CA1095077A - Process for the production of a derivative of phenylacetic acid - Google Patents
Process for the production of a derivative of phenylacetic acidInfo
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- CA1095077A CA1095077A CA280,328A CA280328A CA1095077A CA 1095077 A CA1095077 A CA 1095077A CA 280328 A CA280328 A CA 280328A CA 1095077 A CA1095077 A CA 1095077A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Case 4-337/338/339 CANADA
PROCESS FOR THE PRODUCTION OF A DERIVATIVE OF PHENYLACETIC
ACID
Abstract of the Disclosure The present invention concerns a new process for the produc-tion of a derivative of phenylacetic acid, the o-(2,6-di-chloroanilino)-phenylacetic acid and its salts with bases which have strong antiinflammatory and antirheumatic activity.
In this process a compound of the general formula I
PROCESS FOR THE PRODUCTION OF A DERIVATIVE OF PHENYLACETIC
ACID
Abstract of the Disclosure The present invention concerns a new process for the produc-tion of a derivative of phenylacetic acid, the o-(2,6-di-chloroanilino)-phenylacetic acid and its salts with bases which have strong antiinflammatory and antirheumatic activity.
In this process a compound of the general formula I
Description
~09S077 The present invention coneerns a new process for the production of a derivative of phenylacetic acid. Owing to its strong antiinflammatory and antirheumatic activity, o-(2,6-dichloroanilino)-phenylacetic acid, especially in the form of its sodium salt, has found acceptance as active ingredient for corresponding pharmaceuticals. Processes for the production of said acid are described, e.g., in the British Patent Specifieations Nos. 1,139,332 and 1,183,968 and also in corresponding patent specifications of other countries.
The object of the present invention is a new process for the production of o-(2,6-dichloroanilino)-phenylacetic aeid and its salts with bases. This process is characterized in that a compound of the general formula I
0~
NH
Cl ~ Cl (I) ~J .
wherein X represents the 2-furyl radical, an optionally acetalized 5-formyl-2-furyl radical or the vinyl radical, is subjeeted to an oxidative eleavage reaction and, if desired, the o-(2,6-diehloroanilino)-phe~lylacetic acid is converted into a salt with a base. This process is distinguished by good yields and by easy availability of the starting materials.
The object of the present invention is a new process for the production of o-(2,6-dichloroanilino)-phenylacetic aeid and its salts with bases. This process is characterized in that a compound of the general formula I
0~
NH
Cl ~ Cl (I) ~J .
wherein X represents the 2-furyl radical, an optionally acetalized 5-formyl-2-furyl radical or the vinyl radical, is subjeeted to an oxidative eleavage reaction and, if desired, the o-(2,6-diehloroanilino)-phe~lylacetic acid is converted into a salt with a base. This process is distinguished by good yields and by easy availability of the starting materials.
- 2 - ~ ~
An acetalized 5-formyl 2-furyl radical in a cor-responding starting material of the general formula I is a formyl group which is present in the form of a di-lower alkyl ace~al grouping such as the dimethylacetal, diethyl-acetal and the like, or in the form of a lower alkylene acetal grouping such as the ethylene acetal, propylene acetal, trimethylene acetal and the like.
The oxidative cleavage reaction according to the in-vention is performed with the aid of an oxidant such as ozone,hydrogen peroxide, air, permanganic acid salts, chromic acid salts, metaperiodic acid salts and the like. E.g., ozone is allowed to react, preferably while cooling, with a com-pound of the general formula I and then, if necessary, the ^
cleavage reaction is completed by the addition of a further oxidant, such as a permanganic acid salt or hydrogen peroxide.
In particular, ozone is allowed to react with acompound of the general formula I, wherein X is the 2-furyl radical or a 5--formyl-2-furyl radical optionally acetalized as indicated above, in a solvent not retarding the reaction, such as acetone, methyl ethyl ketone, toluene, dichloro-ethane, pyridine and the like, at a temperature between -70 and +50 or, if X is the 2-furyl radical, between -70 and room temperature, and preferably at about -40, for 1 to 10 minutes, particularly for 4 to 5 minutes, or for a longer time if greater amounts of starting material are to be oxidized~
whereupon an oxidant, such as a permanganic acid salt, , .
~0~35077 e.g. potassium permanganate or hydrogen peroxide or the like, is immediately added together with ~ater or an alkaline aqueous solution, e.g. an aqueous sodium hydroxide solution, and the mixture obtained is allowed to react, preferably with stirring, at a temperature of -40 to room temperature during about 10 minutes to 5 hours, preferably during about 30 minu-tes and 5 hours. The o-(2,6-dichloroanilino)-phenylacetic acid formed by this reaction can be separated by conventional procedures and/or can be converted into a salt with an in-organic or organic base, e.g. into the sodium salt.
The compound of the general formula I, in which X is represented by the vinyl radical, namely the N-~o-allylphenyl)-2,6-dichloroaniline, is oxidi~ed in substantially the same ~anner. If necessary, the after-oxidation of the product of the ozonization, e.g. with a permanganic acid salt, such as potassium permanganate,is performed at a temperature hi~her than room temperature, e.g. at the boiling temperature of the reaction mixture. This however, is also possible in the after~
oxidation of the reaction products of other starting materials.
The starting compound with the 2-furyl radical as X, the ~,6-dichloro-2'-furfuryl-diphe-1lylamine, can be readily prepared for its part by reduction of 2,6-dichloro-2'-furfuroyl-diphenylamine using the Wolff-Kishner reaction, Clemmensen ~eaction9 Bouveault-~lanc reaction or the li~e. If the reduction is performed by means of the Wolff-Kishner reaction, it is advisable to use one to ten moles, preferably 3 to 5 moles, , ~
~0'~5077 of hydra~ine per one mole of 2,6-dichloro-2'-furfuroyl-di-phenylamine in the presence of ethylene glycol, diethylene glycol or triethylene glycol at a temperature of 80 to 200, preferably 130 to 170. The 2,6-dlchloro-2'-furfuroyl-di-phenylamine has also not been described hitherto but can readily be obtained by reacting N-(2,6-dichlorophenyl)-anthranilic acid with furyllithium in an ether type solvent such as dioxan or preferably diethylether or tetrahydrofuran at a temperature from -40 to the boiling temperature of the solvent usedg preferably at a temperature of 0 to room tem-perature.
