CN114773263B - Preparation method of (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline - Google Patents
Preparation method of (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline Download PDFInfo
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- CN114773263B CN114773263B CN202210529767.8A CN202210529767A CN114773263B CN 114773263 B CN114773263 B CN 114773263B CN 202210529767 A CN202210529767 A CN 202210529767A CN 114773263 B CN114773263 B CN 114773263B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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Abstract
The invention relates to a preparation method of (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline, which is characterized in that 2-aminoacetophenone is reacted at a certain temperature in two steps of Grignard addition, selective hydrogenation and the like in an organic solvent to obtain a product (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline. The method has the advantages of multiple sources of raw materials and obvious cost advantage, and the preparation method is more convenient and direct for chiral synthesis of the target, improves the total yield and is beneficial to industrialization.
Description
Technical Field
The invention relates to a preparation method of (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline, in particular to a method for obtaining a product (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline through two-step reactions such as Grignard addition and selective hydrogenation by using 2-amino acetophenone.
Background
The (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline is a key intermediate of a novel bactericide, i.e. an inhibitor of Succinic Dehydrogenase (SDHI) type bactericide, and can inhibit mitochondrial function, prevent energy generation and growth of pathogenic bacteria by interfering with a complex II on a respiratory electron transfer chain of mitochondria of the pathogenic bacteria, and finally cause death of the pathogenic bacteria. Inpyrfluxam is broad-spectrum and efficient, and is used for preventing and treating various diseases of many crops, such as rice sheath blight disease (Rhizoctonia solani), asian soybean rust disease (Phakopsora pachyrhizi), corn rust disease, barley net blotch (Pyrenophora teres), apple scab (Venturia inaequalis), beet root rot and leaf blight. The synthesis method reported in the prior literature mainly adopts 4-bromo-2-methyl-2-pentene as a raw material and adopts an aromatic amine cyclization and resolving agent resolution method for synthesis, and the process is complex, the yield is unstable, the resolution yield is lower, and the yield is difficult to put into the production stage.
Disclosure of Invention
The invention aims to overcome the defects existing in the prior art, and provides a preparation method which is more convenient, improves the total yield by directly chiral synthesis of a target object, is favorable for industrialization of the preparation method of (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline, and obtains a product (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline through two-step reactions such as Grignard addition, selective hydrogenation and the like in an organic solvent at a certain temperature.
The technical scheme for realizing the aim of the invention is as follows: a preparation method of (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline comprises the following steps: (1) Adding 2-aminoacetophenone and isobutene Grignard reagent into an organic solvent at a certain temperature, and carrying out addition and dehydration reaction to obtain an intermediate I;
(2) Adding an intermediate I and a catalyst into an organic solvent at a certain temperature, setting a certain pressure of hydrogen, and carrying out selective hydrogenation reaction to obtain a product (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline;
the reaction formula is:
in the technical scheme, the preparation method specifically comprises the following steps:
(1) Sequentially adding an organic solvent and 2-aminoacetophenone into a reaction container under the protection of nitrogen, uniformly stirring, regulating to a set temperature, dropwise adding an isobutene Grignard reagent, and preserving the temperature until the gas chromatography normalization content of the 2-aminoacetophenone in the total material is less than 1%; quenching reaction with dilute acid, separating liquid and desolventizing to obtain an intermediate I;
(2) Sequentially adding an organic solvent, an intermediate I and a catalyst into the autoclave, uniformly stirring, and then raising the temperature to a set temperature and a set pressure; preserving the temperature until the normalized content of the intermediate I gas chromatography in the total materials is less than 1%; recovering the catalyst after pressure relief, distilling the recovered solvent, and distilling under reduced pressure to obtain a target product (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline;
in the technical scheme, in the step (1), the molar ratio of the 2-amino acetophenone to the isobutene Grignard reagent is 1:1-10, and the molar ratio of the dosage of the organic solvent to the 2-amino acetophenone is 1-10:1; in the step (2), the molar ratio of the intermediate I to the catalyst is 10-20:1, the molar ratio of the dosage of the organic solvent to the intermediate I is 1-10:1, and the pressure of hydrogen is 0.1MPa-6MPa.
In the technical scheme, the reaction temperature in the steps (1) and (2) is-20 to 100 ℃.
In the above technical scheme, the organic solvent in the steps (1) and (2) is any one of halogenated hydrocarbon solvents, aromatic solvents, ether solvents, ester solvents or alcohol solvents, and strong polar solvents containing hetero atoms.
In the above technical scheme, the catalyst in step (2) comprises two parts, namely metal and ligand, wherein the metal part is any one of palladium carbon, raney nickel, palladium acetate, palladium chloride, nickel chloride, ruthenium carbon, rhodium carbon, ruthenium chloride and rhodium chloride; the ligand comprises any one of (4- (N, N-dimethylamino) phenyl di-tert-butylphosphine, bis (2-diphenylphosphino) ether, 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, 2-di-tert-butylphosphine-2 ',4',6' -triisopropylbiphenyl, 2-dicyclohexylphosphorus-2, 4, 6-triisopropylbiphenyl, 2-dicyclohexylphosphine-2, 6-dimethoxybiphenyl, 2-dicyclohexylphosphine-2, 6-diisopropyloxy-1, 1-biphenyl and 1, 2-bis (4-pyridyl) ethane.
