CN112300064A - Synthesis process of 1-methyl-4-aminopiperidine - Google Patents
Synthesis process of 1-methyl-4-aminopiperidine Download PDFInfo
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- CN112300064A CN112300064A CN202011392447.XA CN202011392447A CN112300064A CN 112300064 A CN112300064 A CN 112300064A CN 202011392447 A CN202011392447 A CN 202011392447A CN 112300064 A CN112300064 A CN 112300064A
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- CN
- China
- Prior art keywords
- methyl
- aminopiperidine
- piperidone
- mass ratio
- dichloromethane
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000008569 process Effects 0.000 title claims abstract description 25
- ALOCUZOKRULSAA-UHFFFAOYSA-N 1-methylpiperidin-4-amine Chemical compound CN1CCC(N)CC1 ALOCUZOKRULSAA-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 claims abstract description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 7
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000005457 ice water Substances 0.000 claims description 8
- 230000002194 synthesizing effect Effects 0.000 claims description 7
- 239000008346 aqueous phase Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- 239000002904 solvent Substances 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000002262 Schiff base Substances 0.000 abstract description 3
- 150000004753 Schiff bases Chemical class 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 238000011112 process operation Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- -1 piperidine compound Chemical class 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000010643 digestive system disease Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 208000018685 gastrointestinal system disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a synthesis process of 1-methyl-4-aminopiperidine, which comprises the steps of taking 1-methyl-4-piperidone as a main raw material, taking dichloromethane as a solvent, forming Schiff base by ammonia water, and reducing by sodium borohydride to obtain a target compound 1-methyl-4-aminopiperidine; the raw materials are simple and easy to obtain, the process operation is simple, the reaction condition is mild, and the method is suitable for industrial amplification.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis process of 1-methyl-4-aminopiperidine.
Background
The piperidine compound is an important medical intermediate and a fine chemical raw material, is widely applied to various aspects of medicines, biology, pesticides and the like, and has a wide application range and a wide market prospect. 1-methyl-4-aminopiperidine is also widely used as an important compound. For example, in the field of medicine, the compound is an important intermediate of a plurality of medicines and medicines under research, such as the compound used for synthesizing the medicine of the gastrointestinal disorder and the dyspepsia, and can also be used for synthesizing anti-tumor, anti-virus and anti-oxidation medicines.
The synthesis process of 1-methyl-4-aminopiperidine, especially the industrial production process, has not been studied much at home and abroad. There are mainly the following process routes. (1) 1-methyl-4-piperidone is taken as a main raw material, Schiff base is formed by ammonium formate, and then palladium-carbon is used for hydrogenation reduction to obtain a target product. The second stage of the process adopts palladium-carbon hydrogenation reduction, so that the cost is high, the process risk is high, and the process is not suitable for industrial production. (2) 1-methyl-4-piperidone is taken as a main raw material, ether is taken as a solvent, hydrochloric acid is reacted to prepare a hydrochloride form, methanol is taken as a solvent, a molecular sieve is added, ammonium acetate is used for forming Schiff base, and then sodium cyanoborohydride is used for reduction to obtain the target product. The main raw materials and auxiliary materials of the process are cheaper, but the process is more complex, and the low-boiling-point and extremely flammable diethyl ether is used, so that the process is not suitable for industrial production. In conclusion, the development of a simple and convenient production process of 1-methyl-4-aminopiperidine, which is suitable for industrialization, has important significance.
Disclosure of Invention
In order to solve the problems, the invention discloses a synthesis process of 1-methyl-4-aminopiperidine, which has the advantages of simple and easily obtained raw materials, easily controlled reaction, no high-pressure dangerous operation, no dangerous solvent and simple post-treatment.
