CA2089013A1 - Process for the preparation of 6-hydroxy-2, 5, 7, 8- tetraalkyl-2-(4-aminophenoxymethyl) chromans - Google Patents
Process for the preparation of 6-hydroxy-2, 5, 7, 8- tetraalkyl-2-(4-aminophenoxymethyl) chromansInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
ABSTRACT
A process for the preparation of aminochroman of the general formula I
where R is a lower alkyl group having 1 to 4 C atoms, is described. In this process, nitrochromanone of the general formula II
is reduced using zirconium oxide/isopropanol to produce a mixture of a corresponding aminochromene III
and a corresponding nitrochromene IV
This mixture is then hydrogenated with hydrogen in the presence of a hydrogenation catalyst to produce the final product, of the general formula I.
Aminochroman is an important intermediate in the preparation of hypolipidaemic pharmaceuticals.
A process for the preparation of aminochroman of the general formula I
where R is a lower alkyl group having 1 to 4 C atoms, is described. In this process, nitrochromanone of the general formula II
is reduced using zirconium oxide/isopropanol to produce a mixture of a corresponding aminochromene III
and a corresponding nitrochromene IV
This mixture is then hydrogenated with hydrogen in the presence of a hydrogenation catalyst to produce the final product, of the general formula I.
Aminochroman is an important intermediate in the preparation of hypolipidaemic pharmaceuticals.
Description
~8~13 The invention relates to a novel process for the preparation of 6-hydroxy-2,5,7,8-tetraalXyl-2-(4-amino-phenoxymethyl)chromans (aminochroman) of the general formula R R
() ~}N112 ~ ' in which R denotes a lower alkyi group having 1 to 4 C atoms.
These aminochromans o~ the general formula I are use~ul intermediates for the préparation of hypolipidaemic pharmaceuticals (J. Med. Chem. 1989, 32, p. 421).
It is known from EP-A 207,581 to prepare amino-chromans of ~he general formula I by first converting tetraalkyl-2-(4-nitrophenoxymethyl) chroman-4-one into the corresponding chroman-4-ol using sod~ium borohydride, in a further step dehydrating the chroman-4-ol~to the chroman-3-ene ;
in the presence of p-toluenesulphonic acid an~ in the last step hydrogenating both the nitro group and the~chromene double bond using a hydrogenation catalyst to give the final product. ~ `
This reaction has the disadvantage that a considerable need for working up arises~between the individual ; reaction steps, which impedes converslon of the synthesis to the~industrlal scale. Additionally, reduction using sodium borohydride is expensive in comparison with catalytic reductions and problematic from an ecological point of view as the resulting effluents are polluted with boron.
The object was consequently to develop a simpler synthesis which does not have the said disadvantages.
` . ',~, : ~ : ~ ' ''~ .
! 2 According to the present invention there is provided a process for the preparation of 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-aminophanoxymethyl)chromans of the general formula R
1 0 ~ ~:
where R denotes a lower alkyl group having -1 to 4 C atoms, comprising the steps~of, providing a catalys~ system of an amorphous zirconium~oxide catalyst and isopropanol, reducing 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl)chroman-4-one o~ the~general formula R R
where R is said alkyl group, under pressure in the presence of said catalyst;system to produce a mixture of 6-hydroxy- ~ -:~ 2~5~ 2,5,7,8-tetraalkyl-2-(4-aminophenoxymethyl)-chrom-3-ene of the general formula ~
~2 III
~:
. .
: .
~$~
where R is said alkyl group, and o~ 6-hydroxy~2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl) chrom-3-eneofthegeneral formula R ~ ~ IV
R
: where R is said alkyl group, providing a hydrogenation ;:
catalyst, and hydrogenating said mixture using hydrogen in the presence of said:hydrogenation catalyst.
