CA1249273A - Chromone-8-aldehydes and thiochromone-8-aldehydes, and a process for their preparation - Google Patents
Chromone-8-aldehydes and thiochromone-8-aldehydes, and a process for their preparationInfo
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- CA1249273A CA1249273A CA000450363A CA450363A CA1249273A CA 1249273 A CA1249273 A CA 1249273A CA 000450363 A CA000450363 A CA 000450363A CA 450363 A CA450363 A CA 450363A CA 1249273 A CA1249273 A CA 1249273A
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- 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
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
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- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
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- 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
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- 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
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 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 in position 2
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- 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
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
ABSTRACT
Novel chromone-8-aldehydes and thiochromone-8-aldehydes, useful in making pharmaceutically active dihydropyridines, of the formula
Novel chromone-8-aldehydes and thiochromone-8-aldehydes, useful in making pharmaceutically active dihydropyridines, of the formula
Description
L9~73 ~ he present invention relates to chromone-8-alde-hydes and thiochromone-8-aldehydes and a process for their preparation.
Thiochromones having the structure I are acces-S sible by condensation of thiophenols with benzoylacetic esters in polyphosphoric acid (Bossert, Lieb.Ann. 680, 40 t1964)) o ~ -R
The corresponding 8-formyl derivatives are not access;ble by this route.
Furthermore, the prepara~ion of chromones from
Thiochromones having the structure I are acces-S sible by condensation of thiophenols with benzoylacetic esters in polyphosphoric acid (Bossert, Lieb.Ann. 680, 40 t1964)) o ~ -R
The corresponding 8-formyl derivatives are not access;ble by this route.
Furthermore, the prepara~ion of chromones from
2-hydroxyphenyl ketones and acid chlorides or esters in the presence of base is known (J. Staunton in Barton~
Ollis~ ComprehensiveOrganic Chemistry, Per~amon Press, Oxford 1979, Volume 4, page 673)~
O O
~3 ~ c OH 2) H ~
HoweverO the corresponding 8-aldehydes are not accessible by these routes s;nceO under the same condi-tions, the corresponding coumarins are formed from 2-hydroxybenzaldehydes tJ. Staunton, see above, page 651)~
The present invention relates to new chromone-8-aldehydes and thiochromone-8-aldehydes of the general formula (II~.
Le A 22 133 .
~' R2 l ~ ~_Rl (II) O H
in which R1 repxesents hydrogen, a straight-chain, cyclic or branched aliphatic hydrocarbon radical having l to lO C atoms, an alkyl carboxylate having l to lO C atoms in the alkyl chain; or phenyl, naphthyl, thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, quin-azolyl or quinoxalyl which in each case optionally has l to 5 iden-lQ tical or different substituents from the group comprising halogen, alkyl (l to lO C atoms), alkoxy (l to lO C atoms), alkylthio (l to lO C atoms), alkylsulphinyl (l to lO C atoms), cyano, hydroxyl, nitro, monofluoroalkyl or polyfluoroalkyl (l to 5 C atoms), mono-fluoroalkoxy or polyfluoroalkoxy (l to 5 C atoms), monofluoroalkyl-thio or polyfluoroalkylthio (l to 6 C atoms), amino, monoalkyl amino (l to 5 C atoms) or dialkylamino (l to 5 C atoms in each), R2 represents one to 3 identical or different halogen atoms or hydrogen, A represents a single bond, an alkylene chain (l to 20 C atoms) or an alkenylene chain (2 to 20 C atoms) which can optionally be interrupted by 0 or S, and X represents O or S.
The invention also relates to a process for the pre-paration of compounds of the general formula (II)/ which is char-~2~ 3 - 2a - 23189-5705 acterised in that, in the case of X=S, thiochromones of the general formula (III) ~ 3 --R O ~IIS) ~HR1 O OC~I 3 in which R1~ R2 and A have the abovementioned meaning, are reduced to give benzyl alcohols of the general struc ture tIV), and the benzyl alcohol (IV) ~N ~IV) ~H20~
;s oxidised wi~h oxidising agents to give aldehydes of the formula (II) .
The thioflavones used as starting materials are known or can be prepared by known processes (Bossert, L;eb. Ann. 680, 40 t1964)3.
Inert organic solvents can be employed for ~he redustion to the benzyl alcohol (IV). For example ethers, such as~ for example, dioxane, diethyl ether, tetrahydro-furan or dimethoxyethane, or aromatics, such as, for example, toluene or benzene. Examples of reducing agents ~hich may be mentioned are alkali metal aluminium hydrides, such as, for example, LiAlH4 Dr alkyl aluminium hydrides, such as, for example, diisobutyl aluminium hydride.