In order to achieve the purpose, the invention provides the following technical scheme:
a synthesis process of 1-methyl-4-aminopiperidine comprises the following steps:
(1) mixing 1-methyl-4-piperidone, dichloromethane and ammonia water, and performing reflux reaction for 4-7 hours to obtain an intermediate reaction solution;
(2) cooling the intermediate reaction liquid to 5-10 ℃, adding sodium borohydride, and performing reflux reaction for 6-12 hours;
(3) cooling the reaction liquid obtained in the step (2) to 25-30 ℃, adding the reaction liquid into ice water, dropwise adding concentrated hydrochloric acid to adjust the pH value, stirring for 10min, and filtering to obtain a filtrate;
(4) standing the filtrate for layering, collecting an aqueous phase, adjusting the pH of the aqueous phase with 30% sodium hydroxide, extracting with dichloromethane for three times, combining organic phases, concentrating the organic phases under reduced pressure to obtain a crude product, and rectifying the crude product under reduced pressure to obtain the 1-methyl-4-aminopiperidine.
Further, in the step (1), the mass ratio of the 1-methyl-4-piperidone to the dichloromethane is 1: 3.5 to 5.5.
Further, the mass ratio of the 1-methyl-4-piperidone in the step (1) to the ammonia water is 1: 1.5-2.5; the concentration of the ammonia water is 28%.
Further, the mass ratio of the sodium borohydride in the step (2) to the 1-methyl-4-piperidone in the step (1) is 0.5-1.0: 1.
further, the mass ratio of the ice water in the step (3) to the 1-methyl-4-piperidone in the step (1) is 7-10: 1.
further, in the step (3), the pH value is adjusted to 1-4.
Further, in the step (4), the pH value is adjusted to 8-11.
Further, the mass ratio of the amount of dichloromethane used for extraction to 1-methyl-4-piperidone in the step (4) is 3.5-5.5: 1.
compared with the prior art, the invention has the following advantages and beneficial effects: the synthesis process of the 1-methyl-4-aminopiperidine provided by the invention has the advantages of simple and easily obtained raw materials, easily controlled reaction, no high-pressure dangerous operation, no dangerous solvent and simple post-treatment, and is suitable for industrial amplification.
Detailed Description
The technical solutions provided by the present invention will be described in detail below with reference to specific examples, and it should be understood that the following specific embodiments are only illustrative of the present invention and are not intended to limit the scope of the present invention.
Example 1
113.2g of 1-methyl-4-piperidone, 500g of dichloromethane and 250g of ammonia water are put into a 2L reaction bottle, and stirring is started. The reaction solution is refluxed and reacted for 4 hours until the raw materials are completely reacted. And cooling the reaction liquid to 5-10 ℃ in an ice water bath. 75.6g of sodium borohydride is taken and added into the reaction solution slowly in batches, and the internal temperature is maintained below 30 ℃. After the addition, the reaction is carried out for 6 hours under reflux until the intermediate reaction is completed. Cooling to 25-30 ℃, adding 1000g of ice water, slowly dropwise adding concentrated hydrochloric acid until the pH value is 2-3, and stirring for 10min. Filtering and collecting filtrate. The filtrate was separated and the aqueous phase was collected. And adjusting the pH of the water phase to 9-10 by using 30% sodium hydroxide. The mixture was extracted 3 times with 500g of dichloromethane. And combining organic phases, and concentrating under reduced pressure at 50-55 ℃ until no liquid drips. And (3) carrying out vacuum rectification on the crude product by using a water pump to obtain 78.7g of a product, wherein the yield is 69.0%, and the GC purity is over 98%.
Example 2
The process was scaled up according to the reaction conditions of example 1, with the specific steps:
3.4kg of 1-methyl-4-piperidone, 15kg of dichloromethane and 7.5kg of ammonia water are put into a 50L reaction bottle, and stirring is started. The reaction solution is refluxed and reacted for 7 hours until the raw materials are completely reacted. And cooling the reaction liquid to 5-10 ℃ in an ice water bath. 2.3kg of sodium borohydride is taken and added into the reaction liquid slowly in batches, and the internal temperature is maintained below 30 ℃. After the addition, the reaction is carried out for 12 hours under reflux until the intermediate reaction is completed. Cooling to 25-30 ℃, adding 30kg of ice water, slowly dropwise adding concentrated hydrochloric acid until the pH value is 2-3, and stirring for 10min. Filtering and collecting filtrate. The filtrate was separated and the aqueous phase was collected. And adjusting the pH of the water phase to 9-10 by using 30% sodium hydroxide. It was extracted 3 times with 15kg of dichloromethane each time. And combining organic phases, and concentrating under reduced pressure at 50-55 ℃ until no liquid drips. And (3) carrying out vacuum rectification on the crude product by using a water pump to obtain 2.92kg of product, wherein the yield is 85.3%, and the GC purity is over 98%.
