CN102174011A - Preparation method of 2-piperidinecarboxylic acid, 3-piperidinecarboxylic acid and 4-piperidinecarboxylic acid - Google Patents
Preparation method of 2-piperidinecarboxylic acid, 3-piperidinecarboxylic acid and 4-piperidinecarboxylic acid Download PDFInfo
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- CN102174011A CN102174011A CN 201110070691 CN201110070691A CN102174011A CN 102174011 A CN102174011 A CN 102174011A CN 201110070691 CN201110070691 CN 201110070691 CN 201110070691 A CN201110070691 A CN 201110070691A CN 102174011 A CN102174011 A CN 102174011A
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Abstract
The invention discloses a preparation method of 2-piperidinecarboxylic acid, 3-piperidinecarboxylic acid and 4-piperidinecarboxylic acid. The method is as follows: 2-pyridinecarboxylic acid, 3-pyridinecarboxylic acid and 4-pyridinecarboxylic acid are used as the raw material respectively, hydrogen is used to reduce the raw material to the corresponding piperidinecarboxylic acid in the presence of palladium-carbon catalyst. The method has the advantages of simple route, less side reactions, low hydrogenation pressure and hydrogenation temperature, short hydrogenation time and simple treatment of solid wastes, and is easy to realize industrialization.
Description
Technical field
The present invention relates to the preparation method of Pipecolic Acid, nipecotic acid and 4-piperidine carboxylic acid, belong to the synthetic and preparing technical field of organic chemicals.
Background technology
Pipecolic Acid, nipecotic acid, 4-piperidine carboxylic acid are all the important intermediate of synthetic multiple chiral drug and biologically active substance.Wherein:
Pipecolic Acid is a kind of important rigid annular nonprotein amino acid, and it both can limit the conformation of polypeptide, also can be used as the multi-functional skeleton in the synthetic storehouse of different compounds, so be widely used in the preparation of many chiral drugs and biologically active substance.As, local anaesthetics ropivacaine, antipsychotics thioridazine etc. all is to be that main raw material makes with the Pipecolic Acid.
Nipecotic acid has shown that as a kind of non-albumen beta-amino acids that contains the rigidity piperidine ring neurotransmitter γ-An Jidingsuan (GABA) translocator suppresses active preferably, can be used to synthetic GABA uptake inhibitors, antitumour drug etc.
The 4-piperidine carboxylic acid uses in calm class medicine, anti-heart disorder class medicine in a large number.As be used for synthetic risperidone, fexofenadine hydrochloride, cevimeline, Y-25130, Palonosetron etc.
Because carboxyl is in the nuclear substituted position of piperidines difference, the synthetic method of various piperidine carboxylic acids is also different.
At present, the synthetic method of Pipecolic Acid is divided into mainly that biocatalysis is synthetic, chemical asymmetric synthesis and photochemical catalysis be synthetic.Japan Mercian drugmaker utilizes reorganization ammonia transferring enzyme LAT with similar P5C reductase enzyme L-Methionin to be converted into the L-nipecotic acid.Watanabe etc. are raw material with the diethyl acetamido, adopt chemosynthesis-biology to split integrated process and finally obtain having optically active L-nipecotic acid and D-nipecotic acid.Teoh etc. adopt " one kettle way ", are that raw material has been realized the synthetic of Pipecolic Acid after by hydrogenation-carbonylation cascade reaction with amido diene methyl esters.Pal etc. adopt the HyCOM-TiO of metal Pt surface deposition
2Being photocatalyst, is the synthetic L-nipecotic acid of starting raw material with L-Methionin.
The common method of synthetic nipecotic acid is a hydrogenation nicotinic acid.Freifelder is that catalyzer pressure hydration nicotinic acid in ammonia soln has synthesized nipecotic acid with rhodium (Rh/Al2O3), yield is that same catalyzer of employing such as 88.57%:Valsborg and alkaline medium prepare nipecotic acid through long-time atmospheric hydrogenation, yield is 98%, but rhodium output in platinum family element is minimum, and price is higher.Mcelvain etc. obtain nipecotic acid hydrochloride with platinum oxide (PtO2) shortening with nicotinic acid hydrochloride in water, yield is near 100%.The catalytic activity height of platinum, required mild condition, but poor selectivity easily are the passivation of alkali institute.