The process according to the invention is prefer-ably carr;ed out ;n the range of temperature from -100C
to +60C, in particular in the range from -60C to ~30C.
The reaction ;s normally carried out under normal pressureO but it can also be carried out under elevated pressure.
The reducing agent is added in the amounts Le A 22 133 7~
famil;ar to the expert~ preferably in a minimum of 4 and a max;mum of 8 hydride equivalents.
For the oxidat;on of the benzyl alcohol tIV) to g;ve the aldehyde (II), the same solvents as ~or the reduction can be used, but halogenated hydrorarbons, such as chloro~orm and methylene chloride, or ketones~ such as~ for example, acetone, can also be usedO
It is possible to use as the ox;dis;ng a~ent the transit;on metal oxides customarily used for oxidations, but manganese d;ox;de is preferred.
The ox;dation is normally carried out in the range of temperature trom -3û to +200C, preferably at the boiling po;nt of the particular solvent~ The oxida-tion is normally carried out under normal pressure, but it can also be carried out under elevated pressure.
It is possible to use the oxidising agent in 3 to 20, preferably ;n 5 to 1D, oxidation equivalents. It can also be advantageous to add fresh oxidising agent to the reaction mixture from time to time.
When methyl thioflavone-8-carboxylate is used as the starting materia~, then the course of the reaction can be represented by the diagram below:
COOCH~) - 20 C C~ a OH~) ~' ,~
O H
The invention also relates to a process for the preparat;on of compounds of the general formula (II~
Le A 22 133 which is characterised ;n ~hat, in the case of X=O, chromones of the general formula (V) R2 o ~_R1 ~V) in ~hich R1, R2 and A have the abovement;oned meaning, with the proviso that A is not an alkenylene cha;n, and R3 represents hydrogen or alkyl (having 1 to 10 C atoms)y are reacte~ w;th ozone in the presence of an inert organic solvent and the mixture is then ~orked up under reducing cond;t;ons.
The 8-alkenylchromones used as starting materials are known or can be prepared by known processes (U.S.
Patent 3~340,411~ compare also Synthesis 19829 221)~
Inert solvents for the ozonolysis xh;ch may be mentioned are: chlorinated hydrocarbons~ such as, for example~ methylene chloride~ chloroform or carbon tetra-chLoride, esters9 such as, for example~ ethyl acetate, alcohols, such as~ for example, methanol or ethanol, or ac;ds, such as, for example, formic acid or acetic acid.
The ozonolysis i5 carrie'd out at -100C to 20C, but preferably at -80C to -30C, ~ith subsequent working up under reduc;ng conditions, for example, with dimethyl sulphide, zinc dust, catalytic hydrogenat;on or sodium d;th;on;te.
Only one mole of ozone is used per mole of ole-fine ~V) in order to prevent cleavage of other double bonds.
When 2-cyclohexyl-8-propenylchromone is used, Le A 22 133 -~2~ 3 ~ 6 --then the course of the reaction can be represented by th~
diagram belo~:
O O
~3 ol~~3 c~3;
Of particular interest are compounds of the general formula tII) in wh;ch R1 stands hydrogen, a stra;ght-chain, cyclic or branched aliphatic hydrocarbon radical having 1 to 8 8 atoms, an alkyl carboxylate having 1 to 8 C atoms in the alkyl chain, phenylO naphthyl~ thienyl~
furyl, pyrryl, pyrazolyl, imida~olyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridaz;nyl, pyrimidiyl, pyrazinyl~ quinolyl, isoquinolyl~
indolyl~ benzimidazolyl, quinazolyl or quinoxalyl, the aryl or heteroaryl radicals optionally having one to 5 ident;cal or different substituents frcm the group comprising fluorine, chlorine, bromine~
iodine, alkyl (1 to 8 C atoms)~ alkylthio ~1 to 8 C atoms),alkyl~ulphinyl (1 to 8 C atoms), cyano, hydroxyl, nitro, monofluoroalkyl or polyfluoro-alkyl (1 to 4 C atoms)~ monofluoroalkoxy or poly-fluoroalkoxy (1 to 4 C atoms), monofluoroalkyl-thio or polyfluoroalkylthio (1 to 4 C atoms), amino, monoalkylam;no (1 to 5 C atoms) or dialkyl-amino (1 to 5 C atoms), R2 represents hydrogen or one to three fluorine or chlorine atoms and A represents a s;ngle bond, an alkylene chain (1 to 18 C atoms~, or an alkenylene chain (2 to 18 C atoms) ~h;ch can opt;onally be ;nterrupted by Le _ 22 133 0 or S~ and X represen~s 0 or S.
