CN107827810B - N-乙氧羰基-4-羟基哌啶的合成方法 - Google Patents
N-乙氧羰基-4-羟基哌啶的合成方法 Download PDFInfo
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- QABJNOSERNVHDY-UHFFFAOYSA-N ethyl 4-hydroxypiperidine-1-carboxylate Chemical compound CCOC(=O)N1CCC(O)CC1 QABJNOSERNVHDY-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims abstract description 28
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims abstract description 16
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 claims abstract description 13
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 235000019270 ammonium chloride Nutrition 0.000 claims abstract description 8
- 238000010992 reflux Methods 0.000 claims abstract description 7
- RTGFRSFVOJMWAO-UHFFFAOYSA-N trimethyl(piperidin-4-yl)silane Chemical compound C[Si](C)(C)C1CCNCC1 RTGFRSFVOJMWAO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 238000007789 sealing Methods 0.000 claims abstract description 4
- 230000003197 catalytic effect Effects 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000010030 laminating Methods 0.000 claims description 2
- HRWMSAPIORJYLQ-UHFFFAOYSA-N trimethyl(piperidin-4-yloxy)silane Chemical compound C[Si](C)(C)OC1CCNCC1 HRWMSAPIORJYLQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000007039 two-step reaction Methods 0.000 claims description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 abstract description 5
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- GJQNVZVOTKFLIU-UHFFFAOYSA-N piperidin-1-ium-4-one;chloride Chemical compound Cl.O=C1CCNCC1 GJQNVZVOTKFLIU-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
Classifications
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- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/36—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 no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
本发明公开了N‑乙氧羰基‑4‑羟基哌啶的合成方法，属于有机化学技术领域。在催化量氯化铵存在下，4‑羟基哌啶加入六甲基二硅胺烷中回流反应得到4‑三甲硅氧基哌啶，接着该中间体与碳酸二乙酯在高温下密封反应得到N‑乙氧羰基‑4‑羟基哌啶。该方法具有原料易得，成本低廉，工厂操作简便，收率高的特点。本发明合成中，避免了剧毒品氯甲酸乙酯的使用，为该化合物的合成提供了一种方法。
Description
技术领域：
本发明属于有机化学中技术领域，具体涉及N-乙氧羰基-4-羟基哌啶的合成方法。
背景技术：
N-乙氧羰基-4-羟基哌啶，英文名称：N-ethoxycarbonyl-4-hydroxy piperidine，CAS:65214-82-6，微黄色澄清液体，是重要的医药中间体，可以用来合成钙离子拮抗剂苯磺酸左旋氨氯地平,作为第三代长效二氢吡啶类钙离子拮抗剂，是新一代钙通道阻滞药和降压药。不仅能有效控制血压，毒副反应低，而且可以改善心脏功能，降低心、脑血管病死率及病残危险。
目前N-乙氧羰基-4-羟基哌啶的合成方法报道较少，第一种为4-羟基哌啶和氯甲酸乙酯反应；第二种为4-哌啶酮盐酸盐与氯甲酸乙酯反应后经还原得到。两种方法均使用到剧毒品氯甲酸乙酯，不适合工业化生产。
综上所述，研究N-乙氧羰基-4-羟基哌啶制备方法，探索其合适的合成路线，完成工业化生产工艺的途径探索，还是有很大的必要。
发明内容：
为克服以上缺点，本发明提供了一种新的途径：在催化剂存在下，4-羟基哌啶加入六甲基二硅胺烷中回流反应得到4-三甲硅氧基哌啶，接着该中间体与碳酸二乙酯在高温下密封反应得到N-乙氧羰基-4-羟基哌啶。
N-乙氧羰基-4-羟基哌啶的合成方法，经过两步反应后得到，其特征在于，反应路线如下：
包括如下步骤：
第一步，4-羟基哌啶加入六甲基二硅胺烷中，升温回流反应，反应结束蒸馏掉多余的六甲基二硅胺烷后得到4-三甲硅氧基哌啶；
第二步，4-三甲硅氧基哌啶与碳酸二乙酯在高温下密封反应得到N-乙氧羰基-4-羟基哌啶。
进一步地，第一步中，加入催化量氯化铵，氯化铵加入量为4-羟基哌啶的当量的1-3mol％。
进一步地，第一步中，六甲基二硅胺烷既作反应溶剂又作反应原料。不添加氯化铵时，反应可以进行，但速度明显减慢，20小时内也可以反应完全。
进一步地，第二步中，4-三甲硅氧基哌啶与碳酸二乙酯当量比为1：2-5。
进一步地，第二步中，反应温度为150～180℃。
本发明的优点是：
1、合成路线新颖，原料易得、操作简便、反应收率高。
2、避免了剧毒品氯甲酸乙酯的使用，易于实现工业化。
具体实施方式
实施例1
1、500mL三口瓶内，氮气保护下，加入六甲基二硅基胺烷242.1g(1.50mol)、4-羟基哌啶50.6g(0.50mol)和氯化铵0.27g(5mmol)，加热回流2小时，TLC中控原料反应完全，降温，减压浓缩出剩余的六甲基二硅基胺烷，0-10℃下向残余物中缓慢加入150mL甲醇，室温搅拌1小时，减压浓缩后得黄色油状物产品86.7g，经GC-MS确认结构正确：m/z 173.12，所得产品不经纯化直接进行下步反应。
2、500mL耐压反应釜内，加入碳酸二乙酯295.3g(2.50mol)上步所得产品86.7g(0.50mol)，封闭体系加热至150℃，保温反应6小时，GC中控原料剩余<1％，反应结束，降温，减压蒸出碳酸二乙酯，乙酸乙酯溶解残余物，滴加1M盐酸调pH至1-2，搅拌0.5小时，分层，水层乙酸乙酯萃取一次，有机层合并减压浓缩溶剂后，减压蒸馏得淡黄色油状物产品N-乙氧羰基-4-羟基哌啶58.7g，两步反应收率67.8％，GC含量98.3％，1H-NMR:(400MHz,CDCl3)3.81-3.87(3H,m),2.99-3.06(2H,m),1.84-1.87(2H,m),1.73(2H,ddd,J＝13.1,4.2,3.8Hz),1.48-1.50(2H,m),1.27(3H,t,J＝7.2Hz).
实施例2
1、500mL三口瓶内，氮气保护下，加入六甲基二硅基胺烷242.1g(1.5mol)、4-羟基哌啶50.6g(0.5mol)和氯化铵0.80g(15mmol)，加热回流2小时，TLC中控原料反应完全，降温，减压浓缩出剩余的六甲基二硅基胺烷，0-10℃下向残余物中缓慢加入150mL甲醇，室温搅拌1小时，减压浓缩后得黄色油状物产品86.2g，所得产品不经纯化直接进行下步反应。
2、500mL耐压反应釜内，加入碳酸二乙酯117.5g(0.99mol)上步所得产品86.2g(0.50mol)，封闭体系加热至180℃，保温反应6小时，GC中控原料剩余<1％，反应结束，降温，减压蒸出碳酸二乙酯，乙酸乙酯溶解残余物，滴加1M盐酸调pH至1-2，搅拌0.5小时，分层，水层乙酸乙酯萃取一次，有机层合并减压浓缩溶剂后，减压蒸馏得淡黄色油状物产品N-乙氧羰基-4-羟基哌啶55.1g，两步反应收率64.1％，GC含量98.5％。
实施例3
1、1L三口瓶内，氮气保护下，加入六甲基二硅基胺烷484.2g(3.0mol)、4-羟基哌啶101.1g(1.0mol)和氯化铵0.53g(0.01mol)，加热回流2小时，TLC中控原料反应完全，降温，减压浓缩出剩余的六甲基二硅基胺烷，0-10℃下向残余物中缓慢加入300mL甲醇，室温搅拌1小时，减压浓缩后得黄色油状物产品173.5g，所得产品不经纯化直接进行下步反应。
2、1L耐压反应釜内，加入碳酸二乙酯354.4g(3.0mol)上步所得产品173.5g(1.0mol)，封闭体系加热至160℃，保温反应6小时，GC中控原料剩余<1％，反应结束，降温，减压蒸出碳酸二乙酯，乙酸乙酯溶解残余物，滴加1M盐酸调pH至1-2，搅拌0.5小时，分层，水层乙酸乙酯萃取一次，有机层合并减压浓缩溶剂后，减压蒸馏得淡黄色油状物产品N-乙氧羰基-4-羟基哌啶112.9g，两步反应收率65.2％，GC含量98.2％。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，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。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (4)
1.N-乙氧羰基-4-羟基哌啶的合成方法，从4-羟基哌啶出发，经过两步反应后得到，其特征在于，反应路线如下：
包括如下步骤：
第一步，4-羟基哌啶与六甲基二硅胺烷回流反应，反应结束蒸馏掉多余的六甲基二硅胺烷后得到4-三甲硅氧基哌啶；所述第一步中，加入催化量氯化铵，氯化铵加入量为4-羟基哌啶的当量的1-3mol％；
第二步，4-三甲硅氧基哌啶与碳酸二乙酯在高温下密封反应，降温减压蒸出过量的碳酸二乙酯，乙酸乙酯溶解残余物，滴加1M盐酸调pH至1-2，分层，水层乙酸乙酯萃取，有机层合并减压浓缩溶剂后，减压蒸馏得到N-乙氧羰基-4-羟基哌啶。
2.根据权利要求1所述N-乙氧羰基-4-羟基哌啶的合成方法，其特征在于：所述第一步中，六甲基二硅胺烷既作反应溶剂又作反应原料。
3.根据权利要求1所述N-乙氧羰基-4-羟基哌啶的合成方法，其特征在于：所述第二步中，4-三甲硅氧基哌啶与碳酸二乙酯当量比为1：2-5。
4.根据权利要求1所述N-乙氧羰基-4-羟基哌啶的合成方法，其特征在于：所述第二步中，反应温度为150～180℃。
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