CN1309632A - 新型n-叔丁基羟胺盐 - Google Patents
新型n-叔丁基羟胺盐 Download PDFInfo
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- IYSYLWYGCWTJSG-UHFFFAOYSA-N n-tert-butyl-1-phenylmethanimine oxide Chemical compound CC(C)(C)[N+]([O-])=CC1=CC=CC=C1 IYSYLWYGCWTJSG-UHFFFAOYSA-N 0.000 description 3
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/10—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of unsubstituted hydrocarbon radicals or of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了新的N-叔丁基羟胺与低级羧酸的盐及其制备方法。该盐具有使之在合成中有用的有利性质。
Description
发明领域
本发明涉及N-叔丁基羟胺的新的盐类及其制备方法。该盐在有机合成中用作中间体。
发明背景
N-烷基羟胺类,包括N-叔丁基羟胺是有机合成中重要的中间体,特别是在制备硝酮类、异羟肟酸和C-亚硝基化合物中(D.H.R.Barton中的J.S.Roberts和W.D.Ollis,综合有机化学(ComprehensiveOrganic Chemistry),第2卷,196-201页,Pergamon Press,1979)。
合成N-烷基羟胺类的方法是本领域已知的(D.H.R.Barton中的J.S.Roberts和W.D.Ollis,综合有机化学(Comprehensive OrganieChemistry),第2卷,185-194页,Pergamon Press,1979)。合成这类化合物最普遍的方法涉及比羟胺本身具有更高氧化态的相应含氮化合物的还原反应。因此,硝基、亚硝基和肟衍生物的还原均被使用。
W.D.Emmons(J.Amer.Chem.Soe.,1957,79,5739-5754)描述了通过相应亚胺衍生物与过乙酸的氧化反应制备各种氧杂氮丙啶类。这些氧杂氮丙啶类与含水酸的进一步水解提供了有用的制备N-烷基羟胺类的替代途径。
在一相关方法中,诸如N-叔丁基羟胺的N-烷基羟胺类可通过亚氨醚与过酸的氧化反应以及随后所得的烷氧基氧杂氮丙啶的水解而制备(D.Thomas和D.H.Aue,四面体通迅Tetrahedron Letters,1973,1807-1810)。
羟胺是碱性化合物,并与无机酸,例如氢氯酸和氢溴酸形成盐。与强有机酸,例如草酸和三氟甲磺酸形成的盐也是已知的。
作为游离碱,通常N-烷基羟胺类不特别稳定,例如易于发生大气氧化。为此,制备这类化合物通常更稳定的酸加成盐是有利的。这些盐作为贮存N-烷基羟胺类的手段是特别有利的。
Bayer(DE 35 35 451;EP 0 217 269)描述了一种通过某些芳基醛亚胺与过丙酸反应然后水解形成的氧杂氮丙啶来制备N-烷基取代的羟胺盐酸盐的方法。这种盐酸盐被认为是特别有利的。因此,一般认为除了盐酸盐之外的盐类,例如相应的硫酸盐或硫酸氢盐常常结晶较差或根本不结晶,这是使其制备、分离和处理非常复杂的因素。
已经令人惊讶地发现N-叔丁基羟胺与例如乙酸的低级羧酸形成稳定的盐。这种盐显示了有利的性质,且是本发明的主题。
发明内容
根据本发明提供了式(Ⅰ)所示的盐
(CH3)3CNHOH.RCO2H (Ⅰ)
其中:
R代表氢或C1-4烷基。
特别优选R代表甲基,使式(Ⅰ)化合物成为N-叔丁基乙酸羟胺。
除非另行说明,此处术语“C1-4烷基”指含有1-4个碳原子的直链或支链烷基。这种基团的例子包括甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。
根据本发明还提供了一种制备式(Ⅰ)所示的盐的方法,包括N-叔丁基羟胺(CH3)3CNHOH与低级羧酸RCO2H反应,其中R如上定义。
