CN110483375A - A kind of synthetic method of intermediate 4- piperidones - Google Patents

A kind of synthetic method of intermediate 4- piperidones Download PDF

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Publication number
CN110483375A
CN110483375A CN201910858999.6A CN201910858999A CN110483375A CN 110483375 A CN110483375 A CN 110483375A CN 201910858999 A CN201910858999 A CN 201910858999A CN 110483375 A CN110483375 A CN 110483375A
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piperidones
added
beta
synthetic method
usage amount
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陈建江
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The invention discloses a kind of synthetic methods of intermediate 4- piperidones, the following steps are included: Beta-alanine methyl esters is added in ethyl alcohol, it is placed in reaction kettle, ethylene is added, after mixing, it is cooled to 0-10 DEG C, catalyst promoter and sodium ethoxide is added, stirring is reacted, after the reaction was completed, it is cooled to room temperature, vacuum distillation removal ethyl alcohol；DMF is added into reaction kettle, after being uniformly mixed, is heated to 110-130 DEG C, back flow reaction is carried out under stirring condition, after reacting 1-2h, is down to room temperature, is extracted with ethyl acetate, ethyl acetate is evaporated off, is evaporated under reduced pressure later, the 4- piperidones is made.The synthetic method of the application uses one kettle way, is not necessarily to intermediate purification step, reduces resource waste, and easy to operate, and production technology is brief, and feed stock conversion is high, and lower production costs have high economic benefit.

