CN1668597A - Process for producing 2,3,6-trialkyl-8-fluoro-4-quinoline derivative - Google Patents
Process for producing 2,3,6-trialkyl-8-fluoro-4-quinoline derivative Download PDFInfo
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- CN1668597A CN1668597A CN 03816493 CN03816493A CN1668597A CN 1668597 A CN1668597 A CN 1668597A CN 03816493 CN03816493 CN 03816493 CN 03816493 A CN03816493 A CN 03816493A CN 1668597 A CN1668597 A CN 1668597A
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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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
Abstract
A process for industrially producing a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative useful as an agricultural chemical. The process for producing a 2,3,6-trialkyl-8-fluoro-4-quinoline derivative comprises subjecting 2-fluoroaniline as a starting material to 4-position-selective alkylation and improved Conrad-Limpach synthesis. Thus, the target compound can be efficiently synthesized in one pot in a satisfactory yield.
Description
[background of invention]
Invention field
The present invention relates to a kind of production 2,3, the method for 6-trialkyl-8-fluoro-4-quinoline or its pharmaceutically-acceptable salts, it can be used as agricultural chemicals.
Background technology
2,3,6-trialkyl-8-fluoro-4-quinoline has the agricultural of control WO 01/92231 record and the activity of gardening disease.The application discloses a kind of method of producing this compound according to following reaction scheme.
In the aforesaid method; tertiary butyl aniline at first uses suitable blocking group with amido protecting as initiator; then with SELECTFLUOR (1-(chloro methyl)-4-fluoro-1 as fluoro reagent; 4-diazabicylo [2.2.2] octane) reaction two (a tetrafluoro borates)) is incorporated into amino ortho position with fluorine atom.The deprotection base obtains the 4-tertiary butyl-2-fluoro aniline intermediate.Intermediate carries out enamine with the 2-methyl-acetoacetic ester again and obtains enamine compound, heats cyclisation then and obtains the quinolinol compound.At last, the hydroxyl in the quinolinol compound is acetylation and obtains target compound.In the method, it is synthetic that enamine-cyclization process is known as Conrad-Limpach.But this production process has its deficiency, needs the reaction of 6 steps to make generative process complicated.Further, the productive rate of Conrad-Limpach synthetic product is low especially, to such an extent as to overall yield is very low, is about 4%.Further, to use in this method, typically as expensive fluoro reagent such as SELECTFLUOR.Because fluoro reagent has high pungency and corrodibility, using fluoro reagent in the commercial-scale production process is being disadvantageous aspect expense and the efficient.
Have only several general-purpose industrial production methods optionally to introduce on the target location of fluorine atom to the aromatic ring.Its example comprises with Sodium tetrafluoroborate dediazofluorination and the diazotizing Balz-Schiemann reaction that relates to fragrant amido.But these methods have a lot of industrial problems, because target compound is to make by aromatic series a tetrafluoro borate unstable and severe toxicity.The fluoro of the 2-position of the disclosed 4-alkyl benzene amine of WO01/92231 requires to use strong and stimulating and corrosive fluoro reagent, and is typical in selectfluor.When these fluoro reagent of a large amount of uses, the surface of metal or glass reactor just has been corroded.This just requires with special reactor.Like this, fluoro reagent just is difficult to use with commercial size.
Therefore, just need that development is a kind of to provide 2,3 efficiently, 6-trialkyl-8-fluoro-4-quinoline is again without the method for fluoro reagent.
[summary of the invention]
The inventor has established a kind of production 2,3, the method for 6-trialkyl-8-fluoro-4-quinoline, and its basic two-step reaction of only using uses the 2-fluoroaniline of having introduced fluorine atom, and its low price is as initiator safety and high yield.
Therefore, one object of the present invention just provide a kind of can produce safely and efficiently provide 2,3, the production method of 6-trialkyl-8-fluoro-4-quinoline.
According to an aspect of the present invention, provide a kind of and be used for producing as shown in the formula 2,3 shown in (I) method of 6-trialkyl-8-fluoro-4-quinoline or its salt:
Wherein
R
1The optional C that replaces of representative
1-10Alkyl or C
3-6Cycloalkyl;
R
2The optional C that replaces of representative
1-10Alkyl or C
3-6Cycloalkyl;
R
3The optional C that replaces of representative
1-10Alkyl, C
2-6Alkenyl, phenyl C
1-6Alkyl or C
3-6Cycloalkyl; With
R
4Represent the protecting group of hydrogen atom or hydroxyl,
Described method comprises the steps:
(i) make the alkylation shown in the following formula (II):
With R
1-X (R wherein
1As above define and X representation hydroxy or halogen atom) or R
1 '(R wherein
1 'For with R
1Alkene with identical carbon atoms) under pressure, reaction in the presence of zinc chloride obtains the 4-alkyl shown in the following formula (III)-2-fluorobenzene sulfonamide derivatives:
R wherein
1As above definition; With
(ii) use the alpha-alkyl shown in compound shown in the formula (III) and the formula (IV)-'beta '-ketoester reaction:
R wherein
2And R
3As above definition; R
5Represent C
1-4Alkyl,
Obtain the enamine intermediate shown in the formula V:
R wherein
1, R
2, R
3, and R
5As above definition,
The cyclisation of enamine intermediate is obtained compound, wherein R shown in the formula (I)
4Represent the hydroxyl that the optional protection of protecting group is arranged on hydrogen atom, the 4-position.
[detailed Description Of The Invention]
Definition
In the present invention, alkyl can be straight chain or side chain, can be used as the part of a group or group, and the term of Shi Yonging " halogen atom " is meant fluorine atom, chlorine atom, bromine atoms and iodine atom herein.