The compounds of ~he general formula ~II3 ~hich may be preferably mentioned are those S in ~h;ch R1 represents hydrogen, a s~raight-chain~
branched or cycl;c aliphatic hydrocarbon radical having 1 to 7 C atoms~ an alkyl carboxylate hav;ng 1 to 6 C atoms, phenyl, naphthyl, th;enyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, ;soxazo-lyl, thiazolyl~ pyridyl, pyridaz;nyl~ pyrimidyl, pyrazinyl, qu;nolyl, ;ndolyl, benzimidazoLyl or quinazolyl, the aryl or heteroaryl radicals optionally having one to 4 identical or different substituents from the ~rowp comprising fluorine~
chlorine, bromine, alkyl ~1 to 6 C atoms~, alkyl-thio t1 to 6 C atoms), alkylsutphinyl (1 to 6 C
atoms), cyano, hydroxyL, nitro, monofluoroal~yl or polyfluoroalkyl (1 to 3 C atoms), monofluoro-alkoxy or polyfluoroalkoxy ~1 to ~ C ato~s), amino, monoalkylamino ~1 to ~ C atoms) or d;alkyl-amino (1 to 4 C atoms), R2 represents hydrogen or one to three fluorine atoms, A represents a single bond, an alkylene chain (1 to 16 C atoms) or an alkenylene chain t2 to 12 C
atoms) wh;ch can optionally be interrupted by 0 or S, and X represents 0 or S.
The compounds of the formula (II) according to the invention can be converted in a simple manner by kno~n methods into the 1,4-dihydropyridines (A. Han~zsch, Just. Lieb. Ann. Chem. 215, 1, 1882, Review: U. Eisner, J. Kuthan, Chem.Rev. 7Z, 1 (1972)).
These 1~4-d;hydropyr;dines represent valuable pharmaceutically active compounds which can be used for Le A Z2 133 .
the treatment of circulatory disorders~
Thus the process according to the invention and the ne~ compounds thus prepared represent an advantageous route for the preparat;on of new phar~aceutically active materials.
The examples which follow are in~ended to illus-trate the process according to the invention ~ithout restrict;ng it.
Example 1 O H
4 equ;valents of diisobutyl aluminium hydride (in toLuene) are added to 50 9 of methyl thioflavone-8-carboxylate in tetrahydrofuran at 0C, the m;xture is hydrolysed with dilute sulphuric acid, extracted ~;th ether, and the ether is dried and evaporated.
80X of 8-hydroxymethyl-2-phenyl-4H-thiochromene tmelting pointD 120-122C) are obtained.
20 9 of 8-hydroxymethyl-2-phenyi-4H-thiochromene are dissolved in 500 ml of chloroform and heated to reflux for 10 hours with 5 equivalents of manganese di-oxide, ~hen filtered ~ith suction and the filtrate evaporated. 60X of thioflavone-8-carboxaldehyde tmelting point: 153-157C) ~ere obtained.
1H_NMR ~CDCl3) ~ = 7.3 (s. 1H), 7.45-7.6 (m, 3H) 7~7-7.8 tm, 3H)~ 8.2 (d, J=7 tlz~ 1H), 8~9 td, J=7 Hz, 1H), 10.25 ts, 1H).
Le A 22 133 Example 2 o ~Cl O
~0 mmol of 2-t3-chlorophenyL)-4-oxo-8-propenyl-4H-chromene are dissolved in 60 ml of methylene chloride, and 30 mmol of ozone are passed in at -78C, After addition of 100 mmol of dimethyl suLphide, the m;xture is warmed to room temperature and evaporated in vacuo.
Melt;ng point: 202-206C.
The follow;n~ are prepared ;n analo~ to Example'2:
o ~ A Rl O
MeLtin9 Example_ _ A _ _ , R Poi,nt (C) r~
Ollis~ ComprehensiveOrganic Chemistry, Per~amon Press, Oxford 1979, Volume 4, page 673)~
O O
~3 ~ c OH 2) H ~
HoweverO the corresponding 8-aldehydes are not accessible by these routes s;nceO under the same condi-tions, the corresponding coumarins are formed from 2-hydroxybenzaldehydes tJ. Staunton, see above, page 651)~
The present invention relates to new chromone-8-aldehydes and thiochromone-8-aldehydes of the general formula (II~.
Le A 22 133 .
