CN106883165B - A kind of preparation method of template intermediate - Google Patents
A kind of preparation method of template intermediate Download PDFInfo
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- CN106883165B CN106883165B CN201710001425.8A CN201710001425A CN106883165B CN 106883165 B CN106883165 B CN 106883165B CN 201710001425 A CN201710001425 A CN 201710001425A CN 106883165 B CN106883165 B CN 106883165B
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- template intermediate
- ammonium salt
- quarternary ammonium
- piperidine
- organic solvent
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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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to chemical industry synthesis fields; more particularly to a kind of preparation method of template intermediate; the following steps are included: A, pyridine derivate is added in the autoclave of hydrogen shield gas, catalyst, alkylating reagent, organic solvent are reacted; it is filtered after reaction and removes catalyst; dry organic solvent is taken off, template intermediate piperidine quarternary ammonium salt crude product is obtained；B, template intermediate piperidine quarternary ammonium salt crude product obtained in step A is mixed with organic solvent, mashing stirring filters, obtains template intermediate piperidine quarternary ammonium salt；The template intermediate piperidine quarternary ammonium salt that the present invention is prepared, high income, yield is up to 85% or more, and at low cost, one-step method is made, and reaction step is simple, convenient post-treatment, is suitble to industrialized production.
Description
Technical field
The invention belongs to chemical industry synthesis field more particularly to a kind of preparation methods of template intermediate.
Background technique
Template intermediate piperidine quarternary ammonium salt is the important intermediate in chemical industry synthesis field, and conventional synthesis process is as follows
(being illustrated by taking piperidines quarternary ammonium salt as an example):
Wherein X can for carbonic acid mono-methyl ion, methyl sulfate ion, carbonic acid mono ethyl ester ion or Ethyl Sulfate from
Son；The conventional synthesis process first step is that corresponding piperidine derivative is made through catalytic hydrogenation using pyridine derivate as raw material；
Second step is using piperidine derivative as raw material, through alkyl base reagent (formic acid/formaldehyde, iodomethane, dimethyl carbonate, dimethyl sulfate
Ester, diethyl carbonate, dithyl sulfate etc.) tertiary amine is made；Phase is made using tertiary amine as raw material, through quaternary ammonium reagent in third step
The template intermediate piperidine quarternary ammonium salt answered.
It is studied through the present inventor and finds above-mentioned preparation method, reaction step is cumbersome, yield is lower is difficult to adapt in industry
Metaplasia produces.
Summary of the invention
Technical problem to be solved by the invention is to provide a kind of reaction step is simple, high income is suitble to industrialized production
Template intermediate piperidine quarternary ammonium salt preparation method.
The technical scheme to solve the above technical problems is that a kind of template intermediate, which is characterized in that it is tied
Structure formula is as follows:
R1For methyl or ethyl；R2、R3、R4、R5、R6Respectively methyl, ethyl, isopropyl, tertiary fourth
Base, straight chain, branch C1-C30One of alkyl or cycloalkyl；X is carbonic acid mono-methyl ion, methyl sulfate ion, carbonic acid list
One of ethyl ester ion or Ethyl Sulfate ion.
A kind of preparation method of template intermediate, comprising the following steps:
A, pyridine derivate, catalyst, alkylating reagent, organic is added in the autoclave of hydrogen shield gas
Solvent is reacted, and is filtered after reaction and is removed catalyst, takes off dry organic solvent, it is thick to obtain template intermediate piperidine quarternary ammonium salt
Product；
B, template intermediate piperidine quarternary ammonium salt crude product obtained in step A is mixed with organic solvent, mashing stirring,
It filters, obtains template intermediate piperidine quarternary ammonium salt.
Based on the above technical solution, the present invention can also be improved as follows.
Further, in step, the alkylating reagent is dimethyl carbonate, diethyl carbonate, dimethyl suflfate, sulphur
One or more of diethyl phthalate.
Further, in step, the pyridine derivate structural formula is as follows:
R2、R3、R4、R5、R6Respectively methyl, ethyl, isopropyl, tert-butyl, straight chain, branch C1-
C30One of alkyl or cycloalkyl；Preferably 3,5- lutidines, 3,5- parvoline, 2,6- lutidines, 2,
6- parvoline.
Further, in step, the catalyst is one of palladium carbon, ruthenium carbon, active carbon, palladium aluminium oxide, nickel or several
Kind.
Further, in step, the organic solvent be toluene, methanol, THF, acetonitrile, petroleum ether, n-hexane, DMF,
One or more of ethyl acetate.
Further, in step, the pyridine derivate, alkylating reagent and organic solvent molar ratio are 1:(2-12):
(1-30), the pyridine derivate and the catalyst quality ratio are 1:(0.01-1.0).
Further, in step, the reaction temperature is 50-250 DEG C, pressure 0.10-1.20Mpa.
Further, in stepb, the organic solvent be toluene, methanol, THF, acetonitrile, petroleum ether, n-hexane, DMF,
One or more of dimethyl carbonate, ethyl acetate.