The starting material is 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl)chroman-4 one ~nitro-chromanone) of the general ~ormula : ' ~: ~ HO' ~ ~ Il ~ ~
in whlch~R has the said meaning. :
: This can be prepared, for example, from acetyl-hydroquinone derivatives according to EP Patent 139,421. - :
Preferably,: 6-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one (formula II where R = CH3) is used:as the starting~material. ~:
: 30~ : In the first step the nitrochromanone of formula II
i5 reduced according to the invention in the first step in the presence of the catalyst system, amorphous zirconium oxide/isopropanol, to give a mixture of 6-hydroxy-2,5,7,8- ~:
.
;~
, :
tetraalkyl-2-(4~aminophenoxymethyl)c:hrom-3-ane (aminochromene) of the ganeral formula R ~ ~ ~ 0 ~ NH~ III
in which R has the said meaning, and of 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl)chrom-3-ene (nitrochromene) :
of the general formula ~ ~ ~ 0 ~ N0 ~ ~ ~V , , ~
in which R has the said meaning.
. .
: ~
' ~
`- 2~ 3 The amorphous zirconium oxide employed according to the invention can be prepared in a known manner by precipitation from a zirconyl chloride solution using sodium hydroxide solutionj according to Shibagaki et al. in Bull.
Chem. Soc. Japn. 1988, 61, p. 3283 ff, or using ammonia, according to US Patent 5,030,601, and subsequent drying and calcination.
Expediently, the amorphous zirconium oxid~ has a specific surface area according to BET of between 210 mZ/g and 265 m2/g. Preferably, the amorphous zirconium oxide is obtained by precipitation using ammonia.
The amorphous zirconium oxide obtained from the precipitation process is advantageously subjected to a pretreatment before its use. This is expsdiently carried out by treatment o~ the precipitated and calcined amorphous zirconium oxide in a mobile inert gas atmosphere at 150C to 300OC over a period of 1 h to 24 h.
Expediently, the reaction in the first step is carried out by initially introducing the nitrochromanone of formula II together with the pretreated amorphous zirconium oxide in isopropanol, which functions as a reactant and solvent.
If appropriate, a molecular sieve can be employed to remove water from the equilibrium. In this way, the reaction rate and the selectivity can be favourably influenced.
The reaction rate can be increased by addition of a small amount of a mineral acid, such as, for example, hydrochloric acid.
The reaction is preferably carried out with exclusion of air at pressures between, expediently, 1 bar to 50 bar, preferably 20 bar to 40 bar, and a temperature of, expediently, between 80C to 220C, preferably 160C to 200C.
The reaction is complete after a reaction time of, as a rule, 35 3 h to 10 h.
~ .. ..
6 i~g~3 The nitrochromene o~ ~ormula IV and the amino-chromene of formula III can be isolated from the reaction mixture in the form of a mixture after separating o~f the zirconium oxide catalyst and removing the solvent, the 5 amount of nitrochromene of formula IV usually predomin-ating and aæ a rule being 75% to 8t)~.
However, it i~ also possible to use the reaction solution containing the mixture of nitrochromene of the formula IV and aminochromene of the formula III directly for the subseque~t step after ~eparating off the zirconium oxide catalyst.
In the subsequent step, the said mixture of nitrochromene of formula IV and aminochromene of formula III is hydrogenated to give the final product of formula I using hydro~en in the presence of a hydrogenation catalyst.
Suitable hydrogenation catalysts are expediently noble metal catalysts, such as, ~or example, palladium or platinum applied to inert support materials, such as, for example, carbon or alumina.
Preferably, the hydrogenation is carried out using a palladium catalyst, applied in an amount from 0.5% to 10~ to carbon as an inert support.
The hydrogenation is expediently carried out at a hydrogen pressure of 1 bar to 20 bar, praferably 5 bar to 10 bar, and a temperature of 20C to 50~C, preferably at room temperature.
