踪检测,待原料点消失时终止反应,冷却结晶,析出的固体用丙酮重结晶得中间产物A;
(2)将中间产物A和高碘酸钠溶解于甲醇中,进行搅拌回流反应,TLC跟踪检测,待原料点消失时终止反应,去除未反应的高碘酸钠,旋转蒸发得到中间产物B;
(3)将中间产物B与无水碳酸钾、乙腈、四丁基溴化铵以及烷基化试剂在容器中混合反应,TLC跟踪检测,待原料点消失时终止反应,减压蒸出乙腈,在剩余物中加入水,使碳酸钾溶解,分出有机层,水相用乙酸乙酯萃取,合并有机相,无水Na2SO4干燥过夜;减压蒸去乙酸乙酯,粗产物经柱层析分离纯化,得到最终产物。
优选地,步骤(1)所述碱性条件所述采用的调节剂为碳酸氢钠,所述氨基葡萄糖盐酸盐、乙酰丙酮与碳酸氢钠之间的摩尔比为:1:(1~1.3):(1.3~1.6)。
优选地,步骤(2)中所述中间产物A与高碘酸钠的摩尔比为1:(1.1~1.3),中间产物A在甲醇溶剂中的浓度为0.08~0.12mol/ml。
优选地,步骤(3)中间产物B、无水碳酸钾、四丁基溴化铵、烷基化试剂的摩尔比为1:(2.5~3.5):(0.1~0.3):(2.5~3.5)。
优选地,所述烷基化试剂仍任选自溴乙烷、正溴丁烷、苄基氯中的任一种。
优选地,步骤(3)柱层析洗脱剂为石油醚与乙酸乙酯体积比5:3混合所得的混合液。
本发明的另一目的是提供上述的N-取代烷基化吡咯衍生物或者上述制备方法所得化合物在卷烟加香领域的应用,用作烟丝增香添加剂时的用量为烟丝质量的0.01%~0.03%。
与现有技术相比,本发明的有益效果为:
本申请得到的N-取代烷基化吡咯衍生物应用于卷烟加香,香味不易挥发,高温下能够裂解释放出多种小分子吡咯类挥发性香气成分,使烟气香质、量提高,提高卷烟抽吸品质。
附图说明
附图1是本发明的合成路线图;
附图2是本发明实施例1所得化合物的TG-DTG-DSC热重分析图。
具体实施方式
下面结合实施例对本发明作进一步说明。
实施例1
(1)中间产物A的合成
将D(+)-氨基葡萄糖盐酸盐(431.21mg,2mmol)溶于15mL水中,加入乙酰丙酮(240mg,2.4mmol)和NaHCO3(252mg,3mmol)。回流8h左右,TLC跟踪监测,待原料点消失时终止反应。低温静置约24h后,析出白色,抽滤,滤液用丙酮重结晶得到白色固体2-甲基-3-乙酰基-5-1′2′3′4′-四羟基丁基吡咯(中间产物A)0.418g,收率86%;
中间产物A的1H NMR(D2O,400.1MHz):δ:6.45(s,1H,CH),4.70(s,1H,CH),3.65(m,2H,H-1′,H-4′a),3.58(d,J=2.9Hz,1H,CH),3.47-3.57(dd,J=6.5Hz,1H,CH),2.36(s,3H,CH3),2.32(s,3H,CH3);13CNMR(100.6MHz,D2O):δ:199.9(C=O),137.9(C),130.5(C),119.8(C),108.0(CH=C),73.8(CH),71.2(CH),66.3(CH),62.4(CH2),27.5(CH3),13.1(CH3);HRMS:Calcd for[M+H]+.244.1185,Found:[M+H]+244.1188。
(2)中间产物B的合成
称取高碘酸钠0.385g(1.8mmol),中间产物A(1.5mmol)0.364g,溶于15mml甲醇中,n(高碘酸钠):n(化合物2)=1.2:1,40℃下回流搅拌,反应3h,TLC检测,反应结束后用0.25mol/L的乙醇,除去未反应的NaIO4,旋转蒸发得米黄色固体2-甲基-3-乙酰基-5-醛基吡咯(中间产物B)0.181g,收率80%。
