CN109369521A - A kind of environment-friendly preparation method thereof of 2- chloroquinoline - Google Patents
A kind of environment-friendly preparation method thereof of 2- chloroquinoline Download PDFInfo
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- CN109369521A CN109369521A CN201811240036.1A CN201811240036A CN109369521A CN 109369521 A CN109369521 A CN 109369521A CN 201811240036 A CN201811240036 A CN 201811240036A CN 109369521 A CN109369521 A CN 109369521A
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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
- C07D215/18—Halogen atoms or nitro radicals
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Abstract
The invention discloses a kind of environment-friendly preparation method thereofs of 2- chloroquinoline, the following steps are included: using quinoline N-oxide as raw material, it is dissolved in a certain amount of solvent, inorganic salts, co-catalyst, organic base and phase transfer catalyst is added, forms material system, controls suitable temperature, then will be bis- (trichloromethyl) carbonic ester be dissolved into a certain amount of organic solvent, it is slowly dropped in material system and is reacted, end of reaction obtains 2- chloroquinoline through column chromatography for separation.Preparation method of the present invention is simple, and reaction time is short, does not use phosphorus reagent, and heavy metal free participates in, and compared with prior art, environmental pollution is small, and safe operation is low in cost.This method is applied to the green chlorination reaction of quinoline N-oxide, but is not limited to the preparation of 2- chloroquinoline.
Description
Technical field
The invention belongs to organic intermediates to synthesize field, be related to the preparation of medicine and material, and in particular to a kind of 2- chloroquine
The environment-friendly preparation method thereof of quinoline.
Background technique
Quinoline and isoquinolin are widely used in medical and materialized as a kind of important N- heterocycle compound
It learns, such as anti-asthmatic medicament (Montelukast), anti-snake venom alkali drug and anti-spasm drug etc., therefore N- heterocyclic derivatives
Object is closed to receive great attention in synthesis chemical field.Since C-X key has high response energy in various reaction kinetics,
Also therefore, it has become the basic frameworks in reaction for halogenation N- heterocycle structure, however have challenge since N- heterocycle is introduced directly into halogen
Property, and the halogenation of corresponding N- oxide is relatively easy to, therefore for synthesis halogenation N- heterocyclic compound provide one it is more convenient
Solution, 2 functional groups of most common N- heterocycle, which are combined to strategy, to be passed through on the basis of corresponding N- oxide
It crosses metal catalyzed coupling reaction to obtain, but yield is lower, and selectivity is bad.
The chlorination synthetic method of N- oxide has 2 kinds at present: (1) using POCl3It is straight under reflux conditions as chlorinating agent
Chlorination is connect, or increases PCl5Accelerate reaction.(2) reaction obtains corresponding 2- hydroxyl N jeterocyclic chemistry under high temperature under acetic anhydride environment
Object is closed, uses POCl later3Carry out chlorination.However both of which haves the shortcomings that apparent, is reacted using phosphorus reagent,
It is unfriendly to environment, and POCl3As chlorinating agent, the mole used is 3 times of feed molar amount or more, is had lower anti-
Answer selectivity and reaction yield.Therefore it is the requirement for adapting to green, environmental protection, needs to develop environmental-friendly synthetic method, reduces
Produce the bring environmental pollution of 2- chloroquinoline.
Summary of the invention
The present invention overcomes drawbacks described above existing for the technology of existing synthesis 2- chloroquinoline, and it is more friendly to propose a kind of environment
The preparation method of good 2- chloroquinoline, uses bis- (trichloromethyl) carbonic esters, trichloromethyl chloroformate as chlorination reagent, with quinoline
The reaction of N- oxide, under the action of inorganic salts, co-catalyst and phase transfer catalyst, greatly improves reaction yield, simultaneously
Original technology route pollution on the environment is largely reduced, that is, is expected that by more green, environmental protection method and obtains
2- chloroquinoline.
