CN108484484B - Preparation method of 2-oxo-3-ethyl piperidinecarboxylate - Google Patents
Preparation method of 2-oxo-3-ethyl piperidinecarboxylate Download PDFInfo
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- CN108484484B CN108484484B CN201810497214.2A CN201810497214A CN108484484B CN 108484484 B CN108484484 B CN 108484484B CN 201810497214 A CN201810497214 A CN 201810497214A CN 108484484 B CN108484484 B CN 108484484B
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- oxo
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- diethyl malonate
- piperidinecarboxylate
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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
- C07D211/68—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
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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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
- C07D211/02—Preparation by ring-closure or hydrogenation
Abstract
The invention provides a preparation method of 2-oxo-3-ethyl piperidine formate, which comprises the following steps: s1, uniformly mixing diethyl malonate and an alkali catalyst, and dropwise adding acrylonitrile at 10-50 ℃ to react to obtain 2-cyanoethyl diethyl malonate; s2, reacting the diethyl 2-cyanoethylmalonate, an organic solvent and a Raney cobalt catalyst in a hydrogen environment at 75-130 ℃, and recrystallizing to obtain the ethyl 2-oxo-3-piperidinecarboxylate. Compared with the prior art, the invention has the following beneficial effects: the preparation method of the ethyl 2-oxo-3-piperidinecarboxylate provided by the invention has the advantages of easily available raw materials, simple operation and total yield of more than 77% (improved by 20%) compared with the classical N.F.Albertsm method, thereby being very suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of 2-oxo-3-ethyl piperidine formate, belonging to the technical field of chemical intermediates.
Background
The ethyl 2-oxo-3-piperidinecarboxylate is a fine chemical intermediate, and can be used for preparing melatonin as brain health product. As early as 1949, N.F. Albertsm et al published a synthesis of ethyl 2-oxo-3-piperidinecarboxylate in the journal of chemistry of the United states (JACS). The method adopts condensation reaction of diethyl malonate and acrylonitrile to obtain an intermediate diethyl cyanoethylmalonate, and then the intermediate diethyl cyanoethylmalonate is subjected to hydrogenation cyclization in the presence of a catalyst Raney Ni to obtain a product ethyl 2-oxo-3-piperidinecarboxylate, wherein the total yield of the two steps is 57.3%. The reaction route is as follows:
the synthesis of ethyl 2-oxo-3-piperidinecarboxylate proposed by N.F.Albertsm has become the classical method for the synthesis of this compound. Later scholars often refer to the method of N.F. Albertsm directly when publishing articles. Such as those published in 2016 in Green Chemistry, 2016,18, 1313-1318, by Willis et al.
In 2014, bear kokai et al of Hubei Jinsai pharmaceutical Co., Ltd issued patent CN201410712934 for preparing melatonin, wherein 2-oxo-3-piperidinecarboxylic acid ethyl ester was synthesized by N.F. Albertsm method. However, the intermediate is not catalyzed in the patent, and the aqueous solution of the intermediate is directly used for the next reaction, so that no yield is reported.
As described above, ethyl 2-oxo-3-piperidinecarboxylate reported in the literature at home and abroad from 1949 has been used in the classical N.F.Albertsm method, and the synthesis method has the disadvantage of low yield. Therefore, how to improve the yield of the two-step reaction, reduce the cost of raw materials and reduce the pressure of three-waste treatment is a problem which needs to be solved urgently in the technology for producing the 2-oxo-3-ethyl piperidinecarboxylate intermediate.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of 2-oxo-3-ethyl piperidinecarboxylate.
The invention is realized by the following technical scheme:
the invention provides a preparation method of 2-oxo-3-ethyl piperidine formate, which comprises the following steps:
s1, uniformly mixing diethyl malonate and an alkali catalyst, and dropwise adding acrylonitrile at 10-50 ℃ to react to obtain 2-cyanoethyl diethyl malonate;
s2, reacting the diethyl 2-cyanoethylmalonate, an organic solvent and a Raney cobalt catalyst in a hydrogen environment at 75-130 ℃, and recrystallizing to obtain the ethyl 2-oxo-3-piperidinecarboxylate.
Preferably, the reaction temperature in step S1 is 30-35 ℃.
Preferably, the amount of the base catalyst used in step S1 is 0.3 to 3% by weight of diethyl malonate.
Preferably, the alkali catalyst comprises NaOH, KOH, Na2CO3、K2CO3、NaOC2H5、 NaOC(OH3)3、KOC(CH3)3At least one of (1).
Preferably, the weight ratio of the acrylonitrile to the diethyl malonate in the step S1 is 1 (5-10), and preferably 1 (7.5-8.5).
Preferably, the dropping time of the acrylonitrile is 1-10 h, and preferably 3-6 h.
Preferably, the reaction temperature in step S2 is 100 to 105 ℃.
