CN105111136B - 一种制备3‑甲基‑1‑苯乙基哌啶‑4‑酮或1‑苯乙基哌啶‑4‑酮的方法 - Google Patents
一种制备3‑甲基‑1‑苯乙基哌啶‑4‑酮或1‑苯乙基哌啶‑4‑酮的方法 Download PDFInfo
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- 150000002576 ketones Chemical class 0.000 title abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title abstract description 6
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 title abstract 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000012279 sodium borohydride Chemical group 0.000 claims abstract description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 23
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发公开了一种制备3‑甲基‑1‑苯乙基哌啶‑4‑酮或1‑苯乙基哌啶‑4‑酮的方法。从易得的3‑取代吡啶‑4‑醇出发,与苯乙基‑2‑卤代物成季胺盐后,硼氢化钠选择性还原成烯基醇,再异构化后得到3‑取代‑1‑苯乙基哌啶‑4‑酮。该合成方法简便实用，可操作性强，有利于进一步放大生产。
Description
技术领域
本发明涉及一种制备3-甲基-1-苯乙基哌啶-4-酮或1-苯乙基哌啶-4-酮的方法，属于医药中间体合成领域。
背景技术
在医学研究领域中，麻醉剂和镇痛类药物的研究一直都是研究的热点。羟甲芬太尼作为一种新型强效镇痛麻醉剂,主要用于反恐和军事科学中。3-甲基-1-苯乙基哌啶-4-酮作为合成该药物关键中间体，目前已有的研究并不多。
文献的合成方法主要包括:苯乙胺先与丙烯酸甲酯反生1,4-加成反应，随后在碱存在下反生Dieckmann缩合关环，最后酯酸解后加热脱酸得到目标产生。参考：Org Prepand Proced Int.2008,40,307；4-哌啶酮盐酸盐与苯乙基溴在Cs2CO3存在下乙腈中回流，粗品经过柱层析纯化后得到。参考：Auspex Pharm.US2010/16365；或者该盐酸盐在三乙胺存在下与苯乙醛进行还原胺化后得到。参考：J ChemRes.2005,452；苯乙基溴与4-哌啶醇反应后，再进行Swern氧化后得到。参考:Heterocycles.1998,48,239；
以上工艺方法尽管都可以得到产物，但由于合成步骤长或是需要柱层析纯化以及超低温下进行的Swern氧化或起始原料不易得，反应条件下副产物去除困难等，进一步限制了上述方法在工业化过程中的实际应用。
发明内容
为了克服上述缺陷，本发明从易得的3-取代吡啶-4-醇出发,与苯乙基-2-卤代物成季胺盐后,硼氢化钠选择性还原成烯基醇,再异构化后得到3-取代-1-苯乙基哌啶-4-酮。
一种制备3-甲基-1-苯乙基哌啶-4-酮或1-苯乙基哌啶-4-酮的方法，包括以下步骤：
步骤一、
式Ⅰ化合物与式Ⅱ化合物无溶剂或溶剂中反应得到式Ⅲ化合物；
式Ⅰ化合物与式Ⅱ化合物的摩尔比为1：(1-2.5)；
所述溶剂选自甲基叔丁基醚、乙腈、二氯甲烷、丙酮、1,2-二氯乙烷中的一种；
所述式Ⅰ化合物中R选自H或CH3；所述式Ⅱ化合物中X选自Br、I或OMs；式Ⅱ化合物中R与式Ⅰ化合物中R相同；
反应在20℃～90℃条件下进行；
步骤二、
将步骤一得到的式Ⅲ化合物与NaBH4反应得到3-甲基-1-苯乙基哌啶-4-酮或1-苯乙基哌啶-4-酮(式Ⅳ)；
式Ⅲ化合物与NaBH4的摩尔比为1：(1-5.0)；
本步反应溶剂选自甲醇、乙醇、异丙醇中的一种；
反应温度为-10℃～20℃。
产品纯化采用还原后产物粗品与2,4,6-三硝基苯酚、D-或L-酒石酸或盐酸成盐后乙醇中重结晶，随后在1M氢氧化钠或氢氧化钾条件下游离的方式进行。
发明有益效果
本发明利用了吡啶季胺盐可以在醇溶剂中，选择性还原的特点，将原料吡啶-4-醇还原成烯醇，而烯醇又很容易互变成酮，从而简单方便的得到了目标产物。所采用的起始原料3-取代吡啶-4-醇廉价易得，整个工艺过程操作简单，实用性强，有利于进一步放大生产。
具体实施方式
实施例1
氮-1-苯乙基-3-甲基吡啶-4-醇季胺碘(Ⅲ,R＝CH3)合成：
氮气保护下，在带有机械搅拌的250mL三口瓶内依次加入3-甲基吡啶-4-醇(10.9g，0.1mol)、2-碘乙基苯(25.7g，0.11mol)和二氯甲烷150mL，加入完毕后，室温搅拌过夜，TLC检测反应完毕，次日过滤得到浅黄色固体，该固体用20mL二氯甲烷洗涤，干燥后得到氮-1-苯乙基-3-甲基吡啶-4-醇季胺碘28.3g，收率83％，可以直接用于下步反应。
