CN101638378B - N-烃基取代-3-哌啶酮的合成方法 - Google Patents
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Abstract
本发明涉及一种N-烃基取代-3-哌啶酮的合成方法。该方法包括溴甲基环丙基酮开环，用适当保护基保护酮羰基，再与N-取代伯胺反应，脱保护，直接制备得到N-烃基取代-3-哌啶酮。该合成方法操作简单、方便(无柱色谱分离，只经过一次重结晶，两次减压蒸馏)，合成步骤少，条件温和，产物收率高(总收率为80％)，纯度好，所得到的高纯度的产品可以保存较长时间，适用于工业化生产。
Description
技术领域
本发明涉及一种N-烃基取代-3-哌啶酮的合成方法，它是带一个氮原子作为唯一杂环原子的N-烃基取代-3-哌啶酮的合成方法。
N-烃基取代-3-哌啶酮是有机合成关键中间体(Synthesis，2007，289-293；WO2006010577)，在有机合成中特别是药物合成(WO 2005070407；WO 2005087751；WO2005079497；US 2005070534；Bioorg.& Med.Chem.2004，12，2115-2137；ibid 2005，13，4667-4678；ibid 2007，15，350-364；ibid 2007，15，6208-6226；ibid 2008，116，8447-8465；Bioorg.& Med.Chem.Lett.2005，15，4780-4785；ibid 2008，18，188-193；J.Med.Chem.，1986，29，740-747；ibid 1988，31，486-491)和天然产物全合成(J.Am.Chem.Soc.2008，130，7568-7569；Tetrahedron Lett.1995，36，2235-2238)中应用广泛。目前，关于N-烃基取代-3-哌啶酮的合成报道很少，比较常用的方法如下式所示(中国医药工业杂志，2004，35，385-388；Hel.Chim.Acta.1954，37，178-184；J.Am.Chem.Soc.1953，75，3727-3730；J.Am.Chem.Soc.1949，71，1680-1682；J.Am.Chem.Soc.1933，55，1233-1241)，R为不同的取代基，虽然该合成方法具有一定的通用性，但由于氮烷基化和Dieckmann缩合环化反应的收率一般较低，从而限制了该合成方法的应用。
另一条合成策略如下(Acta Chem.Scan.B 1976，30，884-888)，该方法合成收率中等，但所用的原料较昂贵。
其它文献报道的N-烃基取代-3-哌啶酮合成方法也仅适用于实验室小规模合成(Eur. J.Med.Chem.1981，16，163-169；Croatica Chem.Acta 1991，64，65-77；Biochem.&Biophysical Res.Commun.1991，179，1368-1376；J.Chem.Soc.Perkin Trans.I1999，2277-2280；J.Org.Chem.2007，72，2674-2677)，不适用于工业化规模制备。
发明内容
本发明的目的旨在提供一种新的N-烃基取代-3-哌啶酮的合成方法，可以克服已有技术的缺陷。以廉价易得的商品化原料环丙基甲基酮为原料，建立高效、简洁地合成N-烃基取代-3-哌啶酮6的通用方法。该合成方法操作简单、方便(无柱色谱分离，只经过一次重结晶，两次减压蒸馏)，合成步骤少，条件温和，产物收率高(总收率为80％)，纯度好，所得到的高纯度的产品可以保存较长时间，适用于工业化生产。
本发明提供的N-烃基取代-3-哌啶酮的合成方法包括的反应步骤(在下文的陈述中，特定的合成产物是根据结构式中的编号，用***数字表示)：
X＝Cl、Br、I，R1＝CH3、CH3CH2、CH2CH2，R2＝CH3、CH3CH2、C6H5CH2、4-CH3O-C6H4CH2、C6H5、2-CH3O-C6H4、4-CH3O-C6H4.