中间产物B的1HNMR(CDCL3,400MHz),δ:2.49(s,3H,CH3),2.68(s,3H,CH3),7.32-7.33(d,J=2.44MHz,1H,=CH),9.46(s,1H,CH),10.80(s,1H,NH);13C NMR(100MHz,CDCL3),δ:14.3(CH3),28.22(CH3),123.5(CH),123.8(C),130.1(C);143.6(C),179.1(C=O),194.4(C=O);HRMS calcd For[M+H]+152.0670,found[M+H]+152.0668。
(3)化合物1N-乙基-2-甲基-3-乙酰基-5-醛基吡咯的合成
以四丁基溴化铵(TBAB)为相转移催化剂,乙腈为溶剂,无水碳酸钾作用下,烷基化试剂溴乙烷与中间产物B反应;在25mL圆底烧瓶中加入1.5mmol 0.226g中间产物B,4.5mmol无水碳酸钾,6ml乙腈,0.1g TATB,及4.5mmol溴乙烷C2H5Br加热反应24h,TLC跟踪反应监测。反应结束后,减压蒸出乙腈,在剩余物中加入约10mL水,使碳酸钾溶解,分出有机层,水相用乙酸乙酯萃取(10mL×4次),合并有机相,无水Na2SO4干燥过夜;减压蒸去乙酸乙酯,粗产物经柱层析分离纯化,粗产物经柱层析分离纯化,洗脱剂[V(石油醚):V(乙酸乙酯)]=5:3得黄绿色固体N-乙基-2-甲基-3-乙酰基-5-醛基吡咯0.202g,收率75.3%。
化合物M.p:113-114℃;1HNMR(CDCL3,400MHz),δ:1.30-1.34(d,J=7.16MHz,3H,CH3),2.45(s,3H,CH3),2.61(s,3H,CH3),4.36-4.42(t,2H,CH2),7.26(s,1H,CH=C),9.49(s,1H,CHO),13C NMR(100MHz,CDCL3),δ:11.0(CH3),15.6(CH3),28.3(CH3),40.2(CH2),122.5(CH=C),129.9(C),143.6(C),178.8(CH=O),194.2(C=O);IR(KBr)v:3104,1658,1347,1279,1248,945cm-1;HRMS calcd For[M+H]+180.0985,found[M+H]+180.0982。
将所得化合物进行TG-DTG-DSC热重分析,结果如图1所示。从TG-DTG曲线可看出,从29.9℃-374.9℃之间有明显的失重过程,其失重台阶开始特征点为176.2℃,失重最快的温度在214.9℃,此间失重率基本达100%。374.9℃-620℃之间TG和DTG曲线基本趋于平稳,此阶段化合物基本分解完全。DSC曲线表示化合物的熔化过程:在112.1℃开始熔化后,在114.3℃出现较强吸热主峰,随后在216.8℃出现吸热峰,与214.9℃物质失重最快基本保持一致。
在相同的GC/MS条件下,对所得化合物1在300、600、900℃下的裂解物进行定性分析,用NIST02和WILEY7标准质谱检索化合物并对裂解物含量进行面积归一化分析,结果如下表1所示。烟支的燃烧是一个复杂的过程,当点燃温度上升至300℃时,烟丝中的挥发性成分开始挥发而形成烟气;升至450℃时,烟丝开始焦化;升至600℃时,烟支被点燃而开始燃烧。抽吸时烟支中心温度最高,大概在825℃~850℃。而卷烟纸燃烧线前方0.2~1.0mm处温度最高可达到910℃,此处也是空气与燃烧区接触最多的地方。燃烧区的气相温度相对较低,抽吸过程中的温度变化在600℃-700℃之间,抽吸结束后,燃烧区的固相温度迅速从900℃冷却至600℃。我们把热裂解实验温度分为了300℃,600℃,900℃三个温度,以此模拟人工抽烟的过程为最佳。