The present invention prepares 2- chloroquinoline using quinoline N-oxide as raw material, comprising the following steps:
Firstly, quinoline N-oxide is added in a solvent, it is cooled to 0 DEG C, is stirred continuously lower addition organic base；Control system
Inorganic salts, co-catalyst and phase transfer catalyst is added at -5~0 DEG C in temperature；Continue to cool down, at -15~-10 DEG C slowly
The chlorinating agent for being dissolved in organic solvent is added dropwise, and reacts 4~8h at -15 DEG C~30 DEG C.
Above-mentioned reaction process is shown below:
The separating-purifying process can be carried out according to conventional method in that art, specific as follows: after reaction, be added a little
Water quenching goes out, extracts, organic layer successively alkali cleaning, washing, drying, is concentrated to give crude product 2- chloroquinoline, the crude product can by into
The column of one step chromatographs to obtain sterling.
The solvent used is 1,2- dichloroethanes, methylene chloride, toluene, 1,4- dioxane, acetonitrile, ethyl acetate, stone
One of oily ether, preferably 1,2- dichloroethanes.
The organic base used be one of triethylamine, n,N-Dimethylformamide, pyridine, Tri-n-Propylamine, tri-n-butylamine,
Preferably triethylamine.
The chlorination reagent used be one of trichloromethyl chloroformate, bis- (trichloromethyl) carbonic esters, preferably bis- (three
Chloromethyl) carbonic ester.
The inorganic salts used are sodium chloride or potassium chloride, preferably sodium chloride, wherein used quinoline N-oxide with
The molar ratio of inorganic salts is 1:0.4~0.6.
The co-catalyst used is one of sodium sulfite, sodium dithionite, sodium thiosulfate, preferably sulfurous acid
Sodium, wherein the molar ratio of used quinoline N-oxide and co-catalyst is 1:0.01~0.05.
The phase transfer catalyst is tetrabutylammonium chloride, tri-n-octyl methyl ammonium chloride, benzyltriethylammoinium chloride, 12
One of alkyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, wherein used quinoline N-oxide and phase turn
The molar ratio of shifting catalyst is 1:0.01~0.04.
To obtain target product as much as possible, raw material and chlorination reagent is avoided to waste, preferably, quinoline N- oxygen used
Compound and the molar ratio of bis- (trichloromethyl) carbonic esters and organic base are 1:0.4~1:1.5~3.5, organic solvent and quinoline used
The weight ratio of quinoline N- oxide is 5~20:1.
Chlorizate changes of contents can be detected using liquid chromatogram to monitor reaction process in present invention reaction.
Compared with the prior art, the present invention has the following advantages:
(1) bis- (trichloromethyl) carbonic esters are a kind of safer chlorination reagents, replace thionyl chloride, sulphonyl using it
Chlorine, the generation of the high pollutants such as the avoidable sulfur dioxide such as phosphorus oxychloride, phosphorus pentachloride, phosphorus-containing wastewater, effect on environment are small.
(2) this method simple process, reaction condition is milder, convenient post-treatment, and final products purity and high income, is
A kind of environment-friendly preparation method thereof of environmental-friendly 2- chloroquinoline.
Detailed description of the invention
Fig. 1 be the specific embodiment of the invention 1 in products obtained therefrom 2- chloroquinoline hydrogen nuclear magnetic spectrogram (1H-NMR), nuclear magnetic data
It is as follows:1H NMR (500MHz, DMSO) δ 8.38 (d, J=8.6Hz, 1H), 7.99 (d, J=8.1Hz, 1H), 7.93 (d, J=
8.4Hz, 1H), 7.78 (m, 1H), 7.61 (t, J=7.3Hz, 1H), 7.52 (d, J=8.6Hz, 1H).