具体步骤为：
步骤1：化合物2在卤化氢溶液中反应0.5～2小时，反应温度0℃～80℃，优选是20℃～60℃，经过萃取、干燥、浓缩、用有机溶剂重结晶后得到化合物3。所述的卤化氢优选自氯化氢、溴化氢、碘化氢，特别选自溴化氢、氯化氢。所述的有机溶剂为酯类、醚类、醇类化合物，特别选自***。化合物2与卤化氢的摩尔比为1∶3～5。
步骤2：化合物3在惰性有机溶剂中与醇或酯在酸或路易斯酸催化剂的作用下反应15～30小时，反应温度50℃～110℃，优选70℃～100℃，经过萃取、干燥、浓缩后得到化合物4。所述的惰性有机溶剂选自苯、甲苯。所述的醇可以为甲醇、乙醇、乙二醇，特别选自乙二醇。所述的酯可以为原甲酸三甲酯、原乙酸三甲酯、原甲酸三乙酯、原乙酸三乙酯，特别选自原甲酸三甲酯。所述的酸为硫酸、盐酸、对甲苯磺酸、甲磺酸、三氟甲磺酸或者三氟化硼、三氟甲磺酸三甲基硅酯，特别选自对甲苯磺酸。化合物3、醇或酯与催化剂的摩尔比为1∶5～7∶0.05～0.2。
步骤3：化合物4在惰性有机溶剂或者无溶剂状态下与伯胺在碱存在下反应0.5～2 小时，反应温度50℃～110℃，优选70℃～100℃，经过过滤、浓缩、减压蒸馏得到化合物5。所述的有机溶剂可以为C2～C4的脂肪醚类或脂环醚，特别选自***或四氢呋喃。卤代烃类选自C1～C4的卤代烃，特别选自二氯甲烷或三氯甲烷。特别地该反应可以选自无溶剂状态条件下反应。所述的碱可以为胺类或者无机碱，特别选自苄胺，三乙胺或碳酸钾。所述的伯胺可以为芳基伯胺、苄胺、烷基伯胺。特别选自CH3NH2、CH3CH2NH2、C6H5CH2NH2、4-CH3O-C6H4CH2NH2、C6H5NH2、2-CH3O-C6H4NH2、4-CH3O-C6H4NH2.化合物4、伯胺与碱的摩尔比为1∶3～6∶3～5。
步骤4：化合物5在无机酸的水溶液中反应10～20小时，反应温度70℃～140℃，优选90℃～120℃，经过中和、萃取、干燥、浓缩、减压蒸馏得到化合物6。所述的酸可以为硫酸、盐酸、稀硝酸。特别选自盐酸。化合物5与无机酸摩尔比为1∶10～15。
本发明以廉价易得的化合物2(合成方法见文献Tetrahedron，1987，43，4609-4619)为原料，简洁(总共4步)、高效(总收率为80.5％)、方便(无柱色谱分离，只经过一次重结晶，二次减压蒸馏)合成得到N-烃基取代-3-哌啶酮6。合成步骤少，条件温和，产物收率高(总收率为80％)，纯度好，所得到的高纯度的产品可以保存较长时间，适用于工业化生产。
具体实施方式
以下再结合实施例对本发明作进一步说明。但不应将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例11，5-二溴-2-戊酮7的合成
在1L烧瓶中加入110克化合物2和40％氢溴酸(340mL)，50℃，0.5小时，***萃取，饱和食盐水洗一次，无水硫酸镁干燥，旋干溶剂得159克白色固体7，收率97％，自***中重结晶得到白色针状晶体，熔点29～30℃.1H NMR(400MHz，CDCl3)δ2.15-2.21(2H，m)，2.88(2H，t，J＝6.8Hz)，3.46(2H，t，J＝6.4Hz)，3.9(2H，5)ppm.
实施例21，5-二溴-2-乙二醇缩戊酮8的合成
在2L烧瓶中加入83克化合物7和132克乙二醇，5.9克对甲苯磺酸，苯(1100mL)，回流分水20小时。蒸去苯，用***萃取，饱和食盐水洗一次，无水硫酸镁干燥，旋干溶剂得无色液体95克，收率97％.1H NMR(400MHz，CDCl3)δ1.96-2.02(4H，m)，3.37(2H，s)，3.43(2H，t，J＝6.0Hz)，3.98-4.09(4H，m)ppm.