The synthetic the simplest method of 4-piperidine carboxylic acid is the catalytic reduction of Yi Yansuan.Grob etc. are catalyzer with the Raney's nickel, H
2Be reductive agent, hydro-reduction obtains the 4-piperidine carboxylic acid.Operation pressure is higher, and than higher, investment is big to equipment requirements.And use potassium hydroxide in the reaction process, aftertreatment need neutralize with the vitriol oil, and evaporated under reduced pressure moisture adds the desalination of dissolve with methanol after-filtration again, and underpressure distillation to solid is separated out again.Because repeatedly underpressure distillation energy consumption height, and can produce salinity, therefore useless admittedly processing costs height.
Summary of the invention
The preparation method who the objective of the invention is to a kind of Pipecolic Acid, nipecotic acid and 4-piperidine carboxylic acid, to overcome the defective that above-mentioned prior art exists, the long defective of reaction scheme when promptly overcoming the preparation Pipecolic Acid, overcome preparation during nipecotic acid the catalyzer price high and easily be the defective of alkali institute passivation, operation hypertonia and the solid useless complicated defective of handling when overcoming preparation 4-piperidine carboxylic acid, provide piperidine carboxylic acid all general, more help the synthetic method of industrialization operation.
We realize above-mentioned purpose by the preparation of following steps:
2-pyridine carboxylic acid, water, palladium charcoal are put in the hydrogenation still by weight 1: 5～8: 0.01～0.05, use earlier nitrogen replacement, feed hydrogen again and make its hydrogenation 3～4 hours under certain temperature and pressure, reacted to filter and removed the palladium catalyst charcoal, 50% moisture is removed in underpressure distillation, is cooled to 30 ℃, adds methyl alcohol Pipecolic Acid is separated out, cool to 0 ℃ again, the centrifugal Pipecolic Acid that gets.
3-pyridine carboxylic acid, water, palladium charcoal are put in the hydrogenation still by weight 1: 5～8: 0.01～0.05, use earlier nitrogen replacement, feed hydrogen again and make its hydrogenation 3～4 hours under certain temperature and pressure, reacted to filter and removed the palladium catalyst charcoal, 50% moisture is removed in underpressure distillation, is cooled to 30 ℃, adds methyl alcohol nipecotic acid is separated out, cool to 0 ℃ again, the centrifugal nipecotic acid that gets.
4-pyridine carboxylic acid, water, palladium charcoal are put in the hydrogenation still by weight 1: 5～8: 0.01～0.05, use earlier nitrogen replacement, feed hydrogen and make its hydrogenation 3～4 hours under certain temperature and pressure, reacted to filter and removed the palladium catalyst charcoal, 50% moisture is removed in underpressure distillation, is cooled to 30 ℃, adds methyl alcohol the 4-piperidine carboxylic acid is separated out, cool to 10 ℃ again, the centrifugal 4-piperidine carboxylic acid that gets.
Described catalyzer is the palladium charcoal.
Described hydrogenation temperature is 90～100 ℃.
Described hydrogenation pressure is 4～5Mpa.
The present invention has the following advantages:
1, with the pyridine carboxylic acid for the raw material hydro-reduction obtains piperidine carboxylic acid, reaction scheme is simple, side reaction is few.
2, hydrogenation does not use potassium hydroxide, makes catalyzer with the palladium charcoal, and hydrogenation pressure, hydrogenation temperature are all low when making catalyzer with Raney's nickel, the hydrogenation mild condition, and safety coefficient is big.Hydrogenation time also lacks than with Raney's nickel hydrogenation the time, has saved energy consumption.
3, post-processing operation is simple.Owing to do not use highly basic in the reaction process, do not need with vitriol oil neutralization, only need decompression to steam 50% moisture, be chilled to certain temperature after adding methyl alcohol, separate out can be centrifugal piperidine carboxylic acid, admittedly useless handling is relatively low.
4, reaction yield height.The yield of 4-piperidine carboxylic acid is more than 95%, and the yield of nipecotic acid is more than 85%, and the yield of Pipecolic Acid is more than 85%.
