CN103524457A - Synthetic method of medicinal intermediate acetylpiperidine - Google Patents

Synthetic method of medicinal intermediate acetylpiperidine Download PDF

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Publication number
CN103524457A
CN103524457A CN201310417193.6A CN201310417193A CN103524457A CN 103524457 A CN103524457 A CN 103524457A CN 201310417193 A CN201310417193 A CN 201310417193A CN 103524457 A CN103524457 A CN 103524457A
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Prior art keywords
piperidines
synthetic method
ethanoyl
content
solvent
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李可庆
胡方中
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Jiangsu Jixian Green Chemistry Science & Technology Research Institute Co Ltd
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Jiangsu Jixian Green Chemistry Science & Technology Research Institute Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a synthetic method of a medicinal intermediate acetylpiperidine. The synthetic method comprises the following steps: adding a solvent, piperidine and a NaOH aqueous solution into a reactor in sequence, cooling to minus 10-10 DEG C, dropwise adding acetyl chloride, ethenone or acetic anhydride slowly, performing heat preservation after dropwise adding until the GC normalization method content of the piperidine is less than or equal to 0.5%, standing for demixing, and taking an upper oil layer which is acetylpiperidine, wherein the solvent is methylbenzene, dimethylbenzene, ethyl acetate, methylene chloride or chloroform. The synthetic method disclosed by the invention is easy to operate, simple in equipment, less in three wastes and low in cost.

Description

A kind of synthetic method of medicine intermediate ethanoyl piperidines
Technical field
The present invention relates to a kind of medical cinnamide compound intermediate, relate in particular to the synthetic method of medicine intermediate ethanoyl piperidines.
Background technology
Ethanoyl piperidines, molecular formula C 7h 13nO, molecular weight 127.18, as a kind of medicine intermediate, can participate in the preparation of multiple compounds, ethanoyl piperidines, its chemical formula is as follows:
Figure 2013104171936100002DEST_PATH_IMAGE001
But the complex process of prior art synthesis of acetyl phenylpiperidines, and cost is higher.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of synthetic method of ethanoyl piperidines, technique is simple, and cost is low.
The present invention is by the following technical solutions:
A synthetic method for medicine intermediate ethanoyl piperidines, comprises the following steps:
The first step, the NaOH aqueous solution that is 25-35% by solvent, piperidines, mass concentration drop into reactor successively, are cooled to-10 ℃～10 ℃, slowly drip Acetyl Chloride 98Min., ketene or acetic anhydride, dropwise rear insulation 1-2 hour;
Second step, the content of piperidines is analyzed, if the content of piperidines is greater than 0.5%, continued insulation, until piperidines content≤0.5%; If content≤0.5% of piperidines, enters the 3rd step;
The 3rd step, stratification, get upper strata oil reservoir, i.e. ethanoyl piperidines;
Solvent is toluene, dimethylbenzene, ethyl acetate, methylene dichloride or chloroform.
As preferably, the weight ratio scope of the NaOH aqueous solution and piperidines is 1:1～2:1.
As preferably, the weight ratio scope of solvent and piperidines is 1:1～3:1.
As preferably, the weight ratio scope of Acetyl Chloride 98Min., ketene or acetic anhydride and piperidines is 0.8:1～2:1.
During second step sampling analysis, preferably every 0.3-0.5 hour sampling analysis once.
In above-mentioned steps, to the mensuration of piperidines, can be to measure by the vapor-phase chromatography long-pending method for normalizing of showing up.
Medicine intermediate prepared by the present invention can be widely used in the preparation of pharmaceutical prod, Antiepjleptica (according to carrying out western amine) for example, and Processes and apparatus is simple, cost is low, processing ease, the three wastes are few, does not pollute the environment.
Embodiment
Below by specific embodiment, the present invention is further described in detail.
Embodiment 1
In 500ml round-bottomed flask, add successively 150g toluene, piperidines (content 99%) 85.8g(1mol), the NaOH aqueous solution 160g(1.2mol that mass concentration is 30%), be cooled to-10 ℃, dropping 87.2g(1.1mol) Acetyl Chloride 98Min. (99%), after dropwising, is incubated 1 hour.Sampling analysis is until piperidines content≤0.5%, stratification.Upper strata is the toluene solution of ethanoyl piperidines.The intermediate ethanoyl piperidines 276g that weighs to obtain, analyzes content (GC normalization method) 99.1%.Reaction yield 98.3%.
The chemical equation of this reaction is as follows:
Figure 244579DEST_PATH_IMAGE002
1H NMR(300MHz，CDCl3)：δ4.2(m，2H)，2.8(m，2H)，2.5(m，1H)，2.2(s，3H)，2.1(m，2H)，1.4(m，2H)，1.4(s，9H).
13C NMR(100MHz，CDCl3)：δ166.39，148.81，148.17，141.91，129.90，123.56，115.68，108.45，106.32，101.39，46.95，43.32，26.76，25.62，24.66.
MS [M + H]+ 127.20.
Embodiment 2
In 250ml round-bottomed flask, add successively 75g toluene, piperidines (content 99%) 42.9g(0.5mol), the NaOH aqueous solution 80g(0.6mol that mass concentration is 30%), be cooled to 10 ℃, dropping 43.g6(0.55mol) Acetyl Chloride 98Min. (99%), after dropwising, is incubated 1 hour.Sampling analysis is until piperidines content≤0.5%, stratification.Upper strata is the toluene solution of ethanoyl piperidines.The intermediate ethanoyl piperidinyl-1 37.8g that weighs to obtain, analyzes content (GC normalization method) 99.2%.Reaction yield 98.4%.
1H NMR(300MHz，CDCl3)：δ4.2(m，2H)，2.8(m，2H)，2.5(m，1H)，2.2(s，3H)，2.1(m，2H)，1.4(m，2H)，1.4(s，9H).
13C NMR(100MHz，CDCl3)：δ165.39，154.81，148.17，141.91，129.90，123.56，115.68，108.45，106.32，101.39，46.95，43.32，26.76，25.62，24.66.
MS [M + H]+ 127.21.
Embodiment 3
In 1000ml round-bottomed flask, add successively 300g toluene, piperidines (content 99%) 171.6g(2mol), the NaOH aqueous solution 320g(2.4mol that mass concentration is 30%), be cooled to 0 ℃, dropping 174.4g(2.2mol) Acetyl Chloride 98Min. (99%), after dropwising, is incubated 1 hour.Sampling analysis is until piperidines content≤0.5%, stratification.Upper strata is the toluene solution of ethanoyl piperidines.The intermediate ethanoyl piperidines 553g that weighs to obtain, analyzes content (GC normalization method) 98.8%.Reaction yield 98.4%.
1H NMR(300MHz，CDCl3)：δ4.1(m，2H)，2.8(m，2H)，2.5(m，1H)，2.2(s，3H)，2.1(m，2H)，1.4(m，2H)，1.4(s，9H).
13C NMR(100MHz，CDCl3)：δ165.39，148.81，148.17，141.91，129.90，122.56，115.68，108.45，106.32，101.39，46.95，43.32，26.76，25.62，24.66.
MS [M + H]+ 127.17.
Embodiment 4
In 500ml round-bottomed flask, add successively 20g ethyl acetate, piperidines (content 99%) 20g, the NaOH aqueous solution 20g that mass concentration is 25%, is cooled to 5 ℃, slowly drips the acetic anhydride (99%) of 16g, after dropwising, is incubated 1.5 hours.Sampling analysis is until piperidines GC normalization method content≤0.5% reacts end, stratification.Upper strata is the toluene solution of ethanoyl piperidines.The intermediate ethanoyl piperidines 39g that weighs to obtain, analyzes content (GC normalization method) 98.1%.Reaction yield 99.7%.
1H NMR(300MHz，CDCl3)：δ4.2(m，2H)，2.8(m，2H)，2.5(m，1H)，2.1(s，3H)，2.1(m，2H)，1.4(m，2H)，1.4(s，9H).
13C NMR(100MHz，CDCl3)：δ165.39，148.81，148.17，141.91，129.90，123.56，115.68，108.45，106.32，101.39，46.95，43.32，28.76，25.62，24.66.
MS [M + H]+ 127.17.
Embodiment 5
In 500ml round-bottomed flask, add successively 240g methylene dichloride, piperidines (content 99%) 80g, the NaOH aqueous solution 160g that mass concentration is 35%, is cooled to-5 ℃, slowly drips the ketene (99%) of 160g, after dropwising, is incubated 2 hours.Sampling analysis is until piperidines GC normalization method content≤0.5% reacts end, stratification.Upper strata is the toluene solution of ethanoyl piperidines.The intermediate ethanoyl piperidines 283g that weighs to obtain, analyzes content (GC normalization method) 98.9%.Reaction yield 97.9%.
1H NMR(300MHz，CDCl3)：δ4.2(m，2H)，2.8(m，2H)，2.5(m，1H)，2.2(s，3H)，2.0(m，2H)，1.4(m，2H)，1.4(s，9H).
13C NMR(100MHz，CDCl3)：δ165.39，148.81，147.17，141.91，129.90，123.56，115.68，108.45，106.32，101.39，46.95，43.32，26.76，25.62，24.66.
MS [M + H]+ 127.20.
In addition, the invention is not restricted to above-mentioned embodiment, as long as within not exceeding scope of the present invention, can take variety of way to implement the present invention.

Claims (4)

1. a synthetic method for medicine intermediate ethanoyl piperidines, is characterized in that comprising the following steps:
The first step, the NaOH aqueous solution that is 25-35% by solvent, piperidines, mass concentration drop into reactor successively, are cooled to-10 ℃～10 ℃, slowly drip Acetyl Chloride 98Min., ketene or acetic anhydride, dropwise rear insulation 1-2 hour;
Second step, the content of piperidines is analyzed, if the content of piperidines is greater than 0.5%, continued insulation, until piperidines content≤0.5%;
The 3rd step, stratification, get upper strata oil reservoir, i.e. ethanoyl piperidines;
Solvent is toluene, dimethylbenzene, ethyl acetate, methylene dichloride or chloroform.
2. the synthetic method of medicine intermediate ethanoyl piperidines according to claim 1, is characterized in that: the weight ratio scope of the NaOH aqueous solution and piperidines is 1:1～2:1.
3. the synthetic method of medicine intermediate ethanoyl piperidines according to claim 1, is characterized in that: the weight ratio scope of solvent and piperidines is 1:1～3:1.
4. the synthetic method of medicine intermediate ethanoyl piperidines according to claim 1, is characterized in that: the weight ratio scope of Acetyl Chloride 98Min., ketene or acetic anhydride and piperidines is 0.8:1～2:1.
CN201310417193.6A 2013-09-13 2013-09-13 Synthetic method of medicinal intermediate acetylpiperidine Pending CN103524457A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089897A1 (en) * 2003-04-07 2004-10-21 Glaxo Group Limited Compounds having activity at 5ht2c receptor and uses thereof
CN1599607A (en) * 2001-10-16 2005-03-23 恩都制药公司 Carbinols for the treatment of neuropathic dysfunction
CN102295623A (en) * 2011-05-26 2011-12-28 山东汇海医药化工有限公司 Method for preparing N-acetylmorpholine by using ketene

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1599607A (en) * 2001-10-16 2005-03-23 恩都制药公司 Carbinols for the treatment of neuropathic dysfunction
WO2004089897A1 (en) * 2003-04-07 2004-10-21 Glaxo Group Limited Compounds having activity at 5ht2c receptor and uses thereof
CN102295623A (en) * 2011-05-26 2011-12-28 山东汇海医药化工有限公司 Method for preparing N-acetylmorpholine by using ketene

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
T. H. GRENBY ET AL.: "Biochemical studies of toxic agents. XII. The biosynthesis of n-propylmercapturic acid from n-propyl halides", 《BIOCHEM. J.》, vol. 75, 31 December 1960 (1960-12-31), pages 28 - 33 *
ZHIHUI LIU ET AL.: "Design, Synthesis, Structure, and Acaricidal/Insecticidal Activity of Novel Spirocyclic Tetronic Acid Derivatives Containing an Oxalyl Moiety", 《J. AGRIC. FOOD CHEM.》, vol. 59, 1 November 2011 (2011-11-01), pages 12543 - 12549 *

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Application publication date: 20140122