在本发明的一个方面,或通过从诸如盐酸化物的盐中释放游离碱形成,或直接通过合成形成N-叔丁基羟胺在合适的溶剂,如乙酸乙酯、乙酸异丙酯、乙酸正丁酯、二异丙醚或甲基叔丁基醚中的溶液,该溶液于合适的温度下,用适量的诸如乙酸的低级羧酸处理。
在一优选方面,将乙酸乙酯和乙酸钠加入到N-叔丁基羟胺盐酸盐的水溶液中。
在另一优选方面,将乙酸乙酯、乙酸和氢氧化钠加入到N-叔丁基羟胺盐酸盐的水溶液中。
在其它方面,乙酸N-叔丁基羟铵在原位产生,并可通过有机(乙酸乙酯)层的分离,然后蒸发而进行分离。
特别令人惊讶和有利地是,新型盐乙酸N-叔丁基羟铵可从水相中分配到有机相中。
式(Ⅰ)所示的新型盐可以,如果需要的话,用本领域已知的技术纯化。因此,它们可从合适的溶剂,如甲苯或乙酸乙酯,或从合适的溶剂混合物中重结晶。
但是,最令人惊讶和有利地是,新型盐乙酸N-叔丁基羟铵还可在减压下蒸馏而纯化。
N-叔丁基羟胺(CH3)3CNHOH在文献中是已知的,并可通过本身已知的方法制备。
因此,N-叔丁基羟胺可通过2-甲基-2-硝基丙烷(CH3)3CNO2与例如锌或铝汞合金的还原来制备(J.March,高等有机化学AdvancedOrganic Chemistry,1985(第3版),1103-1104页;有机合成OrganicSyntheses,52卷,77-82)。对于工艺规模,这种方法的缺点在于所需的原料2-甲基-2-硝基丙烷本身制备昂贵,且特别是还原方法需要仔细控制因为其潜在的剧烈放热性质。
N-叔丁基羟胺还可通过Emmons(参见下文)在方案1中概括描述的常用方法适宜地制备,其中R1可代表氢,但也可代表一种或多种其它的合适基团。根据该方案,N-叔丁基胺(2)与苯甲醛(3)反应得到亚胺(4),亚胺再被过酸氧化得到氧杂氮丙啶(5)。然后该氧杂氮丙啶(5)可直接用含水酸水解或可首先重排为硝酮(6),然后硝酮本身被水解。在任一种情况下,水解产生了作为盐的N-叔丁基羟胺(7)和可容易地分离的苯甲醛(3)的混合物。该方法的优点是原料(2)和(3)都相对便宜。此外,苯甲醛(3)在最终水解期间再生,并可便利地分离和循环。另外,如果诸如间氯过苯甲酸的过酸用于亚胺的氧化反应,从中产生的间氯苯甲酸也可被回收然后再氧化。
方案1
通常式(1)所示的新的盐为结晶化合物,其与相应的游离碱N-叔丁基羟胺不同,在贮存期间显示了良好的稳定性,特别是对于大气氧化。
如果需要的话,N-叔丁基羟胺可简单地通过用碱处理从式(Ⅰ)所示的盐中释放出来。
当与氯化N-叔丁基羟铵相比时,式(Ⅰ)所示的新的盐的特别优点在于其拥有令人惊讶的对于热的更大稳定性。因此,采用示差扫描量热法对氯化N-叔丁基羟铵的调查显示该盐在起始温度为+136℃时,进行了剧烈的放热过程(ΔH=-1312J/g)。相反,在相同条件下处理时,乙酸N-叔丁基羟铵没有显著的放热过程。
此外,氯化N-叔丁基羟铵是相当吸湿的,易于从环境中吸水。这种缺点对于乙酸N-叔丁基羟铵不是明显的。
通过下列非限制性实施例阐述本发明。
在Bruker仪器上记录NMR谱,在200MHz记录1H谱,50MHz记录13C谱。在四甲基硅烷(TMS)的低场中以ppm给出化学位移数据。
实施例1
乙酸N-叔丁基羟铵
N-叔丁基羟胺盐酸盐(56g,0.43mol,97%)溶解在水(226g)中,并在氩气下装入1L三颈玻璃瓶。加入乙酸乙酯(246g)和碳酸钾(79g,0.57mol,1.3当量),混合物在+20℃剧烈搅拌1h。两相虹吸至分液漏斗中。分出水相,并用乙酸乙酯(100ml)萃取多次。合并有机相并加入乙酸(28.1g,0.47mol,1.09当量)。蒸除溶剂,得到的澄清的黄绿色油状物用另外的乙酸乙酯(203g)处理,并再次浓缩。将该瓶放在冰箱中,2h后,产物变为晶体。该物质易于粉碎得到淡黄色粉末(63.4g,90%)。该物质用甲苯或乙酸乙酯作为溶剂进行重结晶。
示差扫描量热法显示吸热熔点为+67.7℃。
粉末X-射线衍射分析显示高结晶度。1H NMR(d3-乙腈)δ8.33(s,2H),1.92(s,3H)和1.21(s,9H).13C NMR(d3-乙腈)δ177.5,57.0,23.1和21.3.