As a rule, the uptake of hydrogen is complete after 0.5 h to S h, after which the final product, of ~ormula I, can be i~olated in a sLmple manner by separat-ing off the catalyst and remo~ing the solvent.
Examples A! Preparation o~_the amorphous zirconium oxide Zirconyl chloride octahydrate (ZrOCl2-8H2O) was 3S dissolved in water. The slight turbidity was filtered off, and the solution was ad~us~ed to a content (ZrO2) of 50 g/l using deionised water.
., ' ., , ,: , . , . . . ~ .
.
. 7 ~l3~ 13 Technical ammonia (about 25%) wai~ diluted to a concen-tration of 10~ using deionised water.
2.5 1 o~ deionised water were introduced into a reaction ~essel. The zirconyl chloride solution and the ammonia solution were added in a controlled manner while stirring at 8000 rpm.
The rate of addition of ~he ZrO2 solution was 50 ml/min. The ammonia solution was added in such a way that it was possible to maintain a pH of 7.0 + 0.2 during the resultant precipitation.
. The solids content of the suspension was kept at-about 1% by addition of deionised water.
After precipita~ion was complete, the solid was separated off by filtration. The filter cake was washed several times using ammoniacal water until the Cl- content had been reduced to 0.05%.
The filter cake was then d~ied at 100C, suspended once more, ~iltered and dried again. :
. . Finally, the resulting ZxO2 powder was calcined at 300C for 8 h. The resulting ZrO2 was radiographically amorphous and had a specific surface area according to BET of 240 m2/g.
Example 1: . ~
a) Process for the preparation of a mixture of 6-hydroxy-2,5,7,8-tetra~ethy~2~(4-aminophenoxy-methyl)chrom-3-ene (aminochromene, III) and 6-hydroxy-2~5~7~8-tetramethyl-2-(4-nitrophen methyl)chrom-3-ene (nitrochromene, I~) 2.0 g (5.4 mmol) of 6 hydroxy 2,5,7,8-tetra- -~
methyl-2-(4 nitrophenoxymethyl)chroman-4-one (II) were introduced into an autoclave with exclusion of air together wi~h 5 g of amorphous zirconium oxida (prepared as in A and pretreated for 2 h at 200C with passage of argon), 100 g of isopropanol (dried using molecular ~ieve 4 ~), 1.0 g of molecular sieve 4 ~ (pretreated for 3 h at 300C with passage of argon) and 2.5 ml o~ concentrated hydrochloric acid. After flushing several time~ with :: ' . :~ ....
.~ . .
~90~3 nitrogen, the mixture was heated to a temperature of 190C at a pressure o~ 10 bar while stirring at 750 rpm.
The pressure rose during the course of this to 27-31 bar.
After 6 to 7 h, the reaction mixture wa~ cooled to room S temperature, the amorphous 2irconi~m oxide was separated off and the solvent was evaporated off.
It was possible in this way to obtain 1.9 g of a mixture which contained 57.5% nitrochroMene (IY) and 16.3%
aminochromene (III).
h) Process for the preparation of 6-hydroxy-2,5,7,8-te~ramethyl-2-(4-aminophenoxymethyl)chroman (I~
.. .. . _ . _ 1.9 g of the mixture obtained in Example la and having a content of 73.8~ were introduced into an autoclave with 0.4 g of a palladium-on-carbon catalyst (5% Pd/C) in 60 ml of toluene. After flushing several times with nitrogen and then with hydrogen, the mixture was stirred at 750 rpm at a hydrogen pressure of 8 bar and at room temperature ~24-27C) for 3.5 h to 4 h. The reaction mixture was then freed from ~he catalyst. The solvent was evaporated off. The crude mixture (1.8 g) contained the title product in a yield of 74.3%.
Example 2 Process for the preparation of 6-hydroxy-2,5,7,8-tetra-methyl-2~(4-aminophenoxymethyl)chroman (I) . .