Starting materials with an acetalized 5-formyl-2-furyl-radical X can be prepared by reacting the Grignard reagent obtained from the corresponding acetal of a 5-halo-2-furaldehyde, e.g. an acetal of 5-bromo- or 5-iodo-2-furalde-hyde, and metallic magnesium in a solvent of the ether type, such as tetra~ydrofuran or diethylether, 2-(chloromethyl)-2', 6'-dichloro-diphenylamine. Preferably, the reaction mixture is heated for 1 to 3 hours. The acetals obtained thereby can be converted, if desired, into the corresponding free aldehyde~
the compound of formula I wherein X is the 5-formyl-2-furyl radical, by hydrolysis at room temperature in the presence of dilute sulfuric acid, dilute hydrochloric acid or the like.
N-(o-Allylphenyl) 2,6-dichloroaniline, the compound of formula I with the vinyl radical as X, can be prepared, for example, by treating a vinyl halicle, such as vinyl bromide, ~:0~S077 with metallic magnesium in a solvent of the ether type, such as tetrahydrofuran or diethylether to yield a Grignard reagent, and then reacting the latter with 2-(chloromethyl)-2',6'-dichlorodiphenylamine at an elevated temperature.
The following Example are intended to further explain ~he process according to the invention but axe not to be construed in any way as restricting the scope of the inven-tion. The temperatures are given in degrees Centigrade.
~9S~77 Rxample 1 0.2 g o 2,6-dichloro-2'-furfllroyl-diphenylamine is dissolved in 20 ml of acetone. Ozone is introduced into the solution at a temperature of -50C to -40 for 4 minutes. -Immediately after it, 0.1 ml of hydrogen peroxide, 0.4 ml of 10% a~ueous solution of sodium hydroxide and 0.2 ml of water are added and the resulting mixture is stirred for 3 hours at a temperature of -40 to room temperature. The acetone is distilled off under reduced pressure. 2 ml of water, 0.5 ml of 10% aqueous solution of sodium hydroxide and 5 ml of ethyl acetate are added to the residue and then the aqueous layer is separated. The aqueous layer is acidified with 10% hydro-chloric acid and the resulting crys~alline precipitate is collected by filtration. Recrystallization of the precipitate from an ether-hexane mixture gives o-(2,6-dichloroanilino)-phenylacetic acid melting at 156-157.
The starting compound is prepared as follows:
a) 260 ml of a 10% solution of n-butyllithium in hexane is dropped into a continuously stirred solution composed of 42.5 g of furan, 100 ml of ether and 50 ml of tetrahydrofuran.
Into the resulting furyllithium solution is dropped a solution of 35~2 g of N-(2,6-dichlorophenyl)-anthranilic acid in 300 ml of tetrahydrof~ran at room temperature over a time period of 2 hours. The resulting mixture is stirred at room temperature for 30 minutes, after which 150 ml of ether and 250 ml of water are added. The organic layer is separated, washed with water and dried. The solvent is remove`d by distillation and the residue is recrystallized from isopropyl ether. Thus, 2,6-dichloro-2'-furfuroyl-diphenylamine, melting at 129-130, is obtained as yellow needles.
b) A mixture of 1.0 g of 2,6-dichloro-2'-furfuroyl-di-phenylamine, 4 ml of 100% hydrazine hydrate and 10 ml of di-ethylene glycol is stirred at 120 for 3 hours, after which it is stirred at 160 for 4.5 hours in an apparatus equipped with a device for removing water. 60 ml of water is added, and the resulting mixture is extracted with ethyl acetate. The organic layer is washed with water and dried, from which the solvent is removed by distillation. Chromatographic separation of the residue on silica ~el gives 2,6-dichloro-2'-furfuroyldiphenyl-amine as a colorless liquid. In IR spectrum it shows an ab-sorption of NH at 3320 cm 1. In NMR spectrum it shows a methylene peak at 4.02 ppm.
Example 2 0.6 g of 5-[2-(2,6-dichloranilino)-benzyl~-2-furalde-hyde is dissolved in 10 ml of acetone. Ozone is introduced into the solution for about 3 minutes with stirring, while the :: :
~ !
~095077 solution is kept at a temperature of -50 to -~0. To the reaction mixture are added 0.3 ml of 30% aqueous solution of hydrogen peroxide, 2 ml of 10% caustic soda solution and 2 ml of water The resulting mixture is continuously stirred until it has cooled to room temperature. The acetone is distilled off under reduced pressure. The residue is dissolved in water, and the insoluble portion is removed by extraction wi~h benzene. The aqueous solution is cooled with ice and acidified with acetic acid. The resulting crystalline precipitate is collected by filtration and dried. Recrystallization from a mixture of petroleum ether and ether gives o-(2,6-dichlor-anilino)-phenylacetic acid melting at 156-158.
The starting co-npound is prepared as follows:
a) Into a dried four-necked flask are charged 0.32 g of metallic magnesium and 0.5 ml of anhydrous tetrahydrofuran, to which is added 5 to 6 drops of 5-iodo-2-furaldehyde di-ethylacetal followed by 2 to 3 drops of methyl iodide. The resulting mixture is allowed to stand for a while until an occurrence of the reaction is o~served. Then, stirring is started while keeping the mixture at a temperature of 20C
to 30. With stirring, a solution of 3.9 g of 5-iodo-2-furaldehyde diethylacetal in anhydrous tetrahydrofuran is dropped into the mixture. After completion of the dropping, the resulting mixture is stirred at 40 for one hour and then cooled to room temperature. A solution of 1.7 g of 2-(ch]oro-methyl)-2',6'-dichloro-diphenylamine in 15 ml of tetrahydro-~:
, 1~5077 furan is added, and the resulting mixture is heated underreflux for one hour with stirring. The liquid reaction mixture is poured into a saturated aqueous solutlon of ammonium chloride and thoroughly agitated. Ihe tetrahydrofuran layer is separated, and the aqueous layer is extracted with di-iso~
propyl ether. The extracts are united with the tetrahydro-furan layer, thoroughly washed with sa~urated aqueous solution of sodium chloride and dried on anhydrous potassium carbonate.
The solvents are distilled off under reduced pressure, and the residue is treated with 3 ml of 0.1 N sulfuric acid.
Ethanol is added to the residue with stirring until a homo-geneous mi~ture is formed, and the resulting mixture is allowed to stand overnight. Then, it is concentrated under reduced pressure, mixed with water and extracted with chloroform. The extract layer is washed with saturated aqueous solution of sodium bicarbonate and dried on anhydrous potassium carbonate.
The chloroform is distilled off, and the residue is purified by column chromatography on silica gel, where a 3:1 mixture of chloroform and n-hexane is used as the eluting solvent.
