CN104447538A - Preparation of 2-alkyl-8-aminoquinoline - Google Patents
Preparation of 2-alkyl-8-aminoquinoline Download PDFInfo
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- CN104447538A CN104447538A CN201410722680.8A CN201410722680A CN104447538A CN 104447538 A CN104447538 A CN 104447538A CN 201410722680 A CN201410722680 A CN 201410722680A CN 104447538 A CN104447538 A CN 104447538A
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- quinolylamine
- alkyl
- benzoyl
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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
- C07D215/16—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 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
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a method for preparing 2-alkyl-8-aminoquinoline. The method is characterized by comprising the following steps: (1) preparing benzoyl-8-aminoquinoline under an alkali condition; (2) adding the prepared benzoyl-8-aminoquinoline, alkyl formate, a catalyst and an oxidant into a reaction solvent to react for 8 hours at certain temperature, quenching with water, extracting by using ethyl acetate, washing once by using saturated salt, performing pressure reduction spinning on a crude product to remove the solvent, and recrystalizing by using ethanol, thereby obtaining benzoyl 2-alkyl-8-aminoquinoline; and (3) dissolving benzoyl 2-alkyl-8-aminoquinoline into ethanol, adding concentrated hydrochloric acid to react at 100 DEG C for 24 hours, performing pressure reduction spinning on a reaction mixture, cooling to be 0 DEG C, adjusting the pH value to be alkali by using 3N NaOH, extracting by using dichloromethane, washing once by using saturated salt, spinning off the solvent, and recrystalizing, thereby obtaining 2-alkyl-8-aminoquinoline.
Description
Technical field
The present invention relates to the preparation method of fine-chemical intermediate, be specially a kind of preparation method of 2-alkyl-8-quinolylamine,
Background technology
8-aminoquinoline derivatives is the important intermediate of organic synthesis, is applied to DYE PRODUCTION, the preparation of medicine intermediate, the field such as food inspection and mining.
8-quinolylamine and salicylaldehyde derivatives can produce very strong fluorescent characteristic after reacting the electron rich title complex with rigid structure and complexing of metal ion generated, and are applied to the detection of metal ion content.In analytical chemistry, obtain the attention of chemist, be used to measure trace metal [Kang Xinhuang, assay office, 2001,20 (2): 49-51] in grain.Amino in 8-quinolylamine can generate azo developer with large conjugated system aromatic hydrocarbons generation coupling by in-situ preparation azo, with have colour developing effect after complexing of metal ion, may be used for mensuration [the yellow Zhang Jie that Trace Gold Contained in Ore belongs to, Hu Qiufen, Yang Guangyu etc., assay office, 2003,22 (1): 75-77].
In field of medicaments, 8-aminoquinoline derivatives is for the synthesis of HIV1-RT inhibitor [Rosa MDL, Kim HW, the Gunic E for the treatment of acquired immune deficiency syndrome (AIDS), et al.Bioorg.Med.Chem.Lett.2006,16:4444-4449], and be used for treating uncle's quinoline and chloroquine analog derivative [Bray PG., Deed S of malaria, Fox E, et al.Biochemical Pharmacology, 2005,70:1158-1166].
At present, about the synthetic method of 8-aminoquinoline derivatives report little.Tradition 8-quinolylamine can 8-nitroquinoline be raw material, is obtained by iron powder reducing.But this synthetic method exists a lot of shortcoming, the nitration reaction selectivity as quinoline is low, and the isomer obtained is many, and is difficult to be separated.Also report that 8-quinolylamine can obtain from 8-bromine or 8-chloroquinoline in ammonification under catalyzer, highly basic effect in addition.But about 2-alkyl replace 8-aminoquinoline derivatives synthesis report less.The people such as Hu Aixi in 2009 disclose a kind of preparation method [CN 101602723A] of 2-methyl-8-aminoquinoline.But the synthesis report of the 8-quinolylamine of other 2-positions replacement does not almost have.Here we are from the 8-quinolylamine of acylations, by the alkyl decarboxylic reaction of metal catalytic, successfully achieve the alkylation of quinoline 2-position, then slough acyl group in the basic conditions and obtain the alkylating 8-aminoquinoline derivatives in 2-position.
Summary of the invention
The object of the invention is to provide a kind of preparation method of 2-alkyl-8-quinolylamine.
The present invention also aims to provide the preparation of described 2-alkyl-8-quinolylamine to be that acylations 8-quinolylamine is under metal catalyst, oxygenant effect; in solvent, obtain acylations 2-alkyl-8-aminoquinoline derivatives at a certain temperature through alkyl carboxylic acid depickling alkylation, the acidified deacylated tRNA base of the latter obtains 2-alkyl-8-aminoquinoline derivatives.