~' R2 l ~ ~_Rl (II) O H
in which R1 repxesents hydrogen, a straight-chain, cyclic or branched aliphatic hydrocarbon radical having l to lO C atoms, an alkyl carboxylate having l to lO C atoms in the alkyl chain; or phenyl, naphthyl, thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, quin-azolyl or quinoxalyl which in each case optionally has l to 5 iden-lQ tical or different substituents from the group comprising halogen, alkyl (l to lO C atoms), alkoxy (l to lO C atoms), alkylthio (l to lO C atoms), alkylsulphinyl (l to lO C atoms), cyano, hydroxyl, nitro, monofluoroalkyl or polyfluoroalkyl (l to 5 C atoms), mono-fluoroalkoxy or polyfluoroalkoxy (l to 5 C atoms), monofluoroalkyl-thio or polyfluoroalkylthio (l to 6 C atoms), amino, monoalkyl amino (l to 5 C atoms) or dialkylamino (l to 5 C atoms in each), R2 represents one to 3 identical or different halogen atoms or hydrogen, A represents a single bond, an alkylene chain (l to 20 C atoms) or an alkenylene chain (2 to 20 C atoms) which can optionally be interrupted by 0 or S, and X represents O or S.
The invention also relates to a process for the pre-paration of compounds of the general formula (II)/ which is char-~2~ 3 - 2a - 23189-5705 acterised in that, in the case of X=S, thiochromones of the general formula (III) ~ 3 --R O ~IIS) ~HR1 O OC~I 3 in which R1~ R2 and A have the abovementioned meaning, are reduced to give benzyl alcohols of the general struc ture tIV), and the benzyl alcohol (IV) ~N ~IV) ~H20~
;s oxidised wi~h oxidising agents to give aldehydes of the formula (II) .
The thioflavones used as starting materials are known or can be prepared by known processes (Bossert, L;eb. Ann. 680, 40 t1964)3.
Inert organic solvents can be employed for ~he redustion to the benzyl alcohol (IV). For example ethers, such as~ for example, dioxane, diethyl ether, tetrahydro-furan or dimethoxyethane, or aromatics, such as, for example, toluene or benzene. Examples of reducing agents ~hich may be mentioned are alkali metal aluminium hydrides, such as, for example, LiAlH4 Dr alkyl aluminium hydrides, such as, for example, diisobutyl aluminium hydride.
The process according to the invention is prefer-ably carr;ed out ;n the range of temperature from -100C
to +60C, in particular in the range from -60C to ~30C.
The reaction ;s normally carried out under normal pressureO but it can also be carried out under elevated pressure.
The reducing agent is added in the amounts Le A 22 133 7~
famil;ar to the expert~ preferably in a minimum of 4 and a max;mum of 8 hydride equivalents.
For the oxidat;on of the benzyl alcohol tIV) to g;ve the aldehyde (II), the same solvents as ~or the reduction can be used, but halogenated hydrorarbons, such as chloro~orm and methylene chloride, or ketones~ such as~ for example, acetone, can also be usedO
It is possible to use as the ox;dis;ng a~ent the transit;on metal oxides customarily used for oxidations, but manganese d;ox;de is preferred.
The ox;dation is normally carried out in the range of temperature trom -3û to +200C, preferably at the boiling po;nt of the particular solvent~ The oxida-tion is normally carried out under normal pressure, but it can also be carried out under elevated pressure.
It is possible to use the oxidising agent in 3 to 20, preferably ;n 5 to 1D, oxidation equivalents. It can also be advantageous to add fresh oxidising agent to the reaction mixture from time to time.
When methyl thioflavone-8-carboxylate is used as the starting materia~, then the course of the reaction can be represented by the diagram below:
COOCH~) - 20 C C~ a OH~) ~' ,~
O H
The invention also relates to a process for the preparat;on of compounds of the general formula (II~
Le A 22 133 which is characterised ;n ~hat, in the case of X=O, chromones of the general formula (V) R2 o ~_R1 ~V) in ~hich R1, R2 and A have the abovement;oned meaning, with the proviso that A is not an alkenylene cha;n, and R3 represents hydrogen or alkyl (having 1 to 10 C atoms)y are reacte~ w;th ozone in the presence of an inert organic solvent and the mixture is then ~orked up under reducing cond;t;ons.
The 8-alkenylchromones used as starting materials are known or can be prepared by known processes (U.S.
Patent 3~340,411~ compare also Synthesis 19829 221)~
Inert solvents for the ozonolysis xh;ch may be mentioned are: chlorinated hydrocarbons~ such as, for example~ methylene chloride~ chloroform or carbon tetra-chLoride, esters9 such as, for example~ ethyl acetate, alcohols, such as~ for example, methanol or ethanol, or ac;ds, such as, for example, formic acid or acetic acid.
The ozonolysis i5 carrie'd out at -100C to 20C, but preferably at -80C to -30C, ~ith subsequent working up under reduc;ng conditions, for example, with dimethyl sulphide, zinc dust, catalytic hydrogenat;on or sodium d;th;on;te.