Description

A kind of synthetic method of intermediate 4- piperidones
Technical field
The present invention relates to medicine intermediate fields, more particularly to a kind of synthetic method of intermediate 4- piperidones.
Background technique
Heterocyclic compound is most important one kind of structure in chemical substance, extensive in distributed in nature, be widely used in medicine, The fields such as pesticide, dyestuff and fine chemistry industry.Piperidines, also known as hexahydropyridine are important new type heterocycle class organic intermediate, piperazine Piperidine derivatives are widely used in the fields such as synthesis medicine, pesticide and rubber chemicals.
In Rubber Chemicals Industries, can be used for synthesizing the super vulcanization accelerator of thiurams, such rubber accelerator without Pollution, non-discolouring, the product contacted suitable for light-colour rubber and food；It can be also used for synthesis dithiocarbamates to promote Into agent, this kind of promotor is suitable for latex based article.Wherein in field of medicaments, piperidines are widely used in easing pain, disappear Inflammation, antipsychotic, anesthesia, the synthesis of cholinolytic, antiallergy, anti-hypertension and the drugs such as antitumor；Especially in some minds Through systemic disease, anaphylactia clinical treatment in have irreplaceable status.It is mainly used for synthesizing in pesticide industry Herbicides for use in paddy dimepiperate, this is a kind of selective non-hormone-type thiocarbamate class herbicide, has good hair Exhibition prospect.Piperidones and its derivative are a kind of and its important piperidines, using the carbonyl in its structure and are faced Methylene activity on position can trigger a variety of organic synthesis, and thus deriving many practical medicine, in chemical industry Mesosome, pesticide etc..
Since piperidones and its derivative are widely used, so the research about its synthesis is constantly subjected to widely close Note.Mainly had using the wide synthetic route of friendship at present: (1) being synthesized by raw material of dibasic acid esters, this method initial feed is more honest and clean Valence；(2) it is synthesized by raw material of pyridine-N-oxide, this method operation is relatively complicated；(3) with secondary amine and acrylonitrile or acrylic acid Ester is Material synthesis, and the product yield of this method is higher；(4) through Michael addition, cyclization, the method synthesis of decarboxylation.With top Though method has certain research achievement, still there are some shortcomings, therefore research and develop a kind of highly efficient, easy preparation side Method has important research significance.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of intermediate 4- piperidones, which uses one kettle way, It without intermediate purification step, reduces resource waste, and easy to operate, production technology is brief, and feed stock conversion is high, is produced into This is lower, has high economic benefit.
To achieve the above object, the invention adopts the following technical scheme:
A kind of synthetic method of intermediate 4- piperidones, comprising the following steps:
(1) Beta-alanine methyl esters is added in ethyl alcohol, is placed in reaction kettle, ethylene is added and is cooled to 0- after mixing 10 DEG C, catalyst promoter and sodium ethoxide is added, stirring is reacted, after the reaction was completed, is cooled to room temperature, vacuum distillation removal second Alcohol；
(2) DMF is added into reaction kettle, after being uniformly mixed, is heated to 110-130 DEG C, is returned under stirring condition Stream reaction is down to room temperature, is extracted with ethyl acetate, ethyl acetate is evaporated off, is evaporated under reduced pressure later after reacting 1-2h, is made The 4- piperidones；
The catalyst promoter is PS-AlCl3-SbCl5。
Preferably, the PS-AlCl3-SbCl5Preparation method be, comprising the following steps: Polystyrene powder is added In carbon tetrachloride, it is heated to 80-90 DEG C, AlCl is added3And SbCl5, back flow reaction is carried out under stirring condition, after the reaction was completed, drop It to room temperature, filters, cleaning, it is dry to get the PS-AlCl3-SbCl5。
Preferably, the PS-AlCl3-SbCl5Middle AlCl3Shared mass fraction is 10%, SbCl5Shared mass parts Number is 7%.
Preferably, the usage amount molal volume ratio of the Beta-alanine methyl esters and ethyl alcohol is 1.1-1.5mol/L.
Preferably, the usage amount molar ratio of the Beta-alanine methyl esters and ethylene is 1:1.2-1.4.
Preferably, the usage amount mass ratio of the Beta-alanine methyl esters and catalyst promoter is 4:13-17.
Preferably, the usage amount molar ratio of the Beta-alanine methyl esters and sodium ethoxide is 9:7-9.
Preferably, the usage amount of the DMF and the usage amount volume ratio of ethyl alcohol are 1:1.
The invention has the advantages that
It 1, is raw material using Beta-alanine methyl esters and ethylene, progress addition reaction first carries out condensation reaction later, prepares 4- piperidones is obtained, reaction process is not necessarily to intermediate purification step, and easy to operate, raw material is cheap and easy to get, lower production costs, product High income, it is with good economic efficiency.
2, PS-AlCl is utilized3-SbCl5Catalysis reaction, AlCl are carried out using sodium ethoxide as catalyst for catalyst promoter3- SbCl5The catalytic efficiency of sodium ethoxide can be alleviated, so that reaction is easily controllable, and reduce the generation of by-product.Passing through will AlCl3-SbCl5It is carried on PS, so that AlCl3-SbCl5It can participate in reacting jointly, cooperate, and help catalyst Agent is convenient for being recycled.
Specific embodiment
In order to better understand the present invention, below by embodiment, the present invention is further described, and embodiment is served only for solving The present invention is released, any restriction will not be constituted to the present invention.
Embodiment 1
A kind of synthetic method of intermediate 4- piperidones, comprising the following steps:
(1) Beta-alanine methyl esters is added in ethyl alcohol, is placed in reaction kettle, ethylene is added and is cooled to 0 after mixing DEG C, PS-AlCl is added3-SbCl5And sodium ethoxide, stirring are reacted, after the reaction was completed, are cooled to room temperature, vacuum distillation removal Ethyl alcohol；