实施例2
乙酸N-叔丁基羟铵
在+20℃,将N-叔丁基羟胺盐酸盐(19.7g,98%,0.15mol)溶解在水(40g)中。加入乙酸乙酯(118g)和乙酸钠(19.3g,0.24mol,1.5当量)。最初形成浆液,但随后溶解。2h后,分离蓝橙色相,浓缩得到不透明的黄色油(20.6g,88%),其在冰箱中固化。
色谱纯度(GC):97.0面积%。
实施例3
a)N-亚苄基-叔丁基胺
将甲苯(330g)、苯甲醛(66.0g,0.62mol)和叔丁基胺(50.0g,0.68mol,1.1当量)加入到1L连接Dean-Stark分水器的反应瓶中。该瓶在保持130℃的PEG 400油浴中加热。回流7h后,GC结果指出得到了99.7%转化率。冷却反应混合物并直接用于后续步骤。
在分离实验中,通过蒸发分离产物,其性质如下:
色谱纯度(GC):0.2面积%苯甲醛;99.8面积%N-亚苄基-叔丁基胺。1HNMR(CDCl3)δ1.29(s,9H),7.37(m,3H),7.73(s,2H)和8.26(s,1H).13C NMR(CDCl3)δ29.6,57.1,127.8,128.4,130.0,137.1和155.0.MSm/z 146(M+-15,100%),161(M+,6%).
b)2-叔丁基-3-苯基氧杂氮丙啶
将碳酸钠(65.6g,0.62mol,1当量)溶解在水(400g)中,并冷却到+20℃。间氯过苯甲酸(149.8g,75%,0.65mol,1.05当量)溶解在甲苯(300g)和乙醇(150g)中,并缓慢加热到+20℃。然后将碳酸钠水溶液加入到在2L反应瓶中的上述(a)制备的N-亚苄基-叔丁基胺的甲苯溶液中,该反应瓶浸在冷水浴中(温度<+10℃)。然后间氯过苯甲酸溶液于+20℃经30分钟慢慢加入。GC分析显示在完成加入间氯过苯甲酸溶液之后30分钟,得到了完全的转化。然后排出水相,通过玻璃滤器过滤有机相,并直接送到下列反应步骤。
在分离实验中,分离产物,其性质如下:
色谱纯度(GC):1.9面积%苯甲醛;98.1面积%2-叔丁基-3-苯基氧杂氮丙啶。1H NMR(CDCl3)δ1.17(s,9H),4.68(s,1H)和7.33-7.46(m,5H).13C NMR(CDCl3)δ25.2,58.3,73.5,127.4,128.3,129.6,133.2和135.5.MSm/z 57(100%),177(M+,1%).
c)N-叔丁基苯基硝酮
约600ml步骤(b)的反应混合物放在1L装有Dean-Stark分水器的反应瓶中,并在PEG 400油浴(+130℃)中加热过夜(13h)。根据GC结果,没有残留氧杂氮丙啶。暗褐色溶液用冷水浴(温度<+10℃)冷却到+20℃,然后经K200滤纸过滤。滤液在旋转蒸发器(+50℃)蒸发,余下暗红-棕色油(93.9g),该油几乎立即结晶。1H NMR(CDCl3)δ1.61(s,9H),7.38-7.55(m,3H),7.55(s,1H)和8.27-8.32(m,2H).13C NMR(CDCl3)δ28.2,70.6,128.2,128.6,129.9和130.9.MSm/z 57(100%),177(M+,19%).