Fig. 2 is the mass spectrogram of products obtained therefrom 2- chloroquinoline in the specific embodiment of the invention 1.LC-MS(EI)Calcd for
C9H6ClN[M+1]+(m/z),164.03,found,163.96。
Specific embodiment
Embodiment 1
20mL methylene chloride is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N-oxide is added,
Stirring is opened, is cooled to 0 DEG C of addition 3.035g (30mmol) triethylamine, system temperature control is at -5 DEG C hereinafter, 0.438g is added
(7.5mmol) sodium chloride, 1.305g (0.75mmol) sodium dithionate, 0.136g (0.6mmol) benzyltriethylammoinium chloride, after
It is continuous to be cooled to -10 DEG C hereinafter, the dichloromethane solution of 8mL (7.5mmol) containing 2.222g bis- (trichloromethyls) carbonic ester is added dropwise, and
In reacting 6h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, the hydroxide of organic phase 10mL10%
Sodium solution washing, then washed with 10mL deionized water, (15mL*2) methylene chloride aqueous phase extracted is finally used, organic layer is merged, is used
Anhydrous MgSO4It is dry, it is concentrated to give crude product.Column chromatographic purifying obtains 1.501g product, yield 61.4%.
Embodiment 2
20mL1 is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N- oxidation is added in 2- dichloroethanes
Object opens stirring, is cooled to 0 DEG C of addition 3.035g (30mmol) triethylamine, system temperature control is at -5 DEG C hereinafter, being added
0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyl triethyl ammonium chlorination
Ammonium continues to be cooled to -10 DEG C hereinafter, 1,2-, bis- chloroethene of 8mL (7.5mmol) containing 2.222g bis- (trichloromethyls) carbonic ester is added dropwise
Alkane solution, and in reacting 5h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, organic phase 10mL10%
Sodium hydroxide solution washing, then wash with 10mL deionized water, finally with (15mL*2) 1,2- dichloroethanes aqueous phase extracted, conjunction
And organic layer, with anhydrous MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.903g product, yield
77.83%.
Embodiment 3
20mL1 is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N- oxidation is added in 2- dichloroethanes
Object opens stirring, is cooled to 0 DEG C of addition 3.035g (30mmol) triethylamine, system temperature control is at -5 DEG C hereinafter, being added
0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.167g (0.6mmol) tetrabutylammonium chloride, after
It is continuous to be cooled to -10 DEG C hereinafter, 1, the 2- dichloroethanes that 8mL (7.5mmol) containing 2.222g bis- (trichloromethyls) carbonic ester is added dropwise is molten
Liquid, and in reacting 5h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, the hydrogen of organic phase 10mL10%
Sodium hydroxide solution washing, then washed with 10mL deionized water, (15mL*2) 1,2- dichloroethanes aqueous phase extracted is finally used, is associated with
Machine layer, with anhydrous MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.881g product, yield 76.93%.
Embodiment 4
20mL methylene chloride is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N-oxide is added,
Stirring is opened, is cooled to 0 DEG C of addition 3.035g (30mmol) triethylamine, system temperature control is at -5 DEG C hereinafter, 0.438g is added
(7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyltriethylammoinium chloride continue
Be cooled to -10 DEG C hereinafter, be added dropwise 8mL (7.5mmol) containing 2.222g bis- (trichloromethyls) carbonic ester dichloromethane solution, and in
6h is reacted at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, the sodium hydroxide of organic phase 10mL10%
Solution washing, then washed with 10mL deionized water, (15mL*2) methylene chloride aqueous phase extracted is finally used, merges organic layer, with nothing
Water MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.746g product, yield 71.4%.
Embodiment 5
20mL toluene is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N-oxide is added, opens
Stirring is cooled to 0 DEG C of addition 3.035g (30mmol) triethylamine, and system temperature control is at -5 DEG C hereinafter, 0.438g is added
(7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyltriethylammoinium chloride continue
- 10 DEG C are cooled to hereinafter, the toluene solution of 8mL (7.5mmol) containing 2.222g bis- (trichloromethyls) carbonic ester is added dropwise, and in 25 DEG C
At a temperature of react 6h.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, organic phase is molten with the sodium hydroxide of 10mL10%
Liquid washing, then washed with 10mL deionized water, (15mL*2) toluene aqueous phase extracted is finally used, merges organic layer, with anhydrous MgSO4
It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.453g product, yield 59.43%.
