CN110483376B - Synthesis method of intermediate N-phenyl-4-piperidone - Google Patents
Synthesis method of intermediate N-phenyl-4-piperidone Download PDFInfo
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- B01J21/00—Catalysts comprising the elements, oxides, or hydroxides of magnesium, boron, aluminium, carbon, silicon, titanium, zirconium, or hafnium
- B01J21/10—Magnesium; Oxides or hydroxides thereof
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- 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
Abstract
The invention discloses a synthetic method of an intermediate N-phenyl-4-piperidone, which comprises the following steps: dissolving aniline in ether, adding a catalyst, adding 3-methyl-1, 3, 5-pentanetriol under stirring, heating for reflux reaction, filtering after the reaction is finished, and distilling under reduced pressure to obtain N-phenyl-4-methyl-4-piperidinol; then, demethylation and oxidation reaction are carried out to prepare the N-phenyl-4-piperidone. The synthesis method has the advantages of simple preparation process operation, short production process, high raw material conversion rate, low production cost and high economic benefit.
Description
Technical Field
The invention relates to the field of medical intermediates, in particular to a synthetic method of an intermediate N-phenyl-4-piperidone.
Background
The heterocyclic compound is the most important structure in chemical substances, is widely distributed in the natural world, and is widely applied to the fields of medicines, pesticides, dyes, fine chemical engineering and the like. Piperidine, also known as piperidine, is an important novel heterocyclic organic intermediate, and piperidine derivatives are widely used in the fields of synthetic medicines, pesticides, rubber auxiliaries and the like. In the rubber auxiliary industry, the rubber accelerator can be used for synthesizing thiuram super vulcanization accelerators, has no pollution and no color change, and is suitable for products which are in contact with light-colored rubber and food; it can also be used for synthesizing dithiocarbamates, and the accelerators are suitable for latex products. In the field of medicine, the piperidine compounds are widely applied to synthesis of drugs for analgesia, anti-inflammation, antipsychotic, anesthesia, choline resistance, allergy resistance, hypertension resistance, tumor resistance and the like; especially in the clinical treatment of some nervous system diseases and allergic diseases. The method is mainly used for synthesizing the rice field herbicide pipindone in the pesticide industry, is a selective non-hormone thiocarbamate herbicide and has good development prospect. Piperidone and derivatives thereof are important piperidine compounds, and carbonyl and adjacent methylene activity in the structure of the piperidone can initiate various organic synthesis reactions, so that a plurality of practical medicines, chemical intermediates, pesticides and the like are derived. The N-substituent-4-piperidone as a drug intermediate has important research value in the field of medicine, is widely used for synthesizing medicaments for relieving pain, reducing blood pressure, resisting allergy, resisting tumors and the like, and the research on the compounds becomes a research hotspot in the field of medicament synthesis.
Due to the wide range of applications of piperidone derivatives, research on the synthesis thereof has been receiving extensive attention. The currently used synthetic routes mainly include: (1) the diester is used as a raw material for synthesis, and the initial raw material of the method is cheap; (2) the pyridine oxide is used as a raw material for synthesis, and the method is relatively complex to operate; (3) the method is synthesized by taking secondary amine and acrylonitrile or acrylic ester as raw materials, and the product yield is high; (4) synthesized by Michael addition, cyclization and decarboxylation. Although the method has certain research results, the method still has some defects, so that the research and development of a more efficient and simple preparation method has important research significance.
Chinese patent CN201210163554.4 discloses an N-substituent-4-piperidone compound and its synthesis method, wherein the general formula is: r is C1-C8 alkyl, phenyl or benzyl, etc. The invention is characterized in that appropriate primary amine and 1, 5-dichloro-3-pentanone are selected to carry out ring closure reaction to prepare N-substituent-4-piperidone. The selected 1, 5-dichloro-3-pentanone can be purchased directly or synthesized by two steps: (1) adding thionyl chloride into acrylic acid, and carrying out addition and acyl chlorination to obtain 3-chloropropionyl chloride under the catalysis of N, N-dimethylformamide; (2) introducing ethylene gas into dichloromethane solution of 3-chloropropionyl chloride, and performing Friedel-crafts reaction to obtain the 1, 5-dichloro-3-pentanone. The method has the advantages of wide raw material source, mild reaction conditions, simple operation, low production cost, high yield and good industrial production prospect.
