CA1241016A - Method for the production of nuclear substituted cinnamoylanthranilic acid derivatives - Google Patents
Method for the production of nuclear substituted cinnamoylanthranilic acid derivativesInfo
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- CA1241016A CA1241016A CA000478780A CA478780A CA1241016A CA 1241016 A CA1241016 A CA 1241016A CA 000478780 A CA000478780 A CA 000478780A CA 478780 A CA478780 A CA 478780A CA 1241016 A CA1241016 A CA 1241016A
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Abstract
Abstract:
The invention provides an improved method for producing cinnamoylanthranilic acid compounds having hydroxy and alkoxy substituents. The method involves reacting a nuclear substituted benzaldehyde derivative with a 2-carboxy malonanilic acid and a cyclic amine.
The reaction is carried out in an inert solvent medium and the cyclic amine is employed in a molar ratio of about 2-10 moles per mole of substituted benzaldehyde derivative reactant or 2-carboxy malonanilic acid re-actant. This produces a crystalline precipitate of a cyclic amine salt which can be separated and then treated with an acid reagent to yield the desired compound.
The invention provides an improved method for producing cinnamoylanthranilic acid compounds having hydroxy and alkoxy substituents. The method involves reacting a nuclear substituted benzaldehyde derivative with a 2-carboxy malonanilic acid and a cyclic amine.
The reaction is carried out in an inert solvent medium and the cyclic amine is employed in a molar ratio of about 2-10 moles per mole of substituted benzaldehyde derivative reactant or 2-carboxy malonanilic acid re-actant. This produces a crystalline precipitate of a cyclic amine salt which can be separated and then treated with an acid reagent to yield the desired compound.
Description
o~6 A method for the production of nuclear substituted cinnamoYlanthranilic acid derivatives This invention relates to a novel method for the production of nuclear substituted cinnamoylanthranilic acid derivatives. More particularly, this invention relates to an improved method for the production of nuclear di-substituted cinnamoylanthranilic acid deri-vatives which possess antiallergic properties and thus are useful for treatment of diseases such as asthma, hay fever, atopic dermatitis and urticaria.
Nuclear substituted cinnamoylanthranilic acid derivatives such as N-(3,4-dimethoxycinnamoyl)anthranilic acid are known to exhibit strong antiallergic properties and to be useful for treatment of asthma, hay fever, atopic dermatitis and urticaria, as reported in U.S.
Patent Number 4,070,484; Allergy, 34, 213-219, (1979);
and Igaku no Ayumi, 106, No. 8 576-585 (1978).
~,Z4~0~6 Several methods for producing said derivatives have ~een also disclosed in published Japanese patent application Nos. 7359/73, 42273/74, 42465/74, 43673/74, 43678/74, 158554/75, 158555/75, 158556/75, 139368/76, 38555/80, 38556/80 and 8858/81, and in U.S. Patent No. 3,940,422. O~ the methods disclosed in the above patent re~erences, the process described in published Japanese patent application No. 8858/81 can be operated with ease and efficiency, and thus this process has advantage for production on an industrial scale. The Japanese patent application No. 8858/81 invention is illustrated by the following preferred process embodiment.
A nuclear unsubstituted or substituted benzaldehyde derivative i5 heated with a 2-carboxymalonanilic acid derivative at 80-100C for several hours in a solvent medium such as pyridine, benzene, toluene or xylene tlo-2o times by weight the amount of the benzaldehyde derivative or the
Nuclear substituted cinnamoylanthranilic acid derivatives such as N-(3,4-dimethoxycinnamoyl)anthranilic acid are known to exhibit strong antiallergic properties and to be useful for treatment of asthma, hay fever, atopic dermatitis and urticaria, as reported in U.S.
Patent Number 4,070,484; Allergy, 34, 213-219, (1979);
and Igaku no Ayumi, 106, No. 8 576-585 (1978).
~,Z4~0~6 Several methods for producing said derivatives have ~een also disclosed in published Japanese patent application Nos. 7359/73, 42273/74, 42465/74, 43673/74, 43678/74, 158554/75, 158555/75, 158556/75, 139368/76, 38555/80, 38556/80 and 8858/81, and in U.S. Patent No. 3,940,422. O~ the methods disclosed in the above patent re~erences, the process described in published Japanese patent application No. 8858/81 can be operated with ease and efficiency, and thus this process has advantage for production on an industrial scale. The Japanese patent application No. 8858/81 invention is illustrated by the following preferred process embodiment.