2.0 g (5.4 mmol) of 6-hydroxy-2,5,7,8-tetra-methyl-~-(4-nitrophenoxymethyl)chroman-4-one (II) were introduced into an autoclave with exclusion of air together with 5 g of amorphous zirconium oxide ~prepared as in A, pretreated for 2 h at 200C with passage of ar~on), 80 g of isopropanol (dried using molecular sieve 4 A) and 20 g of toluene. After flushing several times with nitrogen, the mixture was heated to a temperature of 190C at a pressure of 10 bar while stirring at 750 rpm.
The pressure rose during the course of this to 25 bar.
After 5 h, the reaction mixture was cooled to room temperature and the amorphous zirconium oxide was separ-2~9~13 ated off. The resultant solution, containing 71.4% of a mixture of 75.6~ nitrochromene and 24.4% aminochromene according to GC w~s introduced into an autoclave together with 0.4 g of a palladium-on-carbon catalyst (S~ Pd/C).
After ~lushing several tLmes with nitrogen and ~hen with hydrogen, the mixture was stirred at 750 rpm at a hydro-gen pressure of 8 bar and at room temperature (24-27~C) for 1 h. The reaction mixture was then freed from the catalyst and the solvent was evaporated.
The crude product (1.8 g) contained the title product in a yield of 75.1~.
, ,, ~ : . ~ , :
() ~}N112 ~ ' in which R denotes a lower alkyi group having 1 to 4 C atoms.
These aminochromans o~ the general formula I are use~ul intermediates for the préparation of hypolipidaemic pharmaceuticals (J. Med. Chem. 1989, 32, p. 421).
It is known from EP-A 207,581 to prepare amino-chromans of ~he general formula I by first converting tetraalkyl-2-(4-nitrophenoxymethyl) chroman-4-one into the corresponding chroman-4-ol using sod~ium borohydride, in a further step dehydrating the chroman-4-ol~to the chroman-3-ene ;
in the presence of p-toluenesulphonic acid an~ in the last step hydrogenating both the nitro group and the~chromene double bond using a hydrogenation catalyst to give the final product. ~ `
This reaction has the disadvantage that a considerable need for working up arises~between the individual ; reaction steps, which impedes converslon of the synthesis to the~industrlal scale. Additionally, reduction using sodium borohydride is expensive in comparison with catalytic reductions and problematic from an ecological point of view as the resulting effluents are polluted with boron.
The object was consequently to develop a simpler synthesis which does not have the said disadvantages.
` . ',~, : ~ : ~ ' ''~ .
! 2 According to the present invention there is provided a process for the preparation of 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-aminophanoxymethyl)chromans of the general formula R
1 0 ~ ~:
where R denotes a lower alkyl group having -1 to 4 C atoms, comprising the steps~of, providing a catalys~ system of an amorphous zirconium~oxide catalyst and isopropanol, reducing 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl)chroman-4-one o~ the~general formula R R
where R is said alkyl group, under pressure in the presence of said catalyst;system to produce a mixture of 6-hydroxy- ~ -:~ 2~5~ 2,5,7,8-tetraalkyl-2-(4-aminophenoxymethyl)-chrom-3-ene of the general formula ~
~2 III
~:
. .
: .
~$~
where R is said alkyl group, and o~ 6-hydroxy~2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl) chrom-3-eneofthegeneral formula R ~ ~ IV
R
: where R is said alkyl group, providing a hydrogenation ;:
catalyst, and hydrogenating said mixture using hydrogen in the presence of said:hydrogenation catalyst.
The starting material is 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl)chroman-4 one ~nitro-chromanone) of the general ~ormula : ' ~: ~ HO' ~ ~ Il ~ ~
in whlch~R has the said meaning. :
: This can be prepared, for example, from acetyl-hydroquinone derivatives according to EP Patent 139,421. - :
Preferably,: 6-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one (formula II where R = CH3) is used:as the starting~material. ~:
: 30~ : In the first step the nitrochromanone of formula II
i5 reduced according to the invention in the first step in the presence of the catalyst system, amorphous zirconium oxide/isopropanol, to give a mixture of 6-hydroxy-2,5,7,8- ~:
.
