CN111170932A - Preparation method of 2-aminomethyl-5-trifluoromethyl pyridine salt - Google Patents
Preparation method of 2-aminomethyl-5-trifluoromethyl pyridine salt Download PDFInfo
- Publication number
- CN111170932A CN111170932A CN202010033628.7A CN202010033628A CN111170932A CN 111170932 A CN111170932 A CN 111170932A CN 202010033628 A CN202010033628 A CN 202010033628A CN 111170932 A CN111170932 A CN 111170932A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethylpyridine
- aminomethyl
- acid
- cyano
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
Abstract
The invention discloses a preparation method of 2-aminomethyl-5-trifluoromethyl pyridinium, belonging to the technical field of pesticides and pharmaceutical intermediates. The method takes 2-cyano-3-chloro-5-trifluoromethylpyridine as a raw material, hydrogenates in an alcohol solvent and acid in the presence of a metal catalyst, dehydrolyzes molecules while hydrogenating nitrile groups, and processes to obtain a product, namely 2-aminomethyl-5-trifluoromethylpyridine salt. The method has the advantages of reasonable selection of technical routes, short reaction steps, mild reaction conditions, low cost of raw materials, high separation yield and suitability for industrial amplification.
Description
Technical Field
The invention belongs to the technical field of pesticide and medicine intermediate preparation, and particularly relates to a preparation method of 2-aminomethyl-5-trifluoromethyl pyridinium.
Background
2-aminomethyl-5-trifluoromethyl pyridine belongs to a fluorine-containing heterocyclic compound, and is a useful pesticide and a medical intermediate. The literature reports at present that there are four methods for preparing 2-aminomethyl-5-trifluoromethylpyridine or salts:
the first method is to use 2-methoxycarbonyl-5-trifluoromethylpyridine as a starting material, obtain 2-hydroxymethyl-5-trifluoromethylpyridine through two-step reduction, condense the 2-hydroxymethyl-5-trifluoromethylpyridine with phthalimide, and finally generate 2-aminomethyl-5-trifluoromethylpyridine under the action of hydrazine hydrate (reference WO 2011142359).
The reaction equation is:
the method has long reaction steps, expensive raw materials and difficult purchase, and is not suitable for industrialization.
And secondly, reacting 2-bromo-5-trifluoromethylpyridine serving as a starting material with cuprous cyanide at a high temperature of 180 ℃ to generate 2-cyano-5-trifluoromethylpyridine, and reducing the 2-cyano-5-trifluoromethylpyridine under the action of lithium aluminum hydride and sodium hydroxide to generate the 2-aminomethyl-5-trifluoromethylpyridine (references US20050113576, US20040157849 and US 20030158198). The reaction equation is:
the method has high reaction temperature, high danger due to the reduction of lithium aluminum hydride, explosive decomposition in moisture and unsuitability for industrial production.
And thirdly, esterifying 2-hydroxy-5-trifluoromethylpyridine serving as a starting material with trifluoromethylsulfonic anhydride, cyaniding the esterified product with zinc cyanide under the catalysis of palladium tetratriphenylphosphine, and finally hydrogenating and reducing the esterified product to obtain the 2-aminomethyl-5-trifluoromethylpyridine under the catalysis of nickel (reference WO 2003080578). The reaction equation is:
the method has long reaction steps, relatively expensive raw materials and long reaction time, and more importantly, the yield of the final hydrogenation reduction reaction is low and is only 30 percent, and the cost advantage is avoided.
And fourthly, using 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride as a raw material, and carrying out catalytic hydrodechlorination in the presence of palladium carbon and alkali to obtain the 2-aminomethyl-5-trifluoromethylpyridine (reference WO 2008106047). The reaction equation is:
the raw materials are not easy to purchase, and the method needs to synthesize 2-cyano-3-chloro-5-trifluoromethylpyridine, then perform catalytic hydrogenation to obtain 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride, and then perform catalytic hydrogenation dechlorination under the action of a large-dose 50% catalyst palladium carbon to obtain the 2-aminomethyl-5-trifluoromethylpyridine. The process is relatively complicated, the raw material cost is high, and the industrialization is not facilitated.