Only one mole of ozone is used per mole of ole-fine ~V) in order to prevent cleavage of other double bonds.
When 2-cyclohexyl-8-propenylchromone is used, Le A 22 133 -~2~ 3 ~ 6 --then the course of the reaction can be represented by th~
diagram belo~:
O O
~3 ol~~3 c~3;
Of particular interest are compounds of the general formula tII) in wh;ch R1 stands hydrogen, a stra;ght-chain, cyclic or branched aliphatic hydrocarbon radical having 1 to 8 8 atoms, an alkyl carboxylate having 1 to 8 C atoms in the alkyl chain, phenylO naphthyl~ thienyl~
furyl, pyrryl, pyrazolyl, imida~olyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridaz;nyl, pyrimidiyl, pyrazinyl~ quinolyl, isoquinolyl~
indolyl~ benzimidazolyl, quinazolyl or quinoxalyl, the aryl or heteroaryl radicals optionally having one to 5 ident;cal or different substituents frcm the group comprising fluorine, chlorine, bromine~
iodine, alkyl (1 to 8 C atoms)~ alkylthio ~1 to 8 C atoms),alkyl~ulphinyl (1 to 8 C atoms), cyano, hydroxyl, nitro, monofluoroalkyl or polyfluoro-alkyl (1 to 4 C atoms)~ monofluoroalkoxy or poly-fluoroalkoxy (1 to 4 C atoms), monofluoroalkyl-thio or polyfluoroalkylthio (1 to 4 C atoms), amino, monoalkylam;no (1 to 5 C atoms) or dialkyl-amino (1 to 5 C atoms), R2 represents hydrogen or one to three fluorine or chlorine atoms and A represents a s;ngle bond, an alkylene chain (1 to 18 C atoms~, or an alkenylene chain (2 to 18 C atoms) ~h;ch can opt;onally be ;nterrupted by Le _ 22 133 0 or S~ and X represen~s 0 or S.
The compounds of ~he general formula ~II3 ~hich may be preferably mentioned are those S in ~h;ch R1 represents hydrogen, a s~raight-chain~
branched or cycl;c aliphatic hydrocarbon radical having 1 to 7 C atoms~ an alkyl carboxylate hav;ng 1 to 6 C atoms, phenyl, naphthyl, th;enyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, ;soxazo-lyl, thiazolyl~ pyridyl, pyridaz;nyl~ pyrimidyl, pyrazinyl, qu;nolyl, ;ndolyl, benzimidazoLyl or quinazolyl, the aryl or heteroaryl radicals optionally having one to 4 identical or different substituents from the ~rowp comprising fluorine~
chlorine, bromine, alkyl ~1 to 6 C atoms~, alkyl-thio t1 to 6 C atoms), alkylsutphinyl (1 to 6 C
atoms), cyano, hydroxyL, nitro, monofluoroal~yl or polyfluoroalkyl (1 to 3 C atoms), monofluoro-alkoxy or polyfluoroalkoxy ~1 to ~ C ato~s), amino, monoalkylamino ~1 to ~ C atoms) or d;alkyl-amino (1 to 4 C atoms), R2 represents hydrogen or one to three fluorine atoms, A represents a single bond, an alkylene chain (1 to 16 C atoms) or an alkenylene chain t2 to 12 C
atoms) wh;ch can optionally be interrupted by 0 or S, and X represents 0 or S.
The compounds of the formula (II) according to the invention can be converted in a simple manner by kno~n methods into the 1,4-dihydropyridines (A. Han~zsch, Just. Lieb. Ann. Chem. 215, 1, 1882, Review: U. Eisner, J. Kuthan, Chem.Rev. 7Z, 1 (1972)).
These 1~4-d;hydropyr;dines represent valuable pharmaceutically active compounds which can be used for Le A Z2 133 .
the treatment of circulatory disorders~
Thus the process according to the invention and the ne~ compounds thus prepared represent an advantageous route for the preparat;on of new phar~aceutically active materials.
The examples which follow are in~ended to illus-trate the process according to the invention ~ithout restrict;ng it.
Example 1 O H
4 equ;valents of diisobutyl aluminium hydride (in toLuene) are added to 50 9 of methyl thioflavone-8-carboxylate in tetrahydrofuran at 0C, the m;xture is hydrolysed with dilute sulphuric acid, extracted ~;th ether, and the ether is dried and evaporated.
80X of 8-hydroxymethyl-2-phenyl-4H-thiochromene tmelting pointD 120-122C) are obtained.