A nuclear unsubstituted or substituted benzaldehyde derivative i5 heated with a 2-carboxymalonanilic acid derivative at 80-100C for several hours in a solvent medium such as pyridine, benzene, toluene or xylene tlo-2o times by weight the amount of the benzaldehyde derivative or the
2-carboxymalonanilic acid derivative) in the presence of a catalytic amount of a basic compound such as piperidine. The resultant reaction mixture is evaporated and the residue is dissolved in a small amount of an alcohol. The alcoholic solution is poured into ice-water, then hydrochloric acid is added to make the aqueous medium acidic, and the crystalline precipitate which forms is collected by filtration and recrystallized from a suitable organic solvent to yield the desired product.
l 12410~
` Since the desired product in the above described procedure is obtained as a precipitate from an aqueous acidic solution of the evaporated reaction mixture by acidification with a mineral acid, unreacted materials and byproducts which are insoluble in an aqueous acidic solution J are also precipitated, and these components are difficult to ~j remove by recrystallization and thus are contained in the desired product. Hence, the desired product purified by !! recrystallization always contains such impurities and is not I applicable for medicinal purposes without an extensive recrystallization procedure, with a concomitant decrease in product yield.
Accordingly, it is an object of this invention to l provide a process for producing anthranilic acid derivatives 1 which is superior to prior art methods such as that described l in Japanese patent application No. 8858/81.
J It is another object of this invention to provide an improved method for producing nuclear di-substituted cinnamoyl-! anthranilic acid derivatives with a high purity and yield, li which derivatives possess antiallergic properties and thus ¦¦ are useful for treatment of asthma, hay fever, atopic dermatitis i and urticaria.
! Other objects and advantages of this invention willbecome apparent from the accompanying description and examples.
i' 1241016 "
i. .' DESCRIPTION OF THE INVENTION
This invention provides an improved method for the production of nuclear substituted cinnamoylanthranilic acid ' derivatives corresponding to the formula:
i COOH
1 2~CH=CHCONH ~ (I) Ii ' jj where Rl is hydroxyl and R2 is an alkoxyl substituent containing .
j about 1-3 carbon atoms. The said derivatives possess ,1 antiallergic properties, and are useful for treatment of ! diseases caused by allergies, such as asthma, hay fever, I atopic dermatitis and urticaria.
Thus, one or more objects of the present invention are accomplished by the provision of a process which comprises i reacting a nuclear di-substituted benzaldehyde corresponding to the formula:
1, ?l i ? ~ CHO
1I Rl ~ (II) .j ll ~24~0~6 where Rl and R2 are substituents as previously defined, in ~¦ an inert organic solvent with 2-carboxymalonanilic acid corresponding to the formula:
il'' .
i 11 ~ NHCOCH2COOH (III) I.j ~ COOH
~I !
~ and a cyclic amine corresponding to the formula:
(CH2)2 ~
HN X (IV) (CH2)n ~
.1 .
Il where X is a methylene group or an oxygen atom, n is 1 or 2 ¦¦ with the proviso that n is 2 when X is an oxygen atom, and s~id l cyclic amine is employed in a molar ratio of about 2-10 moles ¦ per mole of nuclear substituted benzaldehyde derivative of l formul.(II) or the 2-carboxymalonanilic acid of Formula(III) Il Il .
I I _ 5 I ~24~
I
i! above, to produce a crystalline precipitate of an intermediate ¦¦ compound corresponding to the formula:
. . ,i ' 1,, .
I ' COO~
Rl =0_ CH=C HCoN H ~3 '¦ ~ (CH2) i H (CH2) ~
I! where Rl, R2, X and n are as previously defined; and treating '¦ the said compound ~V) under acidic conditions to yield a jl product corresponding to formula(I) above.
-In the present invention process a specific type of cyclic amine compound is utilized in a molar ratio of j 2-10 moles per mole of the starting material of formula(II) ¦ or (III).above. 8y employing a molar excess of the cyclic ¦~ amine over the benzaldehyde(II) or 2-carboxymalonanilic acid~III) compounds in an inert organic solvent as a reaction medium, the 1~ .
Il i2~1016 intèrmediate of formula(V), i.e., the salt of nuclear substituted ! cinnamoylanthranilic acid derivative and cyclic amine, precipitates as crystals in high yield and purity from the ~ reaction mixture as the reaction proceeds, and thereafter is ~ readily recovered from the reaction mixture. The crystalline compound(V) is substantially free of unreacted materials and 'j byproducts and can be converted easily into the desired l~ free acid product in a high purity form by treatment with an ~ll acidic reagent such as a mineral acid.
ll As demonstrated in the Examples, the optimal yield i! of high purity crystalline salt intermediate is achieved when l! the molar ratio of cyclic amlne to benzaldehyde(II) or i 2-carboxymalonanilic acid~III) is about 3~
l ~hus, by the practice of the present invention process ~ the problems associated with the procedure disclosed in ¦ Japanese patent application No. 8858/81 are eliminated, and il nuclear substituted cinnamoylanthranilic acid derivatives ¦ are prepared efficiently in high yield and purity.
~1 Illustrative of inert organic solvents suitable in 0 il the invention process (i.e., solvents with solubility properties which promote crystallization of the intermediate(V) Ij as the reaction proceeds) are benzehe, toluene, xylene, ethyl ¦¦ acetate and chloroform. Preferred inert organic solvents are il aromatic hydrocarbons such as benzene and toluene. The solvent 5 ~1 is employed in a volume which typically will vary between about 1-30 milliliters per gram of benzaldehyde and 2-carboxymalonanilic acid reactants.