Disclosure of Invention
In order to solve the problems, the invention provides a method for preparing 2-aminomethyl-5-trifluoromethylpyridine salt, which takes 2-cyano-3-chloro-5-trifluoromethylpyridine as a raw material, dechlorinates while carrying out metal catalytic hydrogenation reduction in the presence of an alcohol solvent and acid, and obtains the product 2-aminomethyl-5-trifluoromethylpyridine salt by a one-step method. Short reaction steps, low raw material cost, mild reaction conditions and great industrial production value.
The invention relates to a method for preparing 2-aminomethyl-5-trifluoromethyl pyridine salt, which adopts the technical scheme that the method comprises the following steps: the 2-cyano-3-chloro-5-trifluoromethylpyridine is taken as a raw material, and is hydrogenated under the conditions of an alcohol solvent and acid in the presence of a metal catalyst to obtain the 2-aminomethyl-5-trifluoromethylpyridine salt.
The specific process route is as follows:
further, in the above technical solution, the alcohol solvent comprises methanol, ethanol, n-propanol, isopropanol, n-butanol;
further, in the above technical solution, the acid (HA) comprises one of hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid, and the amount of the acid is 1.0 to 5.0eq for 2-cyano-3-chloro-5-trifluoromethylpyridine;
further, in the above technical scheme, the metal catalyst comprises one of palladium carbon, platinum carbon, rhodium carbon and ruthenium carbon, and the amount of the catalyst is 5-20% of the weight of the substrate 2-cyano-3-chloro-5-trifluoromethylpyridine;
further, in the technical scheme, the reaction temperature is 20-120 ℃;
further, in the above technical scheme, the catalytic hydrogenation pressure range is 0.2-5.0 MPa.
Further, in the above technical scheme, after the reaction is finished, the system is cooled and decompressed, the mother liquor is filtered, the mother liquor is decompressed and concentrated to be thick, heptane is added, the mixture is stirred and crystallized, and the 2-aminomethyl-5-trifluoromethyl pyridinium is obtained after filtering, leaching and drying.
The invention has the beneficial effects
The method has the advantages of reasonable selection of technical routes, short reaction steps, mild reaction conditions, low cost of raw materials, high separation yield and suitability for industrial amplification.
Compared with the prior art, the invention takes 2-cyano-3-chloro-5-trifluoromethylpyridine as a raw material, and in the presence of an alcohol solvent and acid, the metal catalyzes hydrogenation of nitrile group and molecular dechlorination at the same time, so that the target product 2-aminomethyl-5-trifluoromethylpyridine salt is obtained by a one-step method, and the invention has great industrial production value.
Detailed Description
The invention will be further illustrated by the following specific examples
Example 1
To a 500mL autoclave were added 20.85g (0.1mol, 99%, 1.0eq) of 2-cyano-3-chloro-5-trifluoromethylpyridine, 24.1g (0.4mol, 99.5%, 4eq) of acetic acid, 4.55g (54.5% with water) of 5% palladium on carbon wet basis, and 170g of ethanol in that order. And (3) replacing nitrogen and hydrogen in the system for three times, introducing hydrogen until the pressure in the kettle is 2.0-2.5Mpa, controlling the temperature to be 60 ℃, keeping the temperature and reacting for about 5 hours without pressure drop, continuing keeping the temperature and reacting for 5 hours, and sampling and performing HPLC-MS (high performance liquid chromatography-mass spectrometry) central control to finish the reaction of the raw materials.
And (3) cooling the system, relieving pressure, filtering, concentrating the mother liquor under reduced pressure until the system is thick, adding 150g of heptane, stirring, crystallizing, filtering, leaching and drying to obtain 23.1g of 2-aminomethyl-5-trifluoromethyl pyridine acetate with the content of 98.5% and the yield of 96.3%.