Embodiment 6
20mL1 is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N- oxidation is added in 4- dioxane
Object opens stirring, is cooled to 0 DEG C of addition 3.035g (30mmol) triethylamine, system temperature control is at -5 DEG C hereinafter, being added
0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyl triethyl ammonium chlorination
Ammonium continues to be cooled to -10 DEG C hereinafter, the Isosorbide-5-Nitrae-dioxy of 16mL (7.5mmol) containing 2.222g bis- (trichloromethyls) carbonic ester is added dropwise
Six ring solution, and in reacting 6h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, organic phase is used
The sodium hydroxide solution of 10mL10% washs, then is washed with 10mL deionized water, is finally extracted with (15mL*2) 1,2- dichloroethanes
Water intaking phase, merges organic layer, with anhydrous MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.568g product, receives
Rate 64.13%.
Embodiment 7
20mL acetonitrile is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N-oxide is added, opens
Stirring is cooled to 0 DEG C of 3.035 (30mmol) triethylamine of addition, and system temperature control is at -5 DEG C hereinafter, 0.438g is added
(7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyltriethylammoinium chloride continue
- 10 DEG C are cooled to hereinafter, the acetonitrile solution of 16mL (7.5mmol) containing 2.222g bis- (trichloromethyls) carbonic ester is added dropwise, and in 25
6h is reacted at a temperature of DEG C.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, the sodium hydroxide of organic phase 10mL10%
Solution washing, then washed with 10mL deionized water, (15mL*2) 1,2- dichloroethanes aqueous phase extracted is finally used, organic layer is merged,
With anhydrous MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.166g product, yield 47.69%.
Embodiment 8
20mL1 is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N- oxidation is added in 2- dichloroethanes
Object opens stirring, is cooled to 0 DEG C of addition 5.334g (52.5mmol) triethylamine, system temperature control is at -5 DEG C hereinafter, being added
0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyl triethyl ammonium chlorination
Ammonium continues to be cooled to -10 DEG C hereinafter, 1,2-, bis- chloroethene of 16mL (15mmol) containing 4.444g bis- (trichloromethyls) carbonic ester is added dropwise
Alkane solution, and in reacting 5h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, organic phase 10mL10%
Sodium hydroxide solution washing, then wash with 10mL deionized water, finally with (25mL*2) 1,2- dichloroethanes aqueous phase extracted, conjunction
And organic layer, with anhydrous MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.761g product, yield
72.01%.
Embodiment 9
20mL1 is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N- oxidation is added in 2- dichloroethanes
Object opens stirring, is cooled to 0 DEG C of addition 2.286g (22.5mmol) triethylamine, system temperature control is at -5 DEG C hereinafter, being added
0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyl triethyl ammonium chlorination
Ammonium continues to be cooled to -10 DEG C hereinafter, 1, the 2- dichloroethanes of 6mL (6mmol) containing 1.778g bis- (trichloromethyls) carbonic ester is added dropwise
Solution, and in reacting 6h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, organic phase is with 10mL10%'s
Sodium hydroxide solution washing, then washed with 10mL deionized water, (15mL*2) 1,2- dichloroethanes aqueous phase extracted is finally used, is merged
Organic layer, with anhydrous MgSO4It is dry, it is concentrated to give orange-red solution, column chromatographic purifying obtains 1.827g product, yield 74.72%.
Embodiment 10
20mL1 is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N- oxidation is added in 2- dichloroethanes
Object opens stirring, is cooled to 0 DEG C of addition 3.81g (37.5mmol) triethylamine, system temperature control is at -5 DEG C hereinafter, being added
0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyl triethyl ammonium chlorination
Ammonium continues to be cooled to -10 DEG C hereinafter, 1, the 2- bis- of 10mL (11.25mmol) containing 3.332g bis- (trichloromethyls) carbonic ester is added dropwise
Chloroethanes solution, and in reacting 6h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, organic phase is used
The sodium hydroxide solution of 10mL10% washs, then is washed with 10mL deionized water, is finally extracted with (15mL*2) 1,2- dichloroethanes
Water intaking phase, merges organic layer, with anhydrous MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.967g product, receives
Rate 80.45%.