It is characterized in that catalyzer is one or more in venus crystals, Silver Nitrate;
The oxygenant that it is characterized in that using is Potassium Persulphate, one or more in Sodium Persulfate, ammonium persulphate;
The solvent that it is characterized in that using is water, one or more in acetonitrile, dioxane, DMF, tetrahydrofuran (THF);
It is characterized in that certain temperature is 80-90 DEG C.
The present invention compared with prior art has following advantage:
1. the present invention is with 8-quinolylamine for raw material, through depickling alkylation after acylations, obtains acylations 2-alkyl-8-aminoquinoline derivatives, and the latter obtains 2-alkyl-8-quinolylamine through acidolysis deacylated tRNA base.This design route reaction conditions is gentle, easy and simple to handle.
2. the present invention can synthesize various 2-alkyl-8-aminoquinoline derivatives, and alkyl can be three grades of alkyl and secondary alkyl.And traditional method is difficult to obtain three grades, 2-position or secondary alkyl 8-quinolylamine.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment one: a kind of preparation method of 2-alkyl-8-quinolylamine, its synthetic route is:
Embodiment one: a kind of preparation method of 2-alkyl-8-quinolylamine, carry out as follows:
(1) under room temperature, by 8-quinolylamine (1.44g, 10.0mmol), salt of wormwood (2.76g, 20.0mmol) joins in 20mL tetrahydrofuran (THF) respectively, after stirring at room temperature reacts half an hour, be added dropwise to Benzoyl chloride (1.41g, 10.0mmol).React after 12 hours under mixed system room temperature, the extraction that adds water is gone out.Extraction into ethyl acetate (30mL × 2), once, decompression is spin-dried for except desolventizing in saturated common salt washing.Re-crystallizing in ethyl acetate obtains benzoyl-8-quinolylamine (2.23g, productive rate 90%).
1H NMR(400MHz,CDCl
3):10.74(s,1H,NH),8.93-8.96(m,1H),8.83-8.85(m,1H),8.16-8.19(m,1H),8.07-8.10(m,2H),7.54-7.62(m,5H),7.44-7.53(m,1H)。
(2) by benzoyl-8-quinolylamine (0.248g, 1.0mmol), adamantanecarboxylic acid (0.36g, 2.0mmol), venus crystals (18.2mg, 0.1mmol), Silver Nitrate (51mg, 0.3mmol) join (volume ratio 1:1) in acetonitrile solution with Potassium Persulphate (0.54g, 2.0mmol).Mixed solution reacts after 8 hours at 80-90 DEG C, and add water cancellation, extraction into ethyl acetate (15mL × 2), and saturated common salt washing once.Thick product decompression is spin-dried for solvent, and ethyl alcohol recrystallization obtains benzoyl 2-diamantane-8-quinolylamine (productive rate 70%, 0.267g).
1H NMR(400MHz,CDCl
3):11.1(s,1H),8.85-8.87(m,1H),8.11-8.16(m,3H),7.48-7.59(m,6H),2.16-2.19(m,9H),1.82-1.89(m,6H)；
13C NMR(100MHz,CDCl
3):167.1,164.8,137.5,136.5,135.3,134.4,131.8,128.8,127.2,126.6,126.1,121.1,118.5,116.0,42.1,39.8,36.8,28.8。
(3) benzoyl 2-diamantane-8-quinolylamine (0.267g) is dissolved in 10mL ethanol, then adds concentrated hydrochloric acid (1.75mL).Reaction mixture reacts 24 hours at 100 DEG C.0 DEG C is cooled to, by 3N NaOH adjust ph to alkalescence after reaction mixture decompression is spin-dried for.Dichloromethane extraction (15mL × 2).Saturated common salt washing once.After solvent is spin-dried for, ethyl alcohol recrystallization obtains 2-diamantane-8-quinolylamine, and productive rate reaches 85%.
Embodiment two: a kind of preparation method of 2-alkyl-8-quinolylamine, its synthetic route is:
Embodiment two: a kind of preparation method of 2-alkyl-8-quinolylamine, carry out as follows:
(1) under room temperature, by 8-quinolylamine (1.44g, 10.0mmol), salt of wormwood (2.76g, 20.0mmol) joins in 20mL tetrahydrofuran (THF) respectively, after stirring at room temperature reacts half an hour, be added dropwise to Benzoyl chloride (1.41g, 10.0mmol).React after 12 hours under mixed system room temperature, the extraction that adds water is gone out.Extraction into ethyl acetate (30mL × 2), once, decompression is spin-dried for except desolventizing in saturated common salt washing.Re-crystallizing in ethyl acetate obtains benzoyl-8-quinolylamine (2.23g, productive rate 90%).