Example 2
To a 500mL autoclave were added 20.85g (0.1mol, 99%, 1.0eq) of 2-cyano-3-chloro-5-trifluoromethylpyridine, 20.3g (0.2mol, 36%, 2eq) of concentrated hydrochloric acid, 9.9g (68.7% with water) of a 5% rhodium on carbon wet basis, and 170g of methanol in that order. And (3) replacing nitrogen and hydrogen in the system for three times, introducing hydrogen until the pressure in the kettle is 1.0-1.5Mpa, controlling the temperature to be 100 ℃, keeping the temperature for reaction for about 5 hours without pressure drop, continuing keeping the temperature for reaction for 5 hours, and sampling, performing HPLC (high performance liquid chromatography) and HPLC-MS (high performance liquid chromatography-mass spectrometry) to control the reaction of the raw materials.
And (3) cooling the system, relieving pressure, filtering, concentrating the mother liquor under reduced pressure until the system is thick, adding 150g of heptane, stirring, crystallizing, filtering, leaching and drying to obtain 20.8g of 2-aminomethyl-5-trifluoromethylpyridine hydrochloride with the content of 98.7% and the yield of 96.5%.
Example 3
To a 500mL autoclave were added 20.85g (0.1mol, 99%, 1.0eq) of 2-cyano-3-chloro-5-trifluoromethylpyridine, 25.5g (0.13mol, 50%, 1.3eq) of sulfuric acid, 6.5g (61.6% aqueous) of a 5% ruthenium-carbon wet base, and 170g of isopropanol in this order. And (3) replacing nitrogen and hydrogen in the system for three times, introducing hydrogen until the pressure in the kettle is 4.0-4.5Mpa, controlling the temperature to be 30 ℃, keeping the temperature and reacting for about 10 hours without pressure drop, continuing keeping the temperature and reacting for 8 hours, and sampling, performing HPLC (high performance liquid chromatography) and HPLC-MS (high performance liquid chromatography-mass spectrometry) to control the reaction of the raw materials.
And (3) cooling the system, relieving pressure, filtering, concentrating the mother liquor under reduced pressure until the system is thick, adding 150g of heptane, stirring, crystallizing, filtering, leaching and drying to obtain 26.5g of 2-aminomethyl-5-trifluoromethylpyridine sulfate with the content of 98.2% and the yield of 95.0%.
Example 4
To a 500mL autoclave were added 20.85g (0.1mol, 99%, 1.0eq) of 2-cyano-3-chloro-5-trifluoromethylpyridine, 20.3g (0.2mol, 36%, 2eq) of concentrated hydrochloric acid, 9.9g (68.7% with water) of a 5% rhodium on carbon wet basis, and 170g of methanol in that order. And (3) replacing nitrogen and hydrogen in the system for three times, introducing hydrogen until the pressure in the kettle is 0.2-0.5Mpa, controlling the temperature to be 100 ℃, keeping the temperature and reacting for about 10 hours without pressure drop, continuing keeping the temperature and reacting for 8 hours, and sampling, performing HPLC-MS (high performance liquid chromatography-mass spectrometry) to control the reaction, wherein the reaction of the raw materials is finished.
And (3) cooling the system, relieving pressure, filtering, concentrating the mother liquor under reduced pressure until the system is thick, adding 150g of heptane, stirring, crystallizing, filtering, leaching and drying to obtain 20.6g of 2-aminomethyl-5-trifluoromethylpyridine hydrochloride with the content of 98.9% and the yield of 95.8%.
Example 5
To a 500mL autoclave were added 20.85g (0.1mol, 99%, 1.0eq) of 2-cyano-3-chloro-5-trifluoromethylpyridine, 24.1g (0.4mol, 99.5%, 4eq) of acetic acid, 6.9g (54.5% with water) of 5% palladium on carbon wet basis, and 170g of ethanol in that order. And (3) replacing nitrogen and hydrogen in the system for three times, introducing hydrogen until the pressure in the kettle is 4.0-4.5Mpa, controlling the temperature to be 80 ℃, keeping the temperature and reacting for about 2 hours without pressure drop, continuing keeping the temperature and reacting for 1 hour, and sampling and performing HPLC-MS (high performance liquid chromatography-mass spectrometry) central control to finish the reaction of the raw materials.
And (3) cooling the system, relieving pressure, filtering, concentrating the mother liquor under reduced pressure until the system is thick, adding 150g of heptane, stirring, crystallizing, filtering, leaching and drying to obtain 23.0g of 2-aminomethyl-5-trifluoromethyl pyridine acetate with the content of 99.0% and the yield of 96.4%.