The solvent is distilled off from the effluent under reduced pressure and the residue is recrystallized from di-isopropyl ether. Thus, 5-[2-(2,6-dichloranilino)-benzyl]-2-furaldehyde melting at 93-94, is obtained as a white crystal-line product.
10~5077 Example 3 In a four-necked flask of 500 ml capacity which is equlpped with stirrer, gas inlet tube and thermometer, is placed a solution of 34.6 g of 5-~2~(2,6-dichloranilino)-benzyl]-2-furaldehyde in 350 ml of acetone. Into the flask is introduced 4% o~one at a flow rate of 1 liter/minute for a time period of 110 minutes while the content of the flask is stirred and cooled to -~0. Then, 20 ml of 30% aqueous solu-tion of hydrogen peroxide is added, after which 150 ml of 10~/o sodium hydroxide solution is dropped in over a time period of one hour at a tempera~ure of -40 to -20. The resulting mix-ture is allowed to stand for 3 to 4 hours. The acetone is distilled off under reduced pressure, and the hot residue is treated with 100 ml of toluene with stirring. The resulting mixture is continuously stirred at an ice-cooled temperature for 2 to 3 hours, after which the resulting precipitate is collected by ~iltration, washed with 10 ml of cold water and recrystallized from water. Thus, the sodium o-(2,6-dichlor-anilino)-phenylacetate, melting at 271-273 with decomposition in silicone bath, is obtained as white flaky crystals.
The starting compound is prepared as follows:
a) 3.65 g of metallic magnesium is placed in a four-necked flask of 300 ml capacity and activated with iodine, to which are added 7 ml of dry tetrahydrofuran, 1.5 g of S-bromo-2-furaldehyde diethylacetal and 2 to 3 drops of methyl iodide.
: . .
~Q~35~:)7'7 The mixture is allowed to stand until a reaction takes place.
When an occurrence of the reaction is observed, stirring is star~ed. A solution of 35.9 g of 5-bromo~2-furaldehyde di-ethylace~al in 120 ml of tetrahydrofuran is dropped into ~he flask at a temperature of 20-30. After completion of the dropping, the mixture is stirred at room temperature for 2 hours until the reaction is completed. Then, 0.6 g of cuprous iodide is added and the mi~ture is cooled to 5. Subsequently, a solution of 28.7 g of 2-(chloromethyl~-2,6-dichloro-di-phenylamine in 60 ml of tetrahydrofuran is added. The sponta-neous elevation of temperature is left as it is. Subsequently, the mixture is heated under reflux for 30 minutes with stir-ring. The solvent is distilled off under reduced pressure. The residue is combined with 550 ml of di-isopropyl ether and 300 ml of saturated aqueous solution of ammonium chloride. The organic layer is separated, washed with 5% aqueous solution of sodium bicarbonate and dried on sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is mixed with 550 ml of hot n-hexane and allowed to stand over-night. Thereafter, the supernatant layer is taken out by decantation and the solvent is distilled off under reduced pressure. The residue is dissolved in 300 ml of ethanol, com-bined with 35 ml of 0.1 N sulfuric acid, stirred at room tem-perature for 40 minutes, concentrated under reduced pressure, and then extracted with 300 ml of chloroform. The extract layer is washed with 5% aqueous solution of sodium bicarbonate , : ; :
and dried. The chloroform is distilled off, and the residue is purified by a simplified column chromatography by use of 150 g OL silica gel, where a 1:2 mixture of chloroform and n-hexane is used as the eluting solvent. The solvent is re-moved from the effluent by distillation under reduced pressure, and the residue is recrystallized from di-isopropyl ether.
Thus, 5-[2-(2,6-dichloranilino)-benzyl]-2-furaldehyde melting at 91-93, is obtained.
Example 4 A solution of 2.0 g of 5-[2-(2,6-dichloro-anilino)-benzyl]-2-furaldehyde in 30 ml of acetone is treated during 15 minutes with ozone (0.65 millimol of ozone per minute) while maintaining a temperature of -40. Then, 1.2 ml of 30%
aqueous hydrogen peroxide is added, followed by 8.7 ml of a 10% aqueous sodium carbonate solution, the latter being added dropwise over a period of 45 minutes and while maintaining a temperature of -40 to -20. The reaction mixture is stirred at 10 to 20 for 2 hours; the acetone is distilled off under reduced pressure and the aqueous residue is treated with 6 ml of toluene. The mixture is stirred for 3 hours at 0 to 5, the crystalline precipitate is filtered off, washed with a mixture of toluene and ether and recrystallized from 6 ml of 10~5(~77 water. The resulting sodium Z-(2,6-dichloro-anilino)-phenyl-acetate melts a~ 273-279 (with decomposition).
The starting compound is prepared as follows:
a) A mixture of 47.0 g trie~hyl orthoformate and 38.2 g of 5-bromo~2~furaldehyde in 64 ml of absolute ethanol is treated, while stirring and gassing with nitrogen, with 2.1 ml of an anhydrous~ saturated solution of hydrogen chloride gas in ethanol. The solution is heated under reflux for 90 minutes and is evaporated to dryness under reduced pressure. The residue is distilled; the 5-bromo-2-furaldellyde diethylacetal is obtained as colorless oil, b.p. 60/0.05 mm ~Ig.
b) A total of 0.365 g of magnesium is activated with iodine, then treated with 0.7 ml of anhydrous tetrahydrofuran, 2 drops of methyl iodide and 0.15 g of 5-bromo-2-furaldehyde diethylacetal. After the reaction has started, a solution of
An acetalized 5-formyl 2-furyl radical in a cor-responding starting material of the general formula I is a formyl group which is present in the form of a di-lower alkyl ace~al grouping such as the dimethylacetal, diethyl-acetal and the like, or in the form of a lower alkylene acetal grouping such as the ethylene acetal, propylene acetal, trimethylene acetal and the like.
The oxidative cleavage reaction according to the in-vention is performed with the aid of an oxidant such as ozone,hydrogen peroxide, air, permanganic acid salts, chromic acid salts, metaperiodic acid salts and the like. E.g., ozone is allowed to react, preferably while cooling, with a com-pound of the general formula I and then, if necessary, the ^
cleavage reaction is completed by the addition of a further oxidant, such as a permanganic acid salt or hydrogen peroxide.