20 9 of 8-hydroxymethyl-2-phenyi-4H-thiochromene are dissolved in 500 ml of chloroform and heated to reflux for 10 hours with 5 equivalents of manganese di-oxide, ~hen filtered ~ith suction and the filtrate evaporated. 60X of thioflavone-8-carboxaldehyde tmelting point: 153-157C) ~ere obtained.
1H_NMR ~CDCl3) ~ = 7.3 (s. 1H), 7.45-7.6 (m, 3H) 7~7-7.8 tm, 3H)~ 8.2 (d, J=7 tlz~ 1H), 8~9 td, J=7 Hz, 1H), 10.25 ts, 1H).
Le A 22 133 Example 2 o ~Cl O
~0 mmol of 2-t3-chlorophenyL)-4-oxo-8-propenyl-4H-chromene are dissolved in 60 ml of methylene chloride, and 30 mmol of ozone are passed in at -78C, After addition of 100 mmol of dimethyl suLphide, the m;xture is warmed to room temperature and evaporated in vacuo.
Melt;ng point: 202-206C.
The follow;n~ are prepared ;n analo~ to Example'2:
o ~ A Rl O
MeLtin9 Example_ _ A _ _ , R Poi,nt (C) r~
3 bond ~ ~117-119
4 bond ~ 87- 89 -(CH2)9- -H 55- 60 6 bond ~100-105 Le A 22 133 ~l2~2'73 10 ~ ~ Melting A R point ~C) Example _ _ 7 bond - ~ (CH2)3-C~3 il 8 bond -COOC2H5 96-99 C~3 9 bond ~ C-CH3 67-70 ~H3 bond ~ -CtCH3)3 161-164 11 bond ~ 161-164 12 bond -CH3 157-160 13 bond - ~ -OCH3 200-202 Cl 14 bond ~ ~ 203-205 bond ~ Cl 164-170 16 ( ~2 )2 (C~2~2 e~3 17 -0-CH~- ~ 150-156 The fsllowin~ are_~ epared in analoqY to Example l-Example lE: ~ Cl mp 208-210C
Le A 22 133
Le A 22 133
Claims (21)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of formula (II) (II) in which R1 represents hydrogen, a C1-C10 aliphatic hydro-carbon radical, A C1-C10 alkyl carboxylate:
or phenyl, naphthyl, thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, iso-quinolyl, indolyl, benzimidazolyl, quinazolyl or quinoxalyl which in each case optionally has 1-5 halogen, C1-C10-alkyl, C1-C10-alkoxy, C1-C10-alkyl-thio, C1-C10-alkylsulphinyl, cyano, hydroxyl, nitro, C1-C5-monofluoroalkyl or polyfluoroalkyl, C1-C5 monofluoroalkoxy or polyfluoroalkoxy, C1-C6 mono-fluoroalkylthio or polyfluoroalkylthio, amino, C1-C5-monoalkylamino or C1-C5 dialkylamino substituents, R2 represents hydrogen or 1 to 3 halogen atoms, A represents a single bond, a C1-C20 alkylene chain or a C2-C20 alkenylene chain which can optionally be interrupted by oxygen or sulphur, and X represents oxygen or sulphur.
or phenyl, naphthyl, thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, iso-quinolyl, indolyl, benzimidazolyl, quinazolyl or quinoxalyl which in each case optionally has 1-5 halogen, C1-C10-alkyl, C1-C10-alkoxy, C1-C10-alkyl-thio, C1-C10-alkylsulphinyl, cyano, hydroxyl, nitro, C1-C5-monofluoroalkyl or polyfluoroalkyl, C1-C5 monofluoroalkoxy or polyfluoroalkoxy, C1-C6 mono-fluoroalkylthio or polyfluoroalkylthio, amino, C1-C5-monoalkylamino or C1-C5 dialkylamino substituents, R2 represents hydrogen or 1 to 3 halogen atoms, A represents a single bond, a C1-C20 alkylene chain or a C2-C20 alkenylene chain which can optionally be interrupted by oxygen or sulphur, and X represents oxygen or sulphur.
2. A compound according to claim 1, in which R1 represents hydrogen, a C1-C8 aliphatic hydrocarbon radical, a C1-C8 alkyl carboxylate, or a radical from the group comprising phenyl, naphthyl, thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, iso-xazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, isoquinolyl, indolyl, benzimid-azolyl, quinazolyl or quinoxalyl which optionally has 1-5 fluorine, chlorine, bromine, iodine, C1-C8 alkyl, C1-C8 alkylthio, C1-C8 alkylsulphinyl, cyano, hydrox-yl, nitro, C1-C4 monofluoroalkyl or polyfluoroalkyl, C1-C4 monofluoroalkoxy or polyfluoroalkoxy, C1-C4 monofluoroalkylthio or polyfluoroalkylthio, amino, C1-C5 monoalkylamino or C1-C5-dialkylamino substitu-ents, R2 represents hydrogen or one to three fluorine or chlorine atoms, and A represents a single bond, a C1-C18-alkylene chain or a C2-C18-alkenylene chain which can optionally be interrupted by O or S, and X represents O or S.