Comparative example 1
To a 500mL autoclave were added 20.85g (0.1mol, 99%, 1.0eq), 4.55g (54.5% aqueous) of 5% palladium on carbon wet basis and 170g of ethanol in this order. The nitrogen gas and the hydrogen gas are replaced for three times, the hydrogen gas is introduced until the pressure in the kettle is 2.0-2.5Mpa, the temperature is controlled at 60 ℃, the temperature is kept for reaction for about 20 hours, the pressure is basically not reduced, the temperature is kept for reaction for 5 hours, the sampling HPLC (high performance liquid chromatography) is controlled, the system is very complicated, the raw material residue is about 5 percent, the 2-aminomethyl-5-trifluoromethylpyridine is about 38 percent, and one main impurity is a product (secondary amine) obtained by removing one molecule of ammonia gas from two molecules of 2-aminomethyl-5-trifluoromethylpyridine. No post-treatment was performed.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (7)
1. A preparation method of 2-aminomethyl-5-trifluoromethyl pyridine salt is characterized by comprising the following steps: the 2-cyano-3-chloro-5-trifluoromethylpyridine is taken as a raw material, and is hydrogenated under the conditions of an alcohol solvent and acid in the presence of a metal catalyst to obtain the 2-aminomethyl-5-trifluoromethylpyridine salt.
2. The process for preparing 2-aminomethyl-5-trifluoromethylpyridine salt according to claim 1, wherein: the alcohol solvent comprises methanol, ethanol, n-propanol, isopropanol, and n-butanol.
3. The process for preparing 2-aminomethyl-5-trifluoromethylpyridine salt according to claim 1, wherein: the acid comprises one of hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid; the dosage is 1.0 to 5.0eq of 2-cyano-3-chloro-5-trifluoromethylpyridine.
4. The process for preparing 2-aminomethyl-5-trifluoromethylpyridine salt according to claim 1, wherein: the metal catalyst comprises one of palladium carbon, platinum carbon, rhodium carbon and ruthenium carbon; the dosage of the catalyst is 5-20% of the weight of the 2-cyano-3-chloro-5-trifluoromethylpyridine.
5. The process for preparing 2-aminomethyl-5-trifluoromethylpyridine salt according to claim 1, wherein: the reaction temperature is 20-120 ℃.
6. The process for preparing 2-aminomethyl-5-trifluoromethylpyridine salt according to claim 1, wherein: the catalytic hydrogenation pressure range is 0.2-5.0 MPa.
7. The process for the preparation of 2-aminomethyl-5-trifluoromethylpyridine salt according to any of the claims 1 to 6, characterized in that: and after the reaction is finished, cooling the system, relieving pressure, filtering, concentrating the mother liquor under reduced pressure until the system is thick, adding heptane, stirring, crystallizing, filtering, leaching and drying to obtain the 2-aminomethyl-5-trifluoromethyl pyridinium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010033628.7A CN111170932A (en) | 2020-01-13 | 2020-01-13 | Preparation method of 2-aminomethyl-5-trifluoromethyl pyridine salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010033628.7A CN111170932A (en) | 2020-01-13 | 2020-01-13 | Preparation method of 2-aminomethyl-5-trifluoromethyl pyridine salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111170932A true CN111170932A (en) | 2020-05-19 |
Family
ID=70649331
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010033628.7A Pending CN111170932A (en) | 2020-01-13 | 2020-01-13 | Preparation method of 2-aminomethyl-5-trifluoromethyl pyridine salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111170932A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114478365A (en) * | 2022-02-11 | 2022-05-13 | 大连九信作物科学有限公司 | Purification method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1711244A (en) * | 2002-11-20 | 2005-12-21 | 拜尔农科股份有限公司 | Novel process for the preparation of 2-aminomethylpyridine derivative |