1H NMR(400MHz,CDCl
3):10.74(s,1H,NH),8.93-8.96(m,1H),8.83-8.85(m,1H),8.16-8.19(m,1H),8.07-8.10(m,2H),7.54-7.62(m,5H),7.44-7.53(m,1H)。
(2) by benzoyl-8-quinolylamine (0.248g, 1.0mmol), 3-hydroxyl-1-adamantanecarboxylic acid (0.392g, 2.0mmol), venus crystals (18.2mg, 0.1mmol), Silver Nitrate (51mg, 0.3mmol) join (volume ratio 1:1) in acetonitrile solution with Potassium Persulphate (0.54g, 2.0mmol).Mixed solution reacts after 8 hours at 80-90 DEG C, and add water cancellation, extraction into ethyl acetate (15mL × 2), and saturated common salt washing once.Thick product decompression is spin-dried for solvent, and ethyl alcohol recrystallization obtains benzoyl 2-diamantane-8-quinolylamine (productive rate 60%, 0.239g).
1H NMR(400MHz,CDCl
3):11.0(s,1H,NH),8.85-8.87(m,1H),8.11-8.13(m,3H),7.49-7.56(m,6H),2.42(s,2H),2.13(s,2H),2.06-2.09(m,2H),1.98-2.01(m,2H),1.80-1.87(m,4H),1.72(m,2H)；
13C NMR(100MHz,CDCl
3):165.3,164.8,137.4,136.7,135.1,134.3,131.8,127.1,126.7,126.2,121.1,118.4,116.1,69.0,49.4,44.5,43.5,40.9,35.3,30.9；
(3) benzoyl 2-diamantane-8-quinolylamine (0.239g) is dissolved in 10mL ethanol, then adds concentrated hydrochloric acid (1.75mL).Reaction mixture reacts 24 hours at 100 DEG C.0 DEG C is cooled to, by 3N NaOH adjust ph to alkalescence after reaction mixture decompression is spin-dried for.Dichloromethane extraction (15mL × 2).Saturated common salt washing once.After solvent is spin-dried for, ethyl alcohol recrystallization obtains 2-diamantane-8-quinolylamine, and productive rate reaches 86%.
Embodiment three: a kind of preparation method of 2-alkyl-8-quinolylamine, its synthetic route is:
Embodiment three: a kind of preparation method of 2-alkyl-8-quinolylamine, carry out as follows:
(1) under room temperature, by 8-quinolylamine (1.44g, 10.0mmol), salt of wormwood (2.76g, 20.0mmol) joins in 20mL tetrahydrofuran (THF) respectively, after stirring at room temperature reacts half an hour, be added dropwise to Benzoyl chloride (1.41g, 10.0mmol).React after 12 hours under mixed system room temperature, the extraction that adds water is gone out.Extraction into ethyl acetate (30mL × 2), once, decompression is spin-dried for except desolventizing in saturated common salt washing.Re-crystallizing in ethyl acetate obtains benzoyl-8-quinolylamine (2.23g, productive rate 90%).
1H NMR(400MHz,CDCl
3):10.74(s,1H,NH),8.93-8.96(m,1H),8.83-8.85(m,1H),8.16-8.19(m,1H),8.07-8.10(m,2H),7.54-7.62(m,5H),7.44-7.53(m,1H)。
(2) by benzoyl-8-quinolylamine (0.248g, 1.0mmol), hexahydrobenzoic acid (0.256g, 2.0mmol), venus crystals (18.2mg, 0.1mmol), Silver Nitrate (51mg, 0.3mmol) join (volume ratio 1:1) in acetonitrile solution with Potassium Persulphate (0.54g, 2.0mmol).Mixed solution reacts after 8 hours at 80-90 DEG C, and add water cancellation, extraction into ethyl acetate (15mL × 2), and saturated common salt washing once.Thick product decompression is spin-dried for solvent, and ethyl alcohol recrystallization obtains benzoyl 2-diamantane-8-quinolylamine (productive rate 60%, 0.198g).