(2) DMF is added into reaction kettle, after being uniformly mixed, is heated to 110 DEG C, carries out flowing back under stirring condition anti- It answers, after reacting 1h, is down to room temperature, is extracted with ethyl acetate, ethyl acetate is evaporated off, is evaporated under reduced pressure later, the 4- is made Piperidones.
PS-AlCl3-SbCl5Preparation method be, comprising the following steps: by Polystyrene powder be added carbon tetrachloride in, 80 DEG C are heated to, AlCl is added3And SbCl5, back flow reaction is carried out under stirring condition, after the reaction was completed, is down to room temperature, is filtered, clearly It washes, it is dry to get the PS-AlCl3-SbCl5；Wherein AlCl3Shared mass fraction is 10%, SbCl5Shared mass parts Number is 7%.
The usage amount molal volume ratio of Beta-alanine methyl esters and ethyl alcohol is 1.1mol/L；Beta-alanine methyl esters and ethylene make Dosage molar ratio is 1:1.2；The usage amount mass ratio of Beta-alanine methyl esters and catalyst promoter is 4:13；Beta-alanine methyl esters with The usage amount molar ratio of sodium ethoxide is 9:7；The usage amount of DMF and the usage amount volume ratio of ethyl alcohol are 1:1.
The yield of 4- piperidones obtained is 91.7%, purity 99.4%.
Embodiment 2
A kind of synthetic method of intermediate 4- piperidones, comprising the following steps:
(1) Beta-alanine methyl esters is added in ethyl alcohol, is placed in reaction kettle, ethylene is added and is cooled to 10 after mixing DEG C, PS-AlCl is added3-SbCl5And sodium ethoxide, stirring are reacted, after the reaction was completed, are cooled to room temperature, vacuum distillation removal Ethyl alcohol；
(2) DMF is added into reaction kettle, after being uniformly mixed, is heated to 130 DEG C, carries out flowing back under stirring condition anti- It answers, after reacting 2h, is down to room temperature, is extracted with ethyl acetate, ethyl acetate is evaporated off, is evaporated under reduced pressure later, the 4- is made Piperidones.
PS-AlCl3-SbCl5Preparation method it is as described in Example 1.
The usage amount molal volume ratio of Beta-alanine methyl esters and ethyl alcohol is 1.5mol/L；Beta-alanine methyl esters and ethylene make Dosage molar ratio is 1:1.4；The usage amount mass ratio of Beta-alanine methyl esters and catalyst promoter is 4:17；Beta-alanine methyl esters with The usage amount molar ratio of sodium ethoxide is 9:9；The usage amount of DMF and the usage amount volume ratio of ethyl alcohol are 1:1.
The yield of 4- piperidones obtained is 92.3%, purity 99.3%.
Embodiment 3
A kind of synthetic method of intermediate 4- piperidones, comprising the following steps:
(1) Beta-alanine methyl esters is added in ethyl alcohol, is placed in reaction kettle, ethylene is added and is cooled to 0 after mixing DEG C, PS-AlCl is added3-SbCl5And sodium ethoxide, stirring are reacted, after the reaction was completed, are cooled to room temperature, vacuum distillation removal Ethyl alcohol；
(2) DMF is added into reaction kettle, after being uniformly mixed, is heated to 130 DEG C, carries out flowing back under stirring condition anti- It answers, after reacting 1h, is down to room temperature, is extracted with ethyl acetate, ethyl acetate is evaporated off, is evaporated under reduced pressure later, the 4- is made Piperidones.
PS-AlCl3-SbCl5Preparation method it is as described in Example 1.
The usage amount molal volume ratio of Beta-alanine methyl esters and ethyl alcohol is 1.5mol/L；Beta-alanine methyl esters and ethylene make Dosage molar ratio is 1:1.2；The usage amount mass ratio of Beta-alanine methyl esters and catalyst promoter is 4:17；Beta-alanine methyl esters with The usage amount molar ratio of sodium ethoxide is 9:7；The usage amount of DMF and the usage amount volume ratio of ethyl alcohol are 1:1.
The yield of 4- piperidones obtained is 92.9%, purity 99.4%.
Embodiment 4
A kind of synthetic method of intermediate 4- piperidones, comprising the following steps:
(1) Beta-alanine methyl esters is added in ethyl alcohol, is placed in reaction kettle, ethylene is added and is cooled to 10 after mixing DEG C, PS-AlCl is added3-SbCl5And sodium ethoxide, stirring are reacted, after the reaction was completed, are cooled to room temperature, vacuum distillation removal Ethyl alcohol；
(2) DMF is added into reaction kettle, after being uniformly mixed, is heated to 110 DEG C, carries out flowing back under stirring condition anti- It answers, after reacting 2h, is down to room temperature, is extracted with ethyl acetate, ethyl acetate is evaporated off, is evaporated under reduced pressure later, the 4- is made Piperidones.
PS-AlCl3-SbCl5Preparation method it is as described in Example 1.
The usage amount molal volume ratio of Beta-alanine methyl esters and ethyl alcohol is 1.1mol/L；Beta-alanine methyl esters and ethylene make Dosage molar ratio is 1:1.4；The usage amount mass ratio of Beta-alanine methyl esters and catalyst promoter is 4:13；Beta-alanine methyl esters with The usage amount molar ratio of sodium ethoxide is 1:1；The usage amount of DMF and the usage amount volume ratio of ethyl alcohol are 1:1.
The yield of 4- piperidones obtained is 91.7%, purity 99.4%.
Embodiment 5
A kind of synthetic method of intermediate 4- piperidones, comprising the following steps:
(1) Beta-alanine methyl esters is added in ethyl alcohol, is placed in reaction kettle, ethylene is added and is cooled to 5 after mixing DEG C, PS-AlCl is added3-SbCl5And sodium ethoxide, stirring are reacted, after the reaction was completed, are cooled to room temperature, vacuum distillation removal Ethyl alcohol；
(2) DMF is added into reaction kettle, after being uniformly mixed, is heated to 120 DEG C, carries out flowing back under stirring condition anti- It answers, after reacting 2h, is down to room temperature, is extracted with ethyl acetate, ethyl acetate is evaporated off, is evaporated under reduced pressure later, the 4- is made Piperidones.
PS-AlCl3-SbCl5Preparation method it is as described in Example 1.
The usage amount molal volume ratio of Beta-alanine methyl esters and ethyl alcohol is 1.2mol/L；Beta-alanine methyl esters and ethylene make Dosage molar ratio is 1:1.3；The usage amount mass ratio of Beta-alanine methyl esters and catalyst promoter is 4:15；Beta-alanine methyl esters with The usage amount molar ratio of sodium ethoxide is 9:8；The usage amount of DMF and the usage amount volume ratio of ethyl alcohol are 1:1.
The yield of 4- piperidones obtained is 93.7%, purity 99.3%.