In particular, ozone is allowed to react with acompound of the general formula I, wherein X is the 2-furyl radical or a 5--formyl-2-furyl radical optionally acetalized as indicated above, in a solvent not retarding the reaction, such as acetone, methyl ethyl ketone, toluene, dichloro-ethane, pyridine and the like, at a temperature between -70 and +50 or, if X is the 2-furyl radical, between -70 and room temperature, and preferably at about -40, for 1 to 10 minutes, particularly for 4 to 5 minutes, or for a longer time if greater amounts of starting material are to be oxidized~
whereupon an oxidant, such as a permanganic acid salt, , .
~0~35077 e.g. potassium permanganate or hydrogen peroxide or the like, is immediately added together with ~ater or an alkaline aqueous solution, e.g. an aqueous sodium hydroxide solution, and the mixture obtained is allowed to react, preferably with stirring, at a temperature of -40 to room temperature during about 10 minutes to 5 hours, preferably during about 30 minu-tes and 5 hours. The o-(2,6-dichloroanilino)-phenylacetic acid formed by this reaction can be separated by conventional procedures and/or can be converted into a salt with an in-organic or organic base, e.g. into the sodium salt.
The compound of the general formula I, in which X is represented by the vinyl radical, namely the N-~o-allylphenyl)-2,6-dichloroaniline, is oxidi~ed in substantially the same ~anner. If necessary, the after-oxidation of the product of the ozonization, e.g. with a permanganic acid salt, such as potassium permanganate,is performed at a temperature hi~her than room temperature, e.g. at the boiling temperature of the reaction mixture. This however, is also possible in the after~
oxidation of the reaction products of other starting materials.
The starting compound with the 2-furyl radical as X, the ~,6-dichloro-2'-furfuryl-diphe-1lylamine, can be readily prepared for its part by reduction of 2,6-dichloro-2'-furfuroyl-diphenylamine using the Wolff-Kishner reaction, Clemmensen ~eaction9 Bouveault-~lanc reaction or the li~e. If the reduction is performed by means of the Wolff-Kishner reaction, it is advisable to use one to ten moles, preferably 3 to 5 moles, , ~
~0'~5077 of hydra~ine per one mole of 2,6-dichloro-2'-furfuroyl-di-phenylamine in the presence of ethylene glycol, diethylene glycol or triethylene glycol at a temperature of 80 to 200, preferably 130 to 170. The 2,6-dlchloro-2'-furfuroyl-di-phenylamine has also not been described hitherto but can readily be obtained by reacting N-(2,6-dichlorophenyl)-anthranilic acid with furyllithium in an ether type solvent such as dioxan or preferably diethylether or tetrahydrofuran at a temperature from -40 to the boiling temperature of the solvent usedg preferably at a temperature of 0 to room tem-perature.
Starting materials with an acetalized 5-formyl-2-furyl-radical X can be prepared by reacting the Grignard reagent obtained from the corresponding acetal of a 5-halo-2-furaldehyde, e.g. an acetal of 5-bromo- or 5-iodo-2-furalde-hyde, and metallic magnesium in a solvent of the ether type, such as tetra~ydrofuran or diethylether, 2-(chloromethyl)-2', 6'-dichloro-diphenylamine. Preferably, the reaction mixture is heated for 1 to 3 hours. The acetals obtained thereby can be converted, if desired, into the corresponding free aldehyde~
the compound of formula I wherein X is the 5-formyl-2-furyl radical, by hydrolysis at room temperature in the presence of dilute sulfuric acid, dilute hydrochloric acid or the like.
N-(o-Allylphenyl) 2,6-dichloroaniline, the compound of formula I with the vinyl radical as X, can be prepared, for example, by treating a vinyl halicle, such as vinyl bromide, ~:0~S077 with metallic magnesium in a solvent of the ether type, such as tetrahydrofuran or diethylether to yield a Grignard reagent, and then reacting the latter with 2-(chloromethyl)-2',6'-dichlorodiphenylamine at an elevated temperature.
The following Example are intended to further explain ~he process according to the invention but axe not to be construed in any way as restricting the scope of the inven-tion. The temperatures are given in degrees Centigrade.
~9S~77 Rxample 1 0.2 g o 2,6-dichloro-2'-furfllroyl-diphenylamine is dissolved in 20 ml of acetone. Ozone is introduced into the solution at a temperature of -50C to -40 for 4 minutes. -Immediately after it, 0.1 ml of hydrogen peroxide, 0.4 ml of 10% a~ueous solution of sodium hydroxide and 0.2 ml of water are added and the resulting mixture is stirred for 3 hours at a temperature of -40 to room temperature. The acetone is distilled off under reduced pressure. 2 ml of water, 0.5 ml of 10% aqueous solution of sodium hydroxide and 5 ml of ethyl acetate are added to the residue and then the aqueous layer is separated. The aqueous layer is acidified with 10% hydro-chloric acid and the resulting crys~alline precipitate is collected by filtration. Recrystallization of the precipitate from an ether-hexane mixture gives o-(2,6-dichloroanilino)-phenylacetic acid melting at 156-157.
The starting compound is prepared as follows:
a) 260 ml of a 10% solution of n-butyllithium in hexane is dropped into a continuously stirred solution composed of 42.5 g of furan, 100 ml of ether and 50 ml of tetrahydrofuran.
Into the resulting furyllithium solution is dropped a solution of 35~2 g of N-(2,6-dichlorophenyl)-anthranilic acid in 300 ml of tetrahydrof~ran at room temperature over a time period of 2 hours. The resulting mixture is stirred at room temperature for 30 minutes, after which 150 ml of ether and 250 ml of water are added. The organic layer is separated, washed with water and dried. The solvent is remove`d by distillation and the residue is recrystallized from isopropyl ether. Thus, 2,6-dichloro-2'-furfuroyl-diphenylamine, melting at 129-130, is obtained as yellow needles.
b) A mixture of 1.0 g of 2,6-dichloro-2'-furfuroyl-di-phenylamine, 4 ml of 100% hydrazine hydrate and 10 ml of di-ethylene glycol is stirred at 120 for 3 hours, after which it is stirred at 160 for 4.5 hours in an apparatus equipped with a device for removing water. 60 ml of water is added, and the resulting mixture is extracted with ethyl acetate. The organic layer is washed with water and dried, from which the solvent is removed by distillation. Chromatographic separation of the residue on silica ~el gives 2,6-dichloro-2'-furfuroyldiphenyl-amine as a colorless liquid. In IR spectrum it shows an ab-sorption of NH at 3320 cm 1. In NMR spectrum it shows a methylene peak at 4.02 ppm.
Example 2 0.6 g of 5-[2-(2,6-dichloranilino)-benzyl~-2-furalde-hyde is dissolved in 10 ml of acetone. Ozone is introduced into the solution for about 3 minutes with stirring, while the :: :
~ !