;~
, :
tetraalkyl-2-(4~aminophenoxymethyl)c:hrom-3-ane (aminochromene) of the ganeral formula R ~ ~ ~ 0 ~ NH~ III
in which R has the said meaning, and of 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl)chrom-3-ene (nitrochromene) :
of the general formula ~ ~ ~ 0 ~ N0 ~ ~ ~V , , ~
in which R has the said meaning.
. .
: ~
' ~
`- 2~ 3 The amorphous zirconium oxide employed according to the invention can be prepared in a known manner by precipitation from a zirconyl chloride solution using sodium hydroxide solutionj according to Shibagaki et al. in Bull.
Chem. Soc. Japn. 1988, 61, p. 3283 ff, or using ammonia, according to US Patent 5,030,601, and subsequent drying and calcination.
Expediently, the amorphous zirconium oxid~ has a specific surface area according to BET of between 210 mZ/g and 265 m2/g. Preferably, the amorphous zirconium oxide is obtained by precipitation using ammonia.
The amorphous zirconium oxide obtained from the precipitation process is advantageously subjected to a pretreatment before its use. This is expsdiently carried out by treatment o~ the precipitated and calcined amorphous zirconium oxide in a mobile inert gas atmosphere at 150C to 300OC over a period of 1 h to 24 h.
Expediently, the reaction in the first step is carried out by initially introducing the nitrochromanone of formula II together with the pretreated amorphous zirconium oxide in isopropanol, which functions as a reactant and solvent.
If appropriate, a molecular sieve can be employed to remove water from the equilibrium. In this way, the reaction rate and the selectivity can be favourably influenced.
The reaction rate can be increased by addition of a small amount of a mineral acid, such as, for example, hydrochloric acid.
The reaction is preferably carried out with exclusion of air at pressures between, expediently, 1 bar to 50 bar, preferably 20 bar to 40 bar, and a temperature of, expediently, between 80C to 220C, preferably 160C to 200C.
The reaction is complete after a reaction time of, as a rule, 35 3 h to 10 h.
~ .. ..
6 i~g~3 The nitrochromene o~ ~ormula IV and the amino-chromene of formula III can be isolated from the reaction mixture in the form of a mixture after separating o~f the zirconium oxide catalyst and removing the solvent, the 5 amount of nitrochromene of formula IV usually predomin-ating and aæ a rule being 75% to 8t)~.
However, it i~ also possible to use the reaction solution containing the mixture of nitrochromene of the formula IV and aminochromene of the formula III directly for the subseque~t step after ~eparating off the zirconium oxide catalyst.
In the subsequent step, the said mixture of nitrochromene of formula IV and aminochromene of formula III is hydrogenated to give the final product of formula I using hydro~en in the presence of a hydrogenation catalyst.
Suitable hydrogenation catalysts are expediently noble metal catalysts, such as, ~or example, palladium or platinum applied to inert support materials, such as, for example, carbon or alumina.
Preferably, the hydrogenation is carried out using a palladium catalyst, applied in an amount from 0.5% to 10~ to carbon as an inert support.
The hydrogenation is expediently carried out at a hydrogen pressure of 1 bar to 20 bar, praferably 5 bar to 10 bar, and a temperature of 20C to 50~C, preferably at room temperature.
As a rule, the uptake of hydrogen is complete after 0.5 h to S h, after which the final product, of ~ormula I, can be i~olated in a sLmple manner by separat-ing off the catalyst and remo~ing the solvent.
Examples A! Preparation o~_the amorphous zirconium oxide Zirconyl chloride octahydrate (ZrOCl2-8H2O) was 3S dissolved in water. The slight turbidity was filtered off, and the solution was ad~us~ed to a content (ZrO2) of 50 g/l using deionised water.