Compound shown in the formula (I)
The compound that preparation in accordance with the present invention will prepare is 2,3 shown in the formula (I), 6-trialkyl-8-fluoro-4-quinoline.In formula (I), R
1And R
2Independently represent C separately
1-10Alkyl, preferred C
1-6Alkyl, or C
3-6Cycloalkyl.Optional halogen atom, hydroxyl and the C of being comprised of this alkyl
1-4One or more substituting groups of alkoxyl group replace.
Further, in formula (I), R
3Represent C
1-10Alkyl, preferred C
1-6Alkyl, C
2-6Thiazolinyl, phenyl C
1-6Alkyl or C
3-6Cycloalkyl.C
1-10Alkyl can be chosen wantonly and be substituted, and the example of preferred substituted comprises as above-mentioned R
1And R
2Substituting group.
Compound shown in the formula (I) can salify.The example of such salt has: an alkali metal salt, alkaline earth salt, hydrochloride, vitriol, Citrate trianion, oxalate, tosilate and metilsulfate.
The production of compound shown in the formula (I)
Step (i)
Step of the present invention (i) is an alkylated reaction, can carry out according to the record of the open No.944/1983 of Japanese Patent.Especially, exist under the situation of acid catalyst, preferably fluorobenzene amine hydrochlorate and alkylating reagent carry out thermal response and finish Friedel-Crafts reaction under pressure in pressurized vessel.
Alkylating reagent is R
1The compound of-X representative, wherein R
1Suc as formula definition and X representation hydroxy or halogen atom in (I), or have and R
1The alkene that equates carbonatoms.At R
1In the situation of-X (X=OH), preferably use the secondary alcohol or the tertiary alcohol.The consumption of alkylating reagent should correctly be determined.But the consumption of preferred alkyl reagent is about 1 to 10 equivalent, and 1 to 5 equivalent more preferably from about is based on the compound shown in the formula (II).
Preferred Friedel-Crafts catalysts is a protonic acid, and the typical case represents example hydrochloric acid, sulfuric acid etc. and Lewis acid, typical case's representative being used in combination as zinc chloride.More preferably use zinc chloride.Catalyst consumption without limits, catalyst consumption is preferably in 0.25 to 0.5 normal scope.
Temperature of reaction preferred 150 ℃ or more than, considering needs more effective the reaction.Temperature of reaction is more preferably in 150 to 200 ℃ the scope.
In the method according to the invention, application pressure is used to increase the speed of alkylated reaction, strengthens the regioselectivity of alkylated reaction in the 4-position of aromatic ring.From practical experience, pressure can not be lower than 3atm, more preferably arrives in the scope of 10atm 4.
Step (i) generally can be carried out without solvent or in inert solvent such as dithiocarbonic anhydride or nitrobenzyl.Reaction vessel preferably uses withstand voltage Glass Containers or stainless steel vessel.Because stainless surface can be corroded in acid atmosphere, the preferred stainless steel vessel that uses inside that Glass Containers sealing or titanium metal covering are arranged.
Obtain compound shown in the formula (III) by step (i).Compound shown in the formula (III) can utilize the different purifying that carry out of the lipotropy of product and initiator.Especially, product can obtain compound shown in the formula (III) as hexane or ethyl acetate extraction with appropriate organic solvent, and only makes to have more that the initiator of highly water-soluble optionally rests on water layer.Compound shown in the formula (III) also can separate and purifying by distilling.
In the present invention, step (i) step afterwards (ii) comprises enamine and cyclisation thereafter.Enamine and cyclisation also can be finished with one still process afterwards at step (i).Perhaps, after enamine, carry out aftertreatment and enamine compound (V) is taken out from reaction system carry out cyclisation (ii) then with completing steps.
To be the tautomerism physical efficiency exist with the compound shown in the formula (V ') compound shown in the formula V:
R wherein
1, R
2, R
3, and R
5As above definition.
Step (ii)
Step (ii) in, at first make compound shown in compound shown in the formula (III) and the formula (IV) reaction carry out enamine.The R of formula (IV)
2And R
3Corresponding to the R in the compound shown in the formula (I)
2And R
3So, consider target compound, the structure of formula (I) just, the structure of compound can be determined accurately shown in the formula (IV).R
5Represent C
1-4Alkyl, preferable methyl or ethyl.The preferred example of compound comprises 2-methyl-acetoacetic acid methyl esters, 2-methyl-acetoacetic ester, 2-ethyl benzylacetoacetate, 2-ethyl ethylacetoacetate, 2-sec.-propyl methyl aceto acetate and 2-ethyl allylacetylacetate shown in the formula (IV).Consider for example reaction conditions, the consumption of the alpha-alkyl-'beta '-ketoester shown in the formula (IV) can be determined accurately.But the consumption of alpha-alkyl-'beta '-ketoester is about 0.8 to 2.0 equivalent shown in the preferred formula (IV), and more preferably about 1.0 to 1.5 equivalents most preferably are about 1.2 to 1.3 equivalents.
Reaction is preferably carried out having in the presence of acid or the alkaline catalysts.More preferably use acid catalyst.Acid catalyst comprises protonic acid, as acetic acid, trifluoroacetic acid and tosic acid and Lewis acid such as boron trifluoride diethyl ether mixture.Alkaline catalysts comprises piperidines.As use piperidines, preferably use alcohol solvent.In this case, the reaction times generally is longer than the situation of using acid catalyst.
