CN118108659A - Preparation method of 4-aminomethylpiperidine - Google Patents
Preparation method of 4-aminomethylpiperidine Download PDFInfo
- Publication number
- CN118108659A CN118108659A CN202410099293.7A CN202410099293A CN118108659A CN 118108659 A CN118108659 A CN 118108659A CN 202410099293 A CN202410099293 A CN 202410099293A CN 118108659 A CN118108659 A CN 118108659A
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- China
- Prior art keywords
- reaction
- aminomethylpiperidine
- preparation
- heating
- residual liquid
- Prior art date
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- LTEKQAPRXFBRNN-UHFFFAOYSA-N piperidin-4-ylmethanamine Chemical compound NCC1CCNCC1 LTEKQAPRXFBRNN-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 3
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 claims description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000005893 bromination reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- 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
- C07D211/18—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—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 substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to a preparation method of 4-aminomethylpiperidine, in particular to a preparation method of 4-aminomethylpiperidine by taking 4-methylpyridine as a raw material and synthesizing the 4-aminomethylpiperidine in three steps of hydrogenation reduction and high yield through bromination reaction and substitution reaction; the preparation method of the 4-aminomethylpiperidine provided by the synthetic route is a preparation method which has high yield, low cost, easy operation and suitability for industrialization.
Description
Technical Field
The invention relates to the field of medicines, in particular to a preparation method of 4-aminomethylpiperidine.
Background
4-Aminomethylpiperidine is widely used as a synthetic block for drug synthesis, liquid crystal materials and other polymer materials.
The prior Chinese patent CN104557356 reports that the synthetic route of 4-aminomethylpiperidine is that 4-piperidinecarboxylic acid is used as a raw material to synthesize 4-aminomethylpiperidine by three steps of high-temperature ammoniation reaction, dehydration reaction and hydrogenation reduction, and the method has the defects of harsh reaction conditions, lower yield and higher cost.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a preparation method of 4-aminomethylpiperidine.
The invention adopts the following technical scheme:
a method for preparing 4-aminomethylpiperidine, comprising the steps of:
(1) Adding solvent, 4-methylpyridine, NBS and AIBN into a reaction bottle, heating, refluxing and stirring to react for 8 hours, cooling, filtering, concentrating filtrate to dryness, and directly entering the next reaction.
(2) Adding the concentrated residual liquid in the previous step into DMF, adding ammonium chloride, adding sodium azide, heating to 100 0 ℃ for reaction for 6 hours, cooling, adding the reaction liquid into water, extracting with ethyl acetate, concentrating under reduced pressure to dryness, and entering the next step for reaction.
(3) Adding the concentrated residual liquid in the previous step into ethanol, adding a catalyst, replacing by nitrogen, introducing hydrogen, heating to 80 0 ℃, and maintaining the pressure for 4MPa for reaction. After the reaction is finished, filtering, concentrating the filtrate to be dry, and rectifying the residual liquid to obtain 4-aminomethylpiperidine;
Preferably, the solvent in the first step is carbon tetrachloride.
Preferably, the DMF in step two is 3 times the volume.
Preferably, the catalyst in the third step is ruthenium carbon.
The invention has the beneficial effects that:
1) The invention relates to a preparation method of 4-aminomethylpiperidine, in particular to a method for synthesizing 4-aminomethylpiperidine by taking 4-methylpyridine as a raw material through three steps of bromination reaction, substitution reaction and hydrogenation reduction with high yield.
2) The preparation method of the 4-aminomethylpiperidine provided by the invention is a preparation method which has high yield, low cost, easy operation and suitability for industrialization.
Drawings
FIG. 1 is a scheme showing the reaction of 4-aminomethylpiperidine according to the present invention.
Detailed Description
The technical scheme of the present invention will be clearly and completely described in the following examples. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The embodiment provides a preparation method of 4-aminomethylpiperidine, as shown in fig. 1, specifically comprising the following steps:
(1) 200ml of carbon tetrachloride, 20g of 4-methylpyridine, 40g of NBS and 1g of AIBN are added into a reaction bottle, the mixture is heated, refluxed and stirred for reaction for 8 hours, then cooled, filtered, and the filtrate is concentrated to dryness and directly enters the next reaction.
(2) The concentrated residual liquid in the previous step is added into 100ml of DMF, 15g of ammonium chloride is added, 16g of sodium azide is added, the temperature is raised to 100 0 ℃ for reaction for 6 hours, the temperature is reduced, the reaction liquid is added into 300ml of water, the mixture is extracted with 500ml of ethyl acetate, the mixture is concentrated to dryness under reduced pressure, and the mixture enters the next step of reaction.
(3) Adding the concentrated residual liquid in the previous step into 120ml of ethanol, adding 1.5g of ruthenium carbon, introducing hydrogen after nitrogen substitution, heating to 80 0 ℃ and maintaining the pressure for 4MPa reaction. After the reaction is finished, filtering, concentrating the filtrate to be dry, and rectifying the residual liquid to obtain 12.8g of 4-aminomethylpiperidine, wherein the total yield of the three steps is 52%.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the technical scope of the present invention, so that the technical solutions formed by equivalent substitution or equivalent transformation fall within the scope of the present invention.
Claims (4)
1. A method for preparing 4-aminomethylpiperidine, which is characterized by comprising the following steps:
S1, adding a solvent, 4-methylpyridine, NBS and AIBN into a reaction bottle, heating, refluxing, stirring and reacting for 8 hours, cooling, filtering, concentrating filtrate to dryness, and directly entering the next reaction;
s2, adding the concentrated residual liquid obtained in the previous step into DMF, adding ammonium chloride, adding sodium azide, heating to 1000 ℃ for reaction for 6 hours, cooling, adding the reaction liquid into water, extracting with ethyl acetate, concentrating under reduced pressure to dryness, and entering the next step for reaction;
S3, adding the concentrated residual liquid in the previous step into ethanol, adding a catalyst, replacing nitrogen, introducing hydrogen, heating to 800 ℃, and maintaining the pressure for 4MPa for reaction. After the reaction is finished, filtering, concentrating the filtrate to be dry, and rectifying the residual liquid to obtain the 4-aminomethylpiperidine.
2. A process for the preparation of 4-aminomethylpiperidine according to claim 1, wherein: the solvent in S1 is one of carbon tetrachloride, dichloroethane and chloroform.
3. A process for the preparation of 4-aminomethylpiperidine according to claim 1, wherein: the volume of DMF in S2 is 2-8 times.
4. A process for the preparation of 4-aminomethylpiperidine according to claim 1, wherein: the catalyst in S3 is one of ruthenium carbon, palladium carbon and platinum dioxide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410099293.7A CN118108659A (en) | 2024-01-24 | 2024-01-24 | Preparation method of 4-aminomethylpiperidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410099293.7A CN118108659A (en) | 2024-01-24 | 2024-01-24 | Preparation method of 4-aminomethylpiperidine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118108659A true CN118108659A (en) | 2024-05-31 |
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ID=91209689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410099293.7A Pending CN118108659A (en) | 2024-01-24 | 2024-01-24 | Preparation method of 4-aminomethylpiperidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118108659A (en) |
-
2024
- 2024-01-24 CN CN202410099293.7A patent/CN118108659A/en active Pending
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