., ' ., , ,: , . , . . . ~ .
.
. 7 ~l3~ 13 Technical ammonia (about 25%) wai~ diluted to a concen-tration of 10~ using deionised water.
2.5 1 o~ deionised water were introduced into a reaction ~essel. The zirconyl chloride solution and the ammonia solution were added in a controlled manner while stirring at 8000 rpm.
The rate of addition of ~he ZrO2 solution was 50 ml/min. The ammonia solution was added in such a way that it was possible to maintain a pH of 7.0 + 0.2 during the resultant precipitation.
. The solids content of the suspension was kept at-about 1% by addition of deionised water.
After precipita~ion was complete, the solid was separated off by filtration. The filter cake was washed several times using ammoniacal water until the Cl- content had been reduced to 0.05%.
The filter cake was then d~ied at 100C, suspended once more, ~iltered and dried again. :
. . Finally, the resulting ZxO2 powder was calcined at 300C for 8 h. The resulting ZrO2 was radiographically amorphous and had a specific surface area according to BET of 240 m2/g.
Example 1: . ~
a) Process for the preparation of a mixture of 6-hydroxy-2,5,7,8-tetra~ethy~2~(4-aminophenoxy-methyl)chrom-3-ene (aminochromene, III) and 6-hydroxy-2~5~7~8-tetramethyl-2-(4-nitrophen methyl)chrom-3-ene (nitrochromene, I~) 2.0 g (5.4 mmol) of 6 hydroxy 2,5,7,8-tetra- -~
methyl-2-(4 nitrophenoxymethyl)chroman-4-one (II) were introduced into an autoclave with exclusion of air together wi~h 5 g of amorphous zirconium oxida (prepared as in A and pretreated for 2 h at 200C with passage of argon), 100 g of isopropanol (dried using molecular ~ieve 4 ~), 1.0 g of molecular sieve 4 ~ (pretreated for 3 h at 300C with passage of argon) and 2.5 ml o~ concentrated hydrochloric acid. After flushing several time~ with :: ' . :~ ....
.~ . .
~90~3 nitrogen, the mixture was heated to a temperature of 190C at a pressure o~ 10 bar while stirring at 750 rpm.
The pressure rose during the course of this to 27-31 bar.
After 6 to 7 h, the reaction mixture wa~ cooled to room S temperature, the amorphous 2irconi~m oxide was separated off and the solvent was evaporated off.
It was possible in this way to obtain 1.9 g of a mixture which contained 57.5% nitrochroMene (IY) and 16.3%
aminochromene (III).
h) Process for the preparation of 6-hydroxy-2,5,7,8-te~ramethyl-2-(4-aminophenoxymethyl)chroman (I~
.. .. . _ . _ 1.9 g of the mixture obtained in Example la and having a content of 73.8~ were introduced into an autoclave with 0.4 g of a palladium-on-carbon catalyst (5% Pd/C) in 60 ml of toluene. After flushing several times with nitrogen and then with hydrogen, the mixture was stirred at 750 rpm at a hydrogen pressure of 8 bar and at room temperature ~24-27C) for 3.5 h to 4 h. The reaction mixture was then freed from ~he catalyst. The solvent was evaporated off. The crude mixture (1.8 g) contained the title product in a yield of 74.3%.
Example 2 Process for the preparation of 6-hydroxy-2,5,7,8-tetra-methyl-2~(4-aminophenoxymethyl)chroman (I) . .
2.0 g (5.4 mmol) of 6-hydroxy-2,5,7,8-tetra-methyl-~-(4-nitrophenoxymethyl)chroman-4-one (II) were introduced into an autoclave with exclusion of air together with 5 g of amorphous zirconium oxide ~prepared as in A, pretreated for 2 h at 200C with passage of ar~on), 80 g of isopropanol (dried using molecular sieve 4 A) and 20 g of toluene. After flushing several times with nitrogen, the mixture was heated to a temperature of 190C at a pressure of 10 bar while stirring at 750 rpm.