1H NMR(400M H
Z,CDCl
3):10.9(s,0.76H),10.8(s,0.51H),8.81-8.88(m,1.6H),8.73-8.74(m,0.6H),7.91-7.93(m,1H),7.77-7.80(m,3H),7.63-7.69(m,0.8H),7.55-7.59(m,3.2H),7.46-7.51(m,2.8H),7.32-7.36(m,1.5H),3.31(m,0.67H),2.87-2.90(m,1H),2.07-2.10(m,1.76H),2.00-2.02(m,1.5H),1.91-1.94(m,3H),1.81-1.84(m,1.65H),1.66-1.72(m,2.3H),1.47-1.56(m,4.6H),1.25-1.38(m,1.6H)；
13C NMR(100MHz,CDCl3):164.7,163.9,154.1,148.1,136.5,134.1,134.0,133.8,131.9,126.6,126.3,121.5,120.9,118.0,117.3,116.2,115.9,46.5,39.0,33.5,32.7,26.8,26.4,26.2；
(3) benzoyl 2-diamantane-8-quinolylamine (0.239g) is dissolved in 10mL ethanol, then adds concentrated hydrochloric acid (1.75mL).Reaction mixture reacts 24 hours at 100 DEG C.0 DEG C is cooled to, by 3N NaOH adjust ph to alkalescence after reaction mixture decompression is spin-dried for.Dichloromethane extraction (15mL × 2).Saturated common salt washing once.After solvent is spin-dried for, ethyl alcohol recrystallization obtains 2-diamantane-8-quinolylamine, and productive rate reaches 84%.
Claims (5)
1. the preparation method of a kind of 2-alkyl-8-quinolylamine of the present invention, is characterized in that, comprise following processing step:
(1) under room temperature, by 8-quinolylamine, salt of wormwood joins in tetrahydrofuran (THF) respectively, after stirring at room temperature reacts half an hour, is added dropwise to Benzoyl chloride.React after 12 hours under mixed system room temperature, the extraction that adds water is gone out.Extraction into ethyl acetate, once, decompression is spin-dried for except desolventizing in saturated common salt washing.Re-crystallizing in ethyl acetate obtains benzoyl-8-quinolylamine.
(2) by benzoyl-8-quinolylamine, alkyl formate, catalyzer and oxygenant join in reaction solvent.After mixed solution reacts 8 hours at a certain temperature, add water cancellation, extraction into ethyl acetate, and saturated common salt washing once.Thick product decompression is spin-dried for solvent, and ethyl alcohol recrystallization obtains benzoyl 2-alkyl-8-quinolylamine.
(3) benzoyl 2-alkyl-8-quinolylamine is dissolved in ethanol, then adds concentrated hydrochloric acid.Reaction mixture reacts 24 hours at 100 DEG C.0 DEG C is cooled to, by 3N NaOH adjust ph to alkalescence after reaction mixture decompression is spin-dried for.Dichloromethane extraction.Saturated common salt washing once.After solvent is spin-dried for, ethyl alcohol recrystallization obtains 2-alkyl-8-quinolylamine.
2. the preparation method of 2-alkyl-8-quinolylamine as claimed in claim 1, is characterized in that: in described step (1), catalyzer is one or more in venus crystals, Silver Nitrate.
3. the preparation method of 2-alkyl-8-quinolylamine as claimed in claim 1, is characterized in that: the oxygenant that described step (1) uses is Potassium Persulphate, one or more in Sodium Persulfate, ammonium persulphate.
4. the preparation method of 2-alkyl-8-quinolylamine as claimed in claim 1, is characterized in that: the solvent that described step (1) uses is water, one or more in acetonitrile, dioxane, DMF, tetrahydrofuran (THF).
5. the preparation method of 2-alkyl-8-quinolylamine as claimed in claim 1, is characterized in that: described step (1) certain temperature is 80-90 DEG C.
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| CN201410722680.8A CN104447538A (en) | 2014-12-02 | 2014-12-02 | Preparation of 2-alkyl-8-aminoquinoline |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602723A (en) * | 2009-07-10 | 2009-12-16 | 湖南大学 | The preparation method of 2-methyl-8-quinolylamine |
| CN103380118A (en) * | 2010-10-29 | 2013-10-30 | 克林诺株式会社 | Tau imaging probe |
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2014
- 2014-12-02 CN CN201410722680.8A patent/CN104447538A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602723A (en) * | 2009-07-10 | 2009-12-16 | 湖南大学 | The preparation method of 2-methyl-8-quinolylamine |
| CN103380118A (en) * | 2010-10-29 | 2013-10-30 | 克林诺株式会社 | Tau imaging probe |
Non-Patent Citations (2)
| Title |
|---|
| GANG SHAN,等: "A Facile Synthesis of Substituted 2-Alkylquinolines through [3+3] Annulation between 3-Ethoxycyclobutanones and Aromatic Amines at Room Temperature", 《ORGANIC LETTERS》 * |
| SURYANARAYANA VANGAPANDU，等: "Ring-substituted quinolines as potential anti-tuberculosis agents", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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Application publication date: 20150325 |