实施例3N-苄基-3-乙二醇缩哌啶酮9的合成
在500mL烧瓶中加入98克化合物8和187克苄胺，80℃加热1小时。***稀释。过滤后，固体为苄胺的氢溴酸盐，加以回收。滤液先常压蒸出溶剂，再水泵减压蒸除苄胺，然后油泵减压，5～6Pa时收集120℃馏分。得无色液体74克，收率94％.1H NMR(400MHz，CDCl3)δ1.60(2H，t，J＝6.8Hz)，1.70-1.76(2H，m)，2.37(2H，s)，2.40(2H，t，J＝5.2Hz)，3.60(2H，s)，3.87-3.97(4H，m)，7.31(5H，br)ppm.
实施例4N-苄基-3-哌啶酮10的合成
在2L烧瓶中加入42克化合物9和1M盐酸(1500mL)，回流15小时。冷至室温后用碳酸氢钠调至碱性，乙酸乙酯萃取，饱和食盐水洗一次，无水硫酸钠干燥，旋干溶剂得浅黄色液体，-20℃左右时变成固体。减压蒸馏，60Pa时收集110℃的馏分得产物31克，收率91％.1H NMR(400MHz，CDCl3)δ1.91-1.97(2H，m)，2.36(2H，t，J＝6.8Hz)，2.64(2H，t，J＝5.6Hz)，3.00(2H，s)，3.58(2H，s)，7.31(5H，br)ppm.
Claims (8)
1.一种N-烃基取代-3-哌啶酮的合成方法，其特征在于它包括的步骤：
X＝Cl、Br、I，R1＝CH3、CH3CH2，或2R1共同形成CH2CH2；R2＝CH3、CH3CH2、C6H5CH2、4-CH3O-C6H4CH2、C6H5、2-CH3O-C6H4、4-CH3O-C6H4；
具体步骤为：
1)化合物2在卤化氢溶液中反应0.5～2小时，反应温度0℃～80℃，经过萃取、干燥、浓缩、用有机溶剂重结晶后得到化合物3；所述的卤化氢选自氯化氢、溴化氢或碘化氢；
2)化合物3在惰性有机溶剂中与醇或酯在酸催化剂的作用下反应15～30小时，反应温度50℃～110℃，经过萃取、干燥、浓缩后得到化合物4；
所述的醇为甲醇、乙醇或乙二醇；
所述的酯为原甲酸三甲酯、原乙酸三甲酯、原甲酸三乙酯或原乙酸三乙酯；
所述的酸为硫酸、盐酸、对甲苯磺酸、甲磺酸或三氟甲磺酸，或者路易斯酸：三氟化硼或三氟甲磺酸三甲基硅酯；
3)化合物4在惰性有机溶剂或者无溶剂状态下与伯胺在碱存在下反应0.5～2小时，反应温度50℃～110℃，经过过滤、浓缩、减压蒸馏得到化合物5；
所述的伯胺选自CH3NH2、CH3CH2NH2、C6H5CH2NH2、4-CH3O-C6H4CH2NH2、C6H5NH2、2-CH3O-C6H4NH2或4-CH3O-C6H4NH2；
4)化合物5在无机酸的水溶液中反应10～20小时，反应温度70℃～140℃，经过中和、萃取、干燥、浓缩、减压蒸馏得到化合物6。
2.根据权利要求1所述的合成方法，其特征在于步骤1)所述的有机溶剂为***；化合物2与卤化氢的摩尔比为1∶3～5。
3.根据权利要求1所述的合成方法，其特征在于所述的卤化氢是溴化氢。
4.根据权利要求1所述的合成方法，其特征在于步骤2)所述的有机溶剂选自苯、甲苯；化合物3、醇或酯与催化剂的摩尔比为1∶5～7∶0.05～0.2。
5.根据权利要求1所述的合成方法，其特征在于步骤2)所述的醇为乙二醇。
6.根据权利要求1所述的合成方法，其特征在于步骤3)所述的有机溶剂为***或四氢呋喃，二氯甲烷或三氯甲烷；所述的碱选自苄胺，三乙胺或碳酸钾；化合物4、伯胺和碱的摩尔比为1∶3～6∶3～5。
7.根据权利要求1所述的合成方法，其特征在于所述的伯胺为苄胺。
8.根据权利要求1所述的合成方法，其特征在于步骤4)所述的酸为硫酸或盐酸；化合物5与无机酸摩尔比为1∶10～15。
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