~095077 solution is kept at a temperature of -50 to -~0. To the reaction mixture are added 0.3 ml of 30% aqueous solution of hydrogen peroxide, 2 ml of 10% caustic soda solution and 2 ml of water The resulting mixture is continuously stirred until it has cooled to room temperature. The acetone is distilled off under reduced pressure. The residue is dissolved in water, and the insoluble portion is removed by extraction wi~h benzene. The aqueous solution is cooled with ice and acidified with acetic acid. The resulting crystalline precipitate is collected by filtration and dried. Recrystallization from a mixture of petroleum ether and ether gives o-(2,6-dichlor-anilino)-phenylacetic acid melting at 156-158.
The starting co-npound is prepared as follows:
a) Into a dried four-necked flask are charged 0.32 g of metallic magnesium and 0.5 ml of anhydrous tetrahydrofuran, to which is added 5 to 6 drops of 5-iodo-2-furaldehyde di-ethylacetal followed by 2 to 3 drops of methyl iodide. The resulting mixture is allowed to stand for a while until an occurrence of the reaction is o~served. Then, stirring is started while keeping the mixture at a temperature of 20C
to 30. With stirring, a solution of 3.9 g of 5-iodo-2-furaldehyde diethylacetal in anhydrous tetrahydrofuran is dropped into the mixture. After completion of the dropping, the resulting mixture is stirred at 40 for one hour and then cooled to room temperature. A solution of 1.7 g of 2-(ch]oro-methyl)-2',6'-dichloro-diphenylamine in 15 ml of tetrahydro-~:
, 1~5077 furan is added, and the resulting mixture is heated underreflux for one hour with stirring. The liquid reaction mixture is poured into a saturated aqueous solutlon of ammonium chloride and thoroughly agitated. Ihe tetrahydrofuran layer is separated, and the aqueous layer is extracted with di-iso~
propyl ether. The extracts are united with the tetrahydro-furan layer, thoroughly washed with sa~urated aqueous solution of sodium chloride and dried on anhydrous potassium carbonate.
The solvents are distilled off under reduced pressure, and the residue is treated with 3 ml of 0.1 N sulfuric acid.
Ethanol is added to the residue with stirring until a homo-geneous mi~ture is formed, and the resulting mixture is allowed to stand overnight. Then, it is concentrated under reduced pressure, mixed with water and extracted with chloroform. The extract layer is washed with saturated aqueous solution of sodium bicarbonate and dried on anhydrous potassium carbonate.
The chloroform is distilled off, and the residue is purified by column chromatography on silica gel, where a 3:1 mixture of chloroform and n-hexane is used as the eluting solvent.
The solvent is distilled off from the effluent under reduced pressure and the residue is recrystallized from di-isopropyl ether. Thus, 5-[2-(2,6-dichloranilino)-benzyl]-2-furaldehyde melting at 93-94, is obtained as a white crystal-line product.
10~5077 Example 3 In a four-necked flask of 500 ml capacity which is equlpped with stirrer, gas inlet tube and thermometer, is placed a solution of 34.6 g of 5-~2~(2,6-dichloranilino)-benzyl]-2-furaldehyde in 350 ml of acetone. Into the flask is introduced 4% o~one at a flow rate of 1 liter/minute for a time period of 110 minutes while the content of the flask is stirred and cooled to -~0. Then, 20 ml of 30% aqueous solu-tion of hydrogen peroxide is added, after which 150 ml of 10~/o sodium hydroxide solution is dropped in over a time period of one hour at a tempera~ure of -40 to -20. The resulting mix-ture is allowed to stand for 3 to 4 hours. The acetone is distilled off under reduced pressure, and the hot residue is treated with 100 ml of toluene with stirring. The resulting mixture is continuously stirred at an ice-cooled temperature for 2 to 3 hours, after which the resulting precipitate is collected by ~iltration, washed with 10 ml of cold water and recrystallized from water. Thus, the sodium o-(2,6-dichlor-anilino)-phenylacetate, melting at 271-273 with decomposition in silicone bath, is obtained as white flaky crystals.
The starting compound is prepared as follows:
a) 3.65 g of metallic magnesium is placed in a four-necked flask of 300 ml capacity and activated with iodine, to which are added 7 ml of dry tetrahydrofuran, 1.5 g of S-bromo-2-furaldehyde diethylacetal and 2 to 3 drops of methyl iodide.
: . .
~Q~35~:)7'7 The mixture is allowed to stand until a reaction takes place.
When an occurrence of the reaction is observed, stirring is star~ed. A solution of 35.9 g of 5-bromo~2-furaldehyde di-ethylace~al in 120 ml of tetrahydrofuran is dropped into ~he flask at a temperature of 20-30. After completion of the dropping, the mixture is stirred at room temperature for 2 hours until the reaction is completed. Then, 0.6 g of cuprous iodide is added and the mi~ture is cooled to 5. Subsequently, a solution of 28.7 g of 2-(chloromethyl~-2,6-dichloro-di-phenylamine in 60 ml of tetrahydrofuran is added. The sponta-neous elevation of temperature is left as it is. Subsequently, the mixture is heated under reflux for 30 minutes with stir-ring. The solvent is distilled off under reduced pressure. The residue is combined with 550 ml of di-isopropyl ether and 300 ml of saturated aqueous solution of ammonium chloride. The organic layer is separated, washed with 5% aqueous solution of sodium bicarbonate and dried on sodium sulfate. The solvent is distilled off under reduced pressure, and the residue is mixed with 550 ml of hot n-hexane and allowed to stand over-night. Thereafter, the supernatant layer is taken out by decantation and the solvent is distilled off under reduced pressure. The residue is dissolved in 300 ml of ethanol, com-bined with 35 ml of 0.1 N sulfuric acid, stirred at room tem-perature for 40 minutes, concentrated under reduced pressure, and then extracted with 300 ml of chloroform. The extract layer is washed with 5% aqueous solution of sodium bicarbonate , : ; :
and dried. The chloroform is distilled off, and the residue is purified by a simplified column chromatography by use of 150 g OL silica gel, where a 1:2 mixture of chloroform and n-hexane is used as the eluting solvent. The solvent is re-moved from the effluent by distillation under reduced pressure, and the residue is recrystallized from di-isopropyl ether.
Thus, 5-[2-(2,6-dichloranilino)-benzyl]-2-furaldehyde melting at 91-93, is obtained.