Embodiment 11
20mL methylene chloride is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N-oxide is added,
Stirring is opened, is cooled to 0 DEG C of addition 2.967g (37.5mmol) pyridine, system temperature control is at -5 DEG C hereinafter, 0.438g is added
(7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyltriethylammoinium chloride continue
Be cooled to -10 DEG C hereinafter, be added dropwise 16mL (15mmol) containing 4.444g bis- (trichloromethyls) carbonic ester dichloromethane solution, and in
8h is reacted at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, the sodium hydroxide of organic phase 10mL10%
Solution washing, then washed with 10mL deionized water, (25mL*2) methylene chloride aqueous phase extracted is finally used, merges organic layer, with nothing
Water MgSO4It is dry, it is concentrated to give orange-red solution.Column chromatographic purifying obtains 1.070g product, yield 43.77%.
Embodiment 12
20mL1 is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N- oxidation is added in 2- dichloroethanes
Object opens stirring, is cooled to 0 DEG C of addition 6.950g (37.5mmol) tri-n-butylamine, system temperature control is at -5 DEG C hereinafter, being added
0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyl triethyl ammonium chlorination
Ammonium continues to be cooled to -10 DEG C hereinafter, 1,2-, bis- chloroethene of 16mL (15mmol) containing 4.444g bis- (trichloromethyls) carbonic ester is added dropwise
Alkane solution, and in reacting 6h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, organic phase 10mL10%
Sodium hydroxide solution washing, then wash with 10mL deionized water, finally with (25mL*2) 1,2- dichloroethanes aqueous phase extracted, conjunction
And organic layer, with anhydrous MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.644g product, yield
67.23%.
Embodiment 13
20mL1 is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N- oxidation is added in 2- dichloroethanes
Object opens stirring, is cooled to 0 DEG C of addition 2.741g (37.5mmol) n,N-Dimethylformamide, and system temperature is controlled at -5 DEG C
Hereinafter, 0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyl three is added
Ethyl ammonium chloride, continues to be cooled to -10 DEG C hereinafter, the 1 of 16mL (15mmol) containing 4.444g bis- (trichloromethyls) carbonic ester is added dropwise,
2- dichloroethane solution, and in reacting 6h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, organic phase is used
The sodium hydroxide solution of 10mL10% washs, then is washed with 10mL deionized water, is finally extracted with (25mL*2) 1,2- dichloroethanes
Water intaking phase, merges organic layer, with anhydrous MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.345g product, receives
Rate 55.01%.
Embodiment 14
20mL methylene chloride is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N-oxide is added,
Stirring is opened, is cooled to 0 DEG C of addition 5.373g (37.5mmol) Tri-n-Propylamine, system temperature control is at -5 DEG C hereinafter, being added
0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyl triethyl ammonium chlorination
Ammonium continues to be cooled to -10 DEG C hereinafter, the methylene chloride that 16mL (15mmol) containing 4.444g bis- (trichloromethyls) carbonic ester is added dropwise is molten
Liquid, and in reacting 6h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, the hydrogen of organic phase 10mL10%
Sodium hydroxide solution washing, then washed with 10mL deionized water, (15mL*2) methylene chloride aqueous phase extracted is finally used, is merged organic
Layer, with anhydrous MgSO4It is dry, it is concentrated to give red tan solution.Column chromatographic purifying obtains 1.595g product, yield 65.23%.
Embodiment 15
20mL1 is added in four mouthfuls of dry reaction flasks, 2.175g (15mmol) quinoline N- oxidation is added in 2- dichloroethanes
Object opens stirring, is cooled to 0 DEG C of addition 3.81g (37.5mmol) triethylamine, system temperature control is at -5 DEG C hereinafter, being added
0.438g (7.5mmol) sodium chloride, 0.095g (0.75mmol) sodium sulfite, 0.136g (0.6mmol) benzyl triethyl ammonium chlorination
Ammonium continues to be cooled to -10 DEG C hereinafter, 1, the 2- bis- that 10mL (16.88mmol) containing 3.338g is dissolved in trichloromethyl chloroformate is added dropwise
Chloroethanes solution, and in reacting 6h at this temperature.Reaction terminates, and 10mL deionized water is added and is quenched, is layered, organic phase is used
The sodium hydroxide solution of 10mL10% washs, then is washed with 10mL deionized water, is finally extracted with (15mL*2) 1,2- dichloroethanes
Water intaking phase, merges organic layer, dry with anhydrous MgSO4, is concentrated to give red tan solution.Column chromatographic purifying obtains 1.589g product, receives
Rate 64.99%.