The pressure rose during the course of this to 25 bar.
After 5 h, the reaction mixture was cooled to room temperature and the amorphous zirconium oxide was separ-2~9~13 ated off. The resultant solution, containing 71.4% of a mixture of 75.6~ nitrochromene and 24.4% aminochromene according to GC w~s introduced into an autoclave together with 0.4 g of a palladium-on-carbon catalyst (S~ Pd/C).
After ~lushing several tLmes with nitrogen and ~hen with hydrogen, the mixture was stirred at 750 rpm at a hydro-gen pressure of 8 bar and at room temperature (24-27~C) for 1 h. The reaction mixture was then freed from the catalyst and the solvent was evaporated.
The crude product (1.8 g) contained the title product in a yield of 75.1~.
, ,, ~ : . ~ , :
Claims (12)
1. A process for the preparation of 6-hydroxy-
2,5,7,8-tetraalkyl-2-(4-aminophenoxymethyl)chromans of the general formula I
where R denotes a lower alkyl group having 1 to 4 C atoms, comprising the steps of, providing a catalyst system of an amorphous zirconium oxide catalyst and isopropanol, reducing 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl)chroman-4-one of the general formula II
where R is said alkyl group, under pressure in the presence of said catalyst system to produce a mixture of 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-aminophenoxymethyl)-chrom-3-ene of the general formula III
where R is said alkyl group, and of 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl) chrom-3-ene of the general formula IV
where R is said alkyl group, providing a hydrogenation catalyst, and hydrogenating said mixture using hydrogen in the presence of said hydrogenation catalyst.
2. The process of Claim 1, wherein said reducing step is carried out at a pressure in the range of 1 to 50 bar and at a temperature in the range of 80°C to 220°C.
where R denotes a lower alkyl group having 1 to 4 C atoms, comprising the steps of, providing a catalyst system of an amorphous zirconium oxide catalyst and isopropanol, reducing 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl)chroman-4-one of the general formula II
where R is said alkyl group, under pressure in the presence of said catalyst system to produce a mixture of 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-aminophenoxymethyl)-chrom-3-ene of the general formula III
where R is said alkyl group, and of 6-hydroxy-2,5,7,8-tetraalkyl-2-(4-nitrophenoxymethyl) chrom-3-ene of the general formula IV
where R is said alkyl group, providing a hydrogenation catalyst, and hydrogenating said mixture using hydrogen in the presence of said hydrogenation catalyst.
2. The process of Claim 1, wherein said reducing step is carried out at a pressure in the range of 1 to 50 bar and at a temperature in the range of 80°C to 220°C.
3. The process of Claim 1, wherein said reducing step is carried out at a pressure in the range of 20 to 40 bar and at a temperature in the range of 160°C to 200°C.
4. The process of Claim 1, 2, or 3, comprising the step of preparing said amorphous zirconium oxide catalyst further comprising the steps of, precipitating a zirconyl chloride solution by ammoniacal precipitation and subsequently drying and calcinating said precipitated zirconium oxide.
5. The process of Claim 4, comprising the step of subjecting said amorphous zirconium oxide catalyst to pretreatment in a mobile inert gas atmosphere at a temperature in the range of 150°C to 300°C.
6. The process of Claim 1, 2, 3, or 5, wherein said hydrogenation catalyst is one of a platinum and a palladium catalyst applied to an inert support.
7. The process of Claim 4, wherein said hydrogenation catalyst is one of a platinum and a palladium catalyst applied to an inert support.
8. The process of Claim 6, wherein said inert support is carbon and said palladium catalyst is applied to said carbon support in an amount in the range of 0.5% to 10%.