Example 4 A solution of 2.0 g of 5-[2-(2,6-dichloro-anilino)-benzyl]-2-furaldehyde in 30 ml of acetone is treated during 15 minutes with ozone (0.65 millimol of ozone per minute) while maintaining a temperature of -40. Then, 1.2 ml of 30%
aqueous hydrogen peroxide is added, followed by 8.7 ml of a 10% aqueous sodium carbonate solution, the latter being added dropwise over a period of 45 minutes and while maintaining a temperature of -40 to -20. The reaction mixture is stirred at 10 to 20 for 2 hours; the acetone is distilled off under reduced pressure and the aqueous residue is treated with 6 ml of toluene. The mixture is stirred for 3 hours at 0 to 5, the crystalline precipitate is filtered off, washed with a mixture of toluene and ether and recrystallized from 6 ml of 10~5(~77 water. The resulting sodium Z-(2,6-dichloro-anilino)-phenyl-acetate melts a~ 273-279 (with decomposition).
The starting compound is prepared as follows:
a) A mixture of 47.0 g trie~hyl orthoformate and 38.2 g of 5-bromo~2~furaldehyde in 64 ml of absolute ethanol is treated, while stirring and gassing with nitrogen, with 2.1 ml of an anhydrous~ saturated solution of hydrogen chloride gas in ethanol. The solution is heated under reflux for 90 minutes and is evaporated to dryness under reduced pressure. The residue is distilled; the 5-bromo-2-furaldellyde diethylacetal is obtained as colorless oil, b.p. 60/0.05 mm ~Ig.
b) A total of 0.365 g of magnesium is activated with iodine, then treated with 0.7 ml of anhydrous tetrahydrofuran, 2 drops of methyl iodide and 0.15 g of 5-bromo-2-furaldehyde diethylacetal. After the reaction has started, a solution of
3.5 g of 5-bromo-2-furaldehyde diethylace~al in 12 ml o~ an-hydrous tetrahydrofuran is added dropwise while maintaining the temperature at 25 to 30. The reaction mixture is stirred for one hour at 25, cooled to 5 and treated with 0.06 g of cuprous iodide, followed by a solution of 2.87 g of 2-(chloro-methyl-(2',6'-dichloro-diphenylamine in 6 ml of anhydrous tetrahydrofuran, which is added dropwise. The mixture is then heated under reflux for 30 minutes and evaporated to dryness under reduced pressure. The residue is taken up in 30 ml of di-isopropyl ether and 30 ml of an aq~eous ammonium chloride solution. The mixture is thoroughly shaken; the organic phase is separated, washed with a 5~/0 aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue is taken up in 55 ml of boiling n-hexane and the mixture is allowed to stand for 15 hours. The solution is decanted from the solid precipitate and evaporated to dryness under a pressure of 11 mm Hg. The residue is treated with 30 ml of ethanol and 3.5 ml of 0.1-n sulfuric acid. The solution is allowed to stand for 40 minutes at room tempera-ture and concentrated under reduced pressure. The residue is extracted with 30 ml of chloroform; the organic phase is washed with a 0.5 N aqueous sodium bicarbonate solution and with water, dried over magnesium sulfate and concentrated. The brown oily residue is chromatographed, using 20 g of silica gel; fractions 2 to 16, eluted with a 1:2-mixture of chloro-form and n-hexane are combined and evaporated The residue is crystallized from diethyl ether to yield the 5-[2-(2,6-di-chloroanilino)-benzyl]-2-furaldehyde, m.p. 89-91.
Example 5 An ozonized oxygen is introduced for about 7 minutes into a constantly stirred solution of 0.5 g of N-(o-allyl-phenyl)-2,6-dichloroaniline in 10 ml of acetone kept at a 109S[)77 a temperature of -40 to 50. Subsequently, 0.5 g of potassium permanganate is added, and the resulting mixture is reacted at room temperature for one hour and then at the reflux temperature for an additional one hour. The liquid reaction mixture is filtered. The precipitate, namely manganese dioxide, is thoroughly washed with hot water. The filtrate is concentrated and the residue is mixed with wa~er and toluene.
Several drops of 10~/o aqueous solution of sodi~lm hydroxide is added to the mixture at an elevated temperature. The water layer is separated and neutralized with concentrated hydro-chloric acid at an ice-cooled temperature. The resulting crystalline precipitate is collected by filtration, suspended into a small quantity of water and strongly alkalified with 10% sodium hydroxide solution. The alkalified solution is cooled with ice and the resulting crystalline precipita~e is co]lected by filtration. Thus, there is obta~ned sodium o-(2,6-dichloroanilino)-phenylacetate as white crystals melting at 281-284.
The starting compound is prepared as follows:
a) Into a dry four-necked flask is charged 2.72 g of metallic magnesium. A small quantity of iodine is added and the content of the flask is heated to 50 for the sake of activating the magnesium. Subsequently, 5 ml of tetrahydro-furan is added, which is followed by about 2 ml of a solution composed of 12 g of vinyl bromide and 54 ml of tetrahydrofuran.
Then, 1 to 2 drops of methyl iodic?e is added in order to start : . , .
l~9S0~7 the reaction. After the start of reaction, the residual portion of the above-mentioned vinyl bromide solution is slowly added with stirring while the temperature is kept at 40-45. The resulting mixture is kept at 50 for an additional 30 minutes, after which 0.3 g of cuL~rous iodide is added.
Subsequently, a solution of 16.1 g of 2-(chloromethyl)-2'~6'-dichlorodiphenylamine in 55 ml of tetrahydrofuran is added with stirring over a period of 30 minutes. Thereafter, the mixture is heated under ref]ux for 30 minutes to complete the reaction. After cooling, a saturated solution of ammonium chloride is added, and the tetrahydrofuran layer is separated, dried and concentrated. Recrystallization of the residue from n-hexane gives N-(o-allylphenyl)-2,6-dichloroaniline melting at 62-64.
Example 6 A mixture of ozone and oxygen is introduced into a solution of 1.0 g of 2-allyl-2',6'-dichloro-diphenylamine in 20 ml of acetone at a rate of 0.635 millimole of ozone per minute during 11 minutes, while the reaction mixture is continuously stirred and the temperature is kept at -40.
Then at -35 1.0 g of potassium permanganate is added while stirring, and the suspension is stirred for one hour at room ~ J
~ ~ - 17 -10~5077 temperature and for a further hour at 60. The manganese dioxide formed is removed by filtration and the filter cake is washed with little acetone and 40 ml of hot wa~er. The filtrate is evaporated to dryness under reduced pressure.