Further, in stepb, the organic solvent and the template intermediate piperidine quarternary ammonium salt crude product quality ratio
For 1:(0.5-10).
The beneficial effects of the present invention are: pyridine is hydrogenated to piperidines by the present invention, piperidine methyl is melted into N- methyl piperidine, N- first
Phenylpiperidines methyl is melted into three step of salt and synthesizes a step, directly synthesizes template intermediate piperidine quarternary ammonium salt by pyridine derivate,
Its high income, yield is up to 85% or more, and at low cost, one-step method is made, and reaction step is simple, convenient post-treatment, is suitble to industry
Metaplasia produces.
Detailed description of the invention
Fig. 1 is 1 template intermediate nuclear-magnetism carbon spectrogram of the embodiment of the present invention；
Fig. 2 is 1 template intermediate nucleus magnetic hydrogen spectrum figure of the embodiment of the present invention.
Specific embodiment
The principles and features of the present invention are described below, and the given examples are served only to explain the present invention, is not intended to limit
Determine the scope of the present invention.
Embodiment 1
A, by 214.3g (2.0mol) 3,5- lutidines, 540.0g (6.0mol) dimethyl carbonate, 64.0g
(2.0mol) methanol, 10.7g ruthenium carbon (effective content 5%) are added in the autoclave of 2L, close autoclave, and nitrogen is set
It changes 6 times, hydrogen is replaced 6 times, and it is 9.0MPa, after temperature is 150 DEG C that pressurising, which is warming up to Hydrogen Vapor Pressure, Hydrogen Vapor Pressure in reaction process
It can be greatly reduced, heat-insulation pressure keeping reacts 10.0h, and cool down pressure release, filters and removes catalyst, deviates from methanol and dries to obtain faint yellow production
Product crude product 403.6g；
B, 2L there-necked flask is furnished with mechanical stirring, thermometer, drying tube, 403.6g crude product, the 200g that above-mentioned reaction is obtained
N-hexane, 200.0g ethyl acetate are added in 2L there-necked flask, are warming up to 50 DEG C, are beaten 1.0h, are cooled to room temperature suction filtration, 100g is just
Hexane and 100g ethyl acetate mixed solvent elute filter cake, filter cake dry white powdery solids 381.9g, yield are
87.8%, as template intermediate piperidine quarternary ammonium salt.
Nuclear-magnetism carbon composes (D2O, 100MHZ): δ=160.295,67.630,56.437,48.109,38.096,25.849,
17.397。
Nucleus magnetic hydrogen spectrum (D2O, 400MHZ): δ=3.196-3.206 (t, 1H), 3.165-3.174 (t, 1H), 2.903-
2.955 (d, 6H), 2.598-2.661 (t, 2H), 1.918-1.996 (m, 2H), 1.726-1.768 (m, 1H), 0.761-0.778
(d,6H),0.595-0.690(m,1H)
Embodiment 2
A, by 212.3g3,5- lutidines, 538.0g diethyl carbonate, 64.0g (2.0mol) methanol, 15.7g palladium carbon
It is added in the autoclave of 2L, closes autoclave, nitrogen is replaced 6 times, and hydrogen is replaced 6 times, and pressurising is warming up to hydrogen pressure
After power is 9.0MPa, temperature is 200 DEG C, Hydrogen Vapor Pressure can be greatly reduced in reaction process, and heat-insulation pressure keeping reacts 10.0h, cooling
Pressure release filters and removes catalyst, deviates from methanol and dries to obtain light yellow product crude product 386.4g；
B, 2L there-necked flask is furnished with mechanical stirring, thermometer, drying tube, 386.4g crude product, the 200g that above-mentioned reaction is obtained
N-hexane, 200.0g ethyl acetate are added in 2L there-necked flask, are warming up to 50 DEG C, are beaten 1.0h, are cooled to room temperature suction filtration, 100g is just
Hexane and 100g ethyl acetate mixed solvent elute filter cake, filter cake dry white powdery solids 371.3g, yield are
85.5%, as template intermediate piperidine quarternary ammonium salt.