Disclosure of Invention
The invention aims to provide a synthetic method of an intermediate N-phenyl-4-piperidone, which has the advantages of simple preparation process operation, short production process, high raw material conversion rate, lower production cost and higher economic benefit.
In order to achieve the purpose, the invention adopts the following technical scheme:
a synthetic method of an intermediate N-phenyl-4-piperidone comprises the following steps:
(1) dissolving aniline in ether, adding catalyst, adding 3-methyl-1 under stirring,
heating 3, 5-pentanetriol for reflux reaction, filtering after the reaction is finished, and distilling under reduced pressure to prepare N-phenyl-4-methyl-4-piperidinol;
(2) mixing AlCl3Adding into ethanethiol, mixing and stirring, heating to 60-80 deg.C, adding the obtained N-phenyl-4-methyl-4-piperidinol, stirring for reacting for 16-24 hr, cooling to room temperature, stopping reaction, and distilling under reduced pressure to obtain N-phenyl-4-piperidinol;
(3) dissolving the prepared N-phenyl-4-piperidinol in toluene, adding CrO3Heating, keeping the temperature at 60-80 ℃, reacting for 2-3h under the condition of stirring, filtering after the reaction is finished, distilling under reduced pressure, and recrystallizing to obtain the N-phenyl-4-piperidone;
wherein the catalyst is MgO-Al2O3-TiO2A composite oxide.
Preferably, the MgO-Al2O3-TiO2A method for producing a composite oxide, comprising the steps of: dissolving magnesium nitrate and aluminum nitrate in water, adding CTAB, stirring, and adding nanometer TiO2Ultrasonically dispersing the powder at 60-70 deg.C for 1-2h, vigorously stirring at 70-80 deg.C, and adding NaOH and Na dropwise2CO3After the dripping is finished, the mixed solution is continuously stirred for 90-120min, after the stirring is stopped, the mixed solution is kept stand for 36h at the temperature of 70-80 ℃, and then the mixed solution is filtered, washed, dried and calcined for 3-4h at the temperature of 620-750 ℃ to prepare the MgO-Al2O3-TiO2A composite oxide.
Preferably, MgO, Al in the catalyst2O3，TiO2The content mole ratio is 6: 1: 1.
preferably, the MgO-Al2O3-TiO2In the preparation method of the composite oxide, the mass ratio of the consumption of CTAB to the consumption of magnesium nitrateIs 1: 9; NaOH and Na2CO3NaOH and Na in the mixed solution of2CO3Is 3: 1.
preferably, the mass ratio of the aniline to the catalyst is 5: 3-4.
Preferably, the aniline and the 3-methyl-1, 3, 5-pentanetriol are used in a molar ratio of 1: 1.3-1.6.
Preferably, the AlCl is3The molar volume ratio in ethanethiol is 1 mol/L.
Preferably, the AlCl is3And N-phenyl-4-methyl-4-piperidinol in a molar ratio of 1: 1.
preferably, the N-phenyl-4-piperidinol is reacted with CrO3Is 1: 1.2-1.5.
The present invention has the following advantageous effects in that,
1. aniline and 3-methyl-1, 3, 5-pentanetriol are used as raw materials for reaction, the raw materials are cheap and easy to obtain, and the production cost is effectively reduced. Using MgO-Al2O3-TiO2The composite oxide is used as a catalyst for catalytic reaction, so that the conversion rate of raw materials is improved, byproducts are reduced, and the yield is improved.
2. Prepared MgO-Al2O3-TiO2The composite oxide has a large specific surface area and can be fully contacted with reaction raw materials, so that the reaction is carried out more efficiently. Using MgO and Al simultaneously2O3、TiO2The prepared composite oxide is used for catalyzing reaction, so that the coordination catalysis among three oxides is facilitated, and the catalytic efficiency of the catalyst is improved.
Detailed Description
In order to better understand the present invention, the following examples further illustrate the invention, the examples are only used for explaining the invention, not to constitute any limitation of the invention.
Example 1
MgO-Al2O3-TiO2A method for producing a composite oxide, comprising the steps of: dissolving magnesium nitrate and aluminum nitrate in water,adding CTAB into the mixture, stirring the mixture evenly, and adding nano TiO2Ultrasonically dispersing the powder at 60 deg.C for 1-2 hr, vigorously stirring at 70-80 deg.C, and adding NaOH and Na dropwise2CO3Stirring for 90min after the dripping is finished, standing for 36h at 70 ℃, filtering, washing, drying, and standing at 700 ℃ after the stirring is stopped
Calcining for 4h to obtain the MgO-Al2O3-TiO2A composite oxide.