I
1! - 7 241~
The cyclic amine component employed in the invention '~ process possesses a catalytic property for condensing a ¦¦ nuclear di-substituted benzaldehyde derivative and Il 2-carboxymalonanilic acid, and possesses properties which 1~ enhance the formation of insoluble cyclic amine salt of ,¦ cinnamoylanthranilic acid derivativë in an inert solvent ,j medium. Illustrative of the invention cyclic amines are pyrrolidine, piperidine and morpholine. Piperidine is an ¦ exceptional cyclic amine for purposes of the present invention lo 31 process.
!l Acid reagents suitable for the conversion of the ! intermediate(V) compound above into the desired compound(I) Ij include inorganic acids such as hydrochloric acid, sulfuric ! I acid, and the like, and organic acids such as acetic acid or ! p-toluenesulfonic acid. The use of a mineral acid such as ¦¦ hydrochloric acid is preferred.
The nuclear di-substituted benzaldehyde derivatives corresponding to formula(II) which are employed as a starting I¦ material are known compounds, and methods of synthesis are 1I described in the chemical literature. Examples of said aldehydes include 2-hydroxy-3-methoxybenzaldehyde; 3-hydroxy-2-methoxy-benzaldehyde; 3-hydroxy-4-methoxybenzaldehyde;4-hydroxy-3-methoxybenzaldehyde; 3-hydroxy-4-propoxybenzaldehyde:
l 4-hydroxy-3-propoxybenzaldehyde; and the like.
25 ¦ 2-Carboxymalonanilic acid used as a starting material is also a known compound, and can be prepared according to the method described in ~apanese application No. 43673/74.
l - 8 -il. . .
i~
Z410~6 ¦¦ . Since dehydration and decarboxylation reactions occur simultaneously with the formation of the intermediate compound corresponding to formula(V) above, in a preferred Il process embodiment the reaction is conducted with continuous ,I removal of water formed during the reaction course.
As a general procedure, a mixture of a benzaldehyde !! derivative corresponding to formula(II), 2-carboxymalonanilic , acid, and 2-10 moles of cyclic amine corresponding to formula(IV) l (e.g., piperidine) per mole of the benzaldehyde derivative(II) l or 2-carboxymalonanilic acid(III) is dissolved in an inert organic solvent (e.g., benzene or toluene) in a proportion l of about 1-3 liters of solvent per mole of benzaldehyde ¦¦ derivative, and then the resultant reaction solution is ¦¦ heated under reflux for a period of about 3-5 hours with 15 1l continuous removal of water as it is formed during the reaction.
ij After cooling, the precipitated crystalline salt ~! intermediate is recovered by filtration and dissolved with Il heating in water. The resultant aqueous solution is added , dropwise to a dilute mineral acid solution. The crystalline ¦¦ product which precipitates is collected by conventional means !¦ such as filtration, and optionally, recrystallized from an Il organic solvent to provide the desired product corresponding to formula(I~.
1l1 .''1 I! 9 `I ~24~016 ¦ . It is an advantage of the invention process that the cyclic amine that is utilized can be recovered from the filtrate i and recycled in the process.
Il The following Examples are further illustrative of the !¦ present invention. The specific ingredients and processing I parameters are presented as being typical, and various " modifications can be derived in view of the foregoing disclosure j' within the scope of the invention.
.
,' .
. I
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I I .
i `I ~Z~0~6 'i I, EXAMPLE I
This Example illustrates the advantages of preparing j nuclear substituted cinnamoylanthranilic acid derivatives ¦j with a molar excess of cyclic amine in accordance with the ~¦ present invention process.
A.
" A solution of 2.54 g of 4-hydroxy-3-methoxy-benzaldel~yde 3.8 g of 2-carboxymalonanilic acid, and I¦ 4.29 g of piperidine in 17 ml of benzene is heated for il 3 hours under reflux with removal of water of reaction. After ¦¦ completion of the reaction, the reaction mixture is cooled and the precipitated cry,stals are collected by filtration and ¦ dried to obtain 6.34 g of piperidinium N-(4-hydroxy-3-ll methoxycinnamoyl)anthranilate, m.p. 188-189C.
5 ¦ The compound structure is confirmed by elemental analysis, and by IR and NMR spectroscopy.
Il The molar ratio of'piperidine to 4 hydroxy-3-j, methoxybenzaldehyde in the above preparation is 3:1. The ~! same procedure is employed with 3-hydroxy-4-methoxybenzaldehyde !I to synthesize piperidinium N-(3-hydroxy-4-methoxycinnamoyl)-,1 anthranilate, m.p. 197-203C.
I; The same procedure is employed with different molar il ratios of piperidine to 4-hydroxy-3-methoxybenzaldehyde and ¦l 3-hydroxy-4-methoxybenzaldehyde, respectively.