Embodiment
Embodiment 1
(1) hydrogenation
The pressure testing of autoclave nitrogen is to more than the 2Mpa, guarantee that autoclave does not have leakage after, drop into 600g 2-pyridine carboxylic acid; 3600ml water adds 30g palladium carbon catalyst (palladium content 5%), airtight autoclave under nitrogen protection; with nitrogen replacement three times, hydrogen exchange secondary, guarantee in the still under the oxygen free condition; feed hydrogen to 3.5Mpa, be warming up to 80 ℃, begin to inhale H-H reaction; reacted approximately 3 hours; suction hydrogen stops, and improves temperature to 100 ℃ gradually, and hydrogen pressure is added to 5Mpa; continue hydrogenation with this understanding; till not inhaling hydrogen, sampling analysis, tlc; adopt the chromatosheet of coating silica gel G; developping agent is 95% ethanol, after the expansion, dries.With the iodine vapor colour developing, should not show 2-pyridine carboxylic acid spot.Be cooled to 35 ℃, slowly release pressure, with nitrogen material in the still is extruded, remove by filter the palladium catalyst charcoal, filtrate is carried out the next step.
(2) last handling process
Reaction solution in (1) is put in the still kettle, pressure reducing and steaming moisture under vacuum-0.090Mpa, treat that most of moisture steams after, add methyl alcohol, should have solid to separate out in the still, continue to be cooled to 0 ℃, solid is fully separated out.Feed liquid is put to the whizzer centrifugal, just obtain the Pipecolic Acid finished product after wet product are dried.The content of Pipecolic Acid is between 98%～102%, and fusing point: 273～278 ℃ is 85.26% with respect to the molar yield of 2-pyridine carboxylic acid.
Embodiment 2
(1) hydrogenation
The pressure testing of autoclave nitrogen guarantees that to more than the 2Mpa autoclave does not have leakage.In the batching still, drop into 20kg 4-pyridine carboxylic acid, 160kg water and 0.4kg palladium carbon catalyst (palladium content 5%), behind the dissolved dilution, autoclave vacuumizes, and the material in the batching still is sucked in the autoclave, close vacuum, with nitrogen replacement three times, hydrogen exchange secondary, guarantee in the still under the oxygen free condition, feed hydrogen, pressure-controlling slowly is warming up to 80 ℃ at 3～4Mpa, begins to inhale H-H reaction, reacted approximately 3 hours, suction hydrogen stops, and improves temperature to 100 ℃ gradually, and hydrogen pressure is added to 5Mpa, insulation reaction is 3 hours with this understanding, till not inhaling hydrogen, sampling analysis point plate is till no raw material (no fluorescence is shown as reaction end).Be up to the standards, be cooled to 35 ℃, slowly release pressure, material in the still is extruded, remove by filter the palladium catalyst charcoal with nitrogen.Filtrate is carried out the next step.
(2) last handling process
Reaction solution in (1) is pumped in the still kettle, pressure reducing and steaming moisture under vacuum-0.090Mpa, treat that most of moisture steams after, be thick in the pot, add the methyl alcohol of 3 times of charging capacitys, have solid to separate out in the still, continue to be cooled to 10 ℃, solid is fully separated out.Feed liquid is put to the whizzer centrifugal, must 4-piperidine carboxylic acid finished product after wet product are dried.The content of 4-piperidine carboxylic acid is between 98%～102%, and fusing point is greater than 300 ℃, is 96.78% with respect to the molar yield of 4-pyridine carboxylic acid.