The halogenated hydrocarbon solvents in the above technical scheme are dichloromethane, dichloroethane, chloroform and the like, the aromatic solvents are chlorobenzene, toluene, xylene and the like, the ether solvents are tetrahydrofuran, cyclopentyl methyl ether and the like, the ester solvents are methyl acetate, ethyl acetate and the like, the alcohol solvents are methanol, ethanol, isopropanol and the like, and the heteroatom-containing strong polar solvents DMF, DMA, DMSO, NMP, sulfolane, DMI and the like.
In the above technical scheme, in the steps (1) and (2), the reaction temperature is preferably 0-40 ℃.
After the technical scheme is adopted, the invention has the following positive effects:
the invention obtains the product (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline through two-step reactions such as Grignard addition, selective hydrogenation and the like in an organic solvent at a certain temperature, has the advantages of multiple raw material sources and obvious cost advantage, is more convenient in preparation method, improves the total yield by directly chiral synthesizing the target, and is beneficial to industrialization.
Detailed Description
Example 1: intermediate I
Preparing a target product by a small test:
adding 27g (0.20 mol) of 2-aminoacetophenone and 100g of THF into a 1000mL reaction bottle, uniformly stirring and cooling to 0 ℃, dropwise adding 0.6mol (2 mol/L) of isobutene Grignard reagent in 2h, controlling the temperature to be not more than 5 ℃ in the dropwise adding process, stirring for 2h after the dropwise adding, quenching the reaction by 30% hydrochloric acid, controlling the quenching temperature to be not more than 20 ℃, controlling the pH of a quenched aqueous phase to be 2, separating liquid, extracting the aqueous phase once by ethyl acetate, merging the aqueous phase into an organic phase, distilling at normal pressure, recovering THF to obtain 28g of crude intermediate I, and obtaining the product with the yield of 80.9%.
Example 2: (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline
Preparing a target product by a small test:
adding 28g of crude intermediate I, 100g of methanol, 1g of palladium-carbon, 1.5g of ligand 2-dicyclohexylphosphorus-2, 4, 6-triisopropyl biphenyl into a 1L stainless steel high-pressure reaction kettle, setting the hydrogen pressure to be 0.2MPa, slowly heating to 40 ℃ for reaction for 5 hours, cooling, decompressing, filtering and recovering the catalyst, distilling and recovering 92g of methanol, and recovering 92g of recovery rate; recovery Bi Jianya distillation gave >98% of the target (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline 24g in 85% yield, R/(r+s) =92%.
Example 3: preparation of (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline on kilogram scale
Intermediate I:
adding 1.35kg (10 mol) of 2-aminoacetophenone and 1L of THF into a 10L reaction bottle, uniformly stirring and cooling to 0 ℃, dropwise adding 10mol (2 mol/L) of isobutene grignard reagent in 2h, controlling the temperature to be no more than 5 ℃ in the dropwise adding process, stirring for 2h after the dropwise adding, quenching the reaction by 30% hydrochloric acid, controlling the quenching temperature to be no more than 20 ℃, controlling the pH of a quenched water phase to be 2, separating liquid, extracting the water phase once by ethyl acetate, merging the water phase into an organic phase, distilling at normal pressure, recovering the THF to obtain 1.35kg of crude intermediate I, and obtaining the yield of 78%.
(R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline:
adding 1kg of crude intermediate I, 3L of methanol, 5g of palladium acetate, 10g of ligand 4, 5-bis (diphenylphosphino) -9, 9-dimethyl xanthene into a 5L stainless steel high-pressure reaction kettle, setting the hydrogen pressure to be 0.3MPa, slowly heating to 30 ℃ for reaction for 5 hours, cooling, decompressing, distilling and recovering 2.8L of methanol, and recovering 93 percent; recovery Bi Jianya distillation gave >98% of the target (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline 800g in 80% yield, R/(r+s) =95%.
While the foregoing is directed to embodiments of the present invention, other and further details of the invention may be had by the present invention, it should be understood that the foregoing description is merely illustrative of the present invention and that no limitations are intended to the scope of the invention, except insofar as modifications, equivalents, improvements or modifications are within the spirit and principles of the invention.