The enamine reaction also can not use solvent to finish.But general, enamine carries out in inert solvent, as toluene, dimethylbenzene or ethanol, forms azeotropic mixture with water.Enamine preferably is heated to 100 to 140 ℃ to carry out, and removes the water of generation simultaneously by azeotropic, so that reaction goes on.Carry out the middle water that generates in order effectively to remove dereaction, preferably should design reaction vessel.For example, Dean-Stark water trap or suitable dewatering agent such as molecular sieve are incorporated in the reactor effectively to dewater.
Be reflected at the stirring down 2 to 5 hours that refluxes with the toluene solvent.Can pass through the thoroughness of 4-alkyl-2-fluorobenzene sulfonamide derivatives monitoring reaction, for example use the high performance liquid chromatography monitoring reaction.Because reaction is a balanced reaction, initiator can not all consume.Preferably, when the minimizing of 4-alkyl-2-fluorobenzene sulfonamide derivatives stops basically, just finish reaction.This is because even reaction is also further carried out, the enamine compound of disadvantageous reaction shown in the formula V that generates degraded, and sometimes can cause low-yield.
Because the enamine compound that obtains like this is unstable and can decompose rapidly on silica gel, it is difficult separating enamine compound with silica gel chromatography.Preferably use fractionation by distillation.General, enamine compound can separate the cyclization that just carries out next step.
In the present invention, when still during unreacted, just there is a kind of like this worry as initiator in 4-alkyl-2-fluoro aniline in cyclization, promptly the quinolinol compound shown in the formula (VI), just as formula (the I) (R of product
4=H) tautomer, the ketone position of its 4-position can form by product with the amino reaction of 4-alkyl-2-fluoro aniline, and this can significantly reduce productive rate.For avoiding this disadvantageous reaction; in preferred implementation of the present invention; after enamine; in solution, add alkali; as piperidines or triethylamine; make solution that stable alkalescence be arranged, then acetylation reagent such as acetic anhydride or Acetyl Chloride 98Min. are added with the glycylization of unreacted 4-alkyl-2-fluoro aniline still.Suppress amino nucleophilicity like this and also just suppressed production of by-products.Amino protecting group is not limited to ethanoyl, and general general protecting group is all available as acid amide type protecting group such as pivalyl and carbamate type protecting group such as benzyloxycarbonyl and tert-butoxycarbonyl.
Step (ii) in, carry out the cyclization of formula V subsequently by heating.This reaction allows to carry out in appropriate solvent, the preferred reflux temperature at solvent of heating.The example of preferred solvent comprises diphenyl ether, dimethylbenzene, polyphosphoric acid, tetramethyl-benzene, biphenyl, dimethyl formamide and methyl-sulphoxide.
In a preferred embodiment of the present invention, when enamine reaction and cyclization subsequently carry out with one still process, add diphenyl ether in the solution of enamine reaction, mixture heating up is to the boiling point of diphenyl ether, and 250 ℃, toluene is removed in evaporation.This reaction is the multicentre reaction of the intramolecularly dienophile that takes place of thermic, and dienophile wherein is a of enamine, the reaction of beta-unsaturated carbonyl part and benzene nucleus, and this reaction is commonly referred to as " the Conrad-Limpach quinolinol is synthetic ".This reaction also can be reacted at 140 ℃ of reflux temperatures to solvent in xylene solvent.Perhaps, carry out according to the method for WO00/47577 record.Especially, be solvent with the Tripyrophosphoric acid, by being heated to 160 ℃, enamine and cyclization can a step obtain the R shown in the formula (I)
4The quinolinol compound of=H.
Formula (I) compound, wherein R
4=H is a tautomer, also can exist with the form of formula (VI):
R wherein
1, R
2And R
3As above definition.
Cyclization can be by carrying out enamine reaction mixture and the mixed reacting by heating system then of solvent.Perhaps, enamine reaction mixture (wherein toluene is removed by evaporation) is splashed in the boiling solvent.It is very fast that reaction is carried out, and reacts to finish when temperature of reaction reaches 245 to 250 ℃.The reaction soln cool to room temperature, general slow stirring made it the compound that crystallization obtains formula (I), wherein R in 12 hours
4=H is the simplification compound basically.
In the present invention, if necessary, R wherein
4The hydroxyl of the compound 4-position of the formula of=H (I) can be protected with ordinary method.The protecting group of hydroxyl has no particular limits.The special example of preferred protecting group comprises C
1-6Alkyl, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, C
1-6Alkoxy C
1-6Alkyl-carbonyl, C
1-6Alkyl carbonyl oxy C
1-6Alkyl-carbonyl, C
3-6Naphthene base carbonyl and C
3-6Cyclo alkoxy carbonyl.Protecting group can be introduced with the protecting group method in common.For example, when making protecting group, can pass through wherein R with ethanoyl
4The solution of the compound of the formula of=H (I) is dissolved in the acetic anhydride or Acetyl Chloride 98Min. of pyridine and capacity, makes to be reflected at 80 ℃ and to carry out 1 hour, and basal ration obtains as 2,3 of target compound, 6-trialkyl-8-fluoro-4-acetoxyl group quinoline.
After reaction finishes, by evaporating solvent and from normal hexane recrystallization obtain the pure crystal of the compound of formula (I).If wish to get the compound of carbonic ether protection, R wherein then
4The hydroxyl of the compound 4-position of the formula of=H (I) can by with suitable alkali, as sodium hydride carry out alpha proton reaction, then with carbonic ether esterifying reagent reaction, typical as Vinyl chloroformate.On the other hand, if wish to get the compound of alkyl oxide protection, R wherein then
4The compound of the formula of=H (I) can react with alkali such as salt of wormwood, then with alkylating reagent, typically as iodomethane reaction.
[embodiment]
The following examples further specify the present invention.
Embodiment 1: the 4-tertiary butyl-2-fluoroaniline
36% hydrochloric acid of agitator and 5.50ml is put into glass reactor, and (5.24g 0.0383mol) is dissolved in wherein with zinc chloride.While stir be sequentially added into 2-fluoro aniline (10.0ml, 0.104mol) and the trimethyl carbinol (9.90ml, 0.104mol).Glass Containers is contained within the stainless steel pressure container, and it is sealed in case interior pressure leakage.Material in the container is heated to 190 ℃ while stirring and reacts then.Original pressure is about 5atm.Reaction continues 72 hours.After be sure oing that temperature is reduced to satisfaction, open pressurized vessel, in reaction mixture, add ethyl acetate (200ml), stirring the mixture then makes it even.After adding entry (200ml), adjust pH value to 9 with the sodium hydroxide neutralise mixt.Filter out a large amount of brown solid precipitations.Organic layer is separated once more from filtrate and is washed with water.Organic layer concentrates and obtains 16.9g burgundy oily matter.Do reference with standard model, with this material of absolute standard curve method quantitative assay.The result shows that productive rate is 79.2%.
E1-MS：m/z?170(M+H)
+；
1HNMR(CDCl
3)：δ1.26(9H，s，t-Bu)，3.56(br，NH
2)，6.74(1H，t-like，J＝9.3Hz，H6)，6.95(1H，ddd，J＝7.5，2.1，0.7Hz，H
5)，7.94(1H，dd，J＝13.4，1.9Hz，H
3)。
Embodiment 2: the 6-tertiary butyl-8-fluoro-2,3-dimethyl-4-quinolinol
(5.06g 30.3mmol) is dissolved in (120ml) in the toluene, and (5.75ml is 40.6mmol) with tosic acid monohydrate (50mg) to add the 2-methyl-acetoacetic ester then with the 4-tertiary butyl-2-fluoroaniline.Reflux is 3 hours in the reactor that is equipped with Dean-Stark equipment.The reaction soln cool to room temperature.Be sequentially added into diphenyl ether (50ml), piperidines (2.0ml), and acetic anhydride (1.0ml), 30min stirs the mixture.Heat the mixture that is stirred once more, the toluene as solvent is removed in evaporation.Temperature of reaction is elevated to 250 ℃ and keep 10min to finish cyclisation then.The reaction soln cool to room temperature is placed then all night and is made it crystallization.Filter the white crystals that collecting precipitation goes out, wash with normal hexane.The white crystals that obtains obtained the 6-tertiary butyl-8-fluoro-2 in 3 hours in reduced pressure at room temperature, 3-dimethyl-4-quinolinol (4.82g, productive rate 64.5%).
FAB-MS:m/Z 248 (M+H)
+ 1HNMR (CDCl
3): δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH
3), 2.52 (3H, s, CH
3), 7.34 (1H, dd, J=12.9,2.2Hz, H
3-aromatic series), 8.10 (1H, d, J=1.5Hz, H
5-aromatic series), 8.92 (1H, bs, NH).
Embodiment 3: the 6-tertiary butyl-8-fluoro-2,3-dimethyl-4-quinolinol (EMA dropping method)
(5.06g 30.3mmol) is dissolved in (80ml) in the toluene, adds tosic acid monohydrate (50mg) then with the 4-tertiary butyl-2-fluoroaniline.Reflux mixture in the reactor that is equipped with Dean-Stark equipment.With at least 2 hours time, (5.75ml 40.6mmol) dropwise joined in the hot solution will to be dissolved in 2-methyl-acetoacetic ester in the toluene (20ml).After dropwising, reflux is 2 hours again.The reaction soln cool to room temperature.Be sequentially added into diphenyl ether (50ml), piperidines (2.0ml), and acetic anhydride (1.0ml), 30min stirs the mixture.Heat the mixture that is stirred once more, the toluene as solvent is removed in evaporation.Temperature of reaction is elevated to 250 ℃ and keep 10min to finish cyclisation then.The reaction soln cool to room temperature spends the night then to place and makes it crystallization.Filter the white crystals that collecting precipitation goes out, wash with normal hexane.The white crystals that obtains obtained the 6-tertiary butyl-8-fluoro-2 in 3 hours in reduced pressure at room temperature, 3-dimethyl-4-quinolinol (5.17g, productive rate 69.0%).
Embodiment 4: the 6-tertiary butyl-8-fluoro-2,3-dimethyl-4-quinolinol
Polyphosphoric acid (10.8g) is heated to 160 ℃.(1.89g, 11.3mmol) (1.96g, mixture 13.5mmol) stirred the mixture under this temperature 3 hours with the 2-methyl-acetoacetic ester dropwise to add the 4-tertiary butyl-2-fluoroaniline then.Cooled reaction solution adds entry (50ml) then.Extract mixture twice with ethyl acetate (50ml).The merging organic layer also washes with water.Reduction vaporization is removed the solvent in the organic layer that has merged, and obtains oily matter.Oily matter recrystallization from ethyl acetate-normal hexane goes out to obtain the 6-tertiary butyl-8-fluoro-2 of white crystal, 3-dimethyl-4-quinolinol (0.97g, productive rate 34.7%).
FAB-MS:m/z 248 (M+H)
+ 1HNMR (CDCl
3): δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH
3), 2.52 (3H, s, CH
3), 7.33 (1H, dd, J=12.9,2.2Hz, H
3-aromatic series), 8.10 (1H, d, J=1.5Hz, H
5-aromatic series), 8.93 (1H, bs, NH).
Embodiment 5: the 6-tertiary butyl-8-fluoro-2,3-dimethyl-4-quinolinol
(5.06g 30.3mmol) is dissolved in (120ml) in the toluene, and (5.75ml is 40.6mmol) with tosic acid monohydrate (50mg) to add the 2-methyl-acetoacetic ester then with the 4-tertiary butyl-2-fluoroaniline.Reflux is 3 hours in the reactor that is equipped with Dean-Stark equipment.The reaction soln cooling pours in the saturated sodium bicarbonate aqueous solution then, uses ethyl acetate (50ml) extraction again.Filter out solid then with the anhydrous magnesium sulfate drying organic layer.Concentrated filtrate obtains the 5.99g brown oil.Oily matter dissolves in the dimethylbenzene (155ml) and makes a kind of solution, again to its heated and stirred 1 hour.After the reaction soln cooling, evaporation removes and desolvates.Residue obtains the 6-tertiary butyl-8-fluoro-2 with silica gel column chromatography (ethyl acetate-normal hexane=1: 1) purifying, 3-dimethyl-4-quinolinol (845mg, productive rate 11.3%).
FAB-MS:m/z 248 (M+H)
+ 1HNMR (CDCl
3): δ 1.33 (9H, s, t-Bu), 2.13 (3H, s, CH
3), 2.52 (3H, s, CH
3), 7.33 (1H, dd, J=12.9,2.1Hz, H
3-aromatic series), 8.11 (1H, d, J=1.5Hz, H
5-aromatic series), 8.92 (1H, bs, NH).
Embodiment 6: the 6-tertiary butyl-8-fluoro-2,3-dimethyl-4-acetoxyl group quinoline
With among the embodiment 5 preparation the 6-tertiary butyl-8-fluoro-2,3-dimethyl-4-quinolinol (3.93g, 15.9mmol) be dissolved in pyridine (13ml, 159mmol) in.(15ml 159mmol), stirs the mixture and is heated to 80 ℃ and carried out 1 hour to add acetic anhydride.Reduction vaporization is removed as the pyridine of solvent and remaining acetic anhydride and is obtained buttery resistates 4.90g.Oily matter is dissolved in the normal hexane (4.5ml) and makes solution.Add crystal seed in solution, stirring the mixture gently in room temperature obtained a large amount of white crystals in 12 hours.Collect crystal by filtering,, obtained the 6-tertiary butyl-8-fluoro-2 in 12 hours in drying at room temperature, the white crystals of 3-dimethyl-4-acetoxyl group quinoline (2.53g, productive rate 90.1%) with cold normal hexane (4.5ml) washing fast.
FAB-MS:m/z 290 (M+H)
+ 1HNMR (CDCl
3): δ 1.38 (9H, s, t-Bu), 2.26 (3H, s, ethanoyl), 2.52 (3H, s, CH
3), 2.75 (3H, s, CH
3), 7.37 (1H, d, J=1.9Hz, H
5-aromatic series), 7.43 (1H, dd, J=12.9,1.9Hz, H
7-aromatic series).
Embodiment 7: 4-tert-pentyl-2-fluoroaniline
36% hydrochloric acid of agitator and 5.50ml is put into glass reactor, and (5.24g 0.0383mol) is dissolved in wherein with zinc chloride.While stir be sequentially added into 2-fluoro aniline (10.0ml, 0.104mol) and tertiary amyl alcohol (11.4ml, 0.104mol).Glass Containers is encapsulated within the stainless steel pressure container, and it is sealed in case interior pressure leakage.Material in the container is heated to 190 ℃ while stirring and reacts then.Original pressure is about 5atm.Reaction continues 72 hours.After be sure oing that temperature is reduced to satisfaction, open pressurized vessel, in reaction mixture, add ethyl acetate (200ml), stirring makes mixture even then.After adding entry (200ml), adjust pH value to 9 with the sodium hydroxide neutralise mixt.Filter out a large amount of brown solid precipitations.Organic layer is separated once more from filtrate and is washed with water.Organic layer concentrates and obtains 17.5g burgundy oily matter.This oily matter obtains 4-tert-pentyl-2-fluoroaniline with silica gel column chromatography (normal hexane-ethyl acetate=10: 1) purifying, (9.22g, productive rate 49.0%).The glycylization of portion of product is obtained acetylate 4-tert-pentyl-2-fluoro-monoacetylaniline, thereby determine its structure.
E1-MS:m/z 224 (M+H)
+ 1HNMR (CDCl
3): δ 0.67 (3H, t, J=7.3Hz, amyl group-CH
2 CH 3), 1.25 (6H, s, amyl group-CH
3), 1.60 (2H, q, J=7.5Hz, amyl group-
CH 2CH
3), 2.21 (3H, s, ethanoyl-CH
3), 7.03 (1H, dd, J=17.1,1.9Hz, H
3), 7.07 (1H, dd, J=8.3,2.0Hz, H
5), 7.29. (1H, brs, NH), 8.16 (1H, dd, J=8.5,8.5Hz, H
6).
Embodiment 8: 6-tert-pentyl-8-fluoro-2,3-dimethyl-4-quinolinol
(2.00g 11.1mmol) is dissolved in (15ml) in the toluene, and (1.56ml is 11.1mmol) with boron trifluoride diethyl ether complex compound (50ml) to add the 2-methyl-acetoacetic ester then with 4-tert-pentyl-2-fluoroaniline.The reflux mixture is 6 hours in reactor, and this reactor has a top that a flask that has the reflux condensing tube of molecular sieve is housed.The reaction soln cool to room temperature.Be sequentially added into diphenyl ether (50ml), piperidines (0.7ml), and acetic anhydride (0.3ml) stirred the mixture 30 minutes.Heat the mixture that is stirred once more, the toluene as solvent is removed in evaporation.Temperature of reaction is elevated to 250 ℃ and keep 10min to finish cyclisation then.The reaction soln cool to room temperature spends the night then to place and makes it crystallization.Filter the brown crystallization that collecting precipitation goes out, wash with normal hexane.The brown crystallization that obtains obtains 6-tert-pentyl-8-fluoro-2 at reduced pressure at room temperature 3hr, 3-dimethyl-4-quinolinol (1.18g, productive rate 41.0%).
FAB-MS:m/z 263 (M+H)
+ 1HNMR (CDCl
3): δ 0.64 (3H, t, J=7.6Hz, amyl group-CH
2 CH 3), 1.31 (6H, s, amyl group-CH
3), 1.65 (2H, q, J=7.3Hz, amyl group-
CH 2CH
3), 2.14 (3H, s, 2-CH
3), 2.48 (3H, s, 3-CH
3), 2.52 (3H, s, CH
3), 7.29 (1H, dd, J=12.9,1.9Hz, H
7-aromatic series), 8.05 (1H, d, J=1.2Hz, H
5-aromatic series), 8.51 (1H, bs, NH).
Embodiment 9: 6-tert-pentyl-8-fluoro-2,3-dimethyl-4-acetoxyl group quinoline
With among the embodiment 8 preparation 6-tert-pentyl-8-fluoro-2,3-dimethyl-4-quinolinol (1.10g, 4.21mmol) be dissolved in pyridine (3.4ml, 42.1mmol) in.(6.0ml 63.6mmol), stirs the mixture and is heated to 80 ℃ and carried out 2 hours to add acetic anhydride.Reduction vaporization is removed as the pyridine of solvent and remaining acetic anhydride and is obtained the buttery resistates.In resistates, add ethyl acetate (100ml), use saturated brine, 10% aqueous citric acid solution and saturated brine washing then in order respectively.Use the anhydrous magnesium sulfate drying organic layer.Cross filter solid concentrating under reduced pressure filtrate then.Remaining oily matter obtains 6-tert-pentyl-8-fluoro-2 with silica gel column chromatography (normal hexane-ethyl acetate=8: 1) purifying, 3-dimethyl-4-acetoxyl group quinoline (1.22g, productive rate 95.9%).
FAB-MS:m/z 304 (M+H)
+ 1HNMR (CDCl
3): δ 0.68 (3H, t, J=7.3Hz, amyl group-CH
2 CH 3), 1.34 (6H, s, amyl group-CH3), 1.69 (2H, q, J=7.6Hz, amyl group-
CH 2CH
3), 2.26 (3H, s, ethanoyl-CH
3), 2.52 (3Hs 2-CH
3), 2.75 (3H, s, 3-CH
3), 7.32 (1H, d, J=1.7Hz, H
5-aromatic series), 7.37 (1H, dd, J=12.9,2.0Hz, 11
7-aromatic series).
Embodiment 10: the 6-tertiary butyl-8-fluoro-2,3-dimethyl-4-methoxyl group carbonyl phenoxyl quinoline
With the 6-tertiary butyl-8-fluoro-2 of preparation among the embodiment 5, (1.00g 4.05mmol) is dissolved in the anhydrous tetrahydro furan (20ml) 3-dimethyl-4-quinolinol.In argon atmospher and with under ice-cooled, add 60% sodium hydride (160mg), the temperature of mixture returns to room temperature, stirs the mixture 1 hour up to stopping to emit gas.(376ml 4.86mmol) is dissolved among the solution of anhydrous tetrahydro furan (5ml) formation, and room temperature continues to stir 3 hours more dropwise to join methyl-chloroformate then with the ice bath cooling mixture once more.Reaction soln is poured in the frozen water, uses ethyl acetate (50ml) extraction then.Use the anhydrous magnesium sulfate drying organic layer.Cross filter solid concentrating under reduced pressure filtrate then.Resistates obtains the 6-tertiary butyl-8-fluoro-2 with silica gel column chromatography (ethyl acetate-normal hexane=3: 1) purifying, 3-dimethyl-4-methoxyl group carbonyl phenoxyl quinoline (784mg, productive rate 63.5%).
FAB-MS:m/z 306 (M+H)
+ 1HNMR (CDCl
3): δ 1.38 (9H, s, t-Bu), 2.32 (3H, s, 2-CH
3), 2.76 (3H, s, 3-CH
3), 4.00 (3H, s, OCH
3), 7.42 (1H, d, J=1.9Hz, H5-aromatic series), 7.45 (1H, dd, J=12.9,1.9Hz, H
7-aromatic series).
Embodiment 11: the 6-tertiary butyl-8-fluoro-2,3-dimethyl-4-(ethoxymethyl) phenoxyl quinoline
With the 6-tertiary butyl-8-fluoro-2 of preparation among the embodiment 5, (1.00g 4.05mmol) is dissolved in the anhydrous tetrahydro furan (20ml) 3-dimethyl-4-quinolinol.In argon atmospher and with under ice-cooled, add 60% sodium hydride (320mg), the temperature of mixture returns to room temperature, stirs the mixture 1 hour then up to stopping to emit gas.(761ml 8.10mmol) is dissolved among the solution of anhydrous tetrahydro furan (5ml) formation, and room temperature continues to stir 6 hours more dropwise to join ethoxymethyl chlorine then with the ice bath cooling mixture once more.Reaction soln is poured in the frozen water, uses ethyl acetate (50ml) extraction then.Use the anhydrous magnesium sulfate drying organic layer.Cross filter solid concentrating under reduced pressure filtrate then.Resistates obtains the 6-tertiary butyl-8-fluoro-2 with silica gel column chromatography (ethyl acetate-normal hexane=3: 1) purifying, 3-dimethyl-4-(ethoxymethyl) phenoxyl quinoline (145mg, productive rate 11.7%).
FAB-MS:m/z 306 (M+H)
+ 1HNMR (CDCl
3): δ 1.21 (3H, t, J=7.1Hz), 1.36 (9H, s, t-Bu), 2.17 (3H, s, 2-CH
3), 2.53 (3H, s, 3-CH
3), 3.51 (2H, q, J=7.1Hz), 5.53 (2H, s), 7.37 (1H, dd, J=17.3,2.4Hz, H
7-aromatic series), 8.21 (1H, d, J=2.4Hz, 11
5-aromatic series).
Embodiment 12: 4-cyclohexyl-2-fluoroaniline
36% hydrochloric acid of agitator and 5.50ml is put into glass reactor, and (5.24g 0.0383mol) is dissolved in wherein with zinc chloride.While stir be sequentially added into the 2-fluoroaniline (10.0ml, 0.104mol) and hexalin (10.4ml, 0.104mol).Glass Containers is encapsulated within the stainless steel pressure container, and it is sealed in case interior pressure leakage.Then container is heated to 190 ℃ and stir and to react.Original pressure is about 5atm.Reaction continues 72 hours.After be sure oing that temperature is reduced to satisfaction, open pressurized vessel, in reaction mixture, add ethyl acetate (200ml), stirring makes mixture even then.After adding entry (200ml), adjust pH value to 9 with the sodium hydroxide neutralise mixt.Filter out a large amount of brown solid precipitations.Organic layer is separated once more from filtrate and is washed with water.Organic layer concentrates and obtains 15.1g burgundy oily matter.Oily matter obtains 4-cyclohexyl-2-fluoroaniline (6.63g, productive rate 33.0%) with silica gel column chromatography (ethyl acetate-normal hexane=1: 5) purifying.
E1-MS：m/z?194(M+H)
+；
1HNMR(CDCl
3)：δ1.34(6H，m)，1.82(4H，m)，2.39(1H，m)，3.55?2H，(bs，NH
2)，6.73(1H，dd，J＝17.1，8.1Hz)，6.78(1H，dd，J＝8.0，1.9Hz)，6.84(1H，dd，J＝12.4，1.7Hz)。
Embodiment 13: 6-cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol
(5.00g 25.9mmol) is dissolved in (100ml) in the toluene, and (4.77ml is 33.7mmol) with tosic acid monohydrate (50mg) to add the 2-methyl-acetoacetic ester then with 4-cyclohexyl-2-fluoro aniline.Reflux is 3 hours in the reactor that is equipped with Dean-Stark equipment.。The reaction soln cool to room temperature.Be sequentially added into diphenyl ether (50ml), piperidines (2.0ml), and acetic anhydride (1.0ml), 30min stirs the mixture.Heat the mixture that is stirred once more, the toluene as solvent is removed in evaporation.Temperature of reaction is elevated to 250 ℃ and keep 10min to finish cyclisation then.The reaction soln cool to room temperature spends the night then to place and makes it crystallization.Filter the white crystals that collecting precipitation goes out, wash with normal hexane.The white crystals that obtains obtained 6-cyclohexyl-8-fluoro-2 in 3 hours in reduced pressure at room temperature, 3-dimethyl-4-quinolinol (3.56g, productive rate 50.4%).
FAB-MS：m/z?274(M+H)
+；
1HNMR(d
6-DMSO)：δ1.40(6H，m)，1.60(4H，m)，2.41(3H，s)，7.41(1H，d，J＝12.9)，7.68(1H，s)，11.25(1H，s)。
Embodiment 14: 6-cyclohexyl-8-fluoro-2,3-dimethyl-4-acetoxyl group quinoline
With among the embodiment 5 preparation 6-cyclohexyl-8-fluoro-2,3-dimethyl-4-quinolinol (3.00g, 11.0mmol) be dissolved in pyridine (8.70ml, 110mmol) in.To wherein add acetic anhydride (11.2ml, 110mmol) after, stir the mixture and be heated to 80 ℃ and reacted 2 hours.Reduction vaporization is removed as the pyridine of solvent and remaining acetic anhydride.In resistates, add ethyl acetate (100ml), use saturated brine, 10% aqueous citric acid solution and saturated brine washing then in order respectively.Use the anhydrous magnesium sulfate drying organic layer.Cross filter solid concentrating under reduced pressure filtrate then.Remaining oily matter obtains 6-cyclohexyl-8-fluoro-2 with silica gel column chromatography (normal hexane-ethyl acetate=8: 1) purifying, 3-dimethyl-4-acetoxyl group quinoline (3.17g, productive rate 91.2%).
FAB-MS:m/z 317 (M+H)
+ 1HNMR (CDCl
3): δ 1.27 (2H, m), 1.45 (4H, m), 1.90 (4H, m), 2.26 (3H, s, ethanoyl-CH
3), 2.25 (3H, s), 2.52 (3H, s), 2.75 (3H, s), 2.64 (1H, m), 7.25 (2H, m).