12 ml of water, 10 ml of toluene and 1 ml of 10 % aqueous sodium hydroxide solution are added to the residue. The mix,-ture is warmed up to 55 and ~iltered through a layer of Hyflo*-SuperCel filter aid. The aqueous phase is separated and acidified at 0 with conc. hydrochloric acid. The oil which separates is dissolved in ether. The ether phase is dried over magnesium sulfate and evaporated to dryness at 11 mm Hg. The residue is dissolved in 1.5 ml of 10 % aqueous sodium carbonate solution and the solution is cooled, whereupon the sodium-o-(2,6-dichloro-anilino)-phenylacetate crystallines. It is filtered off and dried, m.p. 269-274.
The starting compound is prepared as follows:
In a dried four-necked flask, 1.36 g of metallic magnesium are activated with iodine~ After an addition of 2.5 ml of anhydrous tetrafuran, about 1/10 of a solution of 6.0 g of vinyl bromide in 28 ml of anhydrous tetrahydro-furan is added dropwise at 35. The reaction is initiated by the addition of 2 drops of methyl iodide, and the renlaining solution of vinyl bromide is added dropwise at 40 to 45. The mixture is stirred for 30 minutes at 50.
After the addition of 0.15 g of cuprous iodide, a solution of 8.05 g of 2-(chloromethyl)-2',6'-dichloro-diphenylamine in 28 ml of anhydrous * Trade Mark ' -~: ' ~095077 tetrahydrofuran is added at 30 to 40. The mixture is re-flu~ed fox 30 minutes. After cooling, 50 ml of saturated aqueous ammonium chloride solution is added and the mixture is filtered through a layer of Hyflo*-Super Cel filter aid.
The organic phase is separated from the filtrate, washed with aqueous ammonium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure.
The residue, a brown oil, is crystallized from ether and the by-product which is obtained thereby is removed by fil-tration. The filtrate is evaporated and the residue is crystallized from n-hexane. Thus, 2-allyl-2',6'-dichloro-diphenylamine, m.p. 52-57, is obtained.
Example 5 An ozonized oxygen is introduced for about 7 minutes into a constantly stirred solution of 0.5 g of N-(o-allyl-phenyl)-2,6-dichloroaniline in 10 ml of acetone kept at a 109S[)77 a temperature of -40 to 50. Subsequently, 0.5 g of potassium permanganate is added, and the resulting mixture is reacted at room temperature for one hour and then at the reflux temperature for an additional one hour. The liquid reaction mixture is filtered. The precipitate, namely manganese dioxide, is thoroughly washed with hot water. The filtrate is concentrated and the residue is mixed with wa~er and toluene.
Several drops of 10~/o aqueous solution of sodi~lm hydroxide is added to the mixture at an elevated temperature. The water layer is separated and neutralized with concentrated hydro-chloric acid at an ice-cooled temperature. The resulting crystalline precipitate is collected by filtration, suspended into a small quantity of water and strongly alkalified with 10% sodium hydroxide solution. The alkalified solution is cooled with ice and the resulting crystalline precipita~e is co]lected by filtration. Thus, there is obta~ned sodium o-(2,6-dichloroanilino)-phenylacetate as white crystals melting at 281-284.
The starting compound is prepared as follows:
a) Into a dry four-necked flask is charged 2.72 g of metallic magnesium. A small quantity of iodine is added and the content of the flask is heated to 50 for the sake of activating the magnesium. Subsequently, 5 ml of tetrahydro-furan is added, which is followed by about 2 ml of a solution composed of 12 g of vinyl bromide and 54 ml of tetrahydrofuran.
Then, 1 to 2 drops of methyl iodic?e is added in order to start : . , .
l~9S0~7 the reaction. After the start of reaction, the residual portion of the above-mentioned vinyl bromide solution is slowly added with stirring while the temperature is kept at 40-45. The resulting mixture is kept at 50 for an additional 30 minutes, after which 0.3 g of cuL~rous iodide is added.
Subsequently, a solution of 16.1 g of 2-(chloromethyl)-2'~6'-dichlorodiphenylamine in 55 ml of tetrahydrofuran is added with stirring over a period of 30 minutes. Thereafter, the mixture is heated under ref]ux for 30 minutes to complete the reaction. After cooling, a saturated solution of ammonium chloride is added, and the tetrahydrofuran layer is separated, dried and concentrated. Recrystallization of the residue from n-hexane gives N-(o-allylphenyl)-2,6-dichloroaniline melting at 62-64.
Example 6 A mixture of ozone and oxygen is introduced into a solution of 1.0 g of 2-allyl-2',6'-dichloro-diphenylamine in 20 ml of acetone at a rate of 0.635 millimole of ozone per minute during 11 minutes, while the reaction mixture is continuously stirred and the temperature is kept at -40.
Then at -35 1.0 g of potassium permanganate is added while stirring, and the suspension is stirred for one hour at room ~ J
~ ~ - 17 -10~5077 temperature and for a further hour at 60. The manganese dioxide formed is removed by filtration and the filter cake is washed with little acetone and 40 ml of hot wa~er. The filtrate is evaporated to dryness under reduced pressure.
12 ml of water, 10 ml of toluene and 1 ml of 10 % aqueous sodium hydroxide solution are added to the residue. The mix,-ture is warmed up to 55 and ~iltered through a layer of Hyflo*-SuperCel filter aid. The aqueous phase is separated and acidified at 0 with conc. hydrochloric acid. The oil which separates is dissolved in ether. The ether phase is dried over magnesium sulfate and evaporated to dryness at 11 mm Hg. The residue is dissolved in 1.5 ml of 10 % aqueous sodium carbonate solution and the solution is cooled, whereupon the sodium-o-(2,6-dichloro-anilino)-phenylacetate crystallines. It is filtered off and dried, m.p. 269-274.
The starting compound is prepared as follows:
In a dried four-necked flask, 1.36 g of metallic magnesium are activated with iodine~ After an addition of 2.5 ml of anhydrous tetrafuran, about 1/10 of a solution of 6.0 g of vinyl bromide in 28 ml of anhydrous tetrahydro-furan is added dropwise at 35. The reaction is initiated by the addition of 2 drops of methyl iodide, and the renlaining solution of vinyl bromide is added dropwise at 40 to 45. The mixture is stirred for 30 minutes at 50.
After the addition of 0.15 g of cuprous iodide, a solution of 8.05 g of 2-(chloromethyl)-2',6'-dichloro-diphenylamine in 28 ml of anhydrous * Trade Mark ' -~: ' ~095077 tetrahydrofuran is added at 30 to 40. The mixture is re-flu~ed fox 30 minutes. After cooling, 50 ml of saturated aqueous ammonium chloride solution is added and the mixture is filtered through a layer of Hyflo*-Super Cel filter aid.