表1化合物1的热裂解行为
由以上裂解数据可知,化合物主要裂解出有25种化合物,其中300℃下主要裂解出14种化学成分,主要有醇类、酮类、吡嗪类等物质,如环丙基甲醇、正丁醇、4-[4-(二甲氨基)苯基]3-丁烯-二酮、2,3,5-三甲基-6-丁基吡嗪等;600℃下主要裂解出15种化合物,有酸类、吡咯和烷基化合物,如4-乙基-2-甲基-1H-吡咯、2,4,5-三甲基-3-乙酰基吡咯、二十烷、十八烷和二十四烷等化合物,少量胺类物质含量增加;900℃时,主要裂解出有十六种化合物,其中烯类、醇类和酯类含量增加,如2,4-二甲基-1-庚烯、正丁醇、苯甲酸丁酯和邻苯二甲酸二丁酯等化合物含量呈上升趋势。稠环类化合物减少,如2,3,5-三甲基-6-丁基吡嗪、9-异丙基咔唑等物质在900℃时基本消失。
根据上表裂解成分探讨该类物质的裂解原理,300℃时,部分吡咯环上烷基受热分解发生简单的氧化还原反应,裂解为一些结构简单的醇类和酮类化合物,部分小分子片段之间结合环化生成吡嗪类化合物;600℃时,随着温度进一步的升高结构简单的分子进一步氧化成酸类物质,吡咯环结构基本稳定,少部分分解发生重排和环化,生成稠环类化合物如咔唑、吡嗪类物质等。900℃时,随着温度的升高,裂解更加充分,小分子片段经过不断地重排和反应,胺类和吡咯类化合物含量和种类也不断增加。
实施例2
化合物2N-正丁基-2-甲基-3-乙酰基-5-醛基吡咯的合成
在25mL圆底烧瓶中加入1.5mmol 0.226g实施例1所得中间产物B,4.5mmol无水碳酸钾,6ml乙腈,0.1g TATB(四丁基溴化铵)及正溴丁烷C4H9Br(4.5mmol,0.617g),加热反应24h,TLC跟踪反应监测。其他操作同上,粗产物经柱层析分离纯化,洗脱剂[V(石油醚):V(乙酸乙酯)]=5:3得黄绿色固体0.219g,收率70.6%。
化合物的1HNMR(CDCL3,400MHz),δ:0.92-0.96(t,3H,CH3),1.33-1.39(m,2H,CH2),1.601.69(m,2H,CH2),2.44,(s,3H,CH3),2.59(s,3H,CH3),4.29-4.33(t,2H,CH2),7.25(s,1H,CH),9.47(s,1H,CHO),13C NMR(100MHz,CDCL3),δ:11.4(CH3),13.6(CH3),19.9(CH2),28.3(CH3),32.6(CH2),44.9(CH2),122.4(CH=C),130.2(C),143.8(C),178.8(C=O),194.2(C=O);HRMS calcd For[M+H]+208.1293,found[M+H]+208.1295。
实施例3
化合物3N-苄基-2-甲基-3-乙酰基-5-醛基吡咯的合成
在25mL圆底烧瓶中加入1.5mmol 0.226g实施例1所得中间产物B,4.5mmol无水碳酸钾0.622g,6ml乙腈,0.1gTATB(四丁基溴化铵)及苄基氯(4.5mmol,0.570g),加热反应24h,TLC跟踪反应监测。其他操作同上,粗产物经柱层析分离纯化,洗脱剂[V(石油醚):V(乙酸乙酯)]=5:3得黄绿色固体0.225g,收率62.4%。