| CN1721406A (en) * | 2000-08-25 | 2006-01-18 | 拜尔农科股份有限公司 | Process for the preparation of 2-aminomethylpyridines |
| CN101711154A (en) * | 2007-02-26 | 2010-05-19 | 科森生物科学公司 | carbamate compounds |
| WO2011130342A1 (en) * | 2010-04-14 | 2011-10-20 | Incyte Corporation | FUSED DERIVATIVES AS ΡI3Κδ INHIBITORS |
| CN105745194A (en) * | 2013-11-15 | 2016-07-06 | 拜耳作物科学股份公司 | Catalytic hydrogenation of nitriles |
-
2020
- 2020-01-13 CN CN202010033628.7A patent/CN111170932A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1721406A (en) * | 2000-08-25 | 2006-01-18 | 拜尔农科股份有限公司 | Process for the preparation of 2-aminomethylpyridines |
| CN1711244A (en) * | 2002-11-20 | 2005-12-21 | 拜尔农科股份有限公司 | Novel process for the preparation of 2-aminomethylpyridine derivative |
| CN101711154A (en) * | 2007-02-26 | 2010-05-19 | 科森生物科学公司 | carbamate compounds |
| WO2011130342A1 (en) * | 2010-04-14 | 2011-10-20 | Incyte Corporation | FUSED DERIVATIVES AS ΡI3Κδ INHIBITORS |
| CN105745194A (en) * | 2013-11-15 | 2016-07-06 | 拜耳作物科学股份公司 | Catalytic hydrogenation of nitriles |
Non-Patent Citations (2)
| Title |
|---|
| GUANGYI WANG ET AL.: "Synthesis and Anti-Influenza Activity of Pyridine, Pyridazine, and Pyrimidine C‑Nucleosides as Favipiravir (T-705) Analogues", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 南京药学院: "《制药化学（试用教材）》", 31 December 1973 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114478365A (en) * | 2022-02-11 | 2022-05-13 | 大连九信作物科学有限公司 | Purification method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2300431B1 (en) | Process for the manufacture of an intermediate in the synthesis of dabigatran | |
| CN110862310B (en) | Synthesis method of cyclopropyl methyl ketone | |
| WO2016095136A1 (en) | Method for purifying 1,5-pentanediamine and 1,5-pentanediamine | |
| CN111170932A (en) | Preparation method of 2-aminomethyl-5-trifluoromethyl pyridine salt | |
| CN108558679B (en) | Synthetic method of Parylene A precursor | |
| WO2016055015A1 (en) | Method for preparing sitagliptin intermediate via asymmetrical reduction method | |
| CN111138351A (en) | Synthetic method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate | |
| JPH01193246A (en) | Production of 2,3-dichloropyridine | |
| CN110028436B (en) | Preparation method of Vonoprazan key intermediate | |
| US6958418B2 (en) | Process for preparing vanillylamine hydrochloride | |
| CN111302962A (en) | Rapid method for reducing nitro in aliphatic nitro compound into amino | |
| JP2022523986A (en) | 4-Amino-5-Methyl-1H-Pyridine-2 from 2-Chloro-5-Methyl-4-nitro-Pyridine-1-oxide using Intermediate Compound 2-Chloro-5-Methyl-4-pyridinamine Synthesis of (1H) -one (intermediate compound for synthesizing MR antagonist finelenone) | |
| EP3415500B1 (en) | Method for preparing methylpyrrolidones | |
| CN107089918B (en) | Preparation method of benzhydrylamine hydrochloride | |
| CN100361962C (en) | Preparation method of demebeverine hydrochloride | |
| CN111116378A (en) | Method for synthesizing 1, 8-diaminonaphthalene by selective reduction of 1, 8-dinitronaphthalene | |
| JPH0635423B2 (en) | Method for producing rimantadine | |
| US6340773B1 (en) | Preparation of halogenated primary amines | |
| CN110452172B (en) | Synthesis method of benzocaprolactam | |
| CN107652191B (en) | Purification method of venlafaxine intermediate | |
| CN102173993A (en) | Method for synthesizing 4,6-diamino resorcinol dihydrochloride (DAR) | |
| CN109111371B (en) | Preparation method of hydrazino ethyl acetate hydrochloride | |
| EP2417118B1 (en) | A process for manufacturing zeranol | |
| US6995270B2 (en) | Hydrogenation process | |
| CA2461574C (en) | Process for preparing vanillylamine hyrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200519 |