Claims (8)

1. a kind of synthetic method of intermediate 4- piperidones, which comprises the following steps:
(1) Beta-alanine methyl esters is added in ethyl alcohol, is placed in reaction kettle, ethylene is added and is cooled to 0-10 after mixing DEG C, catalyst promoter and sodium ethoxide is added, stirring is reacted, after the reaction was completed, is cooled to room temperature, vacuum distillation removal second Alcohol；
(2) DMF is added into reaction kettle, after being uniformly mixed, is heated to 110-130 DEG C, carries out flowing back under stirring condition anti- It answers, after reacting 1-2h, is down to room temperature, is extracted with ethyl acetate, ethyl acetate is evaporated off, is evaporated under reduced pressure later, be made described 4- piperidones；
The catalyst promoter is PS-AlCl3-SbCl5。
2. the synthetic method of intermediate 4- piperidones according to claim 1, it is characterised in that: the PS-AlCl3- SbCl5Preparation method be, comprising the following steps: by Polystyrene powder be added carbon tetrachloride in, be heated to 80-90 DEG C, add Enter AlCl3And SbCl5, carry out back flow reaction under stirring condition, after the reaction was completed, be down to room temperature, filter, cleaning, it is dry to get The PS-AlCl3-SbCl5。
3. the synthetic method of intermediate 4- piperidones according to claim 1, it is characterised in that: the PS-AlCl3- SbCl5Middle AlCl3Shared mass fraction is 10%, SbCl5Shared mass fraction is 7%.
4. the synthetic method of intermediate 4- piperidones according to claim 1, it is characterised in that: the Beta-alanine methyl esters Usage amount molal volume ratio with ethyl alcohol is 1.1-1.5mol/L.
5. the synthetic method of intermediate 4- piperidones according to claim 1, it is characterised in that: the Beta-alanine methyl esters Usage amount molar ratio with ethylene is 1:1.2-1.4.
6. the synthetic method of intermediate 4- piperidones according to claim 1, it is characterised in that: the Beta-alanine methyl esters Usage amount mass ratio with catalyst promoter is 4:13-17.
7. the synthetic method of intermediate 4- piperidones according to claim 1, it is characterised in that: the Beta-alanine methyl esters Usage amount molar ratio with sodium ethoxide is 9:7-9.
8. the synthetic method of intermediate 4- piperidones according to claim 1, it is characterised in that: the usage amount of the DMF Usage amount volume ratio with ethyl alcohol is 1:1.
CN201910858999.6A 2019-09-11 2019-09-11 A kind of synthetic method of intermediate 4- piperidones Pending CN110483375A (en)

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Publication number Priority date Publication date Assignee Title
CN1123274A (en) * 1994-08-16 1996-05-29 东国制药株式会社 Process for producing N-allyl-2,5-dimethyl-piperidinol-4-benzoyl ester
CN101497673A (en) * 2009-02-20 2009-08-05 淮海工学院 Process for preparing brominated polystyrene
CN103073546A (en) * 2013-01-31 2013-05-01 吉安市海洲医药化工有限公司 Preparation method of mebhydrolin napadisylate
CN108191741A (en) * 2018-01-22 2018-06-22 济南舜景医药科技有限公司 A kind of synthetic method for bacterial-infection resisting medicine intermediate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1123274A (en) * 1994-08-16 1996-05-29 东国制药株式会社 Process for producing N-allyl-2,5-dimethyl-piperidinol-4-benzoyl ester
CN101497673A (en) * 2009-02-20 2009-08-05 淮海工学院 Process for preparing brominated polystyrene
CN103073546A (en) * 2013-01-31 2013-05-01 吉安市海洲医药化工有限公司 Preparation method of mebhydrolin napadisylate
CN108191741A (en) * 2018-01-22 2018-06-22 济南舜景医药科技有限公司 A kind of synthetic method for bacterial-infection resisting medicine intermediate

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* Cited by examiner, † Cited by third party
Title
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Application publication date: 20191122