3. A compound according to claim 2, wherein X is S.
4. A compound according to claim 1, in which R1 represents hydrogen, a C1-C7 aliphatic hydrocarbon radical, a C1-C6 alkyl carboxylate, or a radical from the group comprising phenyl, naphthyl, thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl, indolyl, benzimidazolyl or quinazolyl which optionally has 1-4 fluorine, chlorine, bromine, C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkylsulphinyl, cyano, hydroxyl, nitro, C1-C3-monofluoroalkyl or polyfluoro-alkyl, C1-C3 monofluoroalkoxy or polyfluoroalkoxy, C1-C3 monofluoroalkylthio or polyfluoroalkylthio, amino, C1-C4 monoalkylamino or C1-C4 dialkylamino substituents, R2 represents hydrogen or 1-3 fluorine atoms, A represents a single bond, a C1-Cl6-alkylene radical or a C2-C12-alkenylene radical which can optionally be interrupted by 0 or S, and X represents 0 or S.
5. A compound according to claim 4, wherein A represents a single bond or C1-C16-alkylene radical which can optionally be interrupted by 0 or S and wherein X is S.
6. A compound according to claim 1, 2 or 3, wherein A is a bond or a -(CH2)2-, -(CH2)9- or -0-CH2- group, R1 is hydrogen or a methyl, n-propyl, tert.butyl, phenyl, 2-chlorophen-yl, 3-chlorophenyl, 4-chlorophenyl, 4-(n-propyl)-phenyl, 4-(tert.butyl)-phenyl, 4-methoxyphenyl, cyclohexyl, 3-pyridyl or 3-thienyl and R2 is hydrogen.
7. A compound according to claim 1, 2 or 3, wherein R1 is phenyl, A is a single bond, R2 is hydrogen and X is sulphur.
8. Thioflavone-8-carboxaldehyde.
9. A process for preparing a compound of the formula II
as defined in claim 1, which process comprises:
A) to prepare a compound of formula II wherein X is S, oxidising a benzyl alcohol of the formula or wherein R1, R2 and A have the meanings given in claim 1, with an oxidising agent to give the aldehyde, or B) to prepare a compound of formula II wherein X is O, reacting a chromone of the formula in which R1, R2 and A have the meanings given in claim 1, with the proviso that A is not an alkenylene chain, and R3 represents hydrogen or C1-C10-alkyl, with ozone in an inert solvent and then working up under reducing conditions.
as defined in claim 1, which process comprises:
A) to prepare a compound of formula II wherein X is S, oxidising a benzyl alcohol of the formula or wherein R1, R2 and A have the meanings given in claim 1, with an oxidising agent to give the aldehyde, or B) to prepare a compound of formula II wherein X is O, reacting a chromone of the formula in which R1, R2 and A have the meanings given in claim 1, with the proviso that A is not an alkenylene chain, and R3 represents hydrogen or C1-C10-alkyl, with ozone in an inert solvent and then working up under reducing conditions.
10. A process according to claim 9, wherein variant A is used and the benzyl alcohol is obtained by reducing a compound of formula wherein R1, R2 and A are as defined in claim 1.
11. A process according to claim 10, wherein the lower alkyl group is methyl.
12. A process according to claim 9, wherein variant B is used and in the chromone which is reacted with ozone A is free of sulphur.
13. A process according to claim 10, wherein an alkali metal aluminium hydride or alkyl aluminium hydrides is employed as the reducing agent.
14. A process according to claim 10, 11 or 13, wherein the reduction is carried out at temperatures from -100°C to 60°C.
15. A process according to claim 9, wherein variant A is used and the oxidation is carried out at a temperature from -30°C
to 200°C.
to 200°C.
16. A process according to claim 9, 10 or 11, wherein variant A is used and manganese dioxide is employed as the oxidis-ing agent.
17. A process according to claim 9, wherein variant B is used and the ozonolysis is carried out at a temperature from -100°C to 20°C.
18. A process according to claim 9, wherein variant B is used and the working up under reducing conditions is carried out with dimethyl sulphide, zinc dust, catalytic hydrogenation or sodium dithionite.
19. A process according to claim 9, wherein variant B
is used and 1 mole of ozone is employed per mole of olefln.
is used and 1 mole of ozone is employed per mole of olefln.