9. The process of Claim 7, wherein said inert support is carbon and said palladium catalyst is applied to said carbon support in an amount in the range of 0.5% to 10%.
10. The process of Claim 1, 2, 3, 5, 7, 8, or 9, wherein said hydrogenating step is carried out at a hydrogen pressure in the range of 1 to 20 bar and at a temperature in the range of 20°C to 50°C.
11. The process of Claim 4, wherein said hydrogenating step is carried out at a hydrogen pressure in the range of 1 to 20 bar and at a temperature in the range of 20°C to 50°C.
12. The process of Claim 6 wherein said hydrogenating step is carried out at a hydrogen pressure in the range of 1 to 20 bar and at a temperature in the range of 20°C to 50°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH53192 | 1992-02-21 | ||
| CH531/92 | 1992-02-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2089013A1 true CA2089013A1 (en) | 1993-08-22 |
Family
ID=4189147
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002089013A Abandoned CA2089013A1 (en) | 1992-02-21 | 1993-02-08 | Process for the preparation of 6-hydroxy-2, 5, 7, 8- tetraalkyl-2-(4-aminophenoxymethyl) chromans |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5284961A (en) |
| EP (1) | EP0556831B1 (en) |
| JP (1) | JPH05255300A (en) |
| KR (1) | KR930017888A (en) |
| AT (1) | ATE129709T1 (en) |
| CA (1) | CA2089013A1 (en) |
| DE (1) | DE59300834D1 (en) |
| DK (1) | DK0556831T3 (en) |
| ES (1) | ES2079218T3 (en) |
| GR (1) | GR3017970T3 (en) |
| TW (1) | TW226995B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000008009A1 (en) * | 1998-08-04 | 2000-02-17 | Sankyo Company, Limited | Process for the preparation of 2-(aminophenoxymethyl) chromans |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6051189A (en) * | 1983-08-30 | 1985-03-22 | Sankyo Co Ltd | Thiazolidine derivative and its preparation |
| DK173350B1 (en) * | 1985-02-26 | 2000-08-07 | Sankyo Co | Thiazolidine derivatives, their preparation and pharmaceutical composition containing them |
| DK0395912T3 (en) * | 1989-05-02 | 1993-12-06 | Lonza Ag | Sintered zirconia powder and process for its preparation |
-
1993
- 1993-02-08 CA CA002089013A patent/CA2089013A1/en not_active Abandoned
- 1993-02-17 KR KR1019930002202A patent/KR930017888A/en active IP Right Grant
- 1993-02-18 ES ES93102567T patent/ES2079218T3/en not_active Expired - Lifetime
- 1993-02-18 AT AT93102567T patent/ATE129709T1/en not_active IP Right Cessation
- 1993-02-18 DK DK93102567.0T patent/DK0556831T3/en active
- 1993-02-18 JP JP5029255A patent/JPH05255300A/en active Pending
- 1993-02-18 EP EP93102567A patent/EP0556831B1/en not_active Expired - Lifetime
- 1993-02-18 DE DE59300834T patent/DE59300834D1/en not_active Expired - Fee Related
- 1993-02-19 US US08/019,587 patent/US5284961A/en not_active Expired - Fee Related
- 1993-03-04 TW TW082101615A patent/TW226995B/zh active
-
1995
- 1995-11-03 GR GR950403066T patent/GR3017970T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0556831A1 (en) | 1993-08-25 |
| US5284961A (en) | 1994-02-08 |
| ES2079218T3 (en) | 1996-01-01 |
| EP0556831B1 (en) | 1995-11-02 |
| TW226995B (en) | 1994-07-21 |
| ATE129709T1 (en) | 1995-11-15 |
| DE59300834D1 (en) | 1995-12-07 |
| KR930017888A (en) | 1993-09-20 |
| GR3017970T3 (en) | 1996-02-29 |
| JPH05255300A (en) | 1993-10-05 |
| DK0556831T3 (en) | 1995-12-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |