CN1244543C - Method for preparing 4-(alkyl)-3-alkoxy-aniline compounds - Google Patents
Method for preparing 4-(alkyl)-3-alkoxy-aniline compounds Download PDFInfo
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- CN1244543C CN1244543C CN 98807249 CN98807249A CN1244543C CN 1244543 C CN1244543 C CN 1244543C CN 98807249 CN98807249 CN 98807249 CN 98807249 A CN98807249 A CN 98807249A CN 1244543 C CN1244543 C CN 1244543C
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
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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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
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Abstract
The invention concerns a method for preparing a compound of formula (I) in which: R<1> represents a C1-C10 alkyl group, linear or branched, an aralkyl group in which the alkyl part is linear and comprises 1 to 3 carbon atoms and the aryl part is selected among the phenyl groups, substituted or not, in particular by one or several C1-C3 alkyl groups, or by several halogen atoms or by one or several nitro radicals; R<2> represents a C1-C16 alkyl group, linear or branched. The compounds of formula (I) are synthesis intermediates useful in particular for preparing quinoline or quinolone derivatives such as 4-hydroxyquinoline-3-carboxylic acid esters.
Description
The present invention relates to from-amino-phenol prepares the method for 4-(alkyl)-3-alkoxyl group-aniline compounds.
More particularly, the present invention relates to synthetic corresponding to the disubstituted benzenes amine of general formula (I):
Wherein
-R
1The C that represents a linearity or branching
1-C
10Alkyl, an aralkyl, wherein moieties is linear and contains 1-3 carbon atom and aryl moiety is selected from unsubstituted or by one or more C
1-C
3Alkyl, by one or more halogen atoms or by phenyl that one or more nitro replaced.
-R
2The C of expression linearity or branching
1-C
16Alkyl.
The compound of general formula (I) is known and constitutes the synthetic intermediate of extremely important meaning, it especially can with alkoxyl group alkylidene group malonic ester type compound carry out condensation and then cyclisation obtain quinoline or Carbostyril derivative, they are mainly used in the healthcare field of people's health care and animal.
In these derivatives, can mention the ester class such as methylbenzoquate (the 7-benzyloxy-6-butyl-1 of 4-hydroxyquinoline-3-carboxylic acid, 4-dihydro-4-oxo-3-quinoline carboxylic acid methyl esters), it is in the healthcare field of animal, especially can be used as anticoccidiosis medicine, and they are used to remain the poultry feed of pasty state (battery-kept).
French Patent number 1 487 336 (ICI Ltd) are known, and it has described the method that begins to prepare the quinoline of 7-alkoxyl group-4-hydroxyl-3-quinoline carboxylic ester type from the 3-acetaminophenol.
Should synthetic comprise: make that aniline-it suits to be substituted on 3 and optional 4 of on respect to ring amido functional group-with alkoxyl group methylene malonate type derivatives reaction, make prepared product make thermal cyclization then.
According to the document; required substituted aniline is following acquisition: by the hydroxy functional group in addition O-alkylation of allyl halide with 3-acetylamino phenol; rearrangement with obtain that corresponding 4-replaces-3-hydroxy-n-Acetanilide; and then utilize suitable halogenide to make hydroxy functional group implement the O-replacement, finally discharge amido functional group by hydrolysis.
Should synthetic involve a large amount of steps, some of them are not optionally and cause producing necessary isolating isomer or by product.
The method that the purpose of this invention is to provide a kind of synthetic disubstituted benzenes amine, it comprises less number of operations and simple and not expensive.
Another object of the present invention provides a kind of like this method, and it obtains required product and easy industrial enforcement with better productive rate.
For this reason, the purpose of this invention is to provide a kind of preparation method of general formula (I) compound as defined above, it is characterized in that it may further comprise the steps:
1) with one at single step, by means of from radicals R
2The identical acylating reagent of C=O deutero-, with between following general formula (II)-amino-phenol
Amido functional group and hydroxy functional group acidylate in addition, form the compound of general formula (III):
2) heating resulting compound (III) in the presence of Friedel and Crafts type catalyzer, carry out the Fries rearrangement reaction and form following compound (IV):
3) optionally the carbonyl functional group on 4 of compound (IV) is reduced, is formed following compound (V):
4) hydroxy functional group is carried out the O-alkylation and by hydrolysis in a kind of alkaline medium make the amido functional group of compound (V) go the protection, obtain required compound (I).
The inventor has now found that, this synthetic route can be improved and improves overall productivity by the above method.
Below the present invention will be described in more detail.
The invention provides from-amino-phenol (II) begins to prepare the method for general formula (I) compound.
According to the present invention, radicals R
1Preferably be selected from the alkyl or the aralkyl of linearity or branching, as methyl, ethyl, n-propyl, sec.-propyl, the cyclopropyl methylene radical, 3-phenyl-propyl group, right-methyl-benzyl, right-the benzyl chloride base, neighbour-benzyl chloride base, the neighbour, right-dichloro benzyl, right-nitrobenzyl and decyl, and more preferably represent benzyl.
Radicals R
2The C of preferred expression linearity or branching
1-C
6Alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, amyl group, 1-ethyl propyl or hexyl are also more preferably represented n-propyl.
The method according to this invention is shown below:
Synthetic route
Step 1:
In this step, amido functional group be protected and-hydroxy functional group of amino-phenol is with same acylating reagent acidylate in addition, the acyl group (R of this reagent
2C=O) have with will be at the identical carbonatoms of carbonatoms of the alkyl of 4 introducings.
Acylating reagent is general formula (R ideally
2C=O)
2The acid anhydrides of O.In this case, R
2The C that represents linearity or branching ideally
1-C
6Alkyl.
It usually at least by stoichiometric consumption, preferably by at least 2 times of equivalents, usually is approximately 2.2 times of normal consumptions and uses.
Carboxyl acyl chloride (R
2COCl) also can use.
In general, suit reaction times of 1-2 hour and usually under the comparatively high temps of the temperature between 100 ℃-200 ℃, preferably make under the boiling point at reaction solvent between-amino-phenol reacts with acylating reagent.
According to an ideal embodiment of the present invention, the solvent of reaction is made up of with corresponding carboxylic acid acylating reagent itself.
Step 2:
The phenolic ester that forms in the first step (III) causes rearrangement reaction by heating in the presence of Friedel and Crafts type catalyzer.Finished the Fries rearrangement reaction by this way.
This reaction obtains neighbour-and right-Acylphenol usually; Yet for the amino-phenol of two acidylates, the ortho position (contraposition of nitrogen-atoms) of observing Sauerstoffatom will be preferential, and this is owing to the steric effect that is connected to the acyl group on the nitrogen.
Be connected to group-C on the nitrogen (=O) R
2Big more, the regioselectivity that helps 4 is just stronger.
Catalyzer is aluminum chloride AlCl preferably
3Preferred use with respect to-amount of amino-phenol is 2 times of normal catalyzer.
For this reaction, might use the solvent that usually is used for Fries reaction and Friedel-Crafts acylation reaction, as oil of mirbane, methylene dichloride, 1,2-ethylene dichloride, chlorobenzene and dichlorobenzene, preferred dichlorobenzene.
Reaction mixture obtains compound (IV) with posthydrolysis.
Step 3:
The acyl group of this step on 4 of compound (IV) carries out reduction reaction.
Reduction reaction is advantageously by being undertaken by hydrogenation in the presence of commercial catalysts, (especially palladium/carbon type catalyzer).
In order to carry out this reaction, use the 4-20 crust, the hydrogen pressure of preferably approximately 12 crust.
As catalyzer, preferably according to using palladium/carbon corresponding to those ratios of ratio commonly used in the commercial run, i.e. 5-10%, humidity is 50%.This catalyzer is with respect to product the to be hydrogenated ratio with 1-2% (w/w), preferably uses in the ratio of 1.4-1.6%.
This reaction is in the presence of a kind of acid that is selected from for example sulfuric acid, phosphoric acid or acetate, preferably carries out in the presence of phosphoric acid or acetate.This acid is preferably with respect to the ratio of the 0.5-2.5mol% that waits to be hydrogenated product, preferably be introduced into about 1.5% ratio.
This reaction is to carry out in protonic solvent, wherein can mention lower alcohol, especially methyl alcohol and ethanol, and glycol monomethyl ether (Ethylene Glycol Methyl ether), single sec.-propyl glycol and 1-methoxyl group-2-propyl alcohol, methyl alcohol or ethanol are preferred.
The temperature of reaction can be 50-100 ℃, preferred about 85 ℃.
Hydrogenation compound (V) can be by in water, precipitating with recovered in solid form simply.
Step 4:
This final step purpose is to make the free hydroxyl group functional group on the compound (V) that obtains in step 3 in advance to do the protection of going of O-replacement and amido functional group.
For this reason, advantageously, use general formula R
1C
lThe compound of suitable muriate type, this depends on required final compound (I), makes muriate and compound (V) in the presence of a kind of alkali such as sodium hydroxide, potassium hydroxide, yellow soda ash or salt of wormwood, especially react in the presence of salt of wormwood.
This is reflected at aprotonic solvent such as acetone, in acetonitrile or the dimethyl formamide (DMF), advantageously in dimethyl formamide, between 50-100 ℃, preferably carry out under about 60 ℃ temperature.
Reaction times generally is 4-8 hour, on average between 5 and 6 hours.
Advantageously, use excessive 1.4-1.9 equivalent, preferred 1.5 normal muriate (R
1Cl).
Use alkali with excessive 1-2 equivalent, preferred 1.7 normal consumptions.
The product that replaces at 3 O-can not separate out, and its direct and alkali reaction makes amido functional group go protection in this case.
In this case, it advantageously reacts in the hydroxylic solvent that is selected from water, ethanol, 2-methyl cellosolve (methylcyclohexane) and 1-methoxyl group-2-propyl alcohol with 5 normal alkali such as sodium hydroxide or potassium hydroxide.
This is reflected between 85-115 ℃ and continues 8-12 hour.
Therefore obtain compound (I).
In a preferred embodiment of the present invention, when method of the present invention was used for 3-(benzyloxy)-4-n-butyl aniline (I ') synthetic, it may further comprise the steps:
1) by means of butyryl oxide will between-amido functional group of amino-phenol (II) and hydroxy functional group acidylate in addition, form the compound of general formula (III '), formula (III ') is corresponding to R wherein
2The compound (III) of expression n-propyl,
2) carry out the Fries rearrangement reaction of compound (III ') in the presence of aluminum chloride, form the compound of general formula (IV '), formula (IV ') is corresponding to R wherein
2Be the compound (IV) of n-propyl,
3) in a kind of acidic medium, carry out selective catalytic hydrogenation in a kind of in methyl alcohol, containing in the presence of 50% wet 10% palladium/carbon catalyst that divides, obtain the compound of general formula (V '), formula (V ') is corresponding to R wherein
2The compound (V) of expression n-propyl,
4) compound (V ') and benzyl chloride are reacted, then in alkaline medium with the reaction mixture hydrolysis.
According to the present invention, it is desirable to, for this intermediate (I) of purifying, by for example precipitating to form corresponding hydrochloride:
The compound of general formula (I) has constituted synthetic intermediate, and it is particularly useful for making 4-hydroxyquinoline-3-carboxylicesters or analogue.
These ester classes generally are the substituted aniline type compound reactions by compound that makes a kind of alkoxyl group alkylidene dialkyl malonate type and general formula (I), subsequently for example according in addition cyclisation and obtaining described in the above document FR-A-1 487 336.
Another object of the present invention is, general formula (I) application of compound when obtaining this derivative.
A further object of the present invention is, utilizes each step of method noted earlier to prepare quinoline, the method for 4-hydroxyquinoline-3-carboxylicesters especially.
The method according to this invention more is specially adapted to 3-(benzyloxy)-4-n-butyl aniline synthetic of general formula (I '), this compound has constituted the key intermediate of methyl benzoquate (7-benzyloxy-6-butyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid methyl esters) in synthetic.
The present invention describes by means of limiting examples given below.
Embodiment
The preparation of embodiment 1:3-(benzyloxy)-4-normal-butyl-aniline (I ')
Step 1
Step 2
From the phenol formula ester that obtains the step 1 by use with respect between initial-be two normal 99%AlCl for the amino-phenol
3Carrying out Fries resets.
In the interpolation process of aluminum chloride, temperature remains under 65 ℃ ± 5 ℃, is increased to 130 ℃ then.
Then, 0.15 normal butyryl chloride is added into into, and reaction mixture kept 45 minutes down at 125-130 ℃.
Reaction mixture subsequently water/propyl alcohol/list-or two-chlorobenzene mixture in be hydrolyzed.
Rearrangement product (IV ') crystallize out also and can separate by following steps:
Step 3
In 100 milliliters stainless steel Sotelem reactor, add the 4.5g product that obtains from step 2 (IV ') successively, 1.1g have the 10%Pd/C of 5096 humidity, a kind of phosphoric acid ethanol solution of the dehydrated alcohol of 40ml and 1.77g (1.47%w/w in dehydrated alcohol).After the reactor closure, the system nitrogen purging, and before pressure being set in 12 crust, use hydrogen purge 3 times.Begin to stir (1500 rev/mins) and heating then.Since 50 ℃, the pressure of record molecular hydrogen descends.In case pressure reaches 7.5 crust, reactor is readjusted 12 crust.Temperature continues to be increased to 85 ℃; In case pressure no longer descends, then stop heating, temperature drops to 25 ℃, and molecular hydrogen is carefully drawn and the reactor nitrogen purging.Reaction mass filters out on the sintered glass material, to reclaim catalyzer.Filtrate neutralizes with the N/2 sodium hydroxide solution.Having under the situation of alcohol reflux filtrate postheating 15 minutes, and be poured in the 200ml cold water.The product precipitation; Stir half a day, filter out with a B ü chner funnel then.Reclaim the hydrogenated products of 3.54g.The purity that is recorded by HPLC is 90%, and the productive rate that obtains pure products is 75%.
Step 4
With the compound that obtains from step 3 of 3g (12.7mmol) (V '), 15ml DMF, the K of 3.6kg
2CO
3(26mmol) benzyl chloride (24mmol) with 3g joins in the 100ml reactor that agitator and condenser are housed.Stirred 6 hours down at 60 ℃.Filter out salt of wormwood, filtrate concentrates under vacuum, and temperature is increased to 125 ℃.Add the ethanol of 15ml, be removed by vacuum distilling subsequently.
Add other 15ml ethanol, mixture is in nitrogen atmosphere, 80-85 ℃ of following heating 30 minutes.It is cooled to 30 ℃, adds the solution of KOH (53mmol) in 3ml water of 3g.Mixture stirs a night down at 85 ℃ in nitrogen.
Mixture distills, and reaches till 115 ℃ until internal temperature.Water and toluene are added in cooling.Be separated two, water extracts, and merges organic phase and also is concentrated into drying.
Add 15ml toluene, the 33%HCl of 2ml Virahol and 5ml.Mixture 70 ℃ and stir under heating 30 minutes to 1 hour, allow it cool off a night then.The crystal that is obtained is filtered out, uses 10ml toluene and 15ml water washing then.They 60 ℃ down dry, reclaim the product (I ') of 2.75g with hydrochloride form, record crystal purity by HPLC and be higher than 97%.Productive rate: 74%.
Embodiment 2-5 has illustrated the flexible embodiment according to the step 3 of the inventive method.
Embodiment 2:
Order adds the BuHBP of 4.5g in 100 milliliters of stainless steel Sotelem reactors, and 1.35g has the 10%Pd/C of 50% humidity, the methanol solution (1.47%w/w in Spectrosol MeOH) of the Spectrosol MeOH of 20ml and a kind of phosphoric acid of 1.25g.Identical among schedule of operation and the embodiment 1.Reclaim the hydrogenated products of 3.71g.The purity that is recorded by HPLC is 92%, and the productive rate that obtains pure products is 80%.
Embodiment 3:
Order adds the BuHBP of 4.5g in 100 milliliters of stainless steel Sotelem reactors, 1.49g the 10%Pd/C with 50% humidity, the methanol solution (1.47%w/w in Spectrosol MeOH) of the Spectrosol MeOH of 20ml and a kind of phosphoric acid of 0.63g.Identical among schedule of operation and the embodiment 1.Reclaim the hydrogenated products of 3.77g.The purity that is recorded by HPLC is 93%, and the productive rate that obtains pure products is 83%.
Embodiment 4:
Order adds the BuHBP of 13.5g in 300 milliliters of stainless steel Sotelem reactors, 4.47g have the 10%Pd/C of 50% humidity, the methanol solution (1.47%w/w in Spectrosol MeOH) of the Spectrosol MeOH of 60ml and a kind of phosphoric acid of 5.64g.Identical among schedule of operation and the embodiment 1.Product is deposited in the 600ml cold water.Reclaim the hydrogenated products of 12g.The purity that is recorded by HPLC is 96%, and the productive rate that obtains pure products is 90%.
Embodiment 5:
Order adds the BuHBP of 4.5g in 100 milliliters of stainless steel Sotelem reactors, and 1.49g has the 10%Pd/C of 50% humidity, a kind of phosphoric acid solution (1.47%w/w in the 2-methoxypropanol) of the pure and mild 1.88g of 2-methoxy propyl of 20ml.Identical among schedule of operation and the embodiment 1.Reclaim the hydrogenated products of 3.93g.The purity that is recorded by HPLC is 70%, and the productive rate that obtains pure products is 65%.
Embodiment 6 and 7 illustrated according to the step 4 of the inventive method can flexible embodiment.
Embodiment 6:
The compound that 3g (12.7mmol) is obtained from step 3 (V '), 15ml DMF, the K of 3g
2CO
3(21.6mmol) benzyl chloride (19.2mmol) with 2.4g joins in the 100ml reactor that agitator and condenser are housed.Stirred 6 hours down at 60 ℃.Filter out salt of wormwood, filtrate concentrates under vacuum, and temperature is increased to 125 ℃.Add the ethanol of 15ml, be removed by vacuum distilling subsequently.
Add the 2-methyl cellosolve of 25ml and the KOH (63.6mmol) of 3.6g.Mixture is stirred a night under 120 ℃ in nitrogen atmosphere.Concentrate and cooling, add water and toluene then.Be separated two, water extracts, and merges organic phase and also is concentrated into drying.
Add 15ml toluene, the 33%HCl of 2ml Virahol and 5ml.Mixture 70 ℃ and stir under heating 30 minutes, cool off a night then.The crystal that is obtained is filtered out, uses 10ml toluene and 15ml water washing then.They are dry under 60 ℃, are recovered to 3-(benzyloxy)-4-n-butylbenzene amine hydrochlorate of 3g.Productive rate: 75%.
Embodiment 7:
Repeat the schedule of operation of embodiment 6, but use 1-methoxyl group-2-propyl alcohol (MPG) to replace 2-methyl cellosolve.
Productive rate: 81%.
Embodiment 8 has illustrated step 1 of the inventive method and 2 flexible embodiment.
The preparation of embodiment 8:3-amide-based small-1-hydroxyl-n-butyl phenyl ketone (BuHBP).
1) 3-amide-based small-O-butyryl radicals phenol (BOBP; Synthesizing III ')
In the flask that mechanical stirrer and condenser are housed, add the 3-amino-phenol of 21.8g and the butyric acid of 30.0g.Add hot suspension until dissolving, drip the butyryl oxide of 67.0g afterwards, simultaneously temperature is remained on about 105 ℃.In order to allow reaction carry through to the end, reaction mass was 140 ℃ of heating 3 hours.When reaction finishes, under vacuum, distill out butyric acid and butyryl oxide.The product that is obtained (BOBP) is an oil, and weight is that 53.2g and purity are about 90-95%.
2) 3-amide-based small-1-hydroxyl-butyryl radicals phenol (BuHBP; Synthesizing IV ')
In the flask that mechanical stirrer, condenser and dropping funnel are housed, add the neighbour-dichlorobenzene of 60g and the AlCl of 60g
3Add being diluted in 53.2g BOBP in 20g neighbour-dichlorobenzene (III '), mixture is 125 ℃-130 ℃ heating 6 hours down, in order that allow reaction finish after this.When reaction was finished, the material water cooling then, after distilling water, used neighbour-dichlorobenzene to make the product precipitation under 10 ℃.Distill out product subsequently and with hexanaphthene washing, then a dry night under 50 ℃ and vacuum.Obtain the BuHBP of 41.4g, its fusing point is 106-107 ℃, and purity is higher than 98.5%.
Embodiment 9 has illustrated the flexible embodiment according to the step 4 of the inventive method.
Embodiment 9: the preparation of butyryl radicals-O-benzylamino phenolate hydrochlorate (I ')
1) O-benzyl amide-based small butylphenol (BzBuBP) is synthetic
With the compound of 11.8g (V '), the N,N-DIMETHYLACETAMIDE of 55ml and the salt of wormwood of 10g join in the flask.At 60 times, added the benzyl chloride of 9.7g through 2 hours.Under 60-65 ℃ through 6 hours after, reaction finishes.Material is 25 ℃ of coolings, by removing by filter the solid in the suspension.By crystallization in Virahol, product concentrates under vacuum, obtains the product (BzBuBP) of 16.4g.2) butyryl radicals-O-benzylamino phenolate hydrochlorate (I ') is synthetic
The BzBuBP of 16.0g is dissolved in the Virahol, adds 20g 50%NaOH then.Mixture kept 12 hours under boiling, thereby finished the saponification process.After reaction finishes, except that desolvating, add water and toluene then by distillation.
After dividing dried up and washing with water, 33%HCl and the 5ml Virahol of 20ml joined in the toluene.The suspension that is obtained heated 1 hour down at 70 ℃, was cooled to room temperature then.Obtain the crystal of the compound (I ') of 11.5g.
Claims (25)
1, the method for preparation following general formula (I) compound,
Wherein
-R
1The C that represents a linearity or branching
1-C
10Alkyl, an aralkyl, wherein moieties is linear and contains 1-3 carbon atom and aryl moiety is selected from unsubstituted or by one or more C
1-C
3Alkyl, by one or more halogen atoms or by the phenyl that one or more nitro replaced,
-R
2The C of expression linearity or branching
1-C
16Alkyl,
It is characterized in that it may further comprise the steps:
1) with a single step, by means of from radicals R
2The identical acylating reagent of C=O deutero-, with between following general formula (II)-amino-phenol
Amido functional group and hydroxy functional group acidylate in addition, form the compound of general formula (III):
2) in the presence of Friedel-Crafts type catalyzer, heat resulting compound (III), carry out the Fries rearrangement reaction and form following compound (IV):
3) optionally the carbonyl functional group on 4 of compound (IV) is reduced, is formed following compound (V):
4) hydroxy functional group is carried out the O-alkylation and by hydrolysis in a kind of alkaline medium make the amido functional group of compound (V) go the protection, obtain required compound (I).
According to the method for claim 1, it is characterized in that 2, the acylating reagent in step 1 is general formula (R
2-C=O)
2The acid anhydrides of O, wherein R
2The C of expression linearity or branching
1-C
16Alkyl.
According to the method for claim 1, it is characterized in that 3, the acylating reagent in step 1 is formula R
2The acyl chlorides of COCl, wherein R
2The C of expression linearity or branching
1-C
16Alkyl.
4, according to any one method in the aforementioned claim, it is characterized in that, the acylating reagent in the step 1 be with respect between initial-stoichiometric amount at least of amino-phenol (II) uses.
According to any one method in the aforementioned claim, it is characterized in that 5, the solvent of step 1 is to be made of together with corresponding carboxylic acid acylating reagent itself.
According to any one method in the aforementioned claim, it is characterized in that 6, the catalyzer that uses in the step 2 is an aluminum chloride.
7, according to any one method in the aforementioned claim, it is characterized in that the selective reduction in the step 3 is undertaken by catalytic hydrogenation.
According to the method for claim 7, it is characterized in that 8, hydrogenation catalyst is made up of palladium/carbon catalyst.
According to the method for claim 7 or 8, it is characterized in that 9, hydrogenation is carried out in protonic solvent.
According to the method for claim 9, it is characterized in that 10, protonic solvent is selected from methyl alcohol and ethanol.
According to any one method among the claim 7-10, it is characterized in that 11, the pressure of molecular hydrogen is between the 4-20 crust.
According to any one method among the claim 7-11, it is characterized in that 12, this hydrogenation carries out in the presence of a kind of acid.
13, according to any one method among the claim 7-12, it is characterized in that temperature of reaction is at 50-100 ℃.
14, according to any one method in the aforementioned claim, it is characterized in that hydroxy functional group is to utilize formula R
1The muriate of Cl and being replaced, wherein R by O-
1The C that represents a linearity or branching
1-C
10Alkyl, an aralkyl, wherein moieties is linear and contains 1-3 carbon atom and aryl moiety is selected from unsubstituted or by one or more C
1-C
3Alkyl, by one or more halogen atoms or by phenyl that one or more nitro replaced.
15, according to any one method in the aforementioned claim, it is characterized in that radicals R
1Be selected from methyl, ethyl, n-propyl, sec.-propyl, the cyclopropyl methylene radical, the 3-phenyl propyl, right-methyl-benzyl, right-the benzyl chloride base, neighbour-benzyl chloride base, neighbour, right-dichloro benzyl, right-nitrobenzyl and decyl.
16, according to any one method in the aforementioned claim, it is characterized in that radicals R
2The C that represents a linearity or branching
1-C
6Alkyl.
According to any one method in the aforementioned claim, it is characterized in that 17, when this method was used for 3-(benzyloxy)-4-n-butyl aniline (I ') synthetic, it may further comprise the steps:
1) by means of butyryl oxide will between-amido functional group of amino-phenol (II) and hydroxy functional group acidylate in addition, form the compound of general formula (III '), formula (III ') is corresponding to R wherein
2The compound (III) of expression n-propyl,
2) carry out the Fries rearrangement reaction of compound (III ') in the presence of aluminum chloride, form the compound of general formula (IV '), formula (IV ') is corresponding to R wherein
2Be the compound (IV) of n-propyl,
3) in a kind of acidic medium, carry out selective catalytic hydrogenation in a kind of in methyl alcohol, containing in the presence of 50% wet 10% palladium/carbon catalyst that divides, obtain the compound of general formula (V '), formula (V ') is corresponding to R wherein
2The compound (V) of expression n-propyl,
4) compound (V ') and benzyl chloride are reacted, then in alkaline medium with the reaction mixture hydrolysis.