Claims (4)
1. A method for preparing (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline, which is characterized by comprising the following steps:
(1) Adding 2-aminoacetophenone and isobutene grignard reagent into an organic solvent at a certain temperature, and carrying out addition and dehydration reaction to obtain an intermediate I, wherein the organic solvent and the 2-aminoacetophenone are sequentially added into a reaction container under the protection of nitrogen, uniformly stirred, then regulated to a set temperature, the isobutene grignard reagent is dropwise added, and the temperature is kept until the gas chromatography normalization content of the 2-aminoacetophenone in the total material is less than 1%; quenching reaction with dilute acid, controlling the quenching temperature to be not more than 20 ℃, controlling the pH value of the quenched water phase to be=2, separating liquid and desolventizing to obtain an intermediate I;
(2) Adding the intermediate I and a catalyst into an organic solvent at a certain temperature, setting the pressure of hydrogen to be 0.1-6 MPa, and carrying out selective hydrogenation reaction to obtain a product (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline, wherein the specific steps are as follows: sequentially adding an organic solvent, an intermediate I and a catalyst into the autoclave, uniformly stirring, and then raising the temperature to a set temperature and a set pressure; preserving the temperature until the normalized content of the intermediate I gas chromatography in the total materials is less than 1%; recovering the catalyst after pressure relief, distilling the recovered solvent, and distilling under reduced pressure to obtain a target product (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline;
the reaction temperature in the step (1) and the step (2) is-20 to 100 ℃;
the catalyst in the step (2) comprises two parts, namely metal and ligand, wherein the metal part is palladium carbon, and the ligand is 2-dicyclohexylphosphorus-2 ',4',6' -triisopropyl biphenyl; the metal part is palladium acetate, and the ligand is any one combination of 4, 5-bis (diphenylphosphino) -9, 9-dimethyl xanthene;
the reaction formula is:
2. the method for preparing (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline according to claim 1, wherein in the step (1), the molar ratio of the 2-aminoacetophenone to the isobutene grignard reagent is 1:1-10, and the molar ratio of the organic solvent to the 2-aminoacetophenone is 1-10:1.
3. The process for producing (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline according to claim 1, wherein the organic solvent in the steps (1) and (2) is any one of a halogenated hydrocarbon solvent, an aromatic solvent, an ether solvent, an ester solvent or an alcohol solvent, and a strongly polar solvent containing a hetero atom.
4. The process for the preparation of (R) -2, 4-trimethyl-1, 2,3, 4-tetrahydroquinoline according to claim 1, wherein the reaction temperature in steps (1) and (2) is from 0 to 40 ℃.
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN88102448A (en) * | 1987-04-30 | 1988-11-16 | 三井石油化学工业株式会社 | Novel nitrogenous compound |
| EP0807625A1 (en) * | 1996-05-16 | 1997-11-19 | Fuji Photo Film Co., Ltd. | 4-(n,n-Dialkylamino)Aniline compounds, photographic processing composition containing the same and color image-forming method |
| WO2010109301A1 (en) * | 2009-03-27 | 2010-09-30 | Isagro Ricerca S.R.L. | Benzamidic compounds having fungicidal activity and relative use |
| CN102958367A (en) * | 2010-06-24 | 2013-03-06 | 住友化学株式会社 | Plant disease control composition and method of controlling plant disease |
| CN105992755A (en) * | 2014-02-07 | 2016-10-05 | 住友化学株式会社 | Method for producing (R)-1,1,3-trimethyl-4-aminoindane |
| CN106103413A (en) * | 2014-03-18 | 2016-11-09 | 住友化学株式会社 | The manufacture method of optically active compound |
| WO2021059146A1 (en) * | 2019-09-26 | 2021-04-01 | Isagro S.P.A. | Process for preparing (r)-4-aminoindane and corresponding amides |
| WO2022014414A1 (en) * | 2020-07-17 | 2022-01-20 | 住友化学株式会社 | Method for producing optically active compound |
-
2022
- 2022-05-16 CN CN202210529767.8A patent/CN114773263B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN88102448A (en) * | 1987-04-30 | 1988-11-16 | 三井石油化学工业株式会社 | Novel nitrogenous compound |
| EP0807625A1 (en) * | 1996-05-16 | 1997-11-19 | Fuji Photo Film Co., Ltd. | 4-(n,n-Dialkylamino)Aniline compounds, photographic processing composition containing the same and color image-forming method |
| WO2010109301A1 (en) * | 2009-03-27 | 2010-09-30 | Isagro Ricerca S.R.L. | Benzamidic compounds having fungicidal activity and relative use |
| CN102958367A (en) * | 2010-06-24 | 2013-03-06 | 住友化学株式会社 | Plant disease control composition and method of controlling plant disease |
| CN105992755A (en) * | 2014-02-07 | 2016-10-05 | 住友化学株式会社 | Method for producing (R)-1,1,3-trimethyl-4-aminoindane |
| CN106103413A (en) * | 2014-03-18 | 2016-11-09 | 住友化学株式会社 | The manufacture method of optically active compound |
| WO2021059146A1 (en) * | 2019-09-26 | 2021-04-01 | Isagro S.P.A. | Process for preparing (r)-4-aminoindane and corresponding amides |
| WO2022014414A1 (en) * | 2020-07-17 | 2022-01-20 | 住友化学株式会社 | Method for producing optically active compound |
Non-Patent Citations (1)
| Title |
|---|
| Gold-Catalyzed Intramolecular Allylic Amination of 2-Tosylaminophenylprop-1-en-3-ols. A Concise Synthesis of (+-)-Angustureine.;Prasath Kothandaraman等;《J. Org. Chem.》;第74卷(第 16期);第5947-5952页，Supporting Information * |
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