'I
1' .4~1 0~6 ' The r~sults as summarized in Table I demonstrate the superiority of the present invention process for the production of a high yield of crystalline nuclear substituted Il cinnamoylanthranilate salt intermediate. Examples II and IV
'l illustrate the conversion of the crystalline piperidinium salts to the desired N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid and N-(3-hydroxy-4-methoxycinnamoyl)anthranilic acid products.
, I .
I~ B.
il In a manner similar to that described in IA above, ¦¦ comparative runs (Table II) are conducted with different molar ¦¦ ratios of morpholine to 4-hydroxy-3-methoxybenzaldehyde and ! 3-hydroxy-4-methoxybenzaldehyde, respectively. The crystalline salt intermediates are morpholinium N-(4-hydroxy-3-methoxy-l cinnamoyl)anthranilate (m.p. 183-185C) and morpholinium i N-(3-hydroxy-4-methoxycinnamoyl)anthranilate (m.p. 133-137C, 1I with decomposition).
Il Examples III and V illustrate the conversion of the I¦ crystalline morpholinium salts to N-(4-hydroxy-3-methoxy-¦¦ cinnamoyl)anthranilic acid and N-(3-hydroxy-4-methoxy-I cinnamoyl)anthranilic acid products of the invention. I
I
, 11 , !l 1~ , Il . .
j - 12 -li ~z~o~ ;
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; In a manner similar to that described in IA above, comparative runs (Table III) are conducted with different molar l¦ ratios of pyrrolidine to 4-hydroxy-3-metho~ybenzaldehyde and ll 3-hydroxy-4-methoxybenzaldehyde, respectively. The crystalline salt intermediates are pyrrolidinium N-(4-hydroxy-3-methoxy-cinnamoyl)anthranilate (m.p. 181-186C) and pyrrolidinium N-(3-hydroxy-4-methoxycinnamoyl)anthranilate (m.p. 175-179C).
~ Examples III and V illustrate the conversion of the ¦! crystalline pyrrolidinium salts to the free acid products of i¦ the invention.
i Similar results are obtained if the benzaldehyde reactant in all of the above described procedures i8 l 3-hydroxy-2-methoxybenzaldehyde or 2-hydroxy-3-methoxy-¦ benzaldehyde.
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I1 ~24~016 j' ~ EXAMPLE II
',l A 10 g quantity of piperidinium N-l4-hydroxy-3-methoxy-cinnamoyl)anthranilate is dissolved in a mixture of 80 ml of Il water and 60 ml of methyl alcohol with heating, and the ~I resultant solution is added dropwise to 85 ml of diluted ~, hydrochloric acid (5 ml of conc. hydrochloric acid and ~0 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at ,j 90-100C under r~duced pressure for 3 hours to yield ¦I N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid (98.5% yield), ¦i m.p. 230-233C. The compound structure is confirmed by jl elemental analysis, and by IR and NMR spectroscopy.
~1 , EXAMPLE III
~ A 10 g quantity of morpholinium N-(4-hydroxy-3-methoxy-I cinnamoyl)anthranilate is dissolved in a mixture of 80 ml of ! water and 60 ml of methyl alcohol with heating, and the "
resultant solution is added dropwise to 85 ml of diluted hydrochloric acid t5 ml of conc. hydrochloric acid and 80 ml of ~, water) with stirring. The precipitated crystals which form are i~ collected by filtration, washed with water and then dried at 'i 90-100C under reduced pressure for 3 hours to yield Ij N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid (82.5~ yield).
il The compound is confirmed as identical to that obtained in I, EXAMPLE II.
!~ Similar results are obtained with pyrrolidinium ~j N-(4-hydroxy-3-methoxycinnamoyl)anthranilate.
!
I' . .
, - 14 -jl 124101~
. XAMPLE IV
A 10 g 4uantity of piperidlnium N-(3-hydroxy-4-methoxy-! cinnamoyl)anthranilate is dissolved in a mixture of 80 ml of l water and 80 ml of methyl alcohol with heating, and the resultant ~jgolution is added dropwise to 85 ml of diluted hydrochloric acid ,l(5 ml of conc. hydrochloric acid and 80 ml of water) with ~ stirring. The precipitated crystals which form are collected ,',by filtration, washed with water and then dried at 90-100C
,lunder reduced pressure for 3 hours to yield N-(3-hydroxy-4-I¦methoxycinnamoyl)anthranilic acid (97.0% yield), m.p. 219-222C.
¦I The compound structure is confirmed by elemental analysis, and ¦~ by IR and NMR spectroscopy.
11 , I ~ EXAMPLE V
' A 10 g quantity of morpholinium N-(3-hydroxy-4-methoxy-l cinnamoy)anthranilate is dissolved in a mixture of 80 ml of ~ water and 60 ml of methyl alcohol with heating, and the resultant ;
jj solution is added dropwise to 85 ml of diluted hydrochloric acid j (5 mlof conc. hydrochloric acid and 80 ml of water) with stirring-, j~ The precipitated crystals which form are collected by filtration, 'I washed with water and then dried at 90-100C under reduced pressure for 3 hours to yield N-t3-hydroxy-4-methoxycinnamoyl)-,l anthranilic acid (74.0% yield). The compound is confirmed as identical to that obtained in EX~IPLE IV.