Embodiment 3
(1) hydrogenation
The pressure testing of autoclave nitrogen guarantees that to more than the 2Mpa autoclave does not have leakage.In the batching still, drop into 100kg 4-pyridine carboxylic acid, 500kg water and 1kg palladium carbon catalyst (palladium content 5%), behind the dissolved dilution, autoclave vacuumizes, and the material in the batching still is sucked in the autoclave, close vacuum, with nitrogen replacement three times, hydrogen exchange secondary, guarantee in the still under the oxygen free condition, feed hydrogen, pressure-controlling slowly is warming up to 90 ℃ at 3～4Mpa, begins to inhale H-H reaction, reacted approximately 3 hours, suction hydrogen stops, and improves temperature to 95 ℃ gradually, and hydrogen pressure is added to 5Mpa, insulation reaction is 3 hours with this understanding, till not inhaling hydrogen, sampling analysis point plate is till no raw material (no fluorescence is shown as reaction end).Be up to the standards, be cooled to 35 ℃, slowly release pressure, material in the still is extruded, remove by filter the palladium catalyst charcoal with nitrogen.Filtrate is carried out the next step.
(2) last handling process
Reaction solution in (1) is pumped in the still kettle, pressure reducing and steaming moisture under vacuum-0.090Mpa, treat that most of moisture steams after, be thick in the pot, add the methyl alcohol of 3 times of charging capacitys, should have solid to separate out in the still, continue to be cooled to 10 ℃, solid is fully separated out.Feed liquid is put to the whizzer centrifugal, must 4-piperidine carboxylic acid finished product after wet product are dried.The content of 4-piperidine carboxylic acid is between 98%～102%, and fusing point is greater than 300 ℃, is 96.89% with respect to the molar yield of 4-pyridine carboxylic acid.
Embodiment 4
(1) hydrogenation
The pressure testing of autoclave nitrogen guarantees that to more than the 2Mpa autoclave does not have leakage.In the batching still, drop into 100kg 3-pyridine carboxylic acid, 600kg water and 3kg palladium carbon catalyst (palladium content 5%), behind the dissolved dilution, autoclave vacuumizes, and the material in the batching still is sucked in the autoclave, close vacuum, with nitrogen replacement three times, hydrogen exchange secondary, guarantee in the still under the oxygen free condition, feed hydrogen, pressure-controlling slowly is warming up to 90 ℃ at 3～4Mpa, begins to inhale H-H reaction, reacted approximately 3 hours, suction hydrogen stops, and improves temperature to 95 ℃ gradually, and hydrogen pressure is added to 5Mpa, insulation reaction is 3 hours with this understanding, till not inhaling hydrogen, sampling analysis point plate is till no raw material (no fluorescence is shown as reaction end).Be up to the standards, be cooled to 35 ℃, slowly release pressure, material in the still is extruded, remove by filter the palladium catalyst charcoal with nitrogen.Filtrate is carried out the next step.
(2) last handling process
Reaction solution in (1) is pumped in the still kettle, pressure reducing and steaming moisture under vacuum-0.090Mpa, treat that most of moisture steams after, be thick in the pot, add the methyl alcohol of 3 times of charging capacitys, should have solid to separate out in the still, continue to be cooled to 10 ℃, solid is fully separated out.Feed liquid is put to the whizzer centrifugal, must the nipecotic acid finished product after wet product are dried.The content of nipecotic acid is greater than 97%, and decomposition temperature is greater than 261 ℃, is 86.92% with respect to the molar yield of 3-pyridine carboxylic acid.
Claims (6)
1. the preparation method of a Pipecolic Acid, nipecotic acid and 4-piperidine carboxylic acid, may further comprise the steps: 2-pyridine carboxylic acid, water, palladium charcoal are put in the hydrogenation still by weight 1: 5～8: 0.01～0.05, use earlier nitrogen replacement, feed hydrogen again and make its hydrogenation 3～4 hours under certain temperature and pressure, reacted to filter and removed the palladium catalyst charcoal, 50% moisture is removed in underpressure distillation, be cooled to 30 ℃, adding methyl alcohol separates out Pipecolic Acid, cool to 0 ℃ again, the centrifugal Pipecolic Acid that gets.
2. the preparation method of a Pipecolic Acid, nipecotic acid and 4-piperidine carboxylic acid, may further comprise the steps: 3-pyridine carboxylic acid, water, palladium charcoal are put in the hydrogenation still by weight 1: 5～8: 0.01～0.05, use earlier nitrogen replacement, feed hydrogen again and make its hydrogenation 3～4 hours under certain temperature and pressure, reacted to filter and removed the palladium catalyst charcoal, 50% moisture is removed in underpressure distillation, be cooled to 30 ℃, adding methyl alcohol separates out nipecotic acid, cool to 0 ℃ again, the centrifugal nipecotic acid that gets.