20. A process for preparing thioflavone-8-carboxaldehyde which comprises refluxing 8-hydroxymethyl-2-phenyl-4H-thiochrom-ene with manganese dioxide in chloroform.
21. A process according to claim 20, wherein the 8-hydroxymethyl-2-phenyl-4H-thiochromene is obtained by reducing methyl thioflavone-8-carboxylate by reaction with diisobutyl aluminium hydride.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833311004 DE3311004A1 (en) | 1983-03-25 | 1983-03-25 | CHROMON AND THIOCHROMON-8 ALDEHYDE AND A METHOD FOR THE PRODUCTION THEREOF |
| DEP3311004.2 | 1983-03-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1249273A true CA1249273A (en) | 1989-01-24 |
Family
ID=6194711
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000450363A Expired CA1249273A (en) | 1983-03-25 | 1984-03-23 | Chromone-8-aldehydes and thiochromone-8-aldehydes, and a process for their preparation |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0123113B1 (en) |
| JP (1) | JPS59176272A (en) |
| KR (1) | KR840008009A (en) |
| AT (1) | ATE37547T1 (en) |
| CA (1) | CA1249273A (en) |
| DE (2) | DE3311004A1 (en) |
| DK (1) | DK108784A (en) |
| ES (2) | ES530801A0 (en) |
| FI (1) | FI841152A (en) |
| HU (1) | HU193561B (en) |
| IL (1) | IL71315A (en) |
| NO (1) | NO841057L (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL89840A (en) * | 1988-04-06 | 1996-10-31 | Lipha | Substituted flavonoid compounds and salts thereof their preparation and pharmaceutical composition containing them |
| US5116954A (en) * | 1988-04-06 | 1992-05-26 | Lipha, Lyonnaise Industrielle Pharmaceutique | Pharmaceutically useful flavonoic compounds containing at least one substituent on the benzopyranone ring moiety |
| GB9707013D0 (en) * | 1997-04-07 | 1997-05-28 | Univ Strathclyde | Halo and/or nitro-substituted flavonoids |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2516922A1 (en) * | 1981-11-25 | 1983-05-27 | Lipha | ACIDS (OXO-4-4H- (1) -BENZOPYRAN-8-YL) ALKANOIC, SALTS AND DERIVATIVES, PREPARATION AND DRUG CONTAINING THEM |
-
1983
- 1983-03-25 DE DE19833311004 patent/DE3311004A1/en not_active Withdrawn
-
1984
- 1984-02-27 DK DK108784A patent/DK108784A/en not_active Application Discontinuation
- 1984-03-16 EP EP84102904A patent/EP0123113B1/en not_active Expired
- 1984-03-16 DE DE8484102904T patent/DE3474303D1/en not_active Expired
- 1984-03-16 AT AT84102904T patent/ATE37547T1/en not_active IP Right Cessation
- 1984-03-19 NO NO841057A patent/NO841057L/en unknown
- 1984-03-21 JP JP59052420A patent/JPS59176272A/en active Pending
- 1984-03-21 ES ES530801A patent/ES530801A0/en active Granted
- 1984-03-22 FI FI841152A patent/FI841152A/en not_active Application Discontinuation
- 1984-03-22 IL IL71315A patent/IL71315A/en unknown
- 1984-03-23 HU HU841176A patent/HU193561B/en not_active IP Right Cessation
- 1984-03-23 CA CA000450363A patent/CA1249273A/en not_active Expired
- 1984-03-24 KR KR1019840001521A patent/KR840008009A/en not_active Application Discontinuation
- 1984-12-31 ES ES539291A patent/ES8601954A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IL71315A0 (en) | 1984-06-29 |
| FI841152A0 (en) | 1984-03-22 |
| ES539291A0 (en) | 1985-11-16 |
| EP0123113A2 (en) | 1984-10-31 |
| HU193561B (en) | 1987-10-28 |
| NO841057L (en) | 1984-09-26 |
| JPS59176272A (en) | 1984-10-05 |
| ES8601954A1 (en) | 1985-11-16 |
| DK108784D0 (en) | 1984-02-27 |
| IL71315A (en) | 1988-12-30 |
| DE3311004A1 (en) | 1984-09-27 |
| ES8507137A1 (en) | 1985-05-01 |
| EP0123113B1 (en) | 1988-09-28 |
| DK108784A (en) | 1984-09-26 |
| ES530801A0 (en) | 1985-05-01 |
| FI841152A (en) | 1984-09-26 |
| EP0123113A3 (en) | 1985-09-25 |
| KR840008009A (en) | 1984-12-12 |
| ATE37547T1 (en) | 1988-10-15 |
| HUT35660A (en) | 1985-07-29 |
| DE3474303D1 (en) | 1988-11-03 |
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