Preferably, the weight ratio of the Raney cobalt catalyst to the diethyl 2-cyanoethylmalonate is (0.03-0.3): 1, preferably (0.1 to 0.15): 1.
preferably, the weight ratio of the organic solvent to the diethyl 2-cyanoethylmalonate is (1-10): 1, the organic solvent is selected from one or more of ethanol, methanol, propanol, butanol and isopropanol.
Preferably, the reaction pressure of the hydrogen is 10-80 kg/cm2Preferably 30 to 40kg/cm2The solvent used for recrystallization is at least one selected from ethanol, isopropanol, butanol, ethyl acetate, butyl acetate, petroleum ether and methyl tert-butyl ether.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method of the ethyl 2-oxo-3-piperidinecarboxylate provided by the invention has the advantages of easily available raw materials, simple operation and total yield of more than 77% (improved by 20%) compared with the classical N.F.Albertsm method, thereby being very suitable for industrial production.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
Example 1
1000mL dry four-neck reaction flask, equipped with mechanical stirring, thermometer, dropping funnel, reflux condenser. 560g (3.5mol) of diethyl malonate and 0.6g (solid powder) of sodium tert-butoxide as a basic catalyst were added, and 70g (1.3mol) of acrylonitrile was added to the dropping funnel. And (3) dropwise adding acrylonitrile into the reaction bottle under stirring, reacting to release heat, and controlling the reaction temperature to be 30-32 ℃ by using a water bath for 4-5 hours. The reaction was stirred at the same temperature for 1 hour.
Transferring the feed liquid into a 1000mL short vacuum column rectification device, removing the raw material diethyl malonate under the vacuum degree of 18-20 mmHg, then increasing the vacuum degree to 0.6-0.8 mmHg, distilling out positive fraction with the distillate temperature of 106-110 ℃ to 227.6g in total, wherein the GC content of the intermediate diethyl 2-cyanoethylmalonate is 98.6%, and the reaction yield is 80.9% (calculated by acrylonitrile).
227.6g of the intermediate, 1000g of isopropanol and 26g of Raney Co catalyst are put into a 2L stainless steel high-pressure reaction kettle. After replacing the air in the autoclave with hydrogen, the pressure of hydrogen was adjusted to 25kg/cm2When the temperature is raised to 75 ℃, the reaction occurs, and cooling water is opened. Controlling the hydrogen input to make the reaction pressure between 30 and 32kg/cm2And (3) stabilizing the reaction, and controlling the temperature of cooling water to react at 95-105 ℃.
After 3.2 hours, hydrogen absorption is stopped, the temperature is cooled to 40 ℃, and the solid Raney Co catalyst is recovered by filtering feed liquid. Transferring the filtrate into a 2000mL reaction bottle, heating to evaporate isopropanol, adding petroleum ether and ethanol 1: 1, recrystallizing 1000mL of the mixture, filtering to obtain a crude product, drying at 60 ℃ in vacuum to obtain 173.5g of a white solid, analyzing by HPLC that the content of the 2-oxo-3-ethyl piperidinecarboxylate is 99.6%, and the yield of the hydrogenation reaction is 95.9%. The total yield of the two-step reaction was 77.5%.
Example 2
Washing and drying a 1000-liter glass lining reaction kettle in N2Under protection, 620kg (3.87kmol) of diethyl malonate and 0.9kg of potassium tert-butoxide solid powder are added. 72kg of acrylonitrile were introduced into the head tank. (1.35kmol) the reactor was started and stirred and acrylonitrile was added dropwise to the reactor over a period of 5 hours at an internal temperature below 35 ℃. After the addition of acrylonitrile, the reaction was carried out at 32 ℃ for 1 hour.
The reaction liquid is transferred from the reaction kettle to a short column rectifying tower of a 1000 liter tower kettle. Starting a vacuum system to enable the vacuum degree to reach 20-25 mmHg, starting a condensation pipe at the top of the tower to cool water for circulation, introducing steam into a reboiler at the bottom of the tower for heating, and performing heat treatment at a reflux ratio of 1: under 1, the solvent diethyl malonate was distilled off. When diethyl malonate is evaporated, starting a multistage Roots vacuum pump of a vacuum system to enable the vacuum degree to reach below 1mmHg, and generating a small amount of distillate with the temperature of 80-120 ℃ at the tower top. When the temperature of the distillate is stabilized at 121 ℃, the material receiving groove is switched to receive 241kg of distillate at 121-125 ℃. GC detects that the content of the intermediate 2-cyanoethyl diethyl malonate is 98.2%. The reaction yield was 82.2% based on acrylonitrile.