I¦ Similar results are obtained with pyrrolidinium 1¦ N- (3-hydroxy-4-metlloxycinnamoyl) anthr\nilate.
Il - 15-il .
l 12410~
` Since the desired product in the above described procedure is obtained as a precipitate from an aqueous acidic solution of the evaporated reaction mixture by acidification with a mineral acid, unreacted materials and byproducts which are insoluble in an aqueous acidic solution J are also precipitated, and these components are difficult to ~j remove by recrystallization and thus are contained in the desired product. Hence, the desired product purified by !! recrystallization always contains such impurities and is not I applicable for medicinal purposes without an extensive recrystallization procedure, with a concomitant decrease in product yield.
Accordingly, it is an object of this invention to l provide a process for producing anthranilic acid derivatives 1 which is superior to prior art methods such as that described l in Japanese patent application No. 8858/81.
J It is another object of this invention to provide an improved method for producing nuclear di-substituted cinnamoyl-! anthranilic acid derivatives with a high purity and yield, li which derivatives possess antiallergic properties and thus ¦¦ are useful for treatment of asthma, hay fever, atopic dermatitis i and urticaria.
! Other objects and advantages of this invention willbecome apparent from the accompanying description and examples.
i' 1241016 "
i. .' DESCRIPTION OF THE INVENTION
This invention provides an improved method for the production of nuclear substituted cinnamoylanthranilic acid ' derivatives corresponding to the formula:
i COOH
1 2~CH=CHCONH ~ (I) Ii ' jj where Rl is hydroxyl and R2 is an alkoxyl substituent containing .
j about 1-3 carbon atoms. The said derivatives possess ,1 antiallergic properties, and are useful for treatment of ! diseases caused by allergies, such as asthma, hay fever, I atopic dermatitis and urticaria.
Thus, one or more objects of the present invention are accomplished by the provision of a process which comprises i reacting a nuclear di-substituted benzaldehyde corresponding to the formula:
1, ?l i ? ~ CHO
1I Rl ~ (II) .j ll ~24~0~6 where Rl and R2 are substituents as previously defined, in ~¦ an inert organic solvent with 2-carboxymalonanilic acid corresponding to the formula:
il'' .
i 11 ~ NHCOCH2COOH (III) I.j ~ COOH
~I !
~ and a cyclic amine corresponding to the formula:
(CH2)2 ~
HN X (IV) (CH2)n ~
.1 .
Il where X is a methylene group or an oxygen atom, n is 1 or 2 ¦¦ with the proviso that n is 2 when X is an oxygen atom, and s~id l cyclic amine is employed in a molar ratio of about 2-10 moles ¦ per mole of nuclear substituted benzaldehyde derivative of l formul.(II) or the 2-carboxymalonanilic acid of Formula(III) Il Il .
I I _ 5 I ~24~
I
i! above, to produce a crystalline precipitate of an intermediate ¦¦ compound corresponding to the formula:
. . ,i ' 1,, .
I ' COO~
Rl =0_ CH=C HCoN H ~3 '¦ ~ (CH2) i H (CH2) ~
I! where Rl, R2, X and n are as previously defined; and treating '¦ the said compound ~V) under acidic conditions to yield a jl product corresponding to formula(I) above.
-In the present invention process a specific type of cyclic amine compound is utilized in a molar ratio of j 2-10 moles per mole of the starting material of formula(II) ¦ or (III).above. 8y employing a molar excess of the cyclic ¦~ amine over the benzaldehyde(II) or 2-carboxymalonanilic acid~III) compounds in an inert organic solvent as a reaction medium, the 1~ .
Il i2~1016 intèrmediate of formula(V), i.e., the salt of nuclear substituted ! cinnamoylanthranilic acid derivative and cyclic amine, precipitates as crystals in high yield and purity from the ~ reaction mixture as the reaction proceeds, and thereafter is ~ readily recovered from the reaction mixture. The crystalline compound(V) is substantially free of unreacted materials and 'j byproducts and can be converted easily into the desired l~ free acid product in a high purity form by treatment with an ~ll acidic reagent such as a mineral acid.
ll As demonstrated in the Examples, the optimal yield i! of high purity crystalline salt intermediate is achieved when l! the molar ratio of cyclic amlne to benzaldehyde(II) or i 2-carboxymalonanilic acid~III) is about 3~
l ~hus, by the practice of the present invention process ~ the problems associated with the procedure disclosed in ¦ Japanese patent application No. 8858/81 are eliminated, and il nuclear substituted cinnamoylanthranilic acid derivatives ¦ are prepared efficiently in high yield and purity.
~1 Illustrative of inert organic solvents suitable in 0 il the invention process (i.e., solvents with solubility properties which promote crystallization of the intermediate(V) Ij as the reaction proceeds) are benzehe, toluene, xylene, ethyl ¦¦ acetate and chloroform. Preferred inert organic solvents are il aromatic hydrocarbons such as benzene and toluene. The solvent 5 ~1 is employed in a volume which typically will vary between about 1-30 milliliters per gram of benzaldehyde and 2-carboxymalonanilic acid reactants.