Embodiment 3
A, by 212.4g3,5- lutidines, 540.0g (6.0mol) dimethyl carbonate, 64.0g (2.0mol) methanol,
11.2g ruthenium carbon (effective content 5%) is added in the autoclave of 2L, closes autoclave, and nitrogen is replaced 6 times, and hydrogen is set
It changes 6 times, it is 9.0MPa, after temperature is 250 DEG C that pressurising, which is warming up to Hydrogen Vapor Pressure, and Hydrogen Vapor Pressure can be greatly reduced in reaction process,
Heat-insulation pressure keeping reacts 10.0h, and cool down pressure release, filters and removes catalyst, deviates from methanol and dries to obtain light yellow product crude product
401.8g；
B, 2L there-necked flask is furnished with mechanical stirring, thermometer, drying tube, 401.8g crude product, the 200g that above-mentioned reaction is obtained
Acetonitrile, 200.0gDMF are added in 2L there-necked flask, are warming up to 50 DEG C, are beaten 1.0h, are cooled to room temperature suction filtration, 100g acetonitrile with
100gDMF mixed solvent elutes filter cake, and filter cake dries to obtain white powdery solids 391.3g, yield 90.16%, as template
Agent intermediate piperidine quarternary ammonium salt.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (5)
1. a kind of preparation method of template intermediate, which comprises the following steps:
A, pyridine derivate, catalyst, alkylating reagent, organic solvent are added in the autoclave of hydrogen shield gas
It is reacted, is filtered after reaction and remove catalyst, taken off dry organic solvent, obtain template intermediate piperidine quarternary ammonium salt crude product；
The pyridine derivate is 3,5- lutidines, and the catalyst is palladium carbon, in ruthenium carbon, active carbon, palladium aluminium oxide, nickel
One or more, the alkylating reagent be dimethyl carbonate；
The reaction temperature is 50-250 DEG C, pressure 0.10-1.20MPa；
B, template intermediate piperidine quarternary ammonium salt crude product obtained in step A is mixed with organic solvent, mashing stirring is taken out
Filter, obtains template intermediate piperidine quarternary ammonium salt；
Its template intermediate structure formula is as follows:
R1For methyl, R3For methyl, R5For methyl, R2、R4、R6Be hydrogen, X be carbonic acid mono-methyl from
Son.
2. a kind of preparation method of template intermediate according to claim 1, which is characterized in that in step, described to have
Solvent is one or more of toluene, methanol, THF, acetonitrile, petroleum ether, n-hexane, DMF, ethyl acetate.
3. a kind of preparation method of template intermediate according to claim 1, which is characterized in that in step, the pyrrole
Piperidine derivatives, alkylating reagent and organic solvent molar ratio are 1:(2-12): (1-30), the pyridine derivate and the catalysis
Agent mass ratio is 1:(0.01-1.0).
4. a kind of preparation method of template intermediate according to claim 1, which is characterized in that in stepb, described to have
Solvent is one of toluene, methanol, THF, acetonitrile, petroleum ether, n-hexane, DMF, dimethyl carbonate, ethyl acetate or several
Kind.
5. a kind of preparation method of template intermediate according to claim 1, which is characterized in that in stepb, described to have
Solvent and the template intermediate piperidine quarternary ammonium salt crude product quality ratio are 1:(0.5-10).
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087640A (en) * | 1992-05-29 | 1994-06-08 | 普罗格特甘布尔药品有限公司 | Novel phosphononosulfonatecompounds compounds, pharmaceutical composition, and the method for treatment abnormal calcium and phosphate metabolism |
| CN1241986A (en) * | 1996-12-31 | 2000-01-19 | 切夫里昂美国公司 | A process for preparing zeolites using substituted-piperidinium cations |
| CN101104146A (en) * | 2006-07-14 | 2008-01-16 | 常州艾坛化学有限公司 | Method for preparing cis-and-trans mixed isomers 3,5-dimethylpiperidine |
| CN105314646A (en) * | 2014-07-29 | 2016-02-10 | 孙红 | AEI-type aluminosilicate molecular sieves, and preparation methods and applications thereof |
| CN105315195A (en) * | 2014-07-29 | 2016-02-10 | 孙红 | Template agent and preparation method therefor and application thereof |
-
2017
- 2017-01-03 CN CN201710001425.8A patent/CN106883165B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1087640A (en) * | 1992-05-29 | 1994-06-08 | 普罗格特甘布尔药品有限公司 | Novel phosphononosulfonatecompounds compounds, pharmaceutical composition, and the method for treatment abnormal calcium and phosphate metabolism |
| CN1241986A (en) * | 1996-12-31 | 2000-01-19 | 切夫里昂美国公司 | A process for preparing zeolites using substituted-piperidinium cations |
| CN101104146A (en) * | 2006-07-14 | 2008-01-16 | 常州艾坛化学有限公司 | Method for preparing cis-and-trans mixed isomers 3,5-dimethylpiperidine |
| CN105314646A (en) * | 2014-07-29 | 2016-02-10 | 孙红 | AEI-type aluminosilicate molecular sieves, and preparation methods and applications thereof |
| CN105315195A (en) * | 2014-07-29 | 2016-02-10 | 孙红 | Template agent and preparation method therefor and application thereof |
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Denomination of invention: A preparation method of template intermediate Effective date of registration: 20211202 Granted publication date: 20190326 Pledgee: Yantai Branch of China Merchants Bank Co.,Ltd. Pledgor: VALIANT Co.,Ltd. Registration number: Y2021980013807 |
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Date of cancellation: 20220823 Granted publication date: 20190326 Pledgee: Yantai Branch of China Merchants Bank Co.,Ltd. Pledgor: VALIANT Co.,Ltd. Registration number: Y2021980013807 |