3. the preparation method of a Pipecolic Acid, nipecotic acid and 4-piperidine carboxylic acid, may further comprise the steps: 4-pyridine carboxylic acid, water, palladium charcoal are put in the hydrogenation still by weight 1: 5～8: 0.01～0.05, use earlier nitrogen replacement, feed hydrogen and make its hydrogenation 3～4 hours under certain temperature and pressure, reacted to filter and removed the palladium catalyst charcoal, 50% moisture is removed in underpressure distillation, be cooled to 30 ℃, adding methyl alcohol separates out the 4-piperidine carboxylic acid, cool to 10 ℃ again, the centrifugal 4-piperidine carboxylic acid that gets.
4. according to the preparation method of claim 1 or 2 or 3 described Pipecolic Acids, nipecotic acid and 4-piperidine carboxylic acid, it is characterized in that: use the palladium charcoal as catalyzer.
5. according to the preparation method of claim 1 or 2 or 3 described Pipecolic Acids, nipecotic acid and 4-piperidine carboxylic acid, it is characterized in that: hydrogenation temperature is 90～100 ℃.
6. according to the preparation method of claim 1 or 2 or 3 described Pipecolic Acids, nipecotic acid and 4-piperidine carboxylic acid, it is characterized in that: hydrogenation pressure is 4～5Mpa.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201110070691 CN102174011A (en) | 2011-03-23 | 2011-03-23 | Preparation method of 2-piperidinecarboxylic acid, 3-piperidinecarboxylic acid and 4-piperidinecarboxylic acid |
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| CN 201110070691 CN102174011A (en) | 2011-03-23 | 2011-03-23 | Preparation method of 2-piperidinecarboxylic acid, 3-piperidinecarboxylic acid and 4-piperidinecarboxylic acid |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524401A (en) * | 2013-10-31 | 2014-01-22 | 江苏宝众宝达药业有限公司 | Synthetic method for (2R, 4R)-4-methyl-2-piperidinecarboxylic acid |
| CN107286227A (en) * | 2016-03-31 | 2017-10-24 | 南京诺云生物科技有限公司 | The new application of the albumen of Streptomyces hirsutus ATCC 19091 |
| CN107286228A (en) * | 2016-03-31 | 2017-10-24 | 南京诺云生物科技有限公司 | The new application of the albumen of Arenimonas donghaensis DSM 18148 |
-
2011
- 2011-03-23 CN CN 201110070691 patent/CN102174011A/en active Pending
Non-Patent Citations (3)
| Title |
|---|
| 《Eur.J.Org.Chem.》 20091231 M.Irfan et al. Continuous Flow Hydrogenation of Functionalized Pyridines 第1327-1334页 1-6 , * |
| 《Izvestiya Vysshikh Uchebnykh Zavedenii, Khimiya i Khimicheskaya Tekhnologiya 》 20041231 Bazurin,A.A et al. Synthesis of 2-piperidinecarboxylic acid and its derivatives 第113-115页 1-6 第47卷, 第6期 * |
| 《有机化学》 20091231 李运波等 3-哌啶甲酸及其衍生物的合成与应用研究进展 第1068-1081页 1-6 第29卷, 第7期 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103524401A (en) * | 2013-10-31 | 2014-01-22 | 江苏宝众宝达药业有限公司 | Synthetic method for (2R, 4R)-4-methyl-2-piperidinecarboxylic acid |
| CN107286227A (en) * | 2016-03-31 | 2017-10-24 | 南京诺云生物科技有限公司 | The new application of the albumen of Streptomyces hirsutus ATCC 19091 |
| CN107286228A (en) * | 2016-03-31 | 2017-10-24 | 南京诺云生物科技有限公司 | The new application of the albumen of Arenimonas donghaensis DSM 18148 |
| CN107286227B (en) * | 2016-03-31 | 2021-01-05 | 南京诺云生物科技有限公司 | Novel use of Streptomyces hirsutus ATCC 19091 protein |
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Application publication date: 20110907 |