241kg of the intermediate, 1200kg of isopropanol and 28kg of Raney Co catalyst are put into a 2L stainless steel high-pressure reaction kettle. After replacing the air in the autoclave with hydrogen, the pressure of hydrogen was adjusted to 25kg/cm2Stirring is started, the temperature is slowly raised to be above 70 ℃ by jacket steam, and the oxygen absorption reaction starts to release heat. At the moment, cooling water is opened for cooling, the reaction temperature is controlled to stably rise to 90-100 ℃ for reaction, and the introduction of hydrogen is controlled to stabilize the pressure at 35-40 kg/cm2And (4) reacting.
After 4.5 hours, hydrogen uptake ceased to continue at 100 deg.C, 35kg/cm2The reaction was carried out for 1 hour.
Cooling the materials in the autoclave to 44 ℃ by cooling water, discharging the residual hydrogen pressure, and then using N2Pressing the material to a filter by gas at N2And filtering under the protection of gas to recover the Raney Co catalyst.
The filtrate is introduced into a 2000L glass lining distillation crystallization kettle, and the solvent isopropanol is distilled off under stirring and heating. Then 660kg of petroleum ether is added while the mixture is hot, the mixture is stirred for 0.5 hour, the mixture is gradually cooled and crystallized, and the stirring is started intermittently to prevent the product from being discharged from the kettle after being agglomerated.
After the crystallization, the solution was centrifuged and filtered, and dried to obtain 184kg of a white solid. The content of HPLC detection is 99.6%, and the yield of hydrogenation reaction is 96.4%.
The total yield of the two-step reaction was 79.2%.
Examples 3 to 8
The operation of the embodiment 2 is repeated in the embodiments 3 to 8, but the raw material diethyl malonate is recycled and re-steamed diethyl malonate is added with fresh substances to reach the required feeding amount; adding 0.5kg of Raney Co catalyst recovered each time, and then putting the Raney Co catalyst into the next kettle for reaction; the product recrystallization operation uses fresh solvent.
The reaction results are given in the following table:
the foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (3)
1. A preparation method of 2-oxo-3-ethyl piperidine formate is characterized by comprising the following steps:
s1, uniformly mixing diethyl malonate and an alkali catalyst, and dropwise adding acrylonitrile at 10-50 ℃ to react to obtain 2-cyanoethyl diethyl malonate; the dosage of the alkali catalyst is 0.3-3% of the weight of diethyl malonate; the base catalyst comprises NaOC (CH)3)3、KOC(CH3)3At least one of; the reaction temperature is 30-35 ℃; the weight ratio of the acrylonitrile to the diethyl malonate is 1 (7.5-8.5);
s2, reacting the diethyl 2-cyanoethylmalonate, an organic solvent and a Raney cobalt catalyst in a hydrogen environment at 75-105 ℃, and recrystallizing to obtain the ethyl 2-oxo-3-piperidinecarboxylate; the weight ratio of the organic solvent to the 2-cyanoethyl diethyl malonate is (1-10): 1, the organic solvent is selected from isopropanol; the weight ratio of the Raney cobalt catalyst to the diethyl 2-cyanoethylmalonate is (0.1-0.15): 1; the reaction pressure of the hydrogen is 25-40 kg/cm2。
2. The method for producing ethyl 2-oxo-3-piperidinecarboxylate according to claim 1, wherein the dropping time of acrylonitrile is 1 to 10 hours.
3. The process for producing ethyl 2-oxo-3-piperidinecarboxylate according to claim 1, wherein the solvent used for recrystallization is at least one selected from ethanol, isopropanol, butanol, ethyl acetate, butyl acetate, petroleum ether, and methyl t-butyl ether.
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Non-Patent Citations (4)
| Title |
|---|
| N-乙酰基-5-甲氧基色胺的化学合成;胡松林等;《化学世界》;20161125(第11期);第699-701页 * |
| Studies toworad (-)-Gymnodimine: Concise Routes to the Spirocyclic and Tetrahydrofuran Moieties;Ju Yang,et al.;《Organic Letters》;20000225;第2卷(第6期);第763-766页 * |
| 色胺;周锡瑞等;《中国医药工业杂志》;19840927(第9期);第28-30页 * |
| 褪黑激素的合成工艺改进;李云等;《中国医药工业杂志》;19990821;第30卷(第8期);第340-341页 * |
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Inventor after: Yao Husheng Inventor after: Zhao Zhulin Inventor after: Zhang Ming Inventor before: Yao Husheng Inventor before: Zhao Zhulin Inventor before: Zhang Ming Inventor before: Chen Bo |
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Denomination of invention: Preparation method of 2-oxo-3-piperidine ethyl formate Effective date of registration: 20230512 Granted publication date: 20210105 Pledgee: Industrial Bank Co.,Ltd. Shanghai Minhang sub branch Pledgor: SHANGHAI JINGWEI CHEMICAL TECHNOLOGY Co.,Ltd. Registration number: Y2023310000184 |
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