I
1! - 7 241~
The cyclic amine component employed in the invention '~ process possesses a catalytic property for condensing a ¦¦ nuclear di-substituted benzaldehyde derivative and Il 2-carboxymalonanilic acid, and possesses properties which 1~ enhance the formation of insoluble cyclic amine salt of ,¦ cinnamoylanthranilic acid derivativë in an inert solvent ,j medium. Illustrative of the invention cyclic amines are pyrrolidine, piperidine and morpholine. Piperidine is an ¦ exceptional cyclic amine for purposes of the present invention lo 31 process.
!l Acid reagents suitable for the conversion of the ! intermediate(V) compound above into the desired compound(I) Ij include inorganic acids such as hydrochloric acid, sulfuric ! I acid, and the like, and organic acids such as acetic acid or ! p-toluenesulfonic acid. The use of a mineral acid such as ¦¦ hydrochloric acid is preferred.
The nuclear di-substituted benzaldehyde derivatives corresponding to formula(II) which are employed as a starting I¦ material are known compounds, and methods of synthesis are 1I described in the chemical literature. Examples of said aldehydes include 2-hydroxy-3-methoxybenzaldehyde; 3-hydroxy-2-methoxy-benzaldehyde; 3-hydroxy-4-methoxybenzaldehyde;4-hydroxy-3-methoxybenzaldehyde; 3-hydroxy-4-propoxybenzaldehyde:
l 4-hydroxy-3-propoxybenzaldehyde; and the like.
25 ¦ 2-Carboxymalonanilic acid used as a starting material is also a known compound, and can be prepared according to the method described in ~apanese application No. 43673/74.
l - 8 -il. . .
i~
Z410~6 ¦¦ . Since dehydration and decarboxylation reactions occur simultaneously with the formation of the intermediate compound corresponding to formula(V) above, in a preferred Il process embodiment the reaction is conducted with continuous ,I removal of water formed during the reaction course.
As a general procedure, a mixture of a benzaldehyde !! derivative corresponding to formula(II), 2-carboxymalonanilic , acid, and 2-10 moles of cyclic amine corresponding to formula(IV) l (e.g., piperidine) per mole of the benzaldehyde derivative(II) l or 2-carboxymalonanilic acid(III) is dissolved in an inert organic solvent (e.g., benzene or toluene) in a proportion l of about 1-3 liters of solvent per mole of benzaldehyde ¦¦ derivative, and then the resultant reaction solution is ¦¦ heated under reflux for a period of about 3-5 hours with 15 1l continuous removal of water as it is formed during the reaction.
ij After cooling, the precipitated crystalline salt ~! intermediate is recovered by filtration and dissolved with Il heating in water. The resultant aqueous solution is added , dropwise to a dilute mineral acid solution. The crystalline ¦¦ product which precipitates is collected by conventional means !¦ such as filtration, and optionally, recrystallized from an Il organic solvent to provide the desired product corresponding to formula(I~.
1l1 .''1 I! 9 `I ~24~016 ¦ . It is an advantage of the invention process that the cyclic amine that is utilized can be recovered from the filtrate i and recycled in the process.
Il The following Examples are further illustrative of the !¦ present invention. The specific ingredients and processing I parameters are presented as being typical, and various " modifications can be derived in view of the foregoing disclosure j' within the scope of the invention.
.
,' .
. I
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I I .
i `I ~Z~0~6 'i I, EXAMPLE I
This Example illustrates the advantages of preparing j nuclear substituted cinnamoylanthranilic acid derivatives ¦j with a molar excess of cyclic amine in accordance with the ~¦ present invention process.
A.
" A solution of 2.54 g of 4-hydroxy-3-methoxy-benzaldel~yde 3.8 g of 2-carboxymalonanilic acid, and I¦ 4.29 g of piperidine in 17 ml of benzene is heated for il 3 hours under reflux with removal of water of reaction. After ¦¦ completion of the reaction, the reaction mixture is cooled and the precipitated cry,stals are collected by filtration and ¦ dried to obtain 6.34 g of piperidinium N-(4-hydroxy-3-ll methoxycinnamoyl)anthranilate, m.p. 188-189C.
5 ¦ The compound structure is confirmed by elemental analysis, and by IR and NMR spectroscopy.
Il The molar ratio of'piperidine to 4 hydroxy-3-j, methoxybenzaldehyde in the above preparation is 3:1. The ~! same procedure is employed with 3-hydroxy-4-methoxybenzaldehyde !I to synthesize piperidinium N-(3-hydroxy-4-methoxycinnamoyl)-,1 anthranilate, m.p. 197-203C.
I; The same procedure is employed with different molar il ratios of piperidine to 4-hydroxy-3-methoxybenzaldehyde and ¦l 3-hydroxy-4-methoxybenzaldehyde, respectively.