Wherein MgO, Al2O3，TiO2The content mole ratio is 6: 1: 1; the mass ratio of the CTAB usage amount to the magnesium nitrate usage amount is 1: 9; NaOH and Na2CO3NaOH and Na in the mixed solution of2CO3Is 3: 1.
example 2
A synthetic method of an intermediate N-phenyl-4-piperidone comprises the following steps:
(1) dissolving aniline in ether, adding a catalyst, adding 3-methyl-1, 3, 5-pentanetriol under stirring, heating for reflux reaction, filtering after the reaction is finished, and distilling under reduced pressure to obtain N-phenyl-4-methyl-4-piperidinol;
(2) mixing AlCl3Adding into ethanethiol, mixing and stirring, heating to 60 deg.C, adding into the obtained N-phenyl-4-methyl-4-piperidinol, stirring for reacting for 16 hr, cooling to room temperature, stopping reaction, and distilling under reduced pressure to obtain N-phenyl-4-piperidinol;
(3) dissolving the prepared N-phenyl-4-piperidinol in toluene, adding CrO3Heating, keeping the temperature at 60 ℃, reacting for 2 hours under the condition of stirring, filtering, distilling under reduced pressure and recrystallizing after the reaction is finished to prepare the N-phenyl-4-piperidone;
wherein the catalyst was MgO-Al prepared in example 12O3-TiO2A composite oxide.
The mass ratio of the aniline to the catalyst is 5: 3. the molar ratio of the aniline to the 3-methyl-1, 3, 5-pentanetriol is 1:1.3。AlCl3the molar volume ratio in the ethanethiol is 1 mol/L; AlCl3And N-phenyl-4-methyl-4-piperidinol in a molar ratio of 1: 1. n-phenyl-4-piperidinol with CrO3Is 1: 1.2.
the yield of the prepared N-phenyl-4-piperidone was 87.4%, and the purity was 99.3%.
Example 3
A synthetic method of an intermediate N-phenyl-4-piperidone comprises the following steps:
(1) dissolving aniline in ether, adding a catalyst, adding 3-methyl-1, 3, 5-pentanetriol under stirring, heating for reflux reaction, filtering after the reaction is finished, and distilling under reduced pressure to obtain N-phenyl-4-methyl-4-piperidinol;
(2) mixing AlCl3Adding into ethanethiol, mixing and stirring, heating to 80 deg.C, adding the obtained N-phenyl-4-methyl-4-piperidinol, stirring for reacting for 24 hr, cooling to room temperature, stopping reaction, and distilling under reduced pressure to obtain N-phenyl-4-piperidinol;
(3) dissolving the prepared N-phenyl-4-piperidinol in toluene, adding CrO3Heating, keeping the temperature at 80 ℃, reacting for 3 hours under the condition of stirring, filtering, distilling under reduced pressure and recrystallizing after the reaction is finished to prepare the N-phenyl-4-piperidone;
wherein the catalyst was MgO-Al prepared in example 12O3-TiO2A composite oxide.
The mass ratio of the aniline to the catalyst is 5: 4. the molar ratio of the aniline to the 3-methyl-1, 3, 5-pentanetriol is 1: 1.6. AlCl3The molar volume ratio in the ethanethiol is 1 mol/L; AlCl3And N-phenyl-4-methyl-4-piperidinol in a molar ratio of 1: 1. n-phenyl-4-piperidinol with CrO3Is 1: 1.5.
the yield of the prepared N-phenyl-4-piperidone was 87.2%, and the purity was 99.4%.
Example 4
A synthetic method of an intermediate N-phenyl-4-piperidone comprises the following steps:
(1) dissolving aniline in ether, adding a catalyst, adding 3-methyl-1, 3, 5-pentanetriol under stirring, heating for reflux reaction, filtering after the reaction is finished, and distilling under reduced pressure to obtain N-phenyl-4-methyl-4-piperidinol;
(2) mixing AlCl3Adding into ethanethiol, mixing and stirring, heating to 60 deg.C, and adding into ethanol
Adding the prepared N-phenyl-4-methyl-4-piperidinol, reacting under stirring, cooling to room temperature after reacting for 24h, stopping reaction, and distilling under reduced pressure to obtain N-phenyl-4-piperidinol;
(3) dissolving the prepared N-phenyl-4-piperidinol in toluene, adding CrO3Heating, keeping the temperature at 60 ℃, reacting for 3 hours under the stirring condition, filtering, distilling under reduced pressure and recrystallizing after the reaction is finished to prepare the N-phenyl-4-piperidone;
wherein the catalyst was MgO-Al prepared in example 12O3-TiO2A composite oxide.
The mass ratio of the aniline to the catalyst is 5: 3. the molar ratio of the aniline to the 3-methyl-1, 3, 5-pentanetriol is 1: 1.6. AlCl3The molar volume ratio in the ethanethiol is 1 mol/L; AlCl3And N-phenyl-4-methyl-4-piperidinol in a molar ratio of 1: 1. n-phenyl-4-piperidinol with CrO3Is 1: 1.2.
the yield of the prepared N-phenyl-4-piperidone was 87.1%, and the purity was 99.1%.
Example 5
A synthetic method of an intermediate N-phenyl-4-piperidone comprises the following steps:
(1) dissolving aniline in ether, adding a catalyst, adding 3-methyl-1, 3, 5-pentanetriol under stirring, heating for reflux reaction, filtering after the reaction is finished, and distilling under reduced pressure to obtain N-phenyl-4-methyl-4-piperidinol;
(2) mixing AlCl3Adding into ethanethiol, mixing, stirring, heating to 80 deg.C, and adding the obtained N-phenyl-4-methyl-4-piperidineReacting alcohol under stirring, cooling to room temperature after reacting for 16h, stopping reaction, and distilling under reduced pressure to obtain N-phenyl-4-piperidinol;
(3) dissolving the prepared N-phenyl-4-piperidinol in toluene, adding CrO3Heating, keeping the temperature at 80 ℃, reacting for 2 hours under the condition of stirring, filtering, distilling under reduced pressure and recrystallizing after the reaction is finished to prepare the N-phenyl-4-piperidone;
wherein the catalyst was MgO-Al prepared in example 12O3-TiO2A composite oxide.
The mass ratio of the aniline to the catalyst is 5: 4. the molar ratio of the aniline to the 3-methyl-1, 3, 5-pentanetriol is 1: 1.3. AlCl3The molar volume ratio in the ethanethiol is 1 mol/L; AlCl3And N-phenyl-4-methyl-4-piperidinol in a molar ratio of 1: 1. n-phenyl-4-piperidinol with CrO3Is 1: 1.5.
the yield of the prepared N-phenyl-4-piperidone was 88.9%, and the purity was 99.5%.
Example 6
A synthetic method of an intermediate N-phenyl-4-piperidone comprises the following steps:
(1) dissolving aniline in ether, adding a catalyst, adding 3-methyl-1, 3, 5-pentanetriol under stirring, heating for reflux reaction, filtering after the reaction is finished, and distilling under reduced pressure to obtain N-phenyl-4-methyl-4-piperidinol;
(2) mixing AlCl3Adding into ethanethiol, mixing and stirring, heating to 70 deg.C, adding the obtained N-phenyl-4-methyl-4-piperidinol, stirring for reacting for 20 hr, cooling to room temperature, stopping reaction, and distilling under reduced pressure to obtain N-phenyl-4-piperidinol;
(3) dissolving the prepared N-phenyl-4-piperidinol in toluene, adding CrO3Heating, keeping the temperature at 70 ℃, reacting for 2-3h under the condition of stirring, filtering after the reaction is finished, distilling under reduced pressure, and recrystallizing to obtain the N-phenyl-4-piperidone;
wherein the catalyst is MgO-A prepared in example 1l2O3-TiO2A composite oxide.
The mass ratio of the aniline to the catalyst is 5: 3. the molar ratio of the aniline to the 3-methyl-1, 3, 5-pentanetriol is 1: 1.5. AlCl3The molar volume ratio in the ethanethiol is 1 mol/L; AlCl3And N-phenyl-4-methyl-4-piperidinol in a molar ratio of 1: 1. n-phenyl-4-piperidinol with CrO3Is 1: 1.4.
the yield of the prepared N-phenyl-4-piperidone was 89.2%, and the purity was 99.5%.
Claims (9)
1. A synthetic method of an intermediate N-phenyl-4-piperidone is characterized by comprising the following steps:
(1) dissolving aniline in ether, adding a catalyst, adding 3-methyl-1, 3, 5-pentanetriol under stirring, heating for reflux reaction, filtering after the reaction is finished, and distilling under reduced pressure to obtain N-phenyl-4-methyl-4-piperidinol;
(2) mixing AlCl3Adding into ethanethiol, mixing and stirring, heating to 60-80 deg.C, adding the obtained N-phenyl-4-methyl-4-piperidinol, stirring for reacting for 16-24 hr, cooling to room temperature, stopping reaction, and distilling under reduced pressure to obtain N-phenyl-4-piperidinol;
(3) dissolving the prepared N-phenyl-4-piperidinol in toluene, adding CrO3Heating, keeping the temperature at 60-80 ℃, reacting for 2-3h under the condition of stirring, filtering after the reaction is finished, distilling under reduced pressure, and recrystallizing to obtain the N-phenyl-4-piperidone;
wherein the catalyst is MgO-Al2O3-TiO2A composite oxide.
2. The method for synthesizing the intermediate N-phenyl-4-piperidone according to claim 1, comprising the following steps: the MgO-Al2O3-TiO2A method for producing a composite oxide, comprising the steps of: dissolving magnesium nitrate and aluminum nitrate in water, adding CTAB, stirring, and adding nanometer TiO2Ultrasonically dispersing the powder at 60-70 deg.C for 1-2h, vigorously stirring at 70-80 deg.C, and adding NaOH and Na dropwise2CO3After the dripping is finished, the mixed solution is continuously stirred for 90-120min, after the stirring is stopped, the mixed solution is kept stand for 36h at the temperature of 70-80 ℃, and then the mixed solution is filtered, washed, dried and calcined for 3-4h at the temperature of 620-750 ℃ to prepare the MgO-Al2O3-TiO2A composite oxide.
3. The method for synthesizing intermediate N-phenyl-4-piperidone according to claim 1 or 2,
the method is characterized in that: MgO, Al in the catalyst2O3，TiO2The content mole ratio is 6: 1: 1.
4. the method for synthesizing the intermediate N-phenyl-4-piperidone as described in claim 2, comprising the following steps: the MgO-Al2O3-TiO2In the preparation method process of the composite oxide, the mass ratio of the consumption of CTAB to the consumption of magnesium nitrate is 1: 9; NaOH and Na2CO3NaOH and Na in the mixed solution of2CO3Is 3: 1.
5. the method for synthesizing the intermediate N-phenyl-4-piperidone according to claim 1, comprising the following steps: the mass ratio of the aniline to the catalyst is 5: 3-4.
6. The method for synthesizing the intermediate N-phenyl-4-piperidone according to claim 1, comprising the following steps: the molar ratio of the aniline to the 3-methyl-1, 3, 5-pentanetriol is 1: 1.3-1.6.
7. The method for synthesizing the intermediate N-phenyl-4-piperidone according to claim 1, comprising the following steps: the AlCl3The molar volume ratio in ethanethiol is 1 mol/L.
8. The method of claim 1The synthesis method of the intermediate N-phenyl-4-piperidone is characterized in that: the AlCl3And N-phenyl-4-methyl-4-piperidinol in a molar ratio of 1: 1.
9. the method for synthesizing the intermediate N-phenyl-4-piperidone according to claim 1, comprising the following steps: the N-phenyl-4-piperidinol and CrO3Is 1: 1.2-1.5.
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| US5891889A (en) * | 1996-04-03 | 1999-04-06 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
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Inventor after: Jin Yueshuang Inventor after: Tang Yiqiang Inventor after: Lu Xuelei Inventor after: Li Shufeng Inventor after: Chen Jianjiang Inventor before: Chen Jianjiang |
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Effective date of registration: 20201010 Address after: No. 146, Fenyuan street, Xinzhou Development Zone, Shanxi Province Applicant after: Shanxi Zhichuang Pharmaceutical Research Technology Co., Ltd Address before: 317500 418 Dian Dian Cun, New River Town, Wenling City, Taizhou, Zhejiang Applicant before: Chen Jianjiang |
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