The organic phase is separated from the filtrate, washed with aqueous ammonium chloride solution, dried over magnesium sulfate and evaporated to dryness under reduced pressure.
The residue, a brown oil, is crystallized from ether and the by-product which is obtained thereby is removed by fil-tration. The filtrate is evaporated and the residue is crystallized from n-hexane. Thus, 2-allyl-2',6'-dichloro-diphenylamine, m.p. 52-57, is obtained.
Claims (9)
1. Process for the production of a derivative of phenyl-acetic acid, characterized in that a compound of the general formula I
(I) wherein X represents the 2-furyl radical, an optionally acetalized 5-formyl-2-furyl radical or the vinyl radical, is subjected to an oxidative cleavage reaction and, if desired, the o-(2,6-dichloroanilino)-phenylacetic acid formed is con-verted into a salt with a base.
(I) wherein X represents the 2-furyl radical, an optionally acetalized 5-formyl-2-furyl radical or the vinyl radical, is subjected to an oxidative cleavage reaction and, if desired, the o-(2,6-dichloroanilino)-phenylacetic acid formed is con-verted into a salt with a base.
2. Process according to Claim 1, in which a compound of the general. formula I is used, wherein X is represented by the 2-furyl radical.
3. Process according to Claim 1, in which a compound of the general formula I is used, wherein X is represented by an optionally acetalized 5-formyl-2-furyl radical.
4. Process according to Claim 3, in which 5-[2-(2,6-di-chloroanilino)-benzyl]-2-furaldehyde is used as starting material.
5. Process according to Claim 1, in which the compound of the general formula I is used, wherein X is represented by the vinyl radical.
6. Process according to Claim 1, in which ozone is used as oxidant.
7. Process according to Claim 1, in which the oxidative cleavage reaction is performed by allowing ozone to react with a compound of the general formula I given in Claim 1 and the cleavage reaction is completed by the addition of a further oxidant.
8. Process according to Claim 7, in which a permanganic acid salt is used as the further oxidant.
9. Process according to Claim 7, in which hydrogen peroxide is used as the further oxidant.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JPSHO51-69013 | 1976-06-12 | ||
| JP6901376A JPS52153928A (en) | 1976-06-12 | 1976-06-12 | Preparation of organic compounds |
| JPSHO51-69014 | 1976-06-12 | ||
| JP6901476A JPS52153929A (en) | 1976-06-12 | 1976-06-12 | Preparation of phenyl acetic acid derivatives |
| JPSHO51-115235 | 1976-09-25 | ||
| JP11523576A JPS5340734A (en) | 1976-09-25 | 1976-09-25 | Preparation of phenylacetic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1095077A true CA1095077A (en) | 1981-02-03 |
Family
ID=27299932
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA280,328A Expired CA1095077A (en) | 1976-06-12 | 1977-06-10 | Process for the production of a derivative of phenylacetic acid |
Country Status (16)
| Country | Link |
|---|---|
| AR (1) | AR218451A1 (en) |
| AT (1) | AT354424B (en) |
| CA (1) | CA1095077A (en) |
| CH (1) | CH630059A5 (en) |
| CS (1) | CS197294B2 (en) |
| DK (1) | DK259377A (en) |
| ES (1) | ES459673A1 (en) |
| FI (1) | FI771824A (en) |
| GR (1) | GR74112B (en) |
| HU (1) | HU176500B (en) |
| NL (1) | NL7706422A (en) |
| NO (1) | NO772036L (en) |
| PL (1) | PL104609B1 (en) |
| PT (1) | PT66660B (en) |
| SE (1) | SE7706777L (en) |
| YU (1) | YU143777A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4551475A (en) * | 1981-02-24 | 1985-11-05 | Ciba-Geigy Corporation | Pharmaceutical preparations for topical application which contain salts of alkanecarboxylic acids |
-
1977
- 1977-06-08 PT PT66660A patent/PT66660B/en unknown
- 1977-06-09 FI FI771824A patent/FI771824A/fi not_active Application Discontinuation
- 1977-06-09 YU YU01437/77A patent/YU143777A/en unknown
- 1977-06-10 SE SE7706777A patent/SE7706777L/en not_active Application Discontinuation
- 1977-06-10 CH CH717777A patent/CH630059A5/en not_active IP Right Cessation
- 1977-06-10 DK DK259377A patent/DK259377A/en unknown
- 1977-06-10 ES ES459673A patent/ES459673A1/en not_active Expired
- 1977-06-10 CA CA280,328A patent/CA1095077A/en not_active Expired
- 1977-06-10 HU HU77CI1749A patent/HU176500B/en unknown
- 1977-06-10 NL NL7706422A patent/NL7706422A/en not_active Application Discontinuation
- 1977-06-10 AT AT411477A patent/AT354424B/en not_active IP Right Cessation
- 1977-06-10 NO NO772036A patent/NO772036L/en unknown
- 1977-06-10 CS CS773850A patent/CS197294B2/en unknown
- 1977-06-10 GR GR53677A patent/GR74112B/el unknown
- 1977-06-11 PL PL1977198782A patent/PL104609B1/en unknown
- 1977-06-13 AR AR268030A patent/AR218451A1/en active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4551475A (en) * | 1981-02-24 | 1985-11-05 | Ciba-Geigy Corporation | Pharmaceutical preparations for topical application which contain salts of alkanecarboxylic acids |
Also Published As
| Publication number | Publication date |
|---|---|
| NO772036L (en) | 1977-12-13 |
| GR74112B (en) | 1984-06-06 |
| CH630059A5 (en) | 1982-05-28 |
| CS197294B2 (en) | 1980-04-30 |
| PT66660A (en) | 1977-07-01 |
| PL198782A1 (en) | 1978-04-10 |
| NL7706422A (en) | 1977-12-14 |
| HU176500B (en) | 1981-03-28 |
| PT66660B (en) | 1978-11-13 |
| SE7706777L (en) | 1977-12-13 |
| YU143777A (en) | 1982-08-31 |
| DK259377A (en) | 1977-12-13 |
| ES459673A1 (en) | 1978-10-01 |
| ATA411477A (en) | 1979-06-15 |
| AR218451A1 (en) | 1980-06-13 |
| FI771824A (en) | 1977-12-13 |
| AT354424B (en) | 1979-01-10 |
| PL104609B1 (en) | 1979-08-31 |
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