18, prepare the method for 4-hydroxyquinoline-3-carboxylicesters, it is characterized in that, it comprises the preparation according to the disubstituted benzenes amine (I) of any one among the claim 1-17.
According to the method for claim 9, it is characterized in that 19, described protonic solvent is a lower alcohol, described lower alcohol is selected from methyl alcohol, ethanol, ethylene glycol monomethyl ether, single sec.-propyl ethylene glycol and 1-methoxyl group-2-propyl alcohol.
According to the method for claim 11, it is characterized in that 20, the pressure of molecular hydrogen is 12 crust.
According to the method for claim 12, it is characterized in that 21, described acid is selected from phosphoric acid, sulfuric acid and acetate, its ratio with respect to product to be hydrogenated is 0.5-2.5mol%.
According to the method for claim 13, it is characterized in that 22, described temperature of reaction is 85 ℃.
23, according to the method for claim 15, it is characterized in that R
1Represent benzyl.
24, according to the method for claim 16, it is characterized in that R
2The representative just-propyl group.
25, according to the method for claim 16, it is characterized in that R
2Be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, amyl group, 1-ethyl propyl and hexyl.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9707444A FR2764601B1 (en) | 1997-06-16 | 1997-06-16 | PROCESS FOR THE PREPARATION OF TYPE 4- (ALKYL) -3- ALCOXY-ANILINE COMPOUNDS |
| FR97/07444 | 1997-06-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1264362A CN1264362A (en) | 2000-08-23 |
| CN1244543C true CN1244543C (en) | 2006-03-08 |
Family
ID=9508025
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 98807249 Expired - Lifetime CN1244543C (en) | 1997-06-16 | 1998-06-16 | Method for preparing 4-(alkyl)-3-alkoxy-aniline compounds |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0994846A1 (en) |
| CN (1) | CN1244543C (en) |
| BR (1) | BR9810037A (en) |
| FR (1) | FR2764601B1 (en) |
| IT (1) | ITTO980522A1 (en) |
| WO (1) | WO1998057921A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100422140C (en) * | 2005-08-04 | 2008-10-01 | 浙江大学 | 3-benzyloxy-4-butylaniline hydrochloride preparation method |
| CN101550087B (en) * | 2009-02-26 | 2012-07-04 | 浙江金伯士药业有限公司 | Method for preparing 3-butyl-4-benzyloxy-aniline |
| CN102816074A (en) * | 2012-08-27 | 2012-12-12 | 万隆化工有限公司 | Synthesis method of p-n-butylaniline |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1070223A (en) * | 1965-03-09 | 1967-06-01 | Ici Ltd | Quinoline derivatives |
| DE3168532D1 (en) * | 1980-11-15 | 1985-03-07 | Fisons Plc | Process for the production of 3-amino-4,6-diacetyl phenol or a derivative thereof |
-
1997
- 1997-06-16 FR FR9707444A patent/FR2764601B1/en not_active Expired - Lifetime
-
1998
- 1998-06-16 WO PCT/FR1998/001264 patent/WO1998057921A1/en not_active Application Discontinuation
- 1998-06-16 CN CN 98807249 patent/CN1244543C/en not_active Expired - Lifetime
- 1998-06-16 EP EP98932216A patent/EP0994846A1/en not_active Withdrawn
- 1998-06-16 IT ITTO980522 patent/ITTO980522A1/en unknown
- 1998-06-16 BR BR9810037-8A patent/BR9810037A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2764601A1 (en) | 1998-12-18 |
| WO1998057921A1 (en) | 1998-12-23 |
| BR9810037A (en) | 2000-09-19 |
| FR2764601B1 (en) | 1999-09-03 |
| CN1264362A (en) | 2000-08-23 |
| EP0994846A1 (en) | 2000-04-26 |
| ITTO980522A1 (en) | 1999-12-16 |
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