As can be seen from example 2, the synthesis process of the invention is stable, has repeatability and is suitable for industrial production.
The technical means disclosed in the invention scheme are not limited to the technical means disclosed in the above embodiments, but also include the technical scheme formed by any combination of the above technical features. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.
Claims (8)
1. A synthesis process of 1-methyl-4-aminopiperidine is characterized by comprising the following steps:
(1) mixing 1-methyl-4-piperidone, dichloromethane and ammonia water, and performing reflux reaction for 4-7 hours to obtain an intermediate reaction solution;
(2) cooling the intermediate reaction liquid to 5-10 ℃, adding sodium borohydride, and performing reflux reaction for 6-12 hours;
(3) cooling the reaction liquid obtained in the step (2) to 25-30 ℃, adding the reaction liquid into ice water, dropwise adding concentrated hydrochloric acid to adjust the pH value, stirring for 10min, and filtering to obtain a filtrate;
(4) standing the filtrate for layering, collecting an aqueous phase, adjusting the pH of the aqueous phase with 30% sodium hydroxide, extracting with dichloromethane for three times, combining organic phases, concentrating the organic phases under reduced pressure to obtain a crude product, and rectifying the crude product under reduced pressure to obtain the 1-methyl-4-aminopiperidine.
2. The process for synthesizing 1-methyl-4-aminopiperidine according to claim 1, wherein the mass ratio of 1-methyl-4-piperidone to dichloromethane in the step (1) is 1: 3.5 to 5.5.
3. The process for synthesizing 1-methyl-4-aminopiperidine according to claim 1, wherein the mass ratio of 1-methyl-4-piperidone to ammonia in the step (1) is 1: 1.5-2.5; the concentration of the ammonia water is 28%.
4. The synthesis process of 1-methyl-4-aminopiperidine according to claim 1, wherein the mass ratio of sodium borohydride in step (2) to 1-methyl-4-piperidone in step (1) is 0.5-1.0: 1.
5. the synthesis process of 1-methyl-4-aminopiperidine according to claim 1, wherein the mass ratio of ice water in the step (3) to 1-methyl-4-piperidone in the step (1) is 7-10: 1.
6. the process for synthesizing 1-methyl-4-aminopiperidine according to claim 1, wherein the pH in the step (3) is adjusted to 1 to 4.
7. The process for synthesizing 1-methyl-4-aminopiperidine according to claim 1, wherein the pH in the step (4) is adjusted to 8 to 11.
8. The process for synthesizing 1-methyl-4-aminopiperidine according to claim 1, wherein the mass ratio of the dichloromethane used for extraction to 1-methyl-4-piperidone in the step (4) is 3.5-5.5: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011392447.XA CN112300064A (en) | 2020-12-02 | 2020-12-02 | Synthesis process of 1-methyl-4-aminopiperidine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011392447.XA CN112300064A (en) | 2020-12-02 | 2020-12-02 | Synthesis process of 1-methyl-4-aminopiperidine |
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| Publication Number | Publication Date |
|---|---|
| CN112300064A true CN112300064A (en) | 2021-02-02 |
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| CN202011392447.XA Pending CN112300064A (en) | 2020-12-02 | 2020-12-02 | Synthesis process of 1-methyl-4-aminopiperidine |
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2020
- 2020-12-02 CN CN202011392447.XA patent/CN112300064A/en active Pending
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| PB01 | Publication | ||
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Application publication date: 20210202 |