3-甲基-1-苯乙基哌啶-4-酮(Ⅳ，R＝CH3)合成：
氮气保护下,将上述第一步得到季胺碘盐加入500mL三口瓶内,接着再加入无水乙醇200mL，冷却至0℃搅拌10分钟。开始分3-5批加入NaBH4固体(6.2g,0.166mol)，加入过程中有明显气泡产生，应待前面加入NaBH4后气泡基本消失后，再接着加入下一批次。整个加入完毕后，撤掉冷浴，升温至10～20℃反应3-5小时，TLC检测反应完毕。将溶剂减压蒸馏，加入水和乙酸乙酯分层萃取，有机层加入折算量的2，4，6-三硝基苯酚后，浓缩至干得到固体，乙醇重结晶。过滤得到的固体加入二氯甲烷和1M氢氧化钠水溶液，萃取干燥，旋蒸后得到14.2g产品3-甲基-1-苯乙基哌啶-4-酮,收率78.9％。
反应式如下：
实施例2
氮-1-苯乙基-3-甲基吡啶-4-醇季胺溴(Ⅲ,R＝CH3)合成：
氮气保护下，在带有机械搅拌的250mL三口瓶内依次加入3-甲基吡啶-4-醇(10.9g，0.1mol)、2-溴乙基苯(27.8g，0.15mol)和乙腈180mL。加入完毕后，升温至90℃搅拌过夜，TLC检测反应完毕，旋干溶剂后，加入MTBE过滤得到类白色固体，该固体用40mL MTBE洗涤，干燥后得到氮-1-苯乙基-3-甲基吡啶-4-醇季胺溴26.5g，收率90％，可以直接用于下步反应。
3-甲基-1-苯乙基哌啶-4-酮(Ⅳ，R＝CH3)合成：
氮气保护下,将上述第一步得到季胺溴盐加入500mL三口瓶内,接着再加入无水甲醇250mL，冷却至0℃搅拌10分钟。开始分5-7批加入NaBH4固体(10.2g,0.27mol)，加入过程中有明显气泡产生，应待前面加入NaBH4后气泡基本消失后，再接着加入下一批次。整个加入完毕后，撤掉冷浴，升温至10～20℃反应3-5小时，TLC检测反应完毕。将溶剂减压蒸馏后，加入水和乙酸乙酯分层萃取，有机层加入折算量的L-酒石酸后，浓缩至干得到固体，乙醇重结晶。过滤得到的固体加入二氯甲烷和1M氢氧化钾水溶液，萃取干燥，旋蒸后得到12.1g产品3-甲基-1-苯乙基哌啶-4-酮,收率62.1％。
反应式如下：
实施例3
氮-1-苯乙基吡啶-4-醇季胺甲磺酸盐(Ⅲ,R＝H)合成：
氮气保护下，在带有机械搅拌的250mL三口瓶内依次加入吡啶-4-醇(9.5g，0.1mol)、甲磺酸苯乙酯(40.0g，0.2mol)和二氯乙烷200mL。加入完毕后，升温至90℃搅拌过夜。TLC检测反应完毕，过滤得到黄色固体，该固体用50毫升冷却的二氯乙烷洗涤，干燥后得到氮-1-苯乙基吡啶-4-醇季胺甲磺酸盐17.5g，收率77％，可以直接用于下步反应。
1-苯乙基哌啶-4-酮(Ⅳ，R＝H)合成：
氮气保护下,将上述第一步得到季胺甲磺酸盐加入500mL三口瓶内,接着再加入无水乙醇280mL，冷却至0℃搅拌10分钟。开始分3-5批加入NaBH4固体(6.4g,0.169mol)，加入过程中有明显气泡产生，应待前面加入NaBH4后气泡基本消失后，再接着加入下一批次。整个加入完毕后，撤掉冷浴，升温至10～20℃反应3-5小时，TLC检测反应完毕。将溶剂减压蒸馏后，加入水和乙酸乙酯分层萃取，有机层加入折算量浓盐酸后，浓缩至干得到固体，乙醇重结晶。过滤得到的固体加入二氯甲烷和1M氢氧化钠水溶液，萃取干燥，旋蒸后得到10.4g产品1-苯乙基哌啶-4-酮,收率66.2％。
反应式如下：
Claims (3)
1.一种制备3-甲基-1-苯乙基哌啶-4-酮或1-苯乙基哌啶-4-酮的方法，其特征在于包括以下步骤：
步骤一、
式I化合物与式II化合物在无溶剂或溶剂中反应得到式III化合物；
式I 式II 式III
式I化合物与式II化合物的摩尔比为1：1-2.5；
本步所述溶剂选自甲基叔丁基醚、乙腈、二氯甲烷、丙酮、1,2-二氯乙烷中的一种；
所述式I化合物中R选自H或CH3；所述式II化合物中X选自Br、I或OMs；式III化合物中R与式I化合物中R相同；
反应在20℃～90℃条件下进行；
步骤二、
将步骤一得到的式III化合物与NaBH4反应得到3-甲基-1-苯乙基哌啶-4-酮或1-苯乙基哌啶-4-酮（式IV）；
式III 式IV
式Ⅲ化合物与NaBH4的摩尔比为1：1-5.0；
本步反应溶剂选自甲醇、乙醇、异丙醇中的一种；
反应温度为-10℃～20℃。
2.根据权利要求1所述制备3-甲基-1-苯乙基哌啶-4-酮或1-苯乙基哌啶-4-酮的方法，其特征在于：产品纯化，向步骤二的得到的产物粗品中加酸形成盐，加入乙醇重结晶，再加入1M氢氧化钠或氢氧化钾游离。
3.根据权利要求2所述制备3-甲基-1-苯乙基哌啶-4-酮或1-苯乙基哌啶-4-酮的方法，其特征在于：所述酸选自2,4,6-三硝基苯酚、D-或L-酒石酸、盐酸中的一种。
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