'I
1' .4~1 0~6 ' The r~sults as summarized in Table I demonstrate the superiority of the present invention process for the production of a high yield of crystalline nuclear substituted Il cinnamoylanthranilate salt intermediate. Examples II and IV
'l illustrate the conversion of the crystalline piperidinium salts to the desired N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid and N-(3-hydroxy-4-methoxycinnamoyl)anthranilic acid products.
, I .
I~ B.
il In a manner similar to that described in IA above, ¦¦ comparative runs (Table II) are conducted with different molar ¦¦ ratios of morpholine to 4-hydroxy-3-methoxybenzaldehyde and ! 3-hydroxy-4-methoxybenzaldehyde, respectively. The crystalline salt intermediates are morpholinium N-(4-hydroxy-3-methoxy-l cinnamoyl)anthranilate (m.p. 183-185C) and morpholinium i N-(3-hydroxy-4-methoxycinnamoyl)anthranilate (m.p. 133-137C, 1I with decomposition).
Il Examples III and V illustrate the conversion of the I¦ crystalline morpholinium salts to N-(4-hydroxy-3-methoxy-¦¦ cinnamoyl)anthranilic acid and N-(3-hydroxy-4-methoxy-I cinnamoyl)anthranilic acid products of the invention. I
I
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; In a manner similar to that described in IA above, comparative runs (Table III) are conducted with different molar l¦ ratios of pyrrolidine to 4-hydroxy-3-metho~ybenzaldehyde and ll 3-hydroxy-4-methoxybenzaldehyde, respectively. The crystalline salt intermediates are pyrrolidinium N-(4-hydroxy-3-methoxy-cinnamoyl)anthranilate (m.p. 181-186C) and pyrrolidinium N-(3-hydroxy-4-methoxycinnamoyl)anthranilate (m.p. 175-179C).
~ Examples III and V illustrate the conversion of the ¦! crystalline pyrrolidinium salts to the free acid products of i¦ the invention.
i Similar results are obtained if the benzaldehyde reactant in all of the above described procedures i8 l 3-hydroxy-2-methoxybenzaldehyde or 2-hydroxy-3-methoxy-¦ benzaldehyde.
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I1 ~24~016 j' ~ EXAMPLE II
',l A 10 g quantity of piperidinium N-l4-hydroxy-3-methoxy-cinnamoyl)anthranilate is dissolved in a mixture of 80 ml of Il water and 60 ml of methyl alcohol with heating, and the ~I resultant solution is added dropwise to 85 ml of diluted ~, hydrochloric acid (5 ml of conc. hydrochloric acid and ~0 ml of water) with stirring. The precipitated crystals which form are collected by filtration, washed with water and then dried at ,j 90-100C under r~duced pressure for 3 hours to yield ¦I N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid (98.5% yield), ¦i m.p. 230-233C. The compound structure is confirmed by jl elemental analysis, and by IR and NMR spectroscopy.
~1 , EXAMPLE III
~ A 10 g quantity of morpholinium N-(4-hydroxy-3-methoxy-I cinnamoyl)anthranilate is dissolved in a mixture of 80 ml of ! water and 60 ml of methyl alcohol with heating, and the "
resultant solution is added dropwise to 85 ml of diluted hydrochloric acid t5 ml of conc. hydrochloric acid and 80 ml of ~, water) with stirring. The precipitated crystals which form are i~ collected by filtration, washed with water and then dried at 'i 90-100C under reduced pressure for 3 hours to yield Ij N-(4-hydroxy-3-methoxycinnamoyl)anthranilic acid (82.5~ yield).
il The compound is confirmed as identical to that obtained in I, EXAMPLE II.
!~ Similar results are obtained with pyrrolidinium ~j N-(4-hydroxy-3-methoxycinnamoyl)anthranilate.
!
I' . .
, - 14 -jl 124101~
. XAMPLE IV
A 10 g 4uantity of piperidlnium N-(3-hydroxy-4-methoxy-! cinnamoyl)anthranilate is dissolved in a mixture of 80 ml of l water and 80 ml of methyl alcohol with heating, and the resultant ~jgolution is added dropwise to 85 ml of diluted hydrochloric acid ,l(5 ml of conc. hydrochloric acid and 80 ml of water) with ~ stirring. The precipitated crystals which form are collected ,',by filtration, washed with water and then dried at 90-100C
,lunder reduced pressure for 3 hours to yield N-(3-hydroxy-4-I¦methoxycinnamoyl)anthranilic acid (97.0% yield), m.p. 219-222C.
¦I The compound structure is confirmed by elemental analysis, and ¦~ by IR and NMR spectroscopy.
11 , I ~ EXAMPLE V
' A 10 g quantity of morpholinium N-(3-hydroxy-4-methoxy-l cinnamoy)anthranilate is dissolved in a mixture of 80 ml of ~ water and 60 ml of methyl alcohol with heating, and the resultant ;
jj solution is added dropwise to 85 ml of diluted hydrochloric acid j (5 mlof conc. hydrochloric acid and 80 ml of water) with stirring-, j~ The precipitated crystals which form are collected by filtration, 'I washed with water and then dried at 90-100C under reduced pressure for 3 hours to yield N-t3-hydroxy-4-methoxycinnamoyl)-,l anthranilic acid (74.0% yield). The compound is confirmed as identical to that obtained in EX~IPLE IV.