Gained target product is detected through nuclear magnetic data, melting point data, mass spectrometric data in embodiment 1~15, and has reported text
It is almost the same to offer middle 2- chloroquinoline.
Fusing point: 37 DEG C -37.5 DEG C.
Claims (9)
1. a kind of environment-friendly preparation method thereof of 2- chloroquinoline characterized by comprising
Quinoline N-oxide is added in organic solvent, is cooled to 0 DEG C, organic base is added under stirring condition；Control system temperature
At -5~0 DEG C, inorganic salts, co-catalyst and phase transfer catalyst is added；Continue to cool down, be slowly added dropwise at -15~-10 DEG C
It is dissolved in the chlorination reagent solution of organic solvent, and reacts 4~8h at -15 DEG C~25 DEG C；End of reaction, by being quenched, washing,
It is dry, it is concentrated to give crude product 2- chloroquinoline.
2. the environment-friendly preparation method thereof of 2- chloroquinoline according to claim 1, which is characterized in that the organic solvent is 1,2- bis-
One of chloroethanes, methylene chloride, toluene, 1,4- dioxane, acetonitrile, ethyl acetate, petroleum ether.
3. the environment-friendly preparation method thereof of 2- chloroquinoline according to claim 1, which is characterized in that the organic base is triethylamine,
One of N,N-dimethylformamide, pyridine, Tri-n-Propylamine, tri-n-butylamine.
4. the environment-friendly preparation method thereof of 2- chloroquinoline according to claim 1, which is characterized in that the chlorination reagent is chloro-carbonic acid
One of trichloromethyl, bis- (trichloromethyl) carbonic esters.
5. the environment-friendly preparation method thereof of 2- chloroquinoline according to claim 1, which is characterized in that the inorganic salts be sodium chloride,
One of potassium chloride.
6. the environment-friendly preparation method thereof of 2- chloroquinoline according to claim 1, which is characterized in that the co-catalyst is sulfurous acid
One of sodium, sodium thiosulfate, sodium dithionite.
7. the environment-friendly preparation method thereof of 2- chloroquinoline according to claim 1, which is characterized in that the phase transfer catalyst is four
Butyl ammonium chloride, tri-n-octyl methyl ammonium chloride, benzyltriethylammoinium chloride, dodecyl trimethyl ammonium chloride, myristyl three
One of ammonio methacrylate.
8. the environment-friendly preparation method thereof of 2- chloroquinoline according to claim 1, which is characterized in that the organic solvent and quinoline N-
Oxide mass ratio is 5~20:1.
9. the environment-friendly preparation method thereof of 2- chloroquinoline according to claim 1, which is characterized in that the quinoline N-oxide, chlorine
Agent, the molar ratio of organic base are 1:0.4~1.0:1.2~3.5.
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| CN201811240036.1A CN109369521B (en) | 2018-10-23 | 2018-10-23 | Green preparation method of 2-chloroquinoline |
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| CN109369521B CN109369521B (en) | 2021-04-27 |
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| CN112239871A (en) * | 2020-10-21 | 2021-01-19 | 南京先进生物材料与过程装备研究院有限公司 | Method for continuously preparing C-2 chloro-substituted quinoline by using electrochemical microchannel reaction device |
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| CN110627716A (en) * | 2019-10-18 | 2019-12-31 | 重庆康乐制药有限公司 | Preparation method of 4, 7-dichloroquinoline |
| CN112239871A (en) * | 2020-10-21 | 2021-01-19 | 南京先进生物材料与过程装备研究院有限公司 | Method for continuously preparing C-2 chloro-substituted quinoline by using electrochemical microchannel reaction device |
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