d)乙酸N-叔丁基羟铵
在500ml瓶中,将N-叔丁基苯基硝酮(44.8g,0.25mol)溶解在甲苯(134g)中。硫酸(27.5g,95-97%,0.27mol,1.1当量)在水(134g)中稀释,并加入到反应瓶中。然后将两相混合物加热到+50℃,剧烈搅拌约2h。此时,GC指出仅剩下0.2面积%的N-叔丁基苯基硝酮。冷却至+20℃后,排出暗红色有机相,并用甲苯(46g)萃取澄清的黄色水相。然后向剩余的水相中加入乙酸(14.8g,0.25mol,1.0当量),再加入氢氧化钠(45%水溶液)直至水相的pH约为5.5。然后加入乙酸乙酯(224g),剧烈搅拌混合物。然后分离有机相,用乙酸乙酯多次萃取含水相。然后蒸发合并的有机部分以剩下油(35.2g)。该物质在减压下蒸馏纯化。在19毫巴/+78℃得到稳定的蒸馏点。低于+70℃回收的馏份1含有2.7g,在+70℃与+80℃之间收集的馏份2含有高粘度的油(28.7g,76%),其放置后以白色固体结晶。
PKa 6.4
色谱纯度(GC):99.4面积%1H NMR(d4-甲醇)δ1.27(s,9H),1.95(s,3H)和5.51(s,NO-H).13CNMR(d4-甲醇)δ22.9,24.1,59.0和180.2.
实施例4
乙酸N-叔丁基羟铵
将2-叔丁基-3-苯基氧杂氮丙啶(30.3g,98.2面积%,0.17mol)溶解在乙醇(90g)中。硫酸(25.7g,95-97%,0.25mol,1.5当量)在水(90g)中稀释,并加入到500ml反应瓶中。反应混合物在+20℃搅拌20h,此时GC显示剩下5.8面积%氧杂氮丙啶。使反应搅拌过周末得到完全转化。蒸发溶剂,且浓缩物在水(90g)和乙酸乙酯(90g)中分配。排出有机相,加入新鲜的乙酸乙酯(150g)和乙酸(10.8g,0.18mol,1.1当量),再加入氢氧化钠(45%水溶液)直至水相的pH值约为5.5。然后分离有机相,经K200滤纸过滤,浓缩后得到油(17.3g)。该物质在20毫巴下蒸馏,收集+72℃之上的馏份,得到立即结晶的澄清的油(11.5g,45%)。
色谱纯度(GC):99.5面积%。
Claims (8)
1.式(Ⅰ)所示的盐
(CH3)3CNHOH.RCO2H (Ⅰ)
其中R代表氢或C1-4烷基。
2.根据权利要求1的盐,该盐是乙酸N-叔丁基羟铵。
3.一种制备根据权利要求1的盐的方法,该方法包括N-叔丁基羟胺(CH3)3CNHOH与低级羧酸RCO2H反应,其中R如权利要求1所定义。
4.一种制备乙酸N-叔丁基羟铵的方法,包括N-叔丁基羟胺(CH3)3CNHOH在合适的溶剂中的溶液与乙酸反应。
5.一种制备乙酸N-叔丁基羟铵的方法,包括在乙酸乙酯存在下,用乙酸钠处理氯化N-叔丁基羟铵在水中的溶液。
6.一种制备乙酸N-叔丁基羟铵的方法,包括在乙酸乙酯存在下,用乙酸和氢氧化钠处理氯化N-叔丁基羟铵在水中的溶液。
7.一种分离根据权利要求5或6制备的乙酸N-叔丁基羟铵的方法,该方法包括分离乙酸乙酯层,然后通过蒸发除去乙酸乙酯。
8.一种纯化乙酸N-叔丁基羟铵的方法,该方法包括在减压下进行蒸馏。
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