I¦ Similar results are obtained with pyrrolidinium 1¦ N- (3-hydroxy-4-metlloxycinnamoyl) anthr\nilate.
Il - 15-il .
Claims (11)
1. A process for the production of a nuclear substituted cinnamoylanthranilic acid derivative corresponding to the formula:
where R1 is hydroxy and R2 is an alkoxyl group containing about 1-3 carbon atoms, which process comprises (1) reacting in an inert organic solvent medium a nuclear substituted benzaldehyde derivative corresponding to the formula:
where R1 and R2 are as previously defined, with 2-carboxy-malonanilic acid and a cyclic amine corresponding to the formula:
where X is a methylene group or an oxygen atom, n is 1 or 2 with the proviso that n is 2 when X is an oxygen atom, and said cyclic amine is employed in a molar ratio of about 2-10 moles per mole of substituted benzaldehyde derivative reactant or 2-carboxymalonanilic acid reactant, to produce a crystalline precipitate of an intermediate compound corresponding to the formula:
where R1, R2, n and X are as previously defined; and (2) treating the intermediate compound with an acidic reagent to yield a nuclear substituted cinnamoylanthranilic acid product corresponding to the first formula above.
where R1 is hydroxy and R2 is an alkoxyl group containing about 1-3 carbon atoms, which process comprises (1) reacting in an inert organic solvent medium a nuclear substituted benzaldehyde derivative corresponding to the formula:
where R1 and R2 are as previously defined, with 2-carboxy-malonanilic acid and a cyclic amine corresponding to the formula:
where X is a methylene group or an oxygen atom, n is 1 or 2 with the proviso that n is 2 when X is an oxygen atom, and said cyclic amine is employed in a molar ratio of about 2-10 moles per mole of substituted benzaldehyde derivative reactant or 2-carboxymalonanilic acid reactant, to produce a crystalline precipitate of an intermediate compound corresponding to the formula:
where R1, R2, n and X are as previously defined; and (2) treating the intermediate compound with an acidic reagent to yield a nuclear substituted cinnamoylanthranilic acid product corresponding to the first formula above.
2. A process in accordance with claim 1 wherein the mixture of reagents in step (1) is heated under reflux with continuous removal of water as it is formed during the reaction.
3. A process in accordance with claim 1 wherein the inert organic solvent is an aromatic hydrocarbon.
4. A process in accordance with claim 1 wherein the inert organic solvent is benzene or toluene.
5. A process in accordance with claim 1 wherein the benzaldehyde reactant is 4-hydroxy-3-methoxybenzaldehyde.
6. A process in accordance with claim 1 wherein the benzaldehyde reactant is 3-hydroxy-4-methoxybenzaldehyde.
7. A process in accordance with claim 1 wherein the cyclic amine is piperidine.
8. A process in accordance with claim 1 wherein the cyclic amine is morpholine.
9. A process in accordance with claim 1 wherein the cyclic amine is pyrrolidine.
10. A process in accordance with claim 1 wherein said nuclear substituted benzaldehyde derivative is 4-hydroxy-3-methoxybenzaldehyde and the resulting nuclear substituted cinnamoylanthranilic acid product is N-(4-hydroxy-3-methoxy-cinnamoyl)anthranilic acid.
11. A process in accordance with claim 1 wherein said nuclear substituted benzaldehyde derivative is 3-hydroxy-4-methoxybenzaldehyde and the resulting nuclear substituted cinnamoylanthranilic acid product is N-(3-hydroxy-4-methoxy-cinnamoyl)anthranilic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/654,231 US4587356A (en) | 1981-09-01 | 1984-09-25 | Process for the production of nuclear substituted cinnamoylanthranilic acid derivatives |
| US654,231 | 1984-09-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1241016A true CA1241016A (en) | 1988-08-23 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000478780A Expired CA1241016A (en) | 1984-09-25 | 1985-04-10 | Method for the production of nuclear substituted cinnamoylanthranilic acid derivatives |
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| Country | Link |
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| CA (1) | CA1241016A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144933A1 (en) * | 2007-05-29 | 2008-12-04 | Université de Montréal | Cinnamoyl inhibitors of transglutaminase |
-
1985
- 1985-04-10 CA CA000478780A patent/CA1241016A/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144933A1 (en) * | 2007-05-29 | 2008-12-04 | Université de Montréal | Cinnamoyl inhibitors of transglutaminase |
| US8614233B2 (en) | 2007-05-29 | 2013-12-24 | Universite De Montreal | Cinnamoyl inhibitors of transglutaminase |
| US9162991B2 (en) | 2007-05-29 | 2015-10-20 | University Of Ottawa | Cinnamoyl inhibitors of transglutaminase |
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