化合物的1HNMR(CDCL3,400MHz),δ:2.28(s,3H,CH3),2.39-2.67(d,2H,CH2),3.33(s,1H,CH),7.0(s,1H,Ar-H),7.10(d,2H,Ar-H),7.24(d,2H,Ar-H),9.48(s,1H,CHO);13CNMR(100MHz,CDCL3),δ:15.6(CH3),27.9(CH3),36.2(CH2),38,9(CH),125.8(Ar-H),129.0(d,2H,Ar-H),135.9(C),139.9(C),145.7(C),147.3(C),182.5(CH=O),198.4(C=O);HRMScalcd For[M+H]+241.1184,found[M+H]+241.1190。
加香试验
将化合物1~3按照不同的量均匀添加到单料烟丝中,卷制成烟支,由评吸专家综合评定打分,评吸结果如下表2所示:
表2卷烟加香结果
其中:
对照1样品为实施例1所得中间产物A。
对照2样品为在实施例1所述制备方法的基础上,采用溴代正丙烷替代溴乙烷进行烷基化反应得到的产物。
对照3样品为采用CN1049616691A中记载的方法,制备得到的N-异丙基-2-甲基-5-甲酰基-3-吡咯甲酸乙酯。
本发明的保护范围不限于上述的实施例,显然,本领域的技术人员可以对本发明进行各种改动和变形而不脱离本发明的范围和精神。倘若这些改动和变形属于本发明权利要求及其等同技术的范围,则本发明的意图也包含这些改动和变形在内。
Claims (8)
2.如权利要求1所述的N-取代烷基化吡咯衍生物的制备方法,其特征在于,包括如下步骤:
(1)碱性条件下,以氨基葡萄糖盐酸盐与乙酰丙酮为原料,在水溶液中加热回流,TLC跟踪检测,待原料点消失时终止反应,冷却结晶,析出的固体用丙酮重结晶得中间产物A;
(2)将中间产物A和高碘酸钠溶解于甲醇中,进行搅拌回流反应,TLC跟踪检测,待原料点消失时终止反应,去除未反应的高碘酸钠,旋转蒸发得到中间产物B;
(3)将中间产物B与无水碳酸钾、乙腈、四丁基溴化铵以及烷基化试剂在容器中混合反应,TLC跟踪检测,待原料点消失时终止反应,减压蒸出乙腈,在剩余物中加入水,使碳酸钾溶解,分出有机层,水相用乙酸乙酯萃取,合并有机相,无水Na2SO4干燥过夜;减压蒸去乙酸乙酯,粗产物经柱层析分离纯化,得到最终产物。
3.如权利要求2所述的制备方法,其特征在于,步骤(1)所述碱性条件所述采用的调节剂为碳酸氢钠,所述氨基葡萄糖盐酸盐、乙酰丙酮与碳酸氢钠之间的摩尔比为:1:(1~1.3):(1.3~1.6)。
4.如权利要求2所述的制备方法,其特征在于,步骤(2)中所述中间产物A与高碘酸钠的摩尔比为1:(1.1~1.3),中间产物A在甲醇溶剂中的浓度为0.08~0.12mol/ml。
5.如权利要求2所述的制备方法,其特征在于,步骤(3)中间产物B、无水碳酸钾、四丁基溴化铵、烷基化试剂的摩尔比为1:(2.5~3.5):(0.1~0.3):(2.5~3.5)。
6.如权利要求2所述的制备方法,其特征在于,所述烷基化试剂仍任选自溴乙烷、正溴丁烷、苄基氯中的任一种。
7.如权利要求2所述的制备方法,其特征在于,步骤(3)柱层析洗脱剂为石油醚与乙酸乙酯体积比5:3混合所得的混合液。
8.如权利要求1所述的N-取代烷基化吡咯衍生物或者权利要求2~7任一项制备方法所得化合物在卷烟加香领域的应用,其特征在于,用作烟丝增香添加剂,用量为烟丝质量的0.01%~0.03%。
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