Claims (7)
1. one kind is used for producing as shown in the formula 2,3 shown in (I) method of 6-trialkyl-8-fluoro-4-quinoline or its salt:
Wherein
R
1The optional C that replaces of representative
1-10Alkyl or C
3-6Cycloalkyl;
R
2The optional C that replaces of representative
1-10Alkyl or C
3-6Cycloalkyl;
R
3The optional C that replaces of representative
1-10Alkyl, C
2-6Alkenyl, phenyl C
1-6Alkyl or C
3-6Cycloalkyl; With
R
4Represent the protecting group of hydrogen atom or hydroxyl,
Described method comprises the steps:
(i) make the alkylation shown in the following formula (II):
With R
1-X (R wherein
1As above define and X representation hydroxy or halogen atom) or R
1 '(R wherein
1 'For with R
1Alkene with identical carbon atoms) under pressure, reaction in the presence of zinc chloride obtains the 4-alkyl shown in the following formula (III)-2-fluoroaniline derivative:
R wherein
1As above definition; With
(ii) use the alpha-alkyl shown in compound shown in the formula (III) and the formula (IV)-'beta '-ketoester reaction:
R wherein
2And R
3As above definition; And R
5Represent C
1-4Alkyl,
Obtain the enamine intermediate shown in the formula V:
R wherein
1, R
2, R
3, and R
5As above definition,
The cyclisation of enamine intermediate obtains compound, wherein R shown in the formula (I)
4Represent the hydroxyl that the optional protection of protecting group is arranged on hydrogen atom and the 4-position.
2. be the 2-methyl-acetoacetic ester according to compound shown in the formula of the process of claim 1 wherein (IV).
3. according in the compound shown in the formula of the process of claim 1 wherein (I), R
1Represent the tertiary butyl, R
2And R
3Represent methylidene, and R
4Represent hydrogen atom.
4. according in the compound shown in the formula of the process of claim 1 wherein (I), R
1Represent the tertiary butyl, R
2And R
3Represent methylidene, and R
4Represent ethanoyl.
5. be the salt acid-adducting salt according to compound shown in the formula of the process of claim 1 wherein (II).
6. according to the process of claim 1 wherein R
4The hydroxyl protecting group of representative is C
1-6Alkyl, C
1-6Alkyl-carbonyl, C
1-6Alkoxy carbonyl, C
1-6Alkoxy C
1-6Alkyl-carbonyl, C
1-6Alkyl carbonyl oxy C
1-6Alkyl-carbonyl, C
3-6Naphthene base carbonyl or C
3-6Cyclo alkoxy carbonyl.
7. according to the process of claim 1 wherein that step (i) and step (ii) carry out with one still process.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002202213 | 2002-07-11 | ||
| JP202213/2002 | 2002-07-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1668597A true CN1668597A (en) | 2005-09-14 |
| CN1307160C CN1307160C (en) | 2007-03-28 |
Family
ID=30112610
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB038164930A Expired - Fee Related CN1307160C (en) | 2002-07-11 | 2003-07-11 | Process for producing 2,3,6-trialkyl-8-fluoro-4-quinoline derivative |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP4541143B2 (en) |
| CN (1) | CN1307160C (en) |
| AU (1) | AU2003280976A1 (en) |
| TW (1) | TW200401767A (en) |
| WO (1) | WO2004007460A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104904720A (en) * | 2014-03-11 | 2015-09-16 | 浙江省化工研究院有限公司 | Sterilization composition containing ZJ5337 and methoxy acrylic ester sterilization agent |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101591123B1 (en) * | 2008-07-15 | 2016-02-02 | 니폰 카야쿠 코., 엘티디. | Mehtod for producing 6-aryloxyquinoline derivative and intermediate thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5828865B2 (en) * | 1978-06-21 | 1983-06-18 | 保土谷化学工業株式会社 | Improved production method of 2↓-chloro↓-4′↓-hydroxy↓-diphenylamine |
| US4436936A (en) * | 1981-06-19 | 1984-03-13 | Ciba-Geigy Corporation | Alkylation and aralkylation of aromatic amines |
| DE3271678D1 (en) * | 1981-11-11 | 1986-07-17 | Shell Int Research | Process for the selective alkylation of an aniline |
| JPS59167545A (en) * | 1983-02-01 | 1984-09-21 | Nippon Kayaku Co Ltd | Production of 3-methyl-4-isopropylaniline |
| TW521072B (en) * | 1997-06-02 | 2003-02-21 | Meiji Seika Kaisha | 4-quinolinol derivatives and fungicides containing the same as an active ingredient used for agriculture and horticulture |
| CN1193017C (en) * | 2000-05-30 | 2005-03-16 | 明治制果株式会社 | Rice blast control agents |
-
2003
- 2003-07-11 AU AU2003280976A patent/AU2003280976A1/en not_active Abandoned
- 2003-07-11 WO PCT/JP2003/008848 patent/WO2004007460A1/en active Application Filing
- 2003-07-11 TW TW92119053A patent/TW200401767A/en not_active IP Right Cessation
- 2003-07-11 JP JP2004521196A patent/JP4541143B2/en not_active Expired - Fee Related
- 2003-07-11 CN CNB038164930A patent/CN1307160C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104904720A (en) * | 2014-03-11 | 2015-09-16 | 浙江省化工研究院有限公司 | Sterilization composition containing ZJ5337 and methoxy acrylic ester sterilization agent |
| CN104904720B (en) * | 2014-03-11 | 2017-08-08 | 浙江省化工研究院有限公司 | A kind of bactericidal composition containing ZJ5337 and methoxy acrylic bactericide |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2003280976A1 (en) | 2004-02-02 |
| CN1307160C (en) | 2007-03-28 |
| TWI320782B (en) | 2010-02-21 |
| JPWO2004007460A1 (en) | 2005-11-10 |
| TW200401767A (en) | 2004-02-01 |
| WO2004007460A1 (en) | 2004-01-22 |
| JP4